CAR T-Cell Therapy Treatment for Diffuse Large B Cell NHL-An Update

Update for recurrent B-cell NHL treated with Yescarta CAR - T cells - side effects are not insignificant.

by Dr. C.H. Weaver M.D. updated 12/2019

The US Food and Drug Administration (FDA) approved the second T-cell therapy that uses chimeric antigen receptor (CAR) technology in 2018.(1) Yescarta (Axicabtagene ciloleucel) received FDA approval for the treatment of patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant.(2)

This approval occurred on the heels of the FDA’s approval of Kymriah (tisagenlecleucel-T), the first therapy CAR technology therapy to be approved.

CAR therapies utilize T-cells (CART T), a patient’s own immune cells that are re-programmed to recognize and kill cancer cells throughout the body. The process involves the removal of some T cells from a patient, and through laboratory processes, these T cells are re-programmed to identify a patient’s cancer cells.

Once the T cells have been programmed to identify a patient’s cancer cells, they are replicated in the laboratory, and infused back into the patient. These re-programmed T cells circulate throughout the body, identifying the cancer cells and mounting an immune attack against them. Simultaneously, the T cells are replicating within the body, so that more of the immune cells can identify and attack the cancer cells.

Long-Term Outcomes of Yescarta

The ZUMA-1 clinical trial enrolled 119 adults with relapsed or refractory large B-cell lymphoma to receive treatment with a chemotherapy regimen of fludarabine and cyclophosphamide followed by a single infusion of Yescarta.

In the ZUMA-1 clinical trial, Yescarta showed durable responses and no new safety concerns in patients with relapsed or refractory large B-cell lymphoma according to 2-year follow-up data published in Lancet Oncology and uptdated at ASH 2019. (2,5)

Overall 83% of treated patients responded to treatment and 58% had a complete response. Thirty-nine patients (39%) had an investigator-assessed ongoing response, with a median duration of response of 11.1 months. The median overall survival was not yet reached.

Fifty patients died from progressive lymphoma while on study, with 6 deaths occurring during the first year follow-up analysis. Four patient deaths were related to adverse events, 2 of which were related to treatment with Yescarta.

With a minimum follow-up of three years after a single infusion of Yescarta (median follow-up of 39.1 months), 47% of patients with refractory large B-cell lymphoma in the ZUMA-1 clinical survive, and the median overall survival was 25.8 months. Greater clarity is also being provided regarding two significant side effects associated with CAR T cell therapy.

  • Cytokine Release Syndrome (CRS): CRS occurred in 94% of patients with a median time to onset of 2 days (range: 1-12 days) and a median duration of 7 days (range: 2-58 days). Key manifestations of CRS include fever (78%), hypotension (41%), tachycardia (28%), hypoxia (22%), and chills (20%). At the first sign of CRS physicians now institute treatment with tocilizumab and/or corticosteroids.
  • Neurologic side effects: Neurologic side effects are reported to occur in 87% of patients, all occurring within the first 8 weeks of therapy. The most common include encephalopathy (57%), headache (44%), tremor (31%), dizziness (21%), aphasia (18%), delirium (17%), insomnia (9%) and anxiety (9%). Prolonged encephalopathy lasting up to 173 days was noted. Serious events including leukoencephalopathy and seizures occurred with Yescarta®. Fatal and serious cases of cerebral edema have occurred in patients treated with Yescarta®.

While the initial FDA approval is for "transplant ineligible patients" there is of course great hope that CAR T cell therapy will also improve the outcomes compared with stem cell transplant used earlier in the disease course. It is of interest that the treatment related mortality from CAR T of ~ 4% and the 3 year disease free survival are similar to that obtained with a standard stem cell transplant. Moreover the neurologic side effects and CRS are not insignificant. Comparative clinical trials may be necessary to determine how the side effects compare to a standard stem cell transplant and whether the additional cost for CAR-T cell therapy is warranted.

Fred Hutchinson Cancer Research Center statement regarding FDA approval of immunotherapy drug Yescarta

Dr. David Maloney, medical director of cellular immunotherapy offered the following statement:

“While the Food and Drug Administration’s first approval of a CAR T-cell therapy impacted a relatively small number of pediatric and young adult patients, today’s decision opens the door for a cellular immunotherapy to treat adults with aggressive lymphoma. There will likely be thousands of lives saved in the next few years because of it.

“The FDA’s ruling validates the revolution under way in the field of cellular immunotherapy, which enables us to engineer patients’ own immune systems to eliminate cancer cells. We at Fred Hutchinson Cancer Research Center believes that by 2025 there will be many approved T- cell therapies for a variety of cancers.

“The current CAR T-cell therapies need to become more effective, more affordable and safer. We need to understand why they do not work for certain people, why they only work in select types of cancer and why they can cause severe, occasionally fatal, side effects.

“To answer these questions, we at Fred Hutch and Seattle Cancer Care Alliance have ongoing clinical trials and will continue to launch new ones. We have shared treatment algorithms and biomarkers that could help prevent serious harm that can be caused by treatment side effects such as cytokine release syndrome and neurotoxicity, and we are working to perfect these methods of averting such dire side effects. We must step up our already intense study of how the immune system interacts with cancer.

“We are poised to make great advances if we can continue to build stronger partnerships with the private sector and see government support grow at a steady pace. Increased collaboration and funding will allow us to make further investments in fundamental research and development so that these experimental therapies become more widely available and affordable.”

Scientists at Fred Hutch are testing new experimental T-cell therapies for breast cancer, leukemia, lymphoma, lung cancer, Merkel cell carcinoma, mesothelioma and multiple myelomas.

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