Peripheral Blood Stem Cen Transplantation: Historical Perspective, Current Status, and Prospects for the Future David Inwards and Anne Kessinger

ARROW ABLATIVE THERAPY folIowed by stem celI rescue is playing an expanding role in the treatment of a variety of malignancies. Previously, the source of stem eells has predomi~ dant1y been limited to allogeneic, syngeneie, or autologous bone marrow. More recent1y, periph'eral blood stem eelIs have been increasingly used. This review will highlight pertinent historical advanees in the establishment of peripheral blood stem eell transplantation (PBSCT) as a viable elinical treatment modality , discuss the current status of PBSCT, and briefly speeulate on future possi'bilities.

M

EARLY DEVELOPMENT OF PERIPHERAL BLQOD STEM CELL TRANSPLANTATlON

The origin of PBSCT dates back to at least 1962, when Goodman and Hodgson demonstrated that donor origin hematopoiesis could be established in mice that reeeived alIogeneic infusions of peripheralleukocytes after supralethal irradiation. l In 1977 Nothdurft et al reported that autologous cryopreserved mononuclear celIs obtained from peripheral blood by apheresis could repopulate the bone marrow of lethalIy irradiated dogs.z The results of in vitro progenitor assays performed on the peripheral blood mononuclear celI product were found to be predictive of engraftment. Crosscirculation studies in irradiated baboons were consistent with the presenee of hematopoietic stem cells in the peripheral blood of primates. 3 The demonstration of peripheral blood stem eells in Illan by Barr and Whang-Peng in 1975 4 enabled investigators to eonsider applying the teehnique of peripheral blood stem eelI transplantation to hu-

mans. Initial reports of PBSCT in humans showed mixed results. MeCarthy and Goldman noted that the peripheral blood of ehronie granuloeytic leukemia patients eontains high levels of progenitor eells and so eolIeeted peripheral blood stem eelIs in 50 patients with ehronie granuloeytie leukemia in ehronie phase. 5 Autologous PBSCT was performed at the point of transformation, and ehronie

Transfusion Medicine Reviews, Vol VI, No 3 (July), 1992: pp 183-190

phase was restored in 94% of these patients. Unfortunately, the duration of second ehronie phase was relatively brief. Cell produets were eryopreserved in liquid nitrogen for as long as 58 months. This report established the ability of eryopreserved peripheral blood stem eelIs to reeonstitute human hematopoiesis in seleeted cases. Initial enthusiasm over the applieation of PBSCT to human disease was tempered by two early reports of failure. In the first, reported by Hershko et al, 6 syngeneic PBSCT failed to eorreet marrow aplasia in a ease of paroxysmal noetumal hemoglobinuria. Bone marrow from the same donor resulted in eomplete marrow reeovery. In the seeond report syngeneic peripheral stem eelIs were given to a patient with Ewing's sareoma who received nonlethal total body irradiation and chemotherapy. 7 In comparison with patients given the same therapy without stem cell support, there was some improvement in the rate of leukocyte reeovery, but the rate of granulocyte, monocyte, and platelet reeovery was not appreeiably aeeelerated. Autologous bone marrow support was found to be superior to syngeneic peripheral stem eell support in this study. Faetors eontributing to these early failures likely inelude the limited number of progenitors infused and the prolonged period over whieh the produets were infused. In 1986 several authors reported sueeess with autologaus PBSCT in disorders other than ehronie granuloeytic leukemia. Reiffers et a1 8 eolleeted peripheral blood stem eells after intensifieation ehemotherapy in a patient with aeute nonlymphoeytie leukemia in remission. These eelIs were eryopreserved and reinfused after marrow ablative therapy at the point of relapse. Complete hematopoietie reeonstitution was aehieved. Korbling et al re-

From the University of Nebraska Medical Center, Omaha, NE. Address reprint requests to David Inwards, MD, Division of Hematology, WI5A, Mayo Clinic, Rochester, MN 55905. Copyright © 1992 by W.B. Saunders Company 0887-7963/92/0603-0003$3.00/0

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ported a successful case of PBSCT in a patient with Burkitt's lymphoma in remission. 9 Stem celI colIection was timed to folIow· intensive chemotherapy. Recovery was rapid, with 500 granulocytes and 50,000 platelets per microliter achieved by day 10 after infusion. B-celI counts were noted to be normal by day 35. Bell et al performed PBSCT on three patients with lymphoid malignancies. 10 Stem celI colIections again folIowed chemotherapy. In two cases stable engraftment was observed. In the third case, engraftment was incomplete and temporary. Notably, residual lymphoma was detected in bone marrow specimens at autopsy in the third case, leaving the cause of graft failure open to debate. Kessinger et al ll demonstrated that engraftment could result from the infusion of cryopreserved peripheral stem celIs collected during steady state without augmentation by previous chemotherapy when they performed PBSCT on two patients with bone marrow involved by breast carcinoma. POTENTIAL ADVANTAGES OF PERIPHERAL BWOD STEM CELL TRANSPLANTATlON OVER BONE MARROW TRANSPLANTATlON

Documentation of the feasibility of PBSCT in humans led to speculation over potential advantages that PBSCT may hold over bone marrow transplantation. Unlike bone marrow, peripheral stem celIs may be colIected without generalor even regional anesthesia. This extends the benefits of stem celI rescue to patients who are unable, or unwilling, to undergo anesthesia. PBSCT also alIows patients with inadequate bone marrow due to previous irradiation of harvest sites, hypocelIularity due to other causes, or marrow involvement by disease to be considered for high-dose therapy and stem celI rescue. In some disease states, peripheral blood may serve as a less tumor contaminated source of stem celIs than bone marrow. This has been documented for multiple myeloma,12 non-Hodgkin's lymphoma,13 and breast cancer. 13 Engraftment after PBSCT with celIs colIected during periods of peripheral stem celI enhancement may be more rapid than after bone marrow transplantation. 9 The infusion of a large number of immunocompetent celIs may make immune reconstitution more rapid after PBSCT than after bone

INWARDS AND KESSINGER

marrow transplantation. 14 This could conceivably result in a reduced incidence of relapse after highdose therapy. TECHNICAL ASPECTS OF PERIPHERAL STEM CELL COLLECTION, CRYOPRESERVATION, AND INFUSION

Apheresis may be performed using either peripheral or central venous access. Peripheral access is often inadequate in patients who have received extensive previous chemotherapy. Subclavian apheresis catheters in cancer patients have a high rate of thrombotic complications. 15 Urokinase infusions are often capable of reestablishing access, and prophylactic heparin infusions prevent these complications. Translumbar placement of inferior vena cava apheresis catheters has been established as an altemative form of central venous access with a lower incidence of thrombotic complications than subclavian catheters. 16 Nonthrombotic complications of apheresis for peripheral stem celI colIection are similar to those encountered in other forms of apheresis, and include hemodynamic effects as welI as citrate-induced effects. 15 ,16 Modifications of protocols have alIowed for successful peripheral blood stem celI colIections using either continuous ar intermittent colIection apheresis with a variety of commercially available celI separators. Each apheresis session lasts approximately 3 to 4 hours. The total number of sessions depends on the target celI count and the effect of any augmentation maneuver that may be applied. Several techniques have been applied to purify the resultant celI product. 17 Red celI contamination and high dimethyl sulfoxide content have been implicated in the genesis of renal toxicity. FicolI gradient centrifugation has been reported to eliminate renal toxicity, but may resuIt in delayed engraftment. 17 Elutriation apheresis of the stem celI product results in some improvement in engraftment rate, butthe rate may still be suboptimal. Repeat apheresis can both eliminate clinical renal toxicity and provide for timely engraftment. 17 Cryopreservation of peripheral blood stem celIs has been accomplished by two basic methods. The initial method involves 10% dimethyl sulfoxide as a cryoprotectant, and controlIed rate freezing followed by storage in a liquid nitrogen freezer. This

PERIPHERAL BLOOD STEM CELL TRANSPLANTATlON

allows for viable storage for at least 58 months. 5 More recent1y, Stiff et al demonstrated that stem cells could be cryopreserved in 5% dimethyl sulfoxide and hydroxyethyl starch without controlled rate freezing, and at a storage temperature of - 80° C. 18 This simplified procedure is less expensive and faster than the previous procedure. Successful engraftment after prolonged cryopreservation of human stem cells by the latter technique remains to be demonstrated. Infusion of peripheral blood stem cells routinely follows thawing in a water bath at or near body temperature. Manipulation of the product may include washing, dilution with autologous plasma, or filtering. 17 The entire product is usually given over a few hours, although some have divided the infusion over 2 days. Side effects of infusion have been associated with larger red cell volumes infused and larger total volumes infused. Hypertension, chills, nausea, and fever have been associated with the former , whereas headaches have been associated with the latter. 17 Tachypnea, elevated serum bilirubin, and renal failure have been associated with the combination of increased red cell volume and total volume. MOBILlZATtON OF PERIPHERAL STEM CELLS

A number of interventions that increase the number of circulating committed progenitors have been identified. These interventions may increase the number of circulating primitive progenitors as well, thus providing for more rapid collection of an adequate number of stem cells to allow for durable reconstitution of hematopoiesis after myeIoablative therapy. To et al documented a 25-fold increase in granulocyte-macrophage colony-forming units (CFU-GM) in the peripheral blood of patients recovering from induction chemotherapy for acute nonlymphoblastic leukemia, and demonstrated that large numbers of these CFU-GM could be collected and cryopreserved. 19 Unfortunately, mobilization in this setting is variable both in degree and timing. 20 Cyclophosphamide given primarily for the purpose of augmenting circulating stem cell Concentrations has been shown to be effective in patients with myeloma, lymphoma, and solid tumors. 21 This approach is not without risk, however, and death has been reported as a complica-

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tion. 21 Extensive previous chemotherapy dampens the mobilization response to chemotherapy in myeloma22 as well as in lymphoma. 23 Factors predicting successful mobilization include Iack of bone marrow involvement by disease, a rapid increase in leukocytes after chemotherapy, and significant chemotherapy-induced neutropenia. 21 Variable timing of mobilization and the lack of rapid progenitor assays make optimal timing of apheresis difficult. Cytokines have also been used to mobilize stem cells. GranuIocyte colony stimuIating factor has been shown to transient1y increase circulating progenitor cells of granulocyte-macrophage, erythroid, and megakaryocytic lineages by up to 100fold in cancer patients. 24 Ratios of different types of peripheral progenitors were unchanged by this intervention. Bone marrow progenitors were not increased. Socinski et al demonstrated that granulocyte-macrophage colony stimulating factor (GMCSF) caused an 18-fold increase in peripheral blood CFU-GM in sarcoma patients.25 Erythroid burst forming units (BFU-E) increased eightfold in peripheral blood, whereas no change was observed in bone marrow CFU-GM or BFU-E. Interleukin-3 (IL-3) has been shown to increase circuIating leveIs of CFU-GM, BFU-E, CFU-mix, and CFUmegakaryocyte in rhesus monkeys. 26 Furthermore, the cOn1bination of IL-3 and GM-CSF was shown to be synergistic with an average 63-fold increase in circulating CFU-GM. Haas et al transplanted six patients with GM-CSF mobilized peripheral blood stem cell autografts and achieved sustained engraftment in all but one patient. 27 The single failure occurred in a patient with rapid progression of disease in the bone marrow. Several investigators have combined chemotherapy and cytokines in an effort to mobilize stem cells. Gianni et al gave high-dose cyclophosphamide folIowed by GM-CSF and observed up to a 1,000-fold increase in peripheral blood CFU-GM in patients with non-Hodgkin's lymphoma. 28 Some of the remarkable mobilization observed in this study is likely due to the fact that all but one of these patients was previously untreated. Essentially the same group of investigators later reported on 20 patients with non-Hodgkin's lymphoma or breast cancer who were given high-dose cyclophosphamide with or without GM-CSF. 29 The combination gave rise to greater than JOO-fold in-

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creases in circulating CFU-GM, BFU-E, and CFU-mix. PREDICTION OF THE ADEQUACY OF AUTOLOGOUS PERIPHERAL STEM CELL COLLECTIONS

Considerable controversy exists in the area of predicting the adequacy of autologous peripheral stem cell collections. Durable engraftment likely requires the infusion of an adequate number of pluripotent stem cells. Unfortunately, no assay is available to measure human pluripotent stem cells. Investigators have attempted to correlate engraftment characteristics with the number of CFU-GM, total nucleated cells, or surface marker defined cell subsets collected or infused. Reiffers et al reviewed hematopoietic reconstitution in 46 PBSCT cases and found that the only prognostic factor was the number of CFU-GM infused. 30 Cell collections were performed during the period of reeovery from chemotherapy. Two cases were classified as graft failures. Platelet reeovery was usually the limiting factor in reconstitution, with 17 patients reaehing 50,000/mm3 more than 30 days after infusion. Juttner et al reported eight eases of PBSCT in aeute nonlymphoeytic leukemia, using stem eells eollected during postchemotherapy reeovery, and found that two of three patients infused with less than 29 x 104 CFU-GM/kg experieneed ineomplete engraftment after an initial rapid recovery of peripheral blood eounts. 31 Investigators from two subsequent studies of PBSCT using mobilized stem eells proposed that the minimum number of CFU-GM/kg infused should be 15 x 10432 and 50 x 104 ,33 respeetively. The latter study again reported the oeeurrence of deereasing peripheral blood counts between days 26 and 40 after initial recovery following PBSCT for aeute nonlymphocytic leukemia. For most patients, this deerease was transient; however, for the two patients reeeiving the lowest number of CFU-GM/kg, this led to incomplete engraftment. The authors speculated that this problem may be a reflection of a proliferative defeet in the recovery phase stem eells in aeute nonlymphoeytie leukemia. Centers that use .nonrecruited peripheral blood stem eells have primarily used the number of total mononuclear eells infused as an indicator of graft adequacy. Kessinger et al demonstrated that, in

this setting, the number of CFU-GM infused did not correlate with engraftment. 34 The median number of CFU-GM infused was 8 x 104 /kg. The number of total mononuclear eells infused was not predictive of engraftment either. Williams et al found the same laek of predictive value for both CFU-GM and total mononuclear cells infused. 3S In this series, 4 of 18 patients had thrombocytopenia «50,000 platelets/mm3 ) beyond 80 days postinfusion. Hematopoietic reeonstitution after the infusion of nonrecruited peripheral blood stem eells is delayed in comparison to that observed after the infusion of recruited stem eells, but permanent engraftment has resulted from the infusion of as few as a median of 0.75 x 104 CFU-GM/kg. 36 An ideal test for peripheral stem eell colleetion adequaey would be inexpensive, reprodueible, rapidly available to direet eollection efforts, and have a close eorrelation with engraftment. Progenitor assays are labor intensive and the results are delayed beyond the time when they could be used to prospectively direet eolleetion efforts. Both total mononuclear eell counts and CFU-GM assays have eonsiderable limitations in regard to predictive value for engraftment. The identification of stem cells by immunofluoreseence flow eytometry assay using antibodies to the differentiation antigens CD34 and CD33 has been suggested as an alternative. 37 Initial results suggest that the number of CD34 + /CD33 + cells infused may be the best predictor of early hematopoietie reeovery yet identified. Further studies are indicated to verify and extend these observations. Marked interlaboratory variability makes the eomparison of CFU-GM data from different eenters extremely diffieult. The eomposition of peripheral blood stem eell eolleetions likely varies depending on the underlying disease, previous therapy, and mobilization proeedures used. As a result, two eolleetions with the same number of CFU-GM and/or the same number of total nucleated eells may differ significantly in their ability to reeonstitute hematopoiesis. The nature of the underlying disease and previous therapy mayaiso influence the mieroenvironment of the bone marrow, thus altering the likelihood of engraftment after the infusion of a given autograft. Finally, the rate of engniftment may differ with different eonditioning regimens. 38 Thus, eriteria for an adequate eolleetion may need to be in referenee to a

PERIPHERAL BLOOD STEM CELL TRANSPLANTATlON

particular conditioning regimen. In summary, crifor adequate peripheral stem cell collections must be established at individual centers, and must be continually reviewed as the patient population and treatment protoeols change.

teńa

CLlNICAL APPLlCATION OF PERIPHERAL BLOOD STEM CELL TRANSPLANTATlON TO SPECIFIC DISORDERS

Patients with a variety of both hematologie and nonhematologie malignancies have been treated with PBSCT. The list of applications ineludes transformed chronic granulocytic leukemia, chronic-phase chronic granulocytic leukemia, acute nonlymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, breast cancer, smalI cell earcinoma of the lung, and neuroblastoma. The optimal role of PBSCT in the management of each of these diseases remains to be defined. As previously noted, the initial documentation of the feasibility of PBSCT in humans was achieved in transformed chronic granulocytic leukemia. 5 This approach has not been widely applied because of the limited duration of the resulting responses. Patients with chronic granulocytic leukemia in ehronic phase have also undergone autologous PBSCT, either early in the course of the disease ar after therapy. Cytogenetic remissions have been reported, although investigators have acknowledged that multiple attempts failed to produee complete remissions. 39 ,40 These results are too preliminary to adequately judge the validity of this approaeh. Collection of stem cells mobilized by induction ehemotherapy for aeute nonlymphoeytic leukemia was first reported in 1984. 19 Investigators postulated that peripheral blood stem cell collections in this setting may be less contaminated with leukemie cells than later steady-state remission bone marrow harvests. In a 1986 case report, Reiffers et al demonstrated that stem cells collected in this manner could reconstitute hematopoiesis after high-dose therapy at the time of relapse. 8 Several subsequent reports verified that hematopoietic reconstitution could be achieved in most patients with acute lymphocytic or nonlymphocytic leukemia after PBSCT. 30,32 Reiffers et al reported tumor

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response data on 21 cases of acute nonlymphocytic leukemia (ANLL) transplanted in first remission, 16 cases of acute lymphocytic leukemia (ALL) in first remission, and 18 cases of acute leukemia transplanted in second remission. 41 A variety of conditioning regimens were used. Both adults and children were ineluded. There were six early deaths. Nine of the 21 first remission ANLL patients were in continuous complete remission 3 to 41 months after transplant. Four of the 16 first remission ALL patients were in continuous complete remission 13 to 34 months after transplant. Four of the 18 second remission patients were in continuous complete remission 6 to 33 months after transplant. A single remission inversion was observed. Korbling et al reported their experienee with PBSCT and autologous bone marrow transplantation in acute leukemia and found no statistically significant difference in disease free survival for these two procedures in first remission ANLL. 42 The signifieance of this finding is unelear because of the limitations of the study. PBSCT was reserved for patients who were felt to have low-risk disease. Furthermare, these patients appear to have received less ehemotherapy before transplantation than did the group that underwent bone marrow transplantation. Patients with non-Hodgkin's lymphoma were among the first to be treated with PBSCT. 9 Suecessful transplantation has been aecomplished with both mobilized lO ,27 and steady state eolleetions. 43 Patients who are candidates for high-dose therapy with stem cell rescue but are ineligible for autologous bone marrow transplantation because of marrow involvement by disease, previous pelvic radiation, or hypocellular marrow are often considered candidates for PBSCT. A recent update of aur series at the University of Nebraska Medical Center ineluded 29 patients with relapsed or refractory nontransformed, low-grade non-Hodgkin's lymphoma and 41 patients with refraetory or relapsed intermediate and high-grade non-Hodgkin's lymphoma. All of these patients had a marrow abnormality that precluded autologous bone marrow transplantation. There were three toxic deaths in the group with low-grade disease. The actuarial event-free survival for patients with low-grade disease was 41 % at 41 months. Their actuarial survival at the same interval was 51%. The actuarial event-free survival for patients with intermediate

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or high-grade disease was 28% at 57 months. Their actuarial survival at the same interval was 39%. These data suggest that PBSCT has the potential to cure patients with relapsed or refractory intermediate and high-grade non-Hodgkin's lymphoma. The indolent nature of low-grade lymphoma and short observation period make speculation on this possibility in low-grade non-Hodgkin's lymphoma premature. Indications for PBSCT in Hodgkin's disease are the same as those in non-Hodgkin's lymphoma. Again, both mobilized and steady-state collections have been successfully used. Korbling et al reported the results of PBSCT in 12 patients with advanced Hodgkin's disease who had received previous radiation to pe1vic sites, but had no evidence of disease invo1ving bone marrow. 44 Mobi1ization was attempted by use of chemotherapy in 8 patients and GM-CSF in 4 patients. One patient died on day 48 before full hematopoietic reconstitution. Seven patients remained in unmaintained complete remission at a median of 318 days after infusion. The largest series of PBSCT in patients with Hodgkin's disease to date is from the University of Nebraska Medical Center.45 Atotal of 56 patients with marrow abnormalities precluding autologous bone marrow transplantation underwent steadystate stem cell collection followed by PBSCT. Bone marrow invo1vement at the time of harvesting was present in 26 patients. The actuarial eventfree survival at 3 years was 37% overall. Patients with bone marrow invo1vement had a 27% actuarial event-free survival, whereas those with uninvolved marrow had a 47% actuarial event-free survival. The favorable outcome in the latter group in comparison with historical autologous bone marrow transplant controls led the investigators to speculate that PBSCT may have a therapeutic role beyond the restoration of hematopoiesis. A recent review by Barlogie and Gahrton summarized the results of the largest studies of PBSCT in multiple myeloma. 22 The majority of these patients received chemotherapy to mobilize stem cells. Some received both bone marrow and peripheral stem cells. The disease status at the time of transplantation as well as the conditioning regimens used varied considerably. Three of the 69 patients experienced early death due to lack of engraftment. Complete responses were observed in less than 30% of cases, whereas approximately

INWARDS AND KESSINGER

50% experienced partial responses. After a median follow-up of 12 to 18 months after PBSCT, 45 of 58 patients remained in complete or partial remission. Ventura et al reported the results of PBSCT in 11 patients with advanced refractory multiple myeloma conditioned with cyclophosphamide, carmustine (BCNU), and etoposide (VP-I6).46 Four partial remissions lasting a median of 7 months were observed. There were no complete remissions. A small number of patients with a variety of solid tumors including breast cancer, 11 small cell carcinoma of the lung,47 and neuroblastoma48 have undergone PBSCT. Modifications of collection procedures have allowed for successful PBSCT in neuroblastoma patients as young as 2V2 years old. 48 PROSPECTS FOR THE FUTURE OF PERIPHERAL BLOOD STEM CELL TRANSPLANTATlON

Mobilization of peripheral stem cells shortens the period of aplasia after PBSCT and would be expected to reduce the morbidity and mortality associated with this procedure. By reducing the number of collections required, and shortening the period of hospitalization, mobilization may also decrease the cost of PBSCT. Further development of mobilization techniques and the addition of growth factors during the postinfusion period may further reduce the toxicity and cost of PBSCT. If the potential advantages of more rapid immune reconstitution and decreased tumor contamination of autografts in PBSCT in comparison with autologous bone marrow transplantation prove to be of clinical significance, peripheral blood may become the preferred source of autologous stem cells for those diseases commonly treated with high-dose therapy and stem cell rescue. This would be even more likely if improved mobilization techniques made PBSCT less toxic and/or less expensive than bone marrow transplantation. Improved conditioning regimens capable of enhanced cytoreduction would increase the appeal of PBSCT in multiple myeloma and solid tumors. Allogeneic PBSCT has several potential advantages over allogeneic bone marrow transplantation. It may be easier to collect stem cells for unrelated transplant, because no general anesthesia is required for peripheral blood stem cell collection. In

PERIPHERAL SLOOD STEM CELL TRANSPLANTATlON

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animal models, density gradient purification techniques have alIowed for the selection of peripheral stem celI alIografts that produce sustained engraftment without graft-versus-host disease. 49 Similar results in humans would be of major consequence. Experience with human alIogeneic PBSCT is extremely limited, though successful engraftment has

been reported in a patient who received T-celldepleted peripheral blood stem cells. 50 This patient died from aspergillus sepsis on day 32, making it impossible to assess whether engraftment was durabIe. Documentation of durable engraftment after human allogeneic PBSCT must precede any widespread application of this procedure.

REFERENCES 1. Goodman JW, Hodgson GS: Evidence for stem cells in the peńpheral blood of mice. Blood 19:702-714, 1962 2. Nothdurft W, Bruch C, Fliedner TM, et al: Studies on the regeneration of the CFU-C population in blood and bone marrow of lethally irradiated dogs after aUlologous transfusion of cryopreserved mononuclear blood cells. Scand J Haematol 19:470-481, 1977 3. Storb R, Graham TC, Epstein RB, et al: Demonstration of hemopoietic stem cells in the peńpheral blood of baboons by cross circulation. Blood 50:537-542, 1977 4. Barr RD, Whang-Peng J, Perry S: Hemopoietic stem cells in human peńpheral blood. Science 190:284-285, 1975 5. McCarthy DM, Goldman JM: Transfusion of circulating stem cells. CRC Cńt Rev Clin Lab Sci 20:1-24, 1984 6. Hershko C, Gale RP, Ho WG, et al: Cure of aplastic anaemia in paroxysmal nocturnal haemoglobinuńa by marrow transfusion from identical twin: Failure of peripheral-Ieucocyte transfusion to correct marrow aplasia. Lancet 1:945-947, 1979 7. Abrams RA, Glaubiger D, Appelbaum FR, et al: Result of attempted hematopoietic reconstitution using isologous, peńpheral blood mononuclear cells: A case report. Blood 56:516520, 1980 8. Reiffers J, Bernard P, David B, et al: Successful autologous transplantation with peńpheral blood hemopoietic cells in a patient with acute leukemia. Exp Hematol 14:312-315, 1986 9. Korbling M, Dorken B, Ho AD, et al: Autologous transplantation of blood-deńved hemopoietic stem cells after myeloablative therapy in a patient with Burkitt's Iymphoma. Blood 67:529-532, 1986 10. Bell AJ, Figes A, Oscier DG, et al: Peńpheral blood stem celi autografts in the treatrnent of Iymphoid malignancies: Initial expeńence in three patients. Br J Haematol 66:63-68, 1987 II. Kessinger A, Arrnitage Ja, Landmark JD, et al: Reconstitution of human hematopoietic function with autologous cryopreserved circulating stem cells. Exp HematoI14:192-196, 1986 12. Greipp PR, Ahmann G, Katzmann JA, et al: Peripheral blood as a source of stem cells in myeloma. B100d 72:243A, 1988 (suppl) (abstr) 13. Sharp JG, Kessinger MA, Pirruccello SJ, et al: Frequency of detection of suspected Iymphoma cells in peńpheral blood stem celi collections, in Dicke KA, Armitage Ja, DickeEvinger MJ (eds): Auto1ogous Bone Marrow Transplantation, Proceedings of the Fifth International Symposium. Omaha, NE, The University of Nebraska Medical Center, 1991

14. Kiese1 S, Pezzutto A, Korb1ing M, et al: Autologous periphera1 b100d stem celi transplantation: Analysis of autografted cells and Iymphocyte recovery. Transplant Proc 21:3084-3088, 1989 15. Haire WD, Edney JA, Landmark m, et al: Thrombotic complications of subclavian apheresis catheters in cancer patients: Prevention with heparin infusion. J Clin Apheresis 5:188-191, 1990 16. Haire WD, Lieberrnan RP, Lund GB, et al: Translumbar infeńor vena cava catheters: Safety and efficacy in peńpheral blood stem celi transplantation. Transfusion 30:511-515, 1990 17. Kessinger A, Schmit-Pokorny K, Smith D, et al: Cryopreservation and infusion of auto1ogous peńpheral blood stem cells. Bone Marrow Transplant 5:25-27, 1990 (suppll) 18. Stiff PJ, Koester AR, Weidner MK, et al: Autologous bone marrow transplantation using unfractionated cells cryopreserved in dimethylsulfoxide and hydroxyethyl starch without controlled rate freezing. Blood 70:974-978, 1987 19. To LB, Haylock ON, Kimber RJ, et al: High 1evels of circulating haemopoietic stem cells in very early remission from acute non-Iymphob1astic leukaemia and their collection and cryopreservation. Br J Haematol 58:399-410, 1984 20. Cantin G, Marchand-Laroche D, Monique-Maude B, et al: Blood-deńved stem cell collection in acute nonlymphob1astic leukemia: Predictive factors for a good yield. Exp Hematol 17:991-996, 1989 21. To LB, Shepperd KM, Hay10ck ON, et al: Single high doses of cyclophosphamide enab1e the collection of high numbers of hemopoietic stem cells from the peńpheral blood. Exp HematoI18:442-447, 1990 22. Bar10gie B, Gahrton G: Bone marrow transp1antation in multip1e mye10ma. Bone Marrow Transplant 7:71-79, 1991 23. Korbling M, Martin H: Transp1antation of hemapheresis-derived hemopoietic stem cells: Anew concept in the treatment of patients with malignant Iymphohemopoietic disorders. Plasma Ther Transfus Technol 9:119-132, 1988 24. Duhrsen U, Villeval JL, Boyd J, et al: Effects of recombinant human granulocyte co1ony-stimulating factor on hematopoietic progenitor cells in cancer patients. Blood 72:20742081, 1988 25. Socinski MA, Cannistra SA, E1ias A, et al: Granu10cytemacrophage colony stimulating factor expands the circulating haemopoietic progenitor cell compartment in man. Lancet 1:1194-1198, 1988 26. Geissler K, Valent P, Mayer P, et al: Recombinant human interleukin-3 expands the pool of circulating hematopoietic progenitor cells in pńmates-Synergism with recombinant hu-

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