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Background: Most patients with advanced-stage indolent non-Hodgkin lymphoma have multiple relapses. We assessed axicabtagene ciloleucel autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory indolent non-Hodgkin lymphoma.Methods: ZUMA-5 is a single-arm, multicentre, phase 2 trial being conducted at 15 medical cancer centres in the USA and two medical cancer centres in France. Patients were eligible if they were aged 18 years or older, with histologically confirmed indolent non-Hodgkin lymphoma (follicular lymphoma or marginal zone lymphoma), had relapsed or refractory disease, previously had two or more lines of therapy (including an anti-CD20 monoclonal antibody with an alkylating agent), and an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients underwent leukapheresis and received conditioning chemotherapy (cyclophosphamide at 500 mg/m2 per day and fludarabine at 30 mg/m2 per day on days -5, -4, and -3) followed by a single infusion of axicabtagene ciloleucel (2 × 106 CAR T cells per kg) on day 0. The primary endpoint was overall response rate (complete response and partial response) assessed by an independent review committee per Lugano classification. The primary activity analysis was done after at least 80 treated patients with follicular lymphoma had been followed up for at least 12 months after the first response assessment at week 4 after infusion. The primary analyses were done in the per-protocol population (ie, eligible patients with follicular lymphoma who had 12 months of follow-up after the first response assessment and eligible patients with marginal zone lymphoma who had at least 4 weeks of follow-up after infusion of axicabtagene ciloleucel). Safety analyses were done in patients who received an infusion of axicabtagene ciloleucel. This study is registered with ClinicalTrials.gov, NCT03105336, and is closed to accrual.Findings: Between June 20, 2017, and July 16, 2020, 153 patients were enrolled and underwent leukapheresis, and axicabtagene ciloleucel was successfully manufactured for all enrolled patients. As of data cutoff (Sept 14, 2020), 148 patients had received an infusion of axicabtagene ciloleucel (124 [84%] who had follicular lymphoma and 24 [16%] who had marginal zone lymphoma). The median follow-up for the primary analysis was 17·5 months (IQR 14·1-22·6). Among patients who were eligible for the primary analysis (n=104, of whom 84 had follicular lymphoma and 20 had marginal zone lymphoma), 96 (92%; 95% CI 85-97) had an overall response and 77 (74%) had a complete response. The most common grade 3 or worse adverse events were cytopenias (104 [70%] of 148 patients) and infections (26 [18%]). Grade 3 or worse cytokine release syndrome occurred in ten (7%) patients and grade 3 or 4 neurological events occurred in 28 (19%) patients. Serious adverse events (any grade) occurred in 74 (50%) patients. Deaths due to adverse events occurred in four (3%) patients, one of which was deemed to be treatment-related (multisystem organ failure).Interpretation: Axicabtagene ciloleucel showed high rates of durable responses and had a manageable safety profile in patients with relapsed or refractory indolent non-Hodgkin lymphoma.Funding: Kite, a Gilead Company. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T-cell (CAR-T) therapy represents the most important advances in cancer immunotherapy, especially in hematological malignancies such as B-cell lymphomas. CAR-T cell therapy has significant activity in poor risk B-cell lymphomas. CAR-T cell therapy is associated with potentially life-threatening toxicities such as cytokine release syndrome (CRS) and neurotoxicity (NT). While CRS pathophysiology and management are well established, the understanding and treatment of NT continues to develop. All current CAR-T products approved for DLBCL have been associated with NT with some differences in their severity. As cell therapies continue to advance and its access broadening, it will be imperative for clinicians to be aware of the signs and symptoms of NT, its stratification and basic management. [ABSTRACT FROM AUTHOR]

Immunoglobulin heavy-chain variable region (IGHV) mutational status and karyotype abnormalities are important prognostic factors in chronic lymphocytic leukemia (CLL). The goal was to assess the impact ofIGHVin CLL patients with isolated favorable genetic aberrations (del13q, trisomy 12, or negative fluorescencein situhybridization [FISH]). We studied 273 CLL patients with bothIGHVmutational status and cytogenetic information: 145 with isolated del13q 49 with sole trisomy 12 and 79 with negative FISH. After a median follow-up of 7.8 years, patients with del13q-unmutatedIGHVhad a shorter time to first treatment (TFT) (2.98 vs. 17.44 years;p < .001) and shorter overall survival (10.45 years vs. not reached;p = .0026). Patients with negative FISH-unmutatedIGHVhad shorter TFT (p = .02) (3.10 vs. 9.75 years,p = .053).IGHVstatus did not influence clinical outcomes in trisomy 12 CLL. In conclusion,IGHVmutational status shows prognostic impact in CLL patients with good prognosis genomic features. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia (CLL) is an incurable disease in need of new therapeutic strategies. The immunomodulatory agent, lenalidomide, has shown activity as salvage therapy for CLL. In this phase II trial, we combined lenalidomide with rituximab in 25 patients (range, 41–79) with refractory/relapsed CLL. Lenalidomide was administered orally on escalating doses, with cycle 1 doses of 2.5 mg daily on days 1–7, 5 mg on days 8–14, and 10 mg on days 15–21 followed by 7 days off. On cycle 2 and beyond, lenalidomide was administered at 20 mg daily on days 1–21. Rituximab was administered at 375 mg/m 2 intravenously on a weekly basis for the first cycle starting on day 15 for 4 doses, with each cycle being 28 days. Treatment was continued until disease progression or toxicity. Overall response rate was 45.8% on intent-to-treat and 61.1% in evaluable patients (all partial responses). Median time to treatment failure was 14.3 months for evaluable patients, and median overall survival was not reached. The most common grade 3/4 toxicity was neutropenia (72% of patients). The most common nonhematologic toxicity was infection (29% of patients). Lenalidomide combined with rituximab showed activity in heavily treated refractory CLL with an acceptable toxicity profile. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukemia remains incurable despite availability of potent chemoimmunotherapy regimens. Allogeneic hematopoietic cell transplantation (HCT) is the only modality that offers the possibility of cure. To identify predictors of progression-free and overall survival, we evaluated outcomes of 43 consecutive patients who received an allograft for advanced CLL. The majority received a reduced intensity conditioning regimen ( n = 37). Donors were HLA matched-related ( n = 18), matched-unrelated ( n = 15), mismatched-unrelated ( n = 7), or umbilical cord blood ( n = 3). The median progression-free (PFS) and overall survival (OS) were 31.4 months and 46.4 months respectively. Twenty (46.5%) patients were alive and in complete remission at a median follow-up of 31.4 months. NRM was higher than previously published series for CLL, likely due to a high burden of comorbidity (22 patients with HCT-CI ≥ 2) and a high proportion receiving HLA mismatched-unrelated donor or umbilical cord blood cells. Presence of del (11q), del(17p), or progressive disease at HCT are independent predictors of worse PFS and OS. New strategies are needed to improve survival outcomes in CLL associated with poor risk cytogenetics. [ABSTRACT FROM AUTHOR]

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]

The article looks at the correlation of the different prognostic markers in chronic lymphocytic leukemia (CLL). It also provides a comprehensive investigation of the therapeutic effects of unmutated IgVH CLL treated standard chemoimmunotherapy, autologous hematopoietic cell transplantation (HCT), high-dose chemotherapy, or allogeneic HCT.

This article examines the mortality rates of chronic lymphocytic leukemia (CLL) in the United States over the past two decades, with a focus on advancements in treatment and potential demographic disparities. Using data from the US Centers for Disease Control and Prevention, the study found that the mortality rate of CLL has decreased from 1999 to 2020, with a greater decline in recent years. Males had a higher mortality rate than females, and non-Hispanic White males had the highest mortality rate among racial groups. The Midwest region and rural areas had the highest mortality rates. The study emphasizes the need for interventions to address these disparities and improve outcomes for individuals with CLL. [Extracted from the article]

Background: Survival following melanoma and chronic lymphocytic leukemia (CLL) have both been individually associated with previous history of non-melanoma skin cancers (specifically keratinocyte carcinomas [KC]). Furthermore, melanoma and CLL have been reported to occur within the same patients. The survival experience of patients with both cancers is understudied, and the role of history of KC is unknown. Additional research is needed to tease apart the independent associations between KC and CLL survival, KC and melanoma survival, and the co-occurrence of all three cancers. Methods: A retrospective cohort study was conducted among patients who were diagnosed with melanoma and/or CLL at a comprehensive cancer center between 2008 and 2020. Multivariable Cox regression models were used to examine the association between history of KC and survival following melanoma and/or CLL with careful consideration of calendar year of diagnosis, treatment regimens and other risk factors. A nested case–control study comparing patients with both CLL and melanoma to those with only CLL or only melanoma was conducted to compare blood parameters across the three groups. Results: A time-dependent association was observed between history of KC and favorable melanoma survival within 4 years following diagnosis and poorer survival post 7 years after melanoma diagnosis. History of KC was not significantly associated with survival following the diagnosis of CLL, after adjustment for clinical factors including historical/concurrent melanoma. Patients with co-occurring melanoma and CLL tended to be diagnosed with melanoma first and had elevated blood parameters including white blood cell and lymphocyte counts as compared with patients who were diagnosed with only melanoma. Conclusions: History of KC was an independent predictor of survival following melanoma but not of CLL. Additional studies are needed to determine if blood parameters obtained at the time of melanoma diagnosis could be used as a cost-effective way to identify those at high risk of asymptomatic CLL for the promotion of earlier CLL diagnosis. [ABSTRACT FROM AUTHOR]

The article comments on a study which reported on the poor outcomes of patients with chronic lymphocytic leukemia (CLL) after the discontinuation of ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase, an important component of the B-cell receptor (BCR). According to the author, targeting the B-cell receptor (BCR) pathway represents an important step in the treatment of CLL.

Two CD19 chimeric antigen receptor (CAR) T cell therapies are now approved by the US Food and Drug Administration for the treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and histological variants: axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) (Neelapu I et al i , [6]; Schuster I et al i , [9]). Clinically, it remains unclear as to when the HLH features of CRS are significant enough to consider treatment with therapies used for non-CAR T-associated HLH, such as etoposide or methotrexate (Neelapu I et al i , [8]). Our case series suggests that the timing of onset of CAR T-associated HLH may differ between patients, with concern when delayed or recurrent HLH symptoms occur with a rising ferritin level, which is when HLH-directed therapies should be considered. [Extracted from the article]

The article presents a case study of a 57-year-old man with a history of hypertension, dyslipidemia,and nephrolithiasis and have asymptomatic lymphocytosis of small mature lymphocytes with clumped chromatin. Topics discussed include Richter's syndrome showing features of Burkitt's lymphoma, in Ibrutinib-treated chronic lymphocytic leukemia (CLL) involving malignant proliferation of small clonal B-lymphoid cells, and immunophenotypic features of Burkitt's lymphoma.

Patient characteristics. treatment type vs continuous variables using Kruskal-Wallis test and treatment type vs categorical variables using Fisher exact test or chi-square test if applicable. Frontline treatment regimens were grouped by type and intensity: R SP 2 sp , R-CHOP or BR, and high-intensity regimens inclusive of cytarabine or autoHCT. [Extracted from the article]

Purpose: Chimeric antigen receptor T-cell (CAR T) therapy is capable of eliciting durable responses in patients with relapsed/refractory (R/R) lymphomas. However, most treated patients relapse. Patterns of failure after CAR T have not been previously characterized, and may provide insights into the mechanisms of resistance guiding future treatment strategies.Methods and Materials: This is a retrospective analysis of patients with R/R large B-cell lymphoma who were treated with anti-CD19 CAR T at a National Cancer Institute-designated Comprehensive Cancer Center between 2015 and 2019. Pre- and posttreatment positron emission/computed tomography scans were analyzed to assess the progression of existing (local failures) versus new, nonoverlapping lesions (de novo failures) and identify lesions at a high risk for progression.Results: A total of 469 pretreatment lesions in 63 patients were identified. At a median follow-up of 12.6 months, 36 patients (57%) recurred. Most (n = 31; 86%) had a component of local failure, and 13 patients (36%) exhibited strictly local failures. Even when progressing, 84% of recurrent patients continued to have a subset of pretreatment lesions maintain positron emission/computed tomography resolution. Lesions at a high risk for local failure included those with a diameter ≥5 cm (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.55-3.55; P < .001), maximum standardized uptake value ≥10 (OR, 2.08; 95% CI, 1.38-3.12; P < .001), or those that were extranodal (OR, 1.49; 95% CI, 1.10-2.04; P = .01). In the 69 patients eligible for survival analysis, those with any lesion ≥5 cm (n = 46; 67%) experienced inferior progression-free survival (hazard ratio, 2.41; 95% CI, 1.15-5.04; P = .02) and overall survival (hazard ratio, 3.36; 95% CI, 1.17-9.96; P = .02).Conclusions: Most patients who recur after CAR T experience a component of local progression. Furthermore, lesions with high-risk features, particularly large size, were associated with inferior treatment efficacy and patient survival. Taken together, these observations suggest that lesion-specific resistance may contribute to CAR T treatment failure. Locally directed therapies to high-risk lesions, such as radiation therapy, may be a viable strategy to prevent CAR T failures in select patients. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T‐cell therapy with axicabtagene ciloleucel (axi‐cel) has considerably improved survival in adults with relapsed/refractory large B‐cell lymphoma. This study reports patient‐reported outcomes (PROs) such as quality of life (QOL) and toxicity in the first 90 days after treatment. Hematologic cancer patients treated with axi‐cel (N = 103, mean age = 61, 39% female) completed SF‐36 or PROMIS‐29 QOL questionnaires prior to treatment and 90 days after. PRO‐Common Terminology Criteria for Adverse Events toxicity items were completed by patients at baseline and 14, 30, 60, and 90 days after treatment. Mixed models examined change in PROs over time. From preinfusion to 90 days later, patients reported improvements in physical functioning, pain, and fatigue (ps < 0.01), but worsening of anxiety (p = 0.02). Patient‐reported toxicities worsened by day 14 with improvement thereafter. The five most severe symptoms at day 14 included fatigue, decreased appetite, dry mouth, diarrhea frequency, and problems with concentration. Results indicate improvement in some domains of QOL over time with transient patient‐reported toxicities. [ABSTRACT FROM AUTHOR]

Advances in the field of immuno-oncology brought chimeric antigen receptor T (CAR T) cell therapy from the bench to the bedside for treatment of relapsed and/or refractory B-cell lymphoid malignancies. Two CAR T products, namely axicabtagene ciloleucel and tisagenlecleucel, are commercially available and represent genetically engineered T cells expressing chimeric receptors for CD19. These CAR T-cell products have undoubtedly revolutionized the treatment of these diseases yielding impressive complete remission rates and improving survival. This review aims at assessing the published evidence pertaining to the efficacy of these two products in the real world practice as enrollment in clinical trials often follows stringent eligibility criteria and involves possible selection bias. Results of various observational analyses from patients treated in the real world setting show comparable results to those reported in clinical trials in terms of efficacy and toxicities. This is certainly noteworthy considering that many of these patients would have been considered ineligible to participate in clinical trials owing to their less than optimal performance scores, among other reasons. We believe that the prohibitive cost of these treatments poses a serious challenge to wider applicability in the less privileged populations throughout the world, especially in developing countries. [ABSTRACT FROM AUTHOR]

Summary: While patients with double‐hit lymphoma (DHL) are now frequently treated with intensive front‐line immunochemotherapy, outcomes for those who fail these regimens and subsequently receive curative‐intent second‐line immunochemotherapy are unknown. We identified 55 such patients who achieved an overall/complete response rate of 29%/11%, median progression‐free/overall survival (PFS/OS) of 2/5·1 months and one‐year PFS/OS of 10/19% following the start of second‐line therapy. These outcomes may serve as a standard against which future second‐line treatment strategies for relapsed/refractory DHL can be measured and justify investigation of non‐cytotoxic therapies in the second‐line setting for these patients. [ABSTRACT FROM AUTHOR]

Purpose: Axicabtagene ciloleucel (axi-cel) is a CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Bridging therapy may be required for lymphoma control during the manufacturing interval between collection of autologous T cells and final CAR T product administration. The optimal bridging therapy is not known and patients are often chemorefractory. We present a case series of patients receiving radiation as a bridge to axi-cel.Methods and Materials: Between December 2017 and October 2018, 12 patients were intended to receive bridging radiation before axi-cel. The group was characterized by highly aggressive disease including 6 of 12 with "double hit" lymphoma and 6 of 12 with disease ≥10 cm in diameter. All patients received 2 to 4 Gy/fraction to a median dose of 20 Gy (range, 6-36.5 Gy). Half of patients received either 30 Gy in 10 fractions or 20 Gy in 5 fractions. Seven patients received concurrent chemotherapy. Eleven patients underwent axi-cel infusion and one did not. Median follow-up was 3.3 months (range, 1.1-12.0 months).Results: No significant toxicities were identified during bridging radiation, and no patient experienced in-field progression of disease before axi-cel infusion. One patient experienced abdominal pain, which resolved after dose reduction. Two patients had out-of-field progression of disease during the bridging period. After axi-cel infusion, 3 of 11 patients (27%) experienced severe cytokine release syndrome or neurotoxicity. At 30 days, the objective response rate was 81.8% (11 of 12 evaluable; 1 stable disease, 1 out-of-field progression), with complete response in 27% (3 of 11). At last follow-up, the best objective response rate was 81.8%, with a complete response attained in 45% (5 of 11). Lymphocyte counts decreased slightly in 10 of 12 patients during radiation (median, 0.25 k/uL).Conclusions: Radiation (with or without concurrent chemotherapy) can be safely administered as a bridge to axi-cel in high-risk lymphoma. Caution should be taken if irradiation is started before apheresis, and lymphocyte counts should be monitored closely throughout. Future investigation is warranted to optimize the use of bridging radiation before CAR T therapy. [ABSTRACT FROM AUTHOR]

We evaluated outcome of 235 primary treatment failure (PTF) diffuse large B-cell lymphoma (DLBCL) patients based on salvage chemotherapy regimen and putative cell-of-origin (COO). Patients were divided into two groups; group A (n = 38) received high-dose cytarabine containing regimen, either DHAP or ESHAP. Patients in group B (n = 197) received ifosfamide, carboplatin, and etoposide (ICE) +/− rituximab. No difference in overall response rates (CR + PR) was observed based on salvage chemotherapy regimen and COO. After adjustment for the presence of ultra high-risk features, overall survival of germinal center B-cell like (GCB) DLBCL patients in group A was not significantly different from survival in group B (HR 0.86, 95% CI 0.46–1.60, p =.64). Similarly, within non-GCB DLBCL cohort, survival in group A was comparable to group B (HR 0.53, 95% CI 0.20–1.44, p =.21). We did not find an outcome difference between two commonly used salvage chemotherapy regimens in patients with PTF DLBCL based on COO. [ABSTRACT FROM AUTHOR]

We investigated whether adding radiation (RT) to systemic therapy improved outcomes in early stage diffuse large B-cell lymphoma (DLBCL) patients with or without double- or triple-hit lymphoma (DHL/THL) biology. This analysis included 183 patients profiled with fluorescent in situ hybridization (FISH) for alterations in MYC, BLC2, and/or BCL6. A total of 146 (80%) were non-DHL/THL, 27 (15%) were DHL, and 10 (6%) were THL. Systemic therapy without RT resulted in inferior freedom from relapse (FFR) (HR: 2.28; 95% CI, 1.10–4.77; p =.02). The median FFR for non-DHL/THL was not reached and was 33 and 22.3 months for DHL and THL, respectively; p <.001. Low-risk (R-IPI <2) DHL/THL patients treated with rituximab-based therapy had 3-year FFR rates of 11% and 71% for systemic therapy without and with RT, respectively; p =.04. No differences in overall survival were observed between the treatment groups. Treatment intensification with RT may improve early stage DHL/THL outcomes. [ABSTRACT FROM AUTHOR]

Background: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7-17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study.Methods: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma-including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma-according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days -5, -4, and -3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway.Findings: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7-28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2-not estimable). The median overall survival was not reached (12·8-not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3-15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up.Interpretation: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma.Funding: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program. [ABSTRACT FROM AUTHOR]

Concordant activation of MYC and BCL-2 oncoproteins in double-hit lymphoma (DHL) results in aggressive disease that is refractory to treatment. By integrating activity-based proteomic profiling and drug screens, polo-like kinase-1 (PLK1) was identified as an essential regulator of the MYC-dependent kinome in DHL. Notably, PLK1 was expressed at high levels in DHL, correlated with MYC expression, and connoted poor outcome. Further, PLK1 signaling augmented MYC protein stability, and in turn, MYC directly induced PLK1 transcription, establishing a feed-forward MYC-PLK1 circuit in DHL. Finally, inhibition of PLK1 triggered degradation of MYC and of the antiapoptotic protein MCL-1, and PLK1 inhibitors showed synergy with BCL-2 antagonists in blocking DHL cell growth, survival, and tumorigenicity, supporting clinical targeting of PLK1 in DHL. [ABSTRACT FROM AUTHOR]

Adoptive T-cell immunotherapy is a rapidly growing field and is shifting the paradigm of clinical cancer treatment. Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor T-cell therapy that was initially developed at the National Cancer Institute and has recently been commercially approved by the US Food and Drug Administration for relapsed or refractory aggressive non-Hodgkin's lymphomas including diffuse large B-cell lymphoma and its variants. The ZUMA-1 Phase I and II clinical trials formed the basis of the US Food and Drug Administration approval of this product, and we discuss the particulars of the clinical trials and the pharmacology of axi-cel. In addition, we review the CD19 chimeric antigen receptor T-specific toxicities of cytokine release syndrome and neurotoxicity, which remain the challenges to the safe delivery of this important therapy for aggressive B-cell lymphomas with poor prognosis. [ABSTRACT FROM AUTHOR]

The role of cutaneous viral infections in the development of non-melanoma skin cancer (NMSC), including cutaneous squamous cell carcinoma (SCC), among chronic lymphocytic leukemia (CLL) and blood and marrow transplant (BMT) patients is not established. CLL (n = 977) and BMT (n = 3587) patients treated at the Moffitt Cancer Center were included in a retrospective cohort study. Human papillomavirus (HPV) and human polyomavirus (HPyV) DNA were examined in a subset of incident SCC tumors. Five-year cumulative incidence of NMSC was 1.42% in both BMT (n = 31 NMSCs) and CLL (n = 18 NMSCs) cohorts. Of the nine SCC tumors examined from each cohort, 22.2% and 33.3% were positive for viral DNA in the transplant (HPV 65, MCV) and CLL (HPV 38, HPV 15, HPyV6) cohort, respectively. Enhanced skin cancer screening of BMT/CLL patients should be conducted to better capture incident NMSCs and examine the role of viral infections in these tumors. [ABSTRACT FROM AUTHOR]

Background T- cell prolymphocytic leukemia (T- PLL) is a rare aggressive hematological malignancy. Alemtuzumab, an anti-CD52 humanized monoclonal antibody, is the treatment of choice for remission induction. Allogeneic hematopoietic cell transplantation (allo-HCT) has been described to induce durable remissions and improve survival, but data is limited. Patients and methods We evaluated clinical outcomes of 11 patients, median age of 56 (range, 43–71) years who underwent allo-HCT for T-PLL. The majority of cases were in the first complete remission (CR1 = 9, CR2 = 1, second partial response PR2 = 1) at time of allo-HCT. Myeloablative conditioning was the most commonly prescribed preparative regimen (n = 8, 73%) and tacrolimus plus sirolimus was most commonly prescribed regimen for graft-versus-host disease prophylaxis (n = 5, 46%). Results The median follow-up for surviving patients was 48 (range, 6–123) months. The 4-year progression-free survival (PFS) and overall survival (OS) were 45% (95% confidence interval (CI) = 13–78%) and 56% (95% CI = 24–89%), respectively. Cumulative incidence of non-relapse mortality (NRM) at 4-year post-transplantation was 34% (95%CI = 14–85%). The 4-year cumulative incidence of relapse/progression was 21% (95% CI = 6–71%). Conclusion Allo-HCT is an effective treatment for T-PLL. Patients must be evaluated for their candidacy for allo-HCT as soon as the diagnosis is confirmed. Efforts are needed to decrease NRM and relapse. [ABSTRACT FROM AUTHOR]

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]

Background: The impact of MYC proto-oncogene, basic helix-loop-helix (MYC) translocations (with or without additional rearrangements involving the B-cell lymphoma 2 [BCL2] or BCL6 genes) on the response to salvage therapy and survival in patients with diffuse large B-cell lymphoma (DLBCL) who experience primary treatment failure is not well defined.Methods: This was a multicenter, retrospective study of the impact of MYC, BCL2, and BCL6 rearrangements in patients with DLBCL who failed to achieve complete remission or relapsed within 6 months after they completed upfront chemoimmunotherapy.Results: The authors examined response to salvage therapy, receipt of hematopoietic cell transplantation (HCT), and survival outcomes in MYC-negative (n = 120), MYC-positive single hit (SH) (n = 20), and MYC-positive double hit/triple hit (DH/TH) (n = 35) cohorts. The overall response rate in these cohorts to first salvage therapy (51%, 50%, and 54%, respectively) and receipt of HCT (52%, 40%, and 43%, respectively) were comparable between the 3 cohorts. The 2-year overall survival rate was 29.9% in the MYC-negative cohort, 0% in the MYC-positive SH cohort, and 9.9% in the MYC-positive DH/TH cohort (P < .001), and no difference was observed between the SH and DH/TH cohorts (P = .8). The higher risk of death for patients with MYC-positive SH DLBCL (hazard ratio, 1.70; 95% confidence interval, 0.98-2.96; P = .06) and those with MYC-positive DH/TH DLBCL (hazard ratio, 2.22; 95% confidence interval, 1.41-3.50; P = .001) persisted after adjusting for covariates. For patients who underwent autologous HCT, the 2-year overall survival rate was 55.4% in the MYC-negative cohort, 0% in the MYC-positive SH cohort, and 19.4% in the MYC-positive DH/TH cohort (P < .001). All 4 MYC-positive patients who underwent allogeneic HCT relapsed in <4 months.Conclusions: Patients with MYC-positive DLBCL who experience primary treatment failure have response rates to similar to those achieved by salvage therapy compared with their MYC-negative counterparts, but their survival is dismal irrespective of additional "hits" and HCT, representing an unmet medical need. Cancer 2017;123:4411-8. © 2017 American Cancer Society. [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]

Immune checkpoints inhibitors have been incorporated into standard treatment protocols for advanced solid tumors. The aim of T-cell-based immune therapy in cancer has been to generate durable clinical benefits for patients, paired with enhanced side effect profiles. The beneficial antitumoral activity of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has been thoroughly demonstrated in certain metastatic malignancies (e.g. melanoma, non-small cell lung cancer, renal cell carcinoma); however, the therapeutic role in lymphoid cancers is complex. Nonetheless, the striking clinical activity seen in early clinical trials of various subtypes of relapsed lymphoma have paved the way for these exciting innovative therapeutic alternatives in these tumors. In this article we assess the literature on the role of the PD-1/PD-L1 pathway in Diffuse Large B-cell lymphoma (DLBCL), and describe future strategies involving these new anticancer agents in this lymphoid neoplasm. [ABSTRACT FROM AUTHOR]

Background: Double-hit lymphomas (DHLs) are collectively defined as B-cell non-Hodgkin lymphomas harboring rearrangements of MYC as well as B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6). To the authors' knowledge, the impact of specific oncogene rearrangements on outcomes of patients with DHL who are treated with immunochemotherapy has not been previously described. Methods: The authors identified patients whose diagnostic tissue specimens underwent metaphase karyotyping or fluorescence in situ hybridization for MYC as well as both BCL2 and BCL6 rearrangements. Cohorts were defined by the presence (+) or absence (-) of rearrangements: MYC+/BCL2+/BCL6- (BCL2-DHL), MYC+/BCL2-/BCL6+ (BCL6-DHL), and MYC+/BCL2+/BCL6+ (triple-hit lymphoma; THL). Results: A total of 117 patients were included in the current analysis (76 BCL2-DHL patients, 16 BCL6-DHL patients, and 25 THL patients). Compared with patients with BCL2-DHL, those with BCL6-DHL were more likely to be classified as having a non-germinal center cell of origin, presented with extranodal disease, and appeared to achieve higher rates of complete response despite receiving intensive induction therapy less frequently. However, patients with BCL6-DHL experienced a shorter median overall survival if achieving an initial complete response compared with patients with BCL2-DHL. Patients with THL experienced survival outcomes similar to those of patients with BCL2-DHL. Conclusions: Recognition of the specific oncogene rearrangements may be of prognostic value and potentially guide future therapeutic strategies for patients with DHL. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphoma (PTCL) encompasses a group of rare and aggressive lymphomas. PTCL, unspecified (PTCLU) is the most common subtype of PTCL, and carries a poor prognosis. The International Prognostic Index (IPI) and the Prognostic Index for PTCLU (PIT) scoring systems are powerful risk-stratification tools in patients with PTCL. The aim of this study was to evaluate whether the neutrophil-to-lymphocyte ratio (NLR) is a prognostic factor in PTCLU. We retrospectively studied 83 patients with diagnosis of PTCLU. In the univariate analysis, NLR ≥ 4 was associated with worse overall survival (HR 3.96, 95% CI 1.92-8.17; p < 0.001). In the multivariate analysis, NLR ≥ 4 was independently associated with worse overall survival after adjustment for the PIT score (HR 4.30, 95% CI 1.90-9.69; p < 0.001), and for the IPI score (HR 2.60, 95% CI 1. 12-6.04; p = 0.03). Our study suggests the NLR could be helpful in refining the survival prognostication in patients with PTCLU. [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 A cytokine release syndrome (CRS) or neurotoxicity described as a chimeric antigen receptor (CAR) T Related Encephalopathy Syndrome (CRES) is one of the main complications while CD19 CAR T has been successful in relapsed/refractory (R/R) B cell malignancies. CRS and/or CRES have been associated with standard biomarkers such as CRP and ferritin but also with cytokines. We report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with R/R DLBCL treated with axicabtagene ciloleucel (axi-cel). Methods Patients treated with commercial axi-cel in Moffitt Cancer Center were included in this study. Serum samples were collected prior to lymphodepleting chemotherapy at baseline and then during hospitalization. Based on 38 serum cytokineś analysis in B-cell acute lymphoblastic leukemia patients treated with 19-28z CAR T and results of published studies, 8 serum proteins were selected to monitor. CRS and CRES were prospectively graded by Lee criteria and CARTOX respectively. Results 41 patients were identified. Median age was 64 years old (76% male). Non-severe (grade 0-2) and severe (grade 3-5) CRS were observed in 93% and 7% respectively while non-severe and severe CRES were observed in 71% and 29% respectively. 2 patients died in the setting of severe toxicity. Baseline CRP, ferritin, IL-6 levels were significantly elevated in the patients who developed severe CRS and/or CRES. Baseline angiopoietin-2/angipoietin-1 ratio (ANG-2/1) was also correlated with severe CRES. In select cases, monitoring of cytokines provided clinical insight that wasńt evident from standard biomarkers. Conclusions We observed correlations between severe toxicities and elevated serum cytokine levels of baseline IL-6 and ANG-2/1 suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with CAR T. Monitoring of cytokines using a POC device is feasible and would be useful clinically. [ABSTRACT FROM AUTHOR]

A cytokine release syndrome (CRS) or neurotoxicity described as a chimeric antigen receptor (CAR) T Related Encephalopathy Syndrome (CRES) is one of the main complications while CD19 CAR T has been successful in relapsed/refractory (R/R) B cell malignancies. CRS and/or CRES have been associated with standard biomarkers such as CRP and ferritin but also with cytokines. We report the results of cytokine analysis using a point of care (POC) device to predict immune-related toxicities in patients with R/R DLBCL treated with axicabtagene ciloleucel (axi-cel). Patients treated with commercial axi-cel in Moffitt Cancer Center were included in this study. Serum samples were collected prior to lymphodepleting chemotherapy at baseline and then during hospitalization. Based on 38 serum cytokineś analysis in B-cell acute lymphoblastic leukemia patients treated with 19-28z CAR T and results of published studies, 8 serum proteins were selected to monitor. CRS and CRES were prospectively graded by Lee criteria and CARTOX respectively. 41 patients were identified. Median age was 64 years old (76% male). Non-severe (grade 0-2) and severe (grade 3-5) CRS were observed in 93% and 7% respectively while non-severe and severe CRES were observed in 71% and 29% respectively. 2 patients died in the setting of severe toxicity. Baseline CRP, ferritin, IL-6 levels were significantly elevated in the patients who developed severe CRS and/or CRES. Baseline angiopoietin-2/angipoietin-1 ratio (ANG-2/1) was also correlated with severe CRES. In select cases, monitoring of cytokines provided clinical insight that wasńt evident from standard biomarkers. We observed correlations between severe toxicities and elevated serum cytokine levels of baseline IL-6 and ANG-2/1 suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with CAR T. Monitoring of cytokines using a POC device is feasible and would be useful clinically. [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]

The article presents a case study of a 50-year-old man with abdominal distension and umbilical bulging. His bone marrow biopsy and core needle biopsy revealed symptoms of CD20, tartrate-resistant acid phosphatase (TRAP) and hairy cell leukaemia (HCL). It was found that treatment with the anticancer drug cladribine improved abdominal distension, splenomegaly and can be used for HCL-associated disorders such as pancytopenia and intra-abdominal lymphadenopathy.