Treatment with fludarabine, cyclophosphamide, and rituximab (FCR) is considered by many to be the standard of care for physically fit patients with chronic lymphocytic leukemia (CLL) who require therapy. Two recent studies published in Blood examined the efficacy of FCR against FC alone and identified specific patient subgroups who are likely to achieve long-term, disease-free survival with FCR treatment, such as those with IGHV-mutated CLL.
The first study, conducted by Kirsten Fischer, MD, from the Department of Internal Medicine and Center of Integrated Oncology at the University of Cologne in Cologne, Germany, and colleagues, included 817 treatment-naïve CLL patients who were also CD20-positive.1 The prospective, randomized, phase III CLL8 trial was conducted in 190 centers across 11 countries. “To our knowledge this randomized trial represents the largest cohort to evaluate the current standard treatment of FCR chemoimmunotherapy in patients with previously untreated CLL,” Dr. Fischer told ASH Clinical News.
Patients were randomized to receive six courses of intravenous fludarabine (25 mg/m2/day) and cyclophosphamide (250 mg/m2/day) for the first three days of each treatment cycle with or without the addition of rituximab (375 mg/m2 administered on day 0 of course 1, and 500 mg/m2 on day 1 of courses 1-6).
At a median follow-up of 5.9 years, median progression-free survival (PFS; the study’s primary endpoint) was 56.8 months for patients in the FCR cohort, compared with 32.9 months for the FC cohort (hazard ratio [HR] = 0.59; 95% CI 0.50-0.69; p<0.001). The median overall survival (OS) was not reached for the FCR cohort and was 86 months for the FC group (HR=0.68; 95% CI 0.54-0.89; p=0.001).
There were fewer deaths in the patients receiving rituximab: 125/408 (30.6%) in the FCR group and 154/409 (37.7%) in the FC group. The most common causes of death were infections, followed by progressive disease and secondary malignancies (including solid tumors and lymphoma). Patients receiving FCR had higher rates of prolonged neutropenia during the first year after treatment compared with those taking FC: 16.6 percent versus 8.8 percent, respectively (p=0.007), though at 12 months post-treatment the rates of neutropenia did not differ between the two treatment cohorts.
Dr. Fischer and colleagues found several factors that were independently associated with shorter PFS and OS, including: FC therapy, del17p CLL, umutated IGHV status, del11q, mutated TP53, and age >65 years. The presence of TP53 mutation, del17p, and unmutated IGHV showed the strongest prognostic impact on both PFS and OS (TABLE).
“The IGHV-mutated group treated with FCR had a significantly longer PFS than those treated with FC (median PFS: not reached for FCR vs. 41.9 months for FC; HR = 0.47 [95% CI 0.33-0.68]; p<0.001),” the authors added. The same relationship was observed for OS after five years (86.3% for FCR vs. 79.8% for FC; p<0.001).
“The long-term, follow-up results are of particular importance in light of the recent advent of novel substances such as ibrutinib, idelalisib, and venetoclax, since they demonstrate that chemoimmunotherapy with FCR may yield very good long-term outcomes in molecularly defined subgroups of patients with CLL,” Dr. Fischer added. “Therefore, novel substances should be tested against this standard before concluding on their definitive value.”
Also, while the benefit of FCR was observed in the OS of younger patients, the authors noted that the study was not designed to differentiate between CLL-related and CLL-unrelated deaths and the competing risk was not analyzed.
The second study, led by Philip A. Thompson, MBBS, from the Department of Leukemia at MD Anderson Cancer Center in Houston, Texas, examined the results of an earlier phase II trial to identify CLL patients who are likely to achieve long-term, disease-free survival with FCR.2 The original phase II study, conducted between 1999 and 2003, demonstrated the superiority of FCR over FC therapy (in terms of rates of complete remission and failure-free survival) and established FCR as the current standard of care for CLL. The current analysis presents long-term data on disease-free survival.
Patients received the following treatment regimen administered every four weeks for a total of six cycles:
- Fludarabine: 25-30 mg/m2 administered on days 2-4 of cycle 1 and days 1 through 3 of cycles 2-6
- Cyclophosphamide: 250-300 mg/m2 administered on days 2-4 of cycle 1 and days 1-3 of cycles 2-6
- Rituximab: 375 mg/m2 administered on day 1 in cycle 1 and 500 mg/m2 in cycles 2-6
The overall response rate was 95 percent among the 300 patients enrolled in the trial, with 72 percent of patients achieving CR, and 43.1 percent of patients achieving minimal residual disease (MRD)-negativity.
MRD-negativity was highly predictive of long-term disease-free survival, particularly in patients with the mutated IGHV gene. After a median follow-up of 12.8 years, PFS was 30.9 percent among all patients (median PFS=6.4 years); for patients with the IGHV mutation, though, PFS was 53.9 percent and those with unmutated IGHV had a PFS of 8.7 percent.
Half (50.7%) of the patients who achieved MRD-negativity post-treatment had the IGHV mutation, with a PFS of 70.9 percent. IGHV-mutated patients with MRD-negativity also had superior long-term survival (87.2% vs. 56.5%; p=0.003). “The high rate of very long-term PFS in patients with mutated IGHV after FCR argues for the continued use of chemoimmunotherapy in this patient subgroup,” the researchers concluded.
Dr. Thompson and colleagues also identified a plateau for patients with mutated IGHV, finding no relapses beyond 10.4 years in 42 patients. “The existence of PFS plateaus in mutated IGHV patients treated with FCR raises the prospect that many of these patients may be cured of their CLL,” the authors wrote. “Further follow-up of the patients in this plateau in the coming years, as well as systematic testing of all patients for MRD, is planned to determine whether this prospect is indeed a reality.”
The researchers noted two limitations of the study: Standard response assessment was based on clinical criteria rather than the results of computed tomography scans, and the patient population was younger and, therefore, more likely to have early-stage CLL.
- Fischer K, Bahlo J, Fink AM, et al. Long term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2015 October 20. [Epub ahead of print]
- Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide and rituximab achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2015 October 22. [Epub ahead of print]
|TABLE. Multivariate Analysis of the Effects of Various Prognostic Factors on PFS and OS|
|Adverse factor||Hazard ratio||p Value (95% CI)|
|Progression-free survival (348 events)|
|Study treatment||FC||1.976||<0.001 (1.59-2.45)|
|IGHV mutational status||Unmutated||1.719||<0.001 (1.33-2.23)|
|Cytogenetic subgroup||Del11q||1.546||<0.001 (1.22-1.97)|
|Cytogenetic subgroup||Del17p||2.916||<0.001 (1.78-4.78)|
|TP53 mutational status||Mutated||2.123||<0.001 (1.40-3.22)|
|Overall survival (173 events)|
|Study treatment||FC||1.538||0.006 (1.14-2.08)|
|Age||≥65 years||1.423||0.018 (1.04-1.20)|
|IGHV mutational status||Unmutated||2.059||<0.001 (1.39-3.05)|
|Cytogenetic subgroup||Del17p||2.715||<0.001 (1.60-4.60)|
|TP53 mutational status||Mutated||3.014||<0.001 (1.89-4.80)|