ACUTE LYMPHOBLASTIC LEUKEMIA LINKER REGIMEN ("CLASSIC") INDUCTION Daunorubicin Vincristine Prednisone

50 mg/m2/day 2 mg 60 mg/m2/day

IV IV PO

L-Asparaginase (E.Coli)

6000 units/m2

IM

Days 1 - 3 Days 1, 8, 15 and 22 Days 1 - 28, then taper if in remission Days 17 - 28

If the Day 14 bone marrow has residual leukemia then give the following IV Day 15 Daunorubicin 50 mg/m2 If the Day 28 bone marrow has residual leukemia then give the following IV Days 29 and 30 Daunorubicin 50 mg/m2/day Vincristine 2 mg IV Days 29 and 36 PO Days 29 - 42 Prednisone 60 mg/m2/day 2 6000 units/m IM Days 29 - 35 L-Asparaginase (E.Coli) 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 Vincristine Prednisone L-Asparaginase (E.Coli)

50 mg/m2/day 2 mg 60 mg/m2/day 12 000 units/m2

IV IV PO IM

Days Days Days Days

165 mg/m2 300 mg/m2

IV IV

Days 1, 4, 8 and 11 Days 1, 4, 8 and 11

690 mg/m2 15 mg/m2 Q6H

CIVI* IV

Day 1 Day 3**

TREATMENT B (CYCLES 2, 4, 6 AND 8)

Teniposide Cytarabine

TREATMENT C (CYCLE 9)

Methotrexate Leucovorin

1 and 2 1 and 8 1 - 14 2, 4, 7, 9, 11 and 14

*Administer

as a continuous IV infusion over 42 hours; **Starting 42 hr after the start of the methotrexate infusion and continue for 12 doses.

CONTINUED ON NEXT PAGE……..

Last Updated on September 24, 2007

LINKER REGIMEN ("CLASSIC") CONTINUED MAINTENANCE THERAPY Methotrexate 6-Mercaptopurine

20 mg/m2/dose 75 mg/m2/day

PO PO

Weekly 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.

Last Updated on September 24, 2007

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 Vincristine Prednisone L-Asparaginase (E.Coli) *Cap

60 mg/m2/day 1.4 mg/m2* 60 mg/m2/day 6000 units/m2

IV IV PO SQ

Days Days Days Days

1-3 1, 8, 15 and 22 1 - 28 17 - 28

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 IV Day 15 Daunorubicin 60 mg/m2 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 Etoposide

*Administer

IV* IV**

Days 1 - 4 Days 1 - 4

IV IV PO SQ

Days 1 - 3 Days 1, 8 and 15 Days 1 - 21 Six doses over 2 weeks

over 2 hours; **Administer over 3 hours.

CONSOLIDATION 2A

Daunorubicin Vincristine Prednisone L-Asparaginase (E.Coli) *Cap

2000 mg/m2/day 500 mg/m2/day

60 mg/m2/day 1.4 mg/m2* 60 mg/m2/day 12000 units/m2

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

Methotrexate Leucovorin 6-Mercaptopurine

60 mg/m2/hour 50 mg/m2 Q6H 75 mg/m2/day

CIVI** IV/PO PO

Days 1 -2 and 15 - 16 See below*** Days 1 - 28

Followed by

*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 PO Daily 6-Mercaptopurine 75 mg/m2/day NOTE: Continue maintenance treatment until in 30 months of continuous complete remission. Reference: Linker CA, et al. J Clin Oncol 2002;20:2464 -71. Last Updated on September 24, 2007

ECOG 2993 - STUDY CLOSED INDUCTION (ALL PATIENTS) INDUCTION PHASE I

Daunorubicin Vincristine Prednisone L-Asparaginase (E.Coli) Methotrexate

60 mg/m2 1.4 mg/m2* 60 mg/m2/day 10000 units/day 12.5 mg

IVP IVP PO IV/IM** IT

Days 1, 8, 15 and 22 Days 1, 8, 15 and 22 Days 1 – 28 Days 17 – 28 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 PEGasparaginase 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 Cytarabine

650 mg/m2 75 mg/m2/day

IV* IV**

6-Mercaptopurine Methotrexate

60 mg/m2/day 12.5 mg

PO IT

Days 1, 15 and 29 Days 1 – 4, 8 – 11, 15 – 18, and 22 – 25 Days 1 – 28 Days 1, 8, 15 and 22***

*Administer

in 250 mL NS over 30 minutes; **Administer in 100 mL D5W over 30 minutes; patient received treatment for occult disease in Phase I, then omit these doses.

***If

the

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.

CONTINUED ON NEXT PAGE…….

Last Updated on September 24, 2007

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 L-Asparaginase (E.Coli) Leucovorin

3000 mg/m2 10 000 units 10 mg/m2

IV* IV** IV/PO

Days 1, 8 and 22 Days 2, 9 and 23 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).

CONTINUED ON NEXT PAGE…………

Last Updated on September 24, 2007

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 Etoposide Vincristine Dexamethasone

75 mg/m2/day 100 mg/m2/day 1.4 mg/m2*** 10 mg/m2/day

IV* IV** IVP PO

Days Days Days Days

1–5 1–5 1, 8, 15 and 22 1 – 28

*Administer

in 500 mL D5W over 30 minutes; **Administer in 500 mL NS over 1 hour; dose is 2 mg.

***Maximum

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. 75 mg/m2/day 100 mg/m2/day

Cytarabine Etoposide *Administer

IV* IV**

Days 1 – 5 Days 1 – 5

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 Cyclophosphamide Cytarabine 6-Thioguanine *Administer

25 mg/m2 650 mg/m2 75 mg/m2 60 mg/m2/day

IVP IV* IV** PO

Days 1, 8, 15 and 22 Day 29 Days 31 – 34 and 38 – 41 Days 29 – 42

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 Etoposide *Administer

75 mg/m2/day 100 mg/m2/day

IV* IV**

Days 1 – 5 Days 1 – 5

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

CONTINUED ON NEXT PAGE…………

Last Updated on September 24, 2007

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 Methotrexate Vincristine

75 mg/m2/day 20 mg/m2/week 1.4 mg/m2*

PO PO/IV IV

Prednisone

60 mg/m2/day

PO

Intrathecal Cytarabine

50 mg

IT

*Maximum

Daily for 2.5 years Once a week for 2.5 years Once every 3 months with prednisone Daily for 5 days every 3 months with vincristine Administer 4 doses, each 3 months apart during maintenance

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.

Last Updated on September 24, 2007

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 Mesna Doxorubicin Vincristine Dexamethasone G-CSF***

300 mg/m2 Q12H 600 mg/m2/day 50 mg/m2 2 mg 40 mg/day 5 mcg/kg BID

IV* CIVI** IV IV PO SQ

Days 1 - 3 Days 1 - 3 Day 4 Days 4 and 11 Days 1 – 4 and 11 – 14 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 Cytarabine Methylprednisolone

CIVI** 800 mg/m2 3000 mg/m2 Q12H IV*** 50 mg BID IV#

G-CSF

5 mcg/kg BID

LeucovorinΩ

15 mg Q6H

PO SQ

Day 1 Days 2 and 3 Days 1 - 3

See below

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.

CONTINUED ON NEXT PAGE………… Last Updated on September 24, 2007

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 Cytarabine

12 mg 100 mg

IT IT

Day 2 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 Unknown risk Low risk

16 treatments 8 treatments 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 Methotrexate Vincristine Prednisone *Take

50 mg TID 20 mg/m2 2 mg 200 mg/day

PO* PO IV PO

Three times daily Once a week Once a month Days 1 - 5 once a month

on an empty stomach.

Repeat cycle every 28 days for 2 years. Reference: Kantarjian HM, et al. J Clin Oncol 2000;18:547 - 61. Last Updated on September 24, 2007

LARSON’S REGIMEN [CALGB STUDY 8811, CALGB 9111] INDUCTION (4 WEEKS IN LENGTH)

Cyclophosphamide Daunorubicin Vincristine Prednisone L-Asparaginase (E.Coli)

1200 mg/m2 45 mg/m2/day 2 mg 60 mg/m2/day 6000 units/m2

IV IV IV PO/IV SQ/IM

Day 1 Days 1 - 3 Days 1, 8, 15 and 22 Days 1 – 21 Days 5, 8, 11, 15, 18 and 22

Dose reduced induction for patient’s aged 60 years of age and older: IV Day 1 Cyclophosphamide 800 mg/m2 IV Days 1 - 3 Daunorubicin 30 mg/m2/day PO/IV Days 1 – 7 Prednisone 60 mg/m2/day

COURSE IIA: EARLY INTENSIFICATION (4 WEEKS IN LENGTH)

Methotrexate INTRATHECAL Cyclophosphamide 6-Mercaptopurine Cytarabine Vincristine L-Asparaginase (E.Coli)

15 mg 1000 mg/m2 60 mg/m2/day 75 mg/m2/day 2 mg 6000 units/m2

IT IV PO SQ IV SQ/IM

Day 1 Day 1 Days 1 – 14 Days 1 – 4 and 8 – 11 Days 15 and 22 Days 15, 18, 22 and 25

COURSE IIB: EARLY INTENSIFICATION CONTINUATION (4 WEEKS IN LENGTH)

Methotrexate INTRATHECAL Cyclophosphamide 6-Mercaptopurine Cytarabine Vincristine L-Asparaginase (E.Coli)

15 mg 1000 mg/m2 60 mg/m2/day 75 mg/m2/day 2 mg 6000 units/m2

IT IV PO SQ IV SQ/IM Days

Day 1 Day 1 Days 1 – 14 Days 1 – 4 and 8 – 11 Days 15 and 22 15, 18, 22 and 25

COURSE III: CNS PROPHYLAXIS AND INTERIM MAINTENANCE (12 WEEKS IN LENGTH) Cranial radiation Methotrexate INTRATHECAL 6-Mercaptopurine Methotrexate

24 15 60 20

Gy mg mg/m2/day mg/m2

IT PO PO

COURSE IV: LATE INTENSIFICATION (8 WEEKS IN LENGTH)

Doxorubicin Vincristine Dexamethasone Cyclophosphamide 6-Thioguanine Cytarabine

30 mg/m2 2 mg 10 mg/m2/day 1000 mg/m2 60 mg/m2/day 75 mg/m2/day

IV IV PO IV PO SQ

Days Days Days Days

1 – 12 1, 8, 15, 22 and 29 1 – 70 36, 43, 50, 57 and 64

Days 1, 8, and 15 Days 1, 8, and 15 Days 1 – 14 Day 29 Days 29 – 42 Days 29 – 32 and 36 - 39

COURSE V: MAINTENANCE (TO CONTINUE UNTIL 24 MONTHS POST-DIAGNOSIS) Vincristine Prednisone 6-Mercaptopurine Methotrexate

2 mg 60 mg/m2/day 60 mg/m2/day 20 mg/m2

IV PO PO PO

Day 1 every 4 weeks Days 1 – 5 of every 4 weeks Days 1 – 28 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.

Last Updated on September 24, 2007

T-CELL ALL NELARABINE (ADULT REGIMEN) Nelarabine

*Administer

1500 mg/m2/day

IV*

Days 1, 3 and 5

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

*Administer

650 mg/m2

IV*

Days 1 - 5

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.

Last Updated on September 24, 2007

ALL - SALVAGE THERAPY CYTARABINE – IDARUBICIN

Cytarabine Idarubicin G-CSF Methotrexate *Administer

diagnosis.

3000 mg/m2/day 40 mg/m2 Not specified 12 mg

IV* IV SQ IT

Days 1 - 5 Day 3 Day 7 until ANC recovery Weekly until CSF clear**

over 3 hours; **Only administer intrathecal therapy if CNS disease is present at

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

*Administer

40 mg/m2

IV*

Days 1 – 5

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

*Administer

52 mg/m2

IV*

Days 1 – 5

over 2 hours.

Repeat cycle every 2 – 6 weeks. Reference: Genzyme Corporation. Clolar package insert. Cambridge, MA: December 2004.

Last Updated on September 24, 2007

ALL B-CELL (L3) SUBTYPE CALGB 9251 CYCLE 1

Cyclophosphamide Prednisone

200 mg/m2/day 60 mg/m2/day

IV PO

Days 1 – 5 Days 1 – 7

CYCLE 2, 4 AND 6 (NOTE: START CYCLE 2 ON DAY 8 OF CYCLE 1)

Ifosfamide Mesna Methotrexate

800 mg/m2/day 200 mg/m2/day 150 mg/m2

IV* IV IV***

Days 1 – 5 3 doses per day** Day 1

Followed by Methotrexate Leucovorin

1350 mg/m2 50 mg/m2

CIVI# IV

Day 1 Starting 36 hours after the start of methotrexate for 1 dose

Followed 6 hours later by Leucovorin

15 mg/m2 Q6H

IV/PO

Vincristine Cytarabine Etoposide Dexamethasone

2 mg 150 mg/m2/day 80 mg/m2/day 10 mg/m2/day

IVP CIVIφ IV* PO

Until methotrexate level is less than 1 x 10-8M Day 1 Days 4 and 5 Days 4 and 5 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 Methotrexate

200 mg/m2/day 150 mg/m2

IV IV*

Days 1 – 5 Day 1

Followed by Methotrexate Leucovorin

1350 mg/m2 50 mg/m2

CIVI** IV

Day 1 Starting 36 hours after the start of methotrexate for 1 dose

Followed 6 hours later by Leucovorin

15 mg/m2 Q6H

IV/PO

Vincristine Doxorubicin Dexamethasone

2 mg 25 mg/m2/day 10 mg/m2/day

IVP IVB PO

*Administer

over 30 minutes; **Administer over 23.5 hours.

Until methotrexate level is less than 1 x 10-8M Day 1 Days 4 and 5 Days 1 – 5

CONTINUED ON NEXT PAGE…..

Last Updated on September 24, 2007

CALGB 9251 CONTINUED INTRATHECAL THERAPY Methotrexate Cytarabine Hydrocortisone

15 mg 40 mg 50 mg

IT IT IT

Day 1 of Cycles 2 - 7 Day 1 of Cycles 2 - 7 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.

Last Updated on September 24, 2007

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 Cyclophosphamide *Administer

60 mg/m2/day 200 mg/m2/day

PO IV*

Days 1 - 5 Days 1 – 5

over 1 hour.

CYCLE A (3 - 4 WEEKS IN LENGTH)

Intrathecal MTX 15mg/Ara-C 40mg/Dexamethasone 4mg IT Vincristine 2 mg IV IV* Methotrexate 150 mg/m2

Days 1 and 5 Day 1 Day 1

Followed by Methotrexate Leucovorin Ifosfamide Teniposide Cytarabine Dexamethasone

1350 mg/m2 See below 800 mg/m2/day 100 mg/m2/day 150 mg/m2 Q12H 10 mg/m2/day

IV** IV/PO*** IV# IV IVφ PO

Day 1 See below Days 1 – 5 Days 4 and 5 Days 4 and 5 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 Vincristine 2 mg IV IV* Methotrexate 150 mg/m2

Day 1 Day 1 Day 1

Followed by Methotrexate Leucovorin Cyclophosphamide Doxorubicin Dexamethasone

1350 mg/m2 See next page 200 mg/m2/day 25 mg/m2/day 10 mg/m2/day

IV** IV/PO*** IV IV# PO

Day 1 See next page Days 1 - 5 Days 4 and 5 Days 1 - 5

CONTINUED ON NEXT PAGE…… Last Updated on September 24, 2007

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

Last Updated on September 24, 2007

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 Cyclophosphamide Mesna Doxorubicin Vincristine Dexamethasone G-CSF#

375 mg/m2 300 mg/m2 Q12H 600 mg/m2/day 50 mg/m2 2 mg 40 mg/day 10 mcg/kg/day

IV IV* CIVI** CIV*** IV PO/IV SQ

Days 1 and 11 Days 1 - 3 Days 1 - 3 Day 4 Days 4 and 11 Days 1 – 4 and 11 – 14 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 Methotrexate Cytarabine Leucovorin

375 mg/m2 IV 2 CIVI* 1000 mg/m 3000 mg/m2 Q12H IV** PO/IV 50 mg***

Days 2 and 8 Day 1 Days 2 and 3 x 1 dose (see below)

Followed 6 hours later by Leucovorin G-CSF

15 mg*** 10 mcg/kg/day

PO/IV SQ

See below 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.

CONTINUED ON NEXT PAGE………… Last Updated on September 24, 2007

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 Cytarabine *Patients

12 mg* 100 mg

IT IT

Day 2 Day 7

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.

Last Updated on September 24, 2007

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 Mesna Doxorubicin Vincristine Dexamethasone Imatinib mesylate G-CSF

300 mg/m2 Q12H 600 mg/m2/day 50 mg/m2 2 mg 40 mg/day 400 mg/day 10 mcg/kg/day

IV* CIVI** CIVI*** IV PO/IV PO SQ

Days 1 - 3 Days 1 - 3 Day 4 Days 4 and 11 Days 1 – 4 and 11 – 14 Days 1 - 14Φ 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).

CONTINUED ON NEXT PAGE……. Last Updated on September 24, 2007

HYPER CVAD + IMATINIB (GLEEVEC®) CONTINUED COURSE 2, 4, 6 AND 8 (PART B)

Methotrexate Leucovorin

1000 mg/m2 50 mg

CIVI* IV**

Day 1 x 1 dose (see notes)

Followed 6 hours later by Leucovorin

15 mg IV Q6H

IV**

See notes (next page)

Cytarabine Imatinib mesylate G-CSF

3000 mg/m2 Q12H 400 mg/dayΦ 10 mcg/kg/day

IV*** PO SQ

Days 2 and 3 Days 1 - 14 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 trimethoprimsulfamethoxazole 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).

CONTINUED ON NEXT PAGE…….

Last Updated on September 24, 2007

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 Cytarabine

12 mg * 100 mg

IT IT

Day 2 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 Vincristine Prednisone

*Administered

600 mg/day 2 mg 200 mg/day

PO IV PO

Daily Q month Days 1 - 5*

once a month, starting the day of vincristine administration.

Reference: Thomas DA, et al. Blood 2004;103:4396 – 407.

Last Updated on September 24, 2007