Search

Graft-versus-host disease (GVHD) is a major factor contributing to mortality and morbidity after allogeneic stem-cell transplantation. Because of the small number of results from well designed, large- scale, clinical studies there is considerable variability in the prevention and treatment of GVHD worldwide. In 2014, to standardise treatment approaches the European Society of Blood and Marrow Transplantation published recommendations on the management of GVHD in the setting of HLA-identical sibling or unrelated donor transplantation in adult patients with haematological malignancies. Here we update these recommendations including the results of study published after 2014. Evidence was searched in three steps: first, a widespread scan of published trials, meta-analyses, and systematic reviews ; second, expert opinion was added for specific issues following several rounds of debate ; and third, a refined search to target debated or rapidly updating issues. On the basis of this evidence and the 2014 recommendations, five members of the EBMT Transplant Complications Working Party created 38 statements on GVHD prophylaxis, drug management, and treatment of acute and chronic GVHD. Subsequently, they created the EBMT GVHD management recommendation expert panel by recruiting 20 experts with expertise in GVHD management. An email-based, two-round Delphi panel approach was used to manage the consensus. Modified National Comprehensive Cancer Network categories for evidence and consensus were applied to the approved statements. We reached 100% consensus for 29 recommendations and 95% consensus for nine recommendations. Key updates to these recommendations include a broader use of rabbit anti-T-cell globulin ; lower steroid doses for the management of grade 2 acute GVHD with isolated skin or upper gastrointestinal tract manifestations ; fluticasone, azithromycin, and montelukast should be used for bronchiolitis obliterans syndrome ; and the addition of newer treatment options for resteroid- refractory acute and chronic GVHD. In addition, we discuss specific aspects of GVHD prophylaxis and management in the setting of haploidentical transplantation and in paediatric patients, but no formal recommendations on those procedures have been provided in this Review. The European Society of Blood and Marrow Transplantation proposes to use these recommendations as a basis for the routine management of GVHD during stem-cell transplantation.

Key Points Question What patient characteristics are associated with benefit from treatment with COVID-19 convalescent plasma (CCP)? Findings This prognostic study of 2287 patients hospitalized with COVID-19 identified a combination of baseline characteristics that predict a gradation of benefit from CCP compared with treatment without CCP. Preexisting health conditions (diabetes, cardiovascular and pulmonary diseases), blood type A or AB, and earlier stage of COVID-19 were associated with a larger treatment benefit. Meaning These findings suggest that simple patient information collected at hospitalization can be used to guide CCP treatment decisions for patients with COVID-19., This prognostic study develops an index for predicting the expected relative COVID-19 convalescent plasma treatment benefit for patients hospitalized for COVID-19 using patients’ baseline characteristics., Importance Identifying which patients with COVID-19 are likely to benefit from COVID-19 convalescent plasma (CCP) treatment may have a large public health impact. Objective To develop an index for predicting the expected relative treatment benefit from CCP compared with treatment without CCP for patients hospitalized for COVID-19 using patients’ baseline characteristics. Design, Setting, and Participants This prognostic study used data from the COMPILE study, ie, a meta-analysis of pooled individual patient data from 8 randomized clinical trials (RCTs) evaluating CCP vs control in adults hospitalized for COVID-19 who were not receiving mechanical ventilation at randomization. A combination of baseline characteristics, termed the treatment benefit index (TBI), was developed based on 2287 patients in COMPILE using a proportional odds model, with baseline characteristics selected via cross-validation. The TBI was externally validated on 4 external data sets: the Expanded Access Program (1896 participants), a study conducted under Emergency Use Authorization (210 participants), and 2 RCTs (with 80 and 309 participants). Exposure Receipt of CCP. Main Outcomes and Measures World Health Organization (WHO) 11-point ordinal COVID-19 clinical status scale and 2 derivatives of it (ie, WHO score of 7-10, indicating mechanical ventilation to death, and WHO score of 10, indicating death) at day 14 and day 28 after randomization. Day 14 WHO 11-point ordinal scale was used as the primary outcome to develop the TBI. Results A total of 2287 patients were included in the derivation cohort, with a mean (SD) age of 60.3 (15.2) years and 815 (35.6%) women. The TBI provided a continuous gradation of benefit, and, for clinical utility, it was operationalized into groups of expected large clinical benefit (B1; 629 participants in the derivation cohort [27.5%]), moderate benefit (B2; 953 [41.7%]), and potential harm or no benefit (B3; 705 [30.8%]). Patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases), with blood type A or AB, and at an early COVID-19 stage (low baseline WHO scores) were expected to benefit most, while those without preexisting conditions and at more advanced stages of COVID-19 could potentially be harmed. In the derivation cohort, odds ratios for worse outcome, where smaller odds ratios indicate larger benefit from CCP, were 0.69 (95% credible interval [CrI], 0.48-1.06) for B1, 0.82 (95% CrI, 0.61-1.11) for B2, and 1.58 (95% CrI, 1.14-2.17) for B3. Testing on 4 external datasets supported the validation of the derived TBIs. Conclusions and Relevance The findings of this study suggest that the CCP TBI is a simple tool that can quantify the relative benefit from CCP treatment for an individual patient hospitalized with COVID-19 that can be used to guide treatment recommendations. The TBI precision medicine approach could be especially helpful in a pandemic.

BACKGROUND Extracorporeal photopheresis (ECP) is an effective treatment. However, protocols differ widely, and some questions, such as the number of cells to be collected or the number of ECP treatment days per treatment cycle, are still unsolved. The aim of this study was to compare a multistep (offline) (Spectra Optia and Macogenic G2) against an integrated (inline) ECP system (Therakos Cellex system) with respect to mononuclear cell (MNC) collection. STUDY DESIGN AND METHODS The number and quality parameters of the MNC products collected were evaluated together with some machine parameters, such as collection time. Comparisons were made through paired sample analysis with the t test. RESULTS Fourteen patients underwent 15 double-paired procedures using both ECP protocols. The average MNC collected in the multistep procedure was 77.4 × 108 , four times more than in the integrated procedure (18.5 × 108 ). MNC purity (84.4% vs. 63.8%) and enrichment (27.9 vs. 5.9) in the product collected were also higher in the multistep procedure. The whole ECP time was higher in the multistep than in the integrated procedure (272 vs. 106 min), but the calculated time to collect 25 × 108 MNCs in the multistep was shorter compared with the one-step procedure (77.8 vs. 172 min). All these differences between the two protocols were statistically significant. CONCLUSIONS These two ECP protocols are different with respect to MNC collection and length of procedure. Some unresolved questions, such as the better MNC dose to inactivate or the number of consecutive days that ECP should be performed for optimal clinical efficacy, require further review.

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.

The majority of adult patients have sexual concerns after post-haematopoietic cell transplantation. Even so, health-care professionals (HCP) do not routinely discuss these problems. We, therefore, surveyed all the members of the European Society for Blood and Marrow Transplantation to evaluate the barriers and facilitators to discussing sexual issues. The 73-item web-survey was completed by 166 registered nurses (RNs) and 126 medical doctors (MDs). Sixty-eight percent reported that they seldom discussed sexual issues. Younger MDs (p < 0.001) and those who work in non-western European countries (p = 0.003), RNs with probably less sexual education themselves (p = 0.002), MDs and RNs who have limited knowledge about sexual complications (p < 0.001) and MDs and RNs who feel uncomfortable discussing sexual issues (p < 0.001) are all less likely to discuss these matters. The major perceived barriers were that patients might be embarrassed if sexual issues were discussed in the presence of a relative (60% RNs, 67% MDs) and that professionals prefer patients to raise sexual issues themselves (54% RNs, 44% MDs). The most important perceived facilitator was for the patient to initiate discussion (≥ 90% for RNs and MDs). Overall, haematopoietic cell transplantation survivors may not be receiving the support on sexual issues they probably need.

The possibility to use CCR5-∆32 umbilical cord blood to cure HIV infection in patients in need of a hematopoietic transplant has been suggested. The less stringent HLA compatibility needed in this type of transplant facilitates the search of a suitable donor having the CCR5-∆32 mutation. To achieve an inventory of CCR5-∆32 cord blood units, the 20,236 best cell quality units of the Spanish Registry were genotyped. Furthermore, their CD34+ and total nucleated cells counts, blood type, gender, HLA and donor's geographical and ancestral origin were analyzed. The results showed 130 (0.64%) units homozygous for the deletion, 2,646 (13.08%) heterozygous and 17,460 (86.28%) did not present the mutation. Interestingly, a significant lower amount of CD34+ cells was found in the CCR5-∆32 homozygous units. In addition, a significant association was found among donor's ancestral origin and the mutation, with a higher percentage of CCR5-∆32 units with a European ancestry. In summary, identification of a relatively high number of CCR5-∆32 units is feasible and will facilitate the development of clinical trials for HIV cure in patients requiring hematopoietic transplantation. Further studies are required to understand the significance of lower cell counts within the CCR5-∆32 homozygous group and its clinical impact.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and nonmalignant diseases. Despite increasing survival rates, long-term morbidity after HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction after HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction after HCT. In this review we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Finally, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae after HCT.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and non-malignant diseases. Despite increasing survival rates, long-term morbidity following HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction following HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction following HCT. In this review, we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and to help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Lastly, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae following HCT.

Introduction: The severity of acute clinical outcomes and mortality in hematologic malignancy (HM) patients infected by SARS-CoV-2 was exhaustively documented in the first weeks of the pandemic. A consistent increased mortality compared to non-cancer patients was observed across studies. In this study we aimed to estimate survival in COVID-19 HM patients by type of malignancy, to describe acute and post-acute clinical outcomes, and to compare outcomes in early and later pandemic periods. Methods: In this population-based registry study sponsored by the Madrid Society of Hematology (Asociación Madrileña de Hematología y Hemoterapia), we collected de-identified data on clinical characteristics, treatment and acute and post-acute outcomes in adult patients with hematologic malignancies and confirmed SARS-CoV-2 infection within the Madrid region of Spain. Our case series included all eligible patients admitted to 26 regional health service hospitals and 5 private healthcare centers between February 28, 2020 and February 18, 2021 with a coverage of 98% on a population of 6.6 million inhabitants. The study outcomes were all-cause mortality, severity of disease (WHO), oxygen support, ICU admission, and follow-up symptoms and signs and complications. Survival probabilities were estimated with the actuarial method and reported overall and stratified by type of malignancy and for two study periods (early cohort,-COVID-19 diagnosis from February 28 to 31 May, 2020, and later cohort, up to February 18, 2021). Results: Of the 1408 patients reported to the HEMATO-MADRID COVID-19 registry, 1166 were included in the present analyses; 839 (72%) had a lymphoid malignancy, including 325 (28%) with non-Hodgkin lymphoma, 50 (4%) with Hodgkin lymphoma and 263 (23%) with multiple myeloma; and 327 (28%) had a myeloid malignancy, including 115 (10%) with myelodysplastic syndrome, 92 (8%) with acute myeloid leukemia (AML) and 87 (7%) with Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms. Overall COVID-19 clinical severity was classified as critical in 19% of patients, severe in 36%, moderate in 22%, and mild in 22%; 10% were admitted to an ICU; 8% were on mechanical ventilation and 19% on noninvasive ventilation. Mild disease increased between early and later period from 15% to 38% of patients; severe disease decreased from 42% to 24%, p At follow-up, 22% reported persistent symptoms related to COVID-19 at 2 months, 16% at 4 months and 14% at 6 months. 381 of 1166 (33%) patients died. Overall 30-day survival was 68%; 2 and 3-month overall survival probabilities were 56% and 53%, respectively. Survival was more favorable for patients with myeloproliferative neoplasms (82%, 69% and 65% at 30-days, 2 and 3 months, respectively) than for those with lymphoid malignancies (68%, 56% and 54%) or myelodysplastic syndrome/acute myeloid leukemia (61%, 51%, 46%), p=001. 285 (37%) patients died in the early period vs 96 (24%) in the later, p Conclusions. A population-based registry in Spain provided strong evidence that although COVID-19 severity decreased over year 1 of the pandemic, mortality remained high, and survival was stable over time in the group of patients with hematological malignancy infected by SARS-Coc-2. A relevant proportion of the infected patients (1 in 6) referred persistent symptoms attributable to COVID-19. The improved clinical management of severe COVID-19 in non-cancer patients that followed the dissemination of evidence-based recommendations did not translate in more favorable survival in patients with hematological malignancies. Research is needed to address the specific characteristics and improve the clinical management of this vulnerable population. Disclosures Martinez-Lopez: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Astellas: Research Funding, Speakers Bureau. Jiménez-Yuste: Pfizer: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding; BioMarin: Consultancy; Sobi: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding. Kwon: Gilead: Honoraria.

BACKGROUND: Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation. Letermovir is an antiviral drug that inhibits the CMV-terminase complex. METHODS: In this phase 3, double-blind trial, we randomly assigned CMV-seropositive transplant recipients, 18 years of age or older, in a 2:1 ratio to receive letermovir or placebo, administered orally or intravenously, through week 14 after transplantation; randomization was stratified according to trial site and CMV disease risk. Letermovir was administered at a dose of 480 mg per day (or 240 mg per day in patients taking cyclosporine). Patients in whom clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) developed discontinued the trial regimen and received anti-CMV treatment. The primary end point was the proportion of patients, among patients without detectable CMV DNA at randomization, who had clinically significant CMV infection through week 24 after transplantation. Patients who discontinued the trial or had missing end-point data at week 24 were imputed as having a primary end-point event. Patients were followed through week 48 after transplantation. RESULTS: From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P

43rd Annual Meeting of the EBMT, 26–29 March 2017, Marseille, France The European Society for Blood and Marrow Transplantation (EBMT) was established in 1974 to enable scientists and physicians to share their experience and develop studies in clinical bone marrow transplantation. Despite advances in treatment, invasive fungal infections (IFI), especially those caused by moulds such as Aspergillus, remain a leading cause of morbidity and mortality in patients with hematological malignancies. There is a continuum of risk of IFI during induction and consolidation therapy, and after hematopoietic cell transplantation. New, evidence-based approaches to the prevention, diagnosis and treatment of IFI were, therefore, of major interest to the over 5000 delegates from 85 countries attending the 43rd EBMT Annual Meeting (EBMT 2017).

Peter Paschka and Hartmut Döhner contributed equally. Background. SARS-CoV-2 infection (COVID-19) has had a great impact worldwide and its mortality has been reported to be higher in patients with haematological malignancies. However, description of its effects and outcomes among recipient of hematopoietic stem cell transplantation (HSCT) is scarce. Objectives. To describe the characteristics, treatment and outcome of COVID-19 in recipients of HSCT reported to the Madrid registry of COVID-19 ("HEMATO-MADRID COVID-19 registry"). Results. Data of 842 patients from 23 hospitals with haematological malignancies and COVID-19 infection were reported in the Madrid registry between March and June 2020. Among those, 87 (10.3%) patients were HSCT recipients: 58 auto-HSCT and 29 allo-HSCT (7 of them from matched related donor (MRD), 12 matched unrelated donor (MUD) and 10 haplo-HSCT). Characteristics of the population are described in Table 1. Median age at COVID-19 infection was 61 years (IQR, 53-67) and 35 patients (40%) were female. Recipients of auto-HSCT with COVID-19 were older and showed a trend towards a higher incidence of arterial hypertension (28% vs 10%, p=0.067) without statistical differences in other comorbidities; active disease requiring treatment at COVID-19 diagnosis was more frequent in auto-HSCT recipients (65% vs. 21%, p Conclusion. In our multicentric experience in a high COVID-19 impacted area, the median time of COVID-19 infection presentation was relatively late in transplanted patients, however shorter in allo-transplanted patients. COVID-19 related mortality was high in HSCT recipients, significantly higher in allo-transplanted patients. Factors associated to this higher mortality should be further investigated to promptly identify high-risk patients since the pandemic is still highly active worldwide. Disclosures Kwon: Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria. Duarte:Incyte Corporation: Other: Has received speaker and advisor fees. Hernandez-Rivas:Rovi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees. Jimenez Yuste:NovoNordisk: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Bayer: Honoraria; Sobi: Consultancy, Honoraria, Research Funding; CSL: Honoraria; Octapharma: Honoraria.

Background Despite prophylaxis, GVHD remains a significant cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation (HCT). ITA is a potent, selective Janus kinase (JAK) 1 inhibitor that has been combined safely with steroids in patients (pts) with acute GVHD. We describe results from a proof-of-concept study evaluating ITA + CNI-based regimens for GVHD prophylaxis. Study Design and Methods GRAVITAS-119 (NCT03320642) was a single-arm, open-label study enrolling pts aged ≥18 y undergoing allogeneic HCT using peripheral blood stem cells from 8/8 or 7/8 matched related or unrelated donors for a hematologic malignancy. Eligible pts were candidates for reduced-intensity conditioning with Karnofsky Performance Status ≥70%. Pts were excluded for prior HCT, JAK inhibitor therapy, or active uncontrolled infection. Pts received oral ITA 200 mg once daily (QD) beginning 3 d before HCT + tacrolimus (Tac)/methotrexate (MTX) or cyclosporine A (CSA)/mycophenolate mofetil (MMF) ± antithymocyte globulin (ATG) per institutional practice. ITA dose reduction/interruption was permitted for toxicity. ITA was reduced to 100 mg QD by Day 90 and discontinued by Day 180 unless pts required systemic GVHD treatment (tx), had malignancy relapse or unacceptable toxicity, or withdrew consent. The primary endpoint was Day 28 hematologic recovery (absolute neutrophil count [ANC] ≥500/mm3 for 3 consecutive measurements and platelets [plt] ≥20,000/mm3 with no transfusions in the preceding 3 d). Secondary endpoints included incidence of acute and chronic GVHD, GVHD- and relapse-free survival (GRFS), overall survival, and safety. Results Sixty-five pts were enrolled and treated with ITA + Tac/MTX (n=41; +ATG, n=8; no ATG, n=33) or ITA + CSA/MMF (n=24; +ATG, n=16; no ATG, n=8). Median (range) age was 65 (25-76) y, and 57% were male. The most common underlying malignancies were acute myeloid leukemia (40%) and myelodysplastic syndrome (26%). Disease risk index was classified as low, intermediate, and high in 11%, 66%, and 23% of pts, respectively. Pts received grafts from matched related (51%), matched unrelated (40%), or single-antigen mismatched unrelated (9%) donors. Busulfan/fludarabine (51%) and a fludarabine/melphalan reduced-intensity regimen (18%) were the most common conditioning regimens; 11% of regimens contained total body irradiation. Median (range) exposure to ITA was 140 (10-187) d; 74% received ITA for >90 d. All pts achieved hematologic recovery. Median (range) time to ANC and plt recovery among patients who had count nadir (ANC Conclusions Results from this small open-label trial in a heterogeneous pt population demonstrated that GVHD prophylaxis with ITA + CNI-based regimens was well tolerated and rates of severe acute GVHD were low. 1 pt with MF did not achieve ANC recovery on Day 28. An ITA + Tac + post-transplant cyclophosphamide cohort is currently being investigated in GRAVITAS-119. Disclosures Shah: Cell Vault: Research Funding; Celgene: Consultancy, Honoraria; Miltenyi Biotec: Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Incyte: Consultancy; TG Therapeutics: Consultancy; Verastim: Consultancy; Lily: Consultancy, Honoraria. Chevallier:Incyte Corporation: Honoraria. Rubio:Medac: Consultancy; MSD: Honoraria; Gilead: Honoraria; Neovii: Research Funding; Novartis: Honoraria. Schroeder:Astellas: Other; Dova Pharmaceuticals: Other; FlatIron Inc: Other; GSK: Other; Gilead Sciences Inc: Other; Novo Nordisk: Other; Genentech Inc: Research Funding; Merck: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Cellect Inc: Research Funding; Janssen: Research Funding; Partners Therapeutics: Other; Pfizer: Other; AbbVie: Consultancy, Honoraria, Speakers Bureau; Fortis: Research Funding; Seattle Genetics: Research Funding; Amgen: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Celgene: Research Funding; PBD Incorporated: Research Funding; Genzyme Sanofi: Other: served on advisory boards and received honoraria or consultant fees, Research Funding. Hardy:Incyte Corporation: Other: Advisory Board Member; Kite/Gilead: Other: Advisory Board Member; American Gene Technologies: Other: DSMB Member. Stiff:Kite, a Gilead Company: Research Funding; Amgen: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding. Solano:Incyte Corporation: Other: Received fees for an advisory role. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Rowley:AbbVie: Current equity holder in publicly-traded company; FATE Therapeutics: Consultancy. Duarte:Incyte Corporation: Other: Has received speaker and advisor fees. Morariu-Zamfir:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Arbushites:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Ding:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Perales:Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Servier: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. OffLabel Disclosure: Itacitinib is a novel JAK1 inhibitor that has not been approved for use in acute GVHD or for any other indication.

Summary Background The introduction of donors other than HLA-matched siblings has been a pivotal change in stem cell transplantation. We aimed to assess the evolution of outcomes within donor groups over time and explore whether donor–recipient HLA disparity might be advantageous in patients with aggressive disease. Methods In this retrospective, multicentre study, we assessed the outcomes for adult patients (≥18 years) with haematological malignancies who underwent their first allogeneic hematopoietic stem cell transplantation (HSCT) between Jan 3, 2001, and Dec 31, 2015, and were reported to the European Society for Blood and Marrow Transplantation. The donor types studied were matched sibling, matched unrelated, mismatched unrelated, haploidentical, and cord blood donors. Unrelated non-cord-blood donors and recipients were typed at the allelic level for HLA-A, HLA-B, HLA-C, and HLA-DRB1. We evaluated trends in overall survival, non-relapse mortality, relapse incidence, progression-free survival, acute and chronic graft-versus-host disease (GVHD), and GVHD-free and relapse-free survival following transplantation from various donor types (matched sibling, matched unrelated, mismatched unrelated, haploidentical, and umbilical cord blood), and compared transplantation outcomes across three epochs (epoch 1: 2001–05; epoch 2: 2006–10; and epoch 3: 2011–15). We used Kaplan-Meier estimators for survival probabilities and cumulative incidence functions accounting for competing risks for probabilities of GHVD, relapse, and non-relapse mortality, using multiple imputations by chained equations to deal with missing data. In epoch 3, we directly compared outcomes by donor group, stratified by a novel three-level disease-risk scheme. Findings We included 106 188 patients in our analysis. The median follow-up was 4·1 years (IQR 1·7–7·7). Overall survival at 3 years increased with all donor groups between epochs 2 and 3 (matched sibling: 54·0% [95% CI 53·1–54·8] to 54·6% [53·6–55·6]; matched unrelated: 49·1% [48·0–50·2] to 51·6% [50·7–52·6]; mismatched unrelated: 37·4% [35·7–39·2] to 41·3% [39·5–43·1]; haploidentical: 34·5% [31·4–37·9] to 44·2% [42·1–46·3]; and cord blood 36·3% [33·9–39] to 43·7% [40·8–46·8]). Improvement in overall survival seems to be driven by a reduction in non-relapse mortality, except in cord blood HSCT recipients, who had a lower relapse incidence. Comparing donor groups across disease-risk strata using the novel disease-risk scheme, overall survival among recipients of matched sibling transplantations remained better than other donor groups except in high-risk disease, where overall survival with matched unrelated transplantations was not different. Interpretation Overall survival following allogeneic stem cell transplantation is improving with substantial progress among recipients of haploidentical and cord blood HSCT. Nonetheless, the traditional donor hierarchy of matched sibling donors followed by matched unrelated donors and then other donors holds. Our findings warrant further investigation and could inform decision making and the development of donor-selection algorithms. Funding The Varda and Boaz Dotan Research Center in Haemato-Oncology, Tel Aviv University, and the Shalvi Foundation for Research.

International audience; Chimeric antigen receptor (CAR) T cells are a novel class of anti-cancer therapy in which autologous or allogeneic T cells are engineered to express a CAR targeting a membrane antigen. In Europe, tisagenlecleucel (Kymriah™) is approved for the treatment of refractory/relapsed acute lymphoblastic leukemia in children and young adults as well as relapsed/refractory diffuse large B-cell lymphoma, while axicabtagene ciloleucel (Yescarta™) is approved for the treatment of relapsed/refractory high-grade B-cell lymphoma and primary mediastinal B-cell lymphoma. Both agents are genetically engineered autologous T cells targeting CD19. These practical recommendations, prepared under the auspices of the European Society of Blood and Marrow Transplantation, relate to patient care and supply chain management under the following headings: patient eligibility, screening laboratory tests and imaging and work-up prior to leukapheresis, how to perform leukapheresis, bridging therapy, lymphodepleting conditioning, product receipt and thawing, infusion of CAR T cells, short-term complications including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, antibiotic prophylaxis, medium-term complications including cytopenias and B-cell aplasia, nursing and psychological support for patients, long-term follow-up, post-authorization safety surveillance, and regulatory issues. These recommendations are not prescriptive and are intended as guidance in the use of this novel therapeutic class.

Background: The role of conditioning intensity and stem cell source on modifying pre-transplantation risk in allogeneic haematopoietic stem cell transplantation (HSCT) is a matter of debate, but crucial when benchmarking centres. Methods: This Retrospective, multicenter exploratory-validation analysis of 9103 patients, (55.5% male, median age 50 years; 1–75 years range) with an allogeneic HSCT between 2010 and 2016 from a matched sibling (N = 8641; 95%) or matched unrelated donor (N = 462; 5%) for acute myeloid (N = 6432; 71%) or acute lymphoblastic (N = 2671; 29%) leukaemia in first complete remission, and reported by 240 centres in 30 countries to the benchmark database of the European Society for Blood and Marrow Transplantation (EBMT) searched for factors associated with use of transplant techniques (standard N = 6375;70% or reduced intensity conditioning N = 2728;30%, respectively bone marrow N = 1945;21% or peripheral blood N = 7158;79% as stem cell source), and their impact on outcome. Findings: Treatment groups differed significantly from baseline population (p

This retrospective study explored the incidence of autoimmune cytopenia (AIC) in 530 paediatric and adult patients with acquired aplastic anaemia (aAA) who underwent first allogeneic HSCT between 2002 and 2012. AIC was a rare complication with a cumulative incidence of AIC at 1, 3, 5 and 10 years post HSCT of 2.5% (1.2–3.9 95% CI), 4.4% (2.6–6.2 95% CI), 4.6% (2.8–6.5 95% CI) and 5.1% (3.1–7.2 95% CI). Overall survival at 5 years after diagnosis of AIC was 85.9% (71–100 95% CI). Twenty-five patients were diagnosed with AIC at a median of 10.6 (2.6–91.5) months post HSCT. Eight (32%) patients were diagnosed with immune thrombocytopenia (ITP), seven (28%) with autoimmune haemolytic anaemia (AIHA), seven (24%) with Evans syndrome and four (16%) with autoimmune neutropenia (AIN). Treatment strategies were heterogeneous. Complete responses were seen in 12 of 25 patients, with death in three patients. In multivariable Cox analysis of a subgroup of 475 patients, peripheral blood stem cell (PBSC) transplant was associated with higher risk of AIC compared with bone marrow (BM) when conditioning regimens contained fludarabine and/or alemtuzumab (2.81 [1.06–7.49 95% CI]; p = 0.038), or anti-thymocyte globulin (ATG) (2.86 [1.11–7.37 95% CI]; p = 0.029). Myeloablative conditioning was associated with a lower risk of AIC compared with reduced intensity conditioning (RIC) in fludarabine and/or alemtuzumab (0.34 [0.12–0.98 95% CI]; p = 0.046) and ATG containing regimens (0.34 [0.12–0.95 95% CI]; p = 0.04). These findings provide clinically useful information regarding the incidence of a rare and potentially life-threatening complication of allogeneic HSCT for aAA, and further support for BM as the preferred stem cell source for transplant of patients with aAA.

Invasive Scedosporium spp. and Lomentospora prolificans infections are an emerging threat in immunocompromised and occasionally in healthy hosts. Scedosporium spp. is intrinsically resistant to most, L. prolificans to all the antifungal drugs currently approved, raising concerns about appropriate treatment decisions. High mortality rates of up to 90% underline the need for comprehensive diagnostic workup and even more for new, effective antifungal drugs to improve patient outcome. For a comprehensive analysis, we identified cases of severe Scedosporium spp. and L. prolificans infections from the literature diagnosed in 2000 or later and the FungiScopeVR registry. For 208 Scedosporium spp. infections solid organ transplantation (n¼58, 27.9%) and for 56 L. prolificans infection underlying malignancy (n¼28, 50.0%) were the most prevalent risk factors. L. prolificans infections frequently presented as fungemia (n¼26, 46.4% versus n¼12, 5.8% for Scedosporium spp.). Malignancy, fungemia, CNS and lung involvement predicted worse outcome for scedosporiosis and lomentosporiosis. Patients treated with voriconazole had a better overall outcome in both groups compared to treatment with amphotericin B formulations. This review discusses the epidemiology, prognostic factors, pathogen susceptibility to approved and investigational antifungals, and treatment strategies of severe infections caused by Scedosporium spp. and L. prolificans, We thank Sabine Wrackmeyer for her private donation to support the project

In many healthcare settings, benchmarking for complex procedures has become a mandatory requirement by competent authorities, regulators, payers and patients to assure clinical performance, cost-effectiveness and safe care of patients. In several countries inside and outside Europe, benchmarking systems have been established for haematopoietic stem cell transplantation (HSCT), but access is not universal. As benchmarking is now integrated into the FACT-JACIE standards, the EBMT and JACIE established a Clinical Outcomes Group (COG) to develop and introduce a universal system accessible across EBMT members. Established systems from seven European countries (United Kingdom, Italy, Belgium, France, Germany, Spain, Switzerland), USA and Australia were appraised, revealing similarities in process, but wide variations in selection criteria and statistical methods. In tandem, the COG developed the first phase of a bespoke risk-adapted international benchmarking model for one-year survival following allogeneic and autologous HSCT based on current capabilities within the EBMT registry core dataset. Data completeness, which has a critical impact on validity of centre comparisons, is also assessed. Ongoing development will include further scientific validation of the model, incorporation of further variables (when appropriate) alongside implementation of systems for clinically meaningful interpretation and governance aiming to maximise acceptance to centres, clinicians, payers and patients across EBMT., The project was supported by funding from EBMT

Diagnosing invasive aspergillosis (IA) has long been challenging due to the inability to culture the causal Aspergillus agent from blood or other body fluids. This shortcoming has fuelled an interest in non-culture-based diagnostic techniques such as the detection of galactomannan (GM) in blood and bronchoalveolar lavage fluid, the detection of 1,3-β-d-glucan (BDG) in blood and the detection of Aspergillus DNA by PCR-based techniques. Past decades have witnessed important improvements in our understanding of the strengths and limitations of antigen assays and in the standardization of PCR-based DNA techniques. These assays are now being incorporated into care pathways and diagnostic algorithms; they help us to steward and monitor antifungal therapies and to predict treatment outcomes.

The hematological malignancies which are the most common indications for auto- and allo-HSCT (e.g., AML/MDS, NHL, MM, and others) are diagnosed at a median age greater than 65 years old.

Several international recommendations address the assessment of graft-versus-host disease (GvHD) after hematopoietic cell transplantation (HCT). This position statement by GvHD experts from the European Society for Blood and Marrow Transplantation (EBMT), the National Institutes of Health (NIH) and the Center for International Blood and Marrow Transplant Research (CIBMTR) reviews the existing guidelines for both acute and chronic GvHD, addresses potential confusions that arise in daily practice and proposes consensus definitions for many key terms. We provide a historical perspective on the currently available guidelines and recommend the Mount Sinai Acute GvHD International Consortium (MAGIC) criteria for acute GvHD and the NIH 2014 criteria for chronic GvHD as the most comprehensive and detailed criteria available. This statement also offers practical guidance for the implementation of these recommendations and a set of consensus definitions for commonly used GvHD terms in order to facilitate future clinical and translational research. To assist the dissemination of these recommendations, a web-application based on this position statement is available ( https://www.uzleuven.be/egvhd ). We believe that adherence to a common set of GvHD assessment criteria is vitally important to improve the quality of data, compare results of retrospective studies and prospective clinical trials, and make therapeutic recommendations based on quality evidence. ispartof: BONE MARROW TRANSPLANTATION vol:53 issue:11 pages:1401-1415 ispartof: location:England status: published

Recommendations on screening and nutritional support for patients undergoing hematopoietic stem cell transplantation (HSCT) have been presented by international nutritional societies, but nutritional practices remain poorly standardized. Following the general policy of the European Society for Blood and Marrow Transplantation (EBMT) to standardize transplantation procedures, the Complications and Quality of Life Working Party and Nursing Research Group carried out a survey among all EBMT centers about their current nutritional practices. The aim of this study was to better understand current practices, differences from available guidelines, and possible barriers for recommended nutritional therapy. Responses from 90 centers (19%) from 23 countries were received. We observed a marked variability in nutritional care between EBMT centers and a substantial lack of standardized operating procedures in screening patients for malnutrition and management of gastrointestinal GVHD. Furthermore, our study confirmed neutropenic diet as standard of care in most centers as well a preference for parenteral nutritional support over enteral. On the basis of these findings, future EBMT efforts will focus on better implementation of international nutritional guidelines into clinical practice.

Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity, which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD, regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms, including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.

Non-graft-versus-host disease (GVHD) ocular complications are generally uncommon after hematopoietic cell transplantation (HCT) but can cause prolonged morbidity affecting activities of daily living and quality of life. Here we provide an expert review of non-GVHD ocular complications in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Complications discussed in this review include cataracts, glaucoma, ocular infections, ocular involvement with malignancy, ischemic microvascular retinopathy, central retinal vein occlusion, retinal hemorrhage, retinal detachment and ocular toxicities associated with medications. We summarize the incidence, risk factors, screening, prevention, and treatment of individual complications and generate evidence-based recommendations. Baseline ocular evaluation before HCT should be considered in all patients who undergo HCT. Follow-up evaluations should be considered according to clinical signs and symptoms and risk factors. Better preventive strategies and treatments remain to be investigated for individual ocular complications after HCT. Both transplantation physicians and ophthalmologists should be knowledgeable about non-GVHD ocular complications and provide comprehensive collaborative team care.

Contains fulltext : 200092.pdf (Publisher’s version ) (Closed access) The European Conference on Infections in Leukaemia (ECIL) updated its guidelines on antifungal prophylaxis for adults using the grading system of IDSA. The guidelines were extended to provide recommendations for other haematological diseases besides AML and recipients of an allogeneic haematopoietic stem cell transplantation (HSCT). Posaconazole remains the drug of choice when the incidence of invasive mould diseases exceeds 8%. For patients undergoing remission-induction chemotherapy for AML and myelodysplastic syndrome (MDS), fluconazole can still offer an alternative provided it forms part of an integrated care strategy that includes screening with biomarkers and imaging. Similarly, aerosolized liposomal amphotericin B combined with fluconazole can be considered for patients at high risk of invasive mould diseases but other formulations of the polyene are discouraged. Fluconazole is still recommended as primary prophylaxis for patients at low risk of invasive mould diseases during the pre-engraftment phase of allogeneic HSCT whereas only a moderate recommendation could be made for itraconazole, posaconazole and voriconazole for patients at high risk. Posaconazole is strongly recommended for preventing invasive mould disease post-engraftment but only when graft-versus-host disease (GvHD) was accompanied by other risk factors such as its severity, use of an alternative donor or when unresponsive to standard corticosteroid therapy. The need for primary prophylaxis for other patient groups was less clear and should be defined by the estimated risk of invasive fungal disease (IFD).

Hematopoietic cell transplantation (HCT) is increasingly used worldwide. This treatment approach is complex and requires specific knowledge and training. The European Society for Blood and Marrow Transplantation (EBMT) identified the need for a set of international recommendations for the clinical training of physicians to qualify them as being competent in performing HCT procedures as well as novel cellular immune therapies and taking care of such patients. The goal is to implement an EBMT HCT-focused global curriculum (EBMT-GC) that can serve as a tool for the development of the HCT sub-specialty worldwide. Despite the diversity and heterogeneity of health and educational systems around the globe, this set of recommendations can be fairly adopted by any national educational and health authorities and can be adjusted to specific conditions and resources of a given country, if needed. The ultimate goal of the EBMT-GC is to define standards for personal knowledge in allogeneic stem cell transplantation for physicians worldwide in order to ensure that all patients will receive treatment by well-trained physicians.

Ocular graft-versus-host disease (GVHD) occurs in more than one-half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity that affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplantation physicians and ophthalmologists through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Recent updates in ocular GVHD regarding pathophysiology, preclinical models, risk factors, prevention, screening, diagnosis, response criteria, evaluation measures, and treatment are discussed. Ocular GVHD involves at least 3 biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have identified several novel pathogenic mechanisms, including the renin angiotensin system and endoplasmic reticulum stress signaling, which can be targeted by therapeutic agents. Numerous studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. The efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important that all health professionals caring for HCT recipients have adequate knowledge of ocular GVHD to provide optimal care. ispartof: Biol Blood Marrow Transplant vol:25 issue:2 pages:e46-e54 ispartof: location:United States status: published

In many healthcare settings, benchmarking for complex procedures has become a mandatory requirement by competent authorities, regulators, payers and patients to assure clinical performance, cost-effectiveness and safe care of patients. In several countries inside and outside Europe, benchmarking systems have been established for haematopoietic stem cell transplantation (HSCT), but access is not universal. As benchmarking is now integrated into the FACT-JACIE standards, the EBMT and JACIE established a Clinical Outcomes Group (COG) to develop and introduce a universal system accessible across EBMT members. Established systems from seven European countries (United Kingdom, Italy, Belgium, France, Germany, Spain, Switzerland), USA and Australia were appraised, revealing similarities in process, but wide variations in selection criteria and statistical methods. In tandem, the COG developed the first phase of a bespoke risk-adapted international benchmarking model for one-year survival following allogeneic and autologous HSCT based on current capabilities within the EBMT registry core dataset. Data completeness, which has a critical impact on validity of centre comparisons, is also assessed. Ongoing development will include further scientific validation of the model, incorporation of further variables (when appropriate) alongside implementation of systems for clinically meaningful interpretation and governance aiming to maximise acceptance to centres, clinicians, payers and patients across EBMT.

In the original version of this article, author ‘Aisha Al-Khinji’ was incorrectly listed as ‘Aisha Ahmed’. This has now been corrected in both the PDF and HTML versions of the article to ‘Aisha Al-Khinji’.

The role of allogeneic hematopoietic cell transplant (allo-HCT) in elderly patients with acute lymphoblastic leukemia (ALL) is unclear. We conducted a prospective study including 110 homogeneously treated patients with ALL aged 50-70 years. Their outcomes were analyzed by intention-to-treat on a donor-versus-no donor basis. Fifty-five patients (50%) underwent human leukocyte antigen (HLA) typing and were considered potential allo-HCT candidates, although only 25 (23%) eventually received an allo-HCT. Among potential allo-HCT candidates, patients with (n = 28) and without (n = 27) an HLA-identical sibling showed similar leukemia-free survival, overall survival (OS) and relapse risk, and the only variable associated with a better outcome was achievement of first complete remission (CR1) after induction therapy. Among the 25 patients who actually received an allo-HCT, the 4-year non-relapse mortality and OS were 42% (95% confidence interval 31-53%) and 37% (95% confidence interval 27-47%), respectively. In conclusion, having an HLA-identical sibling donor was not associated with a better outcome in patients with ALL aged 50-70 years.

Importance The outcome of older patients with acute myeloid leukemia (AML) remains unsatisfactory. Recent studies have shown that HLA-mismatched microtransplant could improve outcomes in such patients. Objective To evaluate outcomes in different age groups among older patients with newly diagnosed AML who receive HLA-mismatched microtransplant. Design, Setting, and Participants This multicenter clinical study included 185 patients with de novo AML at 12 centers in China, the United States, and Spain in the Microtransplantation Interest Group. Patients were divided into the following 4 age groups: 60 to 64 years, 65 to 69 years, 70 to 74 years, and 75 to 85 years. The study period was May 1, 2006, to July 31, 2015. Exposures Induction chemotherapy and postremission therapy with cytarabine hydrochloride with or without anthracycline, followed by highly HLA-mismatched related or fully mismatched unrelated donor cell infusion. No graft-vs-host disease prophylaxis was used. Main Outcomes and Measures The primary end point of the study was to evaluate the complete remission rates, leukemia-free survival, and overall survival in different age groups. Additional end points of the study included hematopoietic recovery, graft-vs-host disease, relapse rate, nonrelapse mortality, and other treatment-related toxicities. Results Among 185 patients, the median age was 67 years (range, 60-85 years), and 75 (40.5%) were female. The denominators in adjusted percentages in overall survival, leukemia-free survival, relapse, and nonrelapse mortality are not the sample proportions of observations. The overall complete remission rate was not significantly different among the 4 age groups (75.4% [52 of 69], 70.2% [33 of 47], 79.1% [34 of 43], and 73.1% [19 of 26). The 1-year overall survival rates were 87.7%, 85.8%, and 77.8% in the first 3 age groups, which were much higher than the rate in the fourth age group (51.7%) ( P = .004, P = .008, and P = .04, respectively). The 2-year overall survival rates were 63.7% and 66.8% in the first 2 age groups, which were higher than the rates in the last 2 age groups (34.2% and 14.8%) ( P = .02, P = .03, P P Conclusions and Relevance Microtransplant achieved a high complete remission rate in AML patients aged 60 to 85 years and higher 1-year overall survival in those aged 60 to 74 years.

We retrospectively compared the clinical outcomes of adults with acute leukemia who received single-unit umbilical cord blood (UCB) transplantation (sUCBT) (n = 135) or stem cell transplant using coinfusion of a UCB graft with CD34+ cells from a third-party donor (Haplo-Cord) (n = 72) at different institutions within the Grupo Espanol de Trasplante Hematopoyetico. In multivariable analysis, patients in the Haplo-Cord group showed more rapid neutrophil (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.5-3.3; P < .001) and platelet recovery (HR, 1.6; 95% CI, 1.2-2.3; P = .015) and lower incidence of chronic graft-versus-host disease (GVHD) (relative risk, 0.5; 95% CI, 0.3-0.8; P = .01). Nonrelapse mortality, relapse, disease-free survival (DFS), and GVHD/relapse-free survival were similar in the 2 groups. Regarding disease-specific outcomes, DFS in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia patients was not significantly different; however, a significantly higher relapse rate was found in patients with AML treated with Haplo-Cord (HR, 2.3; 95% CI, 1-5.4; P = .04). Our study confirms that Haplo-Cord was an effective strategy to accelerate neutrophil and platelet recovery and shows that, in the context of specific treatment platforms, sUCBT and Haplo-Cord offer similar long-term outcomes.

For patients with AML, the best alternative donor remains to be defined. We analyze outcomes of patients who underwent myeloablative umbilical cord blood or haploidentical hemopoietic stem cell transplantation (HSCT) in Spain. Fifty-one patients underwent single umbilical cord blood transplantation supported by a third party donor (Haplo-Cord) between 1999 and 2012, and 36 patients received an haploidentical HSCT with post-transplant cyclophosphamide (PTCY-haplo) between 2012 and 2014 in GETH centers. The Haplo-Cord cohort included a higher proportion of patients with high disease risk index and use of TBI in the conditioning regimen, and hematopoietic cell transplantation-age Comorbidity Age Index was higher in PTCY-haplo patients. Cumulative incidence of neutrophil engraftment was 97% in the Haplo-Cord and 100% in the PTCY-haplo group, achieved in a median of 12 and 17 days, respectively (P = 0.01). Grade II-IV acute GvHD rate was significantly higher in the PTCY-haplo group (9.8% vs 29%, P = 0.02) as well as chronic GvHD rates (20% vs 38%, P = 0.03). With a median follow-up of 61 months for the Haplo-Cord group and 26 months for the PTCY-haplo cohort, overall survival at 2 years was 55% and 59% (P = 0.66), event-free survival was 45% vs 56% (P = 0.46), relapse rate was 27% vs 21% (P = 0.79), and non-relapse mortality was 17% vs 23% (P = 0.54), respectively. In this multicenter experience, Haplo-Cord and PTCY-haplo HSCT offer valid alternatives for patients with AML. Neutrophil engraftment was faster in the Haplo-Cord cohort, with similar survival rates, with higher GvHD rates after haploidentical HSCT.

Among the strategies to optimize engraftment of cord blood (CB) stem cell transplantation (SCT), single CB with the coinfusion of CD34+ stem cells from an HLA-mismatched auxiliary donor (haplo-cord) provides a valid alternative for adult patients without a suitable donor. A total of 132 high-risk adult patients with hematological malignancies from 3 Spanish institutions underwent myeloablative haplo-cord SCT. The median age was 37 years and median weight was 70 kg; 37% had active disease. The median number of postprocessing CB total nucleated and CD34+ cells was 2.4 × 107/kg (interquartile range [IQR], 1.8 to 2.9) and 1.4 × 105/kg (IQR, .9 to 2), respectively. Neutrophil engraftment occurred in a median of 11.5 days (IQR, 10.5 to 16.5) and platelet engraftment at 36 days (IQR, 25.5 to 77). Graft failure was 2% overall and only 9% for CB. Cumulative incidence of acute graft-versus-host disease (GHVD) grades II to IV was 21% and cumulative incidence of chronic GVHD was 21%. Median follow-up was 60 months (range, 3.5 to 163). Overall survival was 43.5%, event-free survival was 38.3%, nonrelapse mortality was 35%, and relapse was 20% at 5 years. Myeloablative haplo-cord SCT results in fast engraftment of neutrophils and platelets, low incidences of acute and chronic GVHD, and favorable long-term outcomes using single CB units with relatively low cell content. Moreover, CB cell dose had no impact on CB engraftment and survival in this study. Therefore, haplo-cord SCT expands donor availability while reducing CB cell dose requirements.

Although new agents have been approved for the treatment of MDS, the only curative approach is allogeneic hematopoietic stem cell transplantation (HSCT) and thus, in particular circumstances this procedure has been proposed as a treatment option for low risk patients. We have retrospectively analyzed the results of HSCT in 291 patients from the Spanish MDS registry with special attention to low risk MDS (LR-MDS) in order to define the variables that could impact their clinical evolution after transplantation. At 2 years OS was 51% and EFS was 50% (95% CI 0.7-4.5 years for OS and 95% CI 0.1-3.9 years for EFS). Among 43 LR-MDS, transplant-related mortality was 28%. At 3 years, OS was 67% (95% CI 264.7-8927.2 days for OS) and EFS was 64% (95% CI 0-9697.2 days for EFS). In the multivariate analysis only cytogenetics retained statistical significant effect on both OS (p=.047) and EFS (p=.046). Conditioning regimen could improve outcome among this subset of patients (OS 86% and RFS 100% for patients receiving RIC regimen). The present study confirms that specific disease characteristic as well as transplant characteristics have a significant impact on transplant outcome. Regarding low risk patients a non-myeloablative conditioning would be preferable especially in cases without high-risk cytogenetics. Copyright (C) 2014 Elsevier Ltd. All rights reserved.

Background: Haploidentical stem cell transplantation (Haplo HSCT) has emerged in the past three decades as an alternative curative option when an HLA match donor is not available. Over time, the use of Haplo has increased dramatically, reaching superimposable results when compared to unrelated and related HSCT strategies, confirming its validity. The widespread use of Haplo mainly relies upon technical advances, control of alloreactivity through graft-versus-host disease (GvHD) prophylaxis combined with a rapid and almost universal probability to find an Haplo donor for any candidate patient. The aim of our study was to provide a picture of acute (aGvHD) and chronic GvHD (cGvHD) incidence in Haplo HSCT across different platform in the past 15 years, where Haplo moved from ex-vivo T-cell depleted (TCD) platform to in-vivo TCD platform to the post-transplantation cyclophosphamide (PTCy). Methods: We compared the outcomes of adult patients receiving a 1st Haplo HSCT for any hematological malignancy according to GvHD prophylaxis - ex-vivo + in-vivo TCD (n=160), in-vivo only TCD (n=507) or PTCy (n=2593) - and reported to the EBMT registry in 2004-2016. Patients with missing data on disease status at last follow-up and GvHD information were excluded. Primary endpoint was GvHD-free & Relapse-free survival (GRFS) with events defined by death or relapse or grade ≥3 aGvHD or extensive (ext) cGvHD. Secondary endpoints were progression-free survival (PFS), overall survival (OS), aGvHD and cGvHD, incidence of relapse (IR) and non-relapse-mortality (NRM). Due to sample size in the first cohort of ex-vivo TCD, multivariate analysis compared only in-vivo TCD vs PTCy cohorts. Table 1 illustrates patients' characteristics. Results: Univariate analysis for 3-year outcomes are reported on table 2. PTCy provides better GRFS, OS, PFS, NRM versus ex-vivo or in-vivo. IR was not significantly different. Likewise, the 3-year CI of cGvHD and ext cGvHD were similar between PTCy, in vivo TCD and ex-vivo TCD (cGvHD 27% [25-29%], 25% [21-29%], 18% [12-25%], p 0.03; ext cGvHD 11% [10-12%], 10% [8-13%], 8% [4-13%], p 0.45). On the contrary the 100-day CI of grade ≥2 aGvHD were lower in the ex-vivo TCD vs PTCy and in-vivo TCD (19% [14-26%], 28% [26-30%], 32% [28-36%], p 0.002) while grade ≥3 aGvHD were lower in the PTCy group vs ex-vivo and in-vivo TCD (9% [8-10%], 11% [7-17%], 14% [11-18%], p After adjustment for diagnosis, patient age, disease status, Karnofsky PS, donor/patient gender and CMV, cell source, conditioning intensity, previous auto and year of transplant, the multivariable model comparing in-vivo TCD and PTCy showed better outcome for PTCy. Compared to in-vivo TCD, the hazards for GRFS was 0.76 for PTCy (p 0.004), the HR for PFS was 0.71 (p 0.001) and the HR for OS was 0.7 (p 0.0008), the HR for NRM was 0.63 (p 0.001). Moreover, compared to in-vivo TCD, PTCy yielded similar hazards for grade≥2 aGvHD (HR: 1.02, p 0.89), grade≥3 aGvHD (HR 0.79, p 0.27), cGvHD (HR 1.17, p 0.37), ext cGvHD (HR 1.18, p 0.52) and relapse (HR 0.8, p 0.1). Variables associated with GRFS were active disease, Karnofsky PS ≥90%, diagnosis, donor/patient gender and CMV. An ancillary analysis evaluating the stem cell source effect in the PTCy cohort only, demonstrates comparable outcome endpoints (OS, PFS, NRM, IR) at 2-year between bone marrow (BM) and peripheral blood (PB) PTCy. In univariate analysis GRFS and the 2-year CI of cGvHD were not different between BM and PB (GRFS 47% [45-50%], 46% [44-49%], p 0.085; 2-year CI of cGvHD 25% [23-28%], 27% [25-30%], p 0.2) while ext cGvHD, 100-day CI of grade ≥2 aGvHD and grade ≥3 aGvHD were lower in BM PTCy vs PB PTCy (ext cGvHD 8% [7-10%], 12% [10-14%], p Compared to BM PTCy, the HR for cGvHD was 1.55 for PB PTCy (p 0.001), the HR for ext cGvHD was 2.04 (p 0.0003), the HR for grade ≥2 aGvHD was 1,94 (p Conclusions: In the present EBMT registry study on more than 3000 patients transplanted from an Haplo donor, we report improved outcome (better GRFS - in spite of comparable chronic GvHD - OS and PFS, lower NRM) and widespread use in different diagnosis setting other than acute leukemia in PTCy platform. PTCy strategy provides a concrete progress into the field: even if cGvHD still represent a major issue, exploitation of BM PTCy seems to protect against most severe GvHD manifestation. Disclosures Mohty: Jazz Pharmaceuticals: Honoraria, Research Funding. Kröger:Sanofi-Aventis: Honoraria; Riemser: Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Medac: Honoraria; JAZZ: Honoraria; DKMS: Research Funding; Celgene: Honoraria, Research Funding. Basak:Celgene: Honoraria; Teva: Honoraria.

Importance Incidence and risk factors of second solid cancers (SSCs) that occur after hematopoietic stem cell transplantation (HSCT) are well documented. However, clinical outcome data of patients who developed an SSC after HSCT are limited. Objective To assess the outcome of patients with an SSC occurring after HSCT from the time of SSC diagnosis. Design, Setting, and Participants This cohort study used data of 4065 patients from 26 countries registered with the European Society for Blood and Marrow Transplantation, which has maintained clinical data since 1977 of patients who received a transplant. Information from all patients who underwent a transplant in Europe and had an SSC diagnosis between January 1, 2000, and December 31, 2014, was extracted. The cohort included patients with 18 different cancers. Data analysis was conducted from September 3, 2017, to March 17, 2018. Main Outcomes and Measures Median and 5-year age-standardized overall survival, causes of death, risk factor multivariate analysis using a clustered Cox proportional hazard regression model, and standardized mortality ratio were calculated for each of the 18 types of SSC. Results In total, 220 617 patients underwent a transplant, of whom only 4065 (1.8%) patients with a second solid cancer after HSCT were included in the study. Among the 4065 patients, 2321 (57.1%) were men and 1744 (42.9%) were women, with a mean (range) age of 59.1 (3.2-82.3) years at diagnosis of second solid cancer. The 5-year age-standardized overall survival was 47% (95% CI, 45%-49%). The 5-year overall survival rate after SSC diagnosis was poor for pancreas, lung, hepatobiliary, esophageal, brain, and gastric cancers, with a median survival between 0.6 and 1 year. The 5-year overall survival was intermediate for endometrial, colorectal, sarcomas, ovarian, bladder, oropharyngeal, and kidney cancers, with a median survival between 2 and 10 years. The 5-year overall survival was more favorable for melanoma, breast, prostate, cervix, and thyroid cancers, with a median survival of 10 or more years. Additional transplant-associated factors for mortality for patients treated with allogeneic HSCT were age at transplant, donor type, conditioning regimen, and graft-vs-host disease. In total, 1777 patients (43.7%) died, of which 1256 (74.8%) were from SSC, 344 (20.5%) from primary disease, and 79 (4.7%) from other causes. Standardized mortality ratio was higher, compared with de novo solid cancers, for melanoma, prostate, breast, kidney, bladder, colorectal, and endometrial cancers but not for the other cancers. Conclusions and Relevance The outcome of SSC is mainly dependent on the type of second cancer; thus, future studies should investigate the reasons the standardized mortality ratio is higher for some cancers to identify whether patients with these cancers should be treated differently and to help in screening and counseling patients who developed an SSC after HSCT.

Uptake and use of recommendations for the diagnosis, severity scoring and management of chronic GVHD: an international survey of the EBMT–NCI Chronic GVHD Task Force

To evaluate the cost-effectiveness of posaconazole vs itraconazole in the prevention of invasive fungal infections (IFIs) in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT).Total hospital-based costs from initial admission for allo-HSCT until day 100 after transplantation were evaluated for 49 patients in whom the clinical efficacy of antifungal prophylaxis with posaconazole vs itraconazole had been previously analyzed and reported. Clinical and economic data were used to determine the incremental costs per IFI avoided and per life-year gained for posaconazole compared with itraconazole. Confidence intervals for the incremental cost-effectiveness ratio (ICER) and a cost-effectiveness acceptability curve were estimated through bootstrapping with the bias-corrected percentile method.According to our analysis, the total cost of allo-HSCT per patient during the 100-day fixed-treatment period was €46,562 in the posaconazole group (n = 33) and €45,080 in the itraconazole group (n = 16). However, the reduction in the incidence of IFI and the improved outcome with posaconazole resulted in a favorable ICER of €11,856 per IFI avoided and €5218 per life-year gained. With the outcomes of the bootstrap procedure, the cost-effectiveness acceptability curve was constructed. Assuming a threshold of €30,000 per life-year gained, the ICER based on life-years gained is acceptable with 75% certainty.This evaluation is based on data from a single-center, non-randomized study. Preference weights or utilities were not available to calculate quality-adjusted life-years. Extra-mural costs were only partially evaluated from a hospital perspective. Indirect costs and economic consequences are not included.This economic evaluation compared direct medical costs associated with posaconazole or itraconazole treatment; the data suggest that posaconazole may be cost-effective as antifungal prophylaxis during the early high-risk neutropenic period and up to 100 days after allo-HSCT.

Hematopoietic cell transplantation (HCT) survivors are at risk for development of late complications and require lifelong monitoring for screening and prevention of late effects. There is an increasing appreciation of the issues related to healthcare delivery and coverage faced by HCT survivors. The 2016 National Institutes of Health Blood and Marrow Transplant Late Effects Initiative included an international and broadly representative Healthcare Delivery Working Group that was tasked with identifying research gaps pertaining to healthcare delivery and to identify initiatives that may yield a better understanding of the long-term value and costs of care for HCT survivors. There is a paucity of literature in this area. Critical areas in need of research include pilot studies of novel and information technology supported models of care delivery and coverage for HCT survivors along with development and validation of instruments that capture patient-reported outcomes. Investment in infrastructure to support this research, such as linkage of databases including electronic health records and routine inclusion of endpoints that will inform analyses focused around care delivery and coverage, is required.

Aim To assess the toxicity, tolerance, steroid-sparing capacity, effectiveness, and response rate to imatinib and dasatinib for the treatment of severe sclerotic chronic graftvs- host disease (scGVHD). Methods This retrospective study analyzed 8 consecutive patients with severe refractory scGVHD who received salvage therapy with imatinib. Patients intolerant and/or refractory to imatinib received dasatinib treatment. Results 7 patients discontinued imatinib treatment (1 achieved complete response, 5 were resistant and/or intolerant, and 1 developed grade IV neutropenia) and 1 patient achieved prolonged partial response, but died due to an infectious complication while on treatment. 5 patients started dasatinib treatment (3 achieved partial responses and discontinued dasatinib, 1 achieved a durable partial response, but died due to a consecutive rapid pulmonary cGVHD progression and 1 with stable disease discontinued treatment due to gastroenteric intolerance). The response rate (partial and/or complete responses) for severe scGVHD was 25% for imatinib and 60% for dasatinib. Conclusion In our series, dasatinib was better tolerated, safer, steroid-sparing, and had a low incidence of infectious complications, which suggests that it may be a more effective therapeutic alternative for patients with refractory scGVHD than imatinib. Treatment of scGVHD with effective antifibrotic drugs such as TKI, which block the kinase fibrotic pathway, may be a safe and effective therapeutic option, but further studies are needed to confirm our findings.

Background and objective Poor mobilisation of peripheral blood stem cells (CD34+ cells) from bone marrow is a frequent reason for not reaching the autologous stem cell transplantation (SCT) procedure in patients diagnosed with lymphoma or myeloma. Plerixafor, a reversible inhibitor of the binding of stromal cell-derived factor 1 to its cognate receptor CXCR4, has demonstrated a higher capacity for the mobilisation of peripheral blood stem cells in combination with granulocyte colony stimulating factor (G-CSF) compared with G-CSF alone. For this reason, plerixafor is now indicated for poor mobiliser myeloma or lymphoma patients. Some studies have recently indicated that a pre-emptive strategy of plerixafor use during first mobilisation, according to the number of CD34+ mobilised cells in peripheral blood or to the harvested CD34+ cells after first apheresis, could avoid mobilisation failures and re-mobilizations, as well as the delay of autologous SCT. The aim of this consensus was to perform a review of published studies on pre-emptive strategy and to establish common recommendations for hospitals in Catalonia and Balearics on the use of pre-emptive plerixafor. Methods For the Consensus, physicians from participant hospitals met to review previous studies as well as previous own data about plerixafor use. The GRADE system was used to qualify the available evidence and to establish recommendations on the use of pre-emptive plerixafor. Results and conclusions After a review of the literature, the expert consensus recommended the administration of pre-emptive plerixafor for multiple myeloma or lymphoma patients with a CD34+ cell count lower than 10 cells/μL in peripheral blood (measured in the morning of day 4 of mobilisation with G-CSF or after haematopoietic recovery in the case of mobilisation with chemotherapy plus G-CSF).

Highlights •One third of HLA-identical sibling donor transplant recipients never ever develop any graft-versus-host disease •This rate of no graft-versus-host disease is significantly higher with male donors in female recipients •Factors associated with no graft-versus-host disease should become a target of precision medicine •Prediction of no graft-versus-host disease could become a decision-guiding tool for early transplantations •Such an approach could spare immunosuppression, improve survival, and reduce costs