Obesity, weight gain, and risk of chronic myeloid leukemia.

To date, little is known about the risk factors for the development of chronic myeloid leukemia (CML). Obesity, measured as body mass index, has been identified as a possible risk factor for several solid tumors as well as some adult hematopoietic malignancies. This case-control study (N = 253 cases and 270 controls), conducted at the University of Texas M. D. Anderson Cancer Center, investigated the role of obesity and adulthood weight gain in CML risk. Cases and controls were similar with respect to smoking, alcohol consumption, and occupational solvent and ionizing radiation exposure. Cases were significantly more likely to have a history of occupational exposure to agricultural chemicals (11% cases versus 3% controls, P = 0.001). Cases were more likely to be obese during adulthood compared with controls at age 25 [odds ratios (OR) = 4.29; 95% confidence intervals (95% CI), 1.63-11.3], at age 40 (OR = 5.12; 95% CI, 1.92-13.6), and at diagnosis (OR = 3.09; 95% CI, 1.56-6.13). Obesity at all ages was found to be an independent risk factor, with a significant dose-response effect. Among participants > or =45 years, cases gained significantly more weight each year between ages 25 and 40 compared with controls (0.78 versus 0.44 kg/y, P < 0.001) with the association strongest among those who gained >1 kg/y between 25 and 40 years of age (OR, 3.63; 95% CI, 1.46-9.04). Our results suggest that obesity and adulthood weight gain play important roles in CML risk. Several plausible biological mechanisms have been proposed and warrant further investigation. In the future, cancer prevention interventions aimed at reducing the incidence of CML could be developed.

The role of craniospinal irradiation in adults with a central nervous system recurrence of leukemia.

BACKGROUND: Although central nervous system (CNS) prophylaxis in patients with leukemia has reduced the incidence of CNS disease recurrence, it still is reported to occur in approximately 5-10% of cases, resulting in a median survival of 6 months. Craniospinal irradiation (CSI) has been shown to improve survival in children who develop a CNS recurrence of acute lymphocytic leukemia (ALL). However, to the authors' knowledge, the role of CSI in adults with a CNS recurrence of leukemia is unknown. METHODS: A retrospective review of adult patients treated with CSI for a CNS recurrence of leukemia identified 16 patients treated between 1986 and 2001. The median age of the patients was 34 years (range, 16-58 years). The diagnoses included seven patients with acute myelogenous leukemia (AML), eight patients with ALL, and one patient with chronic myelogenous leukemia in blast crisis. All patients had achieved a complete disease remission prior to the CNS recurrence. Eleven patients had an isolated CNS recurrence and 5 patients had concurrent disease identified in the blood/bone marrow. The median dose of radiation was 24 grays (Gy) (range, 18-34.5 Gy) to the cranium and 18 Gy (range, 15-30 Gy) to the spine. The median fraction size was 1.8 Gy (range, 1.5-2.0 Gy) to the cranium and 1.5 Gy (range, 1.5-2.0 Gy) to the spine. Fifteen patients were also treated with intrathecal chemotherapy. RESULTS: One patient failed to complete radiation treatment because of disease progression. Thirteen patients achieved a complete response in the cerebrospinal fluid (CSF). The median time to disease progression was 3 months from the first day of CSI and 7 months from CNS recurrence. The median survival was 4 months and 9 months, respectively. No CNS recurrences occurred, but there were 11 bone marrow failures, 2 patients without recurrence at > 5 years, and 3 deaths without a documented site of failure. Thirteen patients had no evidence of disease in the CSF until their death or the time of last follow-up. CONCLUSIONS: CSI with or without intrathecal chemotherapy appears to be effective at eliminating leukemia in the craniospinal axis. However, the eradication of disease in the CNS was not found to be effective at preventing disease recurrence in the bone marrow, and despite improved control of disease in the CNS, adult patients with a CNS recurrence still had a poor prognosis. Furthermore, the rapidly fatal course of disease prevented an assessment of the durability of CNS response to irradiation.

Phase I study of oral topotecan in hematological malignancies.

PURPOSE: In this Phase I, dose-seeking study, we investigated the dose-limiting toxicities (DLTs) and maximal tolerated dose (MTD) of oral topotecan in patients with hematological malignancies. EXPERIMENTAL DESIGN: Patients with myelodysplastic syndromes, myeloproliferative disorders, or relapsed acute myelogenous leukemia were treated with 0.6-1.9 mg/m(2)/day oral topotecan for 5 consecutive days on and 2 days off, for 3 weeks (15 doses/course) followed by 2-4 weeks of rest. The DLTs occurring during the first course of treatment were considered for defining the MTD. Preliminary results of antitumor activity were assessed by examining bone marrow status and peripheral blood cell counts. RESULTS: All 26 patients enrolled in the study were evaluable for toxicity, and 24 patients were evaluable for response. A total of 54 courses were administered. The most frequently reported nonhematological toxicities (percentage of courses) were diarrhea (57%), nausea/vomiting (50%), fatigue (24%), and mucositis (9%). DLTs included grade 3 or 4 nausea/vomiting and diarrhea at 1.9 mg/m(2)/day. The MTD for oral topotecan in patients with hematological malignancies was defined at 1.4 mg/m(2)/day. Hematological toxicity was noted in all 26 patients and with all courses but was not considered dose-limiting. Four (17%) patients achieved a complete response, and six (25%) patients experienced hematological improvement. CONCLUSIONS: Protracted administration of oral topotecan is safe and well tolerated in patients with hematological malignancies. At the dose-schedule used, single-agent oral topotecan has a definite activity in patients with myelodysplastic syndrome and acute myelogenous leukemia and warrants further investigation alone or in combination with other agents.

The proteasome inhibitor PS-341 inhibits growth and induces apoptosis in Bcr/Abl-positive cell lines sensitive and resistant to imatinib mesylate.

BACKGROUND AND OBJECTIVES: Imatinib mesylate (IM) is the choice treatment for Bcr/Abl-positive malignancies. Emergence of resistance to IM warrants the exploration of novel well-tolerated anticancer agents. We intended to evaluate the effect of PS-341 on proliferation, survival, and cellular events in Bcr/Abl-positive cells sensitive and resistant to IM, and to investigate the effect of PS-341 and IM in conjunction. DESIGN AND METHODS: Bcr/Abl-positive cell lines sensitive (p210Bcr/Abl KBM5, p210Bcr/Abl KBM7, and p190Bcr/Abl Z-119) or resistant (KBM5-R) to IM were treated with PS-341 alone or in combination with IM. The effect on cell growth was determined using the MTT assay. Cell-cycle analysis was performed by propidium iodide staining. Apoptosis was evaluated by measurement of sub-G1 DNA content, annexin V binding, and caspase 3 activity assays. Levels of apoptotic proteins, P-IkBalpha, Bcr/Abl, and phosphorylated Bcr/Abl were determined by western blotting. NF-kappaB activity was evaluated by electromobility gel shift assays. RESULTS: PS-341 exerted growth inhibition effects in IM-sensitive and -resistant cells. This phenomenon correlated with accumulation of cells in the G2/M phase of cell cycle; transient downregulation of NFkappaB DNA binding activity; downregulation of Bcl-xL; activation of caspase 3, induction of apoptosis; inhibition of expression and phosphorylation of Bcr/Abl. Sequential combination of PS-341 followed by IM demonstrated a synergistic pro-apoptotic effect in IM-sensitive cells; concomitant exposure was antagonistic. INTERPRETATION AND CONCLUSIONS: PS-341 suppresses growth and induces apoptosis in Bcr/Abl-positive cells sensitive and resistant to IM. The use of PS-341 should be explored in patients with chronic myelogenous leukemia resistant to IM. Trials of combinations of PS-341 and IM require cautious design.

Comparative efficacy and safety of gemtuzumab ozogamicin monotherapy and high-dose cytarabine combination therapy in patients with acute myeloid leukemia in first relapse.

Gemtuzumab ozogamicin was recently approved in the United States for the treatment of older patients with CD33-positive acute myeloid leukemia (AML) in first relapse. However, the lack of randomized clinical trials makes it so difficult to determine which patients are best suited for this compared with other treatment regimens. Results for 128 patients given gemtuzumab ozogamicin in phase II trials were compared with those for 128 patients given high-dose cytarabine (HDAC) combination therapy in different trials Multivariate logistic regression was used to analyze age, duration of first complete remission (CR1), and cytogenetics for potential differences between the groups. rare of overall remission )combined complete remission [CR] plus CR with incomplete platelet recovery [CRp]) following treatment with gemtuzumab ozogamicin or HDAC therapy were 38% and 41%, respectively. Gemtuzumab ozogamicin treatment was associated with a higher overall remission rate compared with HDAC treatment if CR1 duration was 3-10.5 months. In contrast, HDAC treatment was associated with a higher overall remission rate than gemtuzumab ozogamicin treatment if CR1 duration was >19 months. If CR1 duration was between 10.5 and 19 months, the differences in treatment responses were not statistically significant. Thee results reflect the much stronger treatment than with gemtuzumab ozogamicin treatment. Early death (occurring within the first 6 weeks of therapy) was less likely in patients <45 years of age after ADAC and was less likely in patients >75 years of age after gemtuzumab ozogamicin treatment. These data support the recommended use of gemtuzumab ozogamicin as monotherapy in older patients with AML in first relapse, but caution against this use in patients, particularly younger ones, with a long duration of CR1.