Novel Treatment Strategies Emerging for CLL

Jennifer Brown, MD, PhD

Ibrutinib (Imbruvica) and idelalisib (Zydelig) have become standard of care treatments for patients with relapsed or high-risk chronic lymphocytic leukemia (CLL), with ongoing studies in progress to move ibrutinib into a broader frontline indication, according to Jennifer Brown, MD, PhD, at the 2016 ASCO Annual Meeting.¹

For fit and young patients with CLL, the frontline standard currently remains fludarabine, cyclophosphamide, and rituximab (FCR), especially for those with IGHV mutations. For patients with comorbidities or those at an older age, standard options include chlorambucil plus an anti—CD20 antibody or ibrutinib, particularly for those at high-risk. In those with del17p CLL, ibrutinib is preferred as initial therapy followed by the BCL2 inhibitor venetoclax (Venclexta).

"Certainly for relapsed therapy, the kinase inhibitors have moved in, led by ibrutinib. For patients with a long duration of remission to prior chemoimmunotherapy and low-risk cytogenetics, it could be reasonable to repeat chemoimmunotherapy, but that's not going to be the most common," said Brown, from the Dana-Farber Cancer Institute. "For the frontline fit, young patients, chemoimmunotherapy certainly remains the standard, pending ongoing trials."

The newer targeted therapies for patients with CLL come with a distinct set of advantages, Brown explained. They are orally administered, mostly well tolerated, and highly effective, especially for those with high risk or relapsed disease. However, these agents are associated with distinct drawbacks, primarily the length of treatment, as these agents are given indefinitely at a continuous dose. Chemoimmunotherapy is administered for a set 6-month course.

Adding to the treatment decision, little is currently known about the long-term adverse events with ibrutinib and idelalisib. Low-grade, nagging side effects have been seen with these therapies, which become bothersome with long-term treatment, Brown noted. Adding to this, the tolerability appears to worsen with increasing age, and a cure has been seen with FCR for patients with IGHV-mutant CLL, which is an approach that would be hard to abandon. "And of course, there's the question of costs to the patient and the healthcare system," said Brown.

"One of the ways to solve these problems is to find effective, well-tolerated combinations that induce remissions that are deep that might allow us to stop therapy after a relatively short fixed period of time,” she said. “This has the advantage of patient preference, reducing long-term side effects, and reducing costs."

Stopping treatment may preserve sensitivity to ibrutinib, if a subsequent relapsed were to occur, Brown noted. At this point, treatment options following progression on ibrutinib are largely ineffective. In available long-term data, median overall survival (OS) in those with progressive CLL (n = 13) following ibrutinib is just 17.6 months. After a median of 3-years of follow-up, the median OS across the full population has not yet been reached.

Venetoclax is an ideal agent for combination strategies, particularly in combination with ibrutinib, Brown noted. In vivo studies have shown that venetoclax can clear CLL cells that persist following ibrutinib treatment.

As a single-agent, venetoclax demonstrated an objective response rate (ORR) of 79% in patients with relapsed/refractory CLL who received a median of 4 prior regimens.² Twenty-percent of patients had a complete remission (CR). For those with del17p disease, the ORR was 71% and the CR was 16% with venetoclax. The median progression-free survival (PFS) with the BCL2 inhibitor was 25 months in a dose-escalation cohort. In those with del17p CLL, the median PFS was 16 months.

"The complete remission rate really highlights how this drug clears the blood and bone marrow more effectively than the kinase inhibitors," said Brown. "In general, responses were preserved across all groups, although there was a tendency to a lower CR rate in those with bulky nodes, in a kinase inhibitor combination that would likely be obviated, as kinase inhibitors are very potent in bulky nodes."

In April 2016, the FDA approved venetoclax as a second-line therapy for patients with del17p CLL following 1 prior therapy. This indication was based on data from the phase II M13-982 study, which showed a 12-year estimated ORR of 84.7% with venetoclax in del17p CLL. The 12-month PFS rate was 72% and the 12-month OS rate was 86.7%.³

"The main issue that has emerged with venetoclax in its development is tumor lysis, in fact there were some deaths in the early development of the drug from tumor lysis," said Brown. "Much work has gone into risk stratification and management, which is reflected in its approval and prescriber labeling."

For tumor lysis, patients are classified as low-risk if they have a nodal mass of <5 cm and an absolute lymphocyte count (ALC) of <25,000. Median risk is defined as nodal mass of ≥5 cm but <10 cm or an ALC of ≥25,000. Those at high risk have a nodal mass ≥10 cm or a nodal mass ≥5 cm but <10 cm with an ALC ≥25,000.

"Median and high risk patients with impaired renal function received dose escalations inside the hospital," Brown noted. "Strategies are well laid out in the prescriber information, and need to be followed closely for patient safety. Once you get patients through the escalation, the treatment is very well tolerated."

A number of phase II studies are looking at the combination of ibrutinib and venetoclax for patients with CLL. One of these studies is looking at the combination in relapsed/refractory and high-risk populations (NCT02756897). Additionally, a triplet regimen of ibrutinib, venetoclax, and obinutuzumab (Gazyva) is being explored for patients with previously untreated high-risk CLL in a phase II study known as CLL2-GiVe (NCT02758665).

References

1. Brown JR. Targeted Therapy in Chronic Lymphocytic Leukemia: Where are we now? Presented at: 2016 ASCO Annual Meeting; Chicago, Illinois; June 3-7, 2016.
2. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia [published online December 6, 2015]. N Eng J Med. doi:10.1056/NEJMoa1513257.
3. Stilgenbauer S, Eichhorst BF, Schetelig JS, et al. Venetoclax (ABT-199/GDC-0199) monotherapy induces deep remissions, including complete remission and undetectable MRD, in ultra-high risk relapsed/refractory chronic lymphocytic leukemia with 17p deletion: results of the pivotal international phase II study. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract LBA6.