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  • Prevention and Treatment of Acute GVHD in Children, Adolescents and Young Adults
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2020-01-11
    Erin Gatza; Pavan Reddy; SungWon Choi

    Acute graft-versus-host disease (GVHD) continues to be a major cause of morbidity and mortality after allogeneic hematopoietic cell transplant (HCT) in pediatric patients (i.e., children and adolescent and young adults), and limits broader application of the therapy. Pediatric HCT patients have faced major obstacles to access clinical trials that test new agents for GVHD prevention and treatment. According to a recent search, only six clinical trials of interventions for prevention or treatment of acute GVHD were conducted specifically in pediatric patients in the United States over the last decade, eight internationally. In this review, we summarize the studies that were performed and specifically enrolled and reported on pediatric patients after allogeneic HCT and provide a listing of studies currently underway.

  • Hematopoietic Stem Cell Transplantation for Severe Thalassemia Patients from Haploidentical Donors Using Novel Conditioning Regimen
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2020-01-11
    Usanarat Anurathapan; Suradej Hongeng; Samart Pakakasama; Duantida Songdej; Nongnuch Sirachainan; Pongpak Pongphitcha; Ampaiwan Chuansumrit; Pimlak Charoenkwan; Arunee Jetsrisuparb; Kleebsabai Sanpakit; Piya Rujkijyanont; Arunotai Meekaewkunchorn; Yujinda Lektrakul; Pornchanok Iamsirirak; Pacharapan Surapolchai; Somtawin Sirireung; Rosarin Sruamsiri; Pustika Amalia Wahidiyat; Borje S. Andersson

    Patients with severe thalassemia (Thal) commonly have a survival that is significantly shorter than that of the general population. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haplo-identical related donors, we introduced a program consisting of a pharmacological pretransplant immune suppression phase (PTIS), two courses of dexamethasone and fludarabine, followed by pretransplant conditioning with fludarabine-IV Busulfan and post-transplant graft-vs-host disease prophylaxis with cyclophosphamide, Tacrolimus and mycophenolate mofetil. We transplanted 83 consecutive transfusion dependent thalassemia patients (median age 12 years, range 1-28 years) with a minimum follow-up of six months (median 15 months, range 7-53 months); the 3-year projected overall and event-free survival is over 96%, and there have been no secondary graft failures. Of the first 31 patients we had two graft failures, both of them occurring in patients with extremely high titers of anti-donor specific HLA antibodies (anti-DSA), but after adjusting the PTIS to include bortezomib and Rituximab for patients with high titers of anti-DSA, and using pharmacological dose guidance for busulfan, we had no graft failures in the last 52 patients. Six (7%) of 83 patients developed severe GVHD. We conclude, that this is a safe and efficacious approach to allogeneic SCT in Thalassemia, yielding results comparable to those available for patients with fully matched donors.

  • Towards functional immune monitoring in allogeneic stem cell transplant recipients
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2020-01-10
    Swati Naik; Spyridoula Vasileiou; Paibel Aguayo-Hiraldo; Shivani Mukhi; Ghadir Sasa; Caridad Martinez; Robert A Krance; Stephen Gottschalk; Ann Leen

    Serious viral infections, due to delayed immune reconstitution, are a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Thus, many transplant centers prospectively track cellular immune recovery by evaluating absolute cell numbers and the phenotypic profile of reconstituting T cell subsets to identify individuals who are at highest risk of infection. Conventional assessments, however, fail to measure either the antigen specificity or functional capacity of reconstituting cells - both factors that correlate with endogenous antiviral protection. In this pilot study we sought to address this limitation by prospectively investigating the tempo of endogenous immune reconstitution in a cohort of 23 pediatric HSCT patients using both quantitative (flow cytometry) and qualitative (IFNγ ELIspot) measures, which we correlated with either the presence or absence of infections associated with CMV, AdV, EBV, BKV, HHV-6, RSV, Parainfluenza, Influenza and Human Metapneumovirus. We present data spanning 12 months post-transplant demonstrating the influence of conditioning on immune recovery and highlighting the differential impact of active viral replication on the quantity and quality of reconstituting cells. Judicious use of standard (phenotypic) and novel (functional) monitoring strategies can help guide the clinical care and personalized management of allogenic HSCT recipients with infections.

  • Haploidentical transplant with post-transplant cyclophosphamide for T-cell acute lymphoblastic leukemia: a report from the EBMT acute leukemia working party
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2020-01-09
    Ali Bazarbachi; Myriam Labopin; Emanuele Angelucci; Zafer Gülbas; Hakan Ozdogu; Mutlu Arat; Luca de Rosa; Rocco Pastano; Pietro Pioltelli; Rovira Montserrat; Massimo Martino; Fabio Ciceri; Yener Koç; Gerard Socié; Didier Blaise; Concepcion Herrera; Yves Chalandon; Paolo Bernasconi; Mohamad Mohty

    Allogeneic hematopoietic cell transplantation (HCT) is recommended in high-risk patients with T cell acute lymphoblastic leukemia (T-ALL). For patients with no HLA identical donor, haploidentical transplantation (haplo-HCT) is becoming the leading source of stem cell donation. However, data is scarce on predictive factors for outcome in that setting. We identified 122 adults (20% female; median age 31 years; range 18-68) with T-ALL who received a haplo-HCT with post-transplant cyclophosphamide (ptCy) between 2010 and 2017. Median follow-up of living patients was 23 months. The 2-year relapse incidence and non-relapse mortality were 45% and 21%, respectively. The 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 34%, 42% and 27%, respectively. The 2-year LFS and OS were highly influenced by disease status at transplant, being 49% and 55% respectively for first complete remission (CR1), 34% and 50% respectively for CR2, 8% and 12% respectively for patients with active disease. On multivariate analysis, only disease status affected LFS and OS. Transplantation in CR2 negatively affected LFS, whereas active disease at haplo-HCT negatively affected LFS and OS. In conclusion, haplo-HCT with ptCy produced encouraging results in this challenging disease, particularly when performed in CR. Despite the limitation of the small sample size, results were not affected by the type of conditioning, questioning the need for total body irradiation based-myeloablative conditioning (TBI-MAC) in that setting.

  • Relapse- and immunosuppression-free survival after hematopoietic stem-cell transplantation: How can we assess treatment success for complex time-to-event endpoints?
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2020-01-09
    Tobias Bluhmki; Claudia Schmoor; Jürgen Finke; Martin Schumacher; Gérard Socié; Jan Beyersmann

    In most clinical oncology trials, time-to-first-event analyses are used for efficacy assessment, which do often not capture the entire disease process. Instead, the focus may be on more complex time-to-event endpoints, as e.g. the course of disease after the first event or endpoints occurring multiply post randomization. We propose “relapse-free and immunosuppression-free survival” (RIFS) as an innovative and clinically relevant outcome measure for assessing treatment success after hematopoietic stem cell transplantation (SCT). To capture the time-dynamic relationship of multiple episodes of immunosuppressive therapy during follow-up, relapse, and non-relapse mortality, a multistate model is developed. The statistical complexity is that the probability of RIFS is non-monotonic over time; thus, standard time-to-first-event methodology is inappropriate for formal treatment comparisons. Instead, a generalization of the Kaplan-Meier method is used for probability estimation, and simulation-based resampling is suggested as a strategy for statistical inference. We reanalyze data from a recently published phase III trial in 201 leukemia patients after SCT. The study aimed at evaluating long-term treatment success of standard GvHD prophylaxis plus a pre-transplant anti-human-T-lymphocyte immunoglobulin compared to standard prophylaxis alone. Results suggest that treatment increases the long-term probability of RIFS by approximately 30% during the entire follow-up period, which complements the original findings. This article highlights the importance of complex endpoints in oncology. They give deeper insight into the treatment and disease process over time. Multistate models combined with resampling are highlighted as a promising tool to evaluate treatment success beyond standard endpoints. Example code is provided in the Supplementary Materials.

  • Health Care Reimbursement, Service Utilization, and Outcomes among Medicare Beneficiaries with Multiple Myeloma Receiving Autologous Hematopoietic Cell Transplantation in Inpatient and Outpatient Settings
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2020-01-07
    Neil Dunavin; Lih-Wen Mau; Christa L. Meyer; Clint Divine; Al-Ola Abdallah; Susan Leppke; Anita D'Souza; Ellen Denzen; Wael Saber; Linda J. Burns; Siddhartha Ganguly
  • Cellular immunotherapy for refractory DLBCL in the CART era: still a role for allogeneic transplantation?
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2020-01-07
    Peter Dreger; Timothy S. Fenske; Silvia Montoto; Marcelo C. Pasquini; Anna Sureda; Mehdi Hamadani

    Chimeric antigen receptor-engineered T (CART) cells are a promising new treatment option for patients with multiply relapsed and refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Because of the favourable outcome data reported for CART cells, uncertainty is emerging if there is still a role for allogeneic hematopoietic cell transplantation (alloHCT) in the treatment of R/R DLBCL. This paper provides an overview of available evidence and theoretical considerations to put these two types of cellular immunotherapy (CI) into perspective. Altogether, current data suggest that CART cells are preferred now over transplantation as first choice CI in many clinical situations. However, the majority of patients will fail CART therapy, resulting in an unmet medical need where alloHCT could be beneficial. In contrast, employing alloHCT instead of CART cells as 1st CI should be presently restricted to situations where CART cell therapy deems not feasible or useful, such as patients with refractory cytopenia or incipient MDS. However, alloHCT remains a standard treatment option as 1st CI for patients with in chemosensitive R/R DLBCL when CARTs are not available, or transplantation is preferred by the patient. Continuous collection and analysis of CI outcome data by professional registries appear to be of key importance for developing rational strategies of CI allocation and sequencing. Allogeneic hematopoietic cell transplantation (alloHCT) is a potentially curative cellular immunotherapy (CI) for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), and used to be considered as a standard therapeutic option in this setting for eligible patients (1, 2, 3, 4). However, the recent approval of CD19-directed chimeric antigen receptor-engineered T cells (CART cells) for treatment of patients with DLBCL having failed two lines of therapy has added a promising new immunotherapeutic tool to the treatment armory of R/R DLBCL. Because of the favourable outcome data reported for CART cells, uncertainty is emerging if there is still a role for alloHCT in the management of multiply R/R DLBCL. As a result, in some recently proposed treatment algorithms, alloHCT has completely disappeared (5). While CART cell treatment is increasingly used as first CI in patients with multiply R/R DLBCL, the aim of this effort was to identify settings where alloHCT promises to be beneficial in this new treatment landscape. Based on a comprehensive summary of mode of action, efficacy, toxicity, outcome predictors, rescue options, and strengths and limitations of both modalities, a Task Force appointed by the EBMT Lymphoma Working Party and the CIBMTR Lymphoma Working Group (see Supplements for details) developed this proposal for a rational approach to alloHCT at the dawn of the CART era when valid evidence is still sparse.

  • Retrospective multicenter study of extracorporeal photopheresis in steroid-refractory acute and chronic graft-versus-host disease
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2020-01-07
    Gillen Oarbeascoa; Maria Luisa Lozano; Luisa Maria Guerra; Cristina Amunarriz; Concepcion Andon Saavedra; Jose Maria Garcia-Gala; Aurora Viejo; Nuria Revilla; Cynthia Acosta Fleitas; Jose Luis Arroyo; Eva Martinez Revuelta; Andrea Galego; Dolores Hernandez-Maraver; Mi Kwon; Jose Luis Diez-Martin; Cristina Pascual

    Background Extracorporeal photopheresis (ECP) is an established treatment strategy in steroid-refractory GvHD. This study's main objectives were to analyze the clinical response and impact of ECP therapy in steroid dose reduction. Study design and Methods A retrospective observational series of 113 patients from 7 transplant centers was analyzed. 65 patients (58%) had acute GvHD (aGvHD) and 48 (42%) chronic GvHD (cGvHD). All ECP procedures were performed with the off-line system. Results The median number of procedures until initial response was 3, for both aGvHD and cGvHD. ECP was the second-line therapy in 48% of aGvHD cases and 50% in cGvHD. 71% of the cases of aGvHD were grade 3-4 and 69% of the cases of cGvHD were severe. The overall response rate on day 28 in aGvHD was 53% (CR 45%), whereas in cGvHD it was 67% (CR 23%). Skin was the most involved organ, with a response rate of 58% (CR 49%) in aGvHD and 69% (CR 29%) in cGvHD. At the end of ECP treatment, 60% of patients treated for aGvHD that responded were able to stop steroids, with a median dose reduction of 100%. Significant OS differences were observed for patients responding to ECP in aGvHD (HR=4.3, p<0.001) and cGvHD (HR=4.8, p=0.003) patients. Conclusions ECP is a valid therapeutic alternative in patients with steroid-refractory acute and chronic GvHD, permitting significant steroid dose reductions.

  • SUL-109 protects hematopoietic stem cells from apoptosis induced by short-term hypothermic preservation and maintains their engraftment potential
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2020-01-07
    Fatima S.F. Aerts-Kaya; Trudi P. Visser; Burcu Pervin; Aynura Mammadova; Özgür Özyüncü; Gerard Wagemaker; F. Duygu Uçkan-Çetinkaya
  • Incidence and Risk Factors for Acute and Chronic Kidney Injury After Adult Cord Blood Transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2020-01-03
    Victoria Gutgarts; Insara Jaffer Sathick; Junting Zheng; Ioannis Politikos; Sean M. Devlin; Molly A. Maloy; Sergio A. Giralt; Michael Scordo; Valkal Bhatt; Ilya Glezerman; Thangamani Muthukumar; Edgar A. Jaimes; Juliet N. Barker

    While cord blood transplantation (CBT) extends allograft access, patient co-morbidities, chemo-radiation and nephrotoxic medications all contribute to acute kidney injury (AKI) risk. We analyzed AKI in adult myeloablative CBT recipients transplanted 2006-2017 for hematologic malignancies using cyclosporine-A/ mycophenolate mofetil immunosuppression. Maximum grades AKI were calculated using Kidney Disease: Improving Global Outcomes [grade 1 (1.5 - < 2-fold), grade 2 (2 - < 3-fold) or grade 3 (≥ 3-fold) over baseline] definitions. One-hundred and fifty-three patients [median 51 years (range 23-65), 114/153 (75%) acute leukemia, 27/153 (18%) African, 88/153 (58%) cytomegalovirus (CMV) seropositive, median age adjusted hematopoietic cell comorbidity index 3 (range 0-9), median pre-transplant albumin 4.0 gm/dl (range 2.6-5.2)] were transplanted. The day 100 cumulative incidence of grade 1-3 AKI was 83% (95%CI:77-89) (predominantly grade 2, median onset 40 days, range 0-96) and grade 2-3 AKI incidence was 54% (95%CI:46-62) (median onset 43 days, range 0-96). Mean cyclosporine-A (CSA) level preceding AKI onset was high [360 ng/ml, target range 300-350]. In multivariate analysis, African ancestry, addition of haplo-identical CD34+ cells, low day -7 albumin, critical illness/ intensive care admission, and nephrotoxic drug exposure (predominantly CSA and/ or foscarnet) were associated with AKI. In a day 100 landmark analysis, 6% of patients with no prior AKI had chronic kidney disease (CKD) at 2 years versus 43% with prior grade 1 and 38% with prior grades 2-3 AKI (overall p = 0.02). Adult CBT recipients are at significant AKI risk and AKI is associated with increased risk of CKD. Prevention strategies, early recognition, and prompt intervention are critical to mitigate kidney injury.

  • CTLA4Ig Limits Both Incidence and Severity Of Early Cytokine Release Syndrome Following Haploidentical Peripheral Blood Stem Cell Transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2020-01-03
    Sarita Rani Jaiswal; Suparno Chakrabarti

    Early and severe cytokine release syndrome (CRS) is a unique complication of T replete haploidentical transplantation, when post-transplant cyclophosphamide (PTCy) is employed as GVHD prophylaxis without preceeding immunosuppression. This phenomenon has been reported with greater frequency and severity following a mobilised peripheral blood stem cell (PBSC) graft. We report on the incidence, severity and outcome of CRS in 157 patients undergoing PTCy-based haploidentical transplantation.

  • Immunosuppressive Drugs Alter α1-Antitrypsin Production in Hepatocytes: Implications for Epithelial Gap Repair
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-31
    IdoBrami; Dor Ini; Nofit Sassonker; Melody Zaknoun; Tsila Zuckerman; Eli C. Lewis

    Background & Aims : Immunosuppressive drugs are an inherent component of hematopoietic stem cell transplantation (HSCT) for the prevention of acute graft-versus-host disease (GVHD). Circulating α1-antitrypsin (AAT), a serine-protease inhibitor predominantly produced by hepatocytes, which rises during acute phase responses, is lost in patient's stool due to gastrointestinal GVHD, and its augmentation was found to attenuate GVHD. Here, we explore the effect of immunosuppressive drugs on hepatocyte production of AAT and intestinal epithelial gap repair. Approach : The effect of commonly used immunosuppressants on AAT production was examined in vitro using HepG2 cells and primary mouse hepatocytes; and their impact on human intestinal epithelial cell line gap repair was evaluated. Sera from 12 allogeneic-HSCT patients, obtained 14 days post-transplantation, predating the diagnosis of GVHD (n=6) were examined for re-epithelialization, with added clinical-grade AAT. Results : Rapamycin compromised AAT production under inflammatory conditions. Mycophenolate mofetil and cyclosporin A inhibited re-epithelialization; AAT minimized the effect of cyclosporin A. Patient sera displayed superior gap repair with exogenous AAT. Conclusions : Functional insufficiency in circulating AAT may be the result of drug toxicities leading to ineffective gut re-epithelization and compromised gut lining. Taken together, our data strengthen the rationale for incorporating AAT augmentation therapy into immunosuppressive treatment protocols.

  • Donor KIR2DS1-mediated Decreased Relapse and Improved Survival, Depending on Remission Status at HLA-Haploidentical Transplantation with Post-transplantation Cyclophosphamide
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-31
    Kentaro Ido; Hideo Koh; Asao Hirose; Hiroshi Okamura; Shiro Koh; Satoru Nanno; Mitsutaka Nishimoto; Mika Nakamae; Yasuhiro Nakashima; Takahiko Nakane; Masayuki Hino; Hirohisa Nakamae

    HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using post-transplantation cyclophosphamide (PT/Cy-haplo) is becoming the standard of care for patients without HLA-matched related or unrelated donors. PT/Cy-haplo could provide more patients the opportunity to receive allo-HCT, since most patients have more than one available HLA-haploidentical related donor candidate. In PT/Cy-haplo settings, however, an optimal donor selection algorithm has not yet been established. To contribute to the establishment of a donor selection formula based on disease status and killer-cell immunoglobulin-like receptor (KIR) genotype, we retrospectively analyzed 91 patients who received PT/Cy-haplo at our institute. In both patients and donors, HLA allele genotyping was performed for HLA-A, -B, -C, and -DRB1 and 16 KIR genes were genotyped. Patients in complete remission (CR) who underwent PT/Cy-haplo from KIR2DS1-positive donors had significantly lower rates of cumulative incidence of relapse (CIR) than those who underwent PT/Cy-haplo from KIR2DS1-negative donors (1-year CIR, 0.0% vs. 32.6%, P = 0.037; 2-year CIR, 9.2% vs. 42%, P = 0.037). Moreover, PT/Cy-haplo from KIR2DS1-positive donors was significantly associated with improved overall survival (OS) (1-year OS, 91.7% vs. 58.7%, P = 0.010; 2-year OS, 83% vs. 34%, P = 0.010). In contrast, in non-CR individuals, PT/Cy-haplo from KIR2DS1-positive donors did not significantly improve CIR or OS (1-year CIR 56.5% vs. 64.7%, P = 0.973; 2-year CIR, not reached vs. 64.7%, not evaluable; 1-year OS, 25.4% vs. 20.6%, P = 0.418; 2-year OS, 5.1% vs. 20.6%, P = 0.418). Additionally, lower infused CD34+ cell dose, female-to-male transplantation, and acute myeloid leukemia were significantly associated with increased risk of relapse and mortality. In conclusion, the present study demonstrated that graft-versus-leukemia/tumor effects were exerted through donor KIR2DS1 at PT/Cy-haplo when patients have low tumor burdens. It would be worth examining the inclusion of donor KIR genotyping and disease status assessment in establishing optimal donor selection criteria at PT/Cy-haplo.

  • Predictors for Autoimmune Cytopenias after Allogeneic Hematopoietic Cell Transplantation in Children
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-22
    Celina L. Szanto; Jurgen Langenhorst; Coco de Koning; Stefan Nierkens; Marc Bierings; Alwin D.R. Huitema; Caroline A. Lindemans; Jaap J. Boelens

    Development of autoimmune cytopenia (AIC) after allogeneic hematopoietic cell transplantation (HCT) is a serious complication requiring urgent intensification of immunosuppressive therapy. The pathophysiology and predictors of AIC are not completely understood. In this retrospective cohort analysis of 380 pediatric patients, we evaluated the incidence, outcomes, and related various variables, including immune reconstitution markers to AIC. Three hundred eighty patients (median age, 7.4 years; range, .1 to 22.7) were included, of which 30 patients (7.8%) developed AIC in 1 (n = 6), 2 (n = 6), or 3 (n = 16) cell lineages at a median of 133 days (range, 46 to 445) after HCT. Using multivariate analysis we found that chemo-naivety before HCT, acute graft-versus-host disease (aGVHD) grades II to IV, and serotherapy were associated with the development of AIC. Development of AIC was preceded by increased levels of IgM, IgA, and IgG. Immune profiles of total absolute lymphocytes were very similar between AIC patients and control subjects. However, CD3-CD16+CD56+ natural killer cells, CD3+ T cells, CD3+CD4+ T cell subset, and CD3+CD8+ T cell subset were lower in AIC patients. Overall survival was good, at 83% (similar between AIC patients and control subjects). In conclusion, we identified chemo-naivety before HCT, preceding aGVHD grades II to IV, and serotherapy as predictors for development of AIC. Increasing levels of IgM, IgA, and IgG preceded AIC development. These data provide clues to further study the biology of AIC.

    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-28
    Jingmei Hsu; Zhengming Chen; Tsiporah Shore; Usama Gergis; Sebastian Mayer; Adrienne Phillips; Danielle Guarner; Michael Hsu; Melissa M. Cushing; Koen Van Besien

    Background Reduced intensity conditioning (RIC) regimens, improved HLA matching, and better supportive care allow allogeneic stem cell transplant (alloSCT) to be offered to older patients. Only a small percentage of eligible patients between 65 to 74 years actually undergo alloSCT and comprehensive outcome data from the aging population are still lacking. We examined the outcome of older patients who underwent alloSCT using melphalan based reduced intensity conditioning for hematologic malignancies at our institution. Results We identified 125 patients older than 65 years (median 69, range 65 to 77) who underwent matched-related donor (MRD), matched-unrelated donor (MUD) or combined haploidentical/umbilical cord (haplo-cord) alloSCT between 2012 through November, 2017. Among them, 52 (41.6%) and 70 (56%) had intermediate and high/very high CIBMTR disease risk index (DRI). One hundred and eight (85%) patients received fludarabine/melphalan-based RIC regimen with either ATG or alemtuzumab. The median time to neutrophil engraftment was 13 days (8-37) and platelet engraftment was 17 days (9-169). The cumulative Incidence of non-relapse mortality (NRM) was 11.5% at 100 days, and 30.1% and 34.8 % at 1 and 2 years respectively. The cumulative incidence of relapse was 35% and 40% at 1 and 2 years. The cumulative incidence of grade II-IV acute graft versus host disease (aGVHD) at Day 100 and 6 months was 29.5% and 34.5%, and chronic GVHD (cGVHD) at 6, 12 and 24 months was 2.5%, 5.2% and 6.3% respectively. With a median follow up of 32 months, the 1, 2 and 3 year progression free survival (PFS) was 34.6%, 24.4% and 16.5% respectively. The graft GVHD free survival (GRFS) was 24.6%, 16.1% and 9.3% respectively. The 1, 2 and 3-year overall survival (OS) was 44.5%, 30.7% and 26.5% respectively. In multivariable analysis, low albumin was predictive of poor PFS and OS and high HCT Cl and CIBMTR DRI was predictive of worse GRFS. Among long-term survivors, the median karnofsky performance status (KPS) was 80. Conclusions Older patients, even when referred with advanced disease, can benefit from melphalan based alloSCT with HLA-matched or alternative donor sources without discernible impact of donor source on outcome. Using alemtuzumab or ATG based in vivo T-cell depletion, the incidence of chronic GVHD is extremely low. Performance status in survivors is excellent. Better predictors for outcome in this patient population need to be identified.

  • Prior Gemtuzumab Ozogamicin Exposure in Adults With Acute Myeloid Leukemia Does Not Increase Hepatic Veno-occlusive Disease Risk After Allogeneic Hematopoietic Cell Transplantation: A CIBMTR Analysis
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-28
    Vincent T. Ho; Andrew St. Martin; Waleska S. Pérez; Patricia Steinert; Mei-Jie Zhang; Deborah Chirnomas; Caroline J. Hoang; Fausto R. Loberiza; Wael Saber

    Gemtuzumab ozogamicin (GO) therapy prior to allogeneic hematopoietic cell transplantation (alloHCT) has been historically associated with an increased risk of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with acute myeloid leukemia (AML). The current analysis examined VOD/SOS risk and outcomes in a cohort of patients who in recent years reported to the Center for International Blood & Marrow Transplant Research. Adults with AML who had GO exposure prior to myeloablative alloHCT were matched 1:4 by age and disease status at transplant to recipients without GO exposure (controls). A total of 137 patients with GO exposure and 548 matched controls who underwent alloHCT between 2008 and 2011 were included in this analysis. With a median ∼8-year follow-up of survivors, the 5-year overall survival probability was similar in the 2 cohorts: 38% and 38% in the GO-exposed versus control (P = .97) group. Incidence of VOD/SOS and severe VOD/SOS, respectively, at 100 days was 4% (95% confidence interval [CI]: 1-7) and 3% (95% CI: 1-6) in GO-exposed patients and 3% (95% CI: 2-5) and 1% (95% CI: 0-2) in controls. Correspondingly, among patients who developed VOD/SOS, 1-year survival probability after VOD/SOS diagnosis was 33% (95% CI: 5-72) and 27% (95% CI: 11-47) (P = .78). In multivariate analyses, GO exposure prior to alloHCT was not associated with an increased risk of VOD/SOS (odds ratio 1.10; P = .85) or death (hazard ratio 1.08; P = .57). Three (3%) deaths in the GO group and 3 (<1%) deaths in the control group were attributed to VOD/SOS. Our results suggest that GO treatment prior to myeloablative alloHCT in the recent era is not associated with an increased risk of post-transplant VOD/SOS or death.

  • Outcome of Multiple Myeloma With Chromosome 1q Gain and 1p Deletion After Autologous Hematopoietic Stem Cell Transplantation: propensity-score matched analysis
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-24
    Ankur Varma; Dawen Sui; Denái R Milton; Guilin Tang; Neeraj Saini; Omar Hasan; Akash Mukherjee; Jacinth Joy Joseph; Qaiser Bashir; Gabriela Rondon; Samer Srour; Uday R. Popat; Chitra M. Hosing; Yago Nieto; Partow Kebriaei; Amin M. Alousi; Sairah Ahmed; Rohtesh Mehta; Muzaffar H. Qazilbash

    Background The gain/amplification CKS1B gene at chromosome region 1q21 (1q+) is one of the most common genetic aberrations in multiple myeloma (MM). Amplification of CKS1B is frequently associated with the deletion of CDKN2C gene at chromosome region 1p32 (1p-), which is also associated with inferior outcomes. Methods In this retrospective study, we evaluated the outcomes of patients with 1q+ and/or 1p- after high-dose therapy and auto-HCT. From January 2006 to December 2015, 1491 newly diagnosed MM patients underwent upfront high-dose therapy and auto-HCT at our institution. Out of those, 899 had the fluorescent in situ hybridization (FISH) data available. FISH was performed at diagnosis and before the start of induction in 686 (76%) patients, and after the initiation of induction therapy in 213 (24%) patients. We identified 100 patients with 1q+ and/or 1p- by FISH from the cohort of 899 patients. A control group (N=287) with diploid cytogenetics and normal FISH panel was selected from the same cohort. From the above two cohorts, using a propensity-score matched analysis, we identified matched controls for 85 of the 100 patients with 1q+/1p-. Patients were matched for age at auto-HCT, sex, international staging system stage, induction regimen, creatinine level, disease status at auto-HCT, conditioning regimen and maintenance therapy. Results Sixty-seven (79%), 4 (5%) and 14 (16%) patients had 1q+, 1p- or both 1q+ and 1p-, respectively. There was no significant difference in induction therapy, preparative regimen, or maintenance therapy between the 1q+/1p- and control groups. The median follow-up time for all patients was 29.2 months (range: 0.29 -84.96). The cumulative incidence of 100-day non-relapse mortality was 1.2% and 0% for the 1q+/1p- and the control groups, respectively. Forty-two patients (50%) in the 1q+/1p- group achieved complete response compared to 40 patients (47%) in the control group. The estimated 3-year progression-free survival (PFS) and overall survival (OS) rates for the 1q+/1p- and the control groups were 41% and 79%, and 56% and 86%, respectively. Patients in the 1q+/1p- group experienced significant increased risk of progression or death compared with the control group (HR 2.21, CI 1.18-4.16, P=0.014). No significant association between OS in the two groups were observed. The outcome of the 1q+/1p- alone (with no additional high-risk cytogenetics) and the propensity-score matched control groups was also compared. Median PFS for the 1q+/1p- alone subgroup was 26.6 months, compared to 38.8 months for the control group (HR 1.9, CI 0.9-4.08, P=0.09). The median OS had not reached for the 1q+1/p- alone subgroup and was 81.1 months for the control group (HR 1.25, CI 0.3-4.6, P=0.73) Conclusion 1q+/1p- abnormalities with amplification of CKS1B and deletion of CDKN2C genes were associated with shorter PFS when compared to a propensity-score matched group of patients with diploid cytogenetics and normal a FISH panel. The outcomes of 1q+1/p- MM patients have improved with the use of more effective induction, conditioning, and maintenance therapy compared to historical controls, but they still need more effective therapeutic approaches to fully overcome the negative impact of 1q+1/p-.

  • Incidence, Risk Factors, Outcomes and Risk Score Model of Acute Pancreatitis after Allogeneic Hematopoietic Stem Cell Transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-23
    Xing-Lin Wang; Wei Han; Peng Zhao; Xiao Liu; Jing-Zhi Wang; Feng-Rong Wang; Chen-Hua Yan; Yuan-Yuan Zhang; Xiao-Dong Mo; Yu Wang; Hai-Xia Fu; Yu-Hong Chen; Ying-Jun Chang; Lan-Ping Xu; Kai-Yan Liu; Xiao-Jun Huang; Xiao-Hui Zhang

    Acute pancreatitis (AP) has been recognized as an uncommon yet potentially lethal complication following hematopoietic stem cell transplantation. This retrospective, nested, case-control study reviewed data from 5284 consecutive patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between 2009 and 2018 at a single center, identifying 40 patients (0.76%) with AP following allo-HSCT. The diagnosis and severity of AP were established and classified according to the existing criteria. Younger age (P = .008), grade II-IV aGVHD (P = .010), a history of DLI (P = .033) and pre-existing gallstones (P = .003) are independent risk factors of AP after allo-HSCT. Post-transplant AP had a trend to negatively influence overall survival (OS) and nonrelapse mortality (NRM) (P = .063) for allo-HSCT recipients, but no significant difference was found. Patients with moderately severe and severe AP had significantly lower OS (P =.002) and higher NRM (P = .000) than other patients. Based on these findings, a risk score model is also established to predict the occurrence of AP. Our risk score model performed well in terms of discrimination when applied to the derivation samples. The patients were classified into a low-risk group (0-1 point), a medium-risk group (2-3 points) and a high-risk group (4 points or more). Significant difference was observed in AP incidence among the 3 groups. The predictive tool explored by our study might contribute to target high-risk patients and guide personalized AP prevention in allo-HSCT recipients.

  • Allogeneic hemopoietic stem cell transplants in patients with acute myeloid leukemia (AML) prepared with Busulfan Fludarabine (BUFLU) or Thiotepa Busulfan Fludarabine (TBF): a retrospective study.
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-23
    Federica Sora; Carmen Di Grazia; Patrizia Chiusolo; Anna Maria Raiola; Stefania Bregante; Nicola Mordini; Attilio Olivieri; Anna Paola Iori; Francesca Patriarca; Sigal Grisariu; Elisabetta Terruzzi; Alessandro Rambaldi; Simona Sica; Benedetto Bruno; Emanuele Angelucci; Andrea Bacigalupo

    Purpose This is a multicenter retrospective comparison of two myeloablative conditioning regimens in 454 patients with acute myeloid leukemia (AML) in remission: busulfan (4 days) and fludarabine (BUFLU) versus thiotepa, busulfan and fludarabine(TBF). Patients and Methods Eligible for this study were patients allografted between January 2008 and December 2018 in 10 transplant Centers, with AML in first or second remission: 201 patients received BUFLU whereas 253 received TBF. The two groups (BUFLU and TBF) were comparable for age (p=0.13), and adverse AML risk factors (p=0.3). The TBF group had more second remissions and more haploidentical grafts. The donor type included HLA identical siblings, unrelated donors and family haploidentical donors. Results The 5-year cumulative incidence of non-relapse mortality (NRM) was 19% for BUFLU and 22% for TBF (p=0.8), and the 5-year cumulative incidence of relapse was 30% and 15% respectively (P =0.0004). The 5-year actuarial survival was 51% for BUFLU and 68% for TBF (p=0.002). In a multivariate Cox analysis, after correcting for confounding factors, the use of TBF reduced the risk of relapse compared to BUFLU (p=0.03) and the risk of death (p=0.03). In a matched pair analysis of 108 BUFLU patients matched with 108 TBF patients, with the exclusion of HAPLO grafts, TBF reduced the risk of relapse (p=0.006) and there was a trend for improved survival (p=0.07). Conclusions Superior survival of patients receiving TBF, as compared to BUFLU is due to a reduced risk of relapse, with comparable NRM. The survival advantage is independent of donor type and AML risk factors.

  • A Phase 2 Trial of KIR Mismatched Unrelated Donor Transplantation Using In Vivo T-cell Depletion with ATG in AML: Children's Oncology Group AAML05P1 Study
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-21
    Stella M. Davies; Robert Iannone; Todd A. Alonzo; Yi-Cheng Wang; Robert Gerbing; Sandeep Soni; E. Anders Kolb; Soheil Meshinchi; Paul J. Orchard; Linda J. Burns; Shalini Shenoy; Wing Leung

    AML patients receiving killer immunoglobulin-like receptor (KIR) mismatched haploidentical HSCT have improved survival. COG AAML05P1 is a prospective phase 2 trial of unrelated donor (URD) HSCT in which KIR typing of donors was available to the treating physician at donor selection, aiming to determine feasibility (defined as the ability to obtain donor samples from unrelated donors and perform and return KIR data before transplant) of prospective selection of KIR mismatched donors and effect on outcomes. The study accrued 90 evaluable patients. Patients ≤ 30 years old with high risk AML at presentation or relapsed AML were eligible. After enrollment as many as 5 potential URD samples were KIR typed (including gene expression) in a central laboratory and results reported to the treating physician, who made the final donor selection. Cases were categorized as KIR matched or mismatched using different published strategies. Overall survival, disease-free survival (DFS), and relapse did not differ significantly by KIR mismatch. Acute GVHD was significantly lower in recipients of KIR mismatched stem cells (35% vs 60%, p= 0.027). We examined DFS according to time to NK-receptor recovery after HSCT. NKp44 recovery was significantly associated with KIR mismatch and with decreased DFS and increased relapse risk in multivariate Cox analysis (p= 0.006 and 0.009, respectively). We show that prospective selection of URD according to KIR type was feasible, acute GVHD was reduced, but survival did not differ using any model of KIR mismatch. The study enrolled mostly matched transplants, however, so ligand-ligand mismatch was rare and therefore sample size was insufficient to determine potential benefit according to this model. Cord blood recipients demonstrated a trend towards improved DFS with KIR mismatch, but the study was not powered to detect a difference in this small subset of patients. Our data suggest that recovery of NK receptor expression might influence DFS after HSCT.

  • Respiratory Viruses Cause Late Morbidity in Recipients of Hematopoietic Stem Cell Transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-20
    Tina Marinelli; Li Yan A. Wee; Emily Rowe; Rakchha Chhetri; Oisin Friel; Geoffrey Higgins; Peter Bardy; Deepak Singhal; Alyssa Pradhan; Lucy Crawford; Devendra K. Hiwase

    Common respiratory viral infections (CRVI) frequently complicate hematopoietic stem cell transplantation (HSCT). We conducted a retrospective, single centre, observational cohort study to determine the incidence of CRVI in patients who received an allogeneic (allo) or autologous (auto) HSCT at the Royal Adelaide Hospital between 2009 and 2017. The median follow-up was 8.9 and 4.5 years for auto- and allo-HSCT recipients respectively. There were 149 CRVI episodes in 74 patients with Rhinovirus being the most commonly isolated virus (n=81, 47%). The majority of CRVI (113/149, 75.8%) occurred more than 100 days post-HSCT and 67% were diagnosed in the outpatient setting. There was evidence of lower respiratory tract infection (LRTI) in 45.6% (68/149) of CRVI. On multivariate logistic regression analysis, co-viral infections and CMV viremia were independent risk factors for progression of CRVI to LRTI. Ten (6.7%) CRVI episodes resulted in admission to intensive care for ventilatory support and 8 (5.4%) patients died within 30 days of CRVI diagnosis. In our study 10.4% of HSCT-recipients experienced a CRVI post-transplant, primarily causing late morbidity and potentially mortality. Prevention with strict infection control practices, vaccination and patient education is essential.

  • Levaquin gets a pass
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-20
    Armin Rashidi; Thomas Kaiser; Shernan G. Holtan; Tauseef Ur Rehman; Daniel J. Weisdorf; Alexander Khoruts; Christopher Staley

    Antibiotic-induced gut dysbiosis has been associated with poor outcomes after intensive therapy. We evaluated the effect of levofloxacin (LEVO), the most commonly used prophylactic antibacterial antibiotic during intensive chemotherapy and allogeneic hematopoietic cell transplantation (allo-HCT), on the gut microbiota in two cohorts of patients. One cohort included 20 acute leukemia patients undergoing intensive chemotherapy and the other cohort included 20 allo-HCT recipients. 16S rRNA gene sequencing of thrice-weekly collected stool samples permitted a comparison between intervals with no antibacterial antibiotic exposure and those with only LEVO exposure. In mixed effect modeling, the only variables influenced by LEVO were Parabacteroides (regression coefficient -0.063 [99% confidence interval -0.102 to -0.024]) and Blautia (regression coefficient 0.050 [99% confidence interval 0.004 to 0.095]) relative abundances. Other taxa and microbiota diversity were unaffected. Overall, the effect of LEVO on the gut microbiota in these cohorts was mild.

  • Bone marrow transplantation in congenital erythropoietic porphyria: Sustained efficacy but unexpected liver dysfunction
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-14
    Caroline Besnard; Caroline Schmitt; Louise Galmiche-Rolland; Dominique Debray; Monique Fabre; Thierry Molina; Laurent Gouya; Cécile Ged; Martin Castelle; Marina Cavazzana; Elisa Magrin; Bénédicte Neven; Despina Moshous; Stéphane Blanche; Marie-Louise Frémond

    Congenital erythropoietic porphyria (CEP) is a rare disease characterized by erosive photosensitivity and chronic hemolysis due to a defect of the enzyme uroporphyrinogen-III-synthase (UROS). To date, hematopoietic stem-cell transplantation (HSCT) is the only curative therapy for the devastating early and severe form of the disease. We describe six CEP patients treated with HSCT – 3 of them twice after failure of a first graft - between 1994 and 2016 in our center, including two of the very first living patients treated more than 20 years ago. Four patients are doing well 6 to 25 years post HSCT, with near normal biochemical parameters of porphyrin metabolism without the cutaneous or hematological features of CEP. One patient died within the first year after HSCT from severe graft-versus host disease (GVHD). Finally, one child died of unexplained acute hepatic failure one year after HSCT, despite full donor chimerism. Retrospectively, it appears that all but one child had increased transaminase activity with onset from the early post-natal period, which was significantly more marked for the child who died of liver failure. In contrast, liver function values progressively normalized after engraftment for all other children. Liver pathology before HSCT for three patients revealed varying degrees of portal, centrilobular, and perisinusoidal fibrosis, clarification of hepatocytes, and cytosolic porphyrin deposits. Liver porphyrin content in biopsies was more than 60 times the normal values. Despite difficult engraftment, long-term efficacy of HSCT in CEP appears to be favorable and reinforces its benefits for the severe form of CEP. Hepatic involvement requires careful evaluation before and after HSCT and further investigation towards its pathophysiology and care.

  • Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-09
    Upendra Mahat, Seth J. Rotz, Rabi Hanna

    Prolonged thrombocytopenia after HSCT is a strong risk factor for transplant related mortality and morbidity, and no standard treatment guideline exists. Thrombopoietin receptor agonists (TPO-RAs), eltrombopag and romiplostim, increases the platelet production, and are being increasingly used in various conditions with thrombocytopenia. In this review, we present an overview of these TPO-RAs and review their efficacy and safety in prolonged post HSCT thrombocytopenia. Through a systematic literature search, we identified 25 reports describing their use for this indication. Thirteen reports (8 case series and 5 case reports) described the use of eltrombopag in 78 patients with Prolonged Isolated Thrombocytopenia (PIT) and 43 patients with Secondary Failure of Platelet Recovery (SFPR). A consistent and durable response with the rise in platelet counts above 50 × 10 9/L for 7 consecutive days without platelet transfusion was seen in 85 out of 121 patients (Overall Response Rate, ORR 70%). Amongst the responders, 56 were patients with PIT (ORR for PIT of 72%) versus 29 patients with SFPR (ORR for SFPR of 67%). No serious grade 3 or 4 adverse effects were reported. Similarly, 12 reports (6 case series and 6 case reports) described the use of romiplostim in prolonged post HSCT thrombocytopenia (17 patients with PIT and 32 patients with SFPR). Response with the increment of platelet count was described in 40 out of 49 patients (ORR 82%). Amongst the responders, 10 patients had PIT (ORR for PIT of 59%) versus 30 patients had SFPR (ORR for SFPR of 94%). TPO-RAs have an overall favorable response rate for both PIT and SFPR with a reasonable safety profile. However, given the lack of control groups, study heterogeneity, and the potential publication bias, the results should be interpreted with caution.

  • Outcomes of allogeneic hematopoietic stem cell transplantation for ATL with HTLV-1 antibody positive donors
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-09
    Makoto Yoshimitsu, Shigeo Fuji, Atae Utsunomiya, Nobuaki Nakano, Ayumu Ito, Yoshikiyo Ito, Toshihiro Miyamoto, Youko Suehiro, Toshiro Kawakita, Yukiyoshi Moriuchi, Hirohisa Nakamae, Yoshinobu Kanda, Tatsuo Ichinohe, Takahiro Fukuda, Yoshiko Atsuta, Koji Kato

    Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only available curative treatment option for patients with aggressive adult T cell leukemia–lymphoma (ATL). Donor human T cell leukemia virus (HTLV)-1 seropositivity is a critical concern when choosing relative donors, as they are not usually recommended due solely to the occurrence of donor-derived ATL. A previous report suggested that allo-HCT with an HTLV-1-seropositive donor increased ATL-related mortality. We updated the risk assessment for choosing an HTLV-1-seropositive allo-HCT donor for ATL. Our current registry data, which include larger numbers of HTLV-1-seropositive donors and longer observation periods, revealed no significant difference in overall survival [hazard ratio (HR): 0.93, 95% confidence interval (CI): 0.70‒1.24; P = 0.61) or cumulative incidence of either ATL-related (HR: 0.96, 95% CI: 0.64‒1.45; P = 0.80) or non-ATL-related mortality (HR: 0.91, 95% CI: 0.61‒1.37; P = 0.66). Similarly, when considering only ATL patients in complete remission, there was no significant difference in overall survival (HR: 1.02, 95% CI: 0.70‒1.49; P = 0.91) or cumulative incidence of either ATL-related (HR: 1.20, 95% CI: 0.66‒2.20; P=0.54) or non-ATL-related mortality (HR: 0.86, 95% CI: 0.52–1.42; P = 0.66). These data indicate that selecting HTLV-1-seropositive donors might not be contraindicated for patients with ATL receiving allo-HCT if alternative donors are unavailable. Further risk assessment remains to be performed.

  • Early posttransplant spirometry is associated with the development of bronchiolitis obliterans syndrome after allogeneic hematopoietic cell transplant
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-12-09
    Kareem Jamani, Qianchuan He, Yang Liu, Chris Davis, Jesse Hubbard, Gary Schoch, Stephanie J. Lee, Ted Gooley, Mary E.D. Flowers, Guang-Shing Cheng

    Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (allo-HCT) is often diagnosed at a late stage when lung dysfunction is severe and irreversible. Identifying patients early after transplant may offer improved strategies for early detection that could avert the morbidity and mortality of BOS. This study aimed to determine if decline in lung function pre and early post-transplant (days +80-100) are associated with risk of BOS at least 6 months after transplant. In a single center cohort of 2941 allo-HCT recipients, 186 (6%) met NIH criteria for BOS. Pre-transplant and day +80 spirometric parameters were analyzed as continuous variables and included in a multivariable model with other factors such as donor source, graft source, conditioning regimen, use of total body irradiation and immunoglobulin levels. Pre-transplant FEF25-75 (forced expiratory flow between 25-75% maximum), day +80 FEV1 (forced expiratory volume in 1 sec) and day +80 FEF25-75 had the strongest association with increased risk of BOS. Assessment of the multivariable model showed that day +80 FEF25-75 decline added additional risk to the day +80 FEV1 model (p=0.03), while FEV1 decline at day +80 added no additional risk to the day +80 FEF25-75 model (p=0.645). Moreover, day +80 FEF25-75 conferred additional risk when considered with pre-transplant FEF25-75. These results suggest that day +80 FEF25-75 may be more important than FEV1 in predicting the development of BOS. This study highlights the importance of obtaining early posttransplant pulmonary function tests for the potential risk stratification of patients at risk for BOS.

  • Worldwide Network for Blood and Marrow Transplantation Recommendations for Establishing a Hematopoietic Cell Transplantation Program, Part I: Minimum Requirements and Beyond
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-05-06
    Marcelo C. Pasquini, Alok Srivastava, Syed Osman Ahmed, Mahmoud Aljurf, Yoshiko Atsuta, Carol Doleysh, Sebastian Galeano, Eliane Gluckman, Hildegard Greinix, Gregory A. Hale, Parameswaran Hari, Shahrukh K. Hashmi, Naynesh Kamani, Mary J. Laughlin, Dietger Niederwieser, Adriana Seber, Jeffrey Szer, John A. Snowden, Jane Apperley

    Hematopoietic cell transplantation (HCT) is a highly complex procedure that requires a dedicated multidisciplinary team to optimize safety. In addition, institutions may have different needs regarding indications based on regional disease prevalence or may have an interest in developing specialized services. Structured recommendations are not commonly available, however. The Transplant Center and Recipient Issues Standing Committee of the Worldwide Network for Blood and Marrow Transplantation (WBMT) organized a structured review of all pertinent elements for establishing a transplantation program. First, we solicited components from committee members and grouped them into domains (infrastructure, staff, cell processing laboratory, blood banking, laboratory, radiology, pharmacy, HLA testing, ancillary services, and quality). Subsequently, reviewers scored each element on a 7-point scale, ranging from an absolute requirement (score of 1) to not required (score of 7). An independent group of 5 experienced transplantation physicians reviewed the rankings. The minimum requirements for establishing any HCT program were identified among elements with mean score of ≤2.0, and specific elements for allogeneic and autologous HCT were identified. Mean scores of >2.0 to 4.0 were classified as preferred recommendation, and mean scores of >4.0 to ≤ 7.0 were considered ideal recommendations for advanced and complex types of transplantation. This structured set of recommendations guides the prioritization of minimum requirements to establish a transplantation program and set the stage for expansion and further development.

  • Allogeneic Stem Cell Transplantation in Therapy-Related Myelodysplasia after Autologous Transplantation for Lymphoma: A Retrospective Study of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-19
    Daniel Jaimes-Albornoz, Lionel Mannone, Stéphanie Nguyen-Quoc, Yves Chalandon, Patrice Chevallier, Mohamad Mohty, Mathieu Meunier, Marie Robin, Marie-Pierre Ledoux, Gaëlle Guillerm, Jacques-Olivier Bay, Xavier Poiré, Natacha Maillard, Mathieu Leclerc, Etienne Daguindau, Yves Beguin, Marie Thérèse Rubio, Emmanuel Gyan

    Therapy-related myelodysplastic syndrome (t-MDS) after autologous stem cell transplantation (ASCT) is a rare complication with no curative option. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be considered for eligible patients and has been understudied in t-MDS. We report 47 consecutive patients with t-MDS after an ASCT who underwent allo-HSCT with a median age of 58 years (range, 30 to 71 years) at transplantation and a median follow-up of 22 months (range, 0.7 to 107). The median overall survival (OS) was 6.9 months (95% confidence interval [CI], 0 to 19 months). OS rates were 45% (29% to 60%) and 30% (15% to 45%) at 1 and 3 years after transplantation, respectively. On univariate analysis, prior therapy for t-MDS before allo-HSCT (P = .02) and mismatched donors (P = .004) were associated with poor OS. Three-year nonrelapse mortality (NRM) and relapse rates were 44% (25% to 63%) and 41% (22% to 61%), respectively. Mismatched donors (P < .001) were associated with higher NRM and a high-risk MDS (P = .008) with a higher relapse risk. On multivariate analysis, HLA mismatch was associated with higher NRM (hazard ratio, 6.21; 95% CI, 1.63 to 23.62; P = .007). In conclusion, our results suggest that one third of the patients who develop t-MDS after an ASCT for lymphoma are cured after an allo-HSCT. The use of mismatched donors with standard graft-versus-host disease prophylaxis should be avoided in such an indication for allo-HSCT. It will be worthwhile to see if the implementation of cyclophosphamide post-transplantation will improve the outcome with mismatched donors.

  • Worldwide Network for Blood and Marrow Transplantation Recommendations for Establishing a Hematopoietic Stem Cell Transplantation Program in Countries with Limited Resources, Part II: Clinical, Technical, and Socioeconomic Considerations
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-04-17
    Mahmoud Aljurf, Daniel Weisdorf, Shahrukh Hashmi, Amr Nassar, Eliane Gluckman, Mohamad Mohty, Doug Rizzo, Marcelo Pasquini, Mehdi Hamadani, Wael Saber, Parameswaran Hari, Mohamed Kharfan-Dabaja, Navneet Majhail, Usama Gerges, Amir Ali Hamidieh, Fazal Hussain, Alaa Elhaddad, Hossam K Mahmoud, Dietger Niederwieser

    The development of hematopoietic stem cell transplantation (HSCT) programs can face significant challenges in most developing countries because such endeavors must compete with other government health care priorities, including the delivery of basic services. Although this is may be a limiting factor, these countries should prioritize development of the needed expertise to offer state-of-the-art treatments, including transplantation, by providing financial, technological, legal, ethical, and other needed support. This would prove beneficial in providing successful programs customized to the needs of their population and potentially provide long-term cost savings by circumventing the need for their citizens to seek care abroad. The costs of establishing an HSCT program and the costs of the HSCT procedure itself can be substantial barriers in developing countries. In addition, socioeconomic factors intrinsic to specific countries can influence access to HSCT, patient eligibility for HSCT, and timely utilization of HSCT center capabilities. This report describes recommendations from the Worldwide Network for Blood and Marrow Transplantation for establishing HSCT programs, with a specific focus on developing countries, and identifies challenges and opportunities for providing this specialized procedure in resource-constrained settings.

  • Busulfan Pharmacokinetics and Precision Dosing: Are Patients with Fanconi Anemia Different?
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-18
    Parinda A. Mehta, Chie Emoto, Tsuyoshi Fukuda, Brian Seyboth, Ashley Teusink-Cross, Stella M. Davies, Jamie Wilhelm, Kirsten Fuller, Alexander A. Vinks, Farid Boulad

    It is well known that pharmacokinetics (PK)-guided busulfan (BU) dosing increases engraftment rates and lowers hepatotoxicity in patients undergoing hematopoietic cell transplantation (HCT). However, there are no published PK data in patients with Fanconi anemia (FA), who are known to have baseline DNA repair defect and related inherent sensitivity to chemotherapy. In our prospective, multi-institutional study of alternative donor HCT for FA using chemotherapy-only conditioning, we replaced the single dose of total-body irradiation with BU at initial doses of 0.8 to 1.0 mg/kg and 0.6 to 0.8 mg/kg given i.v. every 12 hours for 4 doses. Patients received the first dose of i.v. busulfan on day –8, and blood levels for PK were obtained. PK samples were drawn following completion of infusion. BU PK levels were collected at 2 hours, 2 hours and 15 minutes, and 4, 5, 6, and 8 hours from the start of infusion. The remaining 3 doses of BU were given on days –7 and –6. Thirty-seven patients with available BU PK data with a median age of 9.2 years (range, 4.3 to 44 years) are included in the final analyses. The overall BU PK profile in patients with FA is similar to non-FA patients after considering their body weight. In our cohort, a strong correlation between BU clearance and weight supports current practice of per kilogram dosing. However, not surprisingly, we show that the disease (ie, host) sensitivity related to FA is the main determinant of total dose of BU that can be safely administered to patients in this high-risk population. On the basis of our results, we propose an optimal BU concentration at steady-state level of ≤350 ng/mL (equivalent to total cumulative exposure of 16.4 mg*h/L for 4 doses over 2 days) for patients with FA undergoing HCT. To our knowledge, this is the first and largest report of prospective BU PK in patients with FA undergoing HCT, providing an optimal BU target cutoff to achieve stable donor engraftment while avoiding excessive toxicity.

  • Pediatric and Young Adult Vulvovaginal Graft-versus-Host Disease
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-17
    Stephanie M. Cizek, Javier El-Bietar, Jeremy Rubinstein, Christopher Dandoy, Gregory H. Wallace, Adam Nelson, Pooja Khandelwal, Kasiani C. Myers, Holly R. Hoefgen

    Vulvovaginal graft-versus-host disease (GVHD) is an underdiagnosed and poorly recognized complication of hematopoietic stem cell transplantation (HSCT). Previous studies have reported findings restricted to predominantly adult populations. We report a case series of pediatric and young adult vulvovaginal GVHD, which was identified in 19 patients (median age, 11.8 years; range, 2.4 to 21.9 years) out of a total 302 female patients who underwent transplantation over an 8-year period at a pediatric HSCT center. The majority of patients had concomitant nongenital GVHD; only 1 patient had isolated vulvovaginal GVHD. The median time from bone marrow transplantation to diagnosis of vulvovaginal GVHD was 30 months (range, 2.3 to 97.5 months). A high percentage of the patients in our series were without vulvar or vaginal symptoms (n = 8; 42%), even though 17 patients (89%) presented with grade 3 disease based on current adult grading scales. Vulvar examination findings most frequently included interlabial and clitoral hood adhesions (89%), loss of architecture of the labia minora or clitoral hood (42%), and skin erosions or fissures (37%). Only 5 patients underwent a speculum exam, none of whom had vaginal GVHD. Examination findings of primary ovarian insufficiency (POI) can overlap with those of GVHD, and 6 patients (32%) in our cohort were diagnosed with POI. Only 1 patient was on systemic hormone replacement therapy at the time of vulvovaginal GVHD diagnosis. The majority of patients (n = 16) were treated with topical steroid therapy, with a median time to response of 43 days. Five patients (26%) had a complete response to therapy, and 10 patients (53%) had a partial response. This case series provides valuable insight into pediatric and young adult vulvovaginal GVHD and highlights the need for increased screening for vulvar disease in this population.

  • Genetic susceptibility to hepatic sinusoidal obstruction syndrome in pediatric patients undergoing HSCT
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-29
    Marc Ansari, Kateryna Petrykey, Mohamed Aziz Rezgui, Veronica Del Vecchio, Jacques Cortyl, Reginald-Olivier Ralph, Tiago Nava, Patrick Beaulieu, Pascal St-Onge, Simona Jurkovic Mlakar, Patricia Huezo-Diaz Curtis, Chakradhara Rao S. Uppugunduri, Laurence Lesne, Yves Théoret, Yves Chalandon, Imke H. Bartelink, Jaap-Jan Boelens, Robbert G.M. Bredius, Maja Krajinovic

    Sinusoidal Obstruction Syndrome (SOS) is a well-recognized and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). SOS arises from endothelial cell damage and hepatocellular injury mostly due to the transplantation conditioning regimens but also to other patient, disease and treatment-related factors. Understanding risk factors associated with the development of SOS is critical for early initiation of treatment or prophylaxis. The knowledge about genetic contribution is limited; few studies investigated so far selected set of genes. To get more comprehensive insight in the genetic component, we performed exome-wide association study using genetic variants derived from whole-exome sequencing. The analyses were performed in a discovery cohort composed of 87 pediatric patients undergoing HSCT following busulfan-containing conditioning regimen. Eight lead SNPs were identified after correction for multiple testing and subsequently analyzed in a validation cohort (n=182). Three SNPs were successfully replicated including rs17146905 (p=0.001), rs16931326 (p=0.04) and rs2289971 (p=0.03), located respectively in UGT2B10, BHLHE22 and KIAA1715 genes. UGT2B10 and KIAA1715 were retained in multivariable model while controlling for non-genetic covariates and previously identified risk variants in GSTA1 promoter. The modulation of associations by conditioning regimens was noted, KIAA1715 was dependent on the intensity of conditioning regimen, whereas the effect of UGT2B10 was equally applicable to all of them. Combined effect of associated loci was also observed (p=0.00006) with genotype-related SOS risk of 9.8. This is the first study addressing the genetic component of SOS at an exome-wide level and identifying novel genetic variations conferring higher risk of SOS, which might be useful for personalized prevention and treatment strategies.

  • Longitudinal analysis of ocular disease in children with Mucopolysaccharidosis I after hematopoietic cell transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-29
    Brigitte T.A. van den Broek, Michelle B. van Egmond-Ebbeling, Jens A. Achterberg, Jaap Jan Boelens, Isa C. Vlessert, Hubertus C.M.T. Prinsen, Jaap van Doorn, Peter M. van Hasselt

    Aim Corneal clouding, causing visual impairment, is seen in nearly all patients with Mucopolysaccharidosis type 1 (MPS-1). Hematopoietic cell transplantation (HCT) is able to stabilize disease in many organs. Residual disease in several tissues however is increasingly recognized. Data on the effect of HCT on ocular disease in patients with MPS-1 are contradictory. With this study we aim to clarify the long-term effect of HCT on ocular disease in these patients. Methods Best Corrected Visual Acuity (BCVA), refraction, intra-ocular pressure (IOP), slit-lamp biomicroscopic and fundoscopic examinations including corneal clouding were prospectively collected from MPS-1 patients treated with HCT between 2003 and 2018. The course of corneal clouding and BCVA after HCT were analyzed using a linear mixed model. Other parameters studied were clinical phenotype, age at time of transplantation and hematological enzyme activity after transplantation. Outcomes of additional ophthalmologic tests were described. Additionally, IDUA and AGAL enzyme activities and GAGs concentration in tear fluid were determined. Results 24 engrafted MPS-1 patients were included (92% with >95% chimerism and normal enzyme activity after HCT). Corneal clouding stabilized first years after HCT, but increased rapidly beyond three years (p<0.0001). BCVA and IOP also worsened over time (p=0.01 and p<0.0001, respectively). IDUA activity in tear fluid remained very low in patients (p<0.0001). Conclusion After initial stabilization in the cornea, ongoing ocular disease and low IDUA activity in tear fluid is seen in MPS-1 patients despite treatment with HCT, unveiling a weak spot of current standard therapy. New therapies that overcome these shortcomings are necessary to improve the late outcomes of patients.

  • Clinical outcomes after allogeneic hematopoietic stem cell transplantation in children with juvenile myelomonocytic leukemia: A report from the Japan Society for Hematopoietic Cell Transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-29
    Nao Yoshida, Hirotoshi Sakaguchi, Miharu Yabe, Daiichiro Hasegawa, Asahito Hama, Daisuke Hasegawa, Motohiro Kato, Maiko Noguchi, Kiminori Terui, Yoshiyuki Takahashi, Yuko Cho, Maho Sato, Katsuyoshi Koh, Harumi Kakuda, Hiroyuki Shimada, Yoshiko Hashii, Atsushi Sato, Koji Kato, Kenichiro Watanabe

    Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for juvenile myelomonocytic leukemia (JMML), but few large studies of HSCT for JMML exist. Using data from the Japan Society for Hematopoietic Cell Transplantation registry, we analyzed the outcomes of 129 children with JMML who underwent HSCT between 2000 and 2011. The 5-year overall survival (OS) rate and cumulative incidence of relapse were 64% and 34%, respectively. A regimen of busulfan/fludarabine/melphalan was the most commonly used (59 patients), and provided the best outcomes; the 5-year OS rate reached 73%, and the cumulative incidences of relapse and transplantation-related mortality were 26% and 9%, respectively. In contrast, the use of the irradiation-based myeloablative regimen was the most significant risk factor for OS (hazard ratio [HR], 2.92; P = 0.004) in the multivariate model. In addition, chronic graft-versus-host disease (GVHD) was strongly associated with lower relapse (HR, 0.37; P = 0.029) and favorable survival (HR, 0.22; P = 0.006). The current study has shown that a significant proportion of children with JMML can be cured with HSCT, especially those receiving the busulfan/fludarabine/melphalan regimen. Based on the lower relapse and better survival observed in patients with chronic GVHD, additional treatment strategies that focus on enhancing graft-versus-leukemia effects may further improve survival.

  • Age is a prognostic factor for the overall survival of multiple myeloma patients undergoing upfront autologous hematopoietic stem cell transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-29
    David M. Cordas dos Santos, Rima M Saliba, Romil Patel, Qaiser Bashir, Neeraj Saini, Chitra Hosing, Partow Kebriaei, Issa F. Khouri, Yago Nieto, Uday Popat, Haris Ahmed, Hans C. Lee, Elisabet E. Manasanch, Krina K. Patel, Sheeba K. Thomas, Donna M. Weber, Robert J. Orlowski, Richard E. Champlin, Muzaffar H. Qazilbash

    In this retrospective analysis, we evaluated the impact of age on the outcome of multiple myeloma (MM) patients who received an autologous hematopoietic stem cell transplantation (auto-HCT) at our institution. A total of 1128 patients were divided into the older (> 70 years; 182/16%) and the younger (≤ 70 years; 946/84%) groups. Compared to the younger cohort, older patients had a higher ISS stage (ISS-II 57: 31% vs 215: 23%, ISS-III 52: 28% vs 211: 22%, P = 0.01), higher use of reduced-dose melphalan as conditioning regimen (140 mg/m² 59: 32% vs 29: 3% P = < 0.001) and a higher comorbidity index (HCT-CI median 3 vs 2, P = 0.01). Non-relapse mortality at 1-year post auto-HCT was significantly higher in older patients (7: 4% vs 9: 1%, HR 4.1, P = 0.005). Complete remission rates after auto-HCT for the older and the younger groups were 41% and 46%, respectively. With a median follow-up of 52 months, the 5-year PFS were 24% (95% CI 17-32%) and 37% (95% CI 33-40%) in the older and the younger group, respectively (HR 1.3, P = 0.02). 5-year OS for the older and the younger group were 56% (95% CI 47-64%) and 73% (95% CI 70-76%; P = < 0.001), respectively. Older age emerged as one of the predictors of shorter OS, but not PFS, in the multivariate classification and regression tree (CART) analysis. In conclusion, age ≥ 70 was associated with shorter PFS and OS in multiple myeloma patients who underwent an auto-HCT.

  • Coagulation Disorders after CAR T Cell Therapy: Analysis of 100 Patients with R/R Hematologic Malignancies
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-28
    Ying Wang, Kunming Qi, Hai Cheng, Jiang Cao, Ming Shi, Jianlin Qiao, Zhiling Yan, Guangjun Jing, Bin Pan, Wei Sang, Depeng Li, Xiangmin Wang, Chunling Fu, Feng Zhu, Junnian Zheng, Zhenyu Li, Kailin Xu

    Chimeric antigen receptor (CAR)-T cell therapy, a new immunotherapy for relapsed and refractory (R/R) hematologic malignancies, can be accompanied by adverse events including coagulation disorders. Here, we performed a comprehensive analysis of coagulation parameters in 100 patients with R/R hematologic malignancies after receiving CAR-T cell therapy to illuminate the profiles of coagulation disorders, and to facilitate the management of coagulation disorders. A high incidence of coagulation disorders was observed, including elevated D-dimer (50/100, 50%), increased FDP (45/100, 45%), decreased fibrinogen (23/100, 23%), prolonged APTT (17/100, 17%), and prolonged PT (10/100, 10%). Coagulation disorders occurred mainly during day 6 and day 20 after CAR-T cell infusion. The changes of coagulation parameters were associated with high tumor burden in acute lymphoblastic leukemia (ALL), more lines of prior therapies, lower baseline platelet count, and especially cytokines released syndrome (CRS). Disseminated intravascular coagulation (DIC) was found in 7 patients with grade ≥3 CRS, and indicated a poor prognosis. Our study suggests that coagulation disorders are manageable in most patients after CAR-T cell therapy. Coexistence of DIC and severe CRS is closely related to non-relapsed deaths during the acute toxicity phase, and effective and timely treatment is the key to reduce non-relapse mortality for patients with DIC and severe CRS.

  • Impact of Plerixafor Use at Different Peripheral Blood CD34+ Thresholds on Autologous Stem Cell Collection in Patients with Multiple Myeloma
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-27
    Eshana E. Shah, Rebecca P. Young, Sandy W. Wong, Lloyd E. Damon, Jeffrey L. Wolf, Nina D. Shah, Andrew D. Leavitt, Paula Loeffler, Thomas G. Martin

    Patients with multiple myeloma planning for autologous stem cell transplant must undergo autologous stem cell mobilization, however many unfortunately do not obtain an adequate collection yield. Despite the availability of plerixafor, widespread and uniform use is limited by its cost, and consequently, many institutions have adopted various risk-adapted algorithms. We report our mobilization experience as we have modified our plerixafor algorithm to a more liberal one, expecting greater collection efficiency and mobilization success with higher plerixafor use. A total of 344 mobilization attempts were analyzed, occurring over three time periods and utilizing three different peripheral blood CD34+ cell counts to guide plerixafor use: CD34+ < 15/µL (n = 66), < 20/µL (n = 130), < 40/µL (n = 148). The primary endpoints were to evaluate change in mean plerixafor utilization and apheresis days and to assess the impact on overall mobilization costs. Secondary endpoints were to describe the impact of lenalidomide use on mobilization and to evaluate the rates of mobilization failure. We demonstrate that mean plerixafor utilization increased from 1.32 to 1.65 to 1.74 doses per mobilization (p = 0.026) while mean apheresis days decreased from 2.15 to 2.17 to 1.89 days per mobilization for the < 15/µL, < 20/µL, < 40/µL cohorts (p = 0.011), respectively. The combined cost of plerixafor and apheresis procedures are nearly similar at a threshold of 40/µL compared to 15/µL, while saving 26 apheresis days per 100 patients. In general, there were low rates of mobilization failure across all thresholds. Patients who received more than 6 cycles of lenalidomide demonstrated impaired mobilization, and required more apheresis sessions (p < 0.013) and plerixafor utilization (p < 0.001) to reach target stem cell yields.. Overall, using plerixafor in MM patients with a day 4 pCD34 count of <40/µL is a reasonable and cost-effective strategy to optimize apheresis utilization.

  • Partially CD3+-depleted unrelated and haploidentical donor PSCT has favorable GVHD and survival rates in pediatric hematologic malignancy
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-22
    Alix E. Seif, Yimei Li, Dimitri S. Monos, Stephanie C. Heidemann, Richard Aplenc, David M. Barrett, James T. Casper, Jason L Freedman, Stephan A. Grupp, David A. Margolis, Timothy S. Olson, David T. Teachey, Carolyn A. Keever-Taylor, Yongping Wang, Julie-An M. Talano, Nancy J. Bunin

    Most children who may benefit from stem cell transplantation lack matched related donors. Alternative donor transplantations with unrelated (URD) or partially matched related donors (PMRD) carry increased risks of graft-versus-host-disease (GVHD) and mortality compared to matched related donor transplants. We hypothesized a strategy of partial CD3+/CD19+-depletion for URD or PMRD peripheral stem cell transplantation (PSCT) would attenuate risks of GVHD and mortality. We enrolled 84 pediatric patients with hematologic malignancies at the Children's Hospital of Philadelphia and the Children's Hospital of Wisconsin between April 2005 and February 2015 (NCT00579124: https://clinicaltrials.gov/ct2/show/NCT00579124; NCT01071226: https://clinicaltrials.gov/ct2/show/NCT01071226). Two (2.4%) experienced primary graft failure. Relapse occurred in 23 patients (27.4%; cumulative incidence 26.3%), and 17 patients (20.2%) experienced non-relapse mortality (NRM). Grade III-IV acute GVHD was observed in 18 patients (21.4%), and chronic GVHD was observed and graded as limited in 24 (35.3%) and extensive in 8 (11.7%). Three-year OS was 61.8% (95% CI 50.2 –71.4%) and EFS 52.0% (95% CI 40.3 – 62.4%). Age ≥15 years was associated with decreased OS (p=0.05) and EFS (p=0.05). Relapse was more common in children in second complete remission (p=0.03). Partially CD3+-depleted alternative donor PSCT NRM, OS, and EFS compare favorably with previously published studies of T cell-replete PSCT. Historically, T cell-replete PSCTs have had a high ratio of extensive compared to limited chronic GVHD, which may explain the comparatively low relapse and NRM rates in our study despite similar overall rates of chronic GVHD. Partial T cell-depletion may expand donor options for children with malignant transplant indications lacking matched related donors by mitigating but not eliminating chronic GVHD.

  • Psychological impacts and ways of coping reported by spousal caregivers of hematopoietic cell transplant recipients: a qualitative analysis
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-21
    Shelby Langer, Jean Yi, Nai-Ching Chi, Taryn Lindhorst

    Allogeneic hematopoietic cell transplantation (HCT) is a demanding treatment with well-established medical and psychosocial sequelae. Impacts on significant others are tremendous. Using an unfiltered qualitative approach, we asked spouses (N=15) of HCT recipients to talk about their thoughts and feelings regarding the transplant and their role as caregiver. Recordings were transcribed and independently coded to identify recurrent patterns. Caregivers mentioned both negative and positive psychological impacts of HCT, but the number of negative impacts was greater: 164 versus 34 instances. The most frequently mentioned negative psychological impacts were anxiety/ worry (30 instances), fear (20 instances), feeling overloaded/ overwhelmed (19 instances), and uncertainty (17 instances). Other emergent categories were roles/ responsibilities (49 instances) such as parenting, work, and treatment-related tasks; and coping strategies (55 instances). The latter included both adaptive and maladaptive strategies (75% and 25%, respectively). Despite the preponderance of negatively toned thoughts and feelings, signs of adjustment emerged given mention of positive psychological states such as optimism and gratitude, and adaptive coping strategies such as active coping, use of emotional support, and self-care. Interventions intended to facilitate adaptation to the HCT experience should employ strategies to help caregivers manage symptoms of distress and promote adaptive coping.

  • Post remission consolidation by autologous HCT for AML in CR1, negative implications for subsequent allogeneic HCT in CR2. A Study by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-21
    J.R. Passweg, M. Labopin, M. Christopeit, J. Cornelissen, T. Pabst, G. Socié, N. Russel, I. Yakoub-Agha, D. Blaise, T. Gedde-Dahl, H. Labussière-Wallet, R Malladi, E Forcade, S. Maury, E. Polge, F. Lanza, N.C. Gorin, M. Mohty, A. Nagler

    After autologous hematopoetic cell transplantation, (HCT in 1st complete remission (CR1), patients with acute myeloid leukemia (AML) may relapse and undergo allogeneic HCT in CR2. The aim of this study was to analyze outcome of allogeneic HCT performed in CR2 comparing patients with prior consolidation by autologous HCT vs. patients with chemotherapy consolidation. Included were 2619 adults, with allogeneic HCT in CR2, in 2000-2017 with (n=417) or without (n=2202) prior autologous HCT. Patient groups were not entirely comparable; patients with prior autologous HCT were younger, had less often a favorable cytogenetic profile, had more commonly donors other than matched siblings and more often received reduced intensity conditioning (RIC) conditioning. In multivariate analysis non relapse mortality (NRM) risks in patients with prior autologous HCT were 1.34 (1.07-1.67), p=0.01 after adjustment for age, cytogenetic risk, transplant year, donor, conditioning intensity, sex matching, interval diagnosis-relapse and relapse-allogeneic HCT as compared to chemotherapy consolidation. Similarly, risks of events in leukemia free survival and graft versus host disease, relapse free survival were higher with prior autologous HCT, 1.17 (1.01-1.35), p=0.03 and 1.18 (1.03-1.35) p= 0.02, respectively. Risk of death was also higher 1.13 (0.97-1.32) p=0.1 but this was not significant. Post remission consolidation with autologous HCT for AML in CR1 increases toxicity of subsequent allogeneic HCT in CR2.

  • Reliability and validity of the modified 7-day Lee Chronic-versus-Host Disease Symptom Scale
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-20
    Christopher Teh, Lynn Onstad, Stephanie J. Lee

    Chronic graft-versus-host disease (cGVHD) adversely affects patients’ quality of life, functional status and survival following allogenic hematopoietic cell transplantation. The Lee Symptom Scale is a 30 item scale that was developed to measure the symptoms of cGVHD. Although the original 30-item scale uses a one month recall period, we tested the reliability and validity of a 28 item scale (deleting two items based on supportive care needs rather than symptoms) with a 7-day recall period, a format that is more appropriate for use in clinical trials. Results show the modified 7-day scale is reliable and valid in the modern era and may be used to assess the symptom burden of cGVHD in clinical trials. Using the distribution method, a 5-6 point difference (half a standard deviation) is considered clinically meaningful.

  • Unlicensed umbilical cord blood units provide a safe and effective graft source for a diverse population: A study of 2456 umbilical cord blood recipients.
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-19
    Karen Ballen, Brent R. Logan, Pintip Chitphakdithai, Michelle Kuxhausen, Stephen R. Spellman, Alexia Adams, Rebecca J. Drexler, Merry Duffy, Ann Kemp, Roberta King, Aleksandar Babic, Colleen Delaney, Chatchada Karanes, Joanne Kurtzberg, Lawrence Petz, Andromachi Scaradavou, Elizabeth J Shpall, Clayton Smith, John P. Miller

    Umbilical Cord Blood (UCB) transplant (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the Food and Drug Administration (FDA) required that unrelated UCBT use either licensed UCB or unlicensed UCB via an Investigational New Drug (IND). The National Marrow Donor Program® (NMDP) manages an IND under which 2456 patients (1499 adults and 957 children (564 malignant disease and 393 non-malignant disease) received single or double UCBT between October 2011 and December, 2016. Median age was 31 years (<1 to 81); 50% of children and 36% of adults were non-Caucasian. Median days to neutrophil engraftment (absolute neutrophil count ≥ 500/mm3) were 22, 20 and 19 days and the incidence of engraftment at 42 days was 89%, 88%, and 90% for adult, pediatric malignant, and pediatric non-malignant, respectively. Acute GVHD Grades II-IV was 35%, 32%, and 24%, chronic GVHD was 24%, 26%, and 24% and one year overall survival (OS) was 57%, 71%, and 79% for adults, pediatric malignant, and pediatric non-malignant.. In multivariate analysis, younger age, lower HCT-CI, early stage chemotherapy sensitive disease, and higher performance score predicted improved OS for adults. In a subset analysis of children with malignancies receiving single UCBT, use of either licensed (n=48) or unlicensed UCB (n=382) was associated with similar engraftment and survival. Use of unlicensed UCB units is safe, effective and provides an important graft source for a diverse population.

  • ATG prophylaxis Induces A Decrease in Naïve Th cells to Inhibit the Onset of Chronic GvHD (cGvHD): Results from the Canadian BMT Group (CBMTG) 0801 study
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-19
    Leonie Naeije, Amina Kariminia, Sayeh Abdossamadi, Shima Azad Pour, Peter Subrt, Boris Kuzeljevic, Michael A. Irvine, Irwin Walker, Kirk R. Schultz

    ATG is an established approach to decrease chronic GvHD (cGvHD), yet the exact mechanism is uncertain. To better understand the mechanism of action of ATG in preventing cGvHD we evaluated the day 100 immune reconstitution of known cGvHD cellular biomarkers utilizing patients from the randomized CBMTG 0801 trial which demonstrated a significant impact of ATG on cGvHD. In a separate companion biology study, we evaluated the impact of ATG prophylaxis on cGvHD cellular markers at day 100 in 40 CBMTG 0801 patients. Analysis focused on previously identified cGvHD cellular biomarkers including: a) Naïve helper T (Th) cells, b) recent thymic emigrant (RTE) Th cells; c) CD21low B cells; d) CD56bright NKreg cells; e) Treg cells ST2, Osteopontin, sBAFF, sCD25, TIM-3, MMP3, ICAM-1, CXCL10, and soluble aminopeptidase N. The ATG treated group had a >10-fold decrease in both RTE Naive Th and Naïve Th cells (p < 0.0001), and a 10-fold increase in CD56bright NKreg cells (p < 0.0001). Treg cells, conventional Th cells, CD21low B cells, and all plasma markers were not affected. In the populations most affected by ATG changes in Naïve Th cells were associated with the later development of cGvHD. This analysis suggests that ATG primarily impacts on cGvHD through suppression of Naïve Th cell expansion after transplantation. These associations need to be validated in additional studies.

  • Polyphenolic extract (PE) from olive oil exerts a potent immunomodulatory effect and prevents graft-versus-host disease in a mouse model
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-19
    Isabel Alvarez-Laderas, Teresa L. Ramos, Mayte Medrano, Rocío Caracuel-García, María Victoria Barbado, Marina Sánchez-Hidalgo, Rosario Zamora, Catalina Alarcón-de-la-Lastra, Francisco J. Hidalgo, José Ignacio Piruat, Teresa Caballero-Velázquez, José Antonio Pérez-Simón

    Polyphenols are a group of chemical substances found in plants, with immunomodulatory, anti-proliferative and anti-inflammatory properties that might be useful in the prophylaxis and treatment of graft-versus-host disease (GVHD). Polyphenolic extract (PE) obtained from extra virgin olive oil (EVOO) decreased the activation and proliferation of activated T-cells. In addition, a decreased production of pro-inflammatory cytokines was observed upon exposure to PE. Western-blot assays showed a marked inhibition of Akt phosphorylation and nuclear translocation of NFkB in activated T-cells. In a murine model of acute graft-versus-host disease (GVHD), we observed that mice which received a diet supplemented in PE (600 ppm) presented a higher survival rate and lower risk of developing GVHD when compared with the group that received control diet. Histopathological examination showed a significantly lower gut involvement in mice receiving PE, with a decrease in pro-inflammatory cytokines (Il-2, Il-17 and TNF-α) in serum and the reestablishment of butyrate concentration in the gut. In conclusion, PE obtained from EVOO exerts a potent immunomodulatory effect reducing the activation and proliferation of activated T-cells and the production of pro-inflammatory cytokines. In a murine model of acute GVHD, PE supplemented diet reduced the incidence and severity of the disease and increased survival after transplantation.

  • Evaluation of Cord Blood Total Nucleated and CD34+ Cell Content, Cell Dose and 8-allele HLA-Match by Patient Ancestry
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-19
    Juliet N. Barker, Christopher Mazis, Sean M. Devlin, Eric Davis, Molly A. Maloy, Kristine Naputo, Melissa Nhaissi, Debbie Wells, Andromachi Scaradavou, Ioannis Politikos

    How cord blood (CB) CD34+ cell content and dose, and 8-allele human leukocyte antigen (HLA)-match, vary by patient ancestry is unknown. We analyzed cell content, dose and high-resolution HLA-match of units selected for CB transplantation (CBT) by recipient ancestry. Of 544 units (286 infused, 258 next best back-ups) chosen for 144 racially diverse adult patients (median weight 81 kilograms), the median total nucleated cell (TNC) (x 107) and CD34+ (x 105) content was higher for Europeans than for non-Europeans: 216 versus 197 (p = 0.002) and 160 versus 132 (p = 0.007), respectively. There were marked cell content disparities between ancestry groups with units selected for Africans having the lowest TNC (189 × 107) and CD34+ cell (122 × 105) contents. Units for non-Europeans were also more HLA-mismatched (p = 0.017). When only the 286 transplanted units were analyzed, the adverse effect of reduced cell content was exacerbated by higher weight in some groups. For example, northwestern Europeans (high patient weight, high unit cell content) had the best dosed units whereas Africans (high weight, low unit cell content) had the lowest. In Asians, low cell content was partially compensated by lower weight. Marked differences in 8-allele HLA-match distribution were also observed by ancestry group (e.g. 23% of units for northwestern Europeans were 3-4/8 HLA-matched versus 40% for southern Europeans, 46% for White Hispanics and 51% for Africans). During the study period, 20 additional patients (17 non-European, median weight 98 kilograms) did not receive a CBT due to lack of a suitable graft. CB extends transplant access to most patients but racial disparities exist in cell content, dose and HLA-match.

  • Refractory Thrombocytopenia is a Valid Early Diagnostic Criteria for Hepatic Veno-Occlusive Disease in Children
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-19
    Mostafa M. Embaby, Hemalatha G. Rangarajan, Rolla Abu-Arja, Jeffery J. Auletta, Joseph Stanek, Vinita Pai, Kathleen K. Nicol, Rajinder S. Bajwa

    We compared the incidence of refractory thrombocytopenia (RT) and platelet transfusion requirements (PTR) in 35 children who developed VOD with 35 matched controls who underwent HSCT but did not develop VOD. RT developed in 100% of the VOD patients, at a median of 8 days before VOD diagnosis, as compared to 71.5% of the control group. VOD patients required more platelets transfusions than controls (median PTR 6.9 ml/kg (range: 0.57-17.59) vs. 3.57 ml/kg (range: 0-14.63) in the control group with the difference being statistically significant (P < 0.0001). Numbers of days with platelet requirement, were significantly higher for VOD patients as compared to controls, (median % of days 68% vs. 39%, P = < .0001). The PTR peaked at ∼12 mL/kg/day, 2 days before VOD diagnosis, whereas the PTR in the control population was 5 mL/kg/day. The positive predictive value (PPV) of developing VOD was 88.9% (95% CI: 66.5-97%) in patients who were given >7ml/kg/day of platelets during at risk period of days +3 to +13 after transplant. For patients who got >8ml/kg/day pf platelets, the PPV of developing VOD was 86.7% (95%CI: 61.2 -96.4%). There was no difference in the PTR in patients with mild to moderate VOD as compared to those with severe VOD, however PTR was higher in patients whose VOD did not resolve. The median, average, daily PTR after the diagnosis of VOD in 17 patients who got defibrotide as compared to those who did not get defibrotide was 6.04 ml/kg and 5.72 ml/kg respectively and the difference was not statistically significant (p=0.56). On univariate and multivariate analysis use of intravenous immunoglobulin (IVIG) was significantly associated with VOD (p = 0.0088), however use of IVIG was not significantly associated with fatal VOD. In conclusion RT occurs in 100% of patients at a median of 8 days before VOD diagnosis. VOD should be suspected in any patient with RT after the exclusion of other causes of consumptive thrombocytopenia especially if they are needing >7ml/kg/day of platelets.

  • Tandem Autologous-Autologous versus Autologous-Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Multiple Myeloma: Long-term Follow-Up Results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-11-19
    Sergio Giralt, Luciano J. Costa, David Maloney, Amrita Krishnan, Mingwei Fei, Joseph H. Antin, Claudio Brunstein, Nancy Geller, Stacey Goodman, Parameswaran Hari, Brent Logan, Robert Lowsky, Muzaffar H. Qazilbash, Firoozeh Sahebi, George Somlo, Scott Rowley, Dan T. Vogl, David H Vesole, Edward Stadtmauer

    Allogeneic hematopoietic cell transplantation (HCT) may improve long-term multiple myeloma (MM) control through graft vs myeloma (GVM) effect. The BMT CTN 0102 was a biological assignment trial comparing tandem autologous transplant (auto-auto) vs. autologous followed by reduced intensity allogeneic (auto-allo) transplantation in patients with newly diagnosed MM with standard (N=625) or high-risk (beta 2 microglobulin at diagnosis ≥ 4 mg/dl or deletion of chromosome 13 by conventional karyotyping) disease (N=85). While the initial 3-year analysis showed no difference in progression-free survival (PFS) between arms in either risk group, we hypothesized that long-term follow-up may better capture the impact of GVM. Median follow-up of survivors is over 10 years. Among standard risk patients there was no difference in PFS (HR 1.11, 95% C.I. 0.93- 1.35, P=0.25) or OS (HR 1.03, 95% C.I. 0.82-1.28, P=0.82). The 6-year PFS was 25% in the auto-auto vs. 22% in auto-allo arm(P=0.32), and 6-year overall survival (OS) was 60% and 59% respectively (P=0.85). In the high-risk group, while there was no statistically significant difference in PFS (HR 0.66, 95% C.I. 0.41-1.07, P=0.07) and OS (HR 1.01, 95% C.I. 0.60-1.71, P=0.96), a reduction in 6-year risk of relapse, 77% vs. 47% (P= 0.005), was reflected in better PFS, 13% vs. 31% (P=0.05), but similar OS, 47% vs. 51% (P=0.69). Allogeneic HCT can lead to long-term disease control in patients with high risk MM and needs to be explored in the context of modern therapy.

  • Tandem Autologous Stem Cell Transplantation Improves Outcomes in Newly Diagnosed Multiple Myeloma with Extramedullary Disease and High-Risk Cytogenetics: A Study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-06
    Nico Gagelmann, Diderik-Jan Eikema, Linda Koster, Denis Caillot, Pietro Pioltelli, Juan Bargay Lleonart, Péter Reményi, Didier Blaise, Nicolaas Schaap, Marek Trneny, Jakob Passweg, Rocio Parody Porras, Jean Yves Cahn, Maurizio Musso, Xavier Poiré, Roland Fenk, Maija Itälä-Remes, Vincenzo Pavone, Nicolaus Kröger

    Although high-dose therapy and autologous stem cell transplant combined with novel agents continues to be the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma patients, the impact of tandem autologous or autologous/reduced-intensity allogeneic transplant for patients with extramedullary disease (EMD) and high-risk cytogenetics is not yet defined. Here, we analyzed clinical and cytogenetic data from 488 adult myeloma patients with EMD undergoing single autologous (n = 373), tandem autologous (n = 84), or autologous–allogeneic transplant (n = 31) between 2003 and 2015. At least 1 high-risk abnormality was present in 41% (n = 202), with del(17p) (40%) and t(4;14) (45%) the most frequent. More than 1 high-risk abnormality was found in 54%. High-risk cytogenetics showed worse 4-year overall survival (OS) and progression-free survival (PFS) of 54% and 29%, respectively, versus 78% and 49% for standard-risk cytogenetics (P < .001). Co-segregation of high-risk abnormalities did not seem to affect outcome. Regarding transplant regimen, OS and PFS were 70% and 43% for single autologous versus 83% and 52% for tandem autologous and 88% and 58% for autologous–allogeneic (P = .06 and P = .30). In multivariate analysis high-risk cytogenetics were associated with worse survival (hazard ratio [HR], 2.00; P = .003), whereas tandem autologous significantly improved outcome versus single autologous transplant (HRs, .46 and .64; P = .02 and P = .03). Autologous–allogeneic transplant did not significantly differ in outcome but appeared to improve survival, but results were limited because of small population (HR, .31). In conclusion, high-risk cytogenetics is frequently observed in newly diagnosed myeloma with EMD and significantly worsens outcome after single autologous, whereas a tandem autologous transplant strategy may overcome onset poor prognosis.

  • Understanding and Managing Large B Cell Lymphoma Relapses after Chimeric Antigen Receptor T Cell Therapy
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-04
    Michael Byrne, Olalekan O. Oluwole, Bipin Savani, Navneet S. Majhail, Brian T. Hill, Fredrick L. Locke

    Most patients with large cell lymphoma are cured with frontline chemoimmunotherapy. For individuals with refractory disease and those who relapse after conventional therapies, chimeric antigen receptor (CAR) T cells are an important treatment option and have led to remissions in otherwise refractory patients. In the pivotal trials, durable responses were achieved in approximately 40% to 50% of patients treated with axicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel, indicating that many patients will require subsequent treatment. Failure after CAR T cell therapy is caused by a variety of factors that can be divided into 3 broad categories: tumor intrinsic factors, other host factors, and inadequacies of the CAR T cells. Within this framework, this article reviews possible mechanisms of treatment failures and, based on the timing of relapse, considers potential salvage therapies and opportunities for future clinical studies.

  • Effect of Sirolimus on Immune Reconstitution Following Myeloablative Allogeneic Stem Cell Transplantation: An Ancillary Analysis of a Randomized Controlled Trial Comparing Tacrolimus/Sirolimus and Tacrolimus/Methotrexate (Blood and Marrow Transplant Clinical Trials Network/BMT CTN 0402)
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-02
    Mahasweta Gooptu, Haesook T. Kim, Alan Howard, Sung W. Choi, Robert J. Soiffer, Joseph H. Antin, Jerome Ritz, Corey S. Cutler

    Although allogeneic hematopoietic cell transplantation (HCT) is a potentially curative therapy for hematologic neoplasms, one of its limiting toxicities continues to be graft-versus-host disease, both acute (aGVHD) and chronic (cGVHD). Sirolimus is a mammalian target of rapamycin inhibitor that has proven effective in GVHD prophylaxis in combination with a calcineurin inhibitor, such as tacrolimus. The impact of sirolimus on immune reconstitution has not been comprehensively investigated in vivo thus far, however. Here we present an ancillary analysis of the randomized study BMT-CTN 0402 that examined the effect of sirolimus on immune subsets post-transplantation. We further examine the association between different lymphocyte subsets and outcomes post-transplantation in each arm. BMT-CTN 0402 was a randomized trial (n = 304) comparing 2 GVHD prophylaxis regimens, tacrolimus/sirolimus (Tac/Sir) and tacrolimus/methotrexate (Tac/MTX), in patients with acute myelogenous leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome undergoing myeloablative HLA-matched HCT. There were no differences in 114-day GVHD-free survival (primary endpoint), aGVHD, cGVHD, relapse, or overall survival (OS) between the 2 arms. Of the 304 patients, 264 had available samples for the current immune reconstitution analysis. Blood samples were collected at 1, 3, 6, 12, and 24 months post-HCT. Multiparameter flow cytometry was performed at the project laboratory (Esoterix Clinical Trials Services) in a blinded fashion, and results for the 2 arms were compared. Multivariable Cox regression models, treating each phenotypic parameter as a time-dependent variable, were constructed to study the impact of reconstitution on clinical outcomes. There were no significant differences in patient and transplantation characteristics between the Tac/Sir and Tac/MTX arms in this analysis. Absolute lymphocyte count and CD3+ cell, CD4+ cell, and conventional T cell (Tcon) counts were significantly decreased in the Tac/Sir arm for up to 3 months post-HCT, whereas CD8+ cells recovered even more slowly (up to 6 months) in this arm. Interestingly, there was no clear difference in the absolute number of regulatory T cells (Tregs, defined as CD4+CD25+ cells) between the 2 arms at any point post-HCT; however, the Treg:Tcon ratio was significantly greater in the Tac/Sir arm in the first 3 months after HCT. B lymphocyte recovery was significantly compromised in the Tac/Sir arm from 1 month to 6 months after HCT, whereas natural killer cell reconstitution was not affected in the Tac/Sir arm. In the outcomes analysis, higher numbers of CD3+ cells, CD4+ cells, CD8+ cells, and Tregs were associated with better OS. Neither Treg numbers nor the Treg:Tcon ratio was correlated with GVHD. Our findings indicate that Tac/Sir has a more profound T cell suppressive effect than the combination of Tac/MTX in the early post-transplantation period, and particularly compromises the recovery of CD8+ T cells, which have been implicated in aGVHD. Sirolimus used in vivo with tacrolimus does not appear to result in increased absolute numbers of Tregs, but might have a beneficial effect on the Treg:Tcon balance in the first 3 months after transplantation. Nonetheless, no differences in aGVHD or cGVHD between the 2 arms were observed in the parent randomized trial. Calcineurin-inhibitor free, sirolimus-containing GVHD prophylaxis strategies, incorporating other novel agents, should be investigated further to maximize the potential favorable effect of sirolimus on Treg:Tcon balance in the post-transplantation immune repertoire. Sirolimus significantly compromises B cell recovery in the first 6 months post-HCT, with potential complex effects on cGVHD that merit further study.

  • Allogeneic Hematopoietic Cell Transplantation in the Outpatient Setting
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-06-28
    Noa Granot, Barry E. Storer, Jason P. Cooper, Mary E. Flowers, Brenda M. Sandmaier, Rainer Storb

    Conditioning with fludarabine and low-dose total-body irradiation before allogeneic hematopoietic cell transplantation (HCT) enabled treating older or medically infirm patients with advanced hematologic malignancies in the outpatient setting. Between December 1997 and June 2017, 1037 patients with hematologic malignancies received peripheral blood stem cell (PBSC) grafts from HLA-matched or 1 HLA antigen/allele-mismatched related or unrelated donors. Median age was 58 (range, 18 to 80) years. Serious comorbidities with Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) scores ≥3 were present in 52% of patients. We found that 47% of patients were either never hospitalized or only had an overnight hospital stay for infusion of late-arriving PBSCs while 53% were admitted for a median of 6 days. Main reasons for admission were infection, fever, graft-versus-host disease, and regimen-related toxicity. Two thirds of admissions occurred within 3 weeks of HCT. The 5-year risk of nonrelapse mortality (NRM) was 26% among hospitalized patients and 13% among nonhospitalized patients. Significant risk factors for hospitalization included unrelated transplants, 1 HLA antigen-mismatched transplant, high HCT-CI scores, and diagnosis of nonmyeloma malignancies. Significant risk factors for NRM were hospitalization, older age, unrelated transplants, and high HCT-CI scores. Ambulatory allogeneic HCT is feasible and safe.

  • Myeloablative and Reduced-Intensity Conditioned Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis: A Retrospective Study by the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-05
    Donal McLornan, Richard Szydlo, Linda Koster, Yves Chalandon, Marie Robin, Christine Wolschke, Dietrich Beelen, Gerard Socié, Martin Bornhäuser, Emanuele Angelucci, Dietger Niederwieser, Arnim Gerbitz, Jürgen Finke, Antonin Vitek, Maija Itälä-Remes, Aleksandar Radujkovic, Lothar Kanz, Victoria Potter, Ibrahim Yakoub-Agha

    This retrospective study by the European Society for Blood and Marrow Transplantation analyzed the outcome of 2224 patients with myelofibrosis (MF) who underwent allogeneic stem cell transplantation (allo-SCT) between 2000 and 2014; 781 (35%) underwent myeloablative conditioning (MAC) and 1443 (65%) reduced-intensity conditioning (RIC). Median patient age was 52.9 years (range, 18 to 74 years) and 57.5 years (range, 21 to 76 years) in the MAC and RIC cohorts, respectively. Donor type was similar: matched sibling donors (MAC, 317 [41%]; RIC, 552 [38%]) and unrelated donors (MAC, 464 [59%]; RIC, 891 [62%]). Median time to both neutrophil and platelet (>20 × 109/L) engraftment did not differ between cohorts. Rates of grade II to IV acute GVHD were 28% (MAC) and 31% (RIC; P = NS). Cumulative chronic GVHD rates (limited/extensive) were 22%/27% (MAC) and 19%/31% (RIC; P = .10). Cumulative incidences of nonrelapse mortality (NRM) at 1, 3, and 5 years were 25.5%, 32.2%, and 34.6% (MAC) and 26.3%, 32.8%, and 34.4% (RIC), respectively. There was a trend toward a higher relapse rate with RIC regimens compared with MAC (P = .08); rates at 1, 3, and 5 years were 10.9%, 17.2%, and 20.1% (MAC) and 14%, 19.7%, and 23.2% (RIC), respectively. No significant difference in 5-year probabilities of overall survival (OS) was noted: MAC (53.0%; 95% confidence interval [CI], 49.1% to 56.9%) and RIC (51.0%; 95% CI, 48.3% to 53.7%); P = .78. Regarding the composite end point of GVHD-free/relapse-free survival (GRFS), the unadjusted Kaplan-Meier estimate of 5-year GRFS was 32.4% (95% CI, 29.0% to 36.1%) in the MAC group and 26.1% (95% CI, 23.9% to 28.2%) in the RIC group (P = .001). In the MAC cohort, multivariable analysis confirmed worse OS and NRM with older age (>50 years), using an unrelated donor and a Karnofsky Performance Status of 80 or less. For the RIC cohort, worse OS and NRM were associated with age 60 to 70 years compared with younger recipients, use of a mismatched donor, and poor performance status. In conclusion, although similar OS rates existed for both cohorts overall, this study suggests that MAC should still be used for younger individuals suitable for such an approach due to a trend toward less relapse and an overall suggested advantage of improved GRFS, albeit this should be examined in a more homogeneous cohort. RIC allo-SCT still offers significant survival advantage in the older, fitter MF allograft patient, and optimization to reduce significant relapse and NRM rates is required.

  • Allogeneic Hematopoietic Cell Transplant for HIV Patients with Hematologic Malignancies: The BMT CTN-0903/AMC-080 Trial
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-04
    Richard F. Ambinder, Juan Wu, Brent Logan, Christine M. Durand, Ryan Shields, Uday R. Popat, Richard F. Little, Deborah K. McMahon, Joshua Cyktor, John W. Mellors, Ernesto Ayala, Lawrence D. Kaplan, Ariela Noy, Richard J. Jones, Alan Howard, Stephen J. Forman, David Porter, Carlos Arce-Lara, Joseph C. Alvarnas

    We set out to assess feasibility and safety of allogeneic hematopoietic cell transplant in 17 persons with HIV in a phase II prospective multicenter trial. The primary endpoint was 100-day nonrelapse mortality (NRM). Patients had an 8/8 HLA-matched related or at least a 7/8 HLA-matched unrelated donor. Indications for transplant were acute leukemia, myelodysplasia, and lymphoma. Conditioning was myeloablative or reduced intensity. There was no NRM at 100 days. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) was 41%. At 1 year, overall survival was 59%; deaths were from relapsed/progressive disease (n = 5), acute GVHD (n = 1), adult respiratory distress syndrome (n = 1), and liver failure (n = 1). In patients who achieved complete chimerism, cell-associated HIV DNA and inducible infectious virus in the blood were not detectable. Blood and Marrow Transplant Clinical Trials Network 0903/AIDS Malignancy Consortium 080 was registered at www.clinicaltrials.gov (no. NCT01410344).

  • Drugs as a Frequent Cause of Acute Rash in Patients after CD34+-Selected Peripheral Blood Stem Cell Transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-12
    Skylar Klager, Mario E. Lacouture, Margaret Hannum, Sean M. Devlin, Molly Maloy, Melissa Pulitzer, Ann A. Jakubowski, Alina Markova

    Although histopathological differences have been reported between acute graft-versus-host disease (aGVHD) rash and non-aGVHD rash in CD34+-selected peripheral blood stem cell transplantation (PBSCT) recipients, skin biopsy alone is usually insufficient to determine rash etiology. As such, distinguishing inflammatory non-aGVHD rashes, such as drug eruptions, from cutaneous aGVHD after CD34+-selected PBSCT remains challenging and relies on clinical presentation. This study aimed to identify etiologies of skin rash in the first year after CD34+-selected PBSCT and to assess whether laboratory serologic markers, transplant characteristics, and rash morphology and symptomatology aid in differentiation of cutaneous aGVHD rash versus non-aGVHD rash. We conducted a retrospective study of 243 adult patients who underwent CD34+-selected PBSCT at Memorial Sloan Kettering Cancer Center between 2008 and 2011. Among this cohort of transplant recipients, only 43 patients (17.7%) developed cutaneous aGVHD. A total of 152 patients (63%) were identified with rash within 1 year after PBSCT. The proportion of patients who experienced peripheral eosinophilia was not different between those with an aGVHD versus non-aGVHD rash (P ≥ .90), nor when stratified by CD34+ selection method (Isolex, P = .70; CliniMACS, P≥ .90). The proportion of patients with pruritus was also not different between those with an aGVHD rash versus non-aGVHD rash (P= .20), or when stratified by CD34+ selection modality (Isolex, P = .20; CliniMACS, P = .50). The most common cause of non-aGVHD rash among those with a clear etiology was drug (39% of Isolex; 26% of CliniMACS). Single drug culprits were identified in 51% of drug rashes. The most commonly reported offending agents included antibiotics, keratinocyte growth factor, chemotherapy, and recombinant glycosylated human IL-7.

  • Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-12
    Ibrahim A. Ahmed, Midhat S. Farooqi, Mark T. Vander Lugt, Jessica Boklan, Melissa Rose, Erika D. Friehling, Brandon Triplett, Kenneth Lieuw, Blachy Davila Saldana, Christine M. Smith, Jason R. Schwartz, Rakesh K. Goyal

    Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.

  • Therapeutic Impact and Complications Associated with Surgical Lung Biopsy after Allogeneic Hematopoietic Stem Cell Transplantation in Children
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-06-28
    Bryan V. Dieffenbach, Arin L. Madenci, Andrew J. Murphy, Christopher B. Weldon, Brent R. Weil, Leslie E. Lehmann

    Hematopoietic stem cell transplantation (HSCT) in the pediatric population is associated with pulmonary complications in 25% of recipients. The role of surgical lung biopsy (SLB) remains unclear because of concerns about both the therapeutic impact and morbidity associated with the procedure. A retrospective review of consecutive allogeneic HSCT recipients at Dana-Farber and Boston Children's Hospital Cancer and Blood Disorders Center between 2006 and 2016 was performed. All recipients who underwent SLB during the study period were identified and charts reviewed for perioperative complications, histopathologic findings, and changes in therapy delivered. Pearson's chi-square test and Student's t-test (or appropriate nonparametric test) were used to evaluate the associations between perioperative complication and categorical and continuous variables, respectively. Five hundred fifty-five HSCTs were included, among which 48 SLBs (8.6%) were identified. Median follow-up time was 24 months (range, 0 to 139). Thirty-day postoperative morbidity was 16.7% and 30-day postoperative mortality 10.4% (n = 5). The overall 30-day postoperative complication rate (including mortality) was 20.8% (n = 10). No mortalities were directly attributable to SLB. Definitive diagnoses were identified in 70.8% of SLBs (n = 34), and therapeutic changes occurred in 79.2% (n = 38). Overall, 83.3% of SLBs (n = 40) either provided a diagnosis or led to a change in therapy. SLB has an acceptable risk of perioperative complications in this medically complicated and often severely ill population. In most HSCT patients, SLB aids in defining the etiology of pulmonary infiltrates and can inform therapeutic decisions in patients where noninvasive diagnostic modalities have failed to provide a definitive diagnosis.

  • Transplantation in Children and Adolescents with Acute Lymphoblastic Leukemia from a Matched Donor versus an HLA-Identical Sibling: Is the Outcome Comparable? Results from the International BFM ALL SCT 2007 Study
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-15
    Adriana Balduzzi, Jean-Hugues Dalle, Jacek Wachowiak, Isaac Yaniv, Akif Yesilipek, Petr Sedlacek, Marc Bierings, Marianne Ifversen, Sabina Sufliarska, Krzysztof Kalwak, Arjan Lankester, Jacek Toporski, Lucia Di Maio, Evgenia Glogova, Ulrike Poetschger, Christina Peters

    Eligibility criteria for hematopoietic stem cell transplantation (HSCT) in acute lymphoblastic leukemia (ALL) vary according to disease characteristics, response to treatment, and type of available donor. As the risk profile of the patient worsens, a wider degree of HLA mismatching is considered acceptable. A total of 138 children and adolescents who underwent HSCT from HLA-identical sibling donors (MSDs) and 210 who underwent HSCT from matched donors (MDs) (median age, 9 years; 68% male) in 10 countries were enrolled in the International-BFM ALL SCT 2007 prospective study to assess the impact of donor type in HSCT for pediatric ALL. The 4-year event-free survival (65 ± 5% vs 61 ± 4%; P = .287), overall survival (72 ± 4% versus 68 ± 4%; P = .235), cumulative incidence of relapse (24 ± 4% versus 25 ± 3%; P = .658) and nonrelapse mortality (10 ± 3% versus 14 ± 3%; P = .212) were not significantly different between MSD and MD graft recipients. The risk of extensive chronic (cGVHD) was lower in MD graft recipients than in MSD graft recipients (hazard ratio [HR], .38; P = .002), and the risks of severe acute GVHD (aGVHD) and cGVHD were higher in peripheral blood stem cell graft recipients than in bone marrow graft recipients (HR, 2.06; P = .026). Compared with the absence of aGVHD, grade I-II aGVHD was associated with a lower risk of graft failure (HR, .63; P = .042) and grade III-IV aGVHD was associated with a higher risk of graft failure (HR, 1.85; P = .020) and nonleukemic death (HR, 8.76; P < .0001), despite a lower risk of relapse (HR, .32; P = .021). Compared with the absence of cGVHD, extensive cGVHD was associated with a higher risk of nonleukemic death (HR, 8.12; P < .0001). Because the outcomes of transplantation from a matched donor were not inferior to those of transplantation from an HLA-identical sibling, eligibility criteria for transplantation might be reviewed in pediatric ALL and possibly in other malignancies as well. Bone marrow should be the preferred stem cell source, and the addition of MTX should be considered in MSD graft recipients.

  • Fludarabine and Total-Body Irradiation Conditioning before Ablative Haploidentical Transplantation: Long-Term Safety and Efficacy
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-06-25
    Scott R. Solomon, Melhem Solh, Xu Zhang, Lawrence E. Morris, H. Kent Holland, Asad Bashey

    Although myeloablative conditioning (MAC) before haploidentical donor transplant (HIDT) with post-transplant cyclophosphamide is being increasingly used, the optimal preparative regimen remains unclear. In our initial trial, the feasibility of HIDT following a MAC preparative regimen using fludarabine and 12 Gy of total-body irradiation was demonstrated in 30 patients. We now present long-term outcome results, including an additional 52 patients, now with 47 months (16 to 96) median follow-up. Median patient age was 42 (19 to 61) years. The most common diagnoses were acute myelogenous leukemia (51%) and acute lymphoblastic leukemia (33%), and 39% had a high/very high disease risk index (DRI). Engraftment was universal with no cases of primary or secondary graft failure. Grade 3 to 4 acute graft-versus-host disease (GVHD) and moderate to severe chronic GVHD occurred in 17% and 23%, respectively. Nonrelapse mortality (NRM) was 7% at 1 year and 13% at 4 years. Estimated 4-year overall survival (OS), disease-free survival, and cumulative incidence of relapse (CIR) were 67%, 60%, and 27%, respectively. CIR was significantly higher in patients with high/very high- versus low/intermediate-risk DRI (38% versus 20%, P= .032), which led to inferior 4-year OS (50% versus 77%, P = .001). Median time to systemic immunosuppressive therapy (IST) discontinuation was 7.8 months, with 84% of patients off IST at 2 years post-transplant. Current GHVD-free, relapse-free survival (CGRFS) at 2, 3, and 4 years was 60%, 57%, and 60%, respectively. This approach to MAC HIDT results in universal engraftment; low rates of NRM, infection, and clinically significant GVHD; and relatively rapid IST discontinuation, resulting in high rates of CGRFS and survival.

  • Standardized Semi-structured Psychosocial Evaluation before Hematopoietic Stem Cell Transplantation Predicts Patient Adherence to Post-Transplant Regimen
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-06-24
    Adrienne D. Mishkin, Peter A. Shapiro, Ran Reshef, Sara Lopez-Pintado, Markus Y. Mapara

    In patients undergoing stem cell transplantation (SCT), nonadherence has potential for significant medical impact and potentially life-threatening complications. No study thus far has demonstrated an effective way to predict adherence in SCT recipients. A structured rating scale, the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT), has been shown to predict psychosocial outcomes and medical morbidity in solid organ transplant recipients. We assessed the SIPAT in SCT recipients. We hypothesized that the SIPAT rating would be associated with nonadherence to the post-SCT regimen. We retrospectively studied SCT recipients who had psychiatric evaluations with the SIPAT before SCT. The primary outcome was nonadherence, defined a priori as at least 1 life-threatening nonadherence event in the first 6 months post-transplant. Association of the SIPAT with outcomes was evaluated by logistic regression, and an optimal cutoff score was determined using a receiver operating characteristic curve. Of 85 patients (mean age 47 years; range, 18 to 74 years), 56 (66%) were male, and 43 (50.5%) received autologous SCT. Eighteen (21%) patients were nonadherent. The SIPAT rating, treated as a continuous variable and controlling for autologous versus allogeneic SCT, was significantly associated with nonadherence (per 1 point; odds ratio [OR], 1.162; P< .0001). Allogeneic SCT also conferred a significantly increased risk of nonadherence (OR, 14.184; P= .005). Multivariate analysis stratifying for allogeneic versus autologous transplantation and controlling for age, sex, and disease confirmed an independent association between the SIPAT score and nonadherence. A cutoff score of 18 provided optimal specificity (89.6%) and sensitivity (55.6%) for nonadherence. Nonadherence rates were 58.8% and 11.8% for subjects with SIPAT ratings of 18 and above or 17 and below, respectively (relative risk = 4.98, P < .0001). Psychosocial risk as quantified by the SIPAT correlated with SCT recipients' adherence to the post-transplant regimen, suggesting that this instrument can contribute to medical risk stratification models. Further study should evaluate long-term mortality data and the effects of intervention on psychosocial risks.

  • Successful Outcome in Patients with Fanconi Anemia Undergoing T Cell-Replete Mismatched Related Donor Hematopoietic Cell Transplantation Using Reduced-Dose Cyclophosphamide Post-Transplantation
    Biol. Blood Marrow Transplant. (IF 3.599) Pub Date : 2019-07-12
    Mouhab Ayas, Khawar Siddiqui, Abdullah Al-Jefri, Ali Al-Ahmari, Ibrahim Ghemlas, Hawazen Al-Saedi, Awatif Alanazi, Rafat Jafri, Mohamad F. Ayas, Amal Al-Seraihi

    Allogeneic hematopoietic cell transplantation (HCT) has been shown to restore normal hematopoiesis in patients with Fanconi anemia (FA), with excellent results in matched related donor HCT. Outcomes of alternative donor HCT are less favorable, however. In patients without FA, several reports have documented stable engraftment and/or a low risk of graft-versus-host disease (GVHD) using unmanipulated HLA-mismatched related donors and post-HCT cyclophosphamide (PT-CY) for GVHD prophylaxis. Data on the use of this approach in patients with FA are scarce, and thus we launched a study of HLA-mismatched related donor HCT in these patient. Here we report our findings in 19 patients. The conditioning was fludarabine 30 mg/m2/day for 5 days, antithymocyte globulin 5 mg/kg/day for 4 days, and total body irradiation (total dose, 200 cGy). GVHD prophylaxis was cyclosporine and mycophenolate and reduced doses of PT-CY, 25 mg/kg, on days +3 and +5. All patients exhibited absolute neutrophil count recovery. Grade III-IV acute GVHD occurred in 3 patients, and chronic GVHD occurred in 1 patient. At a mean follow-up of 38.3 ± 5.8 months, the 5-year probability of overall survival for our patients was 89.2% ± 7.2%. The regimen was well tolerated; hemorrhagic cystitis occurred in 7 patients, and severe mucositis occurred in 5 patients. There were 2 deaths; the primary cause of death was severe GVHD in 1 patient and leukemia recurrence in the other. We conclude that in patients with FA lacking a matched related donor, the use of mismatched related HCT with low-dose PT-CY is a viable option; it is well tolerated, with a high rate of engraftment and an acceptable incidence of GVHD.

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