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Allogeneic hematopoietic cell transplantation (allo-HCT) remains the best consolidation strategy for acute myeloid leukemia (AML) with complex karyotype (CK). However, CK is a heterogenous and highly diverse entity. Numerical abnormalities have been associated with a controversial prognosis and AML with only multiple numerical abnormalities known as pure hyperdiploid karyotype (HDK) may have a distinct prognosis after allo-HCT compared to non-pure HDK CK AML. A total of 236 patients were identified within the EBMT registry as having HDK comprising 95 pure (pHDK) and 141 with other cytogenetic abnormalities (HDK+). The 2-year probability of leukemia-free survival (LFS) was 50% for pHDK and 31% for HDK+ (p= 0.003). The 2-year probability of overall survival (OS) was 57% for pHDK and 36% for HDK+ (p= 0.007). The 2-year cumulative incidence of relapse (RI) was 22% for pHDK and 44% for HDK+ (p= 0.001). The 2-year probability of graft-versus-host disease (GvHD)-free and relapse-free survival (GRFS) was 36% for pHDK and 21% for HDK+ (p= 0.01). On multivariate analysis, pHDK remained associated with significantly better LFS, OS and GRFS and lower RI (all p-values <0.004). pHDK AML constitutes probably a distinct cytogenetic entity from HDK+ or other non-hyperdiploid CK AML with better outcomes after allo-HCT.

ATOS is a prospective observational study evaluating the outcome of patients receiving anti-human T-lymphocyte immunoglobulin (ATLG) in unrelated donor transplantation. Primary endpoint was severe GvHD and relapse-free survival (SGRFS). GvHD prophylaxis consisted of ATLG and CSA/ MTX or MMF. Outcome was compared to the ATLG arm of our prospective randomized phase III multicenter trial trial (RCT) [1, 2]. 165 patients, median age 54 (18; 77) years, with haematological malignancies with early (45.5%), intermediate (17.6%), and advanced (37.0%) disease were included. ATLG dose differed between centers according to local practise (median total ATLG dose of 46 (IQR 32–60, range 15–91) mg/kg). Median follow-up was 70 months. Estimated probabilities at 5 years follow up were for SGRFS 0.27, OS 0.52, DFS 0.43, NRM 0.23, relapse 0.34, acute GvhD °III/IV 0.13, severe chronic GvHD 0.27. OS rates differed dependent on disease status. An effect of the given ATLG dose could not be separated from potential center effects. Despite higher age and more advanced disease in ATOS, outcome was similar to the ATLG arm of our RCT. This long-term, multicenter, experience in routine clinical practice confirms the GvHD-protective effect of ATLG without compromising relapse and non-relapse mortality rates.

We retrospectively compared outcomes of 404 MDS patients undergoing 1st matched sibling donor allo-HCT receiving either PTCy-based (n= 66) or other “conventional prophylaxis” (n= 338; mostly calcineurin inhibitor + methotrexate or MMF). Baseline characteristics were balanced, except for higher use of myeloablative regimens in the PTCy group (52.3% vs. 38.2%, p= 0.047). Incidences of neutrophil (Day +28: 89% vs. 97%, p= 0.011) and platelet (Day +100: 89% vs. 97%, p< 0.001) engraftment were lower for PTCy-based. Day +100 cumulative incidences of grade II–IV and III–IV aGVHD, and 5-year CI of extensive cGVHD were 32%, 18% and 18% for PTCy-based and 25% (p= 0.3), 13% (p= 0.4) and 31% (p= 0.09) for the conventional cohort. Five-year OS (51% vs. 52%, p= 0.6) and GRFS (33% vs. 25%, p= 0.6) were similar between groups. Patients receiving PTCy had a trend to a lower cumulative incidence of relapse (20% vs. 33%, p= 0.06), not confirmed on multivariable analysis (p= 0.3). Although higher NRM rates were observed in patients receiving PTCy (32% vs. 21%, p= 0.02) on univariate analysis, this was not confirmed on multivariate analysis (HR 1.46, p= 0.18), and there was no resultant effect on OS (HR 1.20, p= 0.5). Based on these data, PTCy prophylaxis appears to be an attractive option for patients with MDS undergoing MSD allo-HCT.

Therapy-related myeloid neoplasms (t-MN), either myelodysplastic neoplasms (t-MDS) or acute myeloid leukemias (t-AML), have a poor prognosis and allogeneic haematopoietic cell transplantation (allo-HCT) represents the only curative option. In this multicenter, registry-based study, we analyzed outcomes of 378 patients undergoing first allo-HCT between 2006–2017 for t-MN arising secondary to lymphoma treatment. Median age was 58 years at allo-HCT; 222 (59%) had a diagnosis of t-MDS and 156 (41%) of t-AML, respectively. At the time of allo-HCT, 46% of t-MN cases were reported as in complete remission (CR) and 15% of lymphomas were recorded as not in remission. A reduced intensity conditioning regimen was used in 70% of cases. For the entire cohort, 5-year OS, and t-MN PFS, relapse incidence and NRM were 32%, 28%, 35% and 37%, respectively. In multivariable analysis, undergoing allo-HCT with t-MN not in CR and older age were associated with significantly worse OS, PFS and NRM. At 5 years post allo-HCT, the relapse incidence of lymphoma was low at 3%, while the rate of secondary malignancies was 8%. This analysis shows the curative potential of allo-HCT for patients with t-MN arising secondary to lymphoma treatment in approximately a third of patients.

Management of Richter transformation (RT) is particularly challenging, with survival estimates <1 year. We report on outcomes of 66 RT patients undergoing allogeneic-HCT (allo-HCT) between 2008 and 2018 registered with the EBMT. Median age at allo-HCT was 56.2 years (interquartile range (IQR), 51.3–63.1). Median time from RT to allo-HCT was 6.9 months (IQR, 4.9–11) and 28 (42.4%) were in complete remission (CR). The majority underwent reduced intensity conditioning (66.2%) using peripheral blood derived stem cells. Eighteen (27.3%) patients had a matched sibling donor, 24 (36.4%) a matched unrelated donor and the remaining were mismatched. Median follow-up was 6.6 years; 1- and 3- year overall and progression free survival (PFS) (95% CI) was 65% (54–77) and 39% (27–51) and 53% (41–65) and 29% (18–40), respectively. Patients in CR at time of allo-HCT had significantly better 3-year PFS (39% vs.21%, p= 0.032). Cumulative incidences of grade II–IV acute graft versus host disease (GVHD) at day +100 was 41% (95% CI 29–53) and chronic GVHD at 3 years was 53% (95% CI 41–65). High rates of non-relapse mortality (NRM) were observed; 38% (95% CI, 26–50) at 3 years. Although potentially curative, approaches to reduce considerable NRM and chronic GVHD rates are required.

JAK1/2 inhibitor ruxolitinib (RUX) is approved in patients with myelofibrosis but the impact of pretreatment with RUX on outcome after allogeneic hematopoietic stem cell transplantation (HSCT) remains to be determined. We evaluated the impact of RUX on outcome in 551 myelofibrosis patients who received HSCT without (n= 274) or with (n= 277) RUX pretreatment. The overall leukocyte engraftment on day 45 was 92% and significantly higher in RUX responsive patients than those who had no or lost response to RUX (94% vs. 85%, p= 0.05). The 1-year non-relapse mortality was 22% without significant difference between the arms. In a multivariate analysis (MVA) RUX pretreated patients with ongoing spleen response at transplant had a significantly lower risk of relapse (8.1% vs. 19.1%; p= 0.04)] and better 2-year event-free survival (68.9% vs. 53.7%; p= 0.02) in comparison to patients without RUX pretreatment. For overall survival the only significant factors were age > 58 years (p= 0.03) and HLA mismatch donor (p= 0.001). RUX prior to HSCT did not negatively impact outcome after transplantation and patients with ongoing spleen response at time of transplantation had best outcome.

Older adults with acute myeloid leukemia (AML) refractory to initial or reinduction chemotherapy have a dismal prognosis if they do not undergo hematopoietic stem-cell transplantation (HCT). However, data assessing HCT outcomes from different donors are scarce. We evaluated results from a retrospective analysis on patients aged ≥70 years, with AML not in remission who received an allogeneic HCT from HLA-matched sibling donor (MSD), HLA-10/10 matched unrelated donor (MUD), or T-cell replete haploidentical (Haplo) donor, from 2010 to 2021, reported to the ALWP-EBMT database. A total of 360 patients (median age 72 years, range 70–79) were included in the analysis. Median follow-up for the entire population was 35.5 months. Donors were MSD (n= 58), 10/10 HLA-MUD (n= 228), and Haplo (n= 74). A total of 213 (59.2%) patients were primary induction failures, while 147 (40.8%) were in first or subsequent relapse. Graft source was peripheral blood in 92% of the patients. Patients transplanted from Haplo donors more frequently received marrow grafts (p< 0.01) and presented the combination female donor to male recipient (p< 0.01). The overall 2-year rates of overall survival (OS) and leukemia-free survival (LFS) were: 62.4% (95% CI 47.2–74.3) and 47.6% (95% CI 33.1–60.8) for MSD, 43% (95% CI 35.8–49.9), and 37.5% (95% CI 30.7–44.4) for MUD, and 25.9% (95% CI 15.8–37.2), and 26.5% (95% CI 16.3–37.8) for recipients of Haplo transplants. The 2-year cumulative incidence of relapse (RI) was slightly lower for Haplo recipients at 29.6% (95% CI 19–40.9), for MUD it was 30.2% (95% CI 23.9–36.7), and for MSD 34.9% (95% CI 22–48.2); counterbalanced by a higher incidence of non-relapse mortality (NRM) of 43.9% (95% CI 31.6–55.6) for Haplo recipients, 32.2% (95% CI 26–33.1) for MUD and 17.5% (95% CI 8.4–29.3) for MSD. Graft-versus-host disease (GVHD-free, relapse-free survival (GRFS) was 35.3% (95% CI 22.3–48.5) for MSD, 29.6% (95% CI 23.2–36.2) for MUD, and 19.2% (95% CI 10.7–29.6) for Haplo patients. In the multivariate model, compared to the referent group of MSD recipients, the risk of NRM was higher among patients transplanted from Haplo donors ([hazard ratio] HR 5.1, 95% CI 2.23–11.61, p< 0.001) and MUD (HR 3.21, 95% CI 1.48–0.6.94, p= 0.003). Furthermore, both Haplo and MUD were associated with inferior OS, (HR 3.6, 95% CI 1.98–0.6.56, p< 0.001, and HR 2.3, 95% CI 1.37–0.3.88, p= 0.002, respectively), and LFS (HR 2.24, 95% CI 1.31–0.3.84, p= 0.003, and HR 1.64, 95% CI 1.04–0.2.60, p= 0.034, respectively). Patients transplanted from Haplo donors were also associated with worse GFRS (HR 1.72, 95% CI 1.07–2.77, p:0.025) compared with MSD patients. Older adult AML patients with active disease transplanted from MSD experienced prolonged OS and LFS compared to 10/10 MUD and Haplo due to lower NRM. Prospective clinical trials are warranted.

Bortezomib (Vel)- Melphalan 200 mg/m2 (Mel200) (Vel-Mel) has been utilised to intensify conditioning in autologous hematopoietic stem cell transplantation (AHCT) for multiple myeloma (MM). This EBMT registry-based study compared Vel-Mel with Mel200 during upfront AHCT. Between 2010 and 2017, MM patients who received Vel-Mel (n = 292) conditioning were compared with 4,096 Mel200 patients in the same 58 centres. Pre-AHCT, compared to Mel200 patients, Vel-Mel patients had similar International Staging System (ISS) scores and cytogenetic risk profiles; a similar proportion had received bortezomib-based induction (85% and 87.3%, respectively) though they were younger with a better performance status. Vel-Mel patients were more likely to achieve CR post-induction (40.6% vs 20.3%, p < 0.001) and by day 100 of AHCT (CR/VGPR: 70.2 % vs. 57.2%, p < 0.001). There was no difference in 3-year PFS (49% vs 46%, p = 0.06) or early post-AHCT mortality. In multivariable analysis, Vel-Mel associated with inferior PFS (HR: 1.69 (1.27–2.25, p < 0.001) and OS (HR:1.46 (1.14–1.86,p = 0.002), similar to negative effects on PFS of advanced ISS (HR:1.56 (1.33–1.83, p < 0.001), high-risk cytogenetics (HR:1.43(1.18–1.74, p < 0.001) and poor post-induction response(<=PR)(HR: 1.43(1.25–1.62, p < 0.001) Overall, despite superior pre- and post-AHCT responses, there was no improvement in PFS or OS following Vel-Mel. This data supports the findings of the smaller prospective IFM study.

Many older patients with acute myeloid leukaemia die or cannot undergo allogeneic haematopoietic stem-cell transplantation (HSCT) due to toxicity caused by intensive chemotherapy. We hypothesised that replacing intensive chemotherapy with decitabine monotherapy could improve outcomes.

We compared FT14 (fludarabine 150–160 mg/m2, treosulfan 42 g/m2) versus FB4 (fludarabine 150–160 mg/m2, busulfan 12.8 mg/kg) in acute myeloid leukemia (AML) transplanted at primary refractory/relapsed disease. We retrospectively studied: (a) adults diagnosed with AML, (b) recipients of first allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated/sibling donor (2010–2020), (c) HSCT with primary refractory/relapsed disease, (d) conditioning regimen with FT14 or FB4. We studied 346 patients, 113 transplanted with FT14, and 233 with FΒ4. FT14 patients were significantly older, more frequently had an unrelated donor and had received a lower dose of fludarabine. Cumulative incidence (CI) of acute graft-versus-host disease (GVHD) grade III-IV and extensive chronic GVHD was similar. With a median follow-up of 28.7 months, 2-year CI of relapse was 43.4% in FT14 versus 53.2% in FB4, while non-relapse mortality (NRM) was respectively 20.8% versus 22.6%. This led to 2-year leukemia-free survival (LFS) of 35.8% for FT14 versus 24.2% in FB4, and overall survival (OS) of 44.4% versus 34%. Adverse cytogenetics and conditioning regimen independently predicted CI of relapse. Furthermore, conditioning regimen was the only independent predictor of LFS, OS, and GVHD-free/relapse-free survival. Therefore, our real-world multicenter study suggests that FT14 is associated with better outcomes in primary refractory/relapsed AML.

Pre-transplant detectable measurable residual disease (MRD) is still associated with high risk of relapse and poor outcomes in acute myeloid leukemia (AML). We aimed at evaluating the impact of disease burden on prediction of relapse and survival in patients receiving allogeneic hematopoietic cell transplantation (allo-HCT) in first remission (CR1). We identified a total of 3202 adult AML patients, of these 1776 patients were in CR1 and MRD positive and 1426 patients were primary refractory at time of transplant. After a median follow-up of 24.4 months, non-relapse mortality and relapse rate were significantly higher in the primary refractory group compared to the CR1 MRD positive group (Hazards Ratio (HR) = 1.82 (95% CI: 1.47–2.24) p< 0.001 and HR = 1.54 (95% CI: 1.34–1.77), p< 0.001), respectively. Leukemia-free survival (LFS) and overall survival (OS) were significantly worse in the primary refractory group (HR = 1.61 (95% CI: 1.44-1.81), p< 0.001 and HR = 1.71 (95% CI: 1.51–1.94), p< 0.001, respectively). Our real-life data suggest that patients in CR1 and MRD positive at time of transplant could still be salvaged by allo-HCT with a 2-year OS of 63%, if negative MRD cannot be obtained and their outcomes are significantly better than patients transplanted with active disease.

•Comorbidities used to evaluate allogeneic transplantation candidates have differential impact on NRM in low-intensity conditioning settings.•Among prevalent comorbidities, cardiac disease (including arrhythmia and valvular disease) may confer significant additional NRM risk.

Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced intensity conditioning (RIC) is an option for elderly patients with acute lymphoblastic leukemia (ALL). We retrospectively compared results of RIC-allo-HCT from either a matched sibling donor (MSD, n= 209) or matched unrelated donor (MUD, n= 209) with autologous (auto, n= 142) HCT for patients aged 55 years or more treated in first complete remission (CR1) between 2000 and 2018. The probabilities of leukemia-free survival (LFS) at 5 years were 34% for RIC-allo-HCT versus 39% for auto-HCT (p= 0.11) while overall survival (OS) rates were 42% versus 45% (p= 0.23), respectively. The incidence of relapse (RI) and non-relapse mortality (NRM) was 41% versus 51% (p= 0.22) and 25% versus 10% (p= 0.001), respectively. In a multivariate model, using auto-HCT as reference, the risk of NRM was increased for MSD-HCT (Hazard ratio [HR] = 2.1, p= 0.02) and MUD-HCT (HR = 3.08, p< 0.001), which for MUD-HCT translated into a decreased chance of LFS (HR = 1.55, p= 0.01) and OS (HR = 1.62, p= 0.008). No significant associations were found with respect to the risk of relapse. We conclude that for patients with ALL in CR1, aged above 55 years, auto-HCT may be considered a transplant option alternative to RIC-allo-HCT, although its value requires verification in prospective trials.

Blastic plasmacytoid dendritic cell neoplasia (BPDCN) is a rare myeloid malignancy with a generally poor prognosis. Although preliminary evidence suggests that hematopoietic cell transplantation (HCT) could improve outcome in patients with BPDCN, the individual contributions of conditioning and graft-versus-tumor (GVT) effects to HCT success are undefined. We present a retrospective study of 162 adult patients who underwent a first HCT (allogeneic 146, autologous 16) between 2009 and 2017, and were registered with the EBMT. Median age was 57 (range 20–73) years, and disease status at HCT was first complete remission (CR1) in 78%. Among patients receiving allogeneic HCT (alloHCT), myeloablative conditioning (MAC), reduced intensity conditioning (RIC) and in-vivo T-cell depletion (TCD) were used in 54%, 46%, and 59% respectively. Total body irradiation (TBI) was the conditioning backbone in 61% of MAC and 26% of RIC transplants. One-year overall survival (OS) and progression-free survival (PFS) rates were comparable after alloHCT and autologous HCT (autoHCT). Among alloHCT recipients, MAC with TBI significantly improved OS and PFS, independently of CR1, age, Karnofsky index and TCD. Accordingly, MAC (ideally based on TBI) should be preferred for alloHCT recipients with BPDCN. In patients who are not elegible for MAC alloHCT, autoHCT could be considered.

•Mocravimod was safe in allogeneic hematopoietic stem cell transplantation recipients.•Mocravimod reduced blood absolute lymphocyte counts temporarily.•CD4+T cells were more sensitive to mocravimod treatment than CD8+T cells.•Mocravimod did not affect engraftment.

Conditioning protocols for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) are being developed continuously to improve their anti-leukemic efficacy and reduce their toxicity. In this study, we compared the conditioning protocol of fludarabine with melphalan 140 mg/m2(FluMel) with conditioning protocols based on this same backbone but with an additional alkylating agent i.e., either fludarabine/BCNU (also known as carmustine)/melphalan (FBM), or fludarabine/thiotepa/melphalan (FTM) 110 mg/m2. We included 1272 adult patients (FluMel, n= 1002; FBM/FTM, n= 270) with acute myeloid leukemia (AML) with intermediate/poor cytogenetic risk in first complete remission (CR) from the registry of the EBMT Acute Leukemia Working Party. Despite patients in the FBM/FTM group were older (64.1 years vs. 59.8 years, p< 0.001) and had a worse Karnofsky performance score (KPS < 90, 33% vs. 24%, p= 0.003), they showed a better overall survival (OS) (2 y OS: 68.3% vs. 58.1%, p= 0.02) and less non-relapse mortality (NRM) (2 y NRM: 15.8% vs. 22.2%, p= 0.009) compared to patients treated with FluMel. No significant differences were observed in relapse incidence (RI) (2 y RI: 24.9% vs. 23.7%, p= 0.62). In conclusion, the addition of a second alkylating agent (BCNU/carmustine or thiotepa) to FluMel as FBM/FTM conditioning, improves OS in AML patients in first CR with intermediate/poor risk cytogenetics after allo-HCT.

Allogeneic hematopoietic cell transplantation (allo-HCT) is curative for myelofibrosis (MF) but assessing risk-benefit in individual patients is challenging. This complexity is amplified in CALR-mutated MF patients, as they live longer with conventional treatments compared to other molecular subtypes. We analyzed outcomes of 346 CALR-mutated MF patients who underwent allo-HCT in 123 EBMT centers between 2005 and 2019. After a median follow-up of 40 months, the estimated overall survival (OS) rates at 1, 3, and 5 years were 81%, 71%, and 63%, respectively. Patients receiving busulfan-containing regimens achieved a 5-year OS rate of 71%. Non-relapse mortality (NRM) at 1, 3, and 5 years was 16%, 22%, and 26%, respectively, while the incidence of relapse/progression was 11%, 15%, and 17%, respectively. Multivariate analysis showed that older age correlated with worse OS, while primary MF and HLA mismatched transplants had a near-to-significant trend to decreased OS. Comparative analysis between CALR- and JAK2-mutated MF patients adjusting for confounding factors revealed better OS, lower NRM, lower relapse, and improved graft-versus-host disease-free and relapse-free survival (GRFS) in CALR-mutated patients. These findings confirm the improved prognosis associated with CALRmutation in allo-HCT and support molecular profiling in prognostic scoring systems to predict OS after transplantation in MF.

Obesity and diabetes can modulate immune responses, which may impact allogeneic HCT outcomes and GvHD. From the EBMT registry, we included 36,539 adult patients who underwent allogeneic HCT for a hematological malignancy between 2016 and 2020. Of these, 5228 (14%) had obesity (BMI ≥ 30 kg/m2), 1415 (4%) had diabetes (requiring treatment with insulin or oral hypoglycemics), and 688 (2%) had obesity + diabetes pre-transplantation. Compared with patients without diabetes or obesity, the hazard ratio (HR) of grade II–IV acute GvHD was 1.00 (95% confidence interval [CI] 0.94–1.06, p= 0.89) for patients with obesity, 0.95 (CI 0.85–1.07, p= 0.43) for patients with diabetes, and 0.96 (CI 0.82–1.13, p= 0.63) for patients with obesity + diabetes. Non-relapse mortality was higher in patients with obesity (HR 1.08, CI 1.00–1.17, p= 0.047), diabetes (HR 1.40, CI 1.24–1.57, p< 0.001), and obesity + diabetes (HR 1.38, CI 1.16–1.64, p< 0.001). Overall survival after grade II–IV acute GvHD was lower in patients with diabetes (HR 1.46, CI 1.25–1.70, p< 0.001). Pre-transplantation diabetes and obesity did not influence the risk of developing acute GvHD, but pre-transplantation diabetes was associated with poorer survival after acute GvHD.

Allogeneic hematopoietic stem cell transplantation (HCT) is standard treatment for adult high-risk (HR) acute lymphoblastic leukemia (ALL) and contributed to the overall improved outcome. We report a consecutive cohort of prospectively defined HR patients treated on German Multicenter Acute Lymphoblastic Leukemia trials 06/99-07/03 with similar induction/consolidation therapy and HCT in first remission. A total of 542 patients (15-55 years) with BCR-ABL–negative ALL were analyzed. Sixty-seven percent received HCT from matched unrelated donors (MUD) and 32% from matched sibling donors (MSD). The incidence of non-relapse mortality (NRM) was 20% at 5 years. NRM occurred after median 6.6 months; the leading cause (46%) was infection. NRM after MUD decreased from 39% in trial 06/99 to 16% in trial 07/03 (P< .00001). Patient age was the strongest predictor of NRM. The 5-year relapse incidence was 23% using MSD and 25% using MUD. Minimal residual disease (MRD) was the strongest predictor of relapse (45% for molecular failure versus 6% for molecular CR; P< .0001). The median follow-up was 67 months, and the 5-year survival rate was 58%. Age, subtype/high risk feature, MRD status, trial and acute GvHD were significant prognostic factors. We provide a large reference analysis with long follow-up confirming a similar outcome of MSD and MUD HCT and improved NRM for MUD HCT over years. MRD has a strong impact on relapse risk, whereas age was the strongest predictor of NRM. New adapted conditioning strategies should be considered for older patients combined with the goal to reduce the MRD level before stem cell transplantation.

Therapeutic options for patients with AML relapsing after allogeneic HCT range from chemotherapy or hypomethylating agents with or without donor lymphocyte infusions to a 2nd allogeneic HCT. Available data are based on retrospective single center or registry studies. The aim of this multicenter trial was to investigate prospectively intensive conditioning with Thiotepa, Fludarabine and Treosulfan (TFT) for 2nd allogeneic HCT from an alternative unrelated donor in patients with AML relapse > 6 months after a 1st allogeneic HCT. Primary endpoint was disease-free survival (DFS) at one year after 2nd HCT. 50 patients median age 53.5 years, in CR/PR (34%) or active relapse (66%) were included. 33 of 38 patients (86.8%) with available data achieved CR 100 days post transplant. 23 patients were alive and free of relapse at primary endpoint one year after 2nd HCT (DFS rate 0.46, 95%-CI (0.32–0.61). Three-year rates of DFS, relapse, non-relapse mortality, and overall survival were 0.24, 95%-CI (0.13–0.36); 0.36 (0.25–0.52); 0.40 (0.29–0.57); and 0.24 (0.13–0.37). Second HCT with TFT conditioning is feasible and has high anti-leukemic efficacy in chemosensitive or refractory AML relapse after prior allogeneic HCT. Still, relapse rates and NRM after 2nd allogeneic HCT remain a challenge. The trial is registered in the German Clinical Trials Registry (number DRKS00005126).

Acute graft-versus-host disease (aGVHD) is a major life-threatening complication of allogeneic hematopoietic cell transplantation. While most studies report therapy-response of aGVHD including a cumulative grade of skin, liver and intestinal tract manifestations, there is a lack of information specifically on lower gastrointestinal tract aGVHD (GI-GVHD) therapy-response, which is highly relevant in light of novel therapies that target intestinal regeneration such as IL-22, R-spondin or GLP-2. Here we retrospectively analyzed patients who developed GI-GVHD over a 6-year period. A total of 144 patients developed GI-GVHD and 82 (57%) were resistant to glucocorticoid-therapy (SR). The most commonly used second-line therapy was ruxolitinib (74%). Overall and complete response (CR) to ruxolitinib on day 28 were 44.5% and 13%, respectively. SR-GVHD patients experienced a lower 5-year overall survival (OS) (34.8 vs 53.3%, p= 0.0014) and higher incidence of 12-months non-relapse-mortality (39.2 vs 14.3%, p= 0.016) compared to glucocorticoid-sensitive patients. SR-GI-GVHD patients, that achieved a CR on day 28 after ruxolitinib start, experienced a higher OS compared to non-CR patients (p= 0.04). These findings indicate that therapy response of SR-GI-GVHD to different immunosuppressive approaches is still low, and that novel therapies specifically aiming at enhanced intestinal regeneration should be tested in clinical trials.

To determine the survival benefit of allogeneic hematopoietic cell transplantation (allo-HCT) in chronic myelomonocytic leukemias (CMML), we assembled a retrospective cohort of CMML patients 18-70 years old diagnosed between 2000 and 2014 from an international CMML dataset (n = 730) and the EBMT registry (n = 384). The prognostic impact of allo-HCT was analyzed through univariable and multivariable time-dependent models and with a multistate model, accounting for age, sex, CMML prognostic scoring system (low or intermediate-1 grouped as lower-risk, intermediate-2 or high as higher-risk) at diagnosis, and AML transformation. In univariable analysis, lower-risk CMMLs had a 5-year overall survival (OS) of 20% with allo-HCT vs 42% without allo-HCT (P < .001). In higher-risk patients, 5-year OS was 27% with allo-HCT vs 15% without allo-HCT (P = .13). With multistate models, performing allo-HCT before AML transformation reduced OS in patients with lower-risk CMML, and a survival benefit was predicted for men with higher-risk CMML. In a multivariable analysis of lower-risk patients, performing allo-HCT before transformation to AML significantly increased the risk of death within 2 years of transplantation (hazard ratio [HR], 3.19; P < .001), with no significant change in long-term survival beyond this time point (HR, 0.98; P = .92). In higher-risk patients, allo-HCT significantly increased the risk of death in the first 2 years after transplant (HR 1.46; P = .01) but not beyond (HR, 0.60; P = .09). Performing allo-HCT before AML transformation decreases life expectancy in lower-risk patients but may be considered in higher-risk patients.

Limited data is available on factors impacting the outcomes of second hematopoietic cell transplantation (HCT2) in patients with secondary acute myeloid leukemia (sAML). This study aimed to assess HCT2 outcome for sAML comparing reduced-intensity (RIC) to myeloablative (MAC) conditioning. Two hundred and fifteen patients were included: RIC (n= 134), MAC (n= 81). The median follow-up was 41.1 (95% CI: 26.7–69.3) and 28.5 (95% CI: 23.9–75.4) months, respectively. At two years, the relapse incidence (RI) was 58.3% versus 51.1% in RIC and MAC, respectively. The 2-year leukemia free survival (LFS) was 26.6% versus 26%, and the graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) was 16.4% versus 12.1%, while OS was 31.4% and 39.7%, for RIC and MAC respectively. MVA showed a significantly lower RI [hazard ratio (HR) = 0.46 (95% CI, 0.26–0.8, p= 0.006)] and improved LFS [HR = 0.62 (95% CI, 0.39–0.98, p= 0.042)] with MAC versus RIC. The choice of conditioning regimen did not impact non-relapse mortality [HR = 1.14 (95% CI, 0.52–2.5, p= 0.74)], overall survival (OS) [HR = 0.72 (95% CI, 0.44–1.17, p= 0.18)] or GRFS [HR = 0.89 (95% CI, 0.59–1.36, p= 0.6)]. In conclusion, MAC was associated with a lower RI and superior LFS. These results support the use of MAC for eligible patients with sAML who are being considered for HCT2.

•Successful pregnancies are possible among female alloHCT recipients, although birth rate is more than six times lower than in the general population.•Key factors increasing the chance of motherhood were younger age at HCT, non-malignant disease, no TBI or dose <8Gy and RIC/NMA conditioning

Recently a new three-group clinical classification was reported by an International Consortium to stratify CMML patients with regard to prognosis. The groups were defined as follows: (1) Myelodysplastic (MD)-CMML: WBC ≤ 10 × 109/l, circulating immature myeloid cells (IMC) = 0, no splenomegaly; (2) MD/MP (overlap)–CMML: WBC 10–20 × 109/l or WBC ≤ 10 × 109/l but IMC > 0 and/or splenomegaly; (3) Myeloproliferative (MP)-CMML: WBC > 20 × 109/l. By analysing EBMT Registry patients who underwent allo-HCT for CMML between 1997 and 2016, we aimed to determine the impact of this classification on transplantation outcome and to make a comparison with the conventional WHO classification (CMML-0/CMML-1/CMML-2). Patient grouping was based on the data registered at time of transplantation, with IMC replaced by peripheral blasts. Among 151 patients included in the analysis, 38% were classified as MD-CMML, 42% as MD/MP-CMML and 20% as MP-CMML. With a median survival of 17 months in the whole series, MD-CMML patients were distinguished as a low-risk group with higher CR rate at transplant and a longer post-transplant 2-year progression-free survival in comparison to others (44.5% vs 33.5%, respectively), whereas the WHO classification was superior in identifying high-risk patients (CMML-2) with inferior survival outcomes.

Hemophagocytic lymphohistiocytosis (HLH; hemophagocytic syndrome) is a rare syndrome of potentially fatal, uncontrolled hyperinflammation. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in primary, recurrent or progressive HLH, but information about its outcomes in the adult population is limited. We obtained data about 87 adult (≥18 years of age) patients retrospectively reported to the EBMT. The median survival time was 13.9 months. The three and five-year overall survival (OS) was 44% (95% CI 33–54%). Among 39 patients with a follow-up longer than 15 months, only three died. Relapse rate was 21% (95% CI 13–30%), while NRM reached 36% (95% CI 25–46%). Younger patients (<30 years of age) had better prognosis, with an OS of 59% (95% CI 45–73%) at three and five years vs 23% (95% CI 8–37%) for older ones. No difference in survival between reduced and myeloablative conditioning was found. To our knowledge, this is the largest report of adult HLH patients who underwent allo-HSCT. Patients who survive the first period after this procedure can expect a long disease-free survival. Both reduced intensity and myeloablative conditioning have therapeutic potential in adult HLH.

We performed a registry study on therapy-related myeloid neoplasm (t-MN), both therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML) following treatment for breast cancer who underwent a first allogeneic hematopoietic cell transplant (allo-HCT). Of 252 identified female patients (median age 57 years), 77% were transplanted for t-AML and 23% for t-MDS, with a median time from breast cancer diagnosis to the diagnosis of tMN and subsequent allo-HCT of 3.7 and 4.6 years, respectively. At transplant, 191 patients were in remission for breast cancer, while 4 were not (57 missing). T-MN was in a complete remission at the time of transplant in 67% of patients. 2-year overall survival, relapse free-survival, relapse incidence and non-relapse mortality were 50%, 45%, 33%, and 22%, respectively. Multivariable analysis revealed that if the t-MN was not in CR pre-transplant, this was associated with lower OS, RFS, and a higher relapse incidence. Seventeen cases of breast cancer recurrence were recorded after a median of 2.4 years post-transplant, and relapse of primary breast cancer accounted for 7% of deaths. This study indicates that allo-HCT for t-MN following treatment for breast cancer shows encouraging transplant outcomes. The incidence of breast cancer relapse post-transplant remains a cause for concern.

While in vivo T-cell depletion (TCD) is widely used, its benefit in patients with MDS still remains a matter of debate. This study evaluates the impact of TCD on outcomes, and compares ATG and alemtuzumab, in patients with MDS. 1284 patients from the EBMT registry were included in this study with 470 patients in the no-TCD group and 814 in the TCD group (alemtuzumab N= 168; ATG N= 646). At 6 months, aGVHD III-IV cumulative incidences (CI) for no-TCD, ATG or alemtuzumab groups were 13% vs 14% vs 11% (ns), respectively. At 5 years, CI of chronic GVHD were 64% vs 52% vs 51% (p< 0.00017); and CI of relapse was 23% vs 25% vs 39% (p< 0.0001) for no TCD, ATG and alemtuzumab respectively; OS was 47% vs 46% vs 34% (p= 0.009) respectively; and GRFS was 21% vs 28% and 20% (p= 0.045) respectively. In multivariable analysis, ATG improved GRFS, and alemtuzumab decreased OS. Both ATG and alemtuzumab decreased risk of chronic GVHD, but the increased risk of relapse with alemtuzumab is associated with a poor GRFS and suggest to not use alemtuzumab in the setting of allo-SCT for high risk disease.

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for patients with myeloid/lymphoid neoplasm (MLN) with FGFR1rearrangement, but data on overall results are limited. We report on the largest series of patients (n= 22) with FGFR1-rearranged MLN undergoing allo-HCT. Distribution according to cytogenetic subtype was: t(8;13) in 11 cases, t(8;22) in 7 cases, t(6;8) in 2 cases, and other (n= 2). Over a third of patients displayed a chronic myeloproliferative (MPN) phenotype, another third showed MPN features with concomitant lymphoma or acute leukemia, and the remaining ones presented as acute leukemia. After a median follow-up of 4.1 years from transplant, the estimated 5-year survival rate, progression-free survival, non-relapse mortality and relapse incidence was 74%, 63%, 14% and 23%, respectively. Causes of death were relapse/progression (n= 4), graft-versus-host disease (n= 2) and organ toxicity (n= 1). Six patients experienced disease relapse at a median of 6.1 months (range: 2.3–119.6). Two of them achieved complete remission with ponatinib or pemigatinib and were alive at 34.5 and 37 months from relapse, respectively. These data highlight the significant curative potential of allo-HCT in this aggressive disease. Maintenance with tyrosine kinase inhibitors may be a promising approach, at least in cases with detectable residual disease after transplant.

In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m2(FluMel) and fludarabine/treosulfan 42 g/m2(FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n= 1005) or Flu/Treo (n= 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, pvalue 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, pvalue < 0.001) and slightly increased non-relapse mortality (NRM) (25.7% vs. 20.2%, pvalue = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT.

High-dose chemotherapy, followed by autologous hematopoietic stem cell transplantation (auto-HSCT), is an established therapy for patients with hematological malignancies. The age of patients undergoing auto-HSCT and, therefore, the comorbidities, has increased over the last decades. However, the assessment of organ dysfunction prior to auto-HSCT has not been well studied. Therefore, we retrospectively analyzed the association of clinical factors and lung and cardiac function with outcome and complications after conditioning with BEAM (BCNU/carmustine, etoposide, cytarabine, melphalan) or high-dose melphalan in patients undergoing auto-HSCT. This study included 629 patients treated at our institution between 2007 and 2017; 334 and 295 were conditioned with BEAM or high-dose melphalan, respectively. The median follow-up was 52 months (range, 0.2-152) and 50 months (range, 0.5-149), respectively. In the multivariate analysis, we identified that progressive disease, CO-diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, Karnofsky Performance Status (KPS) ≤ 80%, Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score ≥ 4, and age > 70 years were associated with decreased overall survival (OS) in patients treated with BEAM. Similarly, DLCOcSB ≤ 60% of predicted, HCT-CI score ≥ 4, and age > 60 years were identified in patients treated with high-dose melphalan. Abnormalities in DLCOcSB ≤ 60% of predicted were associated with chemotherapy with lung-toxic substances, mediastinal radiotherapy, KPS ≤ 80%, current/previous smoking, and treatment in the intensive care unit. More often, patients with DLCOcSB ≤ 60% of predicted experienced nonrelapse mortality, including pulmonary causes of death. In summary, we identified DLCOcSB ≤ 60% of predicted as an independent risk factor for decreased OS in patients conditioned with BEAM or high-dose melphalan prior to auto-HSCT.

High-dose chemotherapy, followed by autologous hematopoietic stem cell transplantation (auto-HSCT), is an established therapy for patients with hematological malignancies. The age of patients undergoing auto-HSCT and, therefore, the comorbidities, has increased over the last decades. However, the assessment of organ dysfunction prior to auto-HSCT has not been well studied. Therefore, we retrospectively analyzed the association of clinical factors and lung and cardiac function with outcome and complications after conditioning with BEAM (BCNU/carmustine, etoposide, cytarabine, melphalan) or high-dose melphalan in patients undergoing auto-HSCT. This study included 629 patients treated at our institution between 2007 and 2017; 334 and 295 were conditioned with BEAM or high-dose melphalan, respectively. The median follow-up was 52 months (range, 0.2-152) and 50 months (range, 0.5-149), respectively. In the multivariate analysis, we identified that progressive disease, CO-diffusion capacity corrected for hemoglobin (DLCOcSB) ≤ 60% of predicted, Karnofsky Performance Status (KPS) ≤ 80%, Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score ≥ 4, and age > 70 years were associated with decreased overall survival (OS) in patients treated with BEAM. Similarly, DLCOcSB ≤ 60% of predicted, HCT-CI score ≥ 4, and age > 60 years were identified in patients treated with high-dose melphalan. Abnormalities in DLCOcSB ≤ 60% of predicted were associated with chemotherapy with lung-toxic substances, mediastinal radiotherapy, KPS ≤ 80%, current/previous smoking, and treatment in the intensive care unit. More often, patients with DLCOcSB ≤ 60% of predicted experienced nonrelapse mortality, including pulmonary causes of death. In summary, we identified DLCOcSB ≤ 60% of predicted as an independent risk factor for decreased OS in patients conditioned with BEAM or high-dose melphalan prior to auto-HSCT.

Optimal donor choice for a second allogeneic hematopoietic cell transplant (allo-HCT) in relapsed acute lymphoblastic leukemia (ALL) remains undefined. We compared outcomes using HLA-matched unrelated donors (MUD) versus haploidentical donors in this population. Primary endpoint was overall survival (OS). The MUD allo-HCT group comprised 104 patients (male = 56, 54%), median age 36 years, mostly (76%) with B-cell phenotype in complete remission (CR) (CR2/CR3 + = 76, 73%). The 61 patients (male = 38, 62%) in the haploidentical group were younger, median age 30 years (p= 0.002), had mostly (79%) a B-cell phenotype and the majority were also in CR at time of the second allo-HCT (CR2/CR3 + = 40, 66%). Peripheral blood stem cells was the most common cell source in both, but a significantly higher number in the haploidentical group received bone marrow cells (26% vs. 4%, p< 0.0001). A haploidentical donor second allo-HCT had a 1.5-fold higher 2-year OS (49% vs. 31%), albeit not statistically significant (p= 0.13). A longer time from first allo-HCT to relapse was associated with improved OS, leukemia-free survival, graft-versus-host disease-free-relapse-free survival, and lower cumulative incidences of relapse and non-relapse mortality. Results suggest no major OS difference when choosing either a MUD or haploidentical donor for ALL patients needing a second allo-HCT.