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Hematopoietic stem cell transplantation for acute myeloid leukemia: A review
HEMONC 197 27 June 2017 Hematol Oncol Stem Cell Ther (2017) xxx, xxx– xxx
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Hematopoietic cell transplantation in hematological malignancies: Hematopoietic cell transplantation in acute myeloid leukemia
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Adetola Kassim *, Bipin N. Savani
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Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
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Received 13 January 2017; accepted 26 March 2017
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KEYWORDS Acute myeloid leukemia; Allogeneic hematopoietic cell transplantation; Complete remission; Minimal residual disease
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Abstract Increasing numbers of patients are receiving allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). Scientific and clinical advances in supportive care, donor selection, and conditioning regimens have resulted in lower transplant-related mortality, extension of care to a wider population of patients, and improvements in survival. Recent era has witnessed an explosive information about the molecular pathophysiology of AML. By early identification of patients at a high risk of relapse, it is expected that a majority of eligible patients will receive HCT in first complete remission. Novel conditioning regimens have been explored to improve transplant outcomes in AML. Currently, a stem cell source can be found for virtually all patients who have an indication to receive HCT. The area of investigation will likely continue to be of interest in terms of optimizing transplant outcomes. Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
Introduction Allogeneic hematopoietic cell transplantation (HCT) is an effective post-remission consolidation treatment, poten* Corresponding author. E-mail address: [email protected] (A. Kassim).
tially curative, in patients with acute myeloid leukemia (AML) [1]. Since the first report of a successful bone marrow transplant in 1957, there has been steadily increasing numbers of patients receiving HCT for AML [2]. Worldwide, over a third of HCTs are performed as therapy for AML, more than any other diagnosis, while autologous HCT for AML accounts for less than 3% of activity [3].
http://dx.doi.org/10.1016/j.hemonc.2017.05.021 1658-3876/Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Kassim A, Savani BN, Hematopoietic cell transplantation in hematological malignancies: Hematopoietic cell transplantation in acute myeloid leukemia ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.021
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Recent years have witnessed an important role of molecular markers in the management of AML [1,4–6]. In the context of transplant practice, this information adds in to long established challenges about how best to determine their role in selecting patients for HCT. HCT is curative for many patients with AML and assessment of the potential benefit to an individual patient needs to start at diagnosis of AML so that HCT outcome is not compromised by undue delay. This assessment should integrate disease risk, patient comorbidity, and the wishes of the patient to pursue HCT.
HCT in first remission
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In general, patients with favorable risk disease will not benefit from HCT in first complete remission (CR1) due to their relatively low risk of relapse balanced against the risk of transplant-related mortality (TRM) [1,7]. Such patients would be candidates for HCT in a second complete remission (CR2) if that were achieved after relapse [1,8]. However, patients aged over 60 may have poorer outcome in general and might benefit from HCT earlier in the course of their disease [1,7,8]. Patients with adverse risk disease with high risks of relapse of about 70–90% should be offered HCT in an effort to improve their chances of survival [8]. Waiting until a second remission is detrimental as a second CR is by no means assured, and outcomes of HCT in CR2 are generally poorer than those of CR1 [1,9,10]. Decisions about HCT in intermediate-risk AML were less clear-cut in the past and nowadays most patients are considered for HCT in CR1. Patient fitness, availability of a sibling donor or an alternative donor, and the availability of a clinical trial as well as the transplant center experience must be considered when making a decision about HCT. Prognostic scores such as the Hematopoietic Cell Transplant Co-Morbidity Index [11] and the European Society for Blood and Marrow Transplantation (EBMT) score [12] may help to reach a conclusion about the validity of HCT for a given patient. An important point to consider for decision makers is that there should be a survival benefit to HCT of at least 10% for the individual patient compared with standard chemotherapy [7]. The impact of measurable/minimal residual disease (MRD) data may ultimately be the main driver for HCT in CR1 [7,13,14].
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HCT in primary refractory disease
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Many patients with refractory disease will not be able to receive HCT because they are unable to achieve some sort of remission/response after chemotherapy as a result of resistant or rapidly progressive disease. The outcome of such patients is not well described, despite expansion in the range of novel therapies (plus clinical trial options) available to patients who do not respond to induction/reinduction therapy, and the increasing availability of HCT [15,16]. Approximately 8–30% of selected patients who fail to respond to induction therapy may be salvaged by early HCT [15,16], although very few large series data are available.
Sequential chemotherapy as part of the reducedintensity conditioning (RIC) regimen may avoid the need for multiple courses of induction/re-induction chemotherapy cycles to achieve remission prior to transplant [17,18]. The traditional preparative ablative regimens for eligible patients with AML include cyclophosphamide combined with total body irradiation (TBI) or the combination of busulfan and cyclophosphamide. The recently published EBMT-Acute Leukemia Working Party (ALWP) registry study showed that patients with refractory AML have similar outcomes after receiving cyclophosphamide plus intravenous busulfan or cyclophosphamide plus TBI. About a third of patients with primary refractory AML achieved long-term survival with intravenous busulfan plus cyclophosphamide or cyclophosphamide plus TBI conditioning regimen (Fig. 1) [16].
HCT in second remission Relapse occurs in about half of patients with nonpromyelocytic AML depending on underlying risk factors [1,7,18,19]. Five-year survival for patients after first relapse is about 10–30% [19,20]. Advances in the understanding of the biology of the AML stem cell may eventually permit earlier and more accurate identification of patients destined to relapse. Ultimately, HCT will continue to be used more frequently in CR1 for those who are most in need and most likely to benefit. In the meantime, patients who relapse should be considered for HCT. Survival rates after myeloablative conditioning regimen-HCT (MAC-HCT) for AML CR2 are approximately 40–50% [1,8,18]. However, CR2 and longterm survival are often difficult to achieve and are predicted by the duration of first remission, unfavorable cytogenetics markers at diagnosis, age at diagnosis/relapse, prior therapy including HCT and FLT3-ITD positivity, or the presence of other poor prognostic molecular markers [19].
Conditioning regimen Substantial improvement has been achieved in the last decades in HCT outcomes in AML owing to improved supportive care and transplantation techniques, and a larger number of HCT recipients are becoming long-term survivors [21]. Traditionally, high-dose intensity has been the standard approach to eradicating AML in HCT [16,22,23]. The commonly used MAC-HCT regimens employed in AML are cyclophosphamide and TBI or cyclophosphamide and busulfan or fludarabine and busulfan [16,24–26]. AML is predominantly a disease of the middle and later years and many patients are ineligible or are not considered for MAC regimen. RIC-HCT may offer a viable alternative to older patients or those with comorbidities [22]. Dose intensity is reduced in an attempt to reduce TRM while potent immunosuppression is exerted to help with the engraftment and graft-versus-leukemia effect. RIC has been widely introduced over the past 15 years and is now widely used for AML patients, particularly in older or heavily pretreated patients and in those with medical comorbidities.
Please cite this article in press as: Kassim A, Savani BN, Hematopoietic cell transplantation in hematological malignancies: Hematopoietic cell transplantation in acute myeloid leukemia ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.021
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Fig. 1 Overall leukemia-free survival after HCT, according to conditioning regimen. (A) Overall and (B) leukemia-free survival after conditioning with intravenous busulfan-cyclophosphamide versus cyclophosphamide plus TBI. Note. HCT = allogeneic hematopoietic stem cell transplantation; TBI = total body irradiation.
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The role of dose intensity in HCT conditioning for AML has been explored in multiple retrospective studies [22]. Most studies have shown that more intensive regimens control leukemia better, but leukemia-free survival (LFS) is not improved due to excess nonrelapse mortality (NRM). In a prior report, the ALWP of EBMT has shown in a comparison of 315 RIC and 407 MAC recipients, aged >50 years, that NRM was lower with RIC, and relapse was higher, resulting in similar 2-year LFS [27]. Furthermore, a previous meta-
analysis did not show any clear benefit of RIC-HCT, and so MAC-HCT should be used in patients deemed fit [22]. Concerns about increased relapse rates following RIC compared with MAC-HCT have been supported by the preliminary results of the BMT CTN 0901 study [28]. This Phase III randomized study enrolled 218 patients with AML who had less than 5% marrow myeloblasts before transplant. The primary end point was overall survival at 18 months after randomization. However, of the 135 patients who received MAC
Please cite this article in press as: Kassim A, Savani BN, Hematopoietic cell transplantation in hematological malignancies: Hematopoietic cell transplantation in acute myeloid leukemia ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.021
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A. Kassim, B.N. Savani of the alkylating agent [33,34]. A prospective, Phase 2, multicenter trial recently assessed the efficacy of a reduced toxicity conditioning regimen of fludarabine plus antithymocyte globulin plus a higher dose of intravenous busulfan (FB3) for a total dose of 390 mg/m2 in patients with highrisk malignancies not eligible for a fully ablative MAC transplant. At 2 years, the overall survival and LFS rates were 62% and 50%, respectively, with a cumulative incidence of disease progression of 44% at 2 years and NRM of 11%. This study showed that increasing the antitumor efficacy of the reduced toxicity conditioning regimen with FB3 was effective while limiting toxicity [35]. Oudin et al. [36] also recently reported that a reduced toxicity conditioning regimen with higher doses of busulfan (390–520 mg/m2) in combination with fludarabine and antithymocyte globulin was associated with improved outcomes in AML/myelodysplastic syndrome, particularly with improved LFS in patients with favorable or intermediate-risk cytogenetics.
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and the 137 who received RIC regimens, survival at 18 months was not statistically different and was 68% on the RIC and 77% on the MAC arm, on an intention-to-treat analysis. While the study confirmed lower TRMs of 4% versus 16% after RIC versus MAC-HCT, the significantly higher relapse rate of 48% versus 14% for RIC-HCT versus MAC-HCT indicates that randomized studies of dose intensity as well as better agents to deliver an antileukemic effect while not further increasing toxicity are still urgently needed. In the largest study of long-term survival including 2-year survivors who were alive and disease free, the Center of International Blood and Marrow Transplantation Research has shown that the probability of patients with AML remaining alive 10 years after MAC-HCT was 85% [21]. A recently published EBMT study showed that 10-year survival is similar after RIC and MAC, and that 2-year survivors after RIC can expect a similarly favorable outcome as 2-year survivors after MAC [29].
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Novel conditioning regimen
Treosulfan-based conditioning regimen
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In recent years, new conditioning regimens have been explored to improve transplant outcomes in AML [17,22,30,31].
High-dose busulfan and TBI-based MAC regimens are widely regarded as standard conditioning therapies for HCT in patients with AML, especially in advanced disease [22,23,28]. The use of high-dose busulfan or TBI is associated with a substantial toxicity. In an effort to reduce these toxicities, there is an urgent need for less toxic conditioning regimens that maintain the antileukemic, immunosuppressive, and myeloablative characteristics of the conventional conditioning therapies. Treosulfan (a water-soluble, bifunctional alkylating agent) has demonstrated efficacy as an antileukemic and immunosuppressive agent. In contrast to busulfan, treosulfan does not require enzymatic activation and therefore bypasses hepatic metabolism. Pharmacokinetic studies of both single and multiple intravenous infusions of treosulfan have shown low interpatient and intrapatient variability, and do not require levels to adjust the dosing unlike busulfan. Treosulfan targets both committed and uncommitted hematopoietic stem cells have profound antileukemic and immunosuppressive properties. Although limited, recent published data reported encouraging results with limited nonhematological toxicity, even for patients undergoing a second allogeneic HCT [30]. HCT conditioning with treosulfan may be an alternative to commonly used busulfan or TBI-based regimens for AML patients.
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Incorporation into conditioning of radionuclide-labeled antibodies such as 131I-labeled anti-CD45 is another promising novel approach that is to be studied in Phase 3 clinical trial [37].
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FLAMSA intermediate-intensity conditioning regimens The effectiveness of different intermediate-intensity conditioning regimens to enhance graft-versus-leukemia while safely minimizing NRM has been evaluated [22,23]. One such strategy is the so-called sequential conditioning regimen that combines a short course of intensive chemotherapy followed by an RIC-HCT. The Munich group developed the FLAMSA sequential strategy combining a short course of intensive chemotherapy to improve disease control using fludarabine, intermediate-dose cytosine arabinoside, and amsacrine, followed, after a 3 days’ rest, by RIC-HCT. This strategy has shown encouraging results in relapsed or refractory AML patients [17]. In addition, Schmid et al. [32] reported an effective disease control and a low NRM with this strategy in 23 patients with high-risk AML in CR. Similarly, a recent large EBMT study showed that the FLAMSA sequential intermediate-conditioning regimen provides an efficient disease control in intermediate- and high-risk AML patients, including those in CR2 and with secondary AML [31]. The UK Figaro randomized control study comparing the FLAMSA-Busulfan regimen with other RIC-HCT regimens is ongoing to address the issue of dose intensity in RIC regimens.
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Reduced toxicity conditioning
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Relapse remains the greatest challenge after a reduced intensity allograft. To achieve a reduction in relapse risk, investigators are now looking at ways to optimize dose intensity while safely minimizing NRM. A French group previously looked at the use of 3 days of busulfan and found that the results were similar to those achieved with 4 days
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Alternative donor HCT When considering HCT for a patient with AML, the standard approach involves searching for a human leukocyte antigen (HLA)-matched related donor (MRD) or a matched unrelated
Please cite this article in press as: Kassim A, Savani BN, Hematopoietic cell transplantation in hematological malignancies: Hematopoietic cell transplantation in acute myeloid leukemia ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.021
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donor. However, on the basis of average family size, less than 30% of patients will have an HLA-matched sibling donor [38,39]. The use of HLA-matched unrelated donors widened the donor pool, but matched unrelated donor not unavailable to many individuals, in a timely manner for advanced diseases or those belonging to many minority groups. When an HLA-matched donor (related or unrelated) is not available or not suitable to donate, alternative donors may be considered if the patient is likely to benefit from HCT. As increasing numbers of HCTs are performed from nonmatched stem cell sources, HCT procedures will likely continue to improve, thereby allowing us to safely extend this curative treatment strategy to patients without matched donor. Transplants should preferentially be performed on time, preferably in CR1 if indicated and not reserved for CR2 in high-risk patients in the absence of matched donor. Fewer than 20% of high-risk patients will eventually be able to receive HCT in CR2, as the patient will need to survive the relapse and then be fit enough to undergo HCT in CR2 [9]. Currently, a stem cell source can be found for virtually all patients who have an indication to receive HCT. Haploidentical related donor or cord blood transplantations have emerged as alternatives to fill the gap for those patients who do not have MRD or unrelated donor and the outcome of these types of transplantations is expected to be better than chemotherapy alone in transplant-indicated patients with AML. Haploidentical HCT is an attractive transplant procedure as it provides a possibility of transplantation to almost all patients needing an allogeneic HCT. Increasing numbers of patients are receiving haploidentical HCT for treatment of AML with RIC or MAC.
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HCT remains the therapeutic method with the most potent antileukemic activity mediated by the graft-versus-leukemia effect. However, a significant proportion of patients with AML will relapse after HCT. The prognosis for these patients is dismal, with a probability of long-term survival of less than 20% in patients relapsing early after HCT [19]. Remission induction may be offered to fit patients with the goal of consolidation of response by a donor lymphocyte infusion (DLI) or second HCT. An EBMT registry study reported an estimated 2-year survival from relapse of 14% but identified a subgroup of patients with survival of 32% associated with a prior duration of CR of more than 5 months post-HCT, bone marrow blasts less than 25% at relapse, and no history of acute graft-versus-host disease [40]. Data from previous studies have shown that diseasespecific prognostic factors are, in general, the same as those in patients treated with conventional chemotherapy. Minimal residual disease and chimerism status monitoring after HCT may be used as predictors of impending relapse and should be part of routine follow-up for AML patients. A significant number of studies have shown that preemptive administration of DLI based on minimal residual disease and chimerism monitoring, as well as prophylactic DLI
5 in AML patients at high risk of relapse is effective in preventing relapse. A growing body of data suggests that pre-emptive DLI in MRD-positive AML patients is a safe and effective method for preventing relapse. Aggressively weaning immunosuppressive therapy in all high-risk patients with measurable AML is recommended. After the discontinuation of immunosuppressive therapy, we recommend administration of DLI after D+100 in the setting of measurable disease and/or increasing MC. The proliferation of new agents has prompted exploration of post-HCT maintenance therapy such as the flt3 inhibitors, hypomethylating agents, and other epigenetic regulators [19,41].
Autologous HCT Autohematopoietic stem cell transplantation has been used infrequently in recent years but may be considered as postremission therapy in patients who have minimal residual disease negative and do not have high-risk disease [42,43]. Consolidation with autologous HCT may therefore be an option for patients in MRD-negative intermediate-risk AML in CR1 who do not have allogeneic HCT options or in acute promyelocytic leukemia in CR2 [43].
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The authors have no conflict of interests to declare.
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for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome. Biol Blood Marrow Transplant 2014;20:1363–8. Savani BN, Mohty M. Introduction: why alternative donor transplantation and what are the different options and current challenges? Semin Hematol 2016;53:55–6. Slade M, Fakhri B, Savani BN, Romee R. Halfway there: the past, present and future of haploidentical transplantation. Bone Marrow Transplant 2017;52:1–6. Bejanyan N, Oran B, Shanley R, Warlick E, Ustun C, Vercellotti G, et al. Clinical outcomes of AML patients relapsing after matched-related donor and umbilical cord blood transplantation. Bone Marrow Transplant 2014;49:1029–35. Hu B, Vikas P, Mohty M, Savani BN. Allogeneic stem cell transplantation and targeted therapy for FLT3/ITD+ acute
7 myeloid leukemia: an update. Expert Rev Hematol 2014;7:301–15. [42] Keating A, DaSilva G, Perez WS, Gupta V, Cutler CS, Ballen KK, et al. Autologous blood cell transplantation versus HLAidentical sibling transplantation for acute myeloid leukemia in first complete remission: a registry study from the Center for International Blood and Marrow Transplantation Research. Haematologica 2013;98:185–92. [43] Gorin NC, Giebel S, Labopin M, Savani BN, Mohty M, Nagler A. Autologous stem cell transplantation for adult acute leukemia in 2015: time to rethink? Present status and future prospects. Bone Marrow Transplant 2015;50:1495–502.
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Hematopoietic cell transplantation in hematological malignancies: Hematopoietic cell transplantation in acute myeloid leukemia
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Adetola Kassim *, Bipin N. Savani
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Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
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Received 13 January 2017; accepted 26 March 2017
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KEYWORDS Acute myeloid leukemia; Allogeneic hematopoietic cell transplantation; Complete remission; Minimal residual disease
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Abstract Increasing numbers of patients are receiving allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). Scientific and clinical advances in supportive care, donor selection, and conditioning regimens have resulted in lower transplant-related mortality, extension of care to a wider population of patients, and improvements in survival. Recent era has witnessed an explosive information about the molecular pathophysiology of AML. By early identification of patients at a high risk of relapse, it is expected that a majority of eligible patients will receive HCT in first complete remission. Novel conditioning regimens have been explored to improve transplant outcomes in AML. Currently, a stem cell source can be found for virtually all patients who have an indication to receive HCT. The area of investigation will likely continue to be of interest in terms of optimizing transplant outcomes. Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/).
Introduction Allogeneic hematopoietic cell transplantation (HCT) is an effective post-remission consolidation treatment, poten* Corresponding author. E-mail address: [email protected] (A. Kassim).
tially curative, in patients with acute myeloid leukemia (AML) [1]. Since the first report of a successful bone marrow transplant in 1957, there has been steadily increasing numbers of patients receiving HCT for AML [2]. Worldwide, over a third of HCTs are performed as therapy for AML, more than any other diagnosis, while autologous HCT for AML accounts for less than 3% of activity [3].
http://dx.doi.org/10.1016/j.hemonc.2017.05.021 1658-3876/Ó 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article in press as: Kassim A, Savani BN, Hematopoietic cell transplantation in hematological malignancies: Hematopoietic cell transplantation in acute myeloid leukemia ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.021
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Recent years have witnessed an important role of molecular markers in the management of AML [1,4–6]. In the context of transplant practice, this information adds in to long established challenges about how best to determine their role in selecting patients for HCT. HCT is curative for many patients with AML and assessment of the potential benefit to an individual patient needs to start at diagnosis of AML so that HCT outcome is not compromised by undue delay. This assessment should integrate disease risk, patient comorbidity, and the wishes of the patient to pursue HCT.
HCT in first remission
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In general, patients with favorable risk disease will not benefit from HCT in first complete remission (CR1) due to their relatively low risk of relapse balanced against the risk of transplant-related mortality (TRM) [1,7]. Such patients would be candidates for HCT in a second complete remission (CR2) if that were achieved after relapse [1,8]. However, patients aged over 60 may have poorer outcome in general and might benefit from HCT earlier in the course of their disease [1,7,8]. Patients with adverse risk disease with high risks of relapse of about 70–90% should be offered HCT in an effort to improve their chances of survival [8]. Waiting until a second remission is detrimental as a second CR is by no means assured, and outcomes of HCT in CR2 are generally poorer than those of CR1 [1,9,10]. Decisions about HCT in intermediate-risk AML were less clear-cut in the past and nowadays most patients are considered for HCT in CR1. Patient fitness, availability of a sibling donor or an alternative donor, and the availability of a clinical trial as well as the transplant center experience must be considered when making a decision about HCT. Prognostic scores such as the Hematopoietic Cell Transplant Co-Morbidity Index [11] and the European Society for Blood and Marrow Transplantation (EBMT) score [12] may help to reach a conclusion about the validity of HCT for a given patient. An important point to consider for decision makers is that there should be a survival benefit to HCT of at least 10% for the individual patient compared with standard chemotherapy [7]. The impact of measurable/minimal residual disease (MRD) data may ultimately be the main driver for HCT in CR1 [7,13,14].
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HCT in primary refractory disease
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Many patients with refractory disease will not be able to receive HCT because they are unable to achieve some sort of remission/response after chemotherapy as a result of resistant or rapidly progressive disease. The outcome of such patients is not well described, despite expansion in the range of novel therapies (plus clinical trial options) available to patients who do not respond to induction/reinduction therapy, and the increasing availability of HCT [15,16]. Approximately 8–30% of selected patients who fail to respond to induction therapy may be salvaged by early HCT [15,16], although very few large series data are available.
Sequential chemotherapy as part of the reducedintensity conditioning (RIC) regimen may avoid the need for multiple courses of induction/re-induction chemotherapy cycles to achieve remission prior to transplant [17,18]. The traditional preparative ablative regimens for eligible patients with AML include cyclophosphamide combined with total body irradiation (TBI) or the combination of busulfan and cyclophosphamide. The recently published EBMT-Acute Leukemia Working Party (ALWP) registry study showed that patients with refractory AML have similar outcomes after receiving cyclophosphamide plus intravenous busulfan or cyclophosphamide plus TBI. About a third of patients with primary refractory AML achieved long-term survival with intravenous busulfan plus cyclophosphamide or cyclophosphamide plus TBI conditioning regimen (Fig. 1) [16].
HCT in second remission Relapse occurs in about half of patients with nonpromyelocytic AML depending on underlying risk factors [1,7,18,19]. Five-year survival for patients after first relapse is about 10–30% [19,20]. Advances in the understanding of the biology of the AML stem cell may eventually permit earlier and more accurate identification of patients destined to relapse. Ultimately, HCT will continue to be used more frequently in CR1 for those who are most in need and most likely to benefit. In the meantime, patients who relapse should be considered for HCT. Survival rates after myeloablative conditioning regimen-HCT (MAC-HCT) for AML CR2 are approximately 40–50% [1,8,18]. However, CR2 and longterm survival are often difficult to achieve and are predicted by the duration of first remission, unfavorable cytogenetics markers at diagnosis, age at diagnosis/relapse, prior therapy including HCT and FLT3-ITD positivity, or the presence of other poor prognostic molecular markers [19].
Conditioning regimen Substantial improvement has been achieved in the last decades in HCT outcomes in AML owing to improved supportive care and transplantation techniques, and a larger number of HCT recipients are becoming long-term survivors [21]. Traditionally, high-dose intensity has been the standard approach to eradicating AML in HCT [16,22,23]. The commonly used MAC-HCT regimens employed in AML are cyclophosphamide and TBI or cyclophosphamide and busulfan or fludarabine and busulfan [16,24–26]. AML is predominantly a disease of the middle and later years and many patients are ineligible or are not considered for MAC regimen. RIC-HCT may offer a viable alternative to older patients or those with comorbidities [22]. Dose intensity is reduced in an attempt to reduce TRM while potent immunosuppression is exerted to help with the engraftment and graft-versus-leukemia effect. RIC has been widely introduced over the past 15 years and is now widely used for AML patients, particularly in older or heavily pretreated patients and in those with medical comorbidities.
Please cite this article in press as: Kassim A, Savani BN, Hematopoietic cell transplantation in hematological malignancies: Hematopoietic cell transplantation in acute myeloid leukemia ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.021
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Fig. 1 Overall leukemia-free survival after HCT, according to conditioning regimen. (A) Overall and (B) leukemia-free survival after conditioning with intravenous busulfan-cyclophosphamide versus cyclophosphamide plus TBI. Note. HCT = allogeneic hematopoietic stem cell transplantation; TBI = total body irradiation.
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The role of dose intensity in HCT conditioning for AML has been explored in multiple retrospective studies [22]. Most studies have shown that more intensive regimens control leukemia better, but leukemia-free survival (LFS) is not improved due to excess nonrelapse mortality (NRM). In a prior report, the ALWP of EBMT has shown in a comparison of 315 RIC and 407 MAC recipients, aged >50 years, that NRM was lower with RIC, and relapse was higher, resulting in similar 2-year LFS [27]. Furthermore, a previous meta-
analysis did not show any clear benefit of RIC-HCT, and so MAC-HCT should be used in patients deemed fit [22]. Concerns about increased relapse rates following RIC compared with MAC-HCT have been supported by the preliminary results of the BMT CTN 0901 study [28]. This Phase III randomized study enrolled 218 patients with AML who had less than 5% marrow myeloblasts before transplant. The primary end point was overall survival at 18 months after randomization. However, of the 135 patients who received MAC
Please cite this article in press as: Kassim A, Savani BN, Hematopoietic cell transplantation in hematological malignancies: Hematopoietic cell transplantation in acute myeloid leukemia ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.021
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A. Kassim, B.N. Savani of the alkylating agent [33,34]. A prospective, Phase 2, multicenter trial recently assessed the efficacy of a reduced toxicity conditioning regimen of fludarabine plus antithymocyte globulin plus a higher dose of intravenous busulfan (FB3) for a total dose of 390 mg/m2 in patients with highrisk malignancies not eligible for a fully ablative MAC transplant. At 2 years, the overall survival and LFS rates were 62% and 50%, respectively, with a cumulative incidence of disease progression of 44% at 2 years and NRM of 11%. This study showed that increasing the antitumor efficacy of the reduced toxicity conditioning regimen with FB3 was effective while limiting toxicity [35]. Oudin et al. [36] also recently reported that a reduced toxicity conditioning regimen with higher doses of busulfan (390–520 mg/m2) in combination with fludarabine and antithymocyte globulin was associated with improved outcomes in AML/myelodysplastic syndrome, particularly with improved LFS in patients with favorable or intermediate-risk cytogenetics.
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and the 137 who received RIC regimens, survival at 18 months was not statistically different and was 68% on the RIC and 77% on the MAC arm, on an intention-to-treat analysis. While the study confirmed lower TRMs of 4% versus 16% after RIC versus MAC-HCT, the significantly higher relapse rate of 48% versus 14% for RIC-HCT versus MAC-HCT indicates that randomized studies of dose intensity as well as better agents to deliver an antileukemic effect while not further increasing toxicity are still urgently needed. In the largest study of long-term survival including 2-year survivors who were alive and disease free, the Center of International Blood and Marrow Transplantation Research has shown that the probability of patients with AML remaining alive 10 years after MAC-HCT was 85% [21]. A recently published EBMT study showed that 10-year survival is similar after RIC and MAC, and that 2-year survivors after RIC can expect a similarly favorable outcome as 2-year survivors after MAC [29].
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Treosulfan-based conditioning regimen
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In recent years, new conditioning regimens have been explored to improve transplant outcomes in AML [17,22,30,31].
High-dose busulfan and TBI-based MAC regimens are widely regarded as standard conditioning therapies for HCT in patients with AML, especially in advanced disease [22,23,28]. The use of high-dose busulfan or TBI is associated with a substantial toxicity. In an effort to reduce these toxicities, there is an urgent need for less toxic conditioning regimens that maintain the antileukemic, immunosuppressive, and myeloablative characteristics of the conventional conditioning therapies. Treosulfan (a water-soluble, bifunctional alkylating agent) has demonstrated efficacy as an antileukemic and immunosuppressive agent. In contrast to busulfan, treosulfan does not require enzymatic activation and therefore bypasses hepatic metabolism. Pharmacokinetic studies of both single and multiple intravenous infusions of treosulfan have shown low interpatient and intrapatient variability, and do not require levels to adjust the dosing unlike busulfan. Treosulfan targets both committed and uncommitted hematopoietic stem cells have profound antileukemic and immunosuppressive properties. Although limited, recent published data reported encouraging results with limited nonhematological toxicity, even for patients undergoing a second allogeneic HCT [30]. HCT conditioning with treosulfan may be an alternative to commonly used busulfan or TBI-based regimens for AML patients.
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Incorporation into conditioning of radionuclide-labeled antibodies such as 131I-labeled anti-CD45 is another promising novel approach that is to be studied in Phase 3 clinical trial [37].
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FLAMSA intermediate-intensity conditioning regimens The effectiveness of different intermediate-intensity conditioning regimens to enhance graft-versus-leukemia while safely minimizing NRM has been evaluated [22,23]. One such strategy is the so-called sequential conditioning regimen that combines a short course of intensive chemotherapy followed by an RIC-HCT. The Munich group developed the FLAMSA sequential strategy combining a short course of intensive chemotherapy to improve disease control using fludarabine, intermediate-dose cytosine arabinoside, and amsacrine, followed, after a 3 days’ rest, by RIC-HCT. This strategy has shown encouraging results in relapsed or refractory AML patients [17]. In addition, Schmid et al. [32] reported an effective disease control and a low NRM with this strategy in 23 patients with high-risk AML in CR. Similarly, a recent large EBMT study showed that the FLAMSA sequential intermediate-conditioning regimen provides an efficient disease control in intermediate- and high-risk AML patients, including those in CR2 and with secondary AML [31]. The UK Figaro randomized control study comparing the FLAMSA-Busulfan regimen with other RIC-HCT regimens is ongoing to address the issue of dose intensity in RIC regimens.
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Relapse remains the greatest challenge after a reduced intensity allograft. To achieve a reduction in relapse risk, investigators are now looking at ways to optimize dose intensity while safely minimizing NRM. A French group previously looked at the use of 3 days of busulfan and found that the results were similar to those achieved with 4 days
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Alternative donor HCT When considering HCT for a patient with AML, the standard approach involves searching for a human leukocyte antigen (HLA)-matched related donor (MRD) or a matched unrelated
Please cite this article in press as: Kassim A, Savani BN, Hematopoietic cell transplantation in hematological malignancies: Hematopoietic cell transplantation in acute myeloid leukemia ..., Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2017.05.021
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donor. However, on the basis of average family size, less than 30% of patients will have an HLA-matched sibling donor [38,39]. The use of HLA-matched unrelated donors widened the donor pool, but matched unrelated donor not unavailable to many individuals, in a timely manner for advanced diseases or those belonging to many minority groups. When an HLA-matched donor (related or unrelated) is not available or not suitable to donate, alternative donors may be considered if the patient is likely to benefit from HCT. As increasing numbers of HCTs are performed from nonmatched stem cell sources, HCT procedures will likely continue to improve, thereby allowing us to safely extend this curative treatment strategy to patients without matched donor. Transplants should preferentially be performed on time, preferably in CR1 if indicated and not reserved for CR2 in high-risk patients in the absence of matched donor. Fewer than 20% of high-risk patients will eventually be able to receive HCT in CR2, as the patient will need to survive the relapse and then be fit enough to undergo HCT in CR2 [9]. Currently, a stem cell source can be found for virtually all patients who have an indication to receive HCT. Haploidentical related donor or cord blood transplantations have emerged as alternatives to fill the gap for those patients who do not have MRD or unrelated donor and the outcome of these types of transplantations is expected to be better than chemotherapy alone in transplant-indicated patients with AML. Haploidentical HCT is an attractive transplant procedure as it provides a possibility of transplantation to almost all patients needing an allogeneic HCT. Increasing numbers of patients are receiving haploidentical HCT for treatment of AML with RIC or MAC.
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HCT remains the therapeutic method with the most potent antileukemic activity mediated by the graft-versus-leukemia effect. However, a significant proportion of patients with AML will relapse after HCT. The prognosis for these patients is dismal, with a probability of long-term survival of less than 20% in patients relapsing early after HCT [19]. Remission induction may be offered to fit patients with the goal of consolidation of response by a donor lymphocyte infusion (DLI) or second HCT. An EBMT registry study reported an estimated 2-year survival from relapse of 14% but identified a subgroup of patients with survival of 32% associated with a prior duration of CR of more than 5 months post-HCT, bone marrow blasts less than 25% at relapse, and no history of acute graft-versus-host disease [40]. Data from previous studies have shown that diseasespecific prognostic factors are, in general, the same as those in patients treated with conventional chemotherapy. Minimal residual disease and chimerism status monitoring after HCT may be used as predictors of impending relapse and should be part of routine follow-up for AML patients. A significant number of studies have shown that preemptive administration of DLI based on minimal residual disease and chimerism monitoring, as well as prophylactic DLI
5 in AML patients at high risk of relapse is effective in preventing relapse. A growing body of data suggests that pre-emptive DLI in MRD-positive AML patients is a safe and effective method for preventing relapse. Aggressively weaning immunosuppressive therapy in all high-risk patients with measurable AML is recommended. After the discontinuation of immunosuppressive therapy, we recommend administration of DLI after D+100 in the setting of measurable disease and/or increasing MC. The proliferation of new agents has prompted exploration of post-HCT maintenance therapy such as the flt3 inhibitors, hypomethylating agents, and other epigenetic regulators [19,41].
Autologous HCT Autohematopoietic stem cell transplantation has been used infrequently in recent years but may be considered as postremission therapy in patients who have minimal residual disease negative and do not have high-risk disease [42,43]. Consolidation with autologous HCT may therefore be an option for patients in MRD-negative intermediate-risk AML in CR1 who do not have allogeneic HCT options or in acute promyelocytic leukemia in CR2 [43].
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The authors have no conflict of interests to declare.
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