A phase II study to determine relapse-free interval after withdrawal of imatinib therapy in adult patients with chronic phase chronic myeloid leukaemia in stable complete molecular remission (CML08)

Funding

Commercial sector/Industry,Novartis Australia

Scientific enquiries

Dr Dr David Ross

Brief Summary

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. .... 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
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Key Inclusion Criteria

1. Diagnosis of chronic myeloid leukaemia associated with BCR-ABL quantifiable by RQ-PCR at the time of commencing imatinib therapy 2. Treatment with imatinib for at least 3 years 3. No other current or planned anti-leukaemia therapies 4. Sustained complete molecular response of leukaemia (assessed by undetectable levels of BCR-ABL by RQ-PCR in blood or marrow, for 2 years or longer, tested on at least 2 occasions per year and confirmed by the central PCR laboratory at IMVS using a technique wit .... 1. Diagnosis of chronic myeloid leukaemia associated with BCR-ABL quantifiable by RQ-PCR at the time of commencing imatinib therapy 2. Treatment with imatinib for at least 3 years 3. No other current or planned anti-leukaemia therapies 4. Sustained complete molecular response of leukaemia (assessed by undetectable levels of BCR-ABL by RQ-PCR in blood or marrow, for 2 years or longer, tested on at least 2 occasions per year and confirmed by the central PCR laboratory at IMVS using a technique with sensitivity of at least 4 logs) 5. No signs of extramedullary leukaemia 6. ECOG Performance status 0, 1, or 2 (see Section 6.1.2) 7. Female patients must have a negative pregnancy test within one week before starting imatinib OR have been amenorrhoeic for at least two years. All patients of reproductive potential must agree to birth control for the duration of the study monitoring and re-treatment phases. 8. Life expectancy of more than 12 months in the absence of any intervention 9. Patient has given written, informed consent to participate in the study (which includes consent to obtain samples for the correlative study) and has been given the option to participate in tissue banking.
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Key Exclusion Criteria

1. Patient has received another investigational agent within last 2 years.2. Currently receiving imatinib treatment as part of a clinical trial (including Extension Phase of IRIS trial)3. Administration of cytokine therapy (e.g. G-CSF, GM-CSF or SCF) within 4 weeks prior to study entry.4. Atypical BCR-ABL transcript not quantifiable by standard RQ-PCR.5. Another primary malignant disease, except those which do not currently require treatment (adequately treated conditions, such as excised skin c .... 1. Patient has received another investigational agent within last 2 years.2. Currently receiving imatinib treatment as part of a clinical trial (including Extension Phase of IRIS trial)3. Administration of cytokine therapy (e.g. G-CSF, GM-CSF or SCF) within 4 weeks prior to study entry.4. Atypical BCR-ABL transcript not quantifiable by standard RQ-PCR.5. Another primary malignant disease, except those which do not currently require treatment (adequately treated conditions, such as excised skin cancer or cervical intra-epithelial neoplasia would not be considered exclusion criteria. If in doubt, please refer to the Principal Investigator). 6. Another severe and/or life-threatening medical disease. 7. Active liver disease (e.g., chronic active hepatitis, cirrhosis).8. Known diagnosis of human immunodeficiency virus (HIV) infection. 9. History of non-compliance or inability to grant informed consent.10. Prior allogeneic stem cell transplantation11. Interruption of imatinib therapy for a cumulative period in excess of 14 days in the preceding 3 months.
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