Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Related Publications
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy With or Without PSC 833, Peripheral Stem Cell Transplantation, and/or Interleukin-2 in Treating Patients With Acute Myeloid Leukemia

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Closed 15 to 59 NCI CALGB-19808 CALGB-19808, NCT00006363

Objectives

1. Compare the effect of induction chemotherapy with or without PSC 833 (induction chemotherapy [arm II] closed to accrual as of 8/11/03) on disease-free survival and overall survival in patients with previously untreated acute myeloid leukemia.
2. Determine whether post-consolidation immunotherapy with low-dose interleukin-2 (IL-2) and continuous/intermittent high-dose IL-2 improves disease-free survival and overall survival in patients who achieve first complete remission.
3. Determine the effectiveness of three courses of high-dose cytarabine (HiDAC) to cure patients with core-binding factor leukemias.
4. Determine the feasibility and efficacy of intensive post-remission chemotherapy using peripheral blood stem cell transplantation or a novel intensification sequence of HiDAC/high-dose etoposide/filgrastim (G-CSF) followed by two courses of HiDAC in patients with unfavorable cytogenetics in complete remission.

Entry Criteria

Disease Characteristics:

• Histologically confirmed acute myeloid leukemia (AML) with more than 20% blasts in bone marrow by WHO and/or FAB classifications
  • Antecedent myelodysplasia allowed if there was no bone marrow biopsy showing myelodysplastic syndromes over the previous 3 months
  • No acute promyelocytic leukemia (M3)
  • No therapy-related myelodysplastic syndromes or AML
  • No chronic myeloproliferative disorder



• Must also be enrolled on CALGB 9665 unless inaspirable and mandatory leukemic cells cannot be obtained from the blood

Prior/Concurrent Therapy:

Biologic therapy:

• Prior emergency leukapheresis allowed
• Prior growth factor/cytokine support allowed
• No other prior biologic therapy
• Other concurrent myeloid growth factors allowed only if prognostic factors predictive of clinical deterioration are present such as the following:
  • Pneumonia
  • Hypotension
  • Multiorgan dysfunction (sepsis syndrome)
  • Fungal infection

Chemotherapy:

• Prior emergency treatment for hyperleukocytosis with hydroxyurea allowed
• No other prior chemotherapy
• No other concurrent chemotherapy

Endocrine therapy:

• No prior endocrine therapy
• No concurrent hormonal therapy other than steroids for adrenal failure or septic shock or hormones for conditions not related to disease (e.g., insulin for diabetes or estrogens or progestins for gynecologic indications)

Radiotherapy:

• One dose of prior cranial radiotherapy for CNS leukostasis allowed
• No other prior radiotherapy
• No concurrent radiotherapy

Surgery:

• Not specified

Patient Characteristics:

Age:

• 15 to 59

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Other:

• Not pregnant or nursing
• Fertile patients must use effective contraception

Expected Enrollment

A total of 720 patients will be accrued for this study within 4 years.

Outcomes

Comparison of disease-free and overall survival

Toxicity

Outline

This is a randomized, multicenter study.

• Induction Therapy:Patients are randomized to 1 of 2 treatment arms. (Arm II closed to accrual as of 8/11/03.)
  • Arm I: Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1-3. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of cytarabine IV continuously on days 1-5 and daunorubicin IV over 5-10 minutes followed by etoposide IV over 2 hours on days 1 and 2.
  
  
  
  • Arm II (closed to accrual as of 8/11/03): Patients receive PSC 833 IV continuously on days 1-3 and cytarabine, daunorubicin, and etoposide as in arm I. Patients with 20% or greater bone marrow cellularity and greater than 5% leukemia blasts at the end of the first course receive a second course of PSC 833 IV continuously on days 1 and 2 and cytarabine, daunorubicin, and etoposide as in arm I.
  
  
  



• Intensification Therapy: Patients in complete remission receive intensification therapy. Therapy begins no earlier than 2 weeks and no later than 4 weeks after complete remission is attained. Patients are stratified according to cytogenetics (favorable [t(8;21)(q22;q22) or inv(16)(p13;q22) or t(16;16)(p13;q22)] vs unfavorable [all other karyotypes]).
  • Favorable: Patients receive high-dose cytarabine (HiDAC) IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after the prior course and no later than 14 days after hematopoietic recovery for two more courses.
  
  
  
  • Unfavorable: Patients are further divided into two groups based on ability to receive peripheral blood stem cell transplantation (PBSCT) (yes vs no).
    • PBSCT group: Patients receive etoposide IV continuously and HiDAC IV over 2 hours every 12 hours on days 1-4. Patients also receive filgrastim (G-CSF) subcutaneously (SC) daily beginning on day 14 and continuing until peripheral blood stem cell (PBSC) collection is completed. Patients who are not able to undergo PBSCT after HiDAC/etoposide continue treatment in the non-PBSCT group. At least 4 weeks after HiDAC/etoposide recovery, patients receive oral busulfan every 6 hours on days -7 to -4 and etoposide IV over 4 hours on day -3 prior to PBSCT. Patients receive autologous PBSC infusion on day 0. Patients also receive G-CSF SC beginning on day 0 and continuing until hematopoietic recovery.
    
    
    
    • Non-PBSCT group: Patients receive etoposide, HiDAC, and G-CSF as in the PBSCT group. After hematopoietic recovery, patients then receive HiDAC IV over 3 hours every 12 hours on days 1, 3, and 5. Treatment repeats no earlier than 28 days after prior course and no later than 14 days after hematopoietic recovery for one more course.
    
    
    
  
  
  



• Immunotherapy: Patients are again randomized to 1 of 2 treatment arms.
  • Arm I: Patients begin therapy no later than 120 days after the first day of the last course of HiDAC treatment OR day 0 of PBSCT. Patients receive low-dose interleukin-2 (IL-2) SC on days 1-14, 19-28, 33-42, 47-56, 61-70, and 75-90. In addition, patients receive high-dose IL-2 SC on days 15-17, 29-31, 43-45, 57-59, and 71-73.
  
  
  
  • Arm II: Patients are observed and receive no further therapy.
  
  
  

Patients are followed at 1 month, every 2 months for 2 years, every 6 months for 2 years, and then annually for 6 years.

Kolitz JE, Hars V, DeAngelo DJ, et al.: Phase III trial of immunotherapy with recombinant interleukin-2 (rIL-2) versus observation in patients < 60 years with acute myeloid leukemia (AML) in first remission (CR1): preliminary results from Cancer and Leukemia Group B (CALGB) 19808. [Abstract] Blood 110 (11): A-157, 2007.

Radmacher MD, Marcucci G, Paschka P, et al.: MicroRNA (miR) expression signatures in molecular subsets of cytogenetically normal (CN) acute myeloid leukemia (AML): a Cancer and Leukemia Group B (CALGB) study. [Abstract] J Clin Oncol 25 (Suppl 18): A-7010, 359s, 2007.

Kolitz JE, George SL, Marcucci G, et al.: A randomized comparison of induction therapy for untreated acute myeloid leukemia (AML) in patients < 60 years using p-glycoprotein (Pgp) modulation with valspodar (PSC833): preliminary results of Cancer and Leukemia Group B study 19808. [Abstract] Blood 106 (11): A-407, 2005.

Langer C, Maharry K, Mrózek K, et al.: Low Meningioma 1 (MN1) gene expression to predict outcome in cytogenetically normal acute myeloid leukemia (CN-AML): A Cancer and Leukemia Group B (CALGB) study. [Abstract] J Clin Oncol 26 (Suppl 15): A-7011, 2008.

Langer C, Radmacher MD, Ruppert AS, et al.: High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study. Blood 111 (11): 5371-9, 2008.[PUBMED Abstract]

Paschka P, Marcucci G, Ruppert AS, et al.: Wilms Tumor 1 Gene Mutations Independently Predict Poor Outcome in Adults With Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol : , 2008.[PUBMED Abstract]

Langer C, Ruppert, AS, Radmacher MD, et al.: High BAALC expression associates with other molecular prognostic markers, poor outcome and a distinct gene expression signature in cytogenetically normal acute myeloid leukemia (CN AML): a Cancer and Leukemia Group B (CALGB) study. [Abstract] J Clin Oncol 25 (Suppl 18): A-7013, 360s, 2007.

Marcucci G, Maharry K, Radmacher MD, et al.: Gene and microRNA (miRNA) expression signatures and prognostic significance of CEBPA mutations in cytogenetically normal (CN) acute myeloid leukemia (AML) with high-risk molecular features: a Cancer and Leukemia Group B (CALGB) study . [Abstract] Blood 110 (11): A-104, 2007.

Marcucci G, Maharry K, Whitman SP, et al.: High expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk-based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol 25 (22): 3337-43, 2007.[PUBMED Abstract]

Whitman SP, Ruppert AS, Marcucci G, et al.: Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study. Blood 109 (12): 5164-7, 2007.[PUBMED Abstract]

Paschka P, Marcucci G, Ruppert AS, et al.: Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol 24 (24): 3904-11, 2006.[PUBMED Abstract]

Kolitz JE, George SL, Baer MR, et al.: P-glycoprotein (Pgp) modulation in untreated acute myeloid leukemia (AML): Cancer and Leukemia Group B (CALGB) trials in younger and older adults. Ann Hematol 83 (Suppl 1): S103-4, 2004.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Cancer and Leukemia Group B

Jonathan Kolitz, MD, Protocol chair		Ph: 516-562-8970 Email: kolitz@nshs.edu
Richard Larson, MD, Protocol co-chair		Ph: 773-702-6783; 888-824-0200

Registry Information
Official Title		Phase III Randomized Study Of Induction Chemotherapy With or Without MDR-Modulation With PSC-833 (NSC #648265, IND #41121) Followed By Cytogenetic Risk-Adapted Intensification Therapy Followed By Immunotherapy With RIL-2 (NSC #373364, IND #1969) vs. Observation In Previously Untreated Patients With AML < 60 Years
Trial Start Date		2000-11-15
Registered in ClinicalTrials.gov		NCT00006363
Date Submitted to PDQ		2000-08-16
Information Last Verified		2006-04-14
NCI Grant/Contract Number		CA31946

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