Kinetics of Molecular Response to Imatinib in Patients With Chronic Myeloid Leukemia May Predict Persistent Polymerase Chain Reaction Negativity After Imatinib Discontinuation

Abstract

Four patients with a rapid clearance of leukemic cells maintained a molecular response after discontinuation of therapy. We adopted a new, more sensitive technique to detect minimal residual disease that can help to detect those patients who might be the most eligible for discontinuation when they achieve a complete molecular response. Only a restricted group of patients with Philadelphia chromosome—positive (Ph+) CML is able to achieve a complete molecular response (CMR) after treatment with imatinib. Clinical studies evaluating patients who discontinued treatment are ongoing, and initial reports have pointed out that approximately 50% of patients relapsed within 6 months. We report 4 cases of patients who stopped imatinib in sustained CMR, defined as BCR-ABL/ABL levels below a detection threshold of 5-log reduction and undetectable BCR-ABL transcript by qualitative polymerase chain reaction (PCR), either on BM and PB samples, in at least 2 samples. Cessation was due to some degree of toxicity. CCyR was reached within 3 months of imatinib therapy, and CMR was achieved after 12, 6 (2 cases), and 9 months. The duration of treatment before discontinuation was 43, 54, 16, and 51 months, respectively, while the median time of PCR negativity on imatinib was 36 months. Three patients did not relapse and are PCR-negative with a follow-up of 62, 47, and 41 months, respectively. The fourth patient stayed off of treatment in confirmed CMR for 28 months, until an RQ-PCR analysis on PB disclosed a BCR-ABL/ABL ratio of 0.0208%. She refused to restart imatinib, and she is currently off therapy after 1 year with an RQ-PCR still in the MMR range. Minimal residual disease was assessed with a new strategy with multiple PCR reactions on a 82-well plate, increasing the sensitivity to a 6-log reduction. Patients who remained persistently negative at standard PCR techniques behaved like the normal controls. The single patient who relapsed proved to be positive also in samples obtained during the PCR negativity at the standard methods. This report confirms that a molecular response can be sustained after discontinuation of imatinib. All patients were characterized by a rapid clearance of leukemic cells, suggesting that the kinetics of molecular response might predict prolonged remission after imatinib discontinuation. Furthermore, though in the literature all relapses occurred early, we observed a late molecular recurrence, not associated with progression. Finally we adopted a new, more sensitive technique to detect minimal residual disease that can help to detect those patients who can be the most eligible for discontinuation when they achieve a CMR.