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Bertrand Coiffier, MD, PhD
Photo by Larry Young

SAN FRANCISCO—Adding romidepsin to CHOP can enhance the regimen’s efficacy against peripheral T-cell lymphoma (PTCL), but the combination can also induce severe toxicity, results of a phase 1b/2 study have shown.

In patients with previously untreated PTCL, romidepsin plus CHOP elicited an overall response rate of about 69%.

But all patients experienced adverse events, a median of 49 per patient. In addition, rates of hematologic toxicities were high, and 3 patients experienced acute cardiac toxicity.

Bertrand Coiffier, MD, PhD, of CHU Lyon Sud in Pierre Benite, France, presented these findings at the 7th Annual T-cell Lymphoma Forum. Dr Coiffier and other researchers involved in this study receive funds from Celgene, the company developing romidepsin.

“CHOP is widely accepted,” Dr Coiffier noted. “It’s the most-used regimen for peripheral T-cell lymphoma, but it’s not the best one, and we certainly have regimens that do produce more [complete responses] and longer responses.”

He said researchers decided to test romidepsin in combination with CHOP because studies have suggested that romidepsin has very good efficacy in relapsed/refractory peripheral T-cell lymphoma, and the toxicities associated with romidepsin and CHOP alone have been managable.

So the researchers tested the combination in 37 patients with untreated PTCL, most of whom were male (n=20). The median age was 57, and 37.8% were older than 60. About 95% of patients had stage III/IV disease, and about 89% had an ECOG performance status less than 2.

Most patients had angioimmunoblastic T-cell lymphoma (n=17), followed by PTCL not otherwise specified (n=13), ALK- anaplastic large-cell lymphoma (n=3), enteropathy-associated T-cell lymphoma (n=1), hepatosplenic T-cell lymphoma (n=1), primary cutaneous CD4+ small/medium T-cell lymphoma (n=1), and “other” (n=1).

Early DLTs

The researchers used a standard “3+3” dose-escalation scheme, starting with a romidepsin dose of 10 mg/m2 given on days 1 and 8.

In the first 2 cycles, there were 3 dose-limiting toxicities (DLTs)—1 case  of grade 3 syncope, 1 case of grade 3 general status alteration, and 1 case of grade 3 hematologic toxicity (neutropenia and thrombocytopenia) lasting longer than 7 days.

“So we looked at the definition of the criteria for DLT, and we thought that, this time, they were too severe,” Dr Coiffier said. “After a lot of discussion between all the investigators, we decided to modify the criteria for DLT regarding neutropenia or thrombocytopenia and to allow a little more toxicity before saying it’s a DLT.”

A DLT was initially defined as grade 3/4 non-hematologic toxicity, grade 3 hematologic toxicity lasting more than 7 days, or grade 4 hematologic toxicity lasting more than 3 days. The researchers modified the criteria so that hematologic toxicities would not be considered DLTs if they lasted less than 10 days for grade 3 or less than 7 days for grade 4.

When the team decreased the romidepsin dose to 8 mg/m2, they did not observe any DLTs according to the new criteria. The same was true when they raised the dose back up to 10 mg/m2.

There were, however, DLTs when the dose was increased to 12 mg/m2. In cohort 5, there was a case of grade 3 cardiac failure, and in cohort 6, there were 2 cases of grade 3 nausea.

Nevertheless, 12 mg/m2 became the phase 2 dose. In all, 25 patients received romidepsin at that dose.

Safety data

Twenty-six of 37 patients completed the 8 planned cycles of treatment. Five patients discontinued treatment due to progression and 6 due to toxicity (5 due to thrombocytopenia).

“One hundred percent of patients experienced at least one adverse event, but most of them were grade 1 or 2 [84%] and occurred during the first 2 cycles [38%],” Dr Coiffier said. “There were no deaths related to adverse events.”

Severe toxicities occurred during the expansion phase. There was a case of severe peripheral sensory neuropathy that led to treatment discontinuation, and there were 3 cases of acute cardiac toxicity. They all occurred after the first cycle, and none were fatal.

The rate of hematologic toxicity was high. Neutropenia occurred in all patients, thrombocytopenia in 94%, and anemia in 89%.

Grade 3/4 adverse events included neutropenia (85%), thrombocytopenia (35%), febrile neutropenia (19%), general status deterioration (13%), nausea/vomiting (10%), anemia (8%), hypophosphatemia (8%), fatigue (5%), mucositis (5%), decreased appetite (5%), hypocalcemia (3%), hyponatremia (3%), hypokalemia (3%), hypomagnesemia (3%), dysgeusia (3%), and peripheral sensory neuropathy (3%).

Response, survival, and next steps

About 51% of patients (18/35) achieved a complete response, and 17% (n=6) had a partial response. Twenty-six percent of patients (n=9) progressed.

The median follow-up was 30 months. The estimated 1-year progression-free survival was 57%, and the estimated 1-year overall survival was 82%.

“The [overall survival] curve is certainly much better than you would expect with just standard CHOP,” Dr Coiffier noted.

He added that this research has progressed to a phase 3 study comparing romidepsin and CHOP in combination to CHOP alone. There are 7 countries participating (France, Belgium, South Korea, Spain, Italy, Germany, and Portugal), and 100 patients have been enrolled thus far. end hematology article

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