Chapter 104. Acute and Chronic Myeloid Leukemia (Part 8)

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The hematologic toxicity of high-dose cytarabine-based induction regimens has typically been greater than that associated with 7 and 3 regimens. Toxicity with high-dose cytarabine includes myelosuppression, pulmonary toxicity, and significant and occasionally irreversible cerebellar toxicity. All patients treated with high-dose cytarabine must be closely monitored for cerebellar toxicity. Full cerebellar testing should be performed before each dose, and further high-dose cytarabine should be withheld if evidence of cerebellar toxicity develops. This toxicity occurs more commonly in patients with renal impairment and in those over age 60. The increased toxicity observed with high-dose cytarabine has limited the use of this...

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Chapter 104. Acute and Chronic Myeloid Leukemia (Part 8) The hematologic toxicity of high-dose cytarabine-based induction regimens has typically been greater than that associated with 7 and 3 regimens. Toxicity with high-dose cytarabine includes myelosuppression, pulmonary toxicity, and significant and occasionally irreversible cerebellar toxicity. All patients treated with high-dose cytarabine must be closely monitored for cerebellar toxicity. Full cerebellar testing should be performed before each dose, and further high-dose cytarabine should be withheld if evidence of cerebellar toxicity develops. This toxicity occurs more commonly in patients with renal impairment and in those over age 60. The increased toxicity observed with high-dose cytarabine has limited the use of this therapy in elderly AML patients. Supportive Care
Measures geared to supporting patients through several weeks of granulocytopenia and thrombocytopenia are critical to the success of AML therapy. Patients with AML should be treated in centers expert in providing supportive measures. Recombinant hematopoietic growth factors have been incorporated into clinical trials in AML. These trials have been designed to lower the infection rate after chemotherapy. Both G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) have reduced the median time to neutrophil recovery by an average of 5–7 days. This accelerated rate of neutrophil recovery, however, has not generally translated into significant reductions in infection rates or shortened hospitalizations. In most randomized studies, both G-CSF and GM-CSF have failed to improve the CR rate, disease-free survival, or overall survival. Although receptors for both G-CSF and GM-CSF are present on AML blasts, therapeutic efficacy is neither enhanced nor inhibited by these agents. The use of growth factors as supportive care for AML patients is controversial. We favor their use in elderly patients with complicated courses, those receiving intensive postremission regimens, patients with uncontrolled infections, or those participating in clinical trials. Multilumen right atrial catheters should be inserted as soon as patients with newly diagnosed AML have been stabilized. They should be used thereafter for administration of intravenous medications and transfusions, as well as for blood
drawing. Antibiotic-impregnated catheters should be considered if the risk of line- related infection is high. Adequate and prompt blood bank support is critical to therapy of AML. Platelet transfusions should be given as needed to maintain a platelet count >10,000–20,000/µL. We believe that the platelet count should be kept at higher levels in febrile patients and during episodes of active bleeding or DIC. Patients with poor posttransfusion platelet count increments may benefit from administration of platelets from human leukocyte antigen (HLA)-matched donors. RBC transfusions should be administered to keep the hemoglobin level >80 g/L (8 g/dL) in the absence of active bleeding, DIC, or congestive heart failure. Blood products leukodepleted by filtration should be used to avert or delay alloimmunization as well as febrile reactions. Blood products should also be irradiated to prevent transfusion associated graft-versus-host disease (GVHD). Cytomegalovirus (CMV)-negative blood products should be used for CMV- seronegative patients who are potential candidates for allogeneic SCT. Leukodepleted products are also effective for these patients if CMV-negative products are not available. Infectious complications remain the major cause of morbidity and death during induction and postremission chemotherapy for AML. Prophylactic administration of antibiotics in the absence of fever is controversial. Oral nystatin or clotrimazole is recommended to prevent localized candidiasis. For patients who
are herpes simplex virus antibody titer–positive, acyclovir prophylaxis is effective in preventing reactivation of latent oral herpes infections. Fever develops in most patients with AML, but infections are documented in only half of febrile patients. Early initiation of empirical broad-spectrum antibacterial and antifungal antibiotics has significantly reduced the number of patients dying of infectious complications (Chap. 82). An antibiotic regimen adequate to treat gram-negative organisms should be instituted at the onset of fever in a granulocytopenic patient after clinical evaluation, including a detailed physical examination with inspection of the indwelling catheter exit site and a perirectal examination, as well as procurement of cultures and radiographs aimed at documenting the source of fever. Specific antibiotic regimens should be based on antibiotic sensitivity data obtained from the institution at which the patient is being treated. Acceptable regimens include imipenem-cilastin; an antipseudomonal semisynthetic penicillin (e.g., piperacillin) combined with an aminoglycoside; a third-generation cephalosporin with antipseudomonal activity (i.e., ceftazidime or cefepime); or double β-lactam combinations (ceftazidime and piperacillin). Aminoglycosides should be avoided if possible in patients with renal insufficiency. For patients with known immediate-type hypersensitivity reactions to penicillin, aztreonam may be substituted for β-lactams. Aztreonam should be combined with an aminoglycoside or a quinolone antibiotic rather than used alone.
Empirical vancomycin is not given initially in the absence of suspected gram-positive infection or mucositis but should be initiated in neutropenic patients who remain febrile for 3 days; empirical systemic antifungal therapy is added at 7 days if fever persists. Voriconazole has been shown to be equivalent in efficacy and less toxic than amphotericin-B. Caspofungin or liposomal amphotericin are also considered for fungal infections not responsive to first-line therapy or when such therapy is not tolerated. Antibacterial and antifungal antibiotics should be continued until patients are no longer neutropenic, regardless of whether a specific source has been found for the fever.