Treatment of CML

Goal of Therapy Complete molecular remission and cure – Achieve prolonged, durable, nonneoplastic, nonclonal hematopoiesis, – Eradication of any residual cells containing the BCR/ABL transcript

Imatinib Mesylate MOA: competitive inhibition at the ATP binding site of the Abl kinase in the inactive confirmation -> inhibition of tyrosine phosphorylation of proteins in Bcr/ Abl signal transduction Complete hematologic remission rate: 97% at 18 months Side effects: Myelosuppression, fluid retention, nausea, muscle cramps, diarrhea

Proposed Imatinib Treatment Milestones for Newly Diagnosed CML Patients Proposed Course of Action: Continue or stay on the same dose or increase dose Time, monthsMilestoneComments 3Complete hematologic remission WBC < 10,000/microliter, normal blood morphology, hemoglobin and platelet counts and disappearance o f splenomegaly; stay on same dose 6Any cytogenic remissionFor patients on 400 mg/d. continue the same or increase dose: or at 18 monthsComplete cytogenic remission No bone marrow metaphases with t (9;22); stay on same dose Partial cytogenic remission1-35% bone marrow metapahases with t(9;22); increase dose

Allogeneic SCT Criteria for patient Acceptable end organ function Less than 70 years old Have healthy histocompatible donor Criteria for donor Fully matched or mismatched only at one HLA locus

Proposed Imatinib Treatment Milestones for Newly Diagnosed CML Patients Time, monthsMilestone 3No complete hematologic remission 6No cytogenetic remission 12Minor [36-85% bone marrow metaphases with t (9;22)] or no cytogenetic remission 18Partial, minor or no cytogenic remission AnytimeLoss of previously achieved hematologic, cytogenetic or molecular remission

Outcome of SCT Patient (age and phase of disease) Type of Donor Preparative regimen GVHD Posttransplantaion treatment: – BCR/ABL transcript levels are early predictors for hematologic relapse following transplantation – Imatinib