Despite New Treatments in CLL, Comparative Data and Guidance Slow to Emerge

Anthony Mato, MD, MSCE

With newer agents approved for patients with chronic lymphocytic leukemia (CLL), physicians are now challenged with how best to utilize them, according to a presentation by Anthony Mato, MD, MSCE, at the 2nd Annual Live Medical Crossfire: Hematologic Malignancies meeting presented in New York, NY.

The Promise of Combination Therapies

"There have been several molecules that have been approved," said Mato, director of the CLL Program Leukemia Service, Memorial Sloan Kettering Cancer Center. "It is wonderful for providers and patients to have these opportunities, but new challenges have emerged on how to best sequence these therapies, combine these therapies, and how to manage patients who fail all of these therapies either sequentially or in combination."Treatment for patients with CLL has significantly evolved from the historical standard of initial chemotherapy with chlorambucil. To date, chemoimmunotherapy regimens have been exploring the incorporation of monoclonal antibodies and targeted therapy, including Bruton tyrosine kinase (BTK) inhibitors and novel inhibitors of phosphoinositide 3-kinase (PI3K).

The BTK inhibitor ibrutinib (Imbruvica) in combination with standard frontline chemoimmunotherapy fludarabine/cyclophosphamide/rituximab was explored in a recent phase II study as a frontline treatment for patients with CLL who were young and fit.¹ Of the 35 patients evaluable for efficacy, the overall response rate (ORR) was 100%. Furthermore, 57% of patients achieved a complete response with bone marrow minimal residual disease (MRD)-negativity and 83% achieved bone marrow MRD-negativity at best response.

In a similar population setting, ibrutinib was also combined with chemoimmunotherapy fludarabine, cyclophosphamide, and monoclonal antibody obinutuzumab (Gazyva) as frontline treatment.² TP53 aberrations, however, were excluded from the study and all patients (n= 32) were IGHV-mutated. The phase II trial showed an objective response rate of 100%, similar to the previous trial, with 87% of patients achieving bone marrow MRD-negativity after 3 cycles of therapy.

"The take home from this evaluation was that early on in therapy, we see 100% ORR, we see a high proportion of patients who are MRD-negative or MRD-undetectable," said Mato. "So [these are] very active combinations."

Other combinations outside of chemoimmunotherapy are also undergoing evaluation. The phase III MURANO study included 389 patients with relapsed/refractory CLL who were randomized to rituximab plus either venetoclax (Venclexta) (n= 194) or bendamustine (n= 195).³

With a 23 month-median follow up, median progression-free survival (PFS) was not reached in the venetoclax arm compared with 18.1 months (95% CI, 15.8-22.3) in the bendamustine arm (HR, 0.19; 95% CI, 0.13-0.28; P <.0001). Additionally, higher and more durable peripheral blood MRD-negativity rates were obtained with the use of venetoclax and rituximab (Rituxan). Based on these findings, venetoclax was granted a standard FDA approval for patients with CLL following at least 1 prior therapy.

Considerations for Therapy Sequencing

Venetoclax has also proven to be effective in combination with ibrutinib. The phase II CAPTIVATE data demonstrated 100% ORR with the frontline combination.⁴ Of the 164 patients enrolled on the study, 77% of patients tested for MRD-negativity in the peripheral blood after 6 cycles of treatment.A significant proportion of patients of patients with CLL are treated with ibrutinib in the first-line and relapse/refractory setting, noted Mato. For these patients, the reason for discontinuation greatly influences the choice for next therapy, however, data on sequencing following ibrutinib are limited.

A prospective phase II trial looked at venetoclax as monotherapy in patients with CLL who had discontinued either ibrutinib or idelalisib (Zydelig).⁵ For those who discontinued ibrutinib-based therapy (n = 91), the ORR was 60% (n = 59). Additionally, a durable PFS of 24.7 months was observed.

Additionally, data from a retrospective analysis looked at patients who had discontinued treatment with a BTK inhibitor or venetoclax.⁶ For patients who discontinued B-cell receptor kinase inhibitor (KI) treatment based on toxicity, those treated with an alternative KI showed superior PFS when compared with patients who discontinued treatment based on disease progression.

"The take home here was that reasons for discontinuation may be relevant. For patients who discontinued ibrutinib because of toxicity, they could be rescued with idelalisib, for example. For patients who discontinued ibrutinib in the setting of disease progression, an alternative KI didn't do so well. Those patients were probably best suited for venetoclax-based therapy."

Additional considerations need to be considered in the relapsed/refractory setting, added Mato, including repeated prognostic evaluation. "CLL is not a static disease, it is a disease of genetic instability. You can acquire abnormalities and those may influence treatment decision-making."

Comparative Data Lacking

For patients treated with chemoimmunotherapy who develop relapsed/refractory disease, re-challenging chemoimmunotherapy is rarely advised based on limited efficacy and potential risks. Instead, preliminary data have shown promise with novel agents, such as ibrutinib, idelalisib, and venetoclax, after failure of frontline treatment.Although monotherapy and combination therapy in the setting of frontline and relapse/refractory CLL are continuing to be evaluted, Mato noted during his presentation that comparative data are lacking. "If all of these drugs are available for me, how can I pick and choose one combination over another? Additionally, we have no data on sequencing, no comparison to sequential monotherapies, which I think is important," said Mato. "If I give everything upfront, is it any better than doing ibrutinib, idelalisib, and venetoclax sequentially? We have no relevant control tests with the exception of the data from the MURANO trial."

References

1. Davids MS, Kim HT, Brander DM, et al. A multicenter, phase II study of ibrutinib plus FCR (iFCR) as frontline therapy for younger CLL patients. In: Proceedings from the American Society of Hematology 59th Annual Meeting & Exposition; December 9-12, 2017; Atlanta, GA. Abstract 496.
2. Jain N, Thompson PA, Burger JA, et al. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) (iFCG) for previously untreated patients with chronic lymphocytic leukemia (CLL) with mutated IGHV and non-del (17p). J Clin Oncol. 2017;35(suppl; abstr 7522).
3. Seymour JF, Kippes TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018; 378:1107-1120. doi: 10.1056/NEJMoa1713976.
4. Wierda WG, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL). J Clin Oncol. 2018;36 (suppl; abstr 7502).
5. Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;131(151):1704-1711. doi: 10.1182/blood-2017-06-788133.
6. Mato Ar, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050-1056. doi:10.1093/annonc/mdx031.