Autologous hematopoietic cell transplantation for AML in first remission – An abandoned practice or promising approach?

Accepted Manuscript

Autologous Hematopoietic Cell Transplantation for AML in First Remission – an Abandoned Practice or Promising Approach? Moshe Yeshurun MD , Ofir Wolach MD PII: DOI: Reference:

S0037-1963(19)30005-8 https://doi.org/10.1053/j.seminhematol.2019.01.001 YSHEM 50996

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Seminars in Hematology

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22 January 2019 24 January 2019

Please cite this article as: Moshe Yeshurun MD , Ofir Wolach MD , Autologous Hematopoietic Cell Transplantation for AML in First Remission – an Abandoned Practice or Promising Approach?, Seminars in Hematology (2019), doi: https://doi.org/10.1053/j.seminhematol.2019.01.001

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ACCEPTED MANUSCRIPT

Autologous Hematopoietic Cell Transplantation for AML in First Remission – an Abandoned Practice or Promising Approach?

Moshe Yeshuruna, MD and Ofir Wolacha, MD a

Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital, Petah Tikva,

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Israel and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Corresponding author: Moshe Yeshurun, MD, Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital, Jabotinski Street, Petah Tikva, 49100 Israel. Tel:

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+972 50 4065543; e-mail: [email protected]

Disclosure: the authors have nothing to disclose

Abstract

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Patients with acute myeloid leukemia (AML) who achieve complete remission after induction therapy require post remission therapy (PRT) in order to remain disease

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free. The role of autologous hematopoietic cell transplantation (autoHCT) in the PRT setting is controversial and is largely based on older trials that were hampered by

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low transplant realization rates and relatively high non-relapse mortality rates as compared to chemotherapy-based approaches. In this review we summarize current

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data regarding autoHCT in the PRT setting. Most current studies demonstrate that autoHCT is better than chemotherapy-based

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PRT in terms of leukemia free survival (LFS). In most recent studies, autoHCT results in comparable outcomes to alloHCT from matched sibling or matched unrelated donors in patients with intermediate-risk AML in first complete remission and can be considered as a valid alternative. Adverse-risk AML patients do not benefit from autoHCT and should be referred to alloHCT. Minimal residual disease (MRD) is a powerful prognostic factor and may identify patients that could benefit from an autoHCT PRT. As with other PRT approaches,

ACCEPTED MANUSCRIPT MRD negativity at the time of autoHCT is associated with the best outcomes. Prospective risk-adapted approaches that assign patients to autoHCT based on disease-risk and MRD status are ongoing and may pave the way for revisiting

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autoHCT in specific subpopulations of AML patients in first remission.

ACCEPTED MANUSCRIPT Introduction Post-remission therapy (PRT) is an essential component in the treatment of patients with acute myeloid leukemia (AML) after attaining first complete remission (CR). Disease recurrence is inevitable within a few weeks or months without further therapy [1]. The three PRT alternatives are consolidation chemotherapy, autologous hematopoietic cell transplantation (autoHCT) and allogeneic hematopoietic cell

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transplantation (alloHCT). AlloHCT provides the most potent anti-leukemic effect as reflected in almost every trial by significantly reduced relapse rate after alloHCT as compared with the two other PRT modalities. However, this advantage is often compromised by the combined effect of graft-versus-host disease (GVHD) and increased non relapse mortality (NRM) associated with alloHCT. In contrast,

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consolidation chemotherapy and autoHCT are associated with lower NRM, no GVHD and better long-term quality of life; however both are associated with increased risk of leukemia relapse.

AutoHCT was introduced in the past by several groups as a valid PRT approach that

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enables delivery of myeloablative chemo-radiotherapy with reasonable NRM and potential gains in LFS. It grew popular in the 1990’s and early 2000’s, more so in

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Europe than in the United States based on reports from large randomized cooperative trials which compared autoHCT with chemotherapy and alloHCT from

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matched sibling donors [1-5]. More than 27,000 patients who have undergone autoHCT for acute leukemia were reported to the European Society for Blood and

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Marrow Transplantation (EBMT), mostly for AML [6]. Yet, despite its popularity in the past, autoHCT for AML has become more controversial and its use has dropped

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considerably over the years. In 2013, 7633 patients who underwent alloHCT for acute leukemia were reported to the EBMT compared to only 455 patients who underwent autoHCT. In 2017, overall 4032 patients with AML in CR1 were reported to the EBMT, among them 3740 alloHCT and only 292 autoHCT (EBMT survey on transplant activity 2017). Furthermore, while autoHCT still remains an optional PRT modality in AML according to the European Leukemia Network (ELN) recommendations [7], it is no longer listed as an optional PRT modality in the 2017 updated National Comprehensive Cancer Network (NCCN) guidelines [8].

ACCEPTED MANUSCRIPT As a rule, treatment recommendations should be based on the modality which offers the best leukemia-free survival (LFS) and overall survival (OS) [9]. However, when two treatment modalities are equally effective, there is an unequivocal justification for choosing the treatment modality that is less often associated with long term toxicities and disabilities. Furthermore, it may be equally justified to choose among two treatment modalities with similar OS, the one which is less frequently associated

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with major restricting problems, even if it may result in worse LFS. Significant changes have occurred in the last two decades which justify the reassessment of the role of autoHCT in AML. First, there was a steep decline in NRM rates following autoHCT from roughly 15% in the distant past [1-5] to 0%-4% in the more recent era [10, 11]. Additionally, the incorporation of somatic landscape and

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minimal residual disease (MRD) assessment into the prognostic stratification of patients with AML and the recent introduction of novel targeted therapies, may affect the way we should choose and apply PRT’s and may prompt the resurfacing of autoHCT for certain patients with AML. Thus, the purpose of this article is to review

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the most recent updated literature in the field and to explore whether the role of autoHCT in the treatment of AML should be revisited in the era of MRD assessment,

Comparing

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molecular profiling and novel, targeted approaches. autologous

transplantation

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chemotherapy

and

allogeneic

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transplantation: insights from the past decade

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Comparing autologous transplantation to chemotherapy Recently, several trials were published comparing autoHCT to standard consolidation

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chemotherapy for AML in CR1. These trials may be more informative as they apply more current standards of transplant and supportive care (Table 1). In a prospective, randomized phase 3 trial on behalf of the HOVON and SAKK Cooperative Consortium, younger patients (16-60 years) with de novo AML in CR1 were randomized between intensive consolidation chemotherapy (n=259) or autoHCT (n=258) from peripheral blood stem cell (PBSC) grafts. As opposed to previously reported randomized studies that were profoundly affected by the fact that almost half of the patients assigned for autoHCT did not actually receive their assigned

ACCEPTED MANUSCRIPT intervention [1, 4], in the present study, over 90% of patients received their assigned treatment. The autoHCT group showed reduced relapse rates (58% vs 70%, P=0.02), better relapse-free survival (RFS) at 5 years (38% vs. 29%, P=0.065, hazard ratio = 0.82; 95% confidence interval (95%CI), 0.66-1.1) with NRM of 4% versus 1% in the autoHCT and chemotherapy arms, respectively (P=0.02). No difference was noted in OS (44% vs. 41% at 5 years, P=0.86) mainly because patients on the chemotherapy

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arm had more salvage opportunities [11]. In a subsequent retrospective study reported by the same group, the outcomes of 760 patients between 40 and 60 years of age with newly diagnosed AML in CR1, who participated in two consecutive, prospective HOVON–SAKK phase 3 trials were compared according to PRT (alloHCT, n=337; autoHCT, n=152; chemotherapy, n=271). OS was significantly different in the

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favorable, intermediate and adverse leukemia risk groups as categorized by the ELN AML risk classification [11] (OS at 5 years 74±4% in favorable risk, 51±3% in intermediate-I risk, 47±6% in intermediate-II risk and 33±4% in adverse-risk AML). Overall, improved OS was found for alloHCT recipients as compared with patients

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receiving chemotherapy (57±3% vs. 40±3% at 5 years, P<0.001). In addition, OS was significantly improved in recipients of autoHCT as compared with recipients of

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chemotherapy (54±3% vs. 40±3% at 5 years, P=0.02). In intermediate-risk patients, alloHCT and autoHCT significantly improved OS as compared with chemotherapy (60±4% and 54±5%, respectively, vs. 36±4% at 5 years, P<0.001), while OS after

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alloHCT versus autoHCT was not significantly different. However, improved RFS was found in patients with intermediate-risk AML receiving PRT with alloHCT, after either

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myeloablative or reduced intensity conditioning regimens as compared with autoHCT (56±4% versus 39±5% at 5 years, respectively, P=0.04). Based on these

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findings, the authors concluded that alloHCT should be preferred over chemotherapy as PRT in patients with intermediate- and poor-risk AML aged 40–60 years, while autoHCT remains a viable treatment option in patients with intermediate-risk AML [12]. In a small retrospective study, Heinia et al. compared the outcome of AML patients over 65 years in CR1 treated with autoHCT (n=16) or chemotherapy (n=24) and demonstrated the superiority of autoHCT over chemotherapy in terms of PFS (16.3

ACCEPTED MANUSCRIPT months vs. 5.1 months, P=0.0166) and OS (not reached vs. 8.2 months; P=0.0255). The outcome of these older patients treated with autoHCT was comparable to 49 younger patients treated with autoHCT [13]. In a prospective multi-center trial performed by the German Study Alliance Leukemia (SAL) group, 586 patients (aged 15–60 years) with AML in CR1 after double induction therapy were randomized for PRT with either alloHCT (n=172), autoHCT (n=191) or

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chemotherapy (n=223). Age, percentage of CD34-positive blasts, FLT3-ITD allelic ratio, cytogenetic risk, and de novo versus secondary AML were identified as independent prognostic factors and were used to create a risk scoring system that separated patients into 3 prognostic groups (referred in this study as ‘PRT score’). The PRT score separated patients into three groups: favorable (n=190; 3-year

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survival 68%), intermediate (n=198; 49%), and unfavorable (n=64; 20%).In the favorable PRT group, patients given alloHCT (n=60) had a better OS at 3 years as compared to those given chemotherapy (n=56) (82% vs. 55%, p=0·0012) or autoHCT (n=74)(82% vs. 66%, p=0·044). In the intermediate PRT score group, patients given

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autoHCT (n=69) had the best survival (62%, 50–72) compared with those given

p=0·0045) [14].

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chemotherapy (n=72) (62% vs. 41%, p=0·0006) or alloHCT (n=57) (62% vs. 44%,

In a recently published prospective Japanese trial, patients with favorable or

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intermediate-risk AML according to the SWOG risk stratification were randomized to consolidation chemotherapy by high-dose cytarabine (n=45) or autoHCT (n=42). In

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an intention-to-treat analysis, comparable 3-year DFS (41% and 55%), relapse (54% and 41%), NRM (2.4% and 4.8%) and 3-year OS (77% and 68%) were reported,

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respectively. However, these results might have been affected by the different rates of PRT realization: over 90% of patients completed the consolidation chemotherapy plan while only half of patients received the planned autoHCT [15]. A retrospective single center trial from British Columbia reporting on PRT in patients with AML with intermediate-risk karyotype in CR1 applied a propensity scoreadjusted analysis in order to control for inherent bias in treatment selection. The PRT approaches analyzed were alloHCT from matched sibling donors (MSD) (n=46), matched or mismatched unrelated donors (UD/MM) (n=17), autoHCT (n=25) and

ACCEPTED MANUSCRIPT chemotherapy (n=47). Patients that underwent MSD alloHCT had the best OS (HR, 0.4; 95%CI, 0.2-0.8; P=0.009) and LFS (HR, 0.3; 95%CI, 0.2-0.6; P < .001) while autoHCT was comparable to UD/MM and chemotherapy. Of note, there was a higher than expected NRM for autoHCT in this study (15%) [16]. Comparing autologous transplantation to allogeneic transplantation In addition to the studies cited above, several other studies compared specifically

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autologous to allogeneic transplantation. An analysis from the Center for International Blood and Transplant Research (CIBMTR) registry compared retrospectively the transplant outcomes for younger adult patients (19-60 years) with AML in CR1 receiving myeloablative conditioning (MAC) followed by alloHCT

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from matched sibling donors with bone marrow (BM) (n=475) or peripheral blood (PB) (n=428) grafts vs. autoHCT with PB grafts (n=230). At 5 years, the combined effects of NRM (lower in autoHCT) and relapse incidence (higher in autoHCT) translated into inferior LFS for patients undergoing autoHCT (RR 1.32, P=0.01) while OS was not significantly different. For patients aged 40 years or younger, the 5-year

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LFS and OS rates were the same following autoHCT and alloHCT: 57% vs. 60% and 62 vs. 64%, respectively. The authors conclude that autologous peripheral blood may

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provide an acceptable alternative for PRT for patients with AML in CR1, especially in

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the absence of a fully MSD [17].

In a recent sizable (n=2879) retrospective study on behalf of the EBMT, outcomes of

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AML patients in CR1 transplanted from matched unrelated donors (10/10 UD-HCT, n=1302), mismatched unrelated donors (9/10 UD-HCT, n=375) and autoHCT (n=1202) were compared. Matched UD-HCT was associated with the best LFS (HR,

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0.7; P=0.0016), while LFS was similar between autoHCT and 9/10 UD-HCT (HR, 0.8; P=0.2). However, there was no difference in OS between the groups (10/10 UD-HCT vs. autoHCT: HR, 0.98; P=0.84; 9/10 UD-HCT vs. autoHCT: HR, 1.1; P=0.49). In the intermediate-risk patient group OS was similar for patients undergoing autoHCT and 10/10 UD-HCT (HR, 0.95, p = 0.88) while inferior survival was noted for 9/10 UD-HCT as compared to autoHCT (HR, 1.6; P=0.049). These data suggest that autoHCT can serve as a suitable option for patients with intermediate-risk patients lacking a fully HLA-matched donor [18].

ACCEPTED MANUSCRIPT An additional retrospective study on behalf of the Japanese registry, compared the outcomes of adult AML patients in CR1 transplanted from auto-PBSCs (n=375), to alloHCT from MSD with BM (n=521) or PB (n=380) grafts. In multivariate analysis, LFS was similar for all transplant approaches (auto-PBSCT vs. allo-BMT, HR, 1.23; P=0.16 and vs. allo-PBSCT, HR, 1.13; P=0.40, respectively), suggesting that in the absence of a MSD, autoHCT is a viable alternative [19].

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The potential utility of autoHCT in older adults (>50 years) with AML in CR1 was demonstrated in a retrospective study conducted by the EBMT, where outcomes of patients older than 50 years that received reduced intensity conditioning (RIC) alloHCT (n=214) or autoHCT (n=1152) were compared. In this analysis, autoHCT was associated with higher relapse rates, lower NRM, however with comparable LFS and

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OS in CR1 [20].

Comparing autologous transplantation to allogeneic transplantation from alternative graft sources

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Recent studies looked at the utility of autoHCT as compared to alternative graft sources. In a single Chinese center retrospective study, involving patients with

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favorable- and intermediate-risk AML in CR1, the outcomes of 88 patients with autoHCT were compared to those of 107 non-T-cell depleted haploidentical

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transplants (haplo-HCT). The impact of high relapse incidence in the autoHCT group was balanced by low NRM, resulting in similar OS as compared to haplo-HCT

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(79.0±4.6% vs. 80.1±5.0%; P=0.769) and RFS (66.1±5.2% vs. 77.4±4.8%; P=0.079), respectively. In patients with intermediate-risk AML, haplo-HCT yielded better OS

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due to comparable NRM between the groups [21]. In a matched pair-analysis study conducted by the EBMT, the outcomes of 188 nonT-cell depleted haplo-HCT and 356 autoHCT transplants performed for acute leukemia (AML, 71% and ALL, 29%) between the years 2007 and 2012 were compared. Transplant centers with more extensive experience in haplo-HCT (>5 haplo-HCT transplants for acute leukemia) were defined as 'Haploidentical expert' centers, while other centers were designated ‘regular centers’. In MVA, NRM was higher after haplo-HCT in expert (HR, 4.7; P=0.00004) as well as in regular (HR, 8.98;

ACCEPTED MANUSCRIPT P<10-5) centers. Lower relapse incidence was noted for haplo-HCT in expert centers (HR, 0.39; P=0.0003), but in regular centers was similar to that for autoHCT. Center experience with haplo-SCT proved to be crucial to outcome. LFS and OS were higher following autoHCT than haplo-HCT in 'regular centers' (HR, 1.63; P=0.008 and HR, 2.31; P=0.0002, respectively) but similar to those following haplo-HCT in 'expert centers'. Regarding AML only, there was no significant difference for LFS and OS in

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the whole population. However, the OS in the intermediate cytogenetic risk group transplanted in CR1 was superior after autoHCT (71% vs. 58%; P=0.03). These results underscore the importance of expertise when performing haplo-HCT. Furthermore, these data suggest that in the absence of a matched donor, autoHCT should be considered a better alternative than haplo-HCT in AML patients with intermediate

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cytogenetics in CR1, and for patients with acute leukemia in CR1/2 in centers lacking experience with haploHCT [22].

Most of the above summarized studies focused on patient sets of all genetic risk groups. Subgroup analyses within these patient cohorts suggested that only the non-

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adverse cytogenetic patient groups are those who may derive benefit from autoHCT PRT. In line with these findings, in a single center retrospective study from South

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Africa, Novitzky et al. analyzed the outcome of AML patients in CR1 that were treated with MAC autoHCT (n=43) or in-vitro T-cell depleted alloHCT from MSD

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(n=32) and showed that by 3 years, all patients with unfavorable cytogenetics receiving an autologous graft died of disease recurrence whereas one third of

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patients treated with alloHCT survived (0% versus 35%; P=0.05), while patients with low or intermediate cytogenetic risk undergoing autoHCT or alloHCT appeared to

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have similar outcomes [23]. Autologous transplantation in specific genetic subtypes Several studies in recent years tried to explore the efficacy of autoHCT in specific genetic subgroups (Table 2). Schlenk et al. analyzed 124 patients in CR1 with double mutant CEBPA treated on 4 published HOVON/SAKK and 3 German-Austrian AML Study Group (AMLSG) protocols. AlloHCT, autoHCT and chemotherapy were applied in 32, 20 and 72 CR1 patients, respectively. AlloHCT and autoHCT were associated with a significant better RFS as compared to chemotherapy (P<0.001) but this did not

ACCEPTED MANUSCRIPT translate into better OS, mainly due to successful salvage strategies in relapsing patients [24]. Gorin et al. studied the EBMT registry and compared autoHCT and alloHCT in 325 patients with core-binding factor leukemia (inversion 16 and t (8;21)). Higher relapse rates and lower NRM in autoHCT compared to alloHCT resulted in similar LFS in this favorable risk patient subset [25].

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Based on the Japanese transplant registry, Mizutani et al. compared the outcomes of adult AML patients with normal karyotype (NK) in CR1 transplanted from auto-PBSCs (n=177), to alloHCT from MUD BM grafts (n=173). In MVA, LFS was not significantly different between groups (HR, 1.18; P=0.53).

Again, this study suggests that

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autoHCT remains a viable alternative to alloHCT from MUD for patients with NK-AML in CR1 [26].

Versluis et al. reported on 521 patients up to the age of 60 with NK-AML in CR1 with known FLT3/NPM1 mutational status that were enrolled on consecutive prospective

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HOVON/SAKK trials and received one of 4 PRTs: RIC alloHCT (n=68), MAC alloHCT (n=137), autoHCT (n=168) or chemotherapy (n=148). OS and RFS were comparable

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for all interventions for patients with favorable risk (NPM1+/FLT3-). Intermediate risk patients (NPM1-/FLT3- or low FLT3 ITD allelic ratio) seemed to have better OS and

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RFS with a RIC alloHCT as compared to chemotherapy (HR, 0.56; P=0.022 and HR, 0.50; P=0.004, respectively) or autoHCT (HR, 0.60; P=0.046 and HR, 0.60; P=0.043,

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respectively), unlike MAC alloHCT which had similar OS and LFS as chemotherapy and autoHCT. Poor risk (FLT3+ high-mutant to wild-type ratio) had a very poor

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outcome, with low patient numbers hampering a comparison by type of PRT [27]. A recent report from the Acute Leukemia Working Party of the EBMT registry assessed the prognostic impact of FLT3 and NPM1 mutational status in 405 de novo AML patients with normal karyotype in CR1 undergoing autoHCT, most of them receiving a PB-based autograft and non-TBI conditioning (93% and 90%, respectively). The impact of FLT3/NPM1 mutational status was pronounced. Patients with FLT3-/NPM1+ demonstrated the best outcome with 5-year LFS of 62%, OS of 74% and a relapse rate of 35%, while patients with FLT3+/NPM1- did poorly, with 5-

ACCEPTED MANUSCRIPT year LFS and OS of 21% and 33%, respectively and a relapse rate of 79%. In MVA, the combination of molecular markers was the strongest predictor of LFS (FLT3-/NPM1+ (reference), FLT3-/NPM1-: HR 2.39 (1.65-3.46), FLT3+/NPM1+: HR 2.24 (1.33-3.75), FLT3+/NPM1-: HR 5.09 (2.94-8.82) [28]. In a single center retrospective study from Israel, Beyar-Katz et al. compared outcomes based on PRT choice in 79 consecutive AML patients (median age, 47

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(range 18-73) years) with favorable ELN AML. Thirty eight (48%) patients had NPM1+ /FLT3-, 18 (23%) patients had t (8:21) and 23 (29%) were positive for inv(16). Forty patients (50%) received chemotherapy alone, 26 patients (33%) received autoHCT and 13 (16%) underwent alloHCT. The treatment groups were balanced for base line characteristics excluding age that was significantly higher in the chemotherapy only

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group. RFS and OS were significantly superior in AML patients with favorable cytogenetics receiving post-induction high-dose therapy with either autoHCT or alloHCT. Two-year OS was 49%, 80%, and 67% for the chemo, autoHCT and alloHCT groups, respectively (P=0.0026) and NRM at 3 months was 10%, 0% and 15%,

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respectively. Relapse rate was 70% in the chemo group, 15.4% in the autoHCT group and 19.2% in the alloHCT group (P<0.0001)[29].

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transplantation

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The use of minimal residual disease status for selecting patients for autologous

MRD status in CR1 is a powerful prognostic factor for leukemia outcome prediction.

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Measuring MRD with real-time PCR based platforms in patients with core-binding factor leukemia and in patients with mutated NPM1 has been shown to have

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prognostic value [30-32]. Flow-based methods to assess MRD in remission (multiparameter flow cytometry (MFC)) also demonstrate equal prognostic utility in AML [33]. MRD is increasingly reported as a tool to prospectively direct post remission interventions [34, 35] and a recent consensus report from the European LeukemiaNET underscores the importance of this tool in AML prognostication and therapy [36]. Several studies have demonstrated that achieving a negative MRD status before alloHCT is an important milestone that affects post-transplant relapse risk [37, 38]. Much less is known on the prognostic effect of MRD status prior to

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autoHCT in AML. Obviously, the concept of autografting a patient with a stem cell product containing detectable amounts of residual disease is however unsettling, as there is concern that occult clonogenic tumor cells in the infused graft may contribute to relapse. In relapsed acute promyelocytic leukemia (APL), MRD status significantly and adversely affects outcome after autoHCT [39]. Wetzler et al. demonstrated that autoHCT may be a viable PRT approach for patients with

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Philadelphia-positive acute lymphoblastic leukemia (ALL). They treated 19 patients with imatinib plus sequential chemotherapy that resulted in most patients attaining a negative MRD status prior to autoHCT. This strategy led to outcomes after autoHCT that were comparable to those of 15 patients treated with alloHCT in CR1 [40]. These examples from APL and Philadelphia-positive ALL highlight the potential utility of an

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MRD-guided approach for selecting patients for autoHCT. They also demonstrate how novel, targeted agents that are increasingly incorporated to standard care in AML can affect the proportion of patients achieving MRD.

The EORTC/GIMEMA AML-10 trial reported on 31 patients that received autoHCT in remission and that were prospectively evaluated for MRD by MFC (cutoff level of

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3.5X10-4 leukemia cells). Patients with a positive MRD before transplant (n=12, 39%)

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were regarded as high-risk and patients with a negative MRD before transplant (n=19, 61%) were designated low-risk group. MRD was a strong predictor for relapse in this setting: all patients who were in the high-risk group relapsed at a median of 7

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months. In the low risk group, 3 of the 5 relapses rendered MRD positive prior to

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relapse. Pre-HCT MRD status was the most powerful factor linked to relapse in the MVA (P<0.0014) [41]. In a prospective Italian study, AML patients in CR1 with a positive MRD, defined as more than 3.5X10-4 leukemia cells by MFC, had reduced

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RFS and OS after autoHCT as compared to alloHCT (5 years RFS and OS of 14% and 28% for autoHCT [n=28] versus 47% and 44% for alloHCT [n=14]) [33]. A single center Chinese study compared retrospectively the outcomes of 172 patients with AML that underwent autoHCT (n=46) or alloHCT (n=126). Patients in CR1 were potential candidates for alloHCT if MSD or MRD were available. In the absence of a matched donor, autoHCT or sequential consolidation chemotherapy were recommended. No differences in DFS and OS were noted between the autoHCT

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and alloHCT groups. MRD status after one course of consolidation and cytogenetics emerged as independent risk factors for DFS (HR, 2.04, P = 0.049; HR, 1.8, P = 0.007; respectively). In patients with favorable or intermediate risk cytogenetics and negative MRD after one course of consolidation autoHCT and alloHCT resulted in similar DFS (P = 0.270). AutoHCT was inferior in all other scenarios due to increased risk of leukemia relapse [42].

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In a somewhat different approach to pre-transplant MRD assessment, Messina et al. evaluated Wilms’ tumor 1 (WT1) transcript levels in auto-PBSC grafts used for autoHCT in 30 consecutive AML patients in CR1 and assessed their effect on clinical outcome. At diagnosis, all patients had WT1 overexpression. The median WT1 transcript level in the graft of patients who relapsed was significantly higher than of

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those who did not relapse after transplantation (P <.0001). A cut-off level of 80 WT1 copies/ABL 10e4 copies was defined to discriminate between positive and negative grafts. The cut-off level was strongly associated with disease recurrence, DFS and OS [43]. In contrast, Mule et al. found that WT1 expression in auto-PBSC grafts was

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poorly predictive of relapse in a cohort of 72 patients auto-transplanted in remission (sensitivity of 14% and specifity of 94% for prediction of relapse). MFC-based MRD of

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the graft products also performed poorly. Better prediction of relapse was attained when a PCR based approach was applied to detect residual disease based on disease

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specific somatic drivers (such as CBF transcripts or NPM1). In the first year of follow up, no MRD negative patients in this group relapsed, whereas 84% of MRD-positive

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patients relapsed (hazard ratio, 12.45; log-rank, P = .0016) [44]. Taken together, the above described trials suggest that MRD is a powerful predictor

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for relapse and that an integrated risk assessment approach based on cytogenetics and MRD may identify the group of patients with lower risk of relapse in whom alloHCT can be potentially spared and autoHCT be considered in lieu. Indeed, the prospective AML1310 GIMEMA Group phase 2 trial demonstrated the feasibility and efficacy of a risk adapted, MRD-driven PRT allocation program. 515 younger patients (age 18-61) with de-novo AML were assigned to a specific PRT based on ELN AML risk classification. Favorable-risk patients received autoHCT, highrisk patients, alloHCT and intermediate-risk patients were allocated to autoHCT or

ACCEPTED MANUSCRIPT alloHCT, depending on the levels of flow-based MRD after consolidation therapy. Among 341 patients who achieved CR1 and completed one cycle of consolidation, 114 (33%) were allocated to the low-risk category (autoHCT), 122 (36%) to the highrisk category (alloHCT) and 78 (23%) to the intermediate-risk category (autoHCT or alloHCT). In 27 patients (8%) belonging to the intermediate-risk category, MRD was negative and they were to receive autoHCT. Overall, 109 (33%) and 123 (36%) of 341

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patients received autoHCT and alloHCT, respectively. At 2 years, OS and DFS in the low-risk category was 75% and 64%, in the high-risk category 43% and 45%, in the intermediate-risk, MRD-negative fraction 79% and 61%, and in the intermediate-risk MRD-positive group 70% and 67%, respectively. Thus, in the intermediate-risk category, alloHCT can be avoided if MRD is not detectable. However, if MRD remains

[45]. Optimizing the conditioning regimen

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positive, alloHCT can prolong OS and DFS to equalize those of the low-risk category

The combination of busulfan plus melphalan (BU/MEL) has been used by GITMO as

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conditioning regimen in 129 adult AML patients undergoing autoHCT. The 8-year projected OS and LFS rates were 62% and 56%, respectively. The relapse rate was

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46%, and the NRM rate was 4.7% [46]. In a recent retrospective study by Gorin et al. on behalf of the EBMT, outcomes of 853 patients with AML in CR1 undergoing

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autoHCT between the years 2005 and 2013 were compared by pre-transplant conditioning regimen, busulfan plus cyclophosphamide (BU/CY, n=596) vs. busulfan

CE

plus melphalan (BU/MEL, n=257). At 3 years, BU/MEL conditioning was associated with a lower relapse incidence (39.5% vs. 52.2%; HR, 0.65; P=0.003) a better LFS

AC

(55.4% vs. 44.6%; HR, 0.69; P=0.005), and a better OS (73.8% vs. 63%; HR, 0.62; P=0.0007) as compared to BU/CY conditioning, with no difference in the NRM rate (BU/MEL vs. BU/CY, 4.5% vs. 3.2%, respectively) [47]. In a subsequent study published by the same group, the association between type of conditioning and cytogenetic risk group was investigated; 1137 patients received BU/CY and 512 BU/MEL between the years 2000 and 2016. BU/MEL conditioning was associated with better outcomes in patients with poor-risk genetics (defined as poor cytogenetics and/or presence of the FLT3-ITD mutation). In this high-risk group

ACCEPTED MANUSCRIPT BU/MEL was associated with a lower relapse incidence at 5 years (53% vs. 69%; HR, 0.52; P=0.002), a better LFS (42% vs. 25%; HR, 0.54; P=0.002) and a better OS (54% vs. 36%; HR, 0.61; P=0.02). Conditioning type did not seem to affect outcome in the non-high-risk group [48]. Summary Choosing the most appropriate PRT approach for patients with AML in first remission

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is a complicated task. Several factors need to be taken into consideration including the risk for disease resistance, mortality associated with a specific approach, the impact of PRT on the short- and long-term quality of life and of course, the patients’ wishes. In this complicated scenario, autoHCT may offer a balanced and effective

AN US

approach to PRT.

In recent years several studies assessed the safety and efficacy of autoHCT as compared to chemotherapy and/or alloHCT. These trials were comprehensively reviewed herein and include prospective cooperative efforts but also many registry

interpreted with caution.

M

retrospective analyses that are limited by their design and scope and should be

ED

Most current studies demonstrate that autoHCT is better than chemotherapy-based PRT in terms of leukemia free survival (LFS). This outcome may be related in part to

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the significant improvement in supportive care and the optimization of conditioning regimens that result in lower NRM and better disease control with autoHCT in recent

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years. Recent data also highlights the role of autoHCT in patients with intermediaterisk AML, a group of patients that are usually offered alloHCT in first remission. In

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this patient group autoHCT results in comparable outcomes to alloHCT from matched sibling or matched unrelated donors and can be considered as a valid alternative. Other studies highlight the favorable outcome with autoHCT in these patients as compared to alternative donor sources, especially in centers that are less experienced with haploidentical, mismatch and cord-blood allo-transplants. As with any PRT approach, disease relapse including late relapses are a concern after autoHCT; recent data demonstrated that about one-third of patients that relapse after autoHCT can be salvaged with a subsequent alloHCT [49, 50].

ACCEPTED MANUSCRIPT Minimal residual disease (MRD) is a powerful prognostic factor that is increasingly used to inform PRT choices. As with other PRT approaches, MRD negativity at the time of autoHCT is associated with the best outcomes while a positive pre-transplant MRD is associated with high relapse rates. Similar to approaches currently pioneered in the alloHCT setting, targeted approaches to decrease the rate of pre-transplant MRD-positivity as well as post-transplant maintenance strategies may further reduce

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the rates of treatment failure with autoHCT. Prospective risk-adapted approaches that assign patients to an appropriate PRT approach, including autoHCT based on disease-risk and MRD status are already tested within clinical trials and may pave the way for revisiting autoHCT in specific

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subpopulations of AML patients in first remission.

ACCEPTED MANUSCRIPT

References

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[28] R. Shouval, M. Labopin, D. Bomze, et al., FLT3 and NPM1 Are Powerful Determinants of Outcome in Acute Myeloid Leukemia Patients Treated with Autologous Stem Cell Transplantation: An Analysis By the Acute Leukemia Working Party of the EBMT, Blood 132(Suppl 1) (2018) 609-609. [29] O. Beyar-Katz, I. Henig, D. Yehudai, et al., Autologous Stem Cell Transplantation in Favorable Acute Myeloid Leukemia Is Associated with a Better Long-Term Prognosis: a Single Center Experience, Blood 128(22) (2016) 5819-5819. [30] A. Ivey, R.K. Hills, M.A. Simpson, et al., Assessment of Minimal Residual Disease in Standard-Risk AML, The New England journal of medicine 374(5) (2016) 422-33. [31] E. Jourdan, N. Boissel, S. Chevret, et al., Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia, Blood 121(12) (2013) 2213-23. [32] J.A. Yin, M.A. O'Brien, R.K. Hills, et al., Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial, Blood 120(14) (2012) 2826-35. [33] L. Maurillo, F. Buccisano, M.I. Del Principe, et al., Toward optimization of postremission therapy for residual disease-positive patients with acute myeloid leukemia, Journal of clinical oncology : official journal of the American Society of Clinical Oncology 26(30) (2008) 494451. [34] M. Balsat, A. Renneville, X. Thomas, et al., Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia With NPM1 Mutation: A Study by the Acute Leukemia French Association Group, Journal of clinical oncology : official journal of the American Society of Clinical Oncology 35(2) (2017) 185-193. [35] Y. Wang, D.P. Wu, Q.F. Liu, et al., In adults with t(8;21)AML, posttransplant RUNX1/RUNX1T1-based MRD monitoring, rather than c-KIT mutations, allows further risk stratification, Blood 124(12) (2014) 1880-6. [36] G.J. Schuurhuis, M. Heuser, S. Freeman, et al., Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party, Blood 131(12) (2018) 1275-1291. [37] D. Araki, B.L. Wood, M. Othus, et al., Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia: Time to Move Toward a Minimal Residual Disease-Based Definition of Complete Remission?, Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34(4) (2016) 329-36. [38] Y. Zhou, M. Othus, D. Araki, et al., Pre- and post-transplant quantification of measurable ('minimal') residual disease via multiparameter flow cytometry in adult acute myeloid leukemia, Leukemia 30(7) (2016) 1456-64. [39] S. de Botton, A. Fawaz, S. Chevret, et al., Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group, Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23(1) (2005) 120-6. [40] M. Wetzler, D. Watson, W. Stock, et al., Autologous transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia achieves outcomes similar to allogeneic transplantation: results of CALGB Study 10001 (Alliance), Haematologica 99(1) (2014) 111-5. [41] A. Venditti, L. Maurillo, F. Buccisano, et al., Pretransplant minimal residual disease level predicts clinical outcome in patients with acute myeloid leukemia receiving high-dose chemotherapy and autologous stem cell transplantation, Leukemia 17(11) (2003) 2178-82. [42] J. Yao, G. Zhang, C. Liang, et al., Combination of cytogenetic classification and MRD status correlates with outcome of autologous versus allogeneic stem cell transplantation in

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adults with primary acute myeloid leukemia in first remission, Leukemia research 55 (2017) 97-104. [43] C. Messina, A. Candoni, M.G. Carrabba, et al., Wilms' tumor gene 1 transcript levels in leukapheresis of peripheral blood hematopoietic cells predict relapse risk in patients autografted for acute myeloid leukemia, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20(10) (2014) 158691. [44] M.P. Mule, G.N. Mannis, B.L. Wood, et al., Multigene Measurable Residual Disease Assessment Improves Acute Myeloid Leukemia Relapse Risk Stratification in Autologous Hematopoietic Cell Transplantation, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 22(11) (2016) 1974-1982. [45] A. Venditti, O. Piciocchi, A. Candoni, et al., Risk-Adapted, MRD-directed,therapy for young adults with newly diagnosed acute myeloid leukemia: results of the AML1310 trial of the GIMEMA group. Abstract S111, EHA22, (2017). [46] R.M. Lemoli, A. D'Addio, G. Marotta, et al., BU/melphalan and auto-SCT in AML patients in first CR: a 'Gruppo Italiano Trapianto di Midollo Osseo (GITMO)' retrospective study, Bone marrow transplantation 45(4) (2010) 640-6. [47] N.C. Gorin, M. Labopin, T. Czerw, et al., Autologous stem cell transplantation for adult acute myelocytic leukemia in first remission-Better outcomes after busulfan and melphalan compared with busulfan and cyclophosphamide: A retrospective study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT), Cancer 123(5) (2017) 824-831. [48] N.C. Gorin, M. Labopin, D. Blaise, et al., Optimizing the pretransplant regimen for autologous stem cell transplantation in acute myelogenous leukemia: Better outcomes with busulfan and melphalan compared with busulfan and cyclophosphamide in high risk patients autografted in first complete remission: A study from the acute leukemia working party of the EBMT, American journal of hematology 93(7) (2018) 859-866. [49] M. Christopeit, M. Labopin, N.C. Gorin, et al., Allogeneic stem cell transplantation following relapse post autologous stem cell transplantation in adult patients with acute myeloid leukemia: A retrospective analysis of 537 patients from the Acute Leukemia Working Party of the EBMT, American journal of hematology 93(12) (2018) 1532-1542. [50] T. Czerw, M. Labopin, N.C. Gorin, et al., Long-term follow-up of patients with acute myeloid leukemia surviving and free of disease recurrence for at least 2 years after autologous stem cell transplantation: A report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, Cancer 122(12) (2016) 1880-7. [51] N. Novitzky, V. Thomas, L. Abrahams, et al., Increasing dose intensity of anthracycline antibiotics improves outcome in patients with acute myelogenous leukemia, American journal of hematology 76(4) (2004) 319-29.

ACCEPTED MANUSCRIPT Table 1. Comparative studies of autoHCT vs. chemotherapy or alloHCT

Allo SCT Auto SCT Chemothera py

Keat ing et al. [17]

MAC allo BMSCT MAC allo PBSCT

Herr et al. [20]

RIC allo PBSCT

AutoSCT

AC

Auto PBSCT

AutoHSCT

Sara ceni et al. [18]

Miz utan i et al. [19]

Retr ospe ctive CIB MTR regis try stud y Retr ospe ctive EBM T regis try stud y Retr ospe ctive EBM T regis try stud y Retr ospe ctive JSHC T regis

10/10 MUD-allo SCT 9/10 MUD-allo SCT Auto PBSCT allo BMSCT allo PBSCT

n=258 n=259

NR

RR

TRM

OS

58%

4%

5y 44%

70%

1%

5y 41%

Bottom line for autoHSC T Lower relapse, higher TRM, compara ble survival

CR IP T

Pros pecti ve (non -ITT) CR1 pts. Ages 4060 years

49 (18-60)

LFS

OS better compare d to chemo

5y 54%$ 51 (40-60)

337

52 (40-60)

152

52 (40-60)

271

36%

17%

AN US

Chemotherapy

47 (18-60)

N

5y 57%

5y 44%

47%

5%

5y 54%

5y 30%

60%

1%

5y 40%

36 (19-60)

475

5y 61%

20%

19%

5y 64%

40 (19-60)

428

5y 54%

26%

20%

5y 59%

44 (19-60)

230

5y 54%

45%*

8%*

5y 47%

58 (50– 73) 57 (50– 78)

214 1152

OS compabl e to allo SCT in int. patients RFS worse as compare d to allo SCT in int. patients

M

AutoHSCT

Pros pecti ve, ITT CR1 pts. rand. post 2XHi DAC

Age , years (median, range)

ED

Corr nelis sen et al. [12]

Cont ext

PT

Vell eng a et al. [11]

Comparison

CE

Refe renc e

46%

36%

17%

2y 60%

42%

50%*

8%*

2y 53%

49 (18–78)

1202

3y 48%

49%*

4%*

3y 64%

51 (18–76)

1302

3y 58%*

29%

13%

3y 63%

49 (18–69)

375

3y 55%

23%

21%

3y 58%

47 (17-80)

375

5y 60%

33%

8%*

5y 65%

37 (16-73)

521

5y 59%

26%

15%

5y 62%

43 (16-74)

380

5y 51%

28%

21%

5y 55%*

Higher relapse, lower TRM and compara ble OS, LFS

Higher relapse, lower TRM and compara ble OS

Higher relapse, lower TRM and compara ble OS Higher relapse, lower TRM and compara ble OS

ACCEPTED MANUSCRIPT try stud y

Retr ospe ctive singl e cent er

auto SCT allo SCT

132

3y 49%

50%

43 (18– 71)

253

3y 44%

27%*

4%*

3y 65%

25%

3y 53%

CR IP T

Haplo allo SCT

42 (18– 69)

32.5 (16–56)

46

38 (16–59)

126

3y 69%

27%

4%

3y 74%

3y 75%

14%

11%

3y 75%

34 (14-65)

CE

auto SCT

Retr ospe ctive singl e cent er

MAC allo SCT

43

36 (15-58)

32

66.0 (64.2– 72.5)

16 24

39%

14%

27%

15%

NR

5y 56% 5y 63%

Inferior survival in adverse risk patients treated with auto SCT In older patients better PFS, OS

2y 48%

NR

2y 16%

8.2 mos

Auto SCT in older patients compara ble to younger patients

AC

Novi tzky et al. [51]

PT

ED

M

Yao et al. [42]

Auto SCT

AN US

Gori n et al. [22]

Retr ospe ctive EBM T regis try matc hed paire d analy sis

Hein i et al. [13]

auto SCT Chemothera py

Retr ospe ctive singl e cent er

‘Expert’ haplo centers have compara ble outcome s to auto SCT, ‘regular’ haplo centers do worse with haplo SCT Patients with favorabl e or interme diate risk and negative MRD after one course of consolid ation were compara ble to allo SCT Similar outcome for auto and allo SCT in favorabl e/interm ediate risk patients.

68.7 (64.1– 74.4)

ACCEPTED MANUSCRIPT Auto SCT – autologous stem-cell transplantation; allo SCT- allogeneic stem-cell transplantation; BM – bone marrow graft; HiDAC – high-dose cytarabine; Haplo – haploidentical; ITT – intention to treat; rand – randomized; LFS – leukemia free survival; NR – not relevant/not reported; OS – overall survival; Pts. – patients; PB – peripheral blood graft; RR – relapse risk; TRM – treatment related mortality;

Table 2. Comparative studies of autoHCT vs. chemotherapy or alloHCT in specific genetic subgroups

Auto SCT Chemother apy

CEB PAd m

MAC allo SCT

Auto SCT

AC

Vers luis et al. [27]

Sub anal ysis of a pros pecti ve RCT’ s

CE

RIC allo SCT

Chemother apy

N

LFS/RFS

40

32

41

20

45

72

RR

TRM

OS

5y 73%$ 5y 60%

NR

NR

5y OS 63% for all cohort

5y 32%

54 (3760) 44 (1659) 48 (1661) 50 (1860)

68 137 168 148

----------

------

Bott om line for auto SCT

--------

RFS bett er for auto and allo SCT vs/ che mo Simi lar OS NP M1+ /FLT 3simil ar LFS and OS for all appr oac hes

PT

CN in CR1 with kno wn

Age , years (median, range)

CR IP T

Anal ysis of cons ecuti ve pros pecti ve trials

Gen etic sub grou p asse ssed

AN US

Allo SCT

Cont ext

M

Schl enk et al. [24]

Comparison

ED

Ref ere nce

---------

NP M/FLT 3-, NP M+/ Low AR FLT3 Bett er LFS and OS with RIC allo And simil

ACCEPTED MANUSCRIPT ar LFS and OS with all othe r appr oac hes

Auto SCT Haplo allo SCT

Inv 16 allo SCT Inv 16 auto SCT 8:21 allo SCT

AC

8:21 auto SCT

Miz uta ni et al. [26]

Lim vora

Retr ospe ctive EBM T regis try stud y

Auto PBSCT MUD allo BMSCT

MSD allo SCT

3y 41%#

46.5 (18–63)

42

3y 55%

34 (2445)

Core bind ing fact or AML

Retr ospe ctive JSHC T regis try stud y

CN in CR1

Retr ospe

Inte rme

CR IP T

45

54%

2.4%

3y 77%

41%

4.8%

3y 68%

AN US

Favo rabl e or inte rme diat erisk AML

CE

Gori n et al. [25]

Retr ospe ctive , singl e cent er

48 (19– 64)

M

Auto SCT

Favo rabl e or inte rme diat erisk AML

88

3y 66%$

31%*

107

3y 77%

9%

37 (16-62)

64

5y 59%

27%

42 (17-69)

95

5y 66%

32%

34 (16-62)

81

5y 60%

15%*

40 (17-70

85

5y 66%

28%

28 (1642)

5%* 14%

3y 79% 3y 80%

ED

Che n et al. [21]

Chemother apy

Pros pecti ve rand omiz ed trial

PT

Miy amo to et al. [15]

14%* 2%

NR

24%* 6%

49 (3957)

177

5y 58%

36%

7%

5y 64%

39 (3050)

173

5y 64%

18%

17%

5y 66%

46

3y 72%

20%

12%

3y 74%

41

No adv anta ge for auto SCT (ITT anal ysis) , low tran spla nt reali zati on rate ) High er rela pse, low er TRM and com para ble OS Simi lar LFS bet wee n auto and allo SCT. High er relap se and lowe r TRM resul ts in simil ar outc ome s.

MSD allo

ACCEPTED MANUSCRIPT pita k et al. [16]

MUD/MMU D allo SCT Auto SCT

diat e risk pati ents AML

34

17

3y 5%

35%

40%

3y 27%

37

25

3y 46%

40%

15%

3y 48%

3y 25%

68%

2%

3y 35%

42

47

SCT in first com plet e remi ssio n had the best outc ome s. Aut o SCT com para ble to UD/ MM .

CR IP T

Chemother apy

ctive singl e cent er prop ensit y scor e base d anal ysis

significant p value for comparison.

#

Disease free survival (DFS) reported.

$

AC

CE

PT

ED

Relapse free survival (RFS) reported.

M

*

AN US

AR – allelic ratio; AutoHSCT – autologous stem-cell transplantation; alloHSCT- allogeneic stem-cell transplantation; BM – bone marrow graft; CN – cytogenetic normal; HiDAC – high-dose cytarabine; ITT – intention to treat; rand – randomized; LFS – leukemia free survival; MSD – matched siblig donor; MM – mismatch; NR – not relevant/not reported; OS – overall survival; Pts. – patients; PB – peripheral blood graft; RCT’s – randomized controlled trials; RR – relapse risk; TRM – treatment related mortality; UD – unrelated donor.