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.ChemotherapyInitial 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 each50% reduction of the leukocyte count. Unfortunately, cytogenetic remissions with...
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Chapter 104. Acute and Chronic Myeloid Leukemia (Part 16) Chapter 104. Acute and Chronic Myeloid Leukemia (Part 16) Interferon Before imatinib, when allogeneic SCT was not feasible, IFN-α therapy wasthe treatment of choice. Only longer follow-up of patients treated with imatinibwill prove whether IFN-α will still have a role in the treatment of CML. Itsmode(s) of action in CML is still unknown. Chemotherapy Initial management of patients with chemotherapy is currently reserved forrapid lowering of WBCs, reduction of symptoms, and reversal of symptomaticsplenomegaly. Hydroxyurea, a ribonucleotide reductase inhibitor, induces rapiddisease control. The initial dose is 1–4 g/d; the dose should be halved with each50% reduction of the leukocyte count. Unfortunately, cytogenetic remissions withhydroxyurea are uncommon. Busulphan, an alkylating agent that acts on earlyprogenitor cells, has a more prolonged effect. However, we do not recommend itsuse because of its serious side effects, which include unexpected, and occasionallyfatal, myelosuppression in 5–10% of patients; pulmonary, endocardial, andmarrow fibrosis; and an Addison-like wasting syndrome. Autologous SCT Autologous SCT could potentially cure CML if a means to select theresidual normal progenitors, which coexist with their malignant counterparts,could be developed. As a source of autologous hematopoietic stem cells fortransplantation, blood offers certain advantages over marrow (e.g., fasterengraftment for the patient and no general anesthesia for the donor). Normalhematopoietic stem cells appear with increased frequency in the blood of patientswith CML during the recovery phase after chemotherapy and G-CSF. A role forimatinib before stem cell collection to achieve minimal residual disease andfollowing transplantation to maintain this status is currently being investigated.Specifically, several groups store peripheral blood stem cells from patients inmajor or complete molecular remissions. However, only a few cases have beentransplanted following imatinib therapy. Therefore, such approaches should beperformed only in clinical trials. Leukapheresis and Splenectomy Intensive leukapheresis may control the blood counts in chronic-phaseCML; however, it is expensive and cumbersome. It is useful in emergencies whereleukostasis-related complications such as pulmonary failure or cerebrovascularaccidents are likely. It may also have a role in the treatment of pregnant women inwhom it is important to avoid potentially teratogenic drugs. Splenectomy was used in CML in the past because of the suggestion thatevolution to the acute phase might occur in the spleen. However, this does notappear to be the case, and splenectomy is now reserved for symptomatic relief ofpainful splenomegaly unresponsive to imatinib or chemotherapy, or for significantanemia or thrombocytopenia associated with hypersplenism. Splenic radiation isused rarely to reduce the size of the spleen. Minimal Residual Disease The kinetics of BCR/ABL transcript elimination are currently replacingqualitative detection of the BCR/ABL message, in spite of a lack of standardacceptable methodology. A consensus panel has proposed ways to harmonize thedifferent methods and to use a conversion factor so that individual laboratorieswill be able to express BCR/ABL transcript levels on an agreed upon scale. Slow reduction of BCR/ABL transcripts following SCT correlates with thepossibility of hematologic relapse. However, the definition of slow reductiondepends on the preparative regimen (reduced-intensity versus fully myeloablative)and the selection of time-points to measure the transcript levels. While persistentRT-PCR positivity at 6 months was regarded as an indication for additionaltherapy in the past, current studies utilize periods between engraftment and day100 for evaluating the clearance rate of BCR/ABL transcripts and recommendingadditional therapies. Large trials with longer follow-up are needed to establishconsensus guidelines. The randomized trial of imatinib versus IFN-α and cytarabine was the firstto establish the concept of log10 reduction of BCR/ABL transcript from astandardized baseline for untreated patients. This measurement unit was developedinstead of either the transcript numbers expressed per µg of leukocyte RNA or theratio 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 extremelylow probability of relapse, with a median follow-up of 60 months. It is unclearwhether achieving complete molecular remission should still be the goal oftreatment in this disease. These studies also establ ...