If at First You Don't Succeed: Stem-Cell Transplantation for Acute Myeloid Leukemia After First Relapse

Therapy for younger patients with acute myeloid leukemia (AML) is administered with curative intent. After complete remission (CR) is achieved with initial induction therapy, some form of postremission therapy is required to prevent relapse, and the choice is generally between a few courses of high-dose cytarabinebased chemotherapy or one to two courses of chemotherapy followed by allogeneic stem-cell transplantation. The latter comes in a variety of different flavors, most often using fully human leukocyte antigen (HLA) –matched sibling donors, but now with an expanding choice of unrelated, cord blood, or haploidentical donors as well as a range of myeloablative or reduced-intensity pretransplantation conditioning regimens. Randomized trials have failed to show an advantage of autologous transplantation (perhaps because so many of the marrows were contaminated by minimal residual disease that was not detectable with the technology available at that time), and there is no benefit from continued maintenance chemotherapy. It has been difficult to prove that allogeneic transplantation is superior to chemotherapy alone when applied to the broad, biologically heterogeneous population of younger patients with AML. The trials that have been performed are somewhat imperfect in that patients were assigned to transplantation if they had an HLA-matched sibling, rather than being strictly randomly assigned. In addition, many patients declined transplantation, leading to the imaginative so-called donor versus no donor comparisons that were intended to mimic intent-to-treat analyses. A recent meta-analysis of these randomized trials has suggested that allogeneic transplantation in first CR provides the greatest advantage for patients in higher risk groups as defined by cytogenetics and somewhat less benefit for the markedly heterogeneous groups of patients who are characterized as intermediate risk. The relapse rate is lower after allogeneic transplantation because the graft versus leukemia effect makes an important contribution to the overall outcome. This is balanced by higher rates of treatment-related mortality and morbidity, although there have been improvements in transplantation techniques and considerably reduced short-term mortality in recent years. And indeed, even as a card-carrying member of the nontransplanters union, I acknowledge and so inform my patients that the survival after transplantation has never been shown to be worse than with chemotherapy consolidation in the comparative trials. When counseling patients in first remission, most clinicians also mention that the initial decision is only the first part of the calculation, given that patients who relapse can subsequently receive a transplant in second remission. That said, until now, this could only be stated in a general way because there have been virtually no systematic data that address the feasibility and outcome of later transplantation. Problems include the difficulties in achieving a second remission, the development of complications during reinduction that could preclude transplantation, the administrative delays imposed by insurers, delays in identifying unrelated donors if siblings are not available, and an appreciable post-transplantation relapse rate, among others. Hence the importance of the large and unique analysis from the Medical Research Council (MRC) of the United Kingdom that accompanies this editorial. This is a real-world experience in that the MRC enrolls an extraordinarily high fraction of United Kingdom patients with newly diagnosed AML onto clinical trials and has good follow-up of these individuals. The authors focus on 1,271 patients in first relapse, age 16 to 50 years, who had not received an allogeneic transplant in first CR; 19% of these relapsed patients were alive at 5 years after relapse with a major effect of cytogenetic risk category (32% for favorable, 17% for intermediate, and only 7% for high risk). Other salient findings included the following. First, a perhaps higher than expected rate of second CR was achieved in 55% of patients, and the 5-year overall survival of these responders was 34%. The CR rate varied according to risk group and, although it is not stated explicitly, it is likely that the probability of second CR was strongly affected by the duration of first CR. Second, remarkably, 67% of the remitters could receive transplantations in second CR (perhaps because many of these patients had donors who were identified in first CR but chose not to undergo transplantation, and because they were being observed as part of a clinical trial) with a 5-year survival of 44% in those undergoing one of many different types of allogeneic transplantation. It remains to be seen whether such a high fraction of patients could receive transplantations in the United States, but emphasizes the importance of beginning donor searches at the time of diagnosis. Third, chemotherapy alone could have served as salvage treatment for 16% of those achieving second CR who did not undergo JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 10 APRIL 1 2013