Phase II study of perifosine and sorafenib dual-targeted therapy in patients with relapsed or refractory lymphoproliferative diseases.

PURPOSE: To evaluate safety and activity of perifosine and sorafenib combination therapy in patients with lymphoproliferative diseases. EXPERIMENTAL DESIGN: Patients with relapsed and refractory lymphoproliferative diseases received perifosine (50 mg twice daily) for 1 month. Patients achieving less than partial response (PR) after perifosine alone were administered the combination therapy [perifosine plus sorafenib (400 mg twice daily)] until progressive disease (PD) or unacceptable toxicity occurred. The pERK and pAKT in peripheral blood lymphocytes as well as serum cytokine levels were investigated as predictive biomarkers of response. RESULTS: Forty patients enrolled in this study. After 1 month of perifosine alone, 36 who achieved less than PR went on to combination therapy, whereas four patients with chronic lymphocytic leukemia (CLL) who achieved PR continued with perifosine alone for a median of 10 months (range, 4-21). The most common drug-related toxicities were grade 1-2 anemia (17%), thrombocytopenia (9%), diarrhea (25%), joint pain (22%), and hand-foot skin reaction (25%). Three patients experienced grade 3 pneumonitis. Eight patients (22%) achieved PR, 15 (42%) achieved stable disease, and 13 (36%) experienced PD. A 28% PR rate was recorded for 25 patients with Hodgkin lymphoma. Among all patients, median overall survival and progression-free survival were 16 and 5 months, respectively. Early reductions in pERK and pAKT significantly correlated with the probability of clinical response. CONCLUSIONS: Perifosine and sorafenib combination therapy is feasible with manageable toxicity and demonstrates promising activity in patients with Hodgkin lymphoma. The predictive value of pERK and pAKT should be confirmed in a larger patient cohort.

Anemia treatment of lymphoproliferative malignancies with erypoiesis: an overview of state of the art.

Anemia is a common comorbidity of lymphoproliferative malignancies, especially in multiple myeloma. Blood transfusions and ESAs (erythropoiesis stimulating agents) are both possible treatment options, but the latter is often preferred because of the potential risks of unwanted side effects related to blood transfusions. Evidence is accumulating that the use of ESAs in above clinical conditions is safe and effective and not associated with an increase in mortality or serious adverse events. 69.1% of patients achieved a hemoglobin response defined as an increase in hemoglobin of>2g/dl while receiving ESAs and concomitant chemotherapy. If supplemented with iron the hemoglobin response rate can be increased and hence the total dosage and financial cost reduced. A hemoglobin response is often accompanied by an increase in quality of life. HYPO% (hypochromic erythrocytes<5%) is believed to be both a significant positive predictor for the Hb response and also an indicator for iron supplementation if⩾5%. Conventional biochemical markers like serum ferritin concentration and transferrin saturation are not reliable for this use. The effect of EPO stimulating agents as the predictor of the Hb response, quality of life, mortality and the potential adverse events are discussed.

Update of the Texaco mortality study 1947-93: Part I. Analysis of overall patterns of mortality among refining, research, and petrochemical workers.

OBJECTIVE: To update information on the workers of the Texaco mortality study to determine if the patterns of mortality have changed with 16 additional years of follow up. SUBJECTS AND METHODS: All workers were employed for > or = 5 years at company refineries, petrochemical plants, and research laboratories from 1947-93. The cohort now consists of 28,480 employees with an average of > or = 20 years of follow up. RESULTS: The overall mortality, and most cause specific mortalities were lower than or similar to those for the general population of the United States. For white men (86% of the cohort), there were 8873 observed deaths and 11,181 expected resulting in a significantly lower standardised mortality ratio (SMR) of 79. There were significant deficits for all the leading causes of death in the United States including all cancers, cancer of the lung, stroke, heart disease, respiratory disease, and accidents. Slightly increased mortality was found for cancer of the pancreas, cancer of the brain and central nervous system, leukaemia, and cancer of other lymphatic tissue. For cancer of the bone, the SMR was 162 (95% confidence interval (95% CI) 86 to 278), and for benign and unspecified neoplasms, it was 152 (95% CI 109 to 206). Overall mortality patterns for non-white men and women were similar to those for white men. Mortality patterns for white men were also examined by duration of employment, time first employed, location, and by job and process unit. There were significantly increased SMRs for brain cancer for those people employed as laboratory workers and on units with motor oil and for cancer of other lymphatic tissue for people employed on the fluid catalytic cracking unit. CONCLUSIONS: The results of the updated study showed a favourable mortality experience for employees in the Texaco mortality study compared with the United States population. There were a few increases found consistently including, but not limited to, brain cancer and cancer of other lymphatic tissue. These increases led to additional analyses that will be discussed in the accompanying paper.