5-Azacitidine for Myelodysplasia Before Allogeneic Hematopoietic Cell Transplantation

ORIGINAL ARTICLE 5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation

T Field1, J Perkins1, Y Huang2, MA Kharfan-Dabaja1, M Alsina1, E Ayala1, HF Fernandez1, W Janssen1, J Lancet3, L Perez1, D Sullivan1, A List3 and C Anasetti1

1Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 2Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA and 3Department of Hematological Malignancies, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Relapse remains a leading cause for treatment failure plantation (HCT). For patients with International Prog- after hematopoietic cell transplantation (HCT) in patients nostic Scoring System (IPSS) intermediate-2 (INT-2) or with intermediate- or high-risk myelodysplastic syndrome high-risk disease, the average time to AML was shown to (MDS). To discern the impact of 5-azacitine treat- be 1.1 and 0.2 years, and average time to death was 1.2 and ment pretransplant on the risk for relapse after HCT, 0.4 years, respectively.1 With the use of a decision analysis we analyzed the post transplant outcomes of all 54 from MDS and Center for International Blood and consecutive patients with MDS or chronic myelomonocy- Marrow Transplant Research registries and the Fred tic leukemia who received HCT from HLA-compatible Hutchinson Cancer Center, Cutler et al.2 addressed the donors according to pretransplant 5-azacitidine exposure. question regarding optimal timing of MDS patients Thirty patients received a median of four (1–7) cycles of proceeding to HCT. Their model showed that immediate 5-azacitidine, and 24 patients did not receive 5-azacitidine transplantation resulted in improved survival in patients before HCT. The 1-year estimates of overall survival, with INT-2 and high-risk MDS but not in those with earlier relapse-free survival and cumulative incidence of relapse stage disease. Even though benefit was shown with earlier were 47, 41 and 20%, for 5-azacitidine patients and 60, 51 transplant, these patients continue to be at substantial risk and 32%, respectively, for non-5-azacytidine patients. of relapse after HCT. The question of whether pretrans- These observations suggest that outcomes are similar in plant leukemia-type induction chemotherapy provides an both groups with a trend toward decreased early relapse in advantage without toxicities, which would prohibit pro- patients receiving 5-azacitidine. 5-Azacitidine may be of ceeding to transplant, is currently under investigation in value in stabilizing the disease, thereby allowing time for Europe (Allo-MDS2 Â 2 phase III prospective randomized patients to reach transplant and does not appear to affect trial by the European Group for Blood and Marrow transplant outcomes. Transplantation). Bone Marrow Transplantation (2010) 45, 255–260; The approval of 5-azacitidine and decitabine for the doi:10.1038/bmt.2009.134; published online 22 June 2009 treatment of MDS has provided an alternative strategy to Keywords: myelodysplastic syndrome; 5-azacitidine; allo- inhibit disease progression in transplant-eligible patients. geneic hematopoietic cell transplantation; acute myeloid Owing to the survival advantages reported with leukemia 5-azaciticine and the fact that it is relatively well tolerated, its use has become widespread.3,4 To assess the effect of pretransplant 5-azacytidine treatment on post transplant outcomes, we recently reviewed our institutional experience 5 Introduction with INT-2 and high-risk MDS patients. Updated results of that assessment are presented in this report. Myelodysplastic syndrome (MDS) is a malignancy characterized by ineffective hematopoiesis in which the Patients and methods only potential cure is allogeneic hematopoietic cell trans- Patients Medical records of consecutive patients with MDS or Correspondence: Dr T Field or Dr J Perkins, Department of Blood and chronic myelomonocytic leukemia (CMML) who received Marrow Transplantation, H. Lee Moffitt Cancer Center and Research allogeneic HCT between July 2004 and December 2007 Institute, 12902 Magnolia Drive, BMT Program, FOB3, Tampa, were retrospectively reviewed regarding their exposure to FL 33612, USA; E-mails: teresa.field@moffitt.org or janelle.perkins@moffitt.org 5-azacitidine. This medical record review study was part of Received 13 October 2008; revised 19 March 2009; accepted 8 April a larger chart review study which was approved by the 2009; published online 22 June 2009 University of South Florida Institutional Review Board. Pretransplant 5-azacytidine T Field et al 256 Patients included every patient assigned a diagnosis of discrete factors. The OS and RFS results in groups MDS at any time with a BM biopsy; this diagnosis was with and without 5-azacitidine were estimated with the confirmed by hematopathologists at the Moffitt Cancer Kaplan–Meier method. Differences in survival between the Center. Patients were then assigned to two different groups, two groups were compared by the log-rank test. Cox based on whether or not they had received 5-azacytidine at proportional hazards regression model was fitted to assess any time before transplant. the significance of the survival differences between the two groups when adjusting for potential risk factors. The cumulative incidences of relapse, non-relapse mortality, Donors grade 2–4 acute GVHD and grade 3–4 acute GVHD in the All patients and donors had high-resolution molecular groups with and without 5-azacitidine were estimated based typing for HLA-DRB1 and DQB1. Sibling donor and on the life-table method.9 Difference in cumulative patient pairs had low-intermediate resolution molecular incidence between the two groups were compared by the typing of HLA-A, HLA-B and HLA-C, whereas unrelated test for competing risk.10 The proportional hazards donor and patient pairs had sequence-based typing for regression model for cumulative incidence11 was fitted to HLA-A, HLA-B and HLA-C. All patients received assess the significance of the differences in cumulative unmanipulated granulocyte CSF-mobilized peripheral incidence between the two groups when adjusting for blood hematopoietic stem cells. potential risk factors.

Conditioning regimen All patients received a modification of de Lima et al.’s6 BU and fludarabine regimen where the BU dose was adjusted Results to a specific target. Fludarabine 40 mg/m2 was given i.v. daily for 4 days, with each infusion followed immediately Patient characteristics by i.v. BU. The dose of BU for days 1 and 2 was 130 mg/ During the time period specified, 54 consecutive patients m2. After the first infusion of BU, serial blood samples were with MDS and CMML were transplanted; patient char- drawn and sent to the University of Pennsylvania William acteristics are summarized in Table 1. All patients had Pepper Laboratory where pharmacokinetic analysis was MDS disease risk of INT-2 or beyond at some time before performed. The goal was to adjust BU doses for days 3 and transplant or had therapy-induced MDS from previous 4 to achieve an average targeted BU concentration at cancer treatment. steady-state of 800–1000 ng/ml. Patients with mismatched Thirty of the 54 patients received a median of 4 (1–7) unrelated donor grafts were given rabbit anti-thymocyte cycles of 5-azacitidine before HCT. Response to 5- globulin (rabbit ATG). The total dose of rabbit ATG given azacitidine (as defined by Cheson et al.12) included CR was 7.5 mg/kg over 3 days.7 (four patients), partial response (10 patients), stable disease (10 patients), progressive disease (five patients) and aplasia (one patient). Before HCT, disease classifications were Supportive care as follows: RA and RCMD (six patients), RAEB-1 All patients received anti-seizure prophylaxis with loraze- (12 patients), RAEB-2 (two patients), CMML (three pam. GVHD prophylaxis consisted of tacrolimus and patients), progression to AML (three patients) and MTX (15 mg/m2 i.v. on day þ 1 and then 10 mg/m2 i.v. complete response (CR) (four patients) (data not shown). on days þ 3, þ 6 and þ 11) or tacrolimus and mycophe- Twenty-four patients did not receive 5-azacitidine before nolate mofetil (30 mg/kg/day in two divided doses). The HCT. Before HCT, disease category included RA and dose of MTX was adjusted for renal insufficiency. The dose RCMD (seven patients), RCMD-MF (one patient), RAEB- of tacrolimus was adjusted to achieve levels of 10–15 ng/ml 1 (eight patients), RAEB-2 (three patients), CMML-2 (one during the first month after transplantation and gradually patient), progression to AML (one patient) and CR (three decreased later in the absence of GVHD. Acute GVHD was patients) (data not shown). graded by consensus conference criteria.8 Among the 24 patients who did not receive 5-azacitidine, Patients did not routinely receive granulocyte CSF after eight had progressed to AML and 10 (42%) were treated transplant. Antimicrobial prophylaxis consisted of acyclo- with induction chemotherapy. In contrast, among the 30 vir, levofloxacin and either fluconazole or voriconazole. patients who received 5-azacitidine, six had progressed to CMV was assayed weekly by real-time PCR of blood AML and four (13%) were treated with induction samples; when positive, patients were treated with pre- chemotherapy. The difference between the proportion of emptive ganciclovir, valganciclovir, or foscarnet. Trimetho- patients who had progressed to AML before transplant was prim-sulfamethoxazole prophylaxis for Pneumocystis not significant between the groups, but the higher like- carinii infection was given two times weekly. All blood lihood of patients in the no 5-azacytidine cohort receiving products were leukocyte filtered and irradiated for induction chemotherapy did reach statistical significance all patients; CMV-negative donors were selected for (P ¼ 0.03). CMV-negative recipients. Patients in the 5-azacitidine cohort were more likely to receive GVHD prophylactic regimens other than tacroli- Statistical analysis mus plus MTX (P ¼ 0.04) and had shorter post transplant Characteristics of patients are presented as median follow-up times (P ¼ 0.03). Other characteristics were and range for continuous factors and frequencies for similar between the two cohorts.

Bone Marrow Transplantation Pretransplant 5-azacytidine T Field et al 257 Table 1 Patient characteristics for the entire cohort GVHD With Without P-value The cumulative incidences were 79 vs 71% for grade 2–4 5-azacitidine 5-azacitidine GVHD, 13 vs 4% for grade 3–4 GVHD and 76 vs 75% for chronic extensive GVHD (data not shown) in the Total patients, n 30 24 patients treated with vs without 5-azacitidine, respectively Age NS (Figure 1). Pretransplant treatment with 5-azacytidine did Median, years 56 54 not appear to be a signiﬁcant predictor of grade 2–4 acute Range, years (25–69) (33–68) GVHD when evaluated in a multivariate model that Gender NS adjusted for age, donor source, GVHD prophylaxis or Male 20 14 IPSS score. Female 10 10

Disease at diagnosis NS RCMD/RCMD–RARS 8 11 Response to transplantation RAEB-1 10 6 One patient in the 5-azacitidine cohort died of sudden RAEB-2 8 4 death on day 14 after engraftment but before disease CMML-1 2 1 þ CMML-2 1 0 evaluation. All evaluable study patients achieved CR after MDS-MPD 1 1 transplantation, except one patient in the no 5-azacitidine RCMD-MF 0 1 cohort. The cumulative incidence of relapse by the group is Treatment related 7 10 NS shown in Figure 2c. At 1 year post transplant, the cumulative incidence of relapse for patients who did not Therapy of MDS or AML 0.03a Chemotherapy 4 10 receive 5-azacytidine was 32 vs 20% in the patients who did Other 3 1 receive 5-azacytidine. The corresponding values at 2 years None 23 13 were 36 and 31%. There was no significant difference in 5-Azacitidine cycles, n relapse among patients who did or did not receive Median 4 induction chemotherapy before transplantation (data not Range 1–7 shown). Pretransplant treatment with 5-azacytidine did not IPSS at diagnosis NS appear to be a significant predictor of relapse when Low 2 1 evaluated in a multivariate model which adjusted for age, Intermediate-1 12 10 Intermediate-2 10 9 diagnosis of secondary MDS, presence of poor risk High 3 1 cytogenetics, history of progression to AML or IPSS score. CMML 3 1 NE 0 2 Death from non-relapse causes IPSS at transplant NS Low 6 4 The cumulative incidence of non-relapse mortality was not Intermediate-1 10 9 statistically different in the two study cohorts (Figure 2d; Intermediate-2 8 8 P ¼ 0.16). Eleven of 30 (37%) patients in the 5-azacitidine High 3 1 CMML 3 1 cohort died with MDS in remission: causes of death were NE 0 1 pre-existing lymphoma (one patient), sudden death (one Myeloblasts at transplant NS patient), acute or chronic GVHD (four patients), interstitial o5% 12 12 pneumonitis (one patient), pneumonia (one patient), fungal 5–10% 15 8 brain abscess (one patient), adenovirus infection (one 11–20% 1 3 420% 2 1 patient) and unknown (one patient). Seven of 24 (29%) patients in the no 5-azacitidine cohort died with MDS in Peripheral blood stem cell donor NS remission: causes of death were acute or chronic GVHD HLA identical sibling 13 11 HLA matched unrelated 14 9 (two patients), pulmonary hemorrhage (two patients), HLA mismatched unrelated 3 4 infection (two patients) and multiorgan failure (one Median time of follow-up 0.03b patient). Pretransplant treatment with 5-azacytidine did Days 515 899 not appear to be a significant predictor of non-relapse Range 14–1055 51–1163 mortality when evaluated in a multivariate model GVHD prophylaxis, n 0.04a that adjusted for age, history of secondary MDS or TacMMF 8 2 progression to AML, donor source, GVHD prophylaxis TacMTX 22 19 or IPSS score. Other 0 3

Abbreviations: AML ¼ acute myeloid leukemia; CMML ¼ chronic myelo- Overall and relapse-free survival monocytic leukemia; GVHD ¼ graft-versus-host disease; IPSS ¼ Interna- Comparison of overall and relapse-free survival is shown in tional Prognostic Scoring System; MDS ¼ myelodysplastic syndrome; MF ¼ myelo fibrosis; MMF ¼ mycophenolate mofetil; MPD ¼ myeloproli- Figures 2a and b. At 1 year, the overall survival is 60% ferative disorder; MTX ¼ methotrexate; RAEB ¼ refractory anemia with for patients not receiving pretransplant 5-azacytidine and excess of blasts; RCMD/RARS ¼ refractory cytopenia with multilineage 47% for those who received pretransplant 5-azacytidine dysplasia-refractory anemia with ringed sideroblasts; Tac ¼ tacrolimus. (P ¼ 0.25). The corresponding values for relapse-free NS denotes not significant (P40.05). survival are 51 and 41%, respectively (P ¼ 0.3). Pretrans- aFisher’s exact test. bLog-rank test. plant treatment with 5-azacytidine did not appear to be a significant predictor of overall or relapse-free survival when

Bone Marrow Transplantation Pretransplant 5-azacytidine T Field et al 258

1 1 0.9 Vidaza = N 0.9 Vidaza = N Vidaza = Y Vidaza = Y 0.8 p-value = 0.33 0.8 p-value = 0.26 0.7 0.7 0.6 0.6

0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 Cumulative incidence of Grade 2-4 aGVHD 0 Cumulative incidence of Grade 3-4 aGVHD 0 0 20 40 60 80 100 0 20 40 60 80 100 Days Days Figure 1 (a) Cumulative incidence of grade 2–4 GVHD. (b) Cumulative incidence of grade 3–4 GVHD.

1 1 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 p-value = 0.25 p-value = 0.30 Overall Survival 0.2 Vidaza = N 0.2 Vidaza = N

0.1 Vidaza = Y Relapse-free Survival 0.1 Vidaza = Y 0 0 0 200 400 600 800 1000 1200 0 200 400 600 800 1000 1200 Days Days

1 1 0.9 Vidaza = N 0.9 Vidaza = N Vidaza = Y 0.8 Vidaza = Y 0.8 p-value = 0.16 0.7 p-value = 0.66 0.7 0.6 0.6 0.5 0.5 0.4 0.4

of Relapse 0.3 0.3 0.2 0.2 non-relapse Mortality Cumulative Incidence 0.1 0.1 0 Cumulative Incidence of 0 0 200 400 600 800 1000 1200 0 200 400 600 800 1000 1200 Days Days Figure 2 (a) Overall survival. (b) Relapse-free survival. (c) Cumulative incidence of relapse. (d) Cumulative incidence of non-relapse mortality.

evaluated in a multivariate model which adjusted for age, Discussion history of secondary MDS or progression to AML, donor source, GVHD prophylaxis or IPSS score. In this study, treatment with 5-azaciticine before HCT did not signiﬁcantly affect rates of remission, relapse, acute and chronic GVHD and survival after transplant when Patients not receiving previous induction chemotherapy administered to patients with high-risk MDS before HCT. To eliminate the potential confounding risk of pretrans- This study included a subset of patients who received plant induction chemotherapy, we performed an additional induction chemotherapy for high-risk MDS or whose analysis on the subgroup of patients who had not received disease transformed to AML. Conceivably, these AML leukemia chemotherapy at any time before transplant. patients might have a more aggressive disease, placing them There were no statistically signiﬁcant differences between at greater risk for toxicity after HCT and relapse. In the two study cohorts in the cumulative incidence of grade addition, the induction chemotherapy could result in 2–4 (P ¼ 0.39) or grade 3–4 (P ¼ 0.52) acute GVHD, non- toxicities that would preclude HCT. Therefore, there might relapse mortality (P ¼ 0.23), time to progression (P ¼ 0.87), be a bias in that only the healthiest older patients received survival (P ¼ 0.34) or RFS (P ¼ 0.30). induction chemotherapy and proceeded to HCT. When the

Bone Marrow Transplantation Pretransplant 5-azacytidine T Field et al 259 analysis was restricted to patients who did not receive did not have CR. Scott et al.22 described 150 patients with induction chemotherapy, there were still no significant MDS or AML arising out of MDS. In the 38 patients who differences in outcomes when comparing the two study received a non-myeloablative transplant (NMT), 24 re- cohorts according to pretransplant 5-azacitidine. ceived pretransplant induction chemotherapy, with 20 A response to 5-azacitidine was not required for achieving CR. At 3 years, OS, DFS, disease progression favorable transplant outcomes, but a prospective, rando- and non-relapse mortality were reported as 27, 28, 41 and mized trial is needed to address this observation. Addi- 31%, respectively. Comparison with the 112 patients who tional studies to explore whether the combination of received standard myeloablative inductions revealed no pre- and post-HCT 5-azacitidine would improve RFS survival advantage to the NMT due to similar non-relapse would also be intriguing.13 mortality. This was retrospective, and the authors reported Patients with MDS generally are older, usually have that the NMT consisted of higher risk patients; however, more comorbidities and have more advanced disease than when outcomes of patients with less than 5% myeloblasts patients with other transplantable diagnoses. Thus the use at HCT were compared, no significant differences in of HCT has been limited in the past. The recent outcomes were shown. development of reduced intensity-conditioning regimens During the time needed to acquire a suitable HLA donor has provided these patients with the option of HCT where and proceed to transplant, patients who have high-risk age has been less of a prohibitive factor and non-relapse MDS often progress or transform to AML. The definitive mortality is improved compared with myeloablative con- answer to the role of pretransplant therapy, including ditioning.14 Several studies focusing on patients with MDS induction chemotherapy, is still under investigation. and AML, have reported comparisons of reduced intensity Because induction chemotherapy can increase the risk of vs conventional preparative regimens and demonstrated death or prevent proceeding to HCT because of associated comparable disease-free survival (DFS) (39–50%).15–17 toxicities, utilization of 5-azacitidine is an alternative for Reduced intensity regimens used in these reports included patients to control the disease while they await HCT. This fludarabine-based regimens containing low-dose TBI, BU, report suggests that pretransplant administration of or other non-myeloablative agents. 5-azacytidine does not adversely affect post transplant Although the use of reduced intensity-conditioning outcomes. A larger, prospective evaluation is necessary to regimens has decreased transplant-related mortality in confirm these results. most cases, allowing older patients with MDS the opportunity of HCT, the risk of relapse remains an issue. There are few reports of reduced intensity-conditioning Conflict of interest regimens that have evaluated only MDS patients, to assess risk of relapse. Nakamura et al.18 analyzed 43 patients with TF, JP, JL and AL receive support for a separate trial MDS, including 15 progressing to AML, who were given a from Celgene. AL is on the advisory board of Celgene. fludarabine–melphalan regimen. Two-year OS, DFS, re- YH, MK-D, MA, EA, HFF, WJ, JL, SP and DS have no lapse and transplant-related mortality were 54, 51, 16 and conflicts to declare. 35%, respectively. Donor source was not a factor in survival, although there was less relapse when unrelated donors were used (P 0.02). Chan et al.19 described a novel ¼ References regimen of pentostatin, TBI and photopheresis in 18 patients with MDS. In this study, two patients did not 1 Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G engraft and two did not achieve initial CR and died of et al. International scoring system for evaluating prognosis in disease progression. One-year OS, DFS and non-relapse myelodysplastic syndromes. Blood 1997; 89: 2079–2088. mortality were 65, 64 and 14%, respectively. Kroger et al.20 2 Cutler CS, Lee SJ, Greenberg P, Deeg HJ, Perez WS, Anasetti reported on 12 high-risk MDS patients who were given C et al. A decision analysis of allogeneic bone marrow fludarabine, BU and ATG induction. Two-year OS and transplantation for the myelodysplastic syndromes: delayed DFS were 26 and 12%, respectively, with four patients transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 2004; 104: 579–585. dying in remission. 3 Silverman LR, Demakos EP, Peterson BL, Kornblith AB, The studies noted above found that MDS disease Holland JC, Odchimar-Reissig R et al. Randomized controlled category and disease status before HCT affected outcomes trial of azacitidine in patients with the myelodysplastic and responses to the graft-vs-leukemia component of syndrome: a study of the cancer and leukemia group B. J Clin allografting. Several institutions have explored the efficacy Oncol 2002; 20: 2429–2440. of chemotherapy before HCT to reduce the MDS load, in 4 Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli hopes that this will improve HCT outcomes and relapse C, Giagounidis A et al. Efficacy of azacytidine compared with rates. Oran et al.21 reported on MDS (n ¼ 30) and AML that of conventional care regimens in the treatment of higher- (n ¼ 82) patients who were given fludarabine–melphalan as risk myelodysplastic syndromes: a randomized, open-label, conditioning. Twenty-three of the MDS patients received phase III study. www.thelancet.com/oncology. Published online February 18, 2009. pre-HCT chemotherapy. Results varied with remission 5 Field T, Alsina M, Ayala E, Fernandez H, Janssen W, Karfan- status, with 2-year OS of 66% for patients in CR and 23% Dabaja MA et al. Allogeneic hematopoietic cell transplant- for those with active disease and circulating blasts. ation (HCT) for myelodysplastic syndrome (MDS) after Cumulative incidence of non-relapse mortality at 2 years pretransplant 5-azacitidine (Vidaza). Blood 2007; 110: 339b was 20% for patients who had CR and 56% for those who (abstract 5035).

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