CAR T Cells in Advanced R/R Lymphoma: Keeping Patients Alive

Zosia Chustecka

December 11, 2017

ATLANTA — New longer-term clinical data with chimeric antigen receptor (CAR) T cells now reported for patients with refractory and relapsed non-Hodgkin's lymphoma show that the responses are durable in about half of those treated, with the suggestion that for those patients, this therapy looks to be curative.

"This is what everyone has been wanting to know — can the impressive initial responses be sustained over time? What is the durability of these responses?" commented David Maloney, MD, medical director of immunotherapy at the Fred Hutchinson Cancer Research Center in Seattle, Washington.  

The new results are showing complete responses in just over half of patients (54% to 57%) and show that these are maintained in the longer term in most of these patients.

If the response is maintained at 3 to 6 months, it looks like it will be maintained, Dr Maloney commented.

He pointed to new results from a longer follow-up of the ZUMA-1 trial in which patients received a single infusion of axicabtagene ciloleucel (Yescarta, Kite).

At a median follow-up of 15 months, he said, these data show that the risk for relapse in the last 6 to 12 months is extremely low: Forty-two percent of patients remain in remission and 40% of patients exhibit no evidence of cancer.

"This is very, very impressive," Dr Maloney commented. "These are patients who have failed an autologous transplant or were not eligible for a transplant because of refractory disease, and to see any type of a plateau on the progression-free survival curve out at a 1 year or a year and a half is impressive," he commented.

"This is what the field has been waiting for, and this will serve as a benchmark for other products," he commented in an interview with Medscape Medical News. Dr Maloney was not involved in these studies and was approached for comment.

These patients had very advanced disease and would have had no other therapeutic options, he pointed out: They would have died within 6 months.  

Instead, after a single infusion of CAR T cells, these patients with refractory and relapsed lymphoma are still alive.

The longest survivor is a patient who is still alive 7 years after having received CAR T-cell therapy (under James Kochenderfer, MD, from the National Cancer Institute, Bethesda, Maryland). Other investigators report lymphoma survivors at 4 years (Stephen Schuster, MD, from the Abramson Cancer Center and the Perelman School of Medicine, University of Pennsylvania, Philadelphia)  and at 2 years (Sattva Neelapu, MD, from the University of Texas MD Anderson Cancer Center, Houston, Texas).

Longer-term Data Published in NEJM

The new longer-term data with CAR T cells in lymphoma were reported here at the American Society of Hematology (ASH) 2017 Annual Meeting and were simultaneously published in  the New England Journal of Medicine (NEJM).

The report of the ZUMA-1 trial gives details on 111 patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy.

The CAR T-cell product axicabtagene ciloleucel was successfully manufactured for 110 (99%) and administered to 101 (91%) patients.

The objective response rate was 82%, and the complete response rate was 54%.

With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response.

"Long-term follow-up of ZUMA-1 confirms that responses can be durable and the ongoing responses at 24 months suggest that late relapses are uncommon. Patients who are in remission at 6 months tend to stay in remission," commented lead study author, Dr Neelapu.

Dr Sattva Neelapu

"With existing therapy, the median survival for people with this disease is only 6 months. Here, we see more than half of patients — 59% — are still alive over a year after treatment," he said.

In the paper, the team reports that the overall survival rate at 18 months was 52%.

Also new are long-term results in lymphoma with another CAR T-cell product, tisagenlecleucel (Novartis). This product is already approved by the US Food and Drug Administration (FDA) for use in acute lymphocytic leukemia with the trade name Kymriah. It is now awaiting approval for use in lymphoma.

A report of a single-center study with tisagenlecleucel, also published online December 10 in NEJM,  gives details of 28 patients with DLBCL or follicular lymphoma that is refractory to or that relapses after immunochemotherapy and transplantation and have a poor prognosis.

The authors, led by Dr Schuster, report that 18 of 28 patients had a response. Complete remission occurred in 6 of 14 patients with DLBCL  (43%) and in 10 of 14 patients with follicular lymphoma (71%).

Sustained remissions were achieved; at a median follow-up of 28.6 months, 86% of patients with diffuse large B-cell lymphoma who had a response and 89% of patients with follicular lymphoma who had a response had maintained the response.

All patients in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median, 29.3 months) after induction.

In addition, data from the international JULIET trial with tisagenlecleucel were presented at the ASH meeting (abstract 577). Lead investigator, Dr Schuster, gave details on a total of 81 patients with relapsed and refractory DLBCL who were treated at various centers across several countries.  

Dr Stephen Schuster

At 3 months, 26 patients (32%) achieved a complete response, while 5 (6%) achieved a partial response.

For 46 patients with at least 6 months of follow-up, the overall response rate was 37%; 30% of those patients achieved a complete response and 7% achieved a partial response.

"Taken together, our data from both trials show that most patients who are in remission at three months stay in remission," Dr Schuster commented.

"While we don't completely understand why these remissions are so durable, it's exciting and will change how this disease is treated when conventional therapies fail," he said.

"About a third of patients who fail all current therapies, even transplant, could now have a form of therapy that may offer them durable remissions," he said. "We are going to be able to offer patients who don't respond to standard therapies a form of therapy that may, after a single treatment, relieve symptoms and save lives."

Dr Schuster also noted that in the multicenter trial, 26% patients were treated on an outpatient basis.

This international study also showed that this therapeutic approach is viable and can be carried out on a large scale across many different countries. Each therapy is individualized, made for each patient from that patient's own blood. For the JULIET trial, blood collected from patients was frozen and transported to the manufacturing facility in order to generate the CAR T cells, which were then frozen and transported back to the patient.

No new signals of toxicity from CAR T cells were noted in these lymphoma trials. The acute toxicity of cytokine release syndrome and neurologic symptoms can be severe, even life-threatening, but is rare.

"The risk is about 1% to 2%," Dr Maloney told Medscape Medical News. "But these patients have a 100% risk of dying from their lymphoma."   

In an editorial that accompanies the two NEJM publications, Eric Tran, PhD, Dan L. Longo, MD, and Walter J. Urba, MD, PhD, from the Earle A. Chiles Research Institute and the Providence Portland Medical Center, Oregon, declare that the CAR T cells are a "revolutionary treatment for patients with advanced blood cancers."

The two recent approvals of two anti-CD19 CAR T-cell therapies (Kymriah for relapsed or refractory acute lymphoblastic leukemia and Yescarta for relapsed/refractory large B-cell lymphomas ) by the FDA set "a new standard of care for the patients who receive these therapies," write the editorialists.

"However, the approval also comes with substantial economic challenges because of the high cost of care, a challenge that will grow as the indications for these therapies expand in the future. Policies will need to be developed to ensure that eligible patients receive these potentially curative therapies," they add.

Indeed, at the ASH meeting a special session on CAR T cells discussed the economics involved in using these new therapies, with their staggeringly high price tags (Kymriah, $475,000; Yescarta, $373,000), and the conclusion was that the current situation is "unsustainable."

Half of Patients With Lymphoma Don't Respond

The editorialists also point out that "despite the impressive clinical results, approximately half the patients with refractory or relapsed large B-cell lymphomas will not have a durable response after anti-CD19 CAR T-cell therapy."

"The reasons for this variation in response are not completely understood, but a number of strategies are being investigated to enhance the therapeutic efficacy of CAR T cells against lymphoma," they write.

One of these strategies focuses on the antigen being targeted. The two CAR T cells that are already marketed and a third also being developed for lymphoma by Juno all target the CD19 antigen on the B cell.

It appears that in some patients, the lymphoma that persists after treatment begins to express other antigens, such as CD20 and CD22. So one idea is to give these patients treatment with another CAR T cell directed against that other antigen.

Another observation is that the tumor cells themselves begin to release programmed cell death ligand 1 (PD-L1), which can inhibit the function of the CAR T cells, and thus an idea here is to treat these patients with checkpoint PD-L1 or programmed cell death inhibitors.

An analysis of data from the ZUMA trial found that about a third of patients showed loss of the CD19 antigen on the lymphoma cells, while about two thirds of tumors showed evidence of PD-L1.

Work is now underway to overcome these issues in order to increase the proportion of patients who continue responding to the CAR T-cell therapies and, ultimately, remain alive.

The ZUMA-1 study was funded by Kite Pharma Inc (now Gilead Sciences), with some funding from the Leukemia & Lymphoma Society. The JULIET trial was funded by Novartis.

American Society of Hematology (ASH) 2017 Annual Meeting. Abstract 578 (ZUMA-1 trial) and 577 (JULIET trial), both presented December 11, 2017.

N Engl J Med. Published online December 10, 2017. Neelapu et al full text, Schuster et al full text,  Editorial

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