Transplantation As Salvage Therapy For Patients With Matched Siblings

Although there are no randomized trials to prove the point, retrospective comparisons suggest that HCT should be considered for almost all patients of age 55 or less with matched siblings who relapse after an initial remission. There are occasional patients with long first remissions (greater than 2 years according to the MD Anderson data) who may do as well with chemotherapy, reserving transplantation for a subsequent relapse, but such patients are uncommon.37

Whether patients with AML in first relapse should undergo reinduction therapy before proceeding to transplant from a matched sibling is an unresolved question. A study from Seattle of 126 patients transplanted in untreated first relapse reported a 28% 5-year disease-free survival.38 This result is only slightly less than what might be expected for matched sibling transplants for AML in second remission. For example, the European Transplant Group reported a 35% 3-year disease-free survival rate among 459 patients transplanted in second remission from matched siblings.39 However, on an average only approximately 50% of patients in first relapse will be successfully reinduced, 10-15% may die during the reinduction attempt, and others may develop complications that would preclude subsequent transplantation. The results of transplantation in first relapse appear best in those without substantial numbers of circulating blasts. Thus, for those patients with matched siblings where relapse is found early, proceeding straight to allogeneic transplant can be recommended. However, for those with substantial numbers of circulating blasts or those for whom considerable time is required to identify the donor or arrange the logistics for transplantation, reinduction will be necessary.

Discussions of the separate elements of the transplant procedure are included in Chapter 92. However, there have been no randomized trials, addressing the best preparative regimen, source of stem cells, or form of graft-versus-host disease (GvHD) prophylaxis specifically focused on the treatment of AML in first relapse or second remission.

Because of the acute toxicities associated with the high-dose preparative regimens commonly used in the treatment of AML, as well as an increased incidence of GvHD in older patients, allogeneic transplantation in the past was generally restricted to younger patients, generally those less than age 55-60 years. It has long been appreciated that much of the antileukemic effects of allogeneic HCT came from the graft-versus-tumor (GvT) effect. Thus, in an effort to bring the benefits of allogeneic transplantation to an older population of patients, investigators have begun devising strategies to insure allogeneic engraftment without the use of high-dose therapy. A number of reduced-intensity regimens have been developed and used in the treatment of relapsed acute leukemia. These have varied in intensity from low-dose regimens, such as the Seattle regimen consisting of flu-darabine 30 mg/kg for 3 days plus 200 cGy total body irradiation (TBI) with posttransplant mycophenolate mofetil and cyclosporine, to regimens of somewhat greater intensity, such as the busulfan 8 mg/kg, flu-darabine, and antithymocyte globulin regimen.40 The Seattle regimen is able to insure engraftment in the large majority of patients and, in patients ranging in age from 50 to greater than 70 years, has been associated with a 100-day nonrelapse mortality of 5-8% and an overall non-relapse mortality of less than 20%.41 These reduced- intensity regimens have not been, in general, effective for patients in frank relapse, but results in second- remission patients are encouraging. The Seattle group recently reported on a group of 39 patients with AML in second remission who were not candidates for ablative transplants and recorded the disease-free survival at 3 years as slightly in excess of 40%.42

TRANSPLANTATION AS SALVAGE THERAPY FOR PATIENTS WITHOUT MATCHED SIBLINGS Patients with AML in second remission but lacking matched family member donors are candidates for either autologous or matched unrelated HCT. Randomized trials comparing the two have not been reported. Relatively small individual trials of autolo-gous transplantation in second remission report 3-year disease-free survival rates ranging from 21 to 52%, with registry data settling at about 30% disease-free survival.43 Better results can be expected in patients with longer first remissions. A retrospective matched pair analysis of the outcome of 340 patients with AML in second remission treated with either autologous or matched sibling transplantation reported lower relapse rates and somewhat better survival with allo-geneic transplantation (39% vs 30% at 4 years).44 Less data are available about the use of matched unrelated donor transplants for AML in second remission. The 5-year survival rate reported by the National Marrow Donor Program in 473 patients was 31%.45 Similar results have been published from single institutions.46 A case-controlled study was conducted by the European Bone Marrow Transplant Group in which the outcome of 46 recipients of unrelated donor transplants for AML in second remission was compared with twice that many autologous recipients.47 Long-term outcomes, as measured by overall survival, were similar between the groups. While this study has many shortcomings, including its retrospective nature and small sample size, without further data for direction, autologous transplantation might be considered as the best option for older patients and those with more favorable disease characteristics, such as longer first remission, while matched unrelated donor transplantation might be more appropriate for younger patients and those with more unfavorable disease.

Although the amount of data are much more limited, other sources of stem cells are being explored for patients without matched siblings or matched unrelated donors, including the use of haplomismatched donors and the use of cord blood transplants. Both of these approaches are discussed more fully in Chapters 36 and 97.

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