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Leukemia Service and Cellular Therapeutics Center
Memorial Sloan Kettering Cancer Center
New York, New York
Jae Park, MD, has disclosed that he has received consulting fees from Amgen, Allogene, AstraZeneca, Autolus, GlaxoSmithKline, Kite Pharma, Novartis, and Takeda.
This commentary features a selection of questions asked by participants during an ASH 2019 satellite symposium focused on current best practices and emerging directions in CAR T-cell therapy, with responses provided by members of the program faculty.
As of March 2020, the CD19-targeted CAR T-cell therapies axicabtagene ciloleucel and tisagenlecleucel are both approved for use in the United States. Tisagenlecleucel is approved for patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse. Tisagenlecleucel is also approved for adults with relapsed/refractory (R/R) large B-cell lymphoma after ≥ 2 lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from follicular lymphoma, and high-grade B-cell lymphoma. Axicabtagene ciloleucel is also approved for adults with R/R large B-cell lymphoma after ≥ 2 lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from follicular lymphoma, primary mediastinal large B-cell lymphoma, and high-grade B-cell lymphoma.
Timing of CAR T-Cell Therapy in Acute Lymphoblastic Leukemia
Does response rate vary if CD19-targeted CAR T-cell therapy is administered earlier or later in the treatment course?
The response rate is generally similar when CD19-targeted CAR T-cell therapy is administered earlier or later in the treatment course: approximately 70% to 80% in most studies. There are differences, however, in duration of remission and relapse rate after CAR T-cell therapy depending on when the treatment is administered and what the baseline disease burden is.
Should a patient with refractory disease and low disease burden receive an allogeneic stem cell transplant instead of CAR T-cell therapy, if possible?
That is an option. Transplantation does not cure all patients and there are toxicities associated with this procedure; transplant-related mortality remains between 15% and 20%. Although CAR T-cell therapy can be associated with significant toxicity, mortality with this treatment is significantly lower than that observed with transplantation. Although we await data from studies that compare CAR T-cell therapies with standards of care, including transplantation, it is the hope that earlier CAR T-cell therapy might improve outcomes for patients with refractory disease.
What treatments do patients receive after CAR T-cell therapy?
After CAR T-cell therapy, for patients who have achieved remission, there is generally no immediate maintenance or consolidation therapy, but for some, bone marrow transplantation may be a consideration. Once patients have received a single infusion of CAR T-cells, they are monitored closely for recurrence of disease with serial bone marrow biopsy and also observed for B cell aplasia; if relapse occurs, they receive standard salvage therapy.
CAR T-Cell Therapy for Lymphoma
Should patients receive maintenance treatment following CAR T-cell therapy?
As with acute lymphoblastic leukemia, current knowledge of treatment with CAR T-cell therapy is based on data from studies of a single infusion of the CAR T-cells, without maintenance therapy. In general, most people who fail CAR T-cell therapy do so within 3 months, even when there is CAR T-cell expansion, and there are ongoing studies examining the role of additional therapies for these patients. Once a patient maintains remission for 6 months, most responses appear durable, and no maintenance therapy is indicated.
Managing CAR T-Cell–Associated Toxicities
Does toxicity correlate with response to CAR T-cell therapy?
There are interesting data now emerging that suggest that severe toxicity may actually be detrimental to duration of response and overall survival in patients treated with CAR T-cell therapy, so there may be a middle ground where a certain amount of T cell expansion and cytokine-release syndrome and neurotoxicity might indicate better response, but extremes may be detrimental. However, this needs to be tested in a clinical trial setting.
Do you recommend NSAIDs following CAR T-cell therapy?
Any drugs that may injure the kidneys or lead to platelet dysfunction (as NSAIDs can) should be used with caution following CAR T-cell therapy.
Investigational Approaches to Treating Multiple Myeloma With CAR T-Cell Therapy
How do you explain the dose response observed with anti–B-cell maturation antigen (BCMA) CAR T-cell therapy for myeloma?
A dose response was observed with anti-BCMA CAR T-cell therapy for myeloma in multiple phase I studies, including a trial of idecabtagene vicleucel (formerly bb2121). At present, it is unclear why this should be. The effect may be CAR and disease specific; it is possible that by changing a CAR, the clinical outcome may in turn be changed.
How do you sequence CAR T-cell therapy with bispecific antibodies?
This is currently an unanswered question. In myeloma, treatment with bispecific antibodies is currently an experimental approach, as is CAR T-cell therapy, so any decisions would be based on clinical trial inclusion and exclusion criteria. Selected studies of agents further along in clinical trial development for patients with R/R multiple myeloma include the following:
Are there any studies that compare CAR T-cell therapies with standard of care?
Currently, there are no data from studies comparing CAR T-cell therapy with standard care; however, there are currently several ongoing randomized phase III trials comparing CAR T-cell therapies with standard treatment approaches.
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