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Oral Therapy for Chronic Lymphocytic Leukemia in Older Patients and Those with Comorbidities
Bruton tyrosine kinase inhibitors (BTKis) have largely supplanted chemo-immunotherapy in the frontline treatment of chronic lymphocytic leukemia (CLL). Given the further improvement in responses when BTKis are combined with the anti-CD20 monoclonal antibody obinutuzumab or the B-cell lymphoma-2 (BCL2) inhibitor venetoclax, investigators assessed efficacy and safety in older patients and those with comorbidities.
In a phase 3, multicenter, industry-sponsored trial, 211 previously untreated patients older than 65 or younger than 65 and with Cumulative Illness Rating Scale (CIRS) scores >6 were randomized to ibrutinib plus venetoclax or chlorambucil plus obinutuzumab. Patients received three 4-week cycles of daily ibrutinib followed by 12 cycles of daily ibrutinib-venetoclax or six 4-week cycles of chlorambucil-obinutuzumab. Patients with TP53 mutations or deletions were excluded.
At a median follow-up of 28 months, progression-free survival — the primary endpoint — was significantly improved in the ibrutinib-venetoclax arm compared with the chlorambucil-obinutuzumab arm (not reached vs. 21 months; hazard ratio, 0.216; P<0.001). Estimated 24-month PFS also was improved with ibrutinib-venetoclax (84.4% vs. 44.1%), as was achievement of undetectable minimal residual disease (55.7% vs. 21.0%; P<0.001).
Tumor lysis syndrome occurred in no patients in the ibrutinib-venetoclax arm versus six in the chlorambucil-obinutuzumab arm. Diarrhea and pneumonia were more common with ibrutinib-venetoclax, as was atrial fibrillation (14% vs. 2%). There were seven on-treatment deaths in the ibrutinib-venetoclax arm — four during the 3-month ibrutinib lead-in period — compared with two in the chlorambucil-obinutuzumab arm. The risk of cardiac or sudden death was highest in patients with ECOG performance status 2 or CIRS score ≥10 and history of hypertension, cardiovascular disease, or diabetes.
These high response rates with ibrutinib-venetoclax are consistent with observations in other phase 3 trials, and, at an additional 6 months' follow-up, appear durable after completion of fixed-duration treatment. Caution is clearly warranted, however, for the use of ibrutinib in very old individuals and in those with serious cardiovascular comorbidities. Whether other BTKis will be safer, alone or in combination regimens, will require careful assessment in these patients.
Kater AP et al.
Title: Fixed-duration ibrutinib-venetoclax in patients with chronic lymphocytic leukemia and comorbidities.
Source: NEJM Evid 2022 May 13; [e-pub]. (Abstract/FREE Full Text)