Educational theme: Improving front-line treatment in CLL

The next educational theme on the Lymphoma Hub is focusing on the front-line treatment of chronic lymphocytic leukemia (CLL). CLL has a heterogeneous clinical course, ranging from indolent disease where patients do not require treatment for several years, to a very aggressive course with rapid disease progression and poorer patient outcomes.¹

The prognosis of patients with CLL has significantly improved in the past two decades, with the standard of care (SoC) first-line treatment of chemotherapy (e.g., fludarabine and cyclophosphamide, chlorambucil, or bendamustine) in combination with anti-CD20 monoclonal antibodies (e.g., rituximab, obinutuzumab, or ofatumumab).^1,2 More recently, exciting data have been published, prompting a shift from chemoimmunotherapy-based regimens towards small-molecule agents.

Ibrutinib and venetoclax

The superiority of small molecule therapies, like ibrutinib and venetoclax, in the frontline setting has predominantly been demonstrated in three phase III randomized clinical trials covered by Lymphoma Hub – ECOG-ACRIN E1912, ALLIANCE A041202, and iLLUMINATE – which compared ibrutinib alone or in combination with rituximab to standard chemoimmunotherapy.

The ALLIANCE trial (NCT01886872), published in the New England Journal of Medicine, compared bendamustine plus rituximab versus ibrutinib, or ibrutinib plus rituximab in older patients (³ 70 years old) with untreated CLL. The study demonstrated that in this patient population ibrutinib-based therapy resulted in significantly higher progression-free survival (PFS) than bendamustine with rituximab.³ Similarly, the ECOG-ACRIN E1912 trial (NCT02048813) compared fludarabine, cyclophosphamide, and rituximab (FCR) to ibrutinib plus rituximab in younger patients (< 70 years old) with previously untreated CLL. The trial demonstrated that ibrutinib plus rituximab led to superior PFS and overall survival (OS) in younger patients when compared to FCR.⁴ Extended follow-up from the trial (median, 45 months), presented at the 61^st American Society of Hematology (ASH) annual meeting in Orlando, US, demonstrated that the combination of ibrutinib and rituximab continued to provide superior PFS compared to FCR (HR 0.39; 95% CI, 0.26–0.57; p < 0.0001).⁵ The iLLUMINATE (NCT02264574) study, which was published in The Lancet Oncology, compared chlorambucil plus obinutuzumab versus ibrutinib plus obinutuzumab in first-line CLL. Once again, the ibrutinib combination therapy was superior, leading to a better PFS.⁶ All three studies demonstrated that ibrutinib should be the SoC for the majority of frontline patients with CLL, completely changing the treatment dogma in the field.

More recently, the Lymphoma Hub covered the randomized, phase III CLL14 trial, which was published in the New England Journal of Medicine (CLL14, NCT02242942). In this study, investigators compared venetoclax plus obinutuzumab (VenG) versus chlorambucil plus obinutuzumab in previously untreated older patients with CLL and comorbidities. VenG was associated with a superior PFS compared with chlorambucil plus obinutuzumab, which led to its approval by the US Food and Drug Administration (FDA) as a fixed-duration (one year) treatment of patients with CLL in the frontline setting.⁷ Updated data from the CLL14 study, presented at the 61^st ASH annual meeting, demonstrated VenG sustained high response rates, including measurable residual disease (MRD)-negativity, at a median follow-up of 39.6 months, when all patients had been off therapy for a minimum of two years.⁸  VenG reduced the risk of disease worsening or death by 69% compared to chlorambucil plus obinutuzumab (PFS, as assessed by investigator; HR 0.31; 95% CI, 0.22—0.44; p < 0.0001).

Ibrutinib monotherapy and VenG are approved for the first-line treatment of CLL, but there are still certain patient populations who can benefit from FCR-based chemoimmunotherapy. Patients with low-risk CLL (mutated IGHV but without the 17p deletion or a TP53 mutation) achieve remission and long-term benefits with FCR-based regimens and so for this subgroup of patients, chemoimmunotherapy is still considered the most appropriate regimen.⁹ 

The combination of ibrutinib and venetoclax in older patients with high-risk CLL has been studied in a phase II trial  (NCT02756897) and was reported to be an active and tolerable regimen in these patients.¹⁰ Patients had previously untreated CLL with at least one of the following: del(17p), mutated TP53, del(11q), unmutated IGHV, aged ≥65 years. Data presented at the 61^st ASH annual meeting, with a median follow-up of 27 months, reported that responses improved with ongoing therapy (65% of patients achieved bone marrow (BM) U-MRD at 12 months and 75% patients at 24 months).¹¹ See the Lymphoma Hub summary here.