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Abstract: The optimal therapy for steroid-refractory (SR) acute graft-versus-host disease (aGVHD) is undefined. We studied patients with SR aGVHD, comparing extracorporeal photopheresis (ECP; n = 57) and anticytokine therapy (n = 41). In multivariate analyses, ECP, adjusted for steroid dose (odds ratio, 3.42; P = .007), and grade >II aGVHD (odds ratio, 68; P < .001) were independent predictors of response. ECP therapy, adjusted for conditioning regimen intensity and steroid dose, was associated with superior survival (hazard ratio [HR], 4.6; P = .016) in patients with SR grade II aGVHD. Grade >II aGVHD at onset of salvage therapy (HR, 9.4; P < .001) and lack of response to therapy (HR, 3.09; P = .011) were associated with inferior survival. These findings require validation in a prospective randomized study. [Copyright &y& Elsevier]

Measurement of minimal residual disease is routine in diseases such as chronic myelogenous leukemia, precursor B cell acute lymphoblastic leukemia, and acute promyelocytic leukemia because it provides important prognostic information. However, the role of minimal residual disease testing has not been widely adopted in multiple myeloma (MM), with other parameters such as the International Staging System (ISS) and cytogenetic analysis primarily guiding therapy and determination of prognosis. Until recently, achieving a complete response (CR), as defined by the International Myeloma Working Group (IMWG) criteria, was rare in patients with MM. The use of novel agents with or without autologous peripheral blood stem cell transplantation (auto-PBSCT) has significantly increased CR rates, thus increasing overall survival (OS) rates. The majority of patients with MM have persistent levels of residual disease that are below the sensitivity of bone marrow (BM) morphology, protein electrophoresis with immunofixation, and light chain quantitation even after attaining CR and will eventually relapse. Measurement of minimal residual disease by more sensitive methods, and the use of these methods as a tool for predicting patient outcomes and guiding therapeutic decisions, has thus become more relevant. Methods available for monitoring minimal residual disease in MM include PCR and multiparameter flow cytometry (MFC), both of which have been shown to be valuable in other hematologic malignancies; however, neither has become a standard of care in MM. Here, we review current evidence for using minimal residual disease measurement for risk assessment in MM as well as incorporating pretreatment factors and posttreatment minimal residual disease monitoring as a prognostic tool for therapeutic decisions, and we outline challenges to developing uniform criteria for minimal residual disease monitoring. [Copyright &y& Elsevier]

Relapse remains a major cause of death after allogeneic hematopoietic cell transplantation (allo-HCT). Graft-versus-tumor effect is primarily mediated by donor T cells. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a critical inhibitor of T cell proliferation. Single nucleotide polymorphisms (SNPs) in CTLA-4 may affect immune responses. We hypothesized that CTLA-4 SNPs will be associated with disease control after allo-HCT. One hundred sixty-four adult patients with the availability of pretransplantation recipient and donor DNA samples were included in this analysis. Ten tagSNPs of the CTLA-4 gene were identified. Donor CTLA-4 SNP rs4553808 was associated with decreased relapse-free survival (RFS) (P = .019) and overall survival (OS) (P = .033). In multivariable analysis of an additive genetic model, genotype of CTLA-4 SNP rs4553808 was an independent risk factor for inferior RFS (hazard ratio [HR] = 1.73, 95% confidence interval [CI] 1.10-2.71, P = .017) and OS (HR = 1.84, 95% CI 1.13-3.0, P = .015). CTLA-4 SNPs can be used to identify high-risk patient subsets that may benefit from preemptive immunomodulation to decrease relapse rates and improve survival. [ABSTRACT FROM AUTHOR]

Risk factors for acute GVHD (AGVHD), overall survival, and transplant-related mortality were evaluated in adults receiving allogeneic hematopoietic cell transplants (1999-2005) from HLA-identical sibling donors (SDs; n = 3191) or unrelated donors (URDs; n = 2370) and reported to the Center for International Blood and Marrow Transplant Research, Minneapolis, MN. To understand the impact of transplant regimen on AGVHD risk, 6 treatment categories were evaluated: (1) myeloablative conditioning (MA) with total body irradiation (TBI) + PBSCs, (2) MA + TBI + BM, (3) MA + nonTBI + PBSCs, (4) MA + nonTBI + BM, (5) reduced intensity conditioning (RIC) + PBSCs, and (6) RIC + BM. The cumulative incidences of grades B-D AGVHD were 39% (95% confidence interval [CI], 37%-41%) in the SD cohort and 59% (95% CI, 57%-61%) in the URD cohort. Patients receiving SD transplants with MA + nonTBI + BM and RIC + PBSCs had significantly lower risks of grades B-D AGVHD than patients in other treatment categories. Those receiving URD transplants with MA + TBI + BM, MA + nonTBI + BM, RIC + BM, or RIC + PBSCs had lower risks of grades B-D AGVHD than those in other treatment categories. The 5-year probabilities of survival were 46% (95% CI, 44%-49%) with SD transplants and 33% (95% CI, 31%-35%) with URD transplants. Conditioning intensity, TBI and graft source have a combined effect on risk of AGVHD that must be considered in deciding on a treatment strategy for individual patients. [ABSTRACT FROM AUTHOR]

In 2005, the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic graft-versus-host disease (GVHD) proposed a new scoring system for individual organs and an algorithm for calculating global severity (mild, moderate, severe). The Chronic GVHD Consortium was established to test these new criteria. This report includes the first 298 adult patients enrolled at 5 centers of the Consortium. Patients were assessed every 3-6 months using standardized forms recommended by the Consensus Conference. At the time of study enrollment, global chronic GVHD severity was mild in 10% (n=32), moderate in 59% (n=175) and severe in 31% (n=91). Skin, lung or eye scores determined the global severity score in the majority of cases, with the other five organs determining 16% of the global severity scores. Conventional risk factors predictive for onset of chronic GVHD and non-relapse mortality in people with chronic GVHD were not associated with NIH global severity scores. Global severity scores at enrollment were associated with non-relapse mortality (p<0.0001) and survival (p<0.0001); two year overall survival was 62% (severe), 86% (moderate) and 97% (mild). Patients with mild chronic GVHD have a good prognosis, while patients with severe chronic GVHD have a poor prognosis. [ABSTRACT FROM AUTHOR]

Background aims. Previous studies have shown that rapid recovery of the absolute lymphocyte count (ALC) is associated with improved transplant outcomes after related and unrelated donor allogeneic stem cell transplantation (allo-SCT). No consistent association has been reported between lymphocyte recovery and transplant outcome after cord blood transplantation (CBT). Methods. We reviewed the records of 40 consecutive CBT patients at our institution to determine the impact of lymphocyte recovery on transplant outcome. Results. The majority of patients (83%) received CBT for hematologic malignancies. Patients with ALC ≥150/μL at 30 days post-CBT had decreased non-relapse mortality (NRM) ( P = 0.011) and improved survival ( P = 0.013) compared with ALC <150/μL. Patients with ALC <100/μL at 30 days post-CBT had a significantly higher rate of graft failure than those with ALC ≥100/μL (four of 10 versus one of 29; P = 0.011). ALC was positively correlated with the nucleated cell dose and inversely correlated with the patient's age. There was no relationship between disease risk, type of conditioning regimen, anti-thymocyte globulin and number of cord units on ALC recovery. Conclusions. Our results indicate that ALC 30 days post-CBT is a surrogate for engraftment, and that low ALC (<150/μL) identifies an 'at-risk' population of patients after CBT. Studies are needed to determine ways to increase ALC cell numbers post-CBT, including ex vivo-expanded natural killer cells using adoptive immunotherapy, which might improve outcome after CBT. [ABSTRACT FROM AUTHOR]

Posttransplantation diabetes mellitus (PTDM) is a frequent complication after allogeneic stem cell transplantation (allo-SCT), important for its negative impact on cardiovascular health. Risk factors for PTDM are not well defined. We conducted a prospective study to investigate the risk factors and incidence for PTDM in the first 100 days after allo-SCT. A total of 84 patients completed the study, 60% of whom developed PTDM. In a multivariate logistic regression model, pretransplantation c-peptide level (>3.6 ng/mL; odds ratio [OR], 5.9; 95% confidence interval [CI], 1.77-20.22; P = .004), unrelated donor allo-SCT (OR, 4.3; 95% CI, 1.34-14.2; P = .014), and peak steroid dose >1 mg/kg/day (OR, 5.09; 95% CI, 1.19-23.2; P = .035) were identified as independent predictors of PTDM. In addition, overall survival (OS) was inferior in patients with PTDM compared with those without PTDM (mean survival, 2.26 years vs 2.7 years; P = .021). Pretransplantation c-peptide level greater than the cohort median (>3.6 ng/mL) also was associated with inferior OS (mean, 1.7 years vs 2.9 years; P = .012). In a multivariate Cox proportional hazards model, high-risk disease (hazard ratio [HR], 2.34; 95% CI, 1.09-5.28; P = .029) and pretransplantation c-peptide level >3.6 ng/mL (HR, 1.05; 95% CI, 1.01-1.09; P = .013) were independent predictors of OS when adjusted for systemic steroids and regimen intensity. We suspect that diabetes mellitus in the immediate posttransplantation period may be mediated via an inflammatory pathway that contributes to insulin resistance in the host adipose tissue. Our study is the first to report the risk factors of early PTDM in patients undergoing allo-SCT and identifies pretransplantation c-peptide as an independent predictor of diabetes and survival. [ABSTRACT FROM AUTHOR]

The National Institutes of Health (NIH) classification of graft-versus-host disease (GVHD) is a significant improvement over prior classifications, and has prognostic implications. We hypothesized that the NIH classification of GVHD would predict the survival of patients with GVHD treated with extracorporeal photopheresis (ECP). Sixty-four patients with steroid refractory/dependent GVHD treated with ECP were studied. The 3-year overall survival (OS) was 36% (95% confidence interval [CI] 13-59). Progressive GVHD was seen in 39% of patients with any acute GVHD (aGVHD) (classic acute, recurrent acute, overlap) compared to 3% of patients with classic chronic GVHD (cGVHD) (P =.002). OS was superior for patients with classic cGVHD (median survival, not reached) compared to overlap GVHD (median survival, 395 days, 95% CI 101 to not reached) and aGVHD (delayed, recurrent or persistent) (median survival, 72 days, 95% CI 39-152). In univariate analyses, significant predictors of survival after ECP included GVHD subtype, bilirubin, platelet count, and steroid dose. In multivariate analyses overlap plus classic cGVHD was an independent prognostic feature predictive of superior survival (hazard ratio [HR] 0.34, 95% CI 0.14-0.8, p =.014). This study suggests that NIH classification can predict outcome after ECP for steroid refractory/dependent GVHD. [Copyright &y& Elsevier]

Abstract: Chronic graft-versus-host disease (cGVHD), a common complication after stem cell transplant (SCT), has an impact on morbidity and survival. Previous classification of cGVHD has not been reproducible or prognostic for nonrelapse mortality (NRM). Recently the National Institutes of Health (NIH) consensus criteria were proposed, but the ability of this classification to predict outcome of various subtypes of cGVHD is unknown. Patients (N = 110) undergoing an SCT for a hematologic malignancy and surviving until day 100 posttransplant from 2001 to 2003 were studied. The overall survival (OS) using a landmark analysis at day 100 was 44% versus 66% (no GVHD vs. GVHD, P = .026). The OS of patients with various types of GVHD as proposed by the NIH criteria were significantly different (P < .0001). In a univariate analyses, this was more apparent when patients with any acute features of GVHD were compared to classic cGVHD (3-year OS 46% vs. 68%, P = .033). The 3-year NRM for the entire cohort was 21%, and was not affected by presence or absence of GVHD or subtypes of GVHD. In a multivariable analysis, extensive cGVHD (hazard ratio [HR] 0.35, P = .015) and having any acute feature of GVHD after day 100 (HR 3.36, P = .0144) were significant independent predictors of survival. The OS with different NIH subtypes of GVHD after day 100 from SCT varies, and is superior for patients with classic cGVHD. [Copyright &y& Elsevier]

cGVHD exhibits both autoimmune and fibrotic features across multiple organ systems. KD025 is an orally available Rho-associated coiled-coil kinase 2 (ROCK2) selective inhibitor. KD025-208 enrolled 3 cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of cGVHD patients (pts) after 1-3 prior lines of therapy. Treatment was until progression or toxicity. Primary endpoint is overall response rate (ORR) per 2014 NIH response criteria. Additional endpoints include Duration of Response (DOR), corticosteroid (CS) dose reductions, Failure Free Survival (FFS) and Lee Symptom Scale (LSS) score. 17, 16, and 21 pts enrolled in C1, C2, and C3. As of 8Mar19, median duration of follow up was 112, 97 and 64 weeks (wks) respectively. Median age was 52 yrs, median time from cGVHD diagnosis was 20 mos, and median prior lines of therapy was 2. Median duration of treatment was 37, 33, and 39 wks, respectively. 14 pts remained on KD025. Reasons for discontinuation: cGVHD progression (18), voluntary withdrawal (7), relapse of underlying disease (5), investigator decision (5), AE (3), and death (2). ORR [95% CI] was 65% [38, 85] in C1, 69% [41, 89] in C2, and 62% [38, 82] in C3, 65% [51, 77] across all 3 cohorts. Responses were achieved across key subgroups with ORRs of 62% (24/39) in pts with ≥2 prior lines of therapy, 70% (19/27) in pts with ≥4 organs involved and 60% (25/42) in pts with severe cGVHD, and 65% (22/34) in pts refractory to their previous line. CRs were observed in all affected organs except lung; PRs were observed in lung. Median Time to Response was 8.14 wks (IQR 8-12); 4/35 responses occurred after 24 wks. Responses were durable with a Kaplan-Meier median DOR of 34 wks across all cohorts. 57% of responders sustained a response for ≥20 wks. FFS at 6, 12 and 24 mos was 76%, 47% and 33% respectively. Overall survival was 94%, 91% and 83%. Baseline median CS dose was 0.21 mg/kg/day (prednisone eq). During treatment, median CS dose was reduced by 50%. 20% pts discontinued CS. 52% of pts reported a ≥7-point reduction in LSS with median time to improvement 9 wks. AEs were consistent with those expected in cGVHD pts receiving CS. Common AEs were URI 35%, diarrhea 31%, nausea 31%, fatigue 30%, dyspnea 28%, increased LFTs 24%, and peripheral edema 22%. 63% had a Grade ≥3 AE, the most common was dyspnea, 13%. <10% pts experienced Grade 3 anemia, neutropenia, or thrombocytopenia. SAEs, reported in 43%, were not related to KD025. SAEs in >2% were dyspnea (7%), lung infection (6%), hypoxia (4%) and flu-like illness (4%). Three pts discontinued KD025 due to possibly related AEs (C1: diarrhea, headache; C3: fatigue). 3 pts died on study (C3: relapse of leukemia; lung infection; cardiac arrest), all considered unrelated to KD025. Durable and clinically meaningful responses have been seen across all 3 cohorts. KD025 was well tolerated, with sustained responses and encouraging FFS in patients with advanced cGVHD. [ABSTRACT FROM AUTHOR]

The role of high dose chemotherapy (HDC) and stem cell transplant (SCT) in peripheral T-cell lymphoma (PTCL) was studied in 28 patients, from 1988 to 2002. The aim was to determine if subsets recognized by the REAL/WHO classification have different prognoses. Outcome was compared to 86 patients with diffuse large B-cell lymphoma (DLBCL) transplanted during 1986 - 2000. The 3-year overall survival (OS) and event free survival (EFS) were 69% and 50%. Patients with anaplastic large cell lymphoma (ALCL) had a better 3-year OS compared to those with non-ALCL histology (86% vs. 47%, P  = 0.0122). Anaplastic lymphoma kinase (ALK)- positive ALCL patients had a superior EFS compared to ALK-negative ALCL (100% vs. 0; P  = 0.0228). Patients with cutaneous ALCL (ALK-negative) relapsed, but had an indolent course after SCT. Low International Prognostic Index score at relapse predicted for a better 3-year OS (85% vs. 34%, P  = 0.0238). When compared to DLBCL, patients with ALCL had a superior OS (86% vs. 36%, P  = 0.0034) and patients with non-ALCL had a comparable OS. ALCL histology confers better survival compared to non-ALCL and DLBCL histologies. ALK-positive ALCL is associated with the best EFS after relapse with HDC and SCT. The timing of SCT for non-ALCL histology remains to be determined. [ABSTRACT FROM AUTHOR]

Background Ibrutinib is approved for a variety of B-cell malignancies, including CLL and MCL, and for chronic GVHD (cGVHD), failing ≥ 1 line of systemic therapy. Allogeneic HCT is curative for CLL and MCL, but success is limited due to relapse or GVHD morbidity/mortality. We hypothesized that use of ibrutinib early post HCT would optimize outcomes by improving progression-free survival (primary outcome) and decrease incidence of moderate-severe cGVHD (secondary endpoint). We describe our findings regarding safety and feasibility in the first 16 patients (NCT02869633). Methods Adult patients (pts) undergoing T-replete HCT from related or unrelated donors (7/8 or 8/8) without post-transplant cyclophosphamide for CLL (>CR1, or after 1st line if 17p) or MCL (>CR1, or after 1st line if blastoid variant) were enrolled, along with an exploratory cohort of FL and HL (max 10 patients). Use of ibrutinib prior to HCT was permissible. Enrollment was prior to HCT, but pts had to meet secondary eligibility criteria to ensure no critical illness, adequacy of graft and organ function, prior to starting ibrutinib (420 mg daily) between day 60-90. Ibrutinib was continued until 12 m post HCT. Results Sixteen pts (CLL 44%, MCL 13%, FL 25%, HD 13%), median age 49.5 y, underwent HCT from unrelated (94%) or related donors (6%), that were 8/8 (88%) or 7/8 (12%) HLA matched, at a median of 30.2 m after diagnosis. Median follow up from HCT is 5.1 m and 1 y survival is 75%. Regimens included FCR-thymoglobulin (44%), TLI-ATG (31%), Flu Bu (13%) or Flu Mel (12%). GVHD prophylaxis was tacrolimus-MTX (69%) or CSA-MMF (31%). Of the 14 pts eligible to start ibrutinib (> 60 d post HCT), 9 started ibrutinib (64%), while 5 did not (4-not meet secondary eligibility criteria, 1-physician preference). The median starting dose was 140 mg (protocol specified due to drug interactions). Of the 9 pts who started ibrutinib, 2 (22%) had to stop it prematurely (cytopenias, confounded by concomitant medications), 3 (33%) completed therapy and 4 (45%) are on therapy. Table 1 outlines key ≥ grade 3 adverse events (AEs) at any time point after enrollment. In this group of 9 pts, aGVHD grade 0, 1, 3 and 4 was seen in 57%, 22%, 7% and 14%, and cGVHD was seen in 3 pts (7%-mild, 14%-severe). No pts had progression of disease (CR-67%, PR-11%, SD-22%); 2 pts are deceased (1-infection at 14 m post HCT in CR, and 1 from acute GVHD (onset prior to start of ibrutinib with SD). Conclusions Our data in this ongoing study shows that majority of patients could initiate early post HCT ibrutinib and most are expected to tolerate it until 1 y post HCT. No unexpected side effects have been seen with use of ibrutinib early post HCT, and there have been no relapses. [ABSTRACT FROM AUTHOR]

Introduction cGVHD is characterized by an imbalance between effector and regulatory arms of the immune system that results in over production of IL-17 and IL-21. A reduction in the regulatory T (Treg) cells limits the ability of the immune system to re-calibrate this pro-inflammatory environment. KD025 is an oral Rho kinase 2 (ROCK2) selective inhibitor. In vitro data demonstrate KD025 modulates immune homeostasis by shifting the Th17/Treg balance towards Treg. Methods 3 cohorts (C1: 200 mg QD, C2: 200 mg BID, and C3: 400 mg QD) of patients (pts) with cGVHD after 1-3 prior lines of systemic therapy were treated in 28-Day cycles until disease progression. The primary endpoint is overall response rate (ORR) (partial/complete response) per 2014 NIH criteria. Additional endpoints include duration of response (DOR), corticosteroid (CS) dose reductions, Lee Symptom Scale (LSS) score and PD. Blood samples were collected at Cycle 1 Day 1 (C1D1), C2D1, C4D1 and C6D25, and shipped at ambient temperature. PBMC were isolated and kept frozen until analysis. Intracellular expression of IL-17A and FOXP3 was determined by flow cytometry. Results Data as of 6-June-2018 for C1 and C2 are included; C3 data will be available 4Q18. 17 and 16 pts were enrolled in C1 and C2 with median age 52 years, time from cGVHD diagnosis to KD025 treatment of 19 months, and 3 prior regimens. Median duration of treatment was37 (C1) and 33 (C2) weeks. KD025 demonstrated ORR of 65% in C1 and 63% in C2. Responses were rapid (76% at first assessment at 8 weeks) and durable (≥20 weeks) in 82% (C1) and 50% (C2) of responders. Median CS dose was reduced 44% (C1) and 26% (C2). 76% and 56% of pts achieved CS dose reductions. 5/33 (15%) pts discontinued CS. 65% (C1) and 50% (C2) achieved a meaningful improvement (≥7 point reduction) in the LSS score. Common AEs were increased LFTs 42%, URI 33%, anemia 27%, nausea 24%, diarrhea 24% and fatigue 21%. Grade 3+ LFT increases were reported for 6 (18%) pts. 2 pts discontinued treatment due to AEs possibly related to KD025 (headache, diarrhea). SAEs were reported for 11/33 pts, none considered related to KD025. There was no apparent increased risk of infection. Exploratory PD analyses revealed an early increase in the percentage of CD4+ Treg cells by C2D1 with a simultaneous decrease in Th17 cells. The percentage of CD4+ Tregs continued to increase, and the Th17 cells continued to decrease through C6D25. Conclusion KD025 achieved responses with little toxicity. Responses are clinically meaningful with durability, reductions in CS doses and improvement in LSS score. PD data indicate KD025 may restore the Th17/Treg balance. [ABSTRACT FROM AUTHOR]

Introduction Acute graft-vs-host disease (aGVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Less than 50% of patients (pts) achieve sustained responses with first-line corticosteroid (CS) treatment. Retrospective studies demonstrated clinical benefit with the Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib (RUX) in pts with steroid-refractory (SR) aGVHD. Objectives To present updated results from REACH1 (NCT02953678), a phase 2 trial evaluating RUX plus CS in SR aGVHD. Methods REACH1 was a single-arm, open-label, multicenter study. Eligible pts were aged ≥12 years and developed grade II–IV SR aGVHD following allo-HSCT from any donor source for hematologic malignancies. SR aGVHD was defined as GVHD that progressed after 3 days or had not improved after 7 days of primary treatment with methylprednisolone ≥2 mg/kg/d (or equivalent), development of GVHD in another organ after receiving ≥1 mg/kg/d methylprednisolone for skin or skin plus upper gastrointestinal GVHD, or inability to tolerate CS taper. Pts received RUX 5 mg twice daily (BID), with optional increase to 10 mg BID in the absence of cytopenias. The primary endpoint was Day 28 overall response rate (ORR), and the key secondary endpoint was 6-month duration of response (DOR). ORR was defined as the proportion of patients demonstrating a complete response (CR), very good partial response, or partial response. Results The study enrolled 71 pts. Median age was 58 years, and 49.3% were male. Treatment was ongoing in 11 pts (15.5%) at data cutoff (2 Jul 2018). At Day 28, ORR was 54.9% (CR, 26.8%). Responses were observed irrespective of aGVHD grade and SR criteria (Figure 1). Best ORR at any time during treatment was 73.2% (CR, 56.3%). Median (range) time to response was 7 (6–49) days. Median DOR with minimum 6 months follow-up was 345 days for both Day 28 responders (Figure 2) and for pts who had a best overall response at any time during treatment. Four pts (5.6%) had malignancy relapse. Nonrelapse mortality at 6 months was 44.4%. Median overall survival had not been reached for Day 28 responders (Figure 3). The most frequently reported hematologic treatment-emergent adverse events (TEAEs) were anemia (64.8%), thrombocytopenia (62.0%), and neutropenia (47.9%). Cytomegalovirus infection (12.7%), sepsis (12.7%), and bacteremia (9.9%) were the most frequently reported infections. Fatal RUX-related TEAEs were sepsis and pulmonary hemorrhage (1 pt each) and were attributed to both RUX and CS. Conclusion In this first prospective trial of RUX in SR aGVHD, ORR was 54.9% by Day 28 and 73.2% at any time during treatment. Responses were rapid and durable. The AE profile was consistent with expectations for RUX and pts with SR aGVHD. RUX represents a promising therapeutic strategy. [ABSTRACT FROM AUTHOR]

The article discusses on examination of single nucleotide polymorphisms (SNPs) in B-cell activating factor (BAFF) gene for development of (SNPs) chronic form of graft-versus-host-disease (cGVHD). It discusses the relevance of SNPs that resulted in increased production of BAFF with cGVHD pathophysiology since increased BAFF production is associated with the disease. It suggests further studies to be carried out regarding promoter and alternative splicing SNPs and altered BAFF expression.

Chronic graft-versus-host disease (cGVHD) is a severe complication in long-term survivors of allogeneic hematopoietic stem cell transplantation. This disease is challenging to manage clinically due to a lack of validated tools to quantitatively measure skin sclerosis. The current gold standard for measuring skin sclerosis is the NIH Skin Score which has only moderate agreement among clinicians and experts. To more accurately assess skin sclerosis in cGVHD, the Myoton and durometer devices can be used to directly measure biomechanical parameters of the skin. However, the reproducibility of these devices is not known in patients with cGVHD. To determine this reproducibility, three observers independently measured 10 anatomic sites in each of seven patients with sclerotic cGVHD using the Myoton and durometer. Clinical reproducibility was measured by mean pairwise differences (U-statistic) and intraclass correlation coefficients (ICCs) with 95% confidence intervals (CIs). Mean pairwise differences, expressed in true physical units, were used to report typical errors for each anatomic site and device. Mean pairwise differences were less than 11% of the average overall values for all five Myoton parameters and durometer hardness. These were lower for Myoton creep (4.1%), relaxation time (4.7%), and frequency (5.1%) than decrement (9.0%), stiffness (10.4%), and durometer hardness (9.0%). Myoton parameters creep, relaxation time, and frequency showed promise for capturing skin biomechanics more accurately than Myoton stiffness, decrement, or durometer hardness. Mean pairwise differences trended highest in the shin and volar forearm and lowest in the dorsal forearm. The interobserver ICC for overall (averaged across all measured body sites of a patient) creep (0.94; 95% CI 0.87–1.00), relaxation time (0.96; 95% CI 0.90–1.00), and frequency (0.95; 95% CI 0.88–1.00), trended higher than that for decrement (0.43; 95% CI 0.00–0.88), stiffness (0.92; 95% CI 0.81–1.00), and durometer hardness (0.82; 95% CI 0.61–1.00). Similar trends were observed in healthy participants. These findings can help clinicians design better studies to assess therapeutic response to new cGVHD treatments and support the interpretation of future measurements. [ABSTRACT FROM AUTHOR]

The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity and more accurately measures the global burden of disease attributed to GVHD, and it will facilitate biomarker association studies. [ABSTRACT FROM AUTHOR]

Several distinct graft-versus-host disease (GVHD)-related syndromes have been defined by the National Institutes of Health Consensus Conference. We enrolled a prospective cohort of 911 hematopoietic cell transplantation (HCT) recipients at 13 centers between March 2011 and May 2014 to evaluate 4 GVHD syndromes: late acute GVHD (aGVHD), chronic GVHD (cGVHD), bronchiolitis obliterans syndrome, and cutaneous sclerosis. The median age at HCT was 53.7 years. The majority of patients received a peripheral blood stem cell transplant (81%) following nonmyeloablative or reduced-intensity conditioning (55%). Pediatric age group and use of bone marrow and umbilical cord blood grafts were underrepresented in our cohort (≤11%). The cumulative incidence of late aGVHD (late onset and recurrent) was 10% at a median of 5.5 months post-HCT, that of cGVHD was 47% at a median of 7.4 months, that of bronchiolitis obliterans was 3% at a median of 12.2 months, and that of cutaneous sclerosis was 8% at a median onset of 14.0 months. Late aGVHD and bronchiolitis obliterans had particularly high nonrelapse mortality of 23% and 32%, respectively, by 2 years after diagnosis. The probability of late aGVHD- and cGVHD-free, relapse-free survival was 38% at 1 year post-HCT and 26% at 2 years post-HCT. This multicenter prospective study confirms the high rate of late aGVHD and cGVHD syndromes and supports the need for continuous close monitoring and development of more effective GVHD treatment strategies to improve HCT success. [ABSTRACT FROM AUTHOR]

Although allogeneic hematopoietic stem cell transplant (allo-HSCT) is performed to treat otherwise incurable and fatal diseases, transplantation itself can lead to life-threatening complications due to organ damage. Pulmonary complications remain a significant barrier to the success of allo-HSCT. Lung injury, a frequent complication after allo-HSCT, and noninfectious pulmonary deaths account for a significant proportion of non-relapse mortality. Bronchiolitis obliterans syndrome (BOS) is a common and potentially devastating complication. BOS is now considered a diagnostic criterion of chronic graft-versus-host-disease (cGVHD), and National Institutes of Health (NIH) consensus has been published to establish guidelines for diagnosis and monitoring of BOS. It usually occurs within the first 2 years but may develop as late as 5 years after transplantation. Recent prevalence estimates suggest that BOS is likely underdiagnosed, and when severe BOS does occur, current treatments have been largely ineffective. Prevention and effective novel approaches remain the primary tools in the clinician''s arsenal in managing BOS. This article provides an overview of the currently available and novel strategies for BOS, and we also discuss specific preventive interventions to reduce severe BOS after allo-HSCT. Therapeutic trials continue to be needed for this orphan disease. [Copyright &y& Elsevier]

Squamous cell carcinoma (SCC) is among the most common secondary cancers after allogeneic stem cell transplantation (allo-SCT). Several types of human papillomavirus (HPV) are causally linked with SCC of the genital tract and head and neck, and the incidence of these cancers is higher among immunosuppressed patients compared to immunocompetent patients. In June 2006, a quadrivalent HPV vaccine was approved by the Food and Drug Administration (FDA) for females aged 9 to 26 years to prevent cervical warts and vulvar, vaginal, and cervical cancer. FDA approval was granted in October 2009 for males aged 9 to 26 years to prevent genital warts. The quadrivalent HPV vaccine is now available for off-label use, and may be beneficial to patients after allo-SCT. It is time to evaluate the immunogenicity and efficacy in preventing HPV-related squamous cell carcinoma in this population. [Copyright &y& Elsevier]

A letter to the editor is presented which examines whether the repeated use of rituximab and/or combination of immunosuppressive therapy might contribute to the development of progressive multifocal leukoencephalopathy (PML) in a patient with follicular lymphoma.

Summary: Immunomodulatory drugs (IMiDs) have improved survival of patients with multiple myeloma (MM) and comprise the therapeutic backbone at all phases of therapy. Although well‐tolerated, IMiDs increase rates of venous thromboembolism (VTE). In this phase IV, single‐arm pilot study, fifty patients with MM on IMiDs received apixaban 2·5 mg orally twice daily for primary prevention of VTE and were prospectively monitored for six months. The primary safety outcomes were rates of major haemorrhage and clinically relevant non‐major haemorrhage over six months. The primary efficacy outcome was the rate of symptomatic VTE over six months. IMiDs used were lenalidomide (58%) or pomalidomide (42%). During the six‐month evaluation period, no patients experienced major haemorrhage or VTE. Three patients experienced clinically relevant, non‐major haemorrhage which was managed medically, and all were able to resume apixaban. One patient stopped therapy shortly after initiation due to an allergic reaction to apixaban. No patients experienced stroke, myocardial infarction, or death. In this pilot study, low‐dose apixaban was safe and well‐tolerated as a primary prevention therapy of VTE for patients with MM receiving IMiDs. Further studies are needed to validate low‐dose apixaban as a standard primary prevention anti‐thrombotic strategy for patients with MM receiving IMiDs. [ABSTRACT FROM AUTHOR]

Objective: To describe upper dermal microvasculature of healthy human skin in terms of density and size of cutaneous blood vessels, leukocyte velocity, and leukocyte interactions with the endothelium. Methods: We used a reflectance confocal microscope, the VivaScope 1500, to acquire videos of individual cell motion. Results: We found no rolling leukocytes in the upper microvasculature of ten healthy subjects. We observed "paused" leukocytes, that is, leukocytes that temporarily stop, coinciding with the simultaneous stopping of the rest of the blood flow. We imaged more paused (median: 1.0 per subject) and adherent (1.5) leukocytes in the forearm than in the chest (median 0 paused and 0 adherent per subject) per 5 minutes of videos per body site. Leukocytes were paused for a median of 7 seconds in the forearm and 3 seconds in the chest, and we found no correlation between this parameter and the blood vessel or leukocyte size. We visualized blood flow change direction. Flowing leukocyte velocities followed a lognormal distribution and were on average higher in the chest (117 µm/s) than in the forearm (66 µm/s). Conclusion: The proposed method and reported values in healthy skin provide new insights into intact human skin microcirculation. [ABSTRACT FROM AUTHOR]

• In haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide, conditioning intensity and graft source impact graft-versus-host disease (GVHD). • In reduced-intensity conditioning, peripheral blood compared to bone marrow is significantly associated with chronic GVHD. • Older donor age is associated with higher risk of acute GVHD and nonrelapse mortality. Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P =.002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P <.001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P =.01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P =.01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival. [ABSTRACT FROM AUTHOR]

BACKGROUND: Barriers to accessing oral oncolytic therapy include insurance prior authorization, high copays, and limited distribution drug networks. These barriers increase patient stress, reduce physician time spent with patients, and often require additional clinic staff. Treatment models that reduce the impact of these barriers are necessary. Some health system specialty pharmacies embed a pharmacist in the clinic and ship medications from an on-site pharmacy but cannot dispense some limited distribution drugs. OBJECTIVE: To compare access time to oral oncolytic therapy between limited distribution drugs and non-limited distribution drugs before and after integrating a pharmacist and a pharmacy technician into a hematology clinic at a health system specialty pharmacy. METHOD: We reviewed medical records of adult patients who were prescribed oral oncolytic therapy between September 2015 and September 2017 for malignant or benign conditions at our hematology clinic at Vanderbilt University Medical Center, a large academic health system. The primary outcome measure was time to medication access, defined as the number of days from treatment decision to medication shipment. Prescriptions were stratified by time (Time 1: before pharmacist integration; Time 2: after pharmacist integration) and by drug type (limited distribution drug vs non-limited distribution drug). Using proportional odds logistic regression, we assessed whether time to medication access was associated with drug type, time period, and drug type by time interaction. RESULTS: A total of 409 prescriptions were included in the study: 284 non-limited distribution drugs and 125 limited distribution drugs. The median time to medication access was 6 days for limited distribution drugs (interquartile range [IQR], 3-9) and 3 days for non-limited distribution drugs (IQR, 1-6). In Time 1, the access time was significantly longer for limited distribution drugs than for non-limited distribution drugs (odds ratio [OR], 6.3; P <.001). Access time for limited distribution drugs decreased significantly from Time 1 to Time 2 (drug type by time interaction, OR, 0.40; P = .039) but remained similar between time periods for non-limited distribution drugs. CONCLUSION: After integrating a pharmacist and a pharmacy technician into our clinic, the time to access limited distribution drugs was significantly shortened, but it remained slower than for non-limited distribution drugs. The integrated health system specialty pharmacy expedites the time to medication access and outperforms nonintegrated specialty pharmacies in dispensing limited distribution drugs, thereby challenging the value of limited distribution drug networks beyond medical economics. [ABSTRACT FROM AUTHOR]

Background: Haploidentical bone marrow transplant (haplo‐BMT) offers near universal donor availability as a curative modality for individuals with severe sickle cell disease (SCD). However, the required intense immunodepletion is associated with increased infectious complications. A paucity of data exists on immune reconstitution following haplo‐BMT for SCD. Methods: A multi‐institution learning collaborative was developed in the context of a phase II clinical trial of a non‐myeloablative, related haplo‐BMT with post‐transplant cyclophosphamide for SCD. We report results from a cohort of 23 patients for whom immune reconstitution data up to one year were available. Results: Median age was 14.8 years. Out of 23, 18 participants received pre‐conditioning with azathioprine, hydroxyurea, and hypertransfusions. 70% (16/23) of participants had multiple indications for haplo‐BMT. We observed excellent immune reconstitution of CD4, CD8, CD19, and CD56 cellular subsets by 6 months post transplant. Engraftment rate and event‐free survival in this cohort were 100% and 96%, respectively. 70% (16/23) of patients had at least one viral reactivation or infection, including CMV 35% (8/23), HHV‐6 22% (5/23), and polyoma virus 17% (4/23), with no cases of post‐transplant lymphoproliferative disease. Conclusion: Further prospective studies are needed to better characterize immune reconstitution and the immunologic basis for increased viral reactivation following haplo‐BMT with post‐transplant cyclophosphamide for SCD. [ABSTRACT FROM AUTHOR]

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

• Responses are durable with ibrutinib in steroid-refractory or -dependent chronic graft-versus-host disease (cGVHD) • Ibrutinib improves quality of life in steroid-refractory or -dependent cGVHD. • Longer-term ibrutinib is safe and tolerable in steroid-refractory or -dependent cGVHD. 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. [ABSTRACT FROM AUTHOR]

• Data came from 488 patients enrolled in prospective observational studies. • Some objective change measures were associated with overall response assessments. • The sensitivity and specificity parameters of this association need improvement. Assessments of overall improvement and worsening of chronic graft-versus-host disease (GVHD) manifestations by the algorithm recommended by National Institutes of Health (NIH) response criteria do not align closely with those reported by providers, particularly when patients have mixed responses with improvement in some manifestations but worsening in others. To elucidate the changes that influence provider assessment of response, we used logistic regression to generate an overall change index based on specific manifestations of chronic GVHD measured at baseline and 6 months later. We hypothesized that this overall change index would correlate strongly with overall improvement as determined by providers. The analysis included 488 patients from 2 prospective observational studies who were randomly assigned in a 3:2 ratio to discovery and replication cohorts. Changes in bilirubin and scores of the lower gastrointestinal tract, mouth, joint/fascia, lung, and skin were correlated with provider-assessed improvement, suggesting that the main NIH response measures capture relevant information. Conversely, changes in the eye, esophagus, and upper gastrointestinal tract did not correlate with provider-assessed response, suggesting that these scales could be modified or dropped from the NIH response assessment. The area under the receiver operator characteristic curve in the replication cohort was 0.72, indicating that the scoring algorithm for overall change based on NIH response measures is not well calibrated with provider-assessed response. [ABSTRACT FROM AUTHOR]

Background: Estimating the extent of affected skin is an important unmet clinical need both for research and practical management in many diseases. In particular, cutaneous burden of chronic graft‐vs‐host disease (cGVHD) is a primary outcome in many trials. Despite advances in artificial intelligence and 3D photography, progress toward reliable automated techniques is hindered by limited expert time to delineate cGVHD patient images. Crowdsourcing may have potential to provide the requisite expert‐level data. Materials and methods: Forty‐one three‐dimensional photographs of three cutaneous cGVHD patients were delineated by a board‐certified dermatologist. 410 two‐dimensional projections of the raw photos were each annotated by seven crowd workers, whose consensus performance was compared to the expert. Results: The consensus delineation by four of seven crowd workers achieved the highest agreement with the expert, measured by a median Dice index of 0.7551 across all 410 images, outperforming even the best worker from the crowd (Dice index 0.7216). For their internal agreement, crowd workers achieved a median Fleiss's kappa of 0.4140 across the images. The time a worker spent marking an image had only weak correlation with the surface area marked, and very low correlation with accuracy. Percent of pixels selected by the consensus exhibited good correlation (Pearson R = 0.81) with the patient's affected surface area. Conclusion: Crowdsourcing may be an efficient method for obtaining demarcations of affected skin, on par with expert performance. Crowdsourced data generally agreed with the current clinical standard of percent body surface area to assess cGVHD severity in the skin. [ABSTRACT FROM AUTHOR]

• Insulin resistance before HCT is a risk factor for PTDM independent of immunosuppression. • Fasting pretransplant glucose levels identified PTDM susceptibility. • Insulin resistance could be targeted for prevention and treatment of PTDM after HCT. New-onset post-transplant diabetes mellitus (PTDM) occurs frequently after allogeneic hematopoietic cell transplant (HCT). Although calcineurin inhibitors and corticosteroids are assumed to be the cause for hyperglycemia, patients developing PTDM have elevated fasting C-peptide levels before HCT and before immunosuppressive medications. To determine if PTDM results from established insulin resistance present before transplant, we performed oral glucose tolerance tests (OGTTs) and measured whole body, peripheral, and hepatic insulin sensitivity with euglycemic hyperinsulinemic clamps before and 90 days after HLA-identical sibling donor HCT in 20 patients without pretransplant diabetes. HCT recipients were prospectively followed for the development of new-onset PTDM defined as a weekly fasting blood glucose ≥ 126 mg/dL or random blood glucose ≥ 200 mg/dL. During the first 100 days all patients received calcineurin inhibitors, and 11 individuals (55%) were prospectively diagnosed with new-onset PTDM. PTDM diagnosis preceded corticosteroid treatment. During the pretransplant OGTT, elevated fasting (87 mg/dL versus 101 mg/dL; P =.005) but not 2-hour postprandial glucose levels predicted PTDM diagnosis (P =.648). In response to insulin infusion during the euglycemic hyperinsulinemic clamp, patients developing PTDM had lower whole body glucose utilization (P =.047) and decreased peripheral/skeletal muscle uptake (P =.031) before and after transplant, respectively, when compared with non-PTDM patients. Hepatic insulin sensitivity did not differ. Survival was decreased in PTDM patients (2-year estimate, 55% versus 100%; P =.039). Insulin resistance before HCT is a risk factor for PTDM independent of immunosuppression. Fasting pretransplant glucose levels identified PTDM susceptibility, and peripheral insulin resistance could be targeted for prevention and treatment of PTDM after HCT. [ABSTRACT FROM AUTHOR]

Highlights • A significant proportion of allogeneic hematopoietic cell transplantation patients with chronic graft-versus-host disease experience financial burden despite being insured. Nonwhite race, lower mental functioning, and lower activity score are associated with a higher likelihood of financial burden. • Patients with financial burden had poor psychosocial outcomes, such as greater depression/anxiety and difficulty sleeping. ABSTRACT Understanding the socioeconomic impact of chronic graft-versus-host disease (GVHD) on affected patients is essential to help improve their overall well-being. Using data from the Chronic GVHD Consortium, we describe the insurance, employment, and financial challenges faced by these patients and the factors associated with the ability to work/attend school and associated financial burdens. A 15-item cross-sectional questionnaire designed to measure financial concerns, income, employment, and insurance was completed by 190 patients (response rate, 68%; 10 centers) enrolled on a multicenter Chronic GVHD Consortium Response Measures Validation Study. Multivariable logistic regression models examined the factors associated with financial burden and ability to work/attend school. The median age of respondents was 56years, and 87% of the patients were white. A higher proportion of nonrespondents had lower income before hematopoietic cell transplantation and less than a college degree. All but 1 patient had insurance, 34% had faced delayed/denied insurance coverage for chronic GVHD treatments, and 66% reported a financial burden. Patients with a financial burden had greater depression/anxiety and difficulty sleeping. Nonwhite race, lower mental functioning, and lower activity score were associated with a greater likelihood of financial burden. Younger age, early risk disease, and higher mental functioning were associated with a greater likelihood of being able to work/attend school. In this multicenter cohort of patients with chronic GVHD, significant negative effects on finances were observed even with health insurance coverage. Future research should investigate potential interventions to provide optimal and affordable care to at-risk patients and prevent long-term adverse financial outcomes in this vulnerable group. [ABSTRACT FROM AUTHOR]

Highlights • Anatomic skin distribution is described in 182 incident cGVHD Consortium patients. • Erythema, the most common feature, was widespread but spared the lower extremities. • Sclerosis, more common than anticipated, rarely involved the head, neck, and scalp. • Deep sclerotic features were most common in the upper and lower extremities. • A high level of symmetry of extremity involvement was observed. ABSTRACT Little is known about the anatomic distribution of cutaneous chronic graft-versus-host disease (cGVHD). Using data from the cGVHD Consortium Improving Outcomes Assessment Study, we describe the frequency and extent of erythema and superficial and deep sclerosis in 8 anatomic sites in patients with incident disease (ie, new cGVHD diagnosis within 3 months of study entry) receiving systemic therapy. Of 339 patients with incident disease, 182 (54%) had skin involvement. When an extremity was involved, the same type of disease was present contralaterally in 92% of cases, revealing a high level of symmetry. As anticipated, erythema was the most common incident feature; however, sclerotic skin involvement at the time of cGVHD diagnosis was more common than has been suggested by previous studies. Erythema occurred in 155 (85%) and sclerosis in 53 (29%) of the patients with skin involvement (46% and 16%, respectively, of the entire cohort of 339 incident cGVHD cases). Erythema was least common on the lower extremities (n = 71; 39% of patients with skin involvement). Moveable sclerosis was rare on the head, neck, and scalp (n = 4; 2%). Deep sclerosis did not occur in this region, and instead was most likely to occur on the upper extremities (n = 14; 8%) and lower extremities (n = 14; 8%). More than one-half of patients with erythema (n = 107; 58.7%) had diffuse involvement (4 or more of 8 sites involved), compared with less than one-third of those with sclerosis (n = 16; 30.2%). [ABSTRACT FROM AUTHOR]

Highlights • Extracorporeal photopheresis is used to treat chronic graft-versus-host disease. • In a highly pretreated cohort, 62% of patients responded to this treatment. • Treatment was associated with a meaningful decrease in prednisone dose. • Overall, global severity and body surface area redness decreased with treatment. • Response was not associated with frequency of regulatory T cells. Abstract Extracorporeal photopheresis (ECP) is an accepted treatment for chronic graft-versus-host disease (cGVHD); however, the mechanism of action is unclear. We conducted a prospective multicenter clinical trial to assess ECP response rates using the 2005 National Institutes of Health (NIH) consensus criteria and to assess the relationship between regulatory T cells (Tregs) and treatment response (NCT01324908). Eighty-three patients with any NIH subtype of cGVHD were enrolled, irrespective of number of prior lines of treatment, and 6 were subsequently excluded because of the absence of follow-up from cancer relapse, infection, or study withdrawal. Study outcomes were provider-assessed response and formal response by 2005 NIH criteria. Peripheral blood samples were collected at prespecified study visits and were analyzed by flow cytometry for Tregs. In a heavily pretreated cohort of patients, with a median of 2 prior lines of therapy, 62.3% of patients had a provider-assessed response to ECP and 43.5% had response by NIH criteria. These assessments showed only a slight agreement (kappa statistic,.09). In a logistic regression model that included previously identified risk factors such as bilirubin, platelet count, and time from transplant to study entry, no clinical factors were associated with the provider's response assessment. Furthermore, there was no significant difference in percentage of Tregs in blood leukocytes at study entry and completion or in overall change in Treg frequency between ECP responders and nonresponders. ECP was associated with a clinically significant decrease in median prednisone dose (.36 to.14 mg/kg, P <.001) from study entry to last visit and a significant decrease in global severity of cGVHD and total body surface area with erythematous rash. Overall, ECP was able to deliver response using NIH response criteria in a highly pretreated cohort with moderate and severe cGVHD independent of most previous risk factors for adverse outcomes of cGVHD. [ABSTRACT FROM AUTHOR]

Therefore, we performed a single-center pilot study on 41 adult patients who underwent haplo-HCT between January 2014 and July 2017 to determine incidence and risk factors for viral reactivations and infections based on graft source. Based on the median time to CMV reactivation observed in this study, antiviral prophylaxis with novel agents, such as letermovir, which lacks myelosuppressive toxicity, may be particularly beneficial in patients undergoing haplo-HCT with PTCy [[6], [8]]. [Extracted from the article]

Highlight • One-fifth of patients with chronic GVHD struggle with depression or anxiety symptoms. • Psychological distress is associated with worse physical functioning in chronic GVHD. • Psychological distress is associated with worse QOL in chronic GVHD. • Self-reported depression symptoms are associated with lower OS in chronic GVHD. Abstract Data on psychological distress and its association with clinical outcomes in patients with chronic graft-versus-host-disease (GVHD) are lacking. We used data of patients with chronic GVHD (N = 482) from the Chronic GVHD Consortium, a prospective observational multicenter cohort. We examined the relationship between self-reported depression or anxiety symptoms (measured by the Lee Symptom Scale) and patients' quality of life (QOL; measured by the Functional Assessment of Cancer Therapy-General [FACT-G] and the Physical Component Scale [PCS] of the 36-item Short-Form Health Survey), physical functioning (measured by the Human Activity Profile), functional status (measured by the 2-minute walk test), and overall survival (OS). Overall, 19.3% of patients (93/481) reported being moderately to extremely bothered by depression, and 22.8% (110/482) reported being moderately to extremely bothered by anxiety, with 14.1% (68/482) of those reporting being bothered by both. In multivariable models adjusted for clinical covariates, patients with self-reported depression had worse QOL (FACT-G: β = –23.09, P <.001; PCS: β = –4.94, P <.001), physical functioning (β = –8.31, P <.001), functional status (β = –37.21, P =.025), and lower OS (hazard ratio, 1.62; P =.020) compared with those with no depression symptoms. Patients who reported anxiety also had lower QOL (FACT-G: β = –19.47, P <.001; PCS: β = –3.91, P <.001), physical functioning (β = –6.69, P <.001), and functional status (β = –32.42, P =.036) but no difference in OS. Patients with chronic GVHD who report depression or anxiety symptoms have significantly compromised QOL and physical functioning. Self-reported depression is associated with lower OS. Patients with chronic GVHD and self-reported depression or anxiety represent a highly vulnerable population at risk for poor clinical outcomes and substantial morbidity from their illness. [ABSTRACT FROM AUTHOR]

Abstract We recently conducted a randomized double-blind study in which we demonstrated that moderate/severe chronic graft-versus-host disease (cGVHD) but not cGVHD-free survival was reduced in patients receiving anti-T lymphocyte globulin (ATLG) versus placebo. In a companion study we performed immunophenotypic analysis to determine the impact of ATLG on immune reconstitution (IR) and to correlate IR with clinical outcomes. The randomized study (n = 254) included patients (aged 18 to 65 years) who underwent myeloablative transplants for acute myeloid leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia from HLA-matched unrelated donors. Ninety-one patients consented for the companion IR study (ATLG = 44, placebo = 47). Blood samples were collected on days 30, 100, 180, and 360 after hematopoietic cell transplantation (HCT), and multiparameter flow cytometry was performed in a blinded fashion. Reconstitution of CD3+ and CD4+ T cells was delayed up to 6 months post-HCT in the ATLG arm, whereas absolute regulatory T cell (Treg) (CD4+25+127-) numbers were lower only in the first 100 days. Analysis of the CD4+ Treg and conventional T cells (Tconv) (CD4+25–127+) compartments showed a profound absence of naive Tregs and Tconv in the first 100 days post-HCT, with very slow recovery for 1 year. B cell and natural killer cell recovery were similar in each arm. Higher absolute counts of CD3+, CD4+, CD8+ T, Tregs, and Tconv were associated with improved overall survival, progression-free survival, and nonrelapse mortality but not moderate/severe cGVHD. Although ATLG delays CD3+ and CD4+ T cell recovery post-transplant, it has a relative Treg sparing effect after the early post-HCT period, with possible implications for protection from cGVHD. ATLG severely compromises the generation of naive CD4+ cells (Treg and Tconv), potentially affecting the diversity of the TCR repertoire and T cell responses against malignancy and infection. [ABSTRACT FROM AUTHOR]

Highlights • We report a 9% incidence of CLABSI in an outpatient hematopoietic transplant cohort. • Gram-positive cocci were implicated in the majority of CLABSIs. • Matched unrelated and haploidentical donor transplants are at higher risk of CLABSI. • CLABSI may be associated with increased risk of 6-month mortality post-transplant. Abstract Allogeneic hematopoietic cell transplantation (HCT) patients are at an increased risk of developing central line–associated bloodstream infections (CLABSIs) due to prolonged periods of myelosuppression, immunosuppression, and indwelling catheter days. CLABSIs are among the most serious complications in HCT recipients and can lead to prolonged hospitalizations, intensive care unit admissions, lengthy antimicrobial therapies, and increased mortality. There is a lack of data regarding the incidence and risk factors associated with the development of CLABSIs in the HCT population undergoing outpatient transplantation. This was a single-center, retrospective analysis of adult patients who underwent allogeneic HCT between July 2012 and July 2016 in an outpatient transplant unit at a tertiary academic medical center. The primary outcome was the cumulative incidence of CLABSIs from the date of central line placement through the first 100 days post-transplantation. Secondary outcomes included risk factors for CLABSI, number of hospitalizations due to CLABSI, mortality rate at 6 months post-transplantation, and the cumulative incidence, speciation, and presence of multidrug resistance in identified microorganisms. Three hundred fifty-nine patients underwent allogeneic HCT at Vanderbilt University Medical Center and 352 were included for analysis. The cumulative incidence of CLABSIs was 9%, with the majority occurring within the first 30 days post HCT (67%). The use of a matched unrelated donor (MUD) and/or haploidentical donor (odds ratio, 3.993; 95% confidence interval [CI], 1.329 to 12.001; P =.0136) and use of an ablative conditioning regimen (odds ratio, 2.394; 95% CI, 1.052 to 5.446; P =.0374) were independently associated with development of a CLABSI on multivariate analysis. The most common organism implicated in CLABSI was Staphylococcus epidermidis (34%). Patients who developed a CLABSI had an almost 5 times higher risk of mortality at 6 months post-transplantation compared with patients who did not develop a CLABSI (hazard ratio, 4.932; 95% CI, 2.463 to 9.878; P <.001). There is a low incidence of CLABSIs in patients undergoing HCT in the outpatient setting. Patients who underwent HCT using a MUD or haploidentical donor and received ablative conditioning were at higher risk for developing CLABSIs. Overall mortality at 6 months post-transplantation was higher in patients who developed a CLABSI. Additional prospective studies are needed to confirm these observations. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Large, multicenter studies comparing commonly used reduced-intensity conditioning (RIC) approaches in follicular lymphoma (FL) have not been performed. Using the Center for International Blood and Marrow Transplant Research database, we report the outcomes of the 2 most commonly used RIC approaches, fludarabine and busulfan (Flu/Bu) versus fludarabine, cyclophosphamide, and rituximab (FCR) in FL patients. We evaluated 200 FL patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who received RIC with either Flu/Bu (n = 98) or FCR (n = 102) during 2008 to 2014. All patients received peripheral blood grafts, and graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor–based approaches. Median follow-up of survivors in the Flu/Bu and FCR groups was 48 months and 46 months, respectively. On univariate analysis in the Flu/Bu and FCR groups, the 3-year rates of nonrelapse mortality (11% versus 11%, P  = .94), relapse/progression (18% versus 15%, P  = .54), progression-free survival (PFS) (71% versus 74%, P  = .65), and overall survival (OS) (73% versus 81%, P  = .18) were not significantly different. On multivariate analysis no difference was seen between the FCR and Flu/Bu cohorts in terms of grades II to IV (relative risk [RR], 1.06; 95% confidence interval [CI], .59 to 1.93; P  = .84) or grades III to IV (RR, 1.18; 95% CI, .47 to 2.99; P  = .72) acute GVHD, nonrelapse mortality (RR, .83; 95% CI, .38 to 1.82; P  = .64), relapse/progression (RR, .99; 95% CI, .49 to 1.98; P  = .97), PFS (RR, .92; 95% CI, .55 to 1.54; P  = .76), or OS (RR, .70; 95% CI, .40 to 1.23; P  = .21) risk. However, RIC with FCR was associated with a significantly reduced chronic GVHD risk (RR, .52; 95% CI, .36 to .77; P  = .001). RIC with either Flu/Bu or FCR in patients with FL undergoing allo-HCT provides excellent 3-year OS, with acceptable rates of nonrelapse mortality. FCR-based conditioning was associated with a lower risk of chronic GVHD. [ABSTRACT FROM AUTHOR]

Antithymocyte globulin (ATG) is used as prophylaxis against graft-versus-host disease (GVHD). Current dosing regimens for ATG are empiric and weight-based, and do not account for patient-specific factors. Furthermore, the target of ATG, recipient T cells post-cytotoxic chemotherapy, is not a function of recipient weight. We hypothesized the recipient peripheral blood absolute lymphocyte count (ALC) on the day of ATG administration would interact with the dose of ATG administered to predict transplantation outcomes. We retrospectively analyzed 135 patients who received ATG for GVHD prophylaxis for unrelated allogeneic hematopoietic cell transplantation at 3 different doses: 10 mg/kg, 7.5 mg/kg, and 5 mg/kg. There was no difference in 2-year overall survival (OS) among ATG dosing groups; however, deaths from infectious complications were significantly higher with higher doses of ATG (3.7% versus 19% versus 26.7%; P  = .02). Severity of chronic GVHD was lower with higher doses of ATG (28% versus 24% versus 4%; P  = .03). In multivariate analysis, the median peripheral blood ALC on day of ATG administration and the total amount of ATG interacted to predict OS (hazard ratio, .09; P  = .03). For low recipient ALC (10th percentile, or .56 × 10 2 /µL), a higher total ATG dose was associated with a greater risk of death, whereas for high recipient ALC (90th percentile, or 24.96 × 10 2 /µL), a higher ATG dose was associated with a lower risk of death. Our findings suggest that the interaction between ATG and its target, the recipient lymphocyte, could represent a new paradigm for ATG dosing. [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2-inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ≥20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ≥1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869. [ABSTRACT FROM AUTHOR]

Select CMVepitopes drive life-long CD8+ T cell memory inflation, but the extent of CD4 memory inflation is poorly studied. CD4+ T cells specific for human CMV (HCMV) are elevated in HIV+ HCMV+ subjects. To determine whether HCMV epitope--specific CD4+ T cell memory inflation occurs during HIV infection, we used HLA-DR7 (DRB1*07:01) tetramers loaded with the glycoprotein B DYSNTHSTRYV (DYS) epitope to characterize circulating CD4+ T cells in coinfected HLA-DR7+ long-term nonprogressor HIV subjects with undetectable HCMV plasma viremia. DYS-specific CD4+ T cells were inflated among these HIV+ subjects compared with those from an HIV- HCMV+ HLA-DR7+ cohort or with HLA-DR7--restricted CD4+ T cells from the HIVcoinfected cohort that were specific for epitopes of HCMV phosphoprotein-65, tetanus toxoid precursor, EBV nuclear Ag 2, or HIV gag protein. Inflated DYS-specific CD4+ T cells consisted of effector memory or effector memory--RA+ subsets with restricted TCRβ usage and nearly monoclonal CDR3 containing novel conserved amino acids. Expression of this near-monoclonal TCR in a Jurkat cell--transfection system validated fine DYS specificity. Inflated cells were polyfunctional, not senescent, and displayed high ex vivo levels of granzyme B, CX3CR1, CD38, or HLA-DR but less often coexpressed CD38+ and HLA-DR+. The inflation mechanism did not involve apoptosis suppression, increased proliferation, or HIV gag cross-reactivity. Instead, the findings suggest that intermittent or chronic expression of epitopes, such as DYS, drive inflation of activated CD4+ T cells that home to endothelial cells and have the potential to mediate cytotoxicity and vascular disease. [ABSTRACT FROM AUTHOR]

Light chain amyloidosis (AL) results in tissue deposition of misfolded proteins, causing organ dysfunction. In an era of modern therapies, such as bortezomib, reassessment of the benefit of autologous hematopoietic cell transplantation (AHCT) should be considered. In this study, we compared outcomes between patients with AL receiving chemotherapy alone (CT) and those undergoing AHCT. Seventy-four patients with AL were analyzed retrospectively. Two cohorts of patients were studied, those receiving CT (n = 31) and those undergoing AHCT (n = 43). Of the 43 patients in the AHCT cohort, 29 received induction chemotherapy before AHCT, whereas 14 proceeded straight to AHCT without induction therapy. Compared with the CT cohort, patients in the AHCT cohort were younger and had higher ejection fractions, lower brain natriuretic peptide levels, and more severe proteinuria. The majority (87%) of patients in the CT cohort received bortezomib-based treatment. Transplantation-related mortality (TRM) was 7%. Patients receiving AHCT were more likely to achieve complete or very good partial response ( P  = .048). The median progression-free survival (PFS) and overall survival (OS) were superior in the AHCT cohort (not reached versus 9 months; P  < .01 and 74 months versus 8 months; P  = .03, respectively). Multivariable analysis demonstrated that improved PFS (hazard ratio, 3.86; 95% confidence interval [CI] 1.3 to 11.5; P  = .02) and OS (hazard ratio, 5.6; 95% CI, 1.9 to 16; P  < .001) were associated with use of AHCT compared with CT. Patients in the AHCT cohort had deeper and longer durations of response, with superior PFS and OS, compared with those in the CT cohort. Despite the limitations of this study, AHCT should be considered for eligible patients with AL at experienced transplantation centers that can offer this therapy with a low risk of TRM. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Given the limited treatment options for relapsed lymphoma post-allogeneic hematopoietic cell transplantation (post-allo-HCT) and the success of programmed death 1 (PD-1) blockade in classical Hodgkin lymphoma (cHL) patients, anti-PD-1 monoclonal antibodies (mAbs) are increasingly being used off-label after allo-HCT. To characterize the safety and efficacy of PD-1 blockade in this setting, we conducted a multicenter retrospective analysis of 31 lymphoma patients receiving anti-PD-1 mAbs for relapse post-allo-HCT. Twenty-nine (94%) patients had cHL and 27 had ≥1 salvage therapy post-allo-HCT and prior to anti-PD-1 treatment. Median follow-up was 428 days (range, 133-833) after the first dose of anti-PD-1. Overall response rate was 77% (15 complete responses and 8 partial responses) in 30 evaluable patients. At last follow-up, 11 of 31 patients progressed and 21 of 31 (68%) remain alive, with 8 (26%) deaths related to new-onset graft-versus-host disease (GVHD) after anti-PD-1. Seventeen (55%) patients developed treatment-emergent GVHD after initiation of anti-PD-1 (6 acute, 4 overlap, and 7 chronic), with onset after a median of 1, 2, and 2 doses, respectively. GVHD severity was grade III-IV acute or severe chronic in 9 patients. Only 2 of these 17 patients achieved complete response to GVHD treatment, and 14 of 17 required ≥2 systemic therapies. In conclusion, PD-1 blockade in relapsed cHL allo-HCT patients appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment-refractory GVHD. PD-1 blockade post-allo-HCT should be studied further but cannot be recommended for routine use outside of a clinical trial. [ABSTRACT FROM AUTHOR]