From the Journals

Flavopiridol elicits poor response in mantle cell lymphoma, DLBCL



Flavopiridol – also known as alvocidib – showed minimal clinical response in patients with relapsed or refractory mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and other B-cell lymphomas, according to results from a single-center, phase 1/2 trial.

“Promising preclinical data in cell lines derived from MCL and activated DLBCL led to a series of clinical trials of flavopiridol in various hematological malignancies,” wrote Milos D. Miljković, MD, and colleagues in the lymphoid malignancies branch of the National Cancer Institute in Bethesda, Md. The findings were published in a letter to the editor in Leukemia & Lymphoma.

The study included 28 patients with relapsed/refractory MCL, DLBCL, transformed follicular lymphoma, and primary mediastinal B-cell lymphoma who received a hybrid dosing regimen of the novel CDK inhibitor. Flavopiridol was administered as a 30-minute bolus, followed by a 4-hour infusion.

The researchers used an intrapatient dose escalation between the first and successive cycles, in addition to a three-plus-three interpatient escalation, to lessen the risk of tumor lysis syndrome (TLS).

The primary outcomes were the clinical response rate, maximum tolerated dose, dose-limiting toxicities, and toxicity profile of the hybrid dosing regimen.

Of 26 evaluable patients, one patient with DLBCL maintained a partial response for 84 days (overall response rate, 3.8%). One patient with MCL had a 50% decrease in the size of target lesions at 2 months, but this was not sustained at 4 months. In total, nine patients had stable disease for a disease control rate of 38.4%.

“[Flavopiridol] had minimal efficacy in patients with relapsed/refractory non-Hodgkin B-cell lymphoma, casting doubt on the utility of CDK inhibition in this disease,” the researchers wrote.

With respect to safety, there were eight dose-limiting toxicities reported in three patients. These included grade 3 TLS, elevated transaminase levels, hypoalbuminemia, hyperkalemia, non-neutropenic infection, and grade 4 metabolic acidosis and gastrointestinal perforation.

The most common treatment-related toxicities were hematologic, including neutropenia, anemia, thrombocytopenia, leukocytosis, and lymphopenia.

Dr. Miljković and colleagues noted that CDK inhibitor therapy may elicit better responses when used in combination with other agents.

“Ongoing trials of more specific CDK inhibitors in combination with other agents will help elucidate their role in lymphoma treatment,” they wrote.

The trial is sponsored by the National Cancer Institute and the study authors are employees of the National Cancer Institute.

SOURCE: Miljkovic MD et al. Leuk Lymphoma. 2019 Jun 17. doi: 10.1080/10428194.2019.1627540.

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