Soignet SL, Maslak P, Wang Z-G, et al [Mem Sloan – Kettering Cancer Ctr, New York]
Complete Remission After Treatment of Acute Promyelocytic Leukemia with Arsenic Trioxide
N Engl J Med 339: 1341-1348, 1998
Arsenic trioxide induces complete remission in patients with acute promyelocytic leukemia [ APL]. This study of 12 patients with APL following extensive therapy recived arsenic trioxide 0.06 to 0.2 mg/kg body weight per day. Eleven patients achieved complete remission. Induction of apoptosis with caspase activation in leukemic cells was the mechanism by which arsenic trioxide worked. As compared to Trans Retinoic Acid which induced terminal differentiation.
De Botton S, and the European APL Group [Paris Hotel Dieu, Angers, Roven, Nancy; Paris Beaujon]
Incidence, Clinical Features, and Outcome of All Trans-Retinoic Acid Syndrome in 413 Cases of Newly Diagnosed Acute Promyelocytic Leukemia
Blood 92: 2712-2718, 1998
Patients with acute promyelocytic leukemia [APML] treated with All trans-retinoic acid [ATRA], undergo differentiation followed by anthracycline – AraC, chemotherapy thereby increasing the chances of complete remission while reducing the chances of relapse. ATRA syndrome is a fatal complication in patients of APMLon ATRA. This study of 413 patients with APML received ATRA, before or in combination with chemotherapy, 64 patients developed ATRA syndrome characterized by presence of three or more of following signs, fever weight gain, respiratory distress, lung infiltrates, pleural or pericardial effusion, hypotension and renal failure. Five patients died of ATRA syndrome. No significant predictor of ATRA could be identified including pretreatment WBC. Prompt administration of steroids reduces mortality and complications.
Anaissie EJ, Kontoyiannis DP, O’Brien S, et al [Univ of Texas, Houston]
Infections in Patients With Chronic Lymphocytic Leukemia Treated With Fludarabine
Ann Intern Med 129: 559-566, 1998
This study of 402 patients with chronic lymphocytic leukemia who were treated with fludabarine or
Fludabarine plus prednisone major infections problems developed in patients previously treated & in patients who received steroids, high Rai stage III or IV and higher serum creatinine. A high granulocyte count > 1000 cells/mL was protective. Fludarabine treatment results in profound and long lasting depletion of CD4+ T cells leading to opportunistic infections.
Burnett AK, for the MRC Adult Leukaemia Working Party [Univ of Wales, Cardiff]
Presenting White Blood Cell Count and Kinetics of Molecular Remission Predict Prognosis in Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid : Results of the Randomized MRC Trial
Blood 93: 4131-4143, 1999
All-trans retinoic acid [ATRA] has proved as a differentiating agent in Acute Promyelocytic Leukemia [APML].
This study of 239 patients with APML were randomly assigned to short course of ATRP prior to starting chemotherapy or to ATRA be administered with chemotherapy till complete remission, [extended course]. Superior rate of remission were possible [87%] with an extended course of ATRA and thereby had improved relapse risk and higher survival rates. Those with lower total white blood cell did better than those with high total white blood cell. Molecular monitoring with RT-PCR revealed a high risk of relapse – 57% with positive RT-PCR.
Sanz MA, for the PETHEMA Group [Hosp Universitario La Fe, Valencia, Spain; et al]
A Modified AIDA Protocol With Anthracycline-based Consolidation Results in High Antileukemic Efficacy and Reduced Toxicity in Newly Diagnosed PML/RARa-positive Acute Promyelocytic Leukemia
Blood 94: 3015-3021, 1999
The Spanish PETHEMA group recruited 123 newly diagnosed PML/RARa -positive acute promyelocytic leukemia to induction with ATRA + Idarubicin. Those in whom CR received 3 monthly chemotherapy courses with idarubicin, mitoxantrone [ without cytarabine nor etoposide]. 89% achieved CR consolidation treatment has low toxicity and no deaths. Among patients with CR, 2-year DFS was 92%.
The editor comments that this excellent result would suggest deletion of cytarabine and etoposide from consolidation course for the treatment of APL. However further randomized trials are required.
Cassileth PA, Harrington DP, Appelbaum FR, et al [ Univ of Miami Sylvester Comprehensive Cancer Ctr, Fla; Harvard School of Public Health, Boston; Fred Hutchinson Cancer Research Ctr, Seattle; et al]
Chemotherapy Compared with Autologous or Allogeneic Bone Marrow Transplantation in the Management of Acute Myeloid Leukemia in First Remission
N Engl J Med 339: 1649-1656, 1998
This study of 740 patients of AML received standard induction chemotherapy and after complete remission idarubicin and cytarabine [ 2+5]. 113 patients with HLA compatible siblings received allogenic bone marrow and the remaining were assigned to high dose cytarabine or autologous transplantation.
At a median follow-up of four years no difference in DFS among the three groups. This trial revealed fewest relapses from allogeneic bone marrow transplantation and high dose cytarabine, the lowest treatment related mortality and autologous a clear third.
Goldstone A, for the Medical Research Council Adult and Children’s Leukaemia Working Parties [Univ College, London]
The importance of Diagnostic Cytogenetics on Outcome in AML: Analysis of 1,612 Patients entered into the MRC AML 10 Trial
92: 2322-2333, 1998
The prognostic implications of various cytogenetic abnormalities in patients with acute myeloid is well known.
In this study Karyotyping was successful in 1,612 children and adults less than 55 years who had AML and had received various chemotherapy schedule including all-trans retinoic acid. No cytogenetic abnormalities in 680 patients [42%] whereas the remainder were classified into 3 groups based on response to induction, risk of relapse and overall survival, these are the favorable prognostic group with: t[8;21], t[15;17], or inv  despite presence of the cytogenetic abnormalities, those with del[9q], del[7q], 11q23, +8 +21, OR +22 had an intermediate prognosis whereas those with complex cytogenetic changes -5/del[5q], 3q or -7 had poor prognosis. The response to treatment especially with high dose cytosine arabinoside may correlate with in vitro sensitivity of the cells bearing 16 chromosomes lesions and retinoic acid for t[15,17].
Archimbaud E, Ottmann OG, Yin JAL, et al (Hopital Edouard Herriot, Lyon, France; Univ of Frankfurt, Germany; Manchester Royal Infirmary, England; et al)
A Randomized, Double-blind, Placebo-controlled Study With Pegylated Recombinant Human Megakaryocyte Growth and Development Factor (PEG-rHuMGDF) as an Adjunct to Chemotherapy for Adults With De Novo Acute Myeloid Leukemia
Blood 94: 3694-3701, 1999
This study of 108 patients with de novo AML received PEG-rHuMGDF in various doses or placebo and time to transfusion independent platelet recovery, neutrophil recovery and peak platelet count were compared among treatment groups.
The daily doses of PEG-rHuMGDF after chemotherapy for AML administered to recovery of a target platelet count i.e. thrombocytosis platelet > 100 was possible in 52%. This did not result in acceleration in time to platelet recovery nor an improvement in the platelet nadir or the number of platelet transfusions required.
Guido Marcucci, Michael A. Caligiuri, and Clara D. Bloomfield (Division of Hematology and Oncology, Department of Internal Medicine, and Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Comprehensive Cancer Center, Ohio State University, Columbus, Ohio)
Molecular and Clinical Advances in Core Binding Factor Primary Acute Myeloid Leukemia: A Paradigm for Translational Research in Malignant Hematology
Cancer Investigation 2000 Vol. 18 (8) Pg. 768-780
The favorable prognostic cytogenetic aberration in patients with acute myeloid leukemia are (8;21) (q22;q22) and inversion of chromosome 16. These abnormalities are responsible for disruption of genes, encoding the subunits in the core binding factor, involved in regulation of normal hematopoiesis.
The t(8;21)(q22;q22) result in AML1/ETO fusion transcript that play a major role in leukemogenesis. The inv(16) (p13q22) and t(16; 16) (p13; q22) result in fusion transcript CBFb/MYH1 fusion transcript of different sizes. The mechanism by which CBFb/MYH1 lead to leukemia is unclear.
The standard cytogenetic, fluorescence in situ hybridization and comparative genomic hybridization are techniques to detect abnormal karotype sensitive techniques such as RT-PCR have also been useful.
The CBF leukemias are associated with FAB-M2 in 90% and M1 in 6% whereas those with inv(16) have FAB M4 AML and dysplastic eosinophils in bone marrow.
The inv(16)(p13q22) is associated with high leucocyte count and lymphadenopathy and hepatomegaly. Patient with CBF acute leukemia who have received cytarabine intensification have better outlook than bone marrow transplantation and for CBF leukemia AML1/ETO fusion transcript is used for minimal residual disease detection.