Sanz et al. Journal of Hematology & Oncology (2020) 13:46 https://doi.org/10.1186/s13045-020-00882-6 RESEARCH Open Access Post-transplant cyclophosphamide after matched sibling, unrelated and haploidentical donor transplants in patients with acute myeloid leukemia: a comparative study of the ALWP EBMT Jaime Sanz1,2* , Jacques-Emmanuel Galimard3, Myriam Labopin3,4, Boris Afanasyev5, Emanuele Angelucci6, Fabio Ciceri7, Didier Blaise8, Jan J. Cornelissen9, Ellen Meijer10, J. L. Diez-Martin11, Yener Koc12, Montserrat Rovira13,14, Luca Castagna15, Bipin Savani16, Annalisa Ruggeri17, Arnon Nagler18,19, Mohamad Mohty4 and Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) Abstract Background: The use of post-transplant cyclophosphamide (PTCy) is highly effective in preventing graft-versus-host disease (GVHD) in the haploidentical (Haplo) transplant setting and is being increasingly used in matched sibling (MSD) and matched unrelated (MUD) transplants. There is no information on the impact of donor types using homogeneous prophylaxis with PTCy. Methods: We retrospectively compared outcomes of adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) who received a first allogeneic stem cell transplantation (SCT) with PTCy as GVHD prophylaxis from MSD (n = 215), MUD (n = 235), and Haplo (n = 789) donors registered in the EBMT database between 2010 and 2017. Results: The median follow-up was 2 years. Haplo-SCT carried a significantly increased risk of acute grade II–IV GVHD (HR 1.6; 95% CI 1.1–2.4) and NRM (HR 2.6; 95% CI 1.5–4.5) but a lower risk of relapse (HR 0.7; 95% CI 0.5–0.9) that translated to no differences in LFS (HR 1.1; 95% CI 0.8–1.4) or GVHD/relapse-free survival (HR 1; 95% CI 0.8–1.3). Interestingly, the use of peripheral blood was associated with an increased risk of acute (HR 1.9; 95% CI 1.4–2.6) and chronic GVHD (HR 1.7; 95% CI 1.2–2.4) but a lower risk of relapse (HR 0.7; 95% CI 0.5–0.9). (Continued on next page) * Correspondence: sanz_jai@gva.es 1 Hematology Department, Hospital Universitari i Politècnic La Fe, Avinguda Fernando Abril Martorell, 106, 46026 Valencia, Spain 2 CIBERONC, Instituto Carlos III, Madrid, Spain Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sanz et al. Journal of Hematology & Oncology (2020) 13:46 Page 2 of 13 (Continued from previous page) Conclusions: The use of PTCy in patients with AML in CR1 receiving SCT from MSD, MUD, and Haplo is safe and effective. Haplo-SCT had increased risk of acute GVHD and NRM and lower relapse incidence but no significant difference in survival. Keywords: Post-transplant cyclophosphamide, Haploidentical transplant, Alternative donor transplants, Acute leukemia, Allogeneic stem cell transplant Introduction EBMT. The EBMT is a voluntary working group of The use of post-transplant cyclophosphamide (PTCy) more than 600 transplantation centers that are required has proven to be highly effective in preventing graft- to report all consecutive stem cell transplantations and versus-host (GVHD) and reducing non-relapse mortality follow-up once a year. Audits are routinely performed to (NRM) rates in haploidentical (Haplo) hematopoietic determine the accuracy of the data. All transplantation stem cell transplant (SCT) [1–3]. centers are required to obtain written informed consent As a consequence, PTCy is being increasingly used in before data registration with the EBMT in accordance other allogeneic transplant settings, such as SCT from with the 1975 Helsinki Declaration. HLA-matched sibling donors (MSD) [4–6], matched un- related donors (MUD), and mismatched unrelated do- Patient eligibility nors (MMUD) [1–3, 7]. All adults (age ≥ 18 years) with AML in CR1 at trans- Since the first reports of Haplo-SCT using PTCy, there plantation, reported to Promise-EBMT, who underwent has been significant interest in comparing this platform first allogeneic SCT, from an unmanipulated graft, using with those using other donor types such as cord blood PT-Cy from Haplo, MUD, or MSD donors between from unrelated donors [4–6, 8] or bone marrow (BM) or 2010 and 2017, were analyzed. Haplo was defined as peripheral blood (PB) from MSD, MUD, and MMUD recipient-donor number of human leukocyte antigen transplants [9–15]. However, an important limitation of (HLA) mismatches ≥ 2. these studies is that each type of transplant received dif- ferent GVHD prophylaxis. Therefore, comparisons were made of different transplant platforms instead of differ- Endpoints and definitions ent donor types. Two prospective studies compared T The primary endpoint was to compare leukemia-free sur- cell replete Haplo and MSD transplants in acute myeloid vival (LFS) after MSD, MUD, and Haplo donor trans- leukemia (AML) [16] and acute lymphoblastic leukemia plants. Secondary endpoints were neutrophil engraftment, [17] using non-PTCy GVHD prophylaxis with similar re- acute GVHD (aGVHD) and chronic GVHD (cGVHD), re- sults but increased risk of GVHD after Haplo. In lapse incidence, nonrelapse mortality (NRM), GVHD-free addition, safety and feasibility of PTCy-based GVHD and relapse-free survival (GRFS), and overall survival (OS) prophylaxis in transplants using different donor types within the same subgroups and to perform analysis of risk was further evaluated in small single-center prospective factors for each outcome. non-randomized studies showing comparable outcomes Neutrophil recovery was defined as the first day of an in Haplo-SCT compared to 9/10 MUD [18], as well as in absolute neutrophil count of 0.5 × 109/L lasting for 3 or MSD, MUD, and MMUD transplants [19]. more consecutive days. aGVHD and cGVHD were de- The aim of this study was to investigate the impact of fined and graded according to standard criteria [20, 21]. donor type in the outcome of patients with AML under- Relapse was defined as disease recurrence and appear- going unmanipulated allogeneic SCT (allo-SCT) using ance of blasts in the peripheral blood or BM (> 5%) after PTCy as GvHD prophylaxis. We analyzed patients who CR. LFS was calculated until the date of first relapse, received allo-SCT from MSD, MUD, and Haplo for death from any cause, or the last follow-up for patients acute myeloid leukemia (AML) in first complete remis- in CR. NRM was defined as death from any cause other sion (CR1) and reported to the European Society for than relapse. The composite endpoint GRFS was defined Blood and Marrow Transplantation (EBMT) registry as survival without the following events: stage III–IV from 2010 to 2017. aGVHD, severe cGVHD, disease relapse, or death from any cause after SCT [22]. Myeloablative conditioning (MAC) was defined as a regimen containing either total Patients and methods body irradiation with a dose greater than 6 Gray, a total Study design and data source dose of oral busulfan greater than 8 mg/kg, or a total This is a retrospective registry-based analysis on behalf dose of intravenous busulfan > 6.4 mg/kg or melphalan of the Acute Leukaemia Working Party (ALWP) of the at doses > 140 mg/m2. In addition, regimens containing Sanz et al. Journal of Hematology & Oncology (2020) 13:46 Page 3 of 13 2 alkylating agents were considered as MAC. All other other immunosuppressive (IS) drugs, only 47% and 26% regimens were defined as reduced intensity (RIC). of MUD and MSD patients received such combination, respectively. In contrast, a higher proportion of MSD Statistical analysis and MUD patients received 1 or no additional IS drugs Patient characteristics according to donor type were than Haplo patients (p < 0.001). compared using chi-squared tests for categorical and Kruskal-Wallis tests for continuous variables. GRFS, Engraftment LFS, and OS were estimated using the Kaplan-Meier Cumulative incidence of neutrophil recovery at 60 days method. Cumulative incidence functions were used to was 94% (95% CI; 92–95) for Haplo, 98% (95% CI; 95– estimate neutrophil engraftment, aGVHD, cGVHD, re- 99) for MUDs, and 98% (95% CI; 94–99) for MSDs (p = lapse incidence, and NRM. Competing risks were death 0.12). The median time of neutrophil recovery was 19 for relapse incidence and neutrophil engraftment, re- days (range, 2–63), 20 days (range, 2–48), and 19 days lapse for NRM, and relapse or death for aGVHD and (range, 5–64) for Haplo, MUD, and MSD, respectively. cGVHD. Univariate analyses were done using the log- rank test for LFS, GRFS, and OS and Gray’s test for cu- GvHD mulative incidence. Multivariate analyses were per- The cumulative incidence of aGvHD grades II–IV at 100 formed using the Cox proportional hazard model. days was 26% (95% CI; 23–29) for Haplo, 28% (95% CI; 22– Donor type, gender, age at transplantation, perform- 34) for MUD, and 17% (95% CI; 12–23) for MSD (p = ance status, cytogenetic risk group according to the 0.03). The cumulative incidence of aGvHD grades III–IV Medical Research Council [23], type of AML (primary vs was 9% (95% CI; 7–12) for Haplo, 8% (95% CI; 5–11) for secondary) stem cell source, transplantation year, cyto- MUD, and 6% (95% CI; 4–10) for MSD (p = 0.2) (Table 2). megalovirus serostatus, and conditioning regimen were In multivariable analysis (Table 3), Haplo was associated included in the final model. To take into account the with an increased risk of aGvHD grades II–IV, when com- center effect, we introduced a random effect (also named pared with MSD (HR 1.6; 95% CI, 1.08–2.37; p = 0.02). The frailty effect) for each center into the model. The signifi- use of PB as the stem cell source was also associated cance level was fixed at .05, and p values were 2-sided. with a higher risk of aGvHD grades II–IV (HR 1.93; Statistical analyses were performed using R software ver- 95% CI, 1.39–2.67; p < 0.001) and grades III–IV (HR sion 3.2.3 (R Development Core Team, Vienna, Austria) 1.86; 95% CI, 1.1–3.15; p = 0.02) (Table 4). software packages. The cumulative incidence of cGvHD at 2 years was 30% (95% CI; 26–33), 32% (95% CI; 25–39), and 34% Results (95% CI; 26–41) (p = 0.3) for Haplo, MUD, and MSD, Patient and transplantation characteristics respectively (Table 2). The cumulative incidence of ex- Patient, disease, and transplant characteristics of the tensive type cGvHD was 10% (95% CI; 8–13) for Haplo, overall population and according to donor type are sum- 18% (95% CI; 13–25) for MUD, and 14% (95% CI; 9–20) marized in Table 1. Briefly, a total of 1239 patients were for MSD (p = 0.003) (Table 2). In multivariable analysis included in the study, of which 789 were transplanted (Table 4), use of PB was independently associated with a from Haplo, 235 from MUD, and 215 from MSD do- higher risk of cGvHD (HR 1.71; 95% CI, 1.23–2.39; p = nors. Median age of patients was 52 years (range, 18– 0.001) and extensive cGvHD (HR 1.86; 95% CI, 1.15– 76). Forty-seven (6%), 543 (66%), and 239 (29%) had 3.01; p = 0.01). Female donor to male recipient showed standard-, intermediate-, and high-risk cytogenetics, re- also an increased risk of extensive cGvHD (HR 1.71; spectively. Preferred conditioning regimens were thio- 95% CI, 1.14–2.57; p = 0.009). Donor type was not asso- tepa, busulfan, and fludarabine for Haplo (n = 371; 47%) ciated with the risk of cGvHD or extensive cGvHD in and busulfan and fludarabine for MSD (n = 83; 39%) multivariate analysis. and MUD (n = 102; 43%). Haplo patients were older (p < 0.001) and had higher Relapse proportion of secondary AML (p < 0.001), while differ- The median time to relapse was 192 days (range, 3–1750). ences in gender, performance status, and cytogenetic risk The cumulative incidence of relapse at 2 years was 23% category were not statistically significant. Regarding (95% CI; 20–26) for Haplo, 25% (95% CI; 19–31) for MUD, transplant characteristics, Haplo-SCT recipients received and 33% (95% CI; 26–41) for MSD (p = 0.02) (Table 2) more frequently MAC (p = 0.006) and BM as stem cell (Fig. 1). In multivariable analysis (Table 3), Haplo was asso- source (p < 0.001), while the proportion of in vivo T cell ciated with a lower risk of relapse when compared with depletion was higher in MUD transplants (p < 0.001). MSD (HR 0.67; 95% CI, 0.48–0.93; p = 0.02). Other vari- Although the vast majority (93%) of Haplo patients re- ables associated with a decreased risk of relapse were use of ceived GvHD prophylaxis with PTCy combined with 2 MAC (HR 0.56; 95% CI, 0.43–0.77; p < 0.001), PB as the Sanz et al. Journal of Hematology & Oncology (2020) 13:46 Page 4 of 13 Table 1 Patient disease and transplant characteristics according to donor type Characteristics Total MSD MUD Haplo p N = 1239 N = 215 N = 235 N = 789 Age in years, median (range) 52 (18–75) 48 (18–71) 47 (18–74) 54 (18–75) < 0.001 Gender, n (%) 0.9 Male 693 (56) 117 (54) 132 (56) 444 (56) Female 546 (44) 98 (46) 103 (44) 345 (44) Karnofsky performance status, n (%) 0.2 ≥ 90 929 (79) 159 (77) 192 (83) 578 (78) < 90 251 (21) 48 (23) 39 (17) 164 (22) Missing 59 8 4 47 Cytogenetic risk category, n (%) 0.2 Standard 47 (6) 10 (8) 8 (6) 29 (5) Intermediate 543 (66) 92 (70) 87 (60) 364 (66) High 239 (29) 29 (22) 49 (34) 161 (29) Missing 410 84 91 235 Type of AML, n (%) < 0.001 De novo 1046 (84) 188 (87) 216 (92) 642 (81) Secondary 193 (16) 27 (13) 19 (8) 147 (19) Months from diagnosis to transplant, median (range) 5 (1-18) 4 (1-18) 5 (2-18) 5 (1-18) < 0.001 Conditioning intensity, n (%) 0.03 Myeloablative 725 (59) 122 (58) 116 (50) 487 (62) Reduced intensity 500 (41) 87 (42) 115 (50) 298 (38) Missing 14 6 4 4 Type of conditioning, n (%) 0.2 Based on chemotherapy 950 (77) 159 (75) 172 (75) 619 (78) Based on TBI 287 (23) 54 (25) 63 (25) 170 (22) Missing 2 2 0 0 Stem cell source, n (%) < 0.001 Bone marrow 425 (34) 62 (29) 22 (9) 341 (43) Mobilized peripheral blood 814 (66) 152 (71) 213 (91) 448 (57) In vivo T cell depletion, n (%) 164 (13) 29 (13) 63 (27) 72 (9) < 0.001 GvHD prophylaxis, n (%) < 0.001 PTCy + 2 drugs 897 (72) 56 (26) 111 (47) 730 (93) PTCy + 1 drug 265 (21) 108 (50) 111 (47) 46 (6) PTCy only 77 (6) 51 (24) 13 (6) 13 (2) Donor-recipient gender combination, n (%) 0.02 Female donor to male recipient 249 (20) 54 (25) 34 (14) 161 (20) Other combinations 988 (80) 161 (75) 201 (86) 626 (80) Missing 2 0 0 2 Donor-recipient CMV serostatus, n (%) < 0.001 Negative-negative 181 (15) 33 (16) 49 (21) 99 (13) Positive-negative 82 (7) 13 (6) 13 (6) 56 (7) Negative-positive 248 (21) 17 (13) 73 (32) 148 (19) Positive-positive 680 (57) 129 (64) 94 (41) 457 (60) Missing 48 13 6 29 TBI total-body irradiation, CMV cytomegalovirus Sanz et al. Journal of Hematology & Oncology (2020) 13:46 Page 5 of 13 Table 2 Univariable analysis of transplants outcomes according At the last follow-up, 432 patients had died, of which to donor type 290 (65%) were due to a variety of non-relapse causes, Outcome* MSD MUD Haplo p 222 (73%) in Haplo, 36 (52%) in MUD, and 32 (47%) in Acute GvHD, % (95% CI) MSD. The main causes of transplant-related deaths were Grades II–IV 17 (12–23) 28 (22–34) 26 (23–29) 0.03 infections and GvHD, being 107 (39%) and 40 (14%) in Haplo, 13 (20%) and 8 (12%) in MUD, and, 10 (15%) and Grades III–IV 6 (4–10) 8 (5–11) 9 (7–12) 0.2 11 (16%) in MSD cohorts, respectively (Table 5). Chronic GvHD, % (95% CI) Overall 34 (26–41) 32 (25–39) 30 (26–33) 0.3 Survival Extensive type 14 (9–20) 18 (13–25) 10 (8–13) 0.003 For the entire cohort, LFS, OS, and GRFS at 2 years were NRM, % (95% CI) 10 (6–15)) 14 (9–19) 23 (20–26) < 0.001 56% (95%CI; 53–59), 63% (95%CI; 60–66), and 45% RI, % (95% CI) 33 (26–40) 25 (19–31) 23 (20–26) 0.02 (95%CI; 42–48), respectively. LFS was 54% (95% CI; 51–58) for Haplo, 62% (95% CI; LFS, % (95% CI) 57 (49–65) 62 (55–69) 54 (51–58) 0.2 55–69) for MUD, and 57% (95% CI; 49–65) for MSD (p OS, % (95% CI) 64 (56–72) 68 (62–75) 61 (58–65) 0.1 = 0.2) (Fig. 3). In multivariable analysis (Table 4), vari- GRFS, % (95% CI) 45 (37–53) 42 (35–50) 46 (42–50) 0.9 ables associated with better LFS were MAC (HR 0.71; *Acute GvHD: 100-day cumulative incidence; cGvHD, NRM, and RI: cumulative 95% CI, 0.58–0.88; p = 0.001), good- or intermediate- incidence at 2 years; DFS, OS, and GRFS: survival probability at 2 years GvHD graft-versus-host disease, CI confidence interval, NRM non-relapse risk cytogenetics (HR 0.73; 95% CI, 0.58–0.92; p = mortality, RI relapse incidence, LFS leukemia-free survival, OS overall survival, 0.007), and good performance status (HR 0.8; 95% CI, GRFS graft-versus-host disease and relapse-free survival 0.64–0.99; p = 0.04), while higher recipient’s age per 10 years (HR 1.1; 95% CI, 1.02–1.18; p = 0.02) and positive stem cell source (HR 0.74; 95% CI, 0.45–0.99; p = 0.04), CMV serostatus of the recipient (HR 1.27; 95% CI, 1– and standard or intermediate cytogenetic risk category (HR 1.6; p = 0.04) showed worse outcome. 0.58; 95% CI, 0.43–0.78; p < 0.001) (Table 4). OS was 61% (95% CI; 58–65) for Haplo, 68% (95% CI; 62–75) for MUD, and 64% (95% CI; 56–72) for MSD (p NRM and causes of death = 0.1) (Figure 4). Variable that independently correlated The cumulative incidence of NRM at 2 years was 23% with better OS in multivariable analysis were MAC (HR (95% CI; 20–26) for Haplo, 14% (95% CI; 9–19) for 0.76; 95% CI, 0.6–0.96; p = 0.02) and good- or MUD, and 10% (95% CI; 6–15) for MSD (p < 0.001) intermediate-risk cytogenetics (HR 0.7; 95% CI, 0.54– (Table 2) (Fig. 2). In multivariable analysis (Table 3), 0.9; p = 0.005), while higher recipient’s age per 10 years Haplo was associated with an increased risk of NRM was associated with poorer survival (HR 1.22; 95% CI, (HR 2.6; 95% CI, 1.5–4.49; p < 0.001). The other factor 1.12–1.33; p < 0.001) (Table 4). associated with an increased NRM was higher recipient’s GRFS was 46% (95% CI; 42–50) for Haplo, 42% (95% age per 10 years (HR 1.35; 95% CI, 1.19–1.54; p < 0.001) CI; 35–50) for MUD, and 45% (95% CI; 37–53) for MSD (Table 4). (p = 0.9) (Table 2). For GRFS, MAC (HR 0.79; 95% CI, Table 3 Multivariable analysis of transplants outcomes according to donor type MSD MUD Haplo Outcome Reference HR 95% CI p HR 95% CI p Acute GvHD Grades II–IV 1 1.42 0.92–2.19 0.11 1.6 1.08–2.37 0.02 Grades III–IV 1 1.22 0.56–2.64 0.61 1.76 0.92-3.37 0.09 Chronic GvHD Overall 1 0.97 0.64–1.46 0.88 1.22 0.84–1.76 0.92 Extensive type 1 0.98 0.57–1.7 0.95 0.87 0.53–1.42 0.57 NRM 1 1.38 0.73–2.6 0.3 2.6 1.5–4.49 < 0.001 RI 1 0.8 0.54–1.17 0.24 0.67 0.48–0.93 0.02 LFS 1 0.93 0.68–1.29 0.67 1.07 0.82-1.4 0.6 OS 1 0.91 0.64–1.31 0.62 1.17 0.86–1.59 0.32 GRFS 1 1.01 0.76–1.34 0.94 1.03 0.82–1.31 0.8 GvHD graft-versus-host disease, CI confidence interval, NRM non-relapse mortality, RI relapse incidence, LFS leukemia-free survival, OS overall survival, GRFS graft- versus-host disease and relapse-free survival Table 4 Multivariable analysis of transplants outcomes Variable aGvHD II-IV aGvHD III-IV cGvHD Ext. cGvHD Relapse NRM LFS OS GRFS HR p HR p HR p HR p HR p HR p HR p HR p HR p (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) Donor type MSD 1 1 1 1 1 1 1 1 1 MUD 1.39 0.14 1.22 0.61 0.96 0.84 0.98 0.95 0.79 0.22 1.38 0.32 0.93 0.67 0.91 0.59 1.01 0.97 (0.9–2.15) (0.56–2.64) (0.64–1.45) (0.57–1.7) (0.54–1.16) (0.74–2.61) (0.68–1.29) (0.63–1.3) (0.76–1.33) Haplo 1.60 0.02 1.76 0.09 1.21 0.3 0.87 0.57 0.67 0.02 2.60 < 0.001 1.07 0.6 1.17 0.31 1.03 0.8 (1.08–2.37) (0.92–3.37) (0.84–1.75) (0.53–1.42) (0.48–0.93) (1.5–4.49) (0.82–1.4) (0.86–1.6) (0.81–1.3) Patient’s age 1.05 0.29 1.00 0.97 1.03 0.57 0.95 0.48 0.97 0.49 1.35 < 0.001 1.09 0.02 1.21 < 0.001 1.04 0.26 per 10 years1 (0.96–1.17) (0.85–1.18) (0.93–1.14) (0.83–1.09) (0.88–1.06) (1.19–1.54) (1.02–1.18) (1.11–1.32) (0.97–1.11) Karnofsky performance status Sanz et al. Journal of Hematology & Oncology Poor (< 90) 1 1 1 1 1 1 1 1 1 Good (≥ 90) 0.92 0.57 0.76 0.27 0.79 0.13 0.84 0.44 0.88 0.42 0.74 0.08 0.8 0.04 0.83 0.13 0.8 0.03 (0.68–1.24) (0.47–1.23) (0.59–1.07) (0.55–1.3) (0.66–1.19) (0.53–1.04) (0.65–0.99) (0.66–1.06) (0.66–0.97) Patient´s CMV serostatus Negative 1 1 1 1 1 1 1 1 1 (2020) 13:46 Positive 0.97 0.86 1.21 0.49 0.86 0.28 0.62 0.02 1.24 0.16 1.35 0.13 1.27 0.04 1.24 0.1 1.02 0.87 (0.72–1.31) (0.71–2.05) (0.65–1.14) (0.42–0.92) (0.92–1.68) (0.91–1.99) (1–1.6) (0.96–1.6) (0.83–1.24) Cytogenetic risk category Poor 1 1 1 1 1 1 1 1 1 Standard or 0.9 0.48 1.01 0.98 1.08 0.63 0.78 0.26 0.58 <0.001 1.01 0.96 0.73 0.007 0.7 0.005 0.78 0.02 intermediate (0.66–1.22) (0.59–1.7) (0.79–1.48) (0.5–1.21) (0.43–0.78) (0.69–1.48) (0.59–0.92) (0.54–0.9) (0.63–0.96) Not available 0.77 0.17 0.73 0.32 0.92 0.66 0.65 0.11 0.69 0.03 1 1 0.79 0.07 0.81 0.14 0.81 0.08 (0.53–1.12) (0.39–1.36) (0.64–1.34) (0.39–1.1) (0.49–0.97) (0.65–1.54) (0.61–1.02) (0.61–1.07) (0.64–1.03) Type of AML De novo 1 1 1 1 1 1 1 1 1 Secondary 0.86 0.4 1.03 0.92 1 0.98 0.83 0.48 1.20 0.27 1.08 0.67 1.18 0.17 1.20 0.16 1.11 0.36 (0.61–1.22) (0.59–1.79) (0.72–1.37) (0.49–1.4) (0.87–1.64) (0.76–1.55) (0.93–1.49) (0.93–1.54) (0.89–1.38) Time from 0.93 0.24 0.85 0.16 0.86 0.03 0.9 0.29 0.93 0.29 1.02 0.79 0.98 0.6 1 0.93 0.96 0.37 diagnosis to (0.83–1.05) (0.68–1.06) (0.75–0.98) (0.75–1.09) (0.82–1.06) (0.89–1.16) (0.89–1.07) (0.9–1.1) (0.89–1.04) SCT1,2 Conditioning intensity RIC 1 1 1 1 1 1 1 1 1 MAC 1.01 0.93 1.12 0.64 1.04 0.81 0.75 0.17 0.58 <0.001 0.95 0.74 0.71 0.001 0.76 0.02 0.79 0.01 (0.76–1.35) (0.7–1.8) (0.77–1.41) (0.5–1.13) (0.43–0.77) (0.68–1.32) (0.58–0.88) (0.60–0.96) (0.66–0.95) Stem cell source Bone marrow 1 1 1 1 1 1 1 1 1 Peripheral 1.93 < 0.001 1.86 0.02 1.72 0.001 1.86 0.01 0.74 0.04 1.07 0.69 0.9 0.31 0.96 0.73 1.13 0.2 blood (1.39–2.67) (1.1–3.15) (1.24–2.39) (1.15–3.01) (0.55–0.99) (0.76–1.51) (0.73–1.11) (0.75–1.22) (0.93–1.38) Page 6 of 13 Table 4 Multivariable analysis of transplants outcomes (Continued) Variable aGvHD II-IV aGvHD III-IV cGvHD Ext. cGvHD Relapse NRM LFS OS GRFS HR p HR p HR p HR p HR p HR p HR p HR p HR p (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) (95% CI) Donor-recipient gender Other 1 1 1 1 1 1 1 1 1 combinations Female donor 0.87 0.37 1.05 0.85 1.19 0.23 1.71 0.009 0.87 0.4 1.11 0.54 0.99 0.94 1.00 0.97 1.08 0.48 to male recipient (0.63–1.18) (0.63–1.75) (0.9–1.58) (1.14–2.57) (0.64–1.2) (0.79–1.56) (0.79–1.24) (0.79–1.29) (0.88–1.32) Center effect 0.04 0.27 0.01 0.28 0.22 0.06 0.25 0.13 0.28 1 Continuous variable 2 By 2 months increase Sanz et al. Journal of Hematology & Oncology (2020) 13:46 Page 7 of 13 Sanz et al. Journal of Hematology & Oncology (2020) 13:46 Page 8 of 13 Fig. 1 Cumulative incidence of relapse according to the type of transplant Fig. 2 Cumulative incidence of non-relapse mortality according to the type of transplant Sanz et al. Journal of Hematology & Oncology (2020) 13:46 Page 9 of 13 Table 5 Causes of death according to donor type aGVHD and NRM, but lower relapse incidence. As seen Causes of death MSD MUD Haplo in other transplant scenarios, PB was also associated n (%) n (%) n (%) with more GVHD and less relapse. Relapse 36 (53) 31 (48) 75 (27) Due to the retrospective nature of a registry-based Infections 10 (15) 13 (20) 107 (39) study, some potential bias cannot be completely ruled GvHD 11 (16) 8 (12) 40 (14) out. In order to minimize one of the most important, such as the disease status at transplantation, all patients Interstitial pneumonitis 3 (4) 4 (6) 6 (2) included in the analysis had AML in CR1. Although all Sinusoidal obstruction syndrome 0 (0) 1 (2) 7 (3) patients received PTCy prophylaxis as the main inclu- Hemorrhage 1 (1) 1 (1) 4 (1) sion criteria for the study, a variety of conditioning regi- Secondary malignancy 0 (0) 0 (0) 6 (2) mens were used and there were obvious differences in Graft failure 0 (0) 0 (0) 5 (2) additional GvHD prevention strategies, such as in vivo Other 7 (10) 7 (10) 27 (10) TCD or the addition of other IS drugs, depending of the type of donor. In fact, Haplo patients received more fre- quently MAC, BM, and PTCy with 2 IS drugs, while a 0.66–0.95; p = 0.01), good- or intermediate-risk cytogen- higher proportion of MUD patients received in vivo etics (HR 0.78; 95% CI, 0.63–0.96; p = 0.02), and good TCD. Although some of these variables could be ad- performance status (HR 0.8; 95% CI, 0.67–0.97; p = justed in multivariable analysis, TCD and combination 0.02) were associated with improved outcome (Table 4). of IS drugs for GvHD prophylaxis were strongly associ- ated with type of donor and their effect could not be Discussion evaluated. Despite all these pitfalls, we aimed to compare The use of PTCy for GvHD prophylaxis in patients with MSD, MUD, and Haplo using a homogeneous GvHD AML in CR1 receiving SCT from MSD, MUD, and prophylaxis with PTCy in a large series of patients, Haplo is safe and effective, resulting in low rates of which allowed us to segregate the effect of donor from GVHD, especially chronic, in all transplant settings. the effect of GvHD prophylaxis. Using this approach, our results demonstrate that pa- PTCy was highly effective in preventing acute and tients undergoing Haplo-SCT had higher rates of chronic GvHD in MSD, MUD, and Haplo-SCT and Fig. 3 Probability of leukemia-free survival according to the type of transplant Sanz et al. Journal of Hematology & Oncology (2020) 13:46 Page 10 of 13 Fig. 4 Probability of overall survival according to the type of transplant seems to compare favorably with standard GvHD the addition of IS drugs to PTCy enhances its effect and prophylaxis with calcineurin inhibitor and methotrexate reduces the risk of severe chronic GvHD, reducing mor- in MSD and MUD transplants [24]. In fact, the inci- tality and improving survival [6]. dence of GvHD after PTCy seems similar to that re- The most important observation from our study is that, ported with anti-T cell globulin in both scenarios [25], using PTCy as GVHD prophylaxis, NRM was higher in the with the potential advantage of avoiding complications Haplo setting compared with the MSD and MUD cohorts. associated with prolonged TCD. An interesting observa- Previous studies comparing Haplo (with PTCy) with MSD tion was the higher incidence of acute grades II–IV and and MUD transplants (with standard GvHD prophylaxis) a trend towards a higher severe acute GvHD of Haplo- have reported discrepant results in terms of NRM. While SCT compared to MSD transplants. It should be noted some studies reported a higher rate of NRM in Haplo [11, that most previous studies had not been able to demon- 15], some others reported similar [12, 14] or even improved strate this effect [9, 11, 14, 26], probably due to the use outcomes [10]. The reasons of these discrepancies remain of different GvHD prophylaxis for each procedure. In unexplained and are probably multifactorial, but differences fact, Haplo was associated with increased risk of GVHD in transplant platforms could explain, at least in part, some compared to MSD in two prospective studies using simi- of these results. Under similar GvHD prophylaxis, a greater lar non-PTCy transplant platforms [16, 17]. Particularly HLA disparity in the Haplo compared with the MSD and relevant was the low overall chronic and chronic exten- MUD settings could explain a higher NRM. This finding sive GvHD observed in our study in all cohorts, as it has suggests that HLA-matched donors, when available, should been previously reported with PTCy [1, 4, 7, 24, 27]. We remain as the first choice. Although the negative impact of should highlight that we did not observe increased risk Haplo in NRM was partially counterbalanced with a de- of chronic GvHD in Haplo in multivariable analysis. We creased incidence of relapse that translated in similar LFS, could speculate that PTCy abrogates the detrimental ef- other strategies aiming at reducing relapse such as mainten- fect of HLA disparity for this particular outcome, but we ance or MRD-guided therapy with a growing targeted ther- should also consider that most patients in the Haplo co- apy strategies could be investigated. hort received PTCy with a double combination of IS The fact that Haplo was associated with lower risk of re- drugs, while patients in the MSD and MUD cohorts re- lapse deserves special attention. It is possible that this was ceived less intensive GvHD prophylaxis. In fact, a recent a spurious finding since more patients in the Haplo cohort study of the ALWP-EBMT has recently reported that died from NRM and were therefore no longer at risk of Sanz et al. Journal of Hematology & Oncology (2020) 13:46 Page 11 of 13 relapse. However, Haplo procedure could have offered en- Conclusion hanced anti-leukemic efficacy, intriguingly in a way that In patients with AML undergoing allo-SCT, PTCy for was independent of chronic GVHD. Superior graft-versus- GvHD prophylaxis showed promising outcomes. Future leukemia effect of Haplo compared to MSD transplants studies comparing PTCy standard regimens are war- for high-risk AML has already been observed in previous ranted to establish the standard of care. In this specific comparative studies. Two prospective trials with biological scenario, Haplo-SCT had increased risk of acute GVHD randomization from China showed decreased posttrans- and NRM that was counterbalanced by a lower relapse plant minimal residual disease (MRD) positivity [28] or re- incidence that translated into no significant difference in lapse [29] in patients undergoing Haplo, particularly LFS and OS. Haplo-SCT offers a good alternative to relevant for those with detectable pretransplant MRD. In matched donor transplants. addition, a recent retrospective study of EBMT also Abbreviations showed decreased relapse incidence in patients with high- aGVHD: Acute GVHD; allo-SCT: Allogeneic stem cell transplantation; risk cytogenetics undergoing Haplo [15]. ALWP: Acute Leukaemia Working Party; AML: Acute myeloid leukemia; The immunological pressure of Haplo grafts has been BM: Bone marrow; cGVHD: Chronic GVHD; CR1: First complete remission; EBMT: European Society for Blood and Marrow Transplantation; GRFS: GVHD- illustrated with the observation that loss of the mis- free and relapse-free survival; GVHD: Graft-versus-host; Haplo: Haploidentical matched HLA haplotype is a frequent mechanism of es- donors; HLA: Human leukocyte antigen; LFS: Leukemia-free survival; cape associated with relapse [30]. The biological MAC: Myeloablative conditioning; MSD: Matched sibling donors; MUD: Matched unrelated; NRM: Nonrelapse mortality; PB: Peripheral blood; explanation is unknown but NK-mediated alloreactivity PTCy: Post-transplant cyclophosphamide; RIC: Reduced intensity has been previously proposed to induce enhanced effi- conditioning; SCT: Stem cell transplantation; OS: Overall survival cacy and GVHD protection in the context of T cell- Acknowledgements depleted Haplo-SCT [31]. The hypothesis of an in- The authors thank Emmanuelle Polge from the office of the ALWP of EBMT creased anti-leukemic efficacy independent of GvHD of for data collection. Haplo-SCT compared to matched donors in the context of PTCy should be further explored from a clinical and Authors’ contributions Jaime Sanz, Arnon Nagler, and Mohamad Mohty: designed the study. biological point of view. Jacques-Emmanuel Galimard: performed statistical analysis. Myriam Labopin: Despite the risks and benefits of BM over PB have helped for the interpretation of the results. Jaime Sanz: wrote the manu- been widely investigated, the effect of the stem cell script. Boris Afanasyev, Emanuele Angelucci, Fabio Ciceri, Didier Blaise, Jan J. Cornelissen, Ellen Meijer, J.L. Diez-Martin, Yener Koc, Montserrat Rovira, Luca source on transplant outcomes deserves special consid- Castagna and Mohamad Mohty: provided cases for the study. All authors edi- eration. In MUD transplants, BM reduced the risk of ted and approved the manuscript. chronic GVHD in a randomized study [32] and im- Funding proved long-term GRFS and overall survival in a large No funding retrospective registry study [33]. In Haplo-SCT, the use of PB resulted in an increased risk of acute GvHD, un- Availability of data and materials The dataset supporting the conclusions of this article are available in the certain impact of chronic GvHD, and decreased risk of ALWP of EBMT in Paris, Saint Antoine Hospital. relapse in patients with acute leukemia, but not with lymphoma [34, 35]. In the present study, we confirm Ethics approval and consent to participate The scientific board of the ALWP of EBMT approved this study. All patients that PB was associated with increased risk of acute and gave written informed consent for the use of their data. chronic GvHD, less relapses, but no final influence on NRM and survival. Consent for publication Not applicable for individual patient data. This is a pooled analysis. Although most retrospective studies comparing MAC with RIC in patients with AML have suggested Competing interests similar survival, since the latter has been associated The authors declare no competing interests. with increased relapse but reduced NRM [36, 37], we Author details observed a significant reduction of relapse with MAC 1 Hematology Department, Hospital Universitari i Politècnic La Fe, Avinguda that translated into improved survival when compared Fernando Abril Martorell, 106, 46026 Valencia, Spain. 2CIBERONC, Instituto with RIC. Unfortunately, the only randomized study, Carlos III, Madrid, Spain. 3EBMT Paris Office, Hospital Saint Antoine, Paris, France. 4Department of Hematology, Hopital Saint Antoine, Sorbonne designed to address this issue in patients with AML, University, Paris, France. 5First State Pavlov Medical University of St. was closed to patient accrual early due to excess of Petersburg, Raisa Gorbacheva Memorial Research Institute for Paediatric relapse and reduced survival in the RIC cohort [38]. Oncology, Hematology, and Transplantation, St Petersburg, Russia. 6 Department of Haematology, IRCCS Ospedale Policlinico San Martino, Since the efficacy of RIC in SCT mainly relies on Genova, Italy. 7Haematology and BMT, Ospedale San Raffaele s.r.l., Milano, graft-versus-leukemia effect, it may be particularly Italy. 8Programme de Transplantation & Therapie Cellulaire, Centre de relevant to increase conditioning intensity in trans- Recherche en Cancérologie de Marseille, Institut Paoli Calmettes, Marseille, France. 9Department of Hematology, Erasmus MC Cancer Institute, University plant platforms with effective GvHD control such as Medical Center Rotterdam, Rotterdam, The Netherlands. 10Department of with the use of PTCy. Hematology (Br 250), VU University Medical Center, Amsterdam, The Sanz et al. Journal of Hematology & Oncology (2020) 13:46 Page 12 of 13 Netherlands. 11Hematology Department, Hospital GU Gregorio Marañon, 15. Salvatore D, Labopin M, Ruggeri A, et al. 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