Stem Cell Transplantation

Keren Osman Raymond L. Comenzo

Memorial Sloan-Kettering Cancer Center

I. II. III. IV. V.

Overview Allogeneic Stem Cell Transplantation Autologous Stem Cell Transplantation Toxicities Conclusions

GLOSSARY
allogeneic stem cell transplantation A method for delivering high-dose chemothreapy followed by bone marrow or stem cells from a donor. These stem cells are expected to reconstitute the marrow as well as aid in preventing relapse of the disease. autologous stem cell transplantation (SCT) A supportive measure that allows delivery of high-dose chemotherapy. Autologous stem cell transplant involves collection of the patients own stem cells for later use after high-dose chemotherapy in order to decrease the time of potentially life-threatening cytopenias. donor lymphocyte infusions In patients with chronic myeloid leukemia or multiple myeloma who relapse after allogeneic SCT, infusions of lymphocytes from their SCT donors can result in durable remissions.

graft-versus-disease effect A potentially benecial effect of transplant in which donor lymphocytes recognize the disease of the recipient as foreign and aid in the reduction of tumor burden as well as prolongation of remissions. graft-versus-host disease A potentially fatal complication of allogeneic transplantation in which immune cells of the donor graft mount an immune response against tissues of the recipient. hematopoetic stem cells (HSC) Pluripotent progenitor cells capable of both self-renewal and differentiation, and usually CD34 . HSC may be found in the bone marrow, peripheral blood and umbilical cord blood. stem cell mobilization The process of increasing the availability or peripheralization of CD34 cells in the blood, allowing repeated leukapheresis procedures to be performed, if needed, for the collection of CD34 stem cells.

I. OVERVIEW A. Hematopoietic Stem Cells (HSC)

HSC are CD34 pluripotent cells found in the blood and bone marrow that have the capacity to self-renew

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as well as differentiate. The outcomes of stem cell cycling and division are regulated by adhesion molecules and cytokines in poorly understood ways. With hematopoietic stem cell support in either allogeneic or autologous stem cell transplantation (SCT), high doses of chemotherapy and radiation can be administered to patients meeting standard criteria for SCT without incurring prolonged life-threatening periods of pancytopenia. Standard criteria for allogeneic or autologous transplantation usually include an age threshold (less than 55 for allogeneic and 70 for autologous), adequate cardiac, pulmonary, hepatic, and renal function, no signicant comorbid disease, and the capacity to understand and consent to the treatment. Allogeneic stem cell transplantation is useful in the treatment of chronic myeloid leukemia (CML), acute myeloid and lymphoid leukemia (AML, ALL), aplastic anemia (AA), myelodysplasia, multiple myeloma (MM), severe combined immunodecency disorder (SCID), and congenital anemias. Allogeneic grafts contain T lymphocytes that may respond to recipient or host antigens. The success of allogeneic transplant is therefore limited by potentially lethal graft-versus-host disease (GVHD). However, the al-

loreactive potential of the graft may facilitate a graftversus-disease effect. This effect has been developed further in the form of donor lymphocyte infusions (DLI) given months posttransplant in order to treat relapse in CML and MM. Autologous stem cell transplantation has been successful in non-Hodgkins lymphoma and Hodgkins disease (NHL, HD), multiple myeloma, primary systemic amyloidosis (AL), and some solid tumors.

B. Stem Cell Components

Cytotherapeutic components used in SCT include bone marrow, blood mononuclear cells collected after mobilization (peripheral blood stem cells, PBSC), and umbilical cord blood stem cells (Table I). Until the early 1990s, the most commonly used component was bone marrow. After harvesting bone marrow from the donor, the marrow was either immediately infused (allogeneic) or cryopreserved for later use (autologous). Over the past decade it has become routine to use stem cells mobilized and collected from the peripheral blood for autologous transplantation. Moreover, it is likely that mobilized peripheral blood stem

TABLE I Donors, Sources, and Characteristics of Hematopoietic Stem Cell Components

Donors Normal individuals Sources Bone marrow Characteristics Requires general anesthesia and transfusion-transmissible disease testing (TTDT) and is usually used fresh. Component collected in a single procedure. Dosing based on total nucleated cells/kg. Contains potentially alloreactive T cells. Neutrophil recovery in 2 to 3 weeks Requires cytokine stimulation usually with G-CSF, leukapheresis with the possible need for a central venous catheter, TTDT, is usually used fresh and may be used after cryopreservation. Component may be collected in multiple procedures. Dosing is based on CD34 cell counts/kg recipient weight, and usual target is 5 106 CD34 cells/kg. Contains large numbers of T cells possibly made less alloreactive by indirect G-CSF effect. Neutrophil recovery in 10 to 12 days Collected at delivery and requires predelivery planning and consent, TTDT, may be contaminated with maternal lymphocytes, and useful primarily in small recipients because of low cell numbers per component. Dosing guidelines therefore are less well dened. Neutrophil recovery in 3 to 6 weeks. Long-term cryopreservation needed Requires general anesthesia. Component collected in a single procedure. Dosing based on total nucleated cells/kg. May contain tumor cell contamination. Neutrophil recovery in 2 to 4 weeks. Cryopreservation usually needed Requires mobilization that usually can piggyback onto salvage chemotherapy, and leukapheresis with central venous catheter placement. Component may be collected in multiple procedures. Dosing is based on CD34 cell counts with a minimum dose of 2 to 2.5 106 CD34 cells/kg needed to assure trilineage recovery. Extent of prior therapy may impair mobilization capacity. Cryopreservation needed

Peripheral blood

Umbilical cord blood

Patients

Bone marrow

Peripheral blood

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cells will also replace bone marrow for allogeneic transplantation. Autologous stem cell mobilization and collection are often associated with the recovery phase following myelosuppressive salvage therapy. After chemotherapy, patients receive hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) or GM-CSF to enhance rebound hematopoiesis. Stem cell mobilization can also be performed with growth factors alone in either cancer patients or, on an investigational basis, in prescreened healthy donors for allogeneic transplant. Another source of stem cells is umbilical cord blood. To date there have been over 600 transplants performed using umbilical cord blood and the preliminary reports are encouraging. However, technical and ethical aspects of umbilical cord blood collection, storage, and use are not yet comprehensively delineated. Limitations of autologous SCT include the potential for relapse secondary to contamination of stem cell components by clonal tumor cells and the lack of an alloreactive graft-versus-disease effect. Although purging or the selection of CD34 HSC may reduce tumor cells in autologous grafts, a clear-cut benet for such manipulations has not been dened prospectively in randomized trials (Fig. 1). In addition, another area of active investigation remains the manipulation of the immune system after autologous SCT by means of immune modulators such as interleukin2 or with cancer vaccines.

60 and 20%, respectively. Thus allogeneic SCT is currently recommended for patients under 55 in chronic phase with an HLA identical donor. In the case of patients in the accelerated phase or blast phase, age plays a larger role. The survival of patients transplanted in the accelerated phase is worse than that of chronic phase patients. Patients in blast phase have very poor post transplant survival and a high probability of relapse. In patients who relapse after allogeneic SCT for CML, lymphocyte infusions from their SCT donor (DLI) can be effective treatment.

B. Acute Myeloid and Lymphoid Leukemia

Unlike CML where SCT works during the chronic phase, the role of transplantation in AML remains controversial. Sixty-ve to 80% of patients with AML achieve complete remission (CR) with anthracyclinebased induction regimens. However, just under half of these patients will remain in durable remissions with standard consolidation therapy. Following SCT in rst CR the disease-free survival is 46 to 62%. In one study of 95 patients who received allogeneic SCT in rst CR, the 5-year disease-free survival was 52% and the relapse rate was 18%. The advantage of SCT in rst CR was that these patients had only limited exposure to chemotherapy before transplant. Therefore, they tolerated the preparatory regimen better and had fewer infectious complications than more heavily pretreated patients. The issue of timing continues to be debated. In current practice the most signicant prognostic factor is cytogenetics. t(8:21), t(15:17), and inv16 are associated with a favorable prognosis. Eighty-four percent of these patients achieve a CR following high-dose cytarabine treatment. 46(XY), 46 (XX), and deletions of chromosome Y are associated with an intermediate prognosis, and all other cytogenetic abnormalities with a poor prognosis. It is reasonable, then, to perform allo SCT in rst CR for patients with intermediate or poor prognosis and in rst relapse or second CR for those with favorable prognosis. The use of allogeneic SCT for pediatric patients with ALL usually has involved patients in second CR, as the majority of children with ALL experience long-term disease-free survivals with intensive chemotherapy. Allogeneic SCT may be appropriately considered, however, in those patients who have at

II. ALLOGENEIC STEM CELL TRANSPLANTATION A. Chronic Myeloid Leukemia

CML is characterized by a translocation between chromosomes 9 and 22 known as the Philadelphia chromosome [t(9;22)]. This cytogenetic abnormality is important in diagnosis, following response to therapy, and in detecting relapse posttherapy. Left untreated, the median survival from time of diagnosis is approximately 2 to 4 years. Standard therapies include palliative cytoreduction with hydroxyurea, interferon, and allogeneic SCT. Numerous centers have reported the results of allogeneic SCT for CML with HLA identical sibling donors. The overall probabilities of long-term disease-free survival and relapse are about

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diagnosis a white blood cell count 20,000/ l or poor prognosis cytogenetics such as t(4;11), t(8;14), or t(9;22). The presence of extramedullary disease or failure to respond to initial chemotherapy may also provide a basis for consideration of allogeneic SCT. The use of allogeneic SCT in adults with ALL has been complicated by high rates of GVHD and relapse and by the lack of randomized trials in which patients receive allogeneic SCT in rst CR or at relapse.

C. Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria (PNH)

AA is a relatively rare disease with an annual incidence of three cases per million persons in the United States and Europe. Despite best supportive care, 50% of patients die within 6 months of diagnosis. The only effective therapies are either immunosuppression with antithymocyte globulin or allogeneic hematopoietic cell transplantation. PNH is also a rare disease, and approximately 25% of PNH patients develop AA. Allogeneic SCT is potentially curative for AA and PNH patients. The largest experience with transplant for AA and PNH has been with HLA-matched sibling donors. The 20-year survival for these patients now exceeds 85%. Survival has improved because of recognition that graft rejection decreases proportionately to the number of transfusions prior to transplant and because of improvements in conditioning regimens and GVHD prophylaxis with cyclosporine and methotrexate.

eral cytopenias, and a tendency to progress to AML. The pathogenesis of MDS is not completely understood. MDS are associated with certain cytogenetic abnormalities and usually occur during the sixth and seventh decade. The percentage of blasts in the marrow and cytogenetics, where available, remain the most useful prognostic indicators at this time. Many therapies have been used to treat MDS, including hormones, differentiation agents, growth factors, and combination chemotherapy. Chemotherapy has been toxic in older patients with MDS. Experience with SCT for MDS began in the 1980s and, as of 1996, 251 patients had been transplanted at Fred Hutchinson Cancer Center (FHCC) in Seattle, Washington. The 3-year cumulative nonrelapse mortality was 42%, the disease-free survival was 41%, and the incidence of relapse was 17%. Predictors of nonrelapse mortality were increased patient age and disease duration, whereas predictors of relapse were advanced disease and poor risk cytogenetics ( 3 abnormalities, 7). Good prognostic indicators associated with increased disease-free survival were youth, good risk cytogenetics (normal, deletion Y, isolated abnormalities of 5 or 20), and less advanced disease morphology. Currently, it is recommended that allogeneic SCT be considered for patients under 55 years of age who have lifethreatening cytopenias, increased blasts, poor risk cytogenetics, and an appropriate HLA-matched related donor.

E. Non-Hodgkins Lymphoma
Data on allogeneic SCT in patients with NHL are difcult to evaluate because there have been few controlled trials. There has been one study comparing allogeneic and autologous SCT in NHL. Results demonstrated a decreased relapse rate in the allogeneic group,

D. Myelodysplasia
Myelodysplastic syndromes (MDS) encompass a series of clonal stem cell disorders characterized by the impaired maturation of hematopoietic cells, periph-

FIGURE 1 (A) CD34 selected HSC from a patient with multiple myeloma are shown. CD34 cells are heterogeneous with respect to proliferative capacity and lineage commitment. Totipotent stem cells comprise about 5% of the total and have the appearance of small lymphocytes. CD34 cells that are committed to become myeloid or erythroid progenitors appear blastic. (B) A myeloid colony is shown, a colony-forming unit granulocytemacrophage (CFU-GM) having grown in semisolid medium innoculated with mobilized blood CD34 cells. CFU-GM represents the progeny of a single CD34 cell committed to the myeloid lineage. (C) Polymerase chain reaction results using patient-specic primers for the clonal myeloma light chain gene show that contamination is present even after CD34 selection (Gene, plasmid containing patient sequence; BM0, bone marrow at diagnosis; BM12, bone marrow at 1 year). A randomized prospective phase III trial in myeloma failed to demonstrate that CD34 selection to purge contaminating tumor cells increased the response rate or provided a survival benet, although tumor cell contamination of stem cell components was reduced by several logs. See color insert in Volume 1.

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albeit with a higher treatment-related mortality in that group as well. Furthermore, there was no survival advantage for the allogeneic SCT group. Preliminary studies have been conducted with minimally myeloablative regimens supported with allogeneic PBSC. Twenty-one patients with recurrent or primary refractory DLCL were treated and 42% survived disease free beyond 1 year. Further study of so-called miniallo transplants using allogeneic PBSC are clearly warranted in this population. Allogeneic SCT has been employed in select NHL patients who have relapsed after autologous SCT.

sues of timing and patient selection, however, remain controversial, particularly since transfusion therapy alone can provide signicant benets for decades. The development of improved forms of iron chelation therapy, as well as the promise of gene therapy, may inuence the decision to seek early allogeneic SCT. At the same time, however, the availability of SCT with umbilical cord blood stem cells provides enhanced opportunities for successful allogeneic SCT at an early age in many cases.

F. Multiple Myeloma
Standard allogeneic SCT has also been performed in MM patients, usually under the age of 55. Thirty-ve to 60% of all patients receiving HLA-matched allografts achieved CR. The peritransplant mortality in historical cohorts, however, is 40 to 60%, with female gender, stage I disease, one course of prior treatment, and CR prior to SCT being favorable prognostic factors for allogeneic SCT. The long-term survival is about one-third. Encouraging results have been obtained employing allogeneic SCT with less aggressive conditioning regimens, often including Fludarabine and Melphalan instead of cyclophosphamide and total body irradiation, and allogeneic PBSC instead of marrow. Reduced regimen-related toxicities and mortality have been observed in several small studies.

III. AUTOLOGOUS STEM CELL TRANSPLANTATION A. Non-Hodgkins Lymphoma

NHL is the sixth most common cancer in the United States. A subset of patients will be cured with standard chemotherapy but most are not. The rationale for high-dose cytotoxic therapy in NHL began with experimental evidence using mouse models. The survival of murine lymphoma cells was shown to be inversely proportional to the dose of alkylating agents. These data suggested that chemotherapy resistance may be a relative rather than an absolute property, one that could be overcome by high-dose therapy. The rationale, therefore, for autologous transplant was to escalate the doses of chemotherapy and radiation beyond the limits of marrow toxicity in order to overcome resistance to standard-dose therapy. The autologous SCT experience in diffuse large cell lymphoma (DLCL) began in 1995 when a multinational trial in relapsed DLCL compared chemotherapy alone to chemotherapy followed by high-dose therapy with SCT. The EFS at 5 years was found to be 46% for SCT patients and 12% for those who received chemotherapy alone. The criteria for entry into this study were very strict and thus this study suffered from selection bias. Such studies, therefore, have generated debate in the eld regarding the timing of transplant for relapsed DLCL. Currently, data support high-dose therapy with SCT for patients with chemosensitive DLCL for whom primary treatment has failed. Phase III trials are in progress now comparing high-dose therapy with conventional therapy in selected high-risk patients with previously untreated DLCL.

G. Severe Combined Immunodeciency

In 1968, allogeneic bone marrow transplantation was shown to be life-saving treatment in infants with SCID. It appears that T-cell function becomes normal in the majority of patients receiving related HLA identical or HLA haploidentical T-cell depleted marrow grafts. B-cell function, however, remains abnormal in many recipients of haploidentical marrow, leaving a longterm requirement for intravenous immunoglobulin.

H. Congenital Anemias
Thalessemia major, sickle cell anemia, and Fanconis anemia are among the congenital anemias that have been successfully treated with allogeneic SCT. The is-

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In the case of follicular lymphoma, the results of phase II studies indicate that remission duration may be prolonged in relapsed follicular lymphoma after HCT as compared with those patients who received standard chemotherapy. However, no survival advantage has been demonstrated. Because median survival is longer for patients with follicular lymphoma than for patients with other NHL, the long-term effect of transplant, such as secondary AML or MDS, should be considered. Consideration therefore should be given to delaying SCT until relapse. The major cause of treatment failure in NHL is relapse of disease. In the future, approaches to SCT for NHL may remedy this problem by providing better cytoreductive regimens, by performing SCT earlier in the disease process, and nally by consolidating therapy with either radiation or immunotherapy prior to or after SCT.

C. Multiple Myeloma and Primary Systemic Amyloidosis

MM accounts for 1% of all, and 10% of hematologic, malignancies; it also accounts for 20% of the deaths due to hematologoic malignancies annually in the United States. MM is the second most common hematologic malignancy after chronic lymphocytic leukemia. In the year 2000, 13,700 new cases of MM were diagnosed in the United States. The median age at diagnosis is 63 but is getting younger. MM is a clonal B-cell tumor of plasma cells often sensitive to steroids, radiation, and alkylating agents. However, cure has not been achieved with conventional chemotherapy and the median survival remains only 3 to 4 years. The experience with autologous SCT began in the 1980s after it was observed that signicant cytoreductive responses could be achieved in refractory MM patients with increasing doses of intravenous melphalan. The role of autologous SCT for MM has now been rmly established based on the landmark phase III trial conducted by the French Myeloma Study Group published in 1996. Two hundred previously untreated MM patients less than 65 years of age were randomized at diagnosis to receive conventional chemotherapy or high dose therapy with SCT. The response rate (57% vs 81%), the event-free survival at 5 years (10% vs 28%), and the overall survival (12% vs 52%) were signicantly superior in the highdose therapy group. Interestingly, in a populationbased setting, the Nordic Myeloma Study Group has reproduced these ndings. With the use of mobilized blood stem cells, double or tandem transplants have been performed but have not yet been formally assessed in a trial comparing single to double SCT. In addition, the question of the optimal timing of SCT, i.e., early, following induction therapy versus as later as salvage after relapse, has yet to be elucidated. At this time, purging clontypic myeloma contamination from stem cell components with CD34 selection does not increase the complete response rate or provide a survival benet. Primary systemic or AL amyloidosis is a clonal plasma cell and protein conformation disorder in which monoclonal immunoglobulin light chains are deposited as amyloid in critical organs leading to organ dysfunction and early death. By eliminating the

B. Hodgkins Disease
HD is one of the success stories of modern oncology. With conventional chemotherapy, approximately 50% of patients can be cured. However, 25% of patients with HD never achieve CR and a similar percentage of patients who achieve CR will relapse. The poor results in some relapsed patients with salvage chemotherapy led to an interest in high-dose chemotherapy followed by autologous SCT based on the theory that increased dose intensity would increase cell kill. Despite intercenter variability in patient selection, numerous phase II studies reported CR rates greater than 40% after SCT, some reporting rates as high as 70%, with disease-free survival rates as high as 50% at 5 years. Overall, based on these robust phase II results, high-dose chemotherapy with SCT has become an accepted modality of treatment for relapsed or primary refractory HD. Randomized studies have not been performed, but the responses are clearly better than those achieved with conventional salvage chemotherapy. Moreover, the transplant-related mortality is under 5%, making SCT an approach whose safety may be superior to salvage chemotherapy. It is hoped that more effective preparative regimens will be found in the future to improve the survival curve and decrease the rate of relapse.

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cells responsible for producing these light chains, investigators hypothesized that one could halt the deposition process. In patients eligible for autologous SCT, this hypothesis was conrmed using G-CSF for stem cell mobilization and intravenous melphalan for high-dose therapy. CR was achieved in over half of the patients and improvements in all types of amyloid-related organ dysfunction were documented. However, the initial experience at multiple centers was complicated by a 100-day mortality rate that averaged 25%. It became obvious that because of visceral reserve limited by deposition disease, AL patients have greater toxicity in SCT than patients with MM receiving the same high-dose therapy. This has led to improvements in patient selection. One current recommendation is that SCT should not be offered to AL patients with symptomatic cardiac amyloid and recurrent pleural effusions or syncope, or to patients over the age of 50 with more than two major systems compromised by AL (of heart, liver, kidneys, and peripheral nerves). Therefore, autologous SCT for select patients with AL is a new and often effective therapy for an otherwise uniformly fatal disease. Future directions include the development of clinical trials of SCT following heart or liver allografts.

55%, autologous 48%, and chemotherapy 30%, with a statistically signicant improvement in survival for allogeneic and autologous SCT as compared with chemotherapy. However, the North America study group conducted a similar study and found that the 4-year DFS for chemotherapy, autologous HCT, and allogeneic HCT was 35, 37, and 42%, respectively. The most important pretransplant prognostic factor was cytogenetics. Patients with poor risk cytogenetics did better with allogeneic transplant. Overall studies indicate that for patients with AML who lack an HLA-matched sibling donor and who are older than 50, autologous SCT may be a viable option in those with either standard risk or poor risk cytogenetics. In patients with good risk cytogenetics, however, SCT likely represents a form of rst-line salvage therapy if a chemotherapy regimen containing high-dose cytarabine fails.

E. Solid Tumors
Given its success in other diseases, high-dose therapy with autologous SCT has also been attempted in germ cell tumors, neuroblastoma, and breast cancer. Beginning at Indiana University in 1986, a small percentage of patients with germ cell tumors who had multiple relapses were shown to respond to high-dose therapy with SCT. These results were conrmed in multiple other studies, and, more recently, high-dose therapy with SCT has been studied as primary therapy for patients with poor risk primary mediastinal germ cell tumors. Neuroblastoma is a tumor of the peripheral nervous system that affects children under the age of 15. Forty percent of patients have low or intermediate risk tumors and can be treated with conventional therapy to achieve substantial long-term survival. The other 60%, however, cannot achieve long-term survivals with conventional therapy. High-dose therapy and autologous SCT have improved the long-term survival of some high-risk patients. Studies to enhance long-term survival for a larger percentage of patients are ongoing. These involve improved induction regimens, the use of biological agents such as monoclonal antibodies as adjuncts, and modulation of drug resistance. The use of SCT in patients with metastatic (and high-risk) breast cancer is one of the most revealing

D. Chronic and Acute Myeloid Leukemia

There has also been interest in autologous SCT for CML and AML. Autologous SCT may be a reasonable second line therapy in patients with CML who are not eligible for allogeneic transplant and do not respond to interferon. Randomized studies comparing the two have not been performed, but clinical experience demonstrates that although autologous SCT does not cure CML, it may be associated with longer survival compared with conventional treatment. In 1989, a randomized trial in AML patients compared allogeneic and autologous SCT to consolidation chemotherapy. There was no survival advantage or lower relapse rate for chemotherapy or autologous transplant. Further studies were done comparing allogeneic with autologous SCT and salvage chemotherapy. In all studies, patients received allogeneic SCT if they had an HLA-matched sibling and were under 50 years of age. In a major European study at 4 years, allogeneic SCT patients had a disease-free survival of

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medical stories of the recent past. Mobilized blood stem cells made SCT less morbid at a time when American hospitals sought to expand services and income, transplant physicians to develop SCT programs, and biotech companies to nd new markets. Concurrently, breast cancer medicine became a major political affair and breast cancer patients and their families struggled as part of a growing community with decisions about what the best treatments might be. The initial justication for high-dose therapy with SCT was that there was no other therapy that achieved complete responses in metastatic disease. Unfortunately, the appropriate phase III trials, designed to determine whether a survival benet attached to SCT, were difcult to perform for many reasons. Finally, upon their completion (a credit to oncology as a clinical science), overall survival in metastatic breast cancer was not shown to be improved with SCT. Whether the use of autologous SCT for high risk breast cancer will be revisited with new drugs such as bone chelating radiopharmaceuticals is unclear at this time.

parity between donor and recipient. GVHD can occur early in SCT and be immediately life-threatening (acute GVHD), involving the skin, gastrointestinal tract, and liver, or it can occur months after SCT (chronic GVHD) as a deleterious and often debilitating syndrome similar to severe scleroderma, requiring chronic steroid treatment. Selective CD8 T-cell depletion or improved prophylactic regimens, including the use of intravenous cyclosporine and new immunosuppressive agents, such as mycophenolate, may help decrease the incidence of acute GVHD in the HLA identical setting. Moreover, the use of T-celldepleted grafts in the setting of related HLA haploidentical SCT can decrease the incidence of GVHD. Of note, the use of unmanipulated allogeneic PBSC appears to be associated with no increase in acute GVHD but possibly with an increased incidence of chronic GVHD.

B. Regimen-Related Toxicities
The toxicities of both allogeneic and autologous SCT are primarily related to the treatment regimens and include acute bacterial, fungal, or viral infections. Furthermore, the convalescent phase is often marked by gastrointestinal incapacities, marked fatigue, and cognitive difculties. As cytotherapies emerge as a major force in the treatment of cancer, these side effects will become targets for novel drugs and trials, particularly involving the use of agents promising to protect the gastrointestinal tract, such as keratinocyte growth factor.

IV. TOXICITIES A. Graft-versus-Host Disease

Tissue compatibility between human recipients and donor grafts is controlled by the genes of the major histocompatibility complex on chromosome 6. Proteins encoded by these genes are called human leukocyte antigens (HLA), and the HLA system is vastly complex and polymorphic, meaning that related individuals who are HLA identical share haplotypes that have the same genes in them, whereas unrelated individuals who are HLA identical likely have different versions of the same genes (polymorphisms). Scientic interest in graft-versus-host reactions began in the 1950s when the recovery of animals after splenic cell transplants was found to be complicated by a runting syndrome soon to be observed in humans after allogeneic bone marrow transplantation. The development of GVHD is inuenced by the immunocompetence of the recipient, the degree of HLA similarity between donor and recipient, and the number of functional lymphocytes infused. As a rule, GVHD in the setting of allogeneic SCT increases in frequency with the degree of HLA dis-

C. Long-Term Risks and Outcomes

Some of the long-term side effects include a small risk of secondary malignancies and myelodysplasia; lateonset pulmonary problems such as interstitial pneumonitis or bronchiolitis obliterans; disruption of normal growth and development in children; and endocrine, psychosexual, and adjustment disorders. In young patients, the impact of transplantation on fertility may be profound, and cryopreservation of sperm or ova may be a useful option where appropriate. In addition, patients who successfully undergo stem cell transplantation do not necessarily have normal life spans compared to controls with no history of malignancy.

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The future of SCT, then, will involve research to help decrease the risks and improve the long-term outcomes so that patients who are free from disease may go on to lead full and normal lives.

V. CONCLUSIONS
Stem cell transplantation has been established as a useful therapy for hematologic malignancies and some solid tumors. Some patients, however, still die in allogeneic SCT because T lymphocytes cause fatal GVHD and many are not cured in autologous SCT because disease recurs post-SCT. Disease may recur because the tumor was not completely eliminated or because the stem cell component was contaminated with tumor cells that home to sites of prior disease. For these reasons, manipulated or engineered stem cell grafts continue to attract interest. Approaches to graft engineering include methods of T-cell depletion designed to minimize GVHD without compromising the potential for graft-versus-disease effect, as well as purging with monoclonal antibodies or selection of CD34 stem cells in order to eliminate contaminating tumor cells. However, to date, no form of engineered graft has shown itself to be superior to unmanipulated components with respect to survival in phase III trials in autologous SCT or allogeneic HLA identical SCT. In allogeneic-related HLA haploidentical SCT, it is generally agreed that T-cell depletion is required to reduce the risk of acute GVHD. With the apparent superiority of mobilized allogeneic peripheral blood stem cells over bone marrow in a recent large trial, and the promise of minimally myeloablative allogeneic SCT using PBSC, continued success with unmanipulated components is likely to continue. Nevertheless, should the CR rates for autologous SCT in NHL, HD, and MM increase due to advances in treatment, such as the use of new agents or of post-SCT tumor vaccines, the role of tumor cell contamination of stem cell components in disease recurrence post-SCT will likely increase as well. The applications of cytotherapies will evolve and expand over the coming decades. Hematopoietic stem cell transplants may provide methods for inducing lifelong tolerance to xenografts or allow novel treatment of autoimmune diseases, whereas the discovery

and use of nonhematopoietic stem cells may help minimize the toxicities of cancer therapy or cure nonmalignant disorders. For example, the infusion of fetal islet cell progenitors may provide a treatment for severe diabetes. The future of stem cell transplantation and cytotherapies in general will require advances in our understanding of stem cell biology and transplantation immunology and will continue to depend on patients courageous enough to participate in well-designed clinical trials.

See Also the Following Articles

ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS ACUTE MYELOCYTIC LEUKEMIA CHRONIC LYMPHOCYTIC LEUKEMIA CHRONIC MYELOGENOUS LEUKEMIA GRAFT VERSUS LEUKEMIA AND GRAFT VERSUS TUMOR ACTIVITY MULTIPLE MYELOMA NEUROBLASTOMA TRANSFER OF DRUG RESISTANCE GENES TO HEMATOPOIETIC PRECURSORS TRANSGENIC MICE IN CANCER RESEARCH

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