Bijal D. Shah, MD

Bijal D. Shah, MD, associate professor, Department of Malignant Hematology, Moffitt Cancer Center, discusses the use of CAR T-cell therapy in patients with pediatric acute lymphoblastic leukemia (ALL).

Tisagenlecleucel (Kymriah) is approved for pediatric and young adult patients ≤25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. The therapy has been particularly beneficial to patients with extramedullary disease, says Shah, particularly in those with refractory central nervous system disease. This is an area where the monoclonal antibodies blinatumomab (Blincyto) and inotuzumab ozogamicin (Besponsa) have shown much efficacy.

Any patient with refractory disease, irrespective of disease origin, could derive benefit from the CD19-directed CAR T-cell therapy. However, there are some limitations, cautions Shah. For example, the product is only approved for use in patients with B-cell ALL, not those with T-cell ALL. To that end, Autolus Therapeutics is developing a CAR T-cell product that may prove to be beneficial in this subset. Additionally, researchers are evaluating agents targeting CD5, CD7, and CD1A, which could fill the current absence of effective targeted therapies for patients with T-cell ALL, concludes Shah.

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Dr. Shah on the Use of Tisagenlecleucel in Pediatric ALL

Bijal D. Shah, MD, oncologist/hematologist, Moffitt Cancer Center, discusses ongoing trials in the field of mantle cell lymphoma (MCL).

There are approximately 15 MCL-specific trials that are currently recruiting patients, 5 of which are not based around BTK inhibitors, says Shah. Only 2 of those trials include patients who have progressed on a prior BTK inhibitor. That’s not great in the way of research, says Shah. In terms of CAR T-cell therapy, only one product—KTE-C19&mdash;is targeting MCL specifically. Every other trial has grouped MCL patients in with other malignancies.

One of the difficulties with finding effective therapies for patients with MCL is teasing out signals of activity from basket-type trials. In order to develop novel, effective therapies that can help move the field forward, more MCL-specific trials are needed, says Shah. Otherwise, the biological heterogeneity in clinical trials will continue to cloud signals of activity that are specific to patients with MCL.

Dr. Shah on Ongoing Trials in MCL

Bijal D. Shah, MD, associate member, Department of Malignant Hematology, Moffitt Cancer Center, assistant professor of oncology, University of South Florida, discusses challenges with conducting clinical trials in mantle cell lymphoma (MCL).

Mainly, accruing patients for clinical trials is the biggest obstacle that researchers face. In general, MCL is a disease that tends to present in older patients with a median age of 68 years. These patients tend to want to receive their treatment locally. Furthermore, they are less likely to switch from a community oncology center to a large academic center that is farther away unless they have advanced disease, Shah notes. Patients also develop close relationships with their community oncologists, which might make them hesitant to receive care elsewhere.

Moreover, MCL clinical trials tend to have a strict inclusion criteria. As such, it becomes hard for researchers to focus on individual subsets of patients like those with 

 mutations or those with highly proliferative disease. Shah adds that academic centers such as Moffitt Cancer Center, The University of Texas MD Anderson Cancer Center, and John Theurer Cancer Center have large groups of patients with MCL, which makes it easier to develop trials. He adds that although these are the fears that are often communicated, he cannot confirm that they are justified.

Bijal D. Shah, MD, associate member, Moffitt Cancer Center, assistant professor of oncology, University of South Florida, discusses challenges with developing mantle cell lymphoma clinical trials.

Dr. Shah on Challenges With Developing MCL Clinical Trials

Bijal D. Shah, MD, associate member, Department of Malignant Hematology, Moffitt Cancer Center, discusses overcoming resistance to BTK inhibitors in mantle cell lymphoma (MCL).

Ibrutinib (Imbruvica) and acalabrutinib (Calquence) are both FDA approved for patients with relapsed/refractory MCL, but it is not standard practice to give these agents consecutively. This is due in large part to the overlapping mechanisms that drive resistance to these BTK inhibitors, says Shah. Moreover, mutations like 

 tend to create a more aggressive disease, limiting physicians’ ability to salvage with another BTK inhibitor.

Ongoing research is looking at whether an alternative method of blocking the B-cell receptor can overcome resistance to BTK inhibition. For example, an ongoing trial is looking at the combination of duvelisib (Copiktra), a PI3K gamma and delta inhibitor, and the BCL-2 inhibitor venetoclax (Venclexta). The hope is that the combination can attack the B-cell receptor from a different angle, and in doing so indicate whether the downstream mutations are as pivotal in cancer proliferation as believed to be.

Bijal D. Shah, MD, associate member, Department of Malignant Hematology, Moffitt Cancer Center, discusses overcoming resistance to BTK inhibitors in the treatment of mantle cell lymphoma.

Author | Bijal D. Shah, MD

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