PB1888: EFFICACY OF FIRST-LINE TREATMENT FOR CHRONIC LYMPHOCYTIC LEUKEMIA: A BAYESIANNETWORK META-ANALYSIS.
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ABSTRACT:
SUBMITTER: Chanan-Khan A
PROVIDER: S-EPMC9431759 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Project description:Chronic lymphocytic leukemia (CLL) is a biologically heterogeneous illness that primarily afflicts the elderly. For many decades, the initial therapy for most patients requiring treatment was limited to single-agent alkylator therapy. Within the last two decades, we have seen remarkable progress in understanding the biology of CLL and the development of more effective treatment strategies that have employed monoclonal antibodies, such as rituximab (anti-CD20). Furthermore, recognition of the synergy between fludarabine, cyclophosphamide, and rituximab (FCR) prompted investigators to explore the clinical activity of FCR in Phase II and III trials in patients with relapsed/refractory or previously untreated CLL. On the basis of these findings, the US Food and Drug Administration (FDA) recently approved rituximab in combination with fludarabine and cyclophosphamide for the treatment of patients with relapsed/refractory or previously untreated CD20-postive CLL. Recent data from a randomized Phase III trial has confirmed improved overall survival with FCR in patients with previously untreated CLL. However, FCR is not for everyone. More tolerable regimens using rituximab for the elderly and less fit patients are being pursued in clinical trials. Recent Phase II trials have explored potentially less myelosuppressive approaches by using lower doses of fludarabine and cyclophosphamide, replacing fludarabine with pentostatin, and combining rituximab with chlorambucil. Furthermore new biomarkers predictive of early disease progression have prompted investigators to explore the benefits of early treatment with rituximab combined with other agents. In addition to the proven utility of rituximab as a frontline agent for CLL, rituximab has a favorable toxicity profile both as a single agent and in combination with chemotherapy. The majority of adverse events are Grade 1 and 2 infusion-related reactions (fevers, chills, and rigors) and occur with the first dose of rituximab. The improved tolerability observed with second and subsequent infusions allows for shorter infusion times. Rituximab's proven activity and favorable toxicity profile has made it an ideal agent for expanding treatment options for patients with CLL, the majority of whom are elderly.
| S-EPMC3039008 | biostudies-other
Project description:Objectives:With bosutinib proven to be available for frontline treatment, there are currently four frontline treatments as well as an additional strategy with high-dose imatinib for newly diagnosed chronic myeloid leukemia (CML). Due to the lack of direct comparison of high-dose imatinib, dasatinib, nilotinib, and bosutinib, we summarized the evidence to indirectly compare the efficacy among these treatment options. Methods:In total, 14 randomized clinical trials including 5,630 patients were analyzed by direct and mixed-treatment comparisons. Outcomes assessed were the following: complete cytogenetic response at 12 months; major molecular response at 12, 24, and 36 months; deep molecular response at 12, 24, 36, and 60 months; early molecular response at 3 months; progression-free survival (PFS); overall survival (OS); and Grade 3 or 4 adverse events (AEs). Results:The Bayesian network meta-analysis demonstrated that high-dose imatinib was less effective than all new-generation tyrosine kinase inhibitors and had a higher probability of Grade 3 or 4 AEs. For molecular response, 300 mg of nilotinib was likely to be the preferred frontline treatment, as demonstrated by higher response rates and faster, deeper, and longer molecular response. For PFS and OS, there were high likelihoods (79% and 74%, respectively) that 400 mg of nilotinib was the preferred option. For AEs, standard-dose imatinib has the highest probability (65%) of being the most favorable toxicity profile. Conclusion:Considering the efficacy and toxicity profile, it is not recommended to use high-dose imatinib for treatment. This analysis also showed that nilotinib has the highest probability to become the preferred frontline agents for treating CML.
| S-EPMC6163008 | biostudies-other
Project description:Chronic lymphocytic leukemia (cll) is the most common adult leukemia in North America. In Canada, no unified national guideline exists for the front-line treatment of cll; provincial guidelines vary and are largely based on funding. A group of clinical experts from across Canada developed a national evidence-based treatment guideline to provide health care professionals with clear guidance on the first-line management of cll. Consensus recommendations based on available evidence are presented for the first-line treatment of cll.
| S-EPMC6209557 | biostudies-literature
Project description:IntroductionIbrutinib (ibr) monotherapy and the combination of obinutuzumab plus chlorambucil (obi) are approved for previously untreated chronic lymphocytic leukemia (CLL). No trials directly comparing their efficacy are available. Therefore a matching-adjusted indirect comparison (MAIC) was performed to provide insight into their relative efficacy in terms of progression-free survival (PFS) and overall survival (OS). MAIC attempts to adjust for between-trial differences in factors known or suspected to influence treatment effects, to minimize bias.MethodsA MAIC within a Bayesian framework was conducted using individual patient data from the RESONATE-2 study of ibr versus chlorambucil and published data from the CLL11 study of obi versus chlorambucil. Both studies were conducted in patients ineligible for full-dose fludarabine-based therapy. After matching, the reweighted adjusted relative efficacy measure of ibr versus chlorambucil from RESONATE-2 [hazard ratio (HR), 95% credible interval (CrI)] was compared with that of obi versus chlorambucil from CLL11 for each endpoint, using a Bayesian indirect comparison.ResultsOur results suggest that in a population with similar average baseline characteristics to CLL11, ibr would improve PFS and OS outcomes compared to obi. Before matching, the HRs for ibr versus obi were 0.48 [CrI = 0.22-1.02, p(HR <1) = 97%], 0.85 [CrI = 0.44-1.63, p(HR <1) = 69%], and 0.40 [CrI = 0.10-1.54, p(HR <1) = 91%] for PFS by investigator assessment, PFS by independent review committee, and OS, respectively. After matching on all available characteristics the HRs decreased to 0.12 [CrI = 0.02-0.97, p(HR <1) = 98%], 0.24 [CrI = 0.04-1.35, p(HR <1) = 95%], and 0.21 [CrI = <0.01-8.89, p(HR <1) = 79%], respectively. There was a large variance around the treatment effect for OS due to the low number of deaths.ConclusionOur analysis suggests that ibrutinib is highly likely to provide greater PFS benefit than obinutuzumab plus chlorambucil in older or less fit patients with previously untreated CLL. There is also an indication of improvement in OS, albeit with a higher uncertainty due to the low number of events.FundingJanssen-Cilag Ltd.
| S-EPMC5504213 | biostudies-literature
Project description:PI3 kinase (PI3K) activity is critical for survival of neoplastic B cells in patients with chronic lymphocytic leukemia (CLL). Blockade of PI3K signaling with idelalisib is effective for the treatment of relapsed CLL in combination with the anti-CD20 antibody ofatumumab. In this single-arm, open-label, nonrandomized phase 2 study, we investigated the efficacy and safety of idelalisib with ofatumumab in 27 patients with treatment-naïve CLL in need of therapy. Patients were planned to receive idelalisib for 2 monthly cycles, then idelalisib and ofatumumab for 6 cycles, followed by idelalisib indefinitely. The study was closed early and all patients ceased therapy when an increased rate of death as a result of infection was observed on other first-line idelalisib trials. Median time on therapy was 8.1 months, and median duration of follow-up was 39.7 months. We previously reported high rates of hepatotoxicity in a smaller cohort of patients in this trial; toxicities necessitated therapy discontinuation in 15 patients after a median of 7.7 months. The most frequent grade ≥3 adverse events were transaminitis (52% of patients), neutropenia (33%), and colitis/diarrhea (15%). The best overall response rate (ORR) was 88.9%, including 1 complete response. Median progression-free survival (PFS) was 23 months (95% confidence interval [CI], 18-36 months); 11 patients have not yet required second-line therapy. Idelalisib and ofatumumab demonstrated an unacceptable safety profile in the first-line setting, which resulted in a short PFS despite a high ORR. Future development of PI3K inhibitors for use in treatment-naïve CLL will require novel approaches to mitigate toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02135133.
| S-EPMC6457234 | biostudies-literature
Project description:ImportanceOral 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.ObjectiveTo 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 participantsA 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.InterventionsTherapy 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 measuresOutcomes included complete remission, complete remission with incomplete count recovery, and bone marrow U-MRD rate.ResultsEighty 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 relevanceThe 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 registrationClinicalTrials.gov Identifier: NCT02756897.
| S-EPMC8193546 | biostudies-literature
Project description:Most patients with chronic lymphocytic leukemia (CLL) are elderly and/or have comorbidities that may make them ineligible for fludarabine-based treatment. For this population, chlorambucil monotherapy is an appropriate therapeutic option; however, response rates with chlorambucil are low, and more effective treatments are needed. This trial was designed to assess how the addition of rituximab to chlorambucil (R-chlorambucil) would affect safety and efficacy in patients with CLL.Patients with first-line CLL were treated with rituximab (375 mg/m(2) on day 1, cycle one, and 500 mg/m(2) thereafter) plus chlorambucil (10 mg/m(2)/d all cycles; day 1 through 7) for six 28-day cycles. For patients not achieving complete response (CR), six additional cycles of chlorambucil alone could be administered. The primary end point of the study was safety.A total of 100 patients were treated with R-chlorambucil, with a median follow-up of 30 months. Median age of patients was 70 years (range, 43 to 86 years), with patients having a median of seven comorbidities. Hematologic toxicities accounted for most grade 3/4 adverse events reported, with neutropenia and lymphopenia both occurring in 41% of patients and leukopenia in 23%. Overall response rates were 84%, with CR achieved in 10% of patients. Median progression-free survival was 23.5 months; median overall survival was not reached.These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. R-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments.
| S-EPMC4876343 | biostudies-literature
Project description:Ibrutinib is the first in-class, orally administered, Bruton's tyrosine kinase (BTK) inhibitor that abrogates the critical signaling downstream of the B-cell receptor (BCR). This signaling is required for B-cell survival, proliferation and interaction with the microenvironment. Ibrutinib proved active in preclinical models of lymphoproliferative diseases and achieved impressive response rates in heavily pretreated relapsed and refractory (R/R) patients with chronic lymphocytic leukemia (CLL). Ibrutinib prolonged survival compared to standard therapy and mitigated the effect of most poor prognostic factors in CLL, thus becoming the main therapeutic option in high-risk populations. Moreover, compared with standard chemoimmunotherapy (CIT) for adults, ibrutinib causes fewer cytopenias and infections, while having its own unique toxicity profile. Its efficacy in relapsed patients as well as its tolerability have led to its increased use in previously untreated patients, especially in those with poor prognostic markers and/or the elderly. This review elaborates on ibrutinib's unique toxicity profile and the mechanisms of acquired resistance leading to progression on ibrutinib, since both are critical for understanding the obstacles to its first-line use. We will further evaluate the data from ongoing clinical trials in this setting and explore future options for combination therapy.
| S-EPMC5753924 | biostudies-literature
Project description:PurposeThe safety and efficacy of ibrutinib, a once-daily Bruton's tyrosine kinase (BTK) inhibitor, in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was demonstrated in this phase Ib/II study. Extended follow-up up to 8 years is described, representing the longest follow-up for single-agent ibrutinib, or any BTK inhibitor, to date.Patients and methodsPhase Ib/II PCYC-1102 (NCT01105247) and extension study PCYC-1103 (NCT01109069) included patients receiving single-agent ibrutinib in first-line or relapsed/refractory CLL/SLL.ResultsOverall response rate was 89%, with similar rates in first-line (87%; complete response, 35%) and relapsed/refractory settings (89%; 10%). Estimated 7-year progression-free survival (PFS) rates were 83% in first-line and 34% in relapsed/refractory settings. Forty-one patients had CLL progression (n = 11 with Richter's transformation). Median PFS was not reached with first-line ibrutinib. In relapsed/refractory CLL/SLL, median PFS was 52 months overall, 26 months in patients with chromosome 17p deletion, 51 months with 11q deletion, not reached with trisomy 12 or 13q deletion, and 88 months in patients without these cytogenetic abnormalities. Estimated 7-year overall survival rates were 84% in first-line and 55% in relapsed/refractory settings. Grade ≥3 adverse events (AE) in >15% of patients were hypertension (28%), pneumonia (24%), and neutropenia (18%). These grade ≥3 AEs generally declined over time, except hypertension. AEs leading to discontinuation in ≥2 patients were observed only in the relapsed/refractory setting (sepsis, diarrhea, subdural hematoma, and Richter's transformation).ConclusionsWith up to 8 years of follow-up, sustained responses and long-term tolerability of single-agent ibrutinib were observed with treatment of first-line or relapsed/refractory CLL/SLL, including high-risk CLL/SLL.
| S-EPMC8175012 | biostudies-literature
Project description:Novel therapies largely have replaced chemoimmunotherapy as optimal first-line treatment of chronic lymphocytic leukemia (CLL). Approved novel therapies for CLL in the first-line setting include Bruton tyrosine kinase inhibitors, ibrutinib and acalabrutinib, and the BCL2 inhibitor venetoclax. Each of these novel agents has its own unique attributes and they have not been compared head to head in randomized trials. This review summarizes the pivotal trials that led to the approval of novel agents and compares the features of each agent to guide treatment decisions in treatment-naïve CLL. Ongoing studies investigating combinations of novel agents in the first-line setting also are discussed.
| S-EPMC9185694 | biostudies-literature