Experts Dissect 3 Practice-Changing Studies for Newly Diagnosed CLL

Christina T. Loguidice
Published: Monday, Apr 01, 2019
Dr. William G. Wierda
William G. Wierda, MD, PhD
More and more, the role of chemoimmunotherapy (CIT) continues to diminish in the first-line treatment of patients with chronic lymphocytic leukemia (CLL), as the many new agents and combinations introduced in the past 5 years have shown promise in clinical trials and made their way into clinics.1,2 Historically, CIT has been the standard first-line treatment for patients with CLL.

These newer treatments include Bruton tyrosine kinase (BTK) inhibitors, such as ibrutinib (Imbruvica) and acalabrutinib (Calquence), and novel CD20-targeting monoclonal antibodies (mAbs), such as ofatumumab (Arzerra) and obinutuzumab (Gazyva), among others. With such an abundance of new options available or on the horizon, treatment selection has become richer but also more daunting, as factors such as patient age, comorbidities, mutation profile, preferences, and financial picture need to be weighed against, and alongside, safety and efficacy data and dosing schedules.

During an OncLive Peer Exchange®, a panel of CLL experts reviewed findings from studies presented at the 2018 American Society of Hematology (ASH) meeting in December: iLLUMINATE, Alliance A041202, and ECOG E1912. “There have been [these] 3 large phase III clinical trials presented in the frontline setting that I think are really practice changing,” said moderator William G. Wierda, MD, PhD. “And they are small-molecule inhibitor–based therapies versus chemoimmunotherapy-based regimens.”

The experts also provided practical perspectives on selecting patients for the agents that were assessed in these studies and shared their insights on how these agents are changing the initial management of CLL.

Additionally, several panelists noted that they are looking forward to learning the findings of the CLL14 study, which is evaluating the combination of venetoclax (Venclexta) and obinutuzumab versus CIT for patients who have not received prior treatment. The FDA is reviewing a supplemental application for the regimen.

iLLUMINATE Study

The international, randomized, open-label, phase III iLLUMINATE study compared the safety and efficacy of ibrutinib plus obinutuzumab (ibr-G) with chlorambucil plus obinutuzumab (clb-G) as a first-line treatment for CLL or small lymphocytic lymphoma (SLL).3,4 Patients were aged ≥65 years or <65 years with significant comorbidities or high-risk genomic features (ie, Cumulative Illness Rating Scale score >6, creatinine clearance <70 mL/min, and/or del[17p] or TP53 mutation).

After a median follow-up of 31.3 months (interquartile range, 29.4-33.2 ), median progression-free survival (PFS) was significantly longer in the ibr-G group (median not reached) than in the clb-G group (19.0 months; HR, 0.23; P <.0001). The investigator-assessed overall response rate (ORR) was 91% in the ibr-G group and 81% in the clb-G group, with complete response (CR) rates of 41% and 16%, respectively.

“Did we really need this study, given that we have the RESONATE-2 study comparing ibrutinib with chlorambucil?” asked Susan M. O’Brien, MD. RESONATE-2 data led to the FDA approving ibrutinib monotherapy as a first-line treatment for CLL in 2016.5,6 However, she noted that iLLUMINATE now provides evidence that adding a mAb to ibrutinib can improve its efficacy, a finding that was previously observed with chemotherapy and had led to CIT becoming the standard of care for many years.

“[CRs] are not very common with ibrutinib, but in [iLLUMINATE], it does appear that the obinutuzumab is adding to the ibrutinib, at least in the response rate,” O’Brien said. In RESONATE-2, the independent review committee–assessed ORR was 86% with ibrutinib monotherapy and 35% with chlorambucil monotherapy, with CRs occurring in only 4% and 2% of patients in these groups, respectively.5

Following the Peer Exchange program, on January 28, 2019, the FDA approved ibrutinib in combination with obinutuzumab for treatment-naïve CLL or SLL based on the iLLUMINATE data.7 Despite iLLUMINATE’s findings, however, O’Brien said her first choice for older patients requiring first-line therapy would still be ibrutinib alone.

Currently, ibrutinib is the National Comprehensive Cancer Network (NCCN)-preferred first-line regimen for CLL across patient cohorts, including older (≥65 years) and younger (<65 years) patients, those with and without significant comorbidities or frailty, and those with or without del(17p) and/or TP53 mutations.8 Ibr-G and chlorambucil alone or with an anti-CD20 mAb can be considered in the absence of del(17p) or TP53 mutations for frail patients unable to tolerate purine analogues, for older patients, and for younger patients with significant comorbidities.8


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