Time to Next FCR Treatment May Predict Poor Prognosis in CLL


Most CLL patients treated with FCR will experience long-term remissions, but patients who relapse within 24 months have a dismal prognosis.

A remission from chronic lymphocytic leukemia (CLL) lasting less than 2 years after treatment with fludarabine, cyclophosphamide, and rituximab (FCR) was associated with a poor prognosis, similar to that of patients with refractory disease, according to the results of a study published in the European Journal of Cancer.

“Despite limitations of sample size and heterogeneity of salvage treatments, it was evident that a time period of less than 24 months to next treatment after the initial use of FCR was a marker for resistant CLL not amenable to conventional chemoimmunotherapy,” wrote Erel Joffe, of Tel-Aviv University, Israel, and colleagues.“ In these cases, the overall and event-free survival following salvage were similar to that of primary disease refractory to FCR.”

FCR is the standard front-line treatment in young, fit patients diagnosed with CLL, according to the study.

“Most patients treated with this regimen will achieve a complete response with subsequent long-term remissions,” the researchers wrote. “However, a subset of patients, with primary refractory disease or who relapse within the first 2 to 3 years after therapy, have a dismal prognosis, often showing limited responses to subsequent salvage therapies.”

Findings from two previous clinical trials suggest that early progression (within 36 months) of FCR was associated with resistant disease. Here, Joffe and colleagues conducted a retrospective study of 126 patients with CLL that were treated in the “real world” with first-line FCR.

Of the 126 patients, 63 received second-line treatment. These patients were the focus of this analysis. Time to next treatment was calculated from beginning FCR to initiation of second-line therapy. Survival was calculated from the start of salvage therapy.

There was a median follow-up of more than 5 years from first-line therapy, and 37 months from second-line therapy. A time to next treatment that was less than 24 months (TTNT < 24) was associated with a shorter overall survival (OS) and event-free survival, similar to rates seen in patients with primary refractory disease. OS in patients with TTNT < 24 was 19 months compared with 23 months in patients with stable or progressive disease. Event-free survival was 12 months and 9 months, respectively, for these two groups. In contrast, patients with a TTNT of 24 months or longer had an OS of 48 months and an event-free survival of 20 months.

“The use of a 36-month cutoff, described in previous studies, was less discriminatory in our dataset,” the researchers wrote.

Patients who had to stop therapy with FCR because of toxicity had excellent outcomes on second-line therapy. No deaths were observed among 13 patients who received second-line therapy after stopping FCR for toxicity. The median event-free survival in this group was 41 months.

Based on these results, the researchers wrote that TTNT shorter than 24 months “can be considered an independent surrogate marker of a biologically resistant clone.”

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