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The role of allogeneic hematopoietic stem cell transplantation (allo-SCT) in multiple myeloma is controversial. We analyzed the results of 205 patients transplanted in one center during 2000–2017. Transplantation was performed on 75 patients without a previous autologous SCT (upfront-allo), on 74 as tandem transplant (auto-allo), and on 56 patients after relapse. Median overall survival (OS) was 9.9 years for upfront-allo, 11.2 years for auto-allo, and 3.9 years for the relapse group (p = 0.015). Progression-free survival (PFS) was 2.4, 2.4, and 0.9 years, respectively (p < 0.001). Non-relapse mortality at 5 years was 8% overall, with no significant difference between the groups. Post-relapse survival was 4.1 years for upfront-allo and auto-allo, and 2.6 years for the relapse group (p = 0.066). Survival of high-risk patients was reduced. In multivariate analysis, the auto-allo group had improved OS and chronic graft-versus-host disease was advantageous in terms of PFS, OS, and relapse incidence. Late relapses occurred in all groups. Allo-SCT resulted in long-term survival in a small subgroup of patients. Our results indicate that auto-allo-SCT is feasible and could be considered for younger patients in the upfront setting.

We aimed to evaluate the determinants of survival in myelofibrosis patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) and to describe factors predicting the main post-HCT complications. This retrospective study by the European Society for Blood and Marrow Transplantation included 2916 myelofibrosis patients who underwent first allo-HCT from an HLA-identical sibling or unrelated donor between 2000 and 2016. After a median follow-up of 4.7 years from transplant, projected median survival of the series was 5.3 years. Factors independently associated with increased mortality were age ≥ 60 years and Karnofsky Performance Status

While evidence for measurable residual disease (MRD) is a harbinger of inferior outcome in acute myeloid leukemia (AML) patients referred for allogeneic stem cell transplantation (allo-SCT), the exact clinical trajectory of specific patient subsets in this clinical setting is undefined. Using a recently published prognostic cytogenetic model (Canaani et al. Leukemia 2019) we evaluated whether this model applied also to studies of patients with positive MRD. The analysis comprised MRD+ patients in first complete remission undergoing allo-SCT from a matched sibling donor or unrelated donor. Seven hundred and seventy-five patients were evaluated with a median follow-up duration of 22 months. Cytogenetic risk score was favorable, intermediate/FLT3wt intermediate/FLT3-ITD3, and adverse in 15%, 28.3%, 37% and 19.7% of the patients, respectively. Favorable and intermediate/FLT3wt risk patients had 2-year leukemia-free survival rates of 78% and 61%, respectively, compared with only 50% and 37% for intermediate/FLT3-ITD3 and adverse risk patients, respectively (P < .001). In multivariate analysis adverse and intermediate/FLT3-ITD3 risk patients were more likely to experience disease relapse compared with favorable risk patients [hazard ratio (HR) = 3.9, 95% confidence interval (CI), 2.1-7.3; P < .001, and HR = 4.4, CI 95%, 2.4-7.8; P < .001, respectively]. The European society for blood and marrow transplantation cytogenetic risk score is a valuable adjunct for risk stratification of MRD+ AML patients.

To address limitations of the currently used reduced-intensity/myeloablative conditioning (RIC/MAC) classification scheme we aimed to develop a tool that can capture more standardized the conditioning intensity of allogeneic hematopoietic cell transplantation (HCT). We assigned intensity weight scores for frequently used conditioning regimen components and used their sum to generate the transplant conditioning intensity (TCI) score. We retrospectively tested the impact of TCI on 8255 adult (45–65 years) acute myeloid leukemia patients who underwent HCT in first complete remission. A Cox model for early nonrelapse mortality (NRM) yielded a 3-group TCI risk scheme (low, intermediate, high) with respective TCI scores of [1–2], [2.5–3.5] and [4–6]. On multivariate modeling, TCI grouping was highly and better predictive for early (day 100 and 180) NRM, 2-year NRM and relapse (REL) as compared with the RIC/MAC classification. Validation was done on 200 bootstrap samples. Moreover, TCI scoring enabled the identification of a distinct subgroup of RIC and MAC conditioning regimens with an intermediate TCI [2.5–3.5] score that had identical outcomes and which are frequently referred as “reduced toxicity conditioning”. TCI scheme provides an improvement of the RIC/MAC classification. We propose TCI as a new tool to define and measure the conditioning regimen intensity.

Contains fulltext : 248798.pdf (Publisher’s version ) (Open Access) Allogeneic hematopoietic cell transplantation (allo-HCT) remains a treatment option for patients with chronic myeloid leukemia (CML) who fail to respond to tyrosine kinase inhibitors (TKIs). While imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second-generation TKI (2GTKI). We present the results of a prospective non-interventional study performed by the EBMT on 383 consecutive CML patients previously treated with dasatinib or nilotinib undergoing allo-HCT from 2009 to 2013. The median age was 45 years (18-68). Disease status at transplant was CP1 in 139 patients (38%), AP or >CP1 in 163 (45%), and BC in 59 (16%). The choice of 2GTKI was: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. With a median follow-up of 37 months (1-77), 8% of patients developed either primary or secondary graft failure, 34% acute and 60% chronic GvHD. There were no differences in post-transplant complications between the three different 2GTKI subgroups. Non-relapse mortality was 18% and 24% at 12 months and at 5 years, respectively. Relapse incidence was 36%, overall survival 56% and relapse-free survival 40% at 5 years. No differences in post-transplant outcomes were found between the three different 2GTKI subgroups. This prospective study demonstrates the feasibility of allo-HCT in patients previously treated with 2GTKI with a post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients.

Although second allogeneic haematopoietic cell transplantation (allo-HCT2) is a therapeutic option for patients relapsing after first HCT (allo-HCT1), there is limited data on allo-HCT2 in patients with acute lymphoblastic leukaemia (ALL). We retrospectively studied 245 patients receiving allo-HCT2 as a salvage treatment for relapse following allo-HCT1 between the 2000 and 2017. The median age at allo-HCT2 was 34·6 years (range: 18-74). One hundred and one patients (41%) received sibling donor and 144 (59%) unrelated donor allo-HCT2. Acute graft-versus-host disease (GVHD) grade II-IV and III-IV occurred in 33% and 17% of the patients, respectively. The incidence of 2-year total and extensive chronic GVHD was 38% and 19%, respectively. The 2- and 5-year cumulative incidence of non-relapse mortality, relapse incidence, leukaemia-free survival, overall survival and GVHD-free, relapse-free survival (GRFS) were 24% and 26%, 56% and 62%, 20% and 12%, 30% and 14% and 12% & 7%, respectively. In multivariate analysis, factors associated with overall survival were age, time from allo-HCT1 to relapse, conditioning for allo-HCT1, Karnofsky score at allo-HCT2 and donor type for allo-HCT2. In conclusion, outcomes of allo-HCT2 in ALL patients were poor, with only 14% overall survival and 7% GRFS at 5 years with very high relapse incidence.

We performed a retrospective assessment of patient- and transplant-specific characteristics and outcomes for 4142 patients undergoing allogeneic haematopoietic cell transplant for myelofibrosis between 1995 and 2018 across 278 centres. Activity increased steadily across the four analysed eras (

Purpose: Relapsed acute myeloid leukemia (AML) post allogeneic hematopoietic cell transplantation (allo-HCT) has a dismal prognosis. Experimental Design: To assess prognosis of patients with recurrent AML post allo-HCT over time, we analyzed European Society for Blood and Marrow Transplantation registry data of 8,162 adult patients with AML who relapsed between 2000 and 2018 after allo-HCT performed in first complete remission from matched sibling, unrelated, or haploidentical donors. Results: The 2-year overall survival (OS) rate from relapse was 17%. For 3,630 patients, 50 years of age, the year of relapse had no influence on OS (16% for 2000–2004 and 14% for 2015–2018; P = 0.56). Regarding treatment, encouraging results were observed after second allo-HCT, which was performed within 2 years after relapse in 17% of the entire cohort, resulting in a 2-year OS of 30.7%. Conclusions: Outcome after posttransplant relapse among younger patients has improved significantly in recent years, likely reflecting, among other factors, the efficacy of posttransplant salvage including second allo-HCT.

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.

International audience; Full text linksfull-text provider logoActionsFavoritesSharePage navigation Title & authors Abstract Conflict of interest statement Figures References Related information LinkOut - more resourcesJ Hematol Oncol. 2020 Jul 3;13(1):87.doi: 10.1186/s13045-020-00923-0.Post-transplant cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia in first complete remission undergoing allogeneic stem cell transplantation from 10/10 HLA-matched unrelated donorsEolia Brissot 1 2 , Myriam Labopin 3 , Ian Moiseev 4 , J J Cornelissen 5 , Ellen Meijer 6 , Gwendolyn Van Gorkom 7 , Montserrat Rovira 8 , Fabio Ciceri 9 10 , Laimonas Griskevicius 11 , Didier Blaise 12 , Edouard Forcade 13 , Martin Mistrik 14 , Stephan Mielke 15 , Claude Eric Bulabois 16 , Riitta Niittyvuopio 17 , Eric Deconinck 18 , Annalisa Ruggeri 9 10 , Jaime Sanz 19 20 , Alexandros Spyridonidis 21 , Bipin Savani 22 , Sebastian Giebel 23 , Arnon Nagler 24 , Mohamad Mohty 25 26Affiliations PMID: 32620146 PMCID: PMC7333262 DOI: 10.1186/s13045-020-00923-0 Free PMC articleAbstractBackground: Graft-versus-host disease (GVHD) remains a major contributor to mortality and morbidity after allogeneic stem-cell transplantation (allo-HSCT). The updated recommendations suggest that rabbit antithymocyte globulin or anti-T-lymphocyte globulin (ATG) should be used for GVHD prophylaxis in patients undergoing matched-unrelated donor (MUD) allo-HSCT. More recently, using post-transplant cyclophosphamide (PTCY) in the haploidentical setting has resulted in low incidences of both acute (aGVHD) and chronic GVHD (cGVHD). Therefore, the aim of our study was to compare GVHD prophylaxis using either PTCY or ATG in patients with acute myeloid leukemia (AML) who underwent allo-HSCT in first remission (CR1) from a 10/10 HLA-MUD.Methods: Overall, 174 and 1452 patients from the EBMT registry receiving PTCY and ATG were included. Cumulative incidence of aGVHD and cGVHD, leukemia-free survival, overall survival, non-relapse mortality, cumulative incidence of relapse, and refined GVHD-free, relapse-free survival were compared between the 2 groups. Propensity score matching was also performed in order to confirm the results of the main analysis RESULTS: No statistical difference between the PTCY and ATG groups was observed for the incidence of grade II-IV aGVHD. The same held true for the incidence of cGVHD and for extensive cGVHD. In univariate and multivariate analyses, no statistical differences were observed for all other transplant outcomes. These results were also confirmed using matched-pair analysis.Conclusion: These results highlight that, in the10/10 HLA-MUD setting, the use of PTCY for GVHD prophylaxis may provide similar outcomes to those obtained with ATG in patients with AML in CR1.

Limited data are currently available on the outcome of patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (allo‐SCT) with a reduced performance status. We herein present the results of a registry study on 2,936 AML patients undergoing allo‐SCT in first remission (CR1) with a Karnofsky Performance Status (KPS) score less than or equal to 80%. Two‐year leukemia‐free survival (LFS), overall survival (OS) and graft‐versus‐host disease (GVHD)‐free, and relapse‐free survival (GRFS) rates were 54%, 59%, and 41%, respectively. In multivariable analysis, patients with a KPS score = 80% had lower non‐relapse mortality (NRM) and superior OS in comparison to patients with a KPS score, Graft‐versus‐host disease‐free, relapse‐free survival in patients with KPS score < 80% receiving MAC or RIC regimen.

In the original publication, the author Mahmoud Aljurf was omitted from the author list. This author’s affiliation is 'Oncology Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia'. This has been corrected in both the PDF and HTML versions of the original article.

[Objectives] The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma—reduced intensity conditioning (RIC), non‐myeloablative (NMA), myeloablative conditioning (MAC) or Auto‐AlloHCT—on outcomes in patients who had had a prior autologous transplant., [Methods] A retrospective analysis of the EBMT database (1991‐2012) was performed., [Results] A total of 344 patients aged between 40 and 60 years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto‐Allo transplants. At a median follow‐up of 54 months, the probabilities of overall survival (OS) at 5 years were 39% (95% CI 31%‐47%), 45% (95% CI 32%‐57%), 19% (95% CI 6%‐32%) and 34% (95% CI 17%‐51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P = .004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR = 4.1, P < .001) but not after 2002 (HR = 1.2, P = .276)., [Conclusion] From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches.

We report here the results of a retrospective study designed to evaluate outcome of patients with AML with KPS score ≤80% following allo-SCT. The analysis included adult AML patients undergoing allo-SCT in CR1 between 2000 and 2018, with a KPS score at the time of transplant between 50% and 80%. A total of 2,963 patients were identified. Median age at transplant was 55 years (18-77 years). The KPS score was 80% in 85% of the patients and On multivariate analysis, transplant from a MSD was associated with a reduced risk of aGvHD (10/10 UD HR 1.8, 9/10 UD HR 2.4, haplo HR 1.9, CB HR 3.4, p In order to compare outcome following MAC and RIC conditioning regimens the analysis was restricted to patients receiving transplant from MSD or UD. Patients with a KPS score of 80% or In conclusion, allo-SCT is feasible in patients with acute myeloid leukemia in first remission and KPS score ≤80%, with acceptable NRM and survival rates. In patients with a KPS score of 80% a MAC regimen was associated with lower relapse rate, similar NRM and better GRFS as compared to RIC, while in patients with a KPS score

We compared outcomes of 1461 adult patients with acute lymphoblastic leukemia (ALL) receiving hematopoietic cell transplantation (HCT) from a haploidentical (n = 487) or matched unrelated donor (MUD; n = 974) between January 2005 and June 2018. Graft-versus-host disease (GVHD) prophylaxis was posttransplant cyclophosphamide (PTCy), calcineurin inhibitor (CNI), and mycophenolate mofetil (MMF) for haploidentical, and CNI with MMF or methotrexate with/without antithymoglobulin for MUDs. Haploidentical recipients were matched (1:2 ratio) with MUD controls for sex, conditioning intensity, disease stage, Philadelphia-chromosome status, and cytogenetic risk. In the myeloablative setting, day +28 neutrophil recovery was similar between haploidentical (87%) and MUD (88%) (P = .11). Corresponding rates after reduced-intensity conditioning (RIC) were 84% and 88% (P = .47). The 3-month incidence of grade II-IV acute GVHD (aGVHD) and 3-year chronic GVHD (cGVHD) was similar after haploidentical compared with MUD: myeloablative conditioning, 33% vs 34% (P = .46) for aGVHD and 29% vs 31% for cGVHD (P = .58); RIC, 31% vs 30% (P = .06) for aGVHD and 24% vs 29% for cGVHD (P = .86). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 44% and 51% with haploidentical and MUD (P = .56). Corresponding rates after RIC were 43% and 42% (P = .6). In this large multicenter case-matched retrospective analysis, despite the limitations of a registry-based study (ie, unavailability of key elements such as minimal residual disease testing), our analysis indicated that outcomes of patients with ALL undergoing HCT from a haploidentical donor were comparable with 8 of 8 MUD transplantations.

Cyclosporine A (CSA) and methotrexate (MTX) is the standard graft-versus-host disease (GVHD) prophylaxis regimen for matched sibling donor (MSD) allogeneic hematopoietic cell transplantation (allo-HCT). Recently, post-transplantation cyclophosphamide (PTCy) has been shown to be effective in GVHD prevention. In this registry-based study, we compared outcomes of 118 patients treated with PTCy and 1202 patients with CSA/MTX who underwent MSD allo-HCT for acute myelogenous leukemia. In a matched-pair analysis, PTCy was associated with a higher incidence of relapse at 2 years compared with CSA/MTX (41.1% versus 21.3%; P = .039). The incidences of day +180 grade II-IV acute GVHD and 2-year chronic GVHD were comparable in the PTCy and CSA/MTX arms (25.2% versus 25.4% [P = .90] and 42.6% versus 42.6% [P = .84], respectively). Similarly, 2-year leukemia-free survival (LFS; 54.4% versus 74.32%; P = .052), overall survival (OS; 70.6% versus 79.7%; P = .15), and GVHD-free relapse-free survival (GRFS; 38.1% versus 52.5%; P = .49) were not statistically different in the 2 arms. Our data show that GVHD prophylaxis with PTCy is feasible, resulting in similar incidences of GVHD, GRFS, LFS, and OS as seen with conventional CSA/MTX in patients undergoing allo-HCT from an MSD. The higher rate of relapse observed with PTCy needs further evaluation in a prospective study. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Background Steroid-refractory acute graft-versus-host disease (aGVHD) is a serious complication after hematopoietic stem cell transplantation. The long-term outcome of the patients is poor. Various immunosuppressive agents have been proposed as the second-line therapy but none of them has turned out more effective than the others. Extracorporeal photopheresis (ECP) is a treatment option that does not predispose the patients to severe side effects of the immunosuppressive drugs. Study design and methods We analyzed the treatment results of ECP in 52 patients with steroid-refractory or steroid-dependent aGVHD. Eighty-one percent of the patients suffered from a severe, Grade III or IV, aGVHD. ECP was started alone as the second-line treatment in 23 patients and in combination with an immunosuppressive drug in 18 patients. Eleven patients received ECP as the third-line or later treatment. Results A total of 62% of the patients responded, with 48% achieving complete response. In the patients with complete or partial response, the probabilities of survival at 4 years were 54 and 17%, respectively. The outcome of nonresponders was poor. The 1-year overall survivals of the patients with ECP as the second-line treatment either alone or in combination with an immunosuppressive drug or as the third-line treatment were 51, 28, and 18%, respectively. In multivariate analysis, starting ECP no later than 10 days after the start of the first-line treatment correlated with a good response and a consequent survival benefit. Conclusion Extracorporeal photopheresis is an effective and well-tolerated treatment that should be considered as a second-line treatment for aGVHD.

IPSS-R is a well established prognostic factor for transplant outcome in patients with MDS, irrespective whether it is assessed at diagnosis or at transplant. However it is unclear how a change in IPSS-R, e.g. by reducing bone marrow blasts through therapy, would potentially affect transplant results. In particular the decision to treat patients before transplant or perform an upfront allogeneic transplantation can so far not be based on evidence. We did a registry search based in the MDS quality initiative conducted by EBMT to identify transplanted patients with MDS and sufficient data to calculate IPSS-R at diagnosis and before transplant. The search was limited to patients reveiving a first allogeneic stem cell transplantation in the period 2005 -2018. 1482 patients were identified. Median age at alloHCT was 59 (interquartile range 51-64) years, 60% were male. Donors were related in 36%, graft source was PBSC in 85% of cases. Conditioning was standard dose in 33% and reduced intensity in 67%. IPSS-R both at diagnosis and at transplant had a significant impact on OS and RFS after alloHCT. To investigate the effect of a change in IPSS-R between diagnosis and transplant we constructed 3 subgroups: stable IPSS-R, improved IPSS-R, worsened IPSS-R. A change in IPSS-R was noted in 77.5% of patients with prior chemotherapy, 72% with prior HMA and 59.8% of untreated patients. Univariate analysis showed no significant difference in OS or RFS in patients with stable IPSS-R compared to improved or worsened IPSS-R. In patients treated with chemotherapy before transplant OS and RFS was significantly worse with worsened IPSS-R, while this effect was not found in patient treated with hypomethylating agents (HMA) or untreated patients. The same analysis was performed regarding the difference in bone marrow blasts and the cytogenetics score: OS and RFS after transplant were significantly worse with increased blasts (p=0.04 and p=0.001) and a worsened cytogenetic score before transplant (both p In this retrospective analysis from a large cohort of patients with MDS we found that worsening of IPSS-R, blast count or cytogenetic score had a negative prognostic impact in chemotherapy-treated patients, while only worsened blast count and cytogenetics were significant negative factors in HMA-treated or untreated patients. Conversely we did not find a positive effect of improved IPSS-R, decreased blasts or improved cytogenetics in any of the subgroups of treated or untreated patients. Thus for MDS patients receiving an allogeneic transplantation our results provide no clear signal that prior therapy is able to improve transplant outcome. Disclosures Scheid: Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding. Blaise:Jazz Pharmaceuticals: Honoraria. Chevallier:Incyte Corporation: Honoraria. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria.

Aim: Dynamic assessment of trends over time in patient- and transplant-specific characteristics and outcomes for patients undergoing 1st allogeneic haematopoietic cell transplant (allo-HCT) for Myelofibrosis (MF). Methods and Results: A total of 4142 MF patients were analysed who underwent allo-HCT between 1995-2018 (24-year period) across 278 centres based on data reported to the European Society for Blood and Marrow Transplantation. For analysis, 4 cohorts were considered based on year of allo-HCT: 60 years accounted for 8.7% of adults undergoing allo-HCT whereas for 2015-2018 this was 47%. Over time, increasing number of patients with a Karnofsky performance status (KPS) Conclusions: Despite a marked increase over this 24-year period in recipient age, RIC regimen utilisation and use of both URD and MMRD, this comprehensive analysis demonstrates stable OS and EFS rates. However, rates of GVHD have decreased over time, in particular extensive cGVHD. Further work is required to improve both the considerable NRM and relapse rates which remain significant. Disclosures McLornan: JAZZ PHARMA: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau; NOVARTIS: Honoraria, Speakers Bureau. Platzbecker:Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Geron: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Chevallier:Incyte Corporation: Honoraria. Martínez-Lopez:Altum, Hosea: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Vivia Biotech: Honoraria; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; Janssen: Speakers Bureau; Incyte: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding. Yakoub-Agha:Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria.

Recently, an increasing number of patients with acute lymphoblastic leukemia with a poor Karnofsky Performance Status (KPS) score are considered for allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, there is paucity of available data about outcome of this fragile population. We report here the results of a retrospective study designed to evaluate outcome of ALL patients undergoing allo-HCT with KPS score ≤80%. The analysis included ALL patients aged ≥18 years, undergoing allo-HCT in first remission between 2000 and 2018, with a KPS score of 50% to 80% at the time of transplant. A total of 1,010 patients were identified. Median age at transplant was 43 years (18-76 years). Median year of transplant was 2011. The KPS score was =80% in 83% of the patients and On multivariate analysis, transplant from 10/10 UD was associated with higher incidence of aGVHD (HR 1.8, p In conclusion, allo-HCT is feasible in patients with acute lymphoblastic leukemia in first remission and KPS score ≤80%, with acceptable NRM and survival rates. Transplant from a MSD was associated with reduced risk of NRM and aGVHD as compared to 10/10 UD. Interestingly, despite the poor KPS score of the patients included in the analysis, a MAC protocol was associated with similar NRM, lower relapse and better LFS and GRFS as compared to RIC in the selected population. Finally, administration of ATG was associated with reduced acute and chronic GVHD rates.

Transplant outcomes for patients with acute lymphoblastic leukemia (ALL) after haploidentical hematopoietic cell transplantation (haploHCT) with post-transplant cyclophosphamide (PTCy) compared to an HLA matched unrelated donors (MUD) transplantation are unknown. We, therefore retrospectively compared outcomes of 487 patients with ALL who underwent haploHCT with PTCy, reported from the participating centers (TCT-RC and EBMT) from 01/2005 to 06/2018, with a matched cohort of 974 patients (1:2 ratio) who underwent MUD-HCT and were reported to the EBMT. Patients were matched for sex, disease stage (CR1, CR2, other), disease risk (high or others), Philadelphia chromosome status (positive or negative), and conditioning regimen (MAC or RIC). Other significant differences in patient/transplant characteristics were adjusted for. Median age at HCT was 33 years (range: 18-73) for haplo and 36 years (range: 18-76) for MUD; (p=0.024). Median time from diagnosis to transplant was significantly longer in haploHCT (at 6 months: 23% vs. 29%; p=0.024). More patients in the haplo group received a female-to-male transplantation (27% vs. 13%; p With a median follow up of 2 and 3 years in haplo and MUD, respectively, there was no statistical differences in overall survival (OS), (p=0.82); GvHD- and relapse- free survival (GRFS), (p=0.78); relapse rate, (p=0.88); or non-relapse mortality (NRM), (p=0.86) between haplo- and MUD-HCT recipients after adjusting for all covariates. (Fig 1) GvHD rates and severity were not different in patients undergoing haplo compared to those undergoing MUD HCT, possibly due to the use of ATG in 2/3 of patients with MUD HCT. However, mortality related to GVHD was significantly lower in patients undergoing haploHCT (HR= 0.45, p=0.003). We next did subgroup analysis based on conditioning intensity, disease status in first remission, Philadelphia chromosome status, and stem cell source. OS, disease-free survival (DFS), relapse rate and NRM were comparable between patients undergoing haplo and MUD HCT. Engraftment was faster in MUD if RIC was used (HR=0.75, p=0.05), grade 2-4 acute GvHD was lower in haplo if BM was the graft source (HR =0.57, p=0.04). Severe chronic GvHD was lower in haplo if transplant was done in CR1 (HR 0.52, p=0.05) and if BM was the graft source (HR 0.45 p=0.07). In conclusion, in this large retrospective analysis, outcomes of patients with ALL undergoing transplant from a haplo donor with PTCy is comparable with those undergoing an 8/8 MUD transplantations in subgroups analysis and regardless of the disease and Philadelphia chromosome status.

Background Assessment of measurable residual disease (MRD) is rapidly transforming the therapeutic and prognostic landscape of a wide range of hematological malignancies. Its prognostic value in acute lymphoblastic leukemia (ALL) has been established and MRD measured at the end of induction is increasingly used to guide further therapy. Although MRD detectable immediately before allogeneic hematopoietic cell transplantation (HCT) is known to be associated with poor outcomes, it is unclear if or to what extent this differs with different types of conditioning. Methods In this retrospective registry study, we explored whether measurable residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia is associated with different outcomes in recipients of myeloablative total body irradiation (TBI)-based versus chemotherapy-based conditioning. We analyzed outcomes of 2780 patients (median age 38 years, range 18–72) who underwent first HCT in complete remission between 2000 and 2017 using sibling or unrelated donors. Results In 1816 of patients, no disease was detectable, and in 964 patients, MRD was positive. Conditioning was TBI-based in 2122 (76%) transplants. In the whole cohort MRD positivity was a significant independent factor for lower overall survival (OS) and leukemia-free survival (LFS), and for higher relapse incidence (RI), with respective hazard ratios (HR, 95% confidence intervals) of 1.19 (1.02–1.39), 1.26 (1.1–1.44), and 1.51 (1.26–1.8). TBI was associated with a higher OS, LFS, and lower RI with HR of 0.75 (0.62–0.90), 0.70 (0.60–0.82), and 0.60 (0.49–0.74), respectively. No significant interaction was found between MRD status and conditioning. When investigating the impact of MRD separately in the TBI and chemotherapy-based conditioning cohorts by multivariate analysis, we found MRD positivity to be associated with lower OS and LFS and higher RI in the TBI group, and with higher RI in the chemotherapy group. TBI-based conditioning was associated with improved outcomes in both MRD-negative and MRD-positive patients. Conclusions In this large study, we confirmed that patients who are MRD-negative prior to HCT achieve superior outcomes. This is particularly apparent if TBI conditioning is used. All patients with ALL irrespective of MRD status benefit from TBI-based conditioning in the myeloablative setting.

The impact of the use of antithymocyte globulin (ATG) following a total body irradiation (TBI)-based myeloablative conditioning regimen has been poorly explored. We retrospectively analyzed 724 patients who underwent a first allogeneic hematopoietic cell transplantation (allo-HCT) following a TBI-based conditioning regimen for acute myeloid leukemia (AML) and compared the outcomes of 251 (35%) patients who received ATG (ATG group) with 473 (65%) patients who did not (non-ATG group). Median follow-up of surviving patients was 59 months (interquartile range, 28-83). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) for non-ATG and ATG groups in the first 100 days was 33% vs 24%, respectively (P = .0098). The 2-year cumulative incidence of chronic graft-versus-host disease (cGVHD) was reduced significantly in the ATG group in comparison with the non-ATG group (46% vs 34%, P = .003). Using multivariate analysis, in vivo T-cell depletion (ATG group) was independently associated with a decreased incidence of grade II-IV aGVHD (hazard ratio [HR], 0.28; P < .001), grade III-IV aGVHD (HR, 0.21; P < .001), cGVHD (HR, 0.63; P = .02), and nonrelapse mortality (NRM) (HR, 0.54; P = .02). Relapse risk, overall survival, and leukemia-free survival were similar between the 2 groups. Our results suggest that the addition of ATG to TBI-based myeloablative conditioning for allo-HCT in AML patients results in a significant reduction in aGVHD and cGVHD, translating into a significant reduction in NRM without increasing the relapse rate. ispartof: BLOOD ADVANCES vol:3 issue:13 pages:1950-1960 ispartof: location:United States status: published

Allogeneic haematopoietic stem cell transplantation currently represents the primary potentially curative treatment for cancers of the blood and bone marrow. While relapse occurs in approximately 30% of patients, few risk-modifying genetic variants have been identified. The present study evaluates the predictive potential of patient genetics on relapse risk in a genome-wide manner. We studied 151 graft recipients with HLA-matched sibling donors by sequencing the whole-exome, active immunoregulatory regions, and the full MHC region. To assess the predictive capability and contributions of SNPs and INDELs, we employed machine learning and a feature selection approach in a cross-validation framework to discover the most informative variants while controlling against overfitting. Our results show that germline genetic polymorphisms in patients entail a significant contribution to relapse risk, as judged by the predictive performance of the model (AUC = 0.72 [95% CI: 0.63-0.81]). Furthermore, the top contributing variants were predictive in two independent replication cohorts (n = 258 and n = 125) from the same population. The results can help elucidate relapse mechanisms and suggest novel therapeutic targets. A computational genomic model could provide a step toward individualized prognostic risk assessment, particularly when accompanied by other data modalities.

Background Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HSCT). Previous studies have shown that anti- thymocyte globulin (ATG) reduce the incidence of acute and or chronic GVHD after reduced intensity and chemotherapy based myeloablative conditioning regimen pre-HSCT. The impact of the use of ATG following TBI based myeloablative conditioning regimen has been poorly explored. Recent prospective, double-blind phase III study of ATG vs placebo in patients (pts) with MDS or AML following myeloablative conditioning report inferior progression-free survival (PFS) and overall survival (OS) in the ATG arm, especially in the TBI cohort. However, this study includes only small and quite heterogeneous sub-populations within the TBI group. We therefore assessed the effect of ATG in a large homogenous cohort of AML pts undergoing HSCT with TBI and reported to the ALWP of the EBMT. Methods The study included 724 AML pts that underwent HSCT during the years 2008-2016 from a matched sibling (n=412) or 9-10 unrelated donor (n=312), following TBI (>8Gy) based conditioning regimen. All disease statuses were included (CR1=489, CR2=148; refractor=87). Graft source was PB in the majority of pts (n=579, 80%). 251 pts received ATG while 473 did not. Median follow up was 58.8 (28-83) months. The disease and transplant characteristics were similar in both groups except for type of donors, unrelated donor HSCT received ATG in 89% vs 19% in sibling donor HSCT (p Results In univariate analysis, day 100 incidence of acute GVHD II-IV and III-VI was 24.1% vs 33% (p Conclusions The addition of ATG to TBI based conditioning regimen followed by HSCT for AML results in significant reduction of acute and chronic GVHD, translating into a significant reduction in TRM without increasing relapse rate, and a similar LFS or OS.

Background In a previously published study, the authors randomized 108 adult patients with a malignant hematologic disorder undergoing allogeneic bone marrow transplantation from a human leukocyte antigen-identical sibling to receive methylprednisolone (53 patients; MP+) or not to receive methylprednisolone (55 patients; MP-) as a part of graft-versus-host disease (GVHD) prophylaxis. All patients received cyclosporine and methotrexate. The cumulative incidence of acute GVHD was found to be significantly lower among the patients given MP. Methods In the current study, the authors performed a long-term follow-up to discover possible late effects of the intensified GVHD prophylaxis. Results The median follow-up for surviving patients was 24.5 years. In the MP+ group, the overall survival and recurrence-free survival were higher (P = .021 and P = .028, respectively) and the nonrecurrence mortality was lower (P = .003) than in the MP- group. There was a trend toward a lower cumulative incidence and a significantly lower prevalence (P = .031) of chronic GVHD in the MP+ group. There was no difference noted with regard to the rate of disease recurrence or in the incidence of secondary malignancies. Eleven patients in the MP- group but none in the MP+ group died >15 years after transplantation. At the end of follow-up, the overall survival rates in the MP+ and MP- groups were 55% and 20%, respectively, and the recurrence-free survival rates were 49% and 15%, respectively. Conclusions Long-term survival was found to be higher among the patients given MP in addition to cyclosporine and methotrexate. There was marked late nonrecurrence mortality observed in the group not given MP. No adverse late effects caused by the addition of corticosteroid were observed. Cancer 2018;124:727-33. © 2017 American Cancer Society.

We evaluated the role of mismatched third-party hematopoietic stem cells (TPC) in shortening the neutropenia after umbilical cord blood transplantation (UCBT). A TPC graft was given to 7/37 children with UCBT to support engraftment due to anticipated increased risk of nonengraftment (N=6) or active infection (N=1). TPC grafts were collected with apheresis from haploidentical family members. The median UCB and CD34 cell counts were 5.10 (range, 4.13 to 9.98)×10/kg and 5.98 (range, 4.40 to 14.00)×10/kg, respectively. The median time to neutrophil engraftment was shorter in the patients with TPC (12 d; range, 9 to 24 d) than those without (23 d; range, 12 to 44 d) (P=0.010). TPC chimerism was lost in median at 28 (range, 24 to 103) days posttransplant. TPC grafts from mothers engrafted similarly as the grafts from other family members. UCB graft cell count and the use of methotrexate posttransplant strongly contributed to engraftment. TPC may form a valuable transient bridging graft over the neutropenia after UCBT in patients with anticipated high-risk of nonengraftment or toxicity due to pretransplant infections.

Thanks to the recent developments in transplant procedures, an increasing number of patients with acute myeloid leukemia (AML) with a poor Karnofsky Performance Status (KPS) score are currently offered an allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, little data is available about outcome of this fragile population. We report here the results of a retrospective study designed to evaluate outcome of patients with AML undergoing allo-HCT with KPS score ≤80%. The analysis included patients with AML aged ≥18 years, undergoing allo-HCT in first remission between 2000 and 2018, with a KPS score at the time of transplant between 50% and 80%. Patients who received manipulated grafts or had incomplete data about cytogenetics were excluded. Conditioning intensity was defined according to EBMT definitions. A total of 2,963 patients were identified. Median age at transplant was 55 years (18-77 years). Median year of transplant was 2014. The KPS score was =80% in 85% of the patients and Cumulative incidence of grade II-IV and III-IV acute GVHD (aGvHD) was 26% and 8%, respectively. The 2-year cumulative incidence of chronic GVHD (cGvHD) and severe cGVHD was 38% and 18%. Non-relapse mortality (NRM) and relapse incidence (RI) at 2 years were 19% and 27%, respectively. Notably, in the subgroup of patients with KPS On multivariate analysis, transplant from a MSD was associated with a reduced risk of aGvHD (10/10 UD HR 1.8, 9/10 UD HR 2.4, haplo HR 1.9, CB HR 3.4, p In order to compare outcome following MAC and RIC conditioning the analysis was restricted to patients receiving transplant from MSD or UD. Patients with a KPS score =80% or In conclusion, allo-HCT is feasible in patients with acute myeloid leukemia in first remission and KPS score Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Kröger:Sanofi-Aventis: Research Funding; Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding. Socie:Alexion: Consultancy. Blaise:Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Molmed: Consultancy, Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Esteve:Astellas: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Recently, an increasing number of patients with acute lymphoblastic leukemia with a poor Karnofsky Performance Status (KPS) score are considered for allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, there is paucity of available data about outcome of this fragile population. We report here the results of a retrospective study designed to evaluate outcome of ALL patients undergoing allo-HCT with KPS score ≤80%. The analysis included ALL patients aged ≥18 years, undergoing allo-HCT in first remission between 2000 and 2018, with a KPS score of 50% to 80% at the time of transplant. Patients who received manipulated grafts or had incomplete data about cytogenetics were excluded. Conditioning intensity was defined according to EBMT definitions (Aoudjhane M. et al, Leukemia 2005; 19: pp. 2304-2312). A total of 1,010 patients were identified. Median age at transplant was 43 years (18-76 years). Median year of transplant was 2011. The KPS score was =80% in 83% of the patients and On multivariate analysis, transplant from 10/10 UD was associated with higher incidence of aGVHD (HR 1.8, p In conclusion, allo-HCT is feasible in patients with acute lymphoblastic leukemia in first remission and KPS score ≤80%, with acceptable NRM and survival rates. Transplant from a sibling donor was associated with reduced risk of NRM and aGVHD as compared to matched unrelated donor. Interestingly, despite the poor KPS score of the patients included in the analysis, a MAC protocol was associated with similar NRM, lower relapse and better LFS and GRFS as compared to RIC in the selected population. Finally, administration of ATG was associated with reduced acute and chronic GVHD rates. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Socie:Alexion: Consultancy. Kröger:JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding; Sanofi-Aventis: Research Funding; Celgene: Honoraria, Research Funding; DKMS: Research Funding. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Assessment of measurable residual disease (MRD) is rapidly transforming the therapeutic and prognostic landscape of a wide range of hematological malignancies. Its prognostic value in acute lymphoblastic leukemia (ALL) has been established and MRD measured at the end of induction is increasingly used to guide further therapy. Although MRD detectable immediately before allogeneic hematopoietic cell transplantation (HCT) is known to be associated with poor outcomes, it is unclear if or to what extent this differs with different types of conditioning. Therefore, in this retrospective multicenter study we explored if MRD detectable before allogeneic HCT for ALL is associated with different outcomes in recipients of myeloablative TBI-based versus chemotherapy-based conditioning. We analyzed outcomes of 2780 patients (median age 38 years, range 18-72) who underwent first HCT in complete remission between 2000 and 2017 using sibling or unrelated 9/10 or 10/10 matched donors. In 1816 of these patients no disease was detectable before transplantation and in 964 patients MRD was detectable (MRD positivity). Conditioning was TBI-based in 2122 (76%) transplants. In the whole cohort MRD positivity was a significant independent factor for lower overall survival (OS) and leukemia-free survival (LFS), and for higher relapse incidence (RI), with respective hazard ratios (HR, 95% confidence intervals) of 1.19 (1.02-1.39), 1.26 (1.1-1.44), 1.51 (1.26-1.8). TBI was associated with a better OS, LFS and RI with HR of 0.75 (0.62-0.90), 0.70 (0.60-0.82) and 0.60 (0.49-0.74), respectively. No significant interaction was found between MRD status and conditioning. When investigating the impact of MRD separately in the TBI and chemotherapy-based conditioning cohorts by multivariate analysis, we found MRD positivity to be associated with lower OS (HR 1.26, 1.05-1.51) and LFS (HR 1.3,1.1-1.53), and higher RI (HR 1.53, 1.23-1.9) in the TBI group, and with higher RI (HR 1.58, 1.13-2.21) in the chemotherapy group. There was no significant association between MRD and other outcomes in this last cohort. TBI based conditioning was associated with improved OS, LFS, and RI in both MRD negative and MRD positive patients (figure). In this large study we confirmed that patients who are MRD negative prior to HCT achieve superior outcomes. This is particularly apparent if TBI conditioning is used. All patients with ALL irrespective of MRD status benefit from TBI based conditioning in myeloablative setting.

Diagnosis of veno-occlusive disease/sinusoidal obstruction syndrome of the liver: problems of interpretation

In this study, the course of 40 pregnancies in 16 women with essential thrombocythaemia (ET) was analysed retrospectively. Of the pregnancies, 45% were complicated, 55% uncomplicated, and 62% resulted in live birth. The most common complication was spontaneous abortion during the first trimester seen in 33% of all pregnancies and comprising 72% of all complications. Two intrauterine foetal deaths occurred at weeks 22 and 28. Three pregnancies were complicated by eclampsia or pre-eclampsia. Nine of 16 women with 29 pregnancies had at least one complicated pregnancy. In seven of 16 women, all 11 pregnancies were uneventful. The non-pregnancy-related symptoms of ET or the platelet count before conception or during pregnancy did not correlate with the risk of pregnancy complications. Treatment with low-dose acetylsalicylic acid (ASA) alone during pregnancy or platelet-lowering drugs before or during pregnancy reduced the risk of complications.

The predictive value of spontaneous in vitro colony formation of megakaryocytic and erythroid progenitors (154 patients), and defective platelet aggregation responses (55 patients) on the risk of thrombohaemorrhagic complications in patients with essential thrombocythaemia (ET) was evaluated retrospectively. In the in vitro cultures of haematopoietic progenitors, 114/154 patients (74%) showed either spontaneous megakaryocytic or erythroid colony formation or both. Forty-three per cent of patients with any spontaneous colony growth and only 20% of those without this phenomenon had an arterial thrombosis at diagnosis or during the follow-up (P = 0.02). In the whole patient group neither spontaneous megakaryocytic nor spontaneous erythroid colony formation alone predicted the risk of arterial thrombosis. In patients younger than 45 yr of age, the prognostic value of spontaneous megakaryocytic growth was statistically significant: 44% of the patients with spontaneous megakaryocytic colony formation, but only 14% of those without it, experienced arterial thrombosis (P = 0.04). The presence of spontaneous colony formation had no effect on the risk of bleeding complications. Forty-one of the 55 patients (75%) showed abnormalities in the platelet aggregation responses. There was no statistically significant correlation between the platelet function response and the risk of bleeding or thrombotic complications. No correlation was found between the platelet aggregation responses and the presence of spontaneous colony growth. In conclusion, spontaneous colony formation indicated an increased risk of thrombohaemorragic events but the platelet function test had no predictive value for these complications.

Background: In a previously published single-center study (Blood 2000) we randomized 108 consecutive adult patients with a malignant hematological disorder undergoing allogeneic bone marrow transplantation from an HLA-identical sibling donor to receive (n=53) or not to receive (n=55) methylprednisolone (MP+ or MP-, respectively) as a part of graft-versus-host disease (GVHD) prophylaxis. All patients received cyclosporine A and methotrexate. MP administration was initiated on day 14 post-transplantation with 0.5 mg/kg, the dose was increased to 1 mg/kg on day 21 and thereafter tapered and discontinued on day 110. The cumulative incidence of acute GVHD was 19 % among the patients given and 56 % among those not given MP prophylaxis (p=0.0001), and that of grade II-IV acute GVHD 13 and 36 %, respectively (p=0.005). There was a non-significant trend toward a lower cumulative incidence of chronic GVHD (cGVHD) and better survival in the MP+ group. There were fewer infections and the stay at hospital was shorter among the patients given MP prophylaxis. No difference was seen in the relapse rate. We have now carried out a long-term follow-up to find out possible late effects of the intensified GVHD prophylaxis. Results: The median follow-up time of living patients was 24.5 (range 22.7-26.9) years; two patients were lost for follow-up at 37 and 80 months. In the MP+ group the overall survival (OS, p=0.021) (Figure 1) and relapse-free survival (RFS, p=0.024) were significantly higher and the non-relapse mortality (NRM) lower (p=0.003) than in the MP- group. There was a trend toward lower cumulative incidence of cGVHD in the MP+ group (36 vs. 48 %, p=0.17). The prevalence of cGVHD, analyzed with data available from ten years of scheduled follow-up, was significantly (p=0.031) lower in the MP+ group and the difference became more marked with time. Among the patients alive at ten years, none in the MP+ group but 28 % of the patients in the MP- group had active cGVHD. There was no difference in the relapse rate between the MP+ and MP- groups, the cumulative incidences were 36 and 38 %, respectively. Seven patients in each group developed a secondary malignancy, one patient in both groups had two secondary tumors. At 15 years, the survival was 55 % in the MP+ group and 47 % in the MP- group, and the NRM 21 and 30 %, respectively. Thereafter there was marked non-relapse mortality in the MP- group, eleven patients died after this time point, whereas there were no deaths during this period in the MP+ arm. At the end of the follow-up, the OS in the MP+ and MP- groups were 55 and 20 % and the RFS 54 and 18 %, respectively. The causes of the late deaths in the MP- group were: bacterial infection 3, obstructive bronchiolitis 1, acute myocardial infarction 1, intracerebral bleeding 1, sudden death of unknown cause 1, lung cancer 2, colon cancer 1, and esophagus cancer 1. Conclusion: The addition of corticosteroid to cyclosporine and methotrexate in GVHD prophylaxis, resulting in a marked decrease in the incidence of acute GVHD, did not cause adverse late effects. Long-term survival was higher among the patients given MP prophylaxis. Unexpectedly, there was marked late non-relapse mortality in the group not given MP prophylaxis, possibly contributed to by the higher prevalence of cGVHD. Disclosures No relevant conflicts of interest to declare.

This retrospective study reviewed the course of 40 pregnancies in 16 women diagnosed as having essential thrombocythemia (ET). These women were seen at 5 hospitals in Finland in the years 1980-1995. In 10 women, thrombocytosis was identified for the first time during pregnancy. The mean age at the time ET was diagnosed was 27 years, and the median initial platelet count was 1082 x 10 9 /L. The median follow-up interval from the time of diagnosis was 6 years 6 months. Eighteen of the 40 pregnancies (45%) were complicated. Fifteen (38%) ended in miscarriage, all but 2 of them in the first trimester. Three pregnancies ending in a live birth were complicated by eclampsia or preeclampsia. In 7 women, all 11 pregnancies were uneventful. In the other 9 patients, 18 of 29 pregnancies (62%) were complicated. Only 11 of these pregnancies (38%) followed a normal course and had a good outcome. The most common complication, occurring in one third of pregnancies and comprising 72% of all complications, was spontaneous abortion. There were 2 intrauterine fetal deaths. The risk of complications did not appear to relate to either nonpregnancy-related symptoms of ET or to the platelet count before or during pregnancy. Fetal growth was normal in all but 1 of 25 second- or third-trimester pregnancies. Eleven of the 16 women had received treatment for ET. Most commonly, acetylsalicylic acid (ASA) was given in daily doses of 50 to 250 mg. Five patients were on interferon before pregnancy and 3 of them changed to ASA. Pregnancy-related complications occurred in 67% of pregnancies in untreated women. In contrast, none of 13 pregnancies in women treated before or during pregnancy were complicated. The live birth rate was 100% in treated cases and 44% without treatment, This study affirms an increased risk of pregnancy-related complications-particularly early spontaneous abortion-when the mother has ET. Low-dose ASA treatment appears to prevent complications.

Introduction: The reported incidences of sinusoidal obstruction syndrome/veno-occlusive disease of the liver (VOD) have varied widely. In recent reviews the present incidence has been stated to be up to 10-15 %. The differences in the incidences may be due to different patient materials and transplantation methods or differences in the application and interpretation of diagnostic criteria. Modified Seattle criteria (McDonald et al 1993) or Baltimore criteria (Jones et al 1986) are used to establish the diagnosis. The diagnosis is based on a combination of clinical criteria. However, the diagnosis of VOD should only be made if there are no other conditions that could explain the clinical findings. More than one condition causing liver problems may be present at the same time, leaving space for subjective interpretation that could essentially affect the incidence of this disorder. Along with the improving opportunities for prophylaxis and treatment of VOD, it is important to have a correctpicture of its incidence. We evaluated the differential diagnostic component of VOD diagnosis in our single-center material. Patients: The hospital notes of 300 consecutive adult patients treated with allogeneic stem cell transplantation between March 2011 and February 2015 at the Helsinki University Hospital were retrospectively reviewed. All but one had a malignant hematological disease. The most common diagnoses were AML 106, ALL 48, MM 46, NHL 34, and MDS 24. The total of 135 patients (45%) received conventional myeloabative conditioning, CyTBI (n=79) or BuCy (n=56), 151 were given treosulfan in myeloablative (n=77) or reduced (n=74) dose with fludarabine, 5 received BuFlu and 9 other regimen. Of the donors 75 % were unrelated, and 77 % of the grafts were from peripheral blood. All patients received ursodeoxycholic acid (UDCA) prophylaxis. GvHD prophylaxis consisted of CsA and a short course of MTX. ATG was given in transplantations from unrelated donor. Methods: We identified all patients who had a total serum bilirubin concentration exceeding 34 µmol/l during the first three weeks after the transplantation. Among them we evaluated whether they had a weight increase of more than 2 % or 5 % compared to the admission weight. We also registered the clinical notes of liver enlargement, upper right abdomen pain and ascites as well as ultrasound examinations. Results: Of the 300 patients, 54 had a serum bilirubin concentration exceeding 34 µmol/l within three weeks post-transplantation. The peak bilirubin concentration was 35-193 (median 47) µmol/l. Of these patients, 43 showed a weight gain exceeding 2 % and 29 patients exceeding 5 % of the admission weight. Thus, forty-three patients fulfilled the minimum modified Seattle criteria with the 2 % weight gain criterion and 29 with the 5 % criterion (modification, Corbacioglu et al 2012). Two patients had enlarged liver and right upper quadrant pain. No case of abnormal venous blood flow was seen. According to institutional policy, preemptive treatment with defibrotide according to bilirubin levels was started in 10 patients but in most cases discontinued within a few days based on the clinical course. Twenty-eight (65 %) of the 43 patients fulfilling the minimal VOD criteria had other clinical conditions that were regarded by the treating team as a plausible cause for the findings: infection 22, non-conditioning drug effect 4, cholecystitis or cholestasis 2, engraftment syndrome 2, GvHD 1, and hemolysis 1. In the remaining 15 patients there was no obvious alternative cause. Thirteen of these cases were mild, showing no hepatomegaly, and they had not been labelled as VOD. Conclusion: According to the modified Seattle criteria, 15 patients (2% weight criterion) or 10 patients (5 % weight criterion), without an alternative cause to the clinical findings, had VOD. Two patients fulfilled the Baltimore criteria, but as one of them had a simultaneous septic infection, the diagnosis of VOD could not be confirmed. Therefore, depending on the criteria used and the differential diagnostic interpretations, the incidence of VOD in this material was between 5 % and 0.3 %. All cases were mild. UDCA prophylaxis and preemptive defibrotide treatment probably affected the incidence. Differences in differential diagnostic interpretations may contribute significantly to the variable incidences of VOD reported. Disclosures No relevant conflicts of interest to declare.

Abstract 3133 The treatment of multiple myeloma (MM) has been rapidly evolving with the introduction of new drugs, but this disease is still regarded as incurable, with few exceptions. The role of allogeneic stem cell transplantation in the treatment of MM is unclear at present. It offers the possibility to harness the curative potential of the graft-versus-myeloma effect, but high transplant-related mortality, as previously reported, has limited its use. We report our single-center experience of 120 patients treated with allogeneic transplantation at the Helsinki University Central Hospital since the year 2000 showing low transplant-related mortality and a significant proportion of patients achieving prolonged progression-free survival. The median age of the patients was 50 (range 28–65) years. Sixty-three patients were male, 57 female. The immunoglobulin classes were IgG 75, IgA 16, IgD 3, and light chain 26. Forty-nine patients received a myeloablative (MA) conditioning, 71 patients a reduced intensity conditioning (RIC). The MA regimens were cyclophosphamide 120 mg/kg + fractionated TBI 12 Gy, lungs 10 Gy (n= 30) and treosulfan 42 g/m2 + fludarabine 150 mg/m2 (n= 19), the RIC regimens TBI 2 GY (n= 52) or treosulfan 36 g/m2 (n= 19) with fludarabine. In 43 cases allotransplantation, conditioned with low-dose TBI-based regimen, was performed in a preplanned combination with autologous transplantation which preceded the allotransplantation with the median of 5 (range 2–8) months. Overall, 79 patients had an autologous transplantation in their previous history. The number of chemotherapy lines preceding allogeneic transplantation was 1 in 49, 2 in 30, and 3–7 in 41 cases. The median time from the diagnosis of MM to allotransplantation was 10 (range 5–82 ) months in transplantations with MA conditioning and 16 (7–170) months in those with RIC. Of the donors 74 were HLA-matched siblings and 46 unrelated. The graft was from peripheral blood in 99 and from bone marrow in 21 cases. In transplantations with low-dose TBI based conditioning the GVHD prophylaxis consisted of CsA and MMF. The other patients received CsA + MTX, in sibling transplantations with TBI-based MA conditioning added with methylprednisolone. ATG was given in transplantations from an unrelated donor except to patients conditioned with low-dose TBI. The state of the disease preceding the allotransplantation was the following: CR 18 (15 %), VGPR 7 (6 %) PR 82 (68 %), MR 3 (3 %), and progression 10 (8 %). At 100 days post-transplantation 30 patients (25 %) were in CR, 6 (5 %) in VGPR, 63 (53 %) in PR, 2 (2 %) in MR; 2 (2 %) had no change, and 13 (11 %) progressed. Five patients had died. The best response, achieved at the median of 3 (range 0 – 80) months post-transplantation, was CR 53 (44 %), VGPR 6 (5 %), PR 48 (40 %), MR 1 (1 %), NC 2 (2 %), and progression 10 (8 %). The median follow-up of living patients was 62 (range 1–140) months. The cumulative incidence of grade II-IV acute GVHD was 29 %; that of chronic GVHD 65 % (extensive 25 %) in MA transplantations and 80 % (extensive 51 %) in RIC transplantations. Seventy-three patients had disease progression; the cumulative incidence of progression until 10 years was 70%. There was no significant difference in the incidence of progression between MA and RIC transplantations. Thirty-six patients received DLI for the treatment of progression. Fifty-three patients have died, 38 of them in disease progression, and 15 of non-relapse causes. The cumulative incidences of non-relapse mortality (NRM) in MA and RIC transplantations were 0 vs. 3 % at 100 days, 2 vs. 9 % at 1 year and 8 vs. 26 % at 5 years. The survivals of MA and RIC patients were 92 vs. 87% at 1 year, 87 vs. 72% at 2 years, 64 vs. 56% at 5 years, and 49 vs. 35% at 10 years, respectively. The proportion of the whole patient population surviving without disease progression was 26% from 7 years on until the end of follow-up. There was no significant difference in the survival between transplantations from sibling and unrelated donor. In conclusion, the low NRM, particularly in transplantations with myeloablative conditioning, and the significant proportion of patients with long-term progression-free survival suggest a role for allogeneic transplantation in the treatment of myeloma. The optimal combination of modern drug treatment with allogeneic transplantation providing graft-versus myeloma effect should be assessed in clinical trials. Disclosures: No relevant conflicts of interest to declare.

40 pregnancies of 16 women with ET were analyzed retrospectively. In 6 patients ET was diagnosed before the first pregnancy. In 10 patients thrombocytosis was detected for the first time during a pregnancy, and the diagnosis of ET was confirmed in the median of 17 months from the delivery. Of the pregnancies 45% (18/40) were complicated, 55% (22/40) uncomplicated, and 63% (25/40) resulted in live birth. 9/16 women had at least one complicated pregnancy. The most common complication was spontaneous abortion during the first trimester, seen in 33% of all pregnancies and comprising 72% of all complications. 2 intrauterine fetal deaths occurred at weeks 22 and 28. 3 pregnancies were complicated by eclampsia or pre-eclampsia. The non-pregnancy-related symptoms of ET or platelet counts before conception or during pregnancy did not correlate with the risk of complications. The median of maximum platelet counts during the first trimester in 16 pregnancies resulting in live birth was 757 x 109/l (255 – 1561 x 109/l) and in 13 pregnancies ending in pregnancy loss 835 x 109/l (697 – 1525 x 109/l) (p=0.25). The intrauterine fetal deaths occurred with platelet counts 553 and 574 x 109/l. In patients with eclampsia or pre-eclampsia the platelet counts were normal at the onset of the symptoms. Only 2 patients had other ET-related symptoms during pregnancy. 9 patients had ET-related symptoms before or between the pregnancies. In 4 of them the pregnancies were uncomplicated. Treatment for ET was or had been given to 11/16 (67%) women in 13 pregnancies either during the pregnancy or before conception or both. Acetylsalicylic acid (ASA) was given in 10 pregnancies of 9 patients. 2 continued with ASA throughout the pregnancy. In 7 patients ASA was started at 4–27 weeks of gestation, in 4 of them during the first trimester. 7 patients had received platelet lowering drugs before conception. 5 were on interferon (IFN) before conception; 3 of them switched over to ASA after conception, one continued with IFN after a 4-week break from week 15 onwards, one continued with IFN throughout the pregnancy. Both patients on IFN during the pregnancy received also ASA. 2 women had been treated with busulphan before conception; one because of previous recurrent miscarriages successfully before two pregnancies, and the other with no pregnancy planning 26 months before the conception. Pregnancy complications occurred in 18/27 (67%) pregnancies in women without any treatment and in 0/13 pregnancies in those with treatment before or during the pregnancy (p