Chapter 104. Acute and Chronic Myeloid Leukemia (Part 15)

Posttransplantation TreatmentBCR/ABL transcript levels have served as early predictors for hematologic relapse following transplantation. These should facilitate risk-adapted approaches with immunosuppression or TK inhibitor(s), or a combination of the two. Donor leukocyte infusions (without any preparative chemotherapy or GVHDprophylaxis) can induce hematologic and cytogenetic remissions in patients with CML who have relapsed after allogeneic SCT.Imatinib can control CML that has recurred after allogeneic SCT but is sometimes associated with myelosuppression and recurrence of severe GVHD. Imatinib after allogeneic SCT is being studied for prevention of relapse in patientswith advanced disease at the time of transplantation (i.e., patients at high...
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Chapter 104. Acute and Chronic Myeloid Leukemia (Part 15) Chapter 104. Acute and Chronic Myeloid Leukemia (Part 15) Posttransplantation Treatment BCR/ABL transcript levels have served as early predictors for hematologicrelapse following transplantation. These should facilitate risk-adapted approacheswith immunosuppression or TK inhibitor(s), or a combination of the two. Donorleukocyte infusions (without any preparative chemotherapy or GVHDprophylaxis) can induce hematologic and cytogenetic remissions in patients withCML who have relapsed after allogeneic SCT. Imatinib can control CML that has recurred after allogeneic SCT but issometimes associated with myelosuppression and recurrence of severe GVHD.Imatinib after allogeneic SCT is being studied for prevention of relapse in patientswith advanced disease at the time of transplantation (i.e., patients at high risk forrelapse), patients undergoing reduced-intensity transplants, or patients with slowreduction of BCR/ABL message following transplantation. Imatinib has also beencombined with donor lymphocytes to induce rapid molecular remissions in CMLpatients with disease relapse after allogeneic SCT. Of interest are studies withnewer TK inhibitors following transplantation for imatinib-resistant CML. Imatinib Mesylate Imatinib mesylate (Gleevec) functions through competitive inhibition at theATP binding site of the Abl kinase in the inactive conformation, which leads toinhibition of tyrosine phosphorylation of proteins involved in Bcr/Abl signaltransduction. It shows specificity for Bcr/Abl, the receptor for platelet-derivedgrowth factor, and Kit tyrosine kinases. Imatinib induces apoptosis in cellsexpressing Bcr/Abl. In newly diagnosed CML, imatinib (400 mg/d) is more effective than IFN-α and cytarabine. The complete hematologic remission rate, at 18 months, ofpatients treated with imatinib was 97% compared to 69% in patients treated withIFN-α and cytarabine. Similarly, the complete cytogenetic remission rate was 76%with imatinib compared to 14% with IFN-α and cytarabine. All imatinib-treated patients who achieved major molecular remission(26%), defined as ≥3 log reduction in BCR/ABL transcript level at 18 monthscompared to pretreatment level, were progression-free at 5 years. The progression-free survival (PFS) at 5 years for patients achieving complete cytogeneticremission but less pronounced molecular remission is 98%. The 5-year PFS forpatients not achieving complete cytogenetic remission at 18 months was 87%.These results have led to a consensus that molecular responses can be used as atreatment goal in CML. Specific milestones have been developed for chronic-phase CML patients (Table 104-4). For example, chronic-phase CML patients whodo not achieve any cytogenetic remission following six months of imatinib areunlikely to achieve major molecular remission and should be offered othertreatment approaches. Progression to accelerated/blastic phases of the disease was noted in 3% ofpatients treated with imatinib as compared to 8.5% of patients treated with IFN-αand cytarabine during the first year. Over time, the annual incidence of diseaseprogression on imatinib decreased gradually to factor support. Doses family of kinases, addressing the last mechanism of resistance. CML with theT315I mutation is resistant to imatinib, nilotinib, and dasatinib. Dasatinib is approved by the FDA for the treatment of all stages of CMLwith resistance or intolerance to prior therapy, including imatinib. Nilotinib willlikely follow suit. Both are oral agents given twice daily, with toxicity profilessimilar to imatinib with small but significant differences. Dasatinib was shown tocause pleural effusion in 22% of patients with 7% developing grade 3-4 toxicity.Nilotinib was associated with sudden death in six of approximately 550 CMLpatients. A suspected relationship to nilotinib was reported in two of these cases. These new agents have changed the treatment algorithm of CML. Forexample, patients who do not achieve any cytogenetic remission at six months onimatinib will now be offered either dasatinib or SCT. IFN-α, though FDA-approved for CML, will only be offered if all other options have failed. The encouraging results with imatinib have led clinicians to offer it as first-line therapy for newly diagnosed CML patients, including those who otherwisewould have benefited from transplant (e.g., young patients with a matched siblingdonor). Prior exposure to imatinib does not affect transplant outcome. However,delaying BMT for high-risk patients (Sokal/Hasford criteria) may result in diseaseprogression. SCT after disease progression is associated with poorer outcome.Therefor ...