CCG 1952

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.

Note: the cancer.gov pdq includes a bibliography of articles about this trial.

(for abbreviations, see CCG 1961 document)

Treatment for standard risk ALL defined as presenting features of:

• ages 1-9
• WBC less than 50,000/microliter
• FAB L3 blasts less than 25% (patients patients go to the high risk ALL treatment)

Notes:

• Massive lymphadenopathy, massive splenomegaly, and/or large mediastinal mass allowed
• CNS or testicular leukemia allowed
• Allogeneic bone marrow transplant should be considered (if donor available) for patients with Philadelphia chromosome (t[9;22][q34;q11]) or translocation (4;11)(q21;q23)

Protocol initiated, # patients: (date?) 3 years, 590 patients

Specific aims:

• The study will determine whether substitution of oral 6-thioguanine (TG) for oral 6-mercaptopurine (MP) improves event free survival (EFS).
• The study will also determine whether treatment with "triple" IT therapy (methotrexate, ara C, hydrocortisone) rather than IT methotrexate alone improves treatment outcome.

Also:

• Identify response-related factors predictive of relapse among patients by studying the percent of residual marrow blasts at days 7 and 14, the percent of circulating blasts at the same time points, and the amount of minimal residual disease identified in marrow at 3 time points during treatment. Plus, determine whether CSF terminal deoxynucleotidyl transferase (TdT) positivity is predictive of relapse
• Determine the prognostic significance of residual leukemic blasts at specific times during induction therapy: M3 marrow status (greater than 25% blasts) at day 7; M2 status (5%-25% blasts) at day 14; and residual circulating leukemic blasts at days 7 and 14.
• Determine the prognostic significance of residual leukemic burden, as measured by fluorescence-activated cell sorting/leukemic progenitor cell assay, on marrow aspirates acquired at the end of induction therapy, at the beginning of maintenance therapy, and at the completion of all therapy in patients with B-precursor ALL.
• Determine the prognostic significance of residual t(1;19) detected in marrow aspirates by PCR-based analyses of the fusion transcript E2A-PBX1 at the end of induction therapy, at the beginning of maintenance therapy, and at the completion of all therapy.
• Examine the interrelationships among these response-related prognostic factors and their correlation with ploidy, karyotype, and immunophenotype.
• Compare the concentrations of MP and TG red blood cell metabolites (i.e., nucleotides, nucleosides, free bases, and methylated metabolites) during interim maintenance and maintenance therapy, and determine whether low levels of metabolites predict relapse in selected patients.
• Determine the activities of thiopurine methyltransferase and hypoxanthine guanine phosphoribosyl transferase several times during interim maintenance and maintenance treatment, and compare the activities between the two thiopurine treatment groups in selected patients.

4 arms of treatment:

• A1: MP and IT MTX
• A2: MP and TIT
• B1: TG and IT MTX
• B2: TG and TIT

Following Induction, patients who achieve remission are randomly assigned to Regimen A1, A2, B1, or B2. Patients with M3 marrow after 2 weeks or M2 marrow after 4 weeks of Induction or with the following cytogenetic abnormalities proceed to Regimen C.

If a child has leukemic cells in the spinal fluid at the time of diagnosis (CNS involvement), the child receives radiation therapy to the head and spine. Patients with testicular involvement at diagnosis receive radiation to the testes.

CCG 1952 (A1, A2, B1, B2)

• 4 weeks induction (days 0 to 27)
  • Vincristine (VCR) IV (days 0, 7, 14, 21)
  • Prednisone PO (days 0-27)
  • L-Asparaginase (L-Asp) IM (MWF for three weeks)
  • Cytarabine (Ara-C) IT (day 0)
  • Methotrexate (MTX) given IT on days 7 and 28.
• 4 weeks consolidation (days 0 to 27)
  • Predisone is tapered for 10 days (days 0-9).
  • Vincristine IV (day 0)
  • Either 6MP or 6TG given orally for days 1 through 27 depending on the arm
  • Either MTX or triple (MTX, Ara-C, H.C.) given IT on days 7, 14, and 21 depending on the arm.
• 8 weeks Interim Maintenance #1 (days 0 through 55)
  • Vincristine IV (days 0 and 28)
  • Prednisone orally (days 0-4 and 28-32)
  • MTX orally (days 0, 7, 14, 21, 28, 35, 42, and 49)
  • Either 6MP or 6TG given orally for 49 days (days 0 through 48) depending on the arm
• 8 weeks Delayed Intensification #1: (days 0 through 55)
  • Dexamethasone (DXM) (orally days 0-6 and 14-20)
  • Vincristine given IV (days 0, 7 and 14)
  • Doxorubicin (ADR) IV (days 0, 7, and 14)
  • L-Asp given IM (MWF for 2 weeks, 6 doses)
  • Cyclophosphamide (CTX) IV (day 28)
  • Thioguanine (6TG) (orally on days 28-41 for all patients on all arms)
  • Ara-C IV or SQ (days 29-32 and 36-39)
  • Either MTX or triple (MTX, Ara-C, H.C) given IT on days 0, 28, 35 depending on the arm.
• 8 weeks Interim maintainence #2: repeat Interim maintenance #1
• 8 weeks Delayed intesification #2: repeat delayed intensification #1
• Mainenance (2 years for girls, 3 for boys. All time from the start of interim maintanence #1 counts toward the 2 or 3 year maintenance period.)
  • Vincristine given IV monthly
  • Predisone given orally for five days with each VCR injection
  • 6MP given orally daily
  • Methotrexate given orally weekly except when there is an IT
  • Methotrexate given IT every three months.

CCG 1952 C

A child with 25 percent leukemic cells on day 14 of the bone marrow test or the bone marrow test done at diagnosis shows unfavorable characteristics will be assigned to this treatment plan to start on day 14 of induction. Thus, induction then becomes 5 weeks, days 0 to 34:

• 5 weeks induction:
  • days 0 to 14 are as previously described in regimens A and B
  • Prednisone given orally on days 15 - 27
  • Vincristine given IV on days 14 and 21
  • Daunorubicin (Dauno) given IV continuously for 2 days, days 14 through 16.
  • L-Asparaginase (L-Asp) given IM continuing from regular induction MWF, for a total of 9 doses.
  • Methotrcxate (MTX) given IT on days 21 and 35.
• Nine weeks Consolidation: Days 0 to 62..
  • Prednisone taper over days 0 to 10
  • Cyclophosphamide (CPM) given IV on days 0 and 28.
  • Mercaptopurine (6MP) given orally on days 0 - 13 and 28 - 41.
  • Cytarabine (Ara-C) given IV or SQ on days 1-4, 8-11, 29-32 and 36-39.
  • Methotrexate (MTX) given IT on days 7, 14 and 21.
  • Vincristine (VCR) given IV on days 14, 21, 42, and 49.
  • PEG-Asparaginase (PEG) given IM on days 14 and 42.
• Eight weeks Interim Maintenance 1: Days 0-55.
  • Vincristine (VCR) given IV on days 0, 10, 20, 30 and 40.
  • PEG-Asparaginase (PEG) given IM on days 1 and 21.
  • Methotrexate (MTX) given IV on days 0, 10, 20, 30, and 40.
• Eight weeks Delayed Intensification 1: Days 0-55.
  • Dexamthasone (DXM) given orally on days 0-6, and 14-20.
  • Vincristine (VCR) given IV on days 0, 7, 14, 42 and 49.
  • Doxorubincin (ADR) givein IV on days 0, 7 and 14.
  • PEG-Asparaginase (PEG) gevin IM on days 3 and 42.
  • Cyclophosphamide (CPM) given IV on day 28
  • Thioguanine (6TG) given orally on days 28 to 41 .
  • Cytarabine (Ara-C) given IV or SQ on days 29-32 and 36-39.
  • Methotrexate (MTX) given IT on days 28 and 35.
• Interim Maintenance 2: repeat Interim Maintanence #1
• Delayed Intensification 2: repeat Delayed Intensificaiton #1
• Mainenance (2 years for girls, 3 for boys. All time from the start of interim maintanence #1 counts toward the 2 or 3 year maintenance period.)
  • Vincristine given IV monthly
  • Predisone given orally for five days with each VCR injection
  • 6MP given orally daily
  • Methotrexate given orally weekly except when there is an IT
  • Methotrexate given IT every three months.

CCG 1952 D

• Radiotherapy. Craniospinal and/or testicular irradiation using megavoltage equipment (Co60 up to 6 MV x-rays).
  • CNS involvement: Radiation therapy is given daily, Mon-Fri, for 12 days and the IT Methotrexate doses for days 14 and 21 are omitted.
  • Testicular involvement: radiation therapy to the testes during the first three weeks of consolidation (8 doses)
    

Notes

Treatment is based on CCG 1891, regimen B in which delint was admin 2X and found to be favorable.

Thioguanine is being tried because theoretical and in vitro pharmokinetic data suggest that TG is better.

A comment from Becky, the mom of a child on this protocol:

"It is designed to determine if 6TG is a better agent than 6MP. We are on the arm that NEVER gets 6MP. I researched this topic and learned how these to different agents worked (the chemistry side of things). It seems that when 6MP metabolizes through the liver it turns into the same makeup as 6TG, BUT sometimes does not produce the higher levels of RBC thioguanine nucleotides that is necessary to get those little remaining stubborn cells. By giving 6TG they hypothesize that these levels will be higher and thus help the outcome of higher levels of RBC TGN. So far according to Taylor's dr. this is proving to be the case. NOW having said that, 6MP is still a terrific agent and patients that are getting that are still being cured everyday.....and 4% of some of the patients that are on the arm getting 6TG have had what appears to be liver problems; therefore they are adjusting the dose on the study."

Triple ITs are being tried based on low CNS relapse in POG studies that utilize TIT.

No prior treatment for ALL is allowed on this trial.

Comments

Interesting to note that CCG1952A, B never gives methotrexate via IV or IM, it is either oral or IT. IV methotrexate is common in the POG protocols.

They only get doxorubicin and cytoxin in the delints. CCG 1961, for higher risk patients, includes these two drugs in the initial induction/consolidation.