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Because patients who undergo allogeneic hematopoietic cell transplantation (allo-HCT) remain in the vicinity of the transplant center for approximately 90 days posttransplantation, identifying prognostic factors to determine those at immediate higher risk of mortality is essential. A normal serum albumin level generally denotes healthiness. We evaluated the prognostic significance of day 90 hypoalbuminemia (and other clinical, pharmacologic, and laboratory variables) in 163 patients, median age 48 years (range, 19-69 years), who underwent allo-HCT for acute myelogenous leukemia (n = 124) or myelodysplastic syndrome (n = 39). Day 90 hypoalbuminemia (serum albumin <3.0 g/dL) was associated with worse nonrelapse mortality (NRM) and poor overall survival (OS). The estimated 1- and 2-year cumulative incidence rates of NRM were 48% and 52%, respectively, and the corresponding OS rates were 7% and 3%. Serum albumin level <3.0 g/dL and Karnofsky score <80 at day 90 were strong independent predictors of worse NRM and OS in multivariate analysis. These results support day 90 hypoalbuminemia as an adverse prognostic marker for NRM and OS after allo-HCT for acute myelogenous leukemia and myelodysplastic syndrome. [Copyright &y& Elsevier]

Prognostic biomarkers in allogeneic hematopoietic cell transplantation (allo-HCT) are needed to improve risk assessment and help guide therapeutic and surveillance strategies to mitigate the risk of death from the procedure. We previously identified hypoalbuminemia at day +90 post-transplantation as an independent predictor of increased nonrelapse mortality (NRM) and inferior overall survival (OS) in patients with acute myelogenous leukemia and myelodysplastic syndrome who were treated with an allo-HCT. Here, we aim to confirm the prognostic significance of day +90 hypoalbuminemia in 783 patients, median age 52 years (range, 18 to 76), who received an allo-HCT for various hematologic malignancies and bone marrow failure syndromes. Multivariate analysis for NRM demonstrated a negative effect of low serum albumin levels (<3.0 versus 3.0 to 3.5 versus >3.5 g/dL) at day +90 post-transplantation (hazard ratios, 8.03 [95% CI, 3.59 to 17.97] versus 2.84 [95% CI, 1.59 to 5.08] versus reference; P  < .0001). This was also the case for OS (hazard ratios, 6.86 [95% CI, 4.24 to 11.10] versus 1.52 [95% CI, 1.05 to 2.20] versus reference; P  < .0001). Patients with hypoalbuminemia at day +90 post-transplantation are more likely to die from causes other than relapse, particularly infections. This large study confirms the ability of day +90 serum hypoalbuminemia to predict worse NRM and inferior OS. Presence of hypoalbuminemia at day +90 should drive a more rigorous real-time surveillance strategy considering the anticipated high-risk of NRM and poor survival in these patients. Future studies should consider incorporating day +90 serum albumin levels in prognostic models of NRM and OS. [ABSTRACT FROM AUTHOR]

Recognizing the significant biological and clinical heterogeneity of mature T cell and natural killer (NK)/T cell lymphomas, the American Society for Blood and Marrow Transplantation invited experts to develop clinical practice recommendations related to the role of autologous hematopoietic cell transplantation (auto-HCT) and allogeneic HCT (allo-HCT) for specific histological subtypes. We used the GRADE methodology to aid in moving from evidence to decision making and ultimately to generating final recommendations. Auto-HCT in front-line consolidation is recommended in peripheral T cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL), anaplastic large cell lymphoma–anaplastic lymphoma kinase (ALCL-ALK)-negative, NK/T cell (disseminated), enteropathy-associated T cell lymphoma (EATL), and hepatosplenic lymphomas. Auto-HCT in relapsed-sensitive disease is recommended for NK/T cell (localized and disseminated), EATL, subcutaneous panniculitis-like T cell, and ALCL-ALK–positive lymphomas. Auto-HCT is also recommended for PTCL-NOS, AITL, and ALCL-ALK–negative lymphomas if not performed as front-line therapy. Auto-HCT in refractory (primary or relapsed) disease is not recommended for any of the histological subtypes discussed. Allo-HCT in front-line consolidation is recommended for NK/T cell (disseminated), adult T cell leukemia/lymphoma (ATLL; acute and lymphoma type), and hepatosplenic lymphomas. Allo-HCT for relapsed-sensitive disease is recommended for PTCL-NOS, AITL, ALCL-ALK–negative, ALCL-ALK–positive, NK/T cell (localized and disseminated), ATLL (acute, lymphoma type, smoldering/chronic), mycosis fungoides/Sezary syndrome (advanced stage IIB-IVB or tumor stage/extracutaneous), EATL, subcutaneous panniculitis-like T cell, and hepatosplenic lymphoma. Allo-HCT in refractory (primary or relapsed refractory) disease is recommended for any aforementioned histological subtypes. Emerging novel therapies will likely be incorporated into the pretransplantation, peritransplantation, and post-transplantation algorithms (auto-HCT or allo-HCT) with the goals of optimizing efficacy and improving outcomes. We acknowledge that there are unique clinical scenarios not covered by these recommendations that may require individualized decisions. [ABSTRACT FROM AUTHOR]

CAR T cells have been extensively investigated using constructs targeting CD19+ B cells for lymphoid malignancies demonstrating efficacy (Neelapu NEJM 2018; Schuster NEJM 2018). One of the main challenges of adoptive T cell therapy are immune mediated toxicities of cytokine release syndrome (CRS) and neurotoxicity (NT). Despite impressive objective response rates, durable responses are only seen in approximately 40% of patients treated in the pivotal axicabtagene ciloleucel (axi-cel) and tisagenlecleucel trials, highlighting the need for better understanding of the mechanisms of toxicity and efficacy. We aimed to evaluate the association of early biomarkers with severe toxicity and day 90 outcomes in patients treated with commercial axi-cel in a real world setting. Seventy-five patients treated with commercial axi-cel were included in this analysis. Baseline characteristics are summarized in Table 1. Patient serum samples were collected at baseline (within 30 days of conditioning chemotherapy), and then daily thereafter starting at the day of axi-cel infusion. Serum cytokine samples were analyzed using the Ella multiplex assay system. Cytokines analyzed include IL1b, IL2, IL6, IL15, TNFa, IFNg, Angiopoietin 1 and 2, as well as CRP and ferritin. Toxicities were graded daily using ASTCT consensus guidelines and retrospectively confirmed. Outcomes were evaluated at day 90 by the treating physician according to the International Working Group Response Criteria for Malignant lymphoma. P values were calculated using Wilcoxon rank sum test. We observed that baseline levels of CRP (p=0.0018) and Angiopoietin 2/1 ratio (p=0.0092) were associated with grade ≥3 [n=16] neurotoxicity Figure 1A-B). Baseline elevated levels of CRP (p=0.0413) and Ferritin (0.0264) were associated with more grade ≥3 CRS [n=16] (Figure 1C-D). Baseline elevated levels of CRP(p=0.0016), ferritin(p=0.0096) and IL6 (p=0.0029) were associated with poor outcomes at D90 defined as stable disease, progressive disease or death (Figure 1E-G). We demonstrate that baseline biomarker profile can identify patients at highest risk of developing severe toxicity and/or and treatment resistance highlighting the need to validate these findings in prospective studies. Patients in this poor outcome cohort may benefit from clinical trials evaluating prophylactic agents or more combination therapies to ameliorate severe toxicities or increase response rates. [ABSTRACT FROM AUTHOR]

Hypofibrinogenemia can occur after Chimeric Antigen Receptor (CAR) T-cell therapy and is sometimes associated with cytokine release syndrome. Hypofibrinogenemia is associated with increased risk of bleeding as well as thrombosis. Limited literature exists on the incidence, complications and management of hypofibrinogenemia after CAR T-cell therapy. We analyzed medical records on 148 patients who received CD19-directed CAR T-cell therapy for large B-cell lymphomas between 05/2015 and 09/2019. All patients who had at least one serum fibrinogen level measured in the first 30 days after CAR T-cell infusion were included in the analysis. All patients with serum fibrinogen < 200 mg/dL [lowest normal value] had data collected on abnormalities in other coagulation parameters including PTT, PT, INR at the time of nadir serum fibrinogen level. Out of 148 patients, 35 had at least one serum fibrinogen level measured in the first 30 days after CAR T-cell infusion. Nadir serum fibrinogen was < 200 mg/dl in 15/35 patients: 0-100 mg/dl in 9/15 and 100-200 mg/dl in 6/15. At the time of nadir fibrinogen level, 2/15 patients had abnormalities seen in the other 3 coagulation parameters. Of the 15 patients that had serum fibrinogen level < 200 mg/dl, four had a bleeding event and one had a thrombotic event within first 30 days after CAR T-cell infusion but none of these patients had a low fibrinogen level at the time of the bleed. Given concern for increased risk of bleeding, patients with serum fibrinogen level less than 100 mg/dl were given cryoprecipitate infusions. Details of the abnormalities in the coagulation parameters are highlighted in the table. This study describes in detail, hypofibrinogenemia seen in patients treated with CD19-directed CAR T-cell therapy in lymphoma. None of the patients experienced a major bleeding or thrombotic event with low serum fibrinogen level. These descriptive data may be used by clinicians to inform their management of hypofibrinogenemia seen in CAR T-cell patients. [ABSTRACT FROM AUTHOR]

In patients with lymphoma, third space fluid accumulations may develop or worsen during cytokine release syndrome (CRS) associated with chimeric antigen receptor (CAR) T-cell therapy. Pre-existing symptomatic pleural effusions were excluded by the ZUMA-1 trial of axicabtagene ciloleucel (axi-cel) for large B cell lymphoma (LBCL) and variants. The optimal management of effusions that develop before or after axi-cel infusion in LBCL is unknown. We performed a single center retrospective study evaluating 148 patients receiving CD19 CAR T-cell therapy for LBCL between 05/2015 and 09/2019. We identified all patients who developed pleural, pericardial and peritoneal effusions before (pre-CAR-T) or during the first 30 days after CAR T-cell infusion (post-CAR-T). Clinically relevant effusions were considered symptomatic based upon physician documentation. Total effusions and symptomatic effusions were noted in 24% (36/148) and 18% (27/148) of patients, respectively. Among 27 patients with symptomatic effusions, 59% (16/27) were pre-CAR-T effusions, 52% (14/27) persisted after day 30, and 44% (12/27) were malignant effusions. Overall, 67% of symptomatic effusions (18/27) were managed with diuretics, 44% (12/27) with a therapeutic thoracentesis or paracentesis and 33% (9/27) were observed with only supplemental oxygen provided. Six patients required pleural or abdominal catheters with a median indwelling duration of 54 (range, 29, 202) days, although 2 of these patients passed away with these indwelling catheters. Among symptomatic effusions developing only post-CAR-T (n=11), time to onset of effusion was median of 5 (range, 2-11) days and none of these patients required interventional drainage. Table 1 differentiates between effusions based on whether they were present (n = 19) or not (n = 17) prior to CAR T cell infusion. Nearly half of all effusions diagnosed in patients receiving CAR T cell therapy develop after infusion but most can be medically managed. Patients with pre-CAR-T effusions may require procedural drainage or indwelling catheters, as these effusions may persist beyond the acute CRS period. [ABSTRACT FROM AUTHOR]

Introduction One of the main complications of adoptive T cell therapy (ACT) is the en-masse activation of tumor-reactive T cells leading to adverse events. These are classified as cytokine release syndrome (CRS) and CAR T Related Encephalopathy Syndrome (CRES). Here, we report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with relapsed/refractory (R/R) DLBCL treated with axicabtagene ciloleucel (axi-cel). Methods Patients with R/R DLBCL treated with commercial axi-cel were included in this study. To select which cytokines to monitor, we retrospectively analyzed 38 serum cytokines in a cohort of 53 patients with R/R B-ALL who were treated with 19-28z CAR T cells. We observed several cytokines which were significantly elevated in patients with CRS and/or CRES requiring treatment (Figure 1a). Based on this analysis and results of published studies, eight serum proteins were selected, including IL-1b, IL-2, IL-6, IL-15, IFNg, TNFa, and angiopoietin-1 &2 (ANG1/ANG2). We monitored these proteins using a POC device that allows for rapid daily monitoring with a turnaround time of two hours. CRS and CRES were prospectively graded using revised Lee criteria and the CARTOX group respectively. Results A total of 20 patients with R/R DLBCL treated with commercial axi-cel were identified. Median age 64 years (range 43-73). Grades 1-3 CRS were observed in 45%, 40% and 5% of patients respectively. There were no observed grade 0 or grade 4 CRS. There were two patients (10%) who died in the setting of severe toxicity. Patients with grade 5 CRS had higher levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one, which correlated with severity of toxicity r=0.52 (p= 0.039) and r=0.53 (p=0.033) respectively (Fig. 1b). Patients with high grades CRS had elevated levels of IL-15 at day seven (r=0.83, p=0.006). The majority of patients (55%) had grades 1-2 CRES. There were no significant correlations between serum cytokine levels and CRES. Conclusion In this analysis of 20 patients, we observed a correlation between severe CRS and elevated serum cytokine levels of IL-6 and ANG2/ANG1 ratio at day one suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with ACT. While this study is limited by small sample size, our observations correlate with previously published biomarkers data in patients enrolled in clinical trials. In select cases, monitoring of cytokines using the POC device provided clinical insight that wasn't evident from standard biomarkers. For example, one patient who developed delayed CRS had high serum levels of IL-6 but did not have elevated levels of CRP (Fig.1c). We continue to enroll patients to validate cytokines as predictive biomarkers with the goal of informing the development of preventative strategies to mitigate CAR T cell therapy immune related adverse events. [ABSTRACT FROM AUTHOR]

Background Richter syndrome (RS) represents an aggressive disease resulting from transformation of chronic lymphocytic leukemia (CLL) to diffuse large B-cell or Hodgkin lymphoma. In 80% of cases, RS is clonally related to CLL. New therapies like ibrutinib have limited efficacy in RS with anticipated median overall survival (OS) of 3.5 months from the time of CLL transformation. Adriamycin-based regimens combined with rituximab represent the standard induction treatment for RS; and those who demonstrate responsive disease are generally offered an allogeneic hematopoietic cell transplant (allo-HCT) despite the lack of randomized controlled studies. Outcomes following allo-HCT in RS are limited to single-institution case series or registry data. We performed a systematic review of the medical literature to assess the totality of evidence pertaining to the efficacy (or lack thereof) of allo-HCT in RS. Material and methods We performed a comprehensive search of the medical literature using PubMed/Medline and EMBASE on September 28, 2018. We extracted data on clinical outcomes pertaining to the benefits (complete remission [CR], OS and progression-free survival [PFS]) and harms (relapse and non-relapse mortality [NRM]), independently by two authors. Our search identified a total of 240 references. Four studies (n= 72 patients) were eligible for inclusion in this systematic review/meta-analysis (Figure 1). Three single-institution studies were from the United States and one data registry study from the European Society for Blood and Marrow Transplantation. Results Reduced intensity conditioning (RIC) regimens were more commonly prescribed (n=50, 69.4%) and the cell source was predominantly peripheral blood stem cells (n=54, 75%). Post-allograft pooled CR rate (3 studies, n=47 patients) was 33% (95%CI=4-71%) with high heterogeneity among studies (I2 =84.2%). Pooled OS rate (3 studies, n=52 patients) was 54% (95%CI=28-79%) with high heterogeneity among studies (I2 =69.8%) (Figure 2) ; and these 3 studies reported OS at 4-years, 3-years and 2-years, respectively. Pooled PFS (3 studies, n=52 patients) was 30% (95%CI=18-44%) with no heterogeneity among studies (I2 =0). Pooled relapse rates (3 studies, n=52 patients) was 28% (95%CI=9-52%) with high heterogeneity (I2 =62.7%). Pooled NRM associated with allo-HCT was 24% (95%CI=29.4%) with low heterogeneity (I2 =29.4%). Conclusion Allo-HCT is an effective treatment for RS with a resulting pooled OS rate (between 2-4 years) of 54%. One study identified age (< 60 years), chemosensitive disease and use of RIC regimens to be associated with better relapse-free survival. Feasibility and efficacy of combining novel therapies +/- donor lymphocyte infusion(s) should be studied to help reduce the risk of post-transplant relapse. [ABSTRACT FROM AUTHOR]

Cancer associated venous thrombo-embolism (VTE) constitutes major cause of mortality and morbidity in patients with hematological malignancies. There is limited data on the incidence and management of VTE in patients receiving chimeric antigen receptor (CAR) T-cell therapy. We performed a single center retrospective study of 148 patients receiving CD19-directed CAR T-cell therapy for aggressive B-cell lymphomas between 05/2015 and 09/2019 to evaluate the incidence and management of known and new VTE phenomenon between day 0-100 after CAR T-cell infusion. Prophylaxis with anticoagulation (AC) was utilized in 4% (6/148) of patients between day 0-100 after CAR T-cell infusion. 19% (28/148) had known VTE prior to CAR T-cell infusion and 50% (12/28) of these were still on AC at the time of infusion. Of those on AC for prior VTE at the time of infusion, 50% (6/12) had it held between day 0-100 after CAR T-cell infusion due to low platelet count or risk of bleeding, while the remainder continued without interruption. A new episode of VTE, between day 0-100, occurred in 11% (16/148) of patients. None of these patients had previous known VTE. Of these, 75% (12/16) started therapeutic AC, however 42% (5/12) had AC held before day 100 after CAR T-cell infusion due to low platelet count or risk of bleeding. None of the patients that continued therapeutic AC in the 2 cohorts had a bleeding event. Details of the thrombotic events and management with AC are shown in the table. This is the first study to our knowledge that describes in detail the incidence and characteristics of VTE and use of AC in lymphoma patients receiving CAR T-cell therapy. Most patients were managed with AC without complications of recurrent VTE or bleeding. [ABSTRACT FROM AUTHOR]

Background Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of patients with relapsed or refractory large B cell lymphoma with ≥2 prior systemic therapies. This report focuses on high-risk patient populations as well as long-term durability of response, and B cell recovery. Methods In ZUMA-1, eligible patients with refractory large B cell lymphoma underwent leukapheresis and received low-dose conditioning followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg (Neelapu et al. NEJM. 2017; NCT02348216). Outcomes in patients with double-expressor B cell lymphoma (MYC [≥40%] and BCL-2 [≥50%] protein expression by immunohistochemistry [IHC]) or high-grade B cell lymphoma (HGBCL), defined as double- or triple-hit (MYC+ and BCL2+ and/or BCL6+ by fluorescence in situ hybridization) or not otherwise specified (MYC– and >70% Ki67 by IHC) were examined by independent pathology review. The exploratory analysis of normal B cell levels in peripheral blood over time was also performed. A long-term follow-up analysis will be conducted with a data cutoff of August 11, 2018 for all 108 patients, including the HGBCL subgroup. Results As of August 11, 2017, all 108 patients had at least 1 year of follow-up, with a median follow-up of 15.4 months. The objective response rate (ORR) was 82% with a complete response (CR) rate or 58%. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NE) were generally reversible and reported for 12% and 31% of patients, respectively. High-risk genetics were assessed in the 47 evaluable pre-treatment tumor samples: 37 patients (79%) had HGBCL or double-expressor B cell lymphoma and had an ORR of 89% (33/37) including a CR rate of 68% (25/37). Forty-two percent of patients overall had ongoing responses with a median follow-up of 15.4 months including 49% (18/37) of patients with high-risk genetics. Overall, of the 87 evaluable patients, 47% had no detectable B cells at baseline, and the remainder had levels close to or below the lower level of quantification of the assay. In patients with ongoing responses at 12 months post axi-cel infusion, 19 of the 35 (54%) patients with evaluable samples had detectable B cells at 12 months. This suggests B cell recovery in some patients with ongoing response as only 6 of 40 (15%) patients with evaluable samples had detectable B cells at 3 months after axi-cel infusion. Conclusion Patients with high-risk genetics had similar favorable outcomes as observed for the overall study population, with approximately half of these patients (18/37) maintaining CR at ≥ 1 year. At 12 months, B-cell recovery was observed in over half the patients with ongoing remission. Updated safety and efficacy results will be presented with a minimum follow-up of 2 years and a median follow-up of 27.1 months. [ABSTRACT FROM AUTHOR]