Kinetics of Molecular Response to Imatinib in Chronic Myeloid Leukemia Patients May Predict Persistent Polymerase Chain Reaction Negativity after Imatinib Discontinuation.
Authors: Rege-Cambrin Giovanna , Ulisciani Stefano , Mattioli Giovanna , Fava Carmen , Giugliano Emilia , Brunetto Vanessa , Gottardi Enrico , Fava Milena , Saglio Giuseppe 
Published: April 2020

Abstract
Achieving a molecular response after imatinib treatment is considered today the gold standard on Ph+ CML therapy. However, only a restrict group of patients is able to achieve a complete molecular response (CMR). Based on a mathematic model, it has been suggested that imatinb reduces the rate at which differentiated cells are produced from leukaemic stem cells, with no significant effect in reduction of Ph+ stem cells (Michor F et al, Nature 2005). So, cure of the disease is still considered to be restricted to allogeneic bone marrow transplant. Clinical data obtained in patients who stop treatment can be of great value in evaluating the degree of suppression of the neoplastic clone. We report 6 cases of patients with CML in complete cytogenetic remission (CCyR) who interrupted imatinib treatment. Stop was due in 5 cases to some degree of toxicity whereas one male patient decided to stop for personal reasons. All patients were in chronic phase and previously achieved a CCyR within 12 months after imatinib start; major molecular remission (MMR) was observed in 5 cases, and 4 of them also showed a CMR in at least one occasion. After discontinuation, three patients had a molecular or cytogenetic relapse in a period of 3 to 6 months. In these cases, CMR was never reached, or in one case it was delayed in time, being observed after 3 years of treatment, and not confirmed in all subsequent samples. All patients responded again to imatinib treatment. Three other patients did not relapse and are PCR-negative with a follow-up of 18, 22 and 39 months respectively. One of them received imatinib for cytogenetic relapse after IFN + ARA-C, whereas two patients were treated with Peg-IFN and imatinib front-line; Peg-IFN was stopped for toxicity in both cases. At imatinib stop, they all were in sustained complete molecular remission, as defined by undetectable BCR-ABL transcript at RT- and RQ-PCR both on BM and PB samples, in multiple serial samples. In these three patients, CCyR was reached whithin 3 months of imatinib therapy and CMR was achieved after 1 year, 6 months, and 9 months respectively, and never lost. The median duration of treatment before discontinuation was 45,5 months, while the median time of PCR negativity on imatinib was 39 months. In most reported cases, imatinib discontinuation results in relapse after few months (Cortes J et al, Blood 2004; Michor F et al, Nature 2005; Mauro MJ et al, Leuk Res 2004). However, both time of treatment and duration of molecular response were relatively short in these reports. Recently, 12 patients who stopped treatment when in CMR for more than two years have been published (Rousselot P et al, Blood 2007): 6 of them relapsed early whereas 6 remain in CMR after a median follow-up of 18 months. We describe 3 cases who are persistently PCR-negative after imatinib discontinuation, with a median follow-up of 26 months; all of them were characterized by a rapid clearance of leukemic cells after start of imatinib, which allowed to obtain a stable CMR within the first 12 months of treatment. Less than 5% of early CP patients on imatinib achieve CMR in the first year (Brandford S et al, Blood 2006). These data suggest that kinetics of molecular response achievement may predict prolonged response after imatinib discontinuation, possibly reflecting a decline in leukemic stem cell compartement.