Conditioning intensity and peritransplant flow cytometric MRD dynamics in adult AML.

In acute myeloid leukemia (AML), measurable residual disease (MRD) before or after allogeneic hematopoietic cell transplantation (HCT) is an established independent indicator of poor outcome. To address how peri-HCT MRD dynamics could refine risk assessment across different conditioning intensities, we analyzed 810 adults transplanted in first or second remission after myeloablative conditioning (MAC; n = 515) or non-MAC (n = 295) who underwent multiparameter flow cytometry-based MRD testing before as well as 20 to 40 days after allografting. Patients without pre- and post-HCT MRD (MRDneg/MRDneg) had the lowest risks of relapse and highest relapse-free survival (RFS) and overall survival (OS). Relative to those patients, outcomes for MRDpos/MRDpos and MRDneg/MRDpos patients were poor regardless of conditioning intensity. Outcomes for MRDpos/MRDneg patients were intermediate. Among 161 patients with MRD before HCT, MRD was cleared more commonly with a MAC (85 of 104; 81.7%) than non-MAC (33 of 57; 57.9%) regimen (P = .002). Although non-MAC regimens were less likely to clear MRD, if they did, the impact on outcome was greater. Thus, there was a significant interaction between conditioning intensity and "MRD conversion" for relapse (P = .020), RFS (P = .002), and OS (P = .001). Similar findings were obtained in the subset of 590 patients receiving HLA-matched allografts. C-statistic values were higher (indicating higher predictive accuracy) for peri-HCT MRD dynamics compared with the isolated use of pre-HCT MRD status or post-HCT MRD status for prediction of relapse, RFS, and OS. Across conditioning intensities, peri-HCT MRD dynamics improve risk assessment over isolated pre- or post-HCT MRD assessments in patients with AML.

Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen-mismatched donors.

This trial aimed to evaluate the efficacy of sirolimus in addition to cyclosporine (CSP) and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after nonmyeloablative conditioning for HLA class I or II mismatched hematopoietic cell transplantation (HCT). Eligible patients had hematologic malignancies treatable by allogeneic HCT. Conditioning consisted of fludarabine (90 mg/m2) and 2 to 3 Gy total body irradiation. GVHD prophylaxis comprised cyclosporine, mycophenolate mofetil, and sirolimus. The primary objective was to determine whether the cumulative incidence of grade 2 to 4 acute GVHD could be reduced to <70% in HLA class I or II mismatched HCT. The study was closed on December 20, 2018. Seventy-seven participants were recruited between April 14, 2011, and December 12, 2018, of whom 76 completed the study intervention. Median follow-up was 47 months (range, 4-94 months). The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 36% (95% confidence interval [CI], 25-46), meeting the primary end point. The cumulative incidence of nonrelapse morality, relapse/progression, and overall survival was 18% (95% CI, 9-27), 30% (interquartile range, 19-40), and 62% (95% CI, 50-73) after 4 years. In conclusion, the addition of sirolimus to cyclosporine and mycophenolate mofetil resulted in a lower incidence of acute GVHD, thus translating into superior overall survival compared with historical results. This trial was registered at www.clinicaltrials.gov as #NCT01251575.

Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades.

We have used a non-myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation for the past twenty years. During that period, changes in clinical practice have been aimed at reducing morbidity and mortality from infections, organ toxicity, and graft-versus-host disease. We hypothesized that improvements in clinical practice led to better transplantation outcomes over time. From 1997-2017, 1,720 patients with hematologic malignancies received low-dose total body irradiation +/- fludarabine or clofarabine before transplantation from HLA-matched sibling or unrelated donors, followed by mycophenolate mofetil and a calcineurin inhibitor ± sirolimus. We compared outcomes in three cohorts by year of transplantation: 1997 +/- 2003 (n=562), 2004 +/- 2009 (n=594), and 2010 +/- 2017 (n=564). The proportion of patients ≥60 years old increased from 27% in 1997 +/- 2003 to 56% in 2010-2017, and with scores from the Hematopoietic Cell Transplantation Comborbidity Index of ≥3 increased from 25% in 1997 +/- 2003 to 45% in 2010 +/- 2017. Use of unrelated donors increased from 34% in 1997 +/- 2003 to 65% in 2010-2017. When outcomes from 2004 +/- 2009 and 2010-2017 were compared to 1997 +/- 2003, improvements were noted in overall survival (P=.0001 for 2004-2009 and P <.0001 for 2010-2017), profression-free survival (P=.002 for 2004-2009 and P <.0001 for 2010 +/- 2017), non-relapse mortality (P<.0001 for 2004 +/- 2009 and P <.0001 for 2010 +/- 2017), and in rates of grades 2 +/- 4 acute and chronic graft-vs.-host disease. For patients with hematologic malignancies who underwent transplantation with non-myeloablative conditioning, outcomes have improved during the past two decades. Trials reported are registered under ClinicalTrials.gov identifiers: NCT00003145, NCT00003196, NCT00003954, NCT00005799, NCT00005801, NCT00005803, NCT00006251, NCT00014235, NCT00027820, NCT00031655, NCT00036738, NCT00045435, NCT00052546, NCT00060424, NCT00075478, NCT00078858, NCT00089011, NCT00104858, NCT00105001, NCT00110058, NCT00397813, NCT00793572, NCT01231412, NCT01252667, NCT01527045.

Who Enrolls in an Online Cancer Survivorship Program? Reach of the INSPIRE Randomized Controlled Trial for Hematopoietic Cell Transplantation Survivors.

The internet can be a valuable tool in delivering survivorship care to hematopoietic cell transplantation (HCT) cancer survivors. We describe the reach of INSPIRE, an Internet and social media-based randomized controlled trial, to address healthcare and psychosocial needs of HCT survivors. All survivors 2-10 years after HCT for hematologic malignancy or myelodysplasia from 6 transplantation centers in the US were approached by mail and follow-up calls. Eligible participants had access to the Internet, an email address, and did not have active disease in the past 2 years. We used logistic regression to determine characteristics of eligible survivors who were more or less likely to enroll. Of 2578 eligible HCT survivors, 1065 (41%) enrolled in the study. The mean age of enrollees was 56.3 ± 12.6 years (range, 19 to 89 years), 52% were male, and 94% were white. Survivors less likely to enroll included those who were male, age <40 years, and who received an autologous transplant (all P < .001). Compared with white survivors, African Americans were less likely to enroll (P < .001), whereas Native Americans/Alaska Natives were more likely to join the study (P = .03). The reach of the INSPIRE program was broad, including to survivors who traditionally have less access to resources, such as Native Americans/Alaskan Natives and rural residents. Strategies are still needed to improve the enrollment of online studies of survivorship resources for males, young adults, African American, and autologous HCT survivors because their use may improve outcomes.

Early Post-Transplantation Spirometry Is Associated with the Development of Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Cell Transplantation.

Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (allo-HCT) is often diagnosed at a late stage when lung dysfunction is severe and irreversible. Identifying patients early after transplantation may offer improved strategies for early detection that could avert the morbidity and mortality of BOS. This study aimed to determine whether a decline in lung function before and early after (days +80 to +100) allo-HCT are associated with a risk of BOS beyond 6 months post-transplantation. In a single-center cohort of 2941 allo-HCT recipients, 186 (6%) met National Institutes of Health criteria for BOS. Pretransplantation and post-transplantation day +80 spirometric parameters were analyzed as continuous variables and included in a multivariable model with other factors, including donor source, graft source, conditioning regimen, use of total body irradiation, and immunoglobulin levels. Pre-transplantation forced expiratory flow between 25% and 75% of maximum (FEF25-75), day +80 forced expiratory volume in 1 second (FEV1), and day +80 FEF25-75 had the strongest associations with increased risk of BOS. Assessment of the multivariable model showed that a decline in day +80 FEF25-75 added additional risk to the day +80 FEV1 model (P = .03), whereas FEV1 decline at day +80 added no additional risk to the day +80 FEF25-75 model (P = .645). Moreover, day +80 FEF25-75 conferred additional risk when considered with pretransplantation FEF25-75. These results suggest that day +80 FEF25-75 may be more important than FEV1 in predicting the development of BOS. This study highlights the importance of obtaining early post-transplantation pulmonary function tests for the potential risk stratification of patients at risk for BOS.

Azithromycin Use and Increased Cancer Risk among Patients with Bronchiolitis Obliterans after Hematopoietic Cell Transplantation.

Azithromycin exposure during the early phase of allogeneic hematopoietic cell transplantation (HCT) has been associated with an increased incidence of hematologic relapse. We assessed the impact of azithromycin exposure on the occurrence of relapse or new subsequent neoplasm (SN) in patients with bronchiolitis obliterans syndrome (BOS) after HCT who are commonly treated with azithromycin alone or in combination with other agents. In a retrospective study of patients with BOS from 2 large allograft centers, the effect of azithromycin exposure on the risk of relapse or SN was estimated from a Cox model with a time-dependent variable for treatment initiation. The Cox model was adjusted on time-fixed covariates measured at cohort entry, selected for their potential prognostic value. Similar models were used to assess the exposure effect on the cause-specific hazard of relapse, SN, and death free of those events. Sensitivity analyses were performed using propensity score matching. Among 316 patients, 227 (71.8%) were exposed to azithromycin after BOS diagnosis. The corresponding adjusted hazard ratio (HR) in patients exposed to azithromycin versus unexposed was 1.51 (95% confidence interval [CI], 0.90 to 2.55) for relapse or SN, 0.82 (95% CI, 0.37 to 1.83) for relapse, and 2.00 (95% CI, 1.01 to 3.99) for SN. Patients exposed to azithromycin had a significantly lower cause-specific hazard of death free of neoplasm and relapse (adjusted HR, 0.54; 95% CI, 0.34 to 0.89). In conclusion, exposure to azithromycin after BOS after HCT was associated with an increased risk of SN but not relapse.

Bone Health Management After Hematopoietic Cell Transplantation: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

Bone health disturbances commonly occur after hematopoietic cell transplantation (HCT) with loss of bone mineral density (BMD) and avascular necrosis (AVN) foremost among them. BMD loss is related to pretransplantation chemotherapy and radiation exposure and immunosuppressive therapy for graft-versus-host-disease (GVHD) and results from deficiencies in growth or gonadal hormones, disturbances in calcium and vitamin D homeostasis, as well as osteoblast and osteoclast dysfunction. Although the pathophysiology of AVN remains unclear, high-dose glucocorticoid exposure is the most frequent association. Various societal treatment guidelines for osteoporosis exist, but the focus is mainly on menopausal-associated osteoporosis. HCT survivors comprise a distinct population with unique comorbidities, making general approaches to bone health management inappropriate in some cases. To address a core set of 16 frequently asked questions (FAQs) relevant to bone health in HCT, the American Society of Transplant and Cellular Therapy Committee on Practice Guidelines convened a panel of experts in HCT, adult and pediatric endocrinology, orthopedics, and oral medicine. Owing to a lack of relevant prospective controlled clinical trials that specifically address bone health in HCT, the answers to the FAQs rely on evidence derived from retrospective HCT studies, results extrapolated from prospective studies in non-HCT settings, relevant societal guidelines, and expert panel opinion. Given the heterogenous comorbidities and needs of individual HCT recipients, answers to FAQs in this article should be considered general recommendations, with good medical practice and judgment ultimately dictating care of individual patients. Readers are referred to the Supplementary Material for answers to additional FAQs that did not make the core set.

Age and gender differences in financial distress among hematopoietic cell transplant survivors.

PURPOSE: Cancer has long-term financial consequences. Adolescent and young adult (AYA) and middle-aged cancer survivors may experience more financial toxicity than older adults. This study examined age differences in financial distress in hematopoietic cell transplant survivors and whether these differences result from measurement bias, more financial barriers to care, or an overall higher level of distress. METHODS: Hematologic malignancy survivors (n = 1135, 2-10 years post-transplant) completed the Cancer and Treatment Distress Scale (CTXD) and demographics as part of the baseline assessment for a randomized clinical trial. The CTXD has seven subscales, but for this study, we examined the financial distress subscale and the overall score. Item response theory analyses tested for bias by age and gender. Multivariate linear regression tested the association of age and gender with the CTXD scores while controlling for financial barriers to care. RESULTS: No bias was found on the CTXD. AYA (p < 0.01) and middle-aged adults (p < 0.001) reported more financial and overall distress than older (age 65+) adults. The same association of age and financial distress was observed in women (p < 0.01). However, only middle-aged men (p < 0.01) reported more financial and overall distress than older men; AYA men did not (p > 0.18). Financial barriers to care were not associated with financial or overall distress. CONCLUSIONS: Part of the increase in financial distress with younger age may be due to a higher risk of general distress. Policy initiatives to control cancer costs should consider life stage and the unique financial challenges at different ages for men and women.

Ibrutinib for Chronic Graft-versus-Host Disease After Failure of Prior Therapy: 1-Year Update of a Phase 1b/2 Study.

Chronic graft-versus-host disease (cGVHD) is a life-threatening complication of allogeneic stem cell transplantation. In a Phase 1b/2, open-label study (PCYC-1129; ClinicalTrials.gov identifier NCT02195869) involving 42 patients with active cGVHD who were steroid-dependent or -refractory, the activity and safety of ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, was demonstrated. Here we report extended follow-up for patients in this study. After a median follow-up of 26 months (range, .53 to 36.7 months), best overall response rate in the all treated population was 69% (29 of 42), with 13 patients (31%) achieving a complete response and 16 patients (38%) achieving a partial response. Sustained responses of ≥20, ≥32, and ≥44 weeks were seen in 20 (69%), 18 (62%), and 16 (55%) of the 29 responders, respectively. Of 26 patients with ≥2 involved organs, 19 (73%) showed responses in ≥2 organs. Six of 10 patients (60%) with ≥3 involved organs showed responses in ≥3 organs. Eleven of 18 patients (61%) who had sclerosis at baseline showed a sclerotic response (39% with complete response, 22% with partial response). Twenty-seven of 42 patients (64%) reached a corticosteroid dose of <.15 mg/kg/day during the study; 8 discontinued corticosteroid treatment and remained off corticosteroid at study closure. Safety findings for this updated analysis were consistent with the safety profile seen at the time of the original analysis. Common grade ≥3 adverse events (AEs) were pneumonia (n = 6), fatigue (n = 5), and diarrhea (n = 4). The onset of new grade ≥3 AEs decreased from 71% in the first year of treatment to 25% in the second year (n = 12). AEs leading to discontinuation occurred in 18 patients (43%). At a median follow-up of >2 years, ibrutinib continued to produce durable responses in patients with cGVHD who had failed previous systemic therapy. In this pretreated, high-risk population, clinically meaningful benefit and an acceptable safety profile were observed with additional follow-up for ibrutinib. These results demonstrate a substantial advance in the therapeutic management of patients with cGVHD.

Ocular Graft-versus-Host Disease after Hematopoietic Cell Transplantation: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complications Working Party of the European Society of Blood and Marrow Transplantation.

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

Non-Graft-versus-Host Disease Ocular Complications after Hematopoietic Cell Transplantation: Expert Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation.

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

Characteristics of Late Fatal Infections after Allogeneic Hematopoietic Cell Transplantation.

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

An endpoint associated with clinical benefit after initial treatment of chronic graft-versus-host disease.

No gold standard has been established as a primary endpoint in trials of initial treatment of chronic graft-versus-host disease (GVHD), and evidence showing the association of any proposed primary endpoint with clinical benefit has not been conclusively demonstrated. To address this gap, we analyzed outcomes in a cohort of 328 patients enrolled in a prospective, multicenter, observational study within 3 months after diagnosis of chronic GVHD. Complete and partial response, stable disease, and progressive disease were defined according to the 2014 National Institutes of Health Consensus Development Conference on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease. Success was defined as complete or partial response with no secondary systemic treatment or recurrent malignancy at 1 year after enrollment. Success was observed in fewer than 20% of the patients. The burden of disease manifestations at 1 year was lower for patients in this category than for those with stable or progressive disease. Systemic treatment ended earlier, and subsequent mortality was lower among patients with complete or partial response than among those with stable or progressive disease and those who had received secondary systemic treatment. We conclude that survival with a complete or partial response and no previous secondary systemic treatment or recurrent malignancy at 1 year after initial systemic therapy is associated with clinical benefit, a critical characteristic for consideration as a primary endpoint in a pivotal clinical trial. This prospective observational study was registered at www.clinicaltrials.gov as #NCT00637689.

Reversal of Low Donor Chimerism after Hematopoietic Cell Transplantation Using Pentostatin and Donor Lymphocyte Infusion: A Prospective Phase II Multicenter Trial.

In a multicenter, prospective, phase II study we evaluated the safety and efficacy of pentostatin followed by donor lymphocyte infusion (DLI) in patients with low donor Tcell chimerism after allogeneic hematopoietic cell transplantation (HCT). Thirty-six patients with low donor blood CD3 chimerism were enrolled in this study. Thirty-five patients received a total of 41 DLIs after a dose of pentostatin, and 1 patient received pentostatin only. Median donor CD3 chimerism prompting the initiation of pentostatin and DLI was 28% (range, 5% to 47%). Responses (defined by increases in donor CD3 chimerism ≥10% maintained to day 56 post-DLI) were seen in 16 patients (44.4%) with a median rise in CD3 donor chimerism to 64% (range, 48% to 100%). There was a trend for better responses among 21 patients who received first treatment within 100 days after transplant (57% response rate) compared with15 patients who received first treatment more than 100 days after HCT (27% response rate, P = .07). Fourteen patients (39%) developed grades II to IV acute graft-versus-host disease (GVHD) at a median of 10 days (range, 0 to 83) after DLI. Ten patients (28%) developed extensive chronic GVHD. Seventeen patients (47%) developed new grade 4 cytopenias after DLI. There was no difference in relapse between nonresponders and responders. Twenty-eight patients (78%) died, most (n = 21) because of relapse. Five of 16 responders (31%) are alive, all disease-free, at a median of 60 months (range, 21 to 132) after DLI. Six of 20 nonresponders (30%) are alive at a median of 47 months (range, 16 to 100) after DLI, 3 in complete remission. Pentostatin and DLI had acceptable toxicity and appeared to increase low donor CD3 chimerism after HCT but had no impact on mortality.

Quality of Life of Caregivers of Hematopoietic Cell Transplant Recipients.

Caregivers are critical to recipient recovery after hematopoietic cell transplant (HCT); however, little is known about their long-term health and quality of life (QoL). In this study we surveyed 4446 caregiver-recipient pairs in the post-HCT period to describe their QoL and its determinants. In total, 849 caregiver-recipient pairs at a median of 6 years after autologous or allogeneic HCT responded. Among 849 responding caregivers at a median of 6 years post-HCT, 67% of caregivers were women and 68% indicated they were still providing care to the recipient. Mean and median QoL measures of caregivers were at or above general population norms; however, approximately 20% of caregivers reported poor QoL relative to general population norms. Multivariate analysis revealed that caregiver characteristics, including age, gender, and educational attainment, were important determinants of caregiver QoL. Additional determinants of caregiver QoL included recipient QoL, relapse after autologous HCT, and ongoing use of immunosuppression after allogeneic HCT. Additionally, the prevalence of depression and sleep disorders appear to be higher in caregivers than in the general population. We have identified a population of caregivers who may benefit from interventions aimed at improving QoL and health outcomes. HCT clinical practice should also consider caregiver well-being.

Anti-Platelet-Derived Growth Factor Receptor Alpha Chain Antibodies Predict for Response to Nilotinib in Steroid-Refractory or -Dependent Chronic Graft-Versus-Host Disease.

Imatinib has clinical activity in chronic graft-versus-host disease (cGVHD), a significant complication of allogeneic hematopoietic cell transplant. Nilotinib is a tyrosine kinase inhibitor that targets the same receptors as imatinib but with different affinities. We tested the hypothesis that nilotinib is safe and has clinical activity in cGVHD. Thirty-three participants were enrolled in a phase I/II dose escalation and dose extension clinical trial of nilotinib for the treatment of steroid-refractory or- dependent cGVHD (ClinicalTrials.gov, NCT01155817). We assessed safety, clinical response, and pretreatment anti-platelet-derived growth factor receptor alpha chain (anti-PDGFRA) antibody levels. The 200-mg dose was identified as the maximum tolerated dose and used for the phase II dose extension study. At 6 months the incidence of failure-free survival (FFS), cGVHD progression, and nilotinib intolerance resulting in its discontinuation was 50%, 23%, and 23%, respectively. cGVHD responses in skin, joints, and mouth were observed at 3 and 6 months based on improvement in respective National Institutes of Health organ severity scores. Pretreatment anti-PDGFRA antibody levels ≥ .150 optical density as measured by ELISA correlated with longer FFS time (P < .0005) and trended with time until cGVHD progression (P < .06) but not drug intolerance. Nilotinib may be effective for corticosteroid-resistant or -refractory cGVHD in some patients, but its use is limited by intolerable side effects. Selection of patients with high pretreatment anti-PDGFRA antibody levels might improve the risk-to-benefit ratio of nilotinib and better justify its side effects.

Association of Socioeconomic Status with Chronic Graft-versus-Host Disease Outcomes.

Chronic graft-versus host disease (GVHD) is a chronic and disabling complication after hematopoietic cell transplantation (HCT). It is important to understand the association of socioeconomic status (SES) with health outcomes in patients with chronic GVHD because of the impaired physical health and dependence on intensive and prolonged health care utilization needs in these patients. We evaluated the association of SES with survival and quality of life (QOL) in a cohort of 421 patients with chronic GVHD enrolled on the Chronic GVHD Consortium Improving Outcomes Assessment study. Income, education, marital status, and work status were analyzed to determine the associations with patient-reported outcomes at the time of enrollment, nonrelapse mortality (NRM), and overall mortality. Higher income (P = .004), ability to work (P < .001), and having a partner (P = .021) were associated with better mean Lee chronic GVHD symptom scores. Higher income (P = .048), educational level (P = .044), and ability to work (P < .001) also were significantly associated with better QOL and improved activity. In multivariable models, higher income and ability to return to work were both significantly associated with better chronic GVHD Lee symptom scores, but income was not associated with activity level, QOL, or physical/mental functioning. The inability to return to work (hazard ratio, 1.82; P = .019) was associated with worse overall mortality, whereas none of the SES indicators were associated with NRM. Income, race, and education did not have statistically significant associations with survival. In summary, we did not observe an association between SES variables and survival or NRM in patients with chronic GVHD, although we found some association with patient-reported outcomes, such as symptom burden. Higher income status was associated with less severe chronic GVHD symptoms. More research is needed to understand the psychosocial, biological, and environmental factors that mediate this association of SES with major HCT outcomes.

Engagement with INSPIRE, an Online Program for Hematopoietic Cell Transplantation Survivors.

In a secondary analysis of a randomized controlled trial (RCT), we examined participants' engagement with INSPIRE, a personalized online program for hematopoietic cell transplantation (HCT) survivors that focuses on cancer-related distress, depression, fatigue, and health care needs. We approached all adult, 3- to 18-year HCT survivors treated for hematologic malignancy without relapse or second cancer in the previous 2 years for participation in an RCT with either immediate or delayed access to INSPIRE. Participants with immediate access could view the online material at any time. Data included page view tracking, medical records, and patient-reported outcomes, including the Short Form 36 and Cancer and Treatment Distress (CTXD) measures. Of 1322 eligible HCT survivors, 771 (58%) completed the baseline assessment, and 451 received immediate INSPIRE access and were included in analyses. The cohort was 56% male, with a mean age of 52 ± 12.2 years, and 26% received an autologous transplant. Most (77%) logged into the INSPIRE site at least once, and 48% viewed ≥8 pages. Survivors who viewed ≥2 pages were more likely to be age ≥40 years (relative risk [RR], 1.41; 95% confidence interval [CI], 1.10 to 1.80), to be female (RR, 1.22; 95% CI, 1.07 to 1.40), to have chronic graft-versus-host disease (RR, 1.28; 95% CI, 1.08 to 1.51), to be less than 10 years post-HCT (RR, 1.19; 95% CI, 1.01 to 1.39), and to have moderate CTXD distress (RR, 1.34; 95% CI, 1.14 to 1.57). Engagement did not differ by race, education, income, rural/urban residence, computer experience, donor type, or depression (all P ≥ .50). The INSPIRE online program was widely used, including by those who often have reduced access to care after treatment.

Blood and Marrow Transplant Clinical Trials Network Report on the Development of Novel Endpoints and Selection of Promising Approaches for Graft-versus-Host Disease Prevention Trials.

Graft-versus-host disease (GVHD) is a common complication after hematopoietic cell transplantation (HCT) and associated with significant morbidity and mortality. Preventing GVHD without chronic therapy or increasing relapse is a desired goal. Here we report a benchmark analysis to evaluate the performance of 6 GVHD prevention strategies tested at single institutions compared with a large multicenter outcomes database as a control. Each intervention was compared with the control for the incidence of acute and chronic GVHD and overall survival and against novel composite endpoints: acute and chronic GVHD, relapse-free survival (GRFS), and chronic GVHD, relapse-free survival (CRFS). Modeling GRFS and CRFS using the benchmark analysis further informed the design of 2 clinical trials testing GVHD prophylaxis interventions. This study demonstrates the potential benefit of using an outcomes database to select promising interventions for multicenter clinical trials and proposes novel composite endpoints for use in GVHD prevention trials.

Transplant Conditioning with Treosulfan/Fludarabine with or without Total Body Irradiation: A Randomized Phase II Trial in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia.

In this prospective, randomized, phase II "pick the winner" trial we assessed the efficacy of transplant conditioning with treosulfan/fludarabine ± 2 Gy total body irradiation (TBI) in reducing post-transplant relapse in 100 patients, aged 2 to 70 years (median, 57), with myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (n = 51) or acute myeloid leukemia (AML; n = 49). Patients received i.v. treosulfan, 14 g/m2/day on days -6 to -4 and i.v. fludarabine, 30 mg/m2/day on days -6 to -2, alone or combined with 2 Gy TBI (day 0). Donors were related (n = 43) or unrelated (n = 57). When a planned interim analysis showed superior progression-free survival in the TBI arm (P = .04), all subsequent patients received TBI. With a follow-up of 12 to 40 months (median, 20), the 1-year overall survival was 80% for the TBI arm and 69% for the non-TBI arm. The 1-year cumulative incidence of relapse was 22% and 34%, respectively (P = .06). Among patients with low-risk disease the 1-year relapse incidence was 15% and 31% (P = .20) and for patients with high-risk disease, 26% and 36% (P = .18), respectively. Among MDS patients the 1-year relapse incidence was 27% versus 33% (P = .49) and among AML patients 16% versus 35% (P = .05), respectively. The largest difference was among patients with unfavorable cytogenetics, with 1-year relapse incidences of 31% and 63% (P = .18), respectively. Nonrelapse mortality in this high-risk patient population was 9% at 6 months and did not differ between arms. Thus, treosulfan/fludarabine/low-dose TBI provided effective conditioning for allogeneic hematopoietic cell transplantation in high-risk patients up to 70 years of age. The addition of TBI had a more profound effect in patients with AML than in those with MDS. High-risk disease features were associated with a lower overall success rate. Further studies are warranted.