ASH – 2016 Discontinuing Tyrosine Kinase Inhibitors is Feasible in Some Patients with CML

SUMMARY: Chronic Myeloid Leukemia (CML) constitutes a little over 10% of all new cases of leukemia. The American Cancer Society estimates that about 8,220 new CML cases will be diagnosed in the United States in 2016 and about 1,070 patients will die of the disease. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells. The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States including GLEEVEC® (Imatinib), share the same therapeutic target, which is BCR-ABL kinase. Resistance to TKI’s can occur as a result of mutations in the BCR-ABL kinase domain or amplification of the BCR-ABL gene. With the availability of newer therapies for CML, monitoring response to treatment is important. This is best accomplished by measuring the amount of residual disease using Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Molecular response in CML is expressed using the International Scale (IS) as BCR-ABL%, which is the ratio between BCR-ABL and a control gene. BCR-ABL kinase domain point mutations are detected, using the mutational analysis by Sanger sequencing. Majority of the patients receiving a TKI following diagnosis of CML achieve a Complete Cytogenetic Response (CCyR) within 12 months following commencement of therapy and these patients have a life expectancy similar to that of their healthy counterparts. Previously published studies have shown that Deep Molecular Response (BCR-ABL <0.01% on the International Scale – MR4) is a new molecular predictor of long term survival in CML patients and this was achieved in a majority of patients treated with optimized dose of GLEEVEC®. It has been hypothesized based on previous observations, that a subgroup of CML patients experiencing deeper responses (MR3, MR4, and MR4.5), may stay in unmaintained remission even after treatment discontinuation. Despite this observation, stopping CML therapy is currently not a clinical recommendation and should only be considered in the context of a clinical trial.

The European Stop TKI (EURO-SKI) trial was conducted to assess the safety of stopping Tyrosine Kinase Inhibitor therapy in patients with CML, whose leukemia was in Deep Molecular Response (DMR). This trial enrolled 821 patients with chronic phase CML without prior TKI failure, in DMR (BCR-ABL <0.01% on the International Scale – MR4) for at least one year, following treatment with either Imatinib, Nilotinib or Dasatinib. Following cessation of treatment with TKIs, patients were followed up testing by RQ-PCR (Real-time Quantitative Polymerase Chain Reaction) every 4 weeks for the first 6 months followed by every 6 weeks, the first year and every 3 months thereafter. Molecular recurrence was defined by the loss of the Major Molecular Response (BCR-ABL <0.1% IS – MR3) at any one point.

It was noted that after stopping TKI therapy, 62% showed no evidence of molecular recurrence at 6 months, and 52% showed no recurrence at 24 months. Patients who had taken a TKI for more than 5.8 years before stopping, were significantly less likely to experience relapse within the first 6 months and had a Molecular Relapse Free Survival at 6 months of 65.5% compared with 42.6% for those on treatment for 5.8 years or less. Further, each additional year of TKI therapy increased a patient’s chances of maintaining Major Molecular Response successfully at 6 months by 16%, after TKI therapy was discontinued. Most of the patients who experienced molecular recurrence were able to regain their previous remission level, after resuming TKI therapy and none of the patients in the study had progression to advanced stage.

The authors concluded that stopping TKI therapy of CML patients appeared safe and feasible in over 50% of the patients and longer duration of therapy with TKIs (5.8 years or more) prior to stopping therapy with TKIs, was associated with a higher probability of Molecular Recurrence Free Survival. Cessation of Tyrosine Kinase Inhibitors Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response: Results of the Euro-Ski Trial. Mahon F-X, Richter J, Guilhot J, et al. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 787.