CLL Treatment Moves Toward Combo Approaches and CAR T-Cell Therapy

William G. Wierda, MD, PhD

Chronic lymphocytic leukemia (CLL) treatment is moving away from chemoimmunotherapy and toward more novel and targeted approaches, with several clinical trials examining agents alone and in combination, explained William G. Wierda, MD, PhD.

“We're moving away from chemoimmunotherapy in favor of small molecule inhibitor therapy. We will be working more toward combinations, achieving very deep remissions, and looking at minimal residual disease as an endpoint for our treatment,” said Wierda. “The strategies and approaches for patients with CLL will come with the new work that we're doing and the clinical trials we're doing.”

For example, the phase III ASCEND trial demonstrated that the BTK inhibitor acalabrutinib (Calquence) versus rituximab (Rituxan) plus idelalisib (Zydelig) or bendamustine/rituximab led to a 69% reduction in the risk of disease progression or death. At a median follow-up of 16.1 months, the median progression-free survival (PFS) was not reached in the acalabrutinib arm compared to 16.5 months in the rituximab arms (HR, 0.31; 95% CI, 0.20-0.49; P <.0001).

Partly based on these data, the FDA granted a breakthrough therapy designation to acalabrutinib in August 2019 for the treatment of patients with chronic lymphocytic leukemia. The status was also based on results of the phase III ELEVATE-TN (ACE-CL-007) trial, which compared acalabrutinib alone or in combination with obinutuzumab (Gazyva) versus chlorambucil/obinutuzumab in treatment-naïve patients with CLL. Full findings will be presented at an upcoming medical meeting.

Additionally, CAR T-cell therapy is gaining momentum in the CLL space. The ongoing phase I/II TRANSCEND CLL 004 trial, which is examining lisocabtagene maraleucel (liso-cel; JCAR017) in patients with relapsed/refractory CLL and small lymphocytic lymphoma, elicited a best overall response rate of 87% and a complete response rate of 47%.

In an interview with OncLive, Wierda, 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, The University of Texas MD Anderson Cancer Center, discussed the evolving treatment paradigm in CLL and ongoing trials looking at novel approaches.

OncLive: Could you provide an overview of the ASCEND trial? How have these results impacted sequencing?

Wierda: The ASCEND trial was a phase III clinical trial evaluating acalabrutinib versus bendamustine/rituximab or idelalisib/rituximab for patients with relapsed CLL. It was a positive trial, showing improved PFS for patients who received acalabrutinib monotherapy over either idelalisib/rituximab or bendamustine/rituximab. Most of the patients in the comparator arm received idelalisib-based therapy, but it was clearly a trial that showed improvement in outcomes with acalabrutinib.

In terms of sequencing, [these data] demonstrate that acalabrutinib is an option for patients in the relapsed setting as a BTK inhibitor. I would use [acalabrutinib] as an irreversible BTK inhibitor option. The other irreversible BTK inhibitor that we have is ibrutinib (Imbruvica).

How is CAR T-cell therapy being explored in CLL?

CD19-directed CAR T-cell therapy is currently approved for patients with relapsed acute lymphoblastic leukemia (ALL) up to age 25 and in adults with diffuse large B-cell lymphoma that is refractory to treatment. Data have shown durable responses in those two patient categories. In CLL, CAR T-cell therapy is still investigational. The TRANSCEND CLL 004 trial is a phase I/II clinical trial that is ongoing with [liso-cel], which is a CD19-directed CAR T-cell therapy that is being evaluated in patients with CLL.

In the smaller single-center, phase I trials in early development, the reports of activity with CD19-directed CAR T-cell therapy in CLL have reported lower CR rates than we see in other diseases, such as ALL. There is durability, but the complete remission rates have been in the 20% to 30% range, which is relatively low for this strategy, in comparison to ALL where the complete remission rate is 80% to 90%. The TRANSCEND CLL 004 study [has] early results, and those will be updated at the 2019 ASH Annual Meeting. The CR rate appears to be about 50% with that product; it's encouraging. We still need a lot more work with CD19-directed CAR T-cell therapy in CLL, but I'm optimistic.

How is chemoimmunotherapy being utilized in CLL treatment?

Chemoimmunotherapy has been a very active strategy to get patients into remission. Our work over the years had been developing regimens that get as many patients as we can in complete remission. That's at the cost of myelosuppression associated with these multidrug regimens that we developed. We developed combinations of chemoimmunotherapy that got many patients in a deep remission, but it became less relevant for most patients with CLL because they are myelosuppressive and we couldn't give [these regimens] to older patients.

For patients who have a mutated IgHV who received fludarabine and cyclophosphamide plus rituximab (FCR), there is a plateau on the curve—potentially including patients who are cured from the treatment. These patients [typically] have a mutated [IgHV and represent] about 50% of the patients who are progression free more than 10 years after their initial treatment with FCR; this makes it a viable option. We're seeing it used less and less for patients these days because we have better options with the targeted therapies.

At The University of Texas MD Anderson Cancer Center, we are reserving chemoimmunotherapy for patients who we know benefit most from them. Those are the younger patients with a mutated [IgHV]. We're working on new regimens that give less chemotherapy and add targeted therapies to boost the CR rate in order to boost the minimal residual disease—negative rate, and hopefully achieve better results than we have been able to with 6 cycles of standard FCR. Chemoimmunotherapy is less relevant these days. We do see a fair amount of it still being used in the community as a treatment option, but there are substantial phase III data that support using targeted therapy over chemoimmunotherapy now.

What molecular targets are being investigated?

We know from the work that has been done with BTK inhibitors that, if you target the B-cell receptor signaling pathway and block molecules involved in that pathway, we can see responses. BTK is one example of a molecule in that pathway that if we block it, the cells will undergo apoptosis and die, showing that it has therapeutic activity.

PI3K is another member of that signaling pathway that is clearly active when you inhibit it in terms of achieving a response and remission. There are other molecules in that pathway that have been targeted. Syk is one example of a protein that has been targeted for small molecule inhibition. We have seen less activity with monotherapy with Syk inhibitors, but investigators continue to work on those strategies with small molecule inhibitors of other members of the signaling pathway.

The other targeted strategy is BCL-2; we know this is overexpressed in CLL cells. Inhibition and targeting of BCL-2 is very active therapeutically, with the development and responses we see with venetoclax (Venclexta)—based therapy. Perhaps resistance to venetoclax relates to expression of MCL1, which is another member of the BCL-2 family. We are working on strategies to target MCL1, either directly or indirectly, and evaluating those agents in clinical trials.

What other ongoing studies in CLL are you looking forward to seeing the results of?

This will be an interesting 2019 ASH Annual Meeting. A lot of data will be reported out. There is a frontline trial with acalabrutinib that involves evaluating acalabrutinib monotherapy versus acalabrutinib/obinutuzumab versus chemoimmunotherapy in a phase III trial. I'm very excited and anxious to see the results of that trial. [We will soon] see updates on our combinations of targeted therapies, including BTK plus BCL-2, BTK plus BCL-2 plus CD20-directed antibodies. Those combinations are getting patients into very deep remissions. I'm also excited to see the updates with the TRANSCEND trial CLL 004 [with liso-cel].

References

1. Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (idr) or bendamustine (br) in patients with relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL). Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract LB2606.
2. Siddiqi T, Dorritie KA, Soumerai JD, et al. TRANSCEND CLL 004: Minimal residual disease after lisocabtagene maraleucel in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Hematol Oncol. 2019;37(suppl S2):109-110. doi: 10.1002/hon.71_2629.