B-cell acute lymphoblastic leukemia

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Induction therapy

Hyper-CVAD (induction)

Hyper-CVAD: Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone

Regimen

Part A (cycles 1, 3, 5, 7):

• Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours Q12H on days 1-3 (6 total doses)
• Mesna (Mesnex) 600 mg/m2/day IV continuous infusion on days 1-3, starting 1 hour before cytoxan and completed 12 hours after the last dose of cytoxan
• Vincristine (Oncovin) 2mg IV on days 4 & 11
• Doxorubicin (Adriamycin) 50 mg/m2 IV over 24 hours (over 48 hours in patients with ejection fractions (EF) <50%) on day 4
• Dexamethasone (Decadron) 40 mg PO/IV on days 1-4, 11-14

Next cycle to start as soon as absolute neutrophil count is > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

Part B (cycles 2, 4, 6, 8):

• Methotrexate (MTX) 200 mg/m2 IV over 2 hours, then 800 mg/m2 IV over 22 hours on day 1
• Cytarabine (Cytosar) 3000 mg/m2 (1000 mg/m2 for patients ≥60 years old) IV over 2 hours Q12H on days 2 & 3 (4 total doses)
• Folinic acid (Leucovorin) 50 mg IV x1 12 hours after methotrexate is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM

Next cycle to start as soon as absolute neutrophil count is > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

CNS prophylaxis:

• Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
• Cytarabine (Cytosar) 100 mg IT on day 7 OR 8

Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) >1400 IU/L and/or proliferative index percentage of S + G2M ≥14%

For known CNS disease:

• Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT alternating with Cytarabine (Cytosar) 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
• Then Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and Cytarabine (Cytosar) 100 mg IT, given weeks 2 & 4
• Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
  • Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
  • Cytarabine (Cytosar) 100 mg IT on day 7 OR 8

Supportive care:

• One of the following antibiotics:
  • EITHER Ciprofloxacin (Cipro) 500 mg PO BID
  • OR Levofloxacin (Levaquin) 500 mg PO daily
  • OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID
• Fluconazole (Diflucan) 200 mg PO daily
• One of the following antivirals:
  • EITHER Acyclovir (Zovirax) 200 mg PO BID
  • OR Valacyclovir (Valtrex) 500 mg PO daily
• Filgrastim (Neupogen) 10 mcg/kg SC daily starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC >1 x 10^9/L

Certain patient populations (see Kantarjian, et al. 2004) received additional Hyper-CVAD maintenance therapy.

References

1. Cortes J, O'Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995 Sep 15;86(6):2091-7. link to original article PubMed
2. Thomas DA, O'Brien S, Cortes J, Giles FJ, Faderl S, Verstovsek S, Ferrajoli A, Koller C, Beran M, Pierce S, Ha CS, Cabanillas F, Keating MJ, Kantarjian H. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood. 2004 Sep 15;104(6):1624-30. Epub 2004 Jun 3. link to original article contains verified protocol PubMed
3. Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. link to original article contains verified protocol PubMed

Larson/CALGB 8811 regimen (induction)

Regimen

Course I (induction):
For patients <60 years old:

• Cyclophosphamide (Cytoxan) 1200 mg/m2 IV on day 1
• Daunorubicin (Cerubidine) 45 mg/m2 IV on days 1-3
• Vincristine (Oncovin) 2 mg IV on days 1, 8, 15, 22
• Prednisone (Sterapred) 60 mg/m2 PO on days 1-21
• Asparaginase (Elspar) 6000 units/m2 SC on days 5, 8, 11, 15, 18, 22

For patients ≥60 years old:

• Cyclophosphamide (Cytoxan) 800 mg/m2 IV on day 1
• Daunorubicin (Cerubidine) 30 mg/m2 IV on days 1-3
• Vincristine (Oncovin) 2 mg IV on days 1, 8, 15, 22
• Prednisone (Sterapred) 60 mg/m2 PO on days 1-7
• Asparaginase (Elspar) 6000 units/m2 SC on days 5, 8, 11, 15, 18, 22

To be followed by Larson/CALGB 8811 regimen courses II-IV (maintenance).

References

1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed

Linker regimen (induction)

Regimen

• Daunorubicin (Cerubidine) 50 mg/m2 IV on days 1-3
• Vincristine (Oncovin) 2 mg IV on days 1, 8, 15, 22
• Prednisone (Sterapred) 60 mg/m2 PO on days 1-28
• Asparaginase (Elspar) 6000 units/m2 IM on days 17-28

If bone marrow on day 14 has residual leukemia:

• Daunorubicin (Cerubidine) 50 mg/m2 IV on day 15

If bone marrow on day 28 has residual leukemia:

• Daunorubicin (Cerubidine) 50 mg/m2 IV on days 29 & 30
• Vincristine (Oncovin) 2 mg IV on days 29 & 36
• Prednisone (Sterapred) 60 mg/m2 PO on days 29-42
• Asparaginase (Elspar) 6000 units/m2 IM on days 29-35

Central nervous system (CNS) prophylaxis for patients without CNS involvement at diagnosis is started within 1 week of achieving complete remission:

• Cranial radiation, 18 Gy total given in 10 fractions over 12-14 days
• Methotrexate (MTX) 12 mg IT weekly x 6 doses concurrent with radiation

Central nervous system (CNS) treatment for patients with CNS involvement at diagnosis:

• Cranial radiation, 28 Gy total given
• Methotrexate (MTX) 12 mg IT weekly x 10 doses that starts while they are receiving induction therapy, then given monthly during the first year of therapy

To be followed by Linker regimen consolidation therapy.

References

1. Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains verified protocol PubMed
2. Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains verified protocol PubMed

Consolidation therapy

Larson/CALGB 8811 regimen (consolidation)

Preceded by Larson/CALGB 8811 regimen course I (induction).

Regimen

Course II (early intensification):

• Methotrexate (MTX) 15 mg IT on day 1
• Cyclophosphamide (Cytoxan) 1000 mg/m2 IV on day 1
• Mercaptopurine (Purinethol) 60 mg/m2 PO on days 1-14
• Cytarabine (Cytosar) 75 mg/m2 SC on days 1-4, 8-11
• Vincristine (Oncovin) 2 mg IV on days 15 & 22
• Asparaginase (Elspar) 6000 units/m2 SC on days 15, 18, 22, 25

28-day cycles x 2 cycles

Course III (CNS prophylaxis and interim maintenance):

• Cranial radiation, 24 Gy total given in 10 fractions from days 1-12
• Methotrexate (MTX) 15 mg IT on days 1, 8, 15, 22, 29
• Mercaptopurine (Purinethol) 60 mg/m2 PO on days 1-70
• Methotrexate (MTX) 20 mg/m2 PO on days 36, 43, 50, 57, 64

12-week course

Course IV (late intensification):

• Doxorubicin (Adriamycin) 30 mg/m2 IV on days 1, 8, 15
• Vincristine (Oncovin) 2 mg IV on days 1, 8, 15
• Dexamethasone (Decadron) 10 mg/m2 PO on days 1-14
• Cyclophosphamide (Cytoxan) 1000 mg/m2 IV on day 29
• Thioguanine (Tabloid) 60 mg/m2 PO on days 29-42
• Cytarabine (Cytosar) 75 mg/m2 SC on days 29-32, 36-39

8-week course

To be followed by Larson/CALGB 8811 regimen course V (maintenance).

References

1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed

Linker regimen (consolidation)

Preceded by Linker regimen induction therapy.

Regimen

Treatment A (cycles 1, 3, 5, 7):

• Daunorubicin (Cerubidine) 50 mg/m2 IV on days 1 & 2
• Vincristine (Oncovin) 2 mg IV on days 1 & 8
• Prednisone (Sterapred) 60 mg/m2 PO on days 1-14
• Asparaginase (Elspar) 12000 units/m2 IM on days 2, 4, 7, 9, 11, 14

Treatment B (cycles 2, 4, 6, 8):

• Teniposide (Vumon) 165 mg/m2 IV on days 1, 4, 8, 11
• Cytarabine (Cytosar) 300 mg/m2 IV on days 1, 4, 8, 11

Treatment C (cycle 9):

• Methotrexate (MTX) 690 mg/m2 IV over 42 hours on day 1
• Folinic acid (Leucovorin) 15 mg/m2 IV every 6 hours x 12 doses, starting after methotrexate is complete (at 42 hours)

• Prednisone (Sterapred) 60 mg/m2 PO on days 1-14
• Asparaginase (Elspar) 12000 units/m2 IM on days 2, 4, 7, 9, 11, 14

Central nervous system (CNS) prophylaxis for patients without CNS involvement at diagnosis is started within 1 week of achieving complete remission:

• Cranial radiation, 18 Gy total given in 10 fractions over 12-14 days
• Methotrexate (MTX) 12 mg IT weekly x 6 doses concurrent with radiation

To be followed by Linker regimen maintenance therapy.

References

1. Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains verified protocol PubMed content property of HemOnc.org
2. Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains verified protocol PubMed

Maintenance therapy

Hyper-CVAD (maintenance)

Preceded by Hyper-CVAD (induction).

Regimen

• Mercaptopurine (Purinethol) 1000 mg/m2 IV over 1 hour x 5 days
• Methotrexate (MTX) 10 mg/m2 IV over 1 hour x 5 days
• Vincristine (Oncovin) 2mg IV once per month
• Prednisone (Sterapred) 200 mg PO daily x 5 days

Supportive care (for the first 6 months):

• Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) PO BID on Saturday and Sunday
• One of the following antivirals:
  • EITHER Acyclovir (Zovirax) 200 mg PO daily or 3 times per week
  • OR Valacyclovir (Valtrex) 500 mg PO daily or 3 times per week

References

1. Kantarjian H, Thomas D, O'Brien S, Cortes J, Giles F, Jeha S, Bueso-Ramos CE, Pierce S, Shan J, Koller C, Beran M, Keating M, Freireich EJ. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004 Dec 15;101(12):2788-801. link to original article contains verified protocol PubMed

Larson/CALGB 8811 regimen (maintenance)

Preceded by Larson/CALGB 8811 regimen courses II-IV (consolidation).

Regimen

Course V (prolonged maintenance):

• Vincristine (Oncovin) 2 mg IV on day 1
• Prednisone (Sterapred) 60 mg/m2 PO on days 1-5
• Methotrexate (MTX) 20 mg/m2 PO on days 1, 8, 15, 22
• Mercaptopurine (Purinethol) 60 mg/m2 PO on days 1-28

28-day cycles, continue until 24 months from diagnosis

References

1. Larson RA, Dodge RK, Burns CP, Lee EJ, Stone RM, Schulman P, Duggan D, Davey FR, Sobol RE, Frankel SR, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood. 1995 Apr 15;85(8):2025-37. link to original article contains verified protocol PubMed

Linker regimen (maintenance)

Preceded by Linker regimen consolidation therapy.

Regimen

• Methotrexate (MTX) 20 mg/m2 PO weekly x 30 months
• Mercaptopurine (Purinethol) 75 mg/m2 PO daily x 30 months

References

1. Linker CA, Levitt LJ, O'Donnell M, Ries CA, Link MP, Forman SJ, Farbstein MJ. Improved results of treatment of adult acute lymphoblastic leukemia. Blood. 1987 Apr;69(4):1242-8. link to original article contains verified protocol PubMed
2. Linker CA, Levitt LJ, O'Donnell M, Forman SJ, Ries CA. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood. 1991 Dec 1;78(11):2814-22. link to original article contains verified protocol PubMed