Outcome of patients with acute myelogenous leukemia after second salvage therapy

BACKGROUND: Although the prognosis is poor for patients with acute myelogenous leukemia (AML) who have disease recurrence after frontline therapy, this is a general reflection of first salvage therapies. The outcome of patients undergoing second salvage therapy in relation to complete response (CR) rates and survival has not been documented. The authors analyzed the outcome of patients with AML undergoing second salvage therapy, and identified prognostic factors associated with response and survival. METHODS: The records of 594 patients with AML undergoing second salvage therapy from 1980 until 2004 were reviewed. The patient median age was 50 years. Salvage therapy included allogeneic stem cell transplantation (SCT) in 74 patients, standard-dose cytosine arabinoside (ara-C) combinations in 30 patients, high-dose ara-C combinations in 171 patients, non-ara-C combinations in 73 patients, and Phase I-II single agents in 246 patients. RESULTS: Overall, 76 patients (13%) achieved CR. The median CR duration was 7 months. The median survival was 1.5 months, and the 1-year survival rate was 8%. A multivariate analysis of prognostic factors for CR identified the following 6 independent adverse factors: first CR duration < 6 months; second CR duration < 6 months; salvage therapy not including allogeneic SCT; non-inversion 16 AML; platelet counts < 50 x 10(9)/L, and leukocytosis > 50 x 10(9)/L. Patients were divided into low-risk (1-2 adverse factors; 8%), intermediate 1 (3 factors; 20%), intermediate 2 (4 factors; 38%), and high-risk groups (5-6 factors; 33%) with respective CR rates of 54%, 26%, 8%, and 0%. The respective 1-year survival rates were 36%, 21%, 6%, and 1%. A multivariate analysis for survival identified the following 7 independent adverse factors: first CR duration < 12 months; second CR duration < 6 months; bilirubin level > or = 1 mg/dL; albumin level < 3 g/dL; age > 60 years; bone marrow blasts > or = 50%; and year of therapy before 1991. Patients were divided into low-risk (0-2 adverse factors; 39%), intermediate (3 factors; 27%), and high-risk groups (> or = 4 factors; 34%) with estimated 1-year survival rates of 22%, 6%, and 0%, respectively. The respective CR rates were 26%, 8%, and 2%. CONCLUSIONS: The current analysis established the outcome and prognostic factors associated with second salvage therapy in AML. It also proposed risk models and groups that could be used for comparison of results of present and future investigational strategies.     

Survival of severe congenital diaphragmatic hernia has morbid consequences

Background/Purpose

Fetal tracheal occlusion (TO) was developed in an attempt to enhance prenatal lung growth and improve survival in fetuses with severe congenital diaphragmatic hernia (CDH). We conducted a randomized, controlled clinical trial in 24 fetuses with severe left CDH (liver herniated into the thorax and low lung-to-head ratio) to compare survival after endoscopic fetal TO vs standard perinatal care (control) and prospectively followed up the 16 survivors (9 control, 7 TO) to compare neurodevelopmental, respiratory, surgical, growth, and nutritional outcomes.

Methods

At 1 and 2 years old, subjects underwent evaluation consisting of medical and neurological history and physical, developmental testing, nutritional assessment, oxygen saturation and pulmonary function testing, chest radiograph, and echocardiogram. Growth and developmental measures were corrected for prematurity. Data were analyzed by Mann-Whitney rank sum test, Fisher's Exact test, and logistic and linear regression.

Results

Infants with TO were significantly more premature at birth (control vs TO, 37.4 ± 1.0 vs 31.1 ± 1.7 weeks; P < .01). Growth failure (z score for weight <2 SDs below mean) was severe in both groups at 1 year of age (control vs TO, 56% vs 86%; P = .31). There was considerable catch-up growth by age 2 years (growth failure: control vs TO, 22% vs 33%; P = .19). There were no differences in other growth parameters. There were also no differences in neurodevelopmental outcome at 1 and 2 years. Supplemental oxygen at hospital discharge was a significant predictor of worse neurodevelopmental outcome at 1 and 2 years old (P = .05 and P = .02, respectively). Hearing loss requiring amplification has been diagnosed in 44% of the group (control vs TO, 44% vs 43%; P = 1.0).

Conclusions

In this group of infants with severe CDH, there were no differences in outcome at 2 years old despite significant prematurity in the TO group. Oxygen supplementation at hospital discharge identified the most vulnerable group with respect to neurodevelopmental outcome, but all infants had significant growth failure, and hearing impairment is a substantial problem in this population. Severe CDH carries significant risk of chronic morbidity.     

C2 monitoring of cyclosporine in stable renal transplant patients results in lower costs and improved renal function

INTRODUCTION: C2 (2-hour post-absorption levels) monitoring of cyclosporine (CsA) seems to reduce the rate of acute rejection episodes (ARE) without increasing nephrotoxicity during the first months after transplant. There are a few reports on the impact of adopting this strategy in patients with stable renal transplants. We herein report a prospective trial in long-term renal transplant patients (>6 months) monitored by C0 or C3 who were switched to C2 monitoring. METHODS: Seventy-six (mean age = 43 +/- 11 years) kidney transplant patients (mean = 37 +/- 21 months after transplant) receiving CsA, steroids, and azathioprine were switched to C2 monitoring, seeking to achieve a target range of 800 +/- 100 ng/mL. The patients were followed for at least 6 months. RESULTS: At conversion the C2 values of 61% of the patients were above and 17% below the therapeutic range. Six months after conversion there was a significant reduction in BUN (29 +/- 11 vs 27 +/- 10, P < .01), Creatinine (Cr), cholesterol, and triglyceride levels were unchanged. Mean CsA dose was decreased 10% from 244 +/- 63 to 220 +/- 52 (P < .01), implying a net savings of 390 US dollars per patient per year. Among the group of patients who showed a high C2 level, there was also a reduction in BUN (30 +/- 12 vs 27 +/- 10, P < .01) and a nonsignificant decrease in Cr (1.53 +/- 0.6 vs 1.50 +/- 0.6). CONCLUSIONS: C2 monitoring in stable kidney transplant recipients is feasible and safe. The strategy results in reduced drug costs and improved renal function.     

Intravenous itraconazole for prophylaxis of systemic fungal infections in patients with acute myelogenous leukemia and high-risk myelodysplastic syndrome undergoing induction chemotherapy

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 i.v. 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 i.v. ITRA was NCI Grade 3-4 hyperbilirubinemia (6%). CONCLUSIONS: Despite its theoretic advantages, the authors found no evidence that i.v. ITRA is superior to itraconazole capsules, at least when the latter is combined with fluconazole.     

Phase I and pharmacokinetic study of a low-clearance, unilamellar liposomal formulation of lurtotecan, a topoisomerase 1 inhibitor, in patients with advanced leukemia

BACKGROUND: OSI-211 is a low-clearance, unilamellar liposomal formulation of a water-soluble camptothecin analogue, lurtotecan. OSI-211 has significant activity in severe combined immunodeficient mouse models of human leukemia. METHODS: This study was conducted to define the dose-limiting toxicities (DLT) and pharmacokinetics of OSI-211 in patients with refractory myeloid leukemias. Patients with refractory acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP) were eligible. OSI-211 was given as an intravenous infusion over 30 minutes daily for 3 days. The starting dose was 1.5 mg/m2 per day (4.5 mg/m2 per course). The dose was escalated by 50% until Grade 2 toxicity was observed and then by 30-35% until the DLT was defined. Serial plasma and urine samples were collected, and drug levels were determined by high-performance liquid chromatography with fluorescence detection. RESULTS: Twenty patients (18 patients [90%] with AML, and 1 patient each [5%] with MDS and CML-BP) were treated. Mucositis and diarrhea were considered to be the DLTs. The maximum tolerated dose was 3.7 mg/m2 per day. Fourteen of 18 evaluable patients (78%) with AML or MDS achieved transient bone marrow aplasia. The mean systemic clearance of lurtotecan in plasma was 0.946 +/- 1.53 L/hour/m2. Urinary recovery of lurtotecan was 6.66% +/- 5.26% (range, 1.05-18.4%). CONCLUSIONS: Liposomal encapsulation of lurtotecan altered its metabolism significantly. There was no evident correlation between exposure, as measured by plasma pharmacokinetics of lurtotecan, and clinical response or toxicities. OSI-211 merits further study in hematologic malignancies.