Early FCR Lacks Evidence to Change Standard Watch & Wait in Stage Binet A High-Risk CLL

Although fludarabine, cyclophosphamide, and rituximab may be efficient in inducing remission for the treatment of patients with Binet A high-risk chronic lymphocytic leukemia, recent data published in Leukemia suggest there is no evidence that this would be better than the current standard of care, which is the “watch and wait” approach.

Carmen D. Herling

Although fludarabine, cyclophosphamide, and rituximab ([Rituxan], FCR) may be efficient in inducing remission for the treatment of patients with Binet A high-risk chronic lymphocytic leukemia (CLL), recent data published inLeukemiasuggest there is no evidence that this would be better than the current standard of care, which is the “watch and wait” approach.

“In accordance with previous treatment studies in an early-stage CLL, our trial does not provide any evidence that the significant improvement of [event-free survival (EFS)] in this patient population translates into a survival benefit,”Carmen D. Herling, Department I of Internal Medicine and Center of Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany, et al,wrote. “Therefore, “watch and wait” after diagnosis, until “active disease” criteria are met, remains the standard of care, irrespective of unfavorable prognostic features.”

Overall, 824 patients registered for the study in centers in Germany, Switzerland, and Austria (n = 423), as well as France (n = 401). Eight hundred patients were stratified into high-risk (n = 201), which were randomized 1:1 for either FCR chemoimmunotherapy (Hi-FCR) or watch & wait (Hi-W&W), and low-risk for watch & wait (Lo-W&W; n = 599). The primary end point of the study was EFS, and secondary end points included overall response rate (ORR), overall survival (OS), progression-free survival (PFS), adverse events (AEs) related to treatment, molecular response, duration of response, and time to treatment.

In the Hi-FCR arm, 82% of patients received at least 1 dose of treatment and were included in the safety analysis. Eighteen patients withdrew consent after randomization. The median number of cycles administered was 6 (range, 1-6), and 67 patients completed 6 cycles of therapy.

EFS was significantly prolonged in the Hi-FCR arm versus Hi-W&W. After a median follow-up of 55.6 months (range, 0-99.2 months), 36 patients in the Hi-FCR arm (36.0%) had either progressed, received new CLL therapy, or died, compared with 83 patients in the Hi-W&W arm (82.2%). Median EFS was not reached for Hi-FCR but was 18.5 months for Hi-W&W (HR, 0.22; 95% CI, 0.15-0.33;P<.001).

The 5-year EFS was 12.6% in the Hi-W&W arm, 55.2% in the Hi-FCR arm, and 77.1% in the Lo-W&W arm.

Overall, 76.0% of patients in the Hi-FCR arm achieved a response, and 92.7% of patients who had received at least 1 dose of FCR achieved remission. A BM confirmed complete response (CR) was observed in 27 patients (32.9%), and 34 patients (41.5%) had a clinical CR without BM evaluation while 15 patients (18.3) achieved a partial remission. The highest CR rates were achieved in patients who received at least 3 cycles of therapy, wereIGHV-mutant, or had an 11q deletion.

Additionally, 75.5% of patients were minimal residual disease (MRD)-negative at the time of final response in the 53 patients available for four-color flow cytometry from PB compared with 67.9% in the 28 patients available for flow cytometry from BM.

Among high-risk patients with an MRD-negative response to early FCR in PB, the quality of remission with regard to EFS was significant compared with those with an MRD-positive response (HR, 10.68; 95% CI, 3.51-32.55;P<.001).

Investigators noted there was no significant benefit in OS for high-risk patients in either group. The 5-year OS was 82.9% in the Hi-FCR arm versus 79.9% in the Hi-W&W arm (HR, 0.93; 95% CI, 0.41-0.22;P=.864).

Overall, both high-risk groups had a significantly shorter EFS, PFS, and OS compared with the Lo-W&W arm. The Hi-W&W arm had an 8.0 times higher risk of progression, treatment, or death (HR, 8.02; 95% CI, 6.04-10.65;P<.001) compared with the Lo-W&W arm, while the Hi-FCR arm had a 1.8 times higher risk (HR, 1.82; 95% CI, 1.26-2.63; P=.002).

At least 1 study drug was reduced >20% in 24.4% of patients, which most frequently included the doses of fludarabine and cyclophosphamide due to hematologic toxicity. Dose reductions for rituximab were administered to 5 patients.

Grade 3-5 AEs totaling 201 were observed in 61 patients, and 86.2% of these were deemed possibly related to study treatment. The most common types of AEs were hematologic toxicity (61% of patients) and metabolic/laboratory events (22.0%). Recurrent infections included respiratory tract infections (8.5%), fever/infections of unknown origin (3.7%), herpes zoster reactivations (3.7%), and catheter-related infections (2.4%).

Two of the 4 fatal AEs occurred during follow-up, and 2 deaths occurred with no relationship to study therapy.

An elevated risk of disease transformation, secondary malignancies or AIHA related to an early FCR treatment were not detected in the study. One patient in the Hi-FCR arm developed a secondary acute myeloid leukemia (AML) and 2 patients in the Lo-W&W arm developed an AML. Ten additional patients developed Richter’s transformation after a median of 50.1 months, including 2 patients in the Hi-FCR arm, 3 in the Hi-W&W arm, and 5 in the Lo-W&W arm.

“In conclusion, FCR therapy is feasible in Binet A stage CLL and extends EFS and PFS in patients with high-risk disease,” study authors wrote.

The high-risk groups were balanced in terms of country, age, comorbidity, ECOG, white blood count,IGHVmutation status, trisomy 12, and deletion of 17p. However, investigators noted an imbalance in terms of the prevalence of elevated TK; short LDT; male sex, which was more common in the Hi-FCR arm; and deletion of 11q.

“Ongoing and future studies may elucidate, whether the immediate use of such targeted and potentially disease-eradicating therapies (i.e., venetoclax combinations), will be able to overcome adverse disease courses (particularly for patients with del(17p)), and to displace the current standard of care ‘watch and wait’,” the study authors concluded.


Herling CD, Cymbalista F, Gro&szlig;-Ophoff-M&uuml;ller C, et al. Early treatment with FCR versus watch and wait in patients with stage Binet A high-risk chronic lymphocytic leukemia (CLL): a randomized phase 3 trial [Published Online February 18, 2020].Leukemia.https://doi.org/10.1038/s41375-020-0747-7.