Elliot Winton

Granulocyte/macrophage colony-stimulating factor primes human neutrophils for increased diacylglycerol generation in response to chemoattractant

Diacylglycerol; Granulocyte/macrophage colony‐stimulating factor; Formyl‐methionyl‐leucyl‐phenylalanine; Human neutrophil; Respiratory burst

The selective use of AMSA following high-dose cytarabine in patients with acute myeloid leukaemia in relapse: a Leukemia Intergroup Study

Summary. This clinical trial was designed to evaluate the role of high‐dose cytarabine (ara‐C) in the treatment of adults with acute myeloid leukaemia (AML) in first relapse. We also tested the hypothesis that the selective use of AMSA (100 mg/m2/d on days 7, 8 and 9) would increase the complete remission (CR) rate when leukaemia cells remained in the bone marrow immediately following 6 d of Ara‐C (2–3 g/m2/12 h) alone. Of 155 patients evaluable for response, 115 (74%) experienced marked cytoreduction by day 6 and received no further induction chemotherapy; 53 (45%) of these patients achieved CR after one course and 45 (38%) had resistant disease. The 36 patients (23%) with inadequate cytoreduction after the 6 d of ara‐C alone were randomly assigned either to no further chemotherapy (21 patients) or to 3 d of AMSA (15 patients). The CR rates after one course were 14% and 53%, respectively (P= 0001). and the fractions with resistant disease were 76% and 40%, respectively. The fractional reduction of leukaemia cells in the day 6 bone marrow aspirate specimen (P<0.0001) and the reduction in the leukaemia cell mass measured in the day 6 marrow biopsy (P= 0.001) were the strongest predictors for achieving CR versus having residual disease in univariate analyses. The median duration of remission was 5 months, but seven patients (10%) remain in CR after 30–92+ months. Among the 140 patients who received only the 6 d of ara‐C, the pretreatment albumin (P= 0.002) and lactate dehydrogenase (P= 0.01) levels were the strongest predictors of response in univariate analyses, but only the albumin remained significant (P= 0.01) in a stepwise logistic regression analysis. Those patients with albumin >4.0 mg/dl and LDH <125% of normal had a 71% CR rate, and only 16% had resistant disease. Among patients lacking both of these favourable characteristics, only 38% had a CR and 39% had resistant disease. Thus, pretreatment characteristics and rapid cytoreduction in the day 6 bone marrow sample identified a favourable subset of patients with AML in first relapse, some of whom responded quite well to 6 d of ara‐C alone and have had long disease‐free remissions.

Chemotherapy-induced hemolytic uremic syndrome: description of a potential animal model.

Hemolytic uremic syndrome (HUS) is an uncommon complication of chemotherapy that contributes to the morbidity of oncology and bone marrow transplant patients. The pathogenesis is not well understood and no established clinical animal model exists. We studied four rhesus monkeys (RM) that developed fatal HUS following high‐dose chemotherapy. Microangiopathic hemolytic anemia (pre‐Hct 40% and day 5–8 Hct 31 % (P <.05), increased BUN (168 mg/dl), creatinine (8.2 mg/dl), and lactate dehydrogenase (1458 IU/L) (mean day 5–8 measurements) were observed. Platelets counts decreased to 39±15 × 109/l from a mean of 397±31 × 109/L (P < .0001). vWF, ATIII, thrombin:anti‐thrombin complex (T:AT) and prothrombin fragment F1.2 levels were not different from a control group (N = 2). The data presented describe chemotherapy‐induced HUS with typical clinical and laboratory features which may provide an animal model for the study of this important syndrome.

High Dose Chemotherapy Without Hematopoietic Cell Support for the Treatment of Refractory Lymphoma

Conventional dose combination chemotherapy for patients with relapsed or refractory lymphoma is rarely curative. High dose chemotherapy followed by hematopoietic progenitor cell transplant (HPCT) has a clearly defined role in patients who have first relapsed after standard CHOP chemotherapy for lymphoma. However, the role of HPCT is less well defined for patients with chemo-resistant, or chemo-refractory disease. Sixteen patients (15 Non-Hodgkins, 1 Hodgkins Disease) were entered into a phase II study to determine if a dose intensive induction regimen in heavily pre-treated refractory lymphoma patients could permit further consolidation with HPCT. The primary endpoints were survival, response, tox-icity, and resource utilization. The regimen consisted of continuous infusion etoposide I or 2 gm/m2/72 hours, idarubicin 12mg/m2/d for 3 days followed by cytarabine 2gm/m2/72 hours on days 8,9, and 10 (VIC). Fifteen patients were evaluable for objective response. The overall response rate was 53% with 7 patients achieving a partial response and 1 patient achieving a complete response. Of the 8 responders, 6 patients subsequently received high dose chemotherapy followed by HPCT (4 autologous, 2 allogeneic). The median survival was 176 days for the non-responders contrasted with 722 days for the responders. The average duration of hospitalization was 38 days. Toxicity was mainfest primarily as mucositis with a median grade of 3 among the first 13 patients, and a median grade of 2 in three subsequent patients who received an etoposide dose of lgm/m2/72 hours. All patients had an episode of neutro-penic fever and 5 patients developed clinically significant pneumonitis during therapy. The VIC regimen is active in the treatment of chemo-refractory lymphoma with clinically significant differences in survival for patients who respond to therapy. Further modifications to the regimen could include the addition of a topoisomerase I inhibitor for synergy with etoposide, and using VIC as part of a tandem transplant regimen where response to VIC would allow further therapy with a myeloablative induction followed by HPCT.