The Impact of Imatinib Therapy on Adult Philadelphia Positive Acute Lymphoblastic Leukaemia (ALL): Early Results from the UKALL12/ECOG 2993 Study.

Abstract

Modern protocols for the treatment of adults with Philadelphia positive (Ph+ve) ALL produce high complete remission (CR) rates. Despite this, the overall prognosis remains poor. Imatinib, an inhibitor of the BCR-ABL protein tyrosine kinase, may be a useful therapeutic agent for this disease. The arm of the MRC UKALL-XII/ECOG E2993 trial for patients with Ph+ve adult ALL was amended in 2003 to include Imatinib in the treatment protocol. Following induction chemotherapy those in haematological CR went on to receive treatment with Imatinib at 400mg/day, escalated to 600mg/day if tolerated. Those patients with a sibling, matched unrelated donor or related single haplotype match went on to allogeneic transplantation, whilst those with no available donor received an autograft. Chemotherapy alone was given to patients ineligible for a transplant procedure. All patients received Imatinib as maintenance therapy until frank relapse. 30 consecutive patients had a minimum of 12 months follow up. Sufficient data was available in 27 patients. The median age was 45 years (range 15 to 60), 59% were male, 96% were B-lineage, 4% were null lineage. Median white cell count at diagnosis was 24.1 X109/l. Median follow up was 15.6 months. The overall remission rate was 89%. The median time to CR was 28 days (range 19–93 days). Five (19%) patients received an autograft, 15 (56%) received an allograft. and 7 patients (26%) received chemotherapy alone. The event free survival (EFS) and overall survival (OS) at 1 year was 56% and 59% respectively. There were 7 deaths in remission (23%), 6 of which were transplant related. There were 7 relapses, 3 occurred in patients treated with chemotherapy alone, 2 prior to transplantation and 2 following allogeneic transplantation. These results were compared to 236 historic study patients in first CR after the same induction therapy but who did not receive Imatinib. There were no significant differences between the 2 groups with respect to gender, age, WBC or immunophenotype. Four percent received an autograft, 42% received an allograft and 47% received chemotherapy alone. A further 7% received a non-protocol transplant regimen. The EFS and OS of the historic controls was 35% and 56% respectively, with a comparable rate of deaths in remission (22%). Although the superior EFS in the Imatinib treated patients may be confounded by the greater number of allogeneic transplants in that group, the addition of Imatinib, even after achievement of CR does appear to enhance EFS in comparison to that seen in historical controls. Further follow up is needed to confirm an effect on overall survival and an independent anti-leukaemic effect of Imatinib in adult ALL.