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Clinical Trials (PDQ®)

Phase III Randomized Study of Chemotherapy with High-Dose vs Standard-Dose ARA-C plus DNM for Consolidation Therapy Following ARA-C/DNM Induction in Patients with ANLL

Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentClosedunder 65NCISWOG-8600

Objectives

I.  Compare CR rates in patients with acute ANLL given induction therapy with 
high-dose cytosine arabinoside (ARA-C) plus daunomycin (DNM) vs. standard-dose 
ARA-C plus DNM.
II.  Compare the duration of remission among patients receiving any of three 
combinations of induction and consolidation regimens:  standard-dose ARA-C/DNM 
for both induction and consolidation vs. induction with standard-dose 
ARA-C/DNM followed by consolidation with high-dose ARA-C/DNM vs. high-dose 
ARA-C/DNM for both induction and consolidation.
III.  Determine the relative toxicities of these three regimens.
IV.  Determine the feasibility of implementing a predetermined approach to 
supportive care within a multi-institutional cooperative group setting for 
patients receiving intensive chemotherapy for ANLL.

Entry Criteria

Disease Characteristics:


Previously untreated acute non-lymphocytic leukemia

Histologic confirmation of diagnosis by bone marrow aspirate
and biopsy required with:

  Marrow cellularity at least 50%

  Absolute infiltrate of leukemic cells at least 30%

  Requirement for the marrow report prior to registration
  waived when WBC over 100,000 (may begin treatment
  immediately and submit report with initial flow sheets)

Pretreatment bone marrow or peripheral blood sample required
for cell surface marker tests

  Requirement waived if following conditions met:
     WBC less than 10,000
     Total peripheral blasts + promyelocytes + promonocytes
        less than 50% of WBC
     Bone marrow not aspirable (dry tap)


Prior/Concurrent Therapy:


Biologic therapy:
  No prior biologic therapy for ANLL

Chemotherapy:
  No prior chemotherapy for ANLL

Endocrine therapy:
  No prior endocrine therapy for ANLL

Radiotherapy:
  No prior radiotherapy for ANLL

Surgery:
  Not specified


Patient Characteristics:


Age:
  Under 65 (study piloted in patients over age 64 at Ohio
  State University and Cleveland Clinic)

Performance status:
  Not specified

Hematopoietic:
  Not specified

Hepatic:
  Bilirubin not more than 3.0 mg/dl

Renal:
  Not specified

Other:
  All pretreatment tests completed within 7 days prior to
  registration


Expected Enrollment

600 patients will be entered over about 3 years.

Outline

Patients were randomized to Arms I and II for Induction; as of 9/91, only Arm 
I is open.  Upon achieving CR, patients on Arm I are randomized a second time 
to receive Consolidation on Arm III or IV, while those on Arm II are assigned 
nonrandomly to Arm III for Consolidation.
Induction.
Arm I:  2-Drug Combination Chemotherapy.  Standard-dose Cytosine arabinoside 
(Upjohn only), ARA-C, NSC-63878; Daunomycin, DNM, NSC-82151.
Arm II (arm closed as of 9/91):  2-Drug Combination Chemotherapy.  High-dose 
ARA-C; DNM.
Consolidation.
Arm III:  2-Drug Combination Chemotherapy.  High-dose ARA-C; DNM.
Arm IV:  2-Drug Combination Chemotherapy.  Standard-dose ARA-C; DNM.

Published Results

Toyota M, Kopecky KJ, Toyota MO, et al.: Methylation profiling in acute myeloid leukemia. Blood 97 (9): 2823-9, 2001.[PUBMED Abstract]

Fryxell KB, McGee SB, Simoneaux DK, et al.: Methylation analysis of the human multidrug resistance 1 gene in normal and leukemic hematopoietic cells. Leukemia 13 (6): 910-7, 1999.[PUBMED Abstract]

Leith CP, Kopecky KJ, Chen IM, et al.: Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 94 (3): 1086-99, 1999.[PUBMED Abstract]

Li Q, Kopecky KJ, Mohan A, et al.: Estrogen receptor methylation is associated with improved survival in adult acute myeloid leukemia. Clin Cancer Res 5 (5): 1077-84, 1999.[PUBMED Abstract]

Stirewalt DL, Clurman B, Appelbaum FR, et al.: p73 mutations and expression in adult de novo acute myelogenous leukemia. Leukemia 13 (7): 985-90, 1999.[PUBMED Abstract]

Li Q, Kopecky KJ, Mohan A, et al.: Estrogen receptor methylation is associated with improved survival in adult acute myeloid leukemia (AML). [Abstract] Proceedings of the American Society of Clinical Oncology 16: A11, 4a, 1997.

Weick JK, Kopecky KJ, Appelbaum FR, et al.: A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88 (8): 2841-51, 1996.[PUBMED Abstract]

Radich JP, Kopecky KJ, Willman CL, et al.: N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 76 (4): 801-7, 1990.[PUBMED Abstract]

Willman C, Elias L, Griffith B, et al.: Biological parameters associated with therapeutic nonresponsiveness in acute myeloid leukemia (AML). [Abstract] Proceedings of the American Society of Clinical Oncology 8: A-777, 200, 1989.

Related Publications

Lancet JE, Willman CL, Bennett JM: Acute myelogenous leukemia and aging. Clinical interactions. Hematol Oncol Clin North Am 14 (1): 251-67, 2000.[PUBMED Abstract]

Banker D, Willman C, Groudine M, et al.: Cell cycle arrest and therapeutic sensitivity in de novo. [Abstract] Blood 92 (10 suppl 1): A-290, 67a, 1998.

Hogge DE, Willman CL, Kreitman RJ, et al.: Malignant progenitors from patients with acute myelogenous leukemia are sensitive to a diphtheria toxin-granulocyte-macrophage colony-stimulating factor fusion protein. Blood 92 (2): 589-95, 1998.[PUBMED Abstract]

Appelbaum FR, Kopecky KJ: Long-term survival after chemotherapy for acute myeloid leukemia: the experience of the Southwest Oncology Group. Cancer 80 (11 Suppl): 2199-204, 1997.[PUBMED Abstract]

Banker DE, Groudine M, Norwood T, et al.: Measurement of spontaneous and therapeutic agent-induced apoptosis with BCL-2 protein expression in acute myeloid leukemia. Blood 89 (1): 243-55, 1997.[PUBMED Abstract]

Banker DE, Groudine M, Appelbaum FR: Spontaneous and therapeutic agent-induced apoptosis with BCL-2 protein expression in acute myeloid leukemia. [Abstract] Blood 88 (10 suppl 1): A-2649, 665a, 1996.

Beck WT, Grogan TM, Willman CL, et al.: Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: consensus recommendations. Cancer Res 56 (13): 3010-20, 1996.[PUBMED Abstract]

Issa JJ, Kopecky KJ, Appelbaum F, et al.: Estrogen receptor methylation is a favorable prognostic factor in AML. [Abstract] Proceedings of the American Society of Clinical Oncology 15: A1048, 357a, 1996.

Kuss BJ, Deeley RG, Cole SP, et al.: The biological significance of the multidrug resistance gene MRP in inversion 16 leukemias. Leuk Lymphoma 20 (5-6): 357-64, 1996.[PUBMED Abstract]

Liu PP, Wijmenga C, Hajra A, et al.: Identification of the chimeric protein product of the CBFB-MYH11 fusion gene in inv(16) leukemia cells. Genes Chromosomes Cancer 16 (2): 77-87, 1996.[PUBMED Abstract]

Nakamura T, Largaespada DA, Lee MP, et al.: Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet 12 (2): 154-8, 1996.[PUBMED Abstract]

Pearson L, Leith CP, Duncan MH, et al.: Multidrug resistance-1 (MDR1) expression and functional dye/drug efflux is highly correlated with the t(8;21) chromosomal translocation in pediatric acute myeloid leukemia. Leukemia 10 (8): 1274-82, 1996.[PUBMED Abstract]

Viswanatha DS, Chen IM, Liu PP, et al.: Characterization and rapid diagnostic utility of a novel antibody detecting the CBFBeta/SMMHC fusion protein of inversion (16)/t(16;16) associated with acute myeloid leukemia. [Abstract] Blood 88 (10 suppl 1): A-2646, 664a, 1996.

Head D, Kopecky KJ, Weick J, et al.: Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia. Blood 86 (5): 1717-28, 1995.[PUBMED Abstract]

Leith CP, Chen IM, Kopecky KJ, et al.: Correlation of multidrug resistance (MDR1) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: identification of discordant MDR-/efflux+ and MDR1+/efflux- cases. Blood 86 (6): 2329-42, 1995.[PUBMED Abstract]

Mehrotra B, George TI, Kavanau K, et al.: Cytogenetically aberrant cells in the stem cell compartment (CD34+lin-) in acute myeloid leukemia. Blood 86 (3): 1139-47, 1995.[PUBMED Abstract]

Saito M, Helin K, Valentine MB, et al.: Amplification of the E2F1 transcription factor gene in the HEL erythroleukemia cell line. Genomics 25 (1): 130-8, 1995.[PUBMED Abstract]

Shurtleff SA, Meyers S, Hiebert SW, et al.: Heterogeneity in CBF beta/MYH11 fusion messages encoded by the inv(16)(p13q22) and the t(16;16)(p13;q22) in acute myelogenous leukemia. Blood 85 (12): 3695-703, 1995.[PUBMED Abstract]

Slovak ML, Traweek ST, Willman CL, et al.: Trisomy 11: an association with stem/progenitor cell immunophenotype. Br J Haematol 90 (2): 266-73, 1995.[PUBMED Abstract]

Head DR, Kopecky KJ, Willman C, et al.: Treatment outcome with chemotherapy in acute promyelocytic leukemia: the Southwest Oncology Group (SWOG) experience. Leukemia 8 (Suppl 2): S38-41, 1994.[PUBMED Abstract]

Kuss BJ, Deeley RG, Cole SP, et al.: Deletion of gene for multidrug resistance in acute myeloid leukaemia with inversion in chromosome 16: prognostic implications. Lancet 343 (8912): 1531-4, 1994.[PUBMED Abstract]

Nagarajan L, Zavadil J, Claxton D, et al.: Consistent loss of the D5S89 locus mapping telomeric to the interleukin gene cluster and centromeric to EGR-1 in patients with 5q- chromosome. Blood 83 (1): 199-208, 1994.[PUBMED Abstract]

Scott AA, Head DR, Kopecky KJ, et al.: HLA-DR-, CD33+, CD56+, CD16- myeloid/natural killer cell acute leukemia: a previously unrecognized form of acute leukemia potentially misdiagnosed as French-American-British acute myeloid leukemia-M3. Blood 84 (1): 244-55, 1994.[PUBMED Abstract]

Downing JR, Head DR, Curcio-Brint AM, et al.: An AML1/ETO fusion transcript is consistently detected by RNA-based polymerase chain reaction in acute myelogenous leukemia containing the (8;21)(q22;q22) translocation. Blood 81 (11): 2860-5, 1993.[PUBMED Abstract]

Hunger SP, Tkachuk DC, Amylon MD, et al.: HRX involvement in de novo and secondary leukemias with diverse chromosome 11q23 abnormalities. Blood 81 (12): 3197-203, 1993.[PUBMED Abstract]

Betz SA, Foucar K, Head DR, et al.: False-positive flow cytometric platelet glycoprotein IIb/IIIa expression in myeloid leukemias secondary to platelet adherence to blasts. Blood 79 (9): 2399-403, 1992.[PUBMED Abstract]

Morishita K, Parganas E, William CL, et al.: Activation of EVI1 gene expression in human acute myelogenous leukemias by translocations spanning 300-400 kilobases on chromosome band 3q26. Proc Natl Acad Sci U S A 89 (9): 3937-41, 1992.[PUBMED Abstract]

Saikevych IA, Kerrigan DP, McConnell TS, et al.: Multiparameter analysis of acute mixed lineage leukemia: correlation of a B/myeloid immunophenotype and immunoglobulin and T-cell receptor gene rearrangements with the presence of the Philadelphia chromosome translocation in acute leukemias with myeloid morphology. Leukemia 5 (5): 373-82, 1991.[PUBMED Abstract]

Willman CL, Stewart CC, Longacre TL, et al.: Expression of the c-fgr and hck protein-tyrosine kinases in acute myeloid leukemic blasts is associated with early commitment and differentiation events in the monocytic and granulocytic lineages. Blood 77 (4): 726-34, 1991.[PUBMED Abstract]

Noonan KE, Beck C, Holzmayer TA, et al.: Quantitative analysis of MDR1 (multidrug resistance) gene expression in human tumors by polymerase chain reaction. Proc Natl Acad Sci U S A 87 (18): 7160-4, 1990.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Southwest Oncology Group

James Weick, MD, Protocol chair
Ph: 561-965-1864
Email: jweick@aol.com

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

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