Cost-Effectiveness of Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Older Patients With High-Risk Myelodysplastic Syndrome: Analysis of BMT CTN 1102.

PURPOSE: BMT CTN 1102 was a phase III trial comparing reduced-intensity allogeneic hematopoietic cell transplantation (RIC alloHCT) to standard of care for persons with intermediate- or high-risk myelodysplastic syndrome (MDS). We report results of a cost-effectiveness analysis conducted alongside the clinical trial. METHODS: Three hundred eighty-four patients received HCT (n = 260) or standard of care (n = 124) according to availability of a human leukocyte antigen-matched donor. Cost-effectiveness was calculated from US commercial and Medicare perspectives over a 20-year time horizon. Health care utilization and costs were estimated using propensity score-matched cohorts of HCT recipients in the OptumLabs Data Warehouse (age 50-64 years) and Medicare (age 65 years and older). EuroQol 5 Dimension (EQ-5D) surveys of trial participants were used to derive health state utilities. RESULTS: Extrapolated 20-year overall survival for those age 50-64 years was 29% for HCT (n = 105) versus 13% for usual care (n = 44) and 31% for HCT (n = 155) versus 12% for non-HCT (n = 80) for those age 65 years and older. HCT was more effective (+2.36 quality-adjusted life-years [QALYs] for age 50-64 years and +2.92 QALYs for age 65 years and older) and more costly (+$452,242 in US dollars (USD) for age 50-64 years and +$233,214 USD for age 65 years and older) than usual care, with incremental cost-effectiveness ratios of $191,487 (USD)/QALY and $79,834 (USD)/QALY, respectively. For persons age 50-64 years, there was a 29% chance that HCT was cost-effective using a willingness-to-pay (WTP) threshold of $150K (USD)/QALY and 51% at a $200K (USD)/QALY. For persons age 65 years and older, the probability was 100% at a WTP >$150K (USD)/QALY. CONCLUSION: Among patients age 65 years and older with high-risk MDS, RIC HCT is a high-value strategy. For those age 50-64 years, HCT is a lower-value strategy but has similar cost-effectiveness to other therapies commonly used in oncology.

Severity of Chronic Graft-versus-Host Disease and Late Effects Following Allogeneic Hematopoietic Cell Transplantation for Adults with Hematologic Malignancy.

The study aimed to determine the association of chronic graft-versus-host disease (cGVHD) diagnosis and severity with the development of subsequent neoplasms (SN) and nonmalignant late effects (NM-LE) in 2-year disease-free adult survivors following hematopoietic cell transplantation (HCT) for a hematologic malignancy. To do so, we conducted a retrospective analysis of 3884 survivors of HCT for hematologic malignancy in the Center of International Blood and Marrow Transplant Research database. We conducted a landmark analysis at the 2-year post-transplantation date, comparing first SN and NM-LE in survivors with and without cGVHD. The cumulative incidence (CuI) of SN and NM-LE were estimated through 10 years post-HCT in both groups, with death or disease relapse as a competing risk. Cox proportional hazards models were used to evaluate the associations of cGVHD and its related characteristics with the development of SN and NM-LE. The estimated 10-year CuI of SN in patients with GVHD (n = 2669) and patients without cGVHD (n = 1215) was 15% (95% confidence interval [CI], 14% to 17%) versus 9% (7.2% to 11%) (P < .001). cGVHD by 2 years post-HCT was independently associated with SN (hazard ratio [HR], 1.94; 95% CI, 1.53 to 2.46; P < .0001) with a standardized incidence ratio of 3.2 (95% CI, 2.9 to 3.5; P < .0001). Increasing severity of cGVHD was associated with an increased risk of SN. The estimated 10-year CuI of first NM-LE in patients with and without cGVHD was 28 (95% CI, 26% to 30%) versus 13% (95% CI, 11% to 15%) (P < .001). cGVHD by 2 years post-HCT was independently associated with NM-LE (HR, 2.23; 95% CI, 1.81 to 2.76; P < .0001). Multivariate analysis of cGVHD-related factors showed that increasing severity of cGVHD, extensive grade, having both mucocutaneous and visceral involvement, and receiving cGVHD treatment for >12 months were associated with the greatest magnitude of risk for NM-LE. cGVHD was closely associated with both SN and NM-LE in adult survivors of HCT for hematologic malignancy. Patients identified as having more severe involvement and both mucocutaneous and visceral organ involvement may warrant enhanced monitoring and screening for SNs and NM-LEs. However, caution is warranted when interpreting these results, as patients with cGVHD may have more vigilant post-transplantation health care and surveillance for late effects.

Associations of Germline Genetic Variants With Depression and Fatigue Among Hematologic Cancer Patients Treated With Allogeneic Hematopoietic Cell Transplantation.

OBJECTIVE: Depression and fatigue are common among cancer patients and are associated with germline genetic variation. The goal of this pilot study was to examine genetic associations with depression and fatigue in the year after allogeneic hematopoietic cell transplant (HCT). METHODS: Blood was collected from patients and their donors before HCT. Patients completed self-report measures of depression and fatigue before HCT (T1), 90 days post-HCT (T2), and 1 year post-HCT (T3). Of the 384 genetic variants genotyped on a custom Illumina BeadChip microarray, 267 were retained for analysis based on quality control. Main effects of patient and donor variants as well as their interaction were examined using regression analyses. Significant variants were defined as those with a false discovery rate-adjusted p value of <.05. RESULTS: The sample consisted of 59 patient-donor pairs. Mean levels of depression and fatigue did not change significantly over time ( p values of > .41). Increases in depression from T1 to T2 were associated with patient-donor interactions at rs1928040 ( p = 3.0 × 10 -4 ) and rs6311 ( p = 2.0 × 10 -4 ) in HTR2A . Increases in fatigue from T1 to T2 were associated with patient rs689021 in SORL1 ( p = 6.0 × 10 -5 ) and a patient-donor interaction at rs1885884 in HTR2A ( p < 1.0 × 10 -4 ). CONCLUSIONS: Data suggest that variants in genes regulating the serotonergic system ( HTR2A ) and lipid metabolism ( SORL1 ) are associated with changes in depression and fatigue in allogeneic HCT patients, implicating patients' own genetic inheritance as well as that of donors. Additional studies are warranted to confirm these findings.

Pilot Study of Donor-Engrafted Clonal Hematopoiesis Evolution and Clinical Outcomes in Allogeneic Hematopoietic Cell Transplantation Recipients Using a National Registry.

Improved treatment options, such as reduced-intensity conditioning (RIC), enable older patients to receive potentially curative allogeneic hematopoietic cell transplantation (HCT). This progress has led to increased use of older HLA-matched sibling donors. An unintended potential risk associated with older donors is transplantation of donor cells with clonal hematopoiesis (CH) into patients. We aimed to determine the prevalence of CH in older HLA-matched sibling donors pretransplantation and to assess the clinical impact of donor-engrafted CH on HCT outcomes. This was an observational study using donor peripheral blood samples from the Center for International Blood and Marrow Transplant Research repository, linked with corresponding recipient outcomes. To explore engraftment efficiency and evolution of CH mutations following HCT, recipient follow-up samples available through the Bone Marrow Transplant Clinical Trials Network (Protocol 1202) were included. Older donors and patients (both ≥55 years) receiving first RIC HCT for myeloid malignancies were eligible. DNA from archived donor blood samples was used for targeted deep sequencing to identify CH. The associations between donor CH status and recipient outcomes, including acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), overall survival, relapse, nonrelapse mortality, disease-free survival, composite GVHD-free and relapse-free survival, and cGVHD-free and relapse-free survival, were analyzed. A total of 299 donors were successfully sequenced to detect CH. At a variant allele frequency (VAF) ≥2%, there were 44 CH mutations in 13.7% (41 of 299) of HLA-matched sibling donors. CH mostly involved DNMT3A (n = 27; 61.4%) and TET2 (n= 9; 20.5%). Post-HCT samples from 13 recipients were also sequenced, of whom 7 had CH+ donors. All of the donor CH mutations (n = 7/7; 100%) were detected in recipients at day 56 or day 90 post-HCT. Overall, mutation VAFs remained relatively constant up to day 90 post-HCT (median change, .005; range, -.008 to .024). Doubling time analysis of recipient day 56 and day 90 data showed that donor-engrafted CH mutations initially expand then decrease to a stable VAF; germline mutations had longer doubling times than CH mutations. The cumulative incidence of grade II-IV aGVHD at day 100 was higher in HCT recipients with CH+ donors (37.5% versus 25.1%); however, the risk for aGVHD by donor CH status did not reach statistical significance (hazard ratio, 1.35; 95% confidence interval, .61 to 3.01; P = .47). There were no statistically significant differences in the cumulative incidence of cGVHD or any secondary outcomes by donor CH status. In subset analysis, the incidence of cGVHD was lower in recipients of grafts from DNMT3A CH+ donors versus donors without DNMT3A CH (34.4% versus 57%; P = .035). Donor cell leukemia was not reported in any donor-recipient pairs. CH in older HLA-matched sibling donors is relatively common and successfully engrafts and persists in recipients. In a homogenous population (myeloid malignancies, older donors and recipients, RICr, non-cyclophosphamide-containing GVHD prophylaxis), we did not detect a difference in cGVHD risk or other secondary outcomes by donor CH status. Subgroup analyses suggest potential differential effects by clinical characteristics and CH mutations. Larger prospective studies are needed to robustly determine which subsets of patients and CH mutations elicit meaningful impacts on clinical outcomes.

Frailty in Patients with Chronic Graft-versus-Host Disease.

Frailty is an increasingly recognized clinical diagnosis associated with high risk of disability and mortality. Frailty in patients after hematopoietic cell transplantation (HCT) is associated with increased nonrelapse mortality (NRM) and decreased overall survival (OS). Frailty has not been studied extensively in patients with chronic graft-versus-host disease (cGVHD). The objectives of the present study were to assess the prevalence and clinical correlates of frailty and the association of frailty with NRM and OS in patients enrolled in the Chronic GVHD Consortium. Patients were characterized as frail if they met the Fried definition of ≥3 of the following criteria at enrollment: unintentional weight loss, exhaustion, slow walking speed, low physical activity, and weakness. Frailty was assessed retrospectively using surrogate measures for the 5 domains of frailty. Frailty, cGVHD organ scores, and patient-reported outcomes were measured at the time of enrollment. The study included 399 patients from 9 centers in the United States, with 32% characterized as frail and 68% as not frail. The median duration of follow-up from enrollment was 9 years (interquartile range, 7 to 11 years). Frail patients were more likely to be older (P = .004), to have a lower Karnofsky Performance Status (P < .001), to have severe cGVHD (P < .001), and to have gastrointestinal (P < .001), liver (P = .04), or lung cGVHD (P = .002). In a multivariable analysis, older age, increased cGVHD global severity, and thrombocytopenia were statistically significantly associated with frailty when cGVHD organ involvement was excluded. A separate analysis excluding cGVHD severity and including organ involvement showed that lung and liver cGVHD and older age were associated with frailty. Neither corticosteroid use at the time of enrollment nor the maximum recorded dose of corticosteroids before enrollment was associated with frailty. Frail patients had higher NRM than nonfrail patients (P < .001), with a 10-year cumulative incidence of 41% (95% confidence interval [CI], 32% to 49%) versus 22% (95% CI, 17% to 28%). Reciprocally, frailty also was associated with a significantly lower OS (P < .001), with a 10-year OS of 43% (95% CI, 35% to 53%) in frail patients versus 63% (95% CI, 57% to 69%) in nonfrail patients. In multivariable analysis that included the individual domains of frailty, weakness, low physical activity, and slow walking speed were associated with survival. Frail patients also had worse scores on various measures of patient-reported outcomes, including the Short Form (SF)-36, the Lee Symptom Scale, and the trial outcome of the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) index score. Frail patients with cGVHD have significantly worse outcomes than nonfrail patients. Such clinical features as older age and lung and liver cGVHD are associated with frailty. Earlier clinical recognition of frailty in patients with cGVHD may prompt interventions to counteract frailty that could be beneficial for this population.

Three-Year Outcomes in Recipients of Mismatched Unrelated Bone Marrow Donor Transplants Using Post-Transplantation Cyclophosphamide: Follow-Up from a National Marrow Donor Program-Sponsored Prospective Clinical Trial.

The use of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has resulted in reductions in GVHD and improved outcomes in allogeneic hematopoietic cell transplantation (HCT) using HLA-mismatched related donors. We report the 3-year outcomes of the first multicenter prospective clinical trial using PTCy in the setting of mismatched unrelated donor (MMUD) bone marrow HCT. The study enrolled 80 patients, treated with either myeloablative conditioning (MAC; n = 40) or reduced-intensity conditioning (RIC; n = 40), with the primary endpoint of 1-year overall survival (OS). The median follow-up for this study was 34 months (range, 12 to 46 months) in the RIC group and 36 months (range, 18 to 49 months) in the MAC group. Three-year OS and nonrelapse mortality were 70% and 15%, respectively, in the RIC group and 62% and 10% in the MAC group. No GVHD was reported after 1 year. The incidence of relapse was 29% in the RIC group and 51% in the MAC group. OS did not differ based on HLA match grade (63% in the 7/8 strata and 71% in the 4 to 6/8 strata). These encouraging outcomes, which were sustained for 3 years post-HCT, support the continued exploration of MMUD HCT using a PTCy platform. Important future areas to address include relapse reduction and furthering our understanding of optimal donor selection based on HLA and non-HLA factors.

Association of Chronic Graft-versus-Host Disease with Late Effects following Allogeneic Hematopoietic Cell Transplantation for Children with Hematologic Malignancy.

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.

A phase 2 multicenter trial of ofatumumab and prednisone as initial therapy for chronic graft-versus-host disease.

Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD.  This trial was registered at www.clinicaltrials.gov as #NCT01680965.

Chronic Graft-versus-Host Disease, Nonrelapse Mortality, and Disease Relapse in Older versus Younger Adults Undergoing Matched Allogeneic Peripheral Blood Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Analysis.

The effect of chronic graft-versus-host disease (cGVHD) on the risk of nonrelapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research (CIBMTR) analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (age ≥60 years). We included 4429 adults age ≥40 years who underwent a first HLA-matched peripheral blood stem cell alloHCT for acute myelogenous leukemia or myelodysplastic syndrome between 2008 and 2017. We compared outcomes of 4 groups-older adults (≥60 years) and younger adults (40 to 59 years) with cGVHD and older and younger adults without cGVHD-to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse, and overall survival (OS). We treated cGVHD as a time-dependent covariate. The severity of cGVHD was based on the CIBMTR clinical definitions. cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher for older adults versus younger adults. Adults who developed cGVHD as a group had longer OS compared with age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild to moderate cGVHD was associated with longer OS. Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse, and longer OS. Older adults had a higher risk of NRM, but the increased risk of NRM associated with cGVHD did not differ based on age. The development of mild to moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing the risk of relapse. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Nonrelapse mortality among patients diagnosed with chronic GVHD: an updated analysis from the Chronic GVHD Consortium.

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.

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2020 Treatment of Chronic GVHD Report.

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.

National Marrow Donor Program-Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide.

PURPOSE: Hematopoietic cell transplantation (HCT) is curative for hematologic disorders, but outcomes are historically inferior when using HLA-mismatched donors. Despite unrelated donor registries listing > 38 million volunteers, 25%-80% of US patients lack an HLA-matched unrelated donor, with significant disparity across ethnic groups. We hypothesized that HCT with a mismatched unrelated donor (MMUD) using post-transplant cyclophosphamide (PTCy), a novel strategy successful in overcoming genetic disparity using mismatched related donors, would be feasible and increase access to HCT. PATIENTS AND METHODS: We performed a prospective phase II study of MMUD bone marrow HCT with PTCy for patients with hematologic malignancies. The primary end point was 1-year overall survival (OS), hypothesized to be 65% or better. 80 patients enrolled at 11 US transplant centers (December 2016-March 2019). Following myeloablative or reduced-intensity conditioning-based HCT, patients received PTCy on days +3, +4, with sirolimus and mycophenolate mofetil starting on day +5. We compared outcomes to Center for International Blood and Marrow Transplant Research contemporary controls receiving PTCy. RESULTS: Notably, 48% of patients enrolled were ethnic minorities. 39% of pairs were matched for 4-6 out of 8 HLA alleles. The primary end point was met, with 1-year OS of 76% (90% CI, 67.3 to 83.3) in the entire cohort, and 72% and 79% in the myeloablative and reduced-intensity conditioning strata, respectively. Secondary end points related to engraftment and graft-versus-host-disease were reached. Multivariate analysis comparing the study group with other mismatched HCT controls found no significant differences in OS. CONCLUSION: Our prospective study demonstrates the feasibility and effectiveness of HCT with an MMUD in the setting of PTCy. Remarkably, nearly half of the study participants belonged to an ethnic minority population, suggesting this approach may significantly expand access to HCT.

ELN 2017 Genetic Risk Stratification Predicts Survival of Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

European LeukemiaNet (ELN) 2017 risk stratification by genetics is prognostic of outcomes in patients with acute myeloid leukemia (AML). However, the prognostic impact of the 2017 ELN genetic risk stratification after allogeneic hematopoietic cell transplantation (alloHCT) is not well established. We examined the effect of 2017 ELN genetic risk stratification on alloHCT outcomes of AML. We included 500 adult (≥18 years) AML patients in first (n = 370) or second (n = 130) complete remission receiving alloHCT from 2005 to 2016. Patients were classified into favorable (12%), intermediate (57%), and adverse (32%) 2017 ELN risk groups. The Cox proportional hazard model was used to conduct the multivariable analyses of leukemia-free survival (LFS) and overall survival (OS). Relapse and nonrelapse mortality were analyzed by the Fine-Gray regression model. OS at 2 years was 72% in the favorable versus 60% in the intermediate versus 45% in the adverse risk groups (P < .001). In multivariable analyses, the 2017 ELN classifier was an independent predictor of OS after alloHCT with significantly higher overall mortality in the intermediate (hazard ratio [HR] = 1.68, 95% confidence interval [CI], 1.06-2.68; P = .03) and adverse (HR = 2.50, 95% CI, 1.54-4.06; P < .001) risk groups compared to the favorable risk group. Similarly, LFS was worse in the intermediate (HR = 1.63, 95%, CI 1.06-2.53; P = .03) and adverse (HR 2.23, 95% CI, 1.41-3.54; P < .001) risk groups while relapse was higher in the adverse risk group (HR = 2.36, 95% CI, 1.28-4.35; P = .006) as compared to the favorable risk group. These data highlight the prognostic impact of the 2017 ELN genetic risk stratification on the survival of AML patients after alloHCT. Patients in the adverse risk group had the highest risk of relapse and worst survival. Thus the 2017 ELN prognostic system can help identify AML patients who may benefit from clinical trials offering relapse mitigation strategies to improve transplant outcomes.

A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation.

The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype-incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (≥18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.

Sarcopenia and low muscle radiodensity associate with impaired FEV1 in allogeneic haematopoietic stem cell transplant recipients.

BACKGROUND: Quantification of skeletal muscle using computed tomography (CT) is accessible using cancer patients' standard oncologic images. Reduced muscle mass may be related to reduced respiratory muscle strength; however, the impact of this on lung functional parameters is not characterized in adult allogeneic haematopoietic stem cell transplant (alloHCT) recipients. METHODS: A consecutive retrospective series (n = 296) of patients who had alloHCT at a comprehensive cancer centre between March 2005 and April 2015 were included. Pre-transplant CT scans were used to quantify skeletal muscle and adipose tissue at the fourth thoracic (T4) and/or third lumbar (L3) level. Tumour and patient characteristics were recorded, including forced expiratory volume in 1 second (FEV1 ) by spirometry. Regression models were created to characterize predictive relationships. RESULTS: A total of 296 patients (♂n = 161; ♀n = 135) were included, all of whom had chest CT as part of standard care; a subset of these (n = 215, 72.6%) also had abdominal CT. Diagnoses were non-Hodgkins lymphoma (n = 165), acute myeloid leukaemia (n = 66), Hodgkin's disease (n = 14), acute lymphocytic leukaemia (n = 14), myelodysplastic syndromes (n = 18), and other (n = 19). In multivariable linear regression adjusted for sex (P < 0.0001), age (P < 0.0001), haematopoietic cell transplantation-specific co-morbidity index (P = 0.010), and parameters of pulmonary function testing (defined by spirometry, P < 0.0001), both T4 muscle index [ß 0.127 (95% confidence interval 0.019; 0.252), P < 0.0001] and T4 muscle radiodensity [ß 0.132 (95% confidence interval 0.087; 0.505), P = 0.006] were independently associated with FEV1 ; disease risk index (P = 0.877) and Karnofsky performance status (P = 0.548) were not associated with FEV1 . Similar conclusions were obtained when L3 muscle index and radiodensity were considered. Unlike T4, L3 muscle index values can be compared with published cut-off values for sarcopenia. Overall rates of sarcopenia were uniformly higher in the HCT population than in age-matched and sex-matched patients with solid tumours [alloHCT ♂64.7% vs. solid tumour ♂56.6% (P < 0.001); alloHCT ♀57.6% vs. solid tumour ♀36.0% (P < 0.001)]. Significant but moderate correlations (P < 0.001) were found for muscle area and radiodensity between L3 and T4, for both men and women; adipose tissue quantity also correlated significantly (P < 0.001) between L3 and T4 for both men and women. CONCLUSIONS: Lumbar or thoracic CT images are useful for body composition assessment in this population and reveal high rates of sarcopenia, similar to those reported in very elderly patients. Reduced muscle mass and radiodensity associate with impaired FEV1 even after adjustment for clinical covariables including co-morbidities, performance status, disease risk, and mild intrinsic pulmonary disease (chronic obstructive pulmonary disease) defined by spirometry.

Refined National Institutes of Health response algorithm for chronic graft-versus-host disease in joints and fascia.

Implementation of the 2014 National Institutes of Health (NIH) response algorithm for joint/fascia graft-versus-host disease (GVHD) has identified real-world limits to its application. To refine the 2014 NIH response algorithm, we analyzed multicenter prospective observational data from the Chronic GVHD Consortium. The training cohort included 209 patients and the replication cohort included 191 patients with joint/fascia involvement during their course of chronic GVHD. Linear mixed models with random patient effect were used to evaluate correlations between response categories and clinician- or patient-perceived changes in joint status as an anchor of response. Analysis of the training cohort showed that a 2-point change in total photographic range of motion (P-ROM) score was clinically meaningful. The results also suggested that a change from 0 to 1 on the NIH joint/fascia score should not be considered as worsening and suggested that both the NIH joint/fascia score and total P-ROM score, but not individual P-ROM scores, should be used for response assessment. On the basis of these results, we developed an evidence-based refined algorithm, the utility of which was examined in an independent replication cohort. Using the refined algorithm, ∼40% of responses were reclassified, largely mitigating most divergent responses among individual joints and changes from 0 to 1 on the NIH joint/fascia score. The refined algorithm showed robust point estimates and tighter 95% confidence intervals associated with clinician- or patient-perceived changes, compared with the 2014 NIH algorithm. The refined algorithm provides a superior, evidence-based method for measuring therapeutic response in joint/fascia chronic GVHD.

Disability Related to Chronic Graft-versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) is a heterogenous syndrome whose symptoms and treatment are often associated with decreases in functional status and quality of life among survivors of transplantation. We explored definitions of cGVHD-related disability and factors associated with disability in cGVHD. We analyzed 371 patients with cGVHD requiring a new systemic therapy with enrollment and 18-month assessments through the Chronic GVHD Consortium, evaluating disability as a composite endpoint including any 1 of 5 impairments previously defined by Fatobene et al [1] (score 2 or 3 keratoconjunctivitis sicca, score 2 or 3 scleroderma, any diagnosis of bronchiolitis obliterans, score 2 or 3 joint/fasciae involvement, or score 3 esophageal stricture requiring dilation). We also evaluated disability, defined as an ≥8-point decline in a human activity profile (HAP) score or a ≥20% decline in Karnofsky Performance Status (KPS) from enrollment to 18 months. At enrollment, 47% of patients had at least 1 of the 5 Flowers disability features, with 50% of this group acquiring additional impairments at 18 months. Of the 197 patients (53%) with no Flowers disability at enrollment, 50% progressed with disability features at 18 months. We found that any progressive Flowers impairment was associated with a decline in HAP/KPS as well as with increased National Institutes of Health severity scores at 18 months. Enrollment mouth scores and patient-reported eye and skin scores were significantly associated with progressive impairment at 18 months. Progressive disability at 18 months did not predict subsequent nonrelapse mortality. Additional studies to define chronic GVHD related-disability and risk factors are needed to develop this important patient-centered outcome.

The Chronic Graft-versus-Host Disease Failure-Free Survival (cGVHD-FFS) Index.

In clinical trials of chronic graft-versus-host disease (cGVHD), the need to start a new systemic treatment is considered a treatment failure. A composite endpoint called "failure-free survival" (FFS), where events are initiation of a new systemic cGVHD treatment, recurrent malignancy, and death, has been suggested as a possible long-term indicator of success. The goal of the current study was to identify changes in cGVHD manifestations from baseline to 6 months that could accurately predict subsequent longer-term FFS, thereby making it possible to assess outcomes earlier than would otherwise be possible. We used data from 2 prospective, multicenter, observational studies to develop the cGVHD-FFS index. The cGVHD-FFS index was calculated at 6 months, a typical timepoint for assessment of the primary endpoint of phase II cGVHD trials. Subsequent FFS was only 45% within the next 2 years. We found that changes in the scores for the eyes, joint/fascia, and mouth ulcers from baseline to 6 months were associated with subsequent FFS, but the prognostic accuracy of these changes was not adequate for use in trials. Biomarker studies might help to identify criteria that improve prediction of long-term clinical outcomes in patients with cGVHD.

Inferior Outcomes with Cyclosporine and Mycophenolate Mofetil after Myeloablative Allogeneic Hematopoietic Cell Transplantation.

Combination therapy with a calcineurin inhibitor (CNI), such as cyclosporine (CSA) or tacrolimus (Tac), and methotrexate (MTX) or mycophenolate mofetil (MMF) is a widely used approach to graft-versus-host disease (GVHD) prevention. Data on the comparative effectiveness of MMF compared with MTX are limited and conflicting, however. We analyzed data from the Center for International Blood and Marrow Transplant Research for adult patients undergoing first myeloablative hematopoietic cell transplantation (HCT) from an HLA-identical matched related donor (MRD; n = 3979) or matched unrelated donor (URD; n = 4163) using CSA+MMF, CSA+MTX, Tac+MMF, or Tac+MTX for GVHD prevention between 2000 and 2013. Within the MRD cohort, 2252 patients received CSA+MTX, 1391 received Tac+MTX, 114 received CSA+MMF, and 222 received Tac+MMF. Recipients of CSA+MMF had a higher incidence of acute GVHD grade II-IV (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.24 to 2.20; P < .001) and grade III-IV (HR, 1.92; 95% CI, 1.31 to 2.83; P < .001) compared with Tac+MTX. The use of CSA+MMF was also associated with inferior overall survival (OS) (HR, 2.31; 95% CI, 1.73 to 3.09; P < .001) due to higher transplantation-related mortality (TRM) (HR, 4.03; 95% CI, 2.61 to 6.23; P < .001) compared with Tac+MTX. Within the URD cohort, 974 patients received CSA+MTX, 2697 received Tac+MTX, 68 received CSA+MMF, and 424 received Tac+MMF. CSA+MMF was again significantly associated with a higher incidence of grade III-IV acute GVHD (HR, 2.31; 95% CI, 1.57 to 3.42; P <0001), worse OS (HR, 2.36; 95% CI, 1.67 to 3.35; P < .001), and higher TRM (HR, 3.09; 95% CI, 2.00 to 4.77; P < .001), compared with Tac+MTX and other regimens. Thus, this large retrospective comparison of MMF versus MTX in combination with CSA or Tac demonstrates significantly worse GVHD and survival outcomes with CSA+MMF compared with Tac+MTX.