CHAPTER 99 HAIRY-CELL LEUKEMIA
CHAPTER 99 HAIRY-CELL LEUKEMIA
Definition and History
Etiology and Pathogenesis
Spleen and Other Sites
Therapy, Course, and Prognosis
Course and Prognosis
Hairy-cell leukemia is a rare chronic lymphoproliferative disorder of B-lymphocytes that display prominent cytoplasmic projections and that infiltrate the marrow and spleen in a characteristic way. Afflicted individuals are often middle-aged males who present with pancytopenia, splenomegaly, or recurrent serious infections. Treatment with cladribine has greatly improved the prognosis for patients with this disorder.
Acronyms and abbreviations that appear in this chapter include: CFU-E, erythroid colony-forming units; G-CSF, granulocyte colony-stimulating factor; IL-2, interleukin-2; HML-1, human mucosal lymphocyte 1; HTLV-II, human T-cell leukemia virus II; M-CSF, macrophage colony-stimulating; TRAP, tartrate-resistant acid phosphatase.
DEFINITION AND HISTORY
Hairy-cell leukemia is a B-lymphocyte neoplasm that principally involves the marrow and spleen. Reactive marrow fibrosis and blood cytopenias are frequent features. It was first recognized in 1923 by Ewald, who described the condition as leukämische reticuloendotheliose.1 In 1958, Bouroncle recognized the disorder to be a distinct clinicopathologic entity and referred to it as leukemic reticuloendothe-liosis.2 The descriptive term hairy-cell leukemia was coined by Schrek and Donnelly in 1966 to emphasize the irregular cytoplasmic projections of the abnormal mononuclear cells seen in the blood or marrow.3 Until the mid-1980s, the principal treatment modality for this disease was splenectomy, which resulted in transiently improved blood counts. During the past decade, the successful introduction of three effective systemic therapies—interferon-a, pentostatin (2′-deoxycoformycin), and cladribine (2-chlorodeoxyadenosine—has dramatically improved the prognosis of patients with this disease.
ETIOLOGY AND PATHOGENESIS
With 600 new patients being diagnosed annually, the disease hairy-cell leukemia accounts for approximately 2 percent of all adult leukemias in the United States. The disease is very rare in persons of African or Asian descent. It is predominantly a disease of middle-aged males, with a median age at presentation of 52 years. The disease has not been described in children or teenagers. There is a 4:1 male predominance, with Ashkenazi Jewish males being more frequently affected. Familial cases have been described.4,5 The possible association of human T-cell leukemia virus II (HTLV-II) infection with a rare T-cell hairy-cell leukemia variant has been disputed by some investigators.6 Prior exposure to radiation and organic solvents is more frequent among hairy-cell leukemia patients than among healthy persons.7,8 A possible etiologic role of the Epstein-Barr virus has been suggested in the development of the disease hairy-cell leukemia,9 but this has been disputed by other investigators.10 When cytogenetic analyses were performed in 30 patients with hairy-cell leukemia, chromosome 5 was involved in clonal aberrations in 12 (40 percent) patients, most commonly as trisomy 5 or pericentric inversions and interstitial deletions involving band 5q13.11
The normal function and precise site of origin in lymphocytic ontogeny of the hairy cell remains elusive, although it is generally accepted that hairy cells represent clonal expansions of mature B cells with phenotypic features of activation.12 Hairy cells have clonal immunoglobulin gene rearrangements13 and express the pan B-cell surface differentiation antigens CD19, CD20, and CD22, as well as monoclonal surface immunoglobulin.14 These immunologic markers of B-cell differentiation indicate an intermediate level of maturity of the hairy cell. Thus, cell surface markers normally lost in the terminal stages of B-cell maturation and CD20 are present on hairy cells, while early cell surface markers, such as CD10, are absent. Hairy cells express the early plasma cell marker PCA-1, consistent with the notion that they represent a cell at a stage of B-cell development analagous to a pre-plasma cell.15
Hairy cells secrete cytokines, such as tumor necrosis factor a. The cytokines produced by hairy cells may contribute to the impaired hematopoiesis seen in this disease by reducing the number of erythroid colony-forming units (CFU-E).16 Macrophage colony-stimulating factor (M-CSF) induces hairy-cell motility,17 and specific integrin receptors, avb3, have been identified that are responsible for their motile behavior.18
Patients with hairy-cell leukemia generally have the diagnostic triad of pancytopenia, splenomegaly, and circulating hairy cells. Pancytopenia occurs in 50 percent of the patients, and the remaining half usually have a combination of cytopenias. In a series of 102 patients with hairy-cell leukemia, 86 had anemia, 84 thrombocytopenia, and 78 neutropenia at the time of diagnosis.19 On initial presentation, one-quarter of patients present with fatigue and weakness, and another quarter with easy bruising from thrombocytopenia or with opportunistic infections from leukopenia. An additional 25 percent have early satiety or abdominal fullness from splenomegaly. The remaining patients present with an incidental finding of splenomegaly or abnormal blood counts on examination for an unrelated condition.20,21
Splenomegaly, which may be massive, is found in 90 percent of patients.22,23 Hepatomegaly is rarely a significant finding. Palpable lymphadenopathy is distinctly uncommon and when found is usually localized. However, with the advent of computed tomography scans, significant internal adenopathy can be demonstrated in up to one-third of patients with hairy-cell leukemia.24,25 In 3 percent of patients, the disease manifests itself as painful bony lesions, most commonly involving the proximal femur. Patients with skeletal complications tend to have higher tumor burdens, with their marrow being more diffusely infiltrated by hairy-cell leukemia. Diffuse osteoporosis, as well as focal or diffuse osteosclerosis, may occur. Lytic lesions, primarily involving the skeleton, have been reported.26
At diagnosis, up to 30 percent of hairy-cell leukemia patients will have an absolute blood neutrophil count of less than 0.5 × 109/liter. Most patients will demonstrate monocytopenia.27 These cytopenias predispose patients to infection from a wide variety of typical and opportunistic organisms. Impaired interferon production by blood mononuclear cells in hairy-cell leukemia also may enchance the risk for intracellular infections.28 Organisms encountered in febrile hairy-cell leukemia patients include Mycobacterium kansasii (accounting for 5–10 percent of mycobacterial disease in this population), Pneumocystis carinii, aspergillus, histoplasma, cryptococcus, and Toxoplasma gondii.29 During the follow-up of 137 patients with hairy-cell leukemia, 47 had culture-proved infections, 48 had clinically significant infectious episodes without positive cultures, and 48 had no infectious complications.30 Other laboratory abnormalities include liver function test abnormalities in 19 percent, azotemia in 27 percent, and hyperglobulinemia in 18 percent, which may be monoclonal.31 Hypogammaglobulinemia, unlike chronic lymphocytic leukemia, is rare. These paraproteinemias may, in part, contribute to some of the unusual manifestations experienced by some patients with hairy-cell leukemia, including cutaneous vasculitis, leukocytoclastic angiitis, erythema nodosum, and Raynaud’s phenomenon.31 Hypocholesterolemia, mainly due to a low concentration of low-density lipoprotein cholesterol, is a frequent finding in advanced hairy-cell leukemia but is resolved after successful treatment.32,33
In a series of 116 patients with hairy-cell leukemia followed for over two decades, several unusual presentations and complications were encountered, including spontaneous rupture of the spleen; massive splenomegaly from hairy-cell infiltration, with normal blood counts; spinal cord compression with paralysis; protein-losing enteropathy from infiltration of the bowel by hairy cells; and esophageal perforation with a fistulous tract.34 In rare cases, hairy-cell leukemia patients may have serous or chylous ascites, or pleural or pericardial effusions.35 The disease can involve soft tissues and has been implicated as a cause of uveitis in one case report.36
Hairy cells are mononuclear cells with eccentric or central nuclei.37 Nuclear morphology is variable, being round, ovoid, reniform, or convoluted. Nuclear forms tend to have a reticular chromatin pattern. Hairy cells have variable amounts of cytoplasm. This typically is blue-gray in appearance, exhibiting thin cytoplasmic projections (Fig. 99-1). Rarely, granules or broad-shaped inclusions can be seen in the cytoplasm, which correspond to the ribosomal lamellar complex seen on electron microscopy.38 More than 80 percent of patients have absolute neutropenia and monocytopenia.37,39,40 and 41
FIGURE 99-1 Blood fetus. The hairy cells are small to medium in size, have ovoid or reniform nuclei with finely clumped chromatin, and demonstrate abundant, frayed cytoplasm (×1500).
The hairy cells in the marrow aspirate tend to have a slightly coarser reticular chromatin-staining pattern than those found in the blood. The marrow usually contains hairy-cell infiltrates, which in some patients may be patchy or difficult to discern. Marrow involvement may be diffuse or focal. The marrow may be hypocellular, with scant infiltration by hairy cells admixed with residual hematopoietic tissue.37,39 Hairy cells have monotonous round, oval, or spindle-spaced nuclei that are separated by abundant quantities of pale-staining cytoplasm in a fine fibrillar network. This separation of individual hairy-cell nuclei is characteristic and referred to as the “fried-egg” appearance (Fig. 99-2). Because of marked marrow reticulin fibrosis, the marrow is frequently difficult or impossible to aspirate (Fig. 99-3). Fibroblast infiltration and overt collagen fibrosis are generally absent. It has been shown that hairy cells can synthesize and assemble a fibronectin matrix that likely is responsible for the marrow fibrosis characteristic of the disease.42 The pale and delicate network of fibrils is usually recognizable but is often better appreciated with the periodic acid-Schiff stain. Occasionally, the marrow has dilated sinuses with extravasated erythrocytes, similar to the red blood cell lakes that are seen in the spleen.
FIGURE 99-2 Marrow biopsy. Diffuse infiltration by hairy cells with wide spaces between nuclei, a pattern often called “fried-egg” appearance (×2000).
FIGURE 99-3 Marrow biopsy showing marked increase in reticulin fibrils in patients with hairy-cell leukemia (×2500).
SPLEEN AND OTHER SITES
The spleen is usually enlarged, with a median weight of 1300 g.43 On section, the spleen has a dark-red, smooth surface. On light microscopy, the hairy cells involve the splenic red pulp. Later, the white pulp atrophies and is replaced. Red cell lakes are characteristic; these lakes are blood-filled spaces lined by hairy cells that have disrupted the normal sinus architecture.44 These blood-filled spaces are sometimes referred to as pseudosinuses.
Hepatic infiltration is both sinusoidal and portal.44 Lymph node involvement is marked by both sinusoidal and interstitial involvement.45 Bony infiltration can progress from the medullary cavity to the cortex, resulting in osteolytic lesions.46
The hairy-cell cytoplasm usually stains strongly for tartrate-resistant acid phosphatase (TRAP). Isoenzyme 5 acid phosphatase, present in the hairy-cell cytoplasm, resists decolorization by tartrate.47,48 A TRAP stain that involves at least two cells with more than 40 granules or with numerous granules obscuring the nucleus is usually diagnostic. TRAP staining of the fetus of the buffy coat is positive in 90 percent of cases.47 Normal neutrophils and platelets also contain acid phosphatases but are not resistant to decolorization by tartrate. Weak to moderate TRAP staining may occur in other diseases, including prolymphocytic leukemia and lymphoma.49
Hairy cells in hairy-cell leukemia have circumferential cytoplasmic projections. Hairy cells have a few blunt microvilli. The cells of patients with splenic lymphoma with circulating B lymphocytes have more numerous and finer projections that are polarized at one end of the cell (Fig. 99-4).50,51 and 52 Ribosomal lamella complexes can be found in the cytoplasm of hairy cells by transmission electron microscopy in 50 percent of patients.47 This cytoplasmic inclusion is a cylindrical structure composed of a central hollow space and an outer sheath of multiple parallel lamellae, with ribosomal-like granules in the interlamellar space.53 These complexes also have been described in other lymphoproliferative disorders.54
FIGURE 99-4 (A) Scanning and (B) transmission electron micrographs of blood hairy cells showing the characteristic circumferential, villiform cytoplasmic projections (×7000).
Hairy cells express the pan B-cell antigens CD19, CD20, and CD22 but not CD21.13,55,56 Hairy cells have a pattern of surface marker expression that distinguishes them from the neoplastic cells of other lymphoproliferative disorders.57 Most distinctively, hairy cells express high levels of the CD11c, CD22, CD25, and CD103 surface antigens.58 The CD11c antigen, the 150-kD a chain of the 150/95 b2-integrin that ordinarily is expressed on monocytes and neutrophils,58,59 is expressed at levels 30-fold higher than those in chronic lymphocytic leukemia.60
Hairy-cell leukemia was the first B-cell lymphoproliferative disorder identified that expressed CD25, the a chain of the interleukin-2 (IL-2) receptor.61 Serum levels of soluble IL-2 receptor are elevated in hairy-cell leukemia patients and correlate with disease activity following treatment.62 CD103 (Bly-7) has the greatest sensitivity and specificity for hairy-cell leukemia. CD103 is the aE subunit of the aEb7-integrin, known as the human mucosal lymphocyte 1 (HML-1) antigen because HML-1 is primarily expressed by intraepithelial T lymphocytes. This integin is thought to be involved with the process of lymphocyte homing and adhesion.63,64 and 65
CD22 also is expressed more intensely on hairy cells than in other B-cell chronic lymphoproliferative disorders. For example, hairy cells express CD22 at 50-fold higher levels than in chronic lymphocytic leukemia.57 In 26 percent of cases there is weak expression of CD10 (the CALLA antigen), and in 5 percent of cases there is weak expression of CD5.
Multiparameter immunofluorescence analysis is especially useful in identifying hairy cells because it permits identification of cells co-expressing CD11c, CD25, or CD103 antigens, together with a pan B-cell antigen, such as CD19, CD20, or CD22. Using peripheral blood flow cytometry, 92 percent of 161 patients with hairy-cell leukemia had identifiable circulating hairy cells, in some patients representing less than 1 percent of lymphocytes.57 In contrast, a thorough morphologic evaluation of the blood from these same patients revealed hairy cells in only 80 percent.
Immunohistochemistry performed on marrow biopsy samples can aid in the diagnosis of hairy-cell leukemia and is useful for the detection of minimal residual disease following systemic therapies. Most monoclonal antibodies used to detect circulating hairy cells in the blood, including anti-CD103 antibodies, require that the marrow be processed by frozen section, since these antigens are destroyed by fixation and standard processing.67 In contrast, the CD20 antibody (L26) and another monoclonal antibody (DBA.44) can be used to stain hairy cells in routinely processed paraffin sections of the marrow.68,69 and 70 L26 staining is membranous and accentuates the ruffled, abundant cytoplasm of hairy cells, while DBA.44, an undefined antigen, stains in both a cytoplasmic granular and membranous pattern. DBA.44 is not specific for hairy-cell leukemia, since 30 percent of low-grade lymphomas also stain positively with this antibody.
The development of highly effective systemic therapy for hairy-cell leukemia makes distinguishing it from other lymphoproliferative disorders imperative (Table 99-1).
TABLE 99-1 DIFFERENTIAL DIAGNOSIS OF HAIRY-CELL LEUKEMIA
Myelofibrosis usually can be distinguished from hairy-cell leukemia by careful review of the blood and marrow specimens.
Hairy-cell leukemia variant is a unique clinicopathologic entity representing a hybrid between prolymphocytic leukemia and hairy-cell leukemia; the nucleus most closely resembles a prolymphocyte and the cytoplasm a hairy cell.71 Hairy-cell variant cells generally have higher nuclear-to-cytoplasmic ratios, more highly condensed chromatin, and more conspicuous central nucleoli than do the neoplastic cells of patients with classic hairy-cell leukemia.72 Afflicted individuals present with massive splenomegaly and are frequently in a leukemia phase. TRAP staining of hairy-cell variant cells is either negative or only weakly positive. Unlike classical hairy cells, the cells in the variant disease are usually CD25- and CD103-negative. Distinction of hairy-cell leukemia is based on nuclear morphology, the leukemia presentation, the lack of monocytopenia, the aspirable marrow, and the morphologic appearance of the cells seen in the marrow biopsy. Also, on electron microscopy, hairy-cell leukemia variant cells mostly lack ribosomal-lamellar complexes. There is also a blastic variant of hairy-cell leukemia, in which the patients have massive splenomegaly, peripheral adenopathy, and cytopenias.73 These cells stain positively with TRAP and do not express myeloperoxidase. More recently, a new entity, called hairy B-cell lymphoproliferative disorder, has been described in Japan.74 Patients with this disease have splenomegaly without lymphadenopathy and have a persistent lymphocytosis consisting of abnormal lymphocytes with long microvilli. The circulating lymphocytes are polyclonal B cells that are CD25-negative and only weakly TRAP positive.
Splenic lymphoma with circulating villous lymphocytes is a closely related disorder that can be difficult to distinguish from hairy-cell leukemia. Patients with splenic lymphoma with circulating villous lymphocytes also can have massive splenomegaly without lymphadenopathy. However, unlike hairy-cell leukemia, lymphocytosis is common.75 In this disorder, the lymphocytes have more basophilic cytoplasm, and the cytoplasmic projections tend to be polar and more subtle.76 Circulating plasmacytoid cells are frequently noted.51 TRAP staining is either negative or very weakly positive.47,77 The cells express high levels of CD11c but are frequently CD103 negative. Peripheral monocytopenia is usually absent. Sections of spleen show predominantly white pulp involvement resembling that of low-grade lymphoma.75
B-cell prolymphocytic leukemia is often confused with the prolymphocytic variant of hairy cell leukemia. Both disorders generally occur in elderly men with prominent splenomegaly. B-cell prolymphocytic leukemia lymphocytes are only focally TRAP-positive, whereas hairy cell leukemia classic and variant hairy cells are diffusely and strongly positive with TRAP staining. Other splenic lymphomas, including marginal zone lymphoma and monocytoid B-cell lymphoma involving the spleen, also need to be excluded.79,80 Although the morphologic features of these two disorders may approximate hairy cells, they are generally TRAP stain negative.81,82
Hairy-cell leukemia also should be differentiated from mast cell disease, especially when the infiltrates are composed of spindle-shaped cells. Mast cells are shown to contain metachromatic granules on Giemsa staining. The granules also test positive for chloroacetate esterase.83 On immunohistochemical analysis, the cells react with KPI (CDBP), a macrophage marker, but not L26 (CD20). Aged blood samples from patients with B-cell chronic lymphocytic leukemia may demonstrate artifactual cytoplasmic projections due to cytoplasmic distortion, but, unlike hairy cells, they are CD5 positive.84 Leukocytosis in chronic lymphocytic leukemia is more pronounced, and monocytopenia is usually absent.
THERAPY, COURSE, AND PROGNOSIS
INDICATIONS FOR THERAPY
Ninety percent of patients with hairy-cell leukemia require treatment at presentation or sometime during the course of their disease. Standard hematologic parameters for initiating therapy include anemia (hemoglobin < 9 g/dl), thrombocytopenia (platelet count < 50–100 × 109/liter), or neutropenia (absolute neutrophil count < 0.5–1.0 × 109/liter), especially if associated with recurrent, serious infections. Other, less common indications for initiating treatment are symptomatic splenomegaly, leukocytosis with a high proportion of hairy cells (white blood cell count > 20 × 109/liter), bulky or painful lymphadenopathy, vasculitis, and bony involvement.
TREATMENTS OF HISTORICAL INTEREST
Splenectomy Splenectomy was the first standard treatment modality employed in hairy-cell leukemia, since it rapidly reverses peripheral cytopenias. Ninety percent of patients will have improvement in at least one hematologic parameter, and 40 to 60 percent will have normalization of blood counts.85,86 The present indications for splenectomy are active or uncontrolled infections, thrombocytopenic bleeding, massive painful and/or ruptured splenomegaly, and failure to respond to chemotherapy including a purine analog.
Chlorambucil Chlorambucil at 2 to 4 mg orally daily for 6 to 9 months induces a consistent number of hematologic responses. The absolute neutrophil count, however, rarely improves with chlorambucil.89 There are brief reports of the salutory effects of protracted androgen90 and lithium administration in hairy-cell leukemia.91 These treatments are rarely used today, given availability of more effective systemic treatments.
Irradiation Lytic bone lesions, especially in the proximal femur, may be managed with low-dose irradiation, 1500 to 3000 Gy.46,92
Interferon The standard dose recommendation for interferon-a2b is 2 million units/m2 administered subcutaneously three times per week for 12 months, and for interferon-a2a is 3 million units/m2 subcutaneously given daily for 6 months and then decreased to three times per week for an additional 6 months.
The commonest side effect of interferon is a flulike syndrome consisting of fever, myalgias, and malaise. Acetaminophen often ameliorates these symptoms, and tachyphylaxis frequently develops over time. There is an unexpectedly high incidence of second neoplasms in patients after treatment of hairy-cell leukemia with interferon-a2b.99 Of 69 patients followed for a median of 91 months, 13 patients (19 percent) developed a second neoplasm; 6 were of hematopoietic origin, and 7 were adenocarcinomas. The median survival after diagnosis of the second neoplasm was only 9 months.
While interferon-a is an active agent in hairy-cell leukemia, it does not induce the same high complete response rates seen with the purine nucleoside analogs. Accordingly, it is likely that the use of interferon-a in the treatment of hairy-cell leukemia will be reserved for those patients with active infections and therefore unable to undergo purine nucleoside analog therapy, given their associated T-cell immunosuppression.29,107 It also may be useful in patients who have failed prior systemic therapy with a purine nucleoside analog.108
The response rates of several pentostatin clinical trials are summarized in Table 99-2. The standard dose of pentostatin for patients with hairy-cell leukemia is 4 mg/m2 every other week for 3 to 6 months until maximum response is achieved.
Pentostatin-induced toxicities include fever, nausea, vomiting, photosensitivity, and keratoconjunctivitis.118,119 Severe myelosuppression may occur soon after the initiation of pentostatin therapy, especially in those patients with preexisting marrow compromise.114,120 Severe infections, including the disseminated herpes zoster, Escherichia coli, Haemophilus influenzae and pneumococcal and fungal infections were observed soon on after the initiation of pentostatin.119 Pentostatin is best avoided in those patients with active and uncontrolled infections, a poor performance status, or impaired renal function.113 Pentostatin is strongly immunosuppressive.121 During pento-statin therapy and for at least 1 year thereafter, CD4 and CD8 lymphocytes may decrease to levels below 200 cells/µl. Low doses of pentostatin are also potently immunosuppressive.29
Cladribine is the treatment of choice for hairy-cell leukemia. In one large series, 91 percent of 349 patients achieved an initial complete response and 7 percent a partial response, with an overall median duration of response follow-up at 52 months. Response rates to cladribine were independent of prior therapy, including pentostatin. Twenty-six percent of the patients relapsed at a median of 29 months, and, of 53 patients treated with a second course of cladribine at first relapse, 62 percent achieved a complete response. In one study, there was a slight excess of second neoplasms in cladribine-treated patients; in another study there was no such excess.
Fever is the principal toxic effect of cladribine therapy in hairy-cell leukemia, occurring in 42 percent of patients treated. The fever is related to the disappearance of hairy cells and appears most marked in those patients with the greatest pretreatment hairy-cell leukemia burden, manifested principally as splenomegaly. Documented infections unrelated to a peripherally inserted central catheter device used to deliver the cladribine are uncommon. Dermatomal herpes zoster is the most frequent late infection reported.125 Like pentostatin, 2-chlorodeoxyadenosine (cladribine) is also immunosuppressive.107 In one study, there was a tendency toward restoration of CD4 cells at 6 and 12 months,130 while other studies have shown more profound and long-lasting CD4 lymphocytopenia.131
Although in the Scripps Clinic study the time–to–treatment failure rate for complete responders was 16.3 percent at 4 years, there was no obvious plateau on the time–to–treatment failure curve.125 Thus, it is unclear what proportion of patients, if any, will be cured. Twenty-five to fifty percent of patients in morphologic complete remission after cladribine have minimal residual disease detected by immunohistochemical stains of marrow biopsies.132,133 Using the polymerase chain reaction and clonogenic probes derived from the immunoglobulin heavy-chain genes, all seven patients in apparent complete remission following cladribine showed detectable minimal residual disease.134
Cladribine can induce long-lasting complete responses in the vast majority of patients following only a single 7-day infusion. The response rates to cladribine have been shown in several published chemical trials. Relapse rates for complete responders are low, and patients who relapse can be successfully retreated with cladribine. The recommended dose of cladribine is 0.1 mg/kg per day by continuous intravenous infusion for 7 days. The optimum route and method of administration for cladribine remain under investigation. The successful administration of subcutaneous cladribine has been reported,135 as well as a weekly intravenous administration schema.136 These methods of drug delivery remain to be tested in large numbers of patients, and longer follow-up is needed to determine whether these methods of drug administration are equivalent to the continuous intravenous infusion method.
Fludarabine, although rigorously evaluated in patients with chronic lymphocytic leukemia,137,138 has only been evaluated in small numbers of patients with hairy-cell leukemia (see Table 99-2). Although results have been less than dramatic than with other purine nucleoside analogs, some patients with a hariy-cell variant disease did achieve partial responses.139,140 and 141
Granulocyte Colony-Stimulating Factor G-CSF abrogates the early myelosuppressive effects of interferon142 and reverses neutropenia in some hairy-cell leukemia patients. The role of G-CSF in the management of hairy-cell leukemia will likely be principally adjunctive to systemic therapy. It does have a role in the initial treatment of actively infected hairy-cell leukemia patients. Of four patients with hairy-cell leukemia treated with G-CSF at 1 to 6 µg/kg per day for 6 weeks, 3 patients had normalization of their absolute neutrophil count in 1 to 2 weeks.142 A single patient with hairy-cell leukemia and a history of cutaneous vasculitis developed acute neutrophilic dermatosis (Sweet syndrome) following the administration of G-CSF.
COURSE AND PROGNOSIS
Ten percent of patients, usually elderly males with smaller-sized spleens, normal blood counts, and a lower hairy-cell burden, may be observed for protracted intervals, since they generally do not require treatment.143 Prior to the successful application of interferon and purine nucleoside analogs in the treatment of hairy-cell leukemia, patients with hairy-cell leukemia had a median survival time of only 53 months.143 Now, with purine nucleoside analog therapy, overall survival rates in excess of 95 percent at 4 years have been reported.125 Regardless of the curative potential of purine nucleoside analog therapy, patients with hairy-cell leukemia can now anticipate long survival.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn