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

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Treatment of Promyelocytic Leukemia Tretinoin 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) Treatment of Promyelocytic Leukemia Tretinoin 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 vasculature endothelium. Glucocorticoids, chemotherapy, and/or supportive
measures can be effective for management of the retinoic acid syndrome. The mortality of this syndrome is about 10%. Tretinoin (45 mg/m2 per day orally until remission is documented) plus concurrent anthracycline chemotherapy appears to be among the safest and most effective treatments for APL. Unlike patients with other types of AML, patients with this subtype benefit from maintenance therapy with either tretinoin or chemotherapy. Arsenic trioxide produces meaningful responses in up to 85% of patients refractory to tretinoin. The use of arsenic trioxide is being explored as part of initial treatment in clinical trials of APL. Additionally, studies combining arsenic trioxide with tretinoin in the absence of chemotherapy are ongoing. The detection of minimal residual disease by RT-PCR amplification of the t(15;17) chimeric gene product appears to predict relapse. Disappearance of the signal is associated with long-term disease-free survival; its persistence predicts relapse. With increases in the sensitivity of the assay, some patients with persistent abnormal gene product have been found who do not suffer a relapse. Studies are underway to determine whether a critical threshold level of transcripts uniformly predicts for leukemia relapse. Postremission Therapy
Induction of a durable first CR is critical to long-term disease-free survival in AML. However, without further therapy virtually all patients experience relapse. Once relapse has occurred, AML is generally curable only by SCT. Postremission therapy is designed to eradicate residual leukemic cells to prevent relapse and prolong survival. Postremission therapy in AML is often based on age (younger than 55–65 and older than 55–65). For younger patients, most studies include intensive chemotherapy and allogeneic or autologous SCT. High- dose cytarabine is more effective than standard-dose cytarabine. The Cancer and Leukemia Group B (CALGB), for example, compared the duration of CR in patients randomly assigned postremission to four cycles of high (3 g/m2, every 12 h on days 1, 3, and 5), intermediate (400 mg/m2 for 5 days by continuous infusion), 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 AML who were ≤60 years was demonstrated. High-dose cytarabine significantly prolonged 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 patients with other abnormal karyotypes. For older patients, exploration of attenuated intensive therapy that includes either chemotherapy or reduced intensity allogeneic SCT has been pursued. Postremission therapy is a setting for introduction of new agents (Table 104-3).
Table 104-3 Selected New Agents under Study for Treatment of Adults with 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, SCH66336 inhibitors 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, troxacitabine Humanized antibodies Anti-CD33 (SGN33), anti-DR4, anti-DR5, anti-KiR Toxin-conjugated Gemtuzumab ozogamicin (Mylotarg) antibodies Radiolabeled antibodies Yttrium-90-labeled human M195