Chapter 104. Acute and Chronic Myeloid Leukemia (Part 16) Interferon Before imatinib, when allogeneic SCT was not feasible, IFN-α therapy was the treatment of choice. Only longer follow-up of patients treated with imatinib will prove whether IFN-α will still have a role in the treatment of CML. Its mode(s) of action in CML is still unknown. Chemotherapy Initial management of patients with chemotherapy is currently reserved for rapid lowering of WBCs, reduction of symptoms, and reversal of symptomatic splenomegaly. Hydroxyurea, a ribonucleotide reductase inhibitor, induces rapid disease control. The initial dose is 1–4 g/d; the dose should be halved with each 50% reduction of the leukocyte count. Unfortunately, cytogenetic remissions with hydroxyurea are uncommon. Busulphan, an alkylating agent that acts on early progenitor cells, has a more prolonged effect. However, we do not recommend its use because of its serious side effects, which include unexpected, and occasionally fatal, myelosuppression in 5–10% of patients; pulmonary, endocardial, and marrow fibrosis; and an Addison-like wasting syndrome. Autologous SCT Autologous SCT could potentially cure CML if a means to select the residual normal progenitors, which coexist with their malignant counterparts, could be developed. As a source of autologous hematopoietic stem cells for transplantation, blood offers certain advantages over marrow (e.g., faster engraftment for the patient and no general anesthesia for the donor). Normal hematopoietic stem cells appear with increased frequency in the blood of patients with CML during the recovery phase after chemotherapy and G-CSF. A role for imatinib before stem cell collection to achieve minimal residual disease and following transplantation to maintain this status is currently being investigated. Specifically, several groups store peripheral blood stem cells from patients in major or complete molecular remissions. However, only a few cases have been transplanted following imatinib therapy. Therefore, such approaches should be performed only in clinical trials. Leukapheresis and Splenectomy Intensive leukapheresis may control the blood counts in chronic-phase CML; however, it is expensive and cumbersome. It is useful in emergencies where leukostasis-related complications such as pulmonary failure or cerebrovascular accidents are likely. It may also have a role in the treatment of pregnant women in whom it is important to avoid potentially teratogenic drugs. Splenectomy was used in CML in the past because of the suggestion that evolution to the acute phase might occur in the spleen. However, this does not appear to be the case, and splenectomy is now reserved for symptomatic relief of painful splenomegaly unresponsive to imatinib or chemotherapy, or for significant anemia or thrombocytopenia associated with hypersplenism. Splenic radiation is used rarely to reduce the size of the spleen. Minimal Residual Disease The kinetics of BCR/ABL transcript elimination are currently replacing qualitative detection of the BCR/ABL message, in spite of a lack of standard acceptable methodology. A consensus panel has proposed ways to harmonize the different methods and to use a conversion factor so that individual laboratories will be able to express BCR/ABL transcript levels on an agreed upon scale. Slow reduction of BCR/ABL transcripts following SCT correlates with the possibility of hematologic relapse. However, the definition of "slow reduction" depends on the preparative regimen (reduced-intensity versus fully myeloablative) and the selection of time-points to measure the transcript levels. While persistent RT-PCR positivity at 6 months was regarded as an indication for additional therapy in the past, current studies utilize periods between engraftment and day 100 for evaluating the clearance rate of BCR/ABL transcripts and recommending additional therapies. Large trials with longer follow-up are needed to establish consensus guidelines. The randomized trial of imatinib versus IFN-α and cytarabine was the first to establish the concept of log 10 reduction of BCR/ABL transcript from a standardized baseline for untreated patients. This measurement unit was developed instead of either the transcript numbers expressed per µg of leukocyte RNA or the ratio of BCR/ABL to a housekeeping gene on a log scale. In this randomized trial, patients who achieved ≥3 log reduction of BCR/ABL message had an extremely low probability of relapse, with a median follow-up of 60 months. It is unclear whether achieving complete molecular remission should still be the goal of treatment in this disease. These studies also established the value and convenience of using peripheral blood instead of bone marrow testing as a means to assess disease status in patients who achieve complete cytogenetic responses. However, one still needs to consider following CML patients in complete cytogenetic remission and at least major molecular remission with annual cytogenetic bone marrow testing, as these patients are at risk of developing cytogenetic aberrations in t(9;22)-negative cells and secondary MDS/AML. These aberrations in the t(9;22)-negative cells are frequently transient, and their clinical significance is unclear. Such aberrations may occur in 7–10% of imatinib-treated patients. Development of MDS/AML is rare. Treatment of Blast Crisis Treatments for primary blast crisis, including imatinib, are generally ineffective. Only 52% of patients treated with imatinib achieved hematologic remission (21% complete hematologic remission), and the median overall survival was 6.6 months. Patients who achieve complete hematologic remission or whose disease returns to a second chronic phase should be considered for allogeneic SCT. Other approaches include induction chemotherapy tailored to the phenotype of the blast cell followed by imatinib, with or without additional chemotherapy and SCT. Blast crisis following initial therapy with imatinib carries a dismal prognosis even if treated with dasatinib or nilotinib. Further Readings AML Frohling S et al: Genetics of myeloid malignancies: Pathogenetic and clinical implications. J Clin Oncol 23:6285, 2005 [PMID: 16155011] National Comprehensive Cancer Network: Acute myeloid leukemia. Clinical Pra ctice Guidelines in Oncology, Version 1. 2006. http://www.nccn.org/professionals/physician_gls/PDF/aml.pdf Sanz MA et al: Tricks of the trade for the appropriate management of newly diagnosed acute promyelocytic leukemia. Blood 105:3019, 2005 [PMID: 15604216] Tallman MS et al: Drug therapy for acu te myeloid leukemia. Blood 106:1154, 2005 [PMID: 15870183] CML Cortes J, Kantarjian H: New targeted approaches in chronic myeloid leukemia. J Clin Oncol 23:6316, 2005 [PMID: 16155014] Hughes TP et al: Monitoring CML patients responding to treatment wit h tyrosine kinase inhibitors. Review and recommendations for 'harmonizing' current methodology for detecting BCR- ABL transcripts and kinase domain mutations and for expressing results. Blood 108:28, 2006 [PMID: 16522812] National Comprehensive Cancer Net work: Chronic myelogenous leukemia. Clinical Practice Guidelines in Oncology, Version 1. 2007. http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf . Chapter 104. Acute and Chronic Myeloid Leukemia (Part 16) Interferon Before imatinib, when allogeneic SCT was not feasible,. myeloid malignancies: Pathogenetic and clinical implications. J Clin Oncol 23:6285, 2005 [PMID: 16155011] National Comprehensive Cancer Network: Acute myeloid leukemia. Clinical Pra ctice Guidelines. appropriate management of newly diagnosed acute promyelocytic leukemia. Blood 105:3019, 2005 [PMID: 15604216] Tallman MS et al: Drug therapy for acu te myeloid leukemia. Blood 106:1154, 2005 [PMID: