Burkitt lymphoma

Section editor
	Tarsheen Sethi, MD, MSCI Yale University New Haven, CT, USA LinkedIn

20 regimens on this page 27 variants on this page

Note 1: Regimens specifically intended for HIV-related Burkitt lymphoma can be found on the HIV-associated lymphoma page. Note 2: The regimens on this page are primarily intended for the sporadic form of Burkitt lymphoma and some other high-grade B-cell lymphomas. In the future we plan to add regimens for the endemic form of Burkitt lymphoma.

• We have moved How I Treat articles to a dedicated page.
• For pediatric regimens, please visit the pediatric NHL page.

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

NCCN

• NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - B-cell Lymphomas.

Untreated, pre-phase

CVP

CVP: Cyclophosphamide, Vincristine, Prednisone
COP: Cyclophosphamide, Oncovin (Vincristine), Prednisone

Regimen

Study	Dates of enrollment	Evidence
Diviné et al. 2005 (LMB95)	1996-2001	Phase 2
Ribrag et al. 2016 (LMBA-02)	2004-2010	Non-randomized part of phase 3 RCT

Eligibility criteria

• Group B (unresected stage I, non-abdominal stage II and any stage III or IV disease without CNS or bone marrow involvement) or group C (CNS and/or bone marrow involvement)

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² IV once on day 1
• Vincristine (Oncovin) 1 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m²/day IV or PO on days 1 to 7

CNS therapy, prophylaxis (group B)

• Methotrexate (MTX) 15 mg IT once on day 1
• Hydrocortisone (Cortef) (dose not specified) IT once on day 1 (admixed with MTX)

CNS therapy, treatment (group C)

• Methotrexate (MTX) 15 mg IT once per day on days 1, 3, 5
• Cytarabine (Ara-C) 40 mg IT once per day on days 1, 3, 5
• Hydrocortisone (Cortef) (dose not specified) IT once per day on days 1, 3, 5 (admixed with MTX & Ara-C)

One course

Subsequent treatment

• LMB95: COPADM induction
• LMBA-02: COPADM versus R-COPADM induction

References

1. LMB95: Diviné M, Casassus P, Koscielny S, Bosq J, Sebban C, Le Maignan C, Stamattoulas A, Dupriez B, Raphaël M, Pico JL, Ribrag V; GELA; GOELAMS. Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol. Ann Oncol. 2005 Dec;16(12):1928-35. Epub 2005 Nov 10. link to original article contains dosing details in manuscript PubMed
2. LMBA-02: Ribrag V, Koscielny S, Bosq J, Leguay T, Casasnovas O, Fornecker LM, Recher C, Ghesquieres H, Morschhauser F, Girault S, Le Gouill S, Ojeda-Uribe M, Mariette C, Cornillon J, Cartron G, Verge V, Chassagne-Clément C, Dombret H, Coiffier B, Lamy T, Tilly H, Salles G. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet. 2016 Jun 11;387(10036):2402-11. Epub 2016 Apr 11. link to original article contains dosing details in manuscript PubMed NCT00180882

Cyclophosphamide & Prednisone

Regimen variant #1, 1000/300

Study	Dates of enrollment	Evidence
Hoelzer et al. 2014 (GMALL-B-ALL/NHL 2002)	2002-2011	Non-randomized
Oriol et al. 2008	2003-07 to 2006-08	Non-randomized

Note: GMALL-B-ALL/NHL 2002 is fairly similar to the GMALL-R regimen, with some minor differences. See text for details.

Chemotherapy

• Cyclophosphamide (Cytoxan) 200 mg/m² IV over 60 minutes once per day on days 1 to 5

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m²/day IV or PO on days 1 to 5

CNS therapy, prophylaxis

• Cytarabine (Ara-C) 40 mg IT once on day 1, admixed with methotrexate and dexamethasone
• Methotrexate (MTX) 15 mg IT once on day 1, admixed with cytarabine and dexamethasone
• Dexamethasone (Decadron) 20 mg IT once on day 1, admixed with cytarabine and methotrexate

One course

Subsequent treatment

• Oriol et al. 2008: PETHEMA induction; see text for details
• GMALL-B-ALL/NHL 2002: Induction; see text for details

Regimen variant #2, 1000/420

Study	Dates of enrollment	Evidence
Lee et al. 2001 (CALGB 9251)	1992-1996	Non-randomized
Rizzieri et al. 2014 (CALGB 10-002)	2002-05-15 to 2009-09-29	Phase 2

Note: CALGB 9251 is an earlier version of CALGB 10-002 that demonstrated that cranial radiation can be omitted in the treatment of Burkitt lymphoma.

Chemotherapy

• Cyclophosphamide (Cytoxan) 200 mg/m² IV once per day on days 1 to 5

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 7

Supportive therapy

• Allopurinol (Zyloprim) 300 mg PO once per day on days 1 to 14 (includes first week of cycle 2)

Subsequent treatment

• CALGB 9251: See text for details
• CALGB 10-002: CALGB 10-002 induction

References

1. CALGB 9251: Lee EJ, Petroni GR, Schiffer CA, Freter CE, Johnson JL, Barcos M, Frizzera G, Bloomfield CD, Peterson BA. Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of Cancer and Leukemia Group B study 9251. J Clin Oncol. 2001 Oct 15;19(20):4014-22. link to original article PubMed
   1. Update: Rizzieri DA, Johnson JL, Niedzwiecki D, Lee EJ, Vardiman JW, Powell BL, Barcos M, Bloomfield CD, Schiffer CA, Peterson BA, Canellos GP, Larson RA. Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251. Cancer. 2004 Apr 1;100(7):1438-48. link to original article PubMed
2. Oriol A, Ribera JM, Bergua J, Giménez Mesa E, Grande C, Esteve J, Brunet S, Moreno MJ, Escoda L, Hernandez-Rivas JM, Hoelzer D; PETHEMA. High-dose chemotherapy and immunotherapy in adult Burkitt lymphoma: comparison of results in human immunodeficiency virus-infected and noninfected patients. Cancer. 2008 Jul 1;113(1):117-25. link to original article contains dosing details in manuscript PubMed
3. CALGB 10-002: Rizzieri DA, Johnson JL, Byrd JC, Lozanski G, Blum KA, Powell BL, Shea TC, Nattam S, Hoke E, Cheson BD, Larson RA; Alliance for Clinical Trials in Oncology. Improved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: Cancer and Leukemia Group B study 10 002. Br J Haematol. 2014 Apr;165(1):102-11. Epub 2014 Jan 15. link to original article contains dosing details in manuscript link to PMC article PubMed
4. GMALL-B-ALL/NHL 2002: Hoelzer D, Walewski J, Döhner H, Viardot A, Hiddemann W, Spiekermann K, Serve H, Dührsen U, Hüttmann A, Thiel E, Dengler J, Kneba M, Schaich M, Schmidt-Wolf IG, Beck J, Hertenstein B, Reichle A, Domanska-Czyz K, Fietkau R, Horst HA, Rieder H, Schwartz S, Burmeister T, Gökbuget N; German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia. Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood. 2014 Dec 18;124(26):3870-9. Epub 2014 Oct 30. link to original article contains dosing details in manuscript link to PMC article PubMed

Untreated

BASIC

BASIC: Brief, Anthracycline-Sparing, Intensive Cyclophosphamide

Study	Dates of enrollment	Evidence
Kasamon et al. 2012 (J0409)	2005-2010	Non-randomized

Induction

Chemotherapy

• Cyclophosphamide (Cytoxan) 1500 mg/m² IV over 60 minutes once on day 1
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1
• Methotrexate (MTX) 3000 mg/m² IV over 2 hours once on day 8

Glucocorticoid therapy

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1 & 8

Supportive therapy

• Mesna (Mesnex) 900 mg/m² IV in divided doses on day 1
• Leucovorin (Folinic acid) 25 mg/m² IV Q6H, starting 24 hours after start of IV methotrexate, until clearance
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 3 and continuing until post-nadir ANC greater than 500/μL

CNS prophylaxis

• Cytarabine (Ara-C) 100 mg IT once per day on days 1, 4, 11 (also day 8 if no IV MTX given)
• Hydrocortisone (Cortef) 50 mg IT is optional (no parameters given)

14-day cycle for 2 cycles

Consolidation, part 1

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg/kg IV over 1 to 2 hours once per day on days 2 to 5

Supportive therapy

• Mesna (Mesnex) 40 mg/kg/day IV in divided doses on days 2 to 5
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 11 and continuing until post-nadir ANC greater than 1000/μL

One course, followed once post-nadir ANC greater than 1000/μL by:

Consolidation, part 2

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22

4-week course

CNS treatment

• (only given if there was prior CNS involvement):
• Cytarabine (Ara-C) 100 mg IT once per week for 4 doses, then once every other week for 4 doses
• Hydrocortisone (Cortef) 50 mg IT is optional (no parameters given)

References

1. J0409: Kasamon YL, Brodsky RA, Borowitz MJ, Ambinder RF, Crilley PA, Cho SY, Tsai HL, Smith BD, Gladstone DE, Carraway HE, Huff CA, Matsui WH, Bolaños-Meade J, Jones RJ, Swinnen LJ. Brief intensive therapy for older adults with newly diagnosed Burkitt or atypical Burkitt lymphoma/leukemia. Leuk Lymphoma. 2013 Mar;54(3):483-90. Epub 2012 Aug 17. link to original article contains dosing details in manuscript link to PMC article PubMed

CALGB 10-002 regimen

Regimen

Study	Dates of enrollment	Evidence
Rizzieri et al. 2014 (CALGB 10-002)	2002-05-15 to 2009-09-29	Phase 2

Preceding treatment

• Cyclophosphamide & Prednisone pre-phase

Chemotherapy, A portion (cycles 2, 4, 6)

• Ifosfamide (Ifex) 800 mg/m² IV over 60 minutes once per day on days 1 to 5
• Methotrexate (MTX) 150 mg/m² IV bolus once on day 1, then 1350 mg/m² IV continuous infusion over 23.5 hours (total dose per cycle: 1500 mg/m²)
• Vincristine (Oncovin) 2 mg IV push once on day 1
• Cytarabine (Ara-C) 1000 mg/m² IV over 2 hours once per day on days 4 & 5
• Etoposide (Vepesid) 80 mg/m² IV over 60 minutes once per day on days 4 & 5

Glucocorticoid therapy, A portion (cycles 2, 4, 6)

• Dexamethasone (Decadron) 10 mg/m² (route not specified) once per day on days 1 to 5

Targeted therapy, A portion

• Rituximab (Rituxan) as follows:
  • Cycle 2: 50 mg/m² IV once on day 8, then 375 mg/m² IV once per day on days 10 & 12
  • Cycles 4 & 6: 375 mg/m² IV once on day 8

CNS therapy, prophylaxis, A portion (cycles 2, 4, 6)

• Cytarabine (Ara-C) 40 mg IT on day 1
• Methotrexate (MTX) 15 mg IT on day 1
• Hydrocortisone (Cortef) 50 mg IT on day 1

Supportive therapy, A portion (cycles 2, 4, 6)

• Mesna (Mesnex) (dose not specified but presumably equal to ifosfamide dose) mixed with ifosfamide
• Leucovorin (Folinic acid) 25 mg/m² IV or PO once 36 hours after start of IV methotrexate, then 10 mg/m² every 6 hours until methotrexate level less than 50 nmol/L
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 7 and continuing until ANC greater than 500/μL

Chemotherapy, B portion (cycles 3, 5, 7)

• Cyclophosphamide (Cytoxan) 200 mg/m² IV once per day on days 1 to 5
• Methotrexate (MTX) 150 mg/m² IV bolus once on day 1, then 1350 mg/m² IV continuous infusion over 23.5 hours (total dose per cycle: 1500 mg/m²)
• Vincristine (Oncovin) 2 mg IV push once on day 1
• Doxorubicin (Adriamycin) 25 mg/m² IV once per day on days 4 & 5

Glucocorticoid therapy, B portion (cycles 3, 5, 7)

• Dexamethasone (Decadron) 10 mg/m² IV or PO once per day on days 1 to 5

Targeted therapy, B portion (cycles 3, 5, 7)

• Rituximab (Rituxan) 375 mg/m² IV once on day 8

CNS therapy, prophylaxis, B portion (cycles 3, 5, 7)

• Cytarabine (Ara-C) 40 mg IT on day 1
• Methotrexate (MTX) 15 mg IT on day 1
• Hydrocortisone (Cortef) 50 mg IT on day 1

Supportive therapy, B portion (cycles 3, 5, 7)

• Leucovorin (Folinic acid) 50 mg/m² IV or PO once 36 hours after start of IV methotrexate, then 10 mg/m² every 6 hours until methotrexate level less than 50 nmol/L
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 7 and continuing until ANC greater than 500/μL

21-day cycle for 6 cycles

References

1. CALGB 10-002: Rizzieri DA, Johnson JL, Byrd JC, Lozanski G, Blum KA, Powell BL, Shea TC, Nattam S, Hoke E, Cheson BD, Larson RA; Alliance for Clinical Trials in Oncology (ACTION). Improved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: Cancer and Leukemia Group B study 10 002. Br J Haematol. 2014 Apr;165(1):102-11. Epub 2014 Jan 15. link to original article contains dosing details in manuscript link to PMC article PubMed

CODOX-M

CODOX-M: Cyclophosphamide, Oncovin (Vincristine), DOXorubicin, Methotrexate

Regimen variant #1, "Original Magrath"

Study	Dates of enrollment	Evidence
Magrath et al. 1996 (NCI 89-C-41)	1977-1985	Phase 2

Note: This regimen variant is intended for low-risk patients.

Chemotherapy

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once on day 1, then 200 mg/m² IV once per day on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m² IV once per day on days 1 & 8
• Doxorubicin (Adriamycin) 40 mg/m² IV once on day 1
• Methotrexate (MTX) by the following age-based criteria:
  • 65 years old or younger: 300 mg/m² IV over 60 minutes once on day 10, then 2700 mg/m² IV continuous infusion over 23 hours, started on day 10 (total dose per cycle: 3000 mg/m²)
  • Older than 65 years old: 100 mg/m² IV over 60 minutes once on day 10, then 900 mg/m² IV continuous infusion over 23 hours, started on day 10 (total dose per cycle: 1000 mg/m²)

Supportive therapy

• Leucovorin (Folinic acid) 15 mg/m² IV Q3H, starting 36 hours after start of IV methotrexate until 48 hours, then every 6 hours until methotrexate level undetectable
• Leucovorin (Folinic acid) 15 mg PO once 24 hours after intrathecal methotrexate
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 13 and continuing until ANC greater than 1000/μL

CNS therapy, prophylaxis

• Cytarabine (Ara-C) 70 mg IT once per day on days 1 & 3
• Methotrexate (MTX) 12 mg IT once on day 15

3 cycles

Regimen variant #2, "Modified Magrath"

Study	Dates of enrollment	Evidence
LaCasce et al. 2004	NR	Phase 2, fewer than 20 pts

Note: dose reductions for age greater than 65 years were not described in this publication. This is intended for low-risk patients (i.e., single site of disease less than 10 cm with normal LDH).

Chemotherapy

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once per day on days 1 & 2
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 1 & 10
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Methotrexate (MTX) 3000 mg/m² IV once on day 10

CNS therapy, prophylaxis

• Cytarabine (Ara-C) 50 mg IT on day 1
• Methotrexate (MTX) 12 mg IT on day 1
• Hydrocortisone (Cortef) 50 mg IT admixed with all chemotherapy

Supportive therapy

• Leucovorin (Folinic acid) 200 mg/m² IV once 24 hours after start of IV methotrexate, then 15 mg/m² every 6 hours until methotrexate level undetectable
• Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 3 to 8, held for MTX, and restarted after clearance continuing until ANC greater than 1000/μL

3 cycles

References

1. NCI 89-C-41: Magrath I, Adde M, Shad A, Venzon D, Seibel N, Gootenberg J, Neely J, Arndt C, Nieder M, Jaffe E, Wittes RA, Horak ID. Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol. 1996 Mar;14(3):925-34. link to original article contains dosing details in manuscript PubMed
2. UKLG LY06: Mead GM, Sydes MR, Walewski J, Grigg A, Hatton CS, Pescosta N, Guarnaccia C, Lewis MS, McKendrick J, Stenning SP, Wright D; UKLG. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol. 2002 Aug;13(8):1264-74. Erratum in: Ann Oncol. 2002 Dec;13(12):1961. Norbert, P [corrected to Pescosta, N]. link to original article contains dosing details in manuscript PubMed
3. Lacasce A, Howard O, Lib S, Fisher D, Weng A, Neuberg D, Shipp M. Modified Magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicity. Leuk Lymphoma. 2004 Apr;45(4):761-7. link to original article contains dosing details in manuscript PubMed
4. MRC/NCRI LY10: Mead GM, Barrans SL, Qian W, Walewski J, Radford JA, Wolf M, Clawson SM, Stenning SP, Yule CL, Jack AS; UK National Cancer Research Institute Lymphoma Clinical Studies Group; Australasian Leukaemia and Lymphoma Group. A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial). Blood. 2008 Sep 15;112(6):2248-60. Epub 2008 Jul 8. link to original article contains dosing details in manuscript link to PMC article PubMed
5. Maruyama D, Watanabe T, Maeshima AM, Nomoto J, Taniguchi H, Azuma T, Mori M, Munakata W, Kim SW, Kobayashi Y, Matsuno Y, Tobinai K. Modified cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytarabine (IVAC) therapy with or without rituximab in Japanese adult patients with Burkitt lymphoma (BL) and B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and BL. Int J Hematol. 2010 Dec;92(5):732-43. Epub 2010 Dec 1. link to original article contains dosing details in manuscript PubMed

CODOX-M/IVAC

CODOX-M/IVAC: Cyclophosphamide, Oncovin (Vincristine), DOXorubicin, Methotrexate alternating with Ifosfamide, Vepesid (Etoposide), Ara-C (Cytarabine)

Regimen variant #1, "Original Magrath"

Study	Dates of enrollment	Evidence
Magrath et al. 1996 (NCI 89-C-41)	1977-1985	Phase 2

Note: This variant is intended for high-risk patients.

Chemotherapy, CODOX-M portion (cycles 1 & 3)

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once on day 1, then 200 mg/m² IV once per day on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m² IV once per day on days 1 & 8
• Doxorubicin (Adriamycin) 40 mg/m² IV once on day 1
• Methotrexate (MTX) by the following age-based criteria:
  • 65 years old or younger: 300 mg/m² IV over 60 minutes once on day 10, then 2700 mg/m² IV continuous infusion over 23 hours (total dose per cycle: 3000 mg/m²)
  • Older than 65 years old: 100 mg/m² IV over 60 minutes once on day 10, then 900 mg/m² IV continuous infusion over 23 hours (total dose per cycle: 1000 mg/m²)

Supportive therapy, CODOX-M portion (cycles 1 & 3)

• Leucovorin (Folinic acid) 15 mg/m² IV Q3H, starting 36 hours after start of IV methotrexate until 48 hours, then every 6 hours until methotrexate level undetectable
• Leucovorin (Folinic acid) 15 mg PO once 24 hours after intrathecal methotrexate
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 13 and continuing until ANC greater than 1000/μL

CNS prophylaxis, CODOX-M portion (cycles 1 & 3)

• Cytarabine (Ara-C) 70 mg IT once per day on days 1 & 3
• Methotrexate (MTX) 12 mg IT once on day 15

Chemotherapy, IVAC portion (cycles 2 & 4)

• Ifosfamide (Ifex) by the following age-based criteria:
  • 65 years old or younger: 1500 mg/m² IV over 60 minutes once per day on days 1 to 5
  • Older than 65 years old: 1000 mg/m² IV over 60 minutes once per day on days 1 to 5
• Etoposide (Vepesid) 60 mg/m² IV over 60 minutes once per day on days 1 to 5
• Cytarabine (Ara-C) by the following age-based criteria:
  • 65 years old or younger: 2000 mg/m² IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m²)
  • Older than 65 years old: 1000 mg/m² IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 4000 mg/m²)

Supportive therapy, IVAC portion (cycles 2 & 4)

• Mesna (Mesnex) by the following age-based criteria:
  • 65 years old or younger: 300 mg/m² over 1 hour once per day on days 1 to 5 mixed with ifosfamide, then 300 mg/m² IV every four hours twice per day on days 1 to 5
  • Older than 65 years old: 200 mg/m² over 1 hour once per day on days 1 to 5 mixed with ifosfamide, then 200 mg/m² IV every four hours twice per day on days 1 to 5
• Leucovorin (Folinic acid) 15 mg PO once 24 hours after intrathecal methotrexate
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 7 and continuing until ANC greater than 1000/μL

CNS prophylaxis, IVAC portion (cycles 2 & 4)

• Methotrexate (MTX) 12 mg IT once on day 5

4 cycles

Regimen variant #2

Study	Dates of enrollment	Evidence
Mead et al. 2002 (UKLG LY06)	1995-10 to 1999-06	Phase 2

Note: This variant is intended for high-risk patients; modifications to the original NCI 89-C-41 are only in the CODOX-M portion.

Chemotherapy, CODOX-M portion (cycles 1 & 3)

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once on day 1, then 200 mg/m² IV once per day on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1 & 8
• Doxorubicin (Adriamycin) 40 mg/m² IV once on day 1
• Methotrexate (MTX) 1200 mg/m² IV over 60 minutes once on day 10, then 5520 mg/m² IV continuous infusion over 23 hours (total dose per cycle: 6720 mg/m²)

Supportive therapy, CODOX-M portion (cycles 1 & 3)

• Leucovorin (Folinic acid) 192 mg/m² IV once at 36 hours after start of IV methotrexate, then 12 mg/m² IV every 6 hours until MTX level less than 0.05
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 13 and continuing until ANC greater than 1000/μL

CNS prophylaxis, CODOX-M portion (cycles 1 & 3)

• Cytarabine (Ara-C) 70 mg IT once per day on days 1 & 3
• Methotrexate (MTX) 12 mg IT once on day 15

Chemotherapy, IVAC portion (cycles 2 & 4)

• Ifosfamide (Ifex) by the following age-based criteria:
  • 65 years old or younger: 1500 mg/m² IV over 60 minutes once per day on days 1 to 5
  • Older than 65 years old: 1000 mg/m² IV over 60 minutes once per day on days 1 to 5
• Etoposide (Vepesid) 60 mg/m² IV over 60 minutes once per day on days 1 to 5
• Cytarabine (Ara-C) by the following age-based criteria:
  • 65 years old or younger: 2000 mg/m² IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m²)
  • Older than 65 years old: 1000 mg/m² IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 4000 mg/m²)

Supportive therapy, IVAC portion (cycles 2 & 4)

• Mesna (Mesnex) by the following age-based criteria:
  • 65 years old or younger: 300 mg/m² over 1 hour once per day on days 1 to 5 mixed with ifosfamide, then 300 mg/m² IV every four hours twice per day on days 1 to 5
  • Older than 65 years old: 200 mg/m² over 1 hour once per day on days 1 to 5 mixed with ifosfamide, then 200 mg/m² IV every four hours twice per day on days 1 to 5
• Leucovorin (Folinic acid) 15 mg PO once 24 hours after intrathecal methotrexate
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 7 and continuing until ANC greater than 1000/μL

CNS prophylaxis, IVAC portion (cycles 2 & 4)

• Methotrexate (MTX) 12 mg IT once on day 5

4 cycles

Regimen variant #3, "Modified Magrath"

Study	Dates of enrollment	Evidence
LaCasce et al. 2004	NR	Phase 2, fewer than 20 pts

Note: All modifications are in the CODOX-M portion. Also note that dose reductions for age greater than 65 years were not described in this publication. This is intended for high-risk patients.

Chemotherapy, CODOX-M portion (cycles 1 & 3)

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once per day on days 1 & 2
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 1 & 10
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Methotrexate (MTX) 3000 mg/m² IV once on day 10

CNS prophylaxis, CODOX-M portion (cycles 1 & 3)

• Cytarabine (Ara-C) 50 mg IT once per day on days 1 & 3
• Methotrexate (MTX) 12 mg IT on day 1
• Hydrocortisone (Cortef) 50 mg IT admixed with all chemotherapy

Supportive therapy, CODOX-M portion (cycles 1 & 3)

• Leucovorin (Folinic acid) 200 mg/m² IV once 24 hours after start of IV methotrexate, then 15 mg/m² every 6 hours until methotrexate level undetectable
• Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 3 to 8, held for MTX, and restarted after clearance continuing until ANC greater than 1000/μL

Chemotherapy, IVAC portion (cycles 2 & 4)

• Ifosfamide (Ifex) 1500 mg/m² IV over 60 minutes once per day on days 1 to 5
• Etoposide (Vepesid) 60 mg/m² IV over 60 minutes once per day on days 1 to 5
• Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m²)

CNS prophylaxis, IVAC portion (cycles 2 & 4)

• Methotrexate (MTX) 12 mg IT on day 5, admixed with hydrocortisone
• Hydrocortisone (Cortef) 50 mg IT on day 5, admixed with methotrexate

Supportive therapy, IVAC portion (cycles 2 & 4)

• Mesna (Mesnex) 300 mg/m² over 1 hour once per day on days 1 to 5 mixed with ifosfamide, then 300 mg/m² IV every four hours twice per day on days 1 to 5
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6 and continuing until ANC greater than 1000/μL

4 cycles

Regimen variant #4

Study	Dates of enrollment	Evidence
Mead et al. 2008 (MRC/NCRI LY10)	2002-2005	Phase 2

Note: This variant is intended for high-risk patients; modifications to the UKLG LY06 protocol are only in the CODOX-M portion.

Chemotherapy, CODOX-M portion (cycles 1 & 3)

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once on day 1, then 200 mg/m² IV once per day on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once per day on days 1 & 8
• Doxorubicin (Adriamycin) 40 mg/m² IV once on day 1
• Methotrexate (MTX) 300 mg/m² IV over 60 minutes once on day 10, then 2700 mg/m² IV continuous infusion over 23 hours (total dose per cycle: 3000 mg/m²)

Supportive therapy, CODOX-M portion (cycles 1 & 3)

• Leucovorin (Folinic acid) 15 mg/m² IV once at 36 hours after start of IV methotrexate, then 15 mg/m² IV every 3 hours between hours 36 and 48, then 15 mg/m² IV every 6 hours until MTX level less than 0.05
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 13 and continuing until ANC greater than 1000/μL

CNS prophylaxis, CODOX-M portion (cycles 1 & 3)

• Cytarabine (Ara-C) 70 mg IT once per day on days 1 & 3
• Methotrexate (MTX) 12 mg IT once on day 15

Chemotherapy, IVAC portion (cycles 2 & 4)

• Ifosfamide (Ifex) by the following age-based criteria:
  • 65 years old or younger: 1500 mg/m² IV over 60 minutes once per day on days 1 to 5
  • Older than 65 years old: 1000 mg/m² IV over 60 minutes once per day on days 1 to 5
• Etoposide (Vepesid) 60 mg/m² IV over 60 minutes once per day on days 1 to 5
• Cytarabine (Ara-C) by the following age-based criteria:
  • 65 years old or younger: 2000 mg/m² IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m²)
  • Older than 65 years old: 1000 mg/m² IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 4000 mg/m²)

Supportive therapy, IVAC portion (cycles 2 & 4)

• Mesna (Mesnex) by the following age-based criteria:
  • 65 years old or younger: 300 mg/m² over 1 hour once per day on days 1 to 5 mixed with ifosfamide, then 300 mg/m² IV every four hours twice per day on days 1 to 5
  • Older than 65 years old: 200 mg/m² over 1 hour once per day on days 1 to 5 mixed with ifosfamide, then 200 mg/m² IV every four hours twice per day on days 1 to 5
• Leucovorin (Folinic acid) 15 mg PO once 24 hours after intrathecal methotrexate
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 7 and continuing until ANC greater than 1000/μL

CNS prophylaxis, IVAC portion (cycles 2 & 4)

• Methotrexate (MTX) 12 mg IT once on day 5

4 cycles

References

1. NCI 89-C-41: Magrath I, Adde M, Shad A, Venzon D, Seibel N, Gootenberg J, Neely J, Arndt C, Nieder M, Jaffe E, Wittes RA, Horak ID. Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol. 1996 Mar;14(3):925-34. link to original article contains dosing details in manuscript PubMed
2. UKLG LY06: Mead GM, Sydes MR, Walewski J, Grigg A, Hatton CS, Pescosta N, Guarnaccia C, Lewis MS, McKendrick J, Stenning SP, Wright D; UKLG LY06 collaborators. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol. 2002 Aug;13(8):1264-74. Erratum in: Ann Oncol. 2002 Dec;13(12):1961. Norbert, P [corrected to Pescosta, N]. link to original article contains dosing details in manuscript PubMed
3. Lacasce A, Howard O, Lib S, Fisher D, Weng A, Neuberg D, Shipp M. Modified Magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicity. Leuk Lymphoma. 2004 Apr;45(4):761-7. link to original article contains dosing details in manuscript PubMed
4. MRC/NCRI LY10: Mead GM, Barrans SL, Qian W, Walewski J, Radford JA, Wolf M, Clawson SM, Stenning SP, Yule CL, Jack AS; UK National Cancer Research Institute Lymphoma Clinical Studies Group; Australasian Leukaemia and Lymphoma Group. A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial). Blood. 2008 Sep 15;112(6):2248-60. Epub 2008 Jul 8. link to original article contains dosing details in manuscript link to PMC article PubMed
5. Maruyama D, Watanabe T, Maeshima AM, Nomoto J, Taniguchi H, Azuma T, Mori M, Munakata W, Kim SW, Kobayashi Y, Matsuno Y, Tobinai K. Modified cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytarabine (IVAC) therapy with or without rituximab in Japanese adult patients with Burkitt lymphoma (BL) and B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and BL. Int J Hematol. 2010 Dec;92(5):732-43. Epub 2010 Dec 1. link to original article PubMed

COPAD

COPAD: Cyclophosphamide, Oncovin (Vincristine), Prednisone, ADriamycin (Doxorubicin)

Regimen

Study	Dates of enrollment	Evidence
Diviné et al. 2005 (LMB95)	1996-2001	Phase 2, fewer than 20 pts in this subgroup

Eligibility criteria

• Group A (completely resected stage I or abdominal stage II disease)

Chemotherapy

• Cyclophosphamide (Cytoxan) 250 mg/m² IV twice per day on days 2 to 4 (total dose per cycle: 1500 mg/m²)
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 1 & 6
• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 2

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m²/day IV or PO on days 1 to 6

3 cycles; intervals were as short as possible, as soon as the ANC was greater than 1500/μL and platelet count was greater than 100 x 10⁹/L

References

1. LMB95: Diviné M, Casassus P, Koscielny S, Bosq J, Sebban C, Le Maignan C, Stamattoulas A, Dupriez B, Raphaël M, Pico JL, Ribrag V; GELA; GOELAMS. Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol. Ann Oncol. 2005 Dec;16(12):1928-35. Epub 2005 Nov 10. link to original article contains dosing details in manuscript PubMed

COPADM

COPADM: Cyclophosphamide, Oncovin (Vincristine), Prednisone, ADriamycin (Doxorubicin), Methotrexate

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Diviné et al. 2005 (LMB95)	1996-2001	Phase 2
Ribrag et al. 2016 (LMBA-02)	2004-2010	Phase 3 (C)	R-COPADM	Seems to have inferior EFS

Note: This protocol is for group B (unresected stage I, non-abdominal stage II and any stage III or IV disease without CNS or bone marrow involvement) or group C (CNS and/or bone marrow involvement). Diviné et al. 2005 list the dose of HD-MTX as 3 mg/m² but this is presumed to be a typo.

Induction, COPADM #1

Preceding treatment

• COP pre-phase

Chemotherapy

• Cyclophosphamide (Cytoxan) 250 mg/m² IV twice per day on days 2 to 4 (total dose: 1500 mg/m²)
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1
• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 2
• Methotrexate (MTX) 3000 mg/m² IV over 3 hours once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m²/day IV or PO on days 1 to 6

Supportive therapy

• Leucovorin (Folinic acid) 15 mg/m² (route not specified) every 6 hours on days 2 to 4

CNS therapy, prophylaxis (group B)

• Methotrexate (MTX) 15 mg IT once per day on days 2 & 6
• Hydrocortisone (Cortef) (dose not specified) IT once per day on days 2 & 6 (admixed with MTX)

CNS therapy, treatment (group C)

• Methotrexate (MTX) 15 mg IT once per day on days 2, 4, 6
• Cytarabine (Ara-C) 40 mg IT once per day on days 2, 4, 6
• Hydrocortisone (Cortef) (dose not specified) IT once per day on days 2, 4, 6 (admixed with MTX & Ara-C)

One course As soon as the ANC was greater than 1500/μL and platelet count was greater than 100 x 10⁹/L, patients proceeded to:

Induction, COPADM #2

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg/m² IV twice per day on days 2 to 4 (total dose: 3000 mg/m²)
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 1 & 6
• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 2
• Methotrexate (MTX) 3000 mg/m² IV over 3 hours once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m²/day IV or PO on days 1 to 6

Supportive therapy

• Leucovorin (Folinic acid) 15 mg/m² (route not specified) every 6 hours on days 2 to 4

CNS therapy, prophylaxis (group B)

• Methotrexate (MTX) 15 mg IT once per day on days 2 & 6
• Hydrocortisone (Cortef) (dose not specified) IT once per day on days 2 & 6 (admixed with MTX)

CNS therapy, treatment (group C)

• Methotrexate (MTX) 15 mg IT once per day on days 2, 4, 6
• Cytarabine (Ara-C) 40 mg IT once per day on days 2, 4, 6
• Hydrocortisone (Cortef) (dose not specified) IT once per day on days 2, 4, 6 (admixed with MTX & Ara-C)

One course

Subsequent treatment

• As soon as the ANC was greater than 1500/μL and platelet count was greater than 100 x 10⁹/L:
  • LMBA-02, group B: CYM consolidation
  • LMBA-02, group C: CYVE consolidation

References

1. LMB95: Diviné M, Casassus P, Koscielny S, Bosq J, Sebban C, Le Maignan C, Stamattoulas A, Dupriez B, Raphaël M, Pico JL, Ribrag V; GELA; GOELAMS. Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol. Ann Oncol. 2005 Dec;16(12):1928-35. Epub 2005 Nov 10. link to original article contains dosing details in manuscript PubMed
2. LMBA-02: Ribrag V, Koscielny S, Bosq J, Leguay T, Casasnovas O, Fornecker LM, Recher C, Ghesquieres H, Morschhauser F, Girault S, Le Gouill S, Ojeda-Uribe M, Mariette C, Cornillon J, Cartron G, Verge V, Chassagne-Clément C, Dombret H, Coiffier B, Lamy T, Tilly H, Salles G. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet. 2016 Jun 11;387(10036):2402-11. Epub 2016 Apr 11. link to original article PubMed NCT00180882

DA-R-EPOCH

DA-R-EPOCH: Dose Adjusted Rituximab, Etoposide, Prednisone, Oncovin (Vincristine), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin)

Regimen

Study	Evidence
Dunleavy et al. 2013 (NCI 93-C-0133BL)	Phase 2, fewer than 20 pts in this subgroup

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV over 3 hours once on day 1

Chemotherapy

• Etoposide (Vepesid) 50 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 200 mg/m²)
• Vincristine (Oncovin) 0.4 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg/m²)
• Cyclophosphamide (Cytoxan) 750 mg/m² IV over 2 hours once on day 5
• Doxorubicin (Adriamycin) 10 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 40 mg/m²)

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m² PO twice per day on days 1 to 5

Supportive therapy

• Filgrastim (Neupogen) 300 mcg SC once per day, starting on day 6 and continuing until ANC greater than 5000/μL above the nadir level
• Trimethoprim-Sulfamethoxazole (Bactrim DS) one tablet PO TIW
• Omeprazole (Prilosec) 20 mg PO once per day or equivalent
• Docusate (Colace) as needed for constipation
• Sennosides (Senna) as needed for constipation
• Lactulose as needed for constipation

CNS therapy, prophylaxis

• Methotrexate (MTX) as follows:
  • Cycles 3 to 6: 12 mg IT once per day on days 1 & 5

21-day cycle for 6 cycles if ANC greater than 1000/μL and platelets greater than 100 x 10⁹/L If counts are below those levels, check daily CBC and continue growth factor support until counts are adequate and next cycle can start.

Dose and schedule modifications

Note this is different than some other DA-EPOCH regimens!

• Start cycle 1 as described above.
• Obtain CBCs twice per week for nadir measurements.
• If nadir ANC greater than or equal to 500/μL, increase etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• If nadir ANC less than 500/μL, use same doses as last cycle.
• If nadir platelet count less than 25 x 10⁹/L, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
  • Decreases below the cycle 1 starting dose only apply to cyclophosphamide, i.e., the lowest etoposide and doxorubicin would be dosed is at the original cycle 1 dose.

References

1. NCI 93-C-0133_BL: Dunleavy K, Pittaluga S, Shovlin M, Steinberg SM, Cole D, Grant C, Widemann B, Staudt LM, Jaffe ES, Little RF, Wilson WH. Low-intensity therapy in adults with Burkitt's lymphoma. N Engl J Med. 2013 Nov 14;369(20):1915-25. link to original article link to supplement contains dosing details in supplement link to PMC article PubMed NCT00001337
2. HOVON/SAKK 127: Chamuleau MED, Stenner F, Chitu DA, Novak U, Minnema MC, Geerts P, Stevens WBC, Zenz T, van Imhoff GW, Wu KL, Demandt AMP, Kersten MJ, Terpstra WE, Tick LW, Deeren D, Van Den Neste E, Gregor M, Veelken H, Böhmer LH, Caspar CB, Mutsaers P, Refos JM, Sewsaran R, Fu L, Seefat RL, Uyl-de Groot CA, Dirnhofer S, Van Den Brand M, de Jong D, Nijland M, Lugtenburg P. R-CODOX-M/R-IVAC versus DA-EPOCH-R in patients with newly diagnosed Burkitt lymphoma (HOVON/SAKK): final results of a multicentre, phase 3, open-label, randomised trial. Lancet Haematol. 2023 Dec;10(12):e966-e975. Epub 2023 Oct 31. link to original article PubMed EudraCT 2013-004394-27

GMALL-R

GMALL-R: German Multicenter Study Group for the Treatment of Adult Acute Lymphoblastic Leukemia, Rituximab

Study	Dates of enrollment	Evidence
Ribera et al. 2013 (Burkimab)	NR	Phase 2

Note: Numbering of days is based on pre-phase->A->B->C; however, certain patient populations received different ordering of regimen, see below.

Pre-phase

Chemotherapy

• Cyclophosphamide (Cytoxan) 200 mg/m² IV over 60 minutes once per day on days 1 to 5

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m² IV bolus once per day on days 1 to 5

5-day course, followed by:

Induction

Targeted therapy, A cycle

• Rituximab (Rituxan) 375 mg/m² IV over 4 hours once on day 7

Chemotherapy, A cycle

• Vincristine (Oncovin) 2 mg IV bolus once on day 8
• Methotrexate (MTX) by the following age-based criteria:
  • 55 years old or younger: 1500 mg/m² IV continuous infusion over 24 hours, started on day 8
  • Older than 55 years old: 750 mg/m² IV continuous infusion over 24 hours, started on day 8
• Ifosfamide (Ifex) 800 mg/m² IV over 60 minutes once per day on days 8 to 12
• Teniposide (Vumon) 100 mg/m² IV over 60 minutes once per day on days 11 & 12
• Cytarabine (Ara-C) by the following age-based criteria:
  • 55 years old or younger: 150 mg/m² IV over 60 minutes twice per day on days 11 & 12
  • Older than 55 years old: 75 mg/m² IV over 60 minutes twice per day on days 11 & 12

Glucocorticoid therapy, A cycle

• Dexamethasone (Decadron) 10 mg/m² IV bolus once per day on days 8 to 12

Supportive therapy, A cycle

• Leucovorin (Folinic acid) (dose/route/schedule not specified), starting 12 hours after methotrexate infusion

Targeted therapy, B cycle

• Rituximab (Rituxan) 375 mg/m² IV over 4 hours once on day 28

Chemotherapy, B cycle

• Vincristine (Oncovin) 2 mg IV bolus once on day 29
• Methotrexate (MTX) by the following age-based criteria:
  • 55 years old or younger: 1500 mg/m² IV continuous infusion over 24 hours, started on day 29
  • Older than 55 years old: 750 mg/m² IV continuous infusion over 24 hours, started on day 29
• Cyclophosphamide (Cytoxan) 200 mg/m² IV over 60 minutes once per day on days 29 to 33
• Doxorubicin (Adriamycin) 25 mg/m² IV over 15 minutes once per day on days 32 & 33

Glucocorticoid therapy, B cycle

• Dexamethasone (Decadron) 10 mg/m² IV bolus once per day on days 29 to 33

Supportive therapy, B cycle

• Leucovorin (Folinic acid) (dose/route/schedule not specified), starting 12 hours after methotrexate infusion

Targeted therapy, C cycle

• Rituximab (Rituxan) 375 mg/m² IV over 4 hours once on day 49

Chemotherapy, C cycle

• Vindesine (Eldisine) 3 mg/m² (maximum dose of 5 mg) IV bolus once on day 50
• Methotrexate (MTX) by the following age-based criteria, starting on day 50:
  • 55 years old or younger: 1500 mg/m² IV continuous infusion over 24 hours
  • Older than 55 years old: 750 mg/m² IV continuous infusion over 24 hours
• Etoposide (Vepesid) 250 mg/m² IV over 60 minutes once per day on days 53 & 54
• Cytarabine (Ara-C) by the following age-based criteria, on day 54:
  • 55 years old or younger: 2000 mg/m² IV over 3 hours twice per day
  • Older than 55 years old: 1000 mg/m² IV over 3 hours twice per day

Glucocorticoid therapy, C cycle

• Dexamethasone (Decadron) 10 mg/m² IV bolus once per day on days 50 to 54

Supportive therapy, C cycle

• Leucovorin (Folinic acid) (dose/route/schedule not specified), starting 12 hours after methotrexate infusion

Give regimen by the following age- and stage-based criteria:

• Advanced stage and younger than 55 years: A->B->C for 2 courses (6 total cycles)
• Older than 55 years old: Alternate A & B for 3 courses (6 total cycles)
• Localized stage: 4 total cycles (unclear from protocol if this means A alternating with B or A->B->C->A)

Prophylaxis

CNS therapy

• Methotrexate (MTX) 15 mg IT once per day on days 1, 8, 12, 29, 33
• Cytarabine (Ara-C) 40 mg IT once per day on days 1, 8, 12, 29, 33
• Dexamethasone (Decadron) 20 mg IT once per day on days 1, 8, 12, 29, 33

8 doses total

References

1. Burkimab: Ribera JM, García O, Grande C, Esteve J, Oriol A, Bergua J, González-Campos J, Vall-Llovera F, Tormo M, Hernández-Rivas JM, García D, Brunet S, Alonso N, Barba P, Miralles P, Llorente A, Montesinos P, Moreno MJ, Hernández-Rivas JÁ, Bernal T. Dose-intensive chemotherapy including rituximab in Burkitt's leukemia or lymphoma regardless of human immunodeficiency virus infection status: final results of a phase 2 study (Burkimab). Cancer. 2013 May 1;119(9):1660-8. Epub 2013 Jan 29. link to original article contains dosing details in manuscript PubMed NCT00388193

R-CODOX-M

R-CODOX-M: Rituximab, Cyclophosphamide, Oncovin (Vincristine), DOXorubicin, Methotrexate

Regimen

Study	Dates of enrollment	Evidence
Maruyama et al. 2010	2000-04 to 2009-04	Retrospective
Jacobson et al. 2014	NR	Expert Recommendation

Note: In the Jacobson et al. 2014 review, the authors describe a "Modified Magrath regimen of R-CODOX/R-IVAC" based on the timing and dosage of LaCasce et al. 2004. However, LaCasce et al. 2004 did not include rituximab in the schema. Others have published retrospective series of this regimen; doses here are based on the review article. This is for low-risk patients (i.e., single site of disease less than 10 cm with normal LDH).

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once no earlier than day 3
  • Cycles 2 & 3: 375 mg/m² IV once on day 1

Chemotherapy

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once per day on days 1 & 2
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 1 & 15
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Methotrexate (MTX) 3000 mg/m² IV over 2 to 4 hours once on day 15

CNS therapy, prophylaxis

• Cytarabine (Ara-C) 50 mg IT once on day 1
• Methotrexate (MTX) 12 mg IT once on day 1

CNS therapy, treatment (for CSF positive)

• Cytarabine (Ara-C) as follows:
  • Cycle 1: 50 mg IT once per day on days 1 & 5
  • Cycles 2 & 3: 50 mg IT once on day 1
• Methotrexate (MTX) as follows:
  • Cycle 1: 12 mg IT once per day on days 1 & 15
  • Cycles 2 & 3: 12 mg IT once on day 1

Supportive therapy

• Leucovorin (Folinic acid) 200 mg/m² IV once 24 hours after start of IV methotrexate, then 15 mg/m² every 6 hours until methotrexate level undetectable
• Pegfilgrastim (Neulasta) 6 mg SC once on day 3

3 cycles

References

1. Retrospective: Maruyama D, Watanabe T, Maeshima AM, Nomoto J, Taniguchi H, Azuma T, Mori M, Munakata W, Kim SW, Kobayashi Y, Matsuno Y, Tobinai K. Modified cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytarabine (IVAC) therapy with or without rituximab in Japanese adult patients with Burkitt lymphoma (BL) and B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and BL. Int J Hematol. 2010 Dec;92(5):732-43. Epub 2010 Dec 1. link to original article contains dosing details in manuscript PubMed
2. Retrospective: Barnes JA, Lacasce AS, Feng Y, Toomey CE, Neuberg D, Michaelson JS, Hochberg EP, Abramson JS. Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis. Ann Oncol. 2011 Aug;22(8):1859-64. Epub 2011 Feb 21. link to original article PubMed
3. Review: Jacobson C, LaCasce A. How I treat Burkitt lymphoma in adults. Blood. 2014 Nov 6;124(19):2913-20. Epub 2014 Sep 25. link to original article contains dosing details in manuscript PubMed

R-CODOX-M/R-IVAC

R-CODOX-M/R-IVAC: Rituximab, Cyclophosphamide, Oncovin (Vincristine), DOXorubicin, Methotrexate alternating with Rituximab, Ifosfamide, Vepesid (etoposide), Ara-C (Cytarabine)

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Chamuleau et al. 2023 (HOVON/SAKK 127)	2014-08-04 to 2021-09-17	Phase 3 (C)	DA-R-EPOCH	Did not meet primary endpoint of PFS

Note: Regimen details in the manuscript were not as detailed as below, but there were some substantial dosing and timing differences; this study was closed early due to poor accrual.

Targeted therapy, both portions

• Rituximab (Rituxan) as follows:
  • Cycles 1 & 3: 375 mg/m² IV once per day on days 1 & 9
  • Cycles 2 & 4: 375 mg/m² IV once per day on days 3 & 7

Chemotherapy, R-CODOX-M portion (cycles 1 & 3)

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once on day 1, then 200 mg/m² IV once per day on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m² IV once per day on days 1 & 8
• Doxorubicin (Adriamycin) 40 mg/m² IV once on day 1
• Methotrexate (MTX) by the following age-based criteria:
  • 65 years old or younger: 3000 mg/m² IV once on day 10
  • Older than 65 years old: 1000 mg/m² IV once on day 10

Chemotherapy, R-IVAC portion (cycles 2 & 4)

• Ifosfamide (Ifex) by the following age-based criteria:
  • 65 years old or younger: 1500 mg/m² IV once per day on days 1 to 5
  • Older than 65 years old: 1000 mg/m² IV once per day on days 1 to 5
• Etoposide (Vepesid) 60 mg/m² IV once per day on days 1 to 5
• Cytarabine (Ara-C) by the following age-based criteria:
  • 65 years old or younger: 2000 mg/m² IV once per day on days 1 & 2
  • Older than 65 years old: 1000 mg/m² IV once per day on days 1 & 2

4 cycles (R-CODOX-M x 2; R-IVAC x 2)

Regimen variant #2

Study	Evidence
Jacobson et al. 2014	Expert Recommendation

Note: In the Jacobson et al. 2014 review, the authors describe a "Modified Magrath regimen of R-CODOX/R-IVAC" based on the timing and dosage of LaCasce et al. 2004. However, LaCasce et al. 2004 did not include rituximab in the schema. Others have published retrospective series of this regimen; doses here are based on the review article. This is for high-risk patients.

Targeted therapy, both portions

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once no earlier than day 3
  • Cycles 2 to 4: 375 mg/m² IV once on day 1

Chemotherapy, R-CODOX-M portion (cycles 1 & 3)

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once per day on days 1 & 2
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 1 & 15
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Methotrexate (MTX) 3000 mg/m² IV over 2 to 4 hours once on day 15

CNS therapy, prophylaxis, R-CODOX-M portion (cycles 1 & 3)

• Cytarabine (Ara-C) 50 mg IT once per day on days 1 & 3
• Methotrexate (MTX) 12 mg IT once on day 1

CNS therapy, treatment (for CSF positive), R-CODOX-M portion (cycles 1 & 3)

• Cytarabine (Ara-C) as follows:
  • Cycle 1: 50 mg IT once per day on days 1, 3, 5
  • Cycle 3: 50 mg IT once per day on days 1 & 3
• Methotrexate (MTX) as follows:
  • Cycle 1: 12 mg IT once per day on days 1 & 15
  • Cycle 3: 12 mg IT once on day 1

Supportive therapy, R-CODOX-M portion (cycles 1 & 3)

• Leucovorin (Folinic acid) 200 mg/m² IV once 24 hours after start of IV methotrexate, then 15 mg/m² every 6 hours until methotrexate level undetectable
• Pegfilgrastim (Neulasta) 6 mg SC once on day 3

Chemotherapy, R-IVAC portion (cycles 2 & 4)

• Ifosfamide (Ifex) 1500 mg/m² IV over 2 hours once per day on days 1 to 5
• Etoposide (Vepesid) 60 mg/m² IV over 60 minutes once per day on days 1 to 5
• Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m²)

CNS therapy, prophylaxis, R-IVAC portion (cycles 2 & 4)

• Methotrexate (MTX) 12 mg IT once on day 5

CNS therapy, treatment (for CSF positive), R-IVAC portion

• Treatment as per CNS prophylaxis PLUS in cycle 2 only:
• Cytarabine (Ara-C) as follows:
  • Cycle 2: 50 mg IT once on day 3

Supportive therapy, R-IVAC portion (cycles 2 & 4)

• Mesna (Mesnex) 300 mg/m² over 1 hour once per day on days 1 to 5 mixed with ifosfamide, then 300 mg/m² IV every four hours twice per day on days 1 to 5
• Pegfilgrastim (Neulasta) 6 mg SC once on day 6

4 cycles (R-CODOX-M x 2; R-IVAC x 2)

References

1. Maruyama D, Watanabe T, Maeshima AM, Nomoto J, Taniguchi H, Azuma T, Mori M, Munakata W, Kim SW, Kobayashi Y, Matsuno Y, Tobinai K. Modified cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytarabine (IVAC) therapy with or without rituximab in Japanese adult patients with Burkitt lymphoma (BL) and B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and BL. Int J Hematol. 2010 Dec;92(5):732-43. Epub 2010 Dec 1. link to original article contains dosing details in manuscript PubMed
2. Retrospective: Barnes JA, Lacasce AS, Feng Y, Toomey CE, Neuberg D, Michaelson JS, Hochberg EP, Abramson JS. Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis. Ann Oncol. 2011 Aug;22(8):1859-64. Epub 2011 Feb 21. link to original article PubMed
3. Review: Jacobson C, LaCasce A. How I treat Burkitt lymphoma in adults. Blood. 2014 Nov 6;124(19):2913-20. Epub 2014 Sep 25. link to original article contains dosing details in manuscript PubMed
4. HOVON/SAKK 127: Chamuleau MED, Stenner F, Chitu DA, Novak U, Minnema MC, Geerts P, Stevens WBC, Zenz T, van Imhoff GW, Wu KL, Demandt AMP, Kersten MJ, Terpstra WE, Tick LW, Deeren D, Van Den Neste E, Gregor M, Veelken H, Böhmer LH, Caspar CB, Mutsaers P, Refos JM, Sewsaran R, Fu L, Seefat RL, Uyl-de Groot CA, Dirnhofer S, Van Den Brand M, de Jong D, Nijland M, Lugtenburg P. R-CODOX-M/R-IVAC versus DA-EPOCH-R in patients with newly diagnosed Burkitt lymphoma (HOVON/SAKK): final results of a multicentre, phase 3, open-label, randomised trial. Lancet Haematol. 2023 Dec;10(12):e966-e975. Epub 2023 Oct 31. link to original article contains dosing details in manuscript PubMed EudraCT 2013-004394-27

R-CODOX-M (Pegylated liposomal doxorubicin substituted)

R-CODOX-M: Rituximab, Cyclophosphamide, Oncovin (Vincristine), DOXil (Pegylated liposomal doxorubicin), Methotrexate

Regimen

Study	Dates of enrollment	Evidence
Evens et al. 2013 (NU 06H2)	NR	Phase 2

Note: This regimen is for low-risk patients.

Targeted therapy

• Rituximab (Rituxan) 500 mg/m² IV once per day on days 0 & 8

Chemotherapy

• Cyclophosphamide (Cytoxan) 800 mg/m² IV over 60 minutes once on day 1, then 200 mg/m² IV over 60 minutes once per day on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV push once per day on days 1 & 8
• Pegylated liposomal doxorubicin (Doxil) 40 mg/m² IV once on day 1
• Methotrexate (MTX) 300 mg/m² IV over 60 minutes once on day 10, then 2700 mg/m² IV continuous infusion over 23 hours (total dose per cycle: 3000 mg/m²)

CNS therapy, prophylaxis

• Cytarabine (Ara-C) 70 mg IT once on day 1
• Methotrexate (MTX) by the following route-based criteria:
  • LP: 12 mg IT once on day 3
  • Ommaya reservoir: 6 mg IT once on day 3

Supportive therapy

• Leucovorin (Folinic acid) 200 mg/m² IV once 36 hours after start of IV methotrexate, then 15 mg/m² IV every 6 hours until methotrexate level is less than 50 nmol/L
• Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 6 & 7, then on day 14 onwards until ANC greater than 1500/μL

3 cycles (length not specified)

References

1. NU 06H2: Evens AM, Carson KR, Kolesar J, Nabhan C, Helenowski I, Islam N, Jovanovic B, Barr PM, Caimi PF, Gregory SA, Gordon LI. A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma. Ann Oncol. 2013 Dec;24(12):3076-81. Epub 2013 Oct 20. link to original article contains dosing details in manuscript link to PMC article PubMed

R-CODOX-M/R-IVAC (Pegylated liposomal doxorubicin substituted)

R-CODOX-M/R-IVAC: Rituximab, Cyclophosphamide, Oncovin (Vincristine), DOXil (Pegylated liposomal doxorubicin), Methotrexate alternating with Rituximab, Ifosfamide, Vepesid (Etoposide), Ara-C (Cytarabine)

Regimen

Study	Dates of enrollment	Evidence
Evens et al. 2013 (NU 06H2)	NR	Phase 2

Note: This protocol is for high-risk patients.

Targeted therapy, R-CODOX-M portion (cycles 1 & 3)

• Rituximab (Rituxan) 500 mg/m² IV once per day on days 0 & 8

Chemotherapy, R-CODOX-M portion (cycles 1 & 3)

• Cyclophosphamide (Cytoxan) 800 mg/m² IV over 60 minutes once on day 1, then 200 mg/m² IV over 60 minutes once per day on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV push once per day on days 1 & 8
• Pegylated liposomal doxorubicin (Doxil) 40 mg/m² IV once on day 1
• Methotrexate (MTX) 300 mg/m² IV over 60 minutes once on day 10, then 2700 mg/m² IV continuous infusion over 23 hours (total dose per cycle: 3000 mg/m²)

CNS prophylaxis, R-CODOX-M portion (cycles 1 & 3)

• Cytarabine (Ara-C) 70 mg IT once per day on days 1 & 3
• Methotrexate (MTX) 12 mg IT (or 6 mg into Ommaya) once on day 15

Supportive therapy, R-CODOX-M portion (cycles 1 & 3)

• Leucovorin (Folinic acid) 200 mg/m² IV once 36 hours after start of IV methotrexate, then 15 mg/m² IV every 6 hours until methotrexate level is less than 50 nmol/L
• Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 6 & 7, then on day 14 onwards until ANC greater than 1500/μL

Targeted therapy, R-IVAC portion (cycles 2 & 4)

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 0 & either 6 or 7

Chemotherapy, R-IVAC portion (cycles 2 & 4)

• Ifosfamide (Ifex) 1500 mg/m² IV over 3 hours once per day on days 1 to 5
• Etoposide (Vepesid) 60 mg/m² IV over 60 minutes once per day on days 1 to 5
• Cytarabine (Ara-C) 2000 mg/m² IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m²)

CNS prophylaxis, R-IVAC portion (cycles 2 & 4)

• Methotrexate (MTX) as follows:
  • Cycles 2 & 4: 15 mg IT once on day 5

Supportive therapy, R-IVAC portion (cycles 2 & 4)

• Mesna (Mesnex) 500 mg/m² mixed with first ifosfamide, then 1000 mg/m²/day IV continuous infusion over 120 hours (total dose per cycle: 5500 mg/m²)
• Leucovorin (Folinic acid) 15 mg PO every 6 hours on day 6, starting 24 hours after intrathecal methotrexate (total dose per cycle: 60 mg)
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on either day 6 or 7 and continuing until ANC greater than 1500/μL

4 cycles

References

1. NU 06H2: Evens AM, Carson KR, Kolesar J, Nabhan C, Helenowski I, Islam N, Jovanovic B, Barr PM, Caimi PF, Gregory SA, Gordon LI. A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma. Ann Oncol. 2013 Dec;24(12):3076-81. Epub 2013 Oct 20. link to original article contains dosing details in manuscript link to PMC article PubMed

R-COPADM

R-COPADM: Rituximab, Cyclophosphamide, Oncovin (Vincristine), Prednisone, ADriamycin (Doxorubicin), Methotrexate

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ribrag et al. 2016 (LMBA-02)	2004-2010	Phase 3 (E-esc)	COPADM	Superior EFS (primary endpoint) EFS36: 75% vs 62% (HR 0.59, 95% CI 0.38-0.94)

Note: This regimen is for group B (unresected stage I, non-abdominal stage II and any stage III or IV disease without CNS or bone marrow involvement); see manuscript for details about the regimen for group C.

Preceding treatment

• COP pre-phase

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² (maximum dose of 800 mg) IV once per day on days 0 & 6

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg/m²/day IV on days 2 to 4
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1
• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 2
• Methotrexate (MTX) 3000 mg/m² IV once on day 1

Glucocorticoid therapy

• Prednisolone (Millipred) 60 mg/m²/day IV or PO on days 1 to 5

Supportive therapy

• Leucovorin (Folinic acid) (dose/route not specified) on days 2 to 6

CNS therapy, prophylaxis

• Methotrexate (MTX) 15 mg IT once per day on days 2 & 6
• Hydrocortisone (Cortef) (dose not specified) IT once per day on days 2 & 6 (admixed with MTX)

2 cycles (length not specified)

Subsequent treatment

• CYM consolidation

References

1. LMBA-02: Ribrag V, Koscielny S, Bosq J, Leguay T, Casasnovas O, Fornecker LM, Recher C, Ghesquieres H, Morschhauser F, Girault S, Le Gouill S, Ojeda-Uribe M, Mariette C, Cornillon J, Cartron G, Verge V, Chassagne-Clément C, Dombret H, Coiffier B, Lamy T, Tilly H, Salles G. Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial. Lancet. 2016 Jun 11;387(10036):2402-11. Epub 2016 Apr 11. link to original article contains dosing details in supplement PubMed NCT00180882

R-Hyper-CVAD/R-MA

R-Hyper-CVAD/R-MA: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone altenating with Rituximab, Methotrexate, Ara-C (Cytarabine)

Regimen

Study	Dates of enrollment	Evidence
Thomas et al. 2006	2000-02 to 2005-01	Pilot, fewer than 20 pts

Targeted therapy, both portions

• Rituximab (Rituxan) as follows:
  • Cycles 1 & 3: 375 mg/m² IV over 2 to 6 hours once per day on days 1 & 11
  • Cycles 2 & 4: 375 mg/m² IV over 2 to 6 hours once per day on days 2 & 8

Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m²)
• Vincristine (Oncovin) 2 mg IV once per day on days 4 & 11
• Doxorubicin (Adriamycin) 50 mg/m² IV continuous infusion over 24 hours, started on day 4

Glucocorticoid therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4, 11 to 14

Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 72 hours, started on day 1, starting 1 hour prior to cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide (total dose per cycle: 1800 mg/m²)
• Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of chemotherapy, given until WBC greater than 3 x 10⁹/L or bone pain present
• ONE of the following antibiotics:
  • Fluoroquinolone
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg dose/route not specified
• Fluconazole (Diflucan) dose/route not specified
• ONE of the following antivirals:
  • Acyclovir (Zovirax) dose/route not specified
  • Valacyclovir (Valtrex) dose/route not specified

Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Methotrexate (MTX) 1000 mg/m² IV continuous infusion over 24 hours, started on day 1
• Cytarabine (Ara-C) 3000 mg/m² IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m²)

Supportive therapy, MA portion (cycles 2, 4, 6, 8; "Part B")

• Leucovorin (Folinic acid) 50 mg IV once 12 hours after methotrexate is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
• Filgrastim (Neupogen) 10 mcg/kg SC once per day, starting 24 hours after completion of chemotherapy, given until WBC greater than 3 x 10⁹/L or bone pain present
• ONE of the following antibiotics:
  • Fluoroquinolone
  • Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg dose/route not specified
• Fluconazole (Diflucan) dose/route not specified
• ONE of the following antivirals:
  • Acyclovir (Zovirax) dose/route not specified
  • Valacyclovir (Valtrex) dose/route not specified

8 cycles; next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is greater than 3 x 10⁹/L and platelet count greater than 50 x 10⁹/L

CNS prophylaxis, both portions

• Methotrexate (MTX) by the following route-based criteria:
  • LP: 12 mg IT once on day 2
  • Ommaya reservoir: 6 mg IT once on day 2
• Cytarabine (Ara-C) 100 mg IT once 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, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")

• Vincristine (Oncovin) reduced to 1 mg for bilirubin greater than 2 mg/dL or NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted for bilirubin greater than 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 greater than 5 mg/dL or for gastric/small-bowel involvement with Course 1 to reduce duration of myelosuppression given risk of perforation)

Dose modifications, MA portion (cycles 2, 4, 6, 8; "Part B")

• Cytarabine (Ara-C) reduced to 1000 mg/m² for patients greater than or equal to 60 years old, creatinine greater than or equal to 1.5 mg/dL or 0 hour MTX level greater than or equal to 20,000 nmol/L
• Methotrexate (MTX) reduced by 50% for creatinine clearance 10 to 50 mL/min (eliminated for less than 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 dosing details in manuscript PubMed

Consolidation after upfront therapy

Cytarabine & Methotrexate (CYM)

CYM: CYtarabine, Methotrexate

Regimen

Study	Dates of enrollment	Evidence
Diviné et al. 2005 (LMB95)	1996-2001	Phase 2

Eligibility criteria

• Group B (unresected stage I, non-abdominal stage II and any stage III or IV disease without CNS or bone marrow involvement)

Preceding treatment

• COPADM induction

Chemotherapy

• Cytarabine (Ara-C) 100 mg/m²/day IV continuous infusion over 120 hours, started on day 2 (total dose per cycle: 500 mg/m²)
• Methotrexate (MTX) 3000 mg/m² IV over 3 hours once on day 1

Supportive therapy

• Leucovorin (Folinic acid) 15 mg/m² (route not specified) every 6 hours on days 2 to 4

CNS therapy, prophylaxis

• Methotrexate (MTX) 15 mg IT once on day 2
• Cytarabine (Ara-C) 30 mg IT once on day 6
• Hydrocortisone (Cortef) 15 mg IT once per day on days 2 & 6 (admixed with chemo)

2 cycles; intervals were as short as possible, as soon as the ANC was greater than 1500/μL and platelet count was greater than 100 x 10⁹/L

Subsequent treatment

• COPADM maintenance

References

1. LMB95: Diviné M, Casassus P, Koscielny S, Bosq J, Sebban C, Le Maignan C, Stamattoulas A, Dupriez B, Raphaël M, Pico JL, Ribrag V; GELA; GOELAMS. Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol. Ann Oncol. 2005 Dec;16(12):1928-35. Epub 2005 Nov 10. link to original article contains dosing details in manuscript PubMed

Cytarabine & Etoposide (CYVE)

CYVE: CYtarabine, VEpesid (Etoposide)

Regimen

Study	Dates of enrollment	Evidence
Diviné et al. 2005 (LMB95)	1996-2001	Phase 2, fewer than 20 pts in this subgroup

Note: This regimen is for group C (CNS and/or bone marrow involvement). Note the unusual schedule of cytarabine; presumably the low-dose and high-dose portions are given at separate times in the 24 hour period but this detail is not further specified in the manuscript.

Preceding treatment

• COPADM induction

Chemotherapy

• Cytarabine (Ara-C) by the following split schedule:
  • 50 mg/m² IV over 12 hours once per day on days 1 to 5
  • 3000 mg/m² IV over 3 hours once per day on days 2 to 5
• Etoposide (Vepesid) 200 mg/m² IV once per day on days 2 to 5

2 cycles; intervals were as short as possible, as soon as the ANC was greater than 1500/μL and platelet count was greater than 100 x 10⁹/L

Subsequent treatment

• COPAD alternating with CYVE maintenance

References

1. LMB95: Diviné M, Casassus P, Koscielny S, Bosq J, Sebban C, Le Maignan C, Stamattoulas A, Dupriez B, Raphaël M, Pico JL, Ribrag V; GELA; GOELAMS. Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol. Ann Oncol. 2005 Dec;16(12):1928-35. Epub 2005 Nov 10. link to original article contains dosing details in manuscript PubMed

Maintenance after upfront therapy

COPAD/CYVE

COPAD/CYVE: Cyclophosphamide, Oncovin (Vincristine), Prednisone, ADriamycin (Doxorubicin) alternating with CYtarabine, VEpesid (Etoposide)

Regimen

Study	Dates of enrollment	Evidence
Diviné et al. 2005 (LMB95)	1996-2001	Phase 2, fewer than 20 pts in this subgroup

Note: This protocol is for group C (CNS and/or bone marrow involvement). Note that the days of administration for the CYVE cycles are counted from the start of the respective COPAD cycles in the original manuscript, but from 1 here.

Preceding treatment

• CYVE consolidation

Chemotherapy, COPAD portion (cycles 1 & 3)

• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days 1 & 2
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1
• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 2

Glucocorticoid therapy, COPAD portion (cycles 1 & 3)

• Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 5

CNS treatment, COPAD portion

Note: this is only given with the first cycle of maintenance; patients with positive CNS at diagnosis were to also undergo 2400 cGy of cranial irradiation.

• Methotrexate (MTX) as follows:
  • Cycle 1: 15 mg IT once on day 2
• Cytarabine (Ara-C) as follows:
  • Cycle 1: 40 mg IT once on day 2
• Hydrocortisone (Cortef) as follows:
  • Cycle 1: 15 mg IT once on day 2 (admixed with MTX & Ara-C)

Chemotherapy, CYVE portion (cycles 2 & 4)

• Cytarabine (Ara-C) 50 mg/m² SC twice per day on days 1 to 5
• Etoposide (Vepesid) 150 mg/m² IV once per day on days 1 to 3

1-month cycle for 4 cycles

References

1. LMB95: Diviné M, Casassus P, Koscielny S, Bosq J, Sebban C, Le Maignan C, Stamattoulas A, Dupriez B, Raphaël M, Pico JL, Ribrag V; GELA; GOELAMS. Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol. Ann Oncol. 2005 Dec;16(12):1928-35. Epub 2005 Nov 10. link to original article contains dosing details in manuscript PubMed

COPADM

COPADM: Cyclophosphamide, Oncovin (Vincristine), Prednisone, ADriamycin (Doxorubicin), Methotrexate

Regimen

Study	Dates of enrollment	Evidence
Diviné et al. 2005 (LMB95)	1996-2001	Phase 2

Note: This regimen is for group B (unresected stage I, non-abdominal stage II and any stage III or IV disease without CNS or bone marrow involvement).

Preceding treatment

• CYM consolidation

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days 1 & 2
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1
• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 2
• Methotrexate (MTX) 3000 mg/m² IV over 3 hours once on day 1

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m²/day PO on days 1 to 5

Supportive therapy

• Leucovorin (Folinic acid) 15 mg/m² (route not specified) every 6 hours on days 2 to 4

CNS therapy, prophylaxis

• Methotrexate (MTX) 15 mg IT once on day 2
• Hydrocortisone (Cortef) 15 mg IT once on day 2 (admixed with MTX)

One course

References

1. LMB95: Diviné M, Casassus P, Koscielny S, Bosq J, Sebban C, Le Maignan C, Stamattoulas A, Dupriez B, Raphaël M, Pico JL, Ribrag V; GELA; GOELAMS. Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol. Ann Oncol. 2005 Dec;16(12):1928-35. Epub 2005 Nov 10. link to original article contains dosing details in manuscript PubMed