A phase II study of withdrawal of imatinib therapy in adult patients with chronic phase chronic myeloid leukaemia in stable molecular remission

Following the achievement of deep molecular response on tyrosine kinase inhibitors (TKIs) 54 around half of patients with chronic myeloid leukemia (CML) can discontinue TKI and remain in 55 treatment-free remission (TFR). The ALLG CML8 study commenced in July 2006 and enrolled 40 patients with undetectable BCR-ABL1 mRNA (approximately MR4.5 56 ). Molecular relapse was 57 defined as detectable BCR-ABL1 at any level on two consecutive tests or a single value >0.1%. 58 With a median follow-up of 8.6 years (range 5.7-11.2 years) 18 patients remain alive and in TFR 59 (45.0%; 95% confidence interval 31.9% - 63.4%). The latest relapse that occurred was at 27 60 months after stopping imatinib. No patient progressed to advanced phase CML. Twenty-two 61 patients met the criteria for imatinib re-treatment and all regained undetectable molecular 62 response. Twelve of these patients attempted TFR a second time after a median 5.9 years re63 treatment, and 5/12 patients had restarted TKI at last follow-up. Nine patients in long-term TFR 64 were additionally monitored by highly-sensitive BCR-ABL1 DNA PCR in a sufficient number of 65 samples to enable more precise quantification of residual leukemia. The level of BCR-ABL1 DNA decreased from a median of MR5.5 in the first year of TFR to MR6.2 66 in the latest 3 years of TFR. 67 Our results support the long-term safety and remarkable stability of response after imatinib 68 discontinuation in appropriately selected CML patients. Furthermore, serial high sensitivity testing 69 provides a new and unexpected finding: that the level of residual leukemia steadily declines in 70 patients in prolonged TFR