Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience

Acute megakaryocytic leukemia (AMegL) is a rare subtype of acute myeloid leukemia (AML) evolving from primitive megakaryoblasts. Because of its rarity and the lack of precise diagnostic criteria in the past, few series of adults treated with contemporary therapy have been reported. Twenty among 1649 (1.2%) patients with newly diagnosed AML entered on Eastern Cooperative Oncology Group (ECOG) trials between 1984 and 1997 were found to have AMegL. The median age was 42.5 years (range 18-70). Marrow fibrosis, usually extensive, was present in the bone marrow. Of the 8 patients who had cytogenetic studies performed, abnormalities of chromosome 3 were the most frequent. The most consistent immunophenotypic finding was absence of myeloperoxidase in blast cells from 5 patients. In the most typical 3 cases, the leukemic cells were positive for one to 2 platelet-specific antigens in addition to lacking myeloperoxidase or an antigen consistent with a lymphoid leukemia. Myeloid antigens other than myeloperoxidase and selected T-cell antigens (CD7 and/or CD2) were frequently expressed. Induction therapy included an anthracycline and cytarabine in all cases. Complete remission (CR) was achieved in 10 of 20 patients (50%). Two patients remain alive, one in CR at 160+ months. Resistant disease was the cause of induction failure in all but 3 patients. The median CR duration was 10.6 months (range 1-160+ months). The median survival for all patients was 10.4 months (range 1-160+ months). Although half of the patients achieved CR, the long-term outcome is extremely poor, primarily attributable to resistant disease. New therapeutic strategies are needed.     

Legal and ethical aspects of treating critically and terminally ill patients

Legal and ethical aspects of treating critically and terminally ill patients, Edited by Doudera, A.E. and Peters, J.D. (AUPHA Press, Ann Arbor, Michigan, 1982), 344 pages, $27.00.     

Phase I–II trial of mitoxantrone in acute leukemia: an interim report

Summary We evaluated the effect of mitoxantrone (Novantrone®; dihydroxyanthracenedione) in the treatment of refractory acute leukemia and acute leukemia in relapse. In this study, 70 patients are currently evaluable. Of the 25 patients who received mitoxantrone 10 mg/m² × 5, two of 10 with ANLL in relapse, one of five with ALL in relapse achieved complete remission, and one of seven with blastic phase CML responded. At a dose of 12 mg/m² × 5, nine of 22 patients with ANLL in relapse, one of five patients with blastic phase CML and none of the nine patients with ALL responded. At this dose all remissions occurred after one course of treatment. None of the patients with ANLL or ALL refractory to primary therapy achieved a remission. Toxicities encountered with both dose levels were comparable. However, second courses at 12 mg/m² × 5 led to severe stomatitis and prolonged cytopenia. We conclude that mitoxantrone is effective therapy for ANLL in relapse and that 12 mg/m² per day × 5 is the optimal dose schedule. A randomized trial comparing daunorubicin with mitoxantrone in combination with cytarabine in untreated patients with ANLL should answer whether mitoxantrone is less toxic and whether it should replace daunorubicin in standard induction therapy in ANLL.See Table 1     

Music therapy dramatically decreases distress for women hospitalised in a high‐risk obstetrics/gynaecology setting

Bauer CL, Victorson D, Rosenbloom S, Barocas J, Silver RK. Alleviating distress during antepartum hospitalization: a randomized controlled trial of music and recreation therapy. J Women's Health 2010; 19: 523–31.     

Pilot study of ‘Feiji recipe’ in conjunction with chemotherapy on QoL in non‐small cell lung cancer patients. Larger controlled clinical trials are necessary to determine whether the Feiji recipe benefits overall non‐small cell lung cancer

Jian‐Hui Tian, Ling‐Shuang Liu, Zhi‐Ming Shi and Zhi‐Yi Zhou. A randomized controlled pilot trial of ‘Feiji recipe’ on quality of life on non‐small cell lung cancer patients. Am J Chin Med 2010; 38: 15–25.     

A phase I/II trial of a polysaccharide extract from Grifola frondosa (Maitake mushroom) in breast cancer patients: immunological effects

Background  Cancer patients commonly use dietary supplements to “boost immune function”. A polysaccharide extract from Grifola frondosa (Maitake extract) showed immunomodulatory effects in preclinical studies and therefore the potential for clinical use. Whether oral administration in human produces measurable immunologic effects, however, is unknown. Methods  In a phase I/II dose escalation trial, 34 postmenopausal breast cancer patients, free of disease after initial treatment, were enrolled sequentially in five cohorts. Maitake liquid extract was taken orally at 0.1, 0.5, 1.5, 3, or 5 mg/kg twice daily for 3 weeks. Peripheral blood was collected at days −7, 0 (prior to the first dosing), 7, 14, and 21 for ex vivo analyses. The primary endpoints were safety and tolerability. Results  No dose-limiting toxicity was encountered. Two patients withdrew prior to completion of the study due to grade I possibly related side effects: nausea and joint swelling in one patient; rash and pruritus in the second. There was a statistically significant association between Maitake and immunologic function (p < 0.0005). Increasing doses of Maitake increased some immunologic parameters and depressed others; the dose–response curves for many endpoints were non-monotonic with intermediate doses having either immune enhancing or immune suppressant effects compared with both high and low doses. Conclusions  Oral administration of a polysaccharide extract from Maitake mushroom is associated with both immunologically stimulatory and inhibitory measurable effects in peripheral blood. Cancer patients should be made aware of the fact that botanical agents produce more complex effects than assumed, and may depress as well as enhance immune function.     

Pentostatin, chlorambucil and prednisone therapy for B-chronic lymphocytic leukemia: a phase I/II study by the Eastern Cooperative Oncology Group study E1488

Pentostatin is a purine nucleoside analog with demonstrated activity in low-grade lymphoid malignancies. The purpose of this study was to determine the dose of pentostatin (dCF) that could be combined with chlorambucil and prednisone to treat chronic lymphocytic leukemia (CLL), evaluate the toxicity of the resulting regimen and to estimate its efficacy. This was a multi-institutional Eastern Cooperative Oncology Group (ECOG) phase I - II study. Individuals with active B-CLL were eligible if they had no prior treatment or were in sensitive first relapse, provided they had normal renal and hepatic function. Pentostatin was evaluated in combination with orally administered chlorambucil 30 mg/m² and prednisone 80 mg/day, 1 - 5 of each 14-day cycle. The pentostatin dose was 2 mg/m² IV, day 1 for the first 6 patients; 3 mg/m² IV, day 1 for the next 6 patients; and 4 mg/m² IV, day 1 for the last set of 6 patients. Fifty-five patients were entered. Because of increasing toxicity with no apparent improvement in clinical efficacy on escalation of the pentostatin dose, 2 mg/m² was chosen as the phase II dose, and 43 patients were treated at this level. Thirty-nine of these patients were eligible, of which 38 were evaluable for response, 36 of these 38 had no prior treatment. Complete response (CR) manifested by normal bone marrow morphology, peripheral blood counts and resolution of any lymphadenopathy or hepatosplenomegaly occurred in 17 patients (45%). The overall objective response rate was 87%. The median response duration was 33 months and the median survival 5 years. The median time to treatment failure is 32 months. Severe (Grade 3 + ) infections were seen in 31% of patients and included bacterial pneumonia (n = 4), Pneumocystis pneumonia (n = 1), fungal pneumonia (n = 2), urinary tract infection with sepsis (n = 1) and Herpes Zoster (n = 5). Overall, 11 patients had H. Zoster while on study. Due to toxicity, 33% of patients stopped therapy. Pentostatin, chlorambucil and prednisone is a highly active regimen in CLL but cannot be recommended in present form because of an unacceptable incidence of opportunistic infections. These findings add to other recent reports which suggest combination therapy with pentostatin and alkylators are active in B-CLL. However, these combination chemotherapies will need to be combined with appropriate addition of anti-bacterial and anti-viral prophylaxis to reduce infection risk for B-CLL patients.     

Role of nutrients in the development of neonatal immune response

Nutrients exert unique regulatory effects in the perinatal period that mold the developing immune system. The interactions of micronutrients and microbial and environmental antigens condition the post-birth maturation of the immune system, influencing reactions to allergens, fostering tolerance towards the emerging gastrointestinal flora and ingested antigens, and defining patterns of host defense against potential pathogens. The shared molecular structures that are present on microbes or certain plants, but not expressed by human cells, are recognized by neonatal innate immune receptors. Exposure to these activators in the environment through dietary intake in early life can modify the immune response to allergens and prime the adaptive immune response towards pathogens that express the corresponding molecular structures.