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1.
Blood Adv ; 2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35015819

RESUMO

PD-1 blockade enhances the function of anti-tumor T-cells and antibody-dependent cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 follicular lymphoma (FL) patients with rituximab-sensitive disease who relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200mg IV every 3 weeks for up to 16 cycles and rituximab was given at 375mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AE) were liver enzyme abnormalities (3%), diarrhea (3%), nausea (3%), aseptic meningitis (3%) and pancreatitis (3%). Low-grade immune-related AEs were reported for 80% of patients, including diarrhea (43%), liver enzyme abnormalities (33%), thyroid dysfunction (27%), and rash (23%). Grade 3 or 4 immune related AEs occurred in 13% of patients. Treatment-related AEs led to discontinuation in 6 (20%) patients. Overall response rate (primary endpoint) was 67% and complete response rate was 50%. Median progression-free survival (PFS) was 12.6 months (95% CI, 8.2-27.6 months), the 3-year overall survival rate was 97%, and 23% of patients were in remission at a median follow up of 35 months. Presence of a high CD8+ T-effector score at baseline in the tumor was associated with induction of a complete response and improved PFS. In this single arm, phase 2 study, the combination of pembrolizumab and rituximab demonstrates favorable efficacy and safety profile in relapsed FL. This trial is registered at www.clinicaltrials.gov: NCT02446457.

2.
Blood Adv ; 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-35008100

RESUMO

Secondary central nervous system large B-cell lymphoma (SCNSL) is rare with a generally poor prognosis. There is limited data about the role of autologous stem cell transplantation (ASCT) in these high-risk patients. We explored in this study treatment outcomes and prognostic factors for patients with SCNSL who underwent ASCT. We included all consecutive patients who underwent ASCT at our institution. Primary endpoints were progression free survival (PFS) and overall survival (OS). One-hundred two patients were identified. Median age at transplant was 56 (range, 21-71) years. With a median follow-up of 56 (range, 1-256) months, the median PFS and OS were 40 and 88 months, respectively. The 4-year PFS and OS were 48% and 57%, respectively. In univariate analysis, complete remission (CR) at transplant, prior lines of therapy (≤2), normal LDH, and parenchymal involvement were significantly associated with improved PFS. For OS, only CR at transplant and ≤2 prior lines of therapy were associated with improved survival. On multivariable analysis for PFS, CR at transplant (HR 0.278, 95% CI: 0.153-0.506; p=<0.0001) and ≤ 2 prior lines of therapy (HR 0.485, 95% CI: 0.274-0.859; p=0.0131) were significantly associated with superior PFS. Similarly, CR at transplant (HR 0.352, 95% CI: 0.186-0.663; p=0.0013) and ≤ 2 prior lines of therapy (HR 0.476, 95% CI: 0.257-0.882; p=0.0183) were associated with improved survival. In the largest single center study, our findings indicate that ASCT is associated with durable responses and prolonged survival in patients with SCNSL. Patients in CR at transplant and those received less than two lines of therapy have particularly excellent outcomes.

3.
Nat Med ; 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34921238

RESUMO

Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor-T cell therapy with clinically meaningful outcomes demonstrated in patients with relapsed/refractory (r/r) B-cell lymphoma. In a previous pilot study of tisagenlecleucel in r/r follicular lymphoma (FL), 71% of patients achieved a complete response (CR). Here we report the primary, prespecified interim analysis of the ELARA phase 2 multinational trial of tisagenlecleucel in adults with r/r FL after two or more treatment lines or who relapsed after autologous stem cell transplant (no. NCT03568461). The primary endpoint was CR rate (CRR). Secondary endpoints included overall response rate (ORR), duration of response, progression-free survival, overall survival, pharmacokinetics and safety. As of 29 March 2021, 97/98 enrolled patients received tisagenlecleucel (median follow-up, 16.59 months; interquartile range, 13.8-20.21). The primary endpoint was met. In the efficacy set (n = 94), CRR was 69.1% (95% confidence interval, 58.8-78.3) and ORR 86.2% (95% confidence interval, 77.5-92.4). Within 8 weeks of infusion, rates of cytokine release syndrome were 48.5% (grade ≥3, 0%), neurological events 37.1% (grade ≥3, 3%) and immune effector cell-associated neurotoxicity syndrome (ICANS) 4.1% (grade ≥3, 1%) in the safety set (n = 97), with no treatment-related deaths. Tisagenlecleucel is safe and effective in extensively pretreated r/r FL, including in high-risk patients.

4.
Cancer Med ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34791836

RESUMO

BACKGROUND: The single-arm DAWN trial (NCT01779791) of ibrutinib monotherapy in patients with relapsed/refractory follicular lymphoma (FL) showed an overall response rate (ORR) of 20.9% and a median response duration of 19.4 months. This biomarker analysis of the DAWN dataset sought to determine genetic classifiers for prediction of response to ibrutinib treatment. METHODS: Whole exome sequencing was performed on baseline tumor samples. Potential germline variants were excluded; a custom set of 1216 cancer-related genes was examined. Responder- versus nonresponder-associated variants were identified using Fisher's exact test. Classifiers with increasing numbers of genes were created using a greedy algorithm that repeatedly selected genes, adding the most nonresponders to the existing "predicted nonresponders" set and were evaluated with 10-fold cross-validation. RESULTS: Exome data were generated from 88 patient samples and 13,554 somatic mutation variants were inferred. Response data were available for 83 patients (17 responders, 66 nonresponders). Each sample showed 100 to >500 mutated genes, with greater variance across nonresponders. The overall variant pattern was consistent with previous FL studies; 75 genes had mutations in >10% of patients, including genes previously reported as associated with FL. Univariate analysis yielded responder-associated genes FANCA, HISTH1B, ANXA6, BTG1, and PARP10, highlighting the importance of functions outside of B-cell receptor signaling, including epigenetic processes, DNA damage repair, cell cycle/proliferation, and cell motility/invasiveness. While nonresponder-associated genes included well-known TP53 and CARD11, genetic classifiers developed using nonresponder-associated genes included ATP6AP1, EP400, ARID1A, SOCS1, and TBL1XR1, suggesting resistance to ibrutinib may be related to broad biological functions connected to epigenetic modification, telomere maintenance, and cancer-associated signaling pathways (mTOR, JAK/STAT, NF-κB). CONCLUSION: The results from univariate and genetic classifier analyses provide insights into genes associated with response or resistance to ibrutinib in FL and identify a classifier developed using nonresponder-associated genes, which warrants further investigation. TRIAL REGISTRATION: NCT01779791.

5.
J Clin Oncol ; : JCO2101797, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34797699

RESUMO

PURPOSE: Most patients with mantle cell lymphoma (MCL) are older. In this study, we investigated the efficacy and safety of a chemotherapy-free combination with ibrutinib and rituximab (IR) in previously untreated older patients with MCL (age ≥ 65 years). METHODS: We enrolled 50 patients with MCL in this single-institution, single-arm, phase II clinical trial (NCT01880567). Patients with Ki-67% ≥ 50% and blastoid morphology were excluded. Ibrutinib was administered with rituximab up to 2 years with continuation of ibrutinib alone. The primary objective was to assess the overall response rate and safety of IR. In evaluable samples, whole-exome sequencing and bulk RNA sequencing from baseline tissue samples were performed. RESULTS: The median age was 71 years (interquartile range 69-76 years). Sixteen percent of patients had high-risk simplified MCL international prognostic index. The Ki-67% was low (< 30%) in 38 (76%) and moderately high (≥ 30%-50%) in 12 (24%) patients. The best overall response rate was 96% (71% complete response). After a median follow-up of 45 months (interquartile range 24-56 months), 28 (56%) patients came off study for various reasons (including four progression, 21 toxicities, and three miscellaneous reasons). The median progression-free survival and overall survival were not reached, and 3-year survival was 87% and 94%, respectively. None of the patients died on study therapy. Notably, 11 (22%) patients had grade 3 atrial fibrillation. Grade 3-4 myelosuppression was seen in < 5% of patients. Differential overexpression of CCND1, BIRC3, BANK1, SETBP1, AXIN2, and IL2RA was noted in partial responders compared with patients with complete response. CONCLUSION: IR combination is effective in older patients with MCL. Baseline evaluation for cardiovascular risks is highly recommended. Randomized trial is needed for definitive conclusions.

6.
Leuk Lymphoma ; : 1-11, 2021 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-34365878

RESUMO

PI3-kinase p110δ is mainly expressed in lymphocytes and is an attractive therapeutic target in B cell lymphomas. Targeting p110ß may further suppress tumor growth and overcome escape mechanisms. KA2237 is an oral, potent, dual p110ß/p110δ inhibitor. In preclinical studies, KA2237 inhibited p110ß- and p110δ-dependent AKT activation and suppressed proliferation of diverse hematological and epithelial tumors. Twenty-one patients received KA2237 in a first-in-human phase I study (NCT02679196; diffuse large B cell, n = 8; follicular, n = 5; mantle cell, n = 3; chronic lymphocytic leukemia/small lymphocytic lymphoma, n = 3; marginal zone, n = 1; Waldenstrom's, n = 1). Median age 69; median prior therapies 3. Eighty-six percent of patients experienced treatment-related adverse events (TRAEs). Forty-three percent of patients experienced grade ≥3 TRAEs, with rash (n = 3), pneumonia (n = 3), transaminitis (n = 2), and pneumonitis (n = 2) being most common. Thirty-three percent discontinued treatment due to adverse events. KA2237 induced objective responses in indolent and aggressive lymphoma (overall response rate 37%; complete response n = 4, partial response n = 3).

7.
Clin Cancer Res ; 27(22): 6124-6134, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34433649

RESUMO

PURPOSE: Tafasitamab, an Fc-modified, humanized, anti-CD19 monoclonal antibody, in combination with lenalidomide, demonstrated efficacy in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), in the single-arm, phase II L-MIND study (NCT02399085). RE-MIND, a retrospective observational study, generated a historic control for L-MIND to delineate the contribution of tafasitamab to the efficacy of the combination. PATIENTS AND METHODS: Data were retrospectively collected from patients with R/R DLBCL treated with lenalidomide monotherapy for comparison with tafasitamab + lenalidomide-treated patients (L-MIND). Key eligibility criteria were aligned with L-MIND. Estimated propensity score-based Nearest Neighbor 1:1 Matching methodology balanced the cohorts for nine prespecified prognostic baseline covariates. The primary endpoint was investigator-assessed best overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). RESULTS: Data from 490 patients going through lenalidomide monotherapy were collected; 140 qualified for matching with the L-MIND cohort. The primary analysis included 76 patients from each cohort who received a lenalidomide starting dose of 25 mg/day. Cohort baseline covariates were comparable. A significantly better ORR of 67.1% (95% confidence interval, 55.4-77.5) was observed for the combination therapy versus 34.2% (23.7-46.0) for lenalidomide monotherapy [odds ratio, 3.89 (1.90-8.14); P < 0.0001]. Higher CR rates were achieved with combination therapy compared with lenalidomide monotherapy [39.5% (28.4-51.4) vs. 13.2% (6.5-22.9)]. Survival endpoints favored combination therapy. Lenalidomide monotherapy outcomes were similar to previously published data. CONCLUSIONS: RE-MIND enabled the estimation of the additional treatment effect achieved by combining tafasitamab with lenalidomide in patients with R/R DLBCL.

8.
JAMA Oncol ; 7(8): 1213-1219, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34110383

RESUMO

Importance: Oral targeted therapies have advanced the treatment of chronic lymphocytic leukemia (CLL). These therapies include Bruton tyrosine kinase inhibitors, used as monotherapy, and the Bcl-2 inhibitor venetoclax, typically combined with the CD20 monoclonal antibody. Preclinical studies have shown synergy between Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax. Objective: To examine the rate of complete remission, complete remission with incomplete count recovery, and bone marrow-undetectable measurable residual disease (U-MRD) after treatment with the combination of ibrutinib and venetoclax. Design, Setting, and Participants: A single-center, phase 2 nonrandomized trial enrolled patients from August 17, 2016, to June 5, 2018. Participants included previously untreated patients with CLL who met International Workshop on CLL 2008 criteria for treatment indication. Patients were required to have at least 1 of the following features: del(17p), TP53-mutated CLL, del(11q), unmutated immunoglobulin heavy-chain variable gene, or age 65 years or older. Interventions: Therapy consisted of ibrutinib, 420 mg/d, monotherapy for 3 cycles, thereafter combined with venetoclax (standard weekly dose ramp-up to 400 mg/d) for a total of 24 cycles of combination treatment. Responses were assessed at serial points according to International Workshop on CLL 2008 criteria. Measurable residual disease (MRD) was assessed by multicolor flow cytometry with a sensitivity of 10-4. Main Outcomes and Measures: Outcomes included complete remission, complete remission with incomplete count recovery, and bone marrow U-MRD rate. Results: Eighty patients (57 [71%] men) were treated; median age was 65 years (range, 26-83 years). The median follow-up for all 80 patients was 38.5 months (range, 5.6-51.1 months). Five patients discontinued the study during the ibrutinib monotherapy phase; the remaining 75 patients received combination therapy. On an intent-to-treat analysis of combined treatment, 45 (56%) patients achieved bone marrow U-MRD remission at 12 cycles and 53 (66%) patients achieved bone marrow U-MRD remission at 24 cycles. Overall, 60 (75%) patients achieved bone marrow U-MRD remission as their best response. Responses were seen across all high-risk subgroups, independent of the immunoglobulin heavy-chain variable gene mutation status, fluorescence in situ hybridization category, or TP53 mutation. The 3-year progression-free survival was 93%, and 3-year overall survival was 96%. No patient had CLL progression; 2 patients developed Richter transformation. Conclusions and Relevance: The findings of this study suggest that combination therapy with ibrutinib and venetoclax might be beneficial for previously untreated patients with CLL. Remissions appeared to be durable during a follow-up of more than 3 years, with activity seen across high-risk disease subgroups, including those with del(17p)/TP53-mutated CLL. Trial Registration: ClinicalTrials.gov Identifier: NCT02756897.

9.
Leuk Lymphoma ; 62(10): 2400-2407, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33942701

RESUMO

This study aimed to assess the prognostic value of baseline disease distribution for patients with the secondary central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy and radiation (RT). 44 patients with secondary CNS DLBCL were reviewed. Twenty patients had leptomeningeal disease (LMD), and 24 had localized/targetable disease (LTD). Of 8 patients who received stem cell transplantation (SCT) after RT, 6 had LTD with a complete or partial response after RT. Median time to CNS relapse after RT was 10.1 months; 3/24 patients with LTD and 5/15 with LMD had CNS relapse. The median overall survival (OS) was 8 and 20 months for patients with LMD and LTD, respectively (p = 0.20). On multivariable analysis, LTD, receipt of SCT, and response after RT were associated with better OS and CNS-disease-free survival. Patients with localized secondary CNS DLBCL may benefit from RT serving as a bridge to SCT.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/terapia , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/terapia , Recidiva Local de Neoplasia , Prognóstico , Estudos Retrospectivos
11.
Cancer Cell ; 39(6): 845-865.e7, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34019806

RESUMO

The clinical use of molecular targeted therapy is rapidly evolving but has primarily focused on genomic alterations. Transcriptomic analysis offers an opportunity to dissect the complexity of tumors, including the tumor microenvironment (TME), a crucial mediator of cancer progression and therapeutic outcome. TME classification by transcriptomic analysis of >10,000 cancer patients identifies four distinct TME subtypes conserved across 20 different cancers. The TME subtypes correlate with patient response to immunotherapy in multiple cancers, with patients possessing immune-favorable TME subtypes benefiting the most from immunotherapy. Thus, the TME subtypes act as a generalized immunotherapy biomarker across many cancer types due to the inclusion of malignant and microenvironment components. A visual tool integrating transcriptomic and genomic data provides a global tumor portrait, describing the tumor framework, mutational load, immune composition, anti-tumor immunity, and immunosuppressive escape mechanisms. Integrative analyses plus visualization may aid in biomarker discovery and the personalization of therapeutic regimens.

12.
Haematologica ; 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33792219

RESUMO

B-cell non-Hodgkin's lymphoma (B-NHL) encompasses multiple clinically and phenotypically distinct subtypes of malignancy with unique molecular etiologies. Common subtypes of B-NHL such as diffuse large B-cell lymphoma (DLBCL) have been comprehensively interrogated at the genomic level. But rarer subtypes such as mantle cell lymphoma (MCL) remain sparsely characterized. Furthermore, multiple B-NHL subtypes have thus far not been comprehensively compared using the same methodology to identify conserved or subtype-specific patterns of genomic alterations. Here, we employed a large targeted hybrid-capture sequencing approach encompassing 380 genes to interrogate the genomic landscapes of 685 B-NHL tumors at high depth; including DLBCL, MCL, follicular lymphoma (FL), and Burkitt lymphoma (BL). We identified conserved hallmarks of B-NHL that were deregulated in the majority of tumor from each subtype, including the frequent genetic deregulation of the ubiquitin proteasome system (UPS). In addition, we identified subtype-specific patterns of genetic alterations, including clusters of co-occurring mutations and DNA copy number alterations. The cumulative burden of mutations within a single cluster were more discriminatory of B-NHL subtypes than individual mutations, implicating likely patterns of genetic cooperation that contribute to disease etiology. We therefore provide the first cross-sectional analysis of mutations and DNA copy number alterations across major B-NHL subtypes and a framework of co-occurring genetic alterations that deregulate genetic hallmarks and likely cooperate in lymphomagenesis.

14.
J Clin Oncol ; 39(15): 1609-1618, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-33683917

RESUMO

PURPOSE: Phosphatidylinositol-3-kinase (PI3K) inhibitors have shown activity in relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). PI3K inhibitors have been hampered by poor long-term tolerability and toxicity, which interfere with continuous use. Umbralisib, a dual inhibitor of PI3Kδ/casein kinase-1ε, exhibits improved selectivity for PI3Kδ compared with other PI3K inhibitors. This phase IIb trial was designed to evaluate the efficacy and safety of umbralisib in patients with R/R iNHL. PATIENTS AND METHODS: In this multicohort, open-label, phase IIb study, 208 patients with R/R marginal zone, follicular, or small lymphocytic lymphoma (MZL, FL, or SLL) unresponsive to prior treatments (≥ 1 MZL; ≥ 2 FL/SLL), including ≥ 1 anti-CD20-based therapy, were administered umbralisib 800 mg orally once daily until disease progression, unacceptable toxicity, or study withdrawal. Primary end point is overall response rate; secondary end points include time to response, duration of response, progression-free survival, and safety. RESULTS: The median follow-up is 27.7 months (efficacy) and 21.4 months (safety). The overall response rate was 47.1%, and tumor reduction occurred in 86.4% of patients. The median time to response was 2.7-4.6 months. The median duration of response was not reached for MZL, 11.1 months for FL, and 18.3 months for SLL. Median progression-free survival was not reached for MZL, 10.6 months for FL, and 20.9 months for SLL. At least one grade ≥ 3 treatment-emergent adverse event (TEAE) was reported in 53.4% of patients. TEAEs led to umbralisib discontinuation in 32 patients (15.4%). A total of 31 patients (14.9%) discontinued because of a treatment-related adverse event. Grade ≥ 3 TEAEs reported in ≥ 10% of patients: neutropenia (11.5%) and diarrhea (10.1%). Increased ALT/AST (grade ≥ 3) occurred in 6.7%/7.2% of patients. CONCLUSION: Umbralisib achieved meaningful clinical activity in heavily pretreated patients with iNHL. The safety profile was manageable, with a relatively low incidence of immune-mediated toxicities and adverse event-related discontinuations.


Assuntos
Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Linfoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Feminino , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Masculino
15.
Cancer Discov ; 11(6): 1468-1489, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33541860

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constraints of lymphoma growth, supporting the rationale for implementing DNA hypomethylating agents in selected patients with DLBCL. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in preclinical models. This novel classification provides a road map for the biological characterization and therapeutic exploitation of the DLBCL microenvironment. SIGNIFICANCE: In a translational relevant transcriptomic-based classification, we characterized the microenvironment as a critical component of the B-cell lymphoma biology and associated it with the DLBCL clinical behavior establishing a novel opportunity for targeting therapies.This article is highlighted in the In This Issue feature, p. 1307.

16.
Haematologica ; 106(10): 2667-2672, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32732355

RESUMO

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 may be associated with long-term adverse effects such as cytopenia and immune deficiency. In order to characterize these late events, we analyzed 31 patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel at our institution on two clinical trials, ZUMA-1 (clinicaltrials gov. Identifier: NCT02348216) and ZUMA-9 (clinicaltrials gov. Identifier: NCT03153462). Complete blood counts, lymphocyte subsets, and immunoglobulin levels were measured serially until month 24 or progression. Fifteen (48%) patients had grade 3-4 cytopenia, including anemia (five, 16%), neutropenia (nine, 29%), or thrombocytopenia (13, 42%) at day 30. Cytopenia at day 30 was not significantly associated with later diagnosis of myelodysplasia. Among patients with ongoing remission, grade 3-4 cytopenia was observed in one of nine (11%) at 2 years. While peripheral CD8+ T cells recovered early, CD4+ T-cell recovery was delayed with a count of <200/mL in three of nine (33%) patients at 1 year and two of seven (29%) at 2 years. Immunoglobulin G levels normalized in five of nine (56%) patients at 2 years. Thirteen (42%) patients developed grade 3-4 infectious complications, including herpes zoster and Pneumocystis jiroveci pneumonia. These results suggest the need for prolonged monitoring and prophylaxis against opportunistic infections in these patients, to improve the longterm safety of axicabtagene ciloleucel therapy.


Assuntos
Reconstituição Imune , Linfoma Difuso de Grandes Células B , Neutropenia , Antígenos CD19 , Produtos Biológicos , Humanos , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/tratamento farmacológico
17.
Leuk Lymphoma ; 62(1): 58-67, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32924687

RESUMO

R-FND (rituximab, fludarabine, mitoxantrone, and dexamethasone) can induce molecular remissions in indolent lymphoma. The addition of 90yttrium ibritumomab tiuxetan (90YIT) radioimmunotherapy following first-line induction treatment in patients with advanced follicular lymphoma (FL) may improve remission rates. We now report 10-year follow-up results from our sequential treatment approach with an abbreviated regimen of R-FND followed by 90YIT consolidation and rituximab maintenance. Forty-nine patients were enrolled; 47 received treatment. Patients had high-risk (FLIPI score ≥3) FL of grade 1-3A and stage III/IV with adequate hematologic function. Following R-FND, the complete and partial response rates were 91% and 8.5%, respectively. After 90YIT consolidation, the CR rate increased to 97%. The 10-year PFS rate was 49%. The most common non-hematologic, grade 3 or 4 adverse events were fatigue, dyspnea, and myalgia. Five developed myelodysplastic syndrome (MDS). This treatment approach is most appropriate in FLIPI-based high-risk patients whose outlook with standard therapy is inadequate.


Assuntos
Linfoma Folicular , Radioimunoterapia , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/terapia , Rituximab/uso terapêutico , Resultado do Tratamento , Radioisótopos de Ítrio/uso terapêutico
19.
Int J Radiat Oncol Biol Phys ; 109(5): 1414-1420, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33309978

RESUMO

PURPOSE: We report the long-term results of a prospective trial conducted to determine the efficacy and safety of radiation therapy (RT) alone in treating localized mucosa-associated lymphoid tissue (MALT) lymphoma. METHODS AND MATERIALS: Patients with localized MALT lymphoma were eligible and treated with involved field RT to doses of 24 to 39.6 Gy. Relapse-free survival (RFS) was the primary endpoint. Kaplan-Meier analysis was used to estimate RFS, progression-free survival (PFS), and overall survival (OS) defined from time of study entry. Preplanned subgroup analyses were performed based on site of involvement. RESULTS: From 2000 to 2012, 75 patients were accrued; 73 received protocol-specified RT. Median follow-up was 9.8 years. Thirty-four patients had gastric MALT, 17 orbital, 13 head and neck nonorbit, 4 skin, and 5 disease of other sites. Thirteen of 34 patients with gastric MALT were Helicobacter pylori positive at the time of initial diagnosis and underwent 1 to 3 courses of triple antibiotic therapy. All gastric MALT patients had documented persistent MALT without H. pylori on endoscopy before enrollment in the study. All patients achieved a complete response with a median time of 3 months. Eleven patients (15%) had disease relapse, 9 of which were at sites outside the RT field with median time to progression of 38.3 months. Median PFS was 17.5 years, and median RFS and OS were not reached. The 10-year relapse-free rate was 83% (95% confidence interval [CI], 74%-93%). The 10-year PFS rate was 71% (95% CI, 60%-84%). The 10-year OS rate was 86% (95% CI, 77%-96%). RFS, PFS, and OS did not differ by disease site (P = .17, .43, and .50, respectively). All relapses were successfully salvaged. One patient developed metastatic gastric adenocarcinoma and was found to also have recurrent MALT on biopsy. Otherwise, all relapsed patients were alive without evidence of disease at last follow-up, and no patient died of MALT lymphoma. Sixty-seven patients (92%) experienced acute toxicity during radiation, all of which were grade 1 and 2, with only 1 grade 3 toxicity. Twenty-two patients (30%) experienced late toxicity, with only 1 grade 3 toxicity. CONCLUSIONS: This prospective study confirms that RT for MALT lymphoma provides excellent long-term RFS with acceptable rates of toxicity. Current efforts are focused on RT de-escalation in an effort to further avoid treatment-related morbidity. CLINICALTRIALS.GOV: NCT04465162.


Assuntos
Linfoma de Zona Marginal Tipo Células B/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Humanos , Estimativa de Kaplan-Meier , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Orbitárias/patologia , Neoplasias Orbitárias/radioterapia , Intervalo Livre de Progressão , Estudos Prospectivos , Lesões por Radiação/patologia , Dosagem Radioterapêutica , Recidiva , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/radioterapia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/radioterapia , Fatores de Tempo , Resultado do Tratamento
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