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.