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):

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:

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:

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:
  • 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

Hyper-CVAD & Dasatinib (Sprycel) (induction & maintenance)

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

Regimen

For patients with Philadelphia chromosome (Ph+) disease
Part A (cycles 1, 3, 5, 7):

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

Supportive medications:

  • 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:
  • 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
  • Cycle 1 also involved:
    • Hydration options included D5 water or 1/2 NS with 75-100 mEq sodium acetate per liter at 50-100 mL/H
    • Allopurinol to decrease likelihood of tumor lysis syndrome; rasburicase could be used instead for patients with high white blood cell counts at initial presentation
    • Oral sodium bicarbonate (no dosage or frequency listed) on days 1-3

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

  • Methotrexate (MTX) 1000 mg/m2 IV over 24 hours on day 1
  • Cytarabine (Cytosar) 3000 mg/m2 (1000 mg/m2 for patients at least 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
    • Leucovorin rescue with Folinic acid (Leucovorin) 50 mg IV Q6H if methotrexate blood levels were greater than 20 uM at 0 hours after completion of MTX; >1 uM at 24 hours; >0.1 uM at 48 hours
  • Dasatinib (Sprycel) 50 mg PO BID (or, alternatively, 100 mg PO daily) on days 1-14

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

Supportive medications:

  • 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:
  • D5W or 1/2 NS with 75-100 mEq sodium acetate per liter at 100-125 mL/H
  • 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
  • Acetazolamide (Diamox) (no dosage/schedule listed) used if urine pH <7 to promote excretion

CNS prophylaxis:

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 of at least 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:
  • Therapeutic external radiation is given to patients with CNS disease at presentation

Maintenance therapy for 2 years after completing 8 cycles of the intensive Part A and Part B chemotherapy:

28-day cycles x 2 years; maintenance therapy could be interrupted by provider's choice--typically only given to people with at least minimal residual disease (MRD) or more--in month 6 and 13 to give Hyper-CVAD Part A x 1 cycle

Then, after 2 years of maintenance therapy:

References

  1. Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. link to original article contains verified protocol--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas, et al. 2004 and Kantarjian, et al. 2004 PubMed

Hyper-CVAD & Imatinib (Gleevec) (induction & maintenance)

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

Regimen

For patients with Philadelphia chromosome (Ph+) disease
Part A (cycles 1, 3, 5, 7):

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

Supportive medications:

  • 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:
  • 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
  • Cycle 1 also involved:
    • Hydration options included D5 water or 1/2 NS with 75-100 mEq sodium acetate per liter at 50-100 mL/H
    • Allopurinol to decrease likelihood of tumor lysis syndrome; rasburicase could be used instead for patients with high white blood cell counts at initial presentation
    • Oral sodium bicarbonate (no dosage or frequency listed) on days 1-3

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

  • Methotrexate (MTX) 1000 mg/m2 IV over 24 hours on day 1
  • Cytarabine (Cytosar) 3000 mg/m2 (1000 mg/m2 for patients at least 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
    • Leucovorin rescue with Folinic acid (Leucovorin) 50 mg IV Q6H if methotrexate blood levels were greater than 20 uM at 0 hours after completion of MTX; >1 uM at 24 hours; >0.1 uM at 48 hours
  • Imatinib (Gleevec) 400 mg PO daily on days 1-14

Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used absolute neutrophil count > 1 x 10^9/L at least 24 hours off of G-CSF and platelet count > 60 x 10^9/L

Supportive medications:

  • 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:
  • D5W or 1/2 NS with 75-100 mEq sodium acetate per liter at 100-125 mL/H
  • 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
  • Acetazolamide (Diamox) (no dosage/schedule listed) used if urine pH <7 to promote excretion

CNS prophylaxis:

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 of at least 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:
  • Therapeutic external radiation is given to patients with CNS disease at presentation

Maintenance therapy after completing 8 cycles of the intensive Part A and Part B chemotherapy:

28-day cycles x 5 cycles; then, in month 6, Hyper-CVAD Part A x 1 cycle as described above; then resume maintenance therapy, 28-day cycles x 6 cycles; then, in month 13, Hyper-CVAD Part A x 1 cycle as described above

References

  1. Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. link to original article contains verified protocol PubMed

Larson/CALGB 8811 regimen (induction)

Regimen

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

For patients ≥60 years old:

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

If bone marrow on day 14 has residual leukemia:

If bone marrow on day 28 has residual leukemia:

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):

28-day cycles x 2 cycles

Course III (CNS prophylaxis and interim maintenance):

12-week course

Course IV (late intensification):

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):

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

Treatment C (cycle 9):

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

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):

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

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

Relapsed disease

Vincristine liposomal (Marqibo)

Regimen

7-day cycles

References

  1. Jeffrey A. Silverman, Walter Aulitzky, John Lister, Lori Maness, Gary Schiller, Karen Seiter, Scott E. Smith, Wendy Stock, Dina Ben Yehuda, Steven R. Deitcher. Marqibo® (vincristine sulfate liposomes injection; VSLI) Optimizes the Dosing, Delivery, and Pharmacokinetic (PK) Profile of Vincristine Sulfate (VCR) in Adults with Relapsed and Refractory Acute Lymphoblastic Leukemia (ALL). ASH 2010 abstract 2142. link to abstract
  2. Vincristine liposomal (Marqibo) package insert
  3. Marqibo completed trials summary at Talon Therapeutics
  4. FDA drug approval announcement for vincristine sulfate liposome injection (Marqibo) on 8/9/2012
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