Phase III Randomized Study of Dexamethasone Versus Prednisone During Induction and High-Dose Methotrexate With Leucovorin Rescue Versus Escalating-Dose Methotrexate Without Leucovorin Rescue During Interim Maintenance I in Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia.

Dexamethasone Compared With Prednisone During Induction Therapy and Methotrexate With or Without Leucovorin During Maintenance Therapy in Treating Patients With Newly Diagnosed High-Risk Acute Lymphoblastic Leukemia

Note: this outline was patched together from the NCI online protocol and input from parents of kids with ALL. It is summarized here for our convenience, so that we can quickly compare our protocols. We do not guarantee the accuracy of this outline - it is not an official document. You can contact your child's oncologist and ask for the complete protocol document if you are interested in the details of your child's protocol.

This trial on the cancer.gov site.

Classification of newly diagnosed leukemia

All newly diagnosed ALL patients are enrolled in COG AALL03B1, Classification of Acute Lymphoblastic Leukemia.

At diagnosis of ALL, the oncologists at the local hospital determine an initial risk classification as follows:

• standard risk ALL, or SR ALL: B-precursor and WBC less than 50,000/microliter and age 1-9 years
• higher risk ALL, or HR ALL: B-precursor and WBC greater than or equal to 50,000/microliter or age greater or equal to 10 years (note that they go all the way up to 30 years of age)
• infant ALL: less than 1 year is classified separately
• T-cell

(This method of risk classification is known as "NCI/Rome criteria".)

At diagnosis samples of blood/bone marrow aspirate/CFS are taken and studied for cytogenetic/immunophenotype characteristics (see later in the protocol how the results of these tests might effect the treatment.)

HR ALL is treated on AALL0232, as outlined below. SR ALL is treated on AALL0331. The protocols for infant, T-cell, and very high risk will be added to this site when they are available.

AALL0232

Briefly, the four arms are:

• DC: dexamethasone during induction therapy and escalating methotrexate without leucovorin rescue during the first interim maintenance
• DH: dexamethasone during induction therapy and high-dose methotrexate/leucovorin rescue during the first interim maintenance
• PC: prednisone during induction therapy and escalating methotrexate without leucovorin rescue during the first interim maintenance
• PH: prednisone during induction therapy and high-dose methotrexate/leucovorin rescue during the first interim maintenance

What is escalating dose methotrexate?

Escalating dose means that they start with 100 mg/m2 and raise the dose by 50 mg/m2 until toxicity is apparent, meaning that the ANC goes down or mucositis is apparent. The methotrexate is given every 10 days. This is called "Capizzi I methotrexate" and was a component of previous trials, CCG 1961 (arms C/D) and POG 9906, during interim maintenance. The augmented arms of CCG 1961 (arms C/D) proved to give the highest EFS (this information is published as abstracts on the Blood Journal web site, ASH, 2004; click on the ASH (American Society of Hematology) link on the right - ASH Annual Meeting Abstracts. Then click on the 2004 annual meeting abstracts.)

What is high dose methotrexate?

High dose methotrexate (HD MTX) is 5 grams/m2 administered by IV. Leucovorin rescue is used and begins 42 hours after MTX treatment begins and continues until the MTX is cleared. HD MTX was used successfully in BFM-style protocols in conjunction with 6-MP and is also referred to as "Protocol M".

Why dexamethasone vs prednisone?

Dexamethasone seems to work better but has serious (and potentially long-lasting) side effects, prednisone is less toxic. This study aims to find the optimum steroid dosage.

Here is a flow chart for this trial on the Grand Rapids Clinical Oncology Program web site.

Induction, 4 weeks

Arms DC and DH:

• cytarabine intrathecal (IT) on day 1
• vincristine IV on days 1, 8, 15, and 22
• daunorubicin IV on days 1, 8, 15, and 22
• dexamethasone oral or IV twice daily on days 1-14 (10 mg/m2 divided)
• methotrexate intrathecal (IT) on days 8 and 29
• pegaspargase intramuscularly (IM) once on day 4, 5, or 6

Note: Patients with CNS3 disease also receive IT MTX on days 15 and 22

Arms PC and PH:

• cytarabine intrathecal (IT) on day 1
• vincristine IV on days 1, 8, 15, and 22
• daunorubicin IV on days 1, 8, 15, and 22
• prednisone oral or IV twice daily on days 1-28
• methotrexate intrathecal (IT) on days 8 and 29
• pegaspargase intramuscularly (IM) once on day 4, 5, or 6

Note: Patients with CNS3 disease also receive IT MTX on days 15 and 22

Patients in all arms are evaluated at day 29 of induction:

• Patients with M3 disease are removed from study
• Patients with M1 disease and less than 1% minimal residual disease (MRD) proceed to consolidation therapy beginning on day 36
• Patients with M2 disease OR with MI disease and at least 1% MRD receive extended induction therapy for 2 additional weeks.

Extended induction therapy (only for patients with M2 disease or M1 disease with over 1% MRD):

• Arms DC and DH
  • dexamethasone oral or IV twice daily on days 1-14
  • vincristine IV on days 1 and 8
  • daunorubicin IV on day 1
  • pegaspargase IM on day 4, 5, or 6 and are then reevaluated.
• Arms PC and PH
  • prednisone oral or IV twice daily on days 1-14
  • vincristine IV on days 1 and 8
  • daunorubicin IV on day 1
  • pegaspargase IM on day 4, 5, or 6 and are then reevaluated.

Patients on all arms who have M1 disease and less than 1% MRD after extended induction proceed to consolidation therapy and continue as SER patients. All other patients are removed from study (and probably put on the highest risk study).

Note:

• Positive MRD status is defined as greater than (or equal to) 0.1% detectable leukemia cells
• Negative MRD status is defined as less than than 0.1% detectable leukemia cells

However, it looks like it is the "1%" amount that directs the path of treatment at the end of induction(s), although the positive/negative definition is included in the definitions for SER or RER, which in itself directs treatment later on.

Note: CNS 3 patients are assigned to regimen DH with double delayed intensification, 2 extra Induction ITs and craniospinal radiation.

Consolidation (about 7-8 weeks)

Arms DC, DH, PC, PH:

• cyclophosphamide IV over 30 minutes on days 1 and 29
• cytarabine IV or subcutaneously (SC) on days 2-5, 9-12, 30-33, and 37-40
• mercaptopurine (oral) on days 1-14 and 29-42
• vincristine IV on days 15, 22, 43, and 50
• pegaspargase IM on days 15 and 43
• IT MTX on days 1, 8, 15, and 22

Note: Patients with CNS3 disease receive MTX on days 1 and 8 only.

Interim maintenance I

DC (dexamethasone, escalating-dose MTX)

• vincristine IV on days 1, 11, 21, 31, and 41
• escalating-dose MTX IV on days 1, 11, 21, 31, and 41
• pegaspargase IM on days 2 and 22
• IT MTX on days 1 and 21

DH (dexamethasone, high-dose MTX)

• vincristine IV and high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43
• leucovorin calcium IV every 6 hours for at least 3 doses, beginning 42 hours after start of each MTX infusion
• oral MP on days 1-56
• IT MTX on days 1 and 29.

PC (prednisone, escalating-dose MTX) (same as DC in this phase of treatment)

• vincristine IV on days 1, 11, 21, 31, and 41
• escalating-dose MTX IV on days 1, 11, 21, 31, and 41
• pegaspargase IM on days 2 and 22
• IT MTX on days 1 and 21.

PH (prednisone, high-dose MTX) (same as DH in this phase of treatment)

• vincristine IV and high-dose methotrexate IV over 24 hours on days 1, 15, 29, and 43
• leucovorin calcium IV every 6 hours for at least 3 doses, beginning 42 hours after start of each MTX infusion
• oral MP on days 1-56
• IT MTX on days 1 and 29

Delayed intensification(s)

(Note that SER patients received two delayed intensifications.)

Arms DC, DH, PC, PH:

• vincristine IV on days 1, 8, 15, 43, and 50
• oral or IV dexamethasone twice daily on days 1 to 21 for patients age 1 to 12 OR on days 1-7 and 15-21 for patients age 13 and over (NOTE: discontinuous dexamethasone for teen patients)
• doxorubicin IV on days 1, 8, and 15
• pegaspargase IM on day 4, 5, or 6 and day 43
• cyclophosphamide IV on day 29
• cytarabine IV or SC on days 30-33 and 37-40
• oral thioguanine on days 29-42
• IT MTX on days 1, 29, and 36

After delayed intensification I:

• SER patients proceed to interim maintenance II and delayed intensification II
• RER patients proceed directly to maintenance

Interim maintenance II

• vincristine IV on days 1, 11, 21, 31, and 41
• MTX IV on days 1, 11, 21, 31, and 41
• pegaspargase IM on days 2 and 22
• MTX IT on days 1 and 21

Delayed intensification II

• Same as delayed intensification I
• CNS3 patients also receive radiotherapy for 3-10 days, beginning on day 29
• All other SER patients receive prophylactic cranial radiotherapy for 8 days, beginning on day 29
• Patients then proceed to maintenance therapy.

Maintenance therapy

• vincristine IV on days 1, 29, and 57
• oral dexamethasone twice daily on days 1-5, 29-33, and 57-61
• oral MP on days 1-84
• IT MTX on day 1
• oral MTX on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.

Patients with testicular disease may receive testicular radiotherapy for 8 days during one of the first 3 courses of maintenance therapy.

Patients are followed every 2 months for 2 years, every 3 months for 1 year, every 6 months for 1 year, and then annually thereafter.

and this: RER : Randomize and receive SDI
SER : Randomize, receive DDI, and cranial XRT (1200 cGy)