RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with allogeneic or autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. It is not yet known whether stem cell transplantation is more effective than standard chemotherapy in treating acute lymphoblastic leukemia.

PURPOSE: This randomized phase III trial is studying how well stem cell transplantation works compared to standard combination chemotherapy in treating patients with acute lymphoblastic leukemia in first remission.

OBJECTIVES:

• 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.
• Compare the overall treatment outcomes in patients treated with these regimens.
• Determine the effect of imatinib mesylate given after induction therapy in Philadelphia (Ph) chromosome-positive patients in CR.
• Determine the benefit of allogeneic or autologous SCT after imatinib mesylate in Ph chromosome-positive patients.
• Determine the benefit of additional imatinib mesylate administered after allogeneic or autologous SCT in Ph chromosome-positive patients.
• Determine the minimal residual disease in Ph chromosome-positive patients before and after treatment with imatinib mesylate.
• Determine the clinical resistance to imatinib mesylate caused by BCR-ABL gene amplification or mutation in Ph chromosome-positive patients.

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.

PROJECTED ACCRUAL: 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.

• Biological: filgrastim
• Biological: sargramostim
• Drug: asparaginase
• Drug: cyclophosphamide
• Drug: cytarabine
• Drug: daunorubicin hydrochloride
• Drug: dexamethasone
• Drug: etoposide
• Drug: imatinib mesylate
• Drug: leucovorin calcium
• Drug: mercaptopurine
• Drug: methotrexate
• Drug: mitoxantrone hydrochloride
• Drug: prednisone
• Drug: thioguanine
• Drug: vincristine sulfate
• Procedure: allogeneic bone marrow transplantation
• Procedure: autologous bone marrow transplantation
• Procedure: peripheral blood stem cell transplantation
• Radiation: radiation therapy

• Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia-chromosome positive acute lymphoblastic leukaemia confirms superiority of allogeneic transplant over chemotherapy in the pre-imatinib era: Results from the international ALL trial MRC UKALLXII/ECOG2993. Blood. 2009 Feb 24; [Epub ahead of print]
• Mansour MR, Sulis ML, Duke V, Foroni L, Jenkinson S, Koo K, Allen CG, Gale RE, Buck G, Richards S, Paietta E, Rowe JM, Tallman MS, Goldstone AH, Ferrando AA, Linch DC. 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. 2009 Jul 27; [Epub ahead of print]
• Marks DI, Paietta EM, Moorman AV, Richards SM, Buck G, Dewald G, Ferrando A, Fielding AK, Goldstone AH, Ketterling RP, Litzow MR, Luger SM, McMillan AK, Mansour M, Rowe JM, Tallman MS, Lazarus HM. 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 Oct 14; [Epub ahead of print]
• Patel B, Rai L, Buck G, Richards SM, Mortuza Y, Mitchell W, Gerrard G, Moorman AV, Duke V, Hoffbrand AV, Fielding AK, Goldstone AH, Foroni L. 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 Oct 26; [Epub ahead of print]
• Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia (ALL) the greatest benefit is achieved from a matched sibling allogeneic transplant in first complete remission (CR) and an autologous transplant is less effective than conventional consolidation/maintenance chemotherapy in All patients : final results of the international ALL trial (MRC UKALL XII/ ECOG E2993). Blood. 2007 Nov 29; [Epub ahead of print]
• Patel B, Richards SM, Rowe JM, Goldstone AH, Fielding AK. High incidence of avascular necrosis in adolescents with acute lymphoblastic leukaemia: a UKALL XII analysis. Leukemia. 2008 Feb;22(2):308-12. Epub 2007 Nov 8.
• Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, Durrant IJ, Luger SM, Marks DI, Franklin IM, McMillan AK, Tallman MS, Rowe JM, Goldstone AH; Medical Research Council of the United Kingdom Adult ALL Working Party; Eastern Cooperative Oncology Group. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007 Feb 1;109(3):944-50. Epub 2006 Oct 10.
• Juric D, Lacayo NJ, Ramsey MC, Racevskis J, Wiernik PH, Rowe JM, Goldstone AH, O'dwyer PJ, Paietta E, Sikic BI. Differential Gene Expression Patterns and Interaction Networks in BCR-ABL-Positive and -Negative Adult Acute Lymphoblastic Leukemias. J Clin Oncol. 2007 Mar 5; [Epub ahead of print]
• Moorman AV, Harrison CJ, Buck GA, Richards SM, Secker-Walker LM, Martineau M, Vance GH, Cherry AM, Higgins RR, Fielding AK, Foroni L, Paietta E, Tallman MS, Litzow MR, Wiernik PH, Rowe JM, Goldstone AH, Dewald GW. 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. 2006 Dec 14; [Epub ahead of print]
• Lazarus HM, Richards SM, Chopra R, Litzow MR, Burnett AK, Wiernik PH, Franklin IM, Tallman MS, Cook L, Buck G, Durrant IJ, Rowe JM, Goldstone AH. Central nervous system involvement in adult acute lymphoblastic leukemia at diagnosis. Results from the International ALL Trial MRC UKALL-XII/ECOG E2993. Blood. 2006 Mar 23; [Epub ahead of print]
• Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH. Induction therapy for adults with acute lymphoblastic leukemia (ALL): results of over 1,500 patients from the international ALL Trial: MRC UKALL XII / ECOG E2993. Blood. 2005 Aug 16; [Epub ahead of print]
• Paietta E, Racevskis J, Neuberg D, Rowe JM, Goldstone AH, Wiernik PH. 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. 1997 Nov;11(11):1887-90.
• Goldstone AH. Transplants in Adult ALL--? Allo for everyone. Biol Blood Marrow Transplant. 2008 Jan;15(1 Suppl):7-10. Review.
• Ramanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, Vora A, Rowe J, Webb D. Adolescents with acute lymphoblastic leukaemia: Outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer. 2006 Jan 18; [Epub ahead of print]
• Paietta E, Ferrando AA, Neuberg D, Bennett JM, Racevskis J, Lazarus H, Dewald G, Rowe JM, Wiernik PH, Tallman MS, Look AT. Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. Blood. 2004 Jul 15;104(2):558-60. Epub 2004 Mar 25.

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

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:

  • FEV_1 ≥ 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

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

• National Cancer Institute (NCI)
• Medical Research Council