Comparing the efficacy and safety of first-line treatments for chronic lymphocytic leukemia: a network meta-analysis.

The chronic lymphocytic leukemia treatment strategies have transitioned from chemotherapy and chemoimmunotherapy to chemotherapy-free regimens. Frequentist network meta-analysis allows for direct and indirect comparisons between different treatments. Randomized controlled trials assessing first-line treatments were included. Outcomes were progression-free survival (PFS), overall survival, undetectable minimal residual disease, objective response rate, and adverse events. Studies with comparable characteristics also underwent subgroup analysis, stratifying by age, comorbidities, IGHV status, and cytogenetic abnormalities. A total of 30 eligible trials involved 12 818 patients, and 30 treatments were included. Acalabrutinib demonstrated a PFS advantage over ibrutinib and obinutuzumab-venetoclax in patients aged older than 65 years or with unmutated IGHV. In younger patients with comorbidities, acalabrutinib-obinutuzumab had superior PFS compared with ibrutinib-obinutuzumab, ibrutinib-venetoclax, and obinutuzumab-venetoclax. For older patients with comorbidities, acalabrutinib and acalabrutinib-obinutuzumab outperformed obinutuzumab-venetoclax without statistically difference between them. Minimal residual disease-guided ibrutinib-venetoclax surpassed obinutuzumab-venetoclax in patients without comorbidities. Ibrutinib-obinutuzumab exhibited extended PFS benefits compared with obinutuzumab-venetoclax in patients with mutated IGHV or with del(17p) and/or TP53 mutations. Ibrutinib-venetoclax and ibrutinib-obinutuzumab had lower neutropenia rates than obinutuzumab-venetoclax. Ibrutinib-venetoclax had fewer infections than acalabrutinib and acalabrutinib-obinutuzumab. Acalabrutinib-obinutuzumab caused less diarrhea than ibrutinib-venetoclax but more headaches than ibrutinib-obinutuzumab and obinutuzumab-venetoclax. Obinutuzumab-venetoclax had lower hypertension rates than ibrutinib-obinutuzumab. Ibrutinib-venetoclax had fewer arthralgia than acalabrutinib-obinutuzumab. For any grade secondary primary neoplasms, ibrutinib-venetoclax and obinutuzumab-venetoclax was less than acalabrutinib-obinutuzumab. Tailored chemotherapy-free regimens can be selected based on age, comorbidities, IGHV status, and cytogenetic abnormalities to optimize treatment outcomes while considering different adverse events spectra.

Wen T ，Sun G ，Jiang W ，Steiner K ，Bridge S ，Liu P ... -  《-》

Fixed-Duration Acalabrutinib Combinations in Untreated Chronic Lymphocytic Leukemia.

Whether fixed-duration acalabrutinib-venetoclax (with or without obinutuzumab) would result in better progression-free survival than chemoimmunotherapy in patients with untreated chronic lymphocytic leukemia (CLL) is unknown. In this phase 3, open-label trial, we included patients 18 years of age or older who had an Eastern Cooperative Oncology Group performance-status score of 0 to 2 (range, 0 to 5, with higher numbers indicating greater disability) and who did not have a 17p deletion or TP53 mutation. Patients were randomly assigned, in a 1:1:1 ratio, to receive acalabrutinib-venetoclax (acalabrutinib, cycles 1 to 14; venetoclax, cycles 3 to 14), acalabrutinib-venetoclax-obinutuzumab (as above, plus obinutuzumab, cycles 2 to 7), or chemoimmunotherapy with the investigator's choice of fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab (cycles 1 to 6). The primary end point was progression-free survival (acalabrutinib-venetoclax vs. chemoimmunotherapy) in the intention-to-treat population, assessed by blinded independent central review. A total of 867 patients underwent randomization: 291 were assigned to receive acalabrutinib-venetoclax, 286 acalabrutinib-venetoclax-obinutuzumab, and 290 chemoimmunotherapy (of whom 143 received fludarabine-cyclophosphamide-rituximab and 147 bendamustine-rituximab). The median age of the patients was 61 years (range, 26 to 86), 64.5% were men, and 58.6% had unmutated IGHV. Estimated 36-month progression-free survival at a median follow-up of 40.8 months was 76.5% with acalabrutinib-venetoclax, 83.1% with acalabrutinib-venetoclax-obinutuzumab, and 66.5% with chemoimmunotherapy (hazard ratio for disease progression or death with acalabrutinib-venetoclax vs. chemoimmunotherapy, 0.65 [95% confidence interval {CI}, 0.49 to 0.87], P = 0.004; for the comparison of acalabrutinib-venetoclax-obinutuzumab with chemoimmunotherapy, P<0.001). Estimated 36-month overall survival was 94.1% with acalabrutinib-venetoclax, 87.7% with acalabrutinib-venetoclax-obinutuzumab, and 85.9% with chemoimmunotherapy. Neutropenia, the most common adverse event of clinical interest of grade 3 or higher, was reported in 32.3%, 46.1%, and 43.2% in the three groups, respectively; death from coronavirus disease 2019 was reported in 10, 25, and 21 patients in the three groups. Acalabrutinib-venetoclax with or without obinutuzumab significantly prolonged progression-free survival as compared with chemoimmunotherapy in fit patients with previously untreated CLL. (Funded by AstraZeneca; AMPLIFY ClinicalTrials.gov number, NCT03836261.).

Brown JR ，Seymour JF ，Jurczak W ，Aw A ，Wach M ，Illes A ，Tedeschi A ，Owen C ，Skarbnik A ，Lysak D ，Eom KS ，Šimkovič M ，Pavlovsky MA ，Kater AP ，Eichhorst B ，Miller K ，Munugalavadla V ，Yu T ，de Borja M ，Ghia P ，AMPLIFY investigators ，AMPLIFY Investigators ... -  《-》

Fixed-Duration Ibrutinib-Venetoclax in Patients with Chronic Lymphocytic Leukemia and Comorbidities.

Kater AP ，Owen C ，Moreno C ，Follows G ，Munir T ，Levin MD ，Benjamini O ，Janssens A ，Osterborg A ，Robak T ，Simkovic M ，Stevens D ，Voloshin S ，Vorobyev V ，Ysebaert L ，Qin R ，Steele AJ ，Schuier N ，Baeten K ，Caces DB ，Niemann CU ... -  《-》

Phase II Study of Acalabrutinib, Venetoclax, and Obinutuzumab in a Treatment-Naïve Chronic Lymphocytic Leukemia Population Enriched for High-Risk Disease.

Davids MS ，Ryan CE ，Lampson BL ，Ren Y ，Tyekucheva S ，Fernandes SM ，Crombie JL ，Kim AI ，Weinstock M ，Montegaard J ，Walker HA ，Greenman C ，Patterson V ，Jacobson CA ，LaCasce AS ，Armand P ，Fisher DC ，Lo S ，Olszewski AJ ，Arnason JE ，Ahn IE ，Brown JR ... -  《-》

Ibrutinib and Venetoclax for First-Line Treatment of CLL.

Ibrutinib, an inhibitor of Bruton's tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination. We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10-4). A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax. In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.).

Jain N ，Keating M ，Thompson P ，Ferrajoli A ，Burger J ，Borthakur G ，Takahashi K ，Estrov Z ，Fowler N ，Kadia T ，Konopleva M ，Alvarado Y ，Yilmaz M ，DiNardo C ，Bose P ，Ohanian M ，Pemmaraju N ，Jabbour E ，Sasaki K ，Kanagal-Shamanna R ，Patel K ，Jorgensen J ，Garg N ，Wang X ，Sondermann K ，Cruz N ，Wei C ，Ayala A ，Plunkett W ，Kantarjian H ，Gandhi V ，Wierda W ... -  《-》