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Chimeric antigen receptor (CAR) modified T cell therapy has transformed the management of relapsed/refractory B cell malignancies. Despite high overall response rates, relapse post CAR T treatment remains a clinical challenge. Loss of target antigen, specifically CD19, is one well-defined mechanism of disease relapse. The mechanism of CD19 loss and which patients are at higher risk of CD19 loss remain poorly understood. To overcome CD19 loss, CARs targeting multiple antigens are being tested in clinical trials. CD19/20 and CD19/22 bispecific CARs demonstrate cytotoxicity against CD19-negative cells in preclinical studies. These CARs have also shown efficacy, safety, and a relatively low rate of CD19-negative relapse in phase I trials. These small studies suggest that multispecific CAR T cells can deprive lymphomas of escape via antigen loss. However, the selection of an ideal target, the right CAR construct, and whether these multispecific CARs can induce long-term remissions are still under investigation.
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Linfoma , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos de Linfócitos T , Linfócitos T , Imunoterapia Adotiva , Recidiva Local de NeoplasiaRESUMO
Despite significantly improving outcomes in patients with B-cell malignancies, covalent Bruton tyrosine kinase (BTK) inhibitors are limited by toxicities and the development of resistance. Some toxicities can be life-threatening, such as cardiotoxicity. These toxicities result from off-target effects of covalent BTK inhibitors and frequently lead to dose reductions and discontinuations of the drug. Noncovalent BTK inhibitors bind BTK in a unique fashion and, to date, have demonstrated an excellent safety profile as well as efficacy against a variety of B-cell malignancies. In addition, noncovalent BTK inhibitors have, for the first time, demonstrated efficacy in patients who progressed on other BTK inhibitors. Long-term data and comparative studies are needed to further investigate their efficacy and role in the landscape covalent BTK Inhibitors.
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Neoplasias , Inibidores de Proteínas Quinases , Humanos , Tirosina Quinase da Agamaglobulinemia , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias/tratamento farmacológicoRESUMO
The prognosis of relapsed/refractory (R/R) anaplastic large cell lymphoma (ALCL) is poor. Large studies evaluating outcomes of allogeneic haematopoietic cell transplantation (allo-HCT) in systemic R/R ALCL are not available. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we evaluated outcomes of 182 adults (aged ≥18 years) with R/R ALCL undergoing allo-HCT between 2008 and 2019. Non-relapse mortality (NRM), disease relapse/progression (REL), progression-free survival (PFS), and overall survival (OS) were modelled using Cox proportional hazards models. The median (range) follow-up of survivors was 62 (3-148) months. The 1-year NRM was 18%. The 5-year REL, PFS and OS were 32%, 41% and 56% respectively. On multivariable regression analysis African American race (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.6-4.8; p < 0.001) and refractory disease at allo-HCT (HR 3.2, 95% CI 1.6-6.2; p < 0.001) were predictive of inferior OS. Similarly, African-American race (HR 2.1, 95% CI 1.3-3.4; p = 0.003), other minority race (HR 2.5, 95% CI 1.2-5.3; p = 0.02) and refractory disease (HR 2.2, 95% CI 1.2-4.3; p = 0.01) were predictive of inferior PFS. These data, demonstrate that allo-HCT can result in durable disease control in a sizable proportion of patients with R/R ALCL. Refractory disease and racial minority status predicted inferior allo-HCT outcomes. Whether the inferior outcomes of racial minorities with R/R ALCL after allo-HCT are driven by differences in disease biology or disparities in post allo-HCT care, or both, requires further investigation.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Linfoma Anaplásico de Células Grandes , Adulto , Humanos , Adolescente , Linfoma Anaplásico de Células Grandes/terapia , Recidiva Local de Neoplasia , Intervalo Livre de Progressão , Prognóstico , Doença Crônica , Condicionamento Pré-Transplante , Doença Enxerto-Hospedeiro/etiologia , Estudos RetrospectivosRESUMO
Corticosteroids are commonly used for the management of severe toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. However, it remains unclear whether their dose, duration, and timing may affect clinical efficacy. Here, we determined the impact of corticosteroids on clinical outcomes in patients with relapsed or refractory large B-cell lymphoma treated with standard of care anti-CD19 CAR T-cell therapy. Among 100 patients evaluated, 60 (60%) received corticosteroids for management of CAR T-cell therapy-associated toxicities. The median cumulative dexamethasone-equivalent dose was 186 mg (range, 8-1803) and the median duration of corticosteroid treatment was 9 days (range, 1-30). Corticosteroid treatment was started between days 0 and 7 in 45 (75%) patients and beyond day 7 in 15 (25%). After a median follow-up of 10 months (95% confidence interval, 8-12 months), use of higher cumulative dose of corticosteroids was associated with significantly shorter progression-free survival. More importantly, higher cumulative dose of corticosteroids, and prolonged and early use after CAR T-cell infusion were associated with significantly shorter overall survival. These results suggest that corticosteroids should be used at the lowest dose and for the shortest duration and their initiation should be delayed whenever clinically feasible while managing CAR T-cell therapy-associated toxicities.
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Corticosteroides/administração & dosagem , Dexametasona/administração & dosagem , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
INTRODUCTION: The management of relapsed and/or refractory (R/R) large B-cell lymphoma (LBCL) has witnessed dramatic changes in the recent past. Despite the availability of multiple novel immunotherapies in R/R setting, there remains an unmet need for off-the-shelf therapies, particularly in patients with primary refractory, multiply relapsed disease or those experiencing cellular immunotherapy failure. To harness the power of the T-cell mediated immunity, a novel class of drugs called bispecific antibodies (BsAbs) have been developed. These BsAbs are currently under investigation both in frontline and R/R setting and hold the potential to revolutionize the management of LBCL. AREAS COVERED: This review article summarizes the currently available BsAbs, their mode of action, efficacy, and safety data for untreated and R/R LBCL. In addition, the role of these BsAbs in combination with currently available chemoimmunotherapy regimens is also discussed. EXPERT OPINION: Two BsAbs have secured FDA approval for R/R LBCL, with expected approval of more BsAbs (including in earlier treatment lines). These drugs provide a highly efficacious and relatively safe treatment option for patients with highly pretreated disease including relapse after cellular immunotherapies. In addition, these BsAbs provide a platform for chemotherapy-free regimen for older/frail patients.
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Anticorpos Biespecíficos , Imunoterapia , Linfoma Difuso de Grandes Células B , Humanos , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/farmacologia , Imunoterapia/métodos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Animais , Recidiva Local de Neoplasia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/efeitos adversosRESUMO
ABSTRACT: Recent studies demonstrating the feasibility of outpatient chimeric antigen receptor (CAR)-modified T-cell therapy administration are either restricted to CARs with 41BB costimulatory domains or use intensive at-home monitoring. We report outcomes of outpatient administration of all commercially available CD19- and B-cell maturation antigen (BCMA)-directed CAR T-cell therapy using a strategy of no remote at-home monitoring and an early cytokine release syndrome (CRS) intervention strategy. Patients with hematologic malignancies who received CAR T-cell therapy in the outpatient setting during 2022 to 2023 were included. Patients were seen daily in the cancer center day hospital for the first 7 to 10 days and then twice weekly through day 30. The primary end point was to determine 3-, 7-, and 30-day post-CAR T-cell infusion hospitalizations. Early CRS intervention involved administering tocilizumab as an outpatient for grade ≥1 CRS. Fifty-eight patients received outpatient CAR T-cell infusion (33 myeloma, 24 lymphoma, and 1 acute lymphoblastic leukemia). Of these, 17 (41%), 16 (38%), and 9 patients (21%) were admitted between days 0 to 3, 4 to 7, and 8 to 30 after CAR T-cell infusion, respectively. The most common reason for admission was CAR T-cell-related toxicities (33/42). Hospitalization was prevented in 15 of 35 patients who received tocilizumab for CRS as an outpatient. The nonrelapse mortality rates were 1.7% at 1 month and 3.4% at 6 months. In conclusion, we demonstrate that the administration of commercial CAR T-cell therapies in an outpatient setting is safe and feasible without intensive remote monitoring using an early CRS intervention strategy.
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Imunoterapia Adotiva , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Idoso , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/terapia , Pacientes Ambulatoriais , Neoplasias Hematológicas/terapia , Receptores de Antígenos Quiméricos/uso terapêutico , Resultado do Tratamento , Anticorpos Monoclonais Humanizados/uso terapêuticoRESUMO
BCMA-directed chimeric antigen receptor T-cell (CAR T) therapies, including idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), have transformed the treatment landscape for relapsed-refractory multiple myeloma (RRMM), offering remarkable efficacy with hallmark toxicity risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The FDA mandates a 4-week monitoring period at the treatment center as part of a Risk Evaluation and Mitigation Strategy (REMS) to monitor and manage these toxicities, which, while prudent, may add unnecessary challenges related to access and socioeconomic disparities. We sought to assess CRS and ICANS onset and duration, as well as causes of non-relapse mortality (NRM) in real-world BCMA CAR T recipients in order to better inform future changes to the monitoring guidelines for CAR T recipients. This is a retrospective study across four academic centers that examined 129 ide-cel and cilta-cel recipients that received CAR T cell infusions from May 2021 to June 2023. Infusion and toxicities were managed per institutional guidelines in accordance with previously published guidelines. While differences were noted in the incidence and duration of CRS/ ICANS between ide-cel and cilta-cel, late-onset CRS and ICANS were rare after 2 weeks following infusion (0% and 1.6%, respectively). NRM was driven by hemophagocytic lymphohistiocytosis and infections in the early follow-up period (1.1% until Day 29), then by infections through three months post-infusion (1.2%). Our findings suggest that 25% of patients had to relocate for 4 weeks due to distance from the treatment center. With the low risk of CRS and ICANS after 2 weeks, a flexible shorter monitoring period may be reasonable, emphasizing collaboration with referring oncologists to improve NRM.
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Síndrome da Liberação de Citocina , Imunoterapia Adotiva , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Imunoterapia Adotiva/efeitos adversos , Feminino , Pessoa de Meia-Idade , Masculino , Idoso , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/mortalidade , Estudos Retrospectivos , Antígeno de Maturação de Linfócitos B/imunologia , Adulto , Receptores de Antígenos Quiméricos/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/mortalidade , Fatores de TempoRESUMO
Thiotepa/carmustine (TT-BCNU) is a commonly used autologous transplant (ASCT) conditioning regimen for primary DLBCL of the CNS (PCNSL). The total thiotepa dose varies among TT-BCNU recipients, with some centers administering a total dose of 20 mg/kg, while others using 10 mg/kg. We retrospectively assessed the impact of thiotepa dose intensity on ASCT outcomes in 218 adult PCNSL patients who underwent a first ASCT with TT-BCNU conditioning and received either a total thiotepa dose of 10 mg/kg (TT-10 group; N = 90), or 20 mg/kg (TT-20 group; N = 128). The median follow-up of survivors was 22 months. The cumulative incidence of 1-year non-relapse mortality (NRM) for TT-10 and TT-20 cohorts were 6% (95%CI = 2-12%) vs. 4% (95%CI = 1-8%), respectively (p = 0.66). The 3-year cumulative incidence of relapse (15% vs. 13%; p = 0.67), progression-free survival (PFS) (71% vs. 80%; p = 0.25) and overall survival (OS) (79% vs. 83%; p = 0.56) were similar in the TT-10 and TT-20 groups, respectively. On multivariate analysis compared to TT-10, the TT-20 cohort was not associated with significantly different risk of NRM (Hazard ration [HR] = 0.77; p = 0.64), relapse/progression (HR = 0.87; p = 0.74), PFS (HR = 0.80; p = 0.48) or OS (HR = 1.10; p = 0.80). In conclusion thiotepa dose-intensity in TT-BCNU conditioning does not impact ASCT outcomes of PCNSL patients.
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Neoplasias do Sistema Nervoso Central , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Adulto , Humanos , Tiotepa/uso terapêutico , Carmustina/uso terapêutico , Autoenxertos/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Estudos Retrospectivos , Recidiva Local de Neoplasia , Transplante Autólogo , Sistema Nervoso Central/patologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Recidiva , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
Brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is increasingly used for frontline treatment of stage III/IV classical Hodgkin lymphoma (cHL). Peripheral neuropathy (PN) was the most common and treatment-limiting side effect seen in clinical trials but has not been studied in a nontrial setting, in which clinicians may have different strategies for managing it. We conducted a multisite retrospective study to characterize PN in patients who received BV + AVD for newly diagnosed cHL. One hundred fifty-three patients from 10 US institutions were eligible. Thirty-four patients (22%) had at least 1 ineligibility criteria for ECHELON-1, including stage, performance status, and comorbidities. PN was reported by 80% of patients during treatment; 39% experienced grade (G) 1, 31% G2, and 10% G3. In total, BV was modified in 44% of patients because of PN leading to BV discontinuation in 23%, dose reduction in 17%, and temporary hold in 4%. With a median follow-up of 24 months, PN resolution was documented in 36% and improvement in 33% at the last follow-up. Two-year progression-free survival (PFS) for the advanced-stage patients was 82.7% (95% confidence interval [CI], 0.76-0.90) and overall survival was 97.4% (95% CI, 0.94-1.00). Patients who discontinued BV because of PN did not have inferior PFS. In the nontrial setting, BV + AVD was associated with a high incidence of PN. In our cohort, which includes patients who would not have been eligible for the pivotal ECHELON-1 trial, BV discontinuation rates were higher than previously reported, but 2-year outcomes remain comparable.
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Doença de Hodgkin , Doenças do Sistema Nervoso Periférico , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin/uso terapêutico , Doença de Hodgkin/complicações , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Incidência , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Estudos RetrospectivosRESUMO
Loncastuximab tesirine-lpyl (ADC Therapeutics) is an anti-CD19 antibody-drug conjugate which consists of anti-CD19 antibody and cytotoxic alkylating agent, SG3199. Data from preclinical in vitro and animal studies demonstrated its selectivity and efficacy. The phase I LOTIS-1 study for relapsed, refractory B-cell non-Hodgkin lymphoma (NHL) demonstrated efficacy and a tolerable safety profile, with major adverse effects being neutropenia, thrombocytopenia, elevated liver enzymes, and fluid accumulation. Based on pharmacokinetics analysis in this study, a dose of 150 µg/kg every 3 weeks for cycles 1 and 2 followed by 75 µg/kg every 3 weeks until disease progression or intolerability was chosen for the phase II LOTIS-2 study. This study recruited relapsed, refractory diffuse large B-cell lymphoma and confirmed similar safety profile. Overall response rate was 48.6% (24.1% complete response), and overall survival was 9.9 months. Due to its safety and efficacy reported in the above trials, loncastuximab tesirine was recently approved by the US Food and Drug Administration for the treatment of relapsed, refractory diffuse large B-cell lymphoma. Several clinical trials are ongoing to assess its safety and efficacy in NHL in various clinical settings.
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INTRODUCTION: Chimeric antigen receptor (CAR)-modified T-cell therapy has revolutionized the treatment of relapsed/refractory B-cell malignancies including acute lymphoblastic leukemia and non-Hodgkin lymphoma. All of the CARs approved for clinical use in treating B-cell malignancies are directed against a single antigen, CD19. Although the initial response rates are high, a significant number of patients relapse, with antigen loss being one proposed mechanism of treatment failure. Multi-targeted CAR T approaches are now being developed to overcome this limitation of currently approved CAR products. AREAS COVERED: Here, we discuss the mechanism of antigen loss, various bispecific CAR T-cell constructs, and their efficacy and safety in the preclinical as well as clinical settings. EXPERT OPINION: Although CD19 CAR T-cells have significantly improved response rates in relapsed/refractory B-cell malignancies, relapse remains a major barrier to long-term survival. Bispecific CAR T-cells offer an alternative approach to mitigate relapse associated with antigen loss. In B-cell malignancies, various bispecific CAR constructs are being studied. The CD19/CD20 and CD19/CD22 bispecific CARs have shown a favorable efficacy and safety profile in phase I trials. However, larger phase II studies and longer follow-ups are needed to better assess their efficacy and safety in patients with relapsed/refractory B-cell malignancies.
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Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Antígenos CD19 , Humanos , Imunoterapia Adotiva/efeitos adversos , Receptores de Antígenos de Linfócitos T , Recidiva , Linfócitos TRESUMO
Venetoclax, a BCL-2 inhibitor, is highly effective for the treatment of patients with chronic lymphocytic leukemia (CLL) and dependence on alternative proteins may result in resistance to BCL-2 inhibition. Patients with CLL treated with venetoclax as monotherapy at MD Anderson Cancer Center between 05/2012 and 01/2016 were included and pretreatment bone marrow was analyzed by immunohistochemistry (IHC) for BCL-W, BCL-XL, BCL2-A1 and MCL-1. Twenty-seven patients were included. BCL-W + and BCL-2A1+ was found in 15% and 7% of the patients, respectively. Both BCL-XL and MCL-1 were negative in all samples. A higher CR and longer PFS rates were observed in patients with BCL-W+ (p = .60, p = .46), BCL-2A1+ (p = .60, p = .29), and either BCL-W + or BCL-2A1+ (p = .33, p = .20), though not statistically significant. Pretreatment IHC expression of BCL-2 alternative proteins does not predict response to venetoclax in CLL, but may be a surrogate for an indolent biology. Sensitive techniques are needed to explore anti-apoptotic pathways.
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Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , SulfonamidasRESUMO
Neutrophil recovery after autologous hematopoietic cell transplantation (auto-HCT) is affirmed with achievement of an Absolute Neutrophil Count (ANC) of ≥500/uL. There is growing evidence that neutrophils may be observed despite undetectable peripheral ANC counts following autologous hematopoietic cell transplant and are preferentially delivered to sites of inflammation. We report an interesting case that confirms neutrophil tissue delivery to the skin two days prior to evidence of blood engraftment after an auto-HCT.
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OBJECTIVE: To perform a systematic review and meta-analysis evaluating the prevalence of gastrointestinal (GI) symptoms and mortality in patients with coronavirus disease 2019 (COVID-19) diagnosed. METHODS: A systematic search of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus was performed from December 1, 2019 to May 7, 2020. Observational studies including adults with COVID-19 infection and reporting GI symptoms were included. The primary outcome was assessing the weighted pooled prevalence (WPP) of GI symptoms in patients with COVID-19 infection. Secondary outcomes were WPP of overall mortality, and mortality in patients with COVID-19 infection with GI symptoms. RESULTS: A total of 78 studies with 12,797 patients were included. Among GI symptoms (at onset of illness in 6, at admission in 17, data given separately for both in 3, and data unavailable in 52 studies), the WPP of diarrhea was 12.4% (95% CI, 8.2% to 17.1%), I2=94%; nausea and/or vomiting, 9.0% (95% CI, 5.5% to 12.9%), I2=93%; loss of appetite, 22.3% (95% CI, 11.2% to 34.6%, I2=94%; and abdominal pain, 6.2% (95% CI, 2.6% to 10.3%), I2=92%. Mortality among patients with GI symptoms (0.4%; 95% CI, 0% to 1.1%; I2=74%) was similar to overall mortality (2.1%; 95% CI, 0.2% to 4.7%; I2=94%), P=.15. Most studies had high risk of bias and overall quality of evidence was low to very low for all outcomes. CONCLUSION: Gastrointestinal symptoms are seen in up to 1 in 5 patients with COVID-19 infection. More high-quality evidence is needed to confirm these findings and explore factors causing mortality in these patients.