Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia

Abstract

• FCR-treated chronic lymphocytic leukemia patients with mutated IGHV gene achieve long-term PFS, with a plateau on the PFS curve.• MRD-negativity posttreatment is highly predictive of longterm PFS, particularly in patients with mutated IGHV gene.Accurate identification of patients likely to achieve long-progression-free survival (PFS) after chemoimmunotherapy is essential given the availability of less toxic alternatives, such as ibrutinib. Fludarabine, cyclophosphamide, and rituximab (FCR) achieved a high response rate, but continued relapses were seen in initial reports. We reviewed the original 300 patient phase 2 FCR study to identify long-term disease-free survivors. Minimal residual disease (MRD) was assessed posttreatment by a polymerase chain reaction-based ligase chain reaction assay (sensitivity 0.01%). At the median follow-up of 12.8 years, PFS was 30.9% (median PFS, 6.4 years). The 12.8-year PFS was 53.9% for patients with mutated immunoglobulin heavy chain variable (IGHV) gene (IGHV-M) and 8.7% for patients with unmutated IGHV (IGHV-UM). 50.7% of patients with IGHV-M achieved MRD-negativity posttreatment; of these, PFS was 79.8% at 12.8 years. A plateau was seen on the PFS curve in patients with IGHV-M, with no relapses beyond 10.4 years in 42 patients (total follow-up 105.4 patient-years). On multivariable analysis, IGHV-UM (hazard ratio, 3.37 [2.18-5.21]; P < .001) and del(17p) by conventional karyotyping (hazard ratio, 7.96 [1.02-61.92]; P 5 .048) were significantly associated with inferior PFS. Fifteen patients with IGHV-M had 4-color MRD flow cytometry (sensitivity 0.01%) performed in peripheral blood, at a median of 12.8 years posttreatment (range, 9.5-14.7). All were MRD-negative. The high rate of very long-term PFS in patients with IGHV-M after FCR argues for the continued use of chemoimmunotherapy in this patient subgroup outside clinical trials; alternative strategies may be preferred in patients with IGHV-UM, to limit long-term toxicity. (Blood. 2016;127(3):303-309)

Ibrutinib in the real world patient: many lights and some shades

“…While a minority of patients may attain longlasting responses with chemoimmunotherapy, 3,4,5 relapse and treatment-resistant diseases develop in the majority of cases; infections, progressive disease and second primary tumors being the most frequent causes of death. 5 The firstin-class inhibitor of Bruton's tyrosine kinase (BTK), ibrutinib, was welcomed in 2013 as a new paradigm for the treatment of relapsed or refractory CLL, as it produced responses in 71% of the cases in a heavily pre-treated patient population who had few, if any, alternative treatment options.…”

Chronic lymphocytic leukemia (CLL)—Then and now

“…Patients with M-CLL who achieved MRD negative CR had significantly longer PFS (80% vs 37%) and OS (87% vs 56%). These results have shown that patients with M-CLL who are physically fit can achieve long term disease free survival with CIT alone [66]. Major scientific drawbacks of this study were the lack of FISH cytogenetics data and gene mutations by next generation sequencing.…”

Immunoglobulin genes in chronic lymphocytic leukemia: key to understanding the disease and improving risk stratification

“…17 More specifically, M-CLL cases treated with FCR in the context of clinical trials or general practice were independently reported to achieve prolonged responses, often with no detectable minimal residual disease, thus differing significantly from U-CLL cases. [18][19][20] Interestingly, upon treatment with newer therapeutic agents such as ibrutinib and idelalisib, CLL patients appear to benefit equally and experience similar overall responses irrespective of the IGHV mutational status; [21][22][23] however, the follow-up time is still limited thus precluding definitive conclusions. That said, differences have been noted between the two mutational groups regarding certain clinical parameters following the administration of novel drugs, for example, the initial ibrutinib-induced rise in lymphocyte count and also the duration of lymphocytosis is reported to be greater in M-CLL than that found in U-CLL patients.…”