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Durable Responses to CAR T-Cell Therapy in B-Cell Lymphomas

March 2019, Vol 9, No 3

Longer-term follow-up of 2 large pivotal clinical trials in B-cell malignancies has demonstrated continuing remissions after chimeric antigen ­receptor (CAR) T-cell therapy: the ELIANA study in pediatric patients and young adults with relapsed or refractory B-acute lymphoblastic leukemia (B-ALL) and the JULIET study in adult patients with diffuse large B-cell lymphoma (DLBCL). Both updates were presented at a press conference at ASH 2018.

“What we are seeing is a validation that these therapies aren’t just a temporizing measure. Based upon the duration of effectiveness of these therapies, there are patients for whom you really can look at the prospect of a cure,” said ­Joseph C. Alvarnas, MD, Associate Clinical Professor, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope, Duarte, CA. “With longer follow-up, we are becoming more excited that this technology changes the natural history of the disease for some patients.”

The ELIANA Study: Relapsed or Refractory B-ALL

The global pivotal ELIANA clinical trial enrolled patients at 25 centers in 11 countries. In the 24-month follow-up analysis of the ELIANA trial, CAR T-cell therapy with tisagenlecleucel (Kymriah) achieved deep and durable responses without subsequent therapy.

Among 79 evaluable patients (aged 3-24 years), 82% achieved complete responses or complete responses with incomplete blood count recovery within 3 months of the first CAR T-cells infusion. Among those who responded to treatment, 98% were minimal residual disease (MRD)-negative.

At 24 months, the relapse-free survival rate was 62%, and the median duration of remission and median overall survival (OS) had not yet been reached. No new adverse events emerged with longer follow-up.

“This 2-year analysis is an exciting milestone, as it is the longest follow-up to date for a multicenter CAR T-cells trial for patients who have failed to respond to other treatment options,” said lead investigator Stephan A. Grupp, MD, PhD, Director, Cancer Immunotherapy Program, Children’s Hospital of Philadelphia, PA.

“These results indicate that CAR T-cell therapy has potential for long-term disease control. The overall survival in this study is excellent. Seeing that the majority of responding patients from ELIANA are still in remission for this long after a 1-time infusion further establishes Kymriah [tisagenlecleucel] as a truly transformative treatment option,” Dr Grupp said.

Among patients who responded to treatment, relapse-free survival was 66% at 12 months and 18 months, and 62% at 24 months. The OS among all patients who received a CAR T-cell infusion was 76% at 12 months and 70% at 18 months.

Superior duration of response and OS rates were observed in patients who achieved complete response and MRD-negative status, Dr Grupp added.

“It is fascinating that all but 1 of the patients who achieved complete response were MRD-negative, which may identify a potential group that may need no further therapy, including bone marrow transplant,” Dr Grupp emphasized.

The JULIET Study: Relapsed or RefRactory DLBCL

The global phase 2 JULIET clinical trial enrolled 115 patients with relapsed or refractory DLBCL across 4 continents who received treatment with CAR T-cell therapy. Results with an additional 19 months of median follow-up were presented at ASH 2018.

All patients had disease that relapsed or was refractory to at least 2 lines of therapy. The overall response rate was 54% (40% complete response), and 54% of patients with a partial response converted to complete response. Objective response rates were consistent across all subgroups.

The median duration of response and the median OS were not reached among patients with a complete response versus an OS of 11.1 months in all patients who received CAR T-cell therapy.

“These findings are consistent with what we have shown in our single-site studies here at Penn, which is that the majority of patients who go into remission stay in remission,” said principal investigator Stephen J. Schuster, MD, Director, Lymphoma Program, Abram­son Cancer Center, University of Pennsylvania, Philadelphia.

An autologous stem-cell transplant is the only treatment that can extend survival in patients with relapsed or refractory DLBCL, but only approximately 50% of patients are transplant candidates, and the expected 3-year survival rate after transplant is approximately 20%.

“CAR T-cell is potentially a lifesaving therapy for these patients who have failed other options, including transplant,” Dr Schuster noted.

“We are changing the natural history of the disease to the best of our ability,” said senior investigator Richard T. Maziarz, MD, Leader, Bone Marrow Transplant Program, Center for Hematologic Malignancies, Oregon Health & Science University Knight Cancer Institute, Portland, who presented these data.

Safety was consistent with previous reports from the study. No treatment-­related deaths occurred, but 3 patients died within 30 days of CAR T-cell infusion because of disease progression.

In May 2018, the FDA approved the first CAR Ts-cell therapy, tisa­genlecleucel, for use after 2 or more systemic therapies, for the treatment of adults with relapsed or refractory large B-cell lymphoma, including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Tisagenlecleucel was initially approved by the FDA in 2017 for pediatric patients with acute lymphoblastic leukemia.

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