Phase I trial of continuous infusion flavopiridol, a novel cyclin-dependent kinase inhibitor, in patients with refractory neoplasms.

PURPOSE: We conducted a phase I trial of the cyclin-dependent kinase inhibitor, flavopiridol (National Service Center [NSC] 649890), to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacology of flavopiridol given as a 72-hour infusion every 2 weeks. PATIENTS AND METHODS: Seventy-six patients with refractory malignancies with prior disease progression were treated with flavopiridol, with first-cycle pharmacokinetic sampling. RESULTS: Forty-nine patients defined our first MTD, 50 mg/m2/d x 3 with dose-limiting toxicity (DLT) of secretory diarrhea at 62.5 mg/kg/d x 3. Subsequent patients received antidiarrheal prophylaxis (ADP) to define a second MTD, 78 mg/m2/d x 3 with DLT of hypotension at 98 mg/m2/d x 3. Other toxicities included a proinflammatory syndrome with alterations in acute-phase reactants, particularly at doses >50 mg/ m2/d x 3, which in some patients prevented chronic therapy every 2 weeks. In some patients, ADP was not successful, requiring dose-deescalation. Although approximately 70% of patients displayed predictable flavopiridol pharmacology, we observed unexpected interpatient variability and postinfusion peaks in approximately 30% of cases. At the two MTDs, we achieved a mean plasma flavopiridol concentration of 271 nM (50 mg/m2/d x 3) and 344 nM (78 mg/m2/d x 3), respectively. One partial response in a patient with renal cancer and minor responses (n=3) in patients with non-Hodgkin's lymphoma, colon, and renal cancer occurred. CONCLUSION: The MTD of infusional flavopiridol is 50 mg/m2/d x 3 with dose-limiting secretory diarrhea at 62.5 mg/m2/d x 3. With ADP, 78 mg/m2/d x 3 was the MTD, with dose-limiting hypotension at 98 mg/m2/d x 3. Based on chronic tolerability, 50 mg/m2/d x 3 is the recommended phase II dose without ADP. Antitumor effect was observed in certain patients with renal, prostate, and colon cancer, and non-Hodgkin's lymphoma. Concentrations of flavopiridol (200 to 400 nM) needed for cyclin-dependent kinase inhibition in preclinical models were achieved safely.

Management of chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia in Western countries. The diagnosis requires mature-appearing lymphocytes in the peripheral blood to >5 x 10(9)/L. The immunophenotype typically includes B cell antigens CD19, CD20 and CD23, low expression of surface immunoglobulin and CD5+, with other T cell antigens absent. Bone marrow biopsy, although not required for diagnosis, must show at least 30% lymphocytes. Cytogenetic abnormalities are frequent in patients with CLL, and may be associated with poor prognosis. Clinically, most patients are asymptomatic at presentation, with incidental lymphadenopathy and/or hepatosplenomegaly in the routine physical examination. Infections by opportunistic pathogens are the major cause of death. Aggressive transformation occurs in 10% of patients with CLL, most commonly prolymphocytic leukaemia (PLL) and Richter's syndrome. PLL de novo must be differentiated from PLL of an aggressive transformation. The incidences of autoimmune diseases and solid or haemopoietic secondary malignancies are increased in patients with CLL. Clinical stage is the strongest prognostic factor in CLL. There is no indication for early intervention. The current recommendation to start treatment includes disease-related symptoms, massive and/or progressive hepatosplenomegaly or lymphadenopathy, increasing bone marrow failure, autoimmune disease, and recurrent infections. Alkylating agents (e.g. chlorambucil) and nucleoside analogues (e.g. fludarabine) are the most active agents for CLL. Fludarabine induces higher response rates, but no improvement in overall survival has been observed. Fludarabine is the drug of choice for the majority of patients with CLL. Chlorambucil may be helpful for elderly patients with poor performance, and for patients who do not tolerate fludarabine. No drug combination is better than single agents. For patients refractory to initial treatment, referral to a clinical trial is the best choice. Other salvage therapy includes retreatment with the same initial agent (chlorambucil or fludarabine) if initial response was observed, or fludarabine for patients refractory to chlorambucil. Promising new approaches include cycle-active agents, nelarabine, biological therapy such as anti-CD52 monoclonal antibody, bone marrow transplantation, including the use of submyeloablative preparative regimens ('minitransplant') to induce graft-versus-leukaemia effect, and gene therapy. Prophylactic antibacterials and intravenous immunoglobulin should not be used routinely during supportive care. Epoetin may be helpful for patients who have anaemia without obvious cause. Assessment of response to therapy in CLL has been updated by the National Cancer Institute Working Group, and these guidelines are used worldwide for clinical trials.

Chronic lymphocytic leukemia.

The diagnosis and management of chronic lymphocytic leukemia (CLL) is reviewed, including the basic aspects of epidemiology, molecular biology, and cytogenetics with clinical relevance. The importance of immunophenotype in the differential diagnosis of other lymphoproliferative disorders related to CLL, staging, prognostic factors, promising new drugs, and approaches is summarized.