R‐High‐CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY

Although induction immunochemotherapy including high‐dose cytarabine and rituximab followed by high‐dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) is recommended for younger patients (≤65 years old) with untreated mantle cell lymphoma (MCL), no standard induction and HDC regimen has been established. We conducted a phase II study of induction immunochemotherapy of R‐High‐CHOP/CHASER followed by HDC of LEED with ASCT in younger patients with untreated advanced MCL. Eligibility criteria included untreated MCL, stage II bulky to IV, and age 20‐65 years. Patients received 1 cycle of R‐High‐CHOP followed by 3 cycles of CHASER every 3 weeks. Peripheral blood stem cells (PBSC) were harvested during CHASER. LEED with ASCT was delivered to patients who responded to R‐High‐CHOP/CHASER. Primary endpoint was 2‐year progression‐free survival (PFS). From June 2008 to June 2012, 45 patients (median age 59 years; range 38‐65 years) were enrolled. PBSC were successfully harvested from 36 of 43 patients. Thirty‐five patients completed ASCT. Two‐year PFS was 77% (80% CI 68‐84), which met the primary endpoint. Five‐year PFS and overall survival were 52% (95% CI 34‐68%) and 71% (95% CI 51‐84%), respectively. Overall response and complete response rates after induction immunochemotherapy were 96% and 82%, respectively. The most common grade 4 toxicities were hematological. In younger patients with untreated MCL, R‐High‐CHOP/CHASER/LEED with ASCT showed high efficacy and acceptable toxicity, and it can now be considered a standard treatment option.     

Neurological complications after intrathecal liposomal cytarabine application in patients after allogeneic haematopoietic stem cell transplantation

Liposomal cytarabine has been proven to be useful for the prevention and intrathecal treatment of neoplastic meningitis. It has no demonstrable myelosuppressive effects and may therefore be an attractive alternative for prophylaxis and treatment of the central nervous system (CNS) relapse after allogeneic haematopoietic stem cell transplantation (HSCT). The use of liposomal cytarabine had not been reported in HSCT recipients. We retrospectively reviewed the feasibility of liposomal cytarabine in the prophylaxis (n = 2) and treatment (n = 4) of neoplastic meningitis in a cohort of patients after allogeneic HSCT. This report focusses on neurological complications after intrathecal application of liposomal cytarabine. Mild headache was the most commonly reported adverse event. Two patients experienced sacral radiculopathy with irreversible cauda equina syndrome in one patient. Another patient progressed with pre-existing leukencephalopathy. Intrathecal liposomal cytarabine should be used very cautiously in allogeneic HSCT recipients with a history of CNS complications potentially involving cerebral-spinal fluid circulation, since significant neurotoxicity was observed in patients with extensive CNS-directed pre-treatment. The feasibility and safety of liposomal cytarabine in HSCT recipients has to be evaluated in a prospective study.     

STI571/doxorubicin concentration-dependent switch for diverse caspase actions in CML cell line K562

We examined the response of the apoptosis-reluctant CML cell line K562 to doxorubicin alone or in combination with the tyrosine kinase inhibitor STI571. We found that at clinically relevant concentrations, doxorubicin induced differentiation and senescence, but did not induce apoptosis. Doxorubicin induced G(2)/M arrest and mitochondrial transmembrane potential dissipation. Interestingly, drug-induced differentiation could be diminished by caspase inhibitors. STI571 caused a graded response characterized by differentiation at low concentrations and apoptosis at higher. STI571 was not observed to induce senescence. Combination of STI571 and caspase inhibitors protected cells from apoptosis but did not influence differentiation. The diverse mode of action of both drugs contributed to the response observed during combination treatment. An additive effect on proliferation was obtained. The mechanisms contributing to inhibition of cellular proliferation were complex and strongly dependent on the applied drug concentrations. Differentiation or apoptosis were enhanced by combined treatment only in narrow ranges of concentrations. Conclusion: DOX and STI571 along diverse mechanisms contributed to elevated levels of activated caspases which might be then responsible for a switch from differentiation to apoptosis.     

A prospective, randomized, sequential, crossover trial of large-volume versus normal-volume leukapheresis procedures: effect on progenitor cells and engraftment

BACKGROUND: The influence of leukapheresis size on the number of harvested peripheral blood progenitor cells is still unclear. A prospective randomized crossover trial was thus performed, to evaluate the effect of large-volume leukapheresis (LVL) versus normal-volume leukapheresis (NVL) on progenitor cells and engraftment in 26 patients with breast cancer and 15 patients with non-Hodgkin's lymphoma who were eligible for peripheral blood progenitor cell transplantation. STUDY DESIGN AND METHODS: Patients were randomly assigned to undergo either LVL on Day 1 and on Day 2 or vice versa. The number of progenitor cells was evaluated in the harvest and before and after leukapheresis in the peripheral blood. RESULTS: The number of harvested CD34+ cells (4.8 x 10(6) vs. 3.4 x 10(6)/kg body weight, p < 0.001) and colony-forming units-granulocyte-macrophage (3.1 x 10(5) vs. 2.4 x 10(5)/kg body weight, p = 0.0026) was significantly higher for LVL procedures than for NVL procedures. The median extraction efficacy, defined as the difference between the yield in the harvest and the decrease in the total number of CD34+ cells in peripheral blood during leukapheresis, was significantly (p < 0.0001) higher for LVL than for NVL (2.6 x 10(8) and 8 x 10(7), respectively). In patients with breast cancer, the median amount of CD34+ cells in the harvest and the median extraction efficacy were higher for LVL than for NVL (p < 0.0001). This was not found for patients with non-Hodgkin's lymphoma. CONCLUSION: LVL results in a higher yield of CD34+ cells and colony-forming units-granulocyte-macrophage than NVL, but only in patients with breast cancer and with high numbers of CD34+ cells in the peripheral blood before leukapheresis.     

大剂量阿糖胞苷在急非淋白血病患儿体内的药物动力学

目的了解大剂量阿糖胞苷化疗后,患者的药物动力学参数及不良反应.方法采用HPLC法测定患者阿糖胞苷血浓.结果用二室动力学模型拟合,其分布相半衰期为(0.30±0.05)h,消除相半衰期为(0.64土0.11)h.结论首次用药与末次用药的药物动力学参数无显著性差异,表明阿糖胞苷在儿童体内无蓄积.