Minimal Residual Disease Is a Predictor for Progression-Free and Overall Survival in Chronic Lymphocytic Leukemia (CLL) That Is Independent of the Type or Line of Therapy.

The depth of remission in CLL correlates with survival in a large number of trials regardless of the therapy used and the depletion of minimal residual disease (MRD), when reported, is usually associated with improved progression free and overall survival. However it is not clear whether this improved outcome is due to the attainment of MRD negativity or whether MRD eradication is a surrogate for other variables that predict for good response. In order to address the true impact of achieving MRD negativity we present data from 137 patients with CLL who were treated between 1996 and 2007, achieved a good clinical response and had bone marrow examined post-therapy to assess remission status including MRD. The MRD assessment was performed in a single laboratory (HMDS, Leeds, UK) using multicolor flow cytometry capable of detecting minimal residual disease (MRD) to a level of one CLL cell in 10000 leukocytes as recently recommended in the IWCLL Guidelines.

Patients were followed for a median duration of 3.1 years (range 0.2 - 12.7) after treatment with chlorambucil (n=13), fludarabine (n=17), fludarabine and cyclophosphamide (n=58), fludarabine and cyclophosphamide with mitoxantrone and/or rituxumab (n=8), alemtuzumab (n=29), autologous stem cell transplantation (n=7) and various other treatments (n=5). Of these, 48 achieved a complete response (CR), 24 achieved a CR with incomplete marrow recovery (CRi), 27 achieved a nodular partial response (nPR) and 38 achieved a partial response (PR). Altogether 58 individuals (42.3%) were MRD negative at the end of treatment, including 28 CR, 20 CRi, 3 nPR and 7 PR patients. Results of the univariate and multivariate analyses are summarized below:

Age, number of prior therapies and MRD negativity were independently correlated with overall survival. MRD negativity in the marrow at the end of therapy was independently significant in multi-variate analysis including when analysed against age, stage, prior therapy, IWCLL response assessment and cytopenia.

One of the most striking findings was in patients having their first CLL treatment. Of the 58 patients in this series who had achieved a clinical response to first line therapy 24 patients (21 patients following FC, 1 FCR, 1 chlorambucil and 1 fludarabine à autologous SCT) achieved an MRD-negative remission and 34 were MRD-positive. With a median follow-up of 38 months (range 7-153) the 5 year PFS for MRD negative patients was 89% (95% CI 55-97%) compared to 0% for the MRD positive patient (95% CI <1%) and the 5 year OS was 95% (95% C.I. 61-99%) vs 53% (95% C.I. 15-74%) for MRD-negative vs. MRD-positive patients, respectively. Although achieving MRD-negativity with subsequent therapy is relatively beneficial, the greatest differences in outcome were seen in front-line treatment. This data suggests that achieving MRD-negativity after first-line therapy has a profound effect on overall survival.

In conclusion, we demonstrate that achieving MRD negativity in CLL is an independent predictor of survival in multivariate even when a variety of different treatment approaches are considered and regardless of the line of therapy.. This is the strongest evidence yet that achieving MRD negativity is the most appropriate aim of therapy in CLL for patients who are fit enough for such an approach. Furthermore patients who achieve MRD negativity after their first therapy have a 5 year PFS of 89% and a 5 year overall survival of 95% suggesting that the optimal time to attempt to achieve MRD negativity is with first line therapy.

Hillmen:Roche Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees.