Phase 1 dose escalation study of rigosertib by 2-, 4-, or 8-hour infusion twice-weekly in patients with advanced cancer.

CONTEXT: Rigosertib, a potent, multi-kinase inhibitor that selectively induces mitotic arrest and apoptosis in cancer cells and is non-toxic to normal cells, is being developed for the treatment of solid tumors and hematological malignancies. AIMS: To determine the safety, doselimiting toxicities, and clinical activity of rigosertib administered by 2-, 4-, or 8-hour continuous IV infusion twice-a-week for 3 weeks out of a 4-week cycle in patients with advanced solid tumor or hematological malignancies; and to confirm the safety and tolerability of the recommended phase 2 dose (RPTD). SETTINGS AND DESIGN: Phase 1, open-label, dose-escalation study in men and women ≥18 years of age. MATERIALS AND METHODS: An escalation phase optimized the duration of infusion (2, 4, or 8 hours) of 3200 mg rigosertib twice-a-week for 3 weeks of a 4-week cycle; an expansion phase confirmed the maximum tolerated dose (MTD). STATISTICAL ANALYSIS USED: All data summaries were descriptive. PK parameters were estimated using compartmental analysis. RESULTS: 25 patients (16 male, 9 female, 26- 66 years, all Asian) were treated with rigosertib, 16 in the escalation phase; 9 in the expansion phase. MTD was determined to be 3200 mg as a 4-hour infusion and 2400 mg over 4 hours was declared to be the RPTD. Best response was stable disease in 5 of 14 evaluable patients, with a mean (range) of 90 (43-108) days. CONCLUSIONS: 2400 mg rigosertib as a 4-hour infusion was identified as the RPTD. Five patients achieved stable disease lasting 6-16 weeks.

Imatinib mesylate as first‑line therapy in patients with chronic myeloid leukemia in accelerated phase and blast phase: A retrospective analysis.

INTRODUCTION: Imatinib is a bcr‑abl tyrosine kinase inhibitor which has revolutionized the treatment for chronic myeloid leukemia (CML). Even though there is much data on CML chronic phase, there is limited data on imatinib‑naïve advanced phase CML. MATERIALS AND METHODS: We retrospectively analysed 90 patients with advanced phase CML (accelerated phase [AP]: 51 and blast crisis [BC]: 39), patients who received imatinib as frontline therapy. RESULTS: The median age of presentation in CML‑AP and CML‑BC were 32 years (12‑61) and 39 years (8‑59), respectively. Imatinib at 600 mg/day was initiated within 2 weeks of diagnosis. Median time to complete hematological response in both CML‑AP and CML‑BC was 3 months (CML‑AP: 1‑9 months and CML‑BC: 1‑14 months). At 6 months 30 (59%) CML‑AP and 15 (38%) CML‑BC patients achieved major cytogenetic response (MCyR), of them 24 (47%) and 10 (25.6%) being the complete cytogenetic response, respectively. At a median follow‑up of 41 months, the median overall survival in CML‑AP was 61 months, but in CML‑BC it was 14 months. The median progression‑free survival and event‑free survival were 30 months and 23 months in CML‑AP and 14 and 12 months in CML‑BC, respectively. On univariate analysis, performance status (PS), spleen size, and MCyR predicted survival in AP, whereas in BC, platelet count, PS, and early MCyR were predictive. Non‑hematologic and hematologic adverse events were observed in 80% and 60% of patients, respectively. Dose was reduced in 10% of patients for grade IV toxicity and interrupted in 30% for grade III toxicity. CONCLUSION: Front‑line imatinib is an option in advanced phases of CML especially in CML‑AP in low‑resource countries, where stem cell transplantation and alternate TKIs are not available.

Association of CYP3A5*3 polymorphism with development of acute leukemia.

BACKGROUND: CYP3A5 was observed to be an important genetic contributor to inter individual differences in CYP3A-dependent drug metabolism in acute leukemic patients. Loss of CYP3A5 expression was mainly conferred by a single nucleotide polymorphism at 6986A>G (CYP3A5*3). We investigated the association between CYP3A5*3 polymorphism and acute leukemia. MATERIALS AND METHODS: Two hundred and eighty nine acute leukemia cases comprising of 145 acute lymphocytic leukemia (ALL), 144 acute myeloid leukemia and 241 control samples were analyzed for CYP3A5*3 polymorphism using PCR-RFLP method. Statistical analysis was performed with SPSS version (15.0) to detect the association between CYP3A5*3 polymorphism and acute leukemia. RESULTS: The CYP3A5*3 polymorphism 3/3 genotype was significantly associated with acute leukemia development (χ2- 133.53; df-2, P 0.000). When the data was analyzed with respect to clinical variables, mean WBC, blast % and LDH levels were increased in both ALL and AML cases with 3/3 genotype. The epidemiological variables did not contribute to the genotype risk to develop either AML or ALL. CONCLUSION: The results suggest that the CYP3A5*3 polymorphism might confer the risk to develop ALL or AML emphasizing the significance of effective phase I detoxification in carcinogenesis. Association of the polymorphism with clinical variables indicate that the 3/3 genotype might also contribute to poorer survival of the patients.

Epstein-Barr virus as a possible etiologic agent in primary central nervous system lymphoma in immunocompetent individuals.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) occurs in both immunocompetent and immunosuppressed individuals. The role of Epstein-Barr virus (EBV) has been implicated in immunosuppressed individuals but its role is not established in immunocompetent individuals. AIMS: To study the possible role of EBV in PCNSL in immunocompetent individuals. SETTING AND DESIGN: Retrospective study. Materials and Methods: Thirty patients with PCNSL were studied immunohistochemically with antibodies to CD45, CD20, CD3 and EBV latent membrane protein-1 (EBV LMP-1). In situ hybridization was done in 19 patients where enough tissue was available using a specific oligonucleotide probe for EBV-Early RNA (EBER). RESULTS: All the patients were immunocompetent and mean age was 41.6 years. Histologically they were diffuse large cell lymphoma: 25 (83.3%) were B cell, 1(3.3%) was T cell and 4 (13.3%) were unclassified. EBV LMP-1 showed variable membrane and cytoplasmic positivity in 24 (80%) patients. In situ hybridization for EBER was negative in all the 19 patients studied. CONCLUSION: In this region of the world probably EBV has no etiologic role in PCNSL in immunocompetent individuals.

Association of CYP1A1*2 polymorphisms with breast cancer risk: a case control study.

BACKGROUND: The Cytochrome P-4501A1 (CYP1A1) gene, located on chromosome 15q, is involved in the metabolism of carcinogens mainly polycyclic aromatic hydrocarbons as well as estrogen. It is considered as candidate gene for low-penetrance breast cancer susceptibility. Hence the present study aims to discuss the role of CYP1A1 polymorphisms in breast cancer. MATERIALS AND METHODS: A total of 250 breast cancer patients and the same number of healthy age-matched controls were analyzed for the polymorphism of CYP1A1*2 by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: In the present study, association of CYP1A1*2 (Ile 462Val) polymorphism with breast cancer was studied. Only one breast cancer patient was observed to be homozygous for Val allele but none among controls. The frequency of heterozygous Ile/Val genotype was found to be increased significantly in breast cancer patients (68.1%) as compared to controls (51.0%). Higher frequency of heterozygotes for Val allele was observed among premenopausal breast cancer patients and patients with high BMI, positive for HER2/neu status and advanced stage of the disease in comparison to the corresponding groups. No significant association of CYP1A1*2 polymorphism was observed with occupation, estrogen receptor and progesterone receptor status of breast cancer patients. CONCLUSIONS: In conclusion, our results suggest a significant correlation between CYP1A1*2 expression and the occurrence of breast cancer.

PvuII polymorphism of estrogen receptor-α gene in breast cancer.

BACKGROUND: Estrogen receptor (ER) is a ligand-inducible transcription factor that mediates estrogen action in target tissue. Several common polymorphisms of the ERα gene have been reported to be associated with alterations in receptor expression in breast cancer. MATERIALS AND METHODS: A case-control study was designed to compare 250 breast cancer patients with 250 age-matched healthy controls. The frequency distribution of PvuII polymorphism in the ERα gene was assessed by PCR-RFLP method. RESULTS: The frequency of the PP genotype (35.3%) was increased significantly in breast cancer patients when compared to controls (19.8%), with a corresponding increase in P allele frequency (χ2= 16.4; P = 0.0003). The OR for genotypes PP vs. Pp was 1.989 (95% CI: 1.2708 to 3.113). Premenopausal women with breast cancer had an elevated frequency of the PP genotype (22.8%) as compared to postmenopausal women (16.8%). The frequency of the PP genotype was increased in patients positive for ER and HER-2/neu as compared to those with receptor-negative status. The pp and p allele frequencies were increased in progesterone-receptor-negative status. When stage of the disease was considered, both Pp and pp genotype frequencies were elevated in patients with advanced stage breast cancer. The frequency of the P allele and PP genotype frequencies tended to increase with increase in body mass index, whereas the Pp genotype frequency was elevated only in obese patients. The reverse was observed in the case of pp genotype frequency. CONCLUSION: The study thus highlighted the influence of ERα PvuII polymorphism on the development and progression of breast cancer.

Gastrointestinal stromal tumors: a single institution experience of 50 cases.

BACKGROUND: Understanding the molecular pathogenesis of gastrointestinal stromal tumors (GIST) has led to targeted therapy using imatinib mesylate (IM). This retrospective series summarizes our short-term experience with 50 cases of GIST. METHODS: Case records of patients with GIST were analyzed. Tumor size, response to imatinib, and adverse events were evaluated every 3 months. RESULTS: The median age was 50 years (range 28-73). Stomach was the most common site (n=15). Thirty (60%) patients had complete resection of tumor with median progression free survival (PFS) of 12 months. The difference in PFS between intermediate and high risk groups was significant for patients who underwent resection (p=0.016). Thirty-five patients with advanced disease were administered IM 400 mg daily, and complete response was noted in 4 (11.8%); 13 (38.2%) each had partial response and stable disease, and 5 (14.8%) had progressive disease. Responses were not different in groups based on sex, site of primary tumor and number of metastatic sites. At a median follow up of 10 months, 72% patients continue to maintain response. CONCLUSIONS: This short-term study in patients with GIST describes response to therapy with imatinib in these patients.