Clinical efficacy and tumour microenvironment influence of decitabine plus R-CHOP in patients with newly diagnosed diffuse large B-Cell lymphoma: Phase 1/2 and biomarker study.
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SUBMITTER: Zhang MC
PROVIDER: S-EPMC8684715 | biostudies-literature | 2021 Dec
REPOSITORIES: biostudies-literature
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Clinical efficacy and tumour microenvironment influence of decitabine plus R-CHOP in patients with newly diagnosed diffuse large B-Cell lymphoma: Phase 1/2 and biomarker study.
Zhang Mu-Chen MC Fang Ying Y Xu Peng-Peng PP Dong Lei L Shen Rong R Huang Yao-Hui YH Fu Di D Yan Zi-Xun ZX Cheng Shu S Jiang Xu-Feng XF Song Qi Q He Yang Y Zhao Yan Y Lu Min M Ye Jing J Liu Feng F Cheng Lin L Wang Chao-Fu CF Wang Li L Zhao Wei-Li WL
Clinical and translational medicine 20211201 12
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Project description:BackgroundAngioimmunoblastic T-cell lymphoma (AITL) is known for its unfavorable survival prognosis. Chidamide has shown efficacy in relapsed/refractory AITL, but its efficacy in newly diagnosed AITL is uncertain.ObjectiveThis retrospective research aimed to evaluate the effectiveness and safety of chidamide when used with doxorubicin, cyclophosphamide, prednisone, and vincristine (CHOP) in comparison to CHOP by itself for individuals newly diagnosed with AITL, and to examine the impact of transplantation.MethodThis was an analysis that compared outcomes among patients who received chidamide + CHOP on a clinical trial vs. historical controls who received CHOP alone, enrolling a total of sixty-six treatment-naive AITL patients between April 2014 and November 2022. Among them, thirty-three received chidamide in addition to CHOP (chidamide group), while thirty-three received CHOP alone (control group). The clinical characteristics were balanced between the two groups. All patients were scheduled to undergo up to six courses of treatment before transplantation.ResultsThe chidamide group had a significantly longer median overall survival (OS) compared to the control group, with a median OS that was not reached, as opposed to 20 months in the control group (p = 0.002). In the control group, the median progression-free survival (PFS) was 11 months, while in the chidamide group, it was 22 months (p = 0.080). In the high-risk group (IPI ≥ 3), the chidamide group demonstrated notably superior complete response (CR) and overall response rate (ORR) compared to the control cohort (p = 0.002, p = 0.034). The PFS and OS in the chidamide group were not reached, and there were significant differences compared to the control group (p = 0.007, p = 0.003). The median OS of the transplanted group was longer than the non-transplanted group (p = 0.004). On multivariate analysis, chidamide group reduced the hazards of death in the total cohort.ConclusionAs the study was non-random and retrospective, Chidamide combined with chemotherapy should be tested in randomized trials given its potential to improve prognosis in treatment-naive AITL patients. Furthermore, autologous hematopoietic stem cell transplantation (auto-HSCT) has demonstrated enhanced overall survival in individuals with AITL.Clinical trial registrationhttps://clinicaltrials.gov/, NCT03268889.
| S-EPMC11368836 | biostudies-literature
Project description:BackgroundElderly patients with diffuse large B-cell lymphoma (DLBCL) present with poor clinical outcome and intolerance to intensive chemotherapy. Histone deacetylase inhibitors (HDACIs) show anti-lymphoma activities and can be applied to treat DLBCL. This study aimed to evaluate efficacy and safety of oral HDACI tucidinostat (formerly known as chidamide) plus R-CHOP (CR-CHOP) in elderly patients with newly diagnosed DLBCL (International Prognostic Index ≥ 2).ResultsAmong 49 patients, the complete response rate was 86%, with overall response rate achieving 94%. The 2-year progression survival (PFS) and overall survival (OS) rates were 68% (95% CI 52-79) and 83% (95% CI 68-91). Comparing with historical control (NCT01852435), the 2-year PFS and OS rates of double-expressor lymphoma phenotype (DEL) were improved, and negative prognostic effect of histone acetyltransferases CREBBP/EP300 mutations was also mitigated by CR-CHOP. Grade 3-4 neutropenia was reported in 171, grade 3-4 thrombocytopenia in 27, and grade 3 anemia in 11 of 283 cycles. No grade 4 non-hematological adverse event was reported.ConclusionCR-CHOP is effective and safe in elderly patients with newly diagnosed DLBCL. Relevance of DEL phenotype and molecular biomarkers on CR-CHOP response warrants further investigation in DLBCL. Trial registration ClinicalTrial.gov, NCT02753647. Registered on April 28, 2016.
| S-EPMC7585299 | biostudies-literature
Project description:PurposeRituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone administered every 3 weeks (R-CHOP-21) is the standard care for diffuse large B-cell lymphoma (DLBCL). It is unknown whether the dose-dense R-CHOP (R-CHOP-14) could improve the outcome of the disease in Asian population.Materials and methodsNewly diagnosed DLBCL patients were centrally, randomly assigned (1:1) to receive R-CHOP- 14 or R-CHOP-21. R-CHOP-14 was administered every 2 weeks, and R-CHOP-21 was administered every 3 weeks. Primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS), progression-free survival (PFS), response rate and toxicities.ResultsSeven hundred and two patients were randomly assigned to receive R-CHOP-14 (n=349) or R-CHOP-21 (n=353). With a median follow-up of 45.6 months, the two groups did not differ significantly in 3-year DFS (79.6% for R-CHOP-14 vs. 83.2% for R-CHOP-21, p=0.311), 3-year OS (77.5% for R-CHOP-14 vs. 77.6% for R-CHOP-21, p=0.903), or 3-year PFS (63.2% for R-CHOP-14 vs. 66.1% for R-CHOP-21, p=0.447). Patients with an International Prognostic Index (IPI) score ≥ 2 had a poorer prognosis compared to those with an IPI score < 2. Grade 3/4 hematologic and non-hematologic toxicities were manageable and similar between R-CHOP-14 and R-CHOP-21.ConclusionR-CHOP-14 did not improve the outcome of DLBCL compared to R-CHOP-21 in Asian population. With manageable and similar toxicities, both of the two regimens were suitable for Asian DLBCL patients. For high-risk patients with IPI ≥ 2, new combination regimens based on R-CHOP deserve further investigation to improve efficacy.
| S-EPMC6639223 | biostudies-literature
Project description:S0515 was a phase 2 trial to determine whether the addition of bevacizumab to cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) plus rituximab (R-CHOP) would improve progression-free survival (PFS) without adding significant toxicity in patients with newly diagnosed advanced diffuse large B-cell lymphoma. A total of 73 patients were enrolled. For the 64 eligible patients, median age was 68 years, and 60% had International Prognostic Index scores more than or equal to 3. The observed 1- and 2-year PFS estimates were 77% and 69%, respectively. These PFS estimates were not statistically different from the expected PFS for this population if treated with R-CHOP alone. Grade 3 or higher toxicities were observed in 81% of patients, including 2 grade 5 events. The majority of serious toxicities were hematologic but also included 5 patients with gastrointestinal perforations, 4 patients with thrombotic events, and 11 patients who developed grade 2 or 3 left ventricular dysfunction. Higher baseline urine VEGF and plasma VCAM levels correlated with worse PFS and overall survival. In conclusion, the addition of bevacizumab to R-CHOP chemotherapy was not promising in terms of PFS and resulted in increased serious toxicities, especially cardiac and gastrointestinal perforations. This study is registered at www.clinicaltrials.gov as #NCT00121199.
| S-EPMC3418716 | biostudies-literature
Project description:Bortezomib is active in mantle cell lymphoma (MCL), with approval in upfront and relapsed settings. Given inevitable recurrence following induction chemoimmunotherapy, maintenance approaches are a rational strategy to improve clinical outcomes. We conducted a phase II study to evaluate the safety and efficacy of six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus bortezomib (1.3 mg/m2 days 1 and 4 of 21 d cycles) followed by bortezomib maintenance (1.3 mg/m2 days 1, 4, 8, and 11 every 3 months for 2 years). Sixty-five eligible patients were enrolled. The treatment was well tolerated and toxicities were mainly haematological. The rate of grade ?3 peripheral neuropathy was low (5%). With a median follow-up of 6.8 years, 2-year progression-free survival (PFS) was 62%, and 2-year overall survival (OS) was 85%. At 5 years, PFS was 28% and OS was 66%. MCL International Prognostic Index scores were significantly associated with 2-year PFS, but did not predict long-term (?5-year) PFS. Baseline Ki-67 index was significantly associated with survival. Combination R-CHOP with bortezomib followed by maintenance bortezomib appears to improve outcomes compared historically with R-CHOP alone, with prolonged remissions in a subset of patients. These results suggest that inclusion of bortezomib with induction chemotherapy and/or maintenance is promising in MCL and warrants further exploration.
| S-EPMC4710555 | biostudies-literature
Project description:BackgroundPeripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. We conducted an open-label, phase 2 nonrandomised, externally controlled study to evaluate the efficacy and safety of targeted agents plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) (CHOPX) for PTCL in the front-line setting.MethodsEligible patients were ≥18 years of age and newly diagnosed PTCL. Patients in the CHOPX group received standard CHOP at Cycle 1. Specific targeted agents were added from Cycle 2, decitabine if TP53 mut, azacytidine if TET2/KMT2D mut, tucidinostat if CREBBP/EP300 mut, and lenalidomide if without mutations above. Patients in the CHOP group received CHOP for 6 cycles. The primary endpoint was the complete response rate (CRR) at the end of treatment (EOT). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov, NCT04480099.FindingsBetween July 29, 2020, and Sep 22, 2022, 96 patients were enrolled and included for efficacy and safety analysis with 48 in each group. The study met its primary endpoint. CRR at EOT in the CHOPX group was superior to the CHOP group (64.6% vs. 33.3%, OR 0.27, 95%CI 0.12-0.64; p = 0.004). At a median follow-up of 24.3 months (IQR 12.0-26.7), improved median PFS was observed in the CHOPX group (25.5 vs. 9.0 months; HR 0.57, 95%CI 0.34-0.98; p = 0.041). The median OS was similar between two groups (not reached vs. 30.9 months; HR 0.55, 95%CI 0.28-1.10; p = 0.088). The most common grade 3-4 hematological and non-hematological adverse events in the CHOPX group were neutropenia (31, 65%) and infection (5, 10%).InterpretationTargeted agents combined with CHOP demonstrated effective and safe as first-line treatment in PTCL. Biomarker-driven therapeutic strategy is feasible and may lead to promising efficacy specifically toward molecular features in PTCL.FundingThis study was supported by the National Key Research and Development Program (2022YFC2502600) and the General Program of the Shanghai Municipal Health Commission (202040400).
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Project description:Lessons learnedThe combination of ofatumumab and bendamustine in elderly patients with diffuse large B-cell lymphoma demonstrated modest efficacy compared with standard of care.The poor response may have been due to patient age and the high rate of treatment discontinuation.BackgroundThis phase II trial evaluated the efficacy of bendamustine and ofatumumab in elderly patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who were not candidates for rituximab cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).MethodsPatients received IV 90 mg/m2 bendamustine on days 1 and 2 of cycles 1 through 6 and IV 1,000 mg ofatumumab on days 1 and 8 of cycle 1 and on day 1 of cycles 2 through 6. Both drugs were administered at the U.S. Food and Drug Administration-approved dose for combination therapy. All patients received premedications before each infusion of ofatumumab and hematopoietic growth factors. Treatment was administered in 21-day cycles, with restaging after cycle 3 and cycle 6. The primary endpoint was complete response rate (CRR).ResultsTwelve of 21 enrolled patients completed treatment; median age was 83 years. The most common reasons for treatment discontinuation were disease progression (three patients), intercurrent illness (two patients), and death (one patient due to drug-related sepsis and bowel necrosis and one patient due to unknown cause). Thrombocytopenia (14%), neutropenia (10%), diarrhea (10%), vomiting (10%), and dehydration (10%) were the most common grade ≥3 treatment-related adverse events. The overall response rate was 90.5% and the CRR was 33.3%. Median progression-free survival (PFS) and overall survival (OS) were 8.6 and 12.0 months, respectively.ConclusionThe combination of ofatumumab and bendamustine is feasible in elderly patients with DLBCL.
| S-EPMC6693706 | biostudies-literature
Project description:PurposePatients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) historically showed inferior survival with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Phase II studies demonstrated that adding the immunomodulatory agent lenalidomide to R-CHOP improved outcomes in ABC-type DLBCL. The goal of the global, phase III ROBUST study was to compare lenalidomide plus R-CHOP (R2-CHOP) with placebo/R-CHOP in previously untreated, ABC-type DLBCL.MethodsHistology and cell-of-origin type were prospectively analyzed by central pathology prior to random assignment and study treatment. Patients with ABC-DLBCL received lenalidomide oral 15 mg/d, days 1-14/21 plus standard R-CHOP21 versus placebo/R-CHOP21 for six cycles. The primary end point was progression-free survival (PFS) per independent central radiology review.ResultsA total of 570 patients with ABC-DLBCL (n = 285 per arm) were stratified by International Prognostic Index score, age, and bulky disease, and randomly assigned to R2-CHOP or placebo/R-CHOP. Baseline demographics were similar between arms. Most patients completed six cycles of treatment: 74% R2-CHOP and 84% placebo/R-CHOP. The most common grade 3/4 adverse events for R2-CHOP versus placebo/R-CHOP were neutropenia (60% v 48%), anemia (22% v 14%), thrombocytopenia (17% v 11%), and leukopenia (14% v 15%). The primary end point of PFS was not met, with a hazard ratio of 0.85 (95% CI, 0.63 to 1.14) and P = .29; median PFS has not been reached for either arm. PFS trends favoring R2-CHOP over placebo/R-CHOP were seen in patients with higher-risk disease.ConclusionROBUST is the first DLBCL phase III study to integrate biomarker-driven identification of eligible ABC patients. Although the ROBUST trial did not meet the primary end point of PFS in all patients, the safety profile of R2-CHOP was consistent with individual treatments with no new safety signals.
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Project description:Some patients with diffuse large B-cell lymphoma (DLBCL) present with a concurrent indolent lymphoma at diagnosis. Their outcomes in the rituximab era are not fully defined. Using a prospectively followed cohort of 1324 newly diagnosed DLBCL patients treated with immunochemotherapy, we defined the prevalence, characteristics, and outcome of DLBCL with concurrent indolent lymphoma. Compared with patients with DLBCL alone (n = 1153; 87.1%), patients with concurrent DLBCL and follicular lymphoma (FL) (n = 109; 8.2%) had fewer elevations in lactate dehydrogenase, lower International Prognostic Index (IPI), and predominantly germinal center B-cell-like (GCB) subtype, whereas patients with concurrent DLBCL and other indolent lymphomas (n = 62; 4.7%) had more stage III-IV disease and a trend toward higher IPI and non-GCB subtype. After adjusting for IPI, patients with concurrent DLBCL and FL had similar event-free survival (EFS) (hazard ratio [HR] = 0.95) and a trend of better overall survival (OS) (HR = 0.75) compared with patients with DLBCL alone, but nearly identical EFS (HR = 1.00) and OS (HR = 0.84) compared with patients with GCB DLBCL alone. Patients with concurrent DLBCL and other indolent lymphomas had similar EFS (HR = 1.19) and OS (HR = 1.09) compared with patients with DLBCL alone. In conclusion, DLBCL patients with concurrent FL predominantly had the GCB subtype with outcomes similar to that of GCB DLBCL patients. DLBCL patients with concurrent other indolent lymphoma had similar outcomes compared with patients with DLBCL alone. These patients should not be summarily excluded from DLBCL clinical trials.
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Project description:Treatment options for older patients with acute myeloid leukemia (AML) and for patients with relapsed/refractory AML are limited, and outcomes are poor. Decitabine, a hypomethylating agent, is active in patients with myelodysplastic syndrome (MDS) and AML, but its optimal dose and schedule are unknown. We report the efficacy and safety of repeated 10-day cycles of decitabine 20 mg/m(2) administered intravenously over 1 h in 52 newly diagnosed and 102 relapsed/refractory patients. Repeated 10-day cycles of decitabine produced a complete response (CR) in 40% of newly diagnosed older patients with AML, many of whom had adverse prognostic features. The median overall survival (OS) was 318 days but there was prolonged survival in responders of 481 days. Relapsed/refractory patients had a CR rate of 15.7% with a median OS of 177 days. Extramedullary toxicity was mild and the regimen was well tolerated for ongoing post-remission, outpatient maintenance cycles. Responses were durable for over 1 year.
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