Ibrutinib Plus Short‐Course Fludarabine Elicits Encouraging CR Rates in Previously Untreated CLL

Higher rates of complete remission (CR) were achieved with the addition of short-course fludarabine to ibrutinib (Imbruvica) in previously untreated patients with chronic lymphocytic leukemia (CLL), according to results from a phase 2 trial (NCT02514083) recently published in the American Journal of Hematology.1

In a phase 2 pilot trial, investigators set out to evaluate the combination of short‐course fludarabine and continuous ibrutinib, with the goal of debulking CLL cells as well as inducing rapid reductions in T-cell numbers.

Results showed that the overall response rate at 6 months was 93.1% with the combination. Moreover, the complete remission (CR) rate was 20.7% at 6 months, 28.0% at 12 months, and 44.4% at 24 months. Additionally, at 6 months, all evaluable patients were alive and free of disease progression. At 2 years, the estimated progression-free survival (PFS) rate was 91.3% (95% CI, 80.5%-100%), while the estimated overall survival (OS) rate was 95.8% (95% CI, 88.2%-100%).

With regard to safety, 83.0% of treatment-related adverse effects (AEs) were grade 1 to 2 in severity. The addition of 2 cycles of fludarabine to ibrutinib did not increase the risk of high‐grade hematologic toxicities or infection, according to lead author of the study Christopher Pleyer, MD. The most commonly reported grade 3 or higher hematologic AEs included neutropenia (27.6%), leukopenia/lymphopenia (31.0%), and thrombocytopenia (10.3%). Most grade 3 or higher cytopenias were associated with the addition of fludarabine; however, they were resolved with supportive care and continuously administered ibrutinib.

“The combination of ibrutinib and short‐course fludarabine appears to be safe, with no excess toxicities; particularly, there was no prolonged T-cell depletion. The combination appears to be effective, with patients achieving high rates of complete remission,” said Pleyer. “However, we need longer follow-up to determine whether these high rates of CR translate into long-term clinical outcomes, particularly improved PFS and OS.”

In an interview with OncLive, Pleyer, a clinician and hematology consultant at The National Heart, Lung, and Blood Institute, further discussed the phase 2 trial examining fludarabine plus ibrutinib in CLL and SLL, the next steps for the research, and where future efforts should be focused.

OncLive: To start, what would you say has been the biggest development made in the CLL and SLL treatment paradigms in recent years?

Pleyer: CLL and SLL occur predominantly in elderly patients who are in their 60’s and 70’s. In the past couple of years, we have seen tremendous advancements made in CLL. We have fantastic new treatment options available. Overall, we are moving away from a chemoimmunotherapy approach, toward a more targeted approach. The 2 most exciting drugs that are currently available for CLL are BTK inhibitors, such as ibrutinib and BCL-2 inhibitors, such as venetoclax (Venclexta).

You were the lead author of a phase 2 study that evaluated ibrutinib in combination with fludarabine in previously untreated patients with CLL and SLL. Could you discuss this trial?

In this study, we used ibrutinib as a backbone, which was already a well-established therapy for patient with CLL. The goal of the trial was to see whether the addition of 2 short courses offludarabine would improve the quality of responses in patients with CLL.

Specifically, we were looking a re-modulating the T-cell compartment with fludarabine to understand whether that adds any additional value for the treatment of [patients with] CLL. Participants started off by receiving 420 mg of ibrutinib once daily, which is the standard dose, and they continued on this therapy until disease progression or unacceptable toxicity. Fludarabine was then added during the third and fourth month of treatment. At this time, patients received 1 infusion each for 5 days. Following that, ibrutinib monotherapy was continued.

What are the findings that have read out thus far?

Two-year follow-up data are available, but we are still waiting for longer-term [results]. After these 2 years, when we did the primary efficacy analysis, we saw that 40% of patient achieved complete remission (CR) [with the combination]. Notably, this [rate] is slightly higher than what we typically see with ibrutinib as a single agent. The CR rates [with ibrutinib monotherapy are] somewhere between 15% and 20%. It’s important to note that this was not a randomized trial, and it’s difficult to compare trials, but the preliminary results did show encouraging CR rates.

The combination was well tolerated, and no additional toxicities were found. Specifically, with fludarabine, we worry about long-term depletion of T cells; however, this was not shown in the study. We also did not observe a significant increase in the number of infections.

What are some unanswered questions that still need to be addressed?

We did subset analyses of the T cells, as well. We were able to find that 2 T-cell subsets: the regulatory T cells and the follicular helper cells. These are thought to be tumor-sustaining T-cell populations that decrease during therapy. We still need longer follow-up to determine whether this translates into any clinical outcomes for patients.

This was a stepping-stone toward another study that is evaluating the addition of pembrolizumab (Keytruda) to this regimen, so a 3-drug regimen. Pembrolizumab is an immunotherapy that is frequently used in other tumor types, as well. The goal is to harness the T cells and the patient's own immune system to help them fight their cancer

Are any other CLL studies ongoing that you wanted to highlight?

A few studies are currently examining different combinations comprised of targeted drugs, specifically ibrutinib and venetoclax. These agents are already approved; however, the combination of the 2 might be more efficacious for patients. We are looking to induce a minimal residual disease (MRD)–negative state for patients [to get them] to a point where we can no longer detect CLL in the blood.

Ultimately, we hope this will bring us close to a cure, or at least a functional cure where we can limit the duration of therapy that patients receive. The current standard is to continue either of these drugs until progression. However, with the investigational combination, we may be able to provide patients with time-limited therapy.

Where should future research efforts be focused in CLL?

The study that is evaluating the addition of pembrolizumab to this regimen is important. Future research efforts should focus on finding combination therapies where we can induce high rates of undetectable MRD. The ultimate goal is to offer patients time limited therapy where they don't have to continuously take agents for their disease.

Reference

1. Pleyer C, Tian X, Rampertaap S, et al. A phase II study of ibrutinib and short–course fludarabine in previously untreated patients with chronic lymphocytic leukemia. Am J Hematol. Published online August 18, 2020. doi:10.1002/ajh.25968