CHAPTER 141 COLLECTION AND TRANSFUSION OF LEUKOCYTES, DENDRITIC CELLS, AND STEM CELLS
CHAPTER 141 COLLECTION AND TRANSFUSION OF LEUKOCYTES, DENDRITIC CELLS, AND STEM CELLS
MARK E. BRECHER
History of Granulocyte Transfusion
Preclinical Studies of Dogs with Granulocyte Transfusion
Clinical Experience with Granulocyte Transfusion
Granulocyte Concentrates from CML Donors
Controlled Trials of Granulocyte Concentrates from Healthy Donors
Mobilization of Donor Granulocytes and Collection
Indications for Granulocyte Transfusions
Storage of Granulocyte Concentrates
Apheresis-Derived Peripheral Blood Stem Cells
History of Peripheral Blood Stem Cell Transplantation
Stem Cell Mobilization Strategies
Stem Cell Collection for Allogeneic Transplantation
Dose and Enumeration of Stem Cells
Timing of Stem Cell Collections
Mononuclear Cells for Adoptive Immunotherapy
Allogeneic Adoptive Immunotherapy
Autologous Adoptive Immunotherapy
The availability of blood cell components including red cells, platelets, plasma, and plasma proteins has facilitated the treatment of hematologic diseases. Preparation of an effective granulocyte product has been elusive. The advent of recombinant granulocyte-mobilizing cytokines, which recruit large numbers of granulocytes into the blood, the use of hemapheresis instruments to cull the granulocytes from up to 15 liters of blood, and the use of starches to increase the efficiency of the separation of red cells from granulocytes have combined to make granulocyte transfusion of patients with severe reversible neutropenia and serious infections possible.
Stem cell transplantation from blood products has been made possible by using chemotherapeutic agents, cytokines, or combinations of the two to mobilize stem cells from marrow into blood, allowing recovery of sufficient numbers of stem cells by hemapheresis of several blood volumes. In so doing, sufficient CD34 antigen-positive cells can be recovered to engraft an allogeneic or autogeneic recipient.
Blood mononuclear cells of several types can be harvested by hemapheresis and used for immunotherapy. T lymphocytes can be used in their native state or after lymphokine activation. CD34 antigen-positive cells can be harvested and induced to transform into antigen-presenting (dendritic) cells by in vitro treatment with several cytokines. The use of mononuclear cells for immunotherapy of lymphoma, leukemia, or myeloma is becoming more frequent, and these approaches are dependent on hemapheresis to obtain sufficient quantities of cells to have therapeutic effects.
Acronyms and abbreviations that appear in this chapter include: BFU-E, burst-forming unit–erythroid; CD, cluster of differentiation; CFU-GEMM, colony forming unit–granulocyte-erythocyte-monocyte-megakaryocyte; CFU-GM, colony forming unit–granulocyte-macrophage; CML, chronic myelogenous leukemia; G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; LAK, lymphokine-activated killer (cell); TIL, tumor-infiltrating lymphocyte.
HISTORY OF GRANULOCYTE TRANSFUSION
Granulocyte transfusion for the treatment of neutropenia was first explored in 1934 but met with little success.1 It was not until 1953 that the first promising experiments with leukocytes were reported.2 In these experiments, leukocytes transfused into irradiated dogs migrated to sites of infection and were capable of normal phagocytic activity.2
Subsequently, interest in granulocyte transfusions has been cyclical. In the 1960s there was a strong sentiment for the use of granulocyte transfusions. This enthusiasm was fueled by the ability to collect large quantities of granulocytes from patients with CML and the early success with the infusion of these cells to patients with severe granulocytopenia and life-threatening infection.4 However, due to the unavailability of donors and concerns with transfusing malignant cells this practice was abandoned. In the 1970s, following the introduction of blood cell separators capable of harvesting large quantities of granulocytes from healthy donors, there was an overly optimistic view that granulocytes would have substantial clinical impact. However, in the 1980s disillusionment had set in following limited success with healthy-donor granulocyte therapy, and use of this therapy decreased. In the mid-1990s the introduction of recombinant cytokines capable of mobilizing large numbers of healthy-donor granulocytes led to renewed interest in granulocyte therapy.
PRECLINICAL STUDIES OF DOGS WITH GRANULOCYTE TRANSFUSION
Studies in neutropenic dogs with gram-negative sepsis,3,4,5,6 and 7 pneumonia,8,9 or candidemia10,11 and 12 found increased survival with or without antibiotic therapy. A threshold dose of 2 × 108 granulocytes/kg was protective against a lethal infection with Pseudomonas, while there was uniform mortality when doses less than 1.5 × 108 granulocytes/kg were administered. Mean 1 h posttransfusion increments of greater than 200/µl or greater than 500/µl were seen with infusions of at least 2 × 108 and 3 × 108 granulocytes/kg, respectively. Such studies suggested that a clinical benefit from granulocyte transfusions in neutropenic septic patients would be strongly dose-dependent.
CLINICAL EXPERIENCE WITH GRANULOCYTE TRANSFUSION
GRANULOCYTE CONCENTRATES FROM CML DONORS
Cell collections from donors with CML yielded as many as 1 × 1011 phagocytic cells,17,18 and transfusion of these concentrates increased white cell counts and led to improvement in septic neutropenic recipients.19,20 and 21 Leukocyte transfusions from CML donors also caused a more sustained elevation of the white cell count, perhaps because of their content of granulocytic progenitors capable of cell division.17 Patients with CML are rarely available and are not considered to be acceptable blood donors.
CONTROLLED TRIALS OF GRANULOCYTE CONCENTRATES FROM HEALTHY DONORS
There have been seven controlled clinical trials of granulocyte transfusion therapy for the treatment of bacterial sepsis in adults.22,23,24,25,26,27 and 28 These trials were considered successful,23,25,26 partially successful,22,27 or unsuccessful.24,28 A meta-analysis of these studies concluded that the dose of granulocytes transfused (greater than 1 × 1010 granulocytes transfused per day on at least four successive days) and the survival rate of controls (efficacious when the survival of the controls was under 40 percent) were primarily responsible for the disagreements across the reports.29 When the analysis was limited to the five randomized controlled studies,23,24,25,26,27 and 28 granulocyte therapy conferred a significant survival benefit in the following settings: (1) low survival rate of controls (RR = 8.0, 95% CI, 1.5–42), (2) adequate dose of granulocytes (RR = 4.0, 95% CI, 1.2–12), (3) timely marrow recovery; and (4) pretransfusion assessment of compatibility of granulocytes (RR = 8.0, 95% CI, 1.5–42).
Bacterial infection in the neonatal period may be life-threatening because of inadequate granulocyte function or the infant’s inability to mount or sustain neutrophilia because of inadequate reserves of neutrophilic precursors. In septic neonates there have been five studies of the effects of granulocyte therapy,30,31,32,33 and 34 four of which were randomized.31,32,33 and 34 A meta-analysis of these studies found that the only significant predictor of success was a dose of cells greater than 0.5 × 109/kg (RR 18, 95% CI, 1.3–252).29 Granulocyte therapy was not efficacious when buffy coats (as contrasted with granulocyte concentrates) which contained less than 0.5 × 109/kg granulocytes were transfused (RR = 0.74, 95% CI, 0.20–2.7). The effect of a low survival rate of controls did not reach statistical significance; however, the relative risk was large (RR = 13, 95% CI, 0.39–462). The effect of leukocyte compatibility was not assessed in the studies of neonates.
MOBILIZATION OF DONOR GRANULOCYTES AND COLLECTION
Less than five percent of the total body neutrophil pool is in the intravascular space.36,37 These cells have a half-life of only 4 to 10 h in the intravascular compartment.38,39 The collection of large numbers of granulocytes requires the processing of 5 to 14 liters of blood per donation, which can be accomplished within 2 to 3 h. Apheresis procedures are performed with a special centrifuge.39,40 and 41 Donor blood is pumped through the centrifuge and separated, based on density, into three layers. The leukocyte-containing layer is harvested to form the granulocyte concentrate, and the red cells and plasma are returned to the donor. Of historical note is that an alternative, noncentrifugal method of granulocyte collection that exploited the ability of granulocytes to adhere to nylon in the presence of divalent cations was once employed.42 Although filtration leukapheresis was simple and yielded large quantities of granulocytes,27,39,40,42,43,44,45,46,47,48,49,50 and 51 the technique has been abandoned because of the need to heparinize the donor and because of reactions such as severe abdominal pain,52 priapism,53 complement activation in the donor,54,55,56,57 and 58 frequent shaking chills in the recipient,59 and poor survival, in vivo recovery, and chemotactic capability of the collected neutrophils.18,28,60,61,62,63 and 64
Granulocyte collections taken from healthy donors by centrifugal leukapheresis do not routinely yield adequate quantities of phagocytic cells (0.1–0.5 × 1010 granulocytes per liter of donor blood).29,40 This is due to two factors: (1) the difficulty of separating granulocytes from lighter red cells and lymphocytes because of the similarity in their density, and (2) the low number of granulocytes in the circulation. The addition of a rouleaux-inducing sedimenting agent to the blood before it enters the centrifuge enhances the separation of red cells from white cells and increases yields as much as twofold. The most common rouleaux-inducing agents employed are hydroxyethyl starches.17,19,20 and 21 Hydroxyethyl starches are branched-chain polyglucose molecules, or glucans, similar in structure to glycogen but having variable degrees of hydroxyl substitutions on the glucose residues (carbons 2, 3, and 6). Such substances are also used as a synthetic colloid volume expander. Virtually all centrifugal cell separators require the use of cell-sedimenting agents to achieve an adequate granulocyte yield. In the United States two hydroxyethyl starches, hetastarch (Hespan), sometimes referred to as high molecular weight hydroxyethyl starch or HMW-HES, and pentastarch (Pentaspan), sometimes referred to as low molecular weight hydroxyethyl starch, or LMW-HES, are approved and commercially available for human use. Pentastarch was thought to be a superior starch erythrocyte-sedimenting agent due to its lower molecular weight (average pentastarch 260 kDa, versus hetastarch 450 kDa) and consequently more rapid and complete clearance.65 A paired controlled prospective study involving 36 donors from whom collections were alternately made with both starch sedimenting agents found that in 33 of 36 (92%, P < .001) pairs of donors, hetastarch was significantly more efficient in granulocyte collection. Overall, hetastarch provided 1.6-fold greater collections than did pentastarch.66 Donor reactions are not common but can range from mild rashes, rhinorrhea, or paresthesias to anaphylaxis, circulatory failure, pulmonary edema, and others.
Donor granulocyte counts also can be increased prior to donation by the administration of drugs that either mobilize granulocytes from the marrow or cause a shift of granulocytes from the marginal pool to the circulating blood pool.67,68 At present, dexamethasone or another glucocorticoid is administered either orally or by intravenous infusion to raise the donor granulocyte count prior to leukapheresis.20,39,40,68,69 and 70 Various dose schedules have been used, but a typical regimen is 8 mg dexamethasone (or 20–30 mg prednisone) given orally 12 h prior to collection. Leukapheresis yields have increased by 50 to 100 percent after glucocorticoid administration, and their use is routine in most leukapheresis facilities. The effects of hydroxyethyl starch and glucocorticoid administration are additive, and neither has significant adverse effects on the function of the granulocytes.60,68,71,72
Despite the availability of glucocorticoids and erythrocyte sedimenting agents, a dose of greater than 1 × 1010 granulocytes frequently is not achieved with one apheresis collection. This level may be particularly difficult to achieve for the first collection when there has not been time to medicate the donor with glucocorticoids prior to the apheresis collection.
The introduction of cytokines such as G-CSF (Neupogen) for the mobilization of hematopoietic cells has allowed the collection of much larger numbers of granulocytes. Multiple studies employing G-CSF at a dose of 5 to 10 µg/kg per day (300–600 µg given subcutaneously) administered 12 h prior to collection will result in a blood white count in the range of 20–50 × 109/liter range with a three- to sixfold increase in the number of granulocytes collected (4–8 × 1010 granulocytes).73,74,75 and 76 Combining glucocorticoids and cytokines results in even greater efficacy, with mean collections of 0.8–1.1 × 1011 granulocytes.76,77 and 78 Such doses approach the amount of granulocytes that a normal marrow produces in a day (1.5 × 109/kg).79,80
Use of G-CSF is not without problems. Donors complain of bone pain, headaches, fatigue, night sweats, nausea and vomiting, sleep disturbances, and redness or swelling at the injection site.77 Comparison of multiple mobilization schemes suggests that a dose of both G-CSF and glucocorticoids given once on the day prior to collection minimizes side effects and results in a fourfold increase in granulocytes collected over the use of glucocorticoids alone.76,77 and 78 A single dose of 300 µg of G-CSF results in nearly the same elevation in neutrophil count as a 600-µg dose 78. For repeated donations, administration of G-CSF on alternate days maintains the neutrophil count, with decreased side effects and lower cost than a daily regimen.75 In a paired three-arm study, the use of dexamethasone alone resulted in 25 percent of donors reporting insomnia or flushing. With G-CSF, 65 percent had bone pain, headache, insomnia, fatigue, nocturia, or diaphoresis; this increased to 85 percent with combination of dexamethasone and G-CSF.78 There are no known long-term sequelae after the transient administration of G-CSF to healthy donors.
The granulocytes collected following cytokine mobilization are not fully mature, but studies have not identified any significant dysfunction granulocyte dysfunction. Granulocytes appear activated (primed for a respiratory burst), have normal phagocytosis and staphylococcal killing capability in vitro, and have a prolonged half-life in the circulation.73,78,79,80 and 81 There is evidence of degranulation and decreased postinfusion recovery (31% versus 65%), but G-CSF-stimulated granulocytes migrate into skin-window chambers and into sites of inflammation and infection.78 After G-CSF priming of the donor, there are alterations of surface antigen expression with increased expression of adhesion molecules (CD11b, CD14, CD18) and Fc receptors (CD32, CD64).78 The clinical significance of these changes, if any, is not known.
INDICATIONS FOR GRANULOCYTE TRANSFUSIONS
The indications for granulocyte transfusion are not well defined. In general, the patient should have (1) an absolute granulocyte count less than 500/µl (0.5 × 109/liter), (2) fever, (3) an identified responsible microorganism, and (4) no decrease in fever after 48 h of antibiotic treatment. Also, the prognosis without granulocyte therapy in the specific setting should be poor and the prognosis of the underlying disorder should be favorable. When possible, attempts should be made to match for leukocyte antigens and transfuse cytomegalovirus-negative, irradiated cells.
The risk of infection in granulocytopenic patients is related to the severity and duration of the cytopenia.82 The risk of infection increases dramatically when the granulocyte count is below 500/µl (0.5 × 109/liter). An equally important consideration in determining the need for granulocyte transfusion is the status of the patient’s marrow. If early marrow recovery is expected, granulocyte concentrates are probably superfluous. Conversely, if the neutropenia is expected to last for more than several days the patient may benefit from granulocyte transfusions when serious infection is present.
Granulocyte transfusions also have been used successfully in the treatment of infected patients with chronic granulomatous disease. In these patients granulocyte transfusion is indicated if appropriate antibiotic therapy used alone is unsuccessful.83,84,85 and 86
The usefulness of giving prophylactic granulocyte transfusions to neutropenic patients without evidence of infection has been evaluated in several studies.86,87,88,89,90,91 and 92 In a large randomized study, neutropenic patients with leukemia who received prophylactic granulocyte transfusions did not have an overall reduced incidence of infections compared with controls, although the proportion of transfused patients with bacterial septicemia was reduced. Also, prophylactic granulocyte transfusions did not improve the rates of remission, survival, or time to marrow recovery.90 Most other studies agree with these findings. No randomized studies have been done with the G-CSF plus glucocorticoid stimulated granulocyte collections.
Two randomized studies have evaluated the use of prophylactic granulocyte transfusions in patients receiving marrow transplants. One study found fewer infections in transfused patients than in controls.88 In contrast, the other study89 found a decrease in bacterial septicemia in transfused patients but did not observe a reduction in overall infection; survival was not improved. Furthermore, 13 of the 18 patients receiving transfusions developed cytomegalovirus infections, compared with only 6 of 17 controls. Thus, viral infection is a significant additional hazard in severely immunosuppressed patients.
One major drawback to prophylactic granulocyte transfusion is the increased likelihood of transfusion reactions, alloimmunization, lymphocytotoxic antibodies, and refractoriness to future transfusions. Refractoriness to platelet transfusion occurs frequently in patients who are given granulocyte transfusions.87 Although there is some reduction in the incidence of infection, the occurrence of alloimmunization and the absence of clear benefit are major deterrents to the use of prophylactic granulocyte transfusions.
G-CSF mobilized, HLA-matched, ABO compatible granulocytes provided to allogeneic bone marrow transplant recipients resulted in significant and sustained increments in the neutrophil and the platelet count.75 The peak of the neutrophil increment was observed 4 to 12 h following infusion and the rise in the neutrophil count persisted for 25 to 37 h. Nevertheless, three of the ten recipients developed culture-proven bacterial infections during the period of granulocyte infusions.
The general hazards of blood transfusion also apply to granulocyte transfusions. Hemolytic reactions may occur because there are red cells in granulocyte concentrates. ABO-compatible concentrates should be given. Recovery of granulocytes in the recipient 1 h after transfusion is adversely affected by ABO incompatibility.22 The presence of erythrocyte antibodies in the recipient other than AB blood groups should also be ascertained prior to transfusion, but such erythrocyte incompatibilities are not an absolute contraindication to transfusion if the patient’s infection is severe. If necessary, most of the erythrocytes in the concentrate can be removed by differential centrifugation prior to transfusion.
Febrile transfusion reactions occur frequently with granulocyte transfusions.48,59 About 10 percent of recipients have chills and fever after transfusion of cells collected by a centrifugation method, as a result of antileukocytic antibodies in the recipient or pyrogen released from damaged white cells. Glucocorticoids, antihistamines, and meperidine can be given either prophylactically or therapeutically to reduce the frequency or severity of these reactions.
Acute pulmonary insufficiency has been reported with granulocyte transfusion.93 A number of different mechanisms have been proposed. In neutropenic patients with pneumonia it has been postulated that the rapid migration of transfused granulocytes into the infected lung may induce such a reaction.93 Leukoagglutinins in the recipient may result in leukocyte aggregates which embolize to the lung.94 Complement activation and the generation of C5a, which results in granulocyte aggregation or adhesion to endothelial cells, also have been postulated.95 Severe pulmonary reactions with the concomitant use of granulocyte transfusion and amphotericin B have been reported by some observers96 but not by others.97,98 As a precaution, however, amphotericin B and leukocyte transfusion should be administered at different times.
Severely immunosuppressed patients are at risk for other serious complications of granulocyte transfusion. Graft-versus-host disease, sometimes fatal, has occurred in patients receiving intensive chemotherapy and perhaps in neonates.99,100,101,102,103 and 104 In such cases, the concentrate should be irradiated with 2500 rad prior to administration to prevent this occurrence. Severely immunosuppressed patients, especially those undergoing marrow transplantation, also may develop a cytomegalovirus infection, particularly pneumonia, that may be fatal.89 Individuals who do not have serologic evidence of prior cytomegalovirus infection should be selected as donors for immunosuppressed patients.
STORAGE OF GRANULOCYTE CONCENTRATES
It is best to transfuse granulocytes as soon as possible after collection.48,105 Granulocyte concentrates system should not be stored for more than 24 h.
Granulocyte chemotaxis is the first function altered during storage.72,106,107,108 and 109 Changes in phagocytic function, bactericidal capacity, and biochemical functions such as fructose-6-phosphate (hexose monophosphate) shunt activity and oxygen consumption are generally less sensitive indicators of cell damage during storage.
Cell viability and bactericidal capacity seem to be well maintained at either room temperature (22°C) or during refrigerator storage (5°C) for at least 24 h,106,107,108,109,110 and 111 but chemotaxis, chemotaxis-related functions, adherence to endothelial cells, and cell ATP levels are better preserved at 20–24°C.107,108,111,112,113,114,115,116 and 117 Storage of granulocytes is associated with a tendency for hyperadherence and spontaneous aggregation that is more pronounced at 5°C.116 Because of better preservation of function, current practice is to store granulocytes at room temperature when storage is required.
In general, granulocyte concentrates are better preserved in plasma than in other suspension fluids,111 but it is possible that improved storage can be achieved in other optimized solutions.118 Additional glucose may be required when the cell leukocyte count is high119 or when there are significant numbers of contaminating platelets and red cells that compete with the granulocytes for glucose.120 The type of plastic used in the storage bag is another important storage variable.121 Gentle agitation was found to be beneficial in one study122 but not in another.111 It is unclear whether irradiation of granulocyte concentrates prior to transfusion to prevent graft-versus-host disease is associated with alteration in cell function.123,124 The subject of granulocyte preservation has been reviewed.125
Cryopreservation of granulocytes would be an ideal method of storage because it would permit the “banking” of large quantities of cells that would be available when needed. Dimethyl sulfoxide is used as a cryoprotective agent, but there are no satisfactory methods for freezing granulocytes. Post-thaw recovery of viable cells, as measured by phagocytosis, rarely exceeds 25 percent.126,127 and 128
Granulocyte transfusion therapy has been full of promise for several decades. Now, with the ability to reliably collect G-CSF plus steroid-mobilized granulocytes from healthy donors with total doses exceeding 1 × 1011 granulocytes, large randomized trials are needed to define the efficacy, toxicity, and cost-effectiveness of granulocyte transfusions both for prophylaxis in transiently neutropenic patients and for neutropenic patients with progressive bacterial or fungal infections.129
APHERESIS-DERIVED PERIPHERAL BLOOD STEM CELLS
HISTORY OF PERIPHERAL BLOOD STEM CELL TRANSPLANTATION
Within the past 10 years the role of blood stem cells has evolved from research conducted in a few centers to a widely utilized therapeutic modality. Since the initial hypothesis in 1909 that hematopoietic stem cells circulate130 and subsequently, the demonstration of hematopoietic reconstitution following myeloablative irradiation and parabiosis in rodents by Brecher and Cronkite in 1951,131 the potential applications of blood stem cells in humans have emerged. Documentation of cell engraftment in a patient receiving granulocytes derived from a donor with chronic myelogenous leukemia in 1963132 paved the way for the first successfully performed autologous blood stem cell transplant in a patient with chronic myelogenous leukemia in 1979.133 In 1986, successful hematopoietic reconstitution by autologous blood stem cell transplantation was described in a patient with Burkitt lymphoma following marrow-ablative chemotherapy.134 Initially, autologous stem cells collected by leukapheresis were used to shorten the period of pancytopenia following myeloablative chemotherapy in patients undergoing bone marrow transplantation.135,136 Early successes with blood stem cell transplantation involved steady-state harvesting of the circulating hematopoietic stem cells by apheresis without specific mobilization strategies. Engraftment times were comparable to bone marrow transplantation.134,137,138 Unfortunately the number of collections, time, and cost of collection and transplantation of blood stem cells were not yet optimal for the evolving technology to emerge as an alternative to marrow transplantation.139 The development of mobilization techniques to enhance the circulating number of stem cells, optimizing of the timing of apheresis harvests, and progress on characterizing stem cells by immunophenotyping have enabled this transition to occur. Currently, autologous transplantation using blood stem cells is performed more frequently than autologous bone marrow transplants.139,140 and 141
Apheresis-derived blood stem cells offer several benefits over marrow transplants.142 Apheresis collection is feasible on an outpatient basis, avoids general anesthesia, and enables the processing of multiple blood volumes per collection. Blood stem cell collection is suitable for patients whose marrow is infiltrated by disease or fibrosis or who have a history of prior pelvic radiation. Blood stem cells result in a shortened cytopenic period following myeloablative treatment, fewer infectious complications, a lower incidence of tumor cell contamination, decreased transfusion requirements, and a shortened period of hospitalization.135,143,144 Disadvantages include a potentially longer period to obtain an adequate harvest; a greater volume to infuse; maintenance of central venous access, which predisposes to risks for infection and thrombosis145,146; and, in the allogeneic setting, the possibly greater risk of graft-versus-host disease due to the presence of mature lymphocytes in the stem cell suspension.
Technical advances have facilitated the application of peripheral blood stem cell transplantation. These include improved automated blood separators capable of efficient collection of mononuclear cells and the use of cryopreservation and sterile bag systems to pool components from multiple collections.147 Innovations in mobilization techniques, quantification of appropriate stem cell doses to ensure timely engraftment, and optimization of the timing and efficiency of apheresis collections have contributed to the growing use of this stem cell collection strategy.
STEM CELL MOBILIZATION STRATEGIES
Collection of adequate numbers of stem cells from blood requires large volumes to be processed (2–4 blood volumes). Retrieval of this small population of cells is challenging, since very primitive hematopoietic cells comprise only 0.01 to 0.1 percent of circulating leukocytes and 1 to 10 percent of cells obtained from bone marrow.148 Mobilization refers to those techniques which increase the proportion of circulating primitive cells, especially stem cells. Although the exact mechanism(s) by which mobilization occurs is unclear, glucocorticoids, endotoxin, stress, exercise, and dextran have been shown to cause alterations in the concentration of peripheral progenitor cells.149 Mobilization strategies have significantly improved the efficiency of peripheral blood stem cell collection by apheresis and have decreased the number of procedures necessary to achieve target stem cell collection amounts. As a consequence, transplantation using blood stem cells has become an attractive alternative to marrow transplantation.
Myelosuppressive (as opposed to myeloablative) chemotherapy is associated with a recovery phase with increased concentrations in circulating hematopoietic progenitor cells.150,151 A variety of chemotherapeutic agents/regimens can elicit mobilization, which is enhanced depending on the dose and timing of the preceding chemotherapy.152 The effectiveness of mobilization can be assessed by in vitro clonogenic progenitor cell assays of blood. These assays have also been instrumental for quantifying the harvested stem cells after apheresis. Morphologically distinct CFU-GM, BFU-E, and CFU-GEMM colony-forming units can be quantified by colonial growth on cytokine-supplemented semisolid media after incubating 7 to 20 days. However, due to the time required for these assays they primarily provide retrospective information. Flow cytometric “real time” assessment of stem cell content using CD34 antigen has greatly enhanced the clinical utility of stem cell enumeration (see “Dose and Enumeration of Stem Cells”).
Use of high-dose cyclophosphamide to mobilize progenitor cells has been effective in patients with lymphoma, myeloma, and solid tumors.134,153,154 A 14-fold increase in the mean CFU-GM in blood of patients with lymphoma, myeloma, and solid tumors occurred two days after recovering leukocyte counts exceeded 1 × 109/liter.154 Comparison of hematologic recovery times between autologous chemotherapy mobilized stem cell transplants and marrow autotransplants revealed significantly shorter time to attain a neutrophil count of 0.5 × 109/liter (mean of 11 days versus 22 days) and a platelet count of 50 × 109/liter (mean of 14 days versus 32 days).144 In addition, the number of hospital days and blood component transfusions were reduced in the group that received blood stem cells.
CYTOKINES AND CHEMOTHERAPY
When mobilization regimens incorporate cytokines such as G-CSF or GM-CSF in addition to chemotherapy, progenitor cell concentrations increase dramatically over steady-state blood levels.155 A strategy combining chemotherapy and hematopoietic growth factors offers the most effective means for mobilization of progenitor cells. This strategy was first described in the treatment of patients with sarcoma.156 GM-CSF when combined with myelosuppressive chemotherapy produced a 63-fold elevation in circulating progenitors measured as CFU-GM by in vitro culture. GM-CSF priming alone produced a 13-fold increase in CFU-GM, and chemotherapy alone produced only a twofold rise in CFU-GM. The synergistic effect of chemotherapy plus cytokine administration becomes readily apparent when reviewing published experience. In general mobilization with chemotherapy alone affords a 20- to 50-fold increase in circulating CFU-GM. Cytokines or hematopoietic growth factors alone afford a comparable mobilization: G-CSF typically results in a 20- to 50-fold increase in CFU-GM, while GM-CSF results in a modest 10-fold increase in CFU-GM. When cytokines are combined with chemotherapy, mobilization of CFU-GM increases by approximately 70-fold (range 25 to 250 fold).153,157,158,159,160,161,162,163 and 164 A median time to a platelet count of greater than 20 × 109/liter occurred in 10 days in a chemotherapy plus G-CSF mobilized stem cell transplant group, as compared to 17 days in an autologous marrow transplant group.165 The preferred approach is to use harvested blood stem cells as the source of hematopoietic reconstitution.140,162 However, effective mobilization of autologous stem cells in patients may be unsuccessful, depending on the extent of previous chemotherapy/radiation or involvement of the marrow in disease.166
STEM CELL COLLECTION FOR ALLOGENEIC TRANSPLANTATION
Blood stem cell transplantation in the allogeneic setting has evolved at a slower pace due to concerns of graft-versus-host disease that might arise from donor lymphocytes. Fortunately, experience with sibling HLA-matched donors, syngeneic donors, and a second autologous marrow transplantation revealed minimal graft-versus-host disease and few adverse effects on the donor.167,168 and 169 Allogeneic blood stem cell transplantation results in rapid, multi-lineage engraftment following successful mobilization of donor stem cells with G-CSF. Higher doses of G-CSF enhance the progenitor cell harvest beyond that obtained by marrow harvest and have been associated with more rapid engraftment of platelets.170 Initial enthusiasm was offset by reports of chronic graft-versus-host disease, which occurred despite the low numbers of CD3+ cells present in the blood stem-cell suspension following CD34+ cell selection.171,172 Diminishing the graft-versus-host effect while retaining the graft-versus-leukemia effect remains a challenge.173
Reports of significant donor reactions have been infrequent, although cytokine mobilization has been associated with mild bone pain, headache, body aches, fatigue, nausea and vomiting, local reactions at the injection site, insomnia, night sweats, dyspnea, transient changes in serum chemistries, and thrombocytopenia.73,74,143,174,175,176,177,178 and 179 Risks associated with apheresis include citrate toxicity, hypotension, fatigue, and if antecubital access is insufficient, the risks of central venous access. Large-volume leukapheresis collections are typically successful in harvesting sufficient progenitor cells in one or two collections. While clinically significant thrombocytopenia has not been described following administration of G-CSF, stem cell suspension products contain a substantial number of platelets. A drop from preapheresis platelet counts of approximately 28 percent per daily collection has been described, with recovery after about 10 days.179 A predictable 2–4% decrease of the platelet count per liter of whole blood processed occurs in donors.180 Close monitoring of pre-, post- and intraprocedure donor platelet counts is advisable. Strategies to minimize this problem may include shorter collections, longer recovery periods between collections, or the use of thrombopoietin. Salvaging of platelets may provide the most immediate practical solution.181
The long-term effects, and specifically the risk of subsequent hematologic consequences, remain a theoretical concern when exposing healthy donors to hematopoietic growth factors. Several hundred allogeneic blood stem cell donors followed for 2 to 5 years postdonation have not shown an increased risk of hematologic malignancy.139 A prospective study of 19 donors demonstrated that one year after the administration of G-CSF their blood counts were normal and unchanged from predonation counts. Furthermore, following a second course of G-CSF the progenitor content of the peripheral blood stem-cell product was comparable to the first.182
DOSE AND ENUMERATION OF STEM CELLS
The CFU-GM count correlates inversely with the time to detectable engraftment, the length of hospitalization, and the amount of supportive care needed.136,144,183 The correlation between the CFU-GM and CD34 counts reported by several independent investigators,184,185,186 and 187 along with the advent of flow-cytometric quantitation of CD34 cells, has facilitated more rapid and reproducible measurement of putative stem cells in “real time.”
The CD34 antigen is a glycoprotein expressed on the surface of lymphohematopoietic self-renewing stem cells, lineage-committed progenitors, some endothelial cells, embryonic fibroblasts, and marrow stromal cells. Although its functional role has yet to be definitively established, it has been suggested that the CD34 antigen assists in the adhesion and routing of primitive hematopoietic cells during hematopoiesis and differentiation.139 Approximately 1.5 percent of the bone marrow mononuclear cells express CD34. Within this population reside the CFU-GM, BFU-E, and CFU-GEMM capable of short-term hematopoietic reconstitution,176,188,189 as well as the pluripotential self-renewing stem cell, the exact phenotype of which remains controversial. The pluripotential stem cell presumably resides within the CD34+, thy-1dim, CD38–, HLA-DR–, and lineage-specific negative subpopulation (see Chapter 14).162
The blood contains approximately 1 to 10 percent of the CD34+ population in the marrow in the steady state. Mobilization techniques, as discussed above, expand this circulating compartment and enable efficient collection by leukapheresis. The adequacy of a blood stem-cell collection is gauged by the number of CD34+ cells per kilogram of recipient body weight. The minimal threshold of CD34+ cells necessary for neutrophil and platelet recovery after autologous transplantation has ranged from 2 to 5 × 106 per kilogram.166,190,191,195 Higher stem-cell doses have been associated with accelerated platelet engraftment.170 In one study of breast cancer patients, 14 days after transplant, the probability of the platelet count being greater than 20 × 109/liter was 95, 85, 65, or 50 percent with a total infused doses of 10 × 106, 5 × 106, 2 × 106, or 1 × 106 CD34+ cells/kg, respectively. Some transplant physicians have made a distinction between an optimal cell dose for autologous versus allogeneic stem-cell grafts and recommend that the latter contain at least threefold more progenitor cells, although the necessity for this has not been proved.139
Increasing the total dose of CD34+ cells from apheresis-derived collections theoretically should result in a greater likelihood of enduring hematopoietic engraftment. The higher incidence of tumor cell contamination with increased numbers of apheresis collections for autologous stem-cell harvests of breast cancer patients gives pause to the notion that more is better.193 A shortened disease-free survival was observed among breast cancer patients undergoing autologous marrow transplantation who had evidence of micrometastatic disease in the marrow harvested, as measured by immunocytochemical methods.194
A variety of methods for enumeration of CD34+ cells by flow cytometry have been published.148,194,195,196,197,198,199,200,201 and 202 However, comparison of CD34 measurements from different centers is difficult due to differences in methods among laboratories. A multi-institutional study of 21 marrow and blood samples showed a twenty-fold range in results.203 These discrepant observations confirmed results from several smaller studies196,198,204 and emphasize the need for standardization. One approach has been suggested by the International Society for Hematotherapy and Graft Engineering (ISHAGE).205 Counting techniques that incorporate a standard bead into the analysis or volumetric capillary cytometry hold promise for increasing accuracy and reproducibility.206,207 and 208
TIMING OF STEM CELL COLLECTIONS
At present, stem cell collections using continuous flow apheresis equipment depends on processing 1.5 to 4 blood volumes over several hours. Repeated daily collections over 2 to 5 days are used to reach an adequate threshold of stem cells. The adequacy of the collection is dependent on the mode of mobilization, the timing of the collection with respect to the recovering leukocytes, the volume of whole blood processed, and the amount of patient pretreatment.162
Recruitment of noncirculating hematopoietic progenitors during a single large-volume leukapheresis collection (2 to 3 times the donor blood volume) can occur, including a 2.5-fold increase in the CFU-GM when more than 15 liters of whole blood was processed.186,209,210 and 211 However, such results are dependent on the patient’s ability to tolerate prolonged leukapheresis, adequate mobilization, and timing.212
Healthy allogeneic donors treated with G-CSF have a predictable peak in circulating stem cells occurring 5 to 6 days after initiating daily subcutaneous doses of G-CSF of 5 to 10 µg/kg per day.134,143,176,214,216
Timing collections in the autologous setting has been more challenging. Early studies suggested that collections begin when the leukocyte count exceeded 1.0 × 109/L.139,214 While circulating progenitor cells and the total mononuclear count begin to rise concurrently, premature cessation of cytokine administration in these studies likely led to a decrease in circulating progenitors.139 Subsequently, cytokine administration has been continued longer throughout serial collection procedures. Peak levels of circulating progenitors have been reported 2 days after the WBC count exceeds 2 × 109/L,213 12 days after the WBC exceeds 10 × 109/L,167 or when the rebounding WBC reaches 5 × 109/L.157
Unfortunately, the blood white cell and mononuclear cell counts do not correlate with the number of hematopoietic progenitor cells in the blood.217,218 Quantitation of circulating CD34+ cells the day of leukapheresis is a more accurate predictor of the optimal time of stem cell harvest.217,218,219,220,221,222 and 223 A minimum threshold greater than 10 to 30 circulating CD34+ cells per microliter will afford a satisfactory stem cell harvest, although serial collections may still be necessary to attain the appropriate CD34+ dose for transplantation.219,220 and 221 When the circulating progenitors approach or exceed 100 CD34+ cells per microliter, a single leukapheresis may provide all of the CD34+ cells necessary.
The relationship of circulating CD34+ cells with the CD34+ cell yield allows for the optimal timing of stem cell harvests. Thus, fewer collections and a lower volume of pooled product to infuse following myeloablation can be achieved. By combining microvolume fluorometry and an automated analysis, accurate CD34+ cell counts can be made in 30 min. This assay has the potential to expedite optimal timing of stem cell harvests.207,208
Finally, awareness of the phenotype of the patient’s malignant cells is important, since lymphoblastic lymphomas and other hematologic malignancies can occasionally express the CD34 antigen and yield an erroneously high stem cell dose.
MONONUCLEAR CELLS FOR ADOPTIVE IMMUNOTHERAPY
ALLOGENEIC ADOPTIVE IMMUNOTHERAPY
Allogeneic blood cell collection and reinfusion may benefit marrow transplant patients with recurrent leukemia. This form of adoptive immunotherapy utilizes the inherent immune reactivity of apheresis-derived allogeneic leukocytes from the original marrow donor to either prevent recurrence or induce remission. With strategies that manipulate the timing and the dose of donor T lymphocytes infused following transplantation, this therapy attempts to exploit the beneficial graft-versus-leukemia effect while minimizing the risks of graft-versus-host disease. Donor lymphocytes have been used to induce cytogenetic remission in patients with CML who relapsed after transplantation.173,224 Although the role of interferon-a in such therapy has been questioned, the antileukemia effect of reinfused donor lymphocytes in CML patients has been confirmed, yielding a composite clinical response rate of 77 percent.225 Unfortunately, transfusion of allogeneic mononuclear cells from the original donor has not been capable of inducing a durable remission with other hematologic malignancies.224,226 Graft-versus-host disease remains a major complication frequently accompanying this therapy. Of the CML patients who achieved remission, graft-versus-host disease developed in 73 percent (8/11) of patients receiving a total T-cell dose greater than 5 × 107/kg but only in 12.5 percent (1/8) of patients who received a total T-cell dose of 1 × 107/kg.173 Remission in CML can result from donor leukocytes containing as few as 1 × 107 T cells/kg.
AUTOLOGOUS ADOPTIVE IMMUNOTHERAPY
Another application of mononuclear cell collection using apheresis cell separators has been in the preparation of autologous mononuclear cells with antitumor activity. Examples include the production of LAK cells,227,228 TIL,229 and activated dendritic cells (antigen-presenting cells). Each of these applications must be considered experimental at present.
The production of LAK cells may require pretreatment of the patient with IL-2, leukapheresis for the collection of mononuclear cells, ex vivo manipulation of the collected cells to activate and/or purify them, and reinfusion into the patient. In a study of 539 leukapheresis collections, a mean of 3.03 × 1010 lymphocytes were collected in a four-hour procedure.230 High yields of lymphocytes in these procedures result in part from recruitment of these cells into the circulation by prior IL-2 treatment. The culturing, harvesting, and washing of these lymphocyte preparations prior to infusion, rather elaborate processes, have been described.231,232 and 233
Due to the limited success observed with both LAK and TIL cell therapy for metastatic cancer, attention has turned to the collection, purification, activation, and reinfusion of dendritic cells as a means for the production of tumor-specific cytotoxic T cells. Experimental evidence suggests that the presence of tumor inhibits dendritic cell maturation and activation both locally and systemically.234 However, isolated dendritic cells (from marrow or blood) can be concentrated or cultured from CD34+ progenitor cells. These fully functional isolated dendritic cells are subjected to cytokines (such as GM-CSF, IL-4, and TNF-a) and tumor-associated antigen stimulation and have been used as a pulse therapy.233,234,235,236,237,238,239,240 and 241 The identification of antigens such as CD83 and CMRF-44 on dendritic cells may allow the optimization of cytokine mobilization and of the timing of collection of blood dendritic cells, and possibly lead to positive selection techniques similar to those currently used for CD34+ cells.242,243 Preliminary clinical trials with dendritic cells in low-grade B cell lymphoma, prostate cancer, and melanoma have been associated with apparent clinical responses in some patients.239,240 and 241 These early reports, while promising, require further clinical investigation to assess the clinical efficacy.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn