Henry Ford Hospital Medical Journal

Volume 39 Number 2 Article 10

6-1991

Peripheral Stem Cell Transplantation as an Alternative to Bone Marrow Transplantation: An Overview

Nalini Janakiraman

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Recommended Citation Janakiraman, Nalini (1991) "Peripheral Blood Stem Cell Transplantation as an Alternative to Bone Marrow Transplantation: An Overview," Henry Ford Hospital Medical Journal : Vol. 39 : No. 2 , 103-107. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol39/iss2/10

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. Peripheral Blood Stem Cell Transplantation as an Alternative to Bone Marrow Transplantation: An Overview

Nalini Janakiraman, MD'

Slem cells capable of resloring hemalopoiesis following lethal bone marrow injury circulate in Ihc blood of many animals, including humans. When collected ihrough leukapheresis and reinfused following high-dose chenwiherapy, slem cells offer a Irealmenl optiim not currently open lo some patients who are unable lo undergo autologous hone marrow transplantation because of tumor involvement in the pelvis, prior pelvic radiation, or intolerance to general anesthesia. After stem cell infusion, hematologic and immunologic recovery are rapid in comparison lo that after autologous hone marrow reinfusion: however, in some cases engraftment is slower. There is some evidence lhal tumor conlaminalion in the peripheral hlood is much less than in the marrow. In any event, most relapses if malignant disease occur at the site of origin and represent Ireatmeni failure ralher lhan growlh if reinfused malignant cells. Prospective controlled trials are needed to evaluate stem celt in comparistm to autologous hone marrow iransplanlalion. (Henry Ford Hosp Med J 1991:39:103-7)

ematopoietic stem cells capable of restoring hemalopoi­ mia, cells obtained by leukapheresis during the chronic phase H esis when infused following lethal bone marrow injury are have been used for successful engraftment during blast crisis known to circulate in the blood of many animals, including non- treated by myeloablative chemotherapy (7). A prospective study human primates (1,2). Many bone marrow transplant centers of the treatment of aplastic anemia by allogeneic bone marrow now use stem cells obtained from peripheral blood by leukaphe­ transplantation with and without donor buffy coat cells showed resis as an altemative to bone marrow transplantation in some that the addition of buffy coat cells reduced the rejection rate (8). situations (3-5). A high rate of sustained graft and of acute and chronic graft ver­ sus host disease confirmed engraftment of peripheral blood stem cells. Blood-derived granulopoietic proliferation can be Hematopoiesis and Peripheral Blood Stem Cells sustained in long-term cultures (up to eight weeks) with genera­ The hierarchy of the hematopoietic system is depicted in the tion of CFU-GM cells similar to that of bone marrow cells, de­ Figure. The pluripotent stem cells are capable not only of differ­ spite some qualitative differences (9). Finally, an increasing entiation along different lines but also of self-renewal. These numberof patients are now being treated with high-dose chemo­ cells are essential for successful engraftment following high- therapy and autologous peripheral blood stem cell reinfusion. dose chemotherapy. There is currently no assay to measure these cells, and we do not understand fully their phenotypic characteristics. Cultures now performed in the laboratory, e.g., Long-term Engraftment with colony-forming unit- erythroid mega­ Peripheral Blood Stem Cells karyocyte (CFU-GEMM), colony-forming unit-granulocyte In the absence of some form of cell tagging, it is difficult to macrophage (CFU-GM). and burst-forming unit-erythrocyte, prove that the hematopoietic recovery is from infused bone mar­ measure more committed cells. CD-34 antigen, an antigen ex­ row or peripheral blood stem cells and is not spontaneous. Be­ pressed on the surface of stem cells, is used as a marker, but it cause the myeloablative regimen is the same as that used prior may be a marker for a cell which is derived by several multipli­ to allogeneic transplantation, recovery almost certainly results cations beyond the stem cell, closer to the more committed cells. from the engraftment of infused cells. Several reports of follow- Studies in mice, dogs, and baboons have shown that hema­ topoietic cells capable of engraftment circulate in peripheral blood. Multiple canine studies (6) have demonstrated the feasi­ bility of obtaining such cells by and utilizing them to .Submilled for puhlicalion: Augusi 16. 1990. reconstitute hematopoiesis after lethal radiation. Ample evi­ Accepled for publication: ,Seplember 13, 1990, dence shows that stem cells can also be obtained from the pe­ *Division of /Oncology, Henry Ford Hospilal. Address correspondence lo Dr. Janakiraman, Division of Hemalology/Oncology, Henry ripheral blood of human beings. In chronic granulocytic leuke­ Ford Hospital, 2799 W Grand Blvd, Detroit, Ml 48202,

Henry Ford Hosp Med J—Vol 39, No 2, 1991 PBSC Transplantation—Janakiraman 103 reinfusion of malignant cells. If more effective therapy could eliminate residual disease, autologous bone marrow could be

pluripotent stem compared to the use of peripheral blood stem cells more accu­ rately. More rapid hematologic recovery may follow peripheral blood transplantation compared to bone marrow transplantation

•nixed myeloid progenitor lymphoid progenitor (II). Becau.se hematologic recovery is earlier by several days, _|| the risk of infection, the mortality, and the length of hospital stay are reduced. Earlier recovery is attributed to the reinfusion of burst-rorming unll (eryttirold) more committed cells than are provided by the bone marrow. Immunologic reconstitution is also more rapid with peripheral blood stem cell transplantation compared to autologous bone marrow transplantation (11,12). erytfirold megakaryocyte granulocyte/ eosinophil progenitor progenitor progenitor progenitor

Peripheral Blood Stem Cell Collection ©C^ Stem cells are collected by repeated leukapheresis either at red cells neutrophils basophils eosinophils random for several consecutive days (steady state collection) or during recovery from chemotherapy-induced myelosuppression (recovery phase collection). A single leukapheresis in a healthy Figure—Hematopoietic stem and progenitor cells. individual will yield 0.3 x 10'* CFU-GM/kg. About 20 to 30 steady state collections are needed to obtain the number of CFU- GM obtained from bone marrow harvest. This time-consuming procedure may be the only option for some patients who have up for as long as two years confirm long-term engraftment with been extensively pretreated. Kessinger et al (13) required a me­ peripheral blood stem cell transplantation. dian of 8 (range 6 to 17) steady state leukaphercses to collect 0.6 Several studies of peripheral blood stem cell transfusion have X 104 (0 to 98.6) CFU-GM/kg. The granulocyte and platelet en­ suggested a delay of platelet engraftment when compared to graftment durations were similar to autologous bone marrow bone marrow tran.splantation. There may be fewer megakaryo­ transplant (25 days). cyte progenitors in the peripheral blood, and megakaryocyte Richman et al (14) reported in 1976 that during recovery from progenitors are particularly susceptible to the process of leu­ chemotherapy-induced the circulating granulocytic kapheresis, freezing, and thawing. Cultured CFU-GEMM ob­ stem cells (colony-forming unit-culture) increased from 6 to 23 tained from peripheral blood stem cells and stained with mono­ per 2 X 10-'' mononuclear cells plated. Cyclical changes in the clonal antibodies to platelet glycoprotein 111 confirmed fewer concentration of stem cells with a maximum value of 20 times megakaryocyte precursors in the peripheral blood compared to the baseline were demonstrated. They estimated that enough bone marrow (14% versus 87%) (10). This reduction may result stem cells for transplant could be obtained from the peripheral from culture conditions and be overcome by high cell numbers. blood by appropriately timed 17 liter leukapheresis. This information stimulated the increasing use of peripheral blood stem cell transplantation. The number of stem cells col­ Advantages of Peripheral Blood Stem Cells lected following induction and consolidation therapy for acute In patients who have had radiation therapy to the pelvis or myelogenous (AML) in very eariy remission was ade­ who have tumor involvement of the pelvic bone, the bone mar­ quate for transplantation after myeloablative chemotherapy row harvest site, collection of peripheral blood stem cells by (15). Moderately intensive chemotherapy was used to facilitate leukapheresis offers a means to obtain stem cells. This is also stem cell collection in other disease states, i.e., cyclophospha­ true for patients with contraindications to general anesthesia. mide 1.5 or 4 g/M-, doxorubicin 90 mg/M-, and vincristine 1.4 Any other advantages to peripheral blood stem cells are not well mg/M- administered to patients with multiple myeloma (2). The established. It is believed, but not yet proved, that there are median number of leukaphercses needed for recovery phase col­ fewer malignant cells in the peripheral blood than in the bone lection was 4 (range 2 to 6). Use of recovery phase collections marrow. This is difficult to establish because of many complex resulted in more rapid engraftment of . variables such as the different biology of tumors, varied micro- Recently the hematopoietic growth factors have been used to environment between the bone marrow and peripheral blood, increase the number of CFU-GM obtained from peripheral and the unreliability of methods for comparing the bone marrow blood (16,17), but confirmatory long-term follow-up is needed. and peripheral blood. With both autologous bone marrow and After counting the total number of nucleated cells, the cells peripheral blood stem cell transplantation, failure to eradicate are cultured on soft agar to determine the number of CFU-GM. the disease is a much greater problem than the reinfusion of ma­ This measure of the stem cell load generally correlates with time lignant cells. Most relapses occur at sites of original disease and to engraftment. However, the CFU-GM assay requires 14 days. are not disseminated disease which would be consistent wilh Some patients may be apheresed unnecessarily if the CFU-GM

104 Henry Ford Hosp Med J—Vol 39, No 2, 1991 PBSC Transplanlalion—Janakiraman assay subsequently discloses no increase in peripheral blood Risks of peripheral blood stem cell transplantation are pri­ stem cells, A more rapid assay is needed to facilitate decisions marily related to the total volume reinfused and red cell contam­ regarding the timing and number of leukaphereses. The number ination. They include hemoglobinuria (92%), hematuria (80%), of CD-34-positive mononuclear cells in the collection seems to elevated serum bilirubin (43%), elevated semm creatinine (15%), correlate with peripheral blood CFU-GM, and the test is utilized and increase in pulse rate (61%). They are generally mild and re­ in some centers (I). versible (21). The volume reinfused is greater in steady state collections and the red cell contamination is least with density gradient separations. More efficient means of collection and Procedure cryopreservation are needed. Different machines (Hemonetics V50, Fenwall CS3000) are used for leukapheresis (18,19). A protocol aimed at collecting lymphocytes is generally used and a large venous access is re­ Hematopoietic Recovery After quired. In steady state collections, the patients undergo leu­ Peripheral Blood Stem Cell Autograft kapheresis on consecutive days, usually five times a week, unfil The Table contains hematopoietic recovery data on periph­ enough stem cells are obtained (18,20). eral blood stem cell transplantations done for different disease In recovery phase collections, different parameters are used to states in different centers (2,13,22-24). As use ofthe procedure time the leukapheresis. Total monocyte count of l,000/|iL or is very recent, most of these data were published after 1986. 30% of WBC is generally a good indicator of the beginning of Only one major center employs steady state leukapheresis, and the peak of circulating stem cells. Minimal or no bone marrow its engraftment is similar to that of autologous bone marrow involvement and a rise in WBC from 1,000 to 3,000/pL in less transplantation. All others utilize recovery phase collections, re­ than five days are independent variables predictive of high quiring fewer than 5 leukaphereses. The CFU-GM collected is CFU-GM collections. The extent of prior chemotherapy does 10 to 100 times greater than in steady state collections. Rapid not always infiuence the wealth of the collections (15). granulocyte engraftment occurred with all recovery phase col­ Interlaboratory variations in the CFU-GM assay may explain lections. Platelet engraftment is generally acceptable, although the lack of consensus as to the minimum CFU-GM cell dose delay or failure to engraft platelets has been reported (24), un­ needed for hematopoietic reconstitution. Usually a CFU-GM like experience with autologous bone marrow transplantation. dose of more than 30 x lO^'/kg is always associated with engraft­ Juttner et al (22) reported a reduction in platelet counts occur­ ment. In contrast. 1 to 2 x lO^g of CFU-GM cells are needed ring after three to six weeks followed by gradual recovery. Ex­ for autologous bone marrow engraftment. The need for this high planation ofthis observation is not clear, but this secondary fall CFU-GM dose is not known; apparently the peripheral blood in platelet count did not occur after non-AML transplantations. contains fewer stem cells relative to the committed (CFU-GM) Perhaps there is endogenous platelet recovery after six weeks, or cells. Moreover, the accessory (bone marrow) cells needed for cryopreservation may selectively destroy more committed cells, engraftment may be lacking in peripheral blood. causing the transient thrombocytopenia. The product is processed either by elutriation (a type of physi­ Successful engraftment correlates with the cell dose reinfused cal separation), repeat apheresis, or density gradient separation (25). Successful hematopoietic reconstitution was observed in to eliminate red cells and mature white cells. The subsequent all five patients infused with > 30 x 10* CFU-GM/kg but in only freezing procedure is generally similar to bone marrow freezing. two of nine cases infused with fewer cells. On the other hand.

Table Hematopoietic Recovery After Peripheral Blood Stem Cell Autograft

Authors Number of Disease Steady State Leukophereses MNC/kg CFU-GM/kg Platelet (Reference) Patients States Recovery Phase (Range) (Range) (Range) ANC 500 > 20,000 Other

Kessinger 40 Lymphoma Steady state 8 7,03 X 10« 0,6X IO'' 25 days 25 7 patients died prior et al(13) (4,51-I6„36) (0-98,6) (11-112) (7-1,59) to recovery of HS Juttner 12 AML Induction 4 5,3x IQi" 88 x 1 ()-• 11 13 et al (22) (2-6) (35-149) (9-13) (9-77) 3 NHL 5 3,2 x 10"' .34 X 10^ 12 13 (3-5) (48-81) (10-14) (11-14) Reiffers 13 Myeloma Recovery NA 2,9 X Iff* 16 (11-150) cy-7G/M- et al (23) (ffl-18,9) (13-93) 25 days 5 received BM also (50,000) Fermand 8 Myeloma Recovery 3-4 2,6 x I0« 5,5 X 10' 16 34 et al (2) (11-4,2) (2,2-13) (110-25) (10-90) Stiff 7 SCLC Recovery 4-5 3,8±2x I0« 11.4 ±9,9 X lO' 13.14.14 15.44,48+ Significant delay et al (24) 4-BCNU 30'vf Monocytes in platelet LIES 3-BCEP

MNC = mononuclear cells, ANC = absolute neulrophil count. HS = hematopoiesis. AML = acule myeloid leukemia. NHL = non-Hodgkiii"s lymphoma. NA = not available, BM = bone marrow, SCLC = small cell lung cancer, HES - hydroxyethyl starch. HD - Hodgkin's disease.

Henry Ford Hosp Med J—Vol 39. No 2, 1991 PBSC Transplanlalion—Janakiraman 105 bone marrow autografts are successful with 1 to 2 x lO'* CFU- All experienced rapid neutrophil recovery and 18 ofthe 22 had GM/kg. This may be evidence of the poor engrafting efficiency prompt platelet recovery. One patient required reinfusion of of peripheral blood stem cells but could result from a function of bone marrow at six months because of continued platelet defi­ monocytes in the CFU-GM plates or the paucity of stromal cells ciency. The results from this study are comparable to the same in the peripheral blood to facilitate engraftment. authors' results with autologous bone marrow transplantation. Peripheral blood stem cell transplantation in acute leukemia appears to be at least as effective as autologous bone marrow Failure to Engraft transplantation. The stem cells can be collected easily during re­ Failure to engraft following autologous peripheral blood stem covery phase from induction and consolidation. More definitive cell transplantation has been reported only twice (26,27). How­ results await studies on more patients and longer follow-up. ever, by today's standards, too few CFU-GM were reinfused in both cases (3.4 x I0-* and 6.7 x 10^ CFU-GM/kg). Other Malignancies This source of stem cells could reasonably be used for all Results of Peripheral Blood Stem Cell other bone marrow tran.splantation indications. Transplantations in Acute Multiple myeloma is a chemotherapy-responsive B-cell neo­ Three major studies, all from outside the United States, have plasm but is incurable with currently available regimens. Sev­ reported on peripheral blood stem cell transplantations. Reiffers eral attempts at allogeneic and autologous bone marrow trans­ et al (28) from France initially treated nine patients who were in plantation appear promising. Because of the older age of the their ieco/?^/complete remission (CR). Two ofthese patients are patients, autologous bone marrow transplantation is preferred. alive and in continuous complete remission (CCR) with follow- However, multiple myeloma is a malignancy of the bone mar­ up longer than three years. Encouraged, the authors reported the row, and possible therapy with high-dose chemotherapy fol­ treatment of 26 AML patients in first remission. Two died eariy, lowed by autologous peripheral stem cell transplantation is ap­ 13 had leukemic relapse (12 of whom died within a year after pe­ pealing. Active research is in progress (2). ripheral blood stem cell transplantation), and 11 patients are in Other chemotherapy-responsive solid tumors such as breast CCR with a median follow-up of two years. Estimated three- cancer could also be treated with escalated doses of chemother­ year disease-free survival is 33%. apy and autologous stem cell rescue. Frequent involvement of Korbling et al (29) from Germany published the first single bone marrow by such malignancies suggests that peripheral institution comparison of peripheral blood stem cell transplan­ blood may be a safer altemative as the source of stem cells. tation versus autologous bone marrow transplantation. Twenty patients were treated with peripheral blood stem cells collected either during recovery phase or using CSF-GM. Twenty-three Summary patients received autologous bone marrow purged with me- Adequate pluripotent stem cells capable of sustained hemato­ fosfamide. The groups were comparable in age, sex, histologic poietic engraftment can certainly be obtained from peripheral subtype (French-American-British classification), WBC count, blood by repeated leukapheresis. In situafions such as bone mar­ and duration of prior CR. Treatment in both groups consisted of row contamination by malignant cells, radiation to the harvest cyclophosphamide and total body irradiation. The peripheral site, or serious donor risk, peripheral blood may be the only blood stem cell transplant group had earlier WBC recovery and source of stem cells. Despite the discussed advantages, periph­ a shorter hospital stay. There was no difference between the two eral blood will not likely replace bone marrow as the major groups in platelet recovery or disease-free survival. One death source of stem cells. occurred in the autologous bone marrow transplant group and there were no deaths in the peripheral blood stem cell transplant group. Median follow-up was 29 months (peripheral blood stem Acknowledgment cell) and 55 months (autologous bone marrow transplantation). 1 thank Cindy Bonwell for her critical review ofthis article. Juttner et al (1) from Australia published their results of pe­ ripheral blood stem cell transplantation in AML. Collections were performed during very early remission following induc­ tion and consolidation. Ofthe nine patients treated in second re­ References mission, all achieved a CR but all relapsed 2 to 14 months later. 1, Juttner CA. To LB. Haylock DN. et al. Approaches to blood stem cell mo­ bilisation: Initial Australian clinical results. Bone Marrow Transplant 1990: Hematopoiesis was maintained in all. Twenty-two patients with 5(suppl I ):22-4, AML were treated in first remission at a median of 80 days after 2, Fermand JP. Levy Y. Gerota J. et al. Treatment of aggressive multiple my­ CR. Busulfan and cyclophosphamide were administered for eloma by high-do,se chemotherapy and total body irradiation followed by blood myeloablation. Two patients died in remission, one of conges­ stem cells autologous graft. 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