Safety and Toxicity Profiles of CAR T Cell Therapy in Non-Hodgkin Lymphoma: A Systematic Review and Meta-Analysis.

BACKGROUND: The application of CD19-directed chimeric antigen receptor T (CAR T) cell therapy has improved outcomes for thousands of patients with non-Hodgkin B cell lymphoma (NHL). The toxicities associated with various CAR T cell products, however, can be severe and difficult to anticipate. METHODS: In this systematic review and meta-analysis, we set out to determine whether there are measurable differences in common toxicities, including cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), cytopenias, and infections, between CAR T products that are commercially available for the treatment of NHL. RESULTS: After a stringent study selection process, we used a cohort of 1364 patients enrolled in 15 prospective clinical trials investigating the use of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel), and tisagenlecleucel (tisa-cel). We found that the rates of CRS and ICANS were significantly higher with axi-cel as compared to both liso-cel and tisa-cel. Conversely, we demonstrated that rates of all-grade and severe neutropenia were significantly greater with liso-cel. Febrile neutropenia and all-grade infection rates did not differ significantly between products though rates of severe infection were increased with axi-cel. CONCLUSIONS: Overall, this study serves as the first to delineate toxicity profiles associated with various available CAR T products. By better understanding associated toxicities, it may become possible to tailor therapies towards individual patients and anticipate the development of toxicities at earlier stages.

Efficacy and Toxicity of CD19 Chimeric Antigen Receptor T Cell Therapy for Lymphoma in Solid Organ Transplant Recipients: A Systematic Review and Meta-Analysis.

The safety and efficacy of chimeric antigen receptor (CAR) T cell therapy in solid organ transplant recipients is poorly understood, given the paucity of available data in this patient population. There is a theoretical risk of compromising transplanted organ function with CAR T cell therapy; conversely, organ transplantation-related immunosuppression can alter the function of CAR T cells. Given the prevalence of post-transplantation lymphoproliferative disease, which often can be difficult to treat with conventional chemoimmunotherapy, understanding the risks and benefits of delivering lymphoma-directed CAR T cell therapy in solid organ transplant recipients is of utmost importance. We sought to determine the efficacy of CAR T cell therapy in solid organ transplant recipients as well as the associated adverse effects, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and compromised solid organ transplant function. We conducted a systematic review and meta-analysis of adult recipients of solid organ transplant who received CAR T cell therapy for non-Hodgkin lymphoma. Primary outcomes included efficacy, defined as overall response (OR), complete response (CR), progression-free survival, and overall survival, as well as rates of CRS and ICANS. Secondary outcomes included rates of transplanted organ loss, compromised organ function, and alterations to immunosuppressant regimens. After a systematic literature review and 2-reviewer screening process, we identified 10 studies suitable for descriptive analysis and 4 studies suitable for meta-analysis. Among all patients, 69% (24 of 35) achieved a response to CAR T cell therapy, and 52% (18 of 35) achieved a CR. CRS of any grade occurred in 83% (29 of 35), and CRS grade ≥3 occurred in 9% (3 of 35). Sixty percent of the patients (21 of 35) developed ICANS, and 34% (12 of 35) developed ICANS grade ≥3. The incidence of any grade 5 toxicity among all patients was 11% (4 of 35). Fourteen percent of the patients (5 of 35) experienced loss of the transplanted organ. Immunosuppressant therapy was held in 22 patients but eventually restarted in 68% of them (15 of 22). Among the studies included in the meta-analysis, the pooled OR rate was 70% (95% confidence interval [CI], 29.2% to 100%; I2 = 71%) and the pooled CR rate was 46% (95% CI, 25.4% to 67.8%; I2 = 29%). The rates of any grade CRS and grade ≥3 CRS were 88% (95% CI, 69% to 99%; I2 = 0%) and 5% (95% CI, 0% to 21%; I2 = 0%), respectively. The rates of any grade ICANS and ICANS grade ≥3 were 54% (95% CI, 9% to 96%; I2 = 68%) and 40% (95% CI, 3% to 85%; I2 = 63%), respectively. The efficacy of CAR T cell therapy in solid organ transplant recipients is comparable to that in the general population as reported in prior investigational studies, with an acceptable toxicity profile in terms of CRS, ICANS, and transplanted organ compromise. Further studies are needed to determine long-term effects on organ function, sustained response rates, and best practices peri-CAR T infusion period in this patient population.

Nine-year follow-up of lenalidomide plus rituximab as initial treatment for mantle cell lymphoma.

Although chemoimmunotherapy is the current standard of care for initial treatment of mantle cell lymphoma (MCL), newer data suggest that there may be a role for a chemotherapy-free approach. We report the 9-year follow-up results of a multicenter, phase 2 study of lenalidomide plus rituximab (LR) as the initial treatment of MCL. The LR doublet is used as induction and maintenance until progression, with optional discontinuation after 3 years. We previously reported an overall response rate of 92% in evaluable patients, with 64% achieving a complete response. At a median follow-up of 103 months, 17 of 36 evaluable patients (47%) remain in remission. The 9-year progression-free survival and overall survival were 51% and 66%, respectively. During maintenance, hematologic adverse events included asymptomatic grade 3 or 4 cytopenia (42% neutropenia, 5% thrombocytopenia, and 3% anemia) and mostly grade 1 to 2 infections managed in the outpatient setting (50% upper respiratory infections, 21% urinary tract infections, 16% sinusitis, 16% cellulitis, and 13% pneumonia, with 5% requiring hospitalization). More patients developed grade 1 and 2 neuropathy during maintenance therapy (29%) than during induction therapy (8%). Twenty-one percent of patients developed secondary malignancies, including 5% with invasive malignancies, whereas the remainder were noninvasive skin cancers treated with local skin-directed therapy. Two patients permanently discontinued therapy because of concerns of immunosuppression during the COVID-19 pandemic. With long-term follow-up, LR continues to demonstrate prolonged, durable responses with manageable safety as initial induction therapy. This trial was registered at www.clinicaltrials.gov as #NCT01472562.

Long COVID in Cancer: A Matched Cohort Study of 1-year Mortality and Long COVID Prevalence Among Patients With Cancer Who Survived an Initial Severe SARS-CoV-2 Infection.

OBJECTIVES: The long-term effects of severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) infection in patients with cancer are unknown. We examined 1-year mortality and prevalence of long COVID in patients with and without cancer after initial hospitalization for acute COVID-19 infection. METHODS: We previously studied 585 patients hospitalized from March to May 2020 with acute COVID-19 infection at Weill Cornell Medicine (117 patients with cancer and 468 age, sex, and comorbidity-matched non-cancer controls). Of the 456 patients who were discharged, we followed 359 patients (75 cancer and 284 non-cancer controls) for COVID-related symptoms and death, at 3, 6, and 12 months after initial symptom onset. Pearson χ 2 and Fisher exact tests were used to determine associations between cancer, postdischarge mortality, and long COVID symptoms. Multivariable Cox proportional hazards models adjusting for potential confounders were used to quantify the risk of death between patients with and without cancer. RESULTS: The cancer cohort had higher mortality after hospitalization (23% vs 5%, P < 0.001), a hazard ratio of 4.7 (95% CI: 2.34-9.46) for all-cause mortality, after adjusting for smoking and oxygen requirement. Long COVID symptoms were observed in 33% of patients regardless of cancer status. Constitutional, respiratory, and cardiac complaints were the most prevalent symptoms in the first 6 months, whereas respiratory and neurological complaints (eg, "brain fog" and memory deficits) were most prevalent at 12 months. CONCLUSIONS: Patients with cancer have higher mortality after hospitalization for acute severe acute respiratory syndrome coronavirus 2 infections. The risk of death was highest in the first 3 months after discharge. About one-third of all patients experienced long COVID.

Screening Chest CT Prior to Allogenic Hematopoietic Stem Cell Transplantation.

Pulmonary complications constitute a major cause of morbidity and mortality in the post-allogenic hematopoietic stem cell transplantation (alloHSCT) period. Although chest X-ray (CXR) is customarily used for screening, we have used chest computed tomography (CT) scans. To characterize the prevalence of abnormalities and explore their impact on alloHSCT eligibility and outcomes post-transplantation, we conducted a retrospective analysis using real-world data collected at our center for adult patients who were evaluated for alloHSCT between January 2013 and December 2020 and identified 511 eligible patients. The most common primary disease was acute myeloid leukemia, in 49% of patients, followed by myelodysplastic syndrome (23%), lymphoma (11%), and acute lymphocytic leukemia (10%). Abnormal screening chest CT results were found in 199 patients (39%). The most frequent detected abnormality was pulmonary nodule, in 78 patients (35%), followed by consolidation in 42 (19%), ground-glass opacification in 33 (15%), bronchitis and bronchiolitis in 25 (11%), pleural effusions in 14 (6%), and new primary cancer in 7 (2%). CXR detected abnormalities in only approximately one-half of the patients (48%) with an abnormal chest CT scan. Among the 199 patients with an abnormal chest CT scan, 98 (49%) underwent further assessment and/or intervention before transplantation. The most common workup was pulmonary consultation in 32%, followed by infectious diseases consultation in 24%. Lung biopsy was obtained in 20%, and antimicrobial therapy was initiated after confirming an infection diagnosis in 20%. Patients with an abnormal chest CT scan demonstrated worse overall survival (P = .032), nonrelapse mortality (P = .015), and pulmonary-related mortality (P < .001) compared to those with a normal chest CT scan. Our study suggests that pretransplantation screening chest CT is beneficial in uncovering invasive infections and underlying malignancies and allows for appropriate interventions before alloHSCT to prevent potentially serious post-transplantation complications without causing a delay in alloHSCT. Nevertheless, abnormal CT findings prior to transplantation may be associated with overall worse prognosis.

Are novel agents ready to assume the mantle in the frontline treatment of mantle cell lymphoma?

Although chemotherapy has been a mainstay of the frontline treatment of mantle cell lymphoma (MCL) for many years, novel agents-including Bruton kinase inhibitors, immunomodulatory agents, and BCL2 inhibitors-have shown promise in patients with relapsed and refractory disease, and they are also being studied in the frontline setting. This review summarizes the current clinical data for using these novel agents in untreated MCL, both in combination with chemotherapy and singly, and discusses some of the trials currently under way to assess their future potential.

Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies.

B-cell non-Hodgkin lymphomas (B-NHLs) are highly heterogenous by genetic, phenotypic, and clinical appearance. Next-generation sequencing technologies and multi-dimensional data analyses have further refined the way these diseases can be more precisely classified by specific genomic, epigenomic, and transcriptomic characteristics. The molecular and genetic heterogeneity of B-NHLs may contribute to the poor outcome of some of these diseases, suggesting that more personalized precision-medicine approaches are needed for improved therapeutic efficacy. The germinal center (GC) B-cell like diffuse large B-cell lymphomas (GCB-DLBCLs) and follicular lymphomas (FLs) share specific epigenetic programs. These diseases often remain difficult to treat and surprisingly do not respond advanced immunotherapies, despite arising in secondary lymphoid organs at sites of antigen recognition. Epigenetic dysregulation is a hallmark of GCB-DLBCLs and FLs, with gain-of-function (GOF) mutations in the histone methyltransferase EZH2, loss-of-function (LOF) mutations in histone acetyl transferases CREBBP and EP300, and the histone methyltransferase KMT2D representing the most prevalent genetic lesions driving these diseases. These mutations have the common effect to disrupt the interactions between lymphoma cells and the immune microenvironment, via decreased antigen presentation and responsiveness to IFN-γ and CD40 signaling pathways. This indicates that immune evasion is a key step in GC B-cell lymphomagenesis. EZH2 inhibitors are now approved for the treatment of FL and selective HDAC3 inhibitors counteracting the effects of CREBBP LOF mutations are under development. These treatments can help restore the immune control of GCB lymphomas, and may represent optimal candidate agents for more effective combination with immunotherapies. Here, we review recent progress in understanding the impact of mutant chromatin modifiers on immune evasion in GCB lymphomas. We provide new insights on how the epigenetic program of these diseases may be regulated at the level of metabolism, discussing the role of metabolic intermediates as cofactors of epigenetic enzymes. In addition, lymphoma metabolic adaptation can negatively influence the immune microenvironment, further contributing to the development of immune cold tumors, poorly infiltrated by effector immune cells. Based on these findings, we discuss relevant candidate epigenetic/metabolic/immune targets for rational combination therapies to investigate as more effective precision-medicine approaches for GCB lymphomas.

COVID-19 Severity and Outcomes in Patients With Cancer: A Matched Cohort Study.

PURPOSE: SARS-CoV-2 (COVID-19) is a systemic infection. Patients with cancer are immunocompromised and may be vulnerable to COVID-related morbidity and mortality. The objectives of this study were to determine if patients with cancer have worse outcomes compared with patients without cancer and to identify demographic and clinical predictors of morbidity and mortality among patients with cancer. METHODS: We used data from adult patients who tested positive for COVID-19 and were admitted to two New York-Presbyterian hospitals between March 3 and May 15, 2020. Patients with cancer were matched 1:4 to controls without cancer in terms of age, sex, and number of comorbidities. Using Kaplan-Meier curves and the log-rank test, we compared morbidity (intensive care unit admission and intubation) and mortality outcomes between patients with cancer and controls. Among those with cancer, we identified demographic and clinical predictors of worse outcomes using Cox proportional hazard models. RESULTS: We included 585 patients who were COVID-19 positive, of whom 117 had active malignancy, defined as those receiving cancer-directed therapy or under active surveillance within 6 months of admission. Presenting symptoms and in-hospital complications were similar between the cancer and noncancer groups. Nearly one half of patients with cancer were receiving therapy, and 45% of patients received cytotoxic or immunosuppressive treatment within 90 days of admission. There were no statistically significant differences in morbidity or mortality (P = .894) between patients with and without cancer. CONCLUSION: We observed that patients with COVID-19 and cancer had similar outcomes compared with matched patients without cancer. This finding suggests that a diagnosis of active cancer alone and recent anticancer therapy do not predict worse COVID-19 outcomes and therefore, recommendations to limit cancer-directed therapy must be considered carefully in relation to cancer-specific outcomes and death.

An update on options of therapy for aggressive mantle cell lymphoma.

With the emerging application of novel targeted agents in the induction, maintenance and salvage strategies, management of aggressive mantle cell lymphoma is being transformed from high-intensity chemo-immunotherapy applicable to only selected patients, to more personalized treatment incorporating novel agents that are effective and accessible for the majority of the patients. This review summarizes risk-stratified management paradigm for aggressive mantle cell lymphoma, providing context for clinical applications of novel agents and cellular therapy including stem cell transplant and CAR-T.

IMiDs New and Old.

PURPOSE OF REVIEW: IMiDs are a class of biologic agents with immunomodulatory, anti-angiogenic, and direct anti-cancer activities. This review summarizes current data on clinical development and application of IMiDs in non-Hodgkin lymphoma (NHL) subtypes, focusing primarily on lenalidomide, with additional discussion on managing common side effects. RECENT FINDINGS: Improved upon the prototype thalidomide, the second-generation compound lenalidomide has enhanced immunological and anti-cancer properties with fewer side effects, while next-generation small molecule cereblon/E3 ubiquitin ligase modulator CC-122 is in early clinical studies. Lenalidomide is FDA-approved for treatment of relapsed/refractory mantle cell lymphoma as a single agent, as well as in combination with rituximab for R/R follicular lymphoma and marginal zone lymphoma. In addition, numerous clinical trials of lenalidomide, as single agent, in combination with anti-CD20 antibodies, or in combination with chemoimmunotherapy regimens, have shown promise in aggressive and indolent NHL in both the upfront and relapsed/refractory setting. As clinical trials with lenalidomide continue to find success in both indolent and aggressive lymphomas, IMiDs are poised to be important building blocks for combinatorial strategies with antibodies, chemotherapy, novel target agents, and emerging immunotherapy involving immune checkpoint inhibitors and chimeric antigen receptor T cell (CAR-T) therapy. Delineation of treatment-specific and disease-specific biomarkers is an important research objective to gain insight into potential mechanisms of action, and to guide future clinical development.

Disseminated tuberculosis masquerading as a neuroendocrine tumour.

We describe the case of a 61-year-old man from the Dominican Republic admitted with diarrhoea, fevers and weight loss who was found to have lab studies and imaging (including radiolabeled somatostatin positron emission tomography/CT scan) initially consistent with a metastatic neuroendocrine tumour. However, after weeks of workup and multiple inconclusive biopsies, he was diagnosed with disseminated extrapulmonary tuberculosis. Here we examine the data for neuroendocrine tumour and tuberculosis labs and imaging to delineate where these studies overlap. We also analyse the biases and pitfalls in this case that led to a protracted diagnosis.

Venous thromboembolism in patients with B-cell non-Hodgkin lymphoma treated with lenalidomide: a systematic review and meta-analysis.

Lenalidomide is associated with increased risk of thromboembolism (VTE) in patients with multiple myeloma. This risk has not previously been defined in B-cell non-Hodgkin lymphoma (NHL), for which lenalidomide is also an active agent. We conducted a systematic literature search in Ovid MEDLINE (1946 to February 2017), Ovid EMBASE (1974 to February 2017), The Cochrane Library (Wiley), and Web of Science Core Collection for prospective studies evaluating lenalidomide-containing regimens in B-cell NHL with adequate reporting of patient characteristics, total cycles received, and safety data including VTE rates. The primary outcome was VTE events per 100 patient-cycles by meta-analysis using random-effects models. Our literature search identified 1719 citations; 28 articles were included. For all patients with B-cell NHL receiving lenalidomide, the rate of VTE per 100 patient-cycles was 0.77 (95% confidence interval [CI], 0.48-1.12; I2, 67%). The rate for single-agent lenalidomide was 1.09 events per 100 patient-cycles (95% CI, 0.49-1.94; I2, 76%), the rate for lenalidomide plus biologics was 0.49 (95% CI, 0.17-0.97; I2, 59%), and the rate for lenalidomide plus chemotherapy was 0.89 (95% CI, 0.39-1.60; I2, 57%). Rate of VTE events in B-cell NHL patients treated with lenalidomide in clinical trials is similar to the rate in multiple myeloma. The VTE rate appears to be lowest for lenalidomide combined with a biologic compared with single-agent lenalidomide or its combination with chemotherapy. This protocol was registered at www.crd.york.ac.uk/prospero/ as #CRD42017056042.