Williams Hematology



Definition and History

Origin From A Stem Cell Clone

Pluripotential Versus Hematopoietic Stem Cell Lesion

Etiologic Role of the Ph Chromosome

Coexistence of Normal Stem Cells
Progenitor Cell Characteristics in CML

Progenitor Cell Dysfunction

Progenitor Cell Characterization

Effects of BCR-ABL on Cell Adhesion

Molecular Pathology
Clinical Features


Signs and Symptoms

Laboratory Findings

Special Clinical Features
Differential Diagnosis

Diseases Mimicking CML

Ph-Chromosome-Positive Chronic Hematopoietic Stem Cell Diseases

General Considerations

Initial Cytoreduction Therapy

Antisense Oligodeoxynucleotides

Anti–Tyrosine Kinase Drugs



High-Dose Chemotherapy with Autologous Stem Cell Infusion

Allogeneic and Syngeneic Stem Cell Transplantation


Immunotherapy: Adoptive Cell Therapy for Posttransplant Relapse
Course and Prognosis
Detection of Minimal Residual Disease
Related Diseases without the Ph Chromosome

Chronic Neutrophilic Leukemia

Chronic Monocytic Leukemia

Juvenile Myelomonocytic Leukemia

Chronic Myelomonocytic Leukemia

Ph-Chromosome-Negative or BCR-Rearrangement-Negative CML

Ph-Chromosme-Positive Acute Leukemia
Accelerated Phase of Chronic Myelogenous Leukemia



Clinical Features

Laboratory Features

Extramedullary Blast Crisis

Marrow Blast Crisis

Cytogenetic Studies


Course and Prognosis
Chapter References

The chronic myelogenous leukemias include classical chronic myelogenous leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, and chronic neutrophilic leukemia. The term chronic, as a contrast to acute, once had prognostic implications, but, although the terms remain useful for nosology, they no longer reflect an invariable difference in prognosis. For example, acute myelogenous leukemia in children and young adults has a higher remission and cure rate than chronic or juvenile myelomonocytic leukemia in children or adults.
Classical chronic myelogenous leukemia presents with anemia, exaggerated granulocytosis, a large proportion of mature neutrophils, absolute basophilia, normal or elevated platelet counts, and frequently, splenomegaly. The marrow is very hypercellular, and cytogenetic analysis will show a Ph chromosome in 90 percent of cases, and molecular diagnostic analysis will reveal a rearrangement of the BCR gene on chromosome 22 in 99 percent of cases. The disease is usually responsive to hydroxyurea, interferon-a, and cytarabine, and median survival has been extended to about 6 years. Inevitably, an accelerated phase ensues that often terminates in acute leukemia, at which point therapy is usually unsuccessful and survival is measured in weeks or months. Allogeneic stem cell transplantation can cure the disease, especially if applied early in the chronic phase. A group of acute leukemias have a translocation between chromosomes 9 and 22, a molecular alteration similar to classic chronic myelogenous leukemia. The translocation results in the fusion gene encoding an oncoprotein that may be similar in size to that in classical chronic myelogenous leukemia, 210 kDa, whereas in some cases it is smaller, 185 kDa. These acute leukemias may in some cases reflect the presentation of the disease in acute blastic transformation without a preceding chronic phase and in other cases a different phenotype resulting from a similar genotype. The associated genetic alterations that determine these variations are not clear.
Chronic myelomonocytic leukemia has variable presenting features. Anemia may be accompanied by mildly or moderately elevated leukocyte counts and an elevated total monocyte count; a low, normal, or elevated platelet count; splenomegaly sometimes; and, although cytogenetic abnormalities may be present, there is no specific genetic marker of the disease. Juvenile myelomonocytic leukemia occurs in infancy or very early childhood. Anemia, thrombocytopenia, and leukocytosis with monocytosis is usual. The disease is very refractory to treatment, and, even with current maximal therapy and stem cell rescue, cures are very rare.
Chronic neutrophilic leukemia presents with mild anemia and exaggerated neutrophilia with very few immature cells in the blood. Splenomegaly is common. The disease usually occurs after age 60 years and is usually refractory to current treatment approaches. Chronic and juvenile myelomonocytic leukemia and chronic neutrophilic leukemia have a propensity to transition to acute leukemia. Prior to that time morbidity and mortality is related to infection, hemorrhage, or complicating medical conditions.

Acronyms and abbreviations that appear in this chapter include: ALL, acute lymphocytic leukemia; BCR, breakpoint cluster region; CFU-GM, colony forming unit–granulocyte-monocyte; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CMML, chronic myelomonocytic leukemia; FISH, fluorescence in situ hybridization; G, Giemsa; GM-CSF, granulocyte-monocyte colony stimulating factor; GVH, graft-versus-host; HPRT, hypoxanthine phosphoribosyltransferase; IFN-a, interferon a; IRF, interferon regulatory factor; LTC-IC, long-term culture initiating cells; MCP-1, monocyte chemotactic protein-1; MIP-1a, macrophage inflammatory protein-1 alpha; PCR, polymerase chain reaction; Ph, Philadelphia chromosome; Q, quinacrine; Rb, retinoblastoma; RT-PCR, reverse transcriptase–polymerase chain reaction; SCID, severe combined immunodeficiency; TdT, terminal deoxynucleotidyl transferase; TGF-b, transforming growth factor beta; WT, Wilms’ tumor.

Chronic myelogenous leukemia (CML) is a pluripotential stem cell disease that is characterized by anemia, extreme blood granulocytosis and granulocytic immaturity, basophilia, often thrombocytosis, and splenomegaly. The hematopoietic cells contain a reciprocal translocation between chromosome numbers 9 and 22 in over 90 percent of patients, which leads to an overtly foreshortened long arm of one of the chromosome pair number 22 (i.e., 22, 22q-) referred to as the Philadelphia (Ph) chromosome. A rearrangement of the breakpoint cluster region, a segment of the long arm of chromosome 22, is probably present in all subjects with CML, even the 10 percent without an overt 22q- abnormality. The disease has a very high propensity to evolve into an accelerated, rapidly fatal phase resembling acute leukemia.
In 1845, Bennett in Scotland1 and Virchow in Germany2 published descriptions of patients with splenic enlargement, severe anemia, and enormous concentrations of granulocytes in their blood at autopsy. Bennett initially favored an extreme pyemia as the explanation, but Virchow argued against suppuration as a cause. Additional cases were reported by Craige3 and others, and in 1847 Virchow introduced the designation weisses Blut and leukamie (leukemia).4 In 1878 Neumann proposed that the marrow not only was the site of normal blood cell production but was the site from which leukemia originated and used the term myelogene (myelogenous) leukemia.5 Subsequent observations amplified the clinical and laboratory features of the disease, but few fundamental insights were gained until the discovery by Nowell and Hungerford, reported in 1960, that two patients with the disease had an apparent loss of the long arm of chromosome number 21 or 22,6 an abnormality that was quickly confirmed7,8 and 9 and designated the Philadelphia chromosome.7 This observation led to a new approach to diagnosis, a marker to study the pathogenesis of the disease, and a focus for future studies of the molecular pathology of the disease. The availability of more sensitive banding techniques to define the structure of chromosomes10,11 led to the discovery, by Rowley, that the apparent lost chromosomal material on chromosome 22 was part of a reciprocal translocation between chromosomes 9 and 22.12 The discovery that the cellular oncogene, ABL, on chromosome number 9 and a segment of chromosome 22, the breakpoint cluster region, BCR, fuse as a result of the translocation has provided a basis for the study of the molecular cause of the disease13,14 (see “Pathogenesis,” below).
Exposure to very high doses of ionizing radiation can increase the occurrence of CML above the expected frequency in comparable populations. Three major populations, the Japanese exposed to the radiation released by the atomic bomb detonations at Nagasaki and Hiroshima15; British patients with ankylosing spondylitis treated with spine irradiation16,17; and women with uterine cervical carcinoma who required radiation therapy18 had a frequency of CML (as well as acute leukemia) significantly above that expected in comparable unexposed groups. The median latent period was about 4 years in irradiated spondylitics, among whom about 20 percent of the leukemia cases were CML; 9 years in the uterine cervical cancer patients, of whom about 30 percent had CML; and 11 years in the Japanese survivors of the atomic bombs, of whom about 30 percent of the leukemia patients had CML.19 Chemical leukemogens such as benzene and alkylating agents have not been identified as causative agents of CML, although they are well established to produce a dose-dependent increase in acute myelogenous leukemia. DNA topoisomerase II inhibitors may be an exception, since they have been found to have a propensity to induce t(9;22)-positive leukemia.20
Subjects with CML have an increased frequency of HLA antigens CW3 and CW4, suggesting that these may be markers for susceptibility genes for this leukemia.21 Multiple occurrence of CML in families is very infrequent, however. One exception to the absence of a familial pattern has been reported,22 but overall the evidence for inheritance being a causative factor is very weak compared, for example, to chronic lymphocytic leukemia.23
Chronic myelogenous leukemia results from the malignant transformation of a single stem cell. The disease is acquired (somatic mutation), since the identical twin of patients with CML and the offspring of mothers with the disease neither carry the Ph chromosome nor develop the disease.24 The origin of CML from a single hematopoietic stem cell is supported by the following lines of evidence:

The involvement of erythropoiesis, neutrophilopoiesis, eosinophilopoiesis, basophilopoiesis, monocytopoiesis, and thrombopoiesis in chronic phase CML25

The presence of the Ph chromosome (22q-) in erythroblasts; neutrophilic, eosinophilic, and basophilic granulocytes; macrophages; and megakaryocytes26

The presence of a single glucose-6-phosphate dehydrogenase isoenzyme in red cells, neutrophils, eosinophils, basophils, monocytes, and platelets, but not in fibroblasts or other somatic cells in women with CML who are heterozygotes for isoenzymes A and B27,28 and 29

The presence of the Ph translocation only on a structurally anomalous chromosome 9 or 22 of each chromosome pair in every cell analyzed in occasional patients with a structurally dissimilar 9 or 22 chromosome within the pair30,31 and 32

The presence of the Ph chromosome in one but not the other cell lineage of patients who are a mosaic for sex chromosomes, as in Turner syndrome (45X/46XX)33 and Klinefelter syndrome (46XY/47XXY)34

Molecular studies that show variation in the breakpoint of chromosome 22 among different patients with CML but precisely the same breakpoint among cells within a single patient with CML35,36

A combined DNA hybridization-methylation analysis of women who have restriction fragment length polymorphisms at the X-linked locus for hypoxanthine phosphoribosyltransferase (HPRT) which enables distinction of the two alleles of the HPRT gene in heterozygous females coupled with methylation-sensitive restriction enzyme cleavage patterns, which permits delineation of whether cells contain either the maternally derived or the paternally derived copy of the gene37
The foregoing observations placed the parent cell of the clone at least at the level of the hematopoietic stem cell.
Some patients in chronic phase CML have lymphocytes that are derived from the primordial malignant cell. Evidence for this includes: a single isoenzyme for glucose-6-phosphate dehydrogenase has been found in some T and B lymphocytes in women with chronic myelogenous leukemia who are heterozygous for isoenzymes A and B38; blood cells from patients with CML induced to proliferate with Epstein-Barr virus (presumptive B lymphocytes) are of the same glucose-6-phosphate dehydrogenase isoenzyme type, have cytoplasmic immunoglobulin heavy and light chains, and contain the Ph chromosome39; blood lymphocytes stimulated with B-lymphocyte mitogens contain the Ph chromosome40,41; purified B lymphocytes from the blood in chronic phase CML contain an abnormal, elongated phosphoprotein coded for by the chimeric gene resulting from the t(9;22)42; fluorescence in situ hybridization has detected the BCR-ABL fusion gene in about 25 percent of B lymphocytes in patients in chronic phase43 in some but not all patients.44 These findings suggest that B lymphocytes are derived from the malignant clone, placing the lesion closer to, if not in, the pluripotential stem cell.38,39,40,41 and 42 Virtually all studies find that the B-lymphocyte pool is a mosaic, containing both Ph chromosome and BCR-ABL-positive and Ph chromosome or BCR-ABL-negative cells. The studies examining the derivation of T lymphocytes from the malignant clone are more ambiguous but indicate that T lymphocytes are derived from the malignant clone in some but not most patients.38,40,45,46,47,48,49,50,51,52,53 and 54,832 Natural killer cells isolated from patients with chronic phase CML do not contain the BCR-ABL.55 It is possible that myelopoiesis is invariably clonal and lymphopoiesis is an unpredictable mosaic derived largely from normal residual stem cells. This conclusion is supported by the finding that progenitors of T, B, and NK lymphocytes contain the Ph chromosome and BCR-ABL, but most B-cell and all T-cell progenitors derived from the leukemic clone undergo apoptosis, leaving unaffected cells in the blood.56,831,833
Early studies indicated that the Ph chromosome may appear after the initial leukemogenic event.57,58,59 and 60 Patients with CML have developed the Ph chromosome during the course of the disease, have had periods of the disease when the Ph chromosome disappeared,61 or have had Ph-chromosome-positive and Ph-chromosome-negative cells concurrently.62,63,64,65 and 66
Nearly all, if not all, patients with CML have an abnormality of chromosome 22 at a molecular level (BCR rearrangement). Thus, earlier studies indicating an absence of a Ph chromosome were not a valid measure of the normality of chromosome 22. The molecular abnormality in CML involving the ABL gene on chromosome 9 and the BCR gene on chromosome 22 have been established as being the proximate cause of the chronic phase of the disease (see “Molecular Pathology,” below).
Most, if not all, patients with CML have hematopoietic stem cells which, after treatment67,68 and 69 or culture in vitro70,71 and 72; use of special cell isolation techniques73,74; or use of cell transfer to NOD/SCID mice,75 do not have the Ph chromosome76,77 or the BCR-ABL fusion gene.78,79,80 and 81 The switch to Ph-chromosome-negative cells in vitro is associated with a loss of monoclonal glucose-6-phosphate dehydrogenase isoenzyme patterns, indicating the persistence and reemergence of normal polyclonal hematopoiesis rather than reversion to a Ph-chromosome-negative clone.82 Very primitive hematopoietic cells, the so-called long-term culture initiating cells (LTC-IC), are present in Ph-chromosome-negative cytapheresis samples collected during early recovery after chemotherapy for CML.83 These are most commonly present when cells are collected within 3 months of diagnosis.84 Variable levels of BCR-ABL-negative progenitors are found in the CD34+DR– population, but low levels are found in the CD34+CD38– population.85 Preprogenitors for the CD34+DR– cells are predominantly BCR-ABL-negative in both marrow and blood at diagnosis.86 Some cells with surface marker characteristics of very primitive normal hematopoietic cells do express the BCR-ABL gene, however.87 Both normal and leukemic SCID-repopulation cells coexist in the marrow and blood from CML patients in chronic phase, whereas only leukemic SCID repopulating cells are detected in blast crisis.88,89
The leukemic transformation resulting from the BCR-ABL fusion oncogene leads to a marked expansion of erythroid, granulocytic, and megakaryocytic progenitor populations and to a decreased sensitivity of progenitors to regulation.90,91 and 92 This expansion is especially dramatic in the more mature progenitor cell compartment and less so in the primitive progenitor compartments.90,93 The proliferative capacity of individual granulocytic progenitors is decreased compared to normal cells. Thus, the progenitor cell population in marrow and blood expands proportionately more than the increase in granulopoiesis.94,95 Moreover, the progenitors have buoyant density that is lighter than their normal counterparts but similar to hepatic fetal granulopoietic progenitors, suggesting an oncofetal pattern.94 Sensitivity to growth factors and maturation of granulocyte progenitors in culture is similar to normal, however. The marked expansion of the total blood granulocyte pool is the result of a total expansion of granulopoiesis,93,96 with a minor contribution from prolonged intravascular circulation time.97
Erythroid progenitors are expanded, erythroid precursor maturation is blocked at the basophilic erythroblast stage, and the extent of the impairment of erythropoiesis is inversely proportional to the total white cell count.98
Phenotypic differences of stem and progenitor cells in CML patients as compared to normals have been identified.99 For example, a greater proportion of the circulating leukemic CFU-GM express high levels of the adhesion receptor CD44100 and low levels of L-selectin101 in contrast to normal cells. Leukemic CD34+ cells overexpress the P-glycoprotein which determines the multidrug resistance phenotype.102
BCR-ABL-positive progenitors survive less well in long-term culture than do their normal counterparts. Leukemic CFU-GM colonies, unlike normal colonies, decrease in long-term cultures that are deficient in kit ligand,103 whereas their proliferation is favored in the presence of kit ligand.104 Macrophage inflammatory protein-1 alpha (MIP-1a) does not inhibit growth factor-mediated proliferation of CD34+ cells from CML patients as it does CD34+ cells from normal subjects, even though the MIP-1a receptor is expressed.105 Another chemokine, monocyte chemotactic protein-1 (MCP-1), unlike MIP-1a, is an endogenous chemokine that has been found to cooperate with transforming growth factor beta (TGF-b) to inhibit the cycling of primitive normal but not CML progenitors in long-term human marrow cultures.106 Leukemic progenitors are less sensitive than normal progenitors to the antiproliferative effects of TGF-b.107
Primitive progenitors and blast colony-forming cells from patients with CML have decreased adherence to marrow stromal cells.108,109 This defect is normalized if stromal cells are treated with interferon a (IFN-a).109,110 As a result, BCR-ABL-negative progenitors are enriched in the adherent fraction of circulating CD34+ cells in chronic phase CML patients. The most primitive BCR-ABL-positive cells in the blood of patients with CML differ from their normal counterparts. They are increased in frequency and are activated, such that signals that block cell mitosis are bypassed.111
Ph-chromosome-positive colony-forming cells adhere less to fibronectin (as well as to marrow stroma) than do their normal counterparts. Adhesion is fostered as a result of restoration of cooperation between activated b1 integrins and the altered epitopes of CD44.112,113 and 114 CML granulocytes have reduced and altered binding to P-selectin due to modification in the CD15 antigens.115 BCR-ABL-induced defects in integrin function may underlie the abnormal circulation and proliferation of progenitors,116 since growth signaling can occur through the fibronectin receptor.117 IFN-a restores normal integrin-mediated inhibition of hematopoietic progenitor proliferation by the marrow microenvironment.118
BCR-ABL-encoded fusion protein p210bcr–abl binds to actin, and several cytoskeletal proteins are thereby phosphorylated. The p210bcr–abl interacts with actin filaments through an actin-binding domain. BCR-ABL transfection is associated with an increase in spontaneous motility, membrane ruffling, formation of long actin extensions (filopodia), and accelerated rate of protrusion and retraction of pseudopodia on fibronectin-coated surfaces. Alpha-interferon treatment slowly converts the abnormal motility phenotype of BCR-ABL-transformed cells toward normal.119 Integrins regulate the c-ABL-encoded tyrosine kinase activity and its cytoplasmic-nuclear transport.120 The p210bcr–abl abrogates the anchorage requirement but not the growth factor requirement for proliferation.121
In normal cells exposed to IL-3, paxillin tyrosine residues are phosphorylated. In cells transformed by p210bcr–abl, the tyrosines of paxillin, vinculin, p125FAK, talin, and tensin are constitutively phosphorylated. Pseudopodia enriched in focal adhesion proteins122 are present in cells expressing p210bcr–abl.
The genic disturbance became evident with the knowledge that CML was derived from a primitive cell that contains a 22q- abnormality.6,11 The abnormal chromosome contained only 60 percent of the DNA in other G-group chromosomes.123 Cytogenetic analysis indicated the G-group chromosome involved was different from the extra G-group chromosome in Down syndrome, which had been assigned number 21, and thus the former was assigned number 22—even though it proved to be slightly longer than the chromosome involved in Down syndrome.11,124 The Paris Conference on Nomenclature decided not to undo the concept that Down syndrome is trisomy 21, and assigned the Ph chromosome and its normal counterpart, 22.125 Rowley, by using quinacrine (Q) and Giemsa (G) banding, reported in 1973 that the material missing from chromosome 22 was not lost (deleted) from the cell but was translocated to the distal portion of the long arm of chromosome 9.12 The amount of material translocated to chromosome 9 was approximately equivalent to that lost from 22, and it was predicted that the translocation was balanced.12 Moreover the breaks were localized to band 34 on the long arm of 9 and band 11 on the long arm of 22. The classical Ph chromosome is, therefore, t(9;22)(q34;q11), abbreviated t(Ph) (Fig. 94-1). The Ph chromosome can develop on either the maternal or the paternal member of the pair.126

FIGURE 94-1 Schematic diagram of normal chromosome 9 showing the ABL gene between band q34 and qter of chromosome 22, which has the BCR and SIS genes between band q11 and qter. The t(9;22) is shown on the right. The ABL from chromosome 9 is transposed to the chromosome 22 M-bcr sequences, and the terminal portion of chromosome 22 is transposed to the long arm of chromosome 9. The 22q- is the Ph chromosome. bcr, breakpoint cluster region; c-sis, cellular homolog of the viral simian sarcoma virus-transforming gene; IgL, gene for immunoglobulin light chains. (Reprinted with permission from Mutation Res 186:161, 1987.)

The mutations of the ABL gene on chromosome 9 and the BCR gene on chromosome 22 are central to the development of CML (Fig. 94-2).127,128 and 129

FIGURE 94-2 Schematic representation of the normal ABL and BCR genes and of the BCR-ABL fusion transcripts. In the upper portion of the diagram, the possible breakpoint positions in ABL are illustrated by vertical arrows. Note the position immediately upstream of the ABL locus of the 8604Met gene, for which the function is unknown. The BCR gene contains 25 exons, including first (e1′) and second (e2′) exons. The position of the three breakpoint cluster regions, m-bcr, M-bcr, and µ-bcr, is shown. The lower portion of the figure shows the structure of the BCR-ABL messenger RNA fusion transcripts. Breakpoints in µ-bcr result in BCR-ABL transcripts with an e19a2 junction. b or e represents the breakpoint in ABL. The associated number designates the exon (location) at which the break occurs in each gene. (Reprinted with permssion from Blood 88:2376, 1966.)

In 1982 the human cellular homolog, ABL, of the transforming sequence of the Ableson murine leukemia virus, was localized to human chromosome number 9.130 In 1983 ABL was shown to be on the segment of chromosome 9 that is translocated to chromosome 22131 by showing reaction to hybridization probes for ABL only in somatic cell hybrids of human CML cells containing 22q- but not those containing 9q+. ABL is closely homologous to the viral oncogene v-abl, which is the cell-transforming portion of the gene. This gene can induce malignant transformation of cells in culture and can induce leukemia in susceptible mice.132
The ABL gene is rearranged and amplified in cell lines from patients with CML.133 Cell lines and fresh isolates of CML cells contain an abnormal, elongated 8-kb RNA transcript,134,135,136 and 137 which is transcribed from the new chimeric gene produced by the fusion of the 5′ portion of the BCR gene left on chromosome 22 with the 3′ portion of the ABL gene translocated from chromosome 9131 (Fig. 94-3). The fusion mRNA leads to the translation of a unique tyrosine phosphoprotein kinase of 210 kDa (p210bcr–abl), which can phosphorylate tyrosine residues on cellular proteins similar to the action of the v-abl protein product.138,139,140,141 and 142 The anomalous tyrosine kinase is difficult to identify in chronic phase cells because of inhibitors in granulocytes142; molecular variants reflect variations in the breakpoint on chromosome 22.143

FIGURE 94-3 The molecular effects of the Ph chromosome translocation t(9;22)(q34;q11). The upper representation is of the physically joined 5′ BCR and the 3′ ABL regions on chromosome 22. The exons are solid (from chromosome 22, BCR) and hatched (from chromosome 9, ABL). The middle representation depicts transcription of chimeric messenger RNA, and the lower representation is the translated fusion protein with the amino terminus derived from the BCR of 22 and the carboxy terminus from the ABL of 9. (Reprinted with permission from Mutation Res 186:161, 1987.)

The ABL locus contains at least two alleles, one having a 500-bp deletion.144 In normal cells, the ABL protooncogene codes for a tyrosine kinase of molecular weight 145,000, which only is translated in trace quantities and lacks any in vitro kinase activity.139 It is hypothesized that the fusion product expressed by the BCR-ABL gene leads to malignant transformation because of the abnormally regulated phosphorylating activity of the chimeric tyrosine protein kinase.140,141,145,146 Construction of BCR-ABL fusion genes indicated that BCR sequences could also activate a microfilament-binding function, but the tyrosine-kinase and microfilament-binding functions were not linked. Nevertheless, the tyrosine kinase modification of actin filament function has been proposed as a step in leukemogenesis.147
The breakpoints on chromosome 9 are not narrowly clustered, ranging from about 15 to over 40 kb upstream from the most proximate region (first exon) of the ABL gene.130,131,148 The breakpoints on chromosome 22 occur over a very short, approximately 5- to 6-kb, stretch of DNA referred to as the breakpoint cluster region (M-bcr),149,150 which is part of a much longer breakpoint cluster region gene, BCR151,152 (Fig. 94-3). Three main breakpoint cluster regions have been characterized on chromosome 22: major (M-bcr), minor (m-bcr), and micro (µ-bcr). They encode a p210, p190, and p230 fusion proteins, respectively (Fig. 94-2). The overwhelming majority of CML patients have a BCR-ABL fusion gene that encodes a fusion protein of 210 kDa (p210bcr–abl) and for which mRNA transcripts have a b3a2 or a b2a2 fusion junction153 (Fig. 94-2). A BCR-ABL with an e1a2 type of junction has been identified in approximately 50 percent of the Ph-chromosome-positive acute lymphoblastic leukemia cases (see “Ph-Chromosome-Positive Acute Leukemia”) and results in the production of a BCR-ABL protein of 190 kDa (p190bcr–abl). Virtually all CML cases at diagnosis that encode a p210bcr–abl also express BCR-ABL transcripts for p190.154 The biological or clinical significance of these dual transcripts is not known. Transgenic mice expressing p210bcr–abl devel op acute lymphoblastic leukemia in the founder mice, but all transgenic progeny have a myeloproliferative disorder resembling CML.155
The BCR gene encodes a 160-kDa serine-threonine kinase, which, when it oligomerizes, autophosphorylates and transphosphorylates several protein substrates.156 Aberrant methylation of the M-bcr in CML occurs.153 The first exon sequences of the BCR gene potentiate the tyrosine kinase of ABL when they fuse as a result of the translocation.157 The central portion of BCR has homology to DBL, a gene involved in the control of cell division after S-phase of the cell cycle. The C-terminus of BCR has a GTPase-activating protein for p21rac, a member of the RAS family of GTP-binding proteins.158 A reciprocal hybrid gene ABL-BCR is formed on chromosome 9q+, when BCR-ABL fuses on chromosome 22. The ABL-BCR fusion gene actively transcribes in most patients with CML.159
Variations in breakpoints involving smaller stretches of chromosome 9 and rearrangements outside the M-bcr of chromosome 22 can occur.36 In a few cases of CML in which there has been no evident elongation of chromosome 9, molecular probes have shown that ABL is still translocated to chromosome 22.160 In occasional patients with Ph-chromosome-positive CML, the break in chromosome 22 is outside the M-bcr, and there is a failure to transcribe a fusion RNA of the usual type or a fusion RNA is transcribed that does not hybridize with the classical M-bcr cDNA probe.161
In cases in which the Ph chromosome is not found, BCR-ABL may still be located on chromosome 9 (a masked Ph chromosome).162 The BCR gene can recombine with genomically distinct sites on band 11q13 in complex translocations in a region rich in Alu repeat elements.163 ETV6/ABL fusion genes have also been found in BCR-ABL- negative CML.164
The BCR breakpoint site has been examined as a factor in disease prognosis. Some studies have shown no correlation between CML chronicity and breakpoint site, although thrombocytosis may be more common with 3′ breakpoint sites and basophilia with 5′ breakpoint sites.165 No difference in response to IFN-a therapy was noted, and survival was not significantly different, although patients with 3′ deletions tended to have shorter survival.166 A better response to IFN-a in patients with a 3′ rearrangement has been observed by others.167
CML patients with m-bcr breakpoints develop a blast crisis with monocytosis and an absence of splenomegaly and basophilia.168 The p230 encoded by µ-bcr is rarely expressed but has been associated with neutrophilic-CML or thrombocytosis (see “Special Clinical Features”). Other rare breakpoints have been described.169 For example, a case with a 12-bp insert between BCR1 and ABL1 resulted in a BCR-ABL-negative (false negative), Ph-chromosome-positive CML with thrombocythemia.170 Another novel BCR-ABL fusion gene (e6a2) in a patient with Ph-chromosome-negative CML encoded an oncoprotein of 185 kDa.171 Typical CML has also been associated with an e19a2 junction BCR-ABL transcript.172
Experimental support for the hypothesis that p210bcr–abl tyrosoine phosphoprotein kinase is transforming is provided by a retroviral gene transfer system that permits expression of the protein. Mouse marrow cells transfected with BCR-ABL develop clonal outgrowths of immature cells expressing the p210bcr–abl tyrosine kinase. Some clones progress to a malignant phenotype, can be transplanted, and can induce tumors in syngeneic mice.173 Similar studies suggest the p210bcr–abl can transform 3T3 murine fibroblasts if the gag gene sequence from a helper virus cooperates.174 The BCR-ABL gene from a retroviral vector has been expressed in an interleukin-3 (IL-3)-dependent cell line. Clones derived from the infected line transform over months to IL-3 independency; are capable of increased proliferation; and develop chromosomal abnormalities.175
A series of mouse models in which the BCR-ABL was used to induce leukemogenesis have been described.176,177,178,179,180,181,182,183 and 184 Lethally irradiated mice have been reconstituted with marrow enriched for cycling stem cells infected with a BCR-ABL-bearing retrovirus. Fatal diseases with abnormal accumulations of macrophagic, erythroid, mast, and lymphoid cells develop.175 Classical CML did not occur, and complete transformation was not documented. The cell lines from spleen and marrow from mice with a BCR-ABL retrovirus infection were predominantly mast cells; however, these cell lines were shown to spontaneously switch in some cases to either erythroid and megakaryocytic, erythroid, or granulocytic lineages displaying maturation. They were transplantable (transformed) and contained the same proviral inserts as the original mast cell line.185 Murine marrow also has been infected with a retrovirus encoding p210bcr–abl and transplanted into irradiated syngeneic recipients.176 Although several types of hematologic malignancies developed, a syndrome mimicking human CML occurred, also. Mice transgenic for a p190bcr–abl develop an acute lymphocytic leukemia-lymphoma syndrome,177 resembling human Ph-chromosome-positive ALL. When a p210bcr–abl transcript is introduced into a mouse germ line (one-cell fertilized eggs), the p210 founder and progeny transgenic animals developed leukemia of B or T lymphoid or of myeloid origin after a relatively long latency period. In contrast, p190-transgenic mice exclusively developed leukemia of B-cell origin, with a relatively short period of latency. This was felt to be consistent with the apparent indolence of human CML during the chronic phase.178 When transgenic mice express p210 bcr–abl, the transgenes develop ALL, whereas the progeny develop a myeloproliferative disorder.179
BCR-ABL fusion genes can be found in the leukocytes of some normal individuals using a two-step reverse transcriptase polymerase chain reaction assay. Thus, while BCR-ABL may be expressed relatively frequently in hematopoietic cells, only infrequently do the cells acquire the additional changes necessary to produce leukemia.186,187
The tyrosine phosphoprotein kinase activity of the p210bcr–abl has been causally linked to the development of Ph-chromosome-positive leukemia in man.188,189,190,191,192,193,194,195,196,197,198 and 199 The p210bcr–abl interacts with several components of signal transduction pathways191,192 and binds and/or phosphorylates more than 20 cellular proteins in its role as an oncoprotein.193 A subunit of phosphatidylinositol-3′ kinase associates with p210bcr–abl; this interaction is required for the proliferation of BCR-ABL-dependent cell lines and primary CML cells. Wortmannin, a specific inhibitor of the p110 subunit of the kinase, inhibits growth of these cells.194
An RAF-encoded serine-threonine kinase activity is regulated by p210bcr–abl. Downregulation of RAF expression inhibits both BCR-ABL-dependent growth of CML cells and growth-factor-dependent proliferation of normal hematopoietic progenitors.195
The efficiency of cell transformation by BCR-ABL is affected by an adaptor protein that can interrelate tyrosine kinase signals to RAS. The p210bcr–abl also activates multiple alternative pathways of RAS.196 Figure 94-4 demonstrates interaction of p210bcr–abl with various mediators of signal transduction.

FIGURE 94-4 Major intracellular signaling events associated with BCR/ABL. Constitutive activation of ABL protein tyrosine kinase (PTK) induces phosphorylation of the tyrosine moiety of various substrates including autophosphorylation of BCR/ABL and complex formation of BCR/ABL with adaptor proteins. This subsequently activates multiple intracellular signaling pathways including RAS activation and phosphatidylinositol-3′ kinase (P1-3-K) activation pathways. BCR/ABL also activates the c-MYC pathway, which involves ABL-SH2 domain. BCR/ABL inhibits apoptosis possibly, in part, through upregulation of Bcl-2, and alters cellular adhesive properties, possibly by interacting with focal adhesion proteins and the actin cytomatrix. Broken lines indicate hypothetical pathways. ERK, extracellular signal-regulated kinase; MEKK, MEK kinase; JNK, Jun N-terminal kinase; FAK, focal adhesion kinase; Sos, Son-of-sevenless; STAT, signal transducer and activator of transcription. (Reprinted with permission from Curr Opin Hematol 4:3, 1997.)

The adaptor molecule CRKL is a major in vivo substrate for the p210bcr–abl, and it acts to relate p210bcr–abl to downstream effectors. CRKL is a linker-protein which has homology to the v-crk oncogene product. Antibodies to CRKL immunoprecipate paxillin, a focal adhesion protein197 which is phosphorylated by p210bcr–abl. The p210bcr–abl may be physically linked to paxillin by CRKL. CRKL binds to CBL, an oncogene product that induces B-cell and myeloid leukemias in mice.198 The Src homology 3 domains of CRKL do not bind to CBL, but they do bind BCR-ABL. CRKL therefore mediates the oncogenic signal of BCR-ABL to CBL. The p120CBL and the adaptor proteins CRKL and c-CRK also link c-abl, p190bcr–abl, and p210bcr–abl to the phosphatidylinositol-3′ kinase (PI3K) pathway.199 The p120CBL also coprecipitates with the p85 subunit of P13K, CRKL, and c-CRK. The p210bcr–abl may, therefore, induce the formation of multimeric complexes of signaling proteins.200 These complexes contain paxillin and talin and may explain some of the adhesive defects of CML cells.201
Hef2 also binds to CRKL in leukemic tissues of p190bcr–abl transgenic mice. Hef2 is involved in the integrin signaling pathway202 and encodes a protein that accelerates GTP hydrolysis of RAS-encoded proteins and neurofibromin. The latter negatively regulates GM-CSF signaling through RAS in hematopoietic cells.203 P62dok, a constitutively tyrosine-phosphorylated, p120ras GAP-associated protein, which is rapidly tyrosine-phosphorylated upon activation of the c-kit receptor,204 is also associated with ABL.205
NF kappa B activation is also required for p210bcr–abl-mediated transformation.206 The expression of p210bcr–abl leads to activation of NF kappa B-dependent transcription via nuclear translocation.207
Cell lines that express p210bcr–abl also demonstrate constitutive activation of JAKs and STATs, usually STAT5.208 STAT5 is also activated in primary mouse bone marrow cells acutely transformed by the BCR-ABL209; p210bcr–abl coimmunoprecipitates with and constitutively phosphorylates the common beta subunit of the IL-3 and GM-CSF receptors and JAK 2.210 Both ABL and BCR are also multifunctional regulators of a GTP-binding protein family, Rho,211,212 and a growth-factor-binding protein (Grb2), which links tyrosine kinases to RAS and forms a complex with BCR-ABL and the nucleotide exchange factor Sos that leads to activation of RAS.213
The p210bcr–abl also activates Jun kinase and requires Jun for transformation.214 In some CML cells lines, p210bcr–abl is associated with the retinoblastoma (Rb) protein.215 Loss of the neurofibromatosis (NF1) tumor suppressor gene, a RAS GTPase activating protein, is also sufficient to produce a myeloproliferative syndrome in mice akin to human CML due to RAS-mediated hypersensitivity to GM-CSF.216
Whether p210bcr–abl influences the expansion of the malignant clone in CML by inhibition of apoptosis is uncertain. In one study, the survival of normal and CML progenitors was the same after in vitro incubation in serum-deprived conditions and after treatment with x-irradiation or glucocorticoids.217 P210bcr–abl has been found to inhibit apoptosis by delaying the G2/M transition of the cell cycle after DNA damage.218 The p210bcr–abl may also exert an antiapoptotic effect in factor-dependent hematopoietic cells.219,220
P210bcr–abl does not prevent apoptotic death induced by human natural killer or lymphokine-activated killer cells directed against CML or normal cells.221 In accelerated and blast phases, rates of apoptosis were lower in CML neutrophils. G-CSF and GM-CSF considerably decreased the rate of apoptosis in CML neutrophils.222
SIS, the human homolog of the transforming gene of the simian sarcoma virus,223 is found on chromosome 22224 and is translocated to chromosome 9 in the t(9;22)(q34;q11).225 SIS, like v-sis,226 encodes for a protein which is identical to platelet-derived growth factor.227 The SIS gene, which is distant from the breakpoint on chromosome 22, is not expressed in chronic phase cells but can be expressed in the accelerated phase of the disease, although the transcript when expressed is normal in size (4.0 kb).228 Activation of SIS is not thought to be related to the transforming events leading to the chronic phase of CML.
Some patients with CML present with normal telomere length at diagnosis, and this may be associated with response to interferon-a therapy.229 A significant increase in telomerase activity has been noted in blast phase of CML as compared to chronic phase.230
CML accounts for about 15 percent of all cases of leukemia, and the death rate from it is about 0.9 per 100,000 population per year in the United States. The disease occurs slightly more often in men than women but has similar manifestations and a similar course in both sexes. The age-specific mortality rate for CML increases with age from less than 0.1 per 100,000 population between ages 0 to 14 years to about 1 per 100,000 in the mid-40s, to over 8 per 100,000 in octogenarians.231 Although CML occurs in children and adolescents, only about 10 percent of all cases occur in subjects between 5 and 20 years of age. CML represents about 3 percent of all childhood leukemias. There is no concordance of the disease between identical twins.
In the 70 percent of patients who are symptomatic at diagnosis, the most frequent complaints include easy fatigability, loss of sense of well-being, decreased tolerance to exertion, anorexia, abdominal discomfort, and early satiety (related to splenic enlargement), weight loss, and excessive sweating.232,233 and 234 The symptoms are vague, nonspecific, and gradual in onset (weeks to months). A physical examination may detect pallor and splenomegaly. The latter was present in about 90 percent of patients at diagnosis, but with medical care being sought earlier, the presence of splenomegaly is decreasing in frequency at the time of diagnosis.233 Sternal tenderness, especially the lower portion, is common; occasionally, patients will notice it themselves.
Uncommon presenting symptoms include those of dramatic hypermetabolism (night sweats, heat intolerance, weight loss) simulating thyrotoxicosis; acute gouty arthritis, presumably related in part to hyperuricemia; priapism, tinnitus, or stupor from the leukostasis associated with greatly exaggerated blood leukocyte count elevations235,236 and 237; left upper quadrant and left shoulder pain as a consequence of splenic infarction and perisplenitis; vasopressin-responsive diabetes insipidus238,239; and acne urticata associated with hyperhistaminemia.240 Acute febrile neutrophilic dermatosis (Sweet’s syndrome), a perivascular infiltrate of neutrophils in the dermis, can occur. Fever accompanied by painful maculonodular violaceous lesions on trunk, arms, leg, and face are characteristic.241,242 Spontaneous rupture of the spleen is a rare event.243,244 Digital necrosis has been reported as a rare paraneoplastic event.245,246
In an increasing proportion of patients, the disease is discovered, coincidentally, when blood cell counts are measured at a “routine” medical examination.
The presumptive diagnosis of CML can be made from the results of the blood cell counts and examination of the blood film.25,232,233 The hematocrit is decreased in most patients at the time of diagnosis. Red cells are usually only slightly altered, with an increase in variation from small to large size and only occasional misshapen (elliptical or irregular) erythrocytes. Small numbers of nucleated red cells are commonly present. The reticulocyte count is normal or slightly elevated, but clinically significant hemolysis is rare.232,247 A positive direct antiglobulin test may develop in patients during interferon therapy.248 Rare cases of mild erythrocytosis249,250 or erythroid aplasia251,252 have been documented.
The total leukocyte count is always elevated at the time of diagnosis and is nearly always over 25,000/µl (25 × 109/liter); half the patients have total white counts over 100,000/µl (100 × 109/liter)25,232,233 (Fig. 94-5). The total leukocyte count rises progressively in untreated patients. Rare patients may have dramatic cyclic variations in white cell counts of as much as an order of magnitude with cycle intervals of about 60 days.253,254 Granulocytes at all stages of development are present in the blood and are generally normal in appearance. The mean blast cell prevalence is about 3 percent but can range from 0 to 10 percent; progranulocyte prevalence is about 4 percent; myelocytes, metamyelocytes, and bands account for about 40 percent; and segmented neutrophils about 35 percent of total leukocytes (Table 94-1). Hypersegmented neutrophils are commonly present (Plate XIX).

FIGURE 94-5 The total white cell count and platelet count of 90 patients with CML at the time of diagnosis. The cumulative percent of patients is on the ordinate, and the cell count is on the abscissa. Fifty percent of patients had a white cell count over 100 × 109/liter and a platelet count over about 300 × 109/liter at the time of diagnosis.


Neutrophil alkaline phosphatase activity is low or absent in over 90 percent of patients with CML.255,256 and 257 The mRNA for alkaline phosphatase is undetectable in neutrophils of patients with CML.258 The activity increases toward or to normal in the presence of intense inflammation or infection and when the total leukocytic count is decreased to or near normal with treatment.257,259 CML neutrophils regain alkaline phosphatase activity after infusion into leukopenic recipients, suggesting the effect of regulators or factors extrinsic to the neutrophils.260 In vitro, a monocyte-derived soluble mediator is capable of inducing increased alkaline phosphatase activity in neutrophils from CML patients.261 Neutrophil alkaline phosphate is decreased sporadically in a variety of disorders and conditions262 but is decreased markedly and consistently in paroxysmal nocturnal hemoglobinuria,262 hypophosphatasia,263 in about a quarter of patients with idiopathic myelofibrosis, and in patients using androgens. Neutrophil alkaline phosphatase is increased in polycythemia vera, in 25 percent of patients with idiopathic myelofibrosis, in pregnant women, and in subjects with inflammatory disorders or infections.
The proportion of eosinophils is usually not increased, but the absolute eosinophil count is nearly always increased. Rarely, eosinophils may be so prominent as to dominate the granulocytic cells and lead to the designation Ph-positive eosinophilic CML.264,265,266 and 267 An absolute increase in the basophil concentration is present in virtually every patient, and this finding can be useful in preliminary consideration of differential diagnosis.25,268 Basophilic progentior cells are increased in the blood.269 The proportion of basophils is usually not above 10 to 15 percent during chronic phase but may, in rare patients, represent 30 to 80 percent of the total leukocyte count during chronic phase and lead to the designation of Ph-chromosome-positive basophilic CML.270 Unlike mastocytosis, hyperhistaminemia usually is not associated with elevated basophil counts. Cases of exaggerated basophilia and disabling pruritus, urticaria, and gastric hyperacidity have occurred, associated with enormous increases (several hundredfold) of blood histamine concentration.271,272 Granulocytes containing both eosinophilic and basophilic granules are commonly present.273
The total absolute lymphocyte count is increased (mean about 15 × 109/liter) in patients with CML at the time of diagnosis274 as a result of the balanced increase in T-helper and T-suppressor cells.275 B lymphocytes are not increased.275 T lymphocytes also are increased in the spleen.276 Natural killer cell activity is defective in CML patients as a result of decreased maturation of these cells in vivo.277,278 The absolute number of circulating NK cells is decreased in patients with CML. The CD56 bright subset is particularly decreased. These cells are reduced more as CML progresses, and they respond less to stimuli that recruit clonogenic natural killer cells as compared to NK cells from normal subjects.279
The platelet count is elevated in about 50 percent of patients at the time of diagnosis and is normal in most of the rest.280 The platelet count may increase during the course of the chronic phase; platelet counts over 1,000,000/µl (1000 × 109/liter) are not unusual, and platelet counts as high as 5,000,000 to 7,000,000/µl (5000 to 7000 × 109/liter) have occurred. Thrombohemorrhagic complications of thrombocytosis are infrequent. Occasionally, the platelet count may be below normal at the time of diagnosis, but this usually signals an impending progression to the accelerated phase of the disease (see “Accelerated Phase of CML”).
Functional abnormalities of neutrophils (adhesion, emigration, phagocytosis) are mild; are compensated for by high neutrophil concentrations; and do not predispose patients in chronic phase to infections by either usual or opportunistic organisms.281,282 and 283 Platelet dysfunction can occur but is not associated with spontaneous or exaggerated bleeding. A decrease in the second wave of epinephrine-induced platelet aggregation is the most common abnormality and is associated with a deficiency of adenine nucleotides in the storage pool.284,285
Morphology The marrow is markedly hypercellular, and hematopoietic tissue takes up 75 to 90 percent of the marrow volume, fat being reduced markedly.286,287 Granulopoiesis is dominant, with a granulocytic/erythroid ratio of between 10 and 30:1 rather than the normal 2 to 4:1. Erythropoiesis is usually decreased, and megakaryocytes are normal or increased in number. Eosinophils and basophils may be increased, usually in proportion to their increase in the blood. Mitotic figures are increased in number. Macrophages that mimic Gaucher cells in appearance are sometimes seen. This finding is a result of the inability of normal cellular glucocerebrosidase activity to degrade the increased glucocerebroside load associated with markedly increased cell turnover.288 Macrophages also can become engorged with lipids, which, when oxidized and polymerized, yield ceroid pigment. This pigment imparts a granular and bluish cast to the cells after polychrome staining; such cells have been referred to as sea-blue histiocytes288 (Plate IX).
Collagen type III, which takes the silver impregnation stain, is commonly increased at the time of diagnosis (reticulin fibrosis) and is strikingly increased in nearly half the patients289 and is correlated with the proportion of megakaryocytes in the marrow.290,291 Increased fibrosis is correlated also with larger spleen size, more severe anemia, and a higher proportion of marrow and blood blast cells.
Progenitor Cell Growth Cells that form colonies of neutrophils and macrophages or eosinophils (CFUs) are increased in the marrow and blood. The increase in CFUs in marrow is about 20-fold normal and in blood about 500-fold normal. The CFUs are of lighter buoyant density than those in normal marrow.94 More primitive progenitors that can initiate long-term cultures of hematopoiesis are also markedly increased.292 Spontaneous blood-derived granulocyte-macrophage colony growth is common, although CFUs also respond to growth factor stimulation.95
Cytogenetics The marrow and nucleated blood cells of over 90 percent of patients with clinical and laboratory signs that fall within the criteria for the diagnosis of CML contain the Ph chromosome, t(9;22)(q34;q11). The chromosome is present in all blood cell lineages (erythroblasts, granulocytes, monocytes, megakaryocytes, T- and B-cell progenitors) but is not present in the majority of blood B or in most T lymphocytes.45,47 About 70 percent of patients in chronic phase have the classic Ph chromosome in their cells.293 The remaining 20 percent have, in addition, a missing Y chromosome, t(Ph),-Y; an additional C-group chromosome, usually number 8, that is t(Ph),+8; an additional chromosome 22q-, but without the 9q+, that is t(Ph), 22q-, or t(Ph) plus either another stable translocation or another minor clone.74 These variations have not been shown to affect the duration of the chronic phase. Deletion of the Y chromosome occurs in about 10 percent of healthy men over age 60 years.294,295
Variant Ph chromosome translocations occur in about 5 percent of subjects with CML and involve complex rearrangements (three chromosomes), and every chromosome except the Y chromosome can be involved.296,297,298,299 and 300 The Ph chromosome, that is, 22q-, is present, but the gross exchange of chromosomal material involves a chromosome other than 9 (simple variant) or involves exchange of material among chromosomes 9,22, and a third or more chromosomes (complex variant) (Fig. 94-6). High-resolution techniques have indicated that 9q34-qter is transposed to 22q11 in simple as well as complex translocations.301,302 Thus, the fusion of 9q34 with 22q11 seems to occur in the cells of most patients with CML.303 Complex translocations involving chromosome 3 have been notable.303,304 and 305 In rare cases, a reciprocal translocation with a chromosome other than 9 to chromosome 22 is larger than usual, and the posttranslocation shortening of the long arms of 22 is not apparent. This circumstance has been referred to as a masked Ph chromosome or masked translocation, since the 22q- is not evident by microscopic examination,306,307 although t(9;22) may occur as judged by banding techniques or molecular probes.308

FIGURE 94-6 Translocations involved in chronic myelogenous leukemia. The positions of the ABL gene in each of the chromosomes before and after the translocation is noted. The origin of the chromosomal segments in each of the translocated chromosomes is indicated by a bracket on the side of the chromosome. (Reprinted with permission from Rosson D, Reddy EP: Activation of the abl oncogene and its involvement in chromosomal translocations in human leukemia. Mutation Res 195:231, 1988.)

Molecular Probes In a small proportion of patients with a clinical disease analogous to CML, cytogenetic studies do not disclose a classical, variant, or masked Ph chromosome. In these cases, use of a panel of restriction enzymes and Southern blotting analyses with a molecular probe for the breakpoint cluster region on chromosome 22 nearly always detects rearrangement of fragments. This finding has led to the conclusion that virtually all cases of CML have an abnormality of the long arm of chromosome number 22 (BCR-rearrangement).309,310,311,312 and 313 Ph-chromosome-negative CML cells with BCR rearrangement can express the p210bcr–abl, and such patients have a clinical course similar to Ph-chromosome-positive CML.309,312,313,314,315,316 and 317
The ability to identify the molecular consequences of the t(9;22), that is, BCR rearrangement, mRNA transcripts of the mutant fusion gene, and the p210bcr–abl, has resulted in diagnostic tests supplementary to cytogenetic analysis.303 These tests include Southern blot analysis of BCR rearrangement,315,316,317,318 and 319 polymerase chain reaction (PCR) amplification of the abnormal mRNA,320 and a less complex variation on the latter, a hybridization protection assay.321
Southern blot of the DNA extracted from samples of blood cells should be correlated with marrow cytogenetic analysis; some occasional discordant cases in which Southern blot analysis does not detect BCR gene rearrangement but the marrow cells have Ph-chromosome-positive metaphases can occur. Thus, marrow cytogenetic analysis should be performed if patients achieve a complete disappearance of BCR-rearranged cells by Southern blot to avoid overestimating the degree of response.322
The PCR can achieve a sensitivity of 1 positive cell in about 500,000 to 1 million cells. This extreme sensitivity requires special care in analysis and the inclusion of negative controls.323,324,325 and 326
Immunodiagnosis of CML by identification of the p210bcr–abl is possible, also. This tumor-specific protein for CML is unique, based on the amino acids at the junction between the ABL and BCR sequences. Oligopeptides corresponding to the junctional amino acids have been synthesized and used as antigens327,328,329 and 330 to develop specific antibodies to the p210bcr–abl. A multicolor fluorescence in situ hybridization (FISH) method to detect the BCR-ABL fusion in patients with CML is a rapid and sensitive alternative to Southern blot and PCR-dependent methods.331 For diagnostic purposes, FISH appears to be simple, accurate, and sensitive and can detect the various molecular fusions (e.g., b2a2, b3a2, e1a2).332,333 and 334,834 Interphase FISH is faster and more sensitive than cytogenetics to identify the Ph chromosome. If a very low concentration of CML cells is present, interphase FISH may not detect BCR-ABL, so it has limited use for detecting minimal residual disease.335 Hypermetaphase FISH allows up to 500 metaphases per sample to be analyzed in less than 1 h. Several factors influence the false-positive and -negative rates of FISH identification of BCR-ABL, including definition of a fusion signal, nuclear size, and the genomic position of the ABL breakpoint.336
The frequency of cytogenetic analysis can be reduced if patients are monitored by molecular methods such as quantitative Southern blotting, FISH, quantitative Western blotting, or competitive reverse transcriptase–polymerase chain reaction (RT-PCR). Molecular analysis can be performed on blood samples and are therefore much easier to use than cytogenetic analysis of marrow cell metaphases. Southern blotting, Western blotting, and FISH are quantifiable, but their sensitivity is not generally superior to classical cytogenetic methods. Quantitative RT-PCR is the method of choice for monitoring patients for residual disease or reappearance of disease after marrow transplantation. Competitive PCR can detect reappearance of or increasing levels of RNA bcr-abl transcripts prior to clinical relapse in patients after transplantation.337,338 and 339
Uric Acid An increased production of uric acid with hyperuricemia and hyperuricosuria occurs in untreated CML.340 Uric acid excretion is often two to three times normal in patients with CML, and if aggressive therapy leads to rapid cell lysis, excretion of the additional purine load may produce urinary tract blockage from uric acid precipitates. The formation of urinary urate stones is common in patients with CML, and some with latent gout may develop acute gouty arthritis or uric acid nephropathy.341 The likelihood of complications from urate overproduction is greatly increased by starvation, acidosis, renal disease, or diuretic drug therapy.
Serum Vitamin B12-Binding Proteins and Vitamin B12 Binding Proteins and Vitamin B12 Neutrophils contain vitamin B12-binding proteins, including transcobalamin I and III (syn: R-type B12-binding protein or cobalophilin).342,343,344 and 345 Patients with myeloproliferative diseases have an increased serum level of B12-binding capacity, and the source of the protein is principally mature neutrophilic granulocytes.342,343 The increase in transcobalamin level and the resultant increase in vitamin B12 concentration are particularly notable in CML, although any increase in the number of neutrophilic granulocytes such as in leukemoid reactions can be accompanied by an increase in serum B12-binding protein levels and vitamin B12 concentration.345 The serum B12 level in CML patients is increased on the average to over 10 times normal.346 The increase is proportional to the total leukocyte count in untreated patients and falls toward normal levels with treatment, although increased B12 levels commonly persist even after the white cell count is lowered to near normal with therapy.
Rarely pernicious anemia and CML may coexist. In this situation the tissues are vitamin B12 deficient, but the serum vitamin B12 level may be normal because of the elevation in the level of transcobalamin I, a binder with a very high affinity for vitamin B12.346
Serum Lactic Dehydrogenase, Potassium, Calcium, Cholesterol The level of serum lactic dehydrogenase (LDH) is elevated in CML.347 Pseudohyperkalemia due to the release of potassium from white cells during clotting348 and spurious hypoxemia or pseudohypoglycemia from in vitro utilization of oxygen or glucose by granulocytes can occur. Hypercalcemia349 or hypokalemia350 has occurred during the chronic phase of the disease, but such complications are very rare until the disorder transforms to acute leukemia. Elevations in serum and urinary lysozyme levels are features of leukemia with greater monocytic components and are not features of CML.351 Serum cholesterol is decreased in patients with CML,352,353 and the severity of the decrease is correlated with shortened duration of patient survival.353
Two syndromes, thrombocythemia with the Ph chromosome and BCR-ABL rearrangement or thrombocythemia without a Ph chromosome but with the BCR-ABL rearrangement may precede the overt signs of CML or its accelerated phase.354,355,356,357,358,359 and 360 In general, the disease closely mimics classical thrombocythemia initially; marked platelet elevation, extreme megakaryocytic hyperplasia, normal or mildly elevated white cell count, no or very slight myeloid immaturity in the blood, and minimal anemia. In some cases, the absolute basophil count is mildly elevated. About 5 percent of patients with apparent essential thrombocythemia have a Ph chromosome,356 and about 5 to 7 percent of CML patients present with a classical picture of essential thrombocythemia.357,358 Evolution to blast crisis may occur.355,361,362 There is controversy about the frequency of Ph-chromosome-negative, BCR-ABL-positive thrombocythemia and its relationship to chronic myelogenous leukemia.363,364
A rare variant of BCR-ABL-positive CML has been described in which the elevated white cell count is composed principally of mature neutrophils.365,366 Too few cases have been described to be certain of its other phenotypic distinctions, but the white cell count appears to be lower on average (30 to 50,000/µl) at the time of diagnosis than with classical CML (100 to 200,000/µl). Moreover, patients with neutrophilic CML usually do not have basophilia, notable myeloid immaturity in the blood, prominent splenomegaly, or low leukocyte alkaline phosphatase scores. These patients’ cells have the Ph chromosome but have an unusual BCR-ABL fusion gene in that the breakpoint in the BCR gene is between exons 19 and 20 resulting in most of the BCR gene fusing with ABL, which results in a larger fusion protein (230 kDa) as compared to the fusion protein in classical CML (210 kDa) (Fig. 94-2). This correlation between genotype and phenotype was not observed in all cases.367
A very small number of patients with Ph-chromosome-positive myeloproliferative disease have had the breakpoint on the BCR gene in the first intron (m-bcr) resulting in a 190-kDa fusion protein instead of the classical 210-kDa protein observed in patients with CML (Fig. 94-2). The m-bcr molecular lesion is similar to that observed in about 60 percent of patients with BCR rearrangement-positive ALL. In patients with m-bcr CML, monocytes are more prominent, the white cell count lower on average, and basophilia and splenomegaly less prominent than in disease with classical BCR breakpoint (M-bcr). The few cases reported have had a short interval before either myeloid or lymphoid blast transformation has developed.368
About 15 percent of patients present with symptoms or signs referable to leukostasis as a result of the intravascular flow-impeding effects of white cell counts over 300,000/µl (300 × 109/liter).235 Hyperleukocytosis is more prevalent in children with Ph-chromosome-positive CML.236 The effects of total leukocyte counts from 300,000 to 800,000/µl (300 to 800 × 109/liter) include impairment of the circulation of the lung, central nervous system, special sensory organs, and penis, resulting in some combination of tachypnea, dyspnea, cyanosis, dizziness, slurred speech, delirium, stupor, visual blurring, diplopia, retinal vein distention, retinal hemorrhages, papilledema, tinnitus, impaired hearing, or priapism.237 Such symptoms or signs usually respond to the rapid decrease in white cell count by a combination of leukapheresis and hydroxyurea therapy.
CML has an association with lymphoproliferation that can take four principal forms: (1) Patients may develop CML years after irradiation treatment of lymphoma or Hodgkin disease; (2) about one-third of CML patients enter the accelerated phase of the disease by evolution and dedifferentiation of the CML clone into one that supports lymphoblastic proliferation (acute lymphoblastic transformation); (3) patients may have concurrent lymphoproliferative or plasmacytic malignancies and CML. Lymphoma or lymphoblastic leukemia,369,370,371,372 and 373 essential monoclonal gammopathy,374,375 myeloma,376,377,838 or Waldenstrom macroglobulinemia378 have occurred in association with CML. Several cases have been reported of CML emerging in patients with established chronic lymphocytic leukemia (CLL).379,380 A few patients have presented with both diseases occurring simultaneously.365,366 A single case has been reported of lymphocytic leukemoid reaction simulating CLL which regressed as CML emerged.367 In some cases, the CLL lymphocytes have not contained the Ph chromosome, whereas the CML cells did, suggesting the presence of two independent clonal disorders,379,380 and 381 and in other cases the Ph chromosome was present in the myeloid and lymphoid cells indicating a common origin.382 (4) Patients may present with Ph-chromosome-positive acute lymphobl astic leukemia and, following chemotherapy-induced remission, develop the features of typical CML.383
The diagnosis of CML is made on the basis of the characteristic granulocytosis, white cell differential count, increased absolute basophil count, and splenomegaly coupled with the presence of the Ph chromosome or its variants (greater than 95 percent of patients) or a BCR rearrangement on chromosome 22 (greater than 99 percent of patients).
Patients with other chronic hematopoietic stem cell diseases such as polycythemia vera, primary thrombocythemia, or idiopathic myelofibrosis only occasionally have closely overlapping features. For example, the total white cell count is above 30 × 109/liter in over 90 percent of patients with CML and increases inexorably over weeks or months of observation, whereas it is below 30 × 109/liter in over 90 percent of patients with the three other classical chronic hematopoietic stem cell diseases and usually does not change significantly over months to years. Polycythemia vera is associated with an increase in red cell mass and hematocrit and displays clinical signs of plethora; CML does not have these features. Patients with idiopathic myelofibrosis invariably have marked teardrop poikilocytes and other severe red cell shape, size, and chromicity changes and prominent nucleated red cells in the blood; CML rarely has these features. Patients with primary thrombocythemia have a platelet count over 750,000/µl (750 × 109/liter) and usually only mild neutrophilia, the latter white cell findings distinguishing it from the small proportion (10 percent) of CML patients with platelet counts over 750,000/µl (750 × 109/liter) at the time of diagnosis. In addition, patients with the clinical features of polycythemia vera or idiopathic myelofibrosis do not have the Ph chromosome or BCR rearrangement in their blood and marrow cells, except in extremely rare cases. The case of essential thrombocythemia is more complex (see previous section). Increasing awareness of the features of related disorders such as chronic myelomonocytic leukemia and an appreciation that elderly patients are prone to atypical stem cell diseases have minimized the inappropriate diagnosis of Ph-chromosome-negative CML, which should be avoided unless the clinical features are characteri stic of classical CML and a masked Ph chromosome or BCR rearrangement is found. If neutrophil alkaline phosphatase reactivity is normal or elevated and the clinical features are atypical, the diagnosis of CML is unlikely; however, the test is too insensitive and nonspecific to be the deciding factor in the diagnosis.
Reactive leukocytosis can occur with absolute neutrophil counts of 30 to 100,000/µl (30 to 100 × 109/liter). Usually these leukemoid reactions occur in the setting of an overt inflammatory disease, cancer, or infection. If the incitant is not apparent, the absence of granulocytic immaturity, basophilia, splenomegaly, and decreased neutrophil alkaline phosphatase activity would argue against CML. The absence of a cytogenetic or molecular abnormality in chromosome 22 would virtually eliminate classical CML as a consideration.
The precise diagnosis of CML is of help in estimating prognosis for the patient, the choice of drugs for treatment, and the timing of special therapies, such as stem cell transplantation.
The Ph chromosome has been found rarely in patients with apparent polycythemia vera,26,384 polycythemia vera that later evolves into Ph-chromosome-positive CML,385,386 and 387 idiopathic myelofibrosis,265,388,389 or a myelodysplastic syndrome.390,391 Molecular studies to determine the presence of the BCR-ABL were not performed in cases reported before 1985. Primary (essential) thrombocythemia with a Ph chromosome and/or BCR-ABL rearrangement is discussed above in “Special Clinical Features.”
Hyperuricemia and hyperuricosuria are frequent features of CML at diagnosis or in relapse.392 Treatment of hyperuricemia is a function of the elevation of the pretreatment serum uric acid concentration, the blood white cell concentration, spleen size, and the dose of chemotherapy planned. If these variables suggest a high risk for a significant amount of cell lysis. Allopurinol, 300 mg per day, orally, and adequate hydration to maintain a good urine flow should be instituted prior to chemotherapy. If hyperuricemia is extreme, alkalinization of urine can be achieved with sodium bicarbonate . Allopurinol is associated with a high frequency of allergic skin reactions and should be discontinued after the blood leukocyte count and spleen size are decreased and the risk of exaggerated cell lysis has passed.
Treatment of chronic myelogenous leukemia is evolving as new drugs and drug combinations are being applied in clinical trials.393 A current approach for patients under age 60 years is shown in Fig. 94-7. While progress has been made in the treatment of CML, even in the era of IFN-a and new transplantation strategies, most people die of the disease. Only a small fraction of patients are suitable for allogeneic stem cell transplantation, and only a small fraction have a complete cytogenetic response with IFN-a.

FIGURE 94-7 Treatment for a newly diagnosed patient with CML under 60 years of age. It is suggested that patients under 40 years of age with HLA-identical siblings should be treated by allografting soon after diagnosis; those aged 40 to 60 years should receive a trial of IFN-a, and stem cell transplantation should be delayed if they achieve a complete cytogenetic response (CCR). All patients with an HLA-identical sibling should receive a trial of IFN-a. Complete responders should continue on IFN-a. Those who fail to achieve CCR should be considered for treatment by allografting with an alternative donor, usually a volunteer unrelated donor (VUD), or by autografting (A/G) while still in chronic phase (CP). Some centers delay stem cell cryopreservation for those patients already treated with IFN-a rather than preserving stem cells at diagnosis. These guidelines cannot be applied without individual consideration of each patient’s circumstances. (Reprinted with permission from Clin Haematol 10:405, 1997.)

IFN-a is utilized in virtually all patients less than 60 years of age, most patients between 60 and 70, and some patients in older age groups, even in circumstances in which minimal white cell elevation is present. In cases in which the white cell count is markedly elevated, hydroxyurea is used prior to IFN-a. If rapid cytoreduction is required because of signs of the hyperleukocytic syndrome, leukapheresis and hydroxyurea are often combined.
Leukapheresis can control CML only temporarily. For this reason, it is useful in two types of patient: the hyperleukocytic patient in whom rapid cytoreduction can reverse symptoms and signs of leukostasis (e.g., stupor, tinnitus, papilledema, priapism)236,237 and the pregnant patient with CML who can be controlled by leukapheresis treatment without chemotherapy either during the early months of pregnancy when chemotherapy poses a higher risk to the fetus or, in some cases, throughout the pregnancy.394,395 Because of the large body burden of leukocytes in marrow, blood, and spleen, and the high proliferative rate in CML, the leukocyte reduction by apheresis is less efficient than in other types of leukemias.237 Leukapheresis reduces the burden of tumor cells subject to chemotherapeutically induced cytolysis and thus the production and the excretion of uric acid. In hyperleukocytic nonpregnant patients, leukapheresis is best used in conjunction with hydroxyurea to ensure rapid and optimal reduction in white cell count.
Hydroxyurea now is preferred to busulfan for the control of white cell elevation. It is less toxic, may sustain the chronic phase of CML for a longer time, and may permit greater success with stem cell transplantation. Hydroxyurea 1 to 6 g per day, orally, depending on the height of the white cell count, can be used to initiate elective therapy.396 Urgent treatment of extraordinary total white cell counts may require higher doses. The dose of hydroxyurea should be decreased as the total white cell count decreases and is usually given at 1 to 2 g per day when the total white cell count reaches 20,000/µl (20 × 109/liter). Thereafter, dosing should be adjusted individually to keep the white count between 5000 to 15,000/µl (5–15 × 109/liter). Initially, blood cell counts should be obtained 2 to 3 times per week, decreased to every 2 to 6 weeks depending on their stability, but eventually, if stable, may only be required every 2 or 3 months. Patients require chronic administration of hydroxyurea to control the chronic phase of CML usually at a dose of about 0.5 to 2.0 g per day, orally. The drug should be temporarily discontinued if the white cell count drops below 5000/µl (5 × 109/liter). If hydroxyurea is being used in combination with IFN-a, it is usually tapered and discontinued once a hematologic response to IFN-a is observed.
The major side effect of hydroxyurea is an extension of its pharmacological effect, that is, reversible suppression of hematopoiesis, often with megaloblastic erythropoiesis. The median survival of patients with CML treated with hydroxyurea alone is about 5 years (Table 94-2). Studies with high-dose hydroxyurea indicate that marrow metaphase cells in some patients lose the Ph chromosome either partially or completely after such therapy.397 The drug may be very useful in patients at advanced ages, with comorbid conditions, or other factors that limit their tolerance to IFN therapy.


Treatment with IFN-a offers a survival advantage as compared to treatment with hydroxyurea or busulfan alone398,399,400,401,402 and 403 (Table 94-2). IFN-a has a very slowly progressive effect, and patients may require hydroxyurea and/or leukapheresis therapy during the first week or two of IFN-a therapy.
Initiation of Treatment Several guidelines for the use of IFN-a in CML have been published.393,404 While some study groups have reported that doses of 3 × 106 units/m2 injected subcutaneously per day are as effective as higher doses (e.g., 5 × 106 units/m2 per day),399,405 some groups have found that patients receiving 5 × 106 units/m2 per day have the greatest incidence of cytogenetic remission.406 A hematologic response has been observed in up to 80 percent of patients, partial disappearance of Ph-chromosome-positive cells (<35 percent of cells) in 50 percent of patients, and nearly complete cytogenetic responses (<5 percent of cells) in 15 percent of patients, regardless of the patient’s age.407
IFN-a can be started at a dose of 3 million units/day subcutaneously in the evening on a Monday, Wednesday, Friday schedule and then escalated after 1 week to 5 million units/day, three times per week. If symptoms allow, the dose can then be increased to 5 million units/m2, three times per week, for 1 week and then to 5 × 106 units/m2 per day. Doses can be adjusted based on white cell and platelet counts. Hydroxyurea may be used to control the white cell count during any phase of interferon therapy. Hydroxyurea should be adjusted to maintain a white cell count of 5000 to 10,000/µl and generally is discontinued when the white cell count is less than 5000/µl. Greater leukopenia requires reduction or cessation of the interferon dose. Platelet count depressions below 50,000/µl require a decrease in the dose or the frequency of dosing, or even temporary discontinuation of interferon.
Maintenance Therapy IFN-a is usually required continously, although many patients can be maintained in a hematologic remission with one to two doses of 3 to 5 × 106 units/m2 per week. A complete hematologic response within 3 months of initiation of IFN-a is associated with the highest likelihood of a complete cytogenetic response.408 Polyclonal hematopoiesis has been demonstrated after IFN-a induced cytogenetic remission.409 The greater the decrease in Ph-chromosome-positive cells, the greater the duration of survival, but long-term control of disease by IFN-a occurs only in a minority of patients.410 Rare sustained remissions in which the blood cells do not have BCR rearrangment after cessation of treatment do occur.411 After 6 months of therapy, patients with a partial hematologic response or resistant disease are very unlikely (<10 percent) to achieve a later major cytogenetic response.405 Two studies have shown no advantage of IFN-a use compared to hydroxyurea in survival from diagnosis,435,436 but the dose intensity of either IFN-a or hydroxyurea as well as the difference in the compositions of patient populations may contribute to these different results. Meta-analysis of randomized trials comparing IFN-a to other therapies, however, have shown a survival advantage for those treated with IFN-a400 (Table 94-2). However, the most efficacious dose of IFN-a; the benefit, if any, of continuing it in patients who have no cytogenetic response; the timing of its use in relationship to allogeneic stem cell transplantation; and its use in combination with other agents all remain to be determined.393
Mechanism of Action IFN-a’s beneficial effect in CML may relate to a direct inhibition of DNA polymerase activity.412 Expression of interferon regulatory factor (IRF) genes, specifically a high ratio of IRF-1 to IRF-2, may be associated with a good cytogenetic and molecular response.413 IFN-a has also been found to affect Fas-mediated apoptosis in CML.414 The response to IFN-a is correlated with transcript numbers of BCR-ABL.415,840 In CML patients who demonstrate a long-term response to IFN-a, a specific immune response directed against p210bcr–abl occurs.416 The progressive methylation of the ABL promoter correlates inversely with a response to IFN-a.417 The site of M-bcr rearrangement has been reported to be predictive for the response to IFN-a with 5′ breakpoints responding more favorably,418 but others have not found a significant difference in the breakpoint locus and the time to transformation.419
Monitoring Response Hypermetaphase FISH on blood films to detect the frequency of Ph-chromosome-positive cells during IFN-a treatment permits assessment of the response.420,421 Patients with IFN-a who maintain long-term complete cytogenetic responses may remain positive by RT-PCR for mRNAbcr–abl, indicating that the disease is not eradicated.422 The number of mRNAbcr–abl transcripts that persist in patients treated with IFN-a who achieve a complete cytogenetic remission (no Ph-chromosome-positive cells) has been found to vary by as much as four orders of magnitude.423 When quantitative PCR has been used to monitor residual disease in CML during treatment with IFN-a, detection of elevated transcripts may precede signs of hematologic or cytogenetic disease progression by up to 8 months.424 The BCR-ABL can persist as judged by FISH despite negative or very weakly positive levels measured by quantitative RT-PCR. This discordance may be explained by persistance of nonproliferating affected cells that do not express the transcripts.842
Toxic Effects IFN-a requires subcutaneous administration. Its early side effects may include fever, fatigue, sweating, anorexia, headache, muscle pain, nausea, and bone pain. These occur in about 50 percent of patients. Later effects include apathy; agitation; insomnia; depression; bone pain; muscle pain; hepatic, renal, or cardiac dysfunction; immune-hemolytic anemia; thrombocytopenia; and hypothyroidism.425 Elevation of liver enzymes is frequent, and hypertriglyceridemia is nearly universal. Toxicities may necessitate dose reduction or discontinuation of IFN-a. The acute side effects, however, can be minimized by evening doses and premedication with acetaminophen and/or diphenhydramine.
IFN-g is less active than IFN-a in CML,426 but combinations of the interferons may decrease the total dose required and increase the response rate.427 Patients who do not respond to IFN-a may respond to hydroxyurea or busulfan. Development of neutralizing anti-interferon antibodies can occur during treatment.428 Some patients with antibodies who are resistant to recombinant IFN-a respond to lymphoblastoid IFN-a.429
The effect of IFN-a use in patients with marrow fibrosis is controversial. Some reports indicate that it may prevent fibrosis in those responding to treatment,430 whereas others have found that it may speed progression of marrow fibrosis.431
Prolonged administration of IFN-a may adversely affect allogeneic stem cell transplantation outcomes.432 Higher rates of graft failure and posttransplant infections were found in patients pretreated with IFN-a, although there was no influence on GVH disease or relapse rate. Prolonged IFN-a treatment may also adversely affect matched, unrelated donor transplant outcomes.433 IFN-a can induce cytogenetic remission in patients with cytogenetic relapse following stem cell transplantation.434
Cytarabine Daily infusion of low-dose cytarabine (15–30 mg/m2 per day) to outpatients by a portable pump has resulted in control of the disease and a partial decrease or complete absence of metaphase cells containing the Ph chromosome.437 Combinations of hydroxyurea, interferon-a, and cytarabine also are being studied.438 For example, IFN-a2b combined with cytarabine (20mg/m2 for 10 days each month) in chronic phase was associated with a greater proportion of major cytogenetic response at 12 months after randomization and with greater survival prolongation than was IFN-a alone.439
Busulfan Once the mainstay of treatment for the chronic phase, use of busulfan largely has been replaced by IFN-a and/or hydroxyurea.440 It is used primarily as part of the preparative regimen for allografting or autografting. Busulfan in doses of 4 to 6 mg per day orally can be used until the white cell count falls to about 30,000/µl (30 × 109/liter). After stopping the drug, the effect persists for days to weeks, and a further decrease usually occurs toward or to normal levels. Some patients may get a sustained effect and not require further treatment immediately. After reaching its nadir, the total leukocyte count will increase in most patients and require maintenance therapy, which can be as little as 2 mg twice a week, orally. The drug leads to a decrease in the white cell count, decrease in spleen size, increase in the hematocrit, and a restoration of a sense of well-being in about 95 percent of patients treated in the chronic phase. Periodic blood cell counts should be obtained to follow the response of the patient to the drug, and intervals between counts should not extend beyond 4 to 6 weeks in apparently stabilized patients and should be more frequent in unstable patients.
Control of the disease with busulfan does not usually induce disappearance of the Ph chromosome. The intensity of therapy is not sufficient to cause suppression of the abnormal clone. The objective of busulfan therapy has been to control the chronic phase of the disease and eliminate or minimize its morbidity.440
The chronic use of the drug has been associated with a syndrome that simulates adrenal insufficiency manifested by skin pigmentation, weakness, fever, and diarrhea441,442 or with pulmonary fibrosis.443 Prolonged aplasia of the marrow can occur with busulfan444 and in one large series was a cause of death in patients. In some patients who survive aplasia induced by busulfan, prolonged remissions may occur along with disappearance of the Ph chromosome.445
Homoharringtonine Homoharringtonine, a plant alkaloid, has been reported to induce responses, including cytogenetic responses, in patients in late chronic phase.446 Homoharringtonine has also been utilized in combination with IFN-a and cytosine arabinoside.447
Other Cytotoxic Agents The nucleoside analogs, deoxycoformycin and fludarabine do not have a significant effect in chronic phase CML.448
Several other chemotherapeutic agents can control the chronic phase of the disease, notably dibromomannitol.449 Although a wide variety of other agents have been used including melphalan, cyclophosphamide, 6-mercaptopurine, 6-thioguanine, demecolcine, and uracil mustard, they are largely inferior to hydroxyurea in the proportion of patients who respond well to them.450
Intensive multidrug regimens have been used to study whether such an approach can eradicate the Ph-chromosome-positive clone and lead to prolongation of remission or cure of the disease. This approach has not significantly increased survival.451
Vitamin A has been reported to have benefit when used in conjunction with busulfan.452 All trans-retinoic acid and 13 cis-retinoic acid may also play a role in management.453,454 and 455
Anagrelide Anagrelide has been utilized to treat markedly elevated platelet counts in CML, especially where thrombosis or bleeding is present. This agent acts directly to decrease megakaryocyte mass, and it can lead to a precipitous fall in platelet counts.456
Gene target-selective destruction of cells containing the BCR-ABL fusion gene is a theoretical possibility and has been studied in vitro. This approach to therapy is highly specific, but several important issues remain to be resolved regarding delivery of these agents in vivo.457,821,836,837
The p210 product of the BCR-ABL oncogene is a protein phosphokinase and is the principal oncogenic factor in the onset of CML. Drugs that act to prevent the action of this protein kinase are under study and have reached the stage of clinical trials. The experimental agent, referred to as STI 571 is administered daily by mouth. If its therapeutic effects are sufficiently dramatic and sustained and are not countered by exaggerated toxicity, it looms as a new primary mode of therapy for patients in the chronic phase.820,821,835 The drug or its congeners could interrupt the leukemic process and result in reestablishment of polyclonal, normal hematopoiesis.
Splenic irradiation may be useful occasionally in subjects who have entered accelerated or advanced chronic phase and are troubled with extreme splenomegaly with splenic pain, perisplenitis, and encroachment of the spleen on the gastrointestinal tract.458 The result of splenic irradiation is usually short-lived.
Radiotherapy may be useful for extramedullary tumors, which may occur occasionally in bone or soft tissue during the chronic phase.
Splenectomy does not prolong the chronic phase of CML, delay the onset of the accelerated phase, enhance sensitivity to standard or intensive chemotherapy, or prolong survival of patients.459 In carefully selected patients with symptomatic thrombocytopenia unresponsive to chemotherapy and a greatly enlarged spleen, splenectomy may be useful. Postoperative morbidity from infection, thrombosis, or hemorrhage has been high. Splenectomy does not decrease recurrence of disease after therapy. Splenectomy has not been found to influence the severity of GVH disease or survival after allogeneic stem cell transplantation.460
Ph-chromosome-negative stem cells are present in most patients with CML at the time of diagnosis. Techniques to use these cells to reconstitute hematopoiesis after high-dose therapy have been developed.461 Ph-chromosome-negative progenitors can be mobilized with G-CSF and collected from the blood in patients who have responded to prior treatment with IFN-a.462 Such cells can also be collected after recovery from chemotherapy regimens, such as after idarubicin and cytarabine, followed by G-CSF stimulation.461,463 BCR-ABL-negative primitive myeloid cells can be selected for autografting early in chronic phase.464 Patients autografted with Ph-chromosome-negative progenitors after myeloablative conditioning regimens may have long-term remissions in some cases.465,466 There is as yet no evidence that this approach prolongs survival.467
In addition to positive selection of Ph-chromosome-negative progenitors, based on their lack of HLA-DR expression,463 negative selection by purging of BCR-ABL-positive progenitors in vitro can be used. These approaches have included treatment of cell suspensions with either IFN-a, specific T-cell subsets, natural killer cells,468,469 antisense oligonucleotides,470 ribozymes,471 various inhibitors of signal transduction pathways, such as genistein,472 or an inhibitor of the ABL tyrosine kinase.473 In vitro culture of CML marrow favors outgrowth of normal progenitors and offers a means of depleting leukemic progenitors.474 When such techniques have been used to select cells for autografting, most patients have relapsed.475 No randomized trials have been conducted to demonstrate that marrow purged of BCR-ABL-positive progenitors improves remission rates or duration of survival. Thus, although autografting in CML may have therapeutic benefit in select patients, it remains an investigational approach.
Dendritic cells possessing the Ph chromosome that induce CD8+ cytotoxic T cells specific for leukemia cells can be isolated from CML patients.476 The ability to identify CML-specific T cells after transplant has not been uniform, however.477 Such cells could be utilized in a state of minimal disease after autologous stem cell transplantation to achieve a specific anti-CML effect.
Patients in the chronic phase of CML who are less than 65 years of age and who have an identical twin478 or a histocompatible sibling479,480 and 481 or who are less than 55 with access to a histocompatible, unrelated donor482 can be transplanted after intensive therapy, usually cyclophosphamide and fractionated total-body irradiation or a combination of busulfan and cyclophosphamide.
Stem cell transplantation from HLA-compatible siblings results in engraftment and an actual or projected long-term survival in 45 to 70 percent of recipients.483 There is about a 20 percent risk of relapse of CML. Transplanted T lymphocytes, especially if activated by a (mild) GVH reaction, may be an important factor in preventing leukemic relapse. This phenomenon, referred to as graft-versus-leukemia reaction, is thought to suppress the leukemic process through T-cell-mediated cytotoxicity.481 The beneficial effect of graft-versus-leukemia phenomena may be present in blast crisis484 and in chronic phase.485,486 Graft failure is rare in properly conditioned patients in chronic phase. The 5-year probability of survival is about 60 percent for chronic phase patients and about 20 percent for accelerated phase patients.487 The majority of survivors have no evidence of residual leukemia cells.488
The best outcomes are seen in younger patients when the transplant is performed within 1 year of diagnosis.489,490 Choice of pretransplant conditioning does not appear to have an impact on outcome, but previous exposure to busulfan has a negative impact.491 IFN-a does not increase the probability of treatment failure.492 In the first 18 months after the diagnosis of CML, mortality is higher in the patients who have received a stem cell transplant than in the cohort treated without transplants; between 18 to 56 months, mortality is similar in the two groups; and after 56 months, the mortality is lower in the patients who were transplanted.493 Survival after 7 years was 48 percent with transplant and 32 percent with hydroxyurea or IFN-a treatment.493 The relative benefit of marrow as compared to mobilized blood stem cells as the source of the allograft has not been established.494
For younger patients who do not have a histocompatible sibling, utilization of unrelated donor or a mismatched family member as a source of stem cells is feasible. The toxicity of this procedure is greater than that of an HLA-identical sibling donor transplant. Five-year disease-free survival is about 40 percent.495 Younger patients with cytomegalovirus-seronegative donors who are matched at the HLA-DRB1 allele by molecular methods fare better.496 When class I HLA genes are typed with molecular methods, one may expect an improvement in matching and better outcomes using unrelated donors. Cord blood stem cell transplantation from an unrelated donor has also been used in adults with CML.497
The major causes of failure of a stem cell allograft in CML include conditioning regimen-related toxicity, GVH disease, and relapse of leukemia. Prophylaxis of GVH disease may include various methods of T-cell depletion in vitro or in vivo and prevention of the reaction with cyclosporine and methotrexate. Glucocorticoids are the mainstay of treatment for established GVH disease. The risk of leukemia relapse is higher if the allograft is depleted of T cells in vitro. Using non-T-cell-depleted grafts, the 5-year relapse rate is about 20 percent and in unrelated donor transplants, 3 percent.498 The use of unrelated stem cell allografts compensates for the reduced graft-versus-leukemia activity associated with T-cell depletion in patients transplanted in chronic phase.499 Disease status after the allograft can be monitored with cytogenetic studies, PCR, or FISH analysis. A positive PCR assay at 3 months after allogeneic BMT has not been found to correlate with an increased risk of relapse compared with PCR-negative patients. A positive assay 6 months and beyond is associated with subsequent relapse. In one series, 42 percent of patients with a positive PCR assay at 6 to 12 months relapsed versus 3 percent with a negative assay.500 Patients who remain BCR-ABL-positive more than 36 months after a transplant have little propensity for relapse.500 Graft-versus-leukemia may act to suppress minimal residual disease after allogeneic marrow transplantation.501
Infection with cytomegalovirus, fungi, herpes simplex or herpes zoster virus can cause severe morbidity and early posttransplantation mortality, but these causes of death have decreased in frequency significantly. Poorly controlled GVH disease is the major cause of early posttransplantation mortality. The early posttransplantation mortality of about 25 percent has stimulated studies that define the optimal time of transplantation in chronic phase by considering variables such as age, percent blood blasts, spleen size, the likelihood of remaining in chronic phase for a prolonged period, and the probability of successful marrow transplantation in the accelerated phase.502
Marrow transplantation can eradicate the Ph-chromosome-carrying clone and has led to apparent cure of some patients.503 Some believe that marrow transplantation should be undertaken during the first year of chronic phase, if a histocompatible sibling or identical twin donor is available.504 The improvement in survival with hydroxyurea and interferon-a therapy and the exploration of new drug combinations for therapy may influence these recommendations.505 Figure 94-7 outlines possible treatment options. Individual patient preferences enter into the decision.
There is substantial evidence that the effectiveness of allografting in CML is not due solely to the eradication of the leukemic clone with the high-dose chemoradiotherapy conditioning regimens but also to adoptive immunotherapy provided by lymphocytes in the allograft, the graft-versus-leukemia effect.484 This phenomenon has been recreated to produce a therapeutic response by infusion of stem-cell-donor lymphocytes after relapse following allogeneic stem cell transplantation.506,839 Ten million mononuclear cells per kilogram body weight may be enough to achieve a graft-versus-leukemic effect in the absence of GVH disease.507 The overall response rate to such treatment is about 75 percent. The response rate is higher when this approach is employed early after detecting a relapse by PCR.508 This approach may avoid the need for high-dose cytotoxic chemotherapy that would accompany a second transplant procedure.509
The main toxicities of donor-lymphocyte infusion have been induction of GVH disease and myelosuppression. Attempts to diminish these toxicities have included the use of CD8-depleted donor leukocyte infusions and the infusion of smaller numbers of T cells.510,511 Donor lymphocytes can also be transfected with vectors containing the herpes simplex virus genome in a replication defective form. If GVH disease occurs, the lymphocytes can be eradicated with systemic ganciclovir treatment. The ultimate utility of such approaches is still unmeasured.512
Ways to administer more specific immune effector cells have been sought. BCR-ABL-specific T cells with marked cytotoxic activity against CML cells can be generated and amplified from the blood of a normal donor.513,514 HLA-DR1-restricted BRC-ABL (b3a2)-specific, CD4-positive T lymphocytes respond to dendritic cells pulsed with b3a2-peptide and antigen-presenting cells exposed to b3a2-containing cell lysates.515 Peptides derived from the whole sequence of BCR-ABL bind to several class I molecules, allowing specific induction of human cytotoxic T lymphocytes.516 Such BCR-ABL junction peptides, when bound to HLA class I molecules, allow specific induction of human cytotoxic T lymphocytes.517 Whether such cells utilized in adoptive immunotherapy will be more effective than donor leukocytes in preventing or treating relapse is not known.
Several large studies of treatment during the 1970s and early 1980s reported a similar survival of patients with CML treated with standard chemotherapy, that is, busulfan or hydroxyurea, during the chronic phase.518,519,520,521,522,523,524,525 and 526 Median survival ranged from 39 to 47 months, the 5-year survival was about 25 to 35 percent of patients, and the 8-year survival 8 to 17 percent of patients. A large randomized study comparing hydroxyurea to busulfan has shown a significant prolongation of chronic phase with hydroxyurea440 and a further prolongation with IFN-a therapy (Table 94-2). Occasional patients have remained in chronic phase from 10 to 25 years.527,528,529,530,531,532,533 and 534
At the time of diagnosis the variables most closely associated with duration of chronic phase, and thus survival, are percent blasts in the blood, liver and spleen size, and total basophil plus eosinophil count. Using these variables in large numbers of patients, the population segregates into three risk groups: better risk, with a median of survival of about 5.0 years; intermediate risk, with a median survival of 3.5 years; and poor risk, with a median survival of 2.5 years.535,536 and 537 In the better-risk group, 40 percent are alive at 7 years, and in the poor-risk group, 10 percent or fewer are alive at 7 years. These figures are based on large numbers of patients treated principally with busulfan. If prolongation of chronic phase by hydroxyurea and interferon treatment is validated, the median survival in each group may be extended by several years. Prognostic indices, therefore, may be important in interpreting the results of chemical therapies and may have a major role in deciding the timing of stem cell transplantation because of the relatively high peritransplant mortality.502,538 The indices may not have sufficient specificity and sensitivity to be applied to a single patient, however. Studies that link the precise (3-prime) location of the breakpoint in the BCR gene with shortened duration of chronic phase539 have not been confirmed.540 Most patients die as a result of conversion from the chronic to the accelerated phase of the disease even in the era of IFN-a treatment and increased transplant donor availability.541 Spontaneous remissions of CML have been reported,542,543 but t he disease may recur.544
The detection of minimal residual disease by molecular probes makes it possible to identify about one cell in a million that is derived from the CML clone.545 Such studies have detected CML cells in patients who appeared to be free of Ph-chromosome-positive cells by cytogenetic analysis following allogeneic stem cell transplantation.546,547,548 and 549 PCR permits observation of the regression of subclinical disease following therapy, the persistence of subclinical disease following therapy, or the progression of subclinical disease prior to its becoming overt. The stable persistence of subclinical disease does not invariably predict early relapse.546,549 There is an increased risk of misinterpreting negative results of RT-PCR when very small numbers of transcripts are present.325 The dilution threshold for reproducible amplification is 250,000 cells. mRNAbcr–abl can also be detected in single progenitor colonies after culture.550 A good correlation has been found between the proportion of Ph-chromosome-positive metaphase cells and levels of mRNAbcr–abl, and no difference in levels of the fusion mRNA was found between Ph-chromosome-positive and Ph-chromosome-negative, BCR-ABL-positive patients.551 Through utilization of quantitative PCR, an increase of mRNAbcr–abl expression has been found to precede disease progression. This increase was detected up to 16 months before laboratory or clinical parameters showed phenotypic transformation of the malignant clone.5 52 The technique of detecting minimal residual disease is very sensitive but is subject to false-positive reactions.
Tuohey in 1920 described the first recorded case of an unusual sustained neutrophilia with splenomegaly without fever, inflammation, cancer, or another cause of a leukemoid reaction.553 Since that time, about 80 cases have been reported.554,555,556,557,558,559,560,561,562,563,564,565,566,567,568,569,570,571,572,573,574,575,576 and 577 The disease is a clonal hemopathy and a rare form of a clonal myeloproliferative disorder. Some cases may arise in the hematopoietic stem cell, others in a later progenitor cell578 (see Chap 92).
Symptoms and Signs About 90 percent of patients have been over 60 years of age.561,562,563 and 564 Younger patients have been described, however.565 Somewhat more men than women have been reported. Patients may complain of weakness, anorexia, weight loss, abdominal pain, and easy bruising. Symptoms and signs of gouty arthritis occur in about one-third of the cases. The spleen has been enlarged in all cases, and the liver is frequently enlarged. Lymphadenopathy is very infrequent.578 A hemorrhagic tendency is present in some patients.561,564,569,576,579
Laboratory Findings Although some patients may have a normal hemoglobin concentration, most have anemia on presentation. The reticulocytic count is usually between 0.5 and 3.0 percent. The platelet count is rarely below 125,000/µl (125 × 109/liter) and usually is normal. Coagulation times are normal. The total leukocyte count is between 25,000 and 50,000/µl (25 and 50 × 109/liter) in most cases and only rarely exceeds 100,000/µl (100 × 109/liter). Neutrophils make up 90 to 95 percent of the white cells and, although segmented cells usually dominate, occasional cases have 20 to 50 percent band forms. Very infrequent metamyelocytes, myelocytes, and nucleated red cells may be present in occasional patients. Blasts are usually not present in the blood. Neutrophil alkaline phosphatase activity is increased in virtually all cases.
The marrow invariably shows granulocytic hyperplasia with M:E ratios as high as 10:1. Myeloblasts are not overtly increased in number (0.5 to 3.0 percent). Megakaryocytes are either normal or increased in number. Erythropoiesis is usually mildly decreased. Unlike CML, reticulin fibrosis is very unusual. A few cases have been reported with dysplastic features in the marrow (acquired Pelger-Hüet anomaly, erythroid, dysplasia and micromegakaryocytes).580 The Ph chromosome, BCR gene rearrangements, and BCR-ABL transcripts have been absent in the cases that have had such studies.577,581,582,583,584,585 and 586 Occasional, nonrandom abnormalities of chromosomes have been reported.554,561,564,574,583,587,588 Most patients have normal karyotypes. Use of X-chromosome-linked polymorphic genes in blood cells and fluorescence in situ hybridization of chromosome abnormalities have been indicative of a clonal disorder.581,584,585
Serum vitamin-B12-binding protein and vitamin B12 levels are both markedly increased above normal. Serum uric acid concentration is increased, and serum lactic dehydrogenase activity may be increased.
Virtually every case examined postmortem has had liver and splenic enlargement.561,564 Portal hepatic and splenic red pulp infiltrates of neutrophils or islands of extramedullary hematopoiesis with immature myeloid cells and megakaryocytes are characteristic.
Most leukemoid reactions will be associated with an obvious underlying cause such as pancreatitis, carcinoma of the lung, or bacterial infection. Molecular studies to identify BCR gene rearrangement or the presence of BCR-ABL transcripts should distinguish chronic neutrophilic leukemia from neutrophilic-chronic myelogenous leukemia (see “Special Clinical Features”).
There are no systematic studies of treatment. Although busulfan or hydroxyurea may decrease the white count and spleen size transiently,568,571 the disease generally has been difficult to control.
The disease is fatal, with a median survival of about 2 to 3 years and a range of 0.5 to 6 years.561,562,564,569,572 A case of spontaneous remission has been reported.573 The prognosis is considerably worse than CML despite the prevalence of mature neutrophils and the paucity of blasts in most cases. Severe hemorrhage, despite normal platelet counts and coagulation times, has been the cause of death in several patients. Severe infection has occurred in a few patients. Acute myelogenous leukemia has been the terminal event in several cases.559,561,580,583 A remarkable frequency of concordant essential monoclonal gammopathy or myeloma has been described.558,560,563,571,573,575,585,589,590 and 591 In two cases, the extreme neutrophilia proved to be a polyclonal response to plasma cell disorder.585,592 Chronic neutrophilic leukemia has evolved from polycythemia vera or oligoblastic leukemia,593,594 supporting its relationship to the clonal hemopathies.585,595,596 The disease usually afflicts elderly subjects, and cardiac, pulmonary, and vascular diseases contribute to a fatal outcome in most cases.
In 1937, Osgood reviewed his experience with monocytic leukemia and included a case which probably represented the rare disorder chronic monocytic leukemia.597 In 1981, about 28 bona fide cases had been reported, 5 cases were added, and the characteristics were reviewed.598
Patients range from 30 to 80 years of age. Males are affected more frequently than females. Fever, fatigue, and left upper quadrant pain are the most common complaints. Splenomegaly and hepatomegaly are nearly constant findings.598,599 and 600
Anemia is mild. Anisocytosis and poikilocytosis are usually present. The leukocyte count is usually normal or low but can be elevated in a minority of patients. The percent of monocytes is increased, but the absolute monocyte count is often normal in the range of 300 to 1500/µl (0.3 to 1.5 × 109/liter) or mildly elevated. Occasional patients may have more striking monocyte counts. The platelet count may be normal or decreased. Rare nucleated red cells may be present in the blood. The monocytes in the blood contain alpha-naphthol acetate esterase, tartrate-sensitive acid phosphatase, fluoride-sensitive naphthol AS-D acetate esterase, and peroxidase as judged by histochemical tests. The marrow is cellular, often without an increase in monocytes. The Ph chromosome is absent. The leukemic cells are similar to mature monocytes with abundant cytoplasm. Erythrophagocytosis or thrombocytophagocytosis by monocytes may be seen.
The disease is often not recognized, since the total white cell count, the monocyte count, and the number of marrow monocytes may not be elevated until the spleen is removed, usually for diagnostic purposes.598 Following splenectomy, a gradual leukocytosis may develop 3000 to 100,000/µl (3 to 100 × 109/liter).598 The absolute monocyte count increases dramatically, often from under 1000/µl (1 × 109/liter) to as high as 75,000/µl (75 × 109/liter). The marrow may contain more than 50 percent mature monocytes following splenectomy.
The spleen is enlarged (300 to 2500 g). The red pulp is infiltrated with mononuclear cells, often obliterating sinus lumens. Erythrophagocytosis by the mononuclear cells is frequently evident. Liver biopsy may show a mononuclear infiltrate in the sinusoids. Although clinical lymph node enlargement is rare, lymph node biopsies show striking infiltration by leukemic monocytes.
Median survival is about 25 months, and patients often die of septicemia598,599 and 600 or acute monocytic leukemia.601,602 Therapy has not been studied systematically, but neither intensive combination chemotherapy nor glucocorticoids have changed the course of the disease.421
Ph-chromosome-positive, adult-type CML occurring below the age of 15 years makes up about 3 percent of childhood leukemias and about 10 percent of all cases of CML.236,603 Although CML occurs in children of all ages, it is rare under age 5. With the exception of a propensity to present with higher total leukocyte counts and with leukostatic signs or symptoms,236 CML in children has the typical manifestations and course of the disorder as seen in adults.
A disorder different from adult-type CML, which has been designated juvenile myelomonocytic leukemia (juvenile CML), represents about 1.5 percent of childhood leukemias. It occurs most often in infants and children under 4 years of age and is similar in some respects to adult subacute or chronic myelomonocytic leukemia (see Chap. 92).604,605 and 606
This disorder is a clonal hemopathy that originates in an early hematopoietic progenitor cell.607 RAS mutations in hematopoietic cells are present in about 20 percent of patients.608 About 1 of 10 patients with juvenile myelomonocytic leukemia have mutations of NF1 and manifest type 1 neurofibromatosis. This frequency is about 400 times the expected occurrence.609,610 and 611 The linkage between neurofibromin, the protein encoded by the NF1 gene; guanosine triphosphatase-activity proteins; and the activation state of RAS-encoded proteins have led to a postulated sequence of events that may be triggered by the extraordinarily heightened sensitivity of the colony-forming cells in the marrow and blood of infants with the disease to the proliferative effects of granulocytic-monocytic colony stimulating factor. The latter initiates signal transduction from the cell membrane to the nucleus via RAS protein activation.606,612
Symptoms and Signs Infants present with failure to thrive, and children present with malaise, fever, persistent infections, and exaggerated skin, oral, or nasal bleeding. Hepatomegaly can occur. Splenomegaly, sometimes massive, is present in virtually every case. Lymphadenopathy is frequent.604,605 Over half the patients have eczematoid or maculopapular skin lesions613 and xanthomatous lesions, and multiple café au lait spots (neurofibromatosis) may occur also.605 The xanthomas may be the earliest signs of neurofibromatosis.604,605
Laboratory Findings Anemia, thrombocytopenia, and moderate leukocytosis are common. The blood has an increased concentration of monocytes 1000 to 100,000/µl (1 to 100 × 109/liter), immature granulocytes including blast cells, and nucleated red cells. Fetal hemoglobin concentration is increased in about two-thirds of the patients. The marrow aspirate is hypercellular as a result of granulocytic hyperplasia; the number of erythroblasts and of megakaryocytes usually are decreased. Monocytic cells are increased. Leukemic blast cells are present in modest proportions.
Cell culture of blood and marrow shows a striking preponderance of monocytic progenitors, even in the absence of overt monocytosis in the marrow.614,615 Granulocyte-monocyte colony forming cells show a marked tendency to spontaneous growth if adherent (monocytic) cells are not depleted from culture.615 The effect is mediated by a release of large quantities of granulocyte-monocyte colony stimulating factor by monocytes in culture.616
Although clonal chromosome abnormalities have been found in some cases, there is no consistent pattern to the cytogenetic abnormalities, and over half the patients have normal karyotypes. The Ph chromosome is not present.617,618 The phenotype of monosomy 7 syndrome overlaps with juvenile myelomonocytic leukemia, and this cytogenetic abnormalilty is present in about 15 percent of patients.604
The median survival of patients with juvenile CML is less than 2 years.604,605 The disease has been refractory to chemotherapy. Although improvement in survival after stem cell transplantation from a histocompatible sibling occurs,619 cure is uncommon. A minority of patients will have a smoldering course for 1 to 3 years but, thereafter, rapidly progress and succumb to infection or hemorrhage. Some children convert to a full-blown acute myelogenous leukemia with a rapidly fatal outcome. Occasional patients have a very long survival (over 10 years) despite persistence of abnormal blood counts and splenomegaly, independent of the type or intensity of therapy. Younger children (less than 2 years) are more likely to have a protracted course.605 In a study of nine patients, four treated with five or six drug-intensive regimens had a remission of 11 to 27+ months, compared with untreated or lightly treated patients, four of whom died in 7 months.620 Even in the treated patients, complete suppression of the disease did not occur, and treatment protocols to induce and sustain remissions are lacking.615 Future studies of isotretinoin, interleukin-10, interleukin-1 receptor antagonist, GM-CSF antagonist (E21R), and blockers of RAS protein farnesylation hold promise for ameliorating the disease.604
This leukemia is part of the spectrum of clonal myeloid diseases that may have findings that simulate CML. In the past, when rigorous criteria for the diagnosis of CML were not applied, chronic myelomonocytic leukemia was among a heterogenous group of related diseases that were sometimes referred to as Ph-chromosome-negative CML.621
Most patients with chronic myelomonocytic leukemia (CMML) are over 50 years of age, and about 75 percent of cases are over 60 years of age at the time of diagnosis. Cases also have been reported in children and as a complication of polycythemia vera. The onset is usually insidious, and weakness, infection, or exaggerated bleeding may bring patients to medical attention.823,824,825,826,827 and 828 Hepatomegaly and splenomegaly occur in about 40 percent of patients.
The disease is characterized by anemia and blood monocytosis usually in excess of 1,000/µl (1 × 109/liter). The white cell count may be slightly decreased, normal, or moderately elevated. Immature granulocytes may be present in the blood. Blood myeloblasts may be absent or, when present, do not exceed 10 percent of total white cells. Most patients have thrombocytopenia, but normal or elevated platelet counts may occur. The marrow is hypercellular as a result of granulomonocytic hyperplasia; the dominant cells are early myelocytes. The proportions of myeloblasts and progranulocytes are increased but do not exceed 20 percent of marrow cells. Promonocytes also are increased in number. Distinction between poorly granulated myelocytes and promonocytes with primary granules can be difficult. Macronormoblasts and hyper- or hyposegmented (Pelger-Huët) neutrophils are frequent. Despite thrombocytopenia, megakaryocytes are usually present in the marrow. Plasma and urine lysozyme concentrations are nearly always elevated. Eosinophilia may be so prominent in occasional cases that the designation chronic eosinophilic leukemia may be appropriate.264,267,843,844 CMML also is characterized by frequent RAS gene mutations. In some cases, there is homozygous deletion of the genes encoding the macrophage CSF-1 receptor and, also, in “spontaneous” cluster/colony growth in vitro. The latter may be due to autocrine or paracrine production of growth factors such as GM-CSF and IL-3. Chronic myelomonocytic leukemia is closely related clinically to chronic monocytic leukemia and to so-called Philadelphia-chromosome-negative, breakpoint-cluster-region-negative chronic myelogenous leukemia. Translocation between chromosomes 5 and 12, which juxtaposes the gene encoding platelet-derived growth factor beta receptor with the TEL gene, is present in cases of CMML.829 This fusion gene encodes a transforming protein that activates beta R kinase signaling pathways. The RAS gene may also be involved in the transforming events.830
Treatment has been unsatisfactory, and remissions of any duration are rare. The age and performance status of the patient is considered in determining the intensity of treatment. Cytarabine, either standard or low-dose, etoposide, hydroxyurea, and other approaches used for the oligoblastic myelogenous leukemias have been tried with little success (see Chap. 92). Median survival in CMML is about 20 months, with a range from about 10 to over 60 months.
An ever-diminishing proportion of patients with clinical manifestations within the limits usually applied to the diagnosis of CML have neither a Ph chromosome (classical, variant, or masked) nor evidence of rearrangement within the M-bcr on chromosome 22.622,623 This circumstance represents true Ph-chromosome-negative CML, perhaps better referred to as BCR-rearrangement-negative CML. The literature describing Ph-chromosome-negative CML prior to 1987 is difficult to evaluate because many cases were not studied carefully for masked or variant translocations and for BCR gene rearrangement. Ph-chromosome-negative CML is a clonal disease624 which has the propensity for lymphoid as well as myeloid transformation.625,626 and 627 Although most cases of BCR-rearrangement-negative CML cases are closer in manifestations to chronic myelomonocytic leukemia,622,623,628,629,630 and 631 a few residual cases are difficult to distinguish from classical CML.632,633 and 634 In the latter group, absence of acute blast transformation as a terminal event has been observed. As the disease progresses, the patient develops severe cytopenias.633 Some patients have been shown to have transposition of ABL to chromosome 22 but not the classical translocation.635,636 Some cases of hypereosinophilia have been shown to be clonal (neoplastic) myeloproliferative disorders and may have blood and marrow findings similar to CML with eosinophili c dominance637 (see Chap. 68). The hematopoietic cells in these cases do not contain the Ph chromosome or BCR gene rearrangement and have been dubbed chronic eosinophil leukemia.638,639
About 2 percent of cases of acute myelogenous leukemias have the Ph chromosome t(9;22)(q34;q11) in a significant proportion (10 to 100 percent) of leukemic blast cells.640,641,642 and 643 The blast cells have surface antigens characteristic of myeloid leukemias.644 One interpretation of this concurrence is that it represents CML presenting in myeloid blast crisis.645,646,647,648 and 649 The arguments in favor of this proposal are (1) that blast crisis may occur within days after diagnosis of Ph-chromosome-positive CML, (2) that several of the cases presented with additional cytogenetic changes comparable to CML in blast crisis,650 (3) that marked hepatosplenomegaly is present,645,649,650 (4) that platelet counts are normal and basophils exhibit intermittent increases,645,648,649 (5) that a long prodromal period of weakness and weight loss and the appearance of some features of CML, such as granulocytosis, follow treatment with chemotherapy,640,647,651 (6) that Ph-chromosome-positive AML has a very poor prognosis like myeloid blast crisis, (7) that the breakpoint on chromosome 22 in the M-bcr is typical of CML and the product of the fusion BCR-ABL gene is a p210 tyrosine kinase identical to that in classical CML,649,650,651,652,653 and 654 and (8 ) that some patients enter a remission by converting to a phenotype analogous to chronic phase CML.451 An alternative view has been promulgated because (1) most cases of Ph-chromosome-positive AML are a mosaic (normal karyotypes as well as abnormal), (2) the Ph chromosome may appear later in the course of the disease,655 (3) additional chromosomal abnormalities are often different from those seen in the myeloblastic crisis of CML,656,657 and (4) the Ph chromosome in these cases is not associated with breaks in the M-bcr on chromosome 22,652,654,657,658 and 659 the latter being characteristic of CML. Moreover, Ph-chromosome-positive AML has developed following Ph-chromosome-negative oligoblastic leukemia.660 Some cases of Ph-chromosome-positive acute leukemia are myeloid-lymphoid hybrids.661 It appears that Ph-chromosome-positive AML comes in two varieties: one with a break in M-bcr of chromosome 22 with a p210 product, which could be considered analogous to acute blast crisis of CML, and one with a molecular pathology such that the oncogene product is a p190 protein. These distinctions may be important if future therapy is keyed to the specific fusion oncogene product.
About 3 percent of cases of childhood acute lymphocytic leukemia (ALL)662,663,664,665,666,667 and 668 and 20 percent of cases of adult ALL662,666,669 cells contain the Ph chromosome. In children the clinical and laboratory findings in the disease are similar whether the lymphoblasts contain the Ph chromosome or not, but the prognosis is worse for those with the Ph chromosome; lower frequencies of remission, much shorter remission duration, and less chance of cure with chemotherapy.665,667,669 Remission rates and median survivals are also significantly lower in adults with ALL and the Ph chromosome (see Chap. 97). Marrow transplantation may hold hope for successful treatment of this variant of ALL in some patients with a histocompatible donor.668,669
Molecular studies of the chromosomes and cells of patients with ALL indicate the disease is heterogeneous. Some adults and few, if any, children with ALL have the t(9;22)(q34;q11) with a BCR-ABL fusion gene that codes for and expresses the p210bcr–abl tyrosine kinase.651,652,653,670,671,672,673,674,675,676,677,678,679,680,681,682,683,684 and 685 The leukemic cells of some adults with ALL and virtually all children with the disease have the Ph chromosome, but their cells have a rearrangement of the BCR gene that involves sequences outside the 5.8-kb M-bcr. In these cases, a 7.0-kb chimeric RNA is transcribed that directs the translation of a p190bcr–abl product and that also has tyrosine kinase activity.671,686 The Ph-chromosome-positive, 5.8-kb BCR-rearrangement-positive ALL patients may revert to CML after intensive chemotherapy, whereas the Ph-chromosome-positive, BCR-rearrangement-negative ALL patients who enter remission have reappearance of normal hematopoiesis. The former group of Ph-chromosome-positive, BCR-rearrangement-positive ALL is thought to represent presentation of CML in lymphocytic blast crisis; the Ph-chromosome-positive, BCR-rearrangement-negative ALL represents de novo ALL.687,688 The somatic mutation, however, appears to involve a cell that can differentiate into all hematopoietic lineages.689 A subgroup of the latter with concomitant monosomy 7 has been described, also.690 Patients with ALL with the BCR rearrangement restricted to lymphoid cells have a more favorable prognosis than those with BCR rearrangement present in myeloid and lymphoid cells.691,692
Phenotyping of blast cells with panels of antibodies to surface antigens, histochemical reactions, and gene rearrangement probes indicates that Ph-chromosome-positive leukemias also may be biphenotypic (lymphoid and myeloid lineage) and be heterogenous in the site in the BCR gene in which rearrangements occur.662,692
In most cases of CML, the patient’s disease eventually changes to a more aggressive, more symptomatic and troublesome phase, which is poorly responsive to therapy that formerly controlled the chronic phase. The failure of IFN-a, hydroxyurea, or another previously successful modality simultaneously to restore near-normal red cell and white cell counts, decrease spleen size, and maintain a feeling of well-being is the most consistent clinical hallmark of the metamorphosis of the chronic to the accelerated phase of CML.
The terminology used has included acute phase, acute transformation, or blast crisis, but the metamorphosis, which can be acute or blastic, is often more gradual and manifested by severe dyspoiesis, refractory splenomegaly, and extramedullary tumor masses; hence the preference for transformation or accelerated phase to describe this transition from a controllable to an uncontrollable malignancy. Blast crisis is the most severe manifestation of the accelerated phase.
Cytogenetic evidence indicates that the accelerated phase of the disease results from a progressive change in the clone that supported the chronic phase. Often chromosomal abnormalities occur in addition to the Ph chromosome, but the Ph chromosome persists.693,694,695,696 and 697 Progression of the clone to a more malignant one is reflected also in a more disordered growth and maturation pattern of progenitor cells in culture, ultimately mimicking the growth failure of acute leukemia,695 and in increased morphologic and functional abnormalities of blood cells,698,699 and 700 eventuating in a total block in maturation and replacement of blood and marrow by blast cells.
FISH has been used to determine which cells have secondary cytogenetic abnormalities, and these cells often are not the blast cells. This finding suggests that some chromosomal abnormalities merely denote genomic instability.701 About 65 percent of patients have cytogenetic abnormalities in addition to the Ph chromosome. A double Ph chromosome, trisomy 8, and isochromosome 17p are the secondary changes most commonly seen.702 Clonal instability has also been found in cases of lymphoid blast crisis. Clones distinct from those identified later may be detected before overt lymphoid transformation. The identification of these abortive clones suggests clonal instability before the onset of transformation, which might have prognostic value.703
The abnormal mRNA and protein product p210bcr–abl are present in the marrow and blood cells of patients who have transformed to acute leukemia.704,705 and 706 Although the breakpoint site on M-bcr was thought to be correlated with the time of the onset of the accelerated phase,706 subsequent studies have not indicated a correlation between length of chronic phase and the specific site of the BCR-ABL fusion.707 Rare cases have had deletion of the BCR-ABL fusion gene, loss of transcription of the message, and loss of expression of the p210 tyrosine kinase after transformation, the latter finding suggesting the abnormal protein kinase may not play a unique role in sustaining the acute state.708
Numerous molecular changes have been identified in the cells of patients with acute transformation that might contribute to the increased malignant behavior of the CML clone: activation of the N-RAS gene,709,710 rearrangement of the p53 gene,710,711,712 and 713 and hypermethylation of the calcitonin gene714 have been described. One series found p53 mutations in 17 percent of blast crisis patients. An association between a failure of CML cells to express the retinoblastoma gene product and acute blast crisis with a megakaryoblastic phenotype has also been reported.715
Homozygous deletions of the p16 tumor suppressor gene have been associated with lymphoid transformation of CML,716 but such deletions have not been seen in chronic phase and in myeloid blast crisis. P16 is also known as the cyclin-dependent kinase 4 inhibitor gene and is located on chromosome 9p21.717 This gene inhibits a kinase, CDK-4, that regulates a cell cycle checkpoint prior to commitment to DNA synthesis. The Wilms’ tumor (WT) gene on chromosome 11p13 encodes a zinc-finger-motif-containing transcription factor found in CML patients only after progression to blast crisis.718 Overexpression of the EVI-1 gene has also been found in CML blast crisis.719,720 Microsatellite instability has not been found to be involved with progression to blast crisis.721 Roles for BCL-2, c-MYC, and various other genes have also been implicated in the evolution of CML.722,723,724 and 725
The features that signal the conversion of the chronic to the accelerated phase include unexplained fever, bone pain, weakness, night sweats, weight loss, loss of sense of well-being, arthralgias, or left upper quadrant pain. These may occur weeks in advance of laboratory evidence of the accelerated phase. Localized or diffuse lymphadenopathy or enlarging masses in extralymphatic sites containing myeloblasts or Ph-chromosome-positive lymphoblasts may develop. An increase of the basophil count (>10 percent); a decrease of the platelet count to less than 100,000/µl (<100 × 109/liter); an increase in the proportion of blood (>5 percent) or marrow (>10 percent) blasts; new cytogenetic abnormalities; decreased progenitor cell growth in culture; or poor response in blood cell counts and splenic size to therapy for the chronic phase may be evident.726,727 and 728 Splenic enlargement, unresponsive to previously successful cytotoxic therapy, may occur. Symptoms due to histamine excess in basophilic crisis can be present.729
Several of these changes may occur in series or in parallel. The time of onset of transformation and the final appearance of the blastic phase and its clinical expression is unpredictable.
BLOOD FINDINGS726,727 and 728
Anemia may worsen and be associated with increasing poikilocytosis, anisocytosis, and anisochromia. Nucleated red cells may increase in number. These red cell changes may be accentuated further if advancing marrow fibrosis is a feature of the disease, also.
The total leukocyte count may fall without treatment. The proportion of blasts may increase in blood and marrow and may represent 50 to 90 percent of the cells at the time of blastic crisis. Myelocytes decrease in number. Hyposegmented neutrophils (Pelger-Huët cells) may become evident. Basophils may increase and occasionally reach levels of 30 to 80 percent of the total blood leukocytes.
Thrombocytopenia may develop. Giant platelets, micromega-karyocytes, and megakaryocyte fragments may enter the blood.
MARROW FINDINGS726,727 and 728
The marrow findings are widely variable. Marked dysplastic changes in one, two, or three of the major cell lineages; marrow morphology simulating subacute myelomonocytic leukemia; or, in the extreme, florid blastic transformation can occur. Reticulin fibers may increase, and occasionally severe reticulin and collagen fibrosis can develop.
A variety of symptoms or signs may occur as a result of the specific effects of new extramedullary blastic tumors, referred to as extra-medullary blast crisis.730,731,732 and 733 Extramedullary blast crisis is the first manifestation of accelerated phase in about 10 percent of patients with CML. Lymph nodes,731,733,734 serosal surfaces,734,735,736,737 and 738 skin and soft tissue,730,731,732 and 733 breast,733,739 gastrointestinal or genitourinary tract,731,733,740 bone,731,733,741,742,743 and 744 and central nervous system733,745,746,747 and 748 are among the principal areas involved. Isolated or diffuse lymphadenopathy may occur. Bone involvement may lead to severe pain, tenderness, and x-ray changes. The central nervous system involvement is usually meningeal and may be preceded by headache, vomiting, stupor, cranial nerve palsies, and papilledema and is associated with an increase in cells, protein, and the presence of blasts in the spinal fluid.733,746,747 and 748
Appropriate histochemical and immunological tests are required to determine if the extramedullary disease is composed of phenotypic myeloblasts or lymphoblasts. Since the tumor cells may have features of lymphoma cells, the terms granulocytic sarcoma, chloroma, and myeloblastoma can be misnomers, and the term extramedullary blast crisis is used for this circumstance in CML.747,749,750,751 and 752 The lymphoblasts, like the myeloblasts, are Ph-chromosome-positive. A combination of morphology, histochemistry (e.g., peroxidase, lysozyme), terminal transferase assay, and monoclonal antibodies specific for lymphoid or myeloid cells can be used to classify the extramedullary blast cells. It is probable that older reports (1930s to 1960s) of concurrent lymphoma and CML were, in many cases, examples of extramedullary lymphoblast crisis in lymph nodes or other sites.
Most patients with CML enter the accelerated phase by developing acute leukemia. The onset of blast crisis can develop from days753 to decades after diagnosis of CML. The signs and symptoms may include fever, hemorrhage, bone pain, and lymphadenopathy.754,755,756 and 757 The morphology of the acute leukemia is usually myeloblastic or myelomonocytic.755,756 and 757 A substantial proportion of myeloid leukemia in this setting may not have myeloperoxidese demonstrable by cytochemistry.758 The proportion of cases classified as erythroblastic leukemia is about 10 percent based on morphologic features759 but may be as high as 20 percent if the expression of glycophorin-A is used as the determinant.760 Occasional cases have megakaryoblastic transformation.715,761,762 and 763 These cases may be difficult to identify by light microscopy because the megakaryoblasts may be mistaken for lymphoid cells or undifferentiated blasts. Myelofibrosis is a feature of this variant. Antiplatelet glycoprotein antibodies and other monoclonal antiplatelet antibodies are now available as reagents to identify megakaryoblasts without the need for ultrastructural studies.763 Promyelocytic764,765 and 766 and eosinophilic767 blast crises also can occur. Basophilic leukemia is known to be a variant of CML.768 Patients with promyelocytic crisis often have t(15;17) in addition to the Ph chromosome, and some have presented with disseminated intravascular coagulation.769
CML may transform into acute lymphoblastic leukemia in nearly one-third of CML patients in blastic crisis.748,770,771,772,773 and 774 The lymphoid cells generally express terminal deoxynucleotidyl transferase (TdT),770,771 and are of the B-cell lineage,774,775 and 776 as judged by anti-immunoglobulin staining. TdT is a DNA polymerase that adds deoxynucleoside monophosphates from triphosphate substrates to single-stranded DNA by end addition, differing in the latter respect from replicative polymerases.777 The enzyme is present in normal immature thymocytes and the blast cells of nearly all patients with acute lymphoblastic leukemia.778 Rare patients have blasts with a T-lymphocyte phenotype.779,780 and 781 Some cases are biphenotypic, the blasts having both lymphoid and myeloid markers.757,782,783 and 784 Some of these may have myeloperoxidase and express CD33 or CD13. Myeloid to lymphoid clonal succession following autologous transplantation in second chronic phase has been described.785 Patients with lymphoid blast crisis seldom have an intermediate accelerated phase, have less splenomegaly and basophilia, and usually have a higher degree of marrow blast infiltration. Survival is usually somewhat longer in cases of lymphoid as compared to myeloid blast crisis.786
Most large studies have shown four principal changes in patients’ cells prior to, or during, the accelerated phase: additional 22q-, isochromosome 17, trisomy 8, and trisomy 19.787,788 and 789 In addition, a large number of other chromosome abnormalities have been described.790,791,792,793,794,795 and 796 In one study, 63 percent of 73 blast crisis patients had secondary cytogenetic abnormalities, and these were more common in myeloid blast crisis and associated with shorter remission.702 These changes may be features of myeloid blast crisis as compared to lymphoid crisis.788,793 Some abnormalities such as inv 16 have been associated with early transformation to AML.789
In cases where the blastic transformation is in extramedullary sites, like lymph nodes or spleen, the additional cytogenetic abnormalities may be in the cells at those sites, but not in cells in the blood or marrow.797
The treatment approach is predicated on the phenotype of the blast cells in CML patients with blast crisis.
In patients with myeloid phenotypes the approach has been similar to that used for acute myelogenous leukemia: combinations of an anthracycline antibiotic, such as idarubicin or daunorubicin, with intermediate-dose cytosine arabinoside and etoposide. Because this approach produces few remissions and they are of short duration, a variety of other drug combinations incorporating high-dose cytosine arabinoside, methotrexate, busulfan, mitoxantrone, 5-azacytidine, etoposide, hydroxyurea, plicamycin, and others have been used with as yet little significant benefit798,799,800 and 801; 2-chlorodeoxyadenosine has also been used in myeloid blast crisis.802 Tiazofurin, a selective blocker of inosine 5′-phosphate dehydrogenase activity may become useful in treating myeloid blast crisis.803
In patients with lymphoid phenotypes, vincristine sulfate, 1.4 mg/m2 (not to exceed 2 mg/dose) intravenously once per week, and prednisone, 60 mg/m2 orally per day, are the mainstay of treatment.804,805 and 806 A minimum of two cycles of treatment (2 weeks) should be given to judge responsivity. About one-third of patients with lymphoid blast transformation will reenter chronic phase after such treatment, but, since only about a third of patients have lymphoid blasts, this represents a remission rate of only about 10 percent of patients who enter blast crisis. Some relapsed patients become TdT-negative (myeloblastic relapse). However, even if relapsed patients remain TdT-positive, they are not likely to respond to a second treatment. Some therapists argue for a more intensive induction regimen for the patient with lymphoblastic crisis, akin to regimens for de novo adult ALL or high-risk childhood ALL, and report somewhat better results: higher remission rates and longer remissions.807,808 The experience is not yet sufficient to judge the net benefit of such an intensive approach, since remission durations have been modest. TdT-positive, CD10 (CALLA)-positive lymphoblasts may be the lymphoblast phenotype most responsive to vincristine and prednisone.773,808
Stem cell transplantation from a histocompatible twin or sibling has been used in some patients after entry into the blastic phase. Occasional patients have had long-term survival. The 3-year survival is about 15 to 20 percent,809,810 and 811 unlike transplantation in the chronic phase in which the 3-year survival is 50 to 60 percent.483 However, for patients who present in blast crisis, who develop it in the first year of the chronic phase, or who delay transplantation for other reasons, transplantation remains the best hope for long-term survival if a histocompatible donor is available.809,810 Relapse of accelerated phase after allogeneic stem cell transplantation has responded to infusion of donor, in-vitro-selected, cytotoxic T lymphocytes.822
Autografting in accelerated phase or blast crisis, either with stem cells collected during chronic phase812 or with mobilized Ph-chromosome-negative progenitor cells collected upon cell rebound after intensive chemotherapy813 has resulted in apparent prolonged remission in some patients.814,815,816 and 817
Splenectomy may be performed for palliation of painful splenic infarctions or hemorrhage, but complication rates are high.818
The accelerated phase of CML, generally, is a treatment-refractory and morbid state that is fatal in weeks to months in all but a very few patients who have a successful stem cell transplant from a histocompatible donor. Patients with myeloid blast crisis have a median survival of about 5 months,785 while those with lymphoid blast crisis have a median survival of about 12 months. The median survival after evidence of clonal evolution in patients in chronic phase is about 19 months. Poorer survival was seen with abnormalities of chromosome 17, other superimposed translocations, or a high percentage of abnormal metaphases.819 Severe cytopenias from repeated courses of cytotoxic therapy contribute to infections, hemorrhage, and organ dysfunction, especially liver and kidney dysfunction. Opportunistic infections with herpes viruses, cytomegalovirus, or fungi often supervene.

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology



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