Is Fixed-Duration Therapy the New Standard of Care in Frontline Chronic Lymphocytic Leukemia?
Modern fixed-duration therapy has been based on the results shown by 2 approaches: the combination of venetoclax and an anti-CD20 monoclonal antibody and the dual combination of venetoclax and ibrutinib.
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The advent of small molecule inhibitors, both Bruton tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 antagonists, has led to a paradigm shift in the treatment of chronic lymphocytic leukemia (CLL). Fixed-duration (FD) therapy is an appealing approach to initial treatment of CLL from a patient’s and a clinician’s perspective. Patients are interested in being able to stop treatment once the disease is in remission and tend to have better adherence to treatment and laboratory monitoring when therapy is FD. Similarly, mild toxicities can be less burdensome if the treatment duration is finite. Furthermore, the financial burden associated with therapy becomes less of a concern with FD. Although patients will need to continue to be monitored after treatment completion for long-term toxicities, infections, recurrent disease, and the development of resistance, monitoring is generally less intense after FD therapy.
Modern FD therapy has been based on the results shown by 2 approaches: the combination of venetoclax (Venclexta®; Genentech, AbbVie) and an anti-CD20 monoclonal antibody (mAb) and the dual combination of venetoclax and ibrutinib (Imbruvica®; Pharmacyclics, Janssen). Ongoing and recently completed clinical trials are evaluating additional approaches, such as triple combinations of venetoclax plus a BTKi plus an anti-CD20 mAb. The CLL14 trial (NCT02242942) was the first to evaluate FD therapy with a novel small molecule inhibitor: it compared the efficacy of venetoclax in combination with obinutuzumab (Gazyva®; Genentech) to chlorambucil in combination with obinutuzumab in the frontline treatment of patients with preexisting comorbidities or a creatinine clearance of less than 70 mL/min.1 A total of 432 patients were treated. All patients received treatment for an FD of 12 cycles, with cycles lasting 28 days. Patients treated with venetoclax plus obinutuzumab (n=216) had a significantly longer progression-free survival (PFS; HR, 0.35; 95% CI, 0.23-0.53; P<.001).
Also, in the recently reported long-term follow-up of patients treated in CLL14, PFS benefit was maintained at the 5-year follow-up. Most importantly, measurable residual disease (MRD) assessed in the peripheral blood (PB) by allele-specific oligonucleotide PCR assay (ASO-PCR; 3 months of treatment completion, with a sensitivity of 10–4) was 76% in the venetoclax arm compared with 35% in the chlorambucil arm.
Similarly, the MRD rate assessed by ASO-PCR in bone marrow (BM) was 57% vs 17%.1,2 Furthermore, 40% of patients treated in the venetoclax arm achieved MRD remission at 1×10–6 (measured in the PB by next-generation sequencing at the end of treatment) compared with 7% in the comparator arm.
The most common adverse event (AE) was neutropenia in both groups. Among patients treated with venetoclax plus obinutuzumab, grade 3/4 febrile neutropenia and infections occurred in 5% and 18%, respectively. Three patients treated with venetoclax plus obinutuzumab had tumor lysis syndrome. An open question is whether patients with CLL with high-risk features are candidates for FD approaches. Among the 25 patients with TP53 abnormality (del[17p] and/or TP53 mutation) treated with venetoclax in CLL14, the 5-year PFS was 40%. This result is inferior to that observed with ibrutinib monotherapy, which has an estimated 4-year PFS of 79% based on a pooled analysis of patients with treatment-naïve (TN) CLL who received treatment in a continuous fashion.3
BTKi and Venetoclax Combination
Another FD approach consists of combining BTKi and venetoclax. Ibrutinib plus venetoclax is approved by the European Medicines Agency and Health Canada for the frontline treatment of patients 65 years and older or 18 to 64 years with preexisting comorbidities or creatinine clearance of less than 70 mL/min.
The approval is based on the results of 2 randomized trials: GLOW and CAPTIVATE. GLOW (NCT03462719) is a phase 3 trial that compared the efficacy of FD ibrutinib plus venetoclax (ibrutinib monotherapy for first 3 cycles and venetoclax combination for 12 cycles) to FD chlorambucil plus obinutuzumab in the frontline treatment of adult patients with CLL without TP53 abnormality older than 65 years or 18 to 64 years with comorbidities or creatinine clearance of 70 mL/min or less.
There were 211 patients treated: of them, 106 patients received the venetoclax combination. The estimated 30-month PFS rate was 81% in the ibrutinib plus venetoclax arm compared with 36% with chlorambucil plus obinutuzumab. The undetectable MRD (uMRD; assessed by next-generation sequencing with a sensitivity of 10–4 as of 3 months after treatment completion) rate assessed in BM was 52% with ibrutinib plus venetoclax and 17% with chlorambucil plus obinutuzumab.
Similarly, the uMRD rate assessed in PB was 55% vs 39%.4 Among patients treated with ibrutinib plus venetoclax, grade 3/4 neutropenia and infections were observed in 35% and 15%, respectively. Furthermore, grade 3/4 atrial fibrillation occurred in 7% of patients in the ibrutinib plus venetoclax arm.
CAPTIVATE (NCT02910583) is a single-arm phase 2 study that included all comers with TN adult patients 70 years or younger with CLL, with adequate organ functions and ECOG performance status of 0 to 2. Notably, the study included high-risk disease features, including TP53 abnormality. The trial had 2 cohorts: MRD-guided treatment discontinuation and FD treatment cohorts.
All 159 patients in the FD cohort received ibrutinib for the first 3 cycles (with a cycle lasting for 28 days), followed by ibrutinib plus venetoclax for 12 cycles (a total of 15 months of therapy). Twenty-seven patients (17%) had del(17p) or TP53 mutation. The complete response (CR)/CR with incomplete count recovery rate was 56% in all study patients, regardless of del(17p) status. The end-of-treatment uMRD rate (assessed by multicolor flow cytometry with a sensitivity of 10–4) in BM was 62% in patients without TP53 abnormality compared with 41% in patients with TP53 abnormality.5
Similarly, the uMRD rate in PB was 76% vs 81%. The estimated 2-year PFS rate was 96% in the presence of TP53 abnormality and 84% in patients without TP53 abnormality. Like what was observed in GLOW, neutropenia was the most frequent grade 3/4 AE (33%). Overall, the study showed that FD treatment with the ibrutinib plus venetoclax combination is effective for TN patients with CLL, including patients with TP53 abnormality. A phase 2 single-center trial (conducted by our group) also showed that FD therapy with the ibrutinib plus venetoclax combination is an effective initial treatment for patients with high-risk CLL.6 In this single-institution study, patients with at least one of the high-risk features (defined as the presence of one of the following: del[17p], TP53 mutation, unmutated IGHV, del[11q], or 65 years or older) were included. All 120 patients received ibrutinib for the first 3 cycles (a cycle lasting 28 days), followed by ibrutinib plus venetoclax for 24 cycles, a longer period than GLOW and CAPTIVATE. Twenty patients (17%) had del(17p), and 19 (16%) had TP53 mutation. The uMRD (assessed by multicolor flow cytometry in bone marrow with a sensitivity of 10–4) rate was 52% after 12 cycles and 64% after 24 cycles of combination treatment.6-8 Most importantly, the uMRD rate was similar in patients with and without TP53 abnormality. Also, the estimated 4-year PFS was 96% for all patients and 91% for patients with TP53 abnormality. Grade 3/4 neutropenia occurred in 51% of patients, and 10% of the patients experienced grade 3/4 atrial fibrillation. The findings of this study suggest that longer FD may need to be offered to patients with high-risk disease characteristics. Although we await longer follow-up results of the completed FD therapy studies to better refine these approaches based on the unique patient characteristics, several FD studies with different treatment combinations are ongoing.
MAJIC (NCT05057494) is a randomized phase 3 study comparing the efficacy of FD treatment of acalabrutinib plus venetoclax with venetoclax plus obinutuzumab. This study enrolls patients with high-risk disease features, including TP53 abnormality. Similarly, there are several ongoing trials with triple-agent FD therapy: zanubrutinib plus venetoclax plus obinutuzumab (NCT03824483), acalabrutinib plus venetoclax plus obinutuzumab (NCT03836261), and pirtobrutinib plus venetoclax plus obinutuzumab (NCT05536349).
In conclusion, FD therapy in CLL is a treatment option that can be offered to many TN patients. It is a field of active investigation with numerous ongoing clinical trials, and we anticipate that in the years to come, there will be a larger number of FD treatment options for patients with CLL with standard-risk features and patients with high-risk disease.
