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Sep 14, 2012 - Corey S. Cutler, Karen K. Ballen, Mitchell S. Cairo, Bruce M. Camitta, ... Citation: Keating A, Tunes da Silva G, Perez WS, Gupta V, Cutler CS, ...

Published Ahead of Print on September 14, 2012, as doi:10.3324/haematol.2012.062059. Copyright 2012 Ferrata Storti Foundation.

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Autologous blood cell transplantation versus HLA-identical sibling transplantation for acute myeloid leukemia in first complete remission: a registry study from the Center for International Blood and Marrow Transplantation Research by Armand Keating, Gisela Tunes da Silva, Waleska S. Perez, Vikas Gupta, Corey S. Cutler, Karen K. Ballen, Mitchell S. Cairo, Bruce M. Camitta, Richard E. Champlin, James L. Gajewski, Hillard M. Lazarus, Michael Lill, David I. Marks, Chadi Nabhan, Gary J. Schiller, Gerard Socie', Jeffrey Szer, Martin S. Tallman, and Daniel J. Weisdorf Haematologica 2012 [Epub ahead of print] Citation: Keating A, Tunes da Silva G, Perez WS, Gupta V, Cutler CS, Ballen KK, Cairo MS, Camitta BM, Champlin RE, Gajewski JL, Lazarus HM, Lill M, Marks DI, Nabhan C, Schiller GJ, Socie' G, Szer J, Tallman MS, and Weisdorf DJ. Autologous blood cell transplantation versus HLA-identical sibling transplantation for acute myeloid leukemia in first complete remission: a registry study from the Center for International Blood and Marrow Transplantation Research. Haematologica. 2012; 97:xxx doi:10.3324/haematol.2012.062059 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process. Haematologica (pISSN: 0390-6078, eISSN: 1592-8721, NLM ID: 0417435, www.haematologica.org) publishes peer-reviewed papers across all areas of experimental and clinical hematology. The journal is owned by the Ferrata Storti Foundation, a non-profit organization, and serves the scientific community with strict adherence to the principles of open access publishing (www.doaj.org). In addition, the journal makes every paper published immediately available in PubMed Central (PMC), the US National Institutes of Health (NIH) free digital archive of biomedical and life sciences journal literature.

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DOI: 10.3324/haematol.2012.062059

Autologous blood cell transplantation versus HLA-identical sibling

transplantation for acute myeloid leukemia in first complete remission: a registry study from the Center for International Blood and Marrow Transplantation Research Short Title: Autologous PBSC versus allogeneic transplantation for AML CR1

Armand Keating,1 Gisela DaSilva,2 Waleska S. Perez,3 Vikas Gupta,1 Corey S. Cutler,4 Karen K. Ballen,5 Mitchell S. Cairo,6 Bruce M. Camitta,7 Richard E. Champlin,8 James L. Gajewski,9 Hillard M. Lazarus,10 Michael Lill,11 David I. Marks,12 Chadi Nabhan, 13 Gary J. Schiller,14 Gerard Socie',15 Jeffrey Szer,16 Martin S. Tallman, 17 and Daniel J. Weisdorf 18

1

Princess Margaret Hospital, University of Toronto, Ontario, Canada; 2 University of Sao Paulo-

Brazil, Sao Paulo, Brazil; 3 Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI, USA; 4 Dana Farber Cancer Institute, Boston, MA, USA; 5 Massachusetts General Hospital, Boston, MA, USA; 6New York Medical College, Valhalla, NY, USA; 7Children’s Hospital of Wisconsin, Milwaukee, WI, USA; 8MD Anderson Cancer Center, Houston, TX, USA; 9Oregon Health and Science University, Portland, OR, USA; 10University Hospitals Case Medical Center, Cleveland, OH, USA; 11Cedars-Sinai Medical Center, Los Angeles, CA, USA; 12 Bristol Children’s Hospital, Bristol, UK; 13Advocate Lutheran General Hospital, Park Ridge, IL, USA; 14UCLA Center for Health Sciences, Los Angeles, CA, USA; 15 Hopital Saint Louis, Paris, France; 16Royal Melbourne Hospital City Campus, Victoria, Australia; 17 Memorial Sloan Kettering Cancer Center, New York, NY, USA, and

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University

of Minnesota Medical Center, Minneapolis, MN, USA

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Correspondence Daniel J. Weisdorf, MD, Adult Blood and Marrow Transplant Program, University of Minnesota Medical Center, MMC 480, 516 Delaware Street, SE, Minneapolis, Minnesota, 55455, USA. Phone: international +612.6243101. Fax: international +612.6256919. E-mail: [email protected]

Key words: allogeneic, autologous, transplantation, acute myeloid leukemia, peripheral blood stem cells.

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ABSTRACT Background. Optimum post-remission treatment for acute myeloid leukemia in first complete remission remains uncertain. Previous comparisons of autologous versus allogeneic hematopoietic cell transplantation noted higher relapse, but lower treatment-related mortality though using bone marrow grafts with treatment-related mortality of 12-20%. Design and Methods. Recognizing lower treatment-related mortality using autologous peripheral blood grafts, in an analysis of registry data from the Center for International Blood and Transplant Research, we compared treatment-related mortality, relapse, leukemia-free survival, and overall survival for acute myeloid leukemia in first complete remission (median ages 36-44, range 19-60) receiving myeloablative HLA-matched sibling donor (bone marrow, n=475 or peripheral blood, n=428) versus autologous peripheral blood (n=230). Results. Five year cumulative incidence of treatment-related mortality was 19 (95% confidence interval,16-23)%, 20(17-24)% and 8(5-12)% and relapse 20(17-24)% 26(21-30)% and 45(3852)% for allogeneic bone marrow, allogeneic peripheral blood and autologous peripheral blood, respectively. At 5 years, leukemia-free survival and overall survival were similar: allogeneic bone marrow 61(56-65)% and 64(59-68)%; allogeneic peripheral blood 54(49-59)% and 59(5464)%; autologous peripheral blood 47(40-54)% and 54(47-60)%; p=0.13 and 0.19, respectively. In multivariate analysis treatment-related mortality was lower after autologous peripheral blood versus allogeneic bone marrow / peripheral blood [relative risk 0.37(0.20-0.69); p=0.001], but treatment failure (death or relapse) after autologous peripheral blood was significantly more likely [relative risk 1.32(1.06-1.64); p=0.011]. Five year overall survival, however was similar in patients who received an autologous peripheral blood (n=230) [relative risk 1.23(0.98-1.55) p= 0.071] or allogeneic bone marrow / peripheral blood (n=903).

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Conclusions. In the absence of a HLA-matched sibling donor, autologous peripheral blood may provide acceptable alternative post-remission therapy for acute myeloid leukemia first complete remission.

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INTRODUCTION Optimum post-remission strategies for acute myeloid leukemia (AML) in first complete remission (CR1) remain controversial. Autologous (auto) hematopoietic cell transplantation (HCT) with bone marrow (BM) or peripheral blood (PB) versus allogeneic (allo) blood or marrow transplantation (alloBM/PB) from an HLA-matched sibling donor (MSD) are potentially curative for many patients with AML in CR1. At many centers, the preferred approach is alloHCT from MSD or HLA-matched unrelated donors (URD) for patients with intermediate or high risk cytogenetic or molecular abnormalities. Allo HCT has not been shown to benefit certain categories with favourable risk features (1). Consolidation chemotherapy is another option for those with intermediate or favourable risk characteristics (2). For patients without a suitable donor, autologous transplantation is also a valid option (3). Controlled prospective trials comparing consolidation chemotherapy with AutoBM and biological randomization to HLA-identical MSD myeloablative transplantation conducted in the mid-1990’s favored AlloBM because of a lower probability of relapse, despite high treatmentrelated mortality (TRM) of up to 30% (3-7). In all of the prospective studies, and in general during this period, autotransplants were performed with a bone marrow graft and led to TRM rates of 8-20%, considerably more than with consolidation chemotherapy. Since the completion of these trials, the stem cell source for autologous transplantation has shifted from BM to PB. More recent literature suggests a significantly lower TRM with autologous peripheral blood (autoPB) cell transplantation (AutoPB) and many series report TRM 40 years), gender (female vs. male), Karnofsky performance score (≥90% vs. 1), consolidation therapy prior to transplant (none vs. 1 vs. ≥2 vs. unknown), consolidation therapy prior to transplant (standard dose cytarabine vs. high dose cytarabine vs. other drugs vs. no therapy) and year of transplant (1995-1999 vs. 2000-2004). An initial analysis determined cut points for low/high risk groups for two continuous variables (time from diagnosis to transplant and time from CR1 to transplant) by multivariate analysis of overall survival at 5 years, based on pseudo-values and the Wald test statistic. Using the cut points obtained, regression models (generalized linear models with complementary loglog link function) were fitted to each time point for both OS and LFS. The estimated hazard ratios of the final models are shown. Initially, an analysis was performed with each model containing the main effect for type of transplant (AlloBM vs. AlloPB vs. AutoPB). However, risks associated with AlloBM and AlloPB were virtually identical in all analysis, so final models shows only the relative risk (RR) of each outcome for patients receiving any allotransplant (AlloBM/PB) versus those receiving AutoPB. Variables not listed in the final models did not meet the 0.05 levels of significance. All computations were made using the generalized linear model with complementary log-log link function in the statistical package of SAS version 9”. All p-values are two-sided.

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RESULTS Patients and clinical characteristics Eleven hundred thirty three (n=1133) patients met our study criteria: AlloBM (n=475); AlloPB (428) and AutoPB (230) from 205 reporting centers in 38 countries. Median follow-up of survivors for the 3 groups (AlloBM, AlloPB and AutoPB) was 82 (6-149), 61 (4-144), and 62 (1-139) months, respectively. Table 1 shows the patient-, disease- and transplant-related characteristics of the study patients and the decreasing use of autologous transplantation in more recent years of study.

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Treatment-related Mortality (TRM) In univariate analysis (Table 2), TRM at 5 years with AutoPB (8%, 95% CI 5-12) was significantly lower than AlloPB (20%, 95% CI 17-24) or AlloBM (19%, 95% CI 16-23) (p40 years and transplantation before the year 2000. In univariate analysis, TRM at 5 years for transplantation performed between 2000 and 2004 was 10% (95% CI 6-15) for AlloPB and 0% (n=51; 22 disease-free, 29 relapsed) for AutoPB.

Relapse In univariate analysis (Table 2), relapse at 5-years with AutoPB (45%, 95% CI 38-52) was significantly higher than AlloPB (26%, 95% CI 21-30) or AlloBM (20%, 95% CI 17-24) (p40 years) AutoPB recipients, p=0.018 (Table 3). Other independent factors associated with increased relapse were presence of extramedullary disease and transplantation performed after the year 2000 (Table 3). For patients with and without extramedullary disease, the 5 year probabilities of relapse for AlloBM, AlloPB and AutoPB were 21% (95% CI 9-38) and 20% (95% CI 17-24)[p=0.88]; 44% (95% CI 29-60) and 24% (95% CI 19-28) [p=0.013]; 47% (95% CI 25-70) and 45% (95% CI 3852)[0.86], respectively.

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Leukemia-free and overall survival By univariate analysis, the 5 year LFS for AlloBM, AlloPB and AutoPB was 61% (95% CI 56-65), 54% (95% CI 49-59) and 47% (95% CI 40-54), respectively (Table 2) (p=0.13). The univariate pairwise comparisons (pointwise p values at 5 years) showed an advantage for AlloBM over the other two approaches: AlloBM vs. AlloPB [p=0.046]; AlloBM vs. AutoPB [p=0.001]; and AlloPB vs. AutoPB [p=0.13]. In multivariate analysis, allogeneic HCT was associated with a significantly lower risk of treatment failure (relapse or death) at 5 years (Table 3, p=0.01). The only factor associated with increased risk of treatment failure was older age of the recipient at transplant. For patients 40 years) and those with lower Karnofsky scores. For patients 90% Karnofsky score, OS for AlloPB (n=156), AlloBM/PB (n=418), AutoPB (n= 74) was

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identical: 64 (56-72)%, 66 (61-71)%, 63 (51-74)%, respectively. For patients > 40 years age with a Karnofsky score of 40 years, LFS and OS in these older patients was significantly inferior not only with allotransplantation, but also with AutoPB. We also observed more frequent relapse after the more recent transplantations for uncertain reasons, perhaps due to selection of lower risk patients for non-transplant therapies.

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Extramedullary disease was noted as an independent risk factor for higher relapse rate after either transplant approach. Unexpectedly, cytogenetics did not affect outcomes in this study. Patient selection might in

part

explain

the

results.

Most

patients

had

no

cytogenetic

abnormalities

or

favourable/intermediate risk cytogenetics and fewer than 10% had poor risk cytogenetics. One possible explanation for the low frequency of a high risk cohort in the registry cases is initial treatment failure, prior to any consideration of transplantation. It is also possible that missing karyotype and modern molecular analysis for 12-26% of patients may have confounded the results, although outcomes for those with missing cytogenetics were not different from other categories. AutoPB led to higher risks of relapse, as seen in most other studies, and was even higher in patients over 40 (3, 4, 6, 7, 23). The HOVON/SAKK study of peripheral blood autotransplant versus consolidation chemotherapy showed a relatively high relapse rate of 58%, albeit significantly better than after consolidation chemotherapy (70%) (3). An EBMT study compared PB and BM graft sources in patients undergoing autotransplant for AML in CR (24) and reported higher relapse risk with AutoPB (BM, 39% vs. early PB, 56% vs. late PB, 46%, p or =60 years with hematologic neoplasias treated with allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2010;16(7):967-75. 30. Gupta V, Tallman MS, He W, Logan BR, Copelan E, Gale RP, et al. Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis. Blood. 2010;116(11):1839-48. 31. Walter RB, Pagel JM, Gooley TA, Petersdorf EW, Sorror ML, Woolfrey AE, et al. Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission. Leukemia. 2010;24(7):1276-82. 32. Williams BA, Wang XH, Keating A. Clonogenic assays measure leukemia stem cell killing not detectable by chromium release and flow cytometric cytotoxicity assays. Cytotherapy. 2010;12(7):951-60.

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Table 1. Characteristics of patients. Number of patients Number of centers Age at transplant, years Median (range) 19 - 29 30 - 39 40 - 49 50 - 60 Male sex Karnofsky score pre HCT>90% FAB classification M0 M1 M2 M4 M5 M6 M7 AML unclassified WBC at diagnosis, x109/L Median (range) 100 Missing Cytogeneticsb No abnormalities Good Intermediate Poor Unknown Extramedullary disease Time from Diagnosis to HCT, median (range), months Time from CR1 to HCT, median (range), months CNS disease prior to transplant Chemotherapy cycles to achieve CR 1 cycle > 2 cycles Consolidation treatments prior to transplant 1 cycle > 2 cycle No consolidation Missing

Allo BM 475 108

Allo PB 428 123

Auto PB 230 84

P-value

36 (19-60) 146 (31) 164(35) 130 (27) 35 ( 7) 244 (51) 389 (83)

40 (19-60) 90 (21) 112 (26) 153 (36) 73 (17) 236 (55) 332 (79)

44 (19-60) 41 (18) 58 (25) 61 (27) 70 (30) 113 (49) 168 (76)

12 ( 3) 94 (20) 151 (31) 126 (26) 55 (12) 11 ( 2) 4 ( 1) 22 ( 5)

20 ( 5) 66 (16) 121 (28) 78 (18) 76 (18) 13 ( 3) 5 ( 1) 49 ( 11)

9 ( 4) 35 (15) 67 (29) 53 (23) 46 (20) 4 ( 2) 2 ( 1) 14 ( 6)

14 250 (58) 79 (18) 58 (13) 46 (11) 42

13 234 (59) 73 (19) 52 (13) 35 ( 9) 34

18 107 (52) 36 (17) 42 (20) 23 (11) 22

192 (40) 30 ( 6) 106 (22) 26 ( 6) 121 (26) 28 ( 6) 5 (2-32)

195 (46) 12 ( 3) 129 (30) 39 ( 9) 53 (12) 43 (10) 4 (2-15)

105 (46) 15 ( 7) 53 (23) 17 ( 7) 40 (17) 17 ( 7) 5 (1-38)

0.07