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Non-Hispanic Black (NHB) and Hispanic patients with acute myeloid leukemia (AML) have higher mortality rates than non-Hispanic White (NHW) patients despite more favorable genetics and younger age. A discrete survival analysis was performed on 822 adult patients with AML from 6 urban cancer centers and revealed inferior survival among NHB (hazard ratio [HR] = 1.59; 95% confidence interval [CI]: 1.15, 2.22) and Hispanic (HR = 1.25; 95% CI: 0.88, 1.79) patients compared with NHW patients. A multilevel analysis of disparities was then conducted to investigate the contribution of neighborhood measures of structural racism on racial/ethnic differences in survival. Census tract disadvantage and affluence scores were individually calculated. Mediation analysis of hazard of leukemia death between groups was examined across 6 composite variables: structural racism (census tract disadvantage, affluence, and segregation), tumor biology (European Leukemia Network risk and secondary leukemia), health care access (insurance and clinical trial enrollment), comorbidities, treatment patterns (induction intensity and transplant utilization), and intensive care unit (ICU) admission during induction chemotherapy. Strikingly, census tract measures accounted for nearly all of the NHB-NHW and Hispanic-NHW disparity in leukemia death. Treatment patterns, including induction intensity and allogeneic transplant, and treatment complications, as assessed by ICU admission during induction chemotherapy, were additional mediators of survival disparities in AML. This is the first study to formally test mediators for observed disparities in AML survival and highlights the need to investigate the mechanisms by which structural racism interacts with known prognostic and treatment factors to influence leukemia outcomes.

Patients who have undergone hematopoietic stem cell transplant (HSCT) may experience cognitive impairment that can persist after treatment. Several studies have shown that bright light therapy may improve cognition, potentially due to its effects on the circadian system via brain regions that respond preferentially to light. In this double-blind randomized controlled trial, the efficacy of bright light therapy on cognition was examined in HSCT survivors. Forty-seven HSCT survivors at an urban hospital in the United States were screened for mild cognitive impairment, randomized to either bright white light (BWL) or comparison dim red light (DRL) conditions using a block randomization approach, and instructed to use their assigned light box every morning upon awakening for 30 min for 4 weeks. Assessments occurred at baseline, the end of the second week of the intervention, the end of the intervention, and at follow-up (8 weeks later). The primary outcome was objective cognitive function as measured by a global composite score on neuropsychological tests. Secondary outcomes included cognitive performance in individual domains, self-reported cognitive function, fatigue, sleep and sleep quality, and circadian rhythm robustness. Repeated-measures linear mixed models for both objective and self-reported cognitive function indicated significant main effects for time ( ps < 0.05) suggesting significant improvements in both conditions over time. Time by light condition interaction effects were not significant. Models focused on secondary outcomes yielded no significant effects. Both BWL and DRL groups demonstrated significant improvements in objective cognitive and self-reported cognitive function over time, but there was no hypothesized effect of BWL over DRL nor associations with circadian rhythm robustness. Therapeutic effects of both light conditions, practice effects, and/or placebo effects may account for the findings. Trial registration: ClinicalTrials.gov Identifier: NCT02677987 (9 February 2016)

Racial disparities in acute myeloid leukemia (AML) have been reported but the relative contribution of disease versus patient-specific factors including comorbidities and access to care is unclear. We conducted a retrospective analysis of patient characteristics, treatment patterns and outcomes in a racially diverse patient cohort controlling for cytogenetic risk group. Patients were classified into four groups: non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic and Other. We evaluated 106 patients from 84 zipcodes incorporating demographics, clinicopathologic features, treatment patterns and outcomes. We identified significant differences in BMI and geographic poverty based on ethnoracial group, while prognostic mutations in NPM1 and FLT3 did not differ significantly. Utilization of intensive chemotherapy and transplant rate did not differ by ethnoracial group. However, there was a significantly higher use of alternate donor transplants in minority populations. There was a notably increased rate of clinical trial enrollment in NHW patients compared to other groups. In log-rank analysis, NHW patients had increased overall survival (OS) compared to NHB, Hispanic and Other patients (31.6 months vs. 16.7 months vs. 14.3 months, vs 18.1 months, p = 0.021). In bivariate analysis, overall survival was negatively influenced by advanced age and race. Obesity and zip code poverty levels approached statistical significance in predicting OS. In multivariate analysis, the only factors independently influencing OS were race and allogeneic stem cell transplant. These results suggest that race impacts survival in intermediate-risk AML, highlighting the need to dissect biologic and nonbiologic factors that contribute to this disparity.

The reduced-intensity conditioning regimen, fludarabine and melphalan 140 mg/m2 (FM140), is widely adopted in practice. Pharmacokinetic studies report 10-fold interpatient variability in melphalan exposure. We identified low hemoglobin (Hb) and/or creatinine clearance (CrCl), determinants of melphalan pharmacokinetic, as strong predictors of outcomes after high-dose melphalan and autologous transplant. We hypothesized that these variables could predict for outcomes after FM140. Overall survival was shorter in patients with a lower Hb (113 vs. 2536 days; p = 0.004), due to an increased rate of nonrelapse mortality (NRM) ( p = 0.0005). Overall survival was also worse in patients with lower CrCl (75 vs. 317 days; p = 0.003), with a significantly worse nonrelapse mortality ( p = 0.0023). In a multivariate analysis, a higher Hb and CrCl predicted for better overall survival ( p = 0.017). In patients with a lower Hb, the median duration of hospitalization ( p = 0.02) and the mean duration of diarrhea ( p = 0.008) were longer. In patients with a lower CrCl, the median duration of hospitalization ( p = 0.06) and the mean duration of diarrhea ( p = 0.0009) longer, and the rate of infection was higher ( p = 0.02). We show for the first time that Hb and CrCl represent important determinants of outcomes after FM140, suggesting that pharmacokinetic-directed dosing may be beneficial in achieving optimal outcomes.

AIMS: High dose melphalan (HDM) and autologous stem cell transplant (ASCT) is standard of care for multiple myeloma (MM), but there is significant variability in melphalan exposure (area under the plasma drug concentration–time curve, AUC) when using body surface area‐based dosing. Our aim was to establish a method of pharmacokinetic (PK) testing for real‐time melphalan dose adjustments. METHODS: We performed a prospective PK study of melphalan 140 or 200 mg/m(2) in MM patients undergoing ASCT. Twenty MM patients were administered HDM on days −2 and − 1, with PK sampling at 8–10 time points. PK testing was performed on day −2 in all patients, and on day −1 in 5 patients. RESULTS: Less than 20% interpatient variation in the day −2 and − 1 AUC was observed. The day −2 range in AUC (4.95–11.28 mg h/L) confirmed significant interpatient variability. The hypothetical total dose ranged from 133–302 mg/m(2) to achieve the total median AUC. A 4‐time point AUC (0, 30, 150 and 240 min) highly correlated with the AUC from the 8‐time point schedule. A higher AUC correlated with increased risk of febrile neutropenia (P = .05). CONCLUSION: Here we outline the methods to establish novel melphalan dosing using PK testing in MM patients undergoing ASCT to target a desired melphalan AUC.

Introduction: Belumosudil (KD025) is a novel oral selective rho-associated coiled-coil kinase 2 (ROCK2) inhibitor specifically designed for the treatment of cGVHD, an immune-mediated inflammatory and fibrotic disorder. In a previous dose-finding study (KD025-208, N=54), two-thirds of patients, including those with fibrotic and inflammatory manifestations, achieved a partial or complete response with belumosudil. Herein, we report on the top-line results (6 months after the last patient in) from the pivotal phase 2 trial (ROCKstar [KD025-213], N=132). Methods: This phase 2, open-label, randomized, multicenter study evaluated belumosudil 200 mg QD (n=66) and BID (n=66) in patients with cGVHD who received 2 to 5 prior lines of therapy (LOT). Treatment continued until clinically significant progression of cGVHD. The primary end point was overall response rate (ORR), defined per the 2014 National Institutes of Health Consensus Criteria. Additional end points included duration of response (DOR), Lee Symptom Scale (LSS) score, failure-free survival (FFS), corticosteroid (CS) dose reductions and overall survival. The study was powered such that the lower bound of the 95% confidence interval (CI) excludes 30%, with appropriate multiplicity adjustment. Results: At enrollment, the median age was 56 years, the median time from cGVHD diagnosis to enrollment was 29 months, 67% of patients had severe cGVHD, 52% had ≥4 organs involved, 72% had received ≥3 prior LOT (including ibrutinib [n=46] or ruxolitinib [n=38]) and 73% were refractory to their last LOT. The baseline characteristics of both arms were well balanced. With a median follow-up of 8 months, the ORR (95% CI) with belumosudil 200 mg QD and BID was 73% (60%-83%) and 74% (62%-84%), respectively (Table 1). In patients who previously received ruxolitinib (29%), the ORR with belumosudil 200 mg QD and BID was 65% (41%-85%) and 72% (47%-90%), respectively. In patients who previously received ibrutinib (35%), the ORR with belumosudil 200 mg QD and BID was 73% (50%-89%) and 71% (49%-87%), respectively. High ORRs were seen in all patient subgroups, regardless of length of time from diagnosis to treatment, including those with severe cGVHD, involvement of ≥4 organs and a refractory response to prior LOT (Figure 1). The response rate was similar across all affected organs. The median time to response was 4 weeks. Of responders, 49% have maintained response for ≥20 weeks. The median DOR has not yet been reached. Clinically meaningful improvement (≥7-point reduction) in LSS score on consecutive assessments was observed in 39% and 33% of patients in the QD and BID groups, respectively. Both responders (43%) and nonresponders (17%) experienced a clinically meaningful improvement in LSS score. FFS was 77% (69%-84%) at 6 months. CS and calcineurin inhibitor discontinuations were seen in 18% and 13% of patients, respectively. Belumosudil was well tolerated, with >95% relative dose intensity in 83% of patients. Drug discontinuation occurred in 10% of patients due to possible drug-related adverse events (AEs), 3% due to progression of underlying disease and 12% due to progression of cGVHD. AEs were consistent with those expected in patients with cGVHD receiving CS and other immunosuppressants (Table 2). Common AEs included fatigue (32%), diarrhea (29%), nausea (26%), cough (24%), dyspnea (24%), upper respiratory tract infection (23%), peripheral edema (21%) and headache (20%). At least 1 serious AE occurred in 34% of patients. Twenty-three percent of patients had at least 1 liver-related investigation; the most common was increased gamma-glutamyltransferase (11%), and only 1 patient showed an increase in bilirubin. Eight patients died during the study; 5 due to AEs (1 possibly related to belumosudil) and 3 during long-term follow-up (>28 days after last dose). There were no reports of cytomegalovirus reactivation or infection. Conclusion: Treatment with belumosudil at both doses resulted in high ORRs across key subgroups, meeting the primary end point of this pivotal randomized trial in cGVHD. Responses were durable and clinically meaningful, irrespective of patient and cGVHD characteristics, and were seen in patients who previously received ruxolitinib and ibrutinib. Belumosudil was well tolerated, with limited and manageable AEs. Further studies will evaluate its use earlier in disease management. The 12-month data analysis will be presented at ASH 2020. Download : Download high-res image (508KB) Download : Download full-size image Disclosures Cutler: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lee: Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Amgen: Research Funding; Kadmon: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Syndax: Research Funding. Rotta: Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Ramakrishnan: Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cigna: Honoraria. Eiznhamer: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Schueller: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Yang: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Green: Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Aggarwal: Kadmon Corporation, LLC: Consultancy; Angiocrine Bioscience, Inc: Current Employment, Other: stock options. Blazar: BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Fate Therapeutics Inc.: Research Funding; Magenta Therapeutics: Consultancy; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder. Jagasia: Ocugen: Other; Mallinckrodt: Research Funding; Janssen: Research Funding.

Background: Acute graft versus host disease (aGVHD) affects approximately 30–60% of patients after allogeneic hematopoietic stem cell transplantation (HCT) and our ability to predict who develops this complication and their response to treatment is limited. Fecal calprotectin has recently gained popularity as an effective marker of GI inflammation in patients with Inflammatory Bowel Disease (IBD). Methods: Fecal calprotectin and albumin were evaluated as prognostic and predictive markers of aGVHD in 60 adult and pediatric HCT patients. Stool samples were sent for calprotectin quantification prior to starting conditioning, at day 14 post-HCT, at day 28 post-HCT, and at onset of aGVHD ± 2 days. Results: Fecal calprotectin did not differentiate patients with GI-GVHD and non-GI GVHD and did not vary based on severity. However, in patients with steroid-refractory GI aGVHD, significantly higher fecal calprotectin levels were noted. At onset of lower-GI symptoms, steroid refractory patients (n = 3) had a mean fecal calprotectin level of 449 ug/g (range 116–1111 ug/g) and a mean albumin of 1.93 g/dL (range 1.6–2.3 g/dL) compared with a mean fecal calprotectin of 24 ug/g (range 16–31 ug/g) and a mean albumin of 3.3 g/dL (range 2.3–3.9 g/dL) in steroid responsive patients (n = 9) (fecal calprotectin p = 0.032, albumin p = 0.027). Conclusion: Patients with steroid-refractory GI aGVHD had higher fecal calprotectin levels and lower albumin levels than patients with steroid-responsive disease. We recommend further studies to evaluate non-invasive tests with fecal calprotectin in combination with albumin in predicting steroid refractory disease at onset of symptoms to potentially identify patients that may benefit from upfront escalation in GVHD treatment. Keywords: GVHD, Calprotectin, Albumin

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and nonmalignant diseases. Despite increasing survival rates, long-term morbidity after HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction after HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction after HCT. In this review we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Finally, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae after HCT.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and non-malignant diseases. Despite increasing survival rates, long-term morbidity following HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction following HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction following HCT. In this review, we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and to help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Lastly, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae following HCT.

Introduction Inflammatory monocytes are recruited to target organs during acute Graft versus Host Disease (aGVHD). As seen in other autoimmune disorders, inflammatory monocytes play an important role in antigen presentation and cytokine production. These actions allow for a sustained activation and proliferation signal to T-cells. Objective Previous studies have shown that IMP treatment in mouse models of colitis, encephalitis, myocardial infarction and peritonitis markedly reduced monocyte accumulation in the affected end-organs – promoting tissue repair; reducing disease symptoms and increasing survival. Therefore, our objective was to test clinical outcomes after IMP treatment in a mouse model of aGVHD. Methods Murine aGVHD model: BALB/c mice were given 800 cGy total body irradiation, irradiated BALB/c mice were transplanted with 5 × 106 C57BL/6 bone marrow cells and 1 × 106 C57BL/6 spleen cells via tail vein. IMP treatment: IMPs were made with PLGA (Phosphorex Inc, Hopkinton MA) was administered to the recipient mice (1.4 mg/kg body weight) by IV daily starting from day 5 to day 10 after bone marrow transplantation (BMT). PBS at the same volume was used as vehicle control. In vivo bioluminescence imaging: Mice were given an intraperitoneal injection of luciferin (150 mg/kg body weight) and then anesthetized and imaged using the IVIS Imaging system (Xenogen). Imaging data were analyzed and quantified with Living Image Software (Xenogen). Results IMP treated mice had significantly less severe acute GVHD symptoms (average score of 2.48) than the untreated BM+Sp group (average score 3.96) starting at the time of IMP treatment (days 5-10) and remained with significantly reduced symptoms for the 30 day course (Figure 1). IMP treatment also rescued BM+Sp mice from aGVHD associated mortality with a 30-day overall survival of 62% compared to 4% in the untreated BM+Sp group (Figure 2). Intestinal tissue from the IMP treated mice compared to the BM+Sp mice demonstrated less evidence of aGVHD (an average score of 1.25 and 2.75, respectively). Hepatic tissue from the IMP treated mice compared to the BM+Sp mice demonstrated less evidence of aGVHD (an average score of 1.5 and 2.42, respectively) (Figure 3). IMP treatment also significantly reduced INF-γ levels in the intestinal tissues of treated mice compared to untreated BM+Sp mice. In the mice infused with lymphoma cells (A20-luc), IMP treatment reduced aGVHD symptoms and death while preserving the GVL effect. (Figure 4) Conclusions Our results demonstrate that IMPs significantly reduce symptoms and mortality in a murine model of aGVHD while preserving GVL. The reduction in inflammatory monocytes with IMPs leads to a reduction in inflammatory cytokines, hepatic lymphocyte infiltration and intestinal mucosal denudation. These findings highlight the potential of IMP therapy as a specific and potentially safe treatment in acute GVHD.

Summary Immunosenescence is a state of unbalanced immune responsiveness, characterized by a diverse repertoire of seemingly discreet and paradoxical alterations in all aspects of immunity arising in an aging‐associated manner. We asked whether aging‐associated alterations in the ability of apoptotic cells to elicit immunomodulatory responses (innate apoptotic immunity; IAI) or in IAI responses themselves might underlie the confounding aging‐associated anomalies of immunosenescence. We explored this question by examining, as a function of animal age, responsiveness of murine macrophages on the single cell level. We monitored the expression of pro‐ and anti‐inflammatory cytokines cytofluorimetrically in response to pro‐inflammatory Toll‐like receptor (TLR) stimulation and anti‐inflammatory treatment with apoptotic cells. While we found no alterations with age in the potency of apoptotic cells or in the initiation and magnitude of IAI responses, we did identify a cell‐intrinsic deficiency in anti‐inflammatory IAI response termination linked with age and preceding manifestations of immunosenescence. Further, we found that an aging‐associated deficiency in response termination also is evident following TLR stimulation. These surprising observations reveal that a loss of homeostatic immune control with animal age results from the dysregulation of response termination (as distinct from response initiation) and is exerted on the level of transcription. We suggest that, with advancing age, cells become locked into relatively longer‐lived response states. Aging‐associated immune dysfunctions may reflect a diminution in the cellular nimbleness of immune responsiveness.

The reduced-intensity conditioning (RIC) regimen consisting of fludarabine and melphalan 140 mg/m2 (Flu/Mel140) has been widely adopted in clinical practice. Pharmacokinetic (PK) studies report up to 10-fold interpatient variability in melphalan exposure. We previously identified low Hgb and/or creatinine clearance (CrCl), both determinants of melphalan PK, as strong predictors of survival and toxicity after high dose melphalan and autologous transplant. We thus hypothesized that these clinical variables could also predict for outcomes after Flu/Mel140 and hematopoietic stem cell transplantation (HSCT). Day -6 Hgb was grouped as low or high relative to the median ( The median overall survival (OS) was significantly shorter in patients with a lower Hgb compared to a higher Hgb (113 vs. 2536 days; p=0.004). This difference was due to an increased rate of transplant-related mortality (TRM) (26 (81.3%) versus 11 (36.7%) patients; p=0.0005). The median OS was also worse in patients with lower CrCl (75 vs. 317 days; p=0.003), with a significantly worse TRM (10 (90.1%) versus 27 (52.9%); p=0.0023). Multivariate Cox proportional hazards model adjusted for clinical and prognostic factors found that a higher Hgb predicted for better OS (HR 0.12, 95% CI 0.03-0.52; p=0.004) and TRM (HR 0.13, 95% CI 0.03-0.53); p=0.004). A higher Hgb and CrCl predicted for better OS (HR 0.08, 95% CI 0.01-0.63; p=0.017) and trended towards a decreased rate of TRM (HR 0.16, 95% CI 0.02-1.43; p=0.102). We then analyzed toxicity. In patients with a lower Hgb, the median duration of hospitalization (35 vs. 29 days; p=0.02) and the mean duration of diarrhea (14.6 vs. 7.2 days; p=0.008) were longer. In patients with a lower CrCl, the median duration of hospitalization (40 vs. 29 days; p=0.06) and the mean duration of diarrhea (20.9 vs. 8.6 days; p=0.0009) longer, and the rate of infection was higher (90.9% vs. 49.1%; p=0.02). We show for the first time that lower Hgb and CrCl represent important determinants of toxicity and TRM after Flu/Mel140 and HSCT. These findings are consistent with PK studies showing increased melphalan exposure in patients with low Hgb and CrCl. Our data suggest that consideration of clinical factors that affect melphalan exposure and implementation of PK-directed dosing may be beneficial in achieving optimal outcomes after Flu/Mel140.

High dose melphalan (HDM) and autologous stem cell transplantation (ASCT) is standard of care for multiple myeloma (MM). However, ∼40% of patients fail to achieve complete remission, in part due to variability in melphalan exposure (AUC) when using body-surface-area (BSA)-based dosing, which results in suboptimal exposure and response. HDM, 100mg/m2 on day -2 and -1, allows for potential day -1 dose modification if day -2 pharmacokinetic (PK) testing with rapid turnaround is performed. Here we describe a clinically reproducible method of PK testing that allows for real-time HDM dose adjustments. We developed an in-house melphalan assay and performed PK analysis using LC-MS/MS. Adult MM patients were administered HDM on days -2 and -1 prior to ASCT. Blood for PK sampling were drawn at 10 time points post-infusion on day -2 and day -1 in the first 5 patients and day -2 in the remainder. PK parameters were determined from plasma concentration versus time data by a noncompartmental analysis using WinNonlin 8.1. Toxicities up to 30 days after ASCT and day 90 disease response were analyzed. Eighteen patients received 200mg/m2 and 2 received 140mg/m2. Day -2 and -1 AUC correlated well (r=0.8), allowing for a method of dose adjustment using linear, dose-proportional calculations for future PK-directed studies. We observed a 2.3-fold variation in melphalan exposure within our patient cohort, with a median day -2 AUC of 7.49 (range: 4.95-11.28) mg*h/L, confirming significant interpatient variability. We then calculated the theoretical absolute day -1 dose required to target the total median melphalan AUC and compared it to the BSA-based dose. The change in day -1 dose ranged from -124 mg to +206 mg (Figure 1A). When expressed as BSA-based mg/m2/dose, we found that doses ranging from 133-308 mg/m2 were required to target the total median AUC (Figure 1B). Using D-optimality, we determined that reducing blood sampling (4 time points) did not affect AUC prediction, confirmed by comparing mean AUCs between both sampling schedules (7.76 vs. 7.80 mg*h/L; p=0.8193). We examined associations between AUC and clinical outcomes. In modified Poisson regression, higher AUC correlated with increased risk of febrile neutropenia (p=0.05) and a trend towards increased use of antiemetics (p=0.07). Collection of disease response data is ongoing. We report minimal intrapatient variability in melphalan day -2 and -1 AUC allowing a linear, dose-proportional method of dose-adjustment without need for a pre-transplant test dose. Dose adjustment simulations based on patients' PK data demonstrate that large, bi-directional dose adjustments are required to target a median AUC, emphasizing the importance of PK-directed HDM dosing. This novel dosing approach using rapid melphalan PK testing in MM patients undergoing ASCT will decrease interpatient variability and improve myeloma outcomes.

Emerging evidence suggests that psychosocial factors pre-transplant predict survival in cancer patients undergoing hematopoietic stem cell transplantation (HSCT). These studies, however, typically have small sample sizes, short-term follow ups or a limited panel of medical covariates. We extend this research in a large, well-characterized sample of transplant patients, asking whether patients' perceived emotional support and psychological distress predict mortality over 2 years. Prior to transplant, 400 cancer patients (55.5% males; 82.8% White; Mage=50.0 years; 67.0% leukemia, 20.0% lymphoma) were interviewed by a social caseworker, who documented the patients' perceived emotional support and psychological distress. Subsequently, patients received an allogeneic HSCT (51.0% matched-related donor, 42.0% matched-unrelated donor and 7.0% cord blood). HSCT outcomes were obtained from medical records. Controlling for demographic characteristics (age, sex, race/ethnicity and marital status) and medical confounders (disease type, conditioning regimen, remission status, cell dosage, donor and recipient CMV seropositivity, donor sex, comorbidities and disease risk), ratings of good emotional support pre-transplant predicted longer overall survival (hazard ratio (HR)=0.61, 95% confidence interval (CI), 0.42-0.91; P=0.013). Pre-transplant psychological distress was unrelated to survival, however (Ps>0.58). Emotional support was marginally associated with lower rates of treatment-related mortality (HR=0.58, CI, 0.32-1.05; P=0.073). These findings are consistent with the hypothesis that emotional support contributes to better outcomes following HSCT. Future studies should examine whether intervention efforts to optimize emotional resources can improve survival in cancer patients.

We evaluated the feasibility of ruxolitinib therapy followed by a reduced-intensity conditioning (RIC) regimen for patients with myelofibrosis (MF) undergoing transplantation in a 2-stage Simon phase II trial. The aims were to decrease the incidence of graft failure (GF) and nonrelapse mortality (NRM) compared with data from the previous Myeloproliferative Disorders Research Consortium 101 Study. The plan was to enroll 11 patients each in related donor (RD) and unrelated donor (URD) arms, with trial termination if ≥3 failures (GF or death by day +100 post-transplant) occurred in the RD arm or ≥6 failures occurred in the URD. A total of 21 patients were enrolled, including 7 in the RD arm and 14 in the URD arm. The RD arm did not meet the predetermined criteria for proceeding to stage II. Although the URD arm met the criteria for stage II, the study was terminated owing to poor accrual and a significant number of failures. In all 19 transplant recipients, ruxolitinib was tapered successfully without significant side effects, and 9 patients (47%) had a significant decrease in symptom burden. The cumulative incidences of GF, NRM, acute graft-versus-host disease (GVHD), and chronic GVHD at 24 months were 16%, 28%, 64%, and 76%, respectively. On an intention-to-treat basis, the 2-year overall survival was 61% for the RD arm and 70% for the URD arm. Ruxolitinib can be integrated as pretransplantation treatment for patients with MF, and a tapering strategy before transplantation is safe, allowing patients to commence conditioning therapy with a reduced symptom burden. However, GF and NRM remain significant.

Ocular graft-versus-host disease (GVHD) occurs in more than half of patients who develop chronic GVHD after allogeneic hematopoietic cell transplantation (HCT), causing prolonged morbidity, which affects activities of daily living and quality of life. Here we provide an expert review of ocular GVHD in a collaboration between transplant 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 in this review. Ocular GVHD has at least three biological processes: lacrimal gland dysfunction, meibomian gland dysfunction, and corneoconjunctival inflammation. Preclinical models have found several novel pathogenic mechanisms, including renin angiotensin system and endoplasmic reticulum stress signaling that can be targeted by therapeutic agents. Many studies have identified reliable tests for establishing diagnosis and response assessment of ocular GVHD. Efficacy of systemic and topical treatment for ocular GVHD is summarized. It is important for all health professionals taking care of HCT recipients to have adequate knowledge of ocular GVHD for optimal care.

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. ispartof: Biol Blood Marrow Transplant vol:25 issue:2 pages:e46-e54 ispartof: location:United States status: published

Topic Significance & Study Purpose/Background/Rationale Online search engines, forums and social networks can offer an important space to ask questions and share experiences. Symptoms from Graft versus Host Disease (GVHD) can seriously impact the quality of life in patients and the family and/or friends who take care of them. While online searches, forums and social networks has become one of the most popular ways that people learn about diseases, not much is known about which online sources receive the most engagements as measured my sharing on social networks (Facebook, Twitter, Pintrest, Reddit). Methods, Intervention, & Analysis Our objective was to analyze the sites with the most engagement online on the topic of graft versus host disease. We used an online analytical research program (BuzzSumo), which can assess specific content and identify sites that generate the greatest frequency of engagement across social platforms. Our analysis covered activity from 10/2016 to 10/2018. Findings & Interpretation From the analysis of 1852 online articles on GVHD and 32,299 engagements, we found that the social network that was used the most was Facebook and to a much lesser extent Twitter. The Pinterest and Reddit platforms were not engaged on this topic. Most engagement was due to online articles on GVHD for both Facebook and Twitter with a significantly lesser amount of engagement for video content. Articles on GVHD ranging from 1000-3000 words created more engagement than articles that were either very brief ( 3000). Sites that generated the most engagement was from established medical journals and medical news sources. An analysis of 771 Facebook posts on GVHD with 163,555 engagements revealed that images and video posts generated the most engagements and that posts that were >300 characters generated more engagement. An analysis of questions asked online mentioning GVHD revealed that the most common topics were that of “experience” and sites of involvement (gut or skin). Discussion & Implications Online articles and social networks have become integrated into our daily lives. It is important that we start to understand how these information sources are being used by patients, caregivers and health care providers. Our analysis of online engagement on the topic of GVHD is an example of how analytical programs can be used to help understand where and how people are engaging to learn and share their experiences with GVHD.

The development of organ transplantation as a therapy for end-stage organ failure is among the most significant achievements of 20th century medicine, but chronic rejection remains a barrier to achieving long-term success. Current therapeutic regimens consist of immunosuppressive drugs that are efficient at delaying rejection but are associated with significant risks such as opportunistic infections, toxicity, and malignancy. Thus, the induction of specific immune tolerance to transplant antigens is the coveted aim of researchers. The use of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (ECDI)-treated, autoantigen-coupled syngeneic leukocytes has been developed as a specific immunotherapy in preclinical models of autoimmunity and is currently in a phase II clinical trial for the treatment of multiple sclerosis. In this review, we discuss the use of allogeneic ECDI-treated apoptotic donor leukocytes (allo-ECDI-SP) as a strategy for inducing antigen-specific tolerance in allogeneic transplantation. Allo-ECDI-SP therapy induces long-term systemic immune tolerance to transplant antigens by subverting alloimmune recognition and exploiting apoptotic cell uptake pathways to recapitulate innate mechanisms of peripheral tolerance. Lastly, we discuss potential indications and challenges for transitioning allo-ECDI-SP therapy into clinical practice.

Nineteen subjects have more than 18 months' follow-up in a phase IIb tolerance protocol in HLA-mismatched recipients of living donor kidney plus facilitating cell enriched hematopoietic stem cell allografts (FCRx). Reduced intensity conditioning preceded a kidney allograft, followed the next day by FCRx. Twelve have achieved stable donor chimerism and have been successfully taken off immunosuppression (IS). We prospectively evaluated immune reconstitution and immunocompetence. Return of CD4 and CD8 T central and effector memory cell populations was rapid. T-cell receptor (TCR) Excision Circle analysis showed a significant proportion of chimeric cells produced were being produced de novo. The TCR repertoires posttransplant in chimeric subjects were nearly as diverse as pretransplant donors and recipients, and were comparable to subjects with transient chimerism who underwent autologous reconstitution. Subjects with persistent chimerism developed few serious infections when off IS. The majority of infectious complications occurred while subjects were still on conventional IS. BK viruria and viremia resolved after cessation of IS and no tissue-invasive cytomegalovirus infections occurred. Notably, although 2 of 4 transiently or nonchimeric subjects experienced recurrence of their underlying autoimmune disorders, none of the chimeric subjects have, suggesting that self-tolerance is induced in addition to tolerance to alloantigen. No persistently chimeric subject has developed donor-specific antibody, and renal function has remained within normal limits. Patients were successfully vaccinated per The American Society for Blood and Marrow Transplantation guidelines without loss of chimerism or rejection. Memory for hepatitis vaccination persisted after transplantation. Chimeric subjects generated immune responses to pneumococcal vaccine. These data suggest that immune reconstitution and immunocompetence are maintained in persistently chimeric subjects.

Background: Non-Hispanic Black (NHB) and Hispanic patients with Acute Myeloid Leukemia (AML) have higher mortality rates than non-Hispanic white (NHW) patients despite a lower incidence of disease, more favorable genetics and younger age at presentation (Patel. AJCO 2015). It is unknown whether these disparities are linked to disease biology or treatment approach. Prior large database analyses have suggested that differences in AML outcomes may be impacted by socioeconomic factors such as insurance status and household income but lack data regarding treatment details including complications and molecular disease features (Bhatt. Blood Advances 2018). We postulate that increased mortality rates for NHB and Hispanic patients with AML are driven by disparities in treatment patterns when adjusted for baseline disease risk. Methods: We have analyzed data collected on consecutive adult patients diagnosed with AML between 2012 and 2018 from 5 academic cancer centers in Chicago surveying different population subsets using an IRB approved protocol. Figure 1 shows insurance status of the patient cohort by zip code. Cox proportional hazards models will be used to estimate multivariable-adjusted hazard ratios for relapse and mortality. Baseline models will be adjusted for age, gender and race/ethnicity to estimate the hazard ratios for the NHB-NHW and Hispanic-NHW disparities in time to relapse and treatment-related or disease-related mortality. Results: At the time of abstract submission 263 subjects were included in the analysis. The study is actively accruing at all 5 institutions with a database goal of 700 patients. There are significant differences in baseline characteristics by race/ethnicity (Table 1). NHB patients are younger, less likely to be married, and less likely to be privately insured than NHW (20% vs >51%). Hispanic patients are younger and more likely to be uninsured than NHW patients (30% vs 6%), likely reflective of County Hospital patients. In this preliminary dataset, clinical trial enrollment rates were similar by race/ethnicity. The distribution of ELN risk groups (Dohner. Blood 2017) and therapy-related AML (t-AML) cases were also similar by race/ethnicity. Eighty percent of patients received intensive induction chemotherapy (Fig 2). Receipt of intensive therapy did not differ by race but was more prevalent in younger patients and uninsured patients (Table 2), likely related to concerns about outpatient medication coverage. Elderly, adverse ELN risk and t-AML patients were less likely to receive intensive chemotherapy, likely due to poorer performance status in the elderly and potential chemo-resistance in p53mut AML. Treatment complications during induction chemotherapy, as captured by ICU admissions, were significantly lower in NHW patients, and significantly increased in morbidly obese patients. Treatment failure, by IWG criteria, did not differ by race but rather was determined by disease specific factors including ELN group, and t-AML. Relapse risk was higher in FLT3-ITD mutant cases. Allogeneic transplant rates did not differ significantly by race but were higher in adverse ELN groups and in privately insured patients. Two-year survival was affected by individual and disease specific factors including age, Medicare enrollment, t-AML and ELN risk group. Discussion: Our current dataset (n = 263) highlights disparities in treatment approaches in patients with AML. These include i) the preferential utilization of intensive induction chemotherapy in younger patients and those lacking high risk molecular features, and ii), the influence of payer status and molecular risk on utilization of allogeneic stem cell transplant in first remission. Treatment outcomes in AML were also impacted by patient age, morbid obesity, marital status, and payer source in addition to known prognostic disease-specific factors (ELN risk group and t-AML). This large multi-institutional study has advantages over population-based registries (SEER, NCDB) through incorporation of molecular characteristics, treatment responses and tolerability data not available in public datasets, which can provide insight into biologic intermediates contributing to disparities. Ongoing analyses will examine how variables such as the comorbidity index and measures of socioeconomic status interact with molecular risk factors to determine outcomes in this diverse patient population. Disclosures Stock: Research to Practice: Honoraria; Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria. Galvin:Incyte: Consultancy. Altman:prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cancer Expert Now: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; France Foundation: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead. Quigley:Alexion: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; TEVA: Research Funding. Khan:Amgen: Consultancy; Celgene: Consultancy; Incyte: Honoraria; Pfizer: Consultancy; Takeda: Research Funding.

Multiple myeloma (MM) patients are at higher risk for infectious complications, with viral infections having a 10-fold increased incidence compared to the general population. In particular, the risk of varicella zoster virus (VZV) reactivation increases with use of autologous stem cell transplant (ASCT), multiple lines of therapy for relapsed/refractory disease, and proteasome inhibitors (PI) or daratumumab. Since VZV reactivation can lead to significant morbidity and mortality, prophylactic strategies including vaccination are warranted. Until recently, the only available vaccination was a live attenuated vaccine with limited efficacy and generally contraindicated in these patients. An adjuvanted, recombinant vaccine, consisting of the varicella-zoster virus glycoprotein E antigen (Shingrix, GlaxoSmithKline; Triangle Park, NC) is now available. Since the use of this vaccination in MM bas been limited to the post-ASCT setting, we sought to analyze the seroconversion rates and safety of this vaccine in our MM cohort undergoing active anti-myeloma treatment. We evaluated 69 MM patients undergoing active anti-myeloma treatment who were tested at baseline for VZV antibody (Ab) status. The median age was 64 (36-92) years and most patients were female (n=37; 53.6%), African American (n=44; 63.8%), IgG subtype (n=41; 59.4%), and ISS stage 2 (n=27; 39.1%). Six (8.7%) patients were found to have high risk cytogenetics at diagnosis. The median number of prior lines of therapy was 1 (1-7), with 64 (92.8%) patients receiving a PI-based regimen, 54 (78.3%) receiving ASCT, and 7 (10.1%) receiving a daratumumab-based regimen. At the time of vaccination, 30 (43.5%) patients were receiving post-ASCT immunomodulator (IMiD) maintenance, 14 (20.3%) were receiving a PI-based regimen, and 5 (7.2%) were receiving a daratumumab-containing regimen. Five (7.2%) patients had a prior history of VZV infection, 1 (1.4%) patient was previously vaccinated, and 52 (75.4%) patients were actively receiving antiviral prophylaxis with either acyclovir or valacyclovir. To determine vaccine immunogenicity, we used a commercially available anti-VZV ELISA assay which assesses humoral immunity to multiple VZV glycoproteins. Using this test, VZV Ab seropositivity was measured at baseline and after each of the 2 vaccinations. In the entire cohort, 35 (50.7%) patients were found to be VZV Ab negative at baseline. Multivariate modified Poisson regression models with adjustment for prognostic and clinical factors were used to estimate relative risk (RR) and 95% confidence intervals for baseline VZV Ab serostatus. We identified ISS stage 3 (RR 0.43, 95% CI 0.25-0.75; p=0.0003) and prior or current daratumumab-based treatment (RR 0.12, 95% CI 0.03-0.42; p=0.001) as strong predictors of baseline VZV seronegativity; prior shingles (RR 5.03, 95% CI 1.41-17.85; p=0.013) was associated with VZV seropositivity. Forty-four (63.8%) patients received one vaccine dose, 28 (40.6%) received 2 doses, and only 2 (2.9%) refused the vaccine. The median time between both doses was 72 (54-117) days. Rates of seropositivity increased significantly from baseline, both after 1 (n=29, 87.9%; p=0.0002) and 2 (n=25, 92.6%; p=0.0001) doses. Seroconversion from baseline was observed in 13 (81.3%) and 17 (89.5%) patients after 1 and 2 doses, respectively. Two patients failed to seroconvert after 2 doses, one receiving cytotoxic chemotherapy and one receiving a daratumumab. Overall the vaccine was found to be well tolerated, with one patient reporting a grade 1 skin reaction after the first dose, without subsequent reaction with the second dose. We report the first ever experience of the use of the adjuvanted, recombinant zoster vaccine in MM patients receiving active treatment. Given the high rate of initial VZV seronegativity in this population, we were able to show high rates of seroconversion after a single vaccine dose using a commercially available assay. We also demonstrate a high vaccine uptake rate, with minimal adverse events. Finally, we report for the first time strong predictors of baseline VZV seronegativity in MM patients, in particular current or prior use of daratumumab. Complete data on seroconversion, persistence of humoral immunity, and the occurrence of VZV infection after withdrawal of antiviral prophylaxis will be updated at the meeting. Disclosures Galvin: Incyte: Consultancy. Patel:Janssen: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau.

The reduced-intensity conditioning (RIC) regimen consisting of fludarabine and melphalan 140 mg/m2 (Flu/Mel140) prior to allogeneic hematopoietic stem cell transplant (HSCT) has been widely adopted in clinical practice. However, pharmacokinetic (PK) studies report up to a 10-fold interpatient variability in melphalan exposure (AUC). Specifically, melphalan binds to proteins in the red blood cell membrane, leading to higher plasma concentrations in patients with lower hemoglobin. Likewise, since renal elimination contributes significantly to melphalan clearance (~ 40%), the presence of renal impairment also leads to higher concentrations. We previously identified lower hemoglobin and/or creatinine clearance as strong predictors of survival and toxicities after high dose melphalan and autologous transplant. Given this, we hypothesized that clinical variables, in particular, pre-treatment hemoglobin, could predict for outcomes after Flu/Mel140 and HSCT. We analyzed 67 consecutive patients who received Flu/Mel140. In addition to standard clinical parameters, hemoglobin (Hgb) and creatinine clearance (CrCl) on day -6 were obtained. Hemoglobin was grouped as low or high relative to the median ( The median overall survival (OS) was significantly shorter in patients with a lower Hgb (113 vs. 2536 days; p=0.004). This difference was attributed to an increased rate of transplant-related mortality (TRM) in patients with a lower Hgb (n=26; 81.3%) versus a higher Hgb (n=11; 36.7%) (p=0.0005). Time to relapse between patients with a lower and higher Hgb was not different (p=0.89). The median OS in patients with a lower CrCl was significantly worse (75 vs. 317 days; p=0.003). The rate of TRM was also found to be significantly worse in patients with a lower CrCl (n=10; 90.1%) compared to patients with a higher CrCl (n=27; 52.9%) (p=0.0023). Time to relapse was not different between patients with a lower and higher Cr Cl (p=0.29). Patients with both a low Hgb and CrCl experienced a shorter median OS (75 days vs. not reached; p We then analyzed regimen-related toxicities among patients with a lower and higher Hgb and lower and higher CrCl. In patients with a lower hemoglobin, the median duration of hospitalization (35 vs. 29 days; p=0.02) and the mean duration of diarrhea (14.6 vs. 7.2 days; p=0.008) were significantly longer. In patients with a lower CrCl, the median duration of hospitalization (40 vs. 29 days; p=0.06) and the mean duration of diarrhea (20.9 vs. 8.6 days; p=0.0009) were longer, and the rate of infection was higher (90.9% vs. 49.1%; p=0.02). We show for the first time that pre-treatment Hgb and CrCl represent important determinants of clinical outcomes after Flu/Mel140 and HSCT. A lower hemoglobin in particular was strongly associated with a shorter OS and TRM. This is consistent with PK studies showing increased melphalan exposure in patients with low Hgb and CrCl. We conclude that consideration of clinical factors that affect melphalan exposure and implementation of PK-directed dosing may be beneficial in achieving optimal outcomes in patients receiving FluMel140 and HSCT. Figure Disclosures Galvin: Incyte: Consultancy. Patel:Celgene: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Speakers Bureau.