- Email: [email protected]
Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease
Best Practice & Research Clinical Haematology xxx (2015) 1e8
Contents lists available at ScienceDirect
Best Practice & Research Clinical Haematology journal homepage: www.elsevier.com/locate/beha
Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease* Frederick R. Appelbaum* Clinical Research Division, Fred Hutchinson Cancer Research Center, Division of Medical Oncology, University of Washington School of Medicine, 1100 Fairview Avenue North, D5-310, P.O. Box 19024, Seattle, WA 98109-1024, USA
a b s t r a c t Keywords: Acute myeloid leukemia Hematopoeitic cell transplantation Minimal residual disease
Early trials of hematopoietic cell transplantation (HCT) for adults with acute myeloid leukemia (AML) did not generally include measurement of minimal residual disease (MRD) at the time of remission. However, the presence of MRD is now considered to be a powerful predictor of outcome for adults with AML in first complete remission. This raises the question of whether MRD positivity in first remission changes the indications for transplant or the transplant approach itself if patients do proceed to transplant with MRD present. This paper will begin to address these issues in adult AML. © 2015 Published by Elsevier Ltd.
Introduction The indications for hematopoietic cell transplantation (HCT) for adults with acute myeloid leukemia (AML) in first remission (CR1) have been developed based on prospective trials and large metaanalyses [1,2]. These trials, however, did not generally include measures of minimal residual disease (MRD) at the time of remission. Evidence is now accumulating showing that the presence of MRD
* Originally published in Blood. Walter RB et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood 2013; 122:1813e1821. © the American Society of Hematology. * Tel.: þ1 206 667 4412; fax: þ1 206 667 6936. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.beha.2015.10.010 1521-6926/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: Appelbaum FR, Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.10.010
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F.R. Appelbaum / Best Practice & Research Clinical Haematology xxx (2015) 1e8
detected using either quantitative RT-PCR or multi-parametric flow cytometry (MFC) is a powerful predictor of outcome for adults with AML in first complete remission. In this brief review, we will address the issue of whether the presence of MRD in adults with AML in first remission changes the indications for transplantation. We will further address the question of whether, if patients with MRD do proceed to transplantation, any particular approach should be favored. Before approaching these questions, the limitations of the available information should be addressed. First, there is considerable variability in the assays used to detect MRD and there have been no generally accepted methods to standardize such assays among different laboratories. This variability applies both to RT-PCR and to MFC based approaches. Second, there has been no standardization of the timing of MRD measurement after induction or consolidation attempts. Some of the studies referenced in this review measured MRD shortly after initial induction and some only measured it after several months. Finally, in virtually every prospective study reported to date, only a fraction of the patients entered onto the treatment trial actually had a full set of MRD measurements, meaning that study conclusions have been based on subset analyses. As will be discussed, despite these limitations, a reasonably clear picture of the relationship of MRD and clinical outcome in adult AML is emerging. Core binding factor AML Core binding factor (CBF) AMLs, including those characterized by t(8;21) and inv(16), are categorized as being in the favorable risk AML subset, and thus, allogeneic HCT is not generally recommended for adults with CBF AML in first remission. In addition to their favorable prognosis, another unique feature of the CBF AMLs is that sensitive RT-PCR based assays exist capable of measuring minimal residual disease in such patients at the time of first remission. The presence of such sensitive, universally applicable assays raises the question of whether they could be used to identify patients with sub-optimal responses to initial chemotherapy who should be transplanted in first CR, despite the generally favorable prognosis of this disease category. Yin et al. reported on the clinical value of quantitative RT-PCR monitoring of MRD in 278 patients with CBF AML (163 with t(8:21) and 115 with inv(16)) entered in the United Kingdom Medical Research Council AML 15 trial [3]. At remission, normalized to 105 copies of ABL, a >3 log reduction in RUNX1RUNX1T1 bone marrow transcripts for t(8;21) patients and having fewer than 10 copies of CBFB-MYH11 copies in peripheral blood in inv(16) patients were the most significant variables for subsequent relapse risk based on multivariable analysis. MRD levels after consolidation were also informative. At any time after remission induction, the risk of subsequent relapse was 100% for the following: t(8;21) patients with >500 copies in bone marrow or >100 copies in peripheral blood, and inv(16) patients with >50 copies in bone marrow or with >10 copies in peripheral blood. Some of the patients who relapsed responded to subsequent chemotherapy and transplantation, and since allografting was not recommended as part of initial therapy in this trial, no conclusions about the possible value of HCT in first remission for high risk patients could be drawn from this experience. A similar trial was published by Jourdan et al. for the French AML Intergroup [4]. They reported on 176 patients with CBF-AML (90 CBFa and 86 CBFb) treated on CBF-2006. At 36 months, the cumulative incidence of relapse was 22% in those who achieved a 3-log reduction in MRD after the first consolidation cycle versus 54% for those who did not. This translated into relapse-free survival rates of 73% for those who had a 3-log reduction versus 44% for those who did not, and overall survival rates of 90% versus 71%. The presence of MRD was the sole prognostic factor predicting relapse in multivariable analysis that included white cell count, KIT and FLT3 mutational status. Like the MRC trial, allogeneic HCT was not recommended as part of initial therapy, and although some high-risk patients did receive transplants in first remission, the value of that intervention was impossible to measure in this trial. Both the British MRC trial and the French AML Intergroup Trial demonstrate that measurement of MRD after induction is the single most powerful prognostic factor predicting subsequent relapse in CBF AML, but neither trial was designed to test an intervention based on that finding. A trial reported by Zhu et al. from China did attempt to evaluate the role of allogeneic HCT for patients with CBFa with high-risk disease in first CR [5]. A total of 116 eligible patients had MRD status determined after consolidation therapy. According to protocol, those with high-risk disease were to be treated with allogeneic transplantation whereas those with lower risk disease were to be treated with Please cite this article in press as: Appelbaum FR, Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.10.010
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chemotherapy. A total of 47 patients were defined as low-risk based on MRD measurements, with 66 defined as high risk. Only a subset of patients was treated according to protocol intent. Of the 47 low risk patients, 29 were treated with chemotherapy while 18 received transplants in CR1. Among the high-risk patients, 26 received chemotherapy, while 40 were transplanted. In an analysis based on actual treatment received, it appeared that allogeneic HCT in CR1 was able to reduce relapse rates and improve survival compared to chemotherapy for high-risk patients, whereas chemotherapy was superior to transplantation for low-risk patients (Fig. 1). Although seriously flawed by the lack of protocol discipline, this is one of the very few studies with a sizable number of CBF AMLs defined as high risk by virtue of the presence of MRD who were prospectively transplanted in first remission and does suggest a possible advantage to this approach. Intermediate- and high-risk AML Prospective trials and meta-analyses generally support the use of allogeneic HCT for patients with intermediate- and high-risk AML who have achieved a first remission [1,2]. As noted earlier, these studies did not include measurements of MRD in the decision making process. When considering whether MRD measurements should change the approach to patients with intermediate- or high-risk AML, several questions become apparent: (1) What is the outcome of patients with intermediate- or high-risk AML in CR1 with MRD who are not transplanted? (2) What is the outcome of such patients with transplantation? (3) Can adding additional chemotherapy convert patients with AML in CR1 who are MRD positive to an MRD negative state? (4) If it is possible to convert MRDþ patients to MRD-prior to transplant, does such a conversion make any difference? (5) Finally, if the decision is to proceed with transplantation in a patient with MRD, is any particular transplant approach favored? Impact of MRD on outcome of chemotherapy in adults with non-CBF AML Because there is no universally applicable RT-PCR based assay for the measure of MRD in non-CBF AMLs, the majority of trials assessing the impact of MRD on outcome in this disease category have been
Fig. 1. Shown are subgroup analyses of treatment outcomes of patients with t(8;21) AML. (A,D) Relapse. (B,E) Disease-free survival. (C,F) Overall survival [5]. CT, chemotherapy; HSCT, hematopoietic stem cell transplantation. Republished with permission of American Society of Hematology, from MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial. Zhu HH et al., Blood, volume 121, number 20, 2013; permission conveyed through Copyright Clearance Center, Inc.
Please cite this article in press as: Appelbaum FR, Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.10.010
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based on multiparametric flow cytometry (MFC). While not as sensitive as RT-PCR based assays, MFC assays have been developed by expert laboratories that routinely have sensitivities of 0.1%, although a higher level of sensitivity is possible for subsets of leukemias with more frankly aberrant immunophenotypes [6]. One of the first studies reporting on the impact of MRD as measured by MFC on the outcome of adults with AML in CR1 came from San Miguel and colleagues who studied 126 patients who displayed aberrant phenotypes at diagnosis [7]. They found that based on the presence of MRD at the time of first remission, 4 categories of risk could be determined. Eight patients with fewer than 104 cells were at very low risk of relapse; 37 with between 104 and 103 were at low risk; 64 with 103 and 102 cells were at intermediate risk (relapse risk 50%), while the remaining 17 with >102 were at very high risk of relapse. A number of other investigators have since published studies confirming the prognostic importance of the presence of MRD in AML patients treated with chemotherapy. For example, Buccisano et al. reported on 143 adult AML patients and showed that while patients with good or intermediate risk karyotypes who were MRD negative had reasonable disease-free and overall survivals, those with minimal residual disease measured after consolidation therapy had a low likelihood of relapse-free survival (below 20%) whether they had good-, intermediate-, or high-risk cytogenetics [8]. More recently our group reviewed the results of 245 adults with AML who achieved a CR, CR with incomplete platelet recovery (CRp), or CR with incomplete count recovery (CRi) [9]. The group was also analyzed for the presence of MRD at the time of achievement of CR as determined by 10-color MFC. Although pretreatment co-variates such as cytogenetics and FLT3 status were associated with subsequent relapse, their prognostic effect was almost nil once the quality of response (CR, CRp, or CRi) and presence of MRD were taken into account. As shown in Fig. 2, if patients were treated with consolidation chemotherapy without HCT in CR1, the subsequent risk of relapse was >90% for patients with either CRp or CRi, or those with MRD. This translated into a likelihood of survival of less than 15% at 2 years for such patients. These results suggest that the quality of initial response to chemotherapy is the single most important predictor of outcome for patients treated without HCT, and emphasize the very high likelihood of subsequent failure with subsequent chemotherapy if patients do not achieve a good quality CR with initial induction.
Fig. 2. The curves demonstrate the cumulative incidence of relapse (left) and relapse-free survival (right) of 109 patients who achieved a CR without or with MRD, or had a response less than CR (CRp or CRi) with or without MRD. None of these patients received an allogeneic HCT while in remission [9].
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Impact of MRD on outcome of allogeneic HCT for patients with AML Using the same 10-color MFC assay, we studied the impact of the presence of MRD on the outcome of 253 consecutive patients who were treated with myeloablative HCT for AML in either CR1 (n ¼ 183) or CR2 (n ¼ 70) [10,11]. Among patients transplanted in first CR, 3-year estimates of overall survival were 73% (64%e79%) for MRD-negative patients and 32% (17%e48%) for MRD-positive patients (Fig. 3). Similarly, among patients transplanted in second remission, 3-year survival was 73% (57%e83%) for MRD-negative patients versus 44% (21%e65%) for MRD-positive patients. The estimates for relapse were 21% (14%e28%) for MRD-negative CR1 patients versus 58% (41%e72%) for MRD-positive CR1 patients, and 19% (9%e31%) for MRD-negative CR2 patients versus 68% (41%e85%) for CR2 MRDpositive patients. These results thus show that measurement of MRD prior to allogeneic HCT using ablative preparative regimens is highly predictive of relapse and overall survival in patients transplanted in both CR1 and CR2. Nonetheless, even though the outcome is worse for patients with MRD, the outcome of transplantation still appears better than what would be expected in patients with MRD treated without subsequent transplantation. Conversion of patients from MRDþ to MRD-status The observation that the outcome of allogeneic HCT is worse for patients with MRD raises the obvious questions of whether MRDþ patients can be converted to MRD-patients pre-transplant, and whether such conversion changes the outcome of subsequent transplantation. Unfortunately, there are very few studies addressing these questions. One of the more telling studies comes from Maurillo et al. and the group from Rome, Italy [12,13]. They studied 142 patients with de novo AML treated on EORTC/ GIMEMA protocols AML-10, AML-12 and AML-13. Using a cutoff of 3.5 104, after induction 28% of patients (40 of 142) were MRD negative and 72% (102 of 142) were MRD positive. Seven patients relapsed prior to consolidation and 1 died early after consolidation, leaving 134 available for subsequent MRD measurement after receiving two cycles of consolidation. Of these, 34% (46 of 134) were MRD negative and 66% (88 of 134) were MRD positive following consolidation. The authors note that following consolidation 15 patients who were MRD positive after induction converted to MRD negative, and that nine progressed from MRD negative after induction to MRD positive after consolidation. Thus, using the types of consolidation employed on these trials (two cycles of idarubicin, intermediate dose cytarabine [500 mg/m2/q12h on days 1e6] and etoposide), the net gain in MRD negative patients was fewer than 10%. Whether other forms of consolidation would be more effective is unknown. Given the low rate of conversion of MRD-positive to MRD-negative status, it is difficult to judge whether this conversion makes any difference. In the Maurillo study, the 15 patients who converted from MRD positive to MRD negative had a 40% relapse-free survival at 5 years, which was better than the 20% relapse-free survival seen in the group that was MRD positive both after induction consolidation, and the 0% relapse-free survival seen in the small group that progressed from MRD negative after induction to MRD positive after consolidation. Transplantation of MRDþ patients If the decision is to proceed with transplantation in a patient with MRD, is there a preferred approach? One might anticipate that the intensity of the preparative regimen would be of greater importance in patients with MRD. In an effort to address this question, we analyzed the outcome of allogeneic HCT in 241 adult patients with AML undergoing allogeneic HCT after either myeloablative (MA) conditioning (n ¼ 155) or nonmyeloablative (NMA) conditioning (n ¼ 86) [14]. Somewhat surprisingly, the impact of MRD on relapse was similar after NMA and MA conditioning, being approximately 4.5-fold greater in MRDþ patients transplanted using either category of preparative regimen. Specifically, the 3-year relapse estimates were 28% and 57% for MRD- and MRDþ NMA patients, and 22% and 63% for MRD- and MRDþ MA patients. The 3-year overall survival rates were 48% and 41% for MRD- and MRDþ NMA patients and 76% and 25% for MRD- and MRDþ MA patients. These are retrospective data and there were many reasons patients were allocated to receive either NMA or MA conditioning, and so patient selection bias could play a role in these results. Nonetheless, the data Please cite this article in press as: Appelbaum FR, Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.10.010
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Fig. 3. Shown is the association between pre-transplant MRD and post-transplant outcome for AML patients in CR1 and CR2. The solid black lines are patients in CR1 without MRD (n ¼ 147) and the solid dashed lines are patients in CR2 without MRD (n ¼ 52). The solid gray lines are patients in CR1 with MRD (n ¼ 36), and the dashed gray lines represent patients in CR2 with MRD (n ¼ 18) [11].
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Table 1 Impact of MRD on survival.
UCB MURD MMURD
Total
MRDþ
Survival HR
112 334 110
31 (28%) 122 (36%) 47 (43%)
1.01 2.14 1.94
provide no basis for altering the choice of preparative regimen based on the presence or absence of MRD at the time of transplant. The patients included in the above cohort were transplanted from siblings or matched unrelated donors using either bone marrow or peripheral blood as the source of stem cells. More recently, we completed an analysis of 556 patients transplanted using matched unrelated donors (MUD) (n ¼ 334), mismatched unrelated donors (MMUD) (n ¼ 110), or cord blood (CB) (n ¼ 112) between 2006 and 2012 following myeloablative preparative regimens [15]. Overall survival in the CB group appeared to be at least as good as that in the MUD group, with a trend towards higher mortality in the MMURD group. The risk of relapse was higher in both the MUD and MMURD groups compared with the CB group, with an adjusted hazard ratio for MMURD vs CB of 2.29 and for MUD vs CB of 2.14. Of particular interest for the purpose of this discussion is the observation that the presence of MRD prior to transplant negatively impacted relapse rates following both MUD and MMURD transplantation, but had no measureable impact on the risk of relapse or survival following CB transplantation (Table 1). We and others have previously published results showing that relapse rates appear to be less following myeloablative cord blood transplants than seen following the use of matched related or matched unrelated donors [16]. The more recent observations suggest that this increased graft-versus-leukemia effect seen following cord blood transplantation may be able to overcome, at least in part, the deleterious effects of the presence of MRD pre-transplant.
Summary Assays now exist capable of reliably measuring the presence of MRD in the vast majority of patients with AML. In patients with CBF AMLs, the presence of MRD following induction is the single most powerful predictor of subsequent relapse. Although some data exist suggesting that allogeneic HCT in first remission may reduce the risk of relapse and possibly improve survival in patients with MRD, the number and robustness of clinical studies addressing this possibility are limited. For the more common intermediate- and high-risk AMLs, the data are compelling that the presence of MRD following induction chemotherapy greatly increases the risk of subsequent relapse in patients treated either with subsequent chemotherapy or allogeneic transplantation. The impact is especially profound in those treated with just chemotherapy with relapse-free survival rates well below 20%. Transplantation in first remission appears to offer modestly better prospects. Only limited data are available addressing the likelihood that consolidation chemotherapy can convert MRD-positive patients to MRD-negative status, but the limited evidence suggests that this approach will be successful in only a very limited proportion of patients. If the choice is to proceed with transplantation in a patient with MRD, there is no evidence favoring one form of preparative regimen over others, but there are data suggesting that cord blood may be preferred over matched or mismatched unrelated donors.
Conflict of interest Consulting Fees: Adaptive Biotechnologies Corporation; Amgen; Celator; Neumedicines; NMDP; Pfizer. Please cite this article in press as: Appelbaum FR, Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.10.010
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References [1] Oliansky DM, Appelbaum F, Cassileth PA, Keating A, Kerr J, Nieto Y, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myelogenous leukemia in adults: an evidence-based review. Biol Blood Marrow Transpl 2008;14:137e80. [2] Dohner H, Estey EH, Amadori S, Appelbaum FR, Buchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453e74. [3] Yin JA, O'Brien MA, Hills RK, Daly SB, Wheatley K, Burnett AK. Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial. Blood 2012;120:2826e35. [4] Jourdan E, Boissel N, Chevret S, Delabesse E, Renneville A, Cornillet P, et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood 2013;121:2213e23. [5] Zhu HH, Zhang XH, Qin YZ, Liu DH, Jiang H, Chen H, et al. MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial. Blood 2013;121:4056e62. [6] Wood B. 9-color and 10-color flow cytometry in the clinical laboratory. Arch Pathol Lab Med 2006;130:680e90. [7] San Miguel JF, Vidriales MB, Lopez-Berges C, Diaz-Mediavilla J, Gutierrez N, Canizo C, et al. Early immunophenotypical evaluation of minimal residual disease in acute myeloid leukemia identifies different patient risk groups and may contribute to postinduction treatment stratification. Blood 2001;98:1746e51. [8] Buccisano F, Maurillo L, Spagnoli A, Del Principe MI, Fraboni D, Panetta P, et al. Cytogenetic and molecular diagnostic characterization combined to postconsolidation minimal residual disease assessment by flow cytometry improves risk stratification in adult acute myeloid leukemia. Blood 2010;116:2295e303. [9] Chen X, Xie H, Wood BL, Walter RB, Pagel JM, Becker PS, et al. Relation of clinical response and minimal residual disease and their prognostic impact on outcome in acute myeloid leukemia. J Clin Oncol 2015;33:1258e64. [10] Walter RB, Gooley TA, Wood BL, Milano F, Fang M, Sorror ML, et al. Impact of pretransplantation minimal residual disease, as detected by multiparametric flow cytometry, on outcome of myeloablative hematopoietic cell transplantation for acute myeloid leukemia. J Clin Oncol 2011;29:1190e7. [11] Walter RB, Buckley SA, Pagel JM, Wood BL, Storer BE, Sandmaier BM, et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood 2013; 122:1813e21. [12] Buccisano F, Maurillo L, Gattei V, Del Poeta G, Del Principe MI, Cox MC, et al. The kinetics of reduction of minimal residual disease impacts on duration of response and survival of patients with acute myeloid leukemia. Leukemia 2006;20:1783e9. [13] Maurillo L, Buccisano F, Del Principe MI, Del PG, Spagnoli A, Panetta P, et al. Toward optimization of postremission therapy for residual disease-positive patients with acute myeloid leukemia. J Clin Oncol 2008;26:4944e51. [14] Walter RB, Gyurkocza B, Storer BE, Godwin CD, Pagel JM, Buckley SA, et al. Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. Leukemia 2015;29:137e44. [15] Milano F, Gooley TA, Wood BL, Woolfrey AE, Petersdorf EW, Appebaum FR, et al. Minimal residual disease does not impact risk of relapse in myeloablative umbilical cord blood transplant recipients: comparison with matched and mismatched unrelated transplants. Blood 2014 (ASH Annual Meeting Abstracts);124:abstr 2579. [16] Gutman JA, Leisenring W, Appelbaum FR, Woolfrey AE, Delaney C. Low relapse without excessive transplant-related mortality following myeloablative cord blood transplantation for acute leukemia in complete remission: a matched cohort analysis. Biol Blood Marrow Transpl 2009;15:1122e9.
Please cite this article in press as: Appelbaum FR, Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.10.010
Contents lists available at ScienceDirect
Best Practice & Research Clinical Haematology journal homepage: www.elsevier.com/locate/beha
Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease* Frederick R. Appelbaum* Clinical Research Division, Fred Hutchinson Cancer Research Center, Division of Medical Oncology, University of Washington School of Medicine, 1100 Fairview Avenue North, D5-310, P.O. Box 19024, Seattle, WA 98109-1024, USA
a b s t r a c t Keywords: Acute myeloid leukemia Hematopoeitic cell transplantation Minimal residual disease
Early trials of hematopoietic cell transplantation (HCT) for adults with acute myeloid leukemia (AML) did not generally include measurement of minimal residual disease (MRD) at the time of remission. However, the presence of MRD is now considered to be a powerful predictor of outcome for adults with AML in first complete remission. This raises the question of whether MRD positivity in first remission changes the indications for transplant or the transplant approach itself if patients do proceed to transplant with MRD present. This paper will begin to address these issues in adult AML. © 2015 Published by Elsevier Ltd.
Introduction The indications for hematopoietic cell transplantation (HCT) for adults with acute myeloid leukemia (AML) in first remission (CR1) have been developed based on prospective trials and large metaanalyses [1,2]. These trials, however, did not generally include measures of minimal residual disease (MRD) at the time of remission. Evidence is now accumulating showing that the presence of MRD
* Originally published in Blood. Walter RB et al. Significance of minimal residual disease before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second complete remission. Blood 2013; 122:1813e1821. © the American Society of Hematology. * Tel.: þ1 206 667 4412; fax: þ1 206 667 6936. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.beha.2015.10.010 1521-6926/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: Appelbaum FR, Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.10.010
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detected using either quantitative RT-PCR or multi-parametric flow cytometry (MFC) is a powerful predictor of outcome for adults with AML in first complete remission. In this brief review, we will address the issue of whether the presence of MRD in adults with AML in first remission changes the indications for transplantation. We will further address the question of whether, if patients with MRD do proceed to transplantation, any particular approach should be favored. Before approaching these questions, the limitations of the available information should be addressed. First, there is considerable variability in the assays used to detect MRD and there have been no generally accepted methods to standardize such assays among different laboratories. This variability applies both to RT-PCR and to MFC based approaches. Second, there has been no standardization of the timing of MRD measurement after induction or consolidation attempts. Some of the studies referenced in this review measured MRD shortly after initial induction and some only measured it after several months. Finally, in virtually every prospective study reported to date, only a fraction of the patients entered onto the treatment trial actually had a full set of MRD measurements, meaning that study conclusions have been based on subset analyses. As will be discussed, despite these limitations, a reasonably clear picture of the relationship of MRD and clinical outcome in adult AML is emerging. Core binding factor AML Core binding factor (CBF) AMLs, including those characterized by t(8;21) and inv(16), are categorized as being in the favorable risk AML subset, and thus, allogeneic HCT is not generally recommended for adults with CBF AML in first remission. In addition to their favorable prognosis, another unique feature of the CBF AMLs is that sensitive RT-PCR based assays exist capable of measuring minimal residual disease in such patients at the time of first remission. The presence of such sensitive, universally applicable assays raises the question of whether they could be used to identify patients with sub-optimal responses to initial chemotherapy who should be transplanted in first CR, despite the generally favorable prognosis of this disease category. Yin et al. reported on the clinical value of quantitative RT-PCR monitoring of MRD in 278 patients with CBF AML (163 with t(8:21) and 115 with inv(16)) entered in the United Kingdom Medical Research Council AML 15 trial [3]. At remission, normalized to 105 copies of ABL, a >3 log reduction in RUNX1RUNX1T1 bone marrow transcripts for t(8;21) patients and having fewer than 10 copies of CBFB-MYH11 copies in peripheral blood in inv(16) patients were the most significant variables for subsequent relapse risk based on multivariable analysis. MRD levels after consolidation were also informative. At any time after remission induction, the risk of subsequent relapse was 100% for the following: t(8;21) patients with >500 copies in bone marrow or >100 copies in peripheral blood, and inv(16) patients with >50 copies in bone marrow or with >10 copies in peripheral blood. Some of the patients who relapsed responded to subsequent chemotherapy and transplantation, and since allografting was not recommended as part of initial therapy in this trial, no conclusions about the possible value of HCT in first remission for high risk patients could be drawn from this experience. A similar trial was published by Jourdan et al. for the French AML Intergroup [4]. They reported on 176 patients with CBF-AML (90 CBFa and 86 CBFb) treated on CBF-2006. At 36 months, the cumulative incidence of relapse was 22% in those who achieved a 3-log reduction in MRD after the first consolidation cycle versus 54% for those who did not. This translated into relapse-free survival rates of 73% for those who had a 3-log reduction versus 44% for those who did not, and overall survival rates of 90% versus 71%. The presence of MRD was the sole prognostic factor predicting relapse in multivariable analysis that included white cell count, KIT and FLT3 mutational status. Like the MRC trial, allogeneic HCT was not recommended as part of initial therapy, and although some high-risk patients did receive transplants in first remission, the value of that intervention was impossible to measure in this trial. Both the British MRC trial and the French AML Intergroup Trial demonstrate that measurement of MRD after induction is the single most powerful prognostic factor predicting subsequent relapse in CBF AML, but neither trial was designed to test an intervention based on that finding. A trial reported by Zhu et al. from China did attempt to evaluate the role of allogeneic HCT for patients with CBFa with high-risk disease in first CR [5]. A total of 116 eligible patients had MRD status determined after consolidation therapy. According to protocol, those with high-risk disease were to be treated with allogeneic transplantation whereas those with lower risk disease were to be treated with Please cite this article in press as: Appelbaum FR, Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.10.010
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chemotherapy. A total of 47 patients were defined as low-risk based on MRD measurements, with 66 defined as high risk. Only a subset of patients was treated according to protocol intent. Of the 47 low risk patients, 29 were treated with chemotherapy while 18 received transplants in CR1. Among the high-risk patients, 26 received chemotherapy, while 40 were transplanted. In an analysis based on actual treatment received, it appeared that allogeneic HCT in CR1 was able to reduce relapse rates and improve survival compared to chemotherapy for high-risk patients, whereas chemotherapy was superior to transplantation for low-risk patients (Fig. 1). Although seriously flawed by the lack of protocol discipline, this is one of the very few studies with a sizable number of CBF AMLs defined as high risk by virtue of the presence of MRD who were prospectively transplanted in first remission and does suggest a possible advantage to this approach. Intermediate- and high-risk AML Prospective trials and meta-analyses generally support the use of allogeneic HCT for patients with intermediate- and high-risk AML who have achieved a first remission [1,2]. As noted earlier, these studies did not include measurements of MRD in the decision making process. When considering whether MRD measurements should change the approach to patients with intermediate- or high-risk AML, several questions become apparent: (1) What is the outcome of patients with intermediate- or high-risk AML in CR1 with MRD who are not transplanted? (2) What is the outcome of such patients with transplantation? (3) Can adding additional chemotherapy convert patients with AML in CR1 who are MRD positive to an MRD negative state? (4) If it is possible to convert MRDþ patients to MRD-prior to transplant, does such a conversion make any difference? (5) Finally, if the decision is to proceed with transplantation in a patient with MRD, is any particular transplant approach favored? Impact of MRD on outcome of chemotherapy in adults with non-CBF AML Because there is no universally applicable RT-PCR based assay for the measure of MRD in non-CBF AMLs, the majority of trials assessing the impact of MRD on outcome in this disease category have been
Fig. 1. Shown are subgroup analyses of treatment outcomes of patients with t(8;21) AML. (A,D) Relapse. (B,E) Disease-free survival. (C,F) Overall survival [5]. CT, chemotherapy; HSCT, hematopoietic stem cell transplantation. Republished with permission of American Society of Hematology, from MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial. Zhu HH et al., Blood, volume 121, number 20, 2013; permission conveyed through Copyright Clearance Center, Inc.
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based on multiparametric flow cytometry (MFC). While not as sensitive as RT-PCR based assays, MFC assays have been developed by expert laboratories that routinely have sensitivities of 0.1%, although a higher level of sensitivity is possible for subsets of leukemias with more frankly aberrant immunophenotypes [6]. One of the first studies reporting on the impact of MRD as measured by MFC on the outcome of adults with AML in CR1 came from San Miguel and colleagues who studied 126 patients who displayed aberrant phenotypes at diagnosis [7]. They found that based on the presence of MRD at the time of first remission, 4 categories of risk could be determined. Eight patients with fewer than 104 cells were at very low risk of relapse; 37 with between 104 and 103 were at low risk; 64 with 103 and 102 cells were at intermediate risk (relapse risk 50%), while the remaining 17 with >102 were at very high risk of relapse. A number of other investigators have since published studies confirming the prognostic importance of the presence of MRD in AML patients treated with chemotherapy. For example, Buccisano et al. reported on 143 adult AML patients and showed that while patients with good or intermediate risk karyotypes who were MRD negative had reasonable disease-free and overall survivals, those with minimal residual disease measured after consolidation therapy had a low likelihood of relapse-free survival (below 20%) whether they had good-, intermediate-, or high-risk cytogenetics [8]. More recently our group reviewed the results of 245 adults with AML who achieved a CR, CR with incomplete platelet recovery (CRp), or CR with incomplete count recovery (CRi) [9]. The group was also analyzed for the presence of MRD at the time of achievement of CR as determined by 10-color MFC. Although pretreatment co-variates such as cytogenetics and FLT3 status were associated with subsequent relapse, their prognostic effect was almost nil once the quality of response (CR, CRp, or CRi) and presence of MRD were taken into account. As shown in Fig. 2, if patients were treated with consolidation chemotherapy without HCT in CR1, the subsequent risk of relapse was >90% for patients with either CRp or CRi, or those with MRD. This translated into a likelihood of survival of less than 15% at 2 years for such patients. These results suggest that the quality of initial response to chemotherapy is the single most important predictor of outcome for patients treated without HCT, and emphasize the very high likelihood of subsequent failure with subsequent chemotherapy if patients do not achieve a good quality CR with initial induction.
Fig. 2. The curves demonstrate the cumulative incidence of relapse (left) and relapse-free survival (right) of 109 patients who achieved a CR without or with MRD, or had a response less than CR (CRp or CRi) with or without MRD. None of these patients received an allogeneic HCT while in remission [9].
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Impact of MRD on outcome of allogeneic HCT for patients with AML Using the same 10-color MFC assay, we studied the impact of the presence of MRD on the outcome of 253 consecutive patients who were treated with myeloablative HCT for AML in either CR1 (n ¼ 183) or CR2 (n ¼ 70) [10,11]. Among patients transplanted in first CR, 3-year estimates of overall survival were 73% (64%e79%) for MRD-negative patients and 32% (17%e48%) for MRD-positive patients (Fig. 3). Similarly, among patients transplanted in second remission, 3-year survival was 73% (57%e83%) for MRD-negative patients versus 44% (21%e65%) for MRD-positive patients. The estimates for relapse were 21% (14%e28%) for MRD-negative CR1 patients versus 58% (41%e72%) for MRD-positive CR1 patients, and 19% (9%e31%) for MRD-negative CR2 patients versus 68% (41%e85%) for CR2 MRDpositive patients. These results thus show that measurement of MRD prior to allogeneic HCT using ablative preparative regimens is highly predictive of relapse and overall survival in patients transplanted in both CR1 and CR2. Nonetheless, even though the outcome is worse for patients with MRD, the outcome of transplantation still appears better than what would be expected in patients with MRD treated without subsequent transplantation. Conversion of patients from MRDþ to MRD-status The observation that the outcome of allogeneic HCT is worse for patients with MRD raises the obvious questions of whether MRDþ patients can be converted to MRD-patients pre-transplant, and whether such conversion changes the outcome of subsequent transplantation. Unfortunately, there are very few studies addressing these questions. One of the more telling studies comes from Maurillo et al. and the group from Rome, Italy [12,13]. They studied 142 patients with de novo AML treated on EORTC/ GIMEMA protocols AML-10, AML-12 and AML-13. Using a cutoff of 3.5 104, after induction 28% of patients (40 of 142) were MRD negative and 72% (102 of 142) were MRD positive. Seven patients relapsed prior to consolidation and 1 died early after consolidation, leaving 134 available for subsequent MRD measurement after receiving two cycles of consolidation. Of these, 34% (46 of 134) were MRD negative and 66% (88 of 134) were MRD positive following consolidation. The authors note that following consolidation 15 patients who were MRD positive after induction converted to MRD negative, and that nine progressed from MRD negative after induction to MRD positive after consolidation. Thus, using the types of consolidation employed on these trials (two cycles of idarubicin, intermediate dose cytarabine [500 mg/m2/q12h on days 1e6] and etoposide), the net gain in MRD negative patients was fewer than 10%. Whether other forms of consolidation would be more effective is unknown. Given the low rate of conversion of MRD-positive to MRD-negative status, it is difficult to judge whether this conversion makes any difference. In the Maurillo study, the 15 patients who converted from MRD positive to MRD negative had a 40% relapse-free survival at 5 years, which was better than the 20% relapse-free survival seen in the group that was MRD positive both after induction consolidation, and the 0% relapse-free survival seen in the small group that progressed from MRD negative after induction to MRD positive after consolidation. Transplantation of MRDþ patients If the decision is to proceed with transplantation in a patient with MRD, is there a preferred approach? One might anticipate that the intensity of the preparative regimen would be of greater importance in patients with MRD. In an effort to address this question, we analyzed the outcome of allogeneic HCT in 241 adult patients with AML undergoing allogeneic HCT after either myeloablative (MA) conditioning (n ¼ 155) or nonmyeloablative (NMA) conditioning (n ¼ 86) [14]. Somewhat surprisingly, the impact of MRD on relapse was similar after NMA and MA conditioning, being approximately 4.5-fold greater in MRDþ patients transplanted using either category of preparative regimen. Specifically, the 3-year relapse estimates were 28% and 57% for MRD- and MRDþ NMA patients, and 22% and 63% for MRD- and MRDþ MA patients. The 3-year overall survival rates were 48% and 41% for MRD- and MRDþ NMA patients and 76% and 25% for MRD- and MRDþ MA patients. These are retrospective data and there were many reasons patients were allocated to receive either NMA or MA conditioning, and so patient selection bias could play a role in these results. Nonetheless, the data Please cite this article in press as: Appelbaum FR, Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.10.010
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Fig. 3. Shown is the association between pre-transplant MRD and post-transplant outcome for AML patients in CR1 and CR2. The solid black lines are patients in CR1 without MRD (n ¼ 147) and the solid dashed lines are patients in CR2 without MRD (n ¼ 52). The solid gray lines are patients in CR1 with MRD (n ¼ 36), and the dashed gray lines represent patients in CR2 with MRD (n ¼ 18) [11].
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Table 1 Impact of MRD on survival.
UCB MURD MMURD
Total
MRDþ
Survival HR
112 334 110
31 (28%) 122 (36%) 47 (43%)
1.01 2.14 1.94
provide no basis for altering the choice of preparative regimen based on the presence or absence of MRD at the time of transplant. The patients included in the above cohort were transplanted from siblings or matched unrelated donors using either bone marrow or peripheral blood as the source of stem cells. More recently, we completed an analysis of 556 patients transplanted using matched unrelated donors (MUD) (n ¼ 334), mismatched unrelated donors (MMUD) (n ¼ 110), or cord blood (CB) (n ¼ 112) between 2006 and 2012 following myeloablative preparative regimens [15]. Overall survival in the CB group appeared to be at least as good as that in the MUD group, with a trend towards higher mortality in the MMURD group. The risk of relapse was higher in both the MUD and MMURD groups compared with the CB group, with an adjusted hazard ratio for MMURD vs CB of 2.29 and for MUD vs CB of 2.14. Of particular interest for the purpose of this discussion is the observation that the presence of MRD prior to transplant negatively impacted relapse rates following both MUD and MMURD transplantation, but had no measureable impact on the risk of relapse or survival following CB transplantation (Table 1). We and others have previously published results showing that relapse rates appear to be less following myeloablative cord blood transplants than seen following the use of matched related or matched unrelated donors [16]. The more recent observations suggest that this increased graft-versus-leukemia effect seen following cord blood transplantation may be able to overcome, at least in part, the deleterious effects of the presence of MRD pre-transplant.
Summary Assays now exist capable of reliably measuring the presence of MRD in the vast majority of patients with AML. In patients with CBF AMLs, the presence of MRD following induction is the single most powerful predictor of subsequent relapse. Although some data exist suggesting that allogeneic HCT in first remission may reduce the risk of relapse and possibly improve survival in patients with MRD, the number and robustness of clinical studies addressing this possibility are limited. For the more common intermediate- and high-risk AMLs, the data are compelling that the presence of MRD following induction chemotherapy greatly increases the risk of subsequent relapse in patients treated either with subsequent chemotherapy or allogeneic transplantation. The impact is especially profound in those treated with just chemotherapy with relapse-free survival rates well below 20%. Transplantation in first remission appears to offer modestly better prospects. Only limited data are available addressing the likelihood that consolidation chemotherapy can convert MRD-positive patients to MRD-negative status, but the limited evidence suggests that this approach will be successful in only a very limited proportion of patients. If the choice is to proceed with transplantation in a patient with MRD, there is no evidence favoring one form of preparative regimen over others, but there are data suggesting that cord blood may be preferred over matched or mismatched unrelated donors.
Conflict of interest Consulting Fees: Adaptive Biotechnologies Corporation; Amgen; Celator; Neumedicines; NMDP; Pfizer. Please cite this article in press as: Appelbaum FR, Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.10.010
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Please cite this article in press as: Appelbaum FR, Hematopoietic cell transplantation for adults with acute myeloid leukemia with minimal residual disease, Best Practice & Research Clinical Haematology (2015), http://dx.doi.org/10.1016/j.beha.2015.10.010