Cellular and Targeted Therapies Push the Envelope in Hematologic Malignancies

Jeffrey Zonder, MD

The explosion of targeted therapies, along with the rise of cellular therapy, has served to push progress forward in hematologic malignancies, according to Jeffrey Zonder, MD, who added that efforts are now being made to improve toxicity by examining novel approaches that do not require continuous administration.

“We have moved away from a one-size-fits-all approach in lymphoma and leukemia, where we once based treatment decisions on clinical factors or prognostic scoring systems. We're now entering a molecularly-driven era,” says Zonder. “With a better understanding of immune surveillance, cellular therapy has become an important addition to the [arsenal]. Moreover, there has been an explosion of targeted therapies, based on our growing understanding of molecular sub-classifications of different tumors. We are now basing [treatment] on actionable molecular [alterations] rather than [just] clinical presentation.”

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Leukemia and Lymphoma, Zonder, a professor of hematology-oncology at Barbara Ann Karmanos Cancer Institute, Wayne State University, highlighted the impact of CAR T-cell therapy in lymphoma and multiple myeloma and ongoing research efforts in leukemia.

OncLive®: CAR T-cell therapies have been a welcome addition to the lymphoma armamentarium. Could you speak to the lessons learned on the CD19-targeted CAR T-cell products examined in the ZUMA-2 and ZUMA-5 studies?

Zonder: The phase 2 ZUMA-2 study evaluated brexucabtagene autoleucel (Tecartus) in patients with mantle cell lymphoma (MCL) who received at least 3 prior lines of therapy. The ZUMA-5 study looked at axicabtagene ciloleucel (axi-cel; Yescarta) in patients with relapsed, low-grade non-Hodgkin lymphoma (NHL); most of them are follicular lymphomas and a handful of them were marginal zone lymphomas.

Both studies examined different CD19-targeted CAR T-cell products, but both of them showed extremely high response rates in patients who had received multiple prior lines of therapy. Moreover, durable responses were reported in the majority of patients who achieved major complete responses.

We also saw minimal residual disease negativity in many of the patients, which was often durable; [this was the case] in the ZUMA-2 study. Both studies demonstrated the known toxicities of cytokine release syndrome and neurotoxicity, which [were] fortunately manageable in most cases.

Between both studies, about 208 patients [were analyzed], and out of those patients, about 3 therapy-related deaths were reported. Notably, most of the deaths that occurred on the studies were from progressing disease—not from the therapy. This goes to show that, overall, the therapy is safe and effective, even in [patients with] previously treated disease.

Do you see the use of axi-cel expanding beyond its current indication?

The role of CAR T-cell therapy is gradually evolving. Axi-cel has been approved in relapsed diffuse large B-cell lymphoma, but we now have data looking at other types of lymphoma, such as low-grade lymphomas. I believe its role will continue to expand in lymphoma and the implications for which it is approved will grow over time.

What are some challenges faced with this modality?

[We have seen] issues with reimbursement with these drugs, which probably led to the slow adoption [of some of the products]. Even so, the efficacy and the increasingly established overall safety profiles are going to make these products frequently used [in the future].

Shifting to chronic myeloid leukemia (CML), one of the big areas of research is examining when it is safe to discontinue therapy in those who received TKIs. Could you elaborate on the ENESTop trial? What should be taken away from that research?

This is one of several trials that have been conducted in patients with chronic-phase CML who received nilotinib (Tasigna). However, other similar trials are evaluating imatinib (Gleevec).

Additionally, the LAST trial examined the discontinuation of therapy in patients with CML who received any TKIs for chronic-phase CML. The rationale, in all cases, was to determine whether there was a subset of patients in whom you could safely discontinue therapy without the need to reintroduce it.

In the ENESTop trial, investigators looked at patients who were receiving nilotinib in the second-line setting after previously receiving imatinib. These patients received nilotinib for at least 1 year and had at least a 4.5 log reduction in BCR-ABL1 by PCR. Approximately 40% of patients who met the criteria and entered the study were able to remain treatment free after an extended period of follow-up. Most of the others who resumed therapy because of evidence of a molecular relapse were able to recapture the degree of disease suppression that they [previously] had and [experience] a 4.5 log reduction.

The research had been inspired by case reports of patients who were able to discontinue TKIs and experience an extended disease-free period without molecular relapse. The study was a formal attempt to characterize how likely it was for patients to successfully stop therapy.

The importance [of this work] is that patients on indefinite TKIs often have chronic low-grade, or perhaps not so low-grade, adverse effects from therapy. It is important to remember that the therapy is very expensive and requires frequent medical monitoring. If we could get a subset of patients off these agents, it would be a great thing. 

Considering chronic lymphocytic leukemia (CLL), BTK inhibitors have become a key player in treatment; however, they are given continuously. Could you speak to how these agents are being used in up-front therapy? What are the challenges faced with these agents?

BTK inhibitors have established a meaningful role in the up-front treatment of [patients with] CLL. In a randomized study, it was shown to be superior with or without a CD20 antibody added to it compared with bendamustine and rituximab (Rituxan) in older patients. In younger patients who have unmutated IGHV, it was shown to be superior to the combination of fludarabine, cyclophosphamide, and rituximab as induction therapy. At least in these populations, this is 1 option that can be considered for initial therapy. However, we still have to sort out toxicity and the issue that it is indefinite therapy.

The counter argument to BTK inhibitors is the ability to give finite therapy with cytotoxic regimens combined with CD20 antibodies. Still, in terms of having an effective oral regimen, ibrutinib (Imbruvica) represents a very good option. Both ibrutinib and second-generation BTK inhibitors have demonstrated activity in patients with relapsed CLL who experienced disease progression following alkylating agents or venetoclax (Venclexta).

What are some of the latest developments reported in multiple myeloma? Are any ongoing efforts generating excitement?

In the newly diagnosed space, the real movement is around the trials that are supporting the addition of antibody therapy, specifically CD38-directed therapy, to standard regimens. We finally have data from the GRIFFIN study combining daratumumab (Darzalex) with the most standard induction regimen in the United States, which is lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd). We're moving targeted therapy and antibody therapy up front.

In the relapsed space, we're seeing immunotherapy come into play as well as cellular therapy, which is generally targeting BCMA, with consistent efficacy across a host of products. We have seen high response rates in [patients with] heavily pretreated disease, although the responses do not seem to be as durable as the ones we have seen with CD19-directed therapy in patients with lymphoma.

We also have other agents that are targeting BCMA, such as bispecific antibodies and antibody-drug conjugates, that are currently in development. Furthermore, belantamab mafodotin-blmf (Blenrep) recently received regulatory approval in this space and will soon be widely available.

What are some of the key takeaways from this webinar?

Cellular therapies are being developed broadly in the lymphoma and myeloma space. Some of these products are now being explored in other hematologic malignancies, as well. Ultimately, as more data [come to light], I believe [these products are] here to stay.

In multiple myeloma, we're seeing optimization in terms of the timing of monoclonal antibodies, regimens that can be used with CD38 antibodies, and the route of administration with a subcutaneous preparation of daratumumab, which was recently approved. We're also seeing the development of antibodies targeting new targets, such as BCMA. Antibody therapy has definitely had an impact in multiple myeloma. Finally, we're looking to optimize the duration of therapy, to help identify certain patient populations where you can stop TKIs. We're now doing that across malignancies.

Furthermore, we are still awaiting results on 2 studies. Recently, we saw a preliminary assessment comparing induction regimens on the E1A11 study, which was RVd versus carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone in multiple myeloma. This showed fairly similar efficacy results with differing toxicity profiles between the bortezomib- and the carfilzomib-containing arms.

The primary end point of the trial has not yet been reported, which was a second randomization evaluating the duration of lenalidomide maintenance. This study is designed to compare 2 years of maintenance therapy versus indefinite maintenance therapy, until progression.

These data, along with those from another study which assessed early versus delayed transplant followed by indefinite lenalidomide maintenance, can be looked at together and compared with what was discovered with the Intergroupe Francophone du Myélome 2009 study.