Published Ahead of Print on September 29, 2017, as doi: /haematol Copyright 2017 Ferrata Storti Foundation.

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1 Published Ahead of Print on September 29, 2017, as doi: /haematol Copyright 2017 Ferrata Storti Foundation. Mixed phenotype acute leukemia: Outcomes with allogeneic stem cell transplantation, a retrospective study from the Acute Leukemia Working Party of the EBMT by Reinhold Munker, Myriam Labopin, Jordi Esteve, Christoph Schmid, Mohamad Mohty, and Arnon Nagler Haematologica 2017 [Epub ahead of print] Citation: Munker R, Labopin M, Esteve J, Schmid C, Mohty M, and Nagler A. Mixed phenotype acute leukemia: Outcomes with allogeneic stem cell transplantation, a retrospective study from the Acute Leukemia Working Party of the EBMT. Haematologica. 2017; 102:xxx doi: /haematol 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.

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3 of page Abstract D d / dde dddd dddd > t W Dd d de d de ed de dl d dd d l de e dd e dd dl de d de d de dl dd e dd d de dl dd d ed d e dd dl d de dl dd e dd d / D K W Ddd D & dd de ddde K &> / Top of page D d D DW> d dl d e DW> / DW> e / deed ' / > '/> d e / ddde t, K t,k e d ddde t,k DW> W dl DW> dd d DW> / dd dde ^d d

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5 d D> d >> DW> d de dd de dd de Z/ D d/ D ^ D W h D^ d de W md dd Z d d d Z D / D de dddd D / D / W Z Top of page Patients and disease characteristics W d d dde ^d d dee dd d DW> ^ d de d ddd dd e l de dl ddl W l & ded d/ ddd d/ dde d ed dl de dl, ded ee dl / e d dl E d el >/ dd dd de de >/ dd d d d K^ dd ddl Survival, LFS, relapse incidence, NRM, and GvHD d K^ de dl edl/dd d ed d >&^de dl dd e dd d d Z/ dd dl de e dd e EZD dd dl de d de d e dd dl // /s 's, d de dl dd e dd d 's, K^ >&^ d de dd de dd de & d & d Prognostic factors for outcome d d d >&^ Z/ EZD D EZD K^ E d

6 Ds & 's, 's, D d/ >&^ Z/ d >&^ K^ Z/ 's, EZD / d d EZD >&^ K^ D 's, Z/ >&^ K^ W l K^ D D d/ >&^ Z/ / d 's, ^ 's, Z/ EZD >&^ K^ d d d DW> d DW> / d ', 's, EZD Z/ >&^ K^ >&^ ', dd DW> Zd d d EZD Matched-pair analysis / dee DW> dded >> dee dddd D> K >> d DW> >> t DW> D> DW> EZD >&^ ^ ^ d d d Top of page DW> ^d t Dd DW> ^d K de dlk^ d de dl>&^ d Z/ ddl ^ Z W ^Z / ^Z dd ddl d dd e / d d ^d DW> / e de DW> / ddd DW> t,k dd /, DW> dd dd d

7 /DdZ ed dd d /DdZ K dd l /DdZ ddl ddl d /DdZ ^d DW> D> >> 's> ^d dd dd / 's> 's, t /DdZ DW> 's> 's, ', /DdZ d, d/ Z/ / DW> >> D> d ^d D> >> d Dd Zd /DdZ / Dd t,k DW> ddde d d/ / d d D d/ Z/ >&^ ^ d >> de de D d/ DW> d D Z/ D> de > DW> d dd EDdd de d ddd DW> dd tdd &>dd EZ^ :<d DW> dd / DW> In conclusion, consolidation with allohsct in CR1 provides a favorable disease control to adult patients with MPAL with a moderate relapse risk. This resembles the outcome e

8 observed in patients with ALL. The observation of a possible beneficial impact of TBI as part of the conditioning regimen deserves further investigation. / The authors expressed no conflict of interest d W ZD D> : ^ DD E Z Top of page 1 Freireich EJ, Wiernik PH, Steensma DP. The leukemias: a half century of discovery. J Clin Oncol. 2014;32(31): d / ' ZW, > Z deed e e ede ede 3 Weinberg OK, Arber DA. Mixed-phenotype acute leukemia: historical overview and a new definition. Leukemia. 2010;24(11): Steensma DP. Oddballs: Acute leukemias of mixed phenotype and ambiguous origin. Hematol Oncol Clin North Am. 2011;25(6): d z > W E D dde t,k ddde, dddd ee dd dede dedd e ^ Z D Z ^ > Z dddd de e ede ede 7 Wolach O, Stone RM. Mixed phenotype acute leukemia; current challenges in diagnosis and therapy. Curr Opin Hematol. 2017;24(2): Bene MC, Castoldi G, Knapp W, et al. Proposals for the immunologic characterization of acute leukemias. European Group for the Immunologic Characterization of Leukemias (EGIL). Leukemia. 1995;9(10): Borowitz MJ, Bene MC, Harris NL, et al. Acute leukaemias of ambiguous lineage. In Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H et al. eds. World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th Ed. Lyon (France): International Agency for Research on Cancer (IARC Press; 2008; p ). 10 Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20): Deffis-Court M, Alvarado-Ibarra M, Ruiz-Argüelles, et al. Diagnosing and treating mixed phenotype acute leukemia: a multicenter 10-year experience in México. Ann Hematol. 2014;93(4): Wolach O, Stone RM. How I treat: mixed phenotype acute leukemia. Blood. 2015;125(16): Munker R, Brazauskas R, Wang HL, et al. Allogeneic hematopoietic cell transplantation for patients with mixed phenotype acute leukemia. Biol Blood Marrow Transplant. 2016;22(6): Dőhner H, Estey EH, Amadori S, 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(3): e

9 15 Bacigalupo A, Ballen K, Rizzo D, et al. Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant. 2009;15(12): Przepiorka D, Weisdorf D, Martin P, et al Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995;15(6): Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. 1999;18(6): Ho D, Imai K, King G, Stuart E. Matching as Non-parametric Preprocessing for Reducing Model Dependence in Parametric Causal Inference. Political Analysis. 2007;15: Park JA, Ghim TT, Bae KW, et al. Stem cell transplant in the treatment of childhood biphenotypic acute leukemia. Pediatr Blood Cancer. 2009;53(3): dd > Y& & W t DY,^d, dddd ed d eee eee dd ^, ^ d D ^ :, dddd ed d ddd ded dd d, y z > > > Z ddde dd dd de dd D W t& s D D ddd t,k ddde dddd dde dd dded dded dd Negrin RS. Graft-versus-host disease versus graft-versus-leukemia. Hematology Am Soc Hematol Educ Program. 2015;2015: Stern M, de Wreede LC, Brand R, et al. Sensitivity of hematological malignancies to graft-versus-host effects: an EBMT megafile analysis. Leukemia. 2014;28(11): Cahu X, Labopin M, Giebel S, et al. Impact of conditioning with TBI in adult patients with T-cell ALL who receive a myeloablative allogeneic stem cell transplantation: a report from the acute leukemia working party of EBMT. Bone Marrow Transplant. 2016;51(3): de Hamilton BK, Rybicki L, Abounader D, et al. Allogeneic hematopoietic cell transplantation (HCT) adult T-cell acute lymphoblastic leukemia (T-ALL). Biol Blood Marrow Transplant. 2017;23(7): de Scott BL, Pasquini MC, Logan BR, et al. Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol. 2017;35(11): Eckstein OS, Wang L, Punia JN, et al Mixed-phenotype acute leukemia (MPAL) exhibits frequent mutations in DMNT3A and activated signaling genes. Exp Hematol. 2016;44(8): Alexander TB, Gu Z, Choi JK, et al. Genomic landscape of mixed phenotype acute leukemia. Blood. 2016;128(22):454. e

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11 dd ' e dd de W d e d e dd dd d de d e e dd de W l d dd / d dh K d,^d DW> >&^ lm^ W K^ lm^ W Z/ lm^ W EZD lm^ W 's, lm^ W de dd de dd de de e de ed dd d dd dd md dddd ed e de ed dd d de ed dd e dd de ld ddde de d dd dd dd e de dd ld ddd de d dd dd de d dd dd de e de de ld dde de d dd de de d dd de dd d de dd ld dee z dddd dddd dddd dddd dddd dddd dd e dd dd de e dd dd de d de dd Wld ded dd e dd de dd e de ed ed e dd ed Wld dde dd e dd de dd e de de dd e dd dd Wld ded dd d dd dd Wld dde dd d dd dd de e dd dd Wld ede D h dd e de dd de e dd dd Wld eed dd d de ed de d dd ee Wld dee dd e de de de e dd de Wld dee dd e de de dd d de de Wld ede dd e de dd dd e dd de W D & dd d de dd de e dd de Wld edd dd d de ed de d dd ee Wld eee dd d de de de e dd de Wld edd dd d de de dd e de de Wld edd Wld dde D & dd e dd dd de d de dd Wld eee de d dd ed dd e de dd dd e de dd Wld dee de d dd dd de d dd dd Wld ded dd d de de dd d dd dd Wld dde D E & md & md dd d dd dd de e de ed Wld ded de d dd ed dd d dd ed Wld edd dd e de de dd e dd dd Wld ded dd e de dd de e de de Wld dde dd d de de dd e dd ed Ds E W dd d de dd Wld eee de d dd ee dd d de ed de e dd de de e dd de Wld ded dd e dd dd Wld dee dd d de dd Ds E W de d dd de de e dd dd Wld dee de d dd ee de e dd ed Wld dde de e dd de Wld ede dd d de de dd d de dd Wld dee de d dd dd d D Dd/ Z/ dd d dd dd de d de de de d de de Wmd ddd dd d de ed ed d dd ee de d de ed dd d dd dd dd e de de de d de de Wmd ddd dd e de d dd d de de dd e dd dd Wld eed dd e dd dd dd d dd dd Wld dde / W E dd e dd ed de d de de dd d de dd ed e de ee dd d dd ed dd d de ed Wld dde de d de de dd d dd dd dd d de de Wld ded de e dd dd de e dd de dd d dd dd de d de de dd d dd dd de e dd dd Wld ede ^ W dd e de dd de e dd dd Wld eed dd e dd ed de d dd ed dd e de dd dd d de de Wld dee de d dd de de e de dd dd e dd dd D Z/ d/

12 Table 3 Multivariate analysis of major outcomes after transplant RI NRM LFS OS Chronic GVHD HR CI p HR CI p HR CI p HR CI p HR CI p Age per decade < Year of transplant UD vs MSD Female D -> male R < Intermediate cytogenetics (ref) Poor cytogenetics Cytogenetics NA or failed MAC chemo (ref) MAC TBI vs MAC chemo RIC vs MAC chemo In vivo TCD PB vs BM Abbreviations : RI : relapse incidence, NRM : non-relapse mortality, LFS : leukemia-free survival, OS ; over-all survival, GVHD : graft-versus host disease, UD : unrelated donor, MSD : matched-sibling donor, D : donor, R : recipient, NA : not available, MAC : myeloablative conditioning, TBI : total body irradiation, RIC : reduced intensity conditioning, TCD : T-cell depletion, PB : peripheral blood, BM : bone marrow 0.02 dd

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14 Figure legends Figure 1 : Overall survival (OS) of patients with MPAL who underwent allo-sct according to age groups : y, y and 56 y Figure 2 : Leukemia-free survival (LFS) of patients with MPAL who underwent allo-sct according to age groups : y, y and 56 y dd

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17 DATA ON MATCHED-PAIR ANALYSIS A) Comparison ALL with MPAL Nr of controls N median follow-up (patients alive) months ( ) N ALL MPAL Test p-value median follow-up (patients alive) mo ( ) ( ) AGE_median (range) (IQR) 37.7( )( ) YEAR_median (range) 2010( ) 37.5( )( ) 2010( ) age (46.83% ) 226 (46.22% ) age (40.04% ) 197 (40.29% ) age>= (13.13% ) 66 (13.5% ) (12.47% ) 62 (12.68% ) (45.73% ) 225 (46.01% ) (41.79% ) 202 (41.31% ) Time from diagnosis to CR1 5.1(0.4-5(0.2-24)( )( ) 6.4) By classes (in months) (0.03,4.56] 526 (38.37% ) 188 (38.45% ) 0.998

18 (4.56,5.64] 324 (23.63% ) 115 (23.52% ) (5.64,7.34] 318 (23.19% ) 112 (22.9% ) (7.34,24] 203 (14.81% ) 74 (15.13% ) match-sibling donor 749 (54.63% ) 269 (55.01% ) UD 622 (45.37% ) 220 (44.99% ) patient male 868 (63.31% ) 310 (63.39% ) patient female 503 (36.69% ) 179 (36.61% ) donor male 895 (65.28% ) 312 (63.8% ) donor female 476 (34.72% ) 177 (36.2% ) no F->M 1105 (80.6% ) 389 (79.55% ) F->M 266 (19.4% ) 100 (20.45% ) intermediate risk 256 (18.67% ) 101 (20.65% ) <10-4 cytogenetics poor risk 514 (37.49% ) 93 (19.02% ) NA 601 (43.84% ) 295 (60.33% ) Phi neg 232 (32.4% ) 147 (75.38% ) <10-4 Phi pos 484 (67.6% ) 48 (24.62% ) Patient CMV neg 584 (48.67% ) 197 (46.24% ) Patient CMV pos 616 (51.33% ) 229 (53.76% ) missing Donor CMV neg 599 (48.94% ) 201 (46.1% ) 0.39 Donor CMV pos 625 (51.06% ) 235 (53.9% ) missing BM 327 (23.85% ) 120 (24.54% ) 0.76 PB 1044 (76.15% ) 369 (75.46% ) MAC chemo 350 (25.53% ) 130 (26.58% ) MAC TBI 754 (55% ) 254 (51.94% )

19 RIC 267 (19.47% ) 105 (21.47% ) no in vivo TCD 667 (53.92% ) 240 (54.92% ) in vivo TCD 570 (46.08% ) 197 (45.08% ) missing No agvhd II 901 (67.95% ) 316 (68.55% ) agvhd II-IV 425 (32.05% ) 145 (31.45% ) missing Causes of death ALL MPAL N Cardiac toxicity 3 (0.59% ) 0 (0% ) haemorhage 5 (0.98% ) 1 (0.55% ) Failure/Rejection 2 (0.39% ) 2 (1.1% ) VOD 16 (3.13% ) 8 (4.4% ) Infection 95 (18.59% ) 33 (18.13% ) IP 4 (0.78% ) 4 (2.2% ) GVHD 130 (25.44% ) 40 (21.98% ) Original disease 227 (44.42% ) 87 (47.8% ) second malignancy 5 (0.98% ) 1 (0.55% ) other transp related 24 (4.7% ) 6 (3.3% ) missing B) COMPARISON AML WITH MPAL Nr of controls N median follow-up (patients alive) months ( )

20 N AML MPAL Test p-value median follow-up (patients alive) ( ) ( ) AGETX_median (range) (IQR) 40.3( )( ) YEAR_median (range) 2009( ) 38.1( )( ) 2010( ) age (43.7% ) 224 (44.98% ) age (41.5% ) 203 (40.76% ) age>= (14.8% ) 71 (14.26% ) (13.03% ) 65 (13.05% ) (46.1% ) 228 (45.78% ) (40.86% ) 205 (41.16% ) Time from diagnosis to CR1 5(0.1-5(0.2-24)( )( ) 6.4) By classes (in months) (0.03,3.93] 312 (22.1% ) 110 (22.09% ) (3.93,5.08] 429 (30.38% ) 154 (30.92% ) (5.08,6.56] 341 (24.15% ) 118 (23.69% ) (6.56,24] 330 (23.37% ) 116 (23.29% ) match-sibling donor 787 (55.74% ) 275 (55.22% ) UD 625 (44.26% ) 223 (44.78% ) patient male 875 (61.97% ) 313 (62.85% ) patient female 537 (38.03% ) 185 (37.15% ) donor male 936 (66.29% ) 317 (63.65% ) donor female 476 (33.71% ) 181 (36.35% )

21 no F->M 1138 (80.59% ) 397 (79.72% ) F->M 274 (19.41% ) 101 (20.28% ) intermediate risk 430 (30.45% ) 100 (20.08% ) <10-4 cytogenetics poor risk 155 (10.98% ) 97 (19.48% ) NA 827 (58.57% ) 301 (60.44% ) Patient CMV neg 470 (38.21% ) 160 (36.61% ) Patient CMV pos 760 (61.79% ) 277 (63.39% ) missing Donor CMV neg 599 (48.94% ) 201 (46.1% ) Donor CMV pos 625 (51.06% ) 235 (53.9% ) missing BM 328 (23.23% ) 126 (25.3% ) PB 1084 (76.77% ) 372 (74.7% ) MAC chemo 406 (28.75% ) 136 (27.31% ) MAC TBI 670 (47.45% ) 247 (49.6% ) RIC 336 (23.8% ) 115 (23.09% ) no in vivo TCD 693 (55.4% ) 245 (54.93% ) in vivo TCD 558 (44.6% ) 201 (45.07% ) missing No agvhd II 968 (72.18% ) 319 (67.87% ) agvhd II-IV 373 (27.82% ) 151 (32.13% ) missing Causes of death AML MPAL N Cardiac toxicity 2 (0.41% ) 0 (0% ) haemorhage 6 (1.22% ) 1 (0.54% ) Failure/Rejection 3 (0.61% ) 1 (0.54% )

22 VOD 6 (1.22% ) 8 (4.3% ) Infection 93 (18.94% ) 32 (17.2% ) IP 10 (2.04% ) 4 (2.15% ) GVHD 88 (17.92% ) 44 (23.66% ) Original disease 259 (52.75% ) 87 (46.77% ) second malignancy 9 (1.83% ) 1 (0.54% ) other transp related 15 (3.05% ) 8 (4.3% ) missing 36 15

23 Table 2 (Internet only) Multivariate analysis of risk comparing MPAL with AML and ALL (separate comparisons) Outcomes, HR (95% CI) LFS p value OS p value RI p value NRM p value cgvhd p value MPAL AML ALL ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Abbreviations : MPAL : mixed phenotype acute leukemia, AML : acute myelogenous leukemia, HR : hasard ratio, LFS : leukemia-free survival ; OS : overall survival ; RI : relapse incidence, NRM : nonrelapse mortality ; cgvhd : chronic graft-versus host disease HR >> 1 for AML respectively ALL indicates that MPAL has a worse outcome in these comparions