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Contains fulltext : 293484.pdf (Publisher’s version ) (Open Access) From 2016 EBMT and JACIE developed an international risk-adapted benchmarking program of haematopoietic stem cell transplant (HSCT) outcome to provide individual EBMT Centers with a means of quality-assuring the HSCT process and meeting FACT-JACIE accreditation requirements relating to 1-year survival outcomes. Informed by previous experience from Europe, North America and Australasia, the Clinical Outcomes Group (COG) established criteria for patient and Center selection, and a set of key clinical variables within a dedicated statistical model adapted to the capabilities of the EBMT Registry. The first phase of the project was launched in 2019 to test the acceptability of the benchmarking model through assessment of Centers' performance for 1-year data completeness and survival outcomes of autologous and allogeneic HSCT covering 2013-2016. A second phase was delivered in July 2021 covering 2015-2019 and including survival outcomes. Reports of individual Center performance were shared directly with local principal investigators and their responses were assimilated. The experience thus far has supported the feasibility, acceptability and reliability of the system as well as identifying its limitations. We provide a summary of experience and learning so far in this 'work in progress', as well as highlighting future challenges of delivering a modern, robust, data-complete, risk-adapted benchmarking program across new EBMT Registry systems. 01 juni 2023

COVID-19 has significantly impacted the practice of hematopoietic cell transplantation (HCT) and likely affected outcomes of HCT recipients. Early reports document substantially higher case fatality rates for HCT recipients than seen in faced by the general population. Currently we do not have a clear picture of how much of this threat is present within the first year after HCT and how infection rates and outcomes vary with time after HCT. There are important because center-specific survival estimates for reporting purposes focus on 1-year post-HCT mortality. Transplantation centers have dramatically changed their practices in response to the pandemic. At many centers, quality assurance processes and procedures were disrupted, changes that likely affected team performance. Centers have been affected unevenly by the pandemic through time, location, and COVID-19 burdens. Assessment of center-specific survival depends on the ability to adjust for risk factors, such as COVID-19, that are outside center control using consistent methods so that team performance based on controllable risk factors can be ascertained. The Center for International Blood and Marrow Transplantation Research (CIBMTR) convened a working group for the 2020 Center Outcomes Forum to assess the impact of COVID-19 on both patient-specific risks and center-specific performance. This committee reviewed the factors at play and developed recommendations for a process to determine whether adjustments in the methodology to assess center-specific performance are needed.

Background The association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes. Methods This study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied. Results The median age was 55 years (range, 18-83 years). The median PCS was -0.21 (range, -1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was -0.13 (range, -1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM. Conclusions Patients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.

Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.

With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P = .01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P = .0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia.

Preclinical research shows that stress-induced activation of the sympathetic nervous system can promote hematopoietic malignancies via β-adrenoreceptor–mediated molecular pathways. Hematopoietic cell transplant (HCT) recipients exposed to conditions of chronic stress show activation of a conserved transcriptional response to adversity (CTRA) gene expression profile, which in turn is associated with increased relapse and decreased disease-free survival. We conducted a randomized controlled phase 2 biomarker trial testing the impact of the nonselective β-antagonist propranolol on CTRA-related gene expression of 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for 1 week prior to and 4 weeks following HCT. Blood was collected at baseline, day −2, and day +28. Intention-to-treat analyses controlling for demographic characteristics, high-risk disease (International Myeloma Working Group risk score), and tumor stage tested effects on a 53-gene CTRA indicator profile and measures of CTRA-related cellular processes in peripheral blood mononuclear cells. Twelve participants were randomized to the intervention and 13 to the control. Relative to the control group, propranolol-treated patients showed greater decreases from baseline to HCT day −2 and day +28 for both CTRA gene expression (P = .017) and bioinformatic measures of CD16− classical monocyte activation (P = .005). Propranolol-treated patients also showed relative upregulation of CD34+ cell–associated gene transcripts (P = .011) and relative downregulation of myeloid progenitor–containing CD33+ cell–associated gene transcripts (P = .001). Ancillary analyses identified nonsignificant trends toward accelerated engraftment and reduced posttransplant infections in propranolol-treated patients. Peri-HCT propranolol inhibits cellular and molecular pathways associated with adverse outcomes. Changes in these pathways make propranolol a potential candidate for adjunctive therapy in cancer-related HCT.

Allogeneic hematopoietic cell transplantation (alloHCT) is a highly specialized procedure. We surveyed adult transplant centers in the United States (US) and then used data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) (2008–2010) to evaluate associations of center volume, infrastructure, and care delivery models with survival post alloHCT. Based on their 2010 alloHCT volume, centers were categorized as low-volume (≤40 alloHCTs; N = 42 centers, 1900 recipients) or high-volume (>40 alloHCTs; N = 41 centers, 9637 recipients). 100-day survival was 86% (95% CI, 85–87%) in high-volume compared with 83% (95% CI, 81–85%) in low-volume centers (difference 3%; P

Because medical illness is associated with increased inflammation and an increased risk for treatment-resistant major depressive disorder, anti-cytokine therapy may represent a novel, and especially efficacious, treatment for depression. We hypothesized that blockade of the interleukin (IL)-6 signaling pathway with tocilizumab would decrease depression and related symptomatology in a longitudinal cohort of allogeneic hematopoietic stem cell transplantation (HCT) patients, a medically ill population with a significant inflammation and psychopathology. Patients undergoing allogeneic HCT received either a single dose of tocilizumab one day prior to HCT (n = 25), or HCT alone (n = 62). The primary outcome included depressive symptoms at 28 days post HCT; anxiety, fatigue, sleep, and pain were assessed at pretreatment baseline and days +28, +100, and +180 post HCT as secondary outcomes. Multivariate regression demonstrated that preemptive treatment with tocilizumab was associated with significantly higher depression scores at D28 vs. the comparison group (β = 5.74; 95% CI 0.75, 10.73; P = 0.03). Even after adjustment for baseline depressive symptoms, propensity score, and presence of acute graft-versus-host disease (grades II–IV) and other baseline covariates, the tocilizumab-exposed group continued to have significantly higher depression scores compared to the nonexposed group at D28 (β = 4.73; 95% CI 0.64, 8.81; P = 0.02). Despite evidence that IL-6 antagonism would be beneficial, blockade of the IL-6 receptor with tocilizumab among medically ill patients resulted in significantly more—not less—depressive symptoms.

Hematopoietic cell transplantation (HCT) is a well-established treatment to control and/or cure many malignant and non-malignant diseases involving the hematopoietic system and some solid tumors. We report information about HCT procedures performed in the United States (US) in 2018 and analyze trends and outcomes of HCT as reported to the Center for International Blood and Marrow Transplant Research® (CIBMTR®). Overall, compared to 2017, the numbers of allogeneic transplant in the US increased by 1% and numbers of autologous transplants decreased by 5%. Key findings are fewer autologous transplants performed for non-Hodgkin lymphoma and increasing numbers of haploidentical transplants, nearly all of which use post-transplant cyclophosphamide for graft-versus-host disease prophylaxis. There is a continuing increase in transplantations in adults older than 70 years, particularly for acute myeloid leukemia and myelodysplastic syndromes. Survival rates by disease, disease stage, donor type and age are presented. This report, prepared annually by the CIBMTR, provides a snapshot of current transplant activity in the US.

The importance of patient-reported outcomes (PROs) in cellular therapies, including hematopoietic cell transplantation (HCT) is highlighted in this study. Longitudinal collection of PROs in a registry is recommended for several reasons, yet to date, PROs are not routinely collected from HCT patients to augment clinical registry data. The aim of this study was to determine the feasibility of electronic PRO data collection by a national clinical outcomes registry, by assessing differences between who does and does not report PROs. We conducted a cross-sectional pilot collection of PROs from HCT recipients after treatment using computer-adapted tests from the Patient-Reported Outcome Measurement Information System (PROMIS). We implemented centralized data collection through the Center for International Blood and Marrow Transplant Research (CIBMTR) among patients who underwent HCT for myelodysplastic syndromes (MDS), were at least 6 months post-HCT, and spoke English or Spanish. The main objective was identifying patient, disease, and transplant-related differences associated with completion of electronic PROs. Patients were excluded from analysis if they were determined to be ineligible (deceased, did not speak English or Spanish, refused to be contacted by the CIBMTR). A total of 163 patients were contacted and potentially eligible to participate; of these, 92 (56%) enrolled and 89 (55%) completed the PRO assessment. The most frequent reason for incomplete surveys was inability to contact patients (n = 88), followed by declining to participate in the study (n = 37). There were no sociodemographic or age differences between those who completed the PRO survey (n = 89) and eligible nonresponders (n = 155). Patient scores were within 3 points of the US average of 50 for all symptoms and areas of function except physical functioning. Responders and nonresponders did not exhibit meaningfully different sociodemographic characteristics. Difficulty contacting patients posed the greatest barrier and also provided the greatest opportunity for improvement. Once enrolled, survey completion was high. These results support standardizing centralized PRO data collection through the CIBMTR registry.

Background Exposures to DNA-damaging drugs and ionizing radiations increase risks of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods 9028 recipients of hematopoietic cell autotransplants (1995–2010) for Hodgkin lymphoma (HL; n = 916), non-Hodgkin lymphoma (NHL; n = 3546) and plasma cell myeloma (PCM; n = 4566), reported to the CIBMTR, were analyzed for risk of subsequent AML or MDS. Results 335 MDS/AML cases were diagnosed posttransplant (3.7%). Variables associated with an increased risk for AML or MDS in multivariate analyses were: (1) conditioning with total body radiation versus chemotherapy alone for HL (HR = 4.0; 95% confidence interval [1.4, 11.6]) and NHL (HR = 2.5 [1.1, 2.5]); (2) ≥3 versus 1 line of chemotherapy for NHL (HR = 1.9 [1.3, 2.8]); and (3) subjects with NHL transplanted in 2005–2010 versus 1995–1999 (HR = 2.1 [1.5, 3.1]). Using Surveillance, Epidemiology and End Results (SEER) data, we found risks for AML/MDS in HL, NHL and PCM to be 5–10 times the background rate. In contrast, relative risks were 10–50 for AML and approximately 100 for MDS in the autotransplant cohort. Conclusions There are substantial risks of AML and MDS after autotransplants for HL, NHL and PCM.

Unlike unrelated donor registries, transplant centers lack uniform approaches to related donor assessment and deferral. To test whether related donors are at increased risk for donation-related toxicities, we conducted a prospective observational trial of 11,942 related and unrelated donors aged 18-60 years. Bone marrow (BM) was collected at 37 transplant and 78 National Marrow Donor Program centers, and peripheral blood stem cells (PBSC) were collected at 42 transplant and 87 unrelated donor centers in North America. Possible presence of medical comorbidities was verified prior to donation, and standardized pain and toxicity measures were assessed pre-donation, peri-donation, and one year following. Multivariate analyses showed similar experiences for BM collection in related and unrelated donors; however, related stem cell donors had increased risk of moderate [odds ratios (ORs) 1.42; P

T cell–replete post-transplant cyclophosphamide (PTCy)-based protocols have led to increasing use of haploidentical allogeneic hematopoietic cell transplantation (haploHCT). With this approach, bidirectional alloreactivity causing nonengraftment or severe graft-versus-host disease (GVHD) is no a longer major barrier to haploHCT. PTCy eliminates alloreactive lymphocytes but spares CD34+ stem cells and regulatory T lymphocytes, resulting in reliable hematopoietic recovery with relatively low incidence of GVHD. The immediate post-haploHCT course, usually before PTCy administration, is often complicated by cytokine release syndrome (CRS). The predictors of CRS and its effect on outcomes post-transplant have not been fully ascertained. We analyzed the outcomes of 66 patients who received haploHCT at our institution. Using published CRS criteria we identified 48 patients who developed CRS. In multivariate analysis peripheral blood grafts were significantly associated with grade ≥ 2 CRS, compared with bone marrow. Grade ≥ 2 CRS (compared with grade

Significant advances in hematopoietic cell transplantation (HCT) have increased the long-term survivorship of its recipients, but because of unique complications arising from radiation and chemotherapy, recipients require lifelong follow-up. To evaluate current survivorship or long-term follow-up (LTFU) clinics specifically for HCT survivors and to evaluate the potential barriers in their establishment, the American Society for Blood and Marrow Transplantation (ASBMT) Practice Guidelines Committee electronically surveyed 200 HCT programs to gather quantitative and qualitative data about models of care. Among 77 programs (38.5%) that responded, 45% indicated presence of an LTFU clinic; however, LTFU care models varied with respect to services provided, specialist availability, type of patients served, and staffing. Among 55% of programs without an LTFU clinic, 100% agreed that allogeneic HCT survivors have unique needs separate from graft-versus-host disease and that complications could arise during the transition of care either from pediatric to adult settings or away from the HCT center. Lack of expertise, logistics, financial issues, and the observation that 84% of individual practitioners prefer to provide survivorship care were the identified obstacles to establishing new LTFU clinics. The ASBMT hopes that policymakers, HCT providers, and institutions will benefit from the results of this survey and recommends that delivering guidelines-driven screening and expert management of late effects is the goal of first-rate HCT survivorship care.

We conducted a phase 2 study in which patients undergoing allogeneic hematopoietic stem cell transplantation received tocilizumab in addition to standard immune suppression with tacrolimus and methotrexate for graft-versus-host disease prophylaxis. Thirty-five patients were enrolled between January 2015 and June 2016. The median age of the cohort was 66 (range: 22-76). All patients received busulfan-based conditioning, and were transplanted with human leukocyte antigen-matched related or matched unrelated bone marrow or peripheral stem cell grafts. The cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease were 14% (95% CI 5-30) and 3% (95% CI 0-11) at day 100, and 17% (95% CI 7-31) and 6% (95% CI 1-16) at day 180, respectively. Notably, there were no cases of graft-versus-host disease of the lower gastrointestinal tract within the first 100 days. A comparison to 130 matched controls who only received tacrolimus and methotrexate demonstrated a lower cumulative incidence of grades II-IV acute graft-versus-host disease (17% versus 45%, P=0.003) and a significant increase in grades II-IV acute graft-versus-host disease-free survival at six months (69% versus 42%, P=0.001) with tocilizumab, tacrolimus and methotrexate, which was the primary endpoint of the study. Immune reconstitution was preserved in patients treated with tocilizumab, tacrolimus and methotrexate, as T-cell and B-cell subsets recovered to near normal levels by 6-12 months post-transplantation. We conclude that tocilizumab has promising activity in preventing acute graft-versus-host disease, particularly in the lower gastrointestinal tract, and warrants examination in a randomized setting.

Idiopathic pneumonia syndrome (IPS) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT) that typically occurs within the first 100 days after transplantation. Tumor necrosis factor α (TNF-α) has been shown to be a key mediator of IPS, and the TNF-α binding protein etanercept appeared to improve IPS outcomes in small retrospective and prospective studies. IPS also has been observed to occur later (100 days) after HSCT; however, little is known about the disease course and whether a TNF-α-based therapeutic strategy is efficacious in these patients. To address this question, we performed a retrospective analysis of 23 patients who underwent HSCT between 2004 and 2016 at our institution who developed late-onset IPS and received treatment with etanercept and high-dose corticosteroids (CS). Ten of the 23 patients (43%) attained a complete clinical response to etanercept and CS. Responses were significantly more likely to occur in patients who did not require positive pressure ventilation at the time of diagnosis. Those who responded experienced a durable survival benefit, with a 2-year overall survival of 67%. In the 13 patients (57%) who did not respond to etanercept and CS, the median overall survival was only 13 days (range, 1 to 60 days). The difference in 2-year overall survival between responders and nonresponders was statistically significant (67% versus 0%; P .001). These results indicate that late-onset IPS carries high mortality, but that treatment with etanercept and CS has activity and can result in long-term survival in some patients. Prompt diagnosis and early institution of therapy before the need for advanced respiratory support is critical for maximizing responses.

BACKGROUND Allogeneic hematopoietic cell transplantation (HCT) cures many patients, but often with the risk of late effects and impaired quality of life. The value of quantifying patient-reported outcomes (PROs) is increasingly being recognized, but the routine collection of PROs is uncommon. This study evaluated the feasibility of prospective PRO collection by an outcome registry at multiple time points from unselected HCT patients undergoing transplantation at centers contributing clinical data to the Center for International Blood and Marrow Transplant Research (CIBMTR), and then it correlated the PRO data with clinical and demographic data. METHODS The Functional Assessment of Cancer Therapy–Bone Marrow Transplant (FACT-BMT), 36-Item Short Form Health Survey (SF-36), and Pediatric Quality of Life Inventory measures were administered before HCT, on day 100, and at 6 and 12 months. Patients were recruited by the transplant center, but posttransplant PRO collection was managed centrally by the CIBMTR. RESULTS There were 580 eligible patients, and 390 (67%) enrolled. Feasibility was shown by high time-specific retention rates (176 of 238 at 1 year or 74%) and participant satisfaction. Factors associated with higher response rates were an age > 50 years (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.03-2.41; P = .0355), white race (OR, 4.61; 95% CI, 2.66-7.99; P

Atorvastatin administration to both the donors and recipients of matched related donor (MRD) allogeneic hematopoietic cell transplantation (allo-HCT) as acute graft-versus-host disease (GVHD) prophylaxis has been shown to be safe and effective. However, its efficacy as acute GVHD prophylaxis when given only to allo-HCT recipients is unknown. We conducted a phase II study to evaluate the safety and efficacy of atorvastatin-based acute GVHD prophylaxis given only to the recipients of MRD (n = 30) or matched unrelated donor (MUD) (n = 39) allo-HCT, enrolled in 2 separate cohorts. Atorvastatin (40 mg/day) was administered along with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. All patients were evaluable for acute GVHD. The cumulative incidences of grade II to IV acute GVHD at day +100 in the MRD and MUD cohorts were 9.9% (95% confidence interval [CI], 0 to 20%) and 29.6% (95% CI,15.6% to 43.6%), respectively. The cumulative incidences of grade III and IV acute GVHD at day +100 in the MRD and MUD cohorts were 3.4% (95% CI, 0 to 9.7%) and 18.3% (95% CI, 6.3% to 30.4%), respectively. The corresponding rates of moderate/severe chronic GVHD at 1 year were 28.1% (95% CI, 11% to 45.2%) and 38.9% (95% CI, 20.9% to 57%), respectively. In the MRD cohort, the 1-year nonrelapse mortality, relapse rate, progression-free survival, and overall survival were 6.7% (95% CI, 0 to 15.4%), 43.3% (95% CI, 24.9% to 61.7%), 50% (95% CI, 32.1% to 67.9%), and 66.7% (95% CI, 49.8% to 83.6%), respectively. The respective figures for the MUD cohort were 10.3% (95% CI, 8% to 19.7%), 20.5% (95% CI, 7.9% to 33.1%), 69.2% (95% CI, 54.7% to 83.7%), and 79.5% (95% CI, 66.8% to 92.2%), respectively. No grade 4 toxicities attributable to atorvastatin were seen. In conclusion, the addition of atorvastatin to standard GVHD prophylaxis in only the recipients of MRD and MUD allo-HCT appears to be feasible and safe. The preliminary efficacy seen here warrants confirmation in randomized trials.

BackgroundClinical outcomes among allogeneic hematopoietic cell transplant (HCT) recipients are negatively affected by low socioeconomic status (SES), yet the biological mechanisms accounting for this health disparity remain to be elucidated. Among unrelated donor HCT recipients with acute myelogenous leukemia, one recent pilot study linked low SES to increased expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA) in peripheral blood mononuclear cells, which involves up-regulation of pro-inflammatory genes and down-regulation of genes involved in type I interferon response and antibody synthesis.MethodsThis study examined these relationships using additional measures in a larger archival sample of 261 adults who received an unrelated donor HCT for acute myelogenous leukemia to 1) identify cellular and molecular mechanisms involved in SES-related differences in pre-transplant leukocyte transcriptome profiles, and 2) evaluate pre-transplant CTRA biology associations with clinical outcomes through multivariable analysis controlling for demographic-, disease-, and transplant-related covariates.ResultsLow SES individuals showed increases in classic monocyte activation and pro-inflammatory transcription control pathways as well as decreases in activation of nonclassic monocytes, all consistent with the CTRA biological pattern. Transplant recipients in the highest or lowest quartiles of the CTRA pro-inflammatory gene component had a more than 2-fold elevated hazard of relapse (hazard ratio [HR] = 2.47, 95% confidence interval [CI] = 1.44 to 4.24), P = .001; HR = 2.52, 95% CI = 1.46 to 4.34, P = .001) and more than 20% reduction in leukemia-free survival (HR = 1.57, 95% CI = 1.08 to 2.28, P = .012; HR = 1.49, 95% CI = 1.04 to 2.15, P = .03) compared with the middle quartiles.ConclusionsThese findings identify SES- and CTRA-associated myeloid- and inflammation-related transcriptome signatures in recipient pre-transplant blood samples as a potential novel predictive biomarker of HCT-related clinical outcomes.

Although donation of bone marrow (BM) or peripheral blood stem cells (PBSCs) from children to family members undergoing allogeneic transplantation are well-established procedures, studies detailing levels of pain, symptoms, and long-term recovery are lacking. To address this lack, we prospectively enrolled 294 donors age 20% of females and males age 13 to 17 years do not return to baseline pain levels by 1 year after BM donation. Studies aimed at decreasing symptoms and improving recovery in older children are warranted.

The development of reduced-intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RDs) of peripheral blood stem cells (PBSCs). The effects of age on donation efficacy, toxicity, and long-term recovery in RDs are poorly understood. To address this we analyzed hematologic variables, pain, donation-related symptoms, and recovery in 1211 PBSC RDs aged 18 to 79 enrolled in the Related Donor Safety Study. RDs aged > 60 had a lower median CD34+ level before apheresis compared with younger RDs (age > 60, 59 × 106/L; age 41 to 60, 81 × 106/L; age 18 to 40, 121 × 106/L; P < .001). This resulted in older donors undergoing more apheresis procedures (49% versus 30% ≥ 2 collections, P < .001) and higher collection volumes (52% versus 32% > 24 L, P < .001), leading to high percentages of donors aged > 60 with postcollection thrombocytopenia

This secondary analysis of a large, multicenter Blood and Marrow Transplant Clinical Trials Network randomized trial assessed whether patient-reported outcomes (PROs) and socioeconomic status (SES) before hematopoietic stem cell transplantation (HCT) are associated with each other and predictive of clinical outcomes, including time to hematopoietic recovery, acute graft-versus-host disease, hospitalization days, and overall survival (OS) among 646 allogeneic and autologous HCT recipients. Pretransplantation Cancer and Treatment Distress (CTXD), Pittsburgh Sleep Quality Index (PSQI), and mental and physical component scores of the Short-Form 36 were correlated with each other and with SES variables. PROs and SES variables were further evaluated as predictors of clinical outcomes, with the PSQI and CTXD evaluated as OS predictors (P

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

Background CIBMTR previously showed that centralized PRO collection from patients treated at multiple transplant centers (TC) was feasible; however, consenting by sites and the paper mode of collection were logistically challenging. CIBMTR built an electronic system (ePRO), and we report our initial experience. Methods This was a cross-sectional study of patients ≥55 years old with MDS who underwent allogeneic transplant. Additional inclusion criteria were: ≥6 months from transplant, English/Spanish speaking, an active email address. Lists of potentially eligible patients were sent to TCs to confirm eligibility and provide contact details. All further patient contact (email/phone) was then made by the CIBMTR Survey Research Group (SRG). SRG contacted patients by phone to describe the study, then obtained consent electronically. PRO measures were delivered using computerized adaptive testing (CAT). Results TCs provided contact information on 188/273 (69%) potentially eligible patients. The biggest reason for lack of confirmation of eligibility was an inability by the TC to contact the patient (Figure 1). Of the 188, SRG contacted and confirmed eligibility in 164 (87%). 90/164 (55%) enrolled, and 80 (89%) have completed PROs. A median time of 15 minutes (IQR 11.3-20.7) was required for PRO completion. 62 patients did not enroll: 28 lost to follow-up after initial contact and 34 actively declined to participate. Reasons for declining to participate included: lack of interest in research, technology issues, health reasons and study specific concerns. SRG made fewer contact attempts for those who participated (Table 1). Conclusions We show that while the ePRO system is an efficient mechanism to consent patients and collect PRO, many patients do not reach the enrollment stage. The biggest reason for this is lack of initial or subsequent contact, which was noted at every stage (both TC and SRG). It is unknown whether this is due to passive decline by the patient, or to incorrect contact details. Additionally, relying on the TC to provide contact details (engaging TCs as IRB approved-research sites) was time-consuming and inefficient. CIBMTR has moved to central IRB study approval, and begun to collect contact details proactively, achieving a truly centralized mechanism which should allow CIBMTR to establish contact with patients early in the transplant process. Maintaining engagement through the ePRO may help to address ongoing logistic challenges.

Allogeneic hematopoietic cell transplantation (allo-HCT) with reduced-intensity conditioning (RIC) is commonly performed as an inpatient procedure. The feasibility and outcomes of RIC allo-HCT in the outpatient setting is not known. We performed a single-center retrospective cohort study of patients aged ≥ 18years with hematologic malignancies who underwent RIC allo-HCT either in the inpatient or outpatient setting. Donor types included HLA-matched sibling and well-matched unrelated donors. The objectives were to compare the survival, complications, charges, and incidences of relapse, nonrelapse mortality (NRM), and acute and chronic graft-versus-host disease (GVHD) between the 2 groups. Between 2014 and 2017, 151 eligible patients were included, with 116 undergoing RIC allo-HCT in the inpatient setting and 35 patients undergoing RIC allo-HCT in the outpatient setting. Baseline characteristics were comparable between the 2 groups except for a higher proportion of patients with myeloma in the outpatient cohort (inpatient 15.5% versus outpatient 37.1%). The cumulative incidence of grades II to IV acute GVHD (inpatient 25.2% versus outpatient 25.7%), grades III to IV acute GVHD (inpatient 10.4% versus outpatient 8.5%), chronic GVHD (inpatient 38.3% versus outpatient 51.6%), NRM at 1 year (inpatient 10.8% versus outpatient 3.2%), and relapse (inpatient 24.8% versus outpatient 33.2%) did not significantly differ between the 2 cohorts. One-year progression-free survival (inpatient 64.4% versus outpatient 63.6%, P = .39) and overall survival (inpatient 73.8% versus outpatient 82.8%, P = .93) were also not significantly different between the 2 groups. The proportion of patients who developed neutropenic fever (inpatient 25.8% versus outpatient 8.5%, P = .03) and mucositis (inpatient 50.8% versus outpatient 8.5%, P.001) and who required total parenteral nutrition (inpatient 20.6% versus outpatient 5.7%, P = .04) were more frequent in the inpatient cohort. About 51.5% of the outpatient cohort never required hospital admission in the first 100days. Outpatient HCT resulted in significantly lower charges than inpatient HCT in the first 100days (median charges: inpatient $339,621 versus outpatient $247,334; P.001). On multivariate analysis the site of the HCT (outpatient versus inpatient) was not a significant predictor of either overall or progression-free survival. Outpatient RIC allo-HCT is feasible and safe with daily outpatient evaluation and aggressive supportive care resulting in outcomes comparable with those who received the transplant in the inpatient setting.

PURPOSE: This study aimed to develop a survivorship care plan (SCP) that could be individualized to facilitate long-term follow-up care of hematopoietic cell transplantation (HCT) survivors. METHODS: A sample SCP was developed that included two documents- a treatment summary and preventive care recommendations that combined data on treatment exposures routinely submitted by HCT centers to the Center for International Blood and Marrow Transplant Research (CIBMTR) with long-term follow-up guidelines. Focus groups were conducted by phone to characterize the critical patient-centered elements of the SCP. Focus group eligibility criteria included: 1) adult patients >1 year post-HCT and their caregivers (3 groups, n=22); 2) HCT physicians and advanced practice providers (APPs) (2 groups, n=14); 3) HCT nurses/social workers (4 groups, n=17), and 4) community health care professionals (3 groups, n=24). Transcripts were analyzed for saturation of key themes using NVivo 10 software. RESULTS: Patients/caregivers suggested combining the treatment summary and care guidelines into one document. They also requested sections on sexual and emotion health and the immune system. Providers wanted the treatment summary to focus only on what they absolutely must know. Themes were similar across healthcare professionals, though screening for psychosocial issues was emphasized more by the nurses/social workers. All preferred to receive the SCP electronically; however, hardcopy was considered necessary for some patients. All felt the SCP would facilitate appropriate post-HCT care. CONCLUSION: This study highlighted the need for an SCP instrument to facilitate HCT survivorship care. Furthermore, it demonstrated the feasibility and value of engaging HCT patients, caregivers and providers in developing a survivorship care tool. Their feedback was incorporated into a final SCP subsequently tested in a randomized trial.

To study the factors associated with poorer health-related quality of life at 1-year post-allogeneic hematopoietic cell transplantation (alloHCT), a secondary analysis of a prospective feasibility study was performed. Pediatric Quality of Life Inventory questionnaires were collected in 76 children undergoing alloHCT at baseline (within 30 d before transplantation), day 100, 6 months, and 12 months posttransplantation. The global score improved post-HCT (baseline: 67.1, 12 mo: 76.6). Females (odds ratio, 6.5; 95% confidence interval, 1.002-42.17; P=0.04) and patients with low baseline scores (odds ratio, 7.2; 95% confidence interval, 1.07-48.63; P=0.04) had lower scores at 12 months post-HCT and suggest a target group for early interventions such as physical exercise, stress management, and cognitive behavior therapy.

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

Background Chronic GVHD (cGVHD) causes significant morbidity and mortality after alloHCT. Oral proteasome inhibitor, ixazomib (Ixa) regulates dendritic cell maturation, decreases proinflammatory cytokines and modulates GVHD in murine model. The efficacy of Ixa in preventing cGVHD is unknown. Methods We report here a phase 1/2 trial (NCT02250300) evaluating safety and efficacy of Ixa for cGVHD prophylaxis. Adult hematologic malignancy patients (pts) status post a peripheral blood (PB) alloHCT with tacrolimus/methotrexate-based GVHD prophylaxis and no grade 3-4 aGVHD or steroid-refractory aGVHD were eligible. Recipients of matched related donor (MRD) and matched unrelated donor (MUD) alloHCT were enrolled in 2 independent cohorts. In vivo and ex vivo T-cell depletion was not permitted. Oral Ixa was started days 60-90 post-HCT for 4 weekly doses. Primary outcome was cumulative incidence (CI) of cGVHD at 1-yr by NIH criteria. The cGVHD was graded by an Independent Review Panel (IRP). Results No dose-limiting toxicities were seen in phase I and recommended phase II dose was 4 mg. 25 MRD and 26 MUD alloHCT pts were enrolled. The IRP assessed CI of cGVHD at 1-yr was 31% and 37% in MRD and MUD cohorts, respectively. The respective figures for moderate-severe cGVHD were 22% and 28%. 1-yr non-relapse mortality and relapse in MRD and MUD cohorts were 0% and 4% and 20% and 35%, respectively. 1-yr PFS of 80% and 64% and 1-year OS of 92% and 88% were seen in MRD and MUD cohorts, respectively. Serum B-cell activating factor (BAFF) levels before and after Ixa exposure increased significantly in pts who did not develop cGVHD (median, 2459 vs. 6969 pg/mL, p=.001), and in those without moderate/severe cGVHD (median, 2989 vs. 6438 pg/mL, p=.002). Treg counts before and after Ixa (median, 34 vs. 34.5/µL) for the overall cohort were similar. Conclusion Ixa is feasible, safe and potentially effective for cGVHD prophylaxis after PB alloHCT. BAFF level after Ixa may serve as a biomarker for later development of cGVHD.

Purpose: Low socioeconomic status (SES) is associated with adverse outcomes among unrelated donor hematopoietic stem cell transplant (HCT) recipients, but the biologic mechanisms contributing to this health disparity are poorly understood. Therefore, we examined whether social environment affects expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA), which involves upregulation of proinflammatory genes and downregulation of genes involved in type I IFN response and antibody synthesis. Experimental Design: We compared pretransplant leukocyte CTRA gene expression between a group of 78 high versus low SES recipients of unrelated donor HCT for acute myelogenous leukemia in first remission. Post hoc exploratory analyses also evaluated whether CTRA gene expression was associated with poor clinical outcomes. Results: Peripheral blood mononuclear cells collected pre-HCT from low SES individuals demonstrated significant CTRA upregulation compared with matched HCT recipients of high SES. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity, including increased CREB signaling and decreased IRF and GR signaling. High expression of the CTRA gene profile was also associated with increased relapse risk and decreased leukemia-free survival. Conclusions: Low SES is associated with increased expression of the CTRA gene profile, and CTRA gene expression is associated with adverse HCT clinical outcomes. These findings provide a biologic framework within which to understand how social environmental conditions may influence immune function and clinical outcomes in allogeneic HCT. Clin Cancer Res; 22(1); 69–78. ©2015 AACR. See related commentary by Turcotte and Verneris, p. 6

BACKGROUND In hematopoietic cell transplantation (HCT), current risk adjustment strategies are based on clinical and disease-related variables. Although patient-reported outcomes (PROs) predict mortality in multiple cancers, they have been less well studied within HCT. Improvements in risk adjustment strategies in HCT would inform patient selection, patient counseling, and quality reporting. The objective of the current study was to determine whether pre-HCT PROs, in particular physical health, predict survival among patients undergoing autologous or allogeneic transplantation. METHODS In this secondary analysis, the authors studied pre-HCT PROs that were reported by 336 allogeneic and 310 autologous HCT recipients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902 protocol, a study with broad representation of patients who underwent transplantation in the United States. RESULTS Among allogeneic HCT recipients, the pre-HCT Medical Outcomes Study Short Form-36 Health Survey (SF-36) physical component summary (PCS) scale independently predicted overall mortality (hazards ratio, 1.40 per 10-point decrease; P

Prospective validation of the hematopoietic cell transplantation–comorbidity index (HCT-CI) using contemporary patients treated with hematopoietic cell transplantation (HCT) across the Unites States is necessary to confirm its widespread applicability. We performed a prospective observational study including all patients (8115 recipients of allogeneic and 11,652 recipients of autologous HCT) who underwent a first HCT that was reported to the Center for International Blood and Marrow Transplant Research between 2007 and 2009. In proportional hazards models, increased HCT-CI scores were independently associated with increases in hazard ratios for nonrelapse mortality (NRM) (P < .0001) and overall mortality (P < .0001) among recipients of allogeneic HCT. HCT-CI scores of ≥3 were uniformly associated with higher risks for outcomes in both allogeneic and autologous HCT and in all subgroups, regardless of diagnoses, age, and conditioning intensity. Recipients of allogeneic HCT with scores of 1 and 2 who were ages < 18 years or were treated with lower intensity conditioning regimens had similar outcomes compared with those with a score of 0. Higher risks for overall mortality, but not for NRM, were observed among recipients of autologous HCT with scores of 1 and 2 versus 0. Our results confirm the validity the HCT-CI in both allogeneic and autologous HCT. The index should be used as a valid standard-of-care health measure in counseling patients for HCT, in clinical trial design, and in adjusting outcome analyses.

Hematopoietic cell transplantation (HCT) is a complex procedure that requires availability of adequate infrastructure, personnel, and resources at transplantation centers. We conducted a national survey of transplantation centers in the United States to obtain data on their personnel, infrastructure, and care delivery models. A 42-item web-based survey was administered to medical directors of transplantation centers in the United States that reported any allogeneic HCT to the Center for International Blood and Marrow Transplant Research in 2011. The response rate for the survey was 79% for adult programs (85 of 108 centers) and 82% for pediatric programs (54 of 66 centers). For describing results, we categorized centers into groups with similar volumes based on 2010 total HCT activity (adult centers, 9 categories; pediatric centers, 6 categories). We observed considerable variation in available resources, infrastructure, personnel, and care delivery models among adult and pediatric transplantation centers. Characteristics varied substantially among centers with comparable transplantation volumes. Transplantation centers may find these data helpful in assessing their present capacity and use them to evaluate potential resource needs for personnel, infrastructure, and care delivery and in planning for growth.

Objective: Hematopoietic stem cell transplantation (HCT) is a stressful and rigorous medical procedure involving significant emotional and immune challenges. The endocannabinoid (eCB) signaling system is involved in regulation of both the immune system and emotional reactivity, yet little is known about its function during HCT. We investigated the role of the eCB signaling system in a group of HCT recipients. Methods: A total of 19 HCT recipients were enrolled and provided psychosocial data and blood samples at three peri-transplant time points: prior to transplant, hospital discharge, and approximately 100 days post-transplant. Psychosocial factors, inflammatory molecules, and the eCBs were determined and assessed for changes over this period and association with each other. Results: HCT recipients demonstrated significant changes over the peri-transplant period in inflammatory molecules and psychosocial functioning, but not in circulating concentrations of the eCBs. Associations among these variables were most likely to be present pre-transplant and least likely to be present immediately post-transplant, with depressive symptoms and inflammation most significantly associated. The eCB 2-arachidonoylglycerol (2-AG) was significantly, positively associated with both interleukin (IL)-6 and C-reactive protein (CRP) and negatively associated with depressive symptoms. Conclusions: The eCB signaling system may have alternative sources and regulatory mechanisms in addition to the immune system. Given the significant associations with inflammatory molecules and depressive symptoms in the peri-transplant period, it is important to better understand this system and its potential implications in the setting of complex and stressful medical procedures such as HCT.

Variations in cord blood manufacturing and administration are common, and the optimal practice is not known. We compared processing and banking practices at 16 public cord blood banks (CBB) in the United States and assessed transplantation outcomes on 530 single umbilical cord blood (UCB) myeloablative transplantations for hematologic malignancies facilitated by these banks. UCB banking practices were separated into 3 mutually exclusive groups based on whether processing was automated or manual, units were plasma and red blood cell reduced, or buffy coat production method or plasma reduced. Compared with the automated processing system for units, the day 28 neutrophil recovery was significantly lower after transplantation of units that were manually processed and plasma reduced (red cell replete) (odds ratio, .19; P = .001) or plasma and red cell reduced (odds ratio, .54; P = .05). Day 100 survival did not differ by CBB. However, day 100 survival was better with units that were thawed with the dextran-albumin wash method compared with the "no wash" or "dilution only" techniques (odds ratio, 1.82; P = .04). In conclusion, CBB processing has no significant effect on early (day 100) survival despite differences in kinetics of neutrophil recovery.

Background: The development of reduced intensity approaches for allogeneic hematopoietic cell transplantation has resulted in growing numbers of older related donors (RD) of PBSC. The effects of age on donation efficacy, toxicity, and long-term recovery in RD are poorly understood. Methods: We analyzed hematologic variables, pain, donation-related symptoms and recovery in 1211 related PBSC donors aged 18-79 enrolled in the Related Donor Safety Study (RDSafe). Results: RD >60 had a lower median CD34 level pre-apheresis compared to younger RD (age >60, 59x106/L; age 41-60, 81x106/L; age 18-40, 121x106/L; p 24L, p 60 with post-collection thrombocytopenia

Background Repurposing existing medications for antineoplastic purposes can provide a safe, cost-effective, and efficacious means to further augment available cancer care. Clinical and preclinical studies suggest a role for the ß-adrenergic antagonist (ß-blocker) propranolol in reducing rates of tumor progression in both solid and hematologic malignancies. In patients undergoing hematopoietic cell transplantation (HCT), the peri-transplant period is a time of increased activity of the ß-adrenergically-mediated stress response. Methods We conducted a proof-of-concept randomized controlled pilot study assessing the feasibility of propranolol administration to patients between ages 18–75 who received an autologous HCT for multiple myeloma. Feasibility was assessed by enrollment rate, tolerability, adherence, and retention. Results One hundred fifty-four patients underwent screening; 31 (20%) enrolled in other oncology trials that precluded dual trial enrollment and 9 (6%) declined to enroll in the current trial. Eighty-nine (58%) did not meet eligibility requirements and 25 (16%) were eligible; of the remaining eligible patients, all were successfully enrolled and randomized. The most common reasons for ineligibility were current ß-blocker use, age, logistics, and medical contraindications. 92% of treatment arm patients tolerated and remained on propranolol for the study duration; 1 patient discontinued due to hypotension. Adherence rate in assessable patients (n = 10) was 94%. Study retention was 100%. Conclusions Findings show that it is feasible to recruit and treat multiple myeloma patients with propranolol during HCT, with the greatest obstacle being other competing oncology trials. These data support further studies examining propranolol and other potentially repurposed drugs in oncology populations. Trial registration This randomized controlled trial was registered at clinicaltrials.gov with the identifier NCT02420223 on April 17, 2015.

We conducted a phase 2 study in which patients undergoing allogeneic hematopoietic stem cell transplantation received tocilizumab in addition to standard immune suppression with tacrolimus and methotrexate for graft-versus-host disease prophylaxis. Thirty-five patients were enrolled between January 2015 and June 2016. The median age of the cohort was 66 (range: 22-76). All patients received busulfan-based conditioning, and were transplanted with human leukocyte antigen-matched related or matched unrelated bone marrow or peripheral stem cell grafts. The cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease were 14% (95% CI 5-30) and 3% (95% CI 0-11) at day 100, and 17% (95% CI 7-31) and 6% (95% CI 1-16) at day 180, respectively. Notably, there were no cases of graft-versus-host disease of the lower gastrointestinal tract within the first 100 days. A comparison to 130 matched controls who only received tacrolimus and methotrexate demonstrated a lower cumulative incidence of grades II-IV acute graft-versus-host disease (17% versus 45%, P=0.003) and a significant increase in grades II-IV acute graft-versus-host disease-free survival at six months (69% versus 42%, P=0.001) with tocilizumab, tacrolimus and methotrexate, which was the primary endpoint of the study. Immune reconstitution was preserved in patients treated with tocilizumab, tacrolimus and methotrexate, as T-cell and B-cell subsets recovered to near normal levels by 6-12 months post-transplantation. We conclude that tocilizumab has promising activity in preventing acute graft-versus-host disease, particularly in the lower gastrointestinal tract, and warrants examination in a randomized setting.