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February 22, 2020
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KTE-X19 induces durable responses in relapsed, refractory mantle cell lymphoma

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Michael Wang, MD
Michael Wang

ORLANDO — A single infusion of KTE-X19 induced high rates of durable response among patients with relapsed or refractory mantle cell lymphoma, according to results of the phase 2 ZUMA-2 study presented at TCT | Transplantation & Cellular Therapy Meetings.

Researchers reported a 93% overall response rate, the highest reported for patients who failed prior Bruton tyrosine kinase inhibitor therapy. The regimen also appeared well-tolerated.

“We are talking about a desperate patient population with a dismal prognosis,” Michael Wang, MD, professor in the department of lymphoma and myeloma at The University of Texas MD Anderson Cancer Center, told Healio. “We are cautiously optimistic. We need longer follow-up and we need to treat more patients, but these results really seem to mean the difference between life or death for many people with mantle cell lymphoma.”

Patients with relapsed or refractory mantle cell lymphoma experience poor outcomes. Less than half (25% to 42%) of patients who progress after Bruton tyrosine kinase (BTK) inhibition respond to their next therapy. OS typically ranges from 6 months to 10 months, and the majority do not proceed to allogeneic stem cell transplantation.

KTE-X19 (Kite Pharma) is an investigational anti-CD19 chimeric antigen receptor T-cell therapy that contains a CD3-zeta T-cell activation domain and CD28 signaling domain.

Wang and colleagues conducted the multicenter, international ZUMA-2 study to evaluate the therapy for adults with relapsed or refractory mantle cell lymphoma.

All patients had at least one measurable lesion and had ECOG performance status of 0 or 1.

Patients had received one to five prior therapies (median, n = 3), including an anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 monoclonal antibody therapy and ibrutinib (Imbruvica; Pharmacyclics, Janssen) or acalabrutinib (Calquence, AstraZeneca).

Patients who underwent prior allogeneic transplantation, CD19-targeted therapy or CAR T-cell therapy were excluded.

Researchers enrolled 74 patients. After leukapheresis, they underwent bridging therapy for rapidly progressing disease at investigator discretion with ibrutinib, acalabrutinib, rituximab or dexamethasone. Chemotherapy was not allowed. Twenty-three of the 25 patients who received bridging therapy showed increased tumor load on post-bridging therapy PET/CT.

Sixty-nine patients underwent conditioning chemotherapy with fludarabine (30 mg/m2 via IV) and cyclophosphamide (500 mg/m2 IV) on days –5, –4 and –3.

Sixty-eight patients (median age, 65 years; range, 38-79; 84% men) received a single infusion of KTE-X19 dosed at 2 x 106 cells/kg on day 0. The majority had stage IV disease (85%) and intermediate-risk/high-risk Mantle Cell Lymphoma International Prognostic Index score (56%). Six percent had pleomorphic morphology and 25% had blastoid morphology.

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The first tumor assessment was performed at day 28.

ORR served as the primary endpoint. Key secondary endpoints included duration of response, PFS, OS and adverse events.

The primary efficacy analysis included the first 60 treated patients. The safety analysis included all 68 treated patients.

Median follow-up was 12.3 months, and 28 patients (47%) had at least 24 months of follow-up.

Researchers reported a 93% ORR; 67% of patients achieved complete response and 27% achieved partial response. Response rates were consistent across key subgroups.

Median time to initial response was 1 month (range, 0.8-3.1) and median time to complete response was 3 months (range, 0.9-9.3).

Median duration of response had not been reached, as 57% of all patients and 79% of those who achieved complete response remained in remission.

Median follow-up for the first 28 patients treated was 27 months (range, 25.3-32.3), and 43% remained in remission with no additional therapy.

Median OS had not been reached.

All patients experienced treatment-emergent adverse events, the most common of which were pyrexia (any grade, 94%; grade 3, 13%), neutropenia (any grade, 87%; grade 4, 69%), thrombocytopenia (any grade, 74%; grade 4, 35%), anemia (any grade, 68%; grade 3, 50%) and hypotension (any grade, 51%; grade 3, 19%; grade 4, 3%).

Nearly all patients developed cytokine release syndrome (any grade, 91%; grade 3 or higher, 15%), but no patients died of the condition. Median time to onset was 2 days (range, 1-13) and median duration was 11 days.

All cytokine release syndrome cases resolved with treatment. Fifty-nine percent of these patients received tocilizumab (Actemra, Genentech) and 22% received corticosteroids.

Nearly two-thirds (63%) of patients experienced neurologic events (grade 3 or higher, 31%). The most common symptoms included tremor (35%), encephalopathy (31%) and confusional state (21%).

Median time to onset was 7 days (range, 1-31) and median duration was 12 days. Treatment included tocilizumab (26%) and corticosteroids (38%), and 86% of cases resolved.

One patient developed grade 4 cerebral edema. The patient was intubated and treated with aggressive multimodality therapy. The neurotoxicities resolved and the patient remained in complete remission 24 months later.

“The efficacy, reliable and rapid manufacturing, and manageable toxicities identify an important and promising role for KTE-X19 in treating patients with relapsed or refractory mantle cell lymphoma, who have an urgent unmet medical need,” Wang said. – by Mark Leiser

Reference: Wang M, et al. Abstract 1. Presented at: TCT | Transplantation & Cellular Therapy Meetings; Feb. 19-23, 2020; Orlando.

Disclosure: Wang reports research funding from Kite. He also reports research funding or honoraria from, consultant/advisory roles or speakers bureau roles with, or stock or other ownership in AstraZeneca, Celgene, Janssen, Juno, Loxo Oncology, MoreHealth, Novartis, Pharmacyclics and several other pharmaceutical companies. Please see the abstract for all other authors’ relevant financial disclosures.