Novel CLL Regimens Show Promising Efficacy

Suman Kambhampati, MD

BTK inhibitor—based regimens, chimeric antigen receptor (CAR) T-cell therapy, and venetoclax (Venclexta) combined with rituximab (Rituxan) are all novel, therapeutic strategies that recently showed efficacious outcomes in patients with chronic lymphocytic leukemia (CLL), according to Suman Kambhampati, MD.

For example, studies evaluating the BTK inhibitor ibrutinib (Imbruvica) in combination with other agents—such as obinutuzumab (Gazyva), chemoimmunotherapy regimens, venetoclax, and CD19-directed CAR T-cell therapy—all demonstrated encouraging outcomes. Specifically, the combination of ibrutinib and obinutuzumab in the frontline setting for patients with CLL or small lymphocytic lymphoma (SLL) was associated with encouraging data in the phase III iLLUMINATE (PCYC-1130) trial.

Results showed that the combination demonstrated a 77% reduction in the risk of progression or death compared with chlorambucil plus obinutuzumab.¹ Moreover, at a median follow-up of 31 months, the median progression-free survival (PFS), as assessed by an independent review committee, was not reached compared with 19 months for chlorambucil and obinutuzumab (HR, 0.23; 95% CI, 0.15-0.37; P <.0001). Based on these data, the FDA approved the ibrutinib/obinutuzumab combination in January 2019 for treatment-naïve patients with CLL/SLL.

Secondly, findings of a prospective trial demonstrated that anti-CD19 CAR T-cell therapy with CART19 showed a 43% complete response (CR) rate, 94% bone marrow remission rate, and a 78% minimal residual disease (MRD)-negative response rate in patients with CLL who did not achieve a CR following 6 months of ibrutinib treatment.² Based on these encouraging data, the regimen will be further tested in larger trials.

Additionally, the combination of venetoclax and rituximab led to an improved PFS and high rates of undetectable MRD (uMRD) in relapsed/refractory patients.³

OncLive: One of your presentations at the State of the Science SummitTM was on CLL. Could you highlight what is new in this space?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Kambhampati, the co-director of the Blood Cancer Center at Sarah Cannon Cancer Institute, HCA Midwest Health, reflected on the emergence of data in CLL from the 2018 ASH Annual Meeting.Kambhampati: One of the resounding themes of the 2018 ASH Annual Meeting was the introduction of novel drugs. There were also some new themes evolving from the novel drugs, showing that compared with our traditional bones of chemoimmunotherapy, BTK inhibitors—especially ibrutinib—is a practice-changing paradigm both in the young and elderly patient populations. We saw that results were better with ibrutinib-based combinations.

We also saw some unique combinations with chemoimmunotherapy and ibrutinib presented, showing that it produces early and deep MRD-negative responses, which we hope will be translated into a bigger cooperative study group.

Could you discuss the recent FDA approval of ibrutinib and obinutuzumab in upfront CLL?

You alluded to the CAR T-cell therapy data in CLL. What has been reported thus far?

Are there patient populations in CLL that still remain to be challenging to treat, even with these therapeutic advancements?

The deeper responses we are seeing with venetoclax and rituximab is something that is unprecedented, and we are seeing that the responses are not only deep but lasting. Those are the big themes, and in the end, we also saw some really groundbreaking data with cellular therapy with CAR T-cell therapy in pretreated and in upfront CLL. That, again, was very well received at the 2018 ASH Annual Meeting.That study, which is the iLLUMINATE trial, basically shows that it is the first nonchemotherapy combination of ibrutinib and obinutuzumab to be extremely effective in all subgroups of CLL, including those with bulky disease and poor-risk genotypes. The results were outstanding and showed [prolonged] PFS and [responses] than we traditionally see with ibrutinib alone. That led to the approval of the combination in the untreated CLL population.[Researchers from] the University of Pennsylvania presented some really intriguing data [with] ibrutinib, which is typically not associated with deep remissions. Priming patients with ibrutinib at least up to 6 months of ibrutinib followed by CAR T-cell therapy infusions led to deeper remissions and MRD-negative status at a pretty early time point. Having taken care of some of those patients here who participated in that trial is groundbreaking research, which we hope will be supported. Hopefully, we can see early introduction of these cellular therapies in CLL.The challenging cases in CLL, still, are those patients with high comorbidity index—also known as the Cumulative Illness Rating Scale. That is still an unmet need. We need some therapies in our designs, specifically for that group of patients. The new wave of trials is looking into that.

The second unmet need is resistance to novel drugs; what [drug] comes after that is something that is still undefined. The third unmet need is pharmacoeconomics of these drugs. These are costly and, especially when patients are on nonstop therapy, then there is a big aspect of financial toxicity, which needs to be discussed more.

References

1. Moreno C, Greil R, Demirkan F, et al. Ibrutinib + obinutuzumab versus chlorambucil + obinutuzumab as first-line treatment in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL): results from phase 3 iLLUMINATE. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 691.
2. Gill SA, Vides V, Frey NV, et al. Prospective clinical trial of anti-CD19 CAR T cells in combination with ibrutinib for the treatment of chronic lymphocytic leukemia shows a high response rate. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 298.
3. Kater AP, Hillmen P, Eichhorst B, et al. First prospective data on impact of minimal residual disease on long-term clinical outcomes after venetoclax plus rituximab versus bendamustine plus rituximab: phase III MURANO study. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 695.