Life after transplant: are we becoming high maintenance in ... - Nature

Bone Marrow Transplantation (2016) 51, 1423–1430 © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 0268-3369/16 www.nature.com/bmt

REVIEW

Life after transplant: are we becoming high maintenance in AML? AM Brunner, AT Fathi and YB Chen Allogeneic hematopoietic cell transplantation (allo-HCT) for patients with AML is increasingly able to impact the historically poor outcomes in this disease. Nonetheless, even with transplant, the rates of post-HCT relapse are unacceptably high, and remain a great challenge in the treatment of patients with AML. Maintenance therapies after allo-HCT, given to patients at high risk of relapse or with evidence of minimal residual disease (MRD), may provide a way to reduce relapse rates and improve survival. New therapies may offer acceptable toxicity profiles in the post-HCT setting, and investigations are ongoing using hypomethylating agents, histone deacetylase inhibitors, immunomodulatory drugs, targeted tyrosine kinase inhibitors, drug–antibody conjugates and cellular therapies. Future directions in the field of post-HCT therapies may include better risk stratification with MRD, as well as the exploitation of novel mechanisms such as immune checkpoint inhibition and modified chimeric antigen receptor (CAR) T cells. In this mini review, we discuss the current landscape of clinical research in post-HCT maintenance therapies, as well as future therapeutic strategies of interest. Although there is great potential for post-HCT agents to improve AML outcomes, these will need to be evaluated prospectively through well-designed randomized clinical trials. Bone Marrow Transplantation (2016) 51, 1423–1430; doi:10.1038/bmt.2016.160; published online 20 June 2016

AML is a cancer of hematopoietic progenitor cells with a median age at diagnosis of 67 years. For many, particularly those whose disease harbors unfavorable genetic profiles, allogeneic hematopoietic cell transplantation (allo-HCT) provides improved rates of durable remission.1–3 Through expanded donor pools and decreased transplant-related toxicity, including precise HLA-typing techniques, the development of reduced intensity regimens and advent of safer regimens using alternative donor sources, allogeneic HCT has become a standard option for an increasing proportion of AML patients.4–8 Nonetheless, even after allogeneic transplantation, the rate of disease relapse is unacceptably high,9 and remains the primary cause of death following HCT.10 Therefore, new strategies are needed to reduce relapse and maintain remission for patients undergoing allo-HCT for AML. Maintenance therapies given during remission in the post-HCT setting may provide a way to reduce relapse rates, particularly for those with the highest-risk disease. Historically, the off-target toxicity of effective agents for AML, including cytopenias and additional immunosuppression, has limited their use after transplant. More recently, however, a number of novel, more tolerable AML therapies have been discovered,11–13 and there is now significant interest in employing such agents after allo-HCT, potentially offering effective antileukemic activity with a more acceptable toxicity profile. The ideal maintenance agent is well tolerated, received only by those patients who would otherwise relapse, and is able to modify the course of the disease to achieve a sustained remission (Table 1). To meet these criteria, new diagnostics are needed to identify patients destined to relapse, and these patients will require personalized therapy options that are optimally timed post HCT. In this review, we will discuss recent

efforts to develop post-HCT maintenance therapies for AML, and discuss future directions in the field. RECENT PROGRESS IN POST-TRANSPLANT AML MAINTENANCE THERAPIES To date, although a number of studies have addressed therapeutic strategies to treat AML relapse following HCT,14–16 there are limited data regarding post-transplant maintenance strategies. These approaches can be loosely organized according to their various therapeutic categories: treatment with epigenetic modifiers including DNA methyltransferase inhibitors (also termed hypomethylating agents or HMAs) and histone deacetylase inhibitors (HDACi); targeted tyrosine kinase inhibitors (TKIs); immune modulators including thalidomide derivatives; targeted Ab–chemotherapy conjugates; and cellular therapies (Table 2). Several studies have examined the role of HMA therapy after HCT for patients with high-risk disease. In a phase I study, azacitidine was administered to 45 patients between day 30 and the first 2.5 months post transplant, with an intent to treat for up to four cycles.17 Eighty two percent had AML, and the majority (two-thirds) of patients were not in CR at the time of transplant. Azacitidine dosing was limited by thrombocytopenia at 40 mg/m2, and the investigators recommended a dose of 32 mg/m2 IV daily for 5 days in 30 day cycles. At 1 year, the median disease-free survival (DFS) for all patients was 58%. A subsequent smaller analysis18 in patients with AML in CR1 found similar results, but suggested that any benefit may be restricted to those with normal cytogenetics. A phase I/II study by Goodyear et al., and a phase II Alliance study (CALGB 100801) have also evaluated the role of azacitidine post transplant as a maintenance strategy19,20 and as

Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA. Correspondence: Dr Y-B Chen, Division of Hematology/Oncology, Massachusetts General Hospital, Yawkey 9E-9052, 55 Fruit Street, Boston, MA 02114, USA. E-mail: [email protected] Received 12 April 2016; accepted 25 April 2016; published online 20 June 2016

Maintenance after HCT for AML AM Brunner et al

1424 Table 1.

Comparison of timing of post-allo-HCT therapeutic interventions

Maintenance therapy

MRD-trigger

Relapse-trigger

Favorable characteristics Reach largest number of patients with potential Rationale to potentially optimize risk/benefit of beneficial therapy maintenance therapy Lower clinical burden to identify patients Potential to tailor therapy to specific persistent mutations

Limit additional toxicity to transplant population Established pipeline for therapeutic development

Unfavorable Characteristics Excess toxicity seen by entire population Failure to ‘tailor’ therapy to specific patients Difficulty in designing clinical trials

Worse outcomes compared with pre-emptive strategies Salvage is poor in the post-HCT setting

May fail to identify patients who would benefit Resource intensive and unclear monitoring standards MRD currently an evolving field in AML

Abbreviations: allo-HCT = allogeneic hematopoietic cell transplantation; MRD = minimal residual disease.

GvHD prophylaxis.21,22 The Alliance study enrolled 66 patients, but only 42 were able to begin treatment with azacitidine, and just 17 completed all six cycles as planned; overall survival (OS) at 2 years was only 38%. A separate study by Pusic et al.23 administered up to eight cycles of decitabine, as maintenance therapy following myeloablative allo-HCT; 2-year OS was 56% and cumulative incidence of relapse was 28%, and most patients (75%) experienced grade 3–4 hematologic toxicities during the treatment. As more sensitive techniques to detect minimal residual disease (MRD) are being developed, azacitidine is also being explored as pre-emptive therapy—before morphological relapse, but once MRD can be detected. The RELAZA trial initiated therapy in patients with CD34+ AML whose post-transplant CD34+ donor chimerism dropped o80%, and found that although this delayed relapse to a median of 231 days after the decrease in chimerism, most patients ultimately experienced morphological disease relapse.24 Therefore, although the timing of HMA maintenance may need to be explored further, the feasibility of such strategies may be low, given the associated toxicity profile observed thus far. An ongoing randomized clinical trial (NCT00887068) should provide more definitive evidence of the impact of post-transplant azacitidine, and additional trials with oral HMAs are being conducted as well. Recently, trials have examined HDACi as maintenance after allo-HCT for AML as well. Bug et al.,25 as part of the Panobest trial, treated 42 patients, 37 with AML, using panobinostat, starting a median of 98 days following allo-HCT. Most patients in this trial had active disease (67%) at the time of transplant. The preliminary results are favorable, with a 2-year OS of 88% and DFS of 74%, and further follow-up is awaited (NCT01451268). Targeted TKI therapy, directed at specific molecular aberrations, may provide an opportunity for tailored maintenance therapies, similar to that adopted in BCR-ABL-positive malignancies.26–29 To date, post-transplant maintenance with TKIs for patients with AML has been studied primarily in patients with internal tandem duplication mutations, involving the fms-like tyrosine kinase 3 (FLT3-ITD). Treatment of FLT3-ITD AML is challenging due to high relapse rates and significantly shorter remissions. A number of multi-kinase inhibitors30 are being investigated in various phases of therapy including the post-HCT maintenance setting for FLT3ITD AML, including sorafenib, midostaurin, quizartinib, crenolanib and gilteritinib. In a phase I study of 22 patients with FLT3-ITD AML receiving sorafenib maintenance after allo-HCT, PFS at 1 year was 85% and OS was 95%.31 A subsequent analysis showed that 26 patients with FLT3-ITD AML treated with sorafenib maintenance after allo-HCT in CR1 had favorable outcomes compared with a group of contemporary controls with FLT3-ITD AML, with a 3-year OS of 83% compared with 58%; patients had similar rates of non-relapse mortality, but those given sorafenib had markedly lower relapse rates.32 Similar encouraging results with sorafenib in Bone Marrow Transplantation (2016) 1423 – 1430

the maintenance setting have been reported in other trials with pediatric and adult FLT3-ITD-mutated AML.33–37 Importantly, sorafenib did not appear to significantly alter the rates of GvHD in these small studies, and was generally tolerable. Other multikinase inhibitors are being studied as post-transplant maintenance, including quizartinib (AC220); in one study, only 1 of 13 patients relapsed to date during treatment.38 A phase II study evaluated midostaurin as post-transplant or postconsolidation maintenance and reported an encouragingly low relapse rate at 12 months (9.2%),39 with a phase II randomized study currently enrolling (NCT01883362). Crenolanib is also being studied in a similar setting (NCT02400255). Importantly, a large prospective cooperative group international phase III randomized trial is planned to definitely prove the benefit of administering a FLT3 TKI (gilteritinib), as maintenance after allo-HCT for patients with FLT3-ITD AML. Similar target specificity may be achieved with the use of Ab–drug conjugates. The cell surface marker CD33 is expressed on the majority of AML cells; gemtuzumab ozogamicin (GO) is an Ab against CD33 conjugated to the chemotherapy calicheamicin. Oshikawa et al.40 treated 10 younger patients with high-risk AML, with the combination of azacitidine and GO as maintenance after transplant; four patients relapsed in follow-up, but the median number of cycles was only 1.5, with the course limited largely by reversible hematological toxicities. A similar Ab–drug conjugate being currently investigated in the post-transplant maintenance setting is SGN33a, which is an anti-CD33 Ab conjugated to a pyrrolobenzodiazepine dimer (NCT02326584). Immunomodulatory agents have also been investigated as post-transplant remission maintenance strategies in AML. Lenalidomide, a thalidomide derivative, has been of particular interest given its immunomodulatory role and inherent activity in AML.41 A phase II study explored lenalidomide dosed at 10 mg daily for 21 of 28 days, starting a median of 2.5 months post transplant.42 The trial was stopped early because of excessive acute GvHD (aGvHD), but the authors did note some modulation of CD34+ cell chimerism associated with lenalidomide exposure. A separate phase I study is underway to evaluate lenalidomide specifically in patients at high risk of relapse, including AML (NCT01254578). Nonetheless, issues related to aGvHD are likely to limit the adoption of these agents except in defined subgroups.43,44 Selective immune modulation, for instance with checkpoint inhibition via the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) pathways, may be able to offer similar immunomodulatory effects with a more favorable toxicity profile and merit future investigation. Perhaps most established in the post-transplant setting are cellular therapies, specifically donor lymphocyte infusion (DLI). Although DLI therapy alone in the setting of frank relapse appears © 2016 Macmillan Publishers Limited, part of Springer Nature.

© 2016 Macmillan Publishers Limited, part of Springer Nature.

Phase I Sorafenib 200 mg BID starting day +30 to +120 Retrospective Sorafenib 200–400 mg/m2 per day within 18 months of HCT

Retrospective Sorafenib 400 mg BID starting day +30 to +180

Sorafenib35

Sorafenib37

Sorafenib36

Retrospective Sorafenib post transplant

Phase I Sorafenib 200–400 mg BID started day +45 Retrospective Sorafenib 200–400 mg BID Median start day +68 Retrospective Sorafenib 200–400 mg BID

Sorafenib34

Sorafenib33

Sorafenib32

Tyrosine kinase inhibitors Sorafenib31

Panobinostat25

Decitabine23

Azacitidine24

Azacitidine20

Azacitidine21

Azacitidine19

Azacitidine18

Phase I AZA starting day +42 for four cycles Phase I AZA for median 12 cycles starting median day +100 Phase II AZA 32 mg/m2 day +42 to +90 for 6 cycles Phase I AZA as day +7 GvHD ppx Phase I/II AZA 36 mg/m2 day +42 for up to 10 cycles Phase II CD34+ AML or MDS treated when chimerism dropped o80% Phase I Decitabine 5–15 mg/m2 per day for 5 days starting day +50 to +100 Phase I/II Panobinostat 10–40 mg TIW starting median day +98

Study design

Pre-emptive therapy may prevent or delay disease relapse

10 of 20 had improved chimerism 480%. 13 of 20 relapsed at a median of 231 days after MRD. 80% with neutropenia, 65% with thrombocytopenia; 45% with dose reductions 56% 2-year OS, 48% 2-year DFS. 75% w/grade 3–4 toxicities (hematologic). 9 of 22 completed planned 8 cycles

83% 2-year OS vs 58% for control patients, primarily due to relapse. No difference in NRM or cGvHD between groups Patient given sorafenib maintenance reported alive and in CR. Dose reductions required for elevated liver enzymes All 6 patients remained alive/relapse free a median of 12 months post sorafenib. Skin GvHD grade 2 was described in 5 of 6 patients. 1 patient developed MI post sorafenib Median f/u 450 days, 5 patients relapsed, 15/28 on therapy without relapse. 9 patients developed grade 2 or higher GvHD 4/6 maintenance remain in CR. 5/5 MRD+ patients responded. 73% experienced significant AEs; MTD of sorafenib found to be 200 in this population

Sorafenib had a favorable toxicity profile

MRD+ disease may benefit most from TKI therapy. Excessive toxicities, but most treated above pediatric MTD.

Sorafenib is tolerated and inhibits FLT3 at all doses tested

Sorafenib may be an effective maintenance therapy

Sorafenib is tolerated in a variety of treatment scenarios in FLT3-ITD AML

Sorafenib post HCT may improve outcomes by decreasing relapse rates

95% 1-year OS, 85% 1-year PFS. 1-year cGvHD 38%. 1 Sorafenib is safe after HCT DLT (pericardial effusion)

88% 2-year OS, 74% 2-year DFS. 48% with drug-related Panobinostat TIW at 20 mg weekly or AE (hematologic, constitutional, GI) 30 mg every other week is feasible

Recommend 10 mg/m2 per day for 5 days

AZA may prevent aGvHD; 1 DLT of 1° graft failure Initiating AZA may be challenging; Treg populations may modulate response

Challenges to initiating post-transplant azacitidine

Normal karyotype may be more likely to respond

Recommend 32 mg/m2 for 5 days, 4 cycles

Conclusions

After 223 days, 2 relapses and 73% survival. Median platelet engraftment day +22; no grade 3/4 aGvHD 49% 2-year OS, 49% 2-year DFS. Only 16 patients completed 10 cycles

6 with nl cytogenetics in CR at 13+ months. Thrombocytopenia in 2 patients, all patients w/abnl karyotype relapsed 38% 2-year OS. 11% NRM at 100 days. Only 17/42 patients completed 6 planned cycles

58% DFS at 1 year. Cytopenias with AZA.

Outcomes and toxicities

Pediatric FLT3-ITD AML 15 patients, 6 as maintenance, 5 for MRD (2 pre-HCT), and 5 for relapse FLT3-ITD AML No relapse among 7 patients at 1 year; 7/7 alive at 1 7 patients given maintenance, 3 in year. Rash was common, requiring steroids and/or CR at transplant drug discontinuation

FLT3-ITD AML 28 patients reported

FLT3-ITD AML 5 patients as maintenance, 1 as salvage therapy

26 patients with FLT3-ITD AML in CR1 treated w/sorafenib compared with 55 controls FLT3-ITD AML, 1 of 13 as post-HCT maintenance

FLT3-ITD AML 16 CR1, 3 CR2, 3 refractory

42 patients; 37 with AML

22 patients with AML/MDS in CR

20 patients; 17 with AML

37 patients with AML; 32 in CR1 or CR2

9 patients with AML in CR

High-risk AML/MDS; 42/64 patients initiated AZA

9 patients with high-risk AML/MDS

45 patients with high-risk AML/MDS

Number of patients

Selected published maintenance strategies for AML following allogeneic HCT

Epigenetic modifiers Azacitidine17

Agent

Table 2.


1425

Bone Marrow Transplantation (2016) 1423 – 1430

38

Phase I AZA 30 mg/m2 GO 3 mg/m2 Median start day +78.5

Phase I Quizartinib 40–60 mg daily starting median day +56 Phase II Midostaurin 50 mg BID during induction, consolidation and maintenance

Study design

Bone Marrow Transplantation (2016) 1423 – 1430 1.5-year OS 50%. 11 patients relapsed with leukemia. NRM 21%. 12 of 16 alive patients have cGvHD.

33 patients with leukemia; 16 had AML, 9 w/primary induction failure 11 evaluable patients; 4 with AML (refractory or relapsed)

Relapse at 5 years 43% for MRD, 28% for mixed chimerism, 28% prophylactic. Following DLI: 13% aGvHD, 32% cGvHD 3 AML patients in CR had continued responses at 1038, 973, and 662 days. Local inflammatory response; 1 patient with mild hypoxia and BO 2/5 AML relapses. WT1 expression decreased with WT1 +CD8+ T cells. Injection site response. No induction of anti-PR3 or ANCA Both patients treated as post-HCT maintenance (for example, not in relapse) reported alive in CR. Infusion reactions (fever, chills, lymphopenia)

266 patients with AML 343 total patients; 144 prophylactic DLI 5 patients with AML; 3 were in CR

8 patients total; 5 patients with AML in CR1 (4) or CR2 (1) 11 patients 2 patients with AML in morphologic remission post HCT

DLI may benefit patients with refractory disease pre-transplant

DLI administered during mixed chimerism before relapse may improve graft chimerism Prophylactic DLI may reduce relapse with similar NRM

Modified T cells may provide targeted antileukemic activity

Leukemia-specific immune response to vaccine may be safe and effective

DLI for mixed chimerism or in the prophylactic setting may be preferred to an MRD trigger Vaccination against WT1 may be effective when disease burden is low

1 AML patient alive 14 months; 3 died (infection, Chimerism improved, but DLI had relapse). aGvHD in 70% of responders. cGvHD in 5 of 8 excess GvHD toxicity patients alive 100 days AML patients: 8 alive in CR, 3 NRM, 3 relapse deaths. 16 DLI more effective in myeloid cancer of 24 had aGvHD. 8 of 24 had cGvHD. 2 GvHD deaths

10 of 23 patients alive at 9 months. 11/15 were mixed chimeras, 6 of 11 converted to complete. 60% developed aGvHD requiring immunosuppression 36% 3-year OS. 29% 3-year LFS. 4 patients with grade 3–4 aGvHD. DLI had cGvHD 38% vs controls 17%

24 patients received DLI; 14 with AML or MDS

AZA-GO could be administered post transplant for high-risk patients

TKI therapy during induction, consolidation, transplant may improve outcomes

Quizartinib is safe as post-HCT maintenance

Conclusions

5/10 alive; 4 in continuous CR. Improved chimerism in Trial stopped early due to severe aGvHD 1 patient. Grade 3–4 aGvHD in 6/10 patients during first 2 cycles

1-year OS 70%. Higher compared with random database controls. All patients had grade 4 heme toxicities (transient)

12 of 13 patients in remission at the time of report. 3 stopped due to AEs. Common AEs: diarrhea, nausea and neutropenia For all CR1 transplant patients (n = 85), 1-year relapse 9.2%, death 19.5%. Only reported 4 AEs grade 3–4 due to midostaurin maintenance

Outcomes and toxicities

14 AML patients and 9 ALL patients; 15 total patients received DLI Acute leukemia; 50 patients received DLI, 38 with AML

High-risk MDS (n = 1) or AML (n = 9) with del(5q)

10 patients with high-risk AML 2 in CR at HCT 8 not in CR at HCT

FLT3-ITD AML; 149 patients age 18–70. 40 patients treated with post-HCT maintenance

FLT3-ITD AML in remission; 13 patients

Number of patients

Abbreviations: abnl = abnormal; aGvHD = acute GvHD; cGvHD = chronic GvHD; CR = complete remission; DLI = donor lymphocyte infusion; DFS = disease-free survival; FLT3 = fms-like tyrosine kinase 3; GO = gemtuzumab ozogamicin; HCT = hematopoietic cell transplantation; MRD = minimal residual disease; MTD = maximum tolerated dose; nl = normal; NRM = non-relapse mortality; OS = overall survival; TIW = three times a week; TKI = tyrosine kinase inhibitor; Treg = regulatory T-cell; WT1 = Wilms tumor 1.

Cellular therapies (selected studies) Prospective DLI if no GvHD off DLI45 IS; given for patients with mixed chimerism Prospective DLI47 G-CSF primed DLI within day +60 post transplant Retrospective DLI48 Cryopreserved DLI at day +45 to +120 while on CsA 49 Pilot study DLI DLI given on day 30, 60, 90, if no GvHD at day+30 50 DLI Prospective T-cell add-back DLI from day +25 to +100 DLI52 Registry-based survey DLI as prophylaxis, for decreased chimerism or MRD Phase I Vaccine53 WT1 vaccine for HLA-A2402 patients at risk of relapse, at 2-week intervals Phase I Vaccine61 Combination PR1 and WT1 vaccine for HLA-A0201 patients 63 Modified T cells Pilot study WT1-specific CTL clones on day 0, +7, +14, +28

Immune modulation therapy Phase II Lenalidomide42 Lenalidomide 10 mg for days 1–21 started at median +2.5 months

Ab–drug conjugates Gemtuzumab ozogamicin40

Midostaurin39

Quizartinib

Agent

Table 2. (Continued )


1426



OUR CURRENT APPROACH TO MAINTENANCE AFTER ALLO-HCT As delineated above, although a number of strategies are currently being explored to prevent AML relapse after allogeneic transplant, there is insufficient evidence to presently support routine use of post-transplant maintenance strategies. The main reason for this is the lack of phase III clinical data proving a definitive benefit of any maintenance approach, especially given the potential risks, including unknown effects on immune reconstitution and GvHD. In addition, there remains controversy over how to best identify which patients are at a level of risk such that they justify receiving post-transplant maintenance, and, once identified, what therapeutic strategy would be most effective with a favorable toxicity profile (Figure 1). Prognostication for patients with AML at high risk of relapse has increasingly improved. The morphological disease state at the time of allo-HCT is informative; however, it is also becoming clear that the presence of MRD before HCT is a powerful predictor of outcomes among patients with AML. Consistent assessment of MRD in AML has been a slower process compared with other hematologic malignancies due to the heterogeneous molecular composition of AML. However, several stable mutations and cytogenetic abnormalities have been explored as potential markers for MRD assessments,64 including mutations in NPM1,65–67 balanced translocations in core-binding factor leukemias68–71 and PML-RARA in acute promyelocytic leukemia;72 although all of these examples typically do not merit allo-HCT in first remission. Multiparameter flow cytometry assays for MRD offer another means to evaluate for the presence of residual disease after induction, and identify high-risk patients.73–75 Indeed, several analyses point to flow cytometry pre-transplant MRD assessment as a way to risk stratify patients with AML undergoing © 2016 Macmillan Publishers Limited, part of Springer Nature.

1427 Remission MRD relapse Frank relapse Post-transplant disease status

Remission pre-transplant (±MRD status)

Relapse

Pre-emptive

Treatment strategy Maintenance

to have limited utility for AML,14 preventative or prophylactic DLI may have a role by improving donor chimerism among patients with mixed chimerism post transplant,45,46 or among patients with complete donor chimerism, but at high risk for relapse.47–51 A recent analysis from the European Society for Blood and Marrow Transplantation included 343 patients given a DLI while in CR post transplant, the majority (n = 266) with AML.52 One-hundred forty-four patients received DLI without any evidence of leukemia, and the cumulative incidence of relapse in this high-risk cohort was only 28% at 5 years. The optimal use of DLI in the maintenance setting remains uncertain, especially given the significant risk of inducing GvHD. Newer cell-mediated therapies, such as CAR-T cells or tumor vaccines, are encouraging in that they may augment graft vs leukemia effects, although minimizing the risk for GvHD. Vaccine therapies have been employed with some success, with the goal of stimulating an immune response against leukemia Ags. A number of investigators have examined vaccination strategies against Wilms tumor 1 (WT1), a protein frequently over-expressed in AML.53–60 Although the population of patients included in these studies is heterogeneous, several are administering vaccines to patients in remission post HCT.53,55,61 Another strategy for augmenting a graft vs leukemia effect in the post-HCT setting is through customized engineered T cells. Donor-derived CAR-T cells have already shown activity in the relapsed setting for CD19+ malignancies62 and such an approach can be extrapolated to other diseases, as well as the maintenance setting, if appropriate targets can be identified. Chapuis et al.63 performed adoptive transfer of donor-derived WT1-specific CD8+ T cells, generated after stimulation with WT1 peptide. Eleven patients had AML, including two patients in remission, both of whom remain in remission after receiving the modified T cells. Future studies in these high-risk populations using similar approaches will be informative.

Day”0”

Time following transplant

Figure 1. Depiction of post-transplant treatment strategies for patients with AML in morphological remission at the time of transplant. The optimal treatment strategy directs therapy toward only those patients who will eventually relapse with disease, in an effort to alter that disease trajectory. Maintenance therapy is given to all patients; this has the potential to reach patients not otherwise identified at risk of relapse, but may add toxicity to patients who would remain in CR. Pre-emptive therapies use markers of disease recurrence or graft function to provide early intervention before relapse; these may spare excess treatment from patients who otherwise remain in remission (in the green box, bottom), but there may be some patients in this group for whom the intervention is too late. Treatment of patients only once they have frank relapse (pink box) limits toxicity for patients who stay in remission or have subclinical MRD (yellow box), but generally, strategies for this group have had limited success to date.

transplant;75–77 and some studies suggest that patients with detectable MRD in this manner may have relapse rates as high as those transplanted with active morphologic disease.78 The optimal approach to treating patients with AML at high risk of relapse post transplant remains controversial. Take, for example, a patient with intermediate-risk cytogenetics, harboring a FLT3-ITD mutation, with high expression of CD33 on malignant blasts. Is the preferred post-HCT maintenance strategy to initiate hypomethylating therapy after transplant, given the multiple studies to date? Does pre-transplant therapy matter, for instance, if the patient responded favorably to azacitidine as initial therapy? Or, does the FLT3-ITD mutation favor an approach using targeted therapy with a potent FLT3 inhibitor? Although the presence of FLT3-ITD certainly identifies a high-risk population, and early studies suggest that this may be an effective target in the post-transplant setting, this mutation is largely considered a late event and may be lost at disease progression or relapse.79–81 Perhaps, instead, Ab–drug conjugates may therefore be a more favorable approach, but much less is known about the effect of these agents on the graft and potential toxicities to other organs. Given the remaining questions in this field, post-transplant maintenance therapies need to be explored in the context of well-designed clinical trials whenever possible. However, such efforts have been hindered, often until agents receive approval for other indications, highlighting the challenges of drug development in this setting. It is useful to remind ourselves that use of BCR-ABL TKIs after HCT for CML or Ph+ ALL is routine, yet no clinical trial has ever shown a definitive benefit of such a strategy, and the likelihood of conducting such a study remains low. In our practice, although we utilize clinical and disease parameters such as the disease-risk index,82,83 and molecular and cytogenetic characteristics to counsel patients regarding their risk of relapse, we have not yet adopted MRD assays as a pre-transplant metric in AML patients given the lack of standardization. As these assays become better validated, they Bone Marrow Transplantation (2016) 1423 – 1430


1428 may certainly prove to be useful tools, particularly if tied to risk-stratified therapeutic strategies. Indeed, clinical trials evaluating post-HCT maintenance therapy are increasingly incorporating MRD or other biomarker assays, such as tandem duplication PCR for residual FLT3-ITD disease.84 These findings will be critical to understanding how to effectively identify patients, who will benefit from post-HCT maintenance and select from the growing menu of treatment options. Although we have particular interest in developing post-HCT therapies for patients with AML, we currently do not consistently utilize any particular therapy outside of the context of a clinical trial. We do consider the off-label use of FLT3 TKIs (that is, sorafenib) for patients with FLT3-ITD AML after HCT, but acknowledge the lack of definitive data showing benefit, as well as the tenuous access to these agents. Thus, even with our favorable experience in a small number of patients, our findings should be interpreted merely as strong support for definitive randomized trials to determine whether such a strategy should become the standard of care. FUTURE DIRECTIONS IN POST-TRANSPLANT MAINTENANCE FOR AML Mutations and cytogenetic abnormalities that identify AML patients at highest risk of relapse also populate a growing list of potential targets for novel therapies. Certain alterations may be earlier events in the disease, and potentially provide more stable targets for specifically targeted treatment.11 With newer deepsequencing techniques, novel agents may be employed either as maintenance agents for entire subsets of patients—for instance, giving a FLT3 inhibitor to all patients with FLT3-ITD-mutated disease at diagnosis—or used as pre-emptive therapy at the first sign of detectable MRD after transplant. Data to guide the optimal choice between these two options are limited and it certainly also depends on the toxicity of the agent being used. In addition to assessing activity, any clinical trial will also need to consider effects on GvHD and other issues exclusive to the post-transplant population. Although exacerbation of GvHD is a concern, it is also possible that a post-transplant therapy may ameliorate GvHD.22 Newer oral agents may be preferable for maintenance regimens, particularly using dosing schedules that reduce cytopenias, but prolong exposure to these agents. There are also a steadily growing number of agents that are highly targeted to specific leukemogenic pathways with favorable toxicity profiles. One such class of agents is those targeting altered isocitrate dehydrogenase enzymes, IDH1 and IDH2. Selective inhibitors of IDH1 or IDH2 may be appealing for the post-transplant setting given their clinical activity to date and tolerability.85–87 Additional targeted agents directed at other alterations, including HDAC, DOT1L and BET inhibitors, may in time expand our repertoire of post-transplant maintenance strategies. For other patients, developing areas of interest for maintenance strategies may include immune checkpoint inhibition, vaccines or advances in cellular engineering, including modified chimeric Ag receptor T cells. Although emerging new therapies offer significant hope and excitement about the prospects of improving AML survival, their incorporation in the post-HCT setting can be fraught with a number of challenges. The post-HCT period offers unique hurdles in the assessment of drug-specific toxicities; for instance, our experience with sorafenib led to challenges in attributing rashes or diarrhea to the agent, to infectious causes, or to GvHD. These barriers aside, transplant centers will need to collaborate closely and effectively to perform phase III studies that systematically assess maintenance agents. What is more, the heterogeneity of AML demands that any efforts to establish effective post-HCT therapies be done in a coordinated manner that accounts for both the molecular complexity of this disease, as well as its growing number of therapeutics. Bone Marrow Transplantation (2016) 1423 – 1430

CONFLICT OF INTEREST ATF has participated on advisory boards for Agios and Merck and received funding for clinical research from Celgene and Takeda. YBC has received consulting fees from Bayer, Seattle Genetics and Takeda, and funding for clinical research from Celgene, Novartis, Takeda, Bayer and Seattle Genetics. AMB declares no conflict of interest.

ACKNOWLEDGEMENTS AMB is supported in part by National Institutes of Health (NIH) grant T32 CA 71345-18.

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