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The tyrosine kinase inhibitor (TKI) imatinib (Gleevec; Novartis, Basel, Switzerland) is standard therapy for patients with chronic myeloid leukemia (CML).1 Therapy with imatinib is generally well tolerated, and the most common side effects include nausea, diarrhea, fatigue, muscle cramps, rashes, fluid retention, liver enzymes abnormalities, and myelo-suppression.2,3 Myelosuppression is the most common grade 3–4 toxicity, occurring in 35% to 45% of patients treated with imatinib after interferon (IFN)-α failure and in 15% of patients with previously untreated CML.3–5 Anemia has been reported in 45% to 68% of patients in chronic phase treated with imatinib, and is grade 3-4 in 7% of patients after IFN-α failure and in 3% to 7% of those receiving imatinib as initial CML therapy.3–5 The development of myelosuppression, including anemia, in patients with CML has been associated with an inferior outcome.2,5,6 The use of growth factors such as erythropoietic-stimulating agents (recombinant human erythropoietin [EPO] or darbepoietin-α) and granulocyte-colony stimulating factor during therapy with TKI in CML can improve cytopenias and decrease the frequency of interruptions and dose reductions.6,7 Among patients with chronic phase CML receiving therapy with imatinib, erythropoietic-stimulating agents improved hemoglobin (Hb) levels by at least 2 g/dL in 68% of patients.6 Recently, concerns have been raised regarding the safety of erythropoietic-stimulating agents in patients with cancer.8 A meta-analysis showed that the use of erythropoietic-stimulating agents for prophylaxis or treatment of anemia in patients with cancer increases mortality (hazard ratio [HR], 1.17) and decreases overall survival (OS) (HR, 1.06).9 Another meta-analysis reported that erythropoietic-stimulating agents increase the risk for venous thromboembolic events (relative risk, 1.57) and decrease survival (HR, 1.10) in patients with cancer.10 In addition, a randomized trial showed that use of darbepoietin-α was associated with worse survival in patients with cancer-related anemia not receiving chemotherapy.11 Erythropoietic-stimulating agents shortened time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy when it was administered to target an Hb of >12 g/dL.12 Similarly, use of erythropoietic-stimulating agents decreased OS in patients with metastatic breast cancer and nonsmall cell lung cancer.13,14 This evidence led to a revision in the US Food and Drug Administration product labels for erythropoietic-stimulating agents, issuing a black box warning indicating the possibility of shortened survival and cancer progression in cancer patients treated with erythropoietic-stimulating agents when targeting a Hb level of 10 to 12 g/dL.8 For patients with CML and imatinib-induced anemia, there are few treatment options. The American Society of Hematology/American Society of Clinical Oncology guidelines on the use of erythropoietic-stimulating agents in patients with cancer recommends that for patients with chemotherapy-associated anemia and low-risk myelodysplastic syndrome, erythropoietic-stimulating agents should be initiated as Hb approaches or falls below 10 g/dL to increase Hb and decrease transfusions.8 The dose should be decreased by 25% to 40% when Hb reaches the level needed to avoid transfusion or if the rate of Hb increase is >1 g/dL in 2 weeks.8 However, erythropoietic-stimulating agent are frequently used in patients with CML to treat anemia associated with TKI therapy, but the long-term safety of their use in this setting is unknown.6 We thus conducted this analysis to investigate the prognostic impact of erythropoietic-stimulating agent use among patients with CML in chronic phase treated with imatinib and to define the incidence of cardiovascular, cerebrovascular, or thromboembolic episodes in this patient population.

BACKGROUND: Nausea and vomiting in patients with acute myelogenous leukemia (AML) can be from various causes, including the use of high-dose cytarabine. METHODS: The authors compared 2 schedules of palonosetron versus ondansetron in the treatment of chemotherapy-induced nausea and vomiting (CINV) in patients with AML receiving high-dose cytarabine. Patients were randomized to: 1) ondansetron, 8 mg intravenously (IV), followed by 24 mg continuous infusion 30 minutes before high-dose cytarabine and until 12 hours after the high-dose cytarabine infusion ended; 2) palonosetron, 0.25 mg IV 30 minutes before chemotherapy, daily from Day 1 of high-dose cytarabine up to Day 5; or 3) palonosetron, 0.25 mg IV 30 minutes before high-dose cytarabine on Days 1, 3, and 5. RESULTS: Forty-seven patients on ondansetron and 48 patients on each of the palonosetron arms were evaluable for efficacy. Patients in the palonosetron arms achieved higher complete response rates (no emetic episodes plus no rescue medication), but the difference was not statistically significant (ondansetron, 21%; palonosetron on Days 1-5, 31%; palonosetron on Days 1, 3, and 5, 35%; P = .32). Greater than 77% of patients in each arm were free of nausea on Day 1; however, on Days 2 through 5, the proportion of patients without nausea declined similarly in all 3 groups. On Days 6 and 7, significantly more patients receiving palonosetron on Days 1 to 5 were free of nausea (P = .001 and P = .0247, respectively). CONCLUSIONS: The daily assessments of emesis did not show significant differences between the study arms. Patients receiving palonosetron on Days 1 to 5 had significantly less severe nausea and experienced significantly less impact of CINV on daily activities on Days 6 and 7. Cancer 2010. © 2010 American Cancer Society.

BACKGROUND: Acute kidney injury (AKIis a common complication in the treatment of patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS), but, to the authors' knowledge, its clinical relevance has not been detailed to date. The objective of the current study was to identify the incidence, predictors, and outcome for AKI in patients with AML and HR-MDS. METHODS: Data were analyzed from 537 patients with AML or HR-MDS undergoing induction chemotherapy from 1999 to 2007. Predictors for AKI were identified by logistic regression. Eight-week mortality of patients was estimated by the Kaplan-Meier method stratified by the RIFLE criteria, a novel multilevel classification system for AKI based on the percent rise in serum creatinine from baseline (Risk, >50%; Injury, >100%; and Failure, >200% or requiring dialysis). RESULTS: A total of 187 patients (36%) developed AKI. Significant independent risk factors for AKI included the following: age ≥55 years (odds ratio [OR], 1.8), mechanical ventilation (OR, 16), use of vancomycin (OR, 2.3), diuretics (OR, 3.0), amphotericin B lipid formulation (OR, 2.7), vasopressors (OR, 4.9), leukopenia (OR, 1.9), hypoalbuminemia (OR, 1.4), and use of non-fludarabine–based chemotherapy (OR, 2.7). The 8-week mortality rates were 3.8%, 13.6%, 19.6%, and 61.7% for the non-RIFLE, Risk, Injury, and Failure categories, respectively. Patients requiring dialysis (8%) had a median survival of 33 days. Survival of patients who achieved complete remission was favorable, regardless of degree of AKI. CONCLUSIONS: The RIFLE classification for AKI appears to have prognostic utility in predicting mortality in patients with AML or HR-MDS. Relatively mild elevations in creatinine are associated with higher mortality. Strategies to avoid nephrotoxic drugs or fluid overload may be of benefit. Cancer 2010. © 2010 American Cancer Society.

BACKGROUND Systemic fungal infections remain the leading cause of mortality in patients with newly diagnosed acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS). The objective of the current study was to determine whether intravenous itraconazole (I.V. ITRA) reduced the incidence of probable/proven fungal infections in this group of patients, and compare the results with those of a historic control group treated with fluconazole plus itraconazole capsules (F+I). METHODS Patients with AML and high-risk MDS who underwent induction chemotherapy received 200 mg of i.v. itraconazole over 60 minutes every 12 hours during the first 2 days followed by 200 mg given i.v. once daily. RESULTS One hundred patients were enrolled, 96 of whom were evaluable. Approximately 48% of the patients in the group of patients treated with IV ITRA as well as in the F+I group completed prophylaxis. Nine patients (9%) in the study group developed either proven/probable fungal infections (Candida glabrata in 5 patients, C. tropicalis in 1 patient, C krusei in 1 patient, and Fusarium in 2 patients) compared with 3 patients (4%) with proven fungal infection in the historic control group (C. tropicalis in 1 patient and Aspergillus in 2 patients). There were no significant differences noted between the two groups with regard to the percentage of patients who developed proven/probable or possible fungal infection as well as with regard to survival. These results also were obtained after adjusting for relevant prognostic factors (creatinine and bilirubin). The most common toxicity encountered with the use of IV ITRA was NCI Grade 3-4 hyperbilirubinemia (6%). CONCLUSIONS Despite its theoretic advantages, the authors found no evidence that IV ITRA is superior to itraconazole capsules, at least when the latter is combined with fluconazole. Cancer 2004. © 2003 American Cancer Society.

BACKGROUND Fungal infections are a major cause of morbidity and mortality in patients undergoing induction chemotherapy for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). The authors evaluated the efficacy and toxicity of liposomal amphotericin B (L-AmB) compared with a combination of fluconazole plus itraconazole (F+I) as prophylaxis in this setting. METHODS Patients with newly diagnosed AML or high-risk MDS who were undergoing initial induction chemotherapy were randomized to receive either F+I (fluconazole 200 mg orally every 12 hours plus itraconazole tablets 200 mg orally every 12 hours) or L-AmB (3 mg/kg intravenously 3 times per week) in this prospective, open-label study. RESULTS Seventy-two L-AmB-treated patients and 67 F+I-treated patients were enrolled in the study. Of these, 47% of patients completed antifungal prophylaxis without a change in therapy for proven or suspected fungal infection. Three patients in each arm developed a proven fungal infection. Twenty-three percent of the L-AmB-treated patients and 24% of the F+I-treated patients were changed to alternative antifungal therapy because of persistent fever (P value not significant). Nine percent of the L-AmB-treated patients developed pneumonia of unknown etiology compared with 16% of the F+I-treated patients (P value not significant). Increases in serum creatinine levels to > 2 mg/dL (20% for the L-AmB arm vs. 6% for the F+I arm; P = 0.012) and increases in serum bilirubin levels to > 2 mg/dL (43% vs. 22%, respectively; P = 0.021) were more common with L-AmB. Infusion-related reactions were noted in five L-AmB-treated patients. Responses to chemotherapy and induction mortality rates were similar for the two arms. CONCLUSIONS L-AmB and F+I appear similar in their efficacy as antifungal prophylaxis during induction chemotherapy for patients with AML and MDS. L-AmB was associated with higher rates of increased serum bilirubin and creatinine levels. Cancer 2003;97:450–6. © 2003 American Cancer Society. DOI 10.1002/cncr.11094

BACKGROUND: Anemia is an expected consequence of intensive chemotherapy regimens administered to patients with acute leukemia. This study was designed to determine whether epoetin alpha would decrease the number of transfusion events and units of packed erythrocytes (PRBCs) transfused, and the secondary objective was to study the effects of epoetin alpha on quality of life (QOL) and complete remission (CR) rates. METHODS: Patients with acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL), or Burkitt lymphoma (BL) who were receiving frontline myelosuppressive chemotherapy were randomized to receive epoetin alpha or no epoetin during the first 6 cycles of their planned chemotherapy. QOL was assessed by using the Edmonton Symptom Assessment Scale (ESAS) and the Functional Assessment of Cancer Therapy (FACT)-Anemia questionnaires. RESULTS: Fifty-five patients were randomized to receive epoetin alpha, and 54 patients received no epoetin. Transfusion data were available for 79 of 81 evaluable patients (98%) who completed the treatment/observation period. The trial was stopped early because of poor accrual before the target of 123 evaluable patients was met. A mean of 10.6 units of PRBCs over 5 months were administered to those who received epoetin alpha compared with 13 units for those who did not receive epoetin (P = .04). There was no significant difference in QOL as assessed by the FACT-Anemia or ESAS instruments. The CR rate and the 3-year CR duration were not affected adversely by use of epoetin alpha. CONCLUSIONS: Epoetin alpha decreased the number of PRBC transfusions and did not appear to have a negative impact on remission duration. No difference in QOL was observed. Cancer 2012;. © 2011 American Cancer Society.

BACKGROUND: Acute pulmonary failure during remission induction therapy is a serious complication in patients with acute myeloid leukemia (AML). To the authors' knowledge, the course and prognosis of such patients is not well known. METHODS: A total of 1541 patients referred for remission induction chemotherapy of AML or high-risk myelodysplastic syndrome were retrospectively reviewed. RESULTS: A total of 120 (8%) patients developed acute pulmonary failure within 2 weeks of the initiation of chemotherapy; 87 of these patients (73%) died during remission induction, whereas 17 (14%) achieved a complete response. The median survival among the 120 patients with early acute pulmonary failure was 3 weeks. Predictive factors for the development of early acute pulmonary failure by multivariate analysis were: male sex (P = .00038), acute promyelocytic leukemia (P = .00003), poor performance status (P = .001), lung infiltrates at diagnosis (P = .000001), and increased creatinine (P = .000005). Patients who had 0 to 1, 2, 3, or 4 to 5 adverse factors were found to have estimated predictive incidences of acute pulmonary failure of 3%, 13%, 23%, and 34%, respectively. CONCLUSIONS: Preventive approaches at the start of induction therapy in patients at high risk of pulmonary failure may improve the outcome of these patients. Cancer 2010. © 2010 American Cancer Society.

BACKGROUND The optimal antifungal prophylactic regimen for patients with acute myelogenous leukemia (AML) or high-risk myelodysplastic syndrome (MDS) undergoing induction chemotherapy has yet to be identified. A prospective historical control study evaluated the efficacy and safety of amphotericin B lipid complex (ABLC) in this patient population. METHODS Newly diagnosed patients with AML or high-risk MDS who were undergoing induction chemotherapy received prophylactic ABLC 2.5 mg/kg intravenously 3 times weekly. This treatment group was compared with a historical control group that had similar baseline characteristics and received prophylactic liposomal amphotericin B (L-AmB) 3 mg/kg 3 times weekly. The primary endpoint was the incidence of documented or suspected fungal infections during and up to 4 weeks after cessation of prophylaxis. Reported adverse events were used to assess tolerability. RESULTS The overall efficacy of antifungal prophylaxis was similar in patients who received ABLC and patients who received L-AmB (P = 0.95). Among 131 ABLC-treated patients and 70 L-AmB-treated patients who ere assessed for efficacy and safety, 49% of patients in each group completed therapy without developing a documented or suspected fungal infection. Documented fungal infections occurred in 5% of ABLC-treated patients and in 4% of L-AmB-treated patients. Alternative antifungal strategies were required because of persistent fever or pneumonia of unknown pathogen in 28% and 32% of ABLC-treated and L-AmB-treated patients, respectively. Grade 3 and 4 adverse events, therapy discontinuations due to adverse events, and survival rates also were similar between treatment groups. CONCLUSIONS ABLC and L-AmB appeared to have similar efficacy and were tolerated well as antifungal prophylaxis in patients with AML and high-risk MDS who were undergoing induction chemotherapy. Cancer 2004. © 2003 American Cancer Society.