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Emerging Trends In Managing AML

The Role of Bone Marrow Transplantation in Patients with Acute Myeloid Leukemia

By Robert B. Geller, MD

Table of Contents
Allogeneic Bone Marrow Transplantation

Autologous Bone Marrow Transplantation

Allogeneic V Autologous Bone Marrow Transplantation

Conclusions

References

Curing patients of acute myeloid leukemia (AML) relies on two treatment goals: (1) reducing the leukemia burden and achieving normal hematopoiesis with induction chemotherapy, and (2) eradicating residual leukemia cells with more intensive therapy.1-3 Current postremission strategies include further cytoreduction to severe marrow hypoplasia, followed by hematopoietic regeneration with normal marrow progenitors, and administration of intensive myeloablative therapy, followed by bone marrow transplantation (BMT).

Allogeneic marrow reinfusion is generally restricted to patients <= 55 years of age who have a human leukocyte antigen (HLA)-compatible family donor. With the growth of the National Marrow Donor Program, additional patients with high- risk or refractory AML may be considered as appropriate candidates for allogeneic BMT using unrelated volunteer donors.4 Autologous bone marrow rescue is an alternative source of hematopoietic stem cells. Although specific complications related to allogeneic transplantation, such as graft-versus-host disease (GVHD) and interstitial pneumonitis, are avoided or markedly less with autografting, this procedure is associated with an increased risk of relapse related to leukemic contamination of reinfused marrow and the absence of a graft-versus-leukemia effect.

ALLOGENEIC BONE MARROW TRANSPLANTATION

Allogeneic BMT should be considered for patients with AML in first remission, subsequent remission or early relapse, as well as for those with refractory leukemia.5-8 This procedure has the potential to cure AML patients through the myeloablative properties of the preparative regimen and the subsequent graft-versus-leukemia effect in which donor lymphocytes target residual leukemia cells.9-11

The three essential characteristics of preparative regimens for allogeneic BMT _ namely, antileukemic, myeloablative and immunosuppressive properties _ limit treatment to specific chemotherapeutic agents and irradiation. For example, although busulfan has myeloablative and antileukemic properties, it provides little immunosuppression.12 On the contrary, cyclophosphamide is an effective immunosuppressive agent, but has no myeloablative properties and limited antileukemic potential. Accordingly, the two drugs combined yield an efficacious preparative regimen, as does cyclophosphamide plus total body irradiation (TBI).13,14 For this reason, most centers now use preparative regimens incorporating either one of these two combinations. Other chemotherapeutic agents may be added to further enhance antileukemic potential.15,16

Despite the benefits of using normal bone marrow and myeloablative therapy, allogeneic transplantation has several distinct disadvantages. Most clinical trials evaluating this procedure have demonstrated that, although relapse rates are relatively low (10% to 15%), early mortality from transplant-related complications can be significant, ranging from 15% to 30%, depending primarily on patient age and disease status.5

Early complications from allogeneic BMT include adverse effects of the preparative regimen, such as mucositis, hemorrhagic cystitis and hepatic veno-occlusive disease, and, as will be described, bacterial, fungal and viral infections associated with prolonged neutropenia. One of the first potential problems following allogeneic transplantation is graft rejection or poor hematopoietic graft function. As a result of the immunosuppressive properties of the preparative regimen, rejection generally occurs in <5% of patients with transplants from HLA-compatible sibling donors; however, risk of rejection can become significant as antigen disparity increases between the donor and patient. For instance, in patients receiving mismatched sibling- or unrelated- donor transplants, rejection rates range from 10% to 20%.4,17 If T-cell depletion is used to decrease the incidence of GVHD, rates may be even higher.10,18 Poor hematopoietic graft function can occur in patients with allograft for whom the donor marrow yield is poor, but is more frequent following autologous transplantation.

As patients begin to engraft, they are at risk of developing acute GVHD, caused by mature T lymphocytes reinfused with donor marrow. In turn, the risk of infection is increased as a result of prolonged immunosuppression required for GVHD treatment. A major complication of allogeneic BMT, acute GVHD occurs in 30% to 50% of patients receiving compatible sibling marrow and more frequently in mismatched- or unrelated-donor transplants.19 It continues to be the most common cause of morbidity and mortality following allogeneic BMT, with major target organs being the skin, gut and liver. Clinical signs include diffuse rash, voluminous diarrhea, hepatitis and, in more severe cases, bile duct necrosis. Acute GVHD prophylaxis involves combining cytotoxic agents, such as methotrexate, and/or steroids with immunosuppressive drugs, such as cyclosporine. Transplant centers are investigating the role of new immunosuppressive agents, such as FK506,20 and the depletion of T lymphocytes prior to allograft reinfusion in an effort to decrease the incidence and severity of acute GVHD.21,22

Another major complication of allogeneic BMT is chronic GVHD, which generally occurs 3 months after allograft in 30% to 50% of patients.23 Risk increases in older patients and in those who have already developed acute GVHD. Chronic GVHD, the severe forms of which can be debilitating, involves the same target organs affected by acute GVHD, as well as other organs, such as the lungs and endocrine system. Skin manifestations of chronic GVHD may appear similar to a collagen vascular disease, most notably scleroderma, and hypo- or hyperpigmentation with joint contractions may develop. Liver disease can take the form of chronic hepatitis, eventually developing into cirrhosis, and gastrointestinal manifestations may resemble inflammatory bowel disease.

As with many medical phenomena, the effects of acute and chronic GVHD are double-edged. That is, patients have a lower relapse rate, due to the graft-versus- leukemia effect, but also an increased risk of morbidity and mortality from GVHD.9-11 Data from the International Bone Marrow Registry and single transplant centers have shown a graft-versus-leukemia effect in patients undergoing allografts for both acute and chronic leukemia. For those without GVHD, relapse rates can be as high as 40% to 50%, similar to the rates following syngeneic transplantation.

Patients are at great risk for gram-negative and gram-positive infections due to prolonged neutropenia and the breakdown of normal mucosa barriers resulting from the preparative regimen and the use of indwelling catheters.24 Most patients receive prophylactic antibiotics to decrease the incidence of gram- negative infections, and some centers use prophylactic vancomycin to decrease the risk of gram-positive infections associated with indwelling catheters. Prolonged neutropenia also leads to an increased risk of fungal infections, including infections from Candida and Aspergillus species. Most centers employ oral antifungal agents as prophylaxis and amphotericin B early in the course of therapy for refractory fevers.

Reactivation of herpes simplex is a danger early in the neutropenic period and, thus, acyclovir is often given as prophylaxis to seropositive patients.25 Two to three months following BMT, patients are at risk for cytomegalovirus (CMV)-related interstitial pneumonitis, which is much more common in allogeneic than in autologous transplantation.26,27 Patients seropositive for CMV prior to BMT or those who receive bone marrow from seropositive donors are at highest risk. If a seronegative patient receives seronegative donor marrow, CMV-negative blood products should be provided to decrease the risk of CMV infection and disease following transplantation.28

Clinical symptoms of CMV-related interstitial pneumonitis include dyspnea, fever and cough; diagnosis is often confirmed by bronchoalveolar lavage or open lung biopsy. Ganciclovir and immunoglobulin therapy are curative in approximately 50% of patients29 and many centers currently administer ganciclovir as prophylaxis to patients who develop CMV viremia or have a CMV-positive bronchoalveolar lavage culture. Even though CMV is the most common cause of interstitial pneumonitis, bacterial infections, including those caused by Pneumocystis carinii, can also occur; however, with the current use of trimethoprim and sulfamethoxazole prophylaxis following transplantation, P. carinii pneumonia occurs infrequently.30

Growth factors, primarily G-CSF and GM-CSF, have been used following allogeneic marrow reinfusion to accelerate myeloid engraftment and to decrease the incidence of severe infections.31,32 Myeloid engraftment is hastened without an increased risk of GVHD or relapse among patients receiving either growth factor. To date, however, no significant survival benefit has been evident among patients receiving cytokine support after sibling allograft. Furthermore, a recent study of GM-CSF in allogeneic BMT using unrelated donors demonstrated that, although neutrophil recovery was accelerated among GM- CSF-treated patients, overall survival appeared to be lower among these patients, compared to those who did not receive the growth factor; however, relapse rates and the incidence of GVHD were not significantly different between the two groups.33

Prolonged immunosuppression continues to be a problem following allogeneic BMT. Even though neutrophil recovery is apparent by the second or third month following transplantation, immune function remains greatly impaired.34 Immune function may take 6 months to several years to fully recover and recovery may be even slower if patients have acute or chronic GVHD requiring prolonged treatment with agents such as steroids or cyclosporine. Patients are often withdrawn from immunosuppression by 6 months following an uncomplicated allogeneic BMT; otherwise, immunosuppression may continue for several years.

Despite the complications related to allogeneic BMT, outcome has continued to improve over the past decade. For example, among patients with AML in first remission treated with a preparative regimen of busulfan and cyclophosphamide, investigators at Johns Hopkins found that disease-free survival was 32% before 1982 and 62% thereafter, while relapse rates remained in the range of 10% to 20% during this time.5 The substantial improvement in disease-free survival was primarily the result of advancements in supportive care and GVHD prophylaxis, with cyclosporine more effective than cyclophosphamide, methotrexate or both. In addition, after 1982, enhancements in antibacterial and antifungal prophylaxis and the availability of acyclovir for herpetic infections and ganciclovir for CMV infections significantly improved overall survival. Other centers are showing disease-free survival in the range of 60% to 65% for patients transplanted with AML in first remission and 30% to 40% for those transplanted with AML in early relapse or in second or subsequent remission.6,7,14,15

Allogeneic BMT for AML patients is primarily reserved for those " 55 years of age who have an HLA-compatible family donor. Approximately 50% of patients with a new diagnosis of AML are in this age group, with 75% achieving a complete remission. An HLA-compatible sibling donor is available for approximately one-third of patients in remission, of whom 60% are cured following allogeneic BMT. Accordingly, it is estimated that only 7% of all AML patients will be cured using this procedure. To improve overall cure rate, we must continue to find ways to decrease the early mortality related to the procedure and develop alternative strategies for patients without an HLA-compatible sibling donor.

Allografting with unrelated donors may become a viable option for AML patients as the number of potential donors increases through the National Marrow Donor Program (which now has over 1.2 million volunteers) and as procedure-related mortality decreases due to improvements in supportive care, GVHD prophylaxis and molecular typing.

A recent study conducted by Kernan et al4 demonstrates this potential role. In particular, these investigators reported data on 432 leukemia patients who received allogeneic transplants from unrelated volunteer donors. Disease-free survival approached 50% for patients <= 18 years of age with good-prognosis leukemia (ie, AML in first remission, acute lymphoblastic leukemia in first and second remission, chronic myelogenous leukemia in chronic phase) and under 40% for patients > 18 years of age with good-prognosis leukemia. Disease-free survival significantly decreased as the patient's age increased or disease status became less favorable. For now, until further data from well-designed trials substantiate the effectiveness of unrelated-donor transplantation, this procedure should be reserved for patients without a compatible family donor, who have poor-prognosis AML at diagnosis and subsequently achieve remission, as well as for patients with AML refractory to induction therapy.

AUTOLOGOUS BONE MARROW TRANSPLANTATION

Autologous BMT may serve as a curative option for patients who achieve complete remission and have harvestable marrow, but are without a compatible family donor. Because the complications of GVHD and prolonged immunosuppression are avoided with autografting, selected patients up to 65 years of age may be considered as potential candidates. Autografting is deemed inappropriate for patients who are unable to achieve a complete remission and for those who cannot donate remission marrow due to early relapse or poor hematopoietic recovery from consolidation therapy. Relapse resulting from leukemic contamination of reinfused marrow and the absence of a graft-versus-leukemia effect continues to be a major drawback of autologous BMT. Santos et al35 described five principles of maximum therapeutic response in cancer patients undergoing autografting:

the malignancy should be responsive to cytoreductive therapy;
the limiting toxicity of the cytoreductive preparative regimen should be marrow aplasia;
the transplant should be performed at a time of minimal residual disease;
the source of hematopoietic stem cells should be free of clonogenic tumor cells; and
adequate methods for cryopreservation of harvested hematopoietic stem cells should be available.

Autografting as therapy for AML patients in particular has the potential to satisfy all five requirements.

The first objective in autologous BMT is to administer escalating doses of chemotherapy, irradiation or both that are primarily myelotoxic with acceptable levels of extramedullary toxicity. A recent Cancer and Leukemia Group B phase III trial confirmed the role of dose escalation in postremission therapy.36 Patients with a new diagnosis of AML were randomly assigned to one of three postremission chemotherapeutic regimens incorporating escalating doses of ara- C; those randomly assigned to receive the highest dose had a significantly improved disease-free survival.

Because immunosuppression is not required in autografting, preparative regimens can be developed for maximum antileukemic and myeloablative potential without restricting use of cyclophosphamide or TBI. For successful autologous rescue, the procedure should be performed after induction and consolidation therapy when leukemia is in early remission and residual disease is minimal. Further, residual leukemia must respond to dose escalation and preparative regimens must have sufficient antileukemic effect to overcome the absence of a graft-versus-leukemia effect.

Clinical trials of autologous BMT among patients with AML in first remission are difficult to evaluate critically because data generally involve selected groups with varying pretransplant therapy, most of whom have been in remission for at least several months prior to transplantation while receiving consolidation chemotherapy. This difficulty is illustrated by two single-center studies, both of which used unpurged marrow and similar preparative regimens of cyclophosphamide and TBI. Burnett et al37 examined 12 adult patients (median age: 41 years) who received a median of 3 (range: 2 to 4) courses of induction therapy, followed by a median of 6 (range: 3 to 14) courses of consolidation or maintenance chemotherapy prior to autografting. Remission duration ranged from 4 to 22 months (median: 8 months) prior to transplantation. Findings indicated an actuarial relapse rate of 41%, with a prolonged actuarial disease-free survival of 58%. Stewart et al38 studied 13 young patients (median age: 16 years), all of whom received one or two courses of induction therapy, four of whom received one course of consolidation and seven of whom were administered maintenance chemotherapy. Median remission duration prior to transplantation was 4 months. Although patients were given post-transplant therapy with either methotrexate or interferon, disease-free survival was only 22% at 2 years because of a high actuarial relapse rate (67%) and treatment-related complications. The conflicting results of the two studies might be explained by differences in patient selection, pretransplant therapy and duration of remission prior to transplantation.

In an analysis of 448 patients with AML in first remission who underwent autologous BMT at one of 56 European transplant centers, specific pretransplant variables were found to predict disease-free survival.39 Patients with an FAB 1,2 or 3 classification at diagnosis had longer disease-free survival than those with an FAB 4 or 5. Long pretransplant intervals were also associated with improved outcome: at 60 months, disease-free survival was 28% ± 65%, 38% ± 4%, 46% ± 6% and 56% ± 8% for intervals from remission to transplant < 3 months, 4 to 6 months, 7 to 9 months and > 9 months, respectively. In addition, the preparative regimen was shown to be an indicator of outcome.

Despite the problems associated with evaluating results of autologous BMT, several trials have now progressed enough to establish this form of postremission therapy as potentially curative for a substantial number of patients who are not candidates for allogeneic transplantation. Korbling et al40 examined 22 patients in first remission transplanted with marrow incubated with mafosfamide. Actuarial disease-free survival was 61%, with an actuarial relapse rate of 36% (median duration of disease-free follow-up: 31 months). At the Johns Hopkins Oncology Center, 48 patients were transplanted with 4HC-treated marrow early in first remission (median: 2.5 months; range: 1.5 -15 months) following busulfan and cyclophosphamide administration.41 Six patients died from transplant-related complications, while 19 relapsed at a median of 6 months (range: 3 to 18 months) after transplantation, for an actuarial relapse rate of 49%. Twenty-three patients remained in remission for a median of 18 months after autografting (disease-free survival: 41%).

More recently, the transplant team from the University of California at San Francisco has presented encouraging results using a preparative regimen of busulfan and etoposide with 4HC-purged autologous marrow.42 In this study, patients with a new diagnosis of AML received induction chemotherapy with high-dose ara-C and then, once complete remission was achieved, underwent autologous BMT without further therapy. Disease-free survival with a median follow-up of 3 years was 76% ± 9%; however, patient characteristics at diagnosis may have influenced the results. Of 32 patients given transplants, 15 had good-risk cytogenetic abnormalities, t(15;17) and inv(16), which have demonstrated significant cure rates with chemotherapy alone in previous studies. Thus, it is difficult to determine the specific impact of myeloablative therapy followed by autologous BMT for this particular study population. The role of purging in autologous BMT for AML patients in remission continues to be controversial. Although harvested in remission, marrow from AML patients may contain viable leukemia cells, and it is difficult to know to what degree these cells must be removed before reinfusion. Pharmacologic and immunologic techniques, physical separation and other manipulations of the marrow, alone or in combination, have been used to purge occult neoplastic cells from marrow suspensions prior to freezing and storing (Table 1).41,43-55

Table 1. Various purging approaches in autologous bone marrow transplantation.
Pharmacologic agents

4HC 41
Mafosfamide43
Etoposide44
4HC + cisplatinum45
Etoposide + verapamil/CsA46
Alkyl-lysophospholipids 47
Immunologic techniques

PM-81, AML-2-2348
Immunotoxins (CD14, CD13)49]
Photosensitization

Merocyanine 54050
Sulfonated aluminum phthalocyanine51
Hyperthermia52
Combinations

CD33 + etoposide/ara-C53
(CD24 + CD9 + CD10 + C) + mafosfamide54
(CD13 + CD33 + C) + 4HC + etoposide55
4HC = 4-hydroperoxycyclophosphamide; CsA = cyclosporine; ara-C = cytosine arabinoside; C = complement.

The efficacy of chemopurging may be related to the specific technique used. Rowley et al56 found that relapse rate following autologous transplantation for patients with high-risk AML was significantly correlated with percent colony forming unit-granulocyte and macrophage (CFU-GM) surviving the ex vivo chemopurge. Gorin et al57 also reported that the positive correlation between marrow purging with mafosfamide and lower relapse rate was more significant when the mafosfamide dose was adjusted according to the individual sensitivity of CFU-GM progenitor cells.

Several series have shown reasonable results for autologous transplantation without purged marrow. In a study reported by McMillan et al,58 actuarial disease-free survival was 50% among 76 AML patients who received unpurged marrow in first remission following high-dose chemotherapy and 67% among 25 patients who proceeded to a second autograft. Lowenberg et al59 examined 32 patients who received autografts following cyclophosphamide and TBI (8 Gy in a single dose). Relapse-free survival was 35%, with an actuarial relapse rate of 60% at 3 years. Using a similar preparative regimen, except for higher-dose TBI (10 Gy in a single dose), Carella et al60 reported on 21 patients, 13 (62%) of whom were disease-free at 2 to 41 months (median: 15 months) after autologous BMT.

Gorin et al,57 analyzing data from the European Bone Marrow Transplant Group, reported on 263 patients with AML in first remission, including 69 who received autologous marrow purged in vitro with mafosfamide and 194 who received unpurged marrow. Chemotherapeutic agents alone were administered to approximately 50% of patients; remaining patients received chemotherapy and TBI (single-dose or fractionated). No maintenance therapy was administered after transplantation.

In a univariate analysis, a statistically significant difference in relapse rate was noted between patients with and without marrow purging at three years (40% ± 6% versus 59% ± 4%, P = .05); this difference, however, was no longer significant in a multivariate analysis. Purging appeared to be more effective in patients who had a shorter interval between achieving a complete remission and undergoing autologous BMT. In another subgroup analysis, findings for marrow purging were most significant in standard-risk AML patients undergoing autograft following TBI, when compared to those who did not receive TBI (probability of relapse at 3 years: 23% versus 55%, P = .0005; disease-free survival at 4 years: 63% versus 34%, P = .05).

Rowlings et al61 recently presented results from the North American Autologous Bone Marrow Registry for more than 900 patients from 90 institutions between 1989 and 1992. Of 572 patients (median age: 28 years) in first remission, 59% underwent purged-marrow transplantation. Two-year survival for this group (56% ± 6%) was not significantly different from survival among patients receiving an unpurged transplant. Of 266 patients in second remission, 87% underwent a purged marrow transplant, for whom disease-free survival was 36% ± 8%; again, purging was not found to be a significant variable.

Random-assignment trials using identical preparative regimens in patient groups matched for disease characteristics, age, induction and consolidation therapy, remission status and time of transplant are required to properly investigate the usefulness of purging for AML patients undergoing autologous BMT. Such a study would be extremely difficult to complete, even in a setting of international cooperative groups. Despite the difficulty in substantiating a beneficial effect of purging in autologous transplantation, many centers continue to use this technique in AML patients.

When assessing the overall usefulness of purging, associated risks and drawbacks should also be considered along with the possible benefits. Chemopurging markedly prolongs neutropenia and thrombocytopenia and, in turn, increases the risk of poor graft function and failure, which consequently increases medical costs and the patientís hospital stay. With chemopurged transplants, bone- marrow cells are removed during the harvest procedure, exposed to chemotherapeutic agents during purging, frozen and eventually thawed. These manipulations can damage stem cells and, as a result, 5% to 20% of patients undergoing autologous BMT with chemopurging may show signs of poor graft function. Although growth factors have the ability to improve poor graft function, their role in chemopurged BMT has been marginal.62,63 As more selective leukemia markers become available, the ability to purge marrow of leukemia cells without damaging normal stem cells will improve. These markers will enhance the detection of minimal residual disease and, in turn, aid in determining the most suitable time for autografting.

ALLOGENEIC V AUTOLOGOUS BONE MARROW TRANSPLANTATION

Some clinical trials evaluating the role of BMT in AML patients suggest a disease-free survival of > 50% with either allogeneic or autologous transplantation. Furthermore, when data from the North American Autologous Bone Marrow Registry are compared to allogeneic transplant data from the International Bone Marrow Transplant Registry, no significant difference with regard to overall survival is apparent between the two procedures among patients with AML transplanted in first or second remission.61,64 However, such a comparison is difficult to interpret due to biases in registry data and patient selection, as well as other methodologic problems.

Stein et al65 recently presented data from the City of Hope National Medical Center in which autologous and allogeneic BMT for adult patients with AML in first remission were compared. Thirty-one patients (median age: 34 years) underwent autologous BMT with unpurged marrow and 32 (median age: 32 years) underwent allogeneic BMT. White blood cell counts were comparable at diagnosis, but the two treatment populations appeared to be different with regard to cytogenetics and FAB groups. In particular, nine patients in the autologous BMT group versus three in the allogeneic BMT group had a FAB 3 or 4 with eosinophilia classification. Patients who underwent autologous BMT received one course of high-dose ara-C consolidation prior to marrow harvesting and then a preparative regimen of fractionated TBI (1200 rads), VP-16 and cyclophosphamide; those who underwent allogeneic BMT received fractionated TBI (1320 rads) and VP-16, as well as GVHD prophylaxis with cyclosporine and methotrexate. Disease-free survival at 24 months was 68% for patients who received an autograft and 55% for those who received an allograft (P = .35), with a relapse probability of 29% and 13%, respectively (P = .11). The authors concluded that autologous BMT using unpurged marrow following high-dose ara-C consolidation is an acceptable therapeutic alternative for patients with AML in first remission who lack a compatible donor.

Zittoun et al66 recently presented the results of a phase III trial comparing autologous BMT, allogeneic BMT and intensive chemotherapy for patients with AML in first remission. Patients received one or two courses of induction chemotherapy, with an additional course of consolidation chemotherapy to those achieving a complete remission. Patients who had an HLA-identical sibling donor were eligible for allogeneic BMT; remaining patients were randomly assigned to autologous BMT with unpurged marrow or a second course of consolidation chemotherapy with high-dose ara-C. A total of 992 patients entered the trial, with 619 (62%) achieving a complete remission. Of these patients, 333 (54%) received the assigned postremission therapy. Specifically, 137 patients underwent allogeneic BMT; 94, autologous BMT; and 102, further chemotherapy. Reasons for premature withdrawal included toxicity (57 patients), toxic death (32), early relapse (47), refusal (80), protocol violation (10) and loss to follow-up (7).

With a median follow-up of 3 years, overall and disease-free survival for all patients combined were 36% and 40%, respectively. Based on an intent-to-treat evaluation, disease-free survival at 4 years was significantly better (P = .026) for patients undergoing allogeneic (54%) and autologous BMT (49%), compared to those who received intensive chemotherapy (30%); results were statistically comparable for patients in the two transplantation groups; however, overall survival for patients who entered remission was not significantly different among the three postremission treatment arms (59%, 57% and 46%, respectively) because patients who relapsed following intensive chemotherapy were able to receive reinduction therapy and could then be salvaged by autologous BMT. As might be expected, patients undergoing allogeneic BMT have a significantly higher treatment-related mortality rate and increased duration of hospitalization, and those receiving an autograft have a more delayed hematopoietic recovery. Although this study demonstrated no significant difference between autologous and allogeneic BMT with respect to disease-free and overall survival, the difficulty in conducting and interpreting such a trial, primarily because of the large number of patient dropouts, is also apparent.

The Eastern Cooperative Group, Cancer and Leukemia Group B and the Southwestern Oncology Group are currently involved in a trial that compares postremission approaches in patients with a new diagnosis of AML who are <= 50 years of age. For those who achieve a complete remission following induction chemotherapy, an additional course of consolidation therapy is administered. If an HLA-compatible sibling donor is available, allogeneic transplantation is offered; if not, patients are randomly assigned to autologous transplantation using 4HC-purged marrow or high-dose consolidation chemotherapy with ara-C.

The trial suffers from many of the same problems associated with other phase III studies requiring a large number of patients over a prolonged period. For instance, since this trial was developed at least 5 years ago, recent improvements in treatment approaches (eg, more intensive induction and consolidation chemotherapy, more intensive preparative regimens, different strategies for GVHD prophylaxis, myeloid growth factors) have not been incorporated into the study design. However, the effectiveness of each treatment strategy by disease characteristics will be evaluated using data from immunophenotyping and cytogenetic analysis at diagnosis. These data will help to determine the most appropriate postremission approach for specific patient populations stratified by prognostic characteristics.

CONCLUSIONS

Myeloablative therapy followed by allogeneic or autologous BMT definitely offers patients with AML the potential for curative treatment, but both transplantation methods have distinct advantages and disadvantages. The controversy regarding the most effective BMT approach generally exists for those patients with AML in complete remission.

Clearly, autologous BMT is not an option for patients who do not achieve a complete remission, who relapse prior to BMT or who do not have harvestable marrow. In contrast, recent data from the Stanford University and City of Hope transplant groups showed that patients who never achieved a complete remission can achieve this outcome and have a durable disease-free survival after undergoing allogeneic BMT with HLA-compatible sibling donor marrow.8 Patients with advanced myelodysplastic syndrome who are pancytopenic or in the process of transforming to AML also are not considered appropriate candidates for autologous BMT because durable remission marrow is most likely unobtainable; however, data from the Seattle transplant team demonstrated a durable disease-free survival approaching 50% with allogeneic BMT in this poor-risk group.67 Thus, for certain subsets of AML patients, only allogeneic BMT can offer a potential cure.

It is important to acknowledge that the field of BMT is still in its infancy. Allogeneic transplantations have been performed on a large-scale basis only since the early 1980s and, similarly, autografting for acute leukemia is only in its first decade of development. Initially for end-stage leukemia, treatment options incorporating BMT have grown substantially and are now being recommended as front-line therapy for good-risk AML patients. Results for allogeneic and autologous BMT will undoubtedly continue to overlap as enhancements in both procedures are made. With our increasing knowledge of the biology of AML, approaches based on reliable prognostic indicators will soon become available in an effort to achieve optimum treatment results.

Author

Robert B. Geller, MD, is an Associate Progessor of Medicine, Emory University School of Medicine, Atlanta, Georgia.
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO
Robert B. Geller, MD,
The Emory Clinic,
1327 Clifton ROAD, NE,
ROOM 2721,
ATLANTA, GA 30322.

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