REVIEW URRENT C OPINION
Novel strategies to prevent relapse after allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia and myelodysplastic syndromes Natasha Kekre and John Koreth
Purpose of review Relapse of haematological neoplasms after allogeneic haematopoietic stem cell transplantation (HSCT) remains one of the leading causes of death. Treatment of relapse post-HSCT is frequently ineffective and outcomes are poor, necessitating preventive strategies that are reviewed below. Recent findings Current strategies to prevent relapse after HSCT are geared towards four general principles: improving the antitumour effects of conditioning regimens prior to HSCT, improving graft selection and engineering to augment the graft-versus-leukaemia effect, post-HSCT chemotherapeutic interventions to impair growth of residual clonal cells and post-HSCT immune-mediated interventions to enhance the graft-versus-leukaemia effect. Strategies based on cell manipulation, namely natural killer (NK) cell enrichment and adoptive T cell transfer, are emerging. Targeted therapies including vaccinations, FLT3 inhibitors, mAbs and chimeric antigen receptor T cell therapy represent a new avenue of treating acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Studies are underway to incorporate all of these strategies in the clinical setting to determine their impact on relapse and survival after HSCT. Summary The most recent evidence suggests that strategies using NK cell therapy and targeted immune therapies after HSCT may change the current landscape of HSCT for AML and MDS. Keywords acute myeloid leukaemia, myelodysplastic syndromes, relapse, transplantation
INTRODUCTION Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only curative option for many patients with haematologic malignancies including advanced/aggressive acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). HSCT provides an advantage over conventional chemotherapy and autologous stem cell transplant due to the immunologic graft-versus-leukaemia (GVL) effect. However, donor immune responses are also responsible for graft-versus-host disease (GVHD), a significant HSCT-related toxicity. Despite GVL, relapse remains one of the chief causes of morbidity and mortality in allogeneic HSCT recipients. On the basis of data from the Center for International Blood and Marrow Transplant Research, 40–50% of deaths after HSCT are caused by primary disease relapse [1]. The 3-year overall survival (OS) after post-HSCT relapse is a dismal 19% [2]. Unfortunately, novel non-HSCT www.co-hematology.com
therapies targeting myeloid malignancies have not yet been efficacious at eradicating established disease. It is for this reason that strategies are necessary to prevent relapse occurrence after HSCT. Strategies to reduce post-HSCT relapse in AML and MDS are aimed at increasing the effectiveness of conditioning regimens, optimizing donor selection, graft engineering, post-HSCT chemotherapy, prophylactic donor lymphocyte infusion (DLI) or vaccination, and targeted post-HSCT immunologic interventions. Many of these arenas remain under Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Correspondence to John Koreth, MBBS, DPhil, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA. Tel: +1 617 632 2949; fax: +1 617 632 5168; e-mail: [email protected] Curr Opin Hematol 2015, 22:116–122 DOI:10.1097/MOH.0000000000000116 Volume 22 Number 2 March 2015
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Preventing relapse after HSCT in AML and MDS Kekre and Koreth
KEY POINTS Many investigators are working on strategies to prevent relapse in patients with MDS and AML, with cell manipulation and targeted immune therapies dominating the field currently. Strategies aimed at potentiating the beneficial graftversus-leukaemia effect afforded by HSCT will likely lead to long-term durable remissions after HSCT. Prospective trials using maintenance and preemptive therapies after HSCT are underway and will likely have an impact on progression-free survival after HSCT.
investigation and the most recent evidence in support of these strategies is reviewed here.
IMPROVING CONDITIONING REGIMENS Conditioning regimens offer a means to reduce tumour burden and suppress host immunity prior to introduction of the donor graft. A greater understanding of the importance of the therapeutic GVL response after HSCT led to an effort to reduce toxicity from conditioning. Reduced intensity conditioning (RIC) HSCT has since become widely used in patients who would not otherwise tolerate myeloablative conditioning (MAC) due to age or comorbidities. A phase III study randomizing patients to MAC versus RIC HSCT for AML and MDS has been closed early due to better OS observed in the MAC arm (NCT01339910). Although formal outcome evaluation of this study is pending, this suggests that increasing the intensity of conditioning can improve OS after HSCT. These results will need to be interpreted carefully, as increased conditioning intensity potentially offers a greater antineoplastic effect, but is often counterbalanced by the added toxicity of this approach. Conditioning agents with more potent or more specific antileukaemia effect that do not increase toxicity may offer a means to optimize HSCT conditioning. One approach has been to incorporate novel chemotherapeutic agents into HSCT conditioning. Clofarabine, for example, is a second-generation purine nucleoside analogue, with a similar mechanism of action to fludarabine and cladribine, but with an increased antileukaemia effect based on more potent activity against ribonucleotide reductase and DNA polymerase a, resistance to both deamination and phosphorolysis, and longer retention in leukaemic blasts [3]. A recently completed phase II trial using a RIC HSCT regimen added clofarabine to intravenous busulfan and antithymocyte globulin, and demonstrated an OS and disease-free survival
(DFS) of 75 and 69%, respectively [4]. Clofarabine is associated with hepatotoxicity, but to date has not been shown to increase veno-occlusive disease after HSCT [5]. Clofarabine as a substitute for fludarabine does not appear to increase toxicity and may improve relapse post-HSCT, although larger randomized trials substituting in or adding clofarabine to HSCT conditioning are still underway to confirm these findings (NCT00990249, NCT01471444). Treosulfan, an alkylating agent that unlike busulfan is able to bypass hepatic metabolism, has also been evaluated in the conditioning of patients with AML and MDS undergoing HSCT. Although the outcomes in this setting were favourable in the low and intermediate-risk groups, patients with high-risk cytogenetics still had a high cumulative incidence of relapse (43% at 2 years) [6]. In an attempt to improve relapse rates post-HSCT in these high-risk patients, a low dose of total body irradiation was added to conditioning to attempt to improve outcomes without adding significant toxicity to the conditioning regimen. This phase II study demonstrated an improved incidence of relapse of 27% at 2 years post-HSCT in patients with high-risk cytogenetic AML or MDS [7]. Another strategy to increase the intensity of conditioning without impacting toxicity has been targeted radio-immunotherapy, which increases the effective dose of cytotoxic therapy to the bone marrow and sites of haematopoiesis by specifically targeting antigens found on haematopoietic cells. An anti-CD45 antibody radiolabelled with the betaemitter iodine 131 has been incorporated into RIC HSCT to improve local radiation delivery to the bone marrow, spleen and lymph nodes in patients with advanced MDS (defined in the relevant study as greater than 5% blasts in the bone marrow) or active relapsed AML at time of HSCT [8]. Traditionally, higher-risk MDS and relapsed AML represent a group at a high risk of relapse after HSCT, but in this study, the estimated probability of relapse at 1-year postHSCT was 33%, without any transplant-related deaths during that time, similar to the relapse risk for patients going into transplant with better disease control. This does suggest a relatively well tolerated targeted approach for patients with high-risk AML or MDS. Additional studies incorporating anti-CD45 radio-immunotherapy into conditioning for HSCT for patients with AML or MDS are ongoing (NCT00589316, NCT01300572). One concern with iodine-131 as a beta-emitter is that it is associated with a ‘cross-fire effect’ causing toxicity to bystander cells including healthy haematopoietic progenitors and other cells in the marrow microenvironment critical to the normal stem cell niche. One strategy to reduce these limitations has
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been the use of alpha emitters, which have a shorter path length and therefore might have less toxicity to nonhaematopoietic cells. Biodistribution studies in a leukaemic mouse model have demonstrated localized anti-CD45 activity using the radiolabelled alpha emitter astatine-211 [9]. In this model, mice treated with the As-211 anti-CD 45 had a prolonged OS without significant liver or renal toxicity. This model does provide a rationale for investigating astatine-211 in the clinical setting.
DONOR SELECTION AND GRAFT ENGINEERING Although novel conditioning regimens may deepen disease remission prior to HSCT, the GVL effect mediated by donor T and natural killer (NK) cells is a major determinant of its curative ability in AML and MDS. T cells recognize leukaemia cells by tumour antigens presented by HLA, but NK cells can recognize ‘loss of self’ HLA invoked by malignant transformation. The NK antileukaemic response is determined by the net effect of inhibitory and activating signals, for instance via the polymorphic killer-cell immunoglobulin-like receptor (KIR) family. Some inhibitory NK cell receptors (including KIRs) recognize class 1 HLA, which is relevant for NK cell education or ‘licensing’ by which NK cells become functional. Ligands for activating KIR include HLA-C2 that binds to KIR2DS1. HLA-mismatched grafts can involve donor–recipient KIR ligand mismatch and NK cell activation owing to interruption of inhibitory KIR signals resulting in a decreased risk of AML relapse, for both haploidentical [10] and unrelated donors [11,12]. With regard to activating KIR, a large study of seven or eight out of eight HLA-matched unrelated donor HSCT documented protection from AML relapse afforded by KIR2DS1 positive as compared with KIR2DS1-negative donors (26.5 versus 32.5%, respectively) [13]. KIR genotyping therefore may provide a new criterion for donor selection that could be associated with a lower risk of relapse, although this is not yet utilized routinely. Efforts to modulate allogeneic T cells are also being undertaken. One strategy is to selectively deplete haploidentical grafts of alpha/beta positive T cells, which are felt to be responsible for GVHD, and thereby allow for rapid proliferation of donor NK and gamma/delta positive T cells to enhance immune reconstitution and GVL post-HSCT [14]. Although follow-up remains short, this technique is being studied in HSCT recipients to determine its impact on relapse rates (NCT02193880, NCT01810120). Donor NK cell infusion has also been deemed well tolerated and feasible in this 118
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setting [15,16]. These studies have suggested that it can lower the rate of AML progression after HSCT without significantly impacting GVHD rates. Interleukin-2 (IL-2) treatment after adoptive transfer of an NK cell enriched product has also been used to further enhance the activation and proliferation of adoptively transferred NK cells in the recipient [17]. This has led to a favourable rise in NK cells, but can also lead to increases in CD4þ regulatory T cells (Tregs), which may potentially restrict the alloimmune response. Tregs constitutively express CD25 (high-affinity IL-2 receptor) and require IL-2 for their activation, proliferation and survival. Bachanova et al. [18 ] therefore coinfused an IL-2 diptheria toxin fusion protein prior to NK cell infusion to target IL-2 receptor bearing Tregs, and avoid any potential blunting of the GVL effect due to Treg expansion. This significantly improved NK cell activation and expansion and suggests a new approach to preventing relapse in AML patients. The main issues regarding NK cell therapy remain the lack of persistence of NK cells after infusion, cost and limited laboratory experience with ex-vivo NK cell expansion [19]. As Tregs are tolerogenic, they have been utilized to prevent GVHD in patients undergoing haploidentical and umbilical cord blood HSCT [20,21]. A concern with this approach remains the impact that Treg therapy may have on GVL and relapse after HSCT, although antitumour immune responses appear preserved after murine Treg therapy [22]. Clinically, the coinfusion of Tregs as well as conventional T lymphocytes (Tcon) appears sufficient for improved immunologic reconstitution and GVHD prophylaxis without increasing relapse rates. A trial of haploidentical HSCT in patients with highrisk acute leukaemia who were infused with both Tregs and Tcon as part of their protocol was well tolerated, with a low cumulative incidence of relapse, 5% at a median follow-up of 46 months [23 ]. As the biologic understanding of GVL and GVHD improves, better strategies to control relapse without invoking HSCT toxicity will continue to emerge. &&
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POSTHAEMATOPOIETIC STEM CELL TRANSPLANTATION CHEMOTHERAPEUTIC INTERVENTIONS Patients who are at a high risk of relapse after HSCT should be considered for novel post-HSCT interventions that could prolong DFS. One predictor of relapse after HSCT has been monitoring for minimal residual disease (MRD) to identify patients at a high risk of overt clinical relapse. Creating a uniform strategy for quantifying MRD has proven difficult Volume 22 Number 2 March 2015
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Preventing relapse after HSCT in AML and MDS Kekre and Koreth
in AML and MDS, as these diseases represent a large spectrum of molecular and cytogenetic findings and the immunophenotype of neoplastic cells often does not differ markedly from normal haematopoietic progenitors. Although not standardized, MRD as measured by flow cytometry or by molecular PCR (e.g. mutant NPM1 or disease-associated translocations) consistently demonstrates a higher risk of relapse and a shorter OS than patients who are MRD negative after HSCT [24–26]. This remains true when comparing AML patients in first or second complete remission at the time of HSCT [27]. In the future, next-generation sequencing may offer an unbiased high-sensitivity assessment of MRD status in AML and MDS. Loss of donor cell chimerism has also been used as a surrogate for early relapse. Studies have shown that low total and T cell donor chimerism at 30 days and 100 days after HSCT are associated with relapse and impaired survival [28,29]. A preemptive strategy to prevent clinical relapse based on falling chimerism was attempted by Platzbecker et al. [30] for patients with a CD34-specific donor chimerism that fell below 80%. Twenty such patients were treated with azacitidine for up to four cycles for falling chimerism. Half of the patients had recovery of full donor chimerism with no clinical signs of relapse. Eventually, 65% of patients experienced relapse, but treatment with azacitidine was thought to delay this (median time to relapse was 231 days). Although preemptive azacitidine had acceptable toxicity in this study, it is difficult to know whether it improved relapse rates given the lack of a control arm. In addition, relapse was still very prevalent in this study, arguing against any benefit to this preemptive strategy. Azacitidine has not only been used in a riskstratified preemptive manner but also as a potential routine maintenance agent after HSCT. In a dose and schedule-finding study, toxicity with azacitidine after HSCT resulted in an acceptable toxicity profile, with reversible thrombocytopenia being the dose-limiting feature [31]. In fact, it has been suggested that azacitidine may enhance the GVL effect of HSCT by inducing a cytotoxic T-cell response to tumour antigens, while decreasing the rate of GVHD by increasing Tregs [32]. It remains to be determined how this impacts OS and DFS after HSCT in patients with MDS (NCT01995578). As the molecular understanding of AML and MDS continues to evolve, more targeted approaches are being developed. One such target has been FLT-3 internal tandem duplication (FLT3-ITD) in AML. FLT3-ITD mutations are a predictor of poor outcomes in cytogenetically normal AML [33]. Sorafenib, a small molecule inhibitor of Ras kinase
approved for the treatment of renal cell carcinoma and hepatocellular carcinoma, also has activity against FLT3 and other kinases. Sorafenib has demonstrated safety and efficacy in patients with relapsed or refractory FLT3-ITD mutated AML outside of the HSCT setting [34,35]. Early reports in HSCT suggest that the use of sorafenib before HSCT in patients not eligible for cytotoxic therapy, and after HSCT for maintenance or at the time of relapse can lead to durable responses [36]. Midostaurin (PKC412) is a small molecule inhibitor of FLT3, but also has activity against c-kit, PDGFR and VEGFR. It has demonstrated a high rate of complete remission (92%) in a phase I study of FLT3-mutated AML in young patients [37]. Lastly, quizartinib (AC220), an FLT-3 inhibitor that appears to have a higher affinity for FLT-3, has demonstrated activity in relapsed or refractory AML [38]. On the basis of evidence of tolerability and efficacy against AML outside of HSCT, these drugs are now being tested as post-HSCT maintenance therapy (NCT01398501, NCT01883362). RAS and IDH1 represent targets for other small molecule inhibitors that have shown antileukaemic activity in the preclinical setting [39,40]. If results are promising, such targeted agents could change the prognosis of a currently very poor risk group of AML patients. With other molecular aberrations such as TET2, TP53 and DNMT3A emerging as predictors of mortality in AML and MDS patients [41 ], the development of other targeted therapies is likely to follow. &
POSTHAEMATOPOIETIC STEM CELL TRANSPLANTATION IMMUNE-MEDIATED INTERVENTIONS The mainstay of relapse treatment after HSCT, apart from conventional chemotherapy, has been taper of immunosuppressive medications followed by DLI, which can generate a GVL effect, albeit with an increased risk of GVHD. The efficacy of DLI in generating a durable GVL effect for relapsed AML and MDS is however limited. In recent studies of DLI at time of overt relapse after HSCT, OS and DFS remain dismal, with 1-year OS as low as 32% after DLI [42,43]. Prophylactic DLI has also been utilized in an effort to reduce the risk of relapse after HSCT. Recipients of T cell depleted RIC HSCT who did not develop GVHD after rapid immunosuppression taper were given prophylactic DLI [44]. Despite prophylactic DLI, 77% of patients died from disease recurrence, suggesting that DLI alone is not enough to overcome the risk of relapse after HSCT. In patients undergoing DLI at one institution, a comparison of those receiving DLI preemptively
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Myeloid disease Table 1. Summary of new strategies to prevent relapse after haematopoietic stem cell transplantation for acute myeloid leukaemia/myelodysplastic syndromes Strategy
Possible benefits and risks
Improving conditioning regimens Clofarabine as a substitute for fludarabine
More specific antileukaemia effect without adding toxicity
Treosulfan as a substitute for busulfan
Improves hepatic toxicity, but relapse rates remain high
Targeted radio-immunotherapy
Increases cytotoxic therapy to sites of haematopoiesis, but may increase toxicity to normal cells
Donor selection and graft engineering KIR genotyping
KIR incompatibility selects for NK allo-reactive activity against tumour cells
Selective depletion of alpha/beta T cells
Enhances GVL by allowing gamma/delta T cells to proliferate, without increasing GVHD
NK cell infusion
Reduces disease progression by enhancing GVL, but may worsen GVHD
Post-HSCT maintenance therapy Azacitidine
Acceptable toxicity profile, with a possible delay in time to relapse
FLT3 inhibitors
Tolerable and efficacious outside of HSCT, now in early phase HSCT trials
Post-HSCT immune therapies DLI
No relapse reduction in the prophylactic setting, but perhaps in the preemptive setting based on MRD
Tumour-specific vaccines
Well tolerated post-HSCT, with suggestion of durable responses
mAbs and CAR-T cells
Activity against AML in vitro, but not yet demonstrated in the clinical HSCT setting
AML, acute myeloid leukaemia; CAR, chimeric antigen receptor; DLI, donor lymphocyte infusion; GVHD, graft-versus-host disease; GVL, graft-versus-leukaemia; HSCT, haematopoietic stem cell transplantation; MRD, minimal residual disease; NK, natural killer; KIR, killer-cell immunoglobulin-like receptor.
based on MRD status was compared with that of patients receiving DLI at the time of overt relapse. Not surprisingly, patients who underwent preemptive DLI were more likely to respond and had a significantly better 5-year OS than those who received it at the time of relapse (80 versus 40%, respectively) [45]. Although this suggests that DLI can be useful in a preemptive approach, MRD monitoring post-HSCT for AML and MDS has not yet been standardized. Moreover, the use of T cell depletion in both the prophylactic and preemptive DLI strategies employed restricts the generalizability of these results. The main concern with DLI remains the high incidence of GVHD due to the nonspecific nature of the allo-reactive T cells administered in DLI. A more targeted approach has been the use of post-HSCT tumour vaccination to reduce the incidence of relapse. In this approach, the beneficial GVL response from HSCT is amplified by immunization with irradiated, autologous granulocyte–macrophage colony-stimulating factor secreting blast cells early after HSCT. Reactions similar to those seen in vaccine trials for non-HSCT solid tumour patients were observed post-HSCT [46]. This phase I study identified leukaemia cell vaccine post-HSCT to be well tolerated and suggested long-term remission in some patients. A similar phase I trial using a vaccine 120
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targeted at Wilms Tumor-1 protein (WT1), commonly found on human leukaemia cells, also showed durable remissions in AML patients who were not in complete remission at the time of HSCT [47]. Peptide-based vaccines targeted at the tumour antigen NY-ESO-1 have also shown promise in solid tumours such as ovarian cancer and melanoma, and testing in AML and MDS is currently underway (NCT01834248). Other targeted immune approaches against AML and MDS utilize mAbs and chimeric antigen receptor T cells. These treatments have mostly been evaluated in vitro or in early phase I studies, and although they may change the treatment paradigm of AML and MDS, it is imperative to proceed with caution in the setting of HSCT. One example of this has been gemtuzumab ozagamicin, a targeted antineoplastic drug consisting of a recombinant anti-CD33 humanized antibody linked to calicheamicin. Although pooled results from multiple randomized trials have demonstrated a DFS benefit to gemtuzumab ozagamicin, the pooled relative risk of veno-occlusive disease with addition of this drug to conventional chemotherapy is 7.67 (95% confidence interval 1.41–41.74) [48], making it difficult to consider administering it to patients needing HSCT. A newer CD33 antibody–drug conjugate SGN-CD33A [49] and a CD33/CD3 bi-specific T cell Volume 22 Number 2 March 2015
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Preventing relapse after HSCT in AML and MDS Kekre and Koreth
engager [50] have demonstrated in-vitro activity against AML, but will need clinical testing before determining whether they can be safely used in HSCT patients. The IL-3 receptor alpha chain CD123 has also been an immune target of interest in AML, as it is overexpressed on AML blasts. Chimeric antigen receptor T cells have been produced from T cells of AML patients that target CD123 and have demonstrated in-vitro lysis of AML blasts as well as invivo activity in a xenographic model [51 ]. In a mouse model, this same approach showed antileukaemia activity but also eradicated normal haematopoiesis, cautioning against using this outside of HSCT [52]. Nevertheless, mAb therapy as well as chimeric antigen receptor T cell therapy have the potential to improve outcomes of high-risk MDS and AML patients. &&
CONCLUSION Relapse after HSCT remains the leading cause of death for AML and MDS. Treatment of relapse is difficult with limited survival. It is imperative that strategies aimed at preventing relapse post-HSCT continue to be evaluated in this patient population. At present, substitutions in conditioning regimens such as treosulfan or clofarabine are being employed, but these alone are not likely to eradicate the risk of relapse. Strategies aimed at optimizing donor selection and graft manipulation may offer additional long-term benefit in preventing relapse post-HSCT. Such methods are focused on manipulating NK cells and Tregs and provide cautious optimism regarding improving GVL without significant increases in GVHD. Novel targeted therapies against MDS and AML, including small molecule inhibitors, tumour vaccines, mAbs and chimeric antigen receptor T cells, offer future promise for patients who do not respond to standard induction therapies. As techniques to detect MRD advance, treatment of molecular relapse, prior to the development of overt clinical relapse, is likely to depend on these newer targeted therapies, hopefully improving HSCT and non-HSCT outcomes in AML and MDS patients (Table 1). Acknowledgements None. Financial support and sponsorship None. Conflicts of interest None.
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Myeloid disease 23. Martelli MF, Di Ianni M, Ruggeri L, et al. HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse. Blood 2014; 124:638–644. A trial of haploidentical HSCT in patients with high-risk acute leukaemia who were infused with both Tregs and Tcon as part of their protocol was well tolerated, with a low cumulative incidence of relapse, 5% at a median follow-up of 46 months. 24. Shayegi N, Kramer M, Bornhauser M, et al. The level of residual disease based on mutant NPM1 is an independent prognostic factor for relapse and survival in AML. Blood 2013; 122:83–92. 25. Bastos-Oreiro M, Perez-Corral A, Martinez-Laperche C, et al. Prognostic impact of minimal residual disease analysis by flow cytometry in patients with acute myeloid leukemia before and after allogeneic hemopoietic stem cell transplantation. Eur J Haematol 2014; 93:239–246. 26. Bernal T, Diez-Campelo M, Godoy V, et al. Role of minimal residual disease and chimerism after reduced-intensity and myeloablative allo-transplantation in acute myeloid leukemia and high-risk myelodysplastic syndrome. Leuk Res 2014; 38:551–556. 27. Walter RB, Buckley SA, Pagel JM, et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood 2013; 122:1813– 1821. 28. Koreth J, Kim HT, Nikiforow S, et al. Donor chimerism early after reducedintensity conditioning hematopoietic stem cell transplantation predicts relapse and survival. Biol Blood Marrow Transplant 2014; 20:1516–1521. 29. Reshef R, Hexner EO, Loren AW, et al. Early donor chimerism levels predict relapse and survival after allogeneic stem cell transplantation with reducedintensity conditioning. Biol Blood Marrow Transplant 2014; 20:1758–1766. 30. Platzbecker U, Wermke M, Radke J, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2012; 26:381–389. 31. de Lima M, Giralt S, Thall PF, et al. Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study. Cancer 2010; 116:5420–5431. 32. Goodyear OC, Dennis M, Jilani NY, et al. Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML). Blood 2012; 119:3361–3369. 33. Mrozek K, Marcucci G, Nicolet D, et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol 2012; 30:4515–4523. 34. Crump M, Hedley D, Kamel-Reid S, et al. A randomized phase I clinical and biologic study of two schedules of sorafenib in patients with myelodysplastic syndrome or acute myeloid leukemia: a NCIC (National Cancer Institute of Canada) Clinical Trials Group Study. Leuk Lymphoma 2010; 51:252– 260. 35. Metzelder SK, Schroeder T, Finck A, et al. High activity of sorafenib in FLT3ITD-positive acute myeloid leukemia synergizes with allo-immune effects to induce sustained responses. Leukemia 2012; 26:2353–2359. 36. Sammons SL, Pratz KW, Smith BD, et al. Sorafenib is tolerable and improves clinical outcomes in patients with FLT3-ITD acute myeloid leukemia prior to stem cell transplant and after relapse posttransplant. Am J Hematol 2014; 89:936–938. 37. Stone RM, Fischer T, Paquette R, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia 2012; 26:2061–2068.
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38. Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol 2013; 31:3681–3687. 39. Chaturvedi A, Araujo Cruz MM, Jyotsana N, et al. Mutant IDH1 promotes leukemogenesis in vivo and can be specifically targeted in human AML. Blood 2013; 122:2877–2887. 40. Weisberg EL, Nonami A, Chen Z, et al. Up-regulation of IGF-1R by mutant RAS in leukemia and potentiation of RAS signaling inhibitors by small molecule inhibition of IGF-1R. Clin Cancer Res 2014; 20:5483–5495. 41. Bejar R, Stevenson KE, Caughey B, et al. Somatic mutations predict poor & outcome in patients with myelodysplastic syndrome after hematopoietic stemcell transplantation. J Clin Oncol 2014; 32:2691–2698. Molecular aberrations such as TET2, TP53 and DNMT3A are predictors of mortality in AML and MDS patients, despite HSCT. 42. Takami A, Yano S, Yokoyama H, et al. Donor lymphocyte infusion for the treatment of relapsed acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation: a retrospective analysis by the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2014; 20:1785–1790. 43. Bar M, Sandmaier BM, Inamoto Y, et al. Donor lymphocyte infusion for relapsed hematological malignancies after allogeneic hematopoietic cell transplantation: prognostic relevance of the initial CD3þ T cell dose. Biol Blood Marrow Transplant 2013; 19:949–957. 44. Kumar AJ, Hexner EO, Frey NV, et al. Pilot study of prophylactic ex vivo costimulated donor leukocyte infusion after reduced-intensity conditioned allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2013; 19:1094–1101. 45. Krishnamurthy P, Potter VT, Barber LD, et al. Outcome of donor lymphocyte infusion after T cell-depleted allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndromes. Biol Blood Marrow Transplant 2013; 19:562–568. 46. Ho VT, Vanneman M, Kim H, et al. Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation. Proc Natl Acad Sci U S A 2009; 106:15825–15830. 47. Maeda T, Hosen N, Fukushima K, et al. Maintenance of complete remission after allogeneic stem cell transplantation in leukemia patients treated with Wilms tumor 1 peptide vaccine. Blood Cancer J 2013; 3:e130. 48. Kharfan-Dabaja MA, Hamadani M, Reljic T, et al. Gemtuzumab ozogamicin for treatment of newly diagnosed acute myeloid leukaemia: a systematic review and meta-analysis. Br J Haematol 2013; 163:315–325. 49. Kung Sutherland MS, Walter RB, Jeffrey SC, et al. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood 2013; 122:1455–1463. 50. Aigner M, Feulner J, Schaffer S, et al. T lymphocytes can be effectively recruited for ex vivo and in vivo lysis of AML blasts by a novel CD33/CD3bispecific BiTE antibody construct. Leukemia 2013; 27:1107–1115. 51. Mardiros A, Dos Santos C, McDonald T, et al. T cells expressing CD123&& specific chimeric antigen receptors exhibit specific cytolytic effector functions and antitumor effects against human acute myeloid leukemia. Blood 2013; 122:3138–3148. Chimeric antigen receptor T cells have been produced from T cells of AML patients that target CD123 and have demonstrated in-vitro and in-vivo activity against AML blasts. 52. Gill S, Tasian SK, Ruella M, et al. Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Blood 2014; 123:2343–2354.
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Novel strategies to prevent relapse after allogeneic haematopoietic stem cell transplantation for acute myeloid leukaemia and myelodysplastic syndromes Natasha Kekre and John Koreth
Purpose of review Relapse of haematological neoplasms after allogeneic haematopoietic stem cell transplantation (HSCT) remains one of the leading causes of death. Treatment of relapse post-HSCT is frequently ineffective and outcomes are poor, necessitating preventive strategies that are reviewed below. Recent findings Current strategies to prevent relapse after HSCT are geared towards four general principles: improving the antitumour effects of conditioning regimens prior to HSCT, improving graft selection and engineering to augment the graft-versus-leukaemia effect, post-HSCT chemotherapeutic interventions to impair growth of residual clonal cells and post-HSCT immune-mediated interventions to enhance the graft-versus-leukaemia effect. Strategies based on cell manipulation, namely natural killer (NK) cell enrichment and adoptive T cell transfer, are emerging. Targeted therapies including vaccinations, FLT3 inhibitors, mAbs and chimeric antigen receptor T cell therapy represent a new avenue of treating acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Studies are underway to incorporate all of these strategies in the clinical setting to determine their impact on relapse and survival after HSCT. Summary The most recent evidence suggests that strategies using NK cell therapy and targeted immune therapies after HSCT may change the current landscape of HSCT for AML and MDS. Keywords acute myeloid leukaemia, myelodysplastic syndromes, relapse, transplantation
INTRODUCTION Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only curative option for many patients with haematologic malignancies including advanced/aggressive acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). HSCT provides an advantage over conventional chemotherapy and autologous stem cell transplant due to the immunologic graft-versus-leukaemia (GVL) effect. However, donor immune responses are also responsible for graft-versus-host disease (GVHD), a significant HSCT-related toxicity. Despite GVL, relapse remains one of the chief causes of morbidity and mortality in allogeneic HSCT recipients. On the basis of data from the Center for International Blood and Marrow Transplant Research, 40–50% of deaths after HSCT are caused by primary disease relapse [1]. The 3-year overall survival (OS) after post-HSCT relapse is a dismal 19% [2]. Unfortunately, novel non-HSCT www.co-hematology.com
therapies targeting myeloid malignancies have not yet been efficacious at eradicating established disease. It is for this reason that strategies are necessary to prevent relapse occurrence after HSCT. Strategies to reduce post-HSCT relapse in AML and MDS are aimed at increasing the effectiveness of conditioning regimens, optimizing donor selection, graft engineering, post-HSCT chemotherapy, prophylactic donor lymphocyte infusion (DLI) or vaccination, and targeted post-HSCT immunologic interventions. Many of these arenas remain under Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts, USA Correspondence to John Koreth, MBBS, DPhil, Division of Hematologic Malignancies, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA. Tel: +1 617 632 2949; fax: +1 617 632 5168; e-mail: [email protected] Curr Opin Hematol 2015, 22:116–122 DOI:10.1097/MOH.0000000000000116 Volume 22 Number 2 March 2015
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Preventing relapse after HSCT in AML and MDS Kekre and Koreth
KEY POINTS Many investigators are working on strategies to prevent relapse in patients with MDS and AML, with cell manipulation and targeted immune therapies dominating the field currently. Strategies aimed at potentiating the beneficial graftversus-leukaemia effect afforded by HSCT will likely lead to long-term durable remissions after HSCT. Prospective trials using maintenance and preemptive therapies after HSCT are underway and will likely have an impact on progression-free survival after HSCT.
investigation and the most recent evidence in support of these strategies is reviewed here.
IMPROVING CONDITIONING REGIMENS Conditioning regimens offer a means to reduce tumour burden and suppress host immunity prior to introduction of the donor graft. A greater understanding of the importance of the therapeutic GVL response after HSCT led to an effort to reduce toxicity from conditioning. Reduced intensity conditioning (RIC) HSCT has since become widely used in patients who would not otherwise tolerate myeloablative conditioning (MAC) due to age or comorbidities. A phase III study randomizing patients to MAC versus RIC HSCT for AML and MDS has been closed early due to better OS observed in the MAC arm (NCT01339910). Although formal outcome evaluation of this study is pending, this suggests that increasing the intensity of conditioning can improve OS after HSCT. These results will need to be interpreted carefully, as increased conditioning intensity potentially offers a greater antineoplastic effect, but is often counterbalanced by the added toxicity of this approach. Conditioning agents with more potent or more specific antileukaemia effect that do not increase toxicity may offer a means to optimize HSCT conditioning. One approach has been to incorporate novel chemotherapeutic agents into HSCT conditioning. Clofarabine, for example, is a second-generation purine nucleoside analogue, with a similar mechanism of action to fludarabine and cladribine, but with an increased antileukaemia effect based on more potent activity against ribonucleotide reductase and DNA polymerase a, resistance to both deamination and phosphorolysis, and longer retention in leukaemic blasts [3]. A recently completed phase II trial using a RIC HSCT regimen added clofarabine to intravenous busulfan and antithymocyte globulin, and demonstrated an OS and disease-free survival
(DFS) of 75 and 69%, respectively [4]. Clofarabine is associated with hepatotoxicity, but to date has not been shown to increase veno-occlusive disease after HSCT [5]. Clofarabine as a substitute for fludarabine does not appear to increase toxicity and may improve relapse post-HSCT, although larger randomized trials substituting in or adding clofarabine to HSCT conditioning are still underway to confirm these findings (NCT00990249, NCT01471444). Treosulfan, an alkylating agent that unlike busulfan is able to bypass hepatic metabolism, has also been evaluated in the conditioning of patients with AML and MDS undergoing HSCT. Although the outcomes in this setting were favourable in the low and intermediate-risk groups, patients with high-risk cytogenetics still had a high cumulative incidence of relapse (43% at 2 years) [6]. In an attempt to improve relapse rates post-HSCT in these high-risk patients, a low dose of total body irradiation was added to conditioning to attempt to improve outcomes without adding significant toxicity to the conditioning regimen. This phase II study demonstrated an improved incidence of relapse of 27% at 2 years post-HSCT in patients with high-risk cytogenetic AML or MDS [7]. Another strategy to increase the intensity of conditioning without impacting toxicity has been targeted radio-immunotherapy, which increases the effective dose of cytotoxic therapy to the bone marrow and sites of haematopoiesis by specifically targeting antigens found on haematopoietic cells. An anti-CD45 antibody radiolabelled with the betaemitter iodine 131 has been incorporated into RIC HSCT to improve local radiation delivery to the bone marrow, spleen and lymph nodes in patients with advanced MDS (defined in the relevant study as greater than 5% blasts in the bone marrow) or active relapsed AML at time of HSCT [8]. Traditionally, higher-risk MDS and relapsed AML represent a group at a high risk of relapse after HSCT, but in this study, the estimated probability of relapse at 1-year postHSCT was 33%, without any transplant-related deaths during that time, similar to the relapse risk for patients going into transplant with better disease control. This does suggest a relatively well tolerated targeted approach for patients with high-risk AML or MDS. Additional studies incorporating anti-CD45 radio-immunotherapy into conditioning for HSCT for patients with AML or MDS are ongoing (NCT00589316, NCT01300572). One concern with iodine-131 as a beta-emitter is that it is associated with a ‘cross-fire effect’ causing toxicity to bystander cells including healthy haematopoietic progenitors and other cells in the marrow microenvironment critical to the normal stem cell niche. One strategy to reduce these limitations has
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been the use of alpha emitters, which have a shorter path length and therefore might have less toxicity to nonhaematopoietic cells. Biodistribution studies in a leukaemic mouse model have demonstrated localized anti-CD45 activity using the radiolabelled alpha emitter astatine-211 [9]. In this model, mice treated with the As-211 anti-CD 45 had a prolonged OS without significant liver or renal toxicity. This model does provide a rationale for investigating astatine-211 in the clinical setting.
DONOR SELECTION AND GRAFT ENGINEERING Although novel conditioning regimens may deepen disease remission prior to HSCT, the GVL effect mediated by donor T and natural killer (NK) cells is a major determinant of its curative ability in AML and MDS. T cells recognize leukaemia cells by tumour antigens presented by HLA, but NK cells can recognize ‘loss of self’ HLA invoked by malignant transformation. The NK antileukaemic response is determined by the net effect of inhibitory and activating signals, for instance via the polymorphic killer-cell immunoglobulin-like receptor (KIR) family. Some inhibitory NK cell receptors (including KIRs) recognize class 1 HLA, which is relevant for NK cell education or ‘licensing’ by which NK cells become functional. Ligands for activating KIR include HLA-C2 that binds to KIR2DS1. HLA-mismatched grafts can involve donor–recipient KIR ligand mismatch and NK cell activation owing to interruption of inhibitory KIR signals resulting in a decreased risk of AML relapse, for both haploidentical [10] and unrelated donors [11,12]. With regard to activating KIR, a large study of seven or eight out of eight HLA-matched unrelated donor HSCT documented protection from AML relapse afforded by KIR2DS1 positive as compared with KIR2DS1-negative donors (26.5 versus 32.5%, respectively) [13]. KIR genotyping therefore may provide a new criterion for donor selection that could be associated with a lower risk of relapse, although this is not yet utilized routinely. Efforts to modulate allogeneic T cells are also being undertaken. One strategy is to selectively deplete haploidentical grafts of alpha/beta positive T cells, which are felt to be responsible for GVHD, and thereby allow for rapid proliferation of donor NK and gamma/delta positive T cells to enhance immune reconstitution and GVL post-HSCT [14]. Although follow-up remains short, this technique is being studied in HSCT recipients to determine its impact on relapse rates (NCT02193880, NCT01810120). Donor NK cell infusion has also been deemed well tolerated and feasible in this 118
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setting [15,16]. These studies have suggested that it can lower the rate of AML progression after HSCT without significantly impacting GVHD rates. Interleukin-2 (IL-2) treatment after adoptive transfer of an NK cell enriched product has also been used to further enhance the activation and proliferation of adoptively transferred NK cells in the recipient [17]. This has led to a favourable rise in NK cells, but can also lead to increases in CD4þ regulatory T cells (Tregs), which may potentially restrict the alloimmune response. Tregs constitutively express CD25 (high-affinity IL-2 receptor) and require IL-2 for their activation, proliferation and survival. Bachanova et al. [18 ] therefore coinfused an IL-2 diptheria toxin fusion protein prior to NK cell infusion to target IL-2 receptor bearing Tregs, and avoid any potential blunting of the GVL effect due to Treg expansion. This significantly improved NK cell activation and expansion and suggests a new approach to preventing relapse in AML patients. The main issues regarding NK cell therapy remain the lack of persistence of NK cells after infusion, cost and limited laboratory experience with ex-vivo NK cell expansion [19]. As Tregs are tolerogenic, they have been utilized to prevent GVHD in patients undergoing haploidentical and umbilical cord blood HSCT [20,21]. A concern with this approach remains the impact that Treg therapy may have on GVL and relapse after HSCT, although antitumour immune responses appear preserved after murine Treg therapy [22]. Clinically, the coinfusion of Tregs as well as conventional T lymphocytes (Tcon) appears sufficient for improved immunologic reconstitution and GVHD prophylaxis without increasing relapse rates. A trial of haploidentical HSCT in patients with highrisk acute leukaemia who were infused with both Tregs and Tcon as part of their protocol was well tolerated, with a low cumulative incidence of relapse, 5% at a median follow-up of 46 months [23 ]. As the biologic understanding of GVL and GVHD improves, better strategies to control relapse without invoking HSCT toxicity will continue to emerge. &&
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POSTHAEMATOPOIETIC STEM CELL TRANSPLANTATION CHEMOTHERAPEUTIC INTERVENTIONS Patients who are at a high risk of relapse after HSCT should be considered for novel post-HSCT interventions that could prolong DFS. One predictor of relapse after HSCT has been monitoring for minimal residual disease (MRD) to identify patients at a high risk of overt clinical relapse. Creating a uniform strategy for quantifying MRD has proven difficult Volume 22 Number 2 March 2015
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Preventing relapse after HSCT in AML and MDS Kekre and Koreth
in AML and MDS, as these diseases represent a large spectrum of molecular and cytogenetic findings and the immunophenotype of neoplastic cells often does not differ markedly from normal haematopoietic progenitors. Although not standardized, MRD as measured by flow cytometry or by molecular PCR (e.g. mutant NPM1 or disease-associated translocations) consistently demonstrates a higher risk of relapse and a shorter OS than patients who are MRD negative after HSCT [24–26]. This remains true when comparing AML patients in first or second complete remission at the time of HSCT [27]. In the future, next-generation sequencing may offer an unbiased high-sensitivity assessment of MRD status in AML and MDS. Loss of donor cell chimerism has also been used as a surrogate for early relapse. Studies have shown that low total and T cell donor chimerism at 30 days and 100 days after HSCT are associated with relapse and impaired survival [28,29]. A preemptive strategy to prevent clinical relapse based on falling chimerism was attempted by Platzbecker et al. [30] for patients with a CD34-specific donor chimerism that fell below 80%. Twenty such patients were treated with azacitidine for up to four cycles for falling chimerism. Half of the patients had recovery of full donor chimerism with no clinical signs of relapse. Eventually, 65% of patients experienced relapse, but treatment with azacitidine was thought to delay this (median time to relapse was 231 days). Although preemptive azacitidine had acceptable toxicity in this study, it is difficult to know whether it improved relapse rates given the lack of a control arm. In addition, relapse was still very prevalent in this study, arguing against any benefit to this preemptive strategy. Azacitidine has not only been used in a riskstratified preemptive manner but also as a potential routine maintenance agent after HSCT. In a dose and schedule-finding study, toxicity with azacitidine after HSCT resulted in an acceptable toxicity profile, with reversible thrombocytopenia being the dose-limiting feature [31]. In fact, it has been suggested that azacitidine may enhance the GVL effect of HSCT by inducing a cytotoxic T-cell response to tumour antigens, while decreasing the rate of GVHD by increasing Tregs [32]. It remains to be determined how this impacts OS and DFS after HSCT in patients with MDS (NCT01995578). As the molecular understanding of AML and MDS continues to evolve, more targeted approaches are being developed. One such target has been FLT-3 internal tandem duplication (FLT3-ITD) in AML. FLT3-ITD mutations are a predictor of poor outcomes in cytogenetically normal AML [33]. Sorafenib, a small molecule inhibitor of Ras kinase
approved for the treatment of renal cell carcinoma and hepatocellular carcinoma, also has activity against FLT3 and other kinases. Sorafenib has demonstrated safety and efficacy in patients with relapsed or refractory FLT3-ITD mutated AML outside of the HSCT setting [34,35]. Early reports in HSCT suggest that the use of sorafenib before HSCT in patients not eligible for cytotoxic therapy, and after HSCT for maintenance or at the time of relapse can lead to durable responses [36]. Midostaurin (PKC412) is a small molecule inhibitor of FLT3, but also has activity against c-kit, PDGFR and VEGFR. It has demonstrated a high rate of complete remission (92%) in a phase I study of FLT3-mutated AML in young patients [37]. Lastly, quizartinib (AC220), an FLT-3 inhibitor that appears to have a higher affinity for FLT-3, has demonstrated activity in relapsed or refractory AML [38]. On the basis of evidence of tolerability and efficacy against AML outside of HSCT, these drugs are now being tested as post-HSCT maintenance therapy (NCT01398501, NCT01883362). RAS and IDH1 represent targets for other small molecule inhibitors that have shown antileukaemic activity in the preclinical setting [39,40]. If results are promising, such targeted agents could change the prognosis of a currently very poor risk group of AML patients. With other molecular aberrations such as TET2, TP53 and DNMT3A emerging as predictors of mortality in AML and MDS patients [41 ], the development of other targeted therapies is likely to follow. &
POSTHAEMATOPOIETIC STEM CELL TRANSPLANTATION IMMUNE-MEDIATED INTERVENTIONS The mainstay of relapse treatment after HSCT, apart from conventional chemotherapy, has been taper of immunosuppressive medications followed by DLI, which can generate a GVL effect, albeit with an increased risk of GVHD. The efficacy of DLI in generating a durable GVL effect for relapsed AML and MDS is however limited. In recent studies of DLI at time of overt relapse after HSCT, OS and DFS remain dismal, with 1-year OS as low as 32% after DLI [42,43]. Prophylactic DLI has also been utilized in an effort to reduce the risk of relapse after HSCT. Recipients of T cell depleted RIC HSCT who did not develop GVHD after rapid immunosuppression taper were given prophylactic DLI [44]. Despite prophylactic DLI, 77% of patients died from disease recurrence, suggesting that DLI alone is not enough to overcome the risk of relapse after HSCT. In patients undergoing DLI at one institution, a comparison of those receiving DLI preemptively
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Myeloid disease Table 1. Summary of new strategies to prevent relapse after haematopoietic stem cell transplantation for acute myeloid leukaemia/myelodysplastic syndromes Strategy
Possible benefits and risks
Improving conditioning regimens Clofarabine as a substitute for fludarabine
More specific antileukaemia effect without adding toxicity
Treosulfan as a substitute for busulfan
Improves hepatic toxicity, but relapse rates remain high
Targeted radio-immunotherapy
Increases cytotoxic therapy to sites of haematopoiesis, but may increase toxicity to normal cells
Donor selection and graft engineering KIR genotyping
KIR incompatibility selects for NK allo-reactive activity against tumour cells
Selective depletion of alpha/beta T cells
Enhances GVL by allowing gamma/delta T cells to proliferate, without increasing GVHD
NK cell infusion
Reduces disease progression by enhancing GVL, but may worsen GVHD
Post-HSCT maintenance therapy Azacitidine
Acceptable toxicity profile, with a possible delay in time to relapse
FLT3 inhibitors
Tolerable and efficacious outside of HSCT, now in early phase HSCT trials
Post-HSCT immune therapies DLI
No relapse reduction in the prophylactic setting, but perhaps in the preemptive setting based on MRD
Tumour-specific vaccines
Well tolerated post-HSCT, with suggestion of durable responses
mAbs and CAR-T cells
Activity against AML in vitro, but not yet demonstrated in the clinical HSCT setting
AML, acute myeloid leukaemia; CAR, chimeric antigen receptor; DLI, donor lymphocyte infusion; GVHD, graft-versus-host disease; GVL, graft-versus-leukaemia; HSCT, haematopoietic stem cell transplantation; MRD, minimal residual disease; NK, natural killer; KIR, killer-cell immunoglobulin-like receptor.
based on MRD status was compared with that of patients receiving DLI at the time of overt relapse. Not surprisingly, patients who underwent preemptive DLI were more likely to respond and had a significantly better 5-year OS than those who received it at the time of relapse (80 versus 40%, respectively) [45]. Although this suggests that DLI can be useful in a preemptive approach, MRD monitoring post-HSCT for AML and MDS has not yet been standardized. Moreover, the use of T cell depletion in both the prophylactic and preemptive DLI strategies employed restricts the generalizability of these results. The main concern with DLI remains the high incidence of GVHD due to the nonspecific nature of the allo-reactive T cells administered in DLI. A more targeted approach has been the use of post-HSCT tumour vaccination to reduce the incidence of relapse. In this approach, the beneficial GVL response from HSCT is amplified by immunization with irradiated, autologous granulocyte–macrophage colony-stimulating factor secreting blast cells early after HSCT. Reactions similar to those seen in vaccine trials for non-HSCT solid tumour patients were observed post-HSCT [46]. This phase I study identified leukaemia cell vaccine post-HSCT to be well tolerated and suggested long-term remission in some patients. A similar phase I trial using a vaccine 120
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targeted at Wilms Tumor-1 protein (WT1), commonly found on human leukaemia cells, also showed durable remissions in AML patients who were not in complete remission at the time of HSCT [47]. Peptide-based vaccines targeted at the tumour antigen NY-ESO-1 have also shown promise in solid tumours such as ovarian cancer and melanoma, and testing in AML and MDS is currently underway (NCT01834248). Other targeted immune approaches against AML and MDS utilize mAbs and chimeric antigen receptor T cells. These treatments have mostly been evaluated in vitro or in early phase I studies, and although they may change the treatment paradigm of AML and MDS, it is imperative to proceed with caution in the setting of HSCT. One example of this has been gemtuzumab ozagamicin, a targeted antineoplastic drug consisting of a recombinant anti-CD33 humanized antibody linked to calicheamicin. Although pooled results from multiple randomized trials have demonstrated a DFS benefit to gemtuzumab ozagamicin, the pooled relative risk of veno-occlusive disease with addition of this drug to conventional chemotherapy is 7.67 (95% confidence interval 1.41–41.74) [48], making it difficult to consider administering it to patients needing HSCT. A newer CD33 antibody–drug conjugate SGN-CD33A [49] and a CD33/CD3 bi-specific T cell Volume 22 Number 2 March 2015
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Preventing relapse after HSCT in AML and MDS Kekre and Koreth
engager [50] have demonstrated in-vitro activity against AML, but will need clinical testing before determining whether they can be safely used in HSCT patients. The IL-3 receptor alpha chain CD123 has also been an immune target of interest in AML, as it is overexpressed on AML blasts. Chimeric antigen receptor T cells have been produced from T cells of AML patients that target CD123 and have demonstrated in-vitro lysis of AML blasts as well as invivo activity in a xenographic model [51 ]. In a mouse model, this same approach showed antileukaemia activity but also eradicated normal haematopoiesis, cautioning against using this outside of HSCT [52]. Nevertheless, mAb therapy as well as chimeric antigen receptor T cell therapy have the potential to improve outcomes of high-risk MDS and AML patients. &&
CONCLUSION Relapse after HSCT remains the leading cause of death for AML and MDS. Treatment of relapse is difficult with limited survival. It is imperative that strategies aimed at preventing relapse post-HSCT continue to be evaluated in this patient population. At present, substitutions in conditioning regimens such as treosulfan or clofarabine are being employed, but these alone are not likely to eradicate the risk of relapse. Strategies aimed at optimizing donor selection and graft manipulation may offer additional long-term benefit in preventing relapse post-HSCT. Such methods are focused on manipulating NK cells and Tregs and provide cautious optimism regarding improving GVL without significant increases in GVHD. Novel targeted therapies against MDS and AML, including small molecule inhibitors, tumour vaccines, mAbs and chimeric antigen receptor T cells, offer future promise for patients who do not respond to standard induction therapies. As techniques to detect MRD advance, treatment of molecular relapse, prior to the development of overt clinical relapse, is likely to depend on these newer targeted therapies, hopefully improving HSCT and non-HSCT outcomes in AML and MDS patients (Table 1). Acknowledgements None. Financial support and sponsorship None. Conflicts of interest None.
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Volume 22 Number 2 March 2015
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