MRD-Guided Treatment Represents the Future in CLL

William G. Wierda, MD, PhD

Minimal-residual disease (MRD) has become an important prognostic factor in guiding treatment decisions for patients with chronic lymphocytic leukemia (CLL), according to William G. Wierda, MD, PhD. Investigators are using MRD as a proxy for progression-free survival (PFS) to evaluate the efficacy in studies of ibrutinib (Imbruvica) plus venetoclax (Venclexta), as well as studies of CD19-directed CAR T-cell therapies.

“MRD results correlate with PFS, so it is prognostic for how patients do with finite-duration treatment,” Wierda said. “[Patients] get a course of treatment, they [achieve] remission, and [when] they come off treatment, their MRD status clearly correlates with PFS and overall survival. [This has] given us a prognostic tool for outcomes for our patients with fixed-duration treatment.”

In an interview with OncLive^®, Wierda, professor, D.B. Lane Cancer Research Distinguished Professor, section chief of Chronic Lymphocytic Leukemia, center medical director, Department of Leukemia, Division of Cancer Medicine, and executive medical director, Inpatient Medical Services, The University of Texas MD Anderson Cancer Center, discussed the results of the phase 2 CAPTIVATE trial (NCT02910583) and the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198), and looked ahead to what the future holds for MRD in patients with CLL.

OncLive^®: Could you discuss the rationale for CAPTIVATE, which evaluated a fixed-duration regimen with ibrutinib and venetoclax in patients with CLL?

Wierda: The CAPTIVATE study has 2 cohorts. There is an MRD cohort, which we have previously reported on. The primary endpoint for that cohort was to look at the 1-year disease-free survival [DFS] for patients who had achieved a confirmed undetectable MRD among those who were randomized to receive continued ibrutinib single-agent or placebo.

The presentation that I gave at iwCLL [the International Workshop on Chronic Lymphocytic Leukemia] was on the fixed-duration cohort. All 159 patients in this cohort received the same treatment, were previously untreated, and were 70 years old or younger. [These patients] received 3 months of single-agent ibrutinib, followed by 12 cycles of combined ibrutinib and venetoclax. The primary end point for this cohort was to evaluate the complete remission [CR] rate, including CR with incomplete recovery at the end of the combined therapy. [We also wanted to] demonstrate that [the CR rate] is higher than what we would expect with a chemoimmunotherapy regimen, such as fludarabine/cyclophosphamide/rituximab, which has a 40% CR rate.

In this encore presentation of the data, we reported a CR rate of 54% [in] this for this cohort of patients. A significant number of these patients achieved an undetectable MRD status in this cohort, as was also reported for the MRD cohort. There is reduction in the risk for tumor lysis syndrome [TLS] with 3 cycles of lead in ibrutinib monotherapy. [Additionally,] there is a significant reduction in the percentage of patients who would have needed admission, had they not received the 3 cycles of single-agent ibrutinib. This is a well-tolerated combination, and we did not see any increase in toxicity with the combination vs what would have been expected with single-agent ibrutinib or with venetoclax for fixed-duration treatment. These patients are experiencing deep permissions and so far, most of them are enjoying a long remission duration.

What are the clinical implications of these findings? Are there any next steps planned?

There are 2 strategies that can be taken with targeted therapy. One is continuous treatment with a maintenance-type strategy. The other approach is a fixed-duration, or finite-duration treatment, with the intent of getting patients into deep remission and having undetectable MRD status. [This] correlates with a longer PFS.

In terms of the evolution of therapies, at least in our program, most of us are thinking about fixed-duration treatment as an avenue to developing curative therapy. This is a large, international, multicenter trial which demonstrates the feasibility and activity of a combination of targeted therapy and of chemotherapy-free treatment. [Additionally,] it demonstrates high response rates with the expectation of a long remission. Continued work [will be] directed at other novel combinations, and the goals of therapy are to increase the proportion of patients who [have] undetectable MRD. As [such], this is a pathway to developing curative strategies.

Moving on to the TRANSCEND CLL 004 study, what is important about this trial? What were the results?

TRANSCEND CLL 004 is a phase 1/2 trial of liso-cel [lisocabtagene maraleucel; Breyanzi], a CD19-directed CAR [chimeric antigen receptor] T-cell strategy for patients with relapsed or refractory CLL. Right now, there are 3 cohorts for enrollment on this trial. One is a monotherapy cohort, which Tonya Siddiqi, MD, of City of Hope, has previously reported on. The second is a combination cohort looking at liso-cel plus ibrutinib, and the third is a cohort that has just recently opened, and that is examining the combination of liso-cel plus venetoclax. The report that I made at iwCLL this year is an encore presentation of the ibrutinib plus liso-cel cohort.

The rationale for [this combination] comes from work that has been done at several centers in the country. [The work has] demonstrated [that] there is perhaps a reduction in adverse effect [AE] and toxicity severity with the addition of ibrutinib, and an increase in activity with the combination vs CD19-directed CAR-T cell monotherapy.

There are 2 dose levels in this report. Ibrutinib was standard dose. Treatment began with ibrutinib when patients were enrolled, through apheresis and collection and cell production, and then for 90 days after CAR T-cell infusion. Two dose levels of liso-cel [were] given on this trial; 50 million or 100 million. The dose to move forward with this combination was 100 million, and the same dose was selected for the monotherapy arm.

There were 23 patients enrolled in [the lower dose] cohort, and 19 patients in the higher dose [cohort]. The incidence of grade 3 or higher cytokine release syndrome [CRS] was low at less than 10%, and we did not see any grade 3 or higher CRS events in the 100 million dose level.

The incidence of neurotoxicity grade 3 or higher was 22%, and that was manageable with steroids or tocilizumab [Actemra]. We demonstrated tolerability with the combination in this cohort, and activity with a high response rate. Sixty-three percent [of patients were] complete responders, and approximately 90% of patients had MRD undetectable status in the bone marrow.

[This regimen demonstrated] particularly significant activity in a relapsed and refractory population of patients, so we are enthusiastic about this strategy. CD19-directed CAR-T therapy offers something that we do not currently have in our toolbox to manage patients with CLL. Right now, it has demonstrated activity in refractory disease and hopefully, as we gain more experience, we will move it earlier in the treatment algorithm for patients with CLL. The TRANSCEND studies are still enrolling patients in the combination cohorts.

What are the key updates about MRD and CLL? What can we expect in the future?

We have had MRD, and done MRD studies, for many years now, starting with chemoimmunotherapy and now with targeted therapy. The targeted therapy that has allowed us to come back to this discussion has been venetoclax. With venetoclax, we achieve very, very deep remissions and we are seeing very good results with our combination strategies.

[The question now is] how this test will be used to direct therapy. We need to develop strategies and clinical trials that utilize MRD status to direct treatment. That may be directing treatment in terms of duration or switching treatment if we have not achieved an MRD undetectable status at a time point that we feel is necessary. Moving forward, I look forward to using MRD to direct therapy in for patients with CLL, and ultimately, as a tool to help develop curative therapies for our patients.