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

Alternate Title

Stem Cell Transplantation Compared With Standard Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia in First Remission

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Completed	15 to 65	NCI	ECOG-2993 MRC-LEUK-UKALL-XII, EST-4491, INT-0132, NCT00002514

Objectives

1. Compare the duration of complete remission (CR) and survival in patients with acute lymphoblastic leukemia in first remission treated with allogeneic or autologous stem cell transplantation (SCT) vs conventional consolidation and maintenance chemotherapy.
2. Compare the overall treatment outcomes in patients treated with these regimens.
3. Determine the effect of imatinib mesylate given after induction therapy in Philadelphia (Ph) chromosome-positive patients in CR.
4. Determine the benefit of allogeneic or autologous SCT after imatinib mesylate in Ph chromosome-positive patients.
5. Determine the benefit of additional imatinib mesylate administered after allogeneic or autologous SCT in Ph chromosome-positive patients.
6. Determine the minimal residual disease in Ph chromosome-positive patients before and after treatment with imatinib mesylate.
7. Determine the clinical resistance to imatinib mesylate caused by BCR-ABL gene amplification or mutation in Ph chromosome-positive patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed acute lymphoblastic leukemia (ALL)
  • More than 25% lymphoblasts in bone marrow
    • Patients with myeloid antigen expression AND unequivocal lymphoid immunophenotype are eligible
• Philadelphia (Ph) chromosome status determined by cytogenetics, fluorescence in situ hybridization (FISH), and/or RNA analysis
  • Patients determined to be Ph chromosome negative by cytogenetics, but positive for BCR-ABL by FISH or polymerase chain reaction are considered Ph chromosome positive
  • Patients with Ph chromosome-positive disease may be up to age 65
• No myelodysplasia or other antecedent hematologic disorder
• Patients age 50 and under must be HLA typed during induction therapy of study treatment OR provide a written explanation for not undergoing HLA typing
  • A and B typing required
  • C and DR typing done if feasible
• Allogeneic stem cell transplantation patients must meet the following criteria:
  • Appropriate HLA histocompatible donor available
    • Ph chromosome-negative patients must have HLA identical sibling
    • Ph chromosome-positive patients must have HLA identical, HLA-matched unrelated, or haploidentical related donor
• Postinduction therapy:
  • CSF negative for leukemia
  • No occult or overt leukemic meningitis
  • Documented complete remission

Prior/Concurrent Therapy:

Biologic therapy:

• No concurrent umbilical cord allogeneic transplantation

Chemotherapy:

• Not specified

Endocrine therapy:

• Prior corticosteroids for ALL allowed

Radiotherapy:

• Not specified

Surgery:

• Not specified

Other:

• Induction and postinduction therapy:
  • No other prior therapy for ALL
• Postinduction therapy:
  • No concurrent antibiotics

Patient Characteristics:

Age:

• 15 to 65

Performance status:

• Induction therapy:
  • Not specified
• Postinduction therapy:
  • 0-1

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Induction therapy:
  • Direct bilirubin ≤ 2.0 mg/dL
• Postinduction therapy:
  • Direct bilirubin < 2.0 mg/dL
  • SGPT or SGOT < 3 times normal

Renal:

• Induction therapy:
  • Creatinine < 2 mg/dL
• Postinduction therapy:
  • Creatinine ≤ 2 mg/dL
  • Creatinine clearance ≥ 60 mL/min

Cardiovascular:

• Induction and postinduction therapy:
  • No significant cardiac disease requiring digoxin and/or diuretics
  • No major ventricular dysrhythmia requiring medication
  • No ischemic heart disease requiring medication
• Postinduction therapy:
  • Cardiac ejection fraction ≥ 50% for patients under consideration for transplantation

Pulmonary:

• Induction therapy:
  • Not specified
• Postinduction therapy:
  • FEV₁ ≥ 60% of predicted for patients under consideration for transplantation
  • DLCO ≥ 50% of predicted for patients under consideration for transplantation

Other:

• Induction and postinduction therapy:
  • HIV negative
  • No concurrent organ damage or other medical problem (e.g., psychiatric disorder or drug abuse) that would preclude study therapy
  • Not pregnant
• Postinduction therapy:
  • No persistent infection

Expected Enrollment

Approximately 40 patients per year will be accrued for group I (Philadelphia [Ph] chromosome-positive patients) of this study. Approximately 550 patients will be accrued for group II (Ph chromosome-negative patients) of this study within 5 years.

Outcomes

Complete remission

Outline

This is a randomized, multicenter study. Patients are stratified according to age (50 and under vs over 50), time to achieve complete remission (CR) (4 weeks or less vs more than 4 weeks), and Philadelphia (Ph) chromosome status (positive vs negative).

• First induction therapy: Patients receive daunorubicin (DNR) IV over 15-30 minutes and vincristine (VCR) IV over 3-5 minutes on days 1, 8, 15, and 22; oral prednisone (PRED) once daily on days 1-28; and asparaginase (ASP) IV over 30 minutes or intramuscularly on days 17-28. Patients with CNS leukemia at presentation also receive methotrexate (MTX) intrathecally (IT) via an Ommaya reservoir weekly until the CSF is clear. Patients without CNS leukemia at presentation receive MTX IT on day 23 only.
• Second induction therapy: Beginning immediately after first induction therapy, patients receive cyclophosphamide (CTX) IV over 30 minutes on days 1, 15, and 29; cytarabine (ARA-C) IV over 30 minutes on days 1-4, 8-11, 15-18, and 22-25; and oral mercaptopurine (MP) once daily on days 1-28. Patients with CNS leukemia at presentation also undergo concurrent craniospinal irradiation. Patients without CNS leukemia at presentation receive MTX IT on days 1, 8, 15, and 22. Patients with Ph chromosome-positive status receive oral imatinib mesylate once daily for at least 28 days (days 1-28).

  Patients with Ph chromosome-positive status and CR after second induction therapy proceed to group I for autologous or allogeneic stem cell transplantation (SCT). Patients with Ph chromosome-negative status and CR after second induction therapy proceed to group II.

• Group I (Ph chromosome-positive patients):
  • Autologous SCT: Patients receive high-dose consolidation/mobilization chemotherapy comprising ARA-C IV over 3 hours on days 1-3 and mitoxantrone IV immediately after ARA-C administration on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 5 and continuing until blood counts recover.

    Patients then undergo peripheral blood stem cell collection or bone marrow harvesting.

    Patients receive preparative therapy comprising total body irradiation twice daily (5-10 hours apart) on days -6 to -4 and high-dose etoposide (VP-16) IV over 4 hours on day -3. Male patients also undergo radiotherapy boost to the testes on day -6.

    Patients undergo autologous SCT on day 0 and receive sargramostim (GM-CSF) SC once daily beginning 6 hours after the completion of SCT and continuing until blood counts recover.

  • Allogeneic SCT: Patients receive the preparative regimen as in autologous SCT and then undergo allogeneic SCT on day 0. Patients receive GM-CSF as in autologous SCT.
  • Post-SCT imatinib mesylate therapy: After recovery from autologous or allogeneic SCT, patients receive oral imatinib mesylate once daily. Imatinib mesylate therapy continues in the absence of disease progression or unacceptable toxicity.

• Group II (Ph chromosome-negative patients):
  • Intensification therapy: Beginning 4 weeks after the completion of the second induction therapy, patients receive high-dose MTX IV over 2 hours on days 1, 8, and 22; leucovorin calcium IV every 6 hours for 4 doses and then orally every 6 hours for 12 doses beginning 22-24 hours after each MTX infusion; and ASP IV over 30 minutes on days 2, 9, and 23.

    Patients who are ≤ 50 years of age with a histocompatible donor proceed to allogeneic SCT and undergo allogeneic SCT as in group I. Patients who are ≤ 50 years of age without an appropriate donor are randomized to 1 of 2 treatment arms.

  • Arm I (conventional consolidation/maintenance therapy):
    • Conventional consolidation therapy: During course 1, patients receive ARA-C IV over 30 minutes and VP-16 IV over 1 hour on days 1-5; VCR IV on days 1, 8, 15, and 22; and oral dexamethasone on days 1-28. During course 2 (which begins 4 weeks after initiation of course 1 or when blood counts recover), patients receive ARA-C and VP-16 as in course 1. During course 3 (which begins 4 weeks after initiation of course 2 or when blood counts recover), patients receive DNR IV on days 1, 8, 15, and 22; CTX IV over 30 minutes on day 29; ARA-C IV over 30 minutes on days 31-34 and 38-41; and oral thioguanine on days 29-42. During course 4 (which begins 8 weeks after initiation of course 3 or when blood counts recover), patients receive treatment as in course 2.
    • Maintenance therapy: Beginning 4 weeks after initiation of course 4 of consolidation therapy or when blood counts recover, patients receive oral MP daily; MTX orally or IV once weekly; VCR IV once every 12 weeks; and oral PRED for 5 days every 12 weeks. Maintenance therapy continues for 2.5 years after initiation of intensification therapy.

  • Arm II (autologous SCT): Patients undergo autologous SCT as in group I with the exception of high-dose consolidation/mobilization chemotherapy.

Patients are followed every 6 months for 2 years.

Fielding AK, Rowe JM, Richards SM, et al.: Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood 113 (19): 4489-96, 2009.[PUBMED Abstract]

Mansour MR, Sulis ML, Duke V, et al.: Prognostic implications of NOTCH1 and FBXW7 mutations in adults with T-cell acute lymphoblastic leukemia treated on the MRC UKALLXII/ECOG E2993 protocol. J Clin Oncol 27 (26): 4352-6, 2009.[PUBMED Abstract]

Marks DI, Paietta EM, Moorman AV, et al.: T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics and outcome from the large randomised prospective trial (UKALL XII/ECOG 2993). Blood : , 2009.[PUBMED Abstract]

Patel B, Rai L, Buck G, et al.: Minimal residual disease is a significant predictor of treatment failure in non T-lineage adult acute lymphoblastic leukaemia: final results of the international trial UKALL XII/ECOG2993. Br J Haematol : , 2009.[PUBMED Abstract]

Goldstone AH, Richards SM, Lazarus HM, et al.: In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 111 (4): 1827-33, 2008.[PUBMED Abstract]

Paietta E, Li X, Richards S, et al.: Implications for the use of monoclonal antibodies in future adult ALL trials: analysis of antigen expression in 505 B-lineage (B-Lin) ALL patients (pts) on the MRC UKALLXII/ECOG2993 Intergroup trial. [Abstract] Blood 112 (11): A-1907, 2008.

Patel B, Richards SM, Rowe JM, et al.: High incidence of avascular necrosis in adolescents with acute lymphoblastic leukaemia: a UKALL XII analysis. Leukemia 22 (2): 308-12, 2008.[PUBMED Abstract]

Rowe JM, Buck G, Moorman AV, et al.: Standard consolidation/maintenance chemotherapy is consistently superior to a single autologous transplant for adult patients with acute lymphoblastic leukemia: results of the international ALL trial (MRC UKALL XII/ECOG E2993). [Abstract] Blood 112 (11): A-3314, 2008.

Fielding AK, Richards SM, Chopra R, et al.: Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood 109 (3): 944-50, 2007.[PUBMED Abstract]

Fielding AK, Richards SM, Lazarus HM, et al.: Does imatinib change the outcome in Philapdelphia chromosome positive acute lymphoblastic leukaemia in adults? Data from the UKALLXII/ECOG2993 study. [Abstract] Blood 110 (11): A-8, 2007.

Juric D, Lacayo NJ, Ramsey MC, et al.: Differential gene expression patterns and interaction networks in BCR-ABL-positive and -negative adult acute lymphoblastic leukemias. J Clin Oncol 25 (11): 1341-9, 2007.[PUBMED Abstract]

Moorman AV, Harrison CJ, Buck GA, et al.: Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 109 (8): 3189-97, 2007.[PUBMED Abstract]

Juric D, Lacayo NJ, Ramsey MC, et al.: Differential gene expression patterns and interaction networks in BCR/ABL positive and negative adult acute lymphoblastic leukemias. [Abstract] Blood 108 (11): A-1836, 2006.

Lazarus HM, Richards SM, Chopra R, et al.: Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis: results from the international ALL trial MRC UKALL XII/ECOG E2993. Blood 108 (2): 465-72, 2006.[PUBMED Abstract]

Rowe JM, Buck G, Fielding A, et al.: In adults with standard-risk acute lymphoblastic leukemia (ALL) the greatest benefit is achieved from an allogeneic transplant in first complete remission (CR) and an autologous transplant is less effective than conventional consolidation/maintenance chemotherapy: final results of the international ALL trial (MRC UKALL XII/ECOG E2993). [Abstract] Blood 108 (11): A-2, 2006.

Moorman AV, Harrison CJ, Richards SM, et al.: Karyotype is an independent prognostic factor in adult acute lymphoblastic leukaemia (ALL): analysis of cytogenetic data from 1,235 patients on the Medical Research Council (MRC) UKALLXII /Eastern Cooperative Oncology Group (ECOG) 2993 trial. [Abstract] Blood 106 (11): A-331, 2005.

Rowe JM, Buck G, Burnett AK, et al.: Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 106 (12): 3760-7, 2005.[PUBMED Abstract]

Goldstone AH, Lazarus HJ, Richards SM, et al.: The outcome of 551 1st CR transplants in adult ALL from the UKALL XII/ECOG 2993 study. [Abstract] Blood 104 (11): A-615, 2004.

Lazarus HM, Richards SM, Chopra R, et al.: Adult patients with acute lymphoblastic leukemia (ALL) and central nervous system (CNS) leukemia at diagnosis may attain durable complete remissions (CR). Results from the International ALL Trial (MRC UKALL-XII/ECOG E2993) . [Abstract] Blood 104 (11): A-4484, 2004.

Goldstone AH, Chopra R, Buck G, et al.: The outcome of 267 Philadelphia positive adults in the international UKALL12/ECOG E 2993 study. Final analysis and the role of allogeneic transplant in those under 50 years. [Abstract] Blood 102 (11 Pt 1): A-268, 2003.

Rowe JM, Buck G, Burnett AK, et al.: Induction therapy for adults with acute lymphoblastic leukemia (ALL): results of nearly 1,400 patients from the international ALL trial (MRC UKALL XII / ECOG E2993). [Abstract] Blood 102 (11 Pt 1): A-785, 2003.

Ferrando AA, Neuberg D, Dodge RK, et al.: Adult T-cell ALL patients whose lymphoblasts express the HOX11 oncogene have an excellent prognosis when treated with chemotherapy and are not candidates for allogeneic bone marrow transplantaton in first remission. [Abstract] Blood 100 (11 pt 1): A-578, 2002.

Paietta E, Kim H, Racevskis J, et al.: Immunophenotypic characteristics, but not age or secondary cytogenetic changes, affect response and survival of BCR/ABL positive adult acute lymphoblastic leukemia (ALL): ECOG/MRC Intergroup trial, E2993. [Abstract] Blood 100 (11 pt 1): A-2990, 2002.

Goldstone AH, Prentice HG, Durrant J, et al.: Allogeneic transplant (related or unrelated donor) Is the preferred treatment for adult Philadelphia chromosome positive (Ph+) acute lymphoblastic leukaemia (ALL). Results from the international ALL trial (MRC UKALLXII/ECOG E2993). [Abstract] Blood 98 (11 Pt 1): A-3556, 2001.

Paietta E, Kim H, Rowe JM, et al.: Prognostic significance of immunophenotyping and cytogenetics in adult acute lymphoblastic leukemia (ALL): interim analysis of ECOG/MRC phase III intergroup trial, E2993. [Abstract] Blood 98 (11 Pt 1): A-3494, 2001.

Rowe JM, Richards SM, Burnett AK, et al.: Favorable results of allogeneic bone marrow transplantation (BMT) for adults with Philadelphia (Ph)-chromosome-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR): results from the international ALL trial (MRC UKALL XII/ECOG E2993). [Abstract] Blood 98 (11 Pt 1): A-2009, 2001.

Goldstone AH, Richards S, Wiernik PH, et al.: Philadelphia chromosome positive patients with adult acute lymphoblastic leukemia (ALL). Early results from the international ALL trial. [Abstract] Blood 94 (suppl 1): 3071a, 1999.

Rowe JM, Richards S, Wiernik PH, et al.: Allogenic bone marrow transplantation (BMT) for adults with acute lymphoblastic leukemia (ALL) in first complete remission (CR): early results from the international ALL trial. [Abstract] Blood 94 (suppl 1): 732a, 1999.

Paietta E, Racevskis J, Neuberg D, et al.: Expression of CD25 (interleukin-2 receptor alpha chain) in adult acute lymphoblastic leukemia predicts for the presence of BCR/ABL fusion transcripts: results of a preliminary laboratory analysis of ECOG/MRC Intergroup Study E2993. Eastern Cooperative Oncology Group/Medical Research Council. Leukemia 11 (11): 1887-90, 1997.[PUBMED Abstract]

Goldstone AH: Transplants in Adult ALL--? Allo for everyone. Biol Blood Marrow Transplant 15 (1 Suppl): 7-10, 2008.[PUBMED Abstract]

Ramanujachar R, Richards S, Hann I, et al.: Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer 48 (3): 254-61, 2007.[PUBMED Abstract]

Paietta E, Ferrando AA, Neuberg D, et al.: Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. Blood 104 (2): 558-60, 2004.[PUBMED Abstract]

Ferrando AA, Neuberg D, Dodge RK, et al.: Adult T-cell ALL patients whose lymphoblasts express the HOX11 oncogene have an excellent prognosis when treated with chemotherapy and are not candidates for allogeneic bone marrow transplantaton in first remission. [Abstract] Blood 100 (11 pt 1): A-578, 2002.

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Jacob Rowe, MD, Protocol chair		Ph: 972-4-854-2541 Email: rowe@rambam.health.gov.il
Mark Litzow, MD, Protocol co-chair		Ph: 507-284-2511 Email: litzow.mark@mayo.edu

Medical Research Council's Working Party on Leukemia in Adults and Children

Antony H. Goldstone, FRCP, Protocol chair		Ph: 44-20-7380-9678 Email: anthony.golstone@uclh.org

Registry Information
Official Title		Phase III Randomized Trial of Autologous and Allogeneic Stem Cell Transplantation Versus Intensive Conventional Chemotherapy in Acute Lymphoblastic Leukemia in First Remission
Trial Start Date		1993-04-07
Registered in ClinicalTrials.gov		NCT00002514
Date Submitted to PDQ		1996-07-17
Information Last Verified		2007-08-09
NCI Grant/Contract Number		CA21115

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