Prognostic and Predictive Effect of IGHV Mutational Status and Load in Chronic Lymphocytic Leukemia: Focus on FCR and BR Treatments

BACKGROUND: Most important markers in chronic lymphocytic leukemia (CLL) are TP53 abnormalities, including mutations and deletions, and the mutational status of immunoglobulin heavy chain (IGHV) genes. However, some recent publications suggest that the IGHV mutational load could have a prognostic effect on CLL patients. PATIENTS AND METHODS: We performed a single-center retrospective study on 459 patients with productive rearrangement of the B-cell receptor to evaluate the prognostic and predictive role of IGHV mutational status and burden within the germline sequence. In particular we focused on FCR (fludarabine with cyclophosphamide, and rituximab)- (64 naive and 30 relapsed) and BR (bendamustine with rituximab)-treated patients (17 naive and 61 relapsed). A cutoff value of 2% of difference within the IGHV germline was used to define the IGHV mutational status. RESULTS: We reported that unmutated IGHV (U-IGHV) patients were characterized by a significant shorter progression-free survival (PFS) and overall survival (P < .0001) compared with mutated IGHV (M-IGHV) patients. Moreover, treatment-naive M-IGHV patients experienced a long-term disease control after FCR or BR, with PFS reaching a plateau regardless of mutational load. In our series the extent of IGHV gene mutation did not provide further relevant prognostic data over the mutational status. Relapsed patients showed dismal outcome with chemoimmunotherapy regardless of IGHV status or load. CONCLUSION: Our data, together with from those from the literature, confirmed the cutoff value of 2% to define the mutational status of IGHV gene and suggest that FCR/BR are good first-line treatment strategies for M-IGHV patients, whereas U-IGHV patients should be managed with B-cell receptor and/or B-cell lymphoma 2 (BCL2) inhibitors.