Allogeneic Transplantation for Acute Myelogenous Leukemia in CR1

Abstract

The advisability of allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) in first complete remission (CR1) is an increasingly important subject given the enhanced ability to safely perform reduced-intensity/nonmyeloablative-conditioned HCT in older subjects [1Gooley T. Chien J. Perham S. et al.Reduced mortality after allogeneic hematopoietic cell transplantation.N Engl J Med. 2010; 363: 2091-2101Crossref PubMed Scopus (1128) Google Scholar] and its extension to unrelated donors. The latter has complicated conventional donor versus no donor analyses designed to account for the “guarantee time” that HCT recipients, but not chemotherapy-only recipients, must live before HCT [2Wheatley K. Gray R. Commentary: Mendelian randomization—an update on its use to evaluate allogeneic stem cell transplantation in leukaemia.Int J Epidemiol. 2004; 33: 15-17Crossref PubMed Scopus (68) Google Scholar]. In this issue of BBMT, Østgård et al. [3Østgård L. Lund J. NØrgaard J. et al.Impact of allogeneic stem cell transplantation in first complete remission in acute myeloid leukemia: a national population-based cohort study.Biol Blood Marrow Transplant. 2018; 24: 314-323Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar] use the more appropriate Mantel-Byar method, crediting to chemotherapy follow-up time before HCT [2Wheatley K. Gray R. Commentary: Mendelian randomization—an update on its use to evaluate allogeneic stem cell transplantation in leukaemia.Int J Epidemiol. 2004; 33: 15-17Crossref PubMed Scopus (68) Google Scholar]. They also performed landmark analyses, with subjects receiving HCT after a 200-day or, alternatively, 365-day landmark considered in the chemotherapy-only group. Each of these methods, combined with multivariate analyses, found that HCT in CR1 was associated with less relapse, longer survival, and longer relapse-free survival, regardless of patient age (15 to 60 years versus 60 to 70 years) and cytogenetics (“intermediate” versus “adverse,” with HCT not performed in CR1 in patients with “favorable” cytogenetics), confirming other recent reports [4Versluis J. Hazenberg C. Passweg J. et al.Post-remission treatment with allogeneic stem cell transplantation in patients aged 60 years and older with acute myeloid leukaemia: a time-dependent analysis.Lancet Haematol. 2015; 2: e427-e436Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 5Cornelissen J. Verslius J. Passweg J. et al.Comparative therapeutic value of post-remission approaches in patients with acute myeloid leukemia aged 40-60 years.Leukemia. 2015; 29: 1041-1050Crossref PubMed Scopus (105) Google Scholar]. Choice of donor (matched related versus matched unrelated) and intensity of conditioning did not affect these conclusions. This important paper benefits from use of the Danish National Acute Leukemia Registry, ensuring virtually complete data collection for the 1031 subjects who entered CR1; the median follow-up time for all subjects was 2.2 years. Large transplantation-specific registries often cannot report the proportion of patients undergoing HCT while in CR1, making it difficult to assess the role of selection bias. Here, in contrast, only 19% of patients entering CR1 underwent HCT while in CR1, despite the recommendation that all individuals with adverse cytogenetics or a FLT3-ITD mutation do so, whereas HCT in CR1 was at the physician's discretion in patients with intermediate cytogenetics. Between 2000 to 2004 and 2010 to 2014, the proportion undergoing HCT in CR1 increased from 11% to 27%. These rates are similar to the 15% reported by Dutch-Belgian Cooperative Trial Group for Hematology/Oncology and the Swiss Group for Clinical Cancer Research (HOVON/SAKK) in adults age >60 years [4], but contrast with the 45% reported by HOVON/SAKK in adults age 40 to 60 years and particularly with the 60% of adults age <70 years with intermediate or adverse cytogenetics who had undergone HCT while in CR1 at a major US academic center [6Mawad R. Gooley T. Sandhu V. et al.Frequency of allogeneic hematopoietic cell transplantation among patients with high- or intermediate-risk acute myeloid leukemia in first complete remission.J Clin Oncol. 2013; 31: 3883-3888Crossref PubMed Scopus (37) Google Scholar], as well as the 60% reported by the US SWOG group in adults age <60 years with adverse cytogenetics [7Pagel J. Othus M. Garcia-Manero G. et al.Feasibility of allogeneic hematopoietic cell transplantation among high-risk AML patients in first complete remission: results of the transplant objective from the SWOG (S1203) randomized phase III study of induction therapy using standard 7+3 therapy or idarubicin with high-dose cytarabine (IA) versus IA plus vorinostat.Blood. 2016; 128 (ASH abstract): 1166Google Scholar]. Intuitively, given the ability to find donors for “almost any subject for whom HCT is indicated” [8Appelbaum F. Alternative donor transplant for adults with acute leukemia.Best Pract Res Clin Haematol. 2014; 27: 272-277Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar], it seems the higher the proportion of eligible subjects undergoing HCT in CR1, the less the chance of selection bias, leading to performance of HCT only in patients deemed particularly unlikely be harmed. Appelbaum suggested that approximately 30% of all patients with AML will undergo HCT at some time during their illness, with this proportion unaffected by age up to age 70 [9Appelbaum F. Impact of allogeneic hematopoietic cell transplantation on the outcome of older patients with acute myeloid leukemia.Best Pract Res Clin Haematol. 2017; 30: 320-326Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. However, it remains unknown whether the 60% referred to above [6Mawad R. Gooley T. Sandhu V. et al.Frequency of allogeneic hematopoietic cell transplantation among patients with high- or intermediate-risk acute myeloid leukemia in first complete remission.J Clin Oncol. 2013; 31: 3883-3888Crossref PubMed Scopus (37) Google Scholar] will be generally representative irrespective of age. It would be interesting to know whether not only the relative, but also the absolute, reduction in death following HCT, rather than chemotherapy only, in CR1 changed as the proportion of the authors' subjects who underwent HCT increased between 2000 and 2014. Corresponding data on the number of subjects needed to undergo HCT in CR1 to avoid 1 death if no HCT was performed might be worthwhile as well. In principle, the issue of selection bias might be less pressing if our ability to forecast prognosis allowed accurate comparisons between subjects, only some of whom were selected to receive HCT. A “propensity score,” similar to the one used by Østgård et al. [3Østgård L. Lund J. NØrgaard J. et al.Impact of allogeneic stem cell transplantation in first complete remission in acute myeloid leukemia: a national population-based cohort study.Biol Blood Marrow Transplant. 2018; 24: 314-323Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar] and including such covariates as age, performance status, comorbidities, and cytogenetics, might be used for this purpose. However, recent analyses throw doubt on our predictive ability [10Estey E. Gale R.P. How good are we at predicting the fate of someone with acute myeloid leukaemia?.Leukemia. 2017; 31: 1255-1258Crossref PubMed Scopus (24) Google Scholar]. For example, Walter et al. [11Walter R. Othus M. Paietta R. et al.Effect of genetic profiling on prediction of therapeutic resistance and survival in adult acute myeloid leukemia.Leukemia. 2015; 29: 2104-2107Crossref PubMed Scopus (46) Google Scholar] reported that the addition of information on the mutational status of 17 genes to information about age, performance, and cytogenetics resulted in c-statistic values of only ~.75 for prediction of relapse within 12 months of CR1, with a value of 1.0 indicating perfect prediction and .5 indicating no prediction. Under these circumstances, I agree with Østgård et al. [3Østgård L. Lund J. NØrgaard J. et al.Impact of allogeneic stem cell transplantation in first complete remission in acute myeloid leukemia: a national population-based cohort study.Biol Blood Marrow Transplant. 2018; 24: 314-323Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar] that only a randomized trial would serve to indisputably establish the value of HCT in CR1. Of course, given results like those reported by Østgård et al. [3Østgård L. Lund J. NØrgaard J. et al.Impact of allogeneic stem cell transplantation in first complete remission in acute myeloid leukemia: a national population-based cohort study.Biol Blood Marrow Transplant. 2018; 24: 314-323Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar], subjects might be reluctant to participate, particularly those with adverse cytogenetics, who currently fare very poorly without HCT in CR1. A more palatable trial might involve randomization of intermediate-risk subjects between immediate HCT in CR1 and HCT only in the event of relapse, with HCT used as reinduction therapy or in chemotherapy-induced CR2. Retrospective data in such subjects suggest that a strategy of delay results in similar survival as HCT in CR1, and would require many fewer transplantations [12Burnett A. Goldstone A. Hills R. et al.Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission.J Clin Oncol. 2013; 31: 1293-1301Crossref PubMed Scopus (157) Google Scholar]; however, the reported CR2 rate of 54% in the absence of HCT seems high. Although informative, randomized trials such as those described above would leave fewer subjects available for investigation of newer therapeutic modalities to prevent relapse. Examples are the prophylactic use of azacitidine or FLT3 inhibitors post- HCT or, if HCT is infeasible, autologous central memory/naïve CD8+ T cells transduced to express a WT1-specific T cell receptor. However, perhaps most immediately relevant is the development of methods, most commonly multiparameter flow cytometry (MFC), to detect measurable residual disease (MRD). Particularly if persistent or increasing, MRD detected by MFC in morphologic CR1 (or beyond) is well established as associated with subsequent morphologic relapse within 6 to 12 months regardless of whether or not HCT was performed [13Araki D. Wood B. Othus M. et al.Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: time to move toward a minimal residual disease-based definition of complete remission?.J Clin Oncol. 2016; 34: 329-336Crossref PubMed Scopus (286) Google Scholar, 14Terwijn M. van Putten W.L. Kelder A. et al.High prognostic impact of flow cytometric minimal residual disease detection in acute myeloid leukemia: data from the HOVON/SAKK AML 42A study.J Clin Oncol. 2013; 31: 3889-3897Crossref PubMed Scopus (326) Google Scholar]. Although benefit/risk considerations may mitigate against HCT in CR1 if MRD is present, some data suggest that patients with MRD are nonetheless less likely to relapse when undergoing HCT while in CR1. Future work will shed further light on this question and explore interrelations between MRD assessed by MFC, cytogenetics/FISH, and next-generation sequencing. The relevance of MRD may depend on the development of low-intensity therapies for its elimination and evaluation whether such elimination is clinically beneficial, for example, by reducing the risk of relapse after HCT. Financial disclosure: The authors have nothing to disclose. Conflict of interest statement: There are no conflicts of interest to report.