PB1887: NETWORK META-ANALYSIS OF PROGRESSION FREE SURVIVAL IN THE TREATMENT OF RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA
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SUBMITTER: Chanan-Khan A
PROVIDER: S-EPMC9429715 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Project description:The recent development of new antileukemic therapies (anti-CD20 monoclonal antibodies, Bruton tyrosine kinase inhbitors, phosphoinositide 3-kinase inhibitors, and B-cell lymyphoma-2 antagonists) improved the progression-free survival (PFS) compared with selected standard regimens in clinical trials for patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Unfortunately, the relative efficacy of all possible therapeutic options remains unknown because there is no direct evidence for all possible comparisons. We aimed to compare the efficacy and safety of novel agents, chemotherapy, and immunotherapy using a Bayesian network meta-analysis (NMA). Systematic literature review with Bayesian NMA. An extensive systematic literature review of randomized clinical trials for relapsed/refractory CLL was performed. We searched for articles indexed in medical databases (MEDLINE, Embase, The Cochrane Library) and gray literature that could be further implemented into the Bayesian NMA. The systematic search identified 15 randomized trials that formed networks comparing PFS, overall survival (OS), overall response rates, and serious adverse events. Our study showed that all regimens containing novel agents significantly prolonged PFS compared with standard chemoimmunotherapy and immunotherapy. Among targeted drugs, venetoclax (VEN) + rituximab (RTX) had comparable efficacy in terms of PFS to zanubrutinib (ZAN) [hazard ratio (95% credible interval), 1.10 (0.59-2.08)], acalabrutinib (ACA) [0.78 (0.47-1.30)], ibrutinib (IBR) monotherapy [0.72 (0.41-1.27)], and other IBR-based regimens. ZAN was superior to IBR monotherapy [0.65 (0.49-0.86)] but not to ACA [0.71 (0.49-1.02)]. There were no significant differences in OS in any of the above comparisons. All novel therapies have better efficacy than chemoimmunotherapy and immunotherapy regimens. Among novel agents, the relative efficacy of VEN + RTX was similar to all BTKi, while ZAN was superior to IBR and comparable to ACA. PROSPERO CRD42022304330.
| S-EPMC11292688 | biostudies-literature
Project description:Purpose of reviewThere have been significant advances in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL) over the past two decades. However, the intention of treatment remains control of the disease and delay of progression rather than a cure which remains largely elusive. Considering that CLL is mostly seen in older patients, there are multiple factors that play a role in the selection of CLL beyond the frontline treatment. Here, we review the concept of relapsed CLL, factors that predispose to relapse, and therapeutic options available to this patient population. We also review investigational therapies and provide a framework for selection of therapies in this setting.Recent findingsTargeted therapies with continuous BTK inhibitors (BTKi) or fixed duration venetoclax plus anti-CD20 monoclonal antibody therapy have established superiority over chemoimmunotherapy in relapsed CLL and have become the preferred standard of care treatment. The second-generation more selective BTK inhibitors (acalabrutinib and zanubrutinib) have shown improved safety profile compared to ibrutinib. However, resistance to the covalent BTK inhibitors may emerge and is commonly associated with mutations in BTK or other downstream enzymes. The novel non-covalent BTK inhibitors such as pirtobrutinib (Loxo-305) and nemtabrutinib (ARQ 531) are showing promising activities for relapsed CLL refractory to prior covalent BTKi. Other novel therapies such as chimeric antigen receptor (CAR) T cell therapy have also shown significant activities for relapsed and refractory CLL. Measurable residual disease (MRD) assessment has a growing importance in venetoclax-based limited-duration therapy and there is mounting evidence that MRD negativity improves outcomes. However, it remains to be seen if this will become an established clinically significant endpoint. Further, the optimal sequence of various treatment options remains to be determined. Patients with relapsed CLL now have more options for the treatment of the disease. The choice of therapy is best individualized especially in the absence of direct comparisons of targeted therapies, and the coming years will bring more data on the best sequence of use of the therapeutic agents.
| S-EPMC10242240 | biostudies-literature
Project description:IntroductionThe treatment of relapsed/refractory (RR) CLL has been revolutionized by the advent of the new oral inhibitors of B-cell receptor (BCR) signaling and the pro-survival protein, B-cell lymphoma 2 (BCL2). Additionally, new and more potent monoclonal antibodies against CD20 have replaced/may replace rituximab in many settings. Areas covered: Herein, we review the entire therapeutic landscape of RR CLL, with particular attention to the new small-molecule kinase inhibitors and BH3-mimetics. We discuss preclinical data with these agents in CLL, cover available efficacy and safety information, and examine potential resistance mechanisms and possible rational combinations to circumvent them. Expert opinion: The availability of potent and selective inhibitors of BCR signaling and of the anti-apoptotic functions of BCL2 has enormously enhanced our therapeutic armamentarium, with unprecedented efficacy now observed in patients who historically had poor outcomes with chemoimmunotherapy (CIT), e.g., those with deletion 17p/11q and/or IGHV-unmutated disease. The next challenge is to optimally sequence these agents and develop rational combinations that will hopefully lead to deeper and more durable remissions than ever seen before. Indeed, long term relapse free survival, already achievable with CIT in patients with genetically favorable-risk disease, now appears to be a realistic possibility for most patients with CLL.
| S-EPMC6488229 | biostudies-literature
Project description:BackgroundThe emergence of new antileukemic drugs, including Bruton tyrosine kinase inhibitors (BTKis), phosphoinositide 3-kinase inhibitors (PI3Kis), and B-cell lymphoma 2 antagonists (BCL-2a), has significantly improved the outcomes for patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Despite advances in treatment efficacy, the comprehensive safety profile of these novel agents versus traditional chemotherapy and immunotherapy has not been adequately explored, and there have been few direct comparisons.ObjectivesThis study aimed to compare the safety profiles of novel therapeutic agents, chemotherapy, and immunotherapy in patients with relapsed/refractory CLL using a Bayesian network meta-analysis (NMA).MethodsA systematic literature review was conducted to identify randomized clinical trials on relapsed/refractory CLL. The search encompassed major medical databases (MEDLINE, Embase, and CENTRAL) and gray literature, with the aim to integrate the findings into a Bayesian NMA framework for safety outcome assessment.DesignSystematic literature review with Bayesian NMA.ResultsThe systematic search identified 14 randomized trials that formed networks for the comparison of safety outcomes. No differences were shown between therapies in terms of overall adverse events (AEs). However, bendamustine + rituximab had a more favorable safety profile for grade ⩾3 AEs when compared with ibrutinib (risk ratio 0.62 (95% credible interval 0.40-0.86)), acalabrutinib (0.69 (0.45-0.94)), zanubrutinib (0.64 (0.42-0.91)), and venetoclax + rituximab (0.87 (0.79-0.96)). The frequency of grade ⩾3 AEs, serious AEs, and treatment discontinuations and deaths due to AEs was comparable between acalabrutinib, zanubrutinib, and venetoclax + rituximab. There were no significant differences in the safety profiles regarding hematological events, events affecting the quality of life, and infections for most comparisons of venetoclax + rituximab with BTKis. Among BTKi-specific events, zanubrutinib was associated with a higher risk of hypertension (2.96 (1.74-5.16)) and bleeding (1.38 (1.06-1.81)) than acalabrutinib. No differences in the risk of atrial fibrillation were found between acalabrutinib and zanubrutinib (1.56 (0.74-3.34)).ConclusionOur findings showed that venetoclax + rituximab, acalabrutinib, and zanubrutinib have acceptable safety profiles, which indicates that they may be the preferred therapeutic options in the setting of relapsed/refractory CLL.Trial registrationPROSPERO CRD42022304330.
| S-EPMC11465315 | biostudies-literature
Project description:We report the final analysis of the PROLONG study on ofatumumab maintenance in relapsed chronic lymphocytic leukemia (CLL). In all, 480 patients with CLL in complete or partial remission after second- or third-line treatment were randomized 1:1 to ofatumumab (300 mg first week, followed by 1000 mg every 8 weeks for up to 2 years) or observation. Median follow-up duration was 40.9 months. Median progression-free survival was 34.2 and 16.9 months for ofatumumab and observation arms, respectively, (hazard ratio, 0.55 [95% confidence interval, 0.43-0.70]; P < 0.0001). Median time to next treatment for ofatumumab and observation arms, respectively, was 37.4 and 27.6 months (0.72 [0.57-0.91]; P = 0.0044). Overall survival was similar in both arms; median was not reached (0.99 [0.72-1.37]). Grade ≥ 3 adverse events occurred in 62% and 51% of patients in ofatumumab and observation arms, respectively, the most common being neutropenia (23% and 10%), pneumonia (13% and 12%) and febrile neutropenia (6% and 4%). Up to 60 days after the last treatment, four deaths were reported in the ofatumumab arm versus six in the observation arm, none considered related to ofatumumab. Ofatumumab maintenance significantly prolonged progression-free survival in patients with relapsed CLL and was well tolerated.
| S-EPMC6893027 | biostudies-literature
Project description:Venetoclax is approved as monotherapy and in combination with rituximab for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Two Phase 1 studies (M12-175 [NCT01328626]; M13-365 [NCT01682616]) were conducted in which patients who initially responded and then progressed on venetoclax monotherapy could receive added rituximab. Ten patients were evaluated (M12-175, n = 8; M13-365, n = 2), and five (50%) responded again upon addition of rituximab, including three complete and two partial responses. Responses were ongoing after 5-10 months of follow-up. Addition of rituximab was well tolerated. These findings indicate potential clinical benefit with rituximab added to venetoclax post-progression in some patients with R/R CLL.
| S-EPMC9175959 | biostudies-literature
Project description:BackgroundWhile many humanized monoclonal antibodies utilize complement-dependent cytotoxicity, the complement depleting effects of these antibodies and the impact of complement replacement on treatment response are not well-described.MethodsWe conducted a phase 2 trial involving patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Patients were treated with ofatumumab with fresh frozen plasma (FFP) used as a source of complement replacement. The primary endpoint was objective response rate. Correlative endpoints included complement levels (C3 and C4) and complement activity (CH50) which was drawn at baseline and after ofatumumab with FFP administration.ResultsAmong 12 enrolled patients, overall response rate was 83% with two patients (17%) achieving a complete response. While only two (17%) patients had low complement activity at baseline, eight (67%) developed low levels of complement activity after ofatumumab treatment with FFP replacement. The magnitude of complement depletion did not correlate with response. Adverse events were minimal. The combination of ofatumumab and FFP demonstrated tolerability and surprising activity in high-risk CLL patients.ConclusionsThe combination of ofatumumab and FFP demonstrated tolerability and surprising activity in high-risk CLL patients. Complement replacement should be studied further as a minimally toxic approach to improve efficacy of monoclonal antibody-based regimens.
| S-EPMC7430864 | biostudies-literature
Project description:Association between measurable residual disease (MRD) and survival outcomes in chronic lymphocytic leukemia (CLL) has often been reported. However, limited quantitative analyses over large datasets have been undertaken to establish the predictive power of MRD. Here, we provide a comprehensive assessment of published MRD data to explore the utility of MRD in the prediction of progression-free survival (PFS). We undertook two independent analyses, which leveraged available published data to address two complimentary questions. In the first, data from eight clinical trials was modeled via a meta-regression approach, showing that median PFS can be predicted from undetectable MRD rates at 3-6 months of post-treatment. The resulting model can be used to predict the probability of technical success of a planned clinical trial in chemotherapy. In the second, we investigated the evidence for predicting PFS from competing MRD metrics, for example baseline value and instantaneous MRD value, via a joint modeling approach. Using data from four small studies, we found strong evidence that including MRD metrics in joint models improves predictions of PFS compared with not including them. This analysis suggests that incorporating MRD is likely to better inform individual progression predictions. It is therefore proposed that systematic MRD collection should be accompanied by modeling to generate algorithms that inform patients' progression.
| S-EPMC11335580 | biostudies-literature
Project description:Acalabrutinib is a selective irreversible Bruton tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase Ib/II study (NCT02296918) of patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naïve and 26 relapsed/refractory patients were treated with acalabrutinib (100 mg twice daily) until progression and obinutuzumab (cycle 1: 100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15; cycles 2-6: 1,000 mg day 1). Grade 3/4 adverse events occurred in 71% of patients. Overall response rates were 95% (treatment-naïve) and 92% (relapsed/refractory). Thirty-two percent of treatment-naïve and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naïve) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naïve and relapsed/refractory CLL. SIGNIFICANCE: Rituximab plus the less selective BTK inhibitor ibrutinib has not shown benefit in CLL; however, the selective BTK inhibitor acalabrutinib plus the antibody-dependent cellular cytotoxicity-enhanced antibody obinutuzumab yielded durable responses that deepened over time in treatment-naïve and relapsed/refractory CLL, supporting the evaluation of this approach in larger, comparative studies in CLL.This article is highlighted in the In This Issue feature, p. 327.
| S-EPMC8176161 | biostudies-literature
Project description:Chronic lymphocytic leukemia (CLL) cells treated with dasatinib in vitro undergo apoptosis via inhibition of Lyn kinase. Thus, in this study we tested the activity of dasatinib in patients with relapsed CLL.Patients were eligible for this phase II trial if they had documented CLL/SLL and had failed at least 1 prior therapy with a fludarabine-containing regimen and if they required therapy according to NCI-WG criteria. The starting dose of dasatinib was 140 mg daily.Fifteen patients were enrolled, with a median age of 59 and a median of 3 prior regimens. All patients had received fludarabine, and 5 were fludarabine-refractory. Eleven of the 15 (73%) had high risk del(11q) or del(17p) cytogenetics. The primary toxicity was myelosuppression, with grade 3 or 4 neutropenia and thrombocytopenia in 10 and 6 patients, respectively. Partial responses by NCI-WG criteria were achieved in 3 of the 15 patients (20%; 90% CI: 6-44). Among the remaining 12 patients, 5 had nodal responses by physical exam, and 1 patient had a nodal and lymphocyte response but with severe myelosuppression. Pharmacodynamic studies indicated apoptosis in peripheral blood CLL cells within 3 to 6 hours after dasatinib administration, associated with downregulation of Syk (spleen tyrosine kinase) mRNA.Dasatinib as a single agent has activity in relapsed and refractory CLL.
| S-EPMC3108904 | biostudies-literature