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A network meta-analysis of maintenance therapy in chronic lymphocytic leukemia.

ABSTRACT: BACKGROUND:Chronic lymphocytic leukemia (CLL) is incurable through conventional chemoimmunotherapy regimens. Despite durable responses to front-line therapy and sustained remission rates in patients with CLL, a majority of patients eventually relapse in 5 years of initial treatment. The depth of the response may affect the length of response. Maintenance therapies were aimed to deep remissions and extend the period of disease quiescence. Lenalidomide, rituximab and ofatumumab had demonstrated some efficacy as a maintenance therapy compared to no intervention for CLL patients. The relative effect on disease control and safety between different maintenance therapies were unclear. METHODS:We performed a systematic literature review and network meta-analysis to evaluate relative effect on disease control and safety of current available maintenance therapies. We searched PubMed, Embase and Cochrane database up to March 6, 2019. Relevant reference of review article and conference abstract including European Hematology Association Annual Meeting (EHA 2018), American Society of Hematology Annual Meeting (ASH 2018) and American Society of Clinical Oncology Annual Meeting (ASCO 2018) were searched. Randomized controlled trials (RCT) involving current available maintenance therapy including "Lenalidomide", "Rituximab", "Ofatumumab", "Ibrutinib", "Idelalisib", "Venetoclax"and "Obinutuzumab"were eligible. Outcomes of interest included progression-free survival (PFS), overall survival (OS) and serious adverse events (SAE) in CLL patients received subsequent maintenance therapy. Two authors CHL and CL) independently assessed eligibility for all identified citations and extracted data from the original trial reports. The selected studies' risk of bias was assessed following the guidelines of Cochrane Collaboration Handbook. RESULTS:In total, six phase III RCTs with total 1,615 CLL patients were identified. Maintenance therapy using lenalidomide, rituximab, and ofatumumab demonstrated a statistically significant effect in prolongation of progression-free survival (HR:0.37, 95% CI: 0.27-0.50 of lenalidomide; HR:0.50, 95% CI: 0.38-0.66 of rituximab; HR:0.52, 95% CI:0.41-0.66 of ofatumumab, separately) compared with no intervention; however, for overall survival, the effect of maintenance therapy showed no significant difference versus no intervention (HR: 0.89, 95% CI: 0.70-1.14). Lenalidomide showed the best efficacy for PFS (HR: 0.37, 95% CI: 0.27-0.50, Probability of being best treatment: 96%). CONCLUSIONS:Our network meta-analysis provided an integrated overview of relative efficacy and safety of different maintenance therapies in CLL. All maintenance therapies were effective in reducing the risk of disease progression versus no intervention. Based on current best evidence, maintenance therapy with lenalidomide is the most efficacious option.

SUBMITTER: Lee CH

PROVIDER: S-EPMC6988939 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A network meta-analysis of maintenance therapy in chronic lymphocytic leukemia.

Lee Cho-Hao CH Chen Po-Huang PH Lin Chin C Wang Chieh-Yung CY Ho Ching-Liang CL

PloS one 20200129 1

<h4>Background</h4>Chronic lymphocytic leukemia (CLL) is incurable through conventional chemoimmunotherapy regimens. Despite durable responses to front-line therapy and sustained remission rates in patients with CLL, a majority of patients eventually relapse in 5 years of initial treatment. The depth of the response may affect the length of response. Maintenance therapies were aimed to deep remissions and extend the period of disease quiescence. Lenalidomide, rituximab and ofatumumab had demonst ...[more]

PMID: 31995577

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Project description:BackgroundChronic Lymphocytic Leukemia (CLL) pathogenesis has been linked to the prolonged survival and/or apoptotic resistance of leukemic B cells in vivo, and is thought to be due to enhanced survival signaling responses to environmental factors that protect CLL cells from spontaneous and chemotherapy-induced death. Although normally associated with cell migration, the chemokine, CXCL12, is one of the factors known to support the survival of CLL cells. Thus, the signaling pathways activated by CXCL12 and its receptor, CXCR4, were investigated as components of these pathways and may represent targets that if inhibited, could render resistant CLL cells more susceptible to chemotherapy.Methodology/principal findingsTo determine the downstream signaling targets that contribute to the survival effects of CXCL12 in CLL, we took a phosphoproteomics approach to identify and compare phosphopeptides in unstimulated and CXCL12-stimulated primary CLL cells. While some of the survival pathways activated by CXCL12 in CLL are known, including Akt and ERK1/2, this approach enabled the identification of additional signaling targets and novel phosphoproteins that could have implications in CLL disease and therapy. In addition to the phosphoproteomics results, we provide evidence from western blot validation that the tumor suppressor, programmed cell death factor 4 (PDCD4), is a previously unidentified phosphorylation target of CXCL12 signaling in all CLL cells probed. Additionally, heat shock protein 27 (HSP27), which mediates anti-apoptotic signaling and has previously been linked to chemotherapeutic resistance, was detected in a subset (approximately 25%) of CLL patients cells examined.Conclusions/significanceSince PDCD4 and HSP27 have previously been associated with cancer and regulation of cell growth and apoptosis, these proteins may have novel implications in CLL cell survival and represent potential therapeutic targets. PDCD4 also represents a previously unknown signaling target of chemokine receptors; therefore, these observations increase our understanding of alternative pathways to migration that may be activated or inhibited by chemokines in the context of cancer cell survival.

Project description:Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma.We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee.The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib.Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).

Project description:IntroductionRituximab plus fludarabine and cyclophosphamide (RFC) is the standard of care for fit patients with untreated chronic lymphocytic leukemia (CLL); however, its use is limited in 'unfit' (co-morbid and/or full-dose F-ineligible) patients due to its toxicity profile. We conducted a systematic review and Bayesian network meta-analysis (NMA) to determine the relative efficacy of commercially available interventions for the first-line treatment of unfit CLL patients.MethodsFor inclusion in the NMA, studies had to be linked via common treatment comparators, report progression-free survival (PFS), and/or overall survival (OS), and meet at least one of the five inclusion criteria: median cumulative illness score >6, median creatinine clearance ≤70 mL/min, existing co-morbidities, median age ≥70 years, and no full-dose F in the comparator arm. A manual review, validated by external experts, of all studies that met at least one of these criteria was also performed to confirm that they evaluated first-line therapeutic options for unfit patients with CLL.ResultsIn unfit patients, the main NMA (five studies for PFS and four for OS) demonstrated clear preference in terms of PFS for obinutuzumab + chlorambucil (G-Clb) versus rituximab + chlorambucil (R-Clb), ofatumumab + chlorambucil (O-Clb), fludarabine and chlorambucil (median hazard ratios [HRs] 0.43, 0.33, 0.20, and 0.19, respectively), and a trend for better efficacy versus rituximab + bendamustine (R-Benda) and RFC-Lite (median HR 0.81 and 0.88, respectively). OS results were generally consistent with PFS data, (median HR 0.48, 0.53, and 0.81, respectively) for G-Clb versus Clb, O-Clb, and R-Clb 0.35 and 0.81 versus F and R-Benda, respectively); however, the OS findings were associated with higher uncertainty. Treatment ranking reflected improved PFS and OS with G-Clb over other treatment strategies (median rank of one for both endpoints).ConclusionG-Clb is likely to show superior efficacy to other treatment options selected in our NMA for unfit treatment-naïve patients with CLL.FundingF. Hoffmann-La Roche Ltd.

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A network meta-analysis of maintenance therapy in chronic lymphocytic leukemia.

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A network meta-analysis of maintenance therapy in chronic lymphocytic leukemia.

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