Exploring Beyond Chemoimmunotherapy Combinations in CLL

Shagun Arora, MD

Shagun Arora, MD

Eight new agents have been granted FDA approval for the treatment of chronic lymphocytic leukemia (CLL) within the last decade, leaving investigators to now focus on achieving optimal sequencing with these agents.

The wave of approvals began in 2010 with rituximab (Rituxan), followed by obinutuzumab (Gazyva), ibrutinib (Imbruvica), idelalisib (Zydelig), ofatumumab (Arzerra), venetoclax (Venclexta), and most recently, duvelisib (Copiktra). Additionally, there are multiple agents targeting the CLL cell, such as acalabrutinib (Calquence) and umbralisib, currently being explored in clinical trials.

Much effort is being focused on investigating sequencing strategies, according to Shagun Arora, MD, an assistant clinical professor of the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center. Trials have so far investigated ibrutinib in treatment-naïve and relapsed/refractory patients, venetoclax after ibrutinib or idelalisib, venetoclax plus rituximab, ibrutinib plus venetoclax in treatment-naïve and relapsed/refractory patients, and immunotherapy with chimeric antigen receptor (CAR) T-cell therapy.

In a 5-year update of single-agent ibrutinib in treatment-naïve and relapsed/refractory patients with CLL, it was concluded that long-term use of the BTK inhibitor was well tolerated.¹Additionally, there were minimal adverse events (AEs) observed, with the most common AE at 5 years being hypertension.

"The median progression-free survival (PFS) is double what was seen with fludarabine-cyclophosphamide-rituximab (FCR) in relapsed/refractory CLL—and this is with just a single agent," explained Arora. "In deletion 17p [del(17p)], the median overall survival (OS) was 57 months with a 5-year OS of 32%."

However, most of the responses with single-agent ibrutinib were partial responses. Arora added that high-risk cytogenetics and number of prior therapies predicted inferior survival, and more work must be done for patients with del(17p). This is an area of particular need, as chemoimmunotherapy is not effective in patients with del(17p).

Ibrutinib was approved by the FDA in 2016 for the frontline treatment of patients with CLL based on data from the RESONATE-2 trial, which showed that ibrutinib improved PFS by 84% versus chlorambucil in previously untreated patients.²Arora noted that this population was aged 65 years or older, and patients with del(17p) were not included.

In a National Institutes of Health study, which included patents with del(17p) and TP53 mutations, the 24-month PFS for treatment-na&iuml;ve patients was 90%, Arora said.³The MURANO trial investigated venetoclax plus rituximab versus bendamustine plus rituximab in patents with relapsed/refractory CLL. At a 23-month median follow-up, the median PFS was not reached with venetoclax plus rituximab versus 18.1 months (95% CI, 15.8-22.3) with bendamustine plus rituximab (HR, 0.19; 95% CI, 0.13-0.28;P<.0001).⁴The overall response rate was 92% for the venetoclax arm and 72% for the bendamustine arm. These data led to a full FDA approval in June 2018 for venetoclax in CLL regardless of del(17p).

Currently, there are 3 main trials investigating the combination of ibrutinib and venetoclax: CLARITY (ISCRTN13751862), CAPTIVATE (NCT02910583), and a phase II single-center trial at The University of Texas MD Anderson Cancer Center (NCT02756897). "A combination that is being looked at in the world of CLL is ibrutinib with venetoclax—2 oral agents,&rdquo; said Arora. &ldquo;There are some preclinical data saying that there may be synergy, and as we know, they work a little different with ibrutinib being a BTK inhibitor and venetoclax working on BCL-2.&rdquo;

The doses in these trials are the same that are being evaluated in different settings. CLARITY is looking at relapsed/refractory CLL, while CAPTIVATE is enrolling treatment-na&iuml;ve patents. Arora says that these 2 trials are stopping treatment based on minimal residual disease (MRD) status. In CAPTIVATE, if the patients are MRD-negative after 12 cycles, they are being randomized to placebo versus single-agent ibrutinib. In CLARITY, they are stopping therapy all together once MRD negativity is reached.

Arora honed in on the third trial, which is being conducted by Nitin Jain, MD, of The University of Texas MD Anderson Cancer Center. This study is investigating the combination of venetoclax and ibrutinib in patients with high-risk and relapsed/refractory CLL. Of the patients enrolled, 37 are relapsed/refractory, 40 are treatment-na&iuml;ve with high-risk disease, del(17p), del(11q), or are IGVH-unmutated, reported Arora. These patients received venetoclax for 2 years and ibrutinib until progressive disease. Jain is looking at MRD, said Arora; however, the drug is not being stopped based on the results.

Early results from this trial were presented at the 2017 ASH Annual Meeting. Most notably, Arora said, was that at the 12-month mark, 100% of patients were MRD-negative in the bone marrow.⁵The response in the relapsed/refractory setting is less, with 46% of patients achieving MRD negativity.

"We don't know right now what to do with the MRD-negative status," said Arora. "Should we be stopping therapy? Is that the right thing to do? Once most of these data mature, we will have more information on that."

With multiple agents available, Arora said that sequencing has become a major question.

Responses have been observed in patients with CLL treated with venetoclax following treatment with ibrutinib or idelalisib. Although it does not give much direction on sequencing, Arora explained that it shows that venetoclax can be used after kinase inhibitors.

In a study published in Annals of Oncology in 2017, investigators aimed to determine the optimal sequencing of ibrutinib, idelalisib, and venetoclax.⁶This 683-patient multicenter study showed that ibrutinib appeared to be superior to idelalisib when used as the first kinase inhibitor in patients with CLL. If a patient experienced kinase failure, venetoclax proved to be superior to chemoimmunotherapy. Additionally, venetoclax may be superior to idelalisib in the event of ibrutinib failure. Investigators noted that more trials are needed to explore sequencing strategies.

"Most people are going for ibrutinib as their first-line oral therapy for CLL," said Arora.

There are multiple phase III trials that are currently ongoing in patients with CLL. In her conclusion, Arora highlighted ECOG-E1912 (NCT02048813), ALLIANCE A041202 (NCT01886872), and CLL13 (NCT02950051) as studies of interest. The first 2 trials have been enrolled, but the third is still accruing patients.

Additionally, there is a CAR T-cell therapy trial opening at UCSF. This is an open-label, phase I safety and phase II randomized study of JCAR017 in patients with relapsed/refractory CLL or small lymphocytic lymphoma. In this study, which is set to open later in 2018, ibrutinib is being given following infusion of CAR T cells.

References:

1. O&rsquo;Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-na&iuml;ve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience.Blood. 2018;131:1910-1919. doi: 10.1182/blood-2017-10-810044.
2. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia.N Engl J Med. 2015;373:2425-2437. doi: 10.1056/NEJMoa1509388.
3. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukemia with TP53 aberrations: a phase 2, single-arm trial.Lancet Oncol. 2015;16(2):169-176. doi: 10.1016/S1470- 2045(14)71182-9.
4. 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.
5. Jain N, et al. Combined venetoclax and ibrutinib for patients with previously untreated high-risk CLL, and relapsed/refractory CLL: a phase II trial. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract 429.
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.