Molecular remission after reduced intensity allogeneic transplantation in chronic lymphocytic leukemia : a surrogate marker of the GVL effect that predicts survival and overcomes poor prognostic factor

Reduced intensity allogeneic stem cell transplantation (RIC alloSCT) can lead to 50% of progression-free survivors in poor risk relapsed chronic lymphocytic leukemia (CLL). The aims of this study were to assess the rate of molecular remission (MR) and the correlation with relapse risk, and clinical or biological factors. Twenty-nine patients in complete remission (CR) and with an available immunoglobulin heavy chain gene rearrangement (IgH) were monitored for minimal residual disease (MRD) by PCR. Seventy-five percent had an unmutated IgH; 6 patients had a 17p deletion. Median age at transplant was 60 years (range, 44-69). All patients had a relapsed disease after a median number of previous chemotherapy of 3, 29% of patients failed an autologous transplant and 38% were chemorefractory. Donors were HLA identical (n=21) or haploidentical (n=2), or matched unrelated (n=6). Molecular monitoring was performed by nested-PCR on bone marrow using patient-specific primers. For real-time PCR relative quantification was estimated by using a FR3-derived probe. Nine patients (31%) were PCRnegative at the median follow-up of 20 months (range, 6-71) and none of them relapsed. Seven patients (24%) showed a mixed pattern of PCR: 5 of them are in CR at a median follow-up of 30 months (range, 7-61). Thirteen patients (45%) were always PCR-positive: 7 of them relapsed after a median time of 9 months, 4 patients are alive and in CR after a median follow-up of 17 months (range, 3-24). The cumulative incidence of relapse based on the MRD status within the first 6 months after transplant was significantly different between PCR-negative/mixed and PCRpositive patients (p= 0.03). Two-year DFS was 93% and 25% for PCRnegative/ mixed and PCR-positive patients respectively (p=<0.01). In 3 PCR-positive patients that did not relapse a decreasing tumor load was detected by real-time PCR; in 2 PCR-positive patients the tumor load increased and both patients subsequently relapsed. Disease status before transplant, the number of previous lines of therapy, donor type and the occurrence of GVHD did not correlate with the achievement of MR. 50% of 17p deletion patients achieved a mixed/negative PCR status. The telomere length (p=0.52) and the IgH-derived epitope binding affinity on patient HLA class I and II (p=0.29) did not predict the molecular outcome. In summary, the achievement of MR predicts a better survival in poor prognosis and relapsed patients.