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Introduction: Medication nonadherence continues to be challenging for allogeneic hematopoietic cell transplant (HCT) recipients. The risk and severity of chronic graft-versus-host disease (GVHD) are associated with low immunosuppressant concentrations (which can be improved with model-informed precision dosing (MIPD)) and with immunosuppressant nonadherence (which can be improved with acceptable interventions). Methods: With the goals of improving adherence and achieving therapeutic concentrations of immunosuppressants to eliminate GVHD, we characterized the feasibility of using the Medication Event Monitoring (MEMS®) Cap in adult HCT recipients. Results: Of the 27 participants offered the MEMS® Cap at the time of hospital discharge, 7 (25.9%) used it, which is below our a priori threshold of 70%. These data suggest the MEMS® Cap is not feasible for HCT recipients. The MEMS® Cap data were available for a median of 35 days per participant per medication (range: 7–109 days). The average daily adherence per participant ranged from 0 to 100%; four participants had an average daily adherence of over 80%. Conclusions: MIPD may be supported by MEMS® technology to provide the precise time of immunosuppressant self-administration. The MEMS® Cap was used by only a small percentage (25.9%) of HCT recipients in this pilot study. In accordance with larger studies using less accurate tools to evaluate adherence, immunosuppressant adherence varied from 0% to 100%. Future studies should establish the feasibility and clinical benefit of combining MIPD with newer technology, specifically the MEMS® Button, which can inform the oncology pharmacist of the time of immunosuppressant self-administration. [ABSTRACT FROM AUTHOR]

Patients with chronic graft versus host disease (cGVHD) have low circulating regulatory T cells (Tregs). Interleukin-2(IL-2) is a growth factor for Tregs, and clinical trials have explored its use in cGVHD patients. Here we will discuss the biology of IL-2, its rationale for use and results of clinical trials in cGVHD. We also describe its mechanisms of action and alteration in gene expression in T-cell subsets after treatment with low dose IL-2 and photopheresis. Clinical trials using Low dose IL-2 have been done at single centers in small patient series. The majority of the clinical responses seen with IL-2 in cGVHD are classified as partial responses and efficacy as a single agent is limited. Compared to currently approved oral therapies, it has to be administered subcutaneously and requires specialized processing for compounding and storage limiting its widespread use. Its use is associated with constitutional symptoms and local injection site reactions. Local reactions can be easily managed by supportive care practices like rotation of injection sites and premeditations, constitutional symptoms resolve with, dose reduction (25–50%) allowing for continued therapy. Additional studies are needed to define optimal combination strategies with approved agents. Longer acting formulations of IL-2 that require less frequent dosing may also improve patient compliance. [ABSTRACT FROM AUTHOR]

This study reports the incidence of chronic graft versus host disease (GvHD) in allogeneic hematopoietic stem cell transplant (alloHCT) recipients who received SARS-CoV2 vaccination. The overall rates of new and worsening chronic GvHD combined were 14%, with median time from vaccination to GVHD being approximately three to four weeks. A majority of the cases were of mild to moderate severity and primarily localized to either the skin, mouth, or joints. Prior chronic GVHD and recent transplant were associated with higher GVHD rates following COVID-19 vaccination. More prospective studies are needed to provide a definitive mechanism for the impact of SARS-CoV2 vaccination on alloHCT patients. [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic cell transplantation (allo-HCT) and is the main cause of late non-relapse mortality (NRM). Three new agents are now approved to treat cGVHD, of which belumosudil has a unique and dual mechanism of action of i) targeting the Rho-GTPase-associated coiled-coil kinase 2 (ROCK2) in T helper follicular cells (TFH) and TH17 cells, this results in downregulation of proinflammatory cytokines (interleukin −21 and 17), the former in a STAT3-dependent mechanism, ii) inhibition of tissue fibrosis by targeting stress-induced polymerization of G-actin fibrils by inhibiting the Rho-ROCK-MRTF pathway. In this review we describe the epidemiology of cGVHD, its cardinal symptoms, preventive and therapeutic options, including second-line approved therapies in the United States (US). Clinical trial data that led to approval of belumosudil is discussed, in addition to the clinical scenarios in which the approved drugs may be most applicable. Belumosudil is approved for treatment of adult and pediatric patients ≥ 12 years with cGVHD after failing two lines of therapy based on results of the ROCKstar study that showed high overall response rates (ORR), favorable adverse effect profiles, and low rates of severe infections. With the availability of three new agents for treatment of cGVHD, treating physicians have more therapeutic options for patients and have additional options of development new clinical trials using a combination of recently approved drugs. [ABSTRACT FROM AUTHOR]

Patients receiving allogeneic hematopoietic stem cell transplant may experience graft-versus-host disease (GVHD) in which donor immune cells cause an immune reaction in host tissues. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines are highly effective in prevention of severe coronavirus-2019 (COVID-19) disease, but the vaccine can result in immune activation and GVHD. Herein, we report 4 cases of oral manifestations that may have been stimulated by COVID-19 or vaccination with Pfizer or Moderna vaccines. We believe this study is the first to report oral changes driven by an inflammatory/immune mechanism leading to oral symptomatic cGVHD. The clinical impact of this study is early recognition and appropriate management of oral symptomatic cGVHD following COVID-19 disease or SARS-CoV-2 vaccination. [ABSTRACT FROM AUTHOR]

Background: There is a paucity of studies describing the incidence and risk factors for late‐occurring (≥1 year) infectious complications in contemporary survivors of hematopoietic cell transplantation (HCT). Methods: This was a retrospective cohort study of 641 1‐year survivors of HCT, transplanted between 2010 and 2013 as adults, and in remission from their primary disease. Standardized definitions were used to characterize viral, fungal, and bacterial infections. Cumulative incidence of infections was calculated, with relapse/progression considered as a competing risk event. Fine‐Gray subdistribution hazard ratio estimates and 95% confidence intervals (CI) were obtained, adjusted for relevant covariates. Results: Median age at HCT was 55.2 years (range 18.1–78.1 years); 54.0% were survivors of allogeneic HCT. The 5‐year cumulative incidence of a late‐occurring infection for the entire cohort was 31.6%; the incidence of polymicrobial (≥2) infections was 10.1%. In survivors who developed at least one infection, the 5‐year incidence of a subsequent infection was 45.3%. Among allogeneic HCT survivors, patients with acute lymphoblastic (HR = 1.82 95% CI [1.12–2.96]) or myeloid (HR = 1.50 95% CI [1.02–2.20]) leukemia, and those with an elevated HCT‐Comorbidity index score (HR = 1.09 95% CI [1.01–1.17]) were more likely to develop late‐occurring infections; there was an incremental risk associated with severity of graft versus host disease (GVHD) at 1‐year post‐HCT (mild: HR = 2.17, 95% CI [1.09–4.33]; moderate/severe: HR = 3.78, 95% CI [1.90–7.53]; reference: no GVHD). Conclusions: The burden of late‐occurring infections in HCT survivors is substantial, and there are important patient‐ and HCT‐related modifiers of risk over time. These findings may help guide personalized screening and prevention strategies to improve outcomes after HCT. [ABSTRACT FROM AUTHOR]

Grades 2-4 acute graft-versus-host disease (GVHD) occurs in approximately 35% of matched, related donor (MRD) allogeneic hematopoietic cell transplantation (HCT) recipients. We sought to determine if the combination of tacrolimus and s irolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute GVHD and early mortality after allogeneic MRD HCT in a phase 3, multicenter trial. The primary end point of the trial was to compare 114-day grades 2-4 acute GVHD-free survival using an intention-to-treat analysis of 304 randomized subjects. There w as no difference in the probability of day 114 grades 2 -4 acute GVHD-free survival (67% vs 62%, P = .38). Grades 2-4 GVHD was similar in the Tac/Sir and Tac/Mtx arms (26% vs 34%, P = .48). Neutrophil and platelet engraftment were more rapid in the Tac/Sir arm (14 vs 16 days, P < .0 0 1 ; 16 vs 19 days, P = .03). Oropharyngeal mucositis was less severe in the Tac/Sir arm (peak Oral Mucositis Assessment Scale score 0.70 vs 0.96, P < .001), but otherwise toxicity was similar. Chronic GVHD, relapse-free survival, and overall survival at 2 years were no different between study arms (53% vs 45%, P = .06; 53% vs 54%, P = .77; and 59% vs 63%, P = .36). Based on similar long-term outcomes, more rapid engraftment, and less oropharyngeal mucositis, the combination of Tac/Sir is an acceptable alternative to Tac/Mtx after MRD HCT. This study was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; and the trial was registered at www.clinicaltrials.gov as #NCT00406393. (Blood. 2014;124(8):1372-1377) [ABSTRACT FROM AUTHOR]

CD4+ T cell interactions with B cells play a critical role in the pathogenesis of systemic autoimmune diseases such as systemic lupus and chronic graft-versus-host disease (cGVHD). Extrafollicular CD44hiCD62LloPSGL1loCD4+ T cells (PSGL1loCD4+ T cells) are associated with the pathogenesis of lupus and cGVHD, but their causal role has not been established. With murine and humanized MHC-/-HLA-A2+DR4+ murine models of cGVHD, we showed that murine and human PSGL1loCD4+ T cells from GVHD target tissues have features of B cell helpers with upregulated expression of programmed cell death protein 1 (PD1) and inducible T cell costimulator (ICOS) and production of IL-21. They reside in nonlymphoid tissues without circulating in the blood and have features of tissue-resident memory T cells with upregulated expression of CD69. Murine PSGL1loCD4+ T cells from GVHD target tissues augmented B cell differentiation into plasma cells and production of autoantibodies via their PD1 interaction with PD-L2 on B cells. Human PSGL1loCD4+ T cells were apposed with memory B cells in the liver tissues of humanized mice and cGVHD patients. Human PSGL1loCD4+ T cells from humanized GVHD target tissues also augmented autologous memory B cell differentiation into plasma cells and antibody production in a PD1/PD-L2-dependent manner. Further preclinical studies targeting tissue-resident T cells to treat antibody-mediated features of autoimmune diseases are warranted. [ABSTRACT FROM AUTHOR]

• The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (VEN-HMA) as a bridge to allogeneic hematopoietic cell transplantation (alloHCT) is associated with favorable HCT outcomes. • VEN-HMA could allow more patients of older age to proceed to potentially curative alloHCT. • AlloHCT outcomes are particularly good in patients who undergo HCT in complete remission after VEN-HMA therapy. The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in patients with acute myelogenous leukemia (AML) in both the upfront and relapsed/refractory (r/r) settings. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty-two patients with AML (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty-two (68.8%) were in complete remission (CR)/CR with incomplete count recovery at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival (OS) was 62.5%, and disease-free survival was 43.8%. The 1-year nonrelapse mortality rate was 18.8%, and the cumulative incidence of relapse was 37.5%. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3%, and the cumulative incidence of nonrelapse mortality was 9.1%. The cumulative incidence of grade II-IV acute graft-versus-host disease was 43.8%. We conclude that alloHCT after HMA-VEN is therapy associated with favorable allogeneic HCT outcomes in newly diagnosed older patients with AML, as well as those with r/r AML. [ABSTRACT FROM AUTHOR]

• HCT outcomes in ALL patients after Flu/Mel conditioning & Tac/Siro GVHD prophylaxis. • OS and PFS at 4 years were 58% and 44%, respectively. • Cumulative incidences of relapse and NRM at 4 years were 34% and 22%, respectively. • Patients with Philadelphia chromosome–positive (Ph+) status had lower relapse. • This regimen had favorable outcomes in adult ALL patients with Ph+ status. Acute lymphoblastic leukemia (ALL) is associated with poor survival in older adults, and allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning (RIC) has been an increasingly used strategy in this population. At City of Hope we conducted a retrospective analysis of 72 patients who underwent allogeneic HCT with fludarabine and melphalan (FluMel) as the conditioning regimen between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission. Tacrolimus and sirolimus (T/S) were used as graft-versus-host disease (GVHD) prophylaxis. Overall survival and progression-free survival at 4 years post-HCT were 58% and 44%, respectively. The cumulative incidences of relapse/progression and nonrelapse mortality at 4 years were 34% and 22%, respectively. Patients with Philadelphia chromosome–positive (Ph+) ALL had a significantly lower cumulative incidence of relapse/progression (20% versus 48% for patients with Ph-negative status, P =.007). In conclusion, RIC HCT with FluMel conditioning and T/S GVHD prophylaxis was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL. [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]

Highlights • Ruxolitinib use was associated with a reduction in prednisone dose. • The rate of infectious/bacterial infections was high and contributed to the overall mortality. • Ruxolitinib as salvage therapy is promising for chronic graft-versus-host disease refractory to steroids. Abstract Chronic graft-versus-host disease (cGVHD) continues to be a major complication after allogeneic hematopoietic cell transplantation, significantly affecting patients' quality of life. A regimen of systemic corticosteroids is considered first-line therapy but is often associated with inadequate responses and multiple side effects. In patients with refractory disease, an evidenced-based consensus is lacking as to the single best approach to managing symptoms. Ruxolitinib, a selective JAK1/2 inhibitor, has recently gained favor as a second-line approach in patients with steroid-refractory cGVHD. In this retrospective study, we evaluated the outcomes of 46 patients who received ruxolitinib for cGVHD between March 2016 and December 2017 at our institution, and evaluated ruxolitinib's impact at 6 and 12 months, based on the National Institutes of Health Severity Scale, including organ-specific responses, and mean prednisone dose. Furthermore, we present the first reported probability of ruxolitinib's treatment failure-free survival (FFS) in patients with cGVHD. After 12 months of ruxolitinib therapy, complete response, partial response, and stable disease was observed in 13% (n = 6), 30.4% (n = 14), and 10.9% (n = 5) of patients, respectively. The 1-year probability of FFS was 54.2% (95% confidence interval,.388 to.673), and ruxolitinib use was associated with a reduction in prednisone dose. In conclusion, our data, which represent the largest cohort of patients with cGVHD reported to date, support the use of ruxolitinib for cGVHD refractory to steroids and currently available salvage therapies, discontinued due to lack of response and high cost. [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]

We studied adults with acute myeloid leukemia (AML) after haploidentical (n=192) and 8/8 HLA-matched unrelated donor (n=1982), transplantation. Data were obtained from the Center for International Blood and Marrow Transplant Research. Haploidentical recipients received calcineurin inhibitor (CNI), mycophenolate and post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis; 104 patients received myeloablative and 88, reduced intensity conditioning regimens. Matched unrelated donor transplant recipients received CNI with mycophenolate or methotrexate for GVHD prophylaxis; 1245 patients received myeloablative and 737, reduced intensity conditioning regimens. In the myeloablative setting, day-30 neutrophil recovery was lower after haploidentical compared to matched unrelated donor transplants (90% versus 97%, p=0.02). Corresponding rates after reduced intensity conditioning transplants were 93% and 96%, (p=0.25). In the myeloablative setting, 3-month acute grade 2-4 (16% versus 33%, p<0.0001) and 3-year chronic GVHD (30% versus 53%, p<0.0001) were lower after haploidentical compared to matched unrelated donor transplants. Similar differences were observed after reduced intensity conditioning transplants, 19% versus 28%, (p=0.05) and 34% versus 52%, (p=0.002). Among patients receiving myeloablative regimens, 3-year probabilities of overall survival were 45% (95% CI 36-54) and 50% (95% CI 47-53) after haploidentical and matched unrelated donor transplants (p=0.38). Corresponding rates after reduced intensity conditioning transplants were 46% (95% CI 35-56) and 44% (95% CI 0.40-47) (p=0.71). Although statistical power is limited, these data suggests that survival for patients with AML after haploidentical transplantation with posttransplant cyclophosphamide is comparable with matched unrelated donor transplantation. [ABSTRACT FROM AUTHOR]

We sought to determine whether differences in chronic graft-versus-host disease (GVHD) rates would lead to survival differences by comparing 2463 peripheral blood (PB) and 1713 bone marrow (BM) hematopoietic cell transplant recipients. Patients had acute leukemia, chronic myeloid leukemia (CML), or myelodysplastic syndrome, and they received myeloablative conditioning regimens and calcineurin-inhibitor GVHD prophylaxis. There were no significant differences in long-term survival after transplantation of PB and BM, except for patients in first chronic phase CML. For these patients, the 5-year rate of survival was lower after transplantation of PB compared with transplantation of BM (35% versus 56%, P = .001). Although mortality risks were higher in patients with chronic GVHD after both PB (hazard ratio [HR], 1.58; P < .001) and BM (HR 1.73; P < .001) transplantations, its effect on mortality did not differ by graft type ( P = .42). BM is the preferred graft for first chronic phase CML, whereas as either graft is suitable for other leukemias. [ABSTRACT FROM AUTHOR]

Corticosteroids are the accepted primary therapy for acute graft-versus-host disease (GVHD), but durable responses are seen in only about half of the patients. Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0802, a phase 3 multicenter randomized double-blinded trial, was designed to test whether mycophenolate mofetil (MMF) plus corticosteroids was superior to corticosteroids alone as initial therapy for acute GVHD. Patients with newly diagnosed acute GVHD were eligible if they required systemic therapy. Patients were randomized to receive prednisone with either MMF or placebo. The primary end point was acute or chronic GVHD-free survival at day 56 after initiation of therapy. A futility rule for GVHD-free survival at day 56 was met at a planned interim analysis after 235 patients (of 372) were enrolled: 116 MMF, 119 placebo. Baseline characteristics were well balanced between treatment groups including grade and organ distribution of GVHD. GVHD-free survival at day 56, cumulative incidence of chronic GVHD at 12 months, overall survival, Epstein-Barr virus reactivation, severe, life-threatening infections, relapse at 12 months, and quality of life were similar. The addition of MMF to corticosteroids as initial therapy for acute GVHD does not improve GVHD-free survival compared with corticosteroids alone. [ABSTRACT FROM AUTHOR]

The introduction of reduced-intensity conditioning (RIC) regimens made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared with novel nontransplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT with nontransplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age and response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT. [ABSTRACT FROM AUTHOR]

Historically, outcomes of adult patients (pts) with ALL who fail to enter remission with standard induction chemotherapy are very poor. Blinatumomab, a bispecific CD3/CD19 antibody, has shown remarkable activity in relapsed/refractory (r/r) ALL. While allogeneic HCT is the recommended consolidation therapy for r/r ALL pts who respond to salvage therapy, HCT and toxicity outcomes for those who received blinatumomab salvage and HCT remains largely unknown. A retrospective review of r/r ALL pts medical records, who received blinatumomab salvage therapy from 2012 to 2018 at our institution was obtained. Only pts who responded to blinatumomab and underwent HCT were included (n=29). Kaplan-Meier curves and the log-rank test were used to evaluate the overall survival (OS) and progression-free survival (PFS). Cumulative incidence (CI) curves and the Gray test were used to examine the differences in relapse rates and non-relapse mortality (NRM). The median age at the time of HCT was 29 years (range: 19-65), and 8 pts (28%) were over 50 years old. HCT was done in complete remission- (CR)-1 (n=14, 48%) or ≥CR-2, with 2pts receiving blinatumomab salvage after relapse from a prior HCT. Pts received transplant from a matched sibling (n=11), matched unrelated (n= 12), haploidentical donor (n=5) or double umbilical cord blood (n=1) after myeloablative (n=20, including TBI+VP16, n=15) or reduced intensity (n=9) conditioning. The graft source was PBSCs in 25 pts (86.2%). Graft-versus-host disease (GVHD) prophylaxis was tacrolimus/sirolimus-based (n=19, 66%), and post-HCT cyclophosphamide (n=5, 17%) for haploidentical transplants. At the time of salvage therapy initiation, pts had either gross residual (n=22) or minimal residual disease (MRD+) (n=7). Negative MRD remission status was achieved prior to HCT in 15 pts, including those who were MRD+ before blinatumomab salvage. With a median follow up of 21.7 months (mo) (range: 1.1-55.7) for all pts and 6.4 mo for surviving pts, the 1-year OS and PFS were 72.8% (95% CI: 48.5-87.0) and 63.0% (95% CI: 38.8-79.8), respectively (Fig 1). Causes of death post-HCT were GVHD (n=3); NRM (n=4; 3 sepsis and 1 regimen related toxicity) and relapse (n=3). The CI of relapse at 1 and 2 years were 24.9% (95% CI: 8.6-45.3) and 45.9%, (95% CI: 20.3-68.3), respectively. NRM at 100 days was 6.9% (95% CI: 1.2-20.0) and at 12 mo was 12.1% (95% CI: 2.7-29.0). The incidence of grades 3-4 acute GVHD and extensive chronic GVHD at 24 mo were 25.0% (95% CI: 8.7-45.5) and 38.8% (95% CI: 14.2-63.1), respectively. No cases of veno-occlusive disease post-HCT were reported. We present here, for the 1st time, detailed data showing the tolerability and efficacy of HCT following salvage therapy with blinatumomab. No unexpected toxicities were noted post-HCT and the study showed encouraging 1-year OS and PFS with. Longer-term follow-up is ongoing for these patients. [ABSTRACT FROM AUTHOR]

Identification of anti-apoptotic properties of the Bcl2 protein has offered novel treatment options in many malignancies including AML. Venetoclax, a Bcl2 inhibitor, has shown promising results as upfront therapy in elderly patients (pts) and relapse/refractory (R/R) AML, when combined with hypomethylating agents (HMA). Yet, due to the high relapse risk, allogenic HCT remains as the only curative option for these high risk populations. To date, outcomes of HCT after prior therapy with Venetoclax + HMA have not been described. Also, as Venetoclax induces aplasia of antigen presenting cells expressing Bcl2, we hypothesized that pre-HCT treatment with venetoclax may be associated with a lower risk for GvHD. We retrospectively analyzed 26 consecutive AML pts who underwent HCT at our institution from 2016 to 2018 with final line of systemic therapy of venetoclax + HMA. Pts were not eligible for upfront standard induction chemotherapy (n=8) or had R/R disease (n=18). Fifteen pts received ≥2 lines of therapy and 3 had previous HCT. CR/CRi was achieved in 62% (n=16), of which 3 pts had minimal residual disease and the rest (n=10) had persistent disease prior to HCT. Donors were matched related (n=8), matched unrelated (n=16), or haploidentical (n=2). Conditioning regimen was myeloablative (38.5%) or reduced intensity (61.5%). Most pts (n=24, 92.3%) received PBMCs as the graft source. Tacrolimus/Sirolimus (Tac/Sir) was administered in most pts (n=20, 77%) for GvHD prophylaxis. Descriptive statistics were used for baseline characteristics. Kaplan-Meier and cumulative incidence curves were constructed for overall survival (OS), progression-free survival (PFS), relapse, none-relapse mortality (NRM), and aGvHD. Median age at the time of HCT was 59 years (range: 18-73). Median time to neutrophil and platelet engraftment were 17 days (range: 14-20) and 20 days (range: 16-61), respectively. With a median follow up of 4.5 months (range: 1.4-18.6), 6 months relapse rate was 12% (95% CI: 0.16-0.54) and 100 day NRM was 4% (95% CI: 0.02-0.34). Grade II-IV aGvHD at 100 days was noted in 34% (95% CI: 0.15-0.51). One-year OS and PFS for all pts were 72% (95% CI: 0.43-0.88) and 40% (95% CI: 0.16-0.63), respectively. For patients in CR at the time of HCT, 1-year OS was 80% (95%CI: 37-95) and PFS was 38% (95%CI: 0.08-0.69) (Fig 1). Only one patient who had been treated with three lines of systemic therapy prior to HCT experienced veno-occlusive disease. Thus, administration of Venetoclax-based salvage regimen as a bridge to HCT is safe with no added immediate toxicities post-HCT. Our early outcome data are promising for this otherwise high-risk population. Our data also justify further studies on the role and impact of Venetoclax and its anti-Bcl2 properties as a component of the conditioning regimen or as post-HCT maintenance. [ABSTRACT FROM AUTHOR]

Chronic GVHD remains as the major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are the first line of therapy, but outcomes are poor in steroid refractory (SR) patients. Previous reports show that in SR patients, IL-2 therapy results in partial response (PR) associated with increase in regulatory T cells (Tregs). ECP has been used for cGVHD with skin response rates of 40-100%. Based on non-overlapping toxicities and, we prospectively studied a combination of low dose IL-2 + ECP to treat SR-cGVHD. Patients with SR-cGVHD, were treated with low dose IL-2 (1 × 106 U/m2, daily) + ECP for 12 weeks. IL-2 was provided by Prometheus Laboratories. ECP was administered 2 times/week for 4 weeks followed by 2 treatments every 2 weeks for the next 8 weeks. The NIH consensus criteria was used to assess cGVHD severity. PBMC and plasma samples were banked at baseline and on 3-week intervals to assess regulatory T cell (Tregs) and reactive oxygen species (ROS). Of the 12 consented patients, 9 completed the study (2 were not treated due to rapid disease progression before enrollment and 1 died from sepsis at week 11). All enrolled patients (n=10) had scleroderma as the predominant cGVHD manifestation. Median age was 45.6 years (range: 23-66). Median prior lines of therapy were 4.2(range 3-6), 5 patients had prior exposure to ruxolitinib and 4 were on ECP at the enrollment. Donors were fully matched unrelated (n=8), matched sibling (n=1) or mismatched unrelated (n=1). Conditioning regimen was myeloablative (n=5) or reduced intensity (n=4). GVHD prophylaxis was tacrolimus/Sirolimus (tac/sir) (n=6), tac/methotrexate (MTX) (n=2), or Tac/sir/MTX (n=1). Of the 10 enrolled patients, 9 responded to IL-2 + ECP combination (all classified as PR). A 37% dose reduction in steroid dose was noted among 7 patients. The remaining 3 patients were on stable steroid dose at end of study. Only 1 patient had progressive cGVHD in form of scleroderma. ECP+IL-2 therapy was well tolerated with no drug related serious adverse events (SAE). Grade 3-4 AEs included grade 3 metabolic and nutrition (n=8), grade 3 anemia (n=3), and grade 4 atrial flutter (n=1). Infectious complications were noted in 3 patients (one grade 4 [sepsis]). There was a robust increase in Tregs from the baseline mean of 0.755% (range 0.08-1.88) to end of treatment 6.999% (range 0.78-17.13) [p=0.02] Fig 1. Increment in Tregs was seen in patients who were on ECP therapy prior to enrollment (n=4) and in one patient who progressed while on therapy. No correlation was found between the treatment response and ROS levels. In conclusion, the combination of ECP +IL-2 is well tolerated in patients with SR-cGVHD with no apparent increase in infectious complications or other toxicities. Clinical response correlates with a robust increase in Tregs, but no correlation was found with ROS levels. [ABSTRACT FROM AUTHOR]

Despite of the continuous increase in the number of volunteer donors available through the registry, many patients who require an allogeneic hematopoietic cell transplantation (HCT) cannot find a fully-matched donor. While a mismatched unrelated donor (MMUD) is frequently available, it is associated with inferior outcomes and increased risk of graft-versus-host disease (GvHD). Post-transplant cyclophosphamide (PTCy) has been effective in haploidentical HCT, and increasingly used in matched donor HCTs. However, limited data exist in MMUD setting. We conducted a prospective single center trial (NCT 03128359) of PTCy for MMUD HCT with the primary objective of estimating 1-year GvHD-free relapse/progression-free survival (GRFS). As of October 2019, all planned 39 patients have been enrolled with a median follow up of 11 months (range: 1-23). Here we present the preliminary estimate of 1-year GRFS and other HCT outcomes in two strata; myeloablative conditioning (n=19) using Fludarabine (90 mg/m2) and FTBI (1200 cGy) or reduced intensity conditioning (n=19) using Fludarabine (100 mg/m2) and Melphalan (140 mg/m2 or 100 mg/m2 if >60 years old). Patients between 0 to 75 years of age and KPS of ≥70% with hematologic malignancies undergoing HCT from a 7/8 HLA-matched (A-, B-, C-, and DR-) donor were eligible. Patients with donor specific antibodies to the mismatched HLA-locus were excluded. All patient received PBMCs (3-5 × 106/kg) followed by GVHD prophylaxis consisting of PTCy (50 mg/kg for 2 days), Tacrolimus (1 mg), and mycophenolate mofetil (1 gr 3 × a day). Median age at the time of HCT was 53 years (range: 21-72), and 50% of patients were male. Disease risk was low in 47% (n=18), intermediate in 37% (n=14), and high in 16% of the patients (n=6). At transplant, 29 patients were in complete remission, and 9 had active disease. HCT-CI was 0 in six (16%) and 1-2 in 15 (39%) and >2 in 17 (45%) patients. Donors' median age was 32 years (range: 19-53) and donors were mismatched at HLA-A (n=14), -B (n=12), -C (n=8), or DR-loci (n=5). Median number of mismatches was 2 of 12 (range: 1-4). Female to male donor HCT was in 11% of recipients. Neutrophil engraftment occurred in all patients (median time to engraft: 16 days; range 13-35). One-year overall survival (OS) and GRFS were 92% (95% CI: 70-98) and 70% (95% CI: 51-83), respectively. Non-relapse mortality and relapse rate at 1 year were at 8% (95% CI: 2-29) and 13% (95% CI: 5-34), respectively. Cumulative incidence of day 100 acute GvHD grade 2-4 was 50% (95% CI: 35-71) and 1-year chronic GvHD was 56% (95% CI: 39-81). No severe chronic GvHD by the NIH criteria was observed. In conclusion, the data from our phase II trial of PTCy showed highly promising OS/GRFS in patients receiving 7/8 MMUD HCT, and that PTCy in MMUD setting offers an alternative and effective HCT approach for patients who do not have an available matched donor. [ABSTRACT FROM AUTHOR]

Accurate and reproducible methods to diagnose, grade and report acute graft vs. host disease (GVHD) are critical for evaluation of new treatments and biomarkers. BMTCTN 1202 created a biorepository and clinical data bank for the study of GVHD biomarkers and other transplant outcomes. To create a representative study population any pt >10 kg undergoing alloHCT was eligible (Table 1). Symptoms suggestive of GVHD, biopsy results, immunosuppressive medications, and possible etiologies were reported weekly until day 100. An end-point review committee (ERC) performed a near real time adjudication of reported symptoms at their onset and assigned a confidence level (Confirmed, Probable, Possible or Negative) for each organ according to Harris, BBMT, 2016. The final repository included 41,468 annotated biospecimens from 1709 alloHCT patients (pts) transplanted at U.S. centers from 2012-2016. Although 90% of pts developed symptoms at least once, physicians suspected GVHD in only 23% of cases and GVHD was considered the only etiology in 12%. Biopsies (bx) were performed in 40% of pts, most often for upper or lower GI symptoms. Bx results were equivocal in 11% although the range among centers was broad (0-45%). Equivocal results were most likely for skin bx and during the 2nd week after transplant. Systemic steroids were administered to 70% of pts at least once, often for non-GVHD reasons (41% of steroid courses). When GVHD was in the differential diagnosis, systemic steroids were started 81% of the time. The ERC adjudicated 2,008 cases with symptoms suggestive of GVHD onset. In 12.3% of cases the ERC modified either the center reported diagnosis of GVHD (4.6%) or the automated generated severity grade (7.7%). GVHD was diagnosed in 1025 pts and categorized as confirmed (31%), probable (50%), or possible (19%). The proportion of definitive diagnoses (Confirmed or Negative) increased with longer time post-transplant (Fig 1). ERC adjudication substantially lowered the incidence of GVHD grade 2-4 from 30% as reported by centers to 23% (confirmed or probable) by ERC. An adjudicated diagnosis of GVHD strongly associated with 6 month NRM, adjusted for patient age, gender and HLA matching (HR = 2.0, p < 0.001). Adjudicated GVHD grade was also strongly associated with 6 month NRM (Grade 2, HR = 2.1, p < 0.001; Grade 3-4, HR = 7.1, p < 0.001). In summary, the largest prospective observational study of GVHD outcomes demonstrated that symptoms in GVHD target organs are almost universal after transplant, their differential diagnosis is broad, tissue biopsies are infrequently done and their results are often equivocal, and steroids are often prescribed for reasons other than acute GVHD. These limitations undermine the current methods of diagnosis and reporting of acute GVHD on clinical trials. A robust reporting and adjudication system has significant value and may improve the chances of success of prospective clinical trials. [ABSTRACT FROM AUTHOR]