ACUTE LYMPHOBLASTIC LEUKEMIA · ACUTE LYMPHOBLASTIC LEUKEMIA LINKER REGIMEN ("CLASSIC") INDUCTION Daunorubicin 50 mg/m2/day IV Days 1 - 3 Vincristine 2 mg IV Days 1, 8, 15 and 22

ACUTE LYMPHOBLASTIC LEUKEMIA LINKER REGIMEN ("CLASSIC") INDUCTION Daunorubicin 50 mg/m2/day IV Days 1 - 3 Vincristine 2 mg IV Days 1, 8, 15 and 22 Prednisone 60 mg/m2/day PO Days 1 - 28, then taper if

in remission L-Asparaginase (E.Coli) 6000 units/m2 IM Days 17 - 28 If the Day 14 bone marrow has residual leukemia then give the following Daunorubicin 50 mg/m2 IV Day 15 If the Day 28 bone marrow has residual leukemia then give the following Daunorubicin 50 mg/m2/day IV Days 29 and 30 Vincristine 2 mg IV Days 29 and 36 Prednisone 60 mg/m2/day PO Days 29 - 42 L-Asparaginase (E.Coli) 6000 units/m2 IM Days 29 - 35 Patients who do not enter CR after 6 weeks of induction therapy should be considered treatment failures and taken off this protocol. CNS PROPHYLAXIS Should be initiated within 1 week of achieving a CR. 18 Gy of cranial irradiation delivered in 10 fractions over 12 – 14 days. A total of six doses of IT methotrexate 12 mg (each administered one week apart) were administered concurrently by LP. Patients with CNS involvement at diagnosis began their weekly IT methotrexate during induction therapy and received a total of 10 doses. Thereafter, high-risk patients should receive IT methotrexate monthly during the first year of therapy and their dose of cranial radiotherapy was increased to 28 Gy. CONSOLIDATION THERAPY (courses administered approximately monthly after the neutrophil counts increased to greater than 1 x 109/L and platelet counts greater than 100 x 109/L). TREATMENT A (CYCLES 1, 3, 5 AND 7) Daunorubicin 50 mg/m2/day IV Days 1 and 2 Vincristine 2 mg IV Days 1 and 8 Prednisone 60 mg/m2/day PO Days 1 - 14 L-Asparaginase (E.Coli) 12 000 units/m2 IM Days 2, 4, 7, 9, 11 and 14 TREATMENT B (CYCLES 2, 4, 6 AND 8) Teniposide 165 mg/m2 IV Days 1, 4, 8 and 11 Cytarabine 300 mg/m2 IV Days 1, 4, 8 and 11 TREATMENT C (CYCLE 9) Methotrexate 690 mg/m2 CIVI* Day 1 Leucovorin 15 mg/m2 Q6H IV Day 3** *Administer as a continuous IV infusion over 42 hours; **Starting 42 hr after the start of the methotrexate infusion and continue for 12 doses.

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Last Updated on September 24, 2007

LINKER REGIMEN ("CLASSIC") CONTINUED MAINTENANCE THERAPY Methotrexate 20 mg/m2/dose PO Weekly 6-Mercaptopurine 75 mg/m2/day PO Daily NOTE: Oral maintenance therapy was continued until 30 months of continuous complete remission (CCR), and then all therapy was stopped. Reference: Linker CA, et al. Blood 1991;78:2814 – 22.


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LINKER REGIMEN ("INTENSIFIED AND SHORTENED"): Involves 7 courses of therapy given in the order 1A, 1B, 1C, 2A, 2B, 2C, and 3C followed by maintenance therapy. INDUCTION 1A Daunorubicin 60 mg/m2/day IV Days 1 - 3 Vincristine 1.4 mg/m2* IV Days 1, 8, 15 and 22 Prednisone 60 mg/m2/day PO Days 1 - 28 L-Asparaginase (E.Coli) 6000 units/m2 SQ Days 17 - 28 *Cap dose at 2 mg if the patient is older than 40 years of age. If the Day 14 bone marrow has residual leukemia then give the following Daunorubicin 60 mg/m2 IV Day 15 Patients not in remission at the end of Induction 1A received the first intended post-remission treatment course (1B) with high-dose cytarabine plus etoposide. CNS PROPHYLAXIS: 6 doses of IT methotrexate 12 mg. First dose was given at the start of induction therapy during the initial diagnostic LP. Five subsequent doses began with the first course of post-remission chemotherapy and were delivered weekly as tolerated. Patients with CNS disease at diagnosis received 10 intrathecal doses of methotrexate and cranial irradiation 18 Gy after BM remission. CONSOLIDATION 1B AND 2B Cytarabine 2000 mg/m2/day IV* Days 1 - 4 Etoposide 500 mg/m2/day IV** Days 1 - 4 *Administer over 2 hours; **Administer over 3 hours. CONSOLIDATION 2A Daunorubicin 60 mg/m2/day IV Days 1 - 3 Vincristine 1.4 mg/m2* IV Days 1, 8 and 15 Prednisone 60 mg/m2/day PO Days 1 - 21 L-Asparaginase (E.Coli) 12000 units/m2 SQ Six doses over 2 weeks *Cap dose at 2 mg if the patient is older than 40 years of age. CONSOLIDATION 1C, 2C AND 3C Methotrexate 220 mg/m2 IVB* Day 1

Followed by Methotrexate 60 mg/m2/hour CIVI** Days 1 -2 and 15 - 16 Leucovorin 50 mg/m2 Q6H IV/PO See below*** 6-Mercaptopurine 75 mg/m2/day PO Days 1 - 28 *Administer as an IV bolus; **Administer as a continuous infusion over 36 hours; ***Start immediately following completion of the methotrexate infusion. Administer IV Q6H for 3 doses, then change to oral dosing until the methotrexate level is less than 0.05 micromolar/L.

MAINTENANCE THERAPY Methotrexate 20 mg/m2/dose PO Weekly 6-Mercaptopurine 75 mg/m2/day PO Daily NOTE: Continue maintenance treatment until in 30 months of continuous complete remission. Reference: Linker CA, et al. J Clin Oncol 2002;20:2464 -71.



ECOG 2993 - STUDY CLOSED INDUCTION (ALL PATIENTS) INDUCTION PHASE I Daunorubicin 60 mg/m2 IVP Days 1, 8, 15 and 22 Vincristine 1.4 mg/m2* IVP Days 1, 8, 15 and 22 Prednisone 60 mg/m2/day PO Days 1 – 28 L-Asparaginase (E.Coli) 10000 units/day IV/IM** Days 17 – 28 Methotrexate 12.5 mg IT Day 23 *Maximum dose 2 mg; **Administer a test-dose first, if negative proceed with full-dose. If skin-test is positive change to PEG-asparaginase. If administering IV give in 100 mL D5W over 30 minutes. NOTE: If the patient has an allergic reaction to the dose of E.Coli asparaginase, PEG asparaginase can be administered. Wait 1 day after the detection of the allergic reaction to standard E.Coli asparaginase to administer PEG asparaginase. PEG-asparaginase dose is 2500 units/m2 IM only. During induction this dose will be given once every 21 days e.g., during the induction regimen if an allergic reaction occurs at any time to the standard E.Coli asparaginase then only one dose of PEG-asparaginase will be given to complete the day 17 - 28 requirements for asparaginase. During the intensification regimen, PEG-asparaginase will be given only on Days 2 and 23. Asparaginase should be held for pancreatitis, grade 3 or 4hepatotoxicity, DVT or PE, or major hemorrhage. INDUCTION PHASE II To start on Day 29 from the start of Phase I induction. It should be postponed until the WBC is greater than 3 x 109/L in patients with delayed hematological recovery. Cyclophosphamide 650 mg/m2 IV* Days 1, 15 and 29 Cytarabine 75 mg/m2/day IV** Days 1 – 4, 8 – 11,

15 – 18, and 22 – 25 6-Mercaptopurine 60 mg/m2/day PO Days 1 – 28 Methotrexate 12.5 mg IT Days 1, 8, 15 and 22*** *Administer in 250 mL NS over 30 minutes; **Administer in 100 mL D5W over 30 minutes; ***If the patient received treatment for occult disease in Phase I, then omit these doses. NOTE: Patients with CNS leukemia at diagnosis, who receive weekly IT methotrexate during Phase I induction, receive irradiation concurrent with Phase II induction therapy. POST-INDUCTION THERAPY (DEPENDENT ON PHILADELPHIA CHROMOSOME STATUS) CONSOLIDATION THERAPY (FOR PHILADELPHIA CHROMOSOME POSITIVE PATIENTS ONLY) Consolidation starts after the completion of the 2nd phase of induction i.e., at the beginning of week 10 and ending on week 14. Imatinib therapy may be delayed an additional week until week 11 to allow for additional count recovery if desired, but should be started by week 11 regardless of blood count as long as the BM biopsy at the end of Phase II shows no evidence of leukemia. Imatinib mesylate 600 mg/day PO Daily for a minimum of 28

consecutive days* *If the patient is not ready to proceed to HSCT at the completion of 4 weeks of imatinib then the imatinib may be continued for an additional 30 - 60 days. Prolongation after that will require removal from the study.

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ECOG 2993 CONTINUED INTENSIFICATION (FOR PHILADELPHIA CHROMOSOME POSITIVE PATIENTS ONLY) To begin 4 weeks after the completion of the second phase of induction i.e., at the beginning of week 13 and ending on week 16. Methotrexate 3000 mg/m2 IV* Days 1, 8 and 22 L-Asparaginase (E.Coli) 10 000 units IV** Days 2, 9 and 23 Leucovorin 10 mg/m2 IV/PO See below***

*Administer in 500 mL NS (per protocol) over 2 hours. Prior to administration of methotrexate the urine pH must be greater than 7. This can be achieved by administering sodium bicarbonate. Suggested regimens include D5W with 150 mEq NaHCO3/liter at a rate of 100 mL/m2/hour. Alternatively oral sodium bicarbonate can be used at a dose of 3000 mg PO Q3 - 6 hours starting the evening prior to methotrexate administration and for 48 hours thereafter. All patients should received adequate hydration the day of the methotrexate infusion and for 24 hours each dose: suggested fluid is 3000 mL/m2/day; **Administer a test dose, if negative proceed with full-dose and administer IV over 30 minutes in 100 mL D5W; ***Administer in 50 mL D5W, beginning 22 - 24 hours after completion of the methotrexate infusion. Administer IV Q6H x 4 doses then 10mg/m2 PO Q6H for 72 hours. DOSE MODIFICATIONS: If the serum creatinine increases by more than 50% over baseline at 24 hours and/or the methotrexate level is greater than 5 x 10-6M, leucovorin is to be increased to 100 mg PO every 3 hours until the serum methotrexate level decreases to 1 x 10-8M. NOTE: If the patient has an allergic reaction to the dose of E.Coli asparaginase, PEG asparaginase can be administered. Wait 1 day after the detection of the allergic reaction to standard E.Coli asparaginase to administer PEG asparaginase. The dose of PEG-asparaginase is 2500 units/m2 administered IM only. During induction this dose will be given once every 21 days e.g., during the induction regimen if an allergic reaction occurs at any time to the standard E.Coli asparaginase then only one dose of PEG-asparaginase will be given to complete the day 17 - 28 requirements for asparaginase. During the intensification regimen, PEG-asparaginase will be given only on Day 2 and 23. Asparaginase should be held for pancreatitis, grade 3 or 4 hepatotoxicity, DVT or PE, or major hemorrhage CNS PROPHYLAXIS FOR PATIENTS WHO DID NOT PRESENT WITH OCCULT CNS DISEASE AND ARE NOT TO RECEIVE BMT Administer between intensification and consolidation: Cranial irradiation 24 Gy in 12 fractions in the 2 - 3 weeks between intensification and the start of consolidation. Intrathecal therapy with cytarabine 50 mg per dose should be administered weekly for a total of 4 doses during radiotherapy. This should be followed by intrathecal cytarabine 50 mg for a further 4 doses given 3 months apart during maintenance therapy (i.e., for one year).

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ECOG 2993 CONTINUED CONSOLIDATION (FOR PATIENTS WHO ARE PHILADELPHIA CHROMOSOME NEGATIVE; PH+ PATIENTS WILL PROCEED TO A TRANSPLANT FOLLOWING CONSOLIDATION THERAPY) CONSOLIDATION CYCLE I Begin after intensification or harvest when WBC greater than 3 x 109/L and platelets greater than 100 x 109/L. Cytarabine 75 mg/m2/day IV* Days 1 – 5 Etoposide 100 mg/m2/day IV** Days 1 – 5 Vincristine 1.4 mg/m2*** IVP Days 1, 8, 15 and 22 Dexamethasone 10 mg/m2/day PO Days 1 – 28 *Administer in 500 mL D5W over 30 minutes; **Administer in 500 mL NS over 1 hour; ***Maximum dose is 2 mg. CONSOLIDATION CYCLE II Begin 4 weeks from Day 1 of consolidation cycle number 1 or when the WBC is greater than 3 x 109/L. Cytarabine 75 mg/m2/day IV* Days 1 – 5 Etoposide 100 mg/m2/day IV** Days 1 – 5

*Administer in 500 mL D5W over 30 minutes; **Administer in 500 mL NS over 1 hour.

CONSOLIDATION CYCLE III Begin 4 weeks from Day 1 of consolidation cycle number 2 or when WBC greater than 3 x 109/L. Daunorubicin 25 mg/m2 IVP Days 1, 8, 15 and 22 Cyclophosphamide 650 mg/m2 IV* Day 29 Cytarabine 75 mg/m2 IV** Days 31 – 34 and 38 – 41 6-Thioguanine 60 mg/m2/day PO Days 29 – 42 *Administer in 250 mL NS over 30 minutes; **Administer in 100 mL D5W over 30 minutes. CONSOLIDATION CYCLE IV Begin 8 weeks from Day 1 of consolidation cycle number 3 or when WBC greater than 3 x 109/L. Cytarabine 75 mg/m2/day IV* Days 1 – 5 Etoposide 100 mg/m2/day IV** Days 1 – 5

*Administer in 500 mL D5W over 30 minutes; **Administer in 500 mL NS over 1 hour.



ECOG 2993 CONTINUED MAINTENANCE CHEMOTHERAPY To begin 4 weeks after Day 1 of consolidation cycle number 4 or when the WBC is greater than 3 x 109/L. Maintenance should continue for two and a half years from the start of intensification therapy. 6-Mercaptopurine 75 mg/m2/day PO Daily for 2.5 years Methotrexate 20 mg/m2/week PO/IV Once a week for 2.5 years Vincristine 1.4 mg/m2* IV Once every 3 months with

prednisone Prednisone 60 mg/m2/day PO Daily for 5 days every 3 months

with vincristine Intrathecal Cytarabine 50 mg IT Administer 4 doses,

each 3 months apart during maintenance

*Maximum dose 2 mg.

NOTE: Continue maintenance for 2.5 years from start of intensification. References: ECOG Protocol 2993; IRB 232-93; Fielding AK, et al. Blood 2007;109:944 – 50.


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HOELZER ALL L3 (BFM 86) REGIMEN - SEE ALL B-CELL (L3) SUBTYPE SECTION HYPER CVAD This regimen consists of 2 phases: a dose-intensive phase and a maintenance phase. DOSE-INTENSIVE PHASE: Consists of 8 cycles of dose-intensive therapy courses of HyperCVAD alternating with high-dose methotrexate and cytarabine as follows (A, B, A, B, A, B, A, B): COURSE 1, 3, 5 AND 7 (PART A) Cyclophosphamide 300 mg/m2 Q12H IV* Days 1 - 3 Mesna 600 mg/m2/day CIVI** Days 1 - 3 Doxorubicin 50 mg/m2 IV Day 4 Vincristine 2 mg IV Days 4 and 11 Dexamethasone 40 mg/day PO Days 1 – 4 and 11 – 14 G-CSF*** 5 mcg/kg BID SQ Begin 24 hours after the

completion of chemotherapy *Administer over 3 hours every 12 hours for a total of 6 doses; **Start with the cyclophosphamide infusion and continue for at least 6 hours after the last dose of cyclophosphamide; ***G-CSF started 24 hours after chemotherapy versus 5 days after the completion of chemotherapy does not result in any treatment-related morbidity during consolidation. During induction therapy, a delay in the administration of filgrastim may result in a slight increase in the time to ANC recovery, but no apparent increase in the risk of infection (Reference: Weiser MA, et al. Cancer 2002;94:285 - 91). NOTE: Antibacterial, antifungal and antiviral prophylaxis administered during induction and consolidation. COURSE 2, 4, 6 AND 8 (PART B) Methotrexate 200 mg/m2 IV* Day 1

Followed immediately by

Methotrexate 800 mg/m2 CIVI** Day 1 Cytarabine 3000 mg/m2 Q12H IV*** Days 2 and 3 Methylprednisolone 50 mg BID IV# Days 1 - 3 LeucovorinΩ 15 mg Q6H PO See below G-CSF 5 mcg/kg BID SQ Begin 24 hours after the

completion of chemotherapy

*Administer over 2 hours; **Administer as a continuous 24 hour infusion; ***Administer each dose over 2 hours, each 12 hours apart for a total of 4 doses - corticosteroid eye drops should start prior to the first dose of cytarabine, and continue for 48 hours following the last dose of cytarabine; #A total of 6 doses to be administered; ΩStart 24 hours after the completion of the methotrexate infusion. Administer a dose of 15 mg PO Q6H for 8 doses, increasing to 50mg PO Q6H if the methotrexate level is greater than 20 micromol/L at the end of infusion, more than 1 micromol/L 24 hours later, or more than 0.1 micromol/L 48 hours after the end of methotrexate infusion. Continue leucovorin until methotrexate level less than 0.1 micromol/L. NOTE: Antibacterial, antifungal and antiviral prophylaxis administered during induction and consolidation.




HYPER CVAD CONTINUED DOSE MODIFICATION: The vincristine dose was reduced to 1 mg if the bilirubin was more than 2 mg/dL. The doxorubicin dose was reduced by 25% if the bilirubin level was 2 - 3 mg/dL, by 50% if the bilirubin was 3 - 4 mg/dL, and by 75% if the bilirubin was more than 4 mg/dL. The methotrexate dose was reduced by 25% when the SCr was 1.5 - 2 mg/dL and by 50% when the SCr was higher. The cytarabine dose was reduced to 1000 mg/m2 in patients 60 years of age and older, if the SCr was greater than 2 mg/dL, or if the methotrexate level at the end of the methotrexate infusion (0 hours after completion of methotrexate therapy) was 20 micromol/L or more. Subsequent high dose methotrexate/cytarabine courses: Serious toxicities (Grade 3 or 4 myelosuppression-associated complications other than neutropenia or thrombocytopenia) required subsequent dose reductions of 25% to 33%: the methotrexate dose to 750 mg/m2 and then to 500 mg/m2 and then to 250 mg/m2; and the cytarabine dose to 2000 mg/m2 and then to 1500 mg/m2 and then to 1000 mg/m2. CNS PROPHYLAXIS: Patients were categorized according to their expected risk of CNS disease based on a previous multivariate analysis for the prognostic factors for CNS leukemia (References: Kantarjian HM, et al. Blood 1988;72:1784 - 9; Cortes J, et al. Blood 1995;86:2091 - 7). High risk: if LDH was greater than 600 IU/L (NR 25 - 225) or the proliferative index (%S + G2M) was 14% or more; patients with mature B-cell ALL. Low Risk: if neither variable was elevated. Intermediate Risk: If the measurements were not available. Methotrexate 12 mg IT Day 2 Cytarabine 100 mg IT Day 8 Number of treatments dependent upon risk category. High risk patients have 16 IT treatments; Intermediate risk patients have 8 IT treatments and Low risk patients have 4 IT treatments. Total number of treatments: High risk 16 treatments Unknown risk 8 treatments Low risk 4 treatments Patients at low or unknown risk for CNS disease received their 4 or 8 IT treatments on days 2 and 8 of the first two or four cycles of therapy. Patients with CNS disease at presentation receive intrathecal therapy twice weekly until CSF is negative, then per protocol. MAINTENANCE: Patients with mature B-cell ALL receive no maintenance therapy. Philadelphia chromosome positive patients who are HSCT candidates undergo HSCT as soon as possible in CR. 6-Mercaptopurine 50 mg TID PO* Three times daily Methotrexate 20 mg/m2 PO Once a week Vincristine 2 mg IV Once a month Prednisone 200 mg/day PO Days 1 - 5 once a month *Take on an empty stomach. Repeat cycle every 28 days for 2 years. Reference: Kantarjian HM, et al. J Clin Oncol 2000;18:547 - 61.




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LARSON’S REGIMEN [CALGB STUDY 8811, CALGB 9111] INDUCTION (4 WEEKS IN LENGTH) Cyclophosphamide 1200 mg/m2 IV Day 1 Daunorubicin 45 mg/m2/day IV Days 1 - 3 Vincristine 2 mg IV Days 1, 8, 15 and 22 Prednisone 60 mg/m2/day PO/IV Days 1 – 21 L-Asparaginase (E.Coli) 6000 units/m2 SQ/IM Days 5, 8, 11, 15, 18 and 22 Dose reduced induction for patient’s aged 60 years of age and older: Cyclophosphamide 800 mg/m2 IV Day 1 Daunorubicin 30 mg/m2/day IV Days 1 - 3 Prednisone 60 mg/m2/day PO/IV Days 1 – 7 COURSE IIA: EARLY INTENSIFICATION (4 WEEKS IN LENGTH) Methotrexate INTRATHECAL 15 mg IT Day 1 Cyclophosphamide 1000 mg/m2 IV Day 1 6-Mercaptopurine 60 mg/m2/day PO Days 1 – 14 Cytarabine 75 mg/m2/day SQ Days 1 – 4 and 8 – 11 Vincristine 2 mg IV Days 15 and 22 L-Asparaginase (E.Coli) 6000 units/m2 SQ/IM Days 15, 18, 22 and 25 COURSE IIB: EARLY INTENSIFICATION CONTINUATION (4 WEEKS IN LENGTH) Methotrexate INTRATHECAL 15 mg IT Day 1 Cyclophosphamide 1000 mg/m2 IV Day 1 6-Mercaptopurine 60 mg/m2/day PO Days 1 – 14 Cytarabine 75 mg/m2/day SQ Days 1 – 4 and 8 – 11 Vincristine 2 mg IV Days 15 and 22 L-Asparaginase (E.Coli) 6000 units/m2 SQ/IM Days 15, 18, 22 and 25 COURSE III: CNS PROPHYLAXIS AND INTERIM MAINTENANCE (12 WEEKS IN LENGTH) Cranial radiation 24 Gy Days 1 – 12 Methotrexate INTRATHECAL 15 mg IT Days 1, 8, 15, 22 and 29 6-Mercaptopurine 60 mg/m2/day PO Days 1 – 70 Methotrexate 20 mg/m2 PO Days 36, 43, 50, 57 and 64 COURSE IV: LATE INTENSIFICATION (8 WEEKS IN LENGTH) Doxorubicin 30 mg/m2 IV Days 1, 8, and 15 Vincristine 2 mg IV Days 1, 8, and 15 Dexamethasone 10 mg/m2/day PO Days 1 – 14 Cyclophosphamide 1000 mg/m2 IV Day 29 6-Thioguanine 60 mg/m2/day PO Days 29 – 42 Cytarabine 75 mg/m2/day SQ Days 29 – 32 and 36 - 39 COURSE V: MAINTENANCE (TO CONTINUE UNTIL 24 MONTHS POST-DIAGNOSIS) Vincristine 2 mg IV Day 1 every 4 weeks Prednisone 60 mg/m2/day PO Days 1 – 5 of every 4 weeks 6-Mercaptopurine 60 mg/m2/day PO Days 1 – 28 Methotrexate 20 mg/m2 PO Days 1, 8, 15 and 22 References: Larson RA, et al. Blood 1995;85:2025 – 37; Larson RA, et al. Blood 1998;92:1556 – 64.




T-CELL ALL NELARABINE (ADULT REGIMEN) Nelarabine 1500 mg/m2/day IV* Days 1, 3 and 5 *Administer over 2 hours. NOTE: Patients should be closely monitored for neurological and hematologic toxicity. Nelarabine should be discontinued at the first sign of neurological toxicity of NCI-CTC Grade 2 or greater. Repeat cycle every 21 days. Reference: DeAngelo DJ, et al. Blood 2007;109:5136 – 42. NELARABINE (PEDIATRIC REGIMEN) Nelarabine 650 mg/m2 IV* Days 1 - 5 *Administer over 1 hour. NOTE: Patients should be closely monitored for neurological and hematologic toxicity. Nelarabine should be discontinued at the first sign of neurological toxicity of NCI-CTC Grade 2 or greater. Repeat cycle every 21 days. Reference: Berg SL, et al. J Clin Oncol 2005;23:3376 - 82.


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ALL - SALVAGE THERAPY CYTARABINE – IDARUBICIN Cytarabine 3000 mg/m2/day IV* Days 1 - 5 Idarubicin 40 mg/m2 IV Day 3 G-CSF Not specified SQ Day 7 until ANC recovery Methotrexate 12 mg IT Weekly until CSF clear** *Administer over 3 hours; **Only administer intrathecal therapy if CNS disease is present at diagnosis. NOTE: No dose reduction was planned for patients over the age of 50 years. Reference: Camera A, et al. Hematologica 2004;89:145 - 53.

CLOFARABINE - ADULTS Clofarabine 40 mg/m2 IV* Days 1 – 5 *Administer over 1 hour. Repeat cycle every 3 – 6 weeks. Consolidation can be offered at 30 mg/m2 up to 6 cycles every 28 days. Reference: Kantarjian H, et al. Blood 2003;102:2379 – 86. CLOFARABINE - PEDIATRICS Clofarabine 52 mg/m2 IV* Days 1 – 5 *Administer over 2 hours. Repeat cycle every 2 – 6 weeks. Reference: Genzyme Corporation. Clolar package insert. Cambridge, MA: December 2004.




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ALL B-CELL (L3) SUBTYPE CALGB 9251 CYCLE 1 Cyclophosphamide 200 mg/m2/day IV Days 1 – 5 Prednisone 60 mg/m2/day PO Days 1 – 7 CYCLE 2, 4 AND 6 (NOTE: START CYCLE 2 ON DAY 8 OF CYCLE 1) Ifosfamide 800 mg/m2/day IV* Days 1 – 5 Mesna 200 mg/m2/day IV 3 doses per day** Methotrexate 150 mg/m2 IV*** Day 1

Followed by

Methotrexate 1350 mg/m2 CIVI# Day 1 Leucovorin 50 mg/m2 IV Starting 36 hours after the start

of methotrexate for 1 dose

Followed 6 hours later by Leucovorin 15 mg/m2 Q6H IV/PO Until methotrexate level is less than 1 x 10-8M Vincristine 2 mg IVP Day 1 Cytarabine 150 mg/m2/day CIVIφ Days 4 and 5 Etoposide 80 mg/m2/day IV* Days 4 and 5 Dexamethasone 10 mg/m2/day PO Days 1 – 5 *Administer over 1 hour; **Administer prior to ifosfamide, then repeat 4 hours and 8 hours after ifosfamide; ***Administer over 30 minutes; #Administer over 23.5 hours; φAdminister as a continuous infusion over 24 hours. CYCLE 3, 5 AND 7 Cyclophosphamide 200 mg/m2/day IV Days 1 – 5 Methotrexate 150 mg/m2 IV* Day 1

Followed by

Methotrexate 1350 mg/m2 CIVI** Day 1 Leucovorin 50 mg/m2 IV Starting 36 hours after the start

of methotrexate for 1 dose

Followed 6 hours later by Leucovorin 15 mg/m2 Q6H IV/PO Until methotrexate level is less than 1 x 10-8M Vincristine 2 mg IVP Day 1 Doxorubicin 25 mg/m2/day IVB Days 4 and 5 Dexamethasone 10 mg/m2/day PO Days 1 – 5 *Administer over 30 minutes; **Administer over 23.5 hours.

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CALGB 9251 CONTINUED INTRATHECAL THERAPY Methotrexate 15 mg IT Day 1 of Cycles 2 - 7 Cytarabine 40 mg IT Day 1 of Cycles 2 - 7 Hydrocortisone 50 mg IT Day 1 of Cycles 2 - 7 CRANIAL IRRADIATION 24 Gy administered in 12 fractions after the chemotherapy for cycle 7 was completed, but only for patients who had prior bone marrow disease or CNS disease. Cycles 2 – 7 are administered at 21 day intervals. References: Lee EJ, et al. J Clin Oncol 2001;19:4014 – 22; Rizzieri DA, et al. Cancer 2004;100:1438 - 48.





HOELZER ALL L3 (BFM 86) REGIMEN A total of 6 alternating 5-day cycles should be administered (i.e. Pre-phase, A, B, A, B, A, B) PRE-PHASE (1 WEEK IN LENTH) Prednisone 60 mg/m2/day PO Days 1 - 5 Cyclophosphamide 200 mg/m2/day IV* Days 1 – 5

*Administer over 1 hour. CYCLE A (3 - 4 WEEKS IN LENGTH) Intrathecal MTX 15mg/Ara-C 40mg/Dexamethasone 4mg IT Days 1 and 5 Vincristine 2 mg IV Day 1 Methotrexate 150 mg/m2 IV* Day 1

Followed by

Methotrexate 1350 mg/m2 IV** Day 1 Leucovorin See below IV/PO*** See below Ifosfamide 800 mg/m2/day IV# Days 1 – 5 Teniposide 100 mg/m2/day IV Days 4 and 5 Cytarabine 150 mg/m2 Q12H IVφ Days 4 and 5 Dexamethasone 10 mg/m2/day PO Days 1 - 5 *Administer over 30 minutes; **Administer over 23.5 hours. Methotrexate levels to be draw 48 hours and 68 hours after the start of the methotrexate infusion; ***Leucovorin to start 36 hours after the start of the methotrexate infusion. Dosing schedule from the start of the methotrexate infusion as follows: 30 mg/m2 IV at 36 hours, 30 mg/m2 PO at 42 hours, 15mg/m2 PO at 48 hours, and 5mg/m2 PO at 54, 68, and 78 hours. Following analysis of the methotrexate serum concentration, the dose of leucovorin may need to be increased. Dose increases are recommended for the following: If methotrexate level at 42 hours is greater than 0.5 - 5 micromolar, increase the leucovorin dose to 50 mg/m2 IV every 6 hours; If the methotrexate level at 68 hours is greater than 0.01 micromolar, continue leucovorin at 30 mg/m2 IV every 6 hours; #Administer mesna to prevent hemorrhagic cystitis from ifosfamide. Typical regimens include 20% of the ifosfamide dose administered prior to each dose of ifosfamide and then repeated 4 hour and 8 hours after ifosfamide dosing; φAdminister every 12 hours for a total of 4 doses. CYCLE B (3 - 4 WEEKS IN LENGTH) Intrathecal MTX 15mg/Ara-C 40mg/Dexamethasone 4mg IT Day 1 Vincristine 2 mg IV Day 1 Methotrexate 150 mg/m2 IV* Day 1

Followed by Methotrexate 1350 mg/m2 IV** Day 1 Leucovorin See next page IV/PO*** See next page Cyclophosphamide 200 mg/m2/day IV Days 1 - 5 Doxorubicin 25 mg/m2/day IV# Days 4 and 5 Dexamethasone 10 mg/m2/day PO Days 1 - 5

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HOELZER ALL L3 (BFM 86) REGIMEN CONTINUED

*Administer over 30 minutes; **Administer over 23.5 hours. Methotrexate levels to be drawn 48 hours and 68 hours after the start of the methotrexate infusion; ***Leucovorin to start 36 hours after the start of the methotrexate infusion. Dosing schedule from the start of the methotrexate infusion as follows: 30 mg/m2 IV at 36 hours, 30 mg/m2 PO at 42 hours, 15mg/m2 PO at 48 hours, and 5mg/m2 PO at 54, 68, and 78 hours. Following analysis of the methotrexate serum concentration, the dose of leucovorin may need to be increased. Dose increases are recommended for the following: If methotrexate level at 42 hours is greater than 0.5 - 5 micromolar, increase the leucovorin dose to 50 mg/m2 IV every 6 hours; If the methotrexate level at 68 hours is greater than 0.1 micromolar, continue leucovorin at 30 mg/m2 IV every 6 hours; #Administer over 15 minutes. Prophylactic cranial radiation of 24 Gy given to all patients in complete remission after completing 2 cycles i.e., Prephase, A, B, prophylactic cranial radiation, A, B, A, B. Reference: Hoelzer D, et al. Blood 1996;87:495 - 508. HYPER CVAD - SEE ACUTE LYMPHOBLASTIC LEUKEMIA SECTION



HYPER CVAD - RITUXIMAB Consists of 8 courses of dose-intensive therapy courses of HyperCVAD alternating with high-dose methotrexate and cytarabine as described below (i.e., A, B, A, B, A, B, A, B). Cycles were administered every 21 days or earlier if count recovery occurred (at least 14 days apart). COURSE 1, 3, 5 AND 7 (PART A) Rituximabǂ 375 mg/m2 IV Days 1 and 11 Cyclophosphamide 300 mg/m2 Q12H IV* Days 1 - 3 Mesna 600 mg/m2/day CIVI** Days 1 - 3 Doxorubicin 50 mg/m2 CIV*** Day 4 Vincristine 2 mg IV Days 4 and 11 Dexamethasone 40 mg/day PO/IV Days 1 – 4 and 11 – 14 G-CSF# 10 mcg/kg/day SQ Begin 24 hours after the

completion of chemotherapy until ANC recovery

ǂRoutine premedication administered. Rituximab administered on Day 1 and 11 of course 1 and 3 only i.e., courses 5 and 7 without rituximab; *Administer over 2 hours every 12 hours for a total of 6 doses; **Start with the cyclophosphamide infusion and continue until 12 hours after the last dose of cyclophosphamide; ***Administer over 24 hours through a central line; #An evaluation of G-CSF started 24 hours after chemotherapy versus 5 days after the completion of chemotherapy did not result in any treatment-related morbidity during consolidation. NOTE: Consider allopurinol and bicarbonate with first course and continue as necessary based on uric acid levels. COURSE 2, 4, 6 AND 8 (PART B) Rituximabǂ 375 mg/m2 IV Days 2 and 8 Methotrexate 1000 mg/m2 CIVI* Day 1 Cytarabine 3000 mg/m2 Q12H IV** Days 2 and 3 Leucovorin 50 mg*** PO/IV x 1 dose (see below)

Followed 6 hours later by

Leucovorin 15 mg*** PO/IV See below G-CSF 10 mcg/kg/day SQ Begin 24 hours after the

completion of chemotherapy

ǂRoutine premedication administered. Rituximab administered on Day 2 and 8 of courses 2 and 4 only i.e., courses 6 and 8 given without rituximab. *Administer as a continuous 24 hour infusion. Do not start the infusion until the urinary pH is 7 or greater. Urine alkalinization is best achieved with D5W + sodium bicarbonate 100 - 150 mEq/L at a rate of 100 mL/m2/hour. Acetazolomide can be administered if there is difficulty in achieving a urinary pH of 7 or greater; **Cytarabine dose will be determined by the methotrexate level at the end of the 24 hours infusion – see dose modification guidelines. Administer each dose over 2 hours, each 12 hours apart for a total of 4 doses - corticosteroid eye drops should start prior to the first dose of cytarabine, and continue for 48 hours following the last dose of cytarabine; ***Start 12 hours after the completion of the methotrexate infusion. Administer one dose of 50 mg followed 6 hours later by 15 mg PO/IV Q6H for 8 doses until the methotrexate level was less than 0.1 micromolar. Leucovorin could be increased to 50 – 100 mg PO/IV Q4-6H if the methotrexate level is 20 micromol/L or greater at the end of infusion, 1 micromol/L or greater 24 hours later, or more than 0.1 micromol/L 48 hours after the end of methotrexate infusion. Continue leucovorin until methotrexate level less than 0.1 micromol/L.



HYPER CVAD - RITUXIMAB CONTINUED DOSE MODIFICATION: Vincristine dose was reduced to 1 mg if the bilirubin was more than 2 mg/dL or if Grade 2 or greater peripheral neuropathy developed (using NCI CTC). Vincristine was omitted for a bilirubin of greater than 3 mg/dL or for ileus. Doxorubicin dose was reduced by 50% if the bilirubin level was 2 - 3 mg/dL, by 75% if the bilirubin was 3 - 5 mg/dL, and eliminated if the bilirubin was more than 5 mg/dL. Doxorubicin was omitted in the first course for those patients presenting with small bowel or gastric involvement to reduce the length of myelosuppression and risk of perforation. Methotrexate dose was reduced by 50% for patients with a creatinine clearance of 10 – 50 mL/minute, reduced by 25 - 75% for delayed excretion and/or nephrotoxicity with a prior course (dependent on severity) or by 50% for pleural effusions/ascites with drainage of fluid as feasible. Methotrexate was omitted for a creatinine clearance of less than 10 mL/minute. Cytarabine dose was reduced to 1000 mg/m2 in patients 60 years of age and older, if the SCr was greater than 1.5 mg/dL, or if the methotrexate level at the end of the methotrexate infusion (0 hours after completion of methotrexate therapy) was 20 micromol/L or more. NOTE: Patients received prophylactic antibiotics (e.g., quinolone or trimethoprim-sulfamethoxazole, fluconazole QD and acyclovir (or valacyclovir). MAINTENANCE THERAPY: No maintenance therapy is administered with HyperCVAD + Rituximab for Burkitt’s lymphoma. CNS PROPHYLAXIS Methotrexate 12 mg* IT Day 2 Cytarabine 100 mg IT Day 7 *Patients with an Ommaya reservoir received a dose of 6 mg. A total of 16 intrathecal treatments are to be administered. Patients with CNS disease at presentation receive intrathecal therapy twice weekly until CSF cell count normalized and the cytologic examination was negative for the evaluation of malignant disease. The intrathecal therapy then alternated methotrexate and cytarabine weekly for 4 additional doses (including planned intrathecal Days 2 and 7 if course given). The program was then resumed as per prophylaxis protocol until completion of therapy. No prophylactic cranial irradiation was administered. Therapeutic radiation was administered if indicated, e.g., for cranial nerve palsies or intracranial mass (separated from intrathecal or systemic methotrexate by at least 2 weeks). Reference: Thomas DA, et al. Cancer 2006;106:1569 – 80.



PHILADELPHIA CHROMOSOME POSITIVE ALL DASATINIB Dasatinib 70 mg BID PO Continuously DOSE MODIFICATIONS: Dose modifications were permitted for disease progression or toxicity after one cycle of treatment, defined as 28 days. Dose escalation to 100 mg dasatinib twice daily was permitted for patients meeting any of the following criteria: rising percentage of blasts on 2 consecutive hematologic assessments at least 1 week apart, no complete hematologic response within 1 month of dasatinib initiation, no complete cytogenetic response after 3 or more months of dasatinib treatment, or a loss of response achieved with dasatinib. Dose reduction (stepwise to 50 mg BID and subsequently to 40 mg BID) and interruption was permitted according to NCI CTC toxicity criteria. Reference: Ottmann O, et al. Blood 2007;110:2309 - 15. HYPER CVAD + IMATINIB (GLEEVEC®) COURSE 1, 3, 5 AND 7 (PART A) Cyclophosphamide 300 mg/m2 Q12H IV* Days 1 - 3 Mesna 600 mg/m2/day CIVI** Days 1 - 3 Doxorubicin 50 mg/m2 CIVI*** Day 4 Vincristine 2 mg IV Days 4 and 11 Dexamethasone 40 mg/day PO/IV Days 1 – 4 and 11 – 14 Imatinib mesylate 400 mg/day PO Days 1 - 14Φ G-CSF 10 mcg/kg/day SQ Begin 24 hours following

chemotherapy completion and continue until ANC recovery

*Administer over 2 hours every 12 hours for a total of 6 doses; **Start 1 hour prior to cyclophosphamide and continue for 12 hours following the last dose of cyclophosphamide; ***Doxorubicin administered over 24 hours (over 48 hours in patients with reduced ejection fractions less than 50%); ΦPublished reference recommends 400 mg PO Day 1 to Day 14 – a personal communication between Dr Wingard and Dr Thomas verified that the MDACC uses 600 mg PO QD continuously (rather than for 14 days only). NOTE: Course 1 is to be accompanied by adequate hydration and alkalinization and allopurinol to reduce the incidence of tumor lysis syndrome. Oral prophylactic antibiotic therapy with a quinolone or trimethoprim-sulfamethoxazole 1 DS daily for antibacterial coverage, fluconazole 200 mg PO QD; and acyclovir 200 mg PO BID for antiviral prophylaxis. DOSE MODIFICATIONS: Dose of vincristine was reduced to 1 mg if the bilirubin was above 2 mg/dL, and omitted if the total bilirubin was greater than 3 mg/dL or if Grade 3/4 peripheral neuropathy or ileus occurred; Doxorubicin was reduced by 50% for a bilirubin of 2 - 3 mg/dL, by 75% for a bilirubin of 3 - 5 mg/dL and eliminated for a bilirubin greater than 5 mg/dL. Imatinib was reduced to 300 mg for Grade 3/4 hepatotoxicity during intensive chemotherapy courses (400 mg if during maintenance).



http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17496201&ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

HYPER CVAD + IMATINIB (GLEEVEC®) CONTINUED COURSE 2, 4, 6 AND 8 (PART B) Methotrexate 1000 mg/m2 CIVI* Day 1 Leucovorin 50 mg IV** x 1 dose (see notes)

Followed 6 hours later by

Leucovorin 15 mg IV Q6H IV** See notes (next page) Cytarabine 3000 mg/m2 Q12H IV*** Days 2 and 3 Imatinib mesylate 400 mg/dayΦ PO Days 1 - 14 G-CSF 10 mcg/kg/day SQ Begin 24 hours following

chemotherapy completion and until ANC recovery

*Administer as a continuous 24-hour infusion. Do not start the methotrexate infusion until the urinary pH is 7 or greater. Maintain the urinary pH of 7 and above for the duration of the infusion and for 12 - 24 hours after completion of the infusion. Urinary alkalinization can typically be achieved by administering IV fluids with D5W with 150 mEq sodium bicarbonate/L, and infusing at a rate of 100 mL/m2/hour; **Start 12 hours after the completion of the methotrexate infusion and continue at a dose of 15 mg IV Q6H for 8 doses until the methotrexate level is less than 0.1 micromolar; ***Administer over 2 hours, every 12 hours for a total of 4 doses. Dose is to be reduced in patients 60 years of age and older (see dose modification section). Corticosteroid eye drops should start prior to the first dose of cytarabine, and continue until 48 hours following the last dose of cytarabine. ΦPublished reference recommends 400mg PO Day 1 – 14 – a personal communication between Dr Wingard and Dr Thomas verified that the MDACC uses 600mg PO QD continuously (rather than for 14 days only). NOTE: Leucovorin dose was increased to 50 mg IV Q6H based on methotrexate levels. Triggers for an increased dose included a methotrexate level of greater than 20 microM at the end of the methotrexate infusion; greater than 1 microM 24 hours after the infusion; greater than 0.1 microM 48 hours after the infusion. Oral prophylactic antibiotic therapy with a quinolone or trimethoprim-sulfamethoxazole 1 DS daily for antibacterial coverage, fluconazole 200 mg PO QD; and acyclovir 200 mg PO BID for antiviral prophylaxis. DOSE MODIFICATIONS: Cytarabine was reduced to a dose of 1000 mg/m2 for patients aged 60 years and older, if the serum creatinine was above 2 mg/dL, or if the methotrexate level at the end of the infusion (repeated) was greater than 20 microM. Methotrexate dose to be reduced by 50% for a calculate creatinine clearance of 10 - 50 mL/minute, with a decrease by 25 - 50% for delayed excretion, nephrotoxicity, or grade 3 or greater mucositis with prior courses. Imatinib was reduced to 300 mg per day for Grade 3 or 4 hepatotoxicity during intensive chemotherapy courses (400 mg per day if during maintenance).



HYPER CVAD + IMATINIB (GLEEVEC®) CONTINUED CNS PROPHYLAXIS: Patients were categorized according to their expected risk of CNS disease based on a multivariate analysis for the prognostic factors for CNS leukemia (References: Kantarjian HM, et al. Blood 1988;72:1784 - 9; Cortes J, et al. Blood 1995;86:2091 - 7). High risk: if LDH was greater than 600 IU/L (NR 25 - 225) or the proliferative index (%S + G2M) was 14% or more; patients with mature B-cell ALL. Low Risk: if neither variable was elevated. Intermediate Risk: If the measurements were not available. Methotrexate 12 mg * IT Day 2 Cytarabine 100 mg IT Day 7 or 8 *Dose of methotrexate reduced to 6 mg if administered using an Ommaya reservoir. Administer with each course of systemic therapy for a total or either 6 or 8 treatments, depending on risk for CNS relapse. MAINTENANCE: Start after 8 courses of intensive chemotherapy and CONTINUE FOR 13 MONTHS. Imatinib 600 mg/day PO Daily Vincristine 2 mg IV Q month Prednisone 200 mg/day PO Days 1 - 5* *Administered once a month, starting the day of vincristine administration. Reference: Thomas DA, et al. Blood 2004;103:4396 – 407.






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