Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia

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Abstract
An unmutated germ line configuration of the immunoglobulin variable heavy-chain gene (VH) has emerged to be a crucial adverse prognostic factor in chronic lymphocytic leukemia (CLL) under conventional treatment. The purpose of the present study was to investigate whether the VH mutational status retains its prognostic value in CLL also in the setting of autologous stem cell transplantation (SCT). Therefore, we investigated the mutational status in 58 patients with CLL who underwent myeloablative radiochemotherapy with SCT. Rearranged VH genes were analyzed by multiplex polymerase chain reaction (PCR) and direct sequencing using FR1 family–specific primers and JH consensus primers. Twenty patients (34%) showed less than 98% homology compared with germ line VH sequences and were considered as mutated, whereas 38 patients (66%) had an unmutated VH status (median mutational rate of 0%; range, 0%-1.7%). An unmutated VHconfiguration was strongly correlated with the presence of short lymphocyte doubling time (P = .003) and high lymphocyte count (P = .005). Time to clinical relapse and time to recurrence of monoclonal B cells as assessed by consensus IgH CDR3 PCR was significantly shorter in the group with unmutated VH genes (2-year probability 19% versus 0%,P = .0008, and 34% versus 9%, P = .0006, respectively). These results show that in CLL, an unmutated VH gene status of the tumor clone remains an adverse prognostic factor after SCT. Nevertheless, the hitherto only 3 deaths and the median treatment-free interval of 49 months in the unmutated cohort suggest a beneficial effect of SCT for this high-risk population in comparison to conventional treatment.