European Society Of Blood And Marrow Transplantation Research Articles

Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity.

Hematologic toxicity frequently complicates chimeric antigen receptor (CAR) T-cell therapy, resulting in significant morbidity and mortality. In an effort to standardize reporting, the European Hematology Association (EHA) and European Society of Blood and Marrow Transplantation (EBMT) devised the immune effector cell-associated hematotoxicity (ICAHT) grading system, distinguishing between early (day 0-30) and late (after day +30) events based on neutropenia depth and duration. However, manual implementation of ICAHT grading criteria is time-consuming and susceptible to subjectivity and error. To address these challenges, we introduce a novel computational approach, utilizing the R programming language, to automate early and late ICAHT grading. Given the complexities of early ICAHT grading, we benchmarked our approach both manually and computationally in two independent cohorts totaling 1251 patients. Our computational approach offers significant implications by streamlining grading processes, reducing manual time and effort, and promoting standardization across varied clinical settings. We provide this tool to the scientific community alongside a comprehensive implementation guide, fostering its widespread adoption and enhancing reporting consistency for ICAHT.

Amsa/ARA-C Followed By TBI 4 Gy or High Dose Chemotherapy Conditioning Regimens in Primary Refractory AML - Significantly Worse Outcomes in Younger Patients Conditioned with 4 Gy TBI

Background: Allogeneic stem cell transplantation (allo-SCT) plays a fundamental role in the management of acute myeloid leukemia (AML) and is generally recommended for patients with primary induction failure. The optimal conditioning regimen in preparation for SCT in this specific difficult contex has been the subject of continued controversy. Specifically, the role of total body irradiation (TBI) or chemotherapy (CT) as part of sequential conditioning, continues to be central to this debate. With improvement in CT delivery and the introduction of intravenous (IV) busulfan, the utilization of TBI has decreased in popularity. This is a retrospective, multi-center, registry-based, European Society of Blood and Marrow Transplantation (EBMT) study which aimed to compare the outcomes of allo-SCT with amsacrine (AMSA) /cytarabine (ARA-C) followed by TBI conditioning to CT-based conditioning and thus determine certain prognostic factors that could potentially aid in the decision to implement TBI into a patient's conditioning regimen in preparation for allo-SCT. Patients and Methods: For this analysis, we identified 466 adult patients (58.8% male, median age: 55 years, range: 18-75) with primary refractory AML (73.6% de novo) transplanted between the years 2001 and 2021 (median: 2013) from matched sibling donors (MSD) or matched unrelated donors (MUD: 59.2%), who had received AMSA and ARA-C conditioning followed by CT or TBI sequential conditioning. In patients with available cytogenetic data, 50% had intermediate cytogenetics and 50% had poor cytogenetics. Karnofsky score at the time of transplant was >90 in 57.8% of the patients. The majority (73.1%) received a combination cyclosporine (CSA) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis and 92.7% underwent in vivo T-cell depletion. Results: Of the 466 eligible patients identified, 237 (50.8%) received sequential CT-based conditioning following high-dose AMSA/ARA-C with busulfan-fludarabine (BuFlu) or busulfan-cyclophosphamide-fludarabine (BuCyFlu) and 229 received sequential TBI-based conditioning following high-dose AMSA/ARA-C with a total of 4 Gy and cyclophosphamide-fludarabine (CyFlu). In univariate analysis, there was a significant difference in age between the two groups whereby patients receiving CT-based sequential conditioning were older (59.9 years vs 49.7 years, p<0.0001). Moreover, there was a significant difference in the proportions of MSD/MUD between the two groups with 67.9% being allografted from MUD in the CT group compared to 50.2% in the TBI group (p=0.0001). Given the significant interaction between age and conditioning (sequential TBI vs. CT), we stratified our sample by median age (<55 vs >= 55). In patients younger than 55 years, 2-year leukemia-free survival (LFS) was significantly higher in the CT group (51.9% vs 25.1%, p=0.002), as was overall survival (OS) (57.5% vs 38.3%, p=0.021). CT-based sequential conditioning was also associated with higher rates of grades II-IV and III-IV acute GVHD (38.1% vs 24.7%, p=0.02 and 19.8% vs 8.9%, p=0.022). In multivariate analysis, the use of TBI- vs CT-based sequential conditioning significantly influenced relapse (hazard ratio [HR] 1.98, p=0.018), non-relapse mortality (NRM: HR 2.7, p=0.038), LFS (HR 2.03, p=0.004), OS (HR 1.86 p=0.016) and acute GVHD II-IV (HR 0.45, p=0.014). Moreover, age (per 10 years) significantly impacted NRM (HR 2.42, p=0.0005), female to male donor impacted NRM (HR 2.41, p=0.032) and chronic GVHD incidence (HR 2.21, p=0.033) and in vivo T-cell depletion (TCD) impacted chronic GVHD (HR 0.32, p=0.03). In patients 55 years or older, there was no significant difference in post-allo-SCT outcome between patients who received TBI-based vs CT-based sequential conditioning. Conclusion: The above results highlight a significant difference in outcomes in AML patients receiving sequential TBI-based vs CT-based conditioning in preparation for allo-SCT according to age, whereby patients younger than 55 years had significantly worse outcomes after receiving TBI. This was not reflected in patients aged 55 years or more. Although only 4 Gy, these results emphasize the importance of age in the transplant physician's decision to incorporate TBI into conditioning regimens to optimize outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved Post-Transplant Outcomes in Recent Years for AML Patients with Intermediate Karyotype, FLT3-ITD and Wild Type NPM1: A Report from the EBMT Acute Leukemia Working Party

Rationale: Allogeneic hematopoietic cell transplantation (allo-HCT) is recommended in first complete remission (CR1) in acute myeloid leukemia (AML) patients harboring FLT3 internal tandem duplication (FLT3-ITD). However, historically, long-term survival has been poor due to early relapse, particularly for patients with wild-type NPM1. Recently, FLT3 inhibitors in combination with chemotherapy before allo-HCT, or as post-transplant maintenance, have significantly reduced the risk of relapse and improved survival. Here, we assessed real-world changes over time in transplant characteristics and post-transplant outcomes in young AML patients with FLT3 ITD and either NPM-1 mutated or wild type, using a large dataset from the European Society of Blood and Marrow Transplantation (EBMT) registry. Patients and Methods: We identified 1827 adult AML patients (54% female; median age 49 years, range 18-60) with FLT3 ITD, intermediate karyotype and available NPM1 mutation status, allografted between 2012 and 2021 in CR1 from a matched related (32%), matched unrelated (56%) or haploidentical donor (12%). NPM1 was mutated in 72% of patients. At transplant, 834 patients were measurable residual disease (MRD) positive, 464 MRD negative, and 529 were not evaluated or missing. Comorbidity index (CI) was zero in 59% of patients with available data. Conditioning was myeloablative (MAC) in 64% of patients. In vivo T cell depletion (TCD) graft was given to 62% of patients, post-transplant cyclophosphamide (PTCy) to 17%, and 87% received peripheral blood stem cells (PBSC). Most patients (66%) and donors (54%) were cytomegalovirus (CMV) positive. Median follow-up of alive patients was 30 months (IQR 28-32). Results: We compared changes in patient and transplant characteristics over time in 688 (38%) patients transplanted between 2012 and 2016 and 1139 (62%) patients transplanted between 2017 and 2021. Patients transplanted in recent years had a shorter follow up, were more likely to have NPM1 mutation, to be MRD positive, to have a higher CI, to receive a transplant from a haploidentical donor, a CMV positive donor, and to receive PBSC and PTCy. For patients with wild-type NPM1, day 100 acute graft-versus-host disease (GVHD) grade II-IV and grade III-IV were encountered in 29% and 11% of patients transplanted in 2021-2016, respectively, and 21% and 7% for patients transplanted in 2017-2021, respectively. The 2-year cumulative incidence of chronic and extensive chronic GVHD were 32% and 16%, respectively for 2012-2016 and 36% and 20%, respectively for 2017-2021. Over time, the 2-year cumulative incidence of relapse (CIR) significantly decreased from 43% to 31% between the two time periods (p<0.04) and non-relapse mortality (NRM) significantly decreased from 14% to 8% (p<0.05). The 2-year leukemia free survival (LFS) and overall survival (OS) significantly improved over time from 54% to 64% (p<0.02) and from 63% to 71% (p<0.05) respectively, whereas GVHD-free, relapse-free survival (GRFS) improved from 39% to 46% (p=0.08). In multivariate Cox analysis (MVA), transplantation in recent years significantly reduced the CIR (hazard ratio [HR]=0.65; p<0.01), and acute GVHD grade II-IV (HR=0.6; p<0.01) and significantly improved LFS (HR=0.67; p=0.02), OS (HR=0.66; p<0.03), and GRFS (HR=0.77; p<0.05). The use of unrelated donors increased the risk of acute GVHD but reduced the CIR whereas the use of haploidentical donors increased NRM. In vivo TCD reduced the risk of chronic GVHD whereas female donors to male recipients increased it. PTCy decreased the risk of NRM whereas MAC reduced the CIR. For patients with NPM1 mutation, no significant changes over time in post-transplant outcomes were noted except for decreased NRM from 15% for 217 patients transplanted in 2012-2016, to 10% for 288 patients transplanted in 2017-2021 (p<0.02). In MVA, transplantation in recent years did not significantly affect any of the post-transplant outcomes. Conclusion: In AML patients with FLT3 ITD and wild-type NPM1, we noticed a significant decrease over time in the CIR and a significant improvement of LFS, OS and GRFS, likely reflecting the efficacy of FLT-3 inhibitors, including when used as post-transplant maintenance, in this high-risk setting. On the contrary, no significant change over time was noticed in post-transplant outcomes of patients harboring NPM1 mutation.

Current Use of Androgens in Bone Marrow Failure Disorders: A Report from the Severe Aplastic Anemia Working Party (SAAWP) of the European Society of Blood and Marrow Transplantation (EBMT)

Anabolic steroids have been used for several decades in inherited and acquired bone marrow failure (BMF), due to their pleiotropic effects on erythrogenesis, telomere regulation and immune homeostasis. In some inherited disorders, mainly Dyskeratosis Congenita (DC) and Fanconi anemia (FA), they still represent one of the main non-transplant approaches, achieving satisfactory outcomes. In acquired setting, they have been used prior to the availability of anti-thymocyte globulin (ATG) and subsequently, in combination to it, or in refractory/relapsed patients with heterogeneous results. Albeit still in the armamentarium of possible therapeutic options for BMF, their place, optimal timing, and dosage have never been formally defined in aplastic disorders. Here we assembled the so far largest cohort of patients receiving androgens for an idiopathic or an inherited BMF, in order to track their current real-life use, indications, outcomes, and long-term effects in European and EBMT-affiliated centers. We collected data on 274 patients receiving an androgen treatment between 1990 and 2021 across 82 centers. Patients were diagnosed with a severe/very severe BMF in 74% of the cases. Etiology was acquired in 71% (N=192) and inherited in 29% (N=78, missing N=4), with, in this last group, FA (88%) and DC (11%) being predominant, followed by fewer other indications (1%). Male/Female ratio was 1.5. Median age at the time of androgen start was 32 (18-52) years for acquired and 8 (6-12) for inherited BMF, while median time from diagnosis to first androgen use was 4 (0.3-17.6) and 8.5 (0.4-34.9) months respectively. In most cases (78%), patients were transfusion-dependent upon treatment initiation; 91% of inherited versus 54% of acquired cases received androgens before other therapies. In the idiopathic setting these compounds were administered as 2nd ,3rd or further line in 23%, 13% and 10% of the patients, respectively. As to the type of molecules, oxymetholone was most commonly used (48%), followed by danazol (32%), norethandrolone (11%), nandrolone (2%), testosterone (4%) and others (3%). Overall, median duration of androgen treatment was 9 months (IQR:3-26). In 60% of the cases a concomitant immunosuppressive therapy (mainly cyclosporine) was administered. Median follow-up was 77.6 months (95% CI 65.3 - 96). At six months after androgen treatment, complete and partial response rates were 13% and 37% in acquired and 4.5% and 40.9% in inherited BMF patients respectively. In total, 160 patients of this cohort (58%) received an allogeneic hematopoietic cell transplantation (HCT) at the median time of 18.4 months (IQR: 7-43.9) from androgen initiation. The 5-year post-androgen cumulative incidence (CI) of clonal events (leukemic transformation or evolution to secondary PNH) was 1% (95%CI 0-2%) for PNH, 3% (1-6%) for MDS and 1% (0%-3%) for AML. Five-year failure free survival (probability of being alive after androgen treatment, without switching to further lines, including HCT), was 13% (95%CI 6-21%) for inherited and 23% (95%CI 16-30%) for acquired BMF. Five-year overall survival after androgen initiation was instead 79% (95%CI 69-88%) and 64% (95%CI 56-71%) respectively. Taking advantage of long-term follow-up data available for 89 patients, we were also able to highlight androgen-related toxicities that tended to occur with variable post-treatment intervals: while liver, renal and gastro-intestinal toxicities were encountered early after treatment initiation (at a median of 3.4, 5.4 and 6.4 months respectively), endocrinological and psychiatric effects were more delayed (occurring after a median of 15.1 and 18.1 months respectively). Liver dysfunction was the most frequent type of side effect (10%) at 1-year, followed by gastro-intestinal (3%) and renal toxicities (2%). Psychiatric and endocrine side effects were rare, reported in 1% and 2% of the cases respectively at 3 years. Solid neoplasms were also rarely observed (CI of 1% at 3 years before other treatments). In total 3 patients developed a neoplasia at any time during the follow-up. While still in use with a manageable level of toxicities, and low rate of clonal events and secondary neoplasia, this category of therapeutics remains associated with low response rates and its use should be carefully evaluated and reserved to selected cases both in idiopathic and inherited setting.

Antimicrobial prophylaxis in adults and children undergoing hematopoietic cell transplantation: 2021 Polish recommendations

Infections are still a major reason of morbidity and one of the most common causes of death after hematopoietic cell transplantation (HCT). Antimicrobial prophylaxis plays a crucial role in decreasing non-relapse mortality after HCT. The objective of this guideline paper is presentation of current recommendations of antimicrobial prophylaxis for children and adults after hematopoietic cell transplantation, prepared in cooperation of Polish scientific hematological societies. Recommendations were prepared by the working group and finally approved by all 23 Polish transplant centers for children and adults. Existing ECIL (European Conference on Infections in Leukemia) and EBMT (European Society of Blood and Marrow Transplantation) guidelines, as well as results of survey performed among all Polish transplant centers, were the background material for working group. Recommendations are presented in sections dedicated to antibacterial prophylaxis, antifungal prophylaxis, antiviral prophylaxis, as well as prophylaxis of toxoplasmosis and infections with Pneumocystis jiroveci. Recommendations on principles of vaccination against COVID-19 are provided based on the state of knowledge in September 2021. A section on guidelines of environmental prophylaxis is also presented.

Post-Transplant Cyclophosphamide in Acute Leukemia Patients Receiving More Than 5/10 HLA-Mismatched Allogeneic Stem Cell Transplantation: A Study on Behalf of the ALWP of the EBMT

BackgroundPost-transplant cyclophosphamide (PTCy) is a powerful strategy to prevent occurrence of graft-versus-host disease (GvHD) following allogeneic hematopoietic stem cell transplantation (HSCT). Initially developed in the setting of haploidentical HSCT, PTCy has been increasingly used for fully HLA-matched transplants with favorable results.The purpose of this retrospective multi-center study is to evaluate PTCy-based GvHD prevention for patients with acute leukemia receiving a traditionally prohibitive highly mismatched HSCT and to describe their outcome.MethodsThis is a registry-based study employing the data set of the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT). We retrospectively assessed the outcome of adult patients with acute myeloid or lymphoblastic leukemia (AML/ALL), transplanted between 2010 and 2020 with grafts from HLA-mismatched donors with more than 5/10 mismatches using PTCy-based GvHD prophylaxis.ResultsThe study cohort consisted of 59 patients, with a median time of follow up of 20 (95% CI, 14-39) months. The median age was 47 (range, 18-69) years. Forty-four patients had a diagnosis of AML, 14 of ALL and one case of mixed phenotype acute leukemia. At time of transplant, 39 (66%) were in first or second complete remission, 4 (7%) were in later remission and 16 (27%) had active, relapsed or refractory, disease. Conditioning regimens were myeloablative for 54% of cases and peripheral blood was the preferred source of stem cells (64%). All donors were related. Most patients (85%) received a 4/10 HLA-matched transplant, the most commonly mismatched loci were C and DQB1, often with a double mismatch involving the same locus. Two cases of fully mismatched donors were also recorded.PTCy was always associated with other immunosuppressive treatments, especially with the standard combination of calcineurin inhibitors and mycophenolate mofetil. In only 8 cases in vivo T-cell depletion was realized with anti-thymocyte globulin.A large proportion of patients (86%) attained engraftment with a median time of 19 (range, 11-37) days. Only 8 patients did not reach engraftment and all of them died of infection or disease relapse in the first one-hundred days (range, 6-99) after HSCT.Thirty-three patients (58%) did not present any sign of acute GvHD (aGvHD). Cumulative incidence of grade II-IV and grade III-IV aGvHD at day 180 were 30.3% and 14.3%, respectively. At 2 years, the cumulative incidence of chronic GvHD (cGvHD) was 21%, and 7% for extensive cGvHD.Twenty-four patients died during the study period, mostly because of leukemia progression (n=13, 54%), infectious complications (n=6, 25%) and interstitial pneumonia (n=2, 8%). Other causes of death were hemorrhage, GvHD, and another non HSCT-related that accounted for one case (4%) each. At 2 years, the overall survival (OS), leukemia-free survival (LFS), and a GVHD and relapse free survival (GRFS) were 56%, 54% and 47% respectively. Rates of relapse incidence and non-relapse mortality were 28% and 19%, respectively.ConclusionAccording to this preliminary data overview, transplantation in a highly mismatched framework is possible, without unfavorable OS, LFS and GVHD rates. Despite the important limitation of the retrospective non-controlled nature of this analysis, these findings suggest that PTCy-based strategies could help overcome the barrier of HLA-matching and configure a new setting of transplantation, encouraging more in-depth investigations. [Display omitted] DisclosuresLabopin: Jazz Pharmaceuticals: Honoraria. Angelucci: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene BSM: Honoraria, Other: DMC; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini-Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: steering commitee, Speakers Bureau; Vertex Pharmaceuticals: Honoraria, Other: DMC; Crispr therapeutics: Honoraria, Other: DMC; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Mohty: Takeda: Honoraria; Jazz: Honoraria, Research Funding; Gilead: Honoraria; Adaptive Biotechnologies: Honoraria; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Astellas: Honoraria.

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia with Monosomy 7 or Deletion 7q: A Study from the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT)

▪ INTRODUCTIONMonosomy 7 or deletion 7q (-7/7q-) is the most frequent high-risk cytogenetic feature reported in acute myeloid leukemia (AML) and is associated with a dismal outcome after chemotherapy alone. Allogeneic stem cell transplantation (SCT) appears to be the best consolidation strategy in these patients (pts), thereby significantly improving outcomes. Nevertheless, -7/7q- occurs frequently with other high-risk cytogenetic abnormalities such as complex karyotype (CK), monosomal karyotype (MK), monosomy 5 or deletion 5q (-5/5q-), 17p abnormalities (abn(17p)) or inversion/translocation of chromosome 3q26 (inv(3)). The presence of such abnormalities may further influence the outcomes of SCT in pts with -7/7q-. The purpose of this study was to evaluate the role of SCT in AML with -7/7q- in the context of additional cytogenetic abnormalities. METHODSWe selected adult pts with AML and -7/7q- reported to the EBMT registry with a complete cytogenetic report. We included only first SCT from a sibling or unrelated donor (UD) performed between 2000 and 2016. RESULTSA total of 1109 pts were identified. Median age at SCT was 52 year-old (range, 18-76) and median follow-up was 34 months (range, 0.7-193). A diagnosis of secondary AML was reported in 213 pts (19%). At the time of SCT, 702 patients (63%) were in first remission (CR1), 58 (5%) in subsequent remission and 349 (32%) had active disease. Four hundred ninety-six pts received SCT from a sibling donor (45%). Most pts had a Karnofsky's performance status (KPS) of more than 80% at the time of SCT (93%). A myeloablative conditioning regimen was administered in 50% of the pts. In vivo T-cell depletion was part of the regimen in 56% of the pts.The 2-year probability of leukemia-free survival (LFS) and overall survival (OS) were 30% and 36%, respectively. The 2-year probability of non-relapse mortality (NRM) was 20% and the 2-year cumulative incidence of relapse (RI) was 50%. The cumulative incidence of acute graft-versus-host disease (GvHD) was 31% and the 2-year cumulative incidence of chronic GvHD was 31%. The 2-year probability of GvHD and relapse-free survival (GRFS) was 21%. In multivariate analysis, age was not associated with any outcomes. Active disease was significantly associated with increased NRM and RI, which translated into worse LFS, OS and GRFS. Significant higher NRM was associated with UD. Secondary AML was associated with higher NRM and decreased OS. Better KPS correlated significantly with less NRM and better LFS, OS and GRFS.To evaluate the impact of additional cytogenetic abnormalities, we have been able to sort out 5 different groups within the entire cohort. The first group included 523 pts with -7/7q- with or without CK, but without any of the following chromosomal abnormalities: MK, -5/5q-, abn(17p) or inv(3). One hundred ninety-nine pts belonged to the second group that included pts with -7/7q- within MK but without -5/5q-, abn(17p) or inv(3). The third group included 151 pts with -7/7q- in association with -5/5q- but no abn(17p) or inv(3). Group 4 included 125 pts with -7/7q- and abn(17p) but without inv(3). Finally, 111 pts had inv(3) in addition to 7/7q- and were assigned to the fifth group. NRM was similar across all groups. The 2-year probability of LFS was 39.7% for group 1, 28.5% for group 2, 22.5% for group 3, 16.4% for group 4 and 13.7% for group 5 (p<0.001) (see figure). The 2-year probabilities of OS in the 5 groups were 47.7%, 34.9%, 28.2%, 15.9% and 19.7%, respectively (p<0.001). The corresponding 2-year probability of GRFS was 29.7% for group 1, 16.6% for group 2, 14.5% for group 3, 8.1% for group 4 and 8.9% for group 5 (p<0.001). Multivariate analysis confirmed those significant differences across groups. We observed comparable results when the analysis was focused on CR1 pts. CONCLUSIONSSCT in AML pts with -7/7q- provides durable response in one third of the pts. Disease status at the time of transplantation remains the strongest prognostic factor for poor outcomes. The presence of -7/7q- with or without CK in the absence of MK, -5/5q-, abn(17p) or inv(3) was associated with a better survival after SCT. On the contrary, addition of MK, -5/5q-, abn(17p) or inv(3) identifies a sub-group of pts that benefits less from SCT. In these pts, future efforts should focus on prevention of relapse by therapeutic modalities like early withdrawal of immunosuppression, administration of hypomethylating agents, donor lymphocytes infusion or others. [Display omitted] DisclosuresSocié:Alexion Pharmaceuticals, Inc.: Consultancy. Mohty:Sanofi: Honoraria, Speakers Bureau.

Diagnosis, grading and management of toxicities from immunotherapies in children, adolescents and young adults with cancer.

Cancer immunotherapies are associated with remarkable therapeutic response rates but also with unique and severe toxicities, which potentially result in rapid deterioration in health. The number of clinical applications for novel immune effector-cell therapies, including chimeric antigen receptor (CAR)-expressing cells, and other immunotherapies, such as immune-checkpoint inhibitors, is increasing. In this Consensus Statement, members of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Cell Transplantation-Cancer Immunotherapy (HCT-CI) Subgroup, Paediatric Diseases Working Party (PDWP) of the European Society of Blood and Marrow Transplantation (EBMT), Supportive Care Committee of the Pediatric Transplantation and Cellular Therapy Consortium (PTCTC) and MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program collaborated to provide updated comprehensive recommendations for the care of children, adolescents and young adults receiving cancer immunotherapies. With these recommendations, we address emerging toxicity mitigation strategies, we advocate for the characterization of baseline organ function according to age and discipline-specific criteria, we recommend early critical care assessment when indicated, with consideration of reversibility of underlying pathology (instead of organ failure scores) to guide critical care interventions, and we call for researchers, regulatory agencies and sponsors to support and facilitate early inclusion of young patients with cancer in well-designed clinical trials.

Outcomes of Allogeneic Hematopoietic Cell Transplantation with Cord Blood Versus Mismatched Unrelated Donor with Post-Transplant Cyclophosphamide in Acute Myeloid Leukemia: An Analysis from the ALWP of the EBMT

Outcomes of Allogeneic Hematopoietic Cell Transplantation with Cord Blood Versus Mismatched Unrelated Donor with Post-Transplant Cyclophosphamide in Acute Myeloid Leukemia: An Analysis from the ALWP of the EBMT

Outcome of Two Loci Mismatched (≤6/8) Unrelated Donor Hematopoietic Cell Transplantation for Acute Leukemia: ALWP of the EBMT Study

Outcome of Two Loci Mismatched (≤6/8) Unrelated Donor Hematopoietic Cell Transplantation for Acute Leukemia: ALWP of the EBMT Study

Sinusoidal Obstructive Syndrome Among Pediatric and Adolescent and Young Adult Patients: Analysis of Pediatric EBMT Diagnostic and Severity Criteria at MD Anderson

Background: Sinusoidal obstructive syndrome (SOS) is a potentially catastrophic complication of stem cell transplantation (SCT) which disproportionately affects younger patients. The incidence of SOS may vary widely depending on the diagnostic criteria (Baltimore versus Seattle), and delays in initiation of definitive treatment remains the most important predictor of outcome. Recently proposed pediatric diagnostic and severity grading criteria by the European Society of Blood and Marrow Transplantation (EBMT) may offer increased sensitivity and allow for more prompt diagnosis, but the extent to which these have been adopted and/or validated by centers in the United States is unclear. Methods: This is a retrospective analysis of all patients undergoing SCT on the Pediatric service at MD Anderson Cancer Center from 2009-2019. Patient records were reviewed for diagnosis of SOS. Among patients identified with SOS, application of Baltimore, Seattle and pediatric EBMT (pEBMT) criteria were compared. Descriptive statistics were used for data analysis where appropriate. Results: A total of 248 patients received 268 transplants during the study period. Patient characteristics are summarized in Table 1. When Baltimore criteria was used the incidence of SOS was 4.5% (n=12) as compared to 8.2% (n=22) when the Seattle or pEBMT criteria were applied. At diagnosis, the majority of these patients had moderate to very severe disease according to pEBMT criteria. The median time to diagnosis of SOS varied according to diagnostic criteria used, with a trend to earlier diagnosis with pEBMT criteria (13 days post-SCT with pEBMT versus 15 days with Seattle/Baltimore) as shown in Table II. Prior exposure to inotuzumab and gemtuzumab were associated with high rates of SOS (75% and 86% respectively). Anicteric SOS, refractory thrombocytopenia and rising bilirubin from a baseline value on 3 consecutive days or bilirubin ≥2 mg/dL within 72 hours were present in 63.6%, 77.3% and 91% of patients with SOS, when pEBMT criteria were applied. Late-onset SOS (diagnosed after 21 days post-SCT) was present in 22.7% of patients when Seattle or pEBMT criteria were applied (n=5) and could not be diagnosed per Baltimore criteria. Severe SOS was eventually observed in 95% of patients. Severe ascites requiring paracentesis (23%), impaired coagulation (77%), respiratory distress requiring supplemental oxygen and/or invasive pulmonary ventilation ( 55%), delirium (32%), acute kidney injury/KDIGO Stage 3/requiring renal replacement therapy (50%) were observed. Defibrotide treatment was initiated in 55% of patients with a median duration of treatment of 26 (3-74) days and complete resolution of SOS was observed in 42% of these patients. For patients who were initiated on defibrotide on the day of diagnosis (n=7) versus those who were not (range 1-11 days) the median time to complete resolution of SOS was 35 and 20 days respectively (p=0.2). Conclusions: To our knowledge, this is the first reported retrospective analysis of SOS among pediatric and adolescent young adult SCT patients in the United States using pEBMT SOS diagnostic and severity criteria. Our study was limited by small sample size associated with single center analyses. Use of the pEBMT criteria showed a trend to earlier time to diagnosis by a median of two days. This is a potentially clinically significant finding, as a delay in initiation of defibrotide among children with severe SOS, has been associated with statistically significant decreased rates of complete resolution. Inherent flaws of the Baltimore and Seattle criteria are the time restriction and reliance of hyperbilirubinemia for the diagnosis in children and adolescents and young adults. Our retrospective analysis suggests that pEBMT criteria for the diagnosis of SOS among children and young adults may be appropriate, especially given the rates of anicteric and late-onset SOS seen in this population. Disclosures Petropoulos: Foundation for the Accreditation of Cellular Therapy (FACT): Membership on an entity's Board of Directors or advisory committees, Other: Foundation for the Accreditation of Cellular Therapy (FACT). Kebriaei:Amgen: Research Funding; Jazz: Consultancy; Pfizer: Honoraria; Kite: Honoraria. Wierda:Xencor: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; AbbVie: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding. Mahadeo:Recipient of unrestricted medical education grant from Jazz: Research Funding; PI for ATARA EBV CTL Trials: Other: Other .

Reduced Intensity Vs. Myeloablative Conditioning Followed By Allogeneic Stem Cell Transplantation for Patients with Myelodysplastic Syndrome: Long Term Follow-up of a Prospective Randomized EBMT Phase III Study (RICMAC-Trial)

IntroductionRetrospective studies in MDS/sAML suggest that reducing the intensity of the conditioning regimen prior to allogeneic stem cell transplantation reduces the risk of non-relapse mortality but is associated with a higher risk of relapse. A higher risk of relapse after RIC was confirmed in a prospective BMT CTN study but the prospective randomized studies from the EBMT for MDS and sAML did not show a difference in outcome after 2 years (J Clin Oncol. 2017 Jul 1;35(19):2157-2164). Here we present a long term follow-up of the study after a median follow-up of 75 months (range 4-150 months).MethodsWithin the European Society of Blood and Marrow Transplantation (EBMT) we conducted a prospective, multicenter, open label, randomized phase III trial comparing comparing a busulfan based (Busulfan 8mg/kg orally or equivalent dosis intravenously (iv) plus fludarabin 180mg/m²) reduced intensity conditioning regimen (RIC) and a standard myeloablative busulfan (Busulfan 16mg/kg orally or equivalent dosis iv plus cyclophosphamide 120mg/kg) based regimen (MAC) in patients with MDS or sAML (<20 % blasts). Between May 2004 and December 2012, a total of 129 patients were enrolled from 18 centers. Patients were randomly assigned in a 1 : 1 ratio and stratified according to donor, age and blast count.ResultsIn the first report (JCO 2017) the CI of NRM after 1 year was 17% (95% CI 8-26%) after RIC and 25% (95% CI 15-36%) after MAC (p = 0.29). The CI of relapse at 2 years was 17% (95% CI 8-26%) after RIC and 15% (95% CI 6-24%) after MAC (p = 0.6), resulting in a 2 year relapse-free and overall survival of 62% (95% CI 50-74%) and 76% (95% CI 66-87%) after RIC and 58% (95% CI 46-71%) and 63% (95% CI 51-75%) after MAC (p = 0.58 and p = 0.08, respectively). In the current follow-up study, all cases but one who were alive at last report could be updated. The median follow-up is now 75 months in the MAC and 72 months in the RIC arm. Since last follow-up =18 death occurred in both arm (MAC n=8, RIC n=10) 8 relapses (MAC n=4; RIC n=4) and 6 NRM (MAC n=2; RIC n=4). Second allogeneic stem cell transplantation was performed in 18 patients (n=10 in RIC and n=8 in MAC) due to graft failure (n=4) relapse (n=11) and others (n=3). The CI of chronic GvHD at 5 years was 65% (95% CI: 53-78) after RIC and 68% after MAC ((95% CI: 55-81; p = 0.70). At 5 years there was no difference in CI of NRM (22%, 95%CI: 12-32 vs 30% , 95%CI : 19-42, p=0.5) in CI of Relapse (22% , 95% CI: 12-32 vs18%, 95% CI: 8-28, p= 0.7), Relapse free- (57%, 95% CI: 44-69 vs51%, 95% CI: 39-64, p=0.8) and Overall survival (69%, 95% CI: 58-80 vs 53%, 95% CI: 40-65, p=0.15) between RIC and MAC, respectively.ConclusionThis long term follow-up of the prospective randomized EBMT trial confirmed early results that RIC resulted in at least similar long term relapse-free and overall survival as MAC in patients with MDS or sAML. The trial was registered under ClinicalTrials.gov Identifier: NCT01203228. DisclosuresNiederwieser:Miltenyi: Speakers Bureau; Novartis: Research Funding. Platzbecker:Celgene: Research Funding. Scheid:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria. Stelljes:MSD: Consultancy; Amgen: Honoraria; JAZZ: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Heim:Novartis: Research Funding. Bethge:Miltenyi Biotec GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding. Kobbe:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding.

Incidence of Post-Hematopoietic Stem Cell Transplantation (HSCT) Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) without Hyperbilirubinemia at Diagnosis and Efficacy of Defibrotide in an Expanded-Access Program

IntroductionHepatic VOD/SOS is a progressive, potentially life-threatening complication early post-HSCT, or of nontransplant chemotherapy. VOD/SOS diagnosis has been based on Baltimore (≤21 days post-HSCT and bilirubin ≥2 mg/dL plus ≥2 of: hepatomegaly, ascites, weight gain ≥5%) or modified Seattle (≤20 days post-HSCT and ≥2 of: bilirubin >2 mg/dL, hepatomegaly or right upper quadrant pain, weight gain [>5% in defibrotide studies]) criteria. Recent European Society of Blood and Marrow Transplantation (EBMT) VOD/SOS guidelines require elevated bilirubin only for adults diagnosed ≤21 days post-HSCT (the literature suggests bilirubin <2 mg/dL before Day +21 is uncommon) but not for adults with late-onset (diagnosis >21 days post-HSCT) or pediatric patients (~30% of pediatric patients present with anicteric VOD/SOS [ie, bilirubin <2 mg/dL]). EBMT notes that hyperbilirubinemia may be a late finding in the progression of VOD/SOS. Defibrotide is approved to treat hepatic VOD/SOS with renal and/or pulmonary dysfunction post-HSCT in the United States and Canada, and to treat severe hepatic VOD/SOS post-HSCT in patients aged >1 month in the European Union. This post hoc analysis examines incidence of VOD/SOS without elevated bilirubin, and survival in defibrotide-treated, post-HSCT patients in the T-IND program (2007-2016).MethodsPrior to US approval, defibrotide was available through the T-IND expanded-access program. The original protocol required VOD/SOS post-HSCT diagnosed per Baltimore criteria (which require hyperbilirubinemia) or biopsy, and multi-organ dysfunction (MOD). The protocol was amended to include patients without MOD (2009) and with VOD/SOS per modified Seattle criteria (which do not require hyperbilirubinemia; 2012). Patients received defibrotide 25 mg/kg/day (6.25 mg/kg q6h) recommended for ≥21 days.ResultsOf 991 patients in the T-IND with VOD/SOS post-HSCT and recorded bilirubin level at diagnosis, 190 (19%) had bilirubin <2 mg/dL (breakdown by subgroups in the Table), and 801 (81%) had bilirubin ≥2 mg/dL. Of those with bilirubin <2 mg/dL, 133 were pediatric patients aged ≤16 years (24% of all post-HSCT pediatric patients with recorded bilirubin [n=564]), and 57 were adult patients aged >16 years (13% of all post-HSCT adult patients with recorded bilirubin [n=427]). Diagnosis by Day +21 post HSCT (ie, not late onset) was recorded for 135/190 (71%) patients with bilirubin <2 mg/dL (107/133 [80%] pediatric patients; 28/57 [49%] adults).In the overall post-HSCT group treated with defibrotide in the T-IND (n=1000; with and without elevated bilirubin at diagnosis, including 9 patients without bilirubin measurement at diagnosis), Kaplan-Meier estimated Day +100 survival was 58.9% (95% confidence interval [CI], 55.7%-61.9%). Kaplan-Meier estimated Day +100 survival was 85.6% (95% CI, 79.7%-89.9%) for the 190 patients with bilirubin <2 mg/dL at diagnosis and 52.3% (95% CI, 48.7%-55.7%) for the 801 patients with bilirubin ≥2 mg/dL (survival by age subgroups in the Figure). In the overall population of patients with bilirubin <2 mg/dL, 61.1% and 18.4% of patients had ≥1 treatment emergent adverse event (TEAE) and ≥1 treatment related adverse event (TRAE), respectively, and 21.1% had ≥1 hemorrhage event; for patients with bilirubin ≥2 mg/dL: 73.8% had ≥1 TEAE, 21.7% had ≥1 TRAEs, and 31.1% had ≥1 hemorrhage event.Conclusions:In the T-IND, 19% of post-HSCT patients with VOD/SOS had bilirubin <2 mg/dL at diagnosis, including 24% of children. Accordingly, 190 patients would not have been diagnosed if hyperbilirubinemia was a required criterion. Moreover, enrollment prior to 2012 required hyperbilirubinemia (or biopsy), so this percentage may understate the incidence of anicteric VOD/SOS. Of patients with bilirubin <2 mg/dL, 80% of pediatric patients and 49% of adults were diagnosed with VOD/SOS by Day +21 post-HSCT, suggesting that anicteric VOD/SOS may develop in this timeframe not only in pediatric patients but also in a sizeable number of adult patients. Defibrotide showed higher survival in patients with bilirubin <2 mg/dL compared to those with levels ≥2 mg/dL. These results compare favorably with the overall study findings, suggesting that treatment before the onset of hyperbilirubinemia may lead to better outcomes. The safety profile of the T-IND was similar to that of previous studies of defibrotide for the treatment of VOD/SOS.Support: Jazz Pharmaceuticals. [Display omitted] DisclosuresCorbacioglu:Gentium: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria. Kernan:National Cancer Institute: Research Funding. Pagliuca:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ryan:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Tappe:Jazz Pharmaceuticals: Employment, Other: Stock and stock options. Richardson:Karyopharm: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Comorbidity-Associated Risk of Overall Mortality Following Hematopoietic Stem-Cell Transplantation Is Regimen-Dependent: A Study from the Acute Leukemia Working Party of the EBMT

▪Background: Toxicities following allogeneic hematopoietic stem cell transplantation are specific to the conditioning regimen used and its intensity. Therefore, we hypothesized that the hazard of individual comorbidities is dependent on the conditioning agents and their dose. The aim of this analysis was to study, in a regimen specific manner, the impact of individual comorbidities (cardiac disease, severe pulmonary disease, and diabetes mellitus) on mortality.Methods: We included a multi-center cohort of 3,338 patients from the registry of the Acute Leukemia Working Party of the European Society of Blood and Marrow Transplantation (EBMT), who underwent first allogeneic HSCT for treatment of AML in all disease stages, transplanted between 2005 and 2016. Patients included received grafts from a matched sibling or 10/10 HLA-allele matched unrelated donor, and who were conditioned using one of 7 common regimens (Busulfan [BU[/Cyclophposphamide [Cy], Cy/Total Body Irradiation [TBI], Flu [Fludarabine]/Bu at reduced-intensity [RIC] dosage, Flu/Bu at myeloablative [MAC] dosage, Flu/Melphalan [Mel], Flu/Treosulfan [Treo], Flu/TBI). Regimens were excluded from a given analysis if fewer than ten overall mortality events occurred among patients with or without the studied condition. We constructed a multivariable Cox model for the outcome of overall survival, adjusted for key transplantation variables, including patient age, disease status, and donor type among others. For each comorbidity, separate models were constructed within each of the seven regimens, and the comorbidity's hazard ratio was extracted. Using the same method, the hazard ratio across all regimens, as well as in the myeloablative and the reduced-intensity setting, was obtained.Results: The median age was 55 years; 70% of patients were in first complete remission (CR), and 54% of patients received grafts from matched sibling donors. The most common regimens studied were Flu/Bu at a reduced-intensity dose (22%), Flu/Mel (20%) and Bu/Cy (16%, Table 1). We find that the studied comorbidities were associated with different degrees of added risk for overall mortality in each regimen studied. For cardiac disease, hazard ratios (HR) ranged from 1.00 (95% CI: 0.63-1.60) in Flu/Treo to 1.65 (1.15-2.36) in Flu/Bu with myeloablative dose (Figure 1). Among patients with severe pulmonary disease, significant increases in hazard were seen only in patients treated with myeloablative Flu/Bu and Flu/Mel. In diabetes mellitus, no regimens were clearly associated with increased risk of overall mortality. However, Flu+TBI trended strongly toward increased risk with an HR of 1.55 (1.00-2.41, p = 0.051). Greater comorbidity-associated risk was not consistently associated with increasing conditioning, and the hazards associated with each comorbidity in the MAC and RIC settings were broadly overlapping. Similar trends were seen for the outcome of non-relapse mortality, although statistical significance (p < 0.05) was not observed in the setting of low event numbers.Conclusions: These results confirm our hypothesis that comorbidities exert an effect on transplantation outcome in a conditioning regimen-specific manner. Additional study, both retrospective, and prospective, may eventually allow for the precision selection of a conditioning regimen based on the individual patient's physiological status. [Display omitted] DisclosuresFinke:Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Malladi:Roche: Membership on an entity's Board of Directors or advisory committees. Mohty:MaaT Pharma: Consultancy, Honoraria.

European experience and risk factor analysis of donor cell-derived leukaemias/MDS following haematopoietic cell transplantation.

Donor cell leukaemia (DCL) is a rare complication of allogeneic haematopoietic cell transplantation (HCT). We have investigated the prevalence and outcome of donor cell haematology malignancies within centres registered with the European Society of Blood and Marrow transplantation (EBMT). We have sought to identify risk factors to shed light on the pathogenesis of DCL as a model for leukaemogenesis. DCL cases were identified by questionnaire and a follow-up questionnaire requested detailed data. Control subjects from the EBMT registry who had not developed DCL were used for a matched pair analysis to identify risk factors. We identified 38 patients with DCL; the estimated prevalence was 80.5/100,000 transplants. Patients were predominantly treated for haematological malignancy. A clone was retrospectively identified in 7/25 (28%) donors for whom data was available. Overall survival was poor with 29/38 patients dead a median of 11 (range 0-91) months after DCL diagnosis. Matched case-pair analysis identified three factors on multivariate analysis as significantly associated with an increased risk for DCL: use of growth factors within the first 100 days after transplantation, in vivo T-cell depletion and multiple allografts. The risk factors identified, support reduced immune surveillance and replicative stress as pathogenic in the development of DCL.

T‐cell–depleted haploidentical stem cell transplantation results improve with time in adults with acute leukemia: A study from the Acute Leukemia Working Party of the European Society of Blood and Marrow Transplantation (EBMT)

T-cell-depleted, haploidentical transplantations (haplos) are commonly offered to patients who have high-risk, acute leukemia in the absence of a human leukocyte antigen (HLA) full-matched donor. To determine the effect of transplantation period, the authors divided 308 adults with de novo, acute leukemia who underwent T-cell-depleted haplo from 2005 to 2015 into 2 groups, according the year in which they underwent transplantation (2005-2011 [n = 191] and 2012-2015 [n = 117]). The median age was 41 years in patients who underwent transplantation before 2012 and 46 years in those who underwent transplantation after 2012 (P = .04). Most patients had acute myeloid leukemia (75% vs 69%; P = .26) and were in first complete remission (CR1) (55% vs 64%; P = .12) at the time of transplantation. The cumulative incidence of grade 2, 3, and 4 acute graft-versus-host disease (GvHD) and chronic GvHD were not different between the 2 groups (acute GvHD: 20% vs 22% cumulative incidence in patients who underwent haplo before and after 2012, respectively [P = .67]; chronic GvHD: 19% vs 11% cumulative incidence, respectively; P = .12]. The 2-year relapse incidence was 20%, the nonrelapse mortality (NRM) rate was 48%, and no difference was observed over time (21% vs 19% [P = .72] and 54% vs 38% [P = .11] for patients who underwent haplo before and after 2012, respectively). The main cause of NRM was infection. Haplo after 2012 (hazard ratio [HR], 0.57; P = .01), younger age (HR, 0.82; P = .02), and receipt of a reduced-intensity conditioning (RIC) regimen (HR, 0.53; P = .01) were independently associated with lower NRM. The 2-year overall survival rate was 36% and improved after 2012 (29% vs 47% before 2012; P = .02); and it was higher for patients who underwent transplantation in CR1 (41% vs 29%; P = .01). In multivariate analysis, haplo after 2012 (HR, 0.54; P = .003) and receipt of a RIC regimen (HR, 0.54; P = .005) were independently associated with better overall survival. Similarly, leukemia-free survival and GvHD-free/relapse-free survival (GRFS) improved over time: the leukemia-free survival rate was 31% (25% vs 43% in the groups who underwent transplantation before and after 2012, respectively; P = .05), and the GRFS rate was 24% (19% vs 34%, respectively; P = .09). In addition, leukemia-free survival and GRFS improved among patients who received a RIC regimen. The outcome of patients with acute leukemia who underwent T-cell-depleted haplo has improved over time. Cancer 2018;124:2142-50. © 2018 American Cancer Society.

Comparison of Allogeneic Stem Cell Transplantation for Transformed Acute Myeloid Leukemia Derived from MDS, CMML or MPN. a Report of the Chronic Malignancies Working Party of EBMT

IntroductionMyelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukemia (CMML) can progress to acute myeloid leukemia (transformed AML). The aim of this EBMT registry study was to compare 3 year outcome in patients with transformed AMLwho received allogeneic stem cell transplantation according to the primary disease.Patients and MethodsWithin the European Society of Blood and Marrow Transplantation (EBMT) registry, we found 4214 patients (female: 39%, male: 61%) with transformed acute myeloid leukemia, who received allogeneic stem cell transplantation between 2000 and 2014. The primary disease was MDS (n=3541), CMML (n=251) or MPN (n=422). The median age at transplantation was 58 years (range, 18-79) and 59% received a reduced intensity (RIC) conditioning regimen. The majority of the patients received stem cells from an unrelated donor (62%) and 50% were in complete remission at time of transplantation. Within the different groups of primary diseases, MDS patients were more often in CR (53%) than patients with CMML (47%) or MPN (43%). RIC was also more frequently used in MDS patients (65%), than in CMML (64%) and MPN patients (58%).ResultsAfter a median follow up of 46.5 months , the estimated 3 year relapse-free (RFS) and overall survival (OS) for the entire group was 36% (95%CI: 34-38%) and 40% (95% CI: 33-42%), respectively.The cumulative incidence of relapse and non-relapse mortality (NRM) was 37% (95% CI: 35-39%) and 27% (95% CI: 26-29%), respectively.In a univariate analysis, patients with primary disease MDS had a significant better 3 year OS and RFS (41% and 37%) than patients with CMML (36% and 30) and MPN (32% and 25%) (p<0.001), due to a significant lower incidence of relapse at 3 years (35% vs 43% vs 50%, p<0.001). Other risk factors for worse OS were higher patient’s age (>60 years), unrelated donor, not being in complete remission and low Karnofsky index (< 80%), while T-cell depletion, intensity of the conditioning regimen and TBI as conditioning regimen did not influence survival significantly.In a multivariate analysis for OS beside age >60 years (HR 1.31; 95% CI: 1.13-1.52, p<0.001), unrelated donor (HR 1.12; 95% CI: 1.04-1.23, p=0.005), CMV +/- constellation (HR 1.13; 95%CI: 0.99-1.28, p=0.05), Karnofsky index > 80 (HR 0.66; 95% CI: 0.58-0.74, p< 0.001), non CR (HR 1.50; 95% CI: 1.38-1.63, p<0.001) PBSC as stem cell source (HR 0.86; 95% CI:0.75-0.97, p=0.02) and transformed AML from MPN (HR 1.24; 95% CI: 1.085-1.41, p=0.002) remained a significant factor in comparison to transformed AML from MDS, while outcome of transformed AML from CMML did not reach statistical significance in comparison to MDS (HR 1.10; 95% CI: 0.933-1.30, p=0.25)ConclusionThis large EBMT registry study demonstrates that the primary underlying disease influence outcome of transformed acute myeloid leukemia in addition to other risk factors. DisclosuresKröger:Novartis: Honoraria, Research Funding. Maertens:Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy. Kobbe:Jansen: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding.

Autologous Versus Related Versus Unrelated Hematopoietic Stem Cell Transplantation for Adult Patients with NPM1 Mutated/FLT3-ITD Negative Acute Myeloid Leukemia in First Remission: A Study from the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT)

Introduction: Acute myeloid leukemia (AML) in first remission (CR1) with intermediate-risk cytogenetics and isolated NPM1 mutation carries a good prognosis. There is not a clear benefit to perform allogeneic stem cell transplantation (allo-SCT) in CR1, and this procedure is not usually recommended in these patients. High dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) is a good therapeutic alternative in good-risk AML in CR1 associated with lower toxicity. Nevertheless, relapse remains as high as 40% in this subgroup. To evaluate the best consolidation strategy in AML with isolated NPM1 mutation, we retrospectively compared auto-SCT, related (MRD) and fully matched (10/10) unrelated (MUD) allo-SCT within the EBMT registry.Methods: We selected de novo adult AML with intermediate-risk cytogenetics harbouring an isolated NPM1 mutation without FLT3-ITD and transplanted in CR1 between 2005 and 2015.Results: Two hundred and fifty-six patients have been allocated. One hundred and twenty-five patients received an auto-SCT, 72 a MRD and 59 a MUD. Median age at SCT was 52.5-year-old (range, 18.9-77) and median follow-up was 30 months (range, 1.6-109.7). A normal karyotype was found in 86% of auto-SCT and 74% of allo-SCT (p=0.02). Molecular status was available in 55% of patients, with a higher proportion of complete molecular remission (CMR) before auto-SCT than before allo-SCT (84% versus 63%, respectively, p=0.005). There was no difference in the number of induction courses to reach CR1 between groups. The majority of patients have a good performance status at the time of SCT. Peripheral blood was more frequently used as stem cell source in auto-SCT compared to allo-SCT (97% versus 77%, respectively, p<0.01). Total body irradiation was administered in 23% of allo-SCT and in 3% of auto-SCT (p<0.01). Among allo-SCT, a myeloablative conditioning regimen was administered in 57% of the patients. In vivo T-cell depletion was more frequently in MUD than in MRD (70 versus 40%, respectively, p=0.001).The 2-year leukemia-free survival (LFS) was 62% in auto-SCT, 69% in MUD and 81% in MRD (p=0.02 for MRD versus auto-SCT or MUD). The 2-year overall survival (OS) was not significantly different among auto-SCT, MUD and MRD, reaching 82%, 81% and 85%, respectively (p=0.88). The 2-year non-relapse mortality (NRM) was 2.5% in auto-SCT and 7.5% in allo-SCT (p=0.04), without any difference between MRD and MUD. The 2-year cumulative incidence of relapse (RI) was significantly higher after auto-SCT (30%) than after MUD (22%) and MRD (12%, p=0.01). Among patients transplanted in CMR, RI was higher after auto-SCT and LFS was superior after allo-SCT (RI: 21 vs. 11 vs 4%; LFS: 61 vs 74 vs. 91 after auto-SCT, MUD, and MRD, respectively, p=0.04), although this difference did not translate into a different OS (82 vs. 77 vs. 90 after auto-SCT, MUD, and MRD, respectively). In the 28 patients not transplanted in CMR who received an allo-SCT, 2-year RI, LFS and OS were 33% (15-53), 63 (43-83), and 81 (65 - 96%), whereas only 10 patients with persistant MRD received an auto-SCT precluding firm conclusions.In multivariate analysis, MRD versus auto-SCT but not MUD versus auto-SCT was significantly associated with a lower RI (p<0.01 and p=0.13, respectively) and a better LFS (p=0.01 and p=0.31, respectively). Age correlated significantly with higher NRM (p<0.01). Donor type, and age were not significantly associated with OS.Conclusion: Allo-SCT using a sibling donor appears as a good consolidation therapy to prevent relapse for young patients with AML and isolated NPM1 mutation in CR1. Auto-SCT was followed by higher relapse risk and inferior LFS, but similar OS to both allo-SCT modalities. In patients with molecular persistence, allo-SCT was followed by a relatively favourable outcome, but the low number of patients with molecular data included in this series precludes more firm conclusions. The strategy for patients not transplanted in CMR remains to be further evaluated. DisclosuresMaertens:Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy; Astellas: Consultancy, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau. Baerlocher:Geron: Research Funding; Novartis: Research Funding; Janssen: Research Funding.

Allogeneic Stem Cell Transplantation As Salvage Therapy for First Relapse after Autografting in Multiple Myeloma Patients

Despite the significant improvement in outcomes for myeloma patients (pts) in the more recent years (yrs), the disease remains incurable. Because of high morbidity and mortality the role of allo-SCT in treatment of myeloma remains controversial. Registry data from the European Society of Blood and Marrow Transplantation (EBMT) suggest an increasing use of allo-SCT as salvage therapy after failure to auto-SCT. In present single center study we provide data on the use of allo-SCT focusing on pts with first relapse/progressive disease after autografting.A total of 89 pts (males, 62%) with median age of 53y (24-73) relapsed after an autograft (single, 64%; tandem, 36%) and received an allo-SCT during 2000 - 2015 yrs at University of Hamburg were included. The majority of the pts experienced advanced disease (stage III, 80%) and short remission duration after auto-SCT (≤24 mo, 81%) with median of 15 mo (2-91). A total of 76% of pts received a reinduction therapy prior to allo-SCT, whereas 24% did not. Twelve pts (14%) had high risk cytogenetics (defined as detection of del17p and/or t(4;14) by FISH). Twelve pts experienced extramedullary relapses. At time of transplantation pts were in CR (10%), vgPR (22%), PR (27%), SD (16%) or PD (25%). Allo-SCTs were performed mostly with peripheral stem cell (92%) and from unrelated (matched, 40%; mismatched, 32%) donors. Myeloablative conditioning was used in 70% of pts (busulfan-based, 61%; treosulfan-based, 9%). A total of 28 pts (31%) received a maintenance therapy (lenalidomide, 79%) starting at median 6 mo (4-8) post-transplant. Furthermore, 19 pts (24%) received DLIs (positive immunofixation, n=15; prophylaxis, n=4) within a median of 10 mo (4-27).The cumulative incidence (CI) of acute GvHD (grade II-IV) at d100 was 43% (32-55%). The CI of chronic GvHD at 5y post-transplant was 51% (39-63%; mild, n=19, moderate, n=12, severe, n=5). Of the 19 pts receiving DLIs, 5 (26%) developed GvHD (grade II-IV). Six (40%) of 15 pts responded (CR).The CI of TRM at d100 and at 5y were 8% (4-16%) and 19% (12-28%), respectively. We observed improved TRM in pts who didn’t receive radiation before allo-SCT (p=0,03). The CI of relapses at 5y was 61% (49-72%). We observed a trend to lower relapse rate of 29% in pts with longer remission duration (>24 mo, p=0,07).The 5y probability of EFS was 28% (19-39%). The median EFS was 29 mo (22-36). In univariate analysis, we observed decreased survival probability for pts with high risk cytogenetics (p=0,026), remission duration ≤24 mo (p=0,008) and non-responders to salvage therapy (p=0,037). In multivariate analysis the negative impact of remission duration ≤24 mo (HR 6,9; 1,8-25,6; p=0,004) and failure to salvage therapy (HR 3,3; 1,2-9,0; p=0,021) were confirmed. In landmark analysis at d100 we observed improved survival for responding pts (p<0,001), pts in CR (p=0,028), those in "stringent" CR compared to CR (p=0,014) and those with negative MRD (minimal residual disease, FACS, p=0,037). Intriguingly, the median EFS for pts in "stringent" CR was not reached. In landmark analysis at 6 mo we observed improved survival for pts receiving preemptive/prophylactic DLIs (p=0,045).After a median follow up of 48 mo (6-170), the 5y probability of OS was 57% (46-78%). The median OS was 76 mo (42-110). In univariate analysis, we observed decreased survival probability for pts with extramedullary relapse (p=0,039), high risk cytogenetics (p=0,001), remission duration ≤6 mo (p=0,044) and those who received reduced intensity conditioning (p=0,022). In multivariate analysis the negative impacts of extramedullary relapses (HR 7,3; 2,7-20; p<0,001), reduced intensity conditioning (HR 3,5; 1,4-8,5; p=0,006) and short remission duration (HR 2,6; 1,1 - 6,2; p=0,038) were confirmed. In landmark analysis at d100 we observed improved survival for responding pts (p<0,001), pts in CR (p=0,028) and those in "stringent" CR compared to CR (p=0,014). In landmark analysis at 6 mo we observed improved survival for pts receiving DLIs (p<0,001) and maintenance therapy (p=0,002).Allo-SCT being performed as salvage therapy after autograft failure resulted in around 30% 5y EFS. The response on d100 post-transplant, augmented by the MRD detection, seems to be prognostic important and might be used for planning further therapeutic strategies post-transplant. The use of DLIs and maintenance therapy post-transplant represent a possible approach to further improve survival. DisclosuresKröger:Sanofi: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Allogeneic Stem Cell Transplantation in Adult Patients with Acute Myeloid Leukemia and 17p Abnormalities in First Complete Remission: A Study from the Acute Leukemia Working Party (ALWP) of the European Society of Blood and Marrow Transplantation (EBMT)

Introduction: Acute myeloid leukemia (AML) with 17p abnormalities (abn(17p)), usually affecting TP53 locus, carries a very poor prognosis due to high refractoriness to conventional chemotherapy, with long-term survival of less than 5%. Allogeneic stem cell transplantation (SCT) appears as the only potential curative option in high-risk AML. To specifically address outcomes after SCT in patients with abn(17), we retrospectively analysed data from the EBMT registry.Methods:De novo or secondary AML with abnormal karyotype transplanted between 2000 and 2013 have been allocated. From a dataset of 5495 patients with AML undergoing SCT, we included only those patients for whom data were sufficient to confirm the presence of abn(17p) resulting in a loss or a disruption of the TP53 locus.Results: One hundred thirty-nine patients have been selected including 125 patients (90%) in first remission (CR1) and 14 (10%) in second remission. For further analysis, we focused on the 125 patients in CR1. Median age was 54 (range, 18-69) year-old and the median follow-up was 21 (range, 3-146) months. Eighty-five percent of the patients had a de novo AML, while 15% had a secondary AML. Abn(17p) was associated to a monosomal karyotype in 83% of patients, complex karyotype in 91%, monosomy 5 or 5q deletion (-5/5q-) in 55%, monosmy 7 (-7) in 39% and both -5/5q and -7 in 27%, respectively. Median time from diagnosis to CR1 was 57 (range, 18-170) days. Fifty-one (41%) of the patients received a myeloablative conditioning regimen and 73 (59%) had a reduced-intensity conditioning regimen. The vast majority of patients (70%) had a karnofsky performance status of more than 90% at the time of SCT. The 2-year overall survival (OS) and leukemia-free survival (LFS) were 28% and 24%, respectively. The 2-year non-relapse mortality (NRM) was 15%, and 2-yr relapse incidence (RI) was 61%. The cumulative incidence of grade II to IV acute graft-versus-host disease (GvHD) was 24% and that of chronic GvHD was 21%.In multivariate analysis, the presence of a -5/5q- in addition to abn(17p) was significantly and independently associated with worse OS, LFS and higher RI. Age and donor type did not correlate with outcome. Conditioning intensity was not statistically associated with OS, LFS and NRM when adjusted for patients'age.Conclusion: In contrast to the dismal prognosis reported for AML patients harboring abn(17p) undergoing conventional chemotherapy, allogeneic SCT provides long-term responses in about 25% of a selected group of patients harboring this cytogenetic abnormality at diagnosis and transplanted in CR1. Post and pre transplant targeted therapy may further improve results. DisclosuresMilpied:Celgene: Honoraria, Research Funding.