Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

Risk-Adjusted Combination Chemotherapy in Treating Young Patients With Acute Lymphoblastic Leukemia

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III	Treatment	Active	18 and under	Other	MOTOL-ALL-IC-BFM-2002 ALL-IC-BFM-2002, EU-20871, NCT00764907

Objectives

1. To test in a randomized way the type and intensity of reintensification therapy for pediatric patients with acute lymphoblastic leukemia in each risk group: standard-risk (SR), intermediate-risk (IR), and high-risk (HR) group.
2. To compare two shorter elements of reintensification (protocol III x 2 courses) to one (protocol II x 1 course) in terms of effectiveness when cumulative dose of most drugs are the same in both regimen in patients in the standard-risk group.
3. To determine if the increased risk of failure in patients in the intermediate-risk group can be curtailed by a third reintensification element (protocol III x 3 courses vs protocol II x 1 course).
4. To determine if the three reintensification elements (protocol III x 3 courses) achieve the same or better results in high-risk group patients, as compared with current applied HR approach in Berlin-Frankfurt-Münster Group (BFM) or Italian Association of Pediatric Hematology and Oncology (AIEOP).

Entry Criteria

Disease Characteristics:

• Cytologically proven acute lymphoblastic leukemia (ALL)



• No relapse of a previously unrecognized ALL



• Patients must meet one of the following risk criteria:
  • Standard-risk (SR) group meeting all of the following criteria:
    • Blasts < 1,000/μL in peripheral blood (PB) on day 8
    • Aged 1 to < 6 years
    • Initial WBC < 20,000/μL
    • M1 (5%) or M2 (≥ 5% to < 25%) blasts in bone marrow on day 15
    • M1 marrow on day 33
  • Intermediate-risk (IR) group meeting all of the following criteria:
    • Aged < 1 or ≥ 6 years and/or WBC ≥ 20,000/μL
    • Blasts < 1,000/μL in PB on day 8
    • M1 or M2 marrow on day 15
    • M3 (≥ 25%) marrow on day 15 OR meets SR criteria but M3 marrow on day 15 and M1 marrow on day 33
  • High-risk (HR) group meeting ≥ 1 of the following criteria:
    • Meets IR criteria and M3 marrow on day 15 (not SR and M3 on day 15)
    • Blasts ≥ 1,000/μL in PB on day 8
    • M2 or M3 marrow on day 33
    • Translocation t(9;22) [BCR/ABL+] (Philadelphia chromosome-positive) or t(4;11) [MLL/AF4+]



• No secondary ALL

Prior/Concurrent Therapy:

• No steroids or cytostatic drugs within four weeks prior to start of study therapy

Patient Characteristics:

• No Down syndrome
• No other major disease that prohibits study treatment (e.g., severe congenital heart disease)
• Not requiring significant therapy modification owing to study therapy-associated complications
• No complications due to other interventions
• No one with missing data that are needed for the differential diagnosis, or for selection of the proper therapy arm

Expected Enrollment

Outcomes

Disease-free survival
Event-free survival
Overall survival

Outline

This is a partially randomized, multicenter study. Patients are stratified according to risk group (standard risk [SR] vs intermediate risk [IR] vs high risk [HR]). Patients are randomized in reinduction part of the treatment.

• Induction therapy:
  • Protocol I' (SR B-cell precursor [BCP] ALL ): Patients receive methotrexate intrathecally (IT) on days 1, 12, and 33 (and possibly on days 18 and 27); prednisone or prednisolone orally or IV on days 1-28 followed by a taper; vincristine sulfate IV on days 1, 8, 15, 22, and 29; daunorubicin hydrochloride IV over 1 hour on days 8 and 15; and asparaginase IV over 1 hour on days 12, 15, 18, 21, 24, 27, 30, and 33. Patients then receive cyclophosphamide IV over 1 hour on days 36 and 64; oral mercaptopurine once daily on days 36-63; cytarabine IV continuously on days 38-41, 45-48, 52-55, and 59-62; and methotrexate IT on days 45 and 59.
  
  
  
  • Protocol I (SR T-cell ALL, IR, or HR): Patients receive therapy as in Protocol I' except that they also receive daunorubicin hydrochloride on days 22 and 29.
  
  
  

  Approximately 2 weeks after completion of induction therapy, patients proceed to consolidation therapy.




• Consolidation: Patients who have achieved complete cytomorphologic remission proceed to protocol mM or protocol M. Patients in HR group proceed to 3-block consolidation regimen.
  • Protocol mM (BCP-ALL) (SR or IR): Patients receive oral mercaptopurine once daily on days 1-56; medium-dose methotrexate IV over 24 hours and methotrexate IT on days 8, 22, 36, and 50; and leucovorin calcium IV every 6 hours on days 9, 23, 37, and 51.
  
  
  
  • Protocol M (T-cell ALL) (SR or IR): Patients receive mercaptopurine, methotrexate IT, and leucovorin calcium as in protocol mM, and they also receive high-dose (HD) methotrexate IV over 24 hours on days 8, 22, 36, and 50.
  
  
  
  • 3-block consolidation regimen (HR): Patients receive 3 regimen blocks with 2 weeks between blocks. Treatment continues in the absence of unacceptable toxicity.
    • Block HR-1': Patients receive dexamethasone orally or IV 3 times daily on days 1-5; vincristine sulfate IV on days 1-6; HD methotrexate IV over 24 hours on day 1; leucovorin calcium IV every 6 hours, beginning 42 hours after the start of HD methotrexate, for 3 doses; cyclophosphamide IV over 1 hour, every 12 hours, on days 2-4; HD cytarabine IV over 3 hours, every 12 hours, on day 5 (2 doses); asparaginase IV over 2 hours on days 6 and 11; and triple intrathecal therapy (TIT) comprising methotrexate, cytarabine, and prednisone, 3 times on day 1.
    
    
    
    • Block HR-2': Patients receive dexamethasone, HD methotrexate, leucovorin calcium, and asparaginase as in block HR-1'. Patients receive TIT once on day 1 (CNS-negative patients) or twice on days 1 and 5 (CNS-positive patients). Patients also receive vindesine IV on days 1 and 6; ifosfamide IV over 1 hour, every 12 hours, on days 2-4; and daunorubicin hydrochloride IV over 24 hours on day 5.
    
    
    
    • Block HR-3': Patients receive dexamethasone and asparaginase as in block HR-1'; TIT 3 times on day 5; HD cytarabine IV over 3 hours, every 12 hours, on days 1 and 2; and etoposide IV over 1 hour, every 12 hours, on days 3-5.
    
    
    

    Approximately 2 weeks after completion of consolidation therapy, patients proceed to reinduction therapy.

  
  
  



• Reinduction (randomized): Patients in continuous complete remission proceed to protocol II or III. Patients from SR and IR group are randomized to arms I and II; patients from HR group are randomized to arms II and III.
  • Arm I (protocol II x 1 course) (SR-1 or IR-1): Patients receive dexamethasone orally or IV on days 1-21 followed by a taper; vincristine sulfate IV and doxorubicin hydrochloride IV over 1 hour on days 8, 15, 22, and 29; asparaginase IV over 1 hour on days 8, 11, 15, and 18; and methotrexate IT on days 1 and 18. Patients then receive cyclophosphamide IV over 1 hour on day 36; oral thioguanine once daily on days 36-49; cytarabine IV continuously on days 38-41 and 45-48; and methotrexate IT on days 38 and 45.
  
  
  
  • Arm II (protocol III x 2 or 3 courses and interim maintenance therapy [IMT]) (SR-2, IR-2, or HR-1): Patients receive dexamethasone orally or IV three times daily on days 1-14 followed by a taper; vincristine sulfate IV and doxorubicin hydrochloride IV over 1 hour on days 1 and 8; and asparaginase IV over 1 hour on days 1, 4, 8, and 11. Patients then receive cyclophosphamide IV over 1 hour on day 15; oral thioguanine once daily on days 15-28; cytarabine IV continuously on days 17-20 and 24-27; and methotrexate IT on days 17 and 21 (and day 1 if there is initial CNS involvement). Approximately 1 week after completion of protocol III (course 1), patients receive IMT for 10 weeks (SR group) or 4 weeks (IR and HR groups) as described below. Approximately 1 week after completion of IMT, patients receive protocol III as above (course 2). Approximately 1 week after completion of protocol III (course 2), patients in IR and HR group receive IMT for another 4 weeks followed by another course of protocol III (course 3) 1 week later.
    • IMT: Patients receive oral methotrexate once weekly and oral mercaptopurine daily.
  
  
  
  • Arm III (HR-2): Patients receive 1 of the following regimens according to local practices:
    • Regimen HR-2A: Patients receive protocol II as in arm I, rest 1 week and receive IMT for 4 weeks. Approximately 1 week later, patients receive another course of protocol II.
    
    
    
    • Regimen HR-2B: Patients receive treatment as in 3-block consolidation regimen with 3 weeks between each block. Approximately 3 weeks later, patients receive protocol II as in arm I.
    
    
    
  
  
  
  • Cranial radiotherapy (CRT) during reinduction: CNS positive patients (CNS status 3) receive CRT after completion of protocol II (SR, IR, HR-2B) or during the first 1.5-2.5 weeks of IMT (SR, IR, HR-2A). SR and IR patients with T-cell ALL and HR patients receive prophylactic CRT at these same time periods.
  
  
  

  Beginning 2 weeks after completion of reinduction (some patients in HR group also undergo allogeneic stem cell transplantation, as described below), patients proceed to maintenance therapy.




• Maintenance therapy (MT): Patients receive oral mercaptopurine once daily and methotrexate IV once weekly. Each patient subgroup (except HR patients undergoing transplantation) receives MT for a period that brings the total weeks of treatment to 104 weeks, as follows:
  • SR: Patients receive MT for 74 weeks (SR-1) or 61 weeks (SR-2).
  
  
  
  • IR: Patients receive MT for 74 weeks (IR-1) or 57 weeks (IR-2).
  
  
  
  • HR: Patients receive MT for 58 weeks (HR-1), 62 weeks (HR-2A), or 63 weeks (HR-2B).
  
  
  

  Patients with BCP-ALL and in group SR-1 or IR-1 also receive methotrexate IT once in weeks 4, 8, 12, and 16 of MT. Patients with BCP-ALL and in group SR-2 receive methotrexate IT in weeks 4 and 8 of MT.




• Allogeneic stem cell transplantation (ASCT): Some patients in HR group may undergo ASCT (usually bone marrow, but may be peripheral blood or umbilical cord stem cells), (at the time of reinduction therapy) beginning 3-4 weeks after the completion of second protocol III (HR-1), the first protocol II (HR-2A), or completion of the 3-block consolidation regimen (HR-2B).
  • Under 2 years old: Patients receive oral busulfan every 6 hours on days -8 to -5, etoposide IV over 4 hours on day -4, and cyclophosphamide IV over 1 hour on days -3 and -2, and then undergo ASCT on day 0.
  
  
  
  • At least 2 years old: Patients undergo total body irradiation twice daily on days -6 to -4 and receive etoposide IV over 4 hours on day -3, and then undergo ASCT on day 0. Fractionated local radiotherapy, if required, is administered on days -14 to -7.
  
  
  

Trial Contact Information

Trial Lead Organizations

University Hospital Motol

Jan Stary, MD, Principal investigator		Ph: 420-2-2443-6401 Email: jan.stary@lfmotol.cuni.cz

Czech Republic
	Prague
	University Hospital Motol
		Jan Stary, MD	Ph:  420-2-2443-6401
			Email: jan.stary@lfmotol.cuni.cz

Registry Information
Official Title		A Randomized Trial of the I-BFM-SG for the Management of Childhood non-B Acute Lymphoblastic Leukemia
Trial Start Date		2002-11-01
Trial Completion Date		2007-10-31 (estimated)
Registered in ClinicalTrials.gov		NCT00764907
Date Submitted to PDQ		2008-09-24
Information Last Verified		2008-09-29