Toward a new paradigm for CLL treatment

In this issue of Blood, Al-Sawaf and colleagues report on the 6-year results of the CLL14 study, a multicenter open label phase 3 trial for elderly patients with chronic lymphocytic leukemia (CLL) with coexisting conditions.¹ It compared efficacy of fixed duration (FD) treatment with a combination of the bcl2-antagonist venetoclax (Ven) and the anti-CD20 antibody obinutuzumab (Obi) to chlorambucil (Clb) and Obi. Between August 2015 and August 2016, the trial enrolled 432 patients who were treated with 6 cycles of Ven-Obi followed by 6 cycles of Ven or with the traditional Clb-Obi approach. Patients participating in the study were screened for molecular markers of adverse prognosis, including mutations in the immunoglobulin heavy-chain variable region (IGHV) genes, TP53 mutations, and cytogenetic abnormalities. Minimal residual disease (MRD) was determined in peripheral blood and bone marrow at the end of treatment and at several points afterward. Previous interim analyses already clearly demonstrated the superiority of the Ven-Obi combination in terms of progression-free survival (PFS), leading to approval of this combination both by the European Medical Agency and the US Food and Drug Administration (FDA).^2-5 

The study now published in Blood, with all patients being off study for at least 5 years and a median age of patient population of 77 years, allows to draw a number of conclusions.

• First, patients treated with the Ven-Obi combination showed a statistically significant sustained prolongation of PFS compared with patients treated with Clb-Obi (76.2 vs 36.4 months). Overall, the PFS rate was 53% in the Ven-Obi group vs 21.7% after Clb-Obi. Likewise, the time-to-next-treatment rate showed markedly significant superiority in the Ven-Obi group, and overall survival (OS) was only slightly better in the Ven-Obi (78.7%) vs Clb-Obi (69.2%), with a trend toward significance.

• A second important observation of the study is that in the Ven-Obi arm, patients who relapsed more frequently presented with unmutated IGHV genes, deletion of 17p, or TP53 mutations. Vice versa, patients who reached undetectable MRD, as assessed by next-generation sequencing in the peripheral blood, at the end of therapy and maintained for 5 years thereafter had mutated IGHV genes in almost 90% of cases and deletion of 13q as the sole cytogenetic abnormality in 70% of cases. Importantly, MRD levels at the end of treatment seem to be predictive of OS, independent of IGHV mutational status.

• The third significant conclusion from the study comes from the patient-reported outcome questionnaires, showing that patients treated with Ven-Obi experienced better quality of life and a better global health status compared with patients treated with Clb-Obi.

• Finally, at 6 years’ follow-up 30 patients in the Ven-Obi arm had developed second primary malignancies, including solid organ tumors (17) and melanomas (8). This was not significantly different from the Clb-Obi arm and in line with other adverse effects measured at earlier time points.

The CLL14 study was the first to address the question of FD therapy regimens, as opposed to a treat-to-progression strategy. This approach represents the new frontier in CLL therapy and is appealing for several reasons. First, a survey presented at the 2023 American Society of Hematology Annual Meeting showed that patients prefer FD strategies and are willing to accept a higher risk of adverse effects, including tumor lysis syndrome (3%), atrial fibrillation (6%-7%), and fatigue (21%-26%).⁶ FD therapy may also prove cost-effective, although the exact economic impact may differ according to the health system and, therefore, be country specific. A recent publication examining US patients determined that FD Ven-Obi is a cost-effective first-line treatment for CLL patients with comorbidities compared with other options.⁷ 

Importantly, FD therapy does not seem to favor acquisition of mutations in genes and pathways that are targeted by drugs. A recently published article reported that when patients successfully treated with FD ibrutinib (Ibr)-Ven developed progressive disease, their leukemic cells do not acquire mutations in BTK, BCL2, or PLCG2. Conversely, mutations in these genes are common in continuously treated patients developing resistance, which currently represents one of the hardest challenges in CLL therapy. This issue is critical as it would not preclude retreatment strategies.⁸ 

The relevant open question in the field at this point is what is the best combination for FD treatment? Several clinical trials are addressing this question. The GLOW phase 3 trial demonstrated that the combination of Ibr (delivered for the 3 initial cycles) followed by 12 cycles of Ibr-Ven is clearly superior to Clb-Obi.⁹ Similar conclusions have been obtained in the CAPTIVATE trial.¹⁰ Other FD combinations under investigation include acalabrutinib plus Ven (MAJIC, NCT05057494) and triple combinations of acalabrutinib plus Ven plus Obi (NCT03836261) and pirtobrutinib plus Ven plus Obi (NCT05536349). Lastly, the CLL17 trial is comparing Ibr monotherapy vs FD Ven-Obi vs FD Ibr-Ven in previously untreated patients with CLL.

Since the approval of Ibr by the FDA in February 2012, targeted therapy in CLL has continued to evolve. We now have several inhibitors that may be used alone or in combination with other inhibitors or with monoclonal antibodies for front-line therapy. Ongoing studies will likely tell which combination performs best according to patient clinical and molecular characteristics. Similar approaches will also be needed in developing strategies to treat patients who become resistant to front-line agents and who currently represent a pressing unmet clinical need.

Conflict-of-interest disclosure: S.D. declares no competing financial interests.