Targeted Therapy in Chronic Lymphocytic Leukemia (CLL).

The standard of care for the treatment of chronic lymphocytic leukemia (CLL) has traditionally been chemoimmunotherapy. For patients who are unable to tolerate chemotherapy and those with high risk 17p deletions, there were previously few feasible or efficacious treatment options. Novel targeted agents for the treatment of CLL have the potential to offer long-term, durable remissions and offer promising treatment options for those in previously challenging population groups. Current targeted agents in CLL are directed against B cell receptor-associated tyrosine kinases such as BTK and SYK, the downstream PI3-kinase pathway, as well as the antiapoptotic protein BCL-2. The optimal sequencing of these agents has yet to be determined, although the side effect profile differs significantly and may dictate choice of therapy until further randomized data becomes available.

A phase I study of high-dose calcitriol in combination with temozolomide for patients with metastatic melanoma.

BACKGROUND: Temozolomide is efficacious as an oral alternative for patients with metastatic melanoma (MM). Calcitriol has anti-proliferative properties and vitamin D receptor (VDR) polymorphisms are associated with alterations in melanoma susceptibility and progression. METHODS: Tem 150 mg/m2 was administered on days 2-8 and 16-22 every 28 days. Calcitriol was given on days 1 and 15 every 28 days. VDR gene analysis was completed using PCR-RFLP based assays. Tolerability was the primary objective with secondary objectives of time to progression (TTP) and overall survival (OS). RESULTS: Twenty pts with MM were registered. Cytopenias and thrombosis were the most common grade 3 or 4 toxicities. Median TTP was 1.8 mo. Pts with high-risk VDR genotype tt+/-ff (n = 6) had an OS of 3.8 mo from time of enrollment, compared to 7.4 mo for those with non-tt/ff genotypes (n = 11), although not statistically significant (HR = 1.20, 95% CI 0.41-3.53, p = 0.74). CONCLUSIONS: The extended dosing of Tem with calcitriol is a well-tolerated regimen. The trend toward improved OS in non-tt/ff VDR genotypes is consistent with prior studies associating the tt/ff genotype with biologic aggressiveness.

Racial differences in colorectal cancer incidence and mortality in the Women's Health Initiative.

BACKGROUND: Colorectal cancer (CRC) incidence and mortality rates are higher in African-Americans as compared with other racial/ethnic groups. The women's health initiative (WHI) study sample was used to determine whether differences in CRC risk factors explain racial/ethnic differences in incidence and mortality. METHODS: The WHI is a longitudinal study of postmenopausal women recruited from 40 centers. Baseline questionnaires were used to collect sociodemographic and health status information. All CRC diagnoses were centrally adjudicated. Cox regression models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for invasive CRC by race/ethnicity. RESULTS: The study sample included 131,481 (83.7%) White, 14,323 (9.1%) African-American, 6,362 (4.1%) Hispanic, 694 (0.4%) Native American and 4,148 (2.6%) Asian/Pacific Islanders. After a mean follow-up of 10.8 years (SD 2.9), CRC incidence was the highest in African-Americans (annualized rate = 0.14%), followed by Whites and Native Americans (0.12% each), Asian/Pacific Islanders (0.10%), and Hispanics (0.08%). After adjustment for age and trial assignment, Hispanics had a lower risk compared with Whites, HR 0.73 (95% CI: 0.54-0.97) (P = 0.03), and African-Americans had a marginally greater risk, HR 1.16 (95% CI: 0.99-1.34), P = 0.06. Multivariable adjustment attenuated the difference in incidence between African-Americans and Whites (HR 0.99, 95% CI: 0.82-1.20), while strengthening the lower HR for Hispanics (HR 0.68, 95% CI: 0.48-0.97). CONCLUSIONS: African-American/White differences in CRC risk are likely due to sociodemographic/cultural factors other than race. IMPACT: A number of modifiable exposures could be a focus for reducing CRC risk in African-Americans.