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NCI CANCERLIT® Search: Therapy of Acute Myeloid Leukemia - September 2001
Last Modified: November 1, 2001

Table of Contents

CancerMail from the National Cancer Institute

1
UI - 21319830
AU - Minden MD; Dimitroulakos J; Nohynek D; Penn LZ
TI - Lovastatin induced control of blast cell growth in an elderly patient with acute myeloblastic leukemia.
SO - Leuk Lymphoma 2001 Feb;40(5-6):659-62
AD - Department of Cellular and Molecular Biology, Ontario Cancer Institute, University Health Network, Toronto, Canada.
We recently reported that AML cells derived either from cell lines or from patients undergo apoptosis in response to lovastatin, an agent used extensively in the treatment of hypercholesterolemia. The concentration of lovastatin required to achieve this in culture varies from patient to patient, however, the in vitro concentrations required to kill AML cells, can be attained clinically. While in vitro studies assessing responsiveness of leukemic cells to lovastatin were being performed, a 72 year old female presented with relapsed AML. The patient did not desire any further induction therapy. As the patient's cells proved to be sensitive in culture to lovastatin, the patient was offered this drug. In this brief report we describe a case in which there was apparent control of the patient's leukemic blast cells by lovastatin at a dose double the usual recommended dose for hypercholesterolemia. This case illustrates the potential for lovastatin to provide a novel means of controlling leukemic cell growth in AML patients.

2
UI - 21227799
AU - Fanci R; Paci C; Pecile P
TI - Isolation frequency and antimicrobial susceptibility of Pseudomonas aeruginosa bloodstream infections in neutropenic patients with acute leukemia.
SO - J Chemother 2001 Apr;13(2):213-5

3
UI - 21292754
AU - Bruserud O; Foss B; Petersen H
TI - Hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders: studies of granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and Flt-3 ligand (Flt3L).
SO - Eur Cytokine Netw 2001 Apr-Jun;12(2):231-8
AD - Department of Medicine, Haukeland University Hospital and the University of Bergen, N-5021 Bergen, Norway.
The levels of hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders were investigated using a variety of approaches. Firstly, serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF and Flt3-ligand (Flt3L) were examined in acute leukemia patients with treatment-induced cytopenia and complicating bacterial infections. Increased serum levels of both G-CSF and Flt3-ligand (Flt3L) were detected when these patients developed therapy-induced leukopenia, whereas GM-CSF levels were low or undetectable. Development of complicating bacterial infections then increased the serum levels of both G- and GM-CSF, and the Flt3L levels remained high during the infections. Secondly, release of growth factors was characterized for clonogenic T cells that remained in the circulation of acute leukemia patients with chemotherapy-induced cytopenia. CD4(+) and CD8(+) T cells from these patients released high levels of GM-CSF, relatively low levels of IL-3 secretion having been detected, and only a minority of the clones released detectable amounts of Flt3L. Thus, circulating T cells may contribute to the high systemic growth factor levels in cytopenic patients. Thirdly, plasma levels of GM-CSF and interleukin-3 (IL-3) were examined in patients with malignant disorders who received chemotherapy plus G-CSF for stem cell mobilization. Increased levels of GM-CSF and Flt3L were detected both in the patients' plasma and in the stem cell grafts. Despite the increased growth factor levels in neutropenic patients with complicating infections, the occurrence of febrile neutropenia did not have a major impact on normal hematopoietic reconstitution (i.e. duration of treatment-induced neutropenia) after intensive chemotherapy for acute myelogenous leukemia.

4
UI - 21370683
AU - Lishner M; Bar-Sef A; Elis A; Fabian I
TI - Effect of simvastatin alone and in combination with cytosine arabinoside on the proliferation of myeloid leukemia cell lines.
SO - J Investig Med 2001 Jul;49(4):319-24
AD - Department of Medicine, Meir Hospital, Kfar-Saba, Israel. lishnm@internet-zahav.net
BACKGROUND: Cholesterol biosynthesis is regulated by the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Cholesterol and its derivatives are required in high concentrations by neoplastic proliferating cells for both DNA synthesis and cell growth. Thus, inhibition of HMG-CoA reductase could effect cell cycle progression and proliferation. Therefore, we examined the effect of an HMG-CoA reductase inhibitor (simvastatin) alone and in combination with cytosine arabinoside (ARA-C) on the proliferation of two AML cell lines. METHODS: AML blasts derived from two cell lines (HL-60 and AML-2) were incubated with increasing concentrations of either simvastatin alone or simvastatin alone for 24 hours with ARA-C added thereafter. The effect of the drugs on cell proliferation in liquid culture (3H thymidine uptake) and on clonogenic assay was analyzed. RESULTS: We found that the number of proliferating AML blasts (suspension cultures) and colony formations (agar cultures) of both cell lines declined significantly after incubation with simvastatin. Preincubation of both cell lines with simvastatin by the addition of increasing concentrations of ARA-C produced a degree of growth inhibition that was significantly greater than that of the individual compounds. This antigrowth interaction was additive rather than synergistic. CONCLUSIONS: We conclude that simvastatin has a major antiproliferative effect on AML blasts in vitro. Also, the combination of simvastatin and ARA-C significantly enhanced the antiproliferative effect of each drug. These findings may open new avenues in both the laboratory and clinical research of the treatment of leukemia.

5
UI - 21379471
AU - Mele L; Pagano L; Equitani F; Leone G
TI - Case reports. Secondary prophylaxis with liposomal amphotericin B after invasive aspergillosis following treatment for haematological malignancy.
SO - Mycoses 2001;44(5):201-3
We report our recent experience with two cases of invasive pulmonary aspergillosis in patients who were both undergoing chemotherapy, one for acute myeloid leukaemia and the other for primary amyloidosis. Both patients had bad prognostic factors and were in very poor clinical condition, but both recovered from infection after a prolonged therapy with liposomal amphotericin B (AmBisome) without signs of toxicity.

6
UI - 21398082
AU - Nakanishi Y; Kamijo R; Takizawa K; Hatori M; Nagumo M
TI - Inhibitors of cyclooxygenase-2 (COX-2) suppressed the proliferation and differentiation of human leukaemia cell lines.
SO - Eur J Cancer 2001 Aug;37(12):1570-8
AD - Second Department of Oral and Maxillofacial Surgery, School of Dentistry, Showa University, 2-1-1, Kitasenzoku, Ota-ku, Tokyo 145-8515, Japan. nico@senzoku.showa-u.ac.jp
Prostaglandins (PG) are known to play important roles in the proliferation and differentiation of leukaemia cells. The effect of the inhibitors of cyclooxygenase-2 (COX-2), a rate-limiting enzyme for the synthesis of PG, on the proliferation and differentiation of leukaemia cell lines was investigated. COX-2 inhibitors, NS-398 and nabumetone, suppressed the proliferation of U-937 and ML-1 cells by inducing a G0/G1 cell-cycle arrest. Cell-cycle arrest induced by these COX-2 inhibitors was not associated with an upregulation of the cyclin-dependent kinase inhibitors. COX-2 inhibitors also inhibited the differentiation of these cells induced by interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and retinoic acid (RA). Treatment with NS-398 did not suppress the levels of PGs produced by these cells. Although COX-2 antisense oligonucleotide showed a similar inhibitory effect on these cells, its inhibitory effect was smaller than that of NS-398. These results suggest that COX-2 inhibitors may suppress the proliferation and differentiation of leukaemia cells both via COX-2-dependent and -independent pathways.

7
UI - 21152856
AU - Jurcic JG
TI - Antibody therapy for residual disease in acute myelogenous leukemia.
SO - Crit Rev Oncol Hematol 2001 Apr;38(1):37-45
AD - Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, 1275 York Avenue, New York, NY 10021, USA. jurcicj@mskcc.org
The elimination of minimal residual disease remains one of the most promising applications of monoclonal antibody (mAb)-based therapies. An early study showed that treatment with iodine-131 (131I)-labeled anti-CD33 mAb M195 had antileukemic effects when given as postremission therapy to patients with acute promyelocytic leukemia (APL) in second remission. This treatment, however, was limited by significant myelosuppression and by the development of neutralizing human antimouse antibodies. Treatment with native HuM195, a humanized version of murine M195, eliminated minimal residual disease detectable by reverse transcription-polymerase chain reaction (RT-PCR) in 50% of patients. Patients with newly diagnosed APL treated with all-trans retinoic acid followed by HuM195 and consolidation chemotherapy had an 87% 3-year disease-free survival. Radioimmunotherapy with short-ranged, high-energy alpha particle-emitting isotopes may increase the potency of native mAbs while avoiding the nonspecific cytotoxicity of beta-emitting constructs. Targeted alpha particle therapy with bismuth-213-HuM195 showed significant antileukemic activity in patients with relapsed or refractory acute myelogenous leukemia. Antibody-drug conjugates, such as gemtuzumab ozogamicin, composed of a humanized anti-CD33 mAb and calicheamicin, have produced complete remissions in patients with relapsed AML and are likely to be active in the postremission setting.

8
UI - 21255269
AU - Fenaux P; Chomienne C; Degos L
TI - Treatment of acute promyelocytic leukaemia.
SO - Best Pract Res Clin Haematol 2001 Mar;14(1):153-74
AD - Service des Maladies du Sang, CHU, 1 Place de Verdun, Lille, 59037, France.
We review improvements achieved in the treatment of acute promyelocytic leukaemia (APL) over the last ten years. The combination of all- trans retinoic acid (ATRA) and conventional anthracycline-ARA-C chemotherapy (CT) has clearly demonstrated its superiority over CT alone (in terms of relapse and survival) in newly diagnosed APL. Combination treatment probably also reduces the incidence of initial failures, and complete remission (CR) rates greater than 90% are now regularly reported in large multicentre trials. Some randomized studies strongly suggest than prolonged maintenance treatment (for 1 or 2 years) with ATRA and low dose CT, and possibly very early introduction of anthracycline CT during induction treatment (i.e. not after ATRA) may reduce the incidence of relapse. With those treatments, the risk of relapse appears to be only 10-15%, although it remains greater in patients who initially have white blood cell counts (often associated with variant M(3)morphology, short bcr(3)isoform etc.) and patients with residual disease detectable by RT-PCR at the end of consolidation courses.ATRA syndrome remains the major side effect of ATRA treatment. It occurs in 10-15% of patients and is currently fatal in at least 10% of them. Rapid onset of CT and/or high dose steroids should improve its outcome.A sizeable proportion of APL patients who relapse after ATRA and CT can be durably salvaged by the same treatment followed by allogeneic or autologous stem cell transplantation, provided the transplant (in the autologous setting) is RT-PCR negative.Arsenic trioxide can induce CR in most APL patients refractory to ATRA and CT. It acts mainly by inducing apoptosis of APL cells. A place for arsenic trioxide earlier in the treatment of APL must currently be more precisely defined. Another issue in the treatment of APL is reducing the toxicity of first line treatment without increasing the relapse risk. Preliminary findings suggest that this could be achieved by consolidation CT using an anthracycline alone, without cytarabine. Copyright 2001 Harcourt Publishers Ltd.

9
UI - 21255271
AU - Torelli GF; Orsini E; Guarini A; Kell J; Foa R
TI - Developmental approaches in immunological control of acute myelogenous leukaemia.
SO - Best Pract Res Clin Haematol 2001 Mar;14(1):189-209
AD - Dipartimento di Biotecnologie Cellulari ed Ematologia, University 'La Sapienza', Via Benevento 6, Rome, 00161, Italy.
After many years of hope and disillusionment, the possibility of utilizing immune-mediated approaches to control neoplastic clones has become a reality in various haematological malignancies. This is largely a consequence of the continuous advances in knowledge and the progressive development of more refined technologies that have led to a better understanding of the biology of the malignant cells and of the host immune system, to a more precise definition of disease entities and to the design of innovative therapeutic programmes. In this chapter, we will review different immunological strategies that have reached clinical practice in patients with acute myelogenous leukaemia (AML), the focus of this volume, and discuss pre-clinical developments that may in the near future translate into the design of new immunotherapeutic protocols for the management of AML. Treatment of AML with antibody directed therapy will also be discussed. Copyright 2001 Harcourt Publishers Ltd.

10
UI - 21388598
AU - Martin Del Pozo M; Cisneros De La Fuente E; Solano F; Martin ML; De La Serna J
TI - [The retinoic acid syndrome, a complication of acute promyelocytic leukemia therapy]
SO - An Med Interna 2001 Apr;18(4):195-200
AD - Servicio Urgencias Fundacion Hospital de Alcorcon, Madrid.
OBJECTIVE: To describe the retinoic acid syndrome, a complication of therapy with all-trans retinoic acid (ATRA) in acute promyelocitic leukemia (APL). PATIENTS AND METHODS: Retrospective study of five patients with a morphologic diagnosis of APL by the French-American-British (FAB) classification that were treated for remission induction with ATRA and developed the ATRA syndrome. RESULTS: Three patients in newly diagnosed APL and two in leukemia relapse were analyzed. All patients received with ATRA 45 mgrs/m2/day, and three of them also received chemotherapy. Patients developed fever, respiratory distress, pulmonary infiltrates, weight gain and edemas. The onset of this symptom complex occurred from 1 to 11 days after starting treatment and was preceded by an increased in peripheral blood leukocytes. Infections or congestive heart failure were ruled out. The clinical course progressed while patients being treated with wide spectrum antibiotics. Four patients were treated with high doses corticosteroid therapy (dexametasone 10 mgrs intravenously every 12 hours), in three of them full recovery was attained and one died. One patient that did not received steroids died. CONCLUSIONS: The use of all-trans retinoic acid to induce hematologic remission in APL patients is associated in same patients with the development of ATRA syndrome, a life threatening complication. Symptoms begin in the first days of treatment. If this syndrome is suspected, early treatment with high dose steroids should be initiated.

11
UI - 21420148
AU - Mann G; Reinhardt D; Ritter J; Hermann J; Schmitt K; Gadner H; Creutzig U
TI - Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children.
SO - Ann Hematol 2001 Jul;80(7):417-22
AD - St. Anna Children's Hospital, Vienna, Austria.
All-trans retinoic acid (ATRA) is a known inducer of differentiation in acute promyelocytic leukemia. To improve the outcome of children with acute promyelocytic leukemia, ATRA has been applied since 1994 as an additional induction element inthe AML-BFM 93 study. In a retrospective study, we compared 22 children treated with ATRA (median age: 9.3 years; range: 1.8-16.3) with 22 patients receiving conventional therapy (median age: 12.3 years; range: 3.2-16.7). Twenty-one of the children achieved complete remission. Only one patient died early from bleeding complications after 3 days administration of ATRA. In the control group, seven early deaths occurred (Fisher exact test; p<0.04). Two children died from intracerebral hemorrhages. Two patients suffered from sepsis during aplasia after induction therapy, and one child did not respond to treatment. The 5-year overall survival (OS) and event-free survival (EFS) of the children who received ATRA followed by chemotherapy were significantly bettercom-pared with conventionally treated children [OS: 0.87 +/- 0.9 vs 0.45 +/- 0.11, p (log rank) <0.003; EFS: 0.76 +/- 0.11 vs 0.43 +/- 0.11 p (log rank) <0.02]; the median observation time was 2.8 years (19-76 months). However, nearly all children suffered from common side effects such as headache, fever, joint, muscle and bone pain, weight gain, or dermatitis. In three patients, a retinoic acid syndrome was observed. Interruption of ATRA treatment and application of dexamethasone, necessary in 12 children, controlled theadverse effects. ATRA treatment could be resumed in 18 patients. In conclusion, ATRA treatment during induction could avoid early deaths in children with acute promyelocytic leukemia with considerable but manageable toxic side effects.

12
UI - 21303165
AU - Bross PF; Beitz J; Chen G; Chen XH; Duffy E; Kieffer L; Roy S; Sridhara R; Rahman A; Williams G; Pazdur R
TI - Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia.
SO - Clin Cancer Res 2001 Jun;7(6):1490-6
AD - Division of Oncology Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20852, USA. brossp@cder.fda.gov
PURPOSE: Gemtuzumab ozogamicin (Mylotarg; Wyeth Laboratories, Philadelphia, PA) consists of a semisynthetic derivative of calicheamicin, a cytotoxic antibiotic linked to a recombinant monoclonal antibody directed against the CD33 antigen present on leukemic myeloblasts in most patients with acute myeloid leukemia (AML). In this study, we review the preclinical and clinical profiles of this immunoconjugate and the regulatory review that led to marketing approval by the United States Food and Drug Administration. EXPERIMENTAL DESIGN: From the literature and manufacturer's data, we review the activity, tolerability, and pharmacokinetics of gemtuzumab ozogamicin in preclinical and Phase I studies and its activity, efficacy, and side effects in three Phase 2 trials of 142 patients with relapsed AML. RESULTS: In Phase I studies, the major toxicity was myelosuppression, especially neutropenia and thrombocytopenia, resulting from the expression of CD33 on myeloid progenitor cells. The Phase 2 dose was 9 mg/m(2) infused i.v. over 4 h, repeated on day 14. A minority of patients experienced acute infusion-related symptoms, usually transient and occasionally requiring hospitalization. The complete response (CR) rate with full recovery of hematopoiesis was 16%. A subset of patients [CRs with incomplete platelet recovery (CRps)] was identified with blast clearance and neutrophil recovery but incomplete platelet recovery. The duration of responses of CRps appeared to be similar to those of the CRs, although the numbers were small. The question of the equivalence of these response groups was a central issue in the review of this new drug application (NDA). After considerable discussion, the Oncology Drugs Advisory Committee recommended allowing inclusion of CRps resulting in an overall response rate in the Phase 2 studies of 30%. In the subgroup of patients over 60 years of age, the overall response rate was 26%. Response duration was difficult to establish because of the high prevalence of postremission therapies. Tolerability and ease of administration may be improved compared with conventional chemotherapy, except for hepatotoxicity, with 31% of patients exhibiting abnormal liver enzymes. One patient died of liver failure in the Phase 2 trials. CONCLUSIONS: Marketing approval of gemtuzumab ozogamicin was granted on May 17, 2000 by the United States Food and Drug Administration under the Accelerated Approval regulations. Gemtuzumab ozogamicin is indicated for the treatment of patients with CD33 positive AML in first relapse who are 60 years of age or older and who are not considered candidates for cytotoxic chemotherapy. The approved dose was 9 mg/m(2) i.v. over 4 h and repeated in 14 days. Completion of the ongoing studies of gemtuzumab ozogamicin in relapsed AML and initiation of randomized clinical trials comparing the effects of gemtuzumab ozogamicin in combination with conventional induction chemotherapy to conventional chemotherapy alone on survival are mandated to confirm clinical benefit under the accelerated approval Subpart H regulations. Postmarketing reports of fatal anaphylaxis, adult respiratory distress syndrome (ARDS), and hepatotoxicity, especially venoocclusive disease (VOD) in patients treated with gemtuzumab ozogamicin, with and without associated hematopoietic stem cell transplantation (HSCT), have required labeling revisions and the initiation of a registration surveillance program. Tumor lysis and ARDS have been reported in patients with leukocytes above 30,000/ml treated with gemtuzumab ozogamicin; therefore, the reduction of leukocyte counts to below 30,000/ml is recommended prior to treatment. Patients should be carefully monitored for acute hypersensitivity, hypoxia, and delayed hepatotoxicity following treatment with gemtuzumab ozogamicin.

13
UI - 21364820
AU - Woronoff-Lemsi MC; Witz F; Arveux P; Cahn JY; Harousseau JL; GOELAM Sa3 (Groupe Est d'etudes des Leucemies et Autres Maladies du Sang)
TI - [Cost effectiveness of GM-CSF in the treatment of acute myeloblastic leukemia in aged patients: protocol of GOELAM Sa3]
SO - Therapie 2001 Mar-Apr;56(2):131-3
AD - Pharmacie, CHU Besancon, Bd Fleming, 25030 Besancon, France.
A cost-effectiveness analysis was carried out from a randomized placebo-controlled protocol of GM-CSF during and after remission induction treatment for elderly patients with acute myeloid leukemia (AML). A retrospective economic analysis was carried out from the hospital perspective. A total of 240 patients with de novo AML and aged 55 to 75 years were enrolled. Overall survival and disease-free survival were analysed for efficacy within five years and expressed in gained life-years. Analysis was also conducted according to the protocol stratification: 55-64-year-old and 65-75-year-old patients. Global costs were estimated on the basis of patient medical records from inclusion to death or relapse. In all, 83 patients were evaluated from three centres, Besancon, Nancy and Nantes. Costs are expressed in French francs. Overall, total cost per patient amounted to FF 641,778 for placebo patients and to FF 587,048 for GM-CSF patients. For disease free-survival, costs were FF 357,167 for placebo patients and FF 320,736 for GM-CSF patients. For overall survival and disease free-survival the cost savings by GM-CSF were, respectively, FF 54,730 and FF 36,431. In the younger patient group savings were synonymous with GM-CSF. In all cases GM-CSF strategy induced benefit expressed as savings as well as efficacy.

14
UI - 21363217
AU - Dietz AB; Litzow MR; Gastineau DA; Vuk-Pavlovic S
TI - Engineering dendritic cell grafts for clinical trials in cellular immunotherapy of cancer: example of chronic myelogenous leukemia.
SO - Croat Med J 2001 Aug;42(4):428-35
AD - Stem Cell Laboratory, Mayo Clinic Cancer Center, Rochester, MN 55905, USA. dietz.allan@mayo.edu
Dendritic cells are pivotal regulators of immune reactivity and immune tolerance. The observation that dendritic cells can recruit naive T-cells has invigorated cancer immunology and stimulated clinical trials of dendritic cells in immunotherapy. However, variables inherent in preparation and use of dendritic cell grafts remain to be tested. Here we discuss the role of ex vivo dendritic cell processing for in vivo antigen presentation in clinical trials. As an example of the complexity in a clinical trial of dendritic cell vaccines, we present our ongoing trial in immunotherapy of chronic myelogenous leukemia.

15
UI - 21368246
AU - Burnett AK
TI - Introduction: Modern management of acute myeloid leukemia.
SO - Semin Hematol 2001 Jul;38(3 Suppl 6):1-2
AD - University of Wales College of Medicine, Cardiff, UK.

16
UI - 21368248
AU - Lowenberg B
TI - Managing therapy in older adult patients with acute myeloid leukemia.
SO - Semin Hematol 2001 Jul;38(3 Suppl 6):10-6
AD - Department of Hematology, Erasmus University, Rotterdam, The Netherlands.
Acute myeloid leukemia (AML) is predominantly a disease of older adults, with more than 50% of cases occurring in adults over 60 years of age. Treatment of AML in older adults is complicated not only by comorbidities that are common in this patient population, but also by the prevalence, in this age group, of forms of AML with a poor prognosis. The problems encountered and the strategies that have been used to improve the outlook in older adults with AML are presented. The two main strategies for improving outcomes in older adults with AML are to develop effective chemotherapeutic regimens with improved tolerability, and to reduce drug resistance. In studies to identify optimal chemotherapeutic regimens in older adults, a satisfactory balance between efficacy and toxicity has not yet been achieved. Also, the use of growth factors to promote hematopoietic recovery has yet to yield consistent reductions in treatment-related morbidity or mortality. Drug resistance can be modified by inhibiting drug efflux mechanisms or by increasing sensitivity to cytotoxic agents, but these strategies have not yet been shown to significantly affect outcomes. Novel approaches including antibody-targeted and molecular-targeted chemotherapy may have the potential to improve the prognosis for older adults with AML. Copyright 2001 by W.B. Saunders Company.

17
UI - 21368249
AU - Stone RM
TI - Postremission therapy in adults with acute myeloid leukemia.
SO - Semin Hematol 2001 Jul;38(3 Suppl 6):17-23
AD - Dana-Farber Cancer Institute, Boston, MA 02115, USA.
A patient with acute myeloid leukemia (AML) who has achieved remission after induction chemotherapy still harbors 10(9) to 10(10), albeit undetectable, leukemic cells. Optimally, postremission therapy safely reduces the leukemic burden to a level compatible with long-term disease-free survival. Although older adults fare poorly with intensive postremission therapy, young and middle-aged adults can receive either chemotherapy based on high-dose cytarabine or myeloablative therapy in preparation for autologous or, if a histocompatible donor is available, allogeneic stem cell rescue. The rationale for each approach, the prospective trials comparing the various options, and a suggested strategy for choosing among them is presented. Although cytogenetic category at diagnosis is the most important prognostic factor, this feature remains an imperfect guide to postremission therapy. An informal consensus has arisen in favor of chemotherapy for patients with good prognosis and allogeneic transplant for those whose AML displays an adverse karyotype. For the intermediate group, an individualized decision is required and any of the three options is reasonable. Because the relapse rate is so high, new therapies for AML, such as signaling and immunotherapeutic approaches, are the focus of active investigation. Copyright 2001 by W.B. Saunders Company.

18
UI - 21368250
AU - Larson RA
TI - Current use and future development of gemtuzumab ozogamicin.
SO - Semin Hematol 2001 Jul;38(3 Suppl 6):24-31
AD - University of Chicago, Chicago, IL 60637, USA.
The antigen CD33 is expressed on blast cells in 80% to 90% of acute myeloid leukemia (AML) cases but, importantly, is not expressed on pluripotent hematopoietic stem cells or on nonhematologic cells. Gemtuzumab ozogamicin (CMA-676) uses a recombinant humanized anti-CD33 monoclonal IgG4 antibody to deliver the potent cytotoxin, calicheamicin, into cells. Three multicenter trials have evaluated the efficacy and safety of gemtuzumab ozogamicin as a single agent in 142 patients with CD33+ AML in untreated first relapse. The median age was 61 years (range, 22 to 84 years), none had prior myelodysplasia, and all had had a first complete remission lasting > or = 3 months. Two doses of 9 mg/m2 were given 14 days apart by 2-hour intravenous infusion. The overall response rate was 30% (ie, < or = 5% blasts remaining in the bone marrow, neutrophils > or = 1,500/microL, and red blood cell and platelet transfusion independence). There was no significant difference in response rate between patients less than 60 years of age and those > or = 60 years old (34% v 26%, respectively) or between patients whose first remission had lasted less than 12 months or > or = 12 months (28% v 32%, respectively). Overall survival was 31% at 1 year; median survival was 5.9 months. Median relapse-free survival was 6.8 months. An infusion-related syndrome (chills, fever, rigors, nausea, hypotension, and pain) was common. Severe myelosuppression occurred in all patients, but severe mucositis (4%) and infections (23%) were relatively infrequent. Severe hyperbilirubinemia (23%) and elevated hepatic transaminases (18%) were usually transient. Among all 142 patients, the median total hospitalization was 24 days; 16% of patients required < or = 7 days in hospital. Additional studies are currently evaluating gemtuzumab ozogamicin in combination with, or as an alternative to, other standard AML chemotherapy. Copyright 2001 by W.B. Saunders Company.

19
UI - 21368247
AU - Hiddemann W; Buchner T
TI - Current status and perspectives of therapy for acute myeloid leukemia.
SO - Semin Hematol 2001 Jul;38(3 Suppl 6):3-9
AD - German AML Cooperative Group, Munich, Germany.
Intensification of induction and postremission chemotherapies has resulted in a steady improvement in outcomes for adults with acute myeloid leukemia (AML) over the past two decades. The global response to initial therapy is now in the range of 60% to 80%, with 20% to 30% of patients experiencing long-term disease-free survival. Modern methodologies have revealed that cytogenetic aberrations are closely related to treatment outcome and have allowed subgroups of patients to be identified who have AML with a good, intermediate, or poor prognosis. The actions and interactions of cytogenetics and therapy in determining treatment outcome have been investigated in a series of clinical trials conducted by the German AML Cooperative Group. Evidence is presented that therapy and cytogenetics can independently influence outcome. It is hoped that our increasing understanding of the biological mechanisms that dictate disease characteristics will lead to improved outcomes for patients with AML. Copyright 2001 by W.B. Saunders Company.

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