B-cell acute lymphoblastic leukemia

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Induction therapy

Hyper-CVAD (induction)

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

Regimen

Phase II

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

• Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours Q12H on days 1 to 3 (6 total doses)
• Vincristine (Oncovin) 2 mg IV once 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 once daily on days 1 to 4, 11 to 14

Supportive care:

• Mesna (Mesnex) 600 mg/m2/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
• 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

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)

Supportive care:

• Folinic acid (Leucovorin) 50 mg IV x1 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM
• 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

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

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, Cortes J, O'Brien S, Pierce S, Faderl S, Albitar M, Hagemeister FB, Cabanillas FF, Murphy S, Keating MJ, Kantarjian H. Hyper-CVAD program in Burkitt's-type adult acute lymphoblastic leukemia. J Clin Oncol. 1999 Aug;17(8):2461-70. link to original article contains verified protocol PubMed
3. 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
4. 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)

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

Regimen

Phase II

For patients with Philadelphia chromosome (Ph⁺) disease

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

• Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours Q12H on days 1 to 3 (6 total doses)
• Vincristine (Oncovin) 2 mg IV once 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 once daily on days 1 to 4, 11 to 14
• Dasatinib (Sprycel) 50 mg PO BID (or, alternatively, 100 mg PO daily) on days 1 to 14

Supportive care:

• Mesna (Mesnex) 600 mg/m2/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
• 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
• Cycle 1 also involved:
  • Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
  • Allopurinol (Zyloprim) 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 to 3

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

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)
• Dasatinib (Sprycel) 50 mg PO BID (or, alternatively, 100 mg PO daily) on days 1 to 14

Supportive medications:

• Folinic acid (Leucovorin) 50 mg IV x1 12 hours after Methotrexate (MTX) 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 serum methotrexate levels were greater than 20 uM at 0 hours after completion of Methotrexate (MTX); >1 uM at 24 hours; >0.1 uM at 48 hours
• 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
• D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 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

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

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

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:
  • Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
  • Cytarabine (Cytosar) 100 mg IT on day 7
• Therapeutic external radiation is given to patients with CNS disease at presentation

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

Phase II

For patients with Philadelphia chromosome (Ph⁺) disease

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

• Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours Q12H on days 1 to 3 (6 total doses)
• Vincristine (Oncovin) 2 mg IV once 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 once daily on days 1 to 4, 11 to 14
• Imatinib (Gleevec) 400 mg PO daily on days 1 to 14

Supportive care:

• Mesna (Mesnex) 600 mg/m2/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
• 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
• Cycle 1 also involved:
  • Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
  • Allopurinol (Zyloprim) 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 to 3

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

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)
• Imatinib (Gleevec) 400 mg PO daily on days 1 to 14

Supportive medications:

• Folinic acid (Leucovorin) 50 mg IV x1 12 hours after Methotrexate (MTX) 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 serum methotrexate levels were greater than 20 uM at 0 hours after completion of Methotrexate (MTX); >1 uM at 24 hours; >0.1 uM at 48 hours
• 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
• D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 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

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

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 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:
  • 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
• 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:

• Imatinib (Gleevec) 600 mg PO daily on days 1 to 28
• Vincristine (Oncovin) 2 mg IV once on day 1
• Prednisone (Sterapred) 200 mg PO daily on days 1 to 5

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

International ALL Trial (MRC UKALL XII/ECOG E2993)

Regimen

Phase II

To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 90%. There are many local variants of this protocol, including substitution of peg-asparaginase for L-asparaginase.

Phase I, weeks 1 to 4

• Daunorubicin (Cerubidine) 65 mg/m2 IV once per day on days 1, 8, 15, 22
• Vincristine (Oncovin) 1.4 mg/m2 IV once per day on days 1, 8, 15, 22
• Asparaginase (Elspar) 10,000 units IV or IM once per day on days 17 to 28
• Prednisone (Sterapred) 60 mg/m2 PO once daily on days 1 to 28

CNS prophylaxis

• Methotrexate (MTX) 12 mg IT once on day 15

Phase II, weeks 5 to 8

• Cyclophosphamide (Cytoxan) 650 mg/m2 IV once per day on days 1, 15, 29
• Cytarabine (Cytosar) 75 mg/m2 IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25
• Mercaptopurine (Purinethol) 6 mg/m2 PO once per day on days 1 to 28

CNS prophylaxis

• Methotrexate (MTX) 12 mg IT once per day on days 1, 8, 15, 22

To be followed by consolidation portion of the protocol.

References

1. Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains verified protocol PubMed

Larson/CALGB 8811 regimen (induction)

Regimen

Phase II

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

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

For patients ≥60 years old:

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

To be followed by Larson/CALGB 8811 regimen courses II to 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

Regimen

Phase II

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

If bone marrow on day 14 has residual leukemia:

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

If bone marrow on day 28 has residual leukemia:

• Daunorubicin (Cerubidine) 50 mg/m2 IV once on days 29 & 30
• Vincristine (Oncovin) 2 mg IV once on days 29 & 36
• Prednisone (Sterapred) 60 mg/m2 PO once daily on days 29 to 42
• Asparaginase (Elspar) 6000 units/m2 IM on days 29 to 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. Update: 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

R-Hyper-CVAD

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

Regimen

Pilot, <20 patients reported

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

• Rituximab (Rituxan) 375 mg/m2 IV over 2 to 6 hours once on days 1 & 11 (cycles 1 & 3, only)
• Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours Q12H on days 1 to 3 (6 total doses)
• Vincristine (Oncovin) 2 mg IV once on days 4 & 11
• Doxorubicin (Adriamycin) 50 mg/m2 IV over 24 hours on day 4
• Dexamethasone (Decadron) 40 mg PO/IV once daily on days 1 to 4, 11 to 14

Supportive care:

• Mesna (Mesnex) 600 mg/m2/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
• Filgrastim (Neupogen) 10 mcg/kg SC daily starting 24 hours after completion of chemotherapy, given until WBC >3 x 10^9/L or bone pain present
• One of the following antibiotics:
  • EITHER Quinolone
  • OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) dose/route not specified
• Fluconazole (Diflucan) dose/route not specified
• One of the following antivirals:
  • EITHER Acyclovir (Zovirax) dose/route not specified
  • OR Valacyclovir (Valtrex) dose/route not specified

Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is > 3 x 10^9/L and platelet count > 50 x 10^9/L

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

• Rituximab (Rituxan) 375 mg/m2 IV over 2 to 6 hours once on days 2 & 8 (cycles 2 & 4, only)
• Methotrexate (MTX) 1000 mg/m2 IV over 24 hours on day 1
• Cytarabine (Cytosar) 3000 mg/m2 IV over 2 hours Q12H on days 2 & 3 (4 total doses)

Supportive care:

• Folinic acid (Leucovorin) 50 mg IV x1 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM
• Filgrastim (Neupogen) 10 mcg/kg SC daily starting 24 hours after completion of chemotherapy, given until WBC >3 x 10^9/L or bone pain present
• One of the following antibiotics:
  • EITHER Quinolone
  • OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) dose/route not specified
• Fluconazole (Diflucan) dose/route not specified
• One of the following antivirals:
  • EITHER Acyclovir (Zovirax) dose/route not specified
  • OR Valacyclovir (Valtrex) dose/route not specified

Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is > 3 x 10^9/L and platelet count > 50 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

Given each cycle for a total of 16 intrathecal treatments. If CNS disease present, therapy augmented to twice-weekly alternating (MTX, ara-C) treatments until CSF cell count normalizes and cytology is negative, then continues for 4 more alternating weekly treatments; prophylaxis course then resumes.

Dose modifications:

• Cytarabine (Cytosar) reduced to 1000 mg/m2 for patients ≥60 years old, creatinine ≥1.5 mg/dL or 0 hour MTX level ≥ 20 μmol/L
• Vincristine (Oncovin) reduced to 1 mg for bilirubin > 2 mg/dL or NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted for bilirubin > 3 mg/dL or for ileus
• Doxorubicin (Adriamycin) reduced by 50% for bilirubin 2 to 3 mg/dL, by 75% for bilirubin 3 to 5 mg/dL (eliminated for bilirubin > 5 mg/dL or for gastric/small-bowel involvement with Course 1 to reduce duration of myelosuppression given risk of perforation)
• Methotrexate (MTX) reduced by 50% for creatinine clearance 10 to 50 mL/min (eliminated for < 10 mL/min), by 25% to 75% for delayed excretion and/or nephrotoxicity with prior course (dependent on severity) or by 50% for pleural effusions/ascites with drainage of fluid as feasible.

References

1. Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80. link to original article contains verified protocol PubMed

Consolidation therapy

International ALL Trial (MRC UKALL XII/ECOG E2993)

Regimen

Phase II

To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 90%. There are many local variants of this protocol, including substitution of peg-asparaginase for L-asparaginase, and omission of cranial irradiation.

Preceded by induction portion of the protocol.

Phase III, "Intensification"

• Methotrexate (MTX) 3 g/m2 IV once per day on days 1, 8, 22
• Asparaginase (Elspar) 10,000 units (route not specified) once per day on days 2, 9, 23

Supportive medications:

• Folinic acid (Leucovorin) at "standard" doses

3 cycles (length of cycle not specified in original reference)

For patients randomized to transplantation (autologous or allogeneic), no further therapy was specified, except that Ph+ patients were given interferon for another 15 months.

Phase IV, "Consolidation"

Cycle 1

• Cytarabine (Cytosar) 75 mg/m2 IV once per day on days 1 to 5
• Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
• Vincristine (Oncovin) 1.4 mg/m2 IV once per day on days 1, 8, 15, 22
• Dexamethasone (Decadron) 10 mg/m2 PO once per day on days 1 to 28

Cycle 2

To start 4 weeks after Cycle 1

• Cytarabine (Cytosar) 75 mg/m2 IV once per day on days 1 to 5
• Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5

Cycle 3

To start 4 weeks after Cycle 2

• Daunorubicin (Cerubidine) 25 mg/m2 IV once per day on days 1, 8, 15, 22
• Cyclophosphamide (Cytoxan) 650 mg/m2 IV once on day 29
• Cytarabine (Cytosar) 75 mg/m2 IV once per day on days 31 to 34, 38 to 41
• Thioguanine (Tabloid) 60 mg/m2 PO once per day on days 29 to 42

Cycle 4

To start 8 weeks after Cycle 3

• Cytarabine (Cytosar) 75 mg/m2 IV once per day on days 1 to 5
• Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5

CNS Prophylaxis

• Cytarabine (Cytosar) 50 mg IT weekly x 4 weeks, then quarterly x 4 doses (8 doses, total)
• Cranial irradiation to 2400 cGy

To be followed by maintenance portion of the protocol.

References

1. Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains verified protocol PubMed

Larson/CALGB 8811 regimen (consolidation)

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

Regimen

Phase II

Course II (early intensification):

• Methotrexate (MTX) 15 mg IT on day 1
• Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
• Mercaptopurine (Purinethol) 60 mg/m2 PO once daily on days 1 to 14
• Cytarabine (Cytosar) 75 mg/m2 SC once daily on days 1 to 4, 8 to 11
• Vincristine (Oncovin) 2 mg IV once on days 15 & 22
• Asparaginase (Elspar) 6000 units/m2 SC once 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 to 12
• Methotrexate (MTX) 15 mg IT on days 1, 8, 15, 22, 29
• Mercaptopurine (Purinethol) 60 mg/m2 PO once daily on days 1 to 70
• Methotrexate (MTX) 20 mg/m2 PO once on days 36, 43, 50, 57, 64

12-week course

Course IV (late intensification):

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

Phase II

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

• Daunorubicin (Cerubidine) 50 mg/m2 IV once on days 1 & 2
• Vincristine (Oncovin) 2 mg IV once on days 1 & 8
• Prednisone (Sterapred) 60 mg/m2 PO once daily on days 1 to 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 once on days 1, 4, 8, 11
• Cytarabine (Cytosar) 300 mg/m2 IV once on days 1, 4, 8, 11

Treatment C (cycle 9)

• Methotrexate (MTX) 690 mg/m2 IV over 42 hours on day 1
• Prednisone (Sterapred) 60 mg/m2 PO once daily on days 1 to 14
• Asparaginase (Elspar) 12000 units/m2 IM on days 2, 4, 7, 9, 11, 14

Supportive medications:

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

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. Update: 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) - POMP

Preceded by Hyper-CVAD (induction).

POMP: 6-MP, Oncovin, Methotrexate, Prednisone

Regimen

Phase II

Kantarjian et al. 2004 said how many days each drug is given per month, but did not specifically say, for example, that certain drugs are taken on days 1 to 5 of the cycle.

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

Supportive medications:

• Trimethoprim/Sulfamethoxazole (dosage not listed) PO BID on Saturday and Sunday for the first 6 months
• One of the following antivirals:
  • EITHER Acyclovir (Zovirax) 200 mg PO once daily or 3 times per week for the first 6 months
  • OR Valacyclovir (Valtrex) 500 mg PO once daily or 3 times per week for the first 6 months

1-month cycles

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

Hyper-CVAD & Dasatinib (Sprycel)

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

Regimen

Phase II

For patients with Philadelphia chromosome (Ph⁺) disease

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

• Dasatinib (Sprycel) 50 mg PO BID (or, alternatively, 100 mg PO daily) on days 1 to 28
• Vincristine (Oncovin) 2 mg IV once on day 1
• Prednisone (Sterapred) 200 mg PO daily on days 1 to 5

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:

• Dasatinib (Sprycel) 50 mg PO BID (or, alternatively, 100 mg PO daily), continued indefinitely

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

International ALL Trial (MRC UKALL XII/ECOG E2993)

Regimen

Phase II

To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 90%. There are many local variants of this protocol, including substitution of peg-asparaginase for L-asparaginase, and omission of cranial irradiation.

Preceded by consolidation portion of the protocol.

• Vincristine (Oncovin) 1.4 mg/m2 IV once every 3 months
• Prednisone (Sterapred) 60 mg/m2 PO once per day for 5 days every 3 months
• Mercaptopurine (Purinethol) 75 mg/m2 PO once per day
• Methotrexate (MTX) 20 mg/m2 PO or IV once per week

Continue for a total of 2.5 years from the start of phase III.

References

1. Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. link to original article contains verified protocol PubMed

Larson/CALGB 8811 regimen (maintenance)

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

Regimen

Phase II

Course V (prolonged maintenance):

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

Phase II

• 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

Relapsed/refractory

CCE

CCE: Clofarabine, Cyclophosphamide, Etoposide

Regimen, Locatelli et al. 2009

Non-randomized, 25 patients

Patients in Locatelli et al. 2009 were pediatric: ≤15 years old at diagnosis and ≤21 years old at time of treatment.

• Clofarabine (Clolar) 40 mg/m2 IV over 2 hours once per day on days 1 to 5, given first
• Cyclophosphamide (Cytoxan) 400 mg/m2 IV over 1 hour once per day on days 1 to 5
• Etoposide (Vepesid) 150 mg/m2 IV over 2 hours once per day on days 1 to 5
• No patients in Locatelli et al. 2009 had CNS disease at time of treatment, and no patients received CNS prophylaxis.

5-day course. 2 out of 25 patients in Locatelli et al. 2009 received a second course of CCE as consolidation therapy. "Responding patients were given allogeneic HSCT if a suitable donor was immediately available or were given consolidation courses of chemotherapy including multiple agents active against ALL cells, chosen according to the treating physician's preference."

Supportive medications:

• Prophylactic steroids used for patients with >30 x 10⁹ blasts/L in the peripheral blood prior to treatment

References

1. Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. Epub 2009 Aug 29. link to original article contains verified protocol PubMed

Clofarabine (Clolar)

Currently, no positive prospective trials using clofarabine have been published in adults. The retrospective series below reports a variety of regimens used in off-label fashion, based on pediatric regimens.

Regimen

Retrospective

• Clofarabine (Clolar) at a total dose per cycle of 200 to 250 mg/m2

References

1. Retrospective: Barba P, Sampol A, Calbacho M, Gonzalez J, Serrano J, Martínez-Sánchez P, Fernández P, García-Boyero R, Bueno J, Ribera JM. Clofarabine-based chemotherapy for relapsed/refractory adult acute lymphoblastic leukemia and lymphoblastic lymphoma. The Spanish experience. Am J Hematol. 2012 Jun;87(6):631-4. Epub 2012 Mar 19. link to original article PubMed

Ponatinib (Iclusig)

Suspended by FDA on 10/31/13 because of the risk of life-threatening blood clots and severe narrowing of blood vessels. Patients who are currently taking Iclusig and responding to the drug and whose health care professionals determine that the potential benefits outweigh the risks should be treated under a single-patient Investigational New Drug (IND) application or expanded access registry program while FDA's safety investigation continues. For more information on obtaining access to treatment for your patient under an IND, please refer to this website.

Regimen

Phase II

• Ponatinib (Iclusig) 45 mg PO once daily; may be taken either with or without food

given until progression of disease or unacceptable toxicity

References

1. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O'Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88. link to original article contains verified protocol PubMed
2. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, Dipersio J, Deangelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; the PACE Investigators. A Phase 2 Trial of Ponatinib in Philadelphia Chromosome-Positive Leukemias. N Engl J Med. 2013 Nov 1. [Epub ahead of print] link to original article PubMed

Vincristine liposomal (Marqibo)

Regimen, O'Brien et al. 2012 (RALLY)

Phase II

• Vincristine liposomal (Marqibo) 2.25 mg/m2 IV over 1 hour on days 1, 8, 15, 22

28-day cycles, continued until "response achievement, leukemia progression, toxicity, or decision to pursue other therapy"

References

1. O'Brien S, Schiller G, Lister J, Damon L, Goldberg S, Aulitzky W, Ben-Yehuda D, Stock W, Coutre S, Douer D, Heffner LT, Larson M, Seiter K, Smith S, Assouline S, Kuriakose P, Maness L, Nagler A, Rowe J, Schaich M, Shpilberg O, Yee K, Schmieder G, Silverman JA, Thomas D, Deitcher SR, Kantarjian H. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol. 2013 Feb 20;31(6):676-83. Epub 2012 Nov 19. link to original article contains verified protocol PubMed