Chapter 104. Acute and Chronic Myeloid Leukemia (Part 9)

Treatment of Promyelocytic LeukemiaTretinoin is an oral drug that induces the differentiation of leukemic cells bearing the t(15;17). APL is responsive to cytarabine and daunorubicin, but about 10% of patients treated with these drugs die from DIC induced by the release of granule components by dying tumor cells. Tretinoin does not produce DIC but produces another complication called the retinoic acid syndrome. Occurring within the first 3 weeks of treatment, it is characterized by fever, dyspnea, chest pain, pulmonary infiltrates, pleural and pericardial effusions, and hypoxia. The syndrome is related to adhesion of differentiated neoplastic cells to the pulmonary...
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Chapter 104. Acute and Chronic Myeloid Leukemia (Part 9) Chapter 104. Acute and Chronic Myeloid Leukemia (Part 9) Treatment of Promyelocytic Leukemia Tretinoin is an oral drug that induces the differentiation of leukemic cellsbearing the t(15;17). APL is responsive to cytarabine and daunorubicin, but about10% of patients treated with these drugs die from DIC induced by the release ofgranule components by dying tumor cells. Tretinoin does not produce DIC butproduces another complication called the retinoic acid syndrome. Occurringwithin the first 3 weeks of treatment, it is characterized by fever, dyspnea, chestpain, pulmonary infiltrates, pleural and pericardial effusions, and hypoxia. Thesyndrome is related to adhesion of differentiated neoplastic cells to the pulmonaryvasculature endothelium. Glucocorticoids, chemotherapy, and/or supportivemeasures can be effective for management of the retinoic acid syndrome. Themortality of this syndrome is about 10%. Tretinoin (45 mg/m2 per day orally until remission is documented) plusconcurrent anthracycline chemotherapy appears to be among the safest and mosteffective treatments for APL. Unlike patients with other types of AML, patientswith this subtype benefit from maintenance therapy with either tretinoin orchemotherapy. Arsenic trioxide produces meaningful responses in up to 85% of patientsrefractory to tretinoin. The use of arsenic trioxide is being explored as part ofinitial treatment in clinical trials of APL. Additionally, studies combining arsenictrioxide with tretinoin in the absence of chemotherapy are ongoing. The detection of minimal residual disease by RT-PCR amplification of thet(15;17) chimeric gene product appears to predict relapse. Disappearance of thesignal is associated with long-term disease-free survival; its persistence predictsrelapse. With increases in the sensitivity of the assay, some patients with persistentabnormal gene product have been found who do not suffer a relapse. Studies areunderway to determine whether a critical threshold level of transcripts uniformlypredicts for leukemia relapse. Postremission Therapy Induction of a durable first CR is critical to long-term disease-free survivalin AML. However, without further therapy virtually all patients experiencerelapse. Once relapse has occurred, AML is generally curable only by SCT. Postremission therapy is designed to eradicate residual leukemic cells toprevent relapse and prolong survival. Postremission therapy in AML is often basedon age (younger than 55–65 and older than 55–65). For younger patients, moststudies include intensive chemotherapy and allogeneic or autologous SCT. High-dose cytarabine is more effective than standard-dose cytarabine. The Cancer andLeukemia Group B (CALGB), for example, compared the duration of CR inpatients randomly assigned postremission to four cycles of high (3 g/m2, every 12h on days 1, 3, and 5), intermediate (400 mg/m2 for 5 days by continuousinfusion), or standard (100 mg/m2 per day for 5 days by continuous infusion)doses of cytarabine. A dose-response effect for cytarabine in patients with AMLwho were ≤60 years was demonstrated. High-dose cytarabine significantlyprolonged CR and increased the fraction cured in patients with favorable [t(8;21)and inv(16)] and normal cytogenetics, but it had no significant effect on patientswith other abnormal karyotypes. For older patients, exploration of attenuatedintensive therapy that includes either chemotherapy or reduced intensity allogeneicSCT has been pursued. Postremission therapy is a setting for introduction of newagents (Table 104-3). Table 104-3 Selected New Agents under Study for Treatment of Adultswith AML Class of Drugs Example Agent(s) MDR1 modulators Cyclosporine, LY335979 Demethylating agents Decitabine, 5-azacytidine, zebularine Histone deacetylase Suberoylanilide hydroxamic acid (SAHA),inhibitors MS275, LBH589, valproic acid Heavy metals Arsenic trioxide, antimony Farnesyl transferase R115777, SCH66336inhibitors FLT3 inhibitors SU11248, PKC412, MLN518, CHIR-258 HSP-90 antagonists 17-allylaminogeldanamycin (17-AAG) or derivatives BCR-ABL Imatinib (ST1571, Gleevec), dasatinib,PDGFR/KIT inhibitors nilotinib Telomerase inhibitor GRN163L Cell cycle inhibitors Flavopiridol, CYC202 (R-Roscovitine), SNS-032 Nucleoside analogues Clofarabine, troxac ...