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Independent prognostic significance of minimal residual disease status in chronic lymphocytic leukaemia
Marwan Kwok, Andy Rawstron, Abraham Varghese, Paul Evans, Sheila O'Connor, Chi Doughty, Darren Newton, Paul Moreton, Peter Hillmen
The Lancet, Volume 383, Page S66, 26 February 2014
Background: Eradication of minimal residual disease (MRD) is an independent predictor of survival outcome in patients with chronic lymphocytic leukaemia (CLL) receiving fludarabine and cyclophosphamide (FC) or fludarabine, cyclophosphamide, and rituximab (FCR) as first-line treatment. However, the independent prognostic relevance of MRD status in other therapeutic settings is not clear. The goal of this study was to investigate the independent importance of achieving MRD negativity in CLL on progression-free survival (PFS) and overall survival (OS) with different treatments in frontline and relapsed or refractory settings compared with known prognostic markers.
Methods: We included all patients at our centre in Leeds and associated hospitals in West and North Yorkshire who had completed treatment for CLL from 1996 to 2007, achieved at least a partial response, and received an MRD assessment from a bone-marrow specimen after treatment. MRD assessments were done by multiparametric flow cytometry using CD5—CD19 in combination with CD20, CD22, CD32, CD38, CD79b, and CD81 in accordance with the international harmonised approach. 133 patients (17 receiving fludarabine, 65 fludarabine-based combination therapies, 26 alemtuzumab, and 25 other treatment including chlorambucil and autologous stem-cell transplantation) were followed up for a median of 5·2 years (IQR 3·0—7·3) to assess PFS and OS.
Findings: MRD negativity (defined as less than one CLL cell in 10 000 leucocytes) at the end of therapy independently correlated with both PFS (hazard ratio [HR] 3·22 [95% CI 2·09—4·97], Cox proportional hazards model p<0·001) and OS (1·62 [1·12—2·33], p=0·005) in multivariate analysis when analysed against age, disease stage, adverse cytogenetics ([del]17p, [del]11q, or both deletions), previous therapy, the type and line of therapy, clinical response, and cytopenia. Clinical response was significant in univariate analysis for PFS and OS but not in multivariate analysis. The greatest effect of achieving MRD negativity was seen in patients receiving first-line treatment (n=57), with 5-year PFS of 81% in MRD-negative patients (n=24) versus 16% in MRD-positive (n=33) patients and 10-year OS of 53% versus 24%, respectively. MRD-negative patients with (del)17p, (del)11q, or both achieved better PFS (median 59 months vs 31) and OS (78 vs 64) than did MRD-positive individuals without such adverse cytogenetic abnormalities.
Interpretation: MRD status is a powerful independent predictor of survival outcome in CLL across a range of therapeutic approaches including in frontline and relapse settings. MRD negativity is the most appropriate therapeutic goal for CLL patients who are fit enough for such an approach.