The Strategy of the Management of Patients with Chronic Lymphocytic Leukemia in the Post-Induction Period Based on the Results of the Evaluation of Minimal Residual Disease

Background. Although inclusion in the treatment programs of new drugs (including new monoclonal antibodies and targeted therapies) allowed the majority of patients with chronic lymphocytic leukemia (CLL) to achieve remission (complete or partial) after combined therapy virtually all patients relapse, presumably due to the persistence of minimal residual disease (MRD). There is strong evidence that the achievement of a negative status for MRD is the single most important factor predictive of final outcome in patients with CLL treated with chemoimmunotherapy. So, at now, the urgent task is long-term preservation and the deepening of the response, if it is possible. Continuing to administer rituximab to patients who respond to rituximab-based induction is possible option. Currently, there is no consensus about the need for maintenance therapy (MT) for patients with CLL.

Aim. To estimate the importance of maintenance therapy of rituximab in the treatment of patients with CLL.

Methods. Since January 2014, 83 patients were included in the study. Male to female ratio - 1.3:1. We have used NCI revised guidelines (Hallek M., et al., 2008) for treatment initiation, assessment of response and MRD. Induction chemotherapy was conducted under the following programs: RB, RFC, R-CHOP. Evaluation of MRD was performed using 5-color flow cytometry of the bone marrow cells. For the study, we developed an algorithm of patient management in post-induction period on the basis of the results of MRD evaluation. Group 1 (n=23): patients with MRD-negative remissions who were under dynamic observation (without therapy) every 3 month with mandatory evaluation of MRD. Group 2 (n=60): patients with MRD-positive remissions who received MT of Rituximab 500 mg/m2 intravenously every 8 weeks for 2 years. Another 48 patients (Control group) with MRD-positive remissions did not receive MT. MT was began if MRD was detected in the patients from Group 1 within 1 year after the end of chemotherapy, they began maintenance therapy.

Results. Median observation was 18.8 month (5 - 36). The increasing the depth of response (from partial to complete remission) was observed only in group of patients receiving MT - 11.7%. MRD was not detected after 6-12 months of MT in 21.7% (13/60) patients from Group 2.

The frequency of relapses in Group 1 was 52.2% (12/23), in Group 2 - 33.3% (20/60), in Control group - 81.3%. Significant differences were detected between Group 1 and Control group (p=.01) and Group 2 and Control group (p˂.0001). Median progression-free survival was not reached in the rituximab maintenance group, in the Group 2 was 30.4 month (p˃.05) and in the Control group - 24.3 month (p=.02).

MT was begun in the 5 patients from Group 1 because MRD was detected in the first year of observation, but the symptoms of progression disease were absent. After 12 months, 2 patients achieved MRD-negative status.

Significant differences in the incidence of infectious complications between patients with MT and without of MT were not detected (p˃.05).

Conclusion. The conducting of MT patients with CLL allows to achieve increasing the depth achieved remission (clinical and molecular) and increase the duration of its preservation. MT with rituximab may be a means of control over the minimal residual disease and the method of its eradication. The proposed algorithm need further testing to confirm the initial results.