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BACKGROUND: CD30 expression is universal in anaplastic large-cell lymphoma and is expressed in some other peripheral T-cell lymphoma subtypes. Incorporation of brentuximab vedotin into initial therapy for people with CD30-positive peripheral T-cell lymphomas prolonged progression-free survival, but there is room for improvement, especially for people with non-anaplastic large-cell lymphoma subtypes. METHODS: We conducted a multicentre, international, single-arm, phase 2 trial to evaluate the safety and activity of CHEP-BV (cyclophosphamide, doxorubicin, prednisone, brentuximab vedotin, and etoposide) followed by brentuximab vedotin consolidation in patients with CD30-expressing peripheral T-cell lymphomas across five academic centres in the USA and Canada. Adults aged 18 years or older with newly diagnosed, untreated CD30-positive peripheral T-cell lymphomas, Eastern Cooperative Oncology Group score of 0-2, and adequate organ function were eligible to receive six planned cycles of CHEP-BV (ie, 1·8 mg/kg brentuximab vedotin intravenously on day 1, cyclophosphamide 750 mg/m2 intravenously on day 1, doxorubicin 50 mg/m2 intravenously on day 1, etoposide 100 mg/m2 daily intravenously on days 1-3, and prednisone 100 mg daily orally on days 1-5) with prophylactic G-CSF. Patients who responded to the treatment could receive brentuximab vedotin consolidation for up to ten additional cycles either after autologous haematopoietic stem-cell transplantation (HSCT) or directly after CHEP-BV. The primary endpoints were unacceptable toxicity during a 3-plus-3 safety lead-in in participants who received study treatment and completed the safety evaluation period (to confirm the recommended phase 2 dose of brentuximab vedotin in CHEP-BV) and the complete response rate after CHEP-BV induction therapy in participants who received study treatment and had response evaluation. The study was registered at ClinicalTrials.gov (NCT03113500), and this cohort completed the trial. The trial is ongoing with the enrolment of a new cohort. FINDINGS: 54 patients were screened for eligibility and 48 were eligible for the study. The participants (18 [38%] women and 30 [63%] men; 34 [71%] White, four [8%] Black, five [10%] Asian, ten [21%] Hispanic, and 37 [77%] non-Hispanic people) were recruited and enrolled between Dec 4, 2017, and June 14, 2021, and followed up until Aug 25, 2023, when the database was locked for analysis. 48 participants were evaluable for toxicity, and 47 were evaluable for response (one participant died from COVID-19 before response assessment). During the safety lead-in, one of six participants had an unacceptable toxicity (ie, platelet count <10 000 per mm3 in a participant with extensive bone marrow involvement), and the proposed phase 2 dose of 1·8 mg/kg brentuximab vedotin in CHEP-BV was confirmed. At completion of CHEP-BV, 37 of 47 participants had complete response, yielding a complete response rate of 79% (95% CI 64-89). The most common CHEP-BV-related toxicities of grade 3 or higher were neutropenia (14 [29%] of 48), leukopenia (11 [23%]), anaemia (ten [21%]), febrile neutropenia (ten [21%]), lymphopenia (nine [19%]), and thrombocytopenia (nine [19%]). There were no treatment-related deaths. INTERPRETATION: In patients with mostly CD30-expressing peripheral T-cell lymphomas other than non-anaplastic large-cell lymphoma, CHEP-BV (with or without autologous HSCT) followed by brentuximab vedotin consolidation was safe and active. FUNDING: SeaGen, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and the National Cancer Institute of the National Institutes of Health.
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BACKGROUND: Despite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL). PATIENTS/METHODS: We retrospectively identified patients with HIV-cHL from the "Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)" database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4+ T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification. RESULTS: We identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4+ T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4+ cells/µL (P = .95). CONCLUSION: Our findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.
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Infecções por HIV , Doença de Hodgkin , Inibidores de Checkpoint Imunológico , Humanos , Masculino , Doença de Hodgkin/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Adulto , Estudos Retrospectivos , Estados Unidos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/complicações , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/farmacologia , Nivolumabe/uso terapêutico , Nivolumabe/efeitos adversos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Resultado do Tratamento , Anticorpos Monoclonais HumanizadosRESUMO
Tenalisib, a selective phosphoinositide-3-kinase δ/γ, and salt-inducible-kinase-3 inhibitor has shown efficacy and was well-tolerated in patients with T-cell lymphoma (TCL). In vitro studies suggest a synergistic anti-tumor potential for the combination of tenalisib with the histone-deacetylase inhibitor, romidepsin. This multicenter, open-label, phase I/II study was designed to characterize the safety, efficacy and pharmacokinetics of oral tenalisib twice-daily and intravenous romidepsin administered on days 1, 8 and 15 in 28-day cycles in adults with relapsed/refractory TCL. Phase I/dose escalation determined the maximum tolerated dose (MTD)/optimal doses of tenalisib and romidepsin. The phase II/dose expansion assessed the safety and anti-tumor activity of the combination at MTD/optimal dose. Overall, 33 patients were enrolled. In dose escalation, no dose-limiting toxicity was identified. Hence, the recommended doses for dose expansion were tenalisib 800 mg twice daily orally, and romidepsin 14 mg/m2 intravenous. Overall treatment-emergent adverse events of any grade reported in >15% of patients were nausea, thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, decreased appetite, neutropenia, vomiting, fatigue, anemia, dysgeusia, weight loss, diarrhea, and hypokalemia. Twenty-three patients (69.7%) had related grade ≥3 treatment-emergent adverse events. The overall objective response rate in evaluable patients was 63.0% (peripheral TCL: 75% and cutaneous TCL: 53.3%), with a complete response and partial response of 25.9% and 37.0% respectively. The median duration of response was 5.03 months. Co-administration of tenalisib and romidepsin did not significantly alter the pharmacokinetics of romidepsin. Overall, tenalisib and romidepsin combination demonstrated a favorable safety and efficacy profile supporting its further development for relapsed/refractory TCL (clinicaltrials gov. Identifier: NCT03770000).
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Linfoma de Células T Periférico , Linfoma de Células T , Neoplasias Cutâneas , Adulto , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Linfoma de Células T/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Resultado do TratamentoRESUMO
Mantle cell lymphoma (MCL) is a rare non-Hodgkin lymphoma that frequently becomes chemoresistant over time. The distinct mechanisms of ibrutinib and lenalidomide provided a judicious rationale to explore the combination with anti-CD20 immunotherapy. In this phase 1b study (NCT02446236), patients (n = 25) with relapsed/refractory MCL received rituximab with escalating doses of lenalidomide (days 1-21) and ibrutinib 560 mg (days 1-28) of 28-day cycles. The MTD for lenalidomide was 20 mg; most common grade ≥3 adverse events were skin rashes (32%) and neutropenic fever (24%). The best ORR was 88%, CR rate was 83%, and median duration of response (DOR) was 36.92 months (95% CI 33.77, 51.37). Responses were seen even in refractory patients or with high-risk features (e.g. blastoid variant, TP53 mutation, Ki-67 > 30%). R2I was safe and tolerable in patients with R/R MCL.
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Lenalidomida , Linfoma de Célula do Manto , Piperidinas , Rituximab , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/patologia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Resultado do Tratamento , Relação Dose-Resposta a Droga , RecidivaRESUMO
Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.
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Infecções por Vírus Epstein-Barr , Linfoma não Hodgkin , Linfoma de Células T , Linfoma , Trombocitopenia , Humanos , Adolescente , Adulto , Valganciclovir/uso terapêutico , Herpesvirus Humano 4 , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Recidiva Local de Neoplasia , Linfoma não Hodgkin/tratamento farmacológico , Linfoma/tratamento farmacológico , Trombocitopenia/patologiaRESUMO
BACKGROUND: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50â×â106 (dose level 1) or 100â×â106 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198. FINDINGS: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis). INTERPRETATION: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.
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Leucemia Linfocítica Crônica de Células B , Idoso , Feminino , Humanos , Masculino , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Indução de Remissão , Sulfonamidas/uso terapêuticoRESUMO
BACKGROUND: After autologous haematopoietic stem-cell transplantation (HSCT), consolidation with brentuximab vedotin in patients with high-risk relapsed or refractory classic Hodgkin lymphoma has been shown to improve progression-free survival compared with placebo. Brentuximab vedotin plus nivolumab is a safe and effective treatment for relapsed or refractory classic Hodgkin lymphoma; therefore, we aimed to evaluate the safety and activity of this drug combination post-autologous HSCT consolidation in patients with high-risk relapsed or refractory classic Hodgkin lymphoma. METHODS: We did a multicentre phase 2 trial at five centres in the USA. Eligible patients were aged 18 years or older with high-risk relapsed or refractory classic Hodgkin lymphoma, had an ECOG performance status of 0-2, and had adequate organ and bone marrow function. Enrolled patients received brentuximab vedotin (1·8 mg/kg) and nivolumab (3 mg/kg) intravenously starting 30-60 days after autologous HSCT on day 1 of each 21-day cycle for up to 8 cycles. Nivolumab dose reduction was not allowed. Brentuximab vedotin dose reduction to 1·2 mg/kg was permitted. If one drug was discontinued because of a toxic effect, the other could be continued. The primary endpoint was 18-month progression-free survival in all treated patients. This study is registered with ClinicalTrials.gov, number NCT03057795. FINDINGS: Between May 3, 2017, and July 13, 2019, 59 patients were enrolled and received the study therapy. Patients initiated brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT and received a median of 8 cycles (8-8). 34 (58%) of 59 patients were male, 29 (49%) completed 8 cycles of brentuximab vedotin plus nivolumab, and 45 (76%) completed 8 cycles of at least one drug. The median follow-up time was 29·9 months (IQR 24·6-34·8). The 18-month progression-free survival in all 59 patients was 94% (95% CI 84-98). The most common adverse events were sensory peripheral neuropathy (31 [53%] of 59) and neutropenia (25 [42%]), and immune-related adverse events requiring corticosteroids occurred in 17 (29%) of 59 patients. No treatment-related deaths were observed. INTERPRETATION: Brentuximab vedotin plus nivolumab was highly active post-autologous HSCT consolidation for patients with high-risk relapsed or refractory classic Hodgkin lymphoma, most of whom had previous exposure to either brentuximab vedotin or PD-1 blockade. Combination immunotherapy in this setting should be further studied in patients with classic Hodgkin lymphoma with further refinement of the regimen to mitigate toxic effects, particularly in high-risk patients in whom more intensive therapy to prevent relapse is warranted. FUNDING: Bristol Myers Squibb, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and National Cancer Institute of the National Institutes of Health.
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Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Imunoconjugados , Humanos , Adulto , Masculino , Feminino , Brentuximab Vedotin/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Nivolumabe/efeitos adversos , Imunoconjugados/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante AutólogoRESUMO
PURPOSE: Epcoritamab is a subcutaneously administered CD3xCD20 T-cell-engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20+ B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes. PATIENTS AND METHODS: In the dose-expansion cohort of a phase I/II study (ClinicalTrials.gov identifier: NCT03625037), adults with relapsed or refractory CD20+ large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee. RESULTS: As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20-83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell-associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event. CONCLUSION: Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.
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Antineoplásicos , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Adulto , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Antineoplásicos/uso terapêutico , Linfócitos T , Receptores de Antígenos Quiméricos/uso terapêuticoRESUMO
Allogeneic hematopoietic cell transplantation (alloHCT) can potentially salvage large B-cell lymphoma (LBCL) patients experiencing treatment failure after chimeric antigen receptor T-cell therapy (CAR T). Nonetheless, data on the efficacy and toxicities of alloHCT after receipt of CAR T are limited. We report a multicenter retrospective study assessing the safety, toxicities, and outcomes of alloHCT in LBCL patients following CAR T failure. Eighty-eight patients with relapsed, refractory LBCL received an alloHCT following anti-CD19 CAR T failure. The median number of lines of therapy between CAR T infusion and alloHCT was one (range, 0-7). Low intensity conditioning was used in 77% (n=68) and peripheral blood was the most common graft source (86%, n=76). The most common donor types were matched unrelated donor (39%), followed by haploidentical (30%) and matched related donor (26%). Median follow-up of survivors was 15 months (range, 1-72). One-year overall survival, progression-free survival, and graft-versus-host disease-free relapse-free survival were 59%, 45%, and 39% respectively. One-year non-relapse mortality and progression/relapse were 22% and 33% respectively. On multivariate analysis, <2 lines of intervening therapy between CAR T and alloHCT and complete response at time of alloHCT were associated with better outcomes. In conclusion, alloHCT after CAR T failure can provide durable remissions in a subset of patients.
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Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Humanos , Imunoterapia Adotiva/efeitos adversos , Estudos Retrospectivos , Recidiva Local de Neoplasia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/etiologia , Transplante Homólogo , Antígenos CD19RESUMO
Patients with hematologic malignancies have poor outcomes from COVID infection and are less likely to mount an antibody response after COVID infection. This is a retrospective study of adult lymphoma patients who received the COVID vaccine between 12/1/2020 and 11/30/2021. The primary endpoint was a positive anti-COVID spike protein antibody level following the primary COVID vaccination series. The primary vaccination series was defined as 2 doses of the COVID mRNA vaccines or 1 dose of the COVID adenovirus vaccine. Subgroups were compared using Fisher's exact test, and unadjusted and adjusted logistic regression models were used for univariate and multivariate analyses. A total of 243 patients were included in this study; 72 patients (30%) with indolent lymphomas; 56 patients (23%) with Burkitt's, diffuse large B-cell lymphoma (DLBCL), and primary mediastinal B-cell lymphoma (PMBL) combined; 55 patients (22%) with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL); 44 patients (18%) with Hodgkin and T-cell lymphomas (HL/TCL) combined; 12 patients (5%) with mantle cell lymphoma; and 4 patients (2%) with other lymphoma types. One-hundred fifty-eight patients (65%) developed anti-COVID spike protein antibodies after completing the primary COVID vaccination series. Thirty-eight of 46 (83%) patients who received an additional primary shot and had resultant levels produced anti-COVID spike protein antibodies. When compared to other lymphoma types, patients with CLL/SLL had a numerically lower seroconversion rate of 51% following the primary vaccination series whereas patients with HL/TCL appeared to have a robust antibody response with a seropositivity rate of 77% (p = 0.04). Lymphoma patients are capable of mounting a humoral response to the COVID vaccines. Further studies are required to confirm our findings, including whether T-cell immunity would be of clinical relevance in this patient population.
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Vacinas contra COVID-19 , COVID-19 , Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Linfoma de Células T , Adulto , Humanos , Anticorpos , Formação de Anticorpos , COVID-19/prevenção & controle , Vacinas contra COVID-19/imunologia , Estudos Retrospectivos , Glicoproteína da Espícula de Coronavírus/imunologiaRESUMO
Lymphoma patients are at greater risk of severe consequences from COVID-19 infection, yet most reports of COVID-19-associated outcomes were published before the advent of COVID-19 vaccinations and monoclonal antibodies (mAbs). In this retrospective study, we report the real-world outcomes of 68 lymphoma or CLL patients who developed COVID-19 infection during the omicron surge in the US. We found that 34% of patients were hospitalized as a result of COVID-19 infection. The death rate due to COVID-19 was 9% (6/68) in the overall population and 26% (6/23) in hospitalized patients. During the preintervention COVID-19 era, the mortality rate reported in cancer patients was 34%, which increased to 60.2% in hospitalized patients. Thus, the death rates in our study were much lower when compared to those in cancer patients earlier in the pandemic, and may be attributed to modern interventions. In our study, 60% (18/30) of patients with serology data available did not develop anti-COVID-19 spike protein antibodies following vaccination. Most patients (74%, 17/23) who were hospitalized due to COVID-19 infection did not receive COVID-19 mAb treatment. Our results pointed to the importance of humoral immunity and the protective effect of COVID-19 mAbs in improving outcomes in lymphoma patients.
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PURPOSE: Ibrutinib has transformed the management of chronic lymphocytic leukemia (CLL), though its use is limited by toxicity and resistance. In this study, we utilized an "add on" approach for patients who had been treated with ibrutinib in the front-line or relapsed/refractory settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period of treatment-free observation (TFO). PATIENTS AND METHODS: Patients were eligible if they received ibrutinib in any line of therapy for at least 6 months and had detectable MRD (flow cytometry, <1 cell in 10-4 cutoff for U-MRD). U2 was added to ibrutinib, and patients were monitored serially for MRD. Once U-MRD was achieved or a total of 24 cycles were administered, patients entered a period of TFO. The primary study objective was rate of U-MRD. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation. RESULTS: Twenty-eight patients were enrolled of whom 27 were evaluable for efficacy. Patients received ibrutinib for a median of 21 months (range 7-67) prior to study enrollment. Fourteen patients (52%) have achieved U-MRD per protocol whereas 78% had at least one U-MRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. Progression-free survival at 12 months was estimated at 95%. Grade ≥3 adverse events were hypertension 7%, diarrhea 4%, and increased ALT/AST 4%. CONCLUSIONS: This triplet approach utilizes the addition of U2 to ibrutinib as an MRD-driven time-limited therapy. This therapy was well tolerated and effective. TFO following this therapy appears durable in ongoing follow-up.
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Linfocítica Crônica de Células B , Adenina/análogos & derivados , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , PiperidinasRESUMO
INTRODUCTION: The utility of dose escalation after positive positron emission tomography following 2 cycles of ABVD (PET2) for Hodgkin Lymphoma (HL) remains controversial. We describe the United States real-world practice patterns for PET2 positive patients. PATIENTS AND METHODS: Data was collected from 15 sites on PET2 positive HL patients after receiving frontline treatment between January, 2015 and June, 2019. Descriptive analyses between those with therapy change and those continuing initial therapy were assessed. RESULTS: A total of 129 patients were identified; 111 (86%) were treated with ABVD therapy and 18 (14%) with an alternate regimen. At PET2 assessment, 74.4% (96/129) had Deauville score (DS) 4 and 25.6% (33/129) had DS 5. Of the 66 limited stage (LS) patients with PET2 DS score of 4/5, 77.3% (51/66) continued initial therapy and 22.7% (15/66) changed to escalated therapy. The 12-month progression-free survival (PFS) for DS 4/5 LS patients was 67.0% (95% CI; 54.9-81.7) for patients without escalation compared with 51.4% (95% CI; 30.8-85.8) for those who escalated. Of the 63 DS 4/5 patients with advanced stage (AS) disease, 76.2% (48/63) continued initial therapy and 23.8% (15/63) changed to escalated therapy. The 12-month PFS for DS 4/5 AS patients was 38.3% (95% CI: 26.3%-55.7%) for patients without escalation compared with 57.1% (95% CI: 36.3-89.9) for those with escalation. CONCLUSION: A minority of PET2 positive HL patients undergo therapy escalation and outcomes remain overall suboptimal. Improved prognostics markers and better therapeutics are required to improve outcomes for high-risk PET2 positive HL patients.
Assuntos
Doença de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/uso terapêutico , Dacarbazina/uso terapêutico , Doxorrubicina/uso terapêutico , Doença de Hodgkin/diagnóstico por imagem , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Tomografia por Emissão de Pósitrons/métodos , Vimblastina/uso terapêuticoRESUMO
Effective and tolerable treatments are needed for older patients with classical Hodgkin lymphoma. We report results for older patients with classical Hodgkin lymphoma treated in the large phase III ECHELON-1 study of frontline brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A+AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Modified progression-free survival per independent review facility for older versus younger patients (aged ≥60 vs. <60 years) was a pre-specified subgroup analysis; as the ECHELON- 1 study was not powered for these analyses, reported P-values are descriptive. Of 1,334 enrolled patients, 186 (14%) were aged ≥60 years (A+AVD: n=84, ABVD: n=102); results below refer to this age group. Modified progression-free survival per independent review facility was similar in the two arms at 24 months (A+AVD: 70.3% [95% confidence interval (CI): 58.4-79.4], ABVD: 71.4% [95% CI: 60.5-79.8], hazard ratio (HR)=1.00 [95% CI: 0.58-1.72], P=0.993). After a median follow-up of 60.9 months, 5-year progression-free survival per investigator was 67.1% with A+AVD versus 61.6% with ABVD (HR=0.820 [95% CI: 0.494-1.362], P=0.443). Comparing A+AVD versus ABVD, grade 3/4 peripheral neuropathy occurred in 18% versus 3%; any-grade febrile neutropenia in 37% versus 17%; and any-grade pulmonary toxicity in 2% versus 13%, respectively, with three (3%) pulmonary toxicity-related deaths in patients receiving ABVD (none in those receiving A+AVD). Altogether, A+AVD showed overall similar efficacy to ABVD with survival rates in both arms comparing favorably to those of prior series in older patients with advanced-stage classical Hodgkin lymphoma. Compared to ABVD, A+AVD was associated with higher rates of neuropathy and neutropenia, but lower rates of pulmonary-related toxicity. Trials registered at ClinicalTrials.gov identifiers: NCT01712490; EudraCT number: 2011-005450-60.
Assuntos
Doença de Hodgkin , Neutropenia , Doenças do Sistema Nervoso Periférico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/efeitos adversos , Dacarbazina/efeitos adversos , Doxorrubicina/efeitos adversos , Doença de Hodgkin/patologia , Humanos , Estadiamento de Neoplasias , Neutropenia/patologia , Doenças do Sistema Nervoso Periférico/patologia , Vimblastina/uso terapêuticoRESUMO
We performed a multicenter retrospective analysis across 10 US academic medical centers to evaluate treatment patterns and outcomes in patients age ≥60 years with classic Hodgkin lymphoma (cHL) from 2010-2018. Among 244 eligible patients, median age was 68, 63% had advanced stage (III/IV), 96% had Eastern Cooperative Oncology Group performance status (PS) 0-2, and 12% had documented loss of ≥1 activity of daily living (ADL). Medical comorbidities were assessed by the Cumulative Illness Rating Scale-Geriatric (CIRS-G), where n = 44 (18%) had total scores ≥10. Using multivariable Cox models, only ADL loss predicted shorter progression-free (PFS; hazard ratio [HR] 2.13, P = .007) and overall survival (OS; HR 2.52, P = .02). Most patients (n = 203, 83%) received conventional chemotherapy regimens, including doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; 56%), AVD (14%), and AVD with brentuximab vedotin (BV; 9%). Compared to alternative therapies, conventional regimens significantly improved PFS (HR 0.46, P = .0007) and OS (HR 0.31, P = .0003). Survival was similar following conventional chemotherapy in those ages 60-69 vs ≥70: PFS HR 0.88, P = .63; OS HR 0.73, P = .55. Early treatment discontinuation due to toxicity was more common with CIRS-G ≥10 (28% vs 12%, P = .016) or documented geriatric syndrome (28% vs 13%, P = .02). A competing risk analysis demonstrated improved disease-related survival with conventional therapy (HR 0.29, P = .02) and higher mortality from causes other than disease or treatment with high CIRS-G or geriatric syndromes. This study suggests conventional chemotherapy regimens remain a standard of care in fit older patients with cHL, and highlights the importance of geriatric assessments in defining fitness for cHL therapy going forward.
Assuntos
Doença de Hodgkin , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina , Dacarbazina/uso terapêutico , Doxorrubicina/uso terapêutico , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/tratamento farmacológico , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Vimblastina/uso terapêuticoRESUMO
Data addressing prognostication in patients with HIV related Burkitt lymphoma (HIV-BL) currently treated remain scarce. We present an international analysis of 249 (United States: 140; United Kingdom: 109) patients with HIV-BL treated from 2008 to 2019 aiming to identify prognostic factors and outcomes. With a median follow up of 4.5 years, the 3-year progression-free survival (PFS) and overall survival (OS) were 61% (95% confidence interval [CI] 55% to 67%) and 66% (95%CI 59% to 71%), respectively, with similar results in both countries. Patients with baseline central nervous system (CNS) involvement had shorter 3-year PFS (36%) compared to patients without CNS involvement (69%; P < .001) independent of frontline treatment. The incidence of CNS recurrence at 3 years across all treatments was 11% with a higher incidence observed after dose-adjusted infusional etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide (DA-EPOCH) (subdistribution hazard ratio: 2.52; P = .03 vs other regimens) without difference by CD4 count 100/mm3. In multivariate models, factors independently associated with inferior PFS were Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (hazard ratio [HR] 1.87; P = .007), baseline CNS involvement (HR 1.70; P = .023), lactate dehydrogenase >5 upper limit of normal (HR 2.09; P < .001); and >1 extranodal sites (HR 1.58; P = .043). The same variables were significant in multivariate models for OS. Adjusting for these prognostic factors, treatment with cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) was associated with longer PFS (adjusted HR [aHR] 0.45; P = .005) and OS (aHR 0.44; P = .007). Remarkably, HIV features no longer influence prognosis in contemporaneously treated HIV-BL.
Assuntos
Linfoma de Burkitt , Infecções por HIV , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/epidemiologia , Intervalo Livre de Doença , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Recidiva Local de Neoplasia , Rituximab , Reino Unido , Estados Unidos/epidemiologiaRESUMO
Autologous hematopoietic stem cell transplantation (ASCT) is a standard-of-care treatment for many hematologic malignancies. Progression of disease after ASCT is the primary cause of treatment failure. In this Phase Ib trial, we studied the safety and clinical effect of combined checkpoint inhibition therapy (CPIT) with ipilimumab and nivolumab as a consolidation strategy after ASCT for patients with high-risk diffuse large B cell lymphoma (DLBCL), mature T cell lymphoma (TCL), and multiple myeloma (MM). Starting at 14 to 28 days after ASCT, patients received ipilimumab (1 mg/kg i.v. on day 1 of weeks 1, 4, 7, 10, 16, and 22) and nivolumab (3 mg/kg i.v. on day 1 of weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, and 26). Patients received a median of 5 doses of ipilimumab and 8 doses of nivolumab. Thirty-five patients were included in the intent-to-treat population. Ninety-four percent of the patients experienced immune-related adverse events (irAEs) of any grade. Ninety-seven percent of irAEs resolved spontaneously or after holding study drugs and instituting high-dose corticosteroid therapy. Progression-free and overall survival at 18 months post-ASCT for each disease cohort were 85.7% and 100% for primary refractory DLBCL, 28.6% and 57.1% for relapsed DLBCL, not evaluable and 80% for frontline TCL, 25% and 75% for relapsed TCL, 57.1% and 87% for high-risk transplant-naïve MM, and 40% and 100% for MM relapsed within 3 years of first ASCT. We conclude that combined CPIT appears to be tolerable as a consolidation strategy after ASCT and in addition to the potential clinical efficacy observed in some subsets of disease, T cell receptor repertoire, T regulatory cell phenotype, and gut microbiota profiles provide a biologic rationale warranting further study of this approach.