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Chronic graft-versus-host disease (cGVHD) of the lung, or bronchiolitis obliterans syndrome (BOS), is a high-risk disease manifestation associated with poor outcomes. Currently available treatments have demonstrated limited clinical efficacy in this setting. Belumosudil is a novel oral selective rho-associated coiled-coil–containing protein kinase-2 inhibitor that was recently approved by the US Food and Drug Administration in the treatment of cGVHD. We identified 59 subjects with BOS who were enrolled and treated in 2 prospective clinical trials of belumosudil. Patients with BOS had a percentage predicted forced expiratory volume in 1 second (FEV1) of ≤79% at enrollment and clinician attribution of lung disease owing to cGVHD. The National Institutes of Health (NIH) cGVHD lung scores at enrollment were 1 (n = 30, 59%), 2 (n = 23, 39%), or 3 (n = 6, 10%). According to NIH response criteria, the best overall response rate (ORR) for lung cGVHD was 32% (partial response: 17%; complete response: 15%). Response rates were inversely proportional to baseline NIH GVHD lung score at enrollment (lung score 1: ORR 50%; lung score 2: ORR 17%, lung score 3: ORR 0%) (P = .006). In multivariable analysis, male sex, lower baseline NIH cGVHD lung score, and partial response to previous line of cGVHD therapy before enrollment were associated with higher rates of lung-specific response. No significant correlation was identified between pulmonary function evaluations and measures of patient symptoms (NIH lung symptom score or Lee Symptom Scale score for lung). In conclusion, belumosudil treatment was associated with lung-specific clinical responses for subjects with BOS, which were more commonly observed in less advanced disease. Optimization of treatment response evaluations remains a challenge in patients with BOS.

To develop a prognostic model for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) for myelofibrosis (MF). We examined 623 patients undergoing allo-HCT between 2000 - 2016 in the USA (CIBMTR cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients transplanted in Europe (EBMT cohort) (n = 623). Age above 50 (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98 -1.96), and HLA matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with increased hazard of death and were assigned 1 point. Hemoglobin lower than 100g/L at time of transplant (HR, 1.63; 95% CI, 1.2- 2.19), and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25- 2.52), were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points) and high score (5 points) were 69% (95% CI, 61% -76 %), 51 % (95% CI, 46% -56.4 %), and 34% (95% CI, 21% - 49%), respectively (P. < 0.001). Increasing score was predictive of increased transplant related mortality (TRM) (P .0017) but not for relapse (P. 0.12). The derived score was predictive for OS (P. < 0.001) and TRM (P. 0.002) but not relapse (P. 17) in the EBMT cohort as well. The proposed system was prognostic of survival in two large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF on transplant outcomes.

The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, P = .02). No other grade ≥3 adverse events occurred in >10% of itacitinib-treated patients. There were no significant differences between groups at 1 year for nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.

Allogeneic hematopoietic; Cell transplantation; Myelofibrosis Trasplante alogénico; Células hematopoyéticas; Mielofibrosis Trasplantament al·logènic; Cèl·lules hematopoètiques; Mielofibrosi Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P

Chronic graft-versus-host disease (cGVHD) is the leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. To better understand patients at highest risk for nonrelapse mortality (NRM), we analyzed patient-, transplant-, and cGVHD-related variables, risk factors, and causes of nonrelapse deaths in an updated cohort of 937 patients enrolled on 2 prospective, longitudinal observational studies through the Chronic GVHD Consortium. The median follow-up of survivors was 4 years (range, 0.1 months to 12.5 years). Relapse accounted for 25% of the 333 deaths. The cumulative incidence of NRM was 22% at 5 years, and it increased over time at a projected 40% (95% confidence interval, 30%-50%) at 12 years. Centers reported that cGVHD (37.8%) was the most common cause of NRM and was associated with organ failure, infection, or additional causes not otherwise specified. The next most frequent causes without mention of cGVHD were infection (17%) and respiratory failure (10%). In multivariable analysis, an increased risk for NRM was significantly associated with the use of reduced intensity conditioning, higher total bilirubin, National Institutes of Health (NIH) skin score of 2 to 3, NIH lung score of 1 to 3, worse modified Human Activity Profile adjusted activity score, and decreased distance on walk test. To summarize, cGVHD NRM does not plateau but increases over time and is most commonly attributed to GVHD or infection, presumably associated with immunocompromised status. Severe skin and lung cGVHD remain challenging manifestations associated with increased NRM, for which novel therapeutic options that do not predispose patients to infections are needed.

Positive results from recent clinical trials have significantly expanded current therapeutic options for patients with chronic graft-versus-host disease (GVHD). However, new insights into the associations between clinical characteristics of chronic GVHD, pathophysiologic mechanisms of disease, and the clinical and biological effects of novel therapeutic agents are required to allow for a more individualized approach to treatment. The current report is focused on setting research priorities and direction in the treatment of chronic GVHD. Detailed correlative scientific studies should be conducted in the context of clinical trials to evaluate associations between clinical outcomes and the biological effect of systemic therapeutics. For patients who require systemic therapy but not urgent initiation of glucocorticoids, clinical trials for initial systemic treatment of chronic GVHD should investigate novel agents as monotherapy without concurrently starting glucocorticoids, to avoid confounding biological, pathological, and clinical assessments. Clinical trials for treatment-refractory disease should specifically target patients with incomplete or suboptimal responses to most recent therapy who are early in their disease course. Close collaboration between academic medical centers, medical societies, and industry is needed to support an individualized, biology-based strategic approach to chronic GVHD therapy.

IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3 × 3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100mg daily. Attributable grade ≥3 toxicities were rare, with the most common being cytopenias. Eight patients stopped maintenance before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft-vs-host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID infection (n=1). No cases of grade ≥3 acute GVHD were seen, and 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); 1 subject relapsed while receiving maintenance. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (95% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at www.clinicaltrials.gov (#NCT03515512).

The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consisting of both transplant and nontransplant experts, was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by the American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate- and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.

Effective immunosuppressive regimens to prevent the development of graft-versus-host disease (GVHD) are essential to the success of allogeneic hematopoietic cell transplantation (HCT). After revolutionizing haploidentical transplantation, post-transplantation cyclophosphamide (PTCy) is now being evaluated for HCT performed from related and unrelated donors. In this setting, two recent randomized studies have demonstrated lower rates of GVHD and superior GVHD-free, relapse-free survival with PTCy as compared to conventional GVHD prophylaxis. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is currently conducting a large, randomized phase III, multicenter trial (BMT CTN 1703) comparing PTCy/tacrolimus/mycophenolate mofetil to tacrolimus/methotrexate as GVHD prophylaxis regimens in reduced-intensity allogeneic HCT. In this introductory manuscript, we review the ongoing study, highlight its importance to field, and explore the possible implications of results on clinical practice.

The α4s7 integrin is upregulated on naive and memory T cell subsets in patients who subsequently develop gastrointestinal (GI) acute GVHD. Natalizumab (Tysabri®, Biogen Inc.) acts against the α4 subunit that mediates homing of lymphocytes to the GI tract. We initiated a phase II study of natalizumab with corticosteroids for initial treatment of acute GI GVHD. In total, 300 mg IV of natalizumab was given, with steroids initiated up to 3 days prior. Twenty-one subjects were treated, median age was 63 years (range 38–74), and 15 (71%) were male. Eighteen (86%) underwent RIC, 15 (71%) received MUD, and all received PBSCs. Overall GVHD at enrollment was grade II in 4 and grade III in 17. The primary endpoint, day 56 GVHD-free survival rate, was attained in 33.3%. The overall response rate at day 28 and 56 was 57% and 52%, respectively. Six of eight CRs were durable for 1 year. Five experienced toxicity possibly related to natalizumab and ten had infections before day 100. 2-year OS was 43% (95% CI 22–62%) and 2-year NRM was 52% (95% CI 29–71%). Natalizumab with corticosteroids as initial treatment of acute GI GVHD is safe, effective, and durable.

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

While TKI are the preferred first-line treatment for chronic phase (CP) CML, alloHCT remains an important consideration. The aim is to estimate residual life expectancy (RLE) for patients initially diagnosed with CP CML based on timing of alloHCT or continuation of TKI in various settings: CP1 CML, CP2 + [after transformation to accelerated phase (AP) or blast phase (BP)], AP, or BP. Non-transplant cohort included single-institution patients initiating TKI and switched TKI due to failure. CIBMTR transplant cohort included CML patients who underwent HLA sibling matched (MRD) or unrelated donor (MUD) alloHCT. AlloHCT appeared to shorten survival in CP1 CML with overall mortality hazard ratio (HR) for alloHCT of 2.4 (95% CI 1.2-4.9

There is marked paucity of data regarding late effects in adolescents and young adults (AYAs) who undergo myeloablative conditioning (MAC) allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). We evaluated late effects and survival in 826 1-year disease-free survivors of MAC HCT for AYA AML, with an additional focus on comparing late effects based upon MAC type (total body irradiation [TBI] vs high-dose chemotherapy only). The estimated 10-year cumulative incidence of subsequent neoplasms was 4% (95% confidence interval [CI], 2%-6%); 10-year cumulative incidence of nonmalignant late effects included gonadal dysfunction (10%; 95% CI, 8%-13%), cataracts (10%; 95% CI, 7%-13%), avascular necrosis (8%; 95% CI, 5%-10%), diabetes mellitus (5%; 95% CI, 3%-7%), and hypothyroidism (3%; 95% CI, 2%-5%). Receipt of TBI was independently associated with a higher risk of cataracts only (hazard ratio [HR], 4.98; P < .0001) whereas chronic graft-versus-host disease (cGVHD) was associated with an increased risk of cataracts (HR, 3.22; P = .0006), avascular necrosis (HR, 2.49; P = .006), and diabetes mellitus (HR, 3.36; P = .03). Estimated 10-year overall survival and leukemia-free survival were 73% and 70%, respectively, and did not differ on the basis of conditioning type. In conclusion, late effects among survivors of MAC HCT for AYA AML are frequent and are more closely linked to cGVHD than type of conditioning.

It remains unknown whether the administration of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 after allogeneic hematopoietic cell transplantation (HCT) is associated with improved outcomes for patients with chronic myelogenous leukemia (CML). In this registry study, we analyzed clinical outcomes of 390 adult patients with CML who underwent transplantation between 2007 and 2014 and received maintenance TKI following HCT (n = 89) compared with no TKI maintenance (n = 301), as reported to the Center for International Blood and Marrow Transplant Research. All patients received TKI therapy before HCT. The majority of patients had a disease status of first chronic phase at HCT (n = 240; 62%). The study was conducted as a landmark analysis, excluding patients who died, relapsed, had chronic graft-versus-host disease, or were censored before day +100 following HCT. Of the 89 patients who received TKI maintenance, 77 (87%) received a single TKI and the other 12 (13%) received multiple sequential TKIs. The most common TKIs used for maintenance were dasatinib (n = 50), imatinib (n = 27), and nilotinib (n = 27). As measured from day +100, the adjusted estimates for 5-year relapse (maintenance, 35% versus no maintenance, 26%; P = .11), leukemia-free survival (maintenance, 42% versus no maintenance, 44%; P = .65), or overall survival (maintenance, 61% versus no maintenance, 57%; P = .61) did not differ significantly between patients receiving TKI maintenance or no maintenance. These results remained unchanged in multivariate analysis and were not modified by disease status before transplantation. In conclusion, our data from this day +100 landmark analysis do not demonstrate a significant impact of maintenance TKI therapy on clinical outcomes. The optimal approach to TKI administration in the post-transplantation setting in patients with CML remains undetermined. (C) 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

We used a rigorous PRoBE (prospective-specimen collection, retrospective-blinded-evaluation) study design to compare the ability of biomarkers of systemic inflammation and biomarkers of gastrointestinal (GI) tissue damage to predict response to corticosteroid treatment, the incidence of clinically severe disease, 6-month nonrelapse mortality (NRM), and overall survival in patients with acute graft-versus-host disease (GVHD). We prospectively collected serum samples of newly diagnosed GVHD patients (n = 730) from 19 centers, divided them into training (n = 352) and validation (n = 378) cohorts, and measured TNFR1, TIM3, IL6, ST2, and REG3α via enzyme-linked immunosorbent assay. Performances of the 4 strongest algorithms from the training cohort (TNFR1 + TIM3, TNFR1 + ST2, TNFR1 + REG3α, and ST2 + REG3α) were evaluated in the validation cohort. The algorithm that included only biomarkers of systemic inflammation (TNFR1 + TIM3) had a significantly smaller area under the curve (AUC; 0.57) than the AUCs of algorithms that contained ≥1 GI damage biomarker (TNFR1 + ST2, 0.70; TNFR1 + REG3α, 0.73; ST2 + REG3α, 0.79; all P < .001). All 4 algorithms were able to predict short-term outcomes such as response to systemic corticosteroids and severe GVHD, but the inclusion of a GI damage biomarker was needed to predict long-term outcomes such as 6-month NRM and survival. The algorithm that included 2 GI damage biomarkers was the most accurate of the 4 algorithms for all endpoints.

Disease relapse is the leading cause of failure for patients receiving allogeneic hematopoietic cell transplantation (allo-HCT). Maintenance therapy administered after allo-HCT is a promising strategy to reduce the incidence of relapse and enhance the curative potential of allo-HCT. Research investigations and clinical applications of this approach have greatly increased in recent years, with an expanding number of available therapeutic agents to introduce in the posttransplant setting. However, many questions and challenges remain regarding the feasibility and clinical impact of maintenance. In this article, we present four common case scenarios addressing select available therapeutic agents as a framework to review published data and ongoing studies and describe our current standard practice in the rapidly evolving field of maintenance therapy after allo-HCT.

Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality of life among long-term survivors of pediatric HCT. Late effects (LEs) of HCT are well documented in this population, and cGVHD has been identified as a risk factor for subsequent neoplasms (SNs) and several nonmalignant LEs (NM-LEs); however, the reported correlation between cGVHD and LEs varies among studies. We compared LEs occurring ≥2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of LEs. This systematic retrospective analysis used data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large, representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant LEs and NM-LEs in those with a diagnosis of cGVHD and those who never developed cGVHD. The cumulative incidences of any first LE, SN, and NM-LE were estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD versus no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first LEs. The estimated 10-year cumulative incidence of any LE in patients with and without cGVHD was 43% (95% CI, 38% to 48.2%) versus 32% (95% confidence interval [CI], 28.5% to 36.3%) (P.001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any LE (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.68; P = .001) and NM-LE (HR, 1.37; 95% CI, 1.10 to 1.70; P = .006), but not SN (HR, 1.30; 95% CI, .73 to 2.31; P = .38). cGVHD-related factors linked with the development of an NM-LE included having extensive grade cGVHD (HR, 1.60; 95% CI, 1.23 to 2.08; P = .0005), severe cGVHD (HR, 2.25; 95% CI, 1.60 to 3.17; P.0001), interrupted onset type (HR, 1.57; 95% CI, 1.21 to 2.05; P = .0008), and both mucocutaneous and visceral organ involvement (HR, 1.59; 95% CI, 1.24 to 2.03; P = .0002). No significant association between cGVHD-specific variables and SN was identified. Finally, the duration of cGVHD treatment of cGVHD with systemic immunosuppression was not significantly associated with SNs or NM-LEs. cGVHD was more closely associated with NM-LEs than with SNs among survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SNs was strongly associated with the use of myeloablative total body irradiation. cGVHD-related characteristics consistent with a state of greater immune dysregulation were more closely linked to NM-LEs.

Background : Male-specific late effects after hematopoietic cell transplantation (HCT) include genital chronic graft-versus-host disease (GvHD), hypogonadism, sexual dysfunction, infertility, and subsequent malignancies, such as prostate, penile, and testicular cancer. They may be closely intertwined and cause prolonged morbidity and decreased quality of life after HCT. Objective : Here, we provide a systematic review of male-specific late effects in a collaboration between transplant physicians, endocrinologists, urologists, dermatologists, and sexual health professionals through the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research, and the Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation. Study Design : We utilized systematic review methodology to summarize incidence, risk factors, screening, prevention and treatment of these complications and provide consensus evidence-based recommendations for clinical practice and future research. Results : Most of the evidence regarding male GvHD is still based on limited data, precluding strong therapeutic recommendations. We therefore recommend to systematically screen for male genital GvHD regularly and report it to large registries to allow for a better understanding. Future research should also address treatment since little published evidence is available to date. Male-specific endocrine consequences of HCT include hypogonadism which may also affect bone health. Since the evidence is scarce, current recommendations for hormone substitution and/or bone health treatment are based on similar principles as for the general population. Following HCT, sexual health decreases and this topic should be addressed at regular intervals. Future studies should focus on interventional strategies to address sexual dysfunction. Infertility remains prevalent in patients having undergone myeloablative conditioning, which warrants offering sperm preservation in all HCT candidates. Most studies on fertility rely on descriptive registry analysis and surveys, hence the importance of reporting post-HCT conception data to large registries. Although the quality of evidence is low, the development of cancer in male genital organs does not seem more prevalent than in the general population; however, subsequent malignancies in general seem to be more prevalent in males than females, and special attention should be given to skin and oral mucosa. Conclusion : Male-specific late effects, probably more under-reported than female-specific complications, should be systematically considered during the regular follow-up visits of male survivors who have undergone HCT. Care of patients with male-specific late effects warrants close collaboration between transplant physicians and specialists from other involved disciplines. Future research should be directed towards better data collection on male-specific late effects and on studies about the interrelationship between these late effects, to allow the development of evidence based effective management practices.

Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, P=0.049) or high (HR=3.22, P=0.0004) correlated significantly with overall survival. When the molecularly informed CPSS-Mol prognostic model was applied, a high CPSS-Mol score (HR=2 P=0.0079) correlated significantly with overall survival. The most common somatic mutations were in ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased overall survival (HR=1.70 [95% CI: 1.11-2.60], P=0.0147 and HR=2.72 [95% CI: 1.37-5.39], P=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (HR=1.66 [95% CI: 1.11-2.49], P=0.0138, HR=1.79 [95% CI: 1.06-3.03], P=0.0293, and HR=2.94 [95% CI: 1.50-5.79], P=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, P=0.0201). Nonetheless, the impact of TP53 mutations specifically should be interpreted cautiously given their rarity in CMML. We calculated the goodness of fit measured by Harrell’s C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have determined the mutational landscape in patients with CMML who underwent allogeneic HCT, and demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond that provided by the CPSS.

CD19-directed chimerical antigen receptor T-cell (CAR-T) products have gained US Food and Drug Administration approval for systemic large B-cell lymphoma. Because of concerns about potential immune cell-associated neurotoxicity syndrome (ICANS), patients with primary central nervous system (CNS) lymphoma (PCNSL) were excluded from all pivotal CAR-T studies. We conducted a phase 1/2 clinical trial of tisagenlecleucel in a highly refractory patients with PCNSL and significant unmet medical need. Here, we present results of 12 relapsed patients with PCNSL who were treated with tisagenlecleucel and followed for a median time of 12.2 months (range, 3.64-23.5). Grade 1 cytokine release syndrome was observed in 7/12 patients (58.3%), low-grade ICANS in 5/12 (41.6%) patients, and only 1 patient experienced grade 3 ICANS. Seven of 12 patients (58.3%) demonstrated response, including a complete response in 6/12 patients (50%). There were no treatment-related deaths. Three patients had ongoing complete remission at data cutoff. Tisagenlecleucel expanded in the peripheral blood and trafficked to the CNS. Exploratory analysis identified T-cell, CAR T, and macrophage gene signatures in cerebrospinal fluid following infusion when compared with baseline. Overall, tisagenlecleucel was well tolerated and resulted in a sustained remission in 3/7 (42.9%) of initial responders. These data suggest that tisagenlecleucel is safe and effective in this highly refractory patient population. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune "neighborhoods" in which malignant B cells are surrounded by exceptionally high numbers of PD-L1-expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.

Background: Allogeneic HCT continues to be the optimal consolidation strategy for many patients with AML. Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes. We tested the prognostic ability of a modified (mELN) classification system based on available CIBMTR genetic data, to predict post-transplant outcomes. Methods: Adult patients with a diagnosis of AML in first complete remission (CR1) with available pre-transplant cytogenetic and molecular mutational data, receiving a first allogeneic HCT from 2013-2017, were included. Patients were stratified according to mELN genetic classification in three distinct groups: favorable (Fav), intermediate (IM) and adverse (Adv). Clinical outcomes following HCT were compared among groups after adjusting for significant patient, disease, and transplant-related variables. The primary endpoint was disease free survival (DFS). Secondary endpoints were overall survival (OS), non-relapse mortality (NRM), cumulative incidence of relapse, acute GVHD, and chronic GVHD. Cox proportional hazard models were used to compare endpoints among mELN risk groups, age groups and genetic subsets within the adverse-risk group. Results: Demographic characteristics are summarized in Table 1. 2289 patients (Fav, n=181; IM n=1185; and Adv n=923) met the inclusion criteria. Median follow-up for survivors was 35 months. Importantly, 41% of transplant recipients (n=936) were >60 years, 76% (n=1743) had de novo AML and 48% (n=1111) received a myeloablative conditioning regimen. Univariate analysis (UVA) demonstrated significant differences in 2-year OS (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p Initial multivariate analysis (MVA) of mELN risk groups indicated that there was no significant difference in clinical outcomes between the Fav and IM risk groups. Thus, these groups were combined for subsequent analyses. Adv risk (vs. Fav/IM) led to significantly worse OS (HR 1.39 [1.24-1.57] p= This mELN classification effectively stratified both younger (60 y/o) patients for OS (Adv vs. Fav/IM HR for 60: 1.44 [1.21-1.72] p60: 1.41 [1.19-1.66] p60: 1.42 [1.15-1.76] p=0.001). NRM was higher for older patients (>60 y/o) in both the Fav/IM (HR 1.40 [1.10-1.78] p=0.007) and Adv-risk cohorts (HR 1.59 [1.18-2.13] p=0.002). Genetic subset comparisons within the adverse-risk group showed that patients carrying monosomy 5, del(5q) or monosomy 7 had inferior 2-year OS (42.6%, p Conclusion: Stratification using mELN criteria resulted in clear prognostic separation of OS, DFS and relapse in this large cohort of AML patients undergoing allogeneic HCT. While Fav and IM groups had similar OS, DFS and relapse rates; patients in the Adv risk group had the highest risk of relapse and inferior DFS/OS. However, the majority of patients in all cohorts had favorable outcomes for HCT in CR1. Our findings confirm the value of a combined genetic prognostic model in the AML HCT setting and justify the use of this stratification system in future HCT trials. Correlation of genetic subtypes with other important transplant variables, such as conditioning intensity and pre-transplant MRD status deserves further evaluation. There remains a subset of Adv-risk patients for which post-transplant outcomes continue to be poor, even when transplanted in CR1. Novel peri-transplant pre-emptive/therapeutic strategies are urgently needed for this high-risk cohort. Disclosures de Lima: Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding; BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board. Komanduri:Kiadis: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Atara: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kebriaei:Ziopharm: Other: Research Support; Jazz: Consultancy; Kite: Other: Served on advisory board; Amgen: Other: Research Support; Novartis: Other: Served on advisory board; Pfizer: Other: Served on advisory board. Bhatt:National Marrow Donor Program: Research Funding; Rigel Pharmaceuticals: Other; Jazz: Research Funding; Agios: Other: Personal Fees; Incyte: Other: Personal Fees, Research Funding; Takeda: Other: Personal Fees; Partner Therapeutics: Other: Personal Fees; Pfizer: Other, Research Funding; CSL Behring: Other; Tolero Pharmaceuticals: Research Funding; Oncoceutics: Other: Drug support for a trial; Partnership for health analytic research, LLC: Other: Personal Fees; Omeros: Other: Personal Fees; Abbvie: Other: Personal Fees, Research Funding. Saad:Orcabio: Other: research support; Kadmon: Other: research support; Amgen: Other: research support; Incyte Pharmaceuticals: Other: Personal Fees; Magenta Therapeutics: Other: Personal Fees. Copelan:Amgen: Membership on an entity's Board of Directors or advisory committees. Defilipp:Incyte: Research Funding; Regimmune: Research Funding; Syndax Pharmaceuticals: Consultancy. Nishihori:Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Weisdorf:Incyte: Research Funding; FATE Therapeutics: Consultancy.

Chronic graft-versus-host disease (GVHD) is one of most common complications following allogeneic hematopoietic cell transplantation (HCT) and the most significant contributor to morbidity and nonrelapse mortality. The physical burdens and psychosocial difficulties of these patients have not been described systematically. An exploration into the rates and correlates of mood and quality of life (QOL) in patients with chronic GVHD is necessary to develop a clinically relevant, evidence-based intervention to promote well-being. From July 2015 to July 2017, adult allogeneic HCT survivors with established moderate to severe chronic GVHD (N = 52) enrolled in a prospective, longitudinal study at a tertiary academic center. We examined the rates and correlates of depression and anxiety symptoms (Hospital Anxiety and Depression Scale) and explored whether constructs including coping strategies (Coping Inventory for Stressful Situations), symptom burden (Lee Symptom Assessment Scale), physical functioning (Human Activity Profile), and perceived social support (Medical Outcomes Study Social Support Survey) predicted QOL trajectory over time (Functional Assessment of Cancer Therapy-Bone Marrow Transplant) at the baseline, 3-month, and 6-month follow-up. Analyses adjusted for age, sex, chronic GVHD severity, and time since chronic GVHD diagnosis. At the baseline, 3-month, and 6-month follow-up, 32.7%, 31.1%, and 37.8% of patients reported clinically significant depression symptoms, and 30.8%, 20.0%, and 36.4% reported clinically elevated anxiety symptoms, respectively. Adjusting for covariates, greater use of negative emotion-oriented coping (β = 0.20, P = .002), less use of task-oriented coping (β = -0.10, P = .021), worse physical functioning (β = -0.07, P = .004), and higher symptom burden (β = 0.07, P = .002) were independently associated with depression symptoms at baseline. Greater use of negative emotion-oriented coping (β = 0.28, P.001) and worse physical functioning (β = -0.05, P = .034) were independently associated with anxiety at baseline. Patients who used more negative emotion-oriented coping (β = -0.58, P = .035), had less task-oriented (β = 0.40, P = .028) and social diversion-oriented coping (β = 0.35, P = .039), and had higher symptom burden (β = -0.30, P = .001), worse physical functioning (β = 0.32, P.001), and lower perceived social support (β = 6.47, P = .003) at baseline reported poorer QOL over time. The unmet physical and psychosocial needs of patients with chronic GVHD are substantial and warrant investigation into evidence-based interventions that may improve QOL and mood by targeting modifiable psychosocial constructs identified in this study.

We present a single-center retrospective series of allogeneic bone marrow transplantation (BMT) with the use of posttransplant cyclophosphamide (PTCy) in the setting of nonmalignant hematological conditions. Nine patients were treated between 2013 and 2019. Nonmyeloablative conditioning consisted of antithymocyte globulin, fludarabine, low-dose cyclophosphamide, and total body irradiation (200cGy) followed by allogeneic bone marrow infusion. Post-BMT GVHD prophylaxis was with PTCy, tacrolimus, and mycophenolate mofetil. At a median follow-up of 24 months (range 4, 63), all patients are alive, with donor-derived hematopoiesis and free of significant acute or chronic GVHD. Donors were haploidentical (n = 6), fully matched unrelated (n = 2), and fully matched sibling (n = 1). Neutrophil and platelet engraftment occurred at a median of 21 days and 33 days, respectively, after transplantation. Three patients (3/9, 33%) experienced stage 1-2 acute skin GVHD. The only cases of chronic GVHD are in three patients (3/9, 33%) with ocular disease (two mild, one moderate). No patient has required systemic immunosuppression beyond 12 months after BMT. PTCy-based nonmyeloablative allogeneic BMT is safe and effective for nonmalignant hematologic conditions and should be prospectively compared with historical regimens.

At Massachusetts General Hospital, we pioneered simultaneous hematopoietic cell (HCT)/kidney transplantation from HLA-identical related donors for the treatment of hematological malignancies with end-stage renal failure. We have now extended this to HLA-haploidentical donors in a pilot trial. Six recipients, 5 of whom were conditioned with fludarabine, cyclophosphamide, and total-body irradiation, underwent combined HCT/kidney transplantation from haploidentical donors; graft-versus-host disease (GVHD) prophylaxis included post-HCT cyclophosphamide, tacrolimus, and mycophenolate mofetil. One patient died as a result of complications of fludarabine neurological toxicity. No neurological toxicity was observed in subsequent patients who received lower fludarabine doses and more intense postfludarabine dialysis. There were no cases of grade 2 to 4 acute GVHD and 1 case of moderate chronic GVHD by 12 months. One patient experienced relapse of multiple myeloma at 30 months after HCT and died 4 years posttransplantation. Overall, 4 of 6 patients remain alive, without disease relapse and with long-term renal rejection–free survival. This trial was registered at www.clinicaltrials.gov as #NCT01758042.

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

We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31%) and 110 (29%), respectively. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4% (95% confidence interval [CI], 5.8% to 7.0%) in adults, compared with 1.8% (95% CI, 1.4% to 2.3%) in pediatric subjects; P < .001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95% CI, 1.33 to 7.32), 3.86 (95% CI, 1.66 to 8.95), and 5.49 (95% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD. ispartof: BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION vol:25 issue:2 pages:362-368 ispartof: location:United States status: published

Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML), have a poor prognosis. An earlier Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 868 allogeneic hematopoietic cell transplantations (allo-HCTs) performed between 1990 and 2004 showed a 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%, respectively. Modern supportive care, graft-versus-host disease prophylaxis, and reduced-intensity conditioning (RIC) regimens have led to improved outcomes. Therefore, the CIBMTR analyzed 1531 allo-HCTs performed in adults with t-MDS (n = 759) or t-AML (n = 772) between and 2000 and 2014. The median age was 59 years (range, 18 to 74 years) for the patients with t-MDS and 52 years (range, 18 to 77 years) for those with tAML. Twenty-four percent of patients with t-MDS and 11% of those with t-AML had undergone a previous autologous (auto-) HCT. A myeloablative conditioning (MAC) regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Nonrelapse mortality at 5 years was 34% (95% confidence interval [CI], 30% to 37%) for patients with t-MDS and 34% (95% CI, 30% to 37%) for those with t-AML. Relapse rates at 5 years in the 2 groups were 46% (95% CI, 43% to 50%) and 43% (95% CI, 40% to 47%). Five-year OS and DFS were 27% (95% CI, 23% to 31%) and 19% (95% CI, 16% to 23%), respectively, for patients with t-MDS and 25% (95% CI, 22% to 28%) and 23% (95% CI, 20% to 26%), respectively, for those with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low-risk t-MDS and those with t-AML undergoing HCT with MAC while in first complete remission, but worse for those with previous auto-HCT, higher-risk cytogenetics or Revised International Prognostic Scoring System score, and a partially matched unrelated donor. Relapse remains the major cause of treatment failure, with little improvement seen over the past 2 decades. These data mandate caution when recommending allo-HCT in these conditions and indicate the need for more effective antineoplastic approaches before and after allo-HCT. (C) 2021 Published by Elsevier Inc. on behalf of The American Society for Transplantation and Cellular Therapy.