Stephen D. Nimer, MD, sheds light on new strategies and trends in the treatment of patients with hematologic malignancies.
Stephen D. Nimer, MD
As a whole, the field of hematologic oncology is moving away from the use of chemotherapy toward more targeted treatment strategies, a shift that is resulting in improved survival outcomes, explained Stephen D. Nimer, MD.
“The number of new drugs we have has been expanding year by year,” said Nimer, professor of medicine, director, Sylvester Comprehensive Cancer Center, University of Miami Health System. “Every year, the FDA approves half a dozen or a dozen new drugs for the treatment of [patients with] hematologic malignancies. All in all, we're getting more and more specific with our treatments, and patients are living longer.”
As more targeted agents become available, there appears to be a higher likelihood of testing negative for minimal residual disease (MRD)—an important component of prognosis in many of these blood diseases, said Nimer. In acute lymphoblastic leukemia (ALL), MRD negativity has become an additive endpoint beyond complete remission, overall survival, and progression-free survival as evidenced by the single-arm phase II BLAST study, which included conversion from MRD positivity to MRD negativity as a primary endpoint.
Beyond targeted therapies, CAR T-cell therapy has emerged as a viable treatment strategy for patients with ALL and large B-cell lymphoma. The CAR-T products tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta) are both approved for large B-cell lymphoma, and tisagenlecleucel is also approved for ALL. Further follow-up with BCMA-targeted T cells in myeloma and research aimed at enabling T-cell infiltration in solid tumors are ongoing.
However, as more novel therapies come to market, sequencing will undoubtedly become more complex. “Learning how to better combine drugs and identifying which patients will benefit from one subtype to another is really going to take more clinical trials,” explained Nimer.
In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Nimer shed light on new strategies and trends in the treatment of patients with hematologic malignancies.Nimer: We discussed new treatments for hematologic malignancies. There were a few common themes, one of which is moving toward the use of targeted therapies as opposed to chemotherapy. Many of our standard regimens that have been used for a long time are not as effective as some of the more directed therapies. We also heard a lot about antibodies for lymphoma and myeloma, which are turning out to be extremely effective. The development of immune approaches for treating cancer is also replacing some of the traditional chemotherapies.
In acute myeloid leukemia (AML), there is a huge range of new drugs that have been recently approved [by the FDA] for subtypes of the disease. [These advances underscore] the importance of understanding genetics and characterizing each patient’s disease.
Lastly, there was quite a bit of information on MRD. As we develop treatments that can eliminate easily measurable disease, the question becomes how to monitor very tiny amounts of disease. That will help us optimize treatments.When you don't have very good treatments available, MRD is not that important. There have been several publications in AML, myeloma, and chronic lymphocytic leukemia (CLL) showing that the newer therapies are able to eliminate nearly all of the disease. With some of the other therapies, we would find 1 in 1000 or 1 in 10,000 malignant cells. Now, we’re frequently under 1 in 1 million cells. Those techniques involve pathologic complete response-based studies, and sometimes, flow cytometric—based studies.
We're getting better at detecting MRD, and so we're finding the importance of getting to MRD. In chronic myeloid leukemia (CML), the TKIs are probably the best example of rendering patients MRD negative. If a patient is still positive, they will need to be placed on some other type of therapy. In myeloma and in CLL, the techniques have not been applied in the past, and they’re still not uniformly applied. However, there are publications showing that the depth of response correlates with the length of remission, and sometimes, survival outcomes as well.CAR T-cell products have been approved [by the FDA] for ALL and non-Hodgkin lymphoma. We heard a bit about their use in multiple myeloma and they're being tested in solid tumors as well.
The issue is really going to be the duration of response. It's quite an expensive technology. In situations where it's curative, then it makes sense [to use it]. For some of these other diseases, it's going to depend on the setting in which it's given and how long the duration of remission is compared with cure.
There are many new techniques being used to improve immune system response. For each disease, we'll have to see how they counterbalance with other forms of therapy. Venetoclax (Venclexta) is a BH3 mimetic that inhibits the BCL-2 protein family. Initially, it was only thought to be effective in lymphoma, but it turns out to be effective in AML, CLL, and other diseases as well. As we uncover the fundamental mechanisms that are involved in these diseases, we may be able to reduce the number of people who may ultimately need a CAR T-cell approach.Treating elderly patients with AML is still very difficult. Although there are new drugs available, we're still learning how to combine them and whether or not we can affect cures instead of remission. With many of these drugs, the hope is to get a patient into remission and then do a stem cell transplant. The ultimate goal would be to keep more patients who go into remission, in remission.
The question is, “How can we move these drugs upfront?” One issue is that many of these drugs have been FDA approved for patients who are not considered to be fit enough for chemotherapy. We're trying to really define that population better because some of the treatments that are given to these patients replicate the toxicity of chemotherapy. Seeing which treatments can be introduced for which patients at which time point is going to require a lot of randomized trials.
The other component is, we need to keep introducing new drugs. Excitingly, venetoclax and decitabine, or venetoclax and 5-azacitidine are showing a lot of efficacy in AML. In patients who cannot tolerate chemotherapy, [learning] how to incorporate venetoclax into other regimens would be very important, as well as [identifying] other agents that could be added to those combinations.
In myeloma, certain drugs have followed a pretty traditional FDA approval pathway. Daratumumab (Darzalex) for instance, is a highly effective antibody that has been given in the relapsed setting and can also be given as part of initial therapy.It's an incredibly uplifting experience to sit in the audience and to hear all of the progress that's being made. I'm very proud of all that's going on at the Sylvester Comprehensive Cancer Center. Many of the trials with CAR T-cell therapy and IDH1/2 inhibitors are being done at [this institution]. We're very proud to be able to host this meeting and talk about all the research that's going on at our cancer center. We have a very strong precision medicine group. We also have really strong groups in myeloma, lymphoma, and leukemia. Rather than highlight any specific trial, I would say that we have trials open for patients with all types of relapsed or refractory disease. We're also participating in other national trials for frontline treatment as well.