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Tisagenlecleucel induces durable response among adults with pretreated diffuse large B-cell lymphoma
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SAN DIEGO — Chimeric antigen receptor T-cell therapy with tisagenlecleucel induced durable responses among heavily pretreated adults with relapsed or refractory diffuse large B-cell lymphoma, according to 19-month follow-up results from the phase 2 JULIET trial presented at ASH Annual Meeting and Exposition.
Researchers observed efficacy across all predefined subgroups, including elderly patients and those with clinical or biological factors typically associated with poorer prognosis after receipt of other available treatments.
“When you have these aggressive lymphomas, most of the recurrences occur in the first 12 months. When you get to 19 months, you start to really believe that 5 years is possible,” Richard Thomas Maziarz, MD, professor of medicine in the division of hematology and medical oncology at Knight Cancer Institute at Oregon Health & Science University, told HemOnc Today. “No one is at the point of saying ‘cure’ with CAR T, but when you start to see the remission-free survival paralleling survival in general, we have to start to think that it may become a potential outcome for these patients.”
Tisagenlecleucel (Kymriah, Novartis), an anti-CD19 CAR T-cell therapy, is approved for treatment of patients aged 25 years or younger with B-cell precursor acute lymphoblastic leukemia that is refractory or in second relapse. The agent also is approved for treatment of patients with DLBCL, high-grade B-cell lymphoma, or DLBCL arising from follicular lymphoma who received two or more lines of systemic therapy.
The single-arm, open-label JULIET trial evaluated tisagenlecleucel among adults with clinically active relapsed or refractory DLBCL who received at least two lines of prior therapy — including rituximab (Rituxan; Genentech, Biogen) and an anthracycline — and either failed or were ineligible for autologous stem cell transplant.
Overall response rate as assessed by independent review committee served as the primary endpoint.
Results of an interim analysis performed after median follow-up of 14 months showed a 59% ORR; 43% achieved complete response and 16% achieved partial response. The agent also demonstrated a manageable safety profile.
At ASH, Maziarz presented updated results based on median follow-up of 19.3 months.
By data cutoff on May 21, researchers had enrolled 167 patients and infused 115 patients (median age, 56 years; range, 22-76; 23% aged 65 years or older).
Infused patients received a single dose of tisagenlecleucel. Median dose was 3 x 108 CAR-positive viable T cells per kg (range, 0.1 x 108 to 6 x 108).
The majority of infused patients received bridging therapy (90%) and lymphodepleting chemotherapy (93%).
Upon study entry, 77% of infused patients had stage III or stage IV disease, 17% had double-hit or triple-hit disease, 55% had germinal center subtype and 43% had activated B-cell subtype. About half (51%) of patients had received at least three prior lines of antineoplastic therapy (range, 1-6) and 49% underwent prior autologous stem cell transplant.
The efficacy analysis included 99 patients who had at least 3 months of follow-up or discontinued earlier.
Researchers reported an ORR of 54% (95% CI, 43-64); 40% of patients achieved complete response and 13% achieved partial response. ORRs appeared consistent among prognostic subgroups, including those with double-hit or triple-hit lymphoma and those who underwent prior autologous stem cell transplant.
Median duration of response had not been reached, although investigators calculated probabilities that 66% (95% CI, 51-78) would be relapse free at 6 months, and 64% (95% CI, 48-76) would be relapse free at both 12 months and 18 months. Investigators observed no relapses beyond 11 months after infusion.
Duration of response did not differ significantly based on age (< 65 years vs. 65 years), or by relapsed or refractory status.
Median OS was 11.1 months (95% CI, 6.6-not estimable) for all infused patients but had not been reached (95% CI, 21-not estimable) for patients who achieved complete response. Investigators calculated OS probabilities of 48% (95% CI, 38-57) at 12 months and 43% (95% CI, 33-53) at 18 months.
No patients proceeded to autologous or allogeneic stem cell transplant while in remission.
The safety analysis included all infused patients. Within 8 weeks of infusion, grade 3 or grade 4 adverse events of special interest included cytopenia lasting more than 28 days (34%), cytokine release syndrome (23%), infections (19%), febrile neutropenia (15%), neurologic events (11%, including one case of grade 2 cerebral edema) and tumor lysis syndrome (2%).
Sixteen percent of patients received tocilizumab (Actemra, Genentech) for cytokine release syndrome management. Three patients died due to disease progression within 30 days of infusion.
Investigators reported no treatment-related mortality.
“This has been a great example of collaboration within the scientific community in that everyone has come together to share toxicity information and management protocols ... so that all future patients will have a higher chance of getting a better benefit because toxicity can be ameliorated early on,” Maziarz told HemOnc Today. – by Mark Leiser
Reference:
Schuster SJ, et al. Abstract 1684. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosure: Maziarz reports research funding from Novartis; consultant/advisory or board of directors roles with Incyte, Juno Therapeutics and Novartis; honoraria from Incyte, Juno Therapeutics, Kite Therapeutics and Novartis; and patents and royalties from Athersys. Please see the abstract for all other authors’ relevant financial disclosures.