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Pulmonary chronic graft-versus-host disease (PcGVHD) is a devastating complication of allogeneic hematopoietic stem cell transplant (HCT). The 2014 National Institutes of Health cGVHD consensus criteria (NIH criteria) only captures bronchiolitis obliterans syndrome (BOS). In this study, we adapted the 2019 International Society for Heart and Lung Transplantation (ISHLT) criteria of chronic lung allograft dysfunction (CLAD) to define novel phenotypes of PcGVHD and compared the performance of this criteria with the NIH criteria to identify patients with high-risk PcGVHD. We reviewed consecutive patients in a cGVHD natural history protocol (#NCT00092235) and adapted the 2019 CLAD criteria (the adapted criteria) to define PcGVHD as post-HCT forced expiratory volume at 1 second < 80% predicted value, with 4 phenotypes: obstructive, restrictive, mixed obstructive/restrictive, and undefined. An independent adjudication committee evaluated subjects for diagnosis and phenotyping. We identified 166 (47.4%) patients who met the adapted criteria, including obstruction (n = 12, 3.4%), restriction (n = 67, 19.1%), mixed obstruction/restriction (n = 47, 13.4%), and undefined (n = 40, 11.4%). In these patients, less than half (n = 78) met the NIH criteria for BOS (NIH+); the rest (n = 88) did not (NIH−). The NIH− subjects showed increased risk of death compared with those without PcGVHD (hazard ratio = 1.88, 95% confidence interval = 1.20-2.95; P = .006) that was similar to NIH+ subjects (P = .678). Our study demonstrated the potential of the adapted criteria in identifying patients with high-risk PcGVHD that have been missed by the NIH criteria. The adapted criteria could become a valuable tool to better phenotype and study lung disease in cGVHD.

Asparaginases, key agents in treatment of acute lymphoblastic leukemia (ALL), are associated with venous thromboembolism (VTE). While risks of short-acting asparaginase-related VTE is well-known, we studied VTE incidence and risk factors in adult ALL patients treated with and without long-acting pegylated asparaginase (PegA). Single-center, retrospective analysis of 89 ALL patients treated with (n = 61) or without (n = 28) PegA at Greenebaum Comprehensive Cancer Center. Reviewed patient and disease characteristics, treatment, and VTE incidence. VTE during treatment occurred in 31 patients (35%), and was associated with PegA (p = 0.001) and Philadelphia chromosome negativity (p = 0.002). Among PegA recipients, VTE was associated with a significantly higher mean body mass index (BMI) of 31.3 kg/m2 (p = 0.037), and was more common with pre-T/T cell compared to pre-B/B cell ALL (68.2% vs. 33.3%, p = 0.009). Antithrombin-III (ATIII) levels were measured for 26 patients; 16 (61.5%) were

The role of hematopoietic cell transplantation (HCT) in the management of newly diagnosed adult acute myeloid leukemia (AML) is reviewed and critically evaluated in this evidence-based review. An AML expert panel, consisting of both transplant and nontransplant experts, was invited to develop clinically relevant frequently asked questions covering disease- and HCT-related topics. A systematic literature review was conducted to generate core recommendations that were graded based on the quality and strength of underlying evidence based on the standardized criteria established by the American Society of Transplantation and Cellular Therapy Steering Committee for evidence-based reviews. Allogeneic HCT offers a survival benefit in patients with intermediate- and high-risk AML and is currently a part of standard clinical care. We recommend the preferential use of myeloablative conditioning in eligible patients. A haploidentical related donor marrow graft is preferred over a cord blood unit in the absence of a fully HLA-matched donor. The evolving role of allogeneic HCT in the context of measurable residual disease monitoring and recent therapeutic advances in AML with regards to maintenance therapy after HCT are also discussed.

Background CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR-T) has emerged as effective for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as immune effector cell–associated neurotoxicity syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR T-cell therapy in R/R LBCL. Methods Patients (n = 45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria, respectively. Results Twenty-five (56%) patients developed ICANS, 18 (72%) of whom had severe (CTCAE grades 3–4) ICANS. Median time to development of ICANS was 5 days (range, 3–11). Elevated pre-infusion (day 0 [D0]) fibrinogen (517 vs 403 mg/dL, upper limit of normal [ULN] 438 mg/dL, P = 0.01) and D0 lactate dehydrogenase (618 vs 506 units/L, ULN 618 units/L, P = 0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, P < 0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS), or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS. Conclusions ICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, the majority of which were high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.

Chronic graft-versus-host disease (cGVHD) is an important systemic complication of allogeneic haematopoietic stem cell transplantation with heterogeneous, multi-organ involvement that can lead to increased morbidity and mortality. Despite significant advances in understanding the complex pathophysiology driving the disease, curative treatment options remain suboptimal. The past decade, however, has seen much growth in collaborative research efforts and standardization of criteria for clinical trials that have led to discovery of several new second-line therapies in cGVHD. The key to successful cGVHD control and management includes a comprehensive and sustained multidisciplinary effort with emphasis on ancillary and supportive care for these patients. The focus of this review is to summarize the new developments in systemic, organ-specific, and topical treatments in the management of cGVHD that emerged since the 2014 NIH consensus conference.

Subsequent cancer (SC) is a significant cause of morbidity and mortality in long-term survivors after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) and treatment-related immunosuppression have been recognized as risk factors for SC. This study sought to investigate the incidence and risk factors for SC in patients with established cGVHD, assessed separately for onset of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)—categorized into nonmelanoma skin cancer (NMSC)—and all cancers other than NMSC. Two hundred and four patients were enrolled in the prospective cross-sectional cGVHD Natural History Study and underwent comprehensive clinical evaluation. Patients were followed-up with an annual survey. The cumulative incidences of NMSC and cancers other than NMSC with competing risks were estimated separately, and transplantation- and cGVHD-related factors were assessed for association with outcomes using Gray's test and multivariable Cox models. The time period for all analyses began at 2 years postevaluation to restrict analyses to patients presumed to not have had SC present at evaluation. Nineteen patients were diagnosed with NMSC and 19 were diagnosed with cancers other than NMSC, with 10-year cumulative incidences of 15.5% (95% confidence interval, 9.0% to 27.6%) and 13.8% (95% CI, 8.2% to 20.8%), respectively. Age at transplantation (hazard ratio [HR], 1.94; 95% CI, 1.23 to 3.06) and higher C-reactive protein level at evaluation (HR, 9.49; 95% CI, 1.26 to 71.58) were jointly associated with NMSC, and gastrointestinal cGVHD at evaluation (HR, 0.26; 95% CI, 0.09 to 0.78) was associated with reduced risk of NMSC. T cell depletion at transplantation (HR, 3.09; 95% CI, 1.17 to 8.20), lymphoma as an indication for transplantation (HR, 3.96; 95% CI, 1.56 to 10.05), and oral cGVHD severity at evaluation (HR, 4.36; 95% CI, 1.52 to 12.46) were jointly associated with cancers other than NMSC. This study estimates the incidence of SC in a population of allo-HSCT recipients with severe cGVHD and identifies correlations with the subsequent development of SC. These factors seem to differ between NMSC and cancers other than NMSC. Further longitudinal investigations accounting for dynamic and cumulative processes are needed to improve our understanding and management of SC.

Outcomes and life expectancy for patients with multiple myeloma (MM) have improved substantially over the last two decades with advancements in therapy, including autologous stem cell transplantati...

INTRODUCTION: Obesity has become increasingly prevalent worldwide and is a risk factor for many malignancies. We studied the correlation between body mass index (BMI) and the incidence of acute promyelocytic leukemia (APL), non-APL acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and control hospitalized patients without leukemia in the same community. METHODS: Multi-center, retrospective analysis of 71,196 patients: APL (n=200), AML (n=437), ALL (n=103), non-leukemia hospitalized (n=70,456) admitted to University of Maryland and Johns Hopkins Cancer Centers, and University of Maryland Medical Center. RESULTS: Patients with APL had a significantly higher unadjusted mean and median BMI (32.5 kg/m(2) and 30.3 kg/m(2)) than those with AML (28.3 kg/m(2) and 27.1 kg/m(2)), ALL (29.3 kg/m(2) and 27.7 kg/m(2)), and others (29.3 kg/m(2) and 27.7 kg/m(2)) (p

Simple Summary Around 12–38% of acute promyelocytic leukemia (APL) patients carry the FLT3-ITD mutation, which has been associated with several poor-prognosis indicators such as high white blood cell counts, M3v variant morphology, and the bcr3 isoform. We aimed to retrospectively study the impact of FLT3-ITD mutations in APL patients in regard to clinical features, treatment courses, and outcomes. We demonstrate that Sanz high-risk status APL correlates with high FLT3-ITD allelic burdens, with every 1% increase in allelic burden correlating with a 0.6 × 109/L increase in white blood cell count (WBC). The presence of FLT3-ITD was associated with decreased remission rates and higher 5-year mortality from the time of diagnosis. These findings provide novel revelations regarding the features of FLT3-ITD APL, particularly in regard to allelic burden, that warrant further study. Abstract The significance of FLT3-ITD in acute promyelocytic leukemia (APL) is not well-established. We performed a bi-center retrospective study of 138 APL patients, 59 (42.8%) of whom had FLT3-ITD. APL patients with FLT3-ITD had higher baseline white blood cell counts (WBCs) (p < 0.001), higher hemoglobin, (p = 0.03), higher aspartate aminotransferase (p = 0.001), lower platelets (p = 0.004), lower fibrinogen (p = 0.003), and higher incidences of disseminated intravascular coagulation (p = 0.005), M3v variant morphology (p < 0.001), and the bcr3 isoform (p < 0.001). FLT3-ITD was associated with inferior post-consolidation complete remission (CR) (p = 0.02) and 5-year overall survival (OS) of 79.7%, compared to 94.4% for FLT3-WT (wild-type) (p = 0.02). FLT3-ITD was strongly associated with baseline WBCs ≥ 25 × 109/L (odds ratio (OR): 54.4; 95% CI: 10.4–286.1; p < 0.001). High FLT3-ITD allelic burdens correlated with high-risk (HR) Sanz scores and high WBCs, with every 1% increase in allelic burden corresponding to a 0.6 × 109/L increase in WBC. HR APL was associated with a 38.5% increase in allelic burden compared with low-risk (LR) APL (95% CI: 19.8–57.2; p < 0.001). Our results provide additional evidence that FLT3-ITD APL is a distinct subtype of APL that warrants further study to delineate potential differences in therapeutic approach.

Limited information is available regarding clinical and biological properties of fatigue in patients with chronic graft-versus-host disease (cGvHD). Patients with moderate-to-severe cGvHD per NIH criteria were enrolled on a cross-sectional study and categorized as "fatigued" if SF-36 vitality score was

Asparaginases, key agents in treatment of acute lymphoblastic leukemia (ALL), are associated with venous thromboembolism (VTE). While risks of short-acting asparaginase-related VTE is well-known, we studied VTE incidence and risk factors in adult ALL patients treated with and without long-acting pegylated asparaginase (PegA).Single-center, retrospective analysis of 89 ALL patients treated with (n = 61) or without (n = 28) PegA at Greenebaum Comprehensive Cancer Center. Reviewed patient and disease characteristics, treatment, and VTE incidence.VTE during treatment occurred in 31 patients (35%), and was associated with PegA (p = 0.001) and Philadelphia chromosome negativity (p = 0.002). Among PegA recipients, VTE was associated with a significantly higher mean body mass index (BMI) of 31.3 kg/mThis study confirms PegA as a risk factor for VTE in patients with ALL. Risk factors among those receiving PegA include higher BMI and pre-T/T cell ALL. ATIII repletion was not shown to be protective against VTE. There was a higher incidence of VTE in patients who received PegA with non-O compared to O blood type, but the precise correlation is uncertain.

Malignancy relapse remains a major barrier to treatment success in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Chronic graft-versus-host disease (cGVHD) markedly reduces hematologic malignancy relapse risk, but relapses still occur in these patients. Patients (n = 275) with moderate or severe cGVHD were enrolled on the National Cancer Institute (NCI) prospective cross-sectional natural history study (NCT00092235). Subjects were median 36 months after allo-HSCT and were followed subsequently for malignancy relapse and survival. Seventeen patients experienced relapse. In a multivariable model including time-dependent influences on relapse, risk factors associated with increased risk of relapse included shorter time from transplant to cGVHD evaluation (HR 0.279, 95% CI 0.078-0.995) and lower number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.260, 95% CI 0.094-0.719). In a model excluding time-dependent influences on relapse risk, lower number of prior lines of systemic immunosuppressive therapy for cGVHD (HR 0.288, 95% CI 0.103-0.804), lower C4 complement level (HR 0.346, 95% CI 0.129-0.923), and higher body mass index (HR 3.222, 95% CI 1.156-8.974), were all associated with increased relapse risk. Parameters indicating cGVHD severity and activity are associated with risk of malignancy relapse. Classical predictors of relapse after allo-HSCT do not seem to be prognostic.

Key Points CAR T-cell therapy was safe and effective in a DLBCL patient with coexisting autoimmune neuropathy. CD19 CAR T-cell therapy may control refractory autoantibodies and monoclonal gammopathies.

Acute promyelocytic leukemia (APL) is an uncommon cancer, comprising approximately 10% of acute myeloid leukemia (AML) with annual incidence of approximately 1500 cases in the United States (U.S.) ...

Chimeric antigen receptor T-cell(CAR-T) therapy is an increasingly utilized treatment modality with FDA approval for relapsed or refractory(R/R) CD19 positive B-cell Acute Lymphoblastic Leukemia(B-...

Hemophagocytic lymphohistiocytosis (HLH) is a disorder of immune regulation, manifested by fever, pancytopenia, hyperferritiniemia, hypertriglyceridemia, and extensive hemophagocytosis involving the bone marrow and spleen. HLH can occur in adults with an underlying hematopoietic malignancy, or with systemic infections. HLH following hematopoietic stem cell transplantation (HSCT) is unusual, and the diagnosis may be challenging particularly because the diagnostic criteria in the HLH-2004 guidelines overlap with common post-transplant complications such as engraftment syndrome, graft-vs-host disease, and infections. HLH is commonly triggered by viral, bacterial and, less commonly, parasitic infections. Following HSCT, patients with latent Toxoplasma infection may develop systemic disease secondary to reactivation, and rarely this may lead to a HLH physiology, with a very high mortality rate. Herein we describe the successful management of disseminated toxoplasmosis associated with life-threatening HLH using tocilizumab and antimicrobial therapy.

Background: Although bronchiolitis obliterans syndrome (BOS) is a well described manifestation of pulmonary involvement by chronic graft-versus-host disease (PcGvHD), additional pulmonary phenotypes of PcGvHD beyond BOS have not been well-characterized. PcGvHD and chronic lung allograft dysfunction (CLAD) in lung transplant recipients share similar pathophysiological mechanisms. We aim to use an adaptation of the International Society for Heart and Lung Transplantation (ISHLT) CLAD Consensus Criteria to describe PcGvHD phenotypes beyond BOS in order to improve the diagnosis and classification of PcGvHD. Methods: We created a new PcGvHD diagnostic and phenotyping criteria based on the 2019 ISHLT CLAD Consensus Criteria (Table 1). Consecutive patients enrolled in the cross-sectional National Institutes of Health (NIH) natural history protocol (NCT00092235) between October 2004 and January 2020 were analyzed for study inclusion. Diagnosis of CLAD-PcGvHD was made when the following criteria were met: 1). New-onset decline of pulmonary function after allogeneic stem cell transplant (AHCT); 2). Forced expiratory volume in one second (FEV1) < 80% predicted with 10% decrease over less than 2 years; 3). Classification into one of the four CLAD-PcGvHD subtypes, [BOS, restrictive lung syndrome (RLS), mixed BOS/RLS (M) and undefined (UD)] was possible; 4). Other causes of pulmonary dysfunction were excluded. Patients without a diagnosis of cGvHD, NIH-performed pulmonary function test (PFT) or thoracic computed tomography (CT) were excluded. Demographic characteristics, AHCT information, GvHD history and treatment information, PFTs, and CT were collected for all study cohort patients. PFTs were analyzed by two independent pulmonologists and thoracic CT studies by an independent cardiothoracic radiologist. The final diagnosis and classification of PcGvHD per the new criteria were made and confirmed by two independent reviewers. Results: Of a total of 447 patients, 21 patients did not have cGvHD, 76 patients did not have NIH-performed PFT and/or CT, leaving 350 patients for the study cohort. The NIH cGvHD global severity score was 3 (severe) in 76% of patients. Evaluation of the study cohort by the new criteria diagnosed CLAD-PcGvHD in a total of 166 (47.4%) patients, including: 12 (3.4%) BOS, 67 (19.1%) RLS, 47 (13.4%) mixed, and 40 (11.4%) UD. In contrast, only 80 (22.9%) patients had documented diagnosis of BOS according to the NIH 2014 cGvHD consensus criteria, i.e., FEV1 < 75% predicted and FEV1/FVC < 0.7. An additional 52 (14.9%) patients had reduced FEV1, but were unable to be classified by the CLAD-PcGvHD criteria (unclassified, UC), therefore did not meet the diagnosis of Pc-GvHD. Compared to patients with normal FEV1 or UC, patients with CLAD-PcGvHD had poorer Karnofsky performance status (KPS) (p=.0001), more commonly received myeloablative conditioning (p=.047) or busulfan (p=.007), had a higher prevalence of liver cGvHD (p=.001), and required more lines of therapy for cGvHD (p=.0001). Between different CLAD-PcGvHD phenotypes, patients with BOS were older at AHCT (p=.005), had higher FEV1 and hemoglobin-adjusted DLCO (p=.0001 and p=.005, respectively), while patients with RLS had higher frequencies of skin or joint/fascia cGvHD (p=0.001 and p=.003, respectively). Median overall survival (OS) after AHCT was 162 months in patients with CLAD-PcGvHD, unreached in UC, and 310 months in patients with normal FEV1 (p=.007); OS was similar between different PcGvHD phenotypes (p=.154). In multivariate analysis, KPS < 80, FEV1 < 40%, adjusted DLCO < 60%, CLAD-PcGvHD, indication for AHCT being lymphoid malignancy, and black race were independent risk factors for OS (Table 2). Conclusion: The CLAD-PcGvHD criteria involves computed tomography in patient evaluation and encompasses a wide spectrum of lung disease post-AHCT. With this criteria, half of the patients in the NIH cGVHD natural history study could be diagnosed and phenotypically classified. The development of CLAD-PcGvHD was an independent risk factor for post-transplant survival. The proposed criteria could become a valuable all-encompassing clinical tool in studying post-AHCT lung disease and facilitate the study across solid organ and hematopoietic stem cell transplantation. Figure 1 Figure 1. Disclosures Pavletic: Center for Cancer Research: Research Funding; National Cancer Institute: Research Funding; National Institutes of Health: Research Funding; Celgene: Research Funding; Actelion: Research Funding; Eli Lilly: Research Funding; Pharmacyclics: Research Funding; Kadmon: Research Funding.

Introduction Bronchiolitis Obliterans Syndrome (BOS) is a rare but devastating complication of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and is associated with a high morbidity and mortality. There is a dearth of treatment options for BOS and new strategies are needed. Airway neutrophilia is a hallmark of BOS, even in the absence of infection, and neutrophil elastase (NE) is an enzyme that has been implicated in the pathogenesis of BOS. We are conducting a phase 1b study of an oral NE inhibitor, alvelestat, in patients with BOS after HCT . Biomarkers, including the elastin breakdown peptides desmosine/isodesmosine (DES/IDES), and stimulated neutrophil elastase assess direct effect on NE activity. Neo-epitope by-products of collagen type 3 and 6 synthesis (PRO-C3 and PRO-C6) and degradation (C3M and C6M) are measured as biomarkers of fibrosis/tissue modelling Methods Patients age ≥18 years with BOS and chronic GVHD after HCT were recruited to the National Cancer Institute protocol (NCT02669251). This phase 1 study had 2 parts: 8-week intra-patient dose escalation period, followed by a continuation period that allowed for up to 6 months of treatment. Alvelestat was given orally starting at 60mg twice daily, increased every 2 weeks to 120mg twice daily, 180mg twice daily, and finally 240mg twice daily. Peripheral blood samples were collected at baseline and at the end of each dose-escalation stage. Plasma DES/IDES was measured by isotopic dilution liquid chromatography-tandem mass spectrometry (Huang et al Thorax 2012;67:502-508). Ex vivo zymosan stimulated neutrophil elastase activity was measured by ProteaseTag® immunoassay (ProAxsis Ltd, Northern Ireland). PRO-C3, PRO-C6, C3M and C6M were measured by competitive ELISA. (Nordic Biosciences, Denmark). Results are presented as Mean and Standard Error Mean (SEM). Results Between 2016 and 2018, 7 patients were enrolled (3 men and 4 women). Median FEV 1 after bronchodilator at time of enrollment was 44% predicted (range 38-74). All 7 patients were able to tolerate dose escalation of alvelestat up to the maximum dose 240mg twice daily. Preliminary clinical results were previously presented. DES/IDES was elevated at baseline (mean 0.464 (SEM 0.0508) ng/ml, with 6 of 7 subjects above the Upper Limit of Normal (ULN, 0.280 ng/ml)). Levels progressively declined during the dose escalation period to 0.380 (SEM 0.0419) ng/ml by week 8, representing a mean within subject % change from baseline (CFB) of -16.2% (SEM 6.794, Figure 1a) Ex vivo zymosan stimulated elastase activity also showed progressive decrease over the dose escalation period, with some subjects demonstrating 100% suppression (Figure 1b). Collagen synthesis as measured by PRO-C3 and PRO-C6 was increased above ULN at baseline and declined with alvelestat treatment (Figure 1c and 1d). There was no consistent change in collagen degradation biomarkers (C3M, C6M) There was consistency of a suppressive effect on biomarkers of elastase activity and collagen turnover in 6 of 7 treated patients, all of whom had improved or stable lung disease (ranging from change in FEV1 % predicted at end of treatment from +9% to -6%). Conclusion NE can damage lung tissue due to elastin breakdown, pro-inflammatory and pro-fibrotic effects (Sallenave J-M, J Leuk Biol 2015;98:137-139). This is the first evidence of elevated elastase activity as detected by elastin breakdown in patients with BOS and chronic GVHD. Treatment with the selective NE inhibitor, alvelestat was associated with progressive reduction of plasma desmosine levels over 8 weeks of within-subject dose escalation and reduction stimulated neutrophil elastase activity. The consistent suppression of elastase and of collagen synthesis/turnover biomarkers following alvelestat treatment is encouraging for its potential to impact progressive lung fibrosis in BOS and chronic GVHD. Disclosures Parkin: Mereo BioPharma Group: Current Employment. Moore: Mereo BioPharma Group: Current Employment. Pavletic: Center for Cancer Research: Research Funding; National Cancer Institute: Research Funding; National Institutes of Health: Research Funding; Celgene: Research Funding; Actelion: Research Funding; Eli Lilly: Research Funding; Pharmacyclics: Research Funding; Kadmon: Research Funding.

Introduction:Chimeric antigen receptor T-cell (CAR-T) therapy has become an important treatment modality for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, many of these patients have aggressive disease and require a form of bridging therapy (BT) for disease control during CAR-T manufacturing. There is limited data in the literature on the most appropriate form of BT and the impact of BT on clinical outcomes. Methods:We retrospectively analyzed data on 75 patients that received CAR-T therapy at our institution. BT was defined as therapy administered between apheresis and CAR-T infusion. 52 patients received bridging therapy (BT) and 23 did not receive BT (NBT). BT included 10 high dose (HD) steroids, 28 chemotherapy-based regimen (CT), and 14 radiation therapy (RT). CT included cytotoxic chemotherapy, immunotherapy, and targeted therapy. IRB approval was obtained for this study. Statistical analysis was conducted with SAS v9.4. Univariate analysis Cox proportional hazard model was used and p-values for response rate were generated from Fisher's exact test. The methods of generalized linear model and logistic regression were used to associate the toxicity grades and cytopenias with BT, respectively. Results:Many patient and disease characteristics between BT and NBT groups were similar, with minor, non-statistically significant differences (See Fig. 1a). Although while the incidence of stage III/IV patients in the BT and NBT group was comparable (p=0.79), in subgroup analysis, there were significantly more stage III/IV patients in the CT subgroup and NBT than in the RT and HD steroids subgroups (p=0.03). There was a higher incidence of bulky disease (≥10cm) in the BT and all BT subgroups versus (vs) NBT, although this was not significant (p=0.58 and p=0.92). The number of prior lines of therapy was comparable between the BT and NBT groups (p=0.99). However, in subgroup analysis there were significantly more patients in the CT subgroup and NBT that received ≥4 lines of therapy compared with RT and HD steroids subgroups (p=0.02). There was no significant difference in overall response rate (ORR) at last follow up between BT vs NBT and BT subgroups vs NBT with approximately 50% being in complete remission in all cases (p=0.48 and p=0.54). Progression free survival (PFS) and overall survival (OS) were similar in the BT vs NBT (one-year rates of 67% vs 64% and 83% vs 75%, respectively) and this was not statistically significant (p=0.52 and 0.89), see Fig. 1b and 1c. In subgroup analysis PFS was comparable in the BT subgroups (CT 69% and HD steroids 68%) vs NBT group (67%) while RT was lower (51%), although this was not statistically significant (p=0.54). In subgroup analysis OS was slightly worse in the BT subgroups (CT 77%, RT 76%, and HD steroids 72%) vs NBT group (83%) although was not statistically significant (p=0.93). The development of cytokine release syndrome (CRS) was comparable in the BT vs NBT group and in BT subgroups vs NBT (p=0.18 and p=0.53). The median grade of immune effector cell-associated neurotoxicity syndrome (ICANS) was higher in BT than NBT (grade 2 vs 0) and trended towards statistical significance (p=0.09). The development of cytopenias at day +180 following CAR-T therapy was significantly higher in BT (50%) vs NBT (13.3%) and was statistically significant (p= 0.038). Subgroup analysis also showed significantly increased cytopenias at day +180 in CT (58.3%) and RT (57.1%) subgroups (p= 0.04). Conclusion:In our single-institution experience, BT prior to CAR-T therapy is feasible and may preserve CAR-T candidacy in patients with rapidly progressive LBCL. BT does not appear to significantly affect ORR, PFS, and OS. The incidence of CRS was comparable, although there was a higher incidence of ICANS in BT, which trended towards significance, and could be contributed to higher tumor bulk in the BT group. BT patients receiving CT and RT for BT were more likely to experience prolonged cytopenias, likely due to the myelosuppressive impact of BT and previous lines of chemo-immunotherapy agents. In conclusion, in high-risk patients with advanced and/or aggressive disease, BT may provide disease stabilization to CAR-T with a similar toxicity profile compared to NBT patients, although BT patients are more likely to experience prolonged cytopenias after CAR-T therapy. Disclosures Kansagra: Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics:Other: Advisory Board.Hardy:Incyte Corporation:Other: Advisory Board Member;American Gene Technologies:Other: DSMB Member;Kite/Gilead:Other: Advisory Board Member.

Introduction Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a powerful therapy for relapsed and refractory (R/R) B-cell malignancies. A growing body of research suggests that CAR-T therapy can be safe and effective in patients who have previously received allogeneic hematopoietic stem cell transplantation (alloHSCT). "Pseudo-allogeneic" CAR-T therapy refers to manufacture of engineered T-cells collected from an alloHSCT recipient exhibiting 100% donor chimerism. This CAR-T approach poses theoretical risks due to alloreactivity and increased CAR-T toxicity. Most studies to date in this area have enrolled patients with leukemia. We present here a single-center experience with pseudo-allogeneic CAR-T following alloHSCT in 6 patients with large B-cell lymphoma (LBCL). Patients and Methods Patients with R/R LBCL who underwent treatment with axicabtagene ciloleucel (axi-cel) CAR-T after prior alloHSCT were identified. All patients underwent lymphodepletion with cyclophosphamide and fludarabine prior to CAR-T infusion. CAR-T toxicities, namely cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity syndrome (ICANS) were graded in accordance with the 2019 American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. Results Six patients who underwent axi-cel CAR-T due to post-alloHSCT R/R LBCL were identified. All patients had stage ≥II disease. At the time of CAR-T apheresis, all patients had ≥95% donor chimerism and were off immunosuppression, without evidence of GVHD. Manufacturing failure occurred in only one patient (case 2) due to low viability and upon second apheresis, manufacture was successful. All 6 pseudo-allogeneic CAR-T therapy patients tolerated infusion and did not show increased incidence or severity of CRS or ICANS compared to our center's experience with standard CAR-T patients, with only one patient experiencing greater than grade 2 toxicity. Three of six patients developed graft-versus-host disease (GVHD); however, one case was in the setting of PD-1 blockade and two were isolated cutaneous manifestations. There was no incidence of severe GVHD. All three cases of GVHD underwent CAR-T within ten months after alloHSCT, whereas the three patients without GVHD were >1 year post-HSCT at time of CAR-T. Two cases who had donor lymphocyte infusions prior to CAR-T did not develop GVHD. In terms of efficacy, three patients achieved a complete remission. There was no perceptible relationship between the development of GVHD and the response to CAR-T. Four of six had cytopenias at day 30 after CAR-T, with only two exhibiting persistent cytopenias at day 90. Lastly, in this small sample size, no differences were seen in incidence of GVHD or treatment response between haploidentical, matched-related, and matched-unrelated alloHSCT donors. Conclusion In our experience, pseudo-allogeneic CAR-T therapy following alloHSCT appears to be a safe and well-tolerated treatment modality for R/R B-cell lymphoma. The efficacy of this modality will need to be borne out in further studies. Disclosures No relevant conflicts of interest to declare.

Introduction Bronchiolitis Obliterans Syndrome (BOS) is a rare but devastating complication of chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and is associated with a high morbidity and mortality. There is a dearth of treatment options for BOS and new strategies are needed. Airway neutrophilia is a hallmark of BOS, even in the absence of infection, and neutrophil elastase (NE) is an enzyme that has been implicated in the pathogenesis of BOS. We conducted a phase 1 study of an oral NE inhibitor, alvelestat, in patients with BOS after HCT. Methods Patients age ≥18 years with BOS and chronic GVHD after HCT were recruited to the National Cancer Institute protocol (NCT02669251). Patients had stable systemic immunosuppression and FEV1 ≥30% on pulmonary function tests (PFTs). This phase 1 study had 2 parts: 8-week intra-patient dose escalation period, followed by a continuation period that allowed for up to 6 months of treatment. Alvelestat was given orally starting at 60mg twice daily (the dose previously used in patients with chronic lung disease) and increased every 2 weeks as tolerated to 120mg twice daily, 180mg twice daily, and finally 240mg twice daily. Patients continued this dose until completion of the continuation phase, or occurrence of unacceptable toxicity, dose interruption >28 days, or progression of GVHD or BOS. Primary objective was to determine the maximum tolerated dose (MTD) based on dose-limiting toxicities. Secondary objectives included determining pharmacokinetics, markers of NE activity, and markers of inflammation in blood and sputum. PFTs and chronic GVHD evaluations were performed at baseline, 4 weeks and 8 weeks during the dose escalation period, and at 3 months and 6 months during the continuation period. Results Between 2016 and 2018, 7 patients were enrolled (3 men and 4 women). Median FEV1 after bronchodilator at time of enrollment was 44% (range 38-74). All 7 patients were able to tolerate dose escalation of alvelestat up to the maximum dose 240mg twice daily; MTD was not reached. The most common adverse events (AEs) that were possibly related to study treatment were all grade 2, and included increased creatinine (3 patients), ALT or AST elevation (3 patients), and upper respiratory infection (3 patients). The only grade 3 AEs that were possibly related to study drug were gastroenteritis and vomiting requiring hospitalization in 1 patient and pneumonia in 1 patient. Three patients completed the study with 8 weeks + 6 months of treatment. Four patients required dose interruptions, and only 1 of those required dose reduction for grade 3 gastroenteritis (resulting in dehydration and elevated creatinine). Four patients discontinued treatment prior to end of study: 2 patients had dose interruption of >28 days due to adverse events, 1 patient had a decline in FEV1 after pneumonia, and treatment was stopped in 1 patient due to investigator discretion. The median duration of treatment was 6.4 months. Based on NIH chronic GVHD consensus criteria, 6 patients had unchanged disease and 1 patient had progressive disease (decline in FEV1 after pneumonia). Although patients did not achieve the 10% improvement in FEV1 required for an organ response, 2 patients had improvement of 9% in FEV1 and 4 patients had improvement in the Lee chronic GVHD symptom scale lung score. Preliminary pharmacokinetic analyses of the 7 patients showed a linear dose-dependent increase in each exposure metric (steady-state trough and steady-state peak), despite some inter-patient variability. Bronchoalveolar lavage fluid and induced sputum samples are being analyzed for NE activity. Conclusion In this phase 1 study of the oral NE inhibitor, alvelestat, in patients with BOS after HCT, MTD was not reached and the study drug was well tolerated. Six patients had stable disease, while 1 patient had progression in the setting of pneumonia. Two patients notably had improvement in FEV1 of 9%, and 4 patients experienced improvement in symptoms. We have demonstrated that NE inhibition is well tolerated and shows a signal of stabilizing disease in patients with advanced BOS. Further study of the clinical efficacy of alvelestat in BOS after HCT is warranted, especially at an earlier stage of disease and longer duration of drug administration. Disclosures No relevant conflicts of interest to declare.

Key Clinical Message Promyelocytic leukemia is a known medical emergency and requires rapid diagnosis and expedient therapy with differentiating agents. We present an unusual case in which the diagnosis is based on a fine needle aspirate of a humeral mass. Despite lack of systemic involvement, the sarcoma responded to traditional differentiation agents.

Chronic graft-versus-host disease (cGVHD) is the leading late complication after allogeneic hematopoietic stem cell transplantation (HSCT). Many patients receive multiple lines of systemic therapy until cGVHD resolves, but about 15% remain on systemic treatment for more than 7 years after cGVHD diagnosis. This study describes the clinical and biological factors of patients who present with cGVHD persisting for ≥7 years (persistent cGVHD). Patients with persistent cGVHD (n = 38) and those with cGVHD for

The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB-RC) was calculated for treatment-naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB-RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB-RC approximately doubled the likelihood of D14BM clearance (OR = 1·81; 95% CI: 1·24-2·64, P < 0·005). PBB-RC was also associated with improved CR rates (OR per 5% = 1·97; 95% CI: 1·27-3·01, P < 0·005) and overall survival (OS) [hazard ratio (HR) per 5% = 0·67; 95% CI: 0·52-0·87]. African American patients had poorer OS adjusted for PBB-RC (HR = 2·18; 95% CI: 1·13-4·23), while race was not associated with D14BM or CR rate. PBB-RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML.

A beta-elimination reaction generally involves the cleavage of a sigma (σ) bond at the position beta (β) to a pair of electrons that departs a molecule via a nucleophilic leaving group, subsequently leading to the formation of a new pi (π) bond. We describe the importance of β-elimination reactions in the mechanisms of action of two classes of chemotherapeutic agents. First, we evaluate the chemical steps resulting in formation of 5-methyl-cytosine and its disassociation from DNA methytransferase (DNMT) by β-elimination reaction. When carbon 5 (C5) of cytosine is substituted with a nitrogen atom (N) in 5-aza-cytosine analogues, the critical β-elimination reaction cannot proceed, which results in the permanent attachment of 5-aza-cytosine to DNMT. The net outcome is entrapment of the DNMT by 5-aza-cytosine analogues and its eventual degradation, leading to DNA hypomethylation. Second, we analyze the critical role of β-elimination reaction in the activation of cyclophosphamide and ifosfamide. The incapability of undergoing β-elimination results in reduction of the cytotoxic activity of these agents. It appears that the conversion of aldehyde group, in aldophosphamide metabolites of cyclophosphamide and ifosfamide, to carboxyl group by aldehyde dehydrogenase makes the protons on the carbon atom attached to carboxyl group not acidic enough that can be removed under physiologic conditions via initiation of the critical β-elimination reaction. This ultimately culminates in selective cytotoxic effect of these agents against lymphocytes but not hematopoietic and other stem cells with high aldehyde dehydrogenase content.

Background: Early initiation of graft-versus-host disease (GvHD) is driven by donor alloreactive T-lymphocytes directed against recipient's histocompatibility antigens often overexposed during damage to tissues during the conditioning chemotherapy. Palifermin is a truncated form of human recombinant keratinocyte growth factor (KGF, also known as FGF7) that binds to FGF receptor 2b expressed in many epithelia including the epithelium of the epidermis, oral and GI mucosa, urothelium, and thymus, in which it exerts cytoprotective and regenerative effects. Palifermin also has immunomodulatory effects manifested as improvements in thymic function and downregulation of pro-inflammatory cytokines. Palifermin was FDA approved in 2004 at a dose of 60 mcg/kg/day (x3 consecutive days) for prevention of severe oral mucositis in hematologic malignancy patients receiving autologous hematopoietic stem cell transplant (HSCT). A single dose of 180 mcg/kg/day appears to have similar effects. In animal models, palifermin showed efficacy in controlling acute and chronic GvHD. However, subsequent clinical studies did not confirm efficacy for prevention of GvHD or for stimulation of functional thymus recovery using a dose/schedule based on the one that had been approved for autologous HSCT. We conducted a phase 1 study (NCT02356159) to determine the maximal safe single dose level of palifermin administered prior to starting transplant conditioning. Methods: This was an open-label, dose escalation study with standard 3+3 design. Four different dose levels of palifermin (180, 360, 540 and 720 µg/kg) were administered as a single dose on day -7 pretransplant. The reduced-intensity conditioning regimen (cyclophosphamide 1200 mg/m2/day IV and fludarabine 30 mg/m2/day IV), was given on days -6 to -3. Sirolimus, tacrolimus and low-dose post-HSCT methotrexate were used for GvHD prophylaxis. On day 0 all subjects received a peripheral blood stem cell (PBSC) graft from an unrelated donor (MUD) matched at least at HLA-A, -B, -C, -DRB1. Prior to transplant, subjects received one or two cycles of disease-specific lymphodepleting induction chemotherapy (EPOCH-F/R or FLAG). Subjects must have been ≥18 years old with a high-risk hematologic malignancy, Karnofsky performance status ≥60%, and acceptable organ function. The primary objective was to assess safety of palifermin and to recommend the phase 2 study dose. DLT was defined as non-relapse mortality before day 30 post-HSCT regardless of attribution to palifermin and non-hematologic grade ≥4 adverse events (AEs) occurring within 14 days after administration. AEs were recorded according to CTCAEv4. Results: From Oct 2015 to Mar 2019, 18 subjects were enrolled (NHL=7, AML/MDS=5, ALL/LBL=2, CML=2, MPN=1 and MM=1). Kahl's relapse risk was high, standard, and low in 15, 2, and 1 subject, respectively. Median HCT-CI score was 1 (0-4) with median age 47 years (21-66); 14 (78%) were males. Six subjects received dose level 1 (subject #3 was diagnosed with achalasia and grade 4 elevated lipase without radiological signs of pancreatitis, still attributed as DLT possibly related to palifermin). No DLTs occurred afterwards. Three subjects were enrolled onto each of dose levels 2, 3 and 4, with expansion of dose level 4 to 3 more subjects for additional safety exploration. Skin rash and Increased serum amylase or lipase were the most frequent AEs (Table 1A). Grade 3 increased serum amylase and grade 3 possible pancreatitis in subject #3 were the only SAEs attributed to study drug. All subjects engrafted successfully. Day 14 median CD3 and myeloid chimerism was 97% (36-100) and 99% (82-100), respectively, with the median time to 100% CD3 chimerism of 44 days (14-181). Table 1B lists occurrence of GvHD prior to any malignancy relapse. Four subjects had relapsed malignancy, for which 3 received DLI. After a median follow up of 28 months (2-55), 5 subjects have died, 2 malignancy relapses and 3 non-relapse related causes. Conclusion: Palifermin administered at dose four-times higher than previously given in humans is safe to use in patients undergoing MUD peripheral blood HSCT. MTD was not reached. Recommended phase 2 dose for examining efficacy in prevention of GvHD is 720 µg/kg. Disclosures Rubin: NIH/NCI: Ended employment in the past 24 months, Patents & Royalties; KGF/palifermin: Patents & Royalties; Paradigm Shift Therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Palifermin was FDA approved at a dose of 60 mcg/kg/day (x3 consecutive days) for prevention of severe oral mucositis in hematologic malignancy patients receiving autologous hematopoietic stem cell transplant (HSCT).

Background : Chronic Graft-versus-Host Disease (cGVHD) is a multi-organ disorder characterized by immune dysregulation, impaired organ function, and decreased survival. Refractory cGVHD remains an unmet need with limited effective treatment options. Janus kinase (JAK) inhibition targeting JAK-STAT is promising in cGVHD due to this multifaceted pathway's key role in immune cell development, function, and inflammation. Baricitinib is a JAK1/2 inhibitor FDA-approved at 2 mg daily for treatment of rheumatoid arthritis, and which has shown therapeutic promise in preclinical models of GVHD. Herein, we report the preliminary analysis results of a phase 1/2 study exploring the efficacy and safety of the JAK 1/2 inhibitor baricitinib in therapy-refractory cGVHD. Methods : Patients (pts) with therapy-refractory moderate-severe cGVHD per NIH criteria were enrolled on an NCI sponsored treatment protocol (NCT02759731). This is a phase 1/2 single center, single arm study of baricitinib starting at an oral dose of 2 mg daily, given for 28-day cycles, with intra-patient dose escalation to 4 mg daily after 3 months (mos) for a total of 12 cycles. Adverse events (AEs) were monitored and graded per CTCAEv4.3. Clinical responses were measured every 3 mos per the 2014 NIH cGVHD Response Criteria. The primary efficacy endpoint was ORR (CR+PR) at 6 mos; if PR or SD, pts were treated for up to 12 mos and monitored for 12 mos post-completion. Subjects self-report questionnaires included the Lee symptom bother scale (LSS). Peripheral blood samples were collected for pharmacokinetic and correlative studies at several time points throughout study. Results: Twenty pts with refractory cGVHD were enrolled. Median patient age was 54 years (24-68), 55% female, 90% Caucasian. Median time from cGVHD diagnosis to study enrollment was 36.8 mos, with median baseline KPS of 80%. cGVHD NIH global score was severe in all pts (due to sclerotic skin in all except one oral), involving a median of 4 (2-6) organs, and treated with a median of 4 (2-7) lines of prior systemic therapy including ibrutinib in 3. At study enrollment, all but 3 (85%) were on concurrent systemic immunosuppression, including steroids for 12 (60%) at a median dose of 10 mg (2.5-30) prednisone daily. ORR at 6-months was 63% (95% CI 47-87%), with durable responses seen in 7 of 8 evaluable pts at 12-mos. ORR at any time was 90% (85-100%), with median time to ORR of 1.4 mos (1.4-6.3). Organ-specific responses were seen in all involved organs except for lungs (11 organ-specific CRs at 6-mos). Clinically significant improvements in LSS (≥ 6-point reduction) were seen in 7 of 14 (50%) evaluable pts at 6-mos. Median steroid dose-reduction of 4 mg prednisone daily was achieved in 6 (50%) of those on steroids at enrollment. With a median follow up of 24.2 mos, median failure-free survival (FFS) was 20.6 mos (19-NR). 1- and 2-year FFS was 74% (57-97%) and 37% (18-78%), respectively. Of the 8 evaluable pts who completed study, 3 progressed at a median of 7.3 mos (6.9-11.9) after drug discontinuation. No DLT was observed with the 2 mg dose of baricitinib; 16/20 (80%) pts reached dose-escalation to 4 mg at 3 mos. Three pts required dose-reductions: two due to neutropenia, and one due to refractory myalgias. Common AEs, possibly treatment-related, included upper respiratory infection (URI) (13), neutropenia (6), hypophosphatemia (12), and hypertriglyceridemia (5). Asymptomatic, transient reactivation of CMV occurred in 6, EBV in 7, BK viruria in 5 - none of which required treatment. HPV-related eyelid papilloma developed in 2, with no visual changes. One patient with EBV viremia/lymphadenopathy at enrollment was diagnosed with biopsy-proven EBV-PTLD Conclusion: The JAK 1/2 inhibitor baricitinib appears well-tolerated and effective for pts with severe cGVHD who progressed through multiple lines of prior therapy. Responses were achieved rapidly and seen across all involved organs, except lungs. Full study results for a total of 31 pts are expected in early 2022. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Baricitinib is currently FDA-approved in the U.S. for treatment of rheumatoid arthritis at a dose of 2 mg by mouth once daily.

Background Allogeneic stem cell transplantation (AlloSCT) is a curative procedure for many hematologic neoplasms. Majority of the AlloSCT require an initial hospitalization and a mortality rate of up to 8% during the SCT hospitalization has been previously reported (Ballen et al, 2014 BBMT). Role of patient-, disease- and transplant-related factors in predicting early mortality during transplant hospitalization has not been previously investigated. We sought to analyze the predictors of inpatient mortality in patients undergoing AlloSCT from a large administrative database, National Inpatient Sample (NIS). Methods International Classification of Diseases, Ninth Revision (ICD-9) procedure codes were used to identify patients undergoing AlloSCT in the 2002-2015 NIS database whereas ICD-9 diagnosis codes were used to assess complications of Allo-SCT. Early transplant-related mortality was defined as death during the hospitalization for SCT. Chi-square was used for categorical data comparisons (p Results During the study period of 2002-2015, we identified 68,296 hospitalizations (median age 50 years and 58% male) undergoing inpatient AlloSCT (baseline characteristics in table 1 & figure 1); death occurred in 5,198 (7.6%). Age Conclusion Our analysis identified novel prognostic and predictive factors associated with higher inpatient mortality during SCT hospitalization. Identifying at risk patients can provide an opportunity for early intervention and improving post-transplant outcomes.

Background: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are known complications of chimeric antigen receptor T-cell (CAR-T) therapy. These clinical syndromes develop as a result of CAR-T activation, proliferation, and tumor lysis with resultant cytokine secretion. In prior reports of CD19 CAR-T therapy patients, those who developed ICANS showed evidence of endothelial activation and disruption of the blood-brain barrier as a result of cytokine release while only approximately one-third demonstrated changes on Brain MRI (Gust et al. Cancer Discov 2017). As such, further predictive markers and studies are needed to identify patients at risk for ICANS to allow for expedited management and improved outcomes. Herein we report a single-center analysis exploring glycolytic activity on PET/CT and the association with clinical outcomes for patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) after CAR-T therapy. Methods: An organ-based evaluation of uninvolved sites was conducted in R/R DLBCL patients (n=32) who underwent CD19 CAR-T therapy with evaluable PET/CT imaging at baseline immediately prior to CAR-T therapy and at 30 days post-infusion (D+30). All patients in this analysis were treated with axicabtagene ciloleucel as standard of care therapy after 2 or more lines of therapy. Tumor metabolic volume (TMV) and mean standard uptake value (SUVmean) of various organs were quantified using ROVER [Region of interest (ROI) visualization, evolution, and image registration] software (ABX advanced biochemical compounds GmbH, Radeberg, Germany). Statistical analysis was completed using STATA 14 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). All tests were performed after testing the normality distribution assumption. Temporal changes were assessed using paired t-tests, and between-group analyses were completed with two-sample t-tests. Results: SUVmean increased significantly after CAR-T therapy in the following organs (D+30 v baseline pre-CAR-T PET/CT): cerebral cortex (8.23 v 7.09, p=0.036), cerebellum (6.26 v 5.56, p=0.024), basal ganglia (9.22 v 7.61, p=0.005), parotid gland (1.61 v 1.42, p=0.004), liver (2.47 v 2.17, p=0.002), spleen (2.08 v 1.84, p=0.043), and pancreas (1.76 v 1.48, p Conclusion: For patients with R/R DLBCL undergoing CD19 CAR-T therapy, significantly increased CNS glycolytic activity is seen on PET/CT at D+30 post-infusion when compared to baseline. Interestingly, these changes do not correlate with development of ICANS or lymphoma response; however, changes in cortical activity were associated with CRS grade ≥2. Overall, our findings illustrate a functional and radiographic link between cytokine release and subsequent disruption of the blood-brain barrier as quantified by increased cortical glycolysis 30 days post-CAR-T therapy. While findings are limited by small sample size, further validation in a larger data set is warranted. Disclosures Hutnick: Kite/Gilead: Other: Yescarta Speakers Bureau, Speakers Bureau. Badros:Celgene Corporation: Consultancy; Amgen: Consultancy.

Adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of R/R B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy. Herein, we describe a patient with Philadelphia chromosome-positive B-ALL who relapsed after CD19-directed CAR-T therapy, but subsequently responded to the combination of blinatumomab and the tyrosine kinase inhibitor ponatinib, with the achievement of a complete remission lasting 12 months.

Introduction Relapse and graft failure continue to be 2 major problems after allogeneic HSCT. DLI and/or SCB are capable of inducing complete remission in relapsed disease. However, DLI and SCB are associated with significant risks such as graft versus host disease (GVHD) or aplasia. There is a paucity of information regarding DLI/SCB safety, efficacy and toxicity. A better understanding of the risks and benefits of DLI/SCB after HSCT is an important unmet need. Objectives Our objectives are to provide descriptive characteristics of patients receiving DLI or SCB and information regarding the provided cell therapy (CD3+ and/or CD34+ cell dose). We also aim to evaluate relapses, donor chimerism, graft failure, GVHD, DFS and OS after cellular therapy. Methods Retrospective chart review was completed on all patients who received either DLI or SCB at University of Maryland from 2005-2018. Data were analyzed using SPSS v.25.0, SAS v9.4, and R-software v3.5.1. Continuous variables were summarized as median (range), and categorical variables were presented using frequencies (%). Qualitative and quantitative differences between groups were analyzed by the chi-square and the Fisher's exact test for categorical and the Mann Whitney test for continuous variables. The Kaplan-Meier method was used to estimate the OS and GVHD-free survival with the corresponding 95% confidence interval (CI); the log-rank test was used to compare the survival probabilities for different patients' groups. Results A total of 65 patients underwent either DLI or SCB from 2005-2018. Of these, 38 received DLI, and 27 received SCB. Relapsed disease was the most common indication in 78.9% and 61.5% of DLI and SCB, respectively. The average CD3+/kg dose was 5.6 × 10^6 for DLI and 9 × 10^7 for SCB. Average CD34+/kg dose was 3.8 × 10^6 for SCB patients. One-year OS rate was 54.2% for DLI and 37.5% for SCB. Two-year OS rate of OS was 50.3% for DLI and 26.8% for SCB. Remission rates from relapsed disease were 43.4% for DLI and 31.3% for SCB. One-year GVHD-free survival following cell therapy was 51.2% for DLI and 34.4% for SCB. This dropped to 35.3% for DLI and 24.6% for SCB at two years. The differences seen in OS and GVHD between the 2 cohorts were not statistically significant. Conclusion Our overall survival data is favorable compared to recently published data. However, this comes at the expense of GVHD with long-term rates of GVHD-free survival measuring 25-35%. The use of unmanipulated cryopreserved SCB for relapse disease is underreported in the literature. We observed comparable long-term survival and GVHD in both cohorts. Cellular therapy with DLI or SCB remains a viable treatment modality with reasonable long-term outcomes for relapsed/refractory hematologic malignancies after allogeneic HSCT.

Introduction Treatment options for relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) post-chimeric antigen receptor therapy (CAR-T) are limited. Here, we report the successful treatment of R/R DLBCL with programmed cell death 1 (PD1) inhibition post-allogeneic CAR-T. Case Report A previously healthy 26-year-old Caucasian man developed B-symptoms and cervical lymphadenopathy. Biopsy revealed DLBCL, activated B-cell subtype, double expressor and Ki-67 >80%. PET/CT scan revealed disease above and below the diaphragm. He achieved a partial response (PR) after R-CHOP, progressive disease (PD) after R-ICE, stable disease (SD) after R-ESHAP, and PD one month after autologous CD19-targeted CAR-T with CTL019 (CD3ζ/4-1BB). He then received R-lenalidomide (len) with radiation (24 Gy) to his mediastinal mass achieving a PR, followed by a myeloablative (Cy/TBI-12 Gy) allogeneic stem cell transplant (aSCT) from his 10/10 HLAmatched brother. He achieved 100% donor chimerism 30 days post-aSCT (D+30). Despite persistent full donor chimerism, D+60 PET/CT showed PD with confirmed relapse upon biopsy. Immunosuppression was discontinued, and ibrutinib with len was started, followed by donor lymphocyte infusion (DLI) which led to a mixed response. He then continued on ibrutinib with weekly temsirolimus and received a second DLI achieving a PR, with PD shortly thereafter. He next proceeded to allogeneic CAR-T with axicabtagene-ciloleucel (CD3ζ/CD28), complicated by grade 1 cytokine release syndrome without neurotoxicity. Three weeks post-CAR-T, he developed diplopia due to a cranial nerve palsy. Brain MRI showed new pontine T2 changes. Cerebrospinal fluid (CSF) was negative for lymphoma and infection, but notable for T-cell predominance. One month postCAR-T, PET/CT showed a complete metabolic response (CMR). Repeat brain MRI was unchanged. Two months later, he developed dizziness and intractable nausea, and repeat brain MRI showed a new lesion in the inferior cerebellar vermis, with resolution of previous pontine change. Evaluation of the CSF and peripheral blood revealed no CAR T-cell persistence, and PET/CT confirmed disease relapse in the cerebellum and mediastinum. Patient then received focal radiation (24 Gy) to his cerebellar lesion along with pembrolizumab 200 mg IV every 3 weeks, after which his neurologic symptoms resolved. MRI one day after radiation showed near-complete resolution of enhancing vermis lesion. After 3 cycles of pembrolizumab, PET/CT showed a CMR, with no active disease on brain MRI. Three months into PD1-inhibition therapy, his disease remains in CMR, without GVHD nor treatment-related toxicities. Conclusion This case illustrates the efficacy of allogeneic CAR-T after failure of autologous CAR-T and aSCT. Furthermore, PD1 inhibition can be used safely after allogeneic CAR-T, underscoring the need for prospective clinical studies.