Burkitt lymphoma

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Untreated

Note: Burkitt-like lymphoma is not considered an entity by the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue 2008 criteria. The correct terminology is "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma." However, Burkitt-like lymphoma is still used in common parlance and the term is retained here; treatment is usually similar to treatment for Burkitt lymphoma but regimens evaluated on Diffuse large B-cell lymphoma are also sometimes used.

BASIC

BASIC: Brief, Anthracycline-Sparing, Intensive Cyclophosphamide

Regimen

Non-randomized

Induction

• Cyclophosphamide (Cytoxan) 1500 mg/m2 IV over 1 hour once on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (max dose of 2 mg) IV once on day 1
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
• Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 8
• Methotrexate (MTX) 3000 mg/m2 IV over 2 hours on day 8

CNS prophylaxis:

• Cytarabine (Cytosar) 100 mg IT (50 mg of Hydrocortisone optional) on days 1, 4, 11 (also day 8 if no IV MTX given)

Supportive medications:

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

14-day cycles x 2 cycles, then:

Intensification

• Rituximab (Rituxan) 375 mg/m2 IV once on day 1
• Cyclophosphamide (Cytoxan) 50 mg/kg IV over 1 to 2 hours once per day on days 2 to 5

Supportive medications:

• 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 >1000/uL

One course, followed by:

• Rituximab (Rituxan) 375 mg/m2 IV once per week x 4 doses, once post-nadir ANC > 1000/uL

CNS treatment (only given in prior CNS involvement):

• Cytarabine (Cytosar) 100 mg IT (50 mg of Hydrocortisone optional) once per week x 4 doses, then once every other week x 4 doses

References

1. 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 verified protocol PubMed

CALGB 10 002

Regimen, Rizzieri et al. 2014 (CALGB 10 002)

Phase II

Cycle 1

• Cyclophosphamide (Cytoxan) 200 mg/m2 IV once per day on days 1 to 5
• Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 7

Supportive medications:

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

One-week cycle, followed by alternation of the following:

Cycles 2, 4, 6

• Ifosfamide (Ifex) 800 mg/m2 IV over 1 hour once per day on days 1 to 5
• Dexamethasone (Decadron) 10 mg/m2 (route not specified) once per day on days 1 to 5
• Methotrexate (MTX) 150 mg/m2 IV load, followed by 1.35 g/m2 over 23.5 hours on day 1
• Vincristine (Oncovin) 2 mg IV push once on day 1
• Cytarabine (Cytosar) 1000 mg/m2 IV over 2 hours once per day on days 4 & 5
• Etoposide (Vepesid) 80 mg/m2 IV over 1 hour once per day on days 4 & 5
• Rituximab (Rituxan) as follows:
  • Rituximab (Rituxan) 50 mg/m2 IV once on cycle 2 day 8
  • Rituximab (Rituxan) 375 mg/m2 IV once per day on cycle 2 days 10 & 12
  • Rituximab (Rituxan) 375 mg/m2 IV once on day 8 of cycles 4 & 6

CNS prophylaxis (for patients without CNS involvement):

• Cytarabine (Cytosar) 40 mg intrathecal on day 1
• Methotrexate (MTX) 15 mg intrathecal on day 1
• Hydrocortisone (Cortef) 50 mg intrathecal on day 1

Supportive medications:

• Mesna (Mesnex) (dose not specified but presumably equal to ifosfamide dose) mixed with Ifosfamide (Ifex)
• Folinic acid (Leucovorin) 25 mg/m2 IV or PO once 36 hours after start of IV Methotrexate (MTX), then 10 mg/m2 Q6H until methotrexate level < 0.05
• Filgrastim (Neupogen) 5 mcg/kg SQ once per day, starting on day 7 and continuing until ANC > 500/uL

21-day cycles

Cycles 3, 5, 7

• Cyclophosphamide (Cytoxan) 200 mg/m2 IV once per day on days 1 to 5
• Dexamethasone (Decadron) 10 mg/m2 PO or IV once per day on days 1 to 5
• Methotrexate (MTX) 150 mg/m2 IV load, followed by 1.35 g/m2 over 23.5 hours on day 1
• Vincristine (Oncovin) 2 mg IV push once on day 1
• Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 4 & 5
• Rituximab (Rituxan) 375 mg/m2 IV once on day 8 of cycles 3, 5, 7

CNS prophylaxis (for patients without CNS involvement):

• Cytarabine (Cytosar) 40 mg intrathecal on day 1
• Methotrexate (MTX) 15 mg intrathecal on day 1
• Hydrocortisone (Cortef) 50 mg intrathecal on day 1

Supportive medications:

• Folinic acid (Leucovorin) 50 mg/m2 IV or PO once 36 hours after start of IV Methotrexate (MTX), then 10 mg/m2 Q6H until methotrexate level < 0.05
• Filgrastim (Neupogen) 5 mcg/kg SQ once per day, starting on day 7 and continuing until ANC > 500/uL

21-day cycles

References

1. 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 verified protocol PubMed

CODOX-M/IVAC

CODOX-M: Cyclophosphamide, Oncovin, DOXorubicin, M ethotrexate

IVAC: Ifosfamide, Vepesid (etoposide), AC Ara-C (cytarabine)

Regimen #1 "Original Macgrath"

Phase II

Part 1: CODOX-M

• Cyclophosphamide (Cytoxan) 800 mg/m2 IV once on day 1; 200 mg/m2 IV once per day on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m2 IV once on days 1, 8
• Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1

Age 65 years or younger:

• Methotrexate (MTX) 300 mg/m2 IV over 1 hour on day 10
• Methotrexate (MTX) 2700 mg/m2 IV over next 23 hours on day 10

Age more than 65 years:

• Methotrexate (MTX) 100 mg/m2 IV over 1 hour on day 10
• Methotrexate (MTX) 900 mg/m2 IV over next 23 hours on day 10

CNS prophylaxis:

• Cytarabine (Cytosar) 70 mg intrathecal on days 1, 3
• Methotrexate (MTX) 12 mg intrathecal on day 15

Supportive medications:

• Folinic acid (Leucovorin) 15 mg/m2 IV Q3H, starting 36 hours after start of IV Methotrexate (MTX) until 48 hours, then Q6H until methotrexate level undetectable
• Folinic acid (Leucovorin) 15 mg PO once 24 hours after intrathecal Methotrexate (MTX)
• Filgrastim (Neupogen) 5 mcg/kg SQ once per day, starting on day 13 and continuing until ANC >1,000/uL

Part 2: IVAC

Age 65 years or younger:

• Ifosfamide (Ifex) 1500 mg/m2 IV over 1 hour once per day on days 1 to 5
• Etoposide (Vepesid) 60 mg/m2 IV over 1 hour once per day on days 1 to 5
• Cytarabine (Cytosar) 2 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses)

Age more than 65 years:

• Ifosfamide (Ifex) 1000 mg/m2 IV over 1 hour on days 1 to 5
• Etoposide (Vepesid) 60 mg/m2 IV over 1 hour on days 1 to 5
• Cytarabine (Cytosar) 1 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses)

CNS prophylaxis:

• Methotrexate (MTX) 12 mg intrathecal on day 5

Supportive medications:

• Age 65 years or younger: Mesna (Mesnex) 300 mg/m2 (mixed with Ifosfamide (Ifex)) over 1 hour, then 300mg/m2 IV every four hours x 2, on days 1 to 5
• Age more than 65 years: Mesna (Mesnex) 200 mg/m2 (mixed with Ifosfamide (Ifex)) over 1 hour, then 200mg/m2 IV every four hours x 2, on days 1 to 5
• Folinic acid (Leucovorin) 15 mg PO once 24 hours after intrathecal methotrexate
• Filgrastim (Neupogen) 5 mcg/kg SQ once per day, starting on day 7 and continuing until ANC >1,000/uL

Regimen #2, LaCasce et al. 2004 "Modified Macgrath"

Phase II, <20 patients reported

All modifications are in Part 1: CODOX-M. Also note that dose reductions for age > 65 years were not described in this publication.

Part 1: CODOX-M

• Cyclophosphamide (Cytoxan) 800 mg/m2 IV once on days 1, 2
• Vincristine (Oncovin) 1.4 mg/m2 (max dose of 2 mg) IV once 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 (all treatments admixed with 50 mg Hydrocortisone (Cortef)):

• Cytarabine (Cytosar) 50 mg intrathecal on days 1 (all patients), day 3 (high-risk only)
• Methotrexate (MTX) 12 mg intrathecal on day 1

Supportive medications:

• Folinic acid (Leucovorin) 200 mg/m2 IV once 24 hours after start of IV Methotrexate (MTX), then 15 mg/m2 Q6H until methotrexate level undetectable
• Filgrastim (Neupogen) 5 mcg/kg SQ once per day on days 3 to 8, held for MTX, and restarted after clearance continuing until ANC >1,000/uL

Part 2: IVAC

• Ifosfamide (Ifex) 1500 mg/m2 IV over 1 hour once per day on days 1 to 5
• Etoposide (Vepesid) 60 mg/m2 IV over 1 hour once per day on days 1 to 5
• Cytarabine (Cytosar) 2 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses)

CNS prophylaxis:

• Methotrexate (MTX) 12 mg admixed with 50 mg Hydrocortisone (Cortef) intrathecal on day 5

Supportive medications:

• Mesna (Mesnex) 300 mg/m2 (mixed with Ifosfamide (Ifex)) over 1 hour, then 300mg/m2 IV every four hours x 2, on days 1 to 5
• Filgrastim (Neupogen) 5 mcg/kg SQ once per day, starting on day 6 and continuing until ANC >1,000/uL

High-risk patients receive 2 cycles each of R-CODOX-M and R-IVAC (alternating). Low-risk patients (i.e. single site of disease <10cm with normal LDH) receive 3 cycles of R-CODOX-M.

References

1. 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 verified protocol PubMed
2. 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 verified protocol 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 verified protocol PubMed
4. 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 verified protocol 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 verified protocol PubMed

DA-R-EPOCH

DA-R-EPOCH: Dose Adjusted Rituximab, Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin

Synonyms: DA-EPOCH-R, EPOCH-R, REPOCH

Structured Concept: C63461 (NCI-T), C1882521 (NCI-MT/UMLS)

Regimen, Dunleavy et al. 2008, Dunleavy et al. 2013

Phase II

Note: the abstract references Wilson et al. 2002 for dosing, however this is the DA-EPOCH regimen (no rituximab). Thus, we are extrapolating that rituximab was given on day 1 of each cycle based on similar protocols in DLBCL and PMBCL.

• Rituximab (Rituxan) 375 mg/m2 IV once per cycle or day 1 before the start of EPOCH (depending on reference)
• Etoposide (Vepesid) 50 mg/m2/day (total dose of 200 mg/m2) IV continuous infusion on days 1 to 4
• Prednisone (Sterapred) 60 mg/m2 PO BID on days 1 to 5
• Vincristine (Oncovin) 0.4 mg/m2/day (total dose of 1.6 mg/m2) IV continuous infusion on days 1 to 4
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once over 15 minutes on day 5
• Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1 to 4

CNS prophylaxis:

• Methotrexate (MTX) IT (dose and # of cycles not specified)

Supportive medications: Filgrastim (Neupogen) dose not specified once per day, starting on day 6 and continuing until ANC greater than 5 × 10e9/L above the nadir level

21-day cycles x 6 cycles OR 21-day cycles x 3 to 6 cycles for 1 cycle beyond CR for a minimum of 3 cycles, if HIV-positive

Dose-adjustments for EPOCH protocol, based on Wilson et al. 2002:

• Start cycle 1 as described above.
• Obtain CBCs twice per week for nadir measurements.
• If nadir ANC >500, increase etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• If nadir ANC <500 on 1 or 2 measurements, use same doses as last cycle.
• If nadir ANC <500 on at least 3 measurements, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• Or if nadir platelet count <25 on at least 1 measurement, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• Dose adjustments below the cycle 1 starting dose only applies to cyclophosphamide. The lowest etoposide and doxorubicin would be dosed at the original cycle 1 dose.
• Can start new cycle every 21 days if ANC >1,000 and platelets >100. If counts are below those levels, check daily CBC and continue growth factor support until counts are adequate and next cycle can start.

References

1. Dunleavy K, Little RF, Pittaluga S, Grant N, Shovlin M, Steinberg S, Yarchoan R, Janik J, Jaffe ES, Wilson WH. A prospective study of dose-adjusted (DA) EPOCH with rituximab in adults with newly diagnosed Burkitt lymphoma: a regimen with high efficacy and low toxicity. Ann Oncol 19(suppl4):83-84, abstr.9. 2008 Jun. link to original article contains protocol
2. 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 contains verified protocol PubMed

GMALL-R

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

Regimen, Ribera et al. 2013 (Burkimab)

Phase II

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

Prephase

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

Cycle A

• Rituximab (Rituxan) 375 mg/m2 IV over 4 hours once on day 7
• Vincristine (Oncovin) 2 mg IV bolus once on day 8
• Methotrexate (MTX) 1500 mg/m2 IV over 24 hours once on day 8
  • Older than 55 years: reduce Methotrexate (MTX) dose by 50%
• Ifosfamide (Ifex) 800 mg/m2 IV over 1 hour once per day on days 8 to 12
• Dexamethasone (Decadron) 10 mg/m2 IV bolus once per day on days 8 to 12
• Teniposide (Vumon) 100 mg/m2 IV over 1 hour once per day on days 11 & 12
• Cytarabine (Cytosar) 150 mg/m2 IV over 1 hour BID on days 11 & 12
  • Older than 55 years: reduce Cytarabine (Cytosar) dose by 50%

Supportive medications:

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

Cycle B

• Rituximab (Rituxan) 375 mg/m2 IV over 4 hours once on day 28
• Vincristine (Oncovin) 2 mg IV bolus once on day 29
• Methotrexate (MTX) 1500 mg/m2 IV over 24 hours once on day 29
  • Older than 55 years: reduce Methotrexate (MTX) dose by 50%
• Cyclophosphamide (Cytoxan) 200 mg/m2 IV over 1 hour once per day on days 29 to 33
• Dexamethasone (Decadron) 10 mg/m2 IV bolus once per day on days 29 to 33
• Doxorubicin (Adriamycin) 25 mg/m2 IV over 15 minutes once per day on days 32 & 33

Supportive medications:

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

Cycle C

• Rituximab (Rituxan) 375 mg/m2 IV over 4 hours once on day 49
• Vindesine (Eldisine) 3 mg/m2 (maximum dose 5 mg) IV bolus once on day 50
• Methotrexate (MTX) 1500 mg/m2 IV over 24 hours once on day 50
  • Older than 55 years: reduce Methotrexate (MTX) dose by 50%
• Dexamethasone (Decadron) 10 mg/m2 IV bolus once per day on days 50 to 54
• Etoposide (Vepesid) 250 mg/m2 IV over 1 hour once per day on days 53 & 54
• Cytarabine (Cytosar) 2000 mg/m2 IV over 3 hours BID on day 54
  • Older than 55 years: reduce Cytarabine (Cytosar) dose by 50%

Supportive medications:

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

Give regimen as follows:

• Advanced stage and younger than 55 years: A->B->C x 2 courses (6 total cycles)
• Older than 55 years: Alternate A & B x 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)

CNS Prophylaxis

• Methotrexate (MTX) 15 mg intrathecal once on days 1, 8, 12, 29, 33
• Cytarabine (Cytosar) 40 mg intrathecal once on days 1, 8, 12, 29, 33
• Dexamethasone (Decadron) 20 mg intrathecal once on days 1, 8, 12, 29, 33

8 doses total

References

1. 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 verified protocol PubMed

LMB

Regimen, Diviné et al. 2005 (LMB95)

Phase II

To be added

References

1. 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 PubMed

R-CODOX-M/R-IVAC

R-CODOX-M: Rituximab, Cyclophosphamide, Oncovin, DOXorubicin, M ethotrexate

R-IVAC: Rituximab, Ifosfamide, Vepesid (etoposide), AC Ara-C (cytarabine)

Regimen

Expert Recommendation

In a 2014 review article, 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 by Jacobson and LaCasce.

Part 1: R-CODOX-M

• Rituximab (Rituxan) 375 mg/m2 IV no earlier than day 3 of cycle 1, then day 1 of each subsequent cycle
• Cyclophosphamide (Cytoxan) 800 mg/m2 IV once on days 1 & 2
• Vincristine (Oncovin) 1.4 mg/m2 (max dose of 2 mg) IV once 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 Prophylaxis:

• Cytarabine (Cytosar) 50 mg intrathecal once on day 1 (admixed with MTX) and again on day 3 in high-risk patients
• Methotrexate (MTX) 12 mg intrathecal once on day 1

CNS Treatment (for CSF positive): Treatment as per CNS prophylaxis PLUS:

• Cytarabine (Cytosar) 50 mg intrathecal once on day 5 of cycle 1 only
• Methotrexate (MTX) 12 mg intrathecal once on day 15 of cycle 1 only

Supportive medications:

• Folinic acid (Leucovorin) 200 mg/m2 IV once 24 hours after start of IV Methotrexate (MTX), then 15 mg/m2 Q6H until methotrexate level undetectable
• Pegfilgrastim (Neulasta) 6 mg SC once on day 3

Part 2: R-IVAC

• Rituximab (Rituxan) 375 mg/m2 IV once on day 1
• Ifosfamide (Ifex) 1500 mg/m2 IV over 2 hours once per day on days 1 to 5
• Etoposide (Vepesid) 60 mg/m2 IV over 1 hour once per day on days 1 to 5
• Cytarabine (Cytosar) 2 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses total)

CNS Prophylaxis:

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

CNS Treatment (for CSF positive): Treatment as per CNS prophylaxis PLUS:

• Cytarabine (Cytosar) 50 mg intrathecal once on day 3 of cycle 1 only

Supportive medications:

• Mesna (Mesnex) 300 mg/m2 (mixed with Ifosfamide (Ifex)) over 1 hour, then 300mg/m2 IV every four hours x 2, on days 1 to 5
• Pegfilgrastim (Neulasta) 6 mg SC once on day 6

Patients with "extensive disease and elevated LDH" receive 2 cycles each of R-CODOX-M and R-IVAC (alternating). Patients with low-risk disease (i.e. single site of disease <10cm with normal LDH) receive 3 cycles of R-CODOX-M.

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 verified protocol PubMed
2. 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. 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 verified protocol PubMed

R-CODOX-M/R-IVAC (Doxil substituted)

R-CODOX-M: Rituximab, Cyclophosphamide, Oncovin, DOXil, M ethotrexate

R-IVAC: Rituximab, Ifosfamide, Vepesid (etoposide), AC Ara-C (cytarabine)

Regimen

Phase II

Low risk patients (R-CODOX-M alone)

• Rituximab (Rituxan) 500 mg/m2 IV once on days 0 & 8
• Cyclophosphamide (Cytoxan) 800 mg/m2 IV over 1 hour once on day 1; 200 mg/m2 IV over 1 hour once per day on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m2 (max dose of 2 mg) IV push once on days 1 & 8
• Doxorubicin liposomal (Doxil) 40 mg/m2 IV once "per protocol" on day 1
• Methotrexate (MTX) 300 mg/m2 IV over 1 hour, followed by 2700 mg/m2 IV over next 23 hours on day 10

CNS Prophylaxis:

• Cytarabine (Cytosar) 70 mg intrathecal once on day 1
• Methotrexate (MTX) 12 mg intrathecal (or 6 mg into Ommaya) once on day 3

Supportive medications:

• Folinic acid (Leucovorin) 200 mg/m2 IV once 36 hours after start of IV Methotrexate (MTX), then 15 mg/m2 IV Q6H until methotrexate level is <5 X 10-8
• Filgrastim (Neupogen) 5 mcg/kg SQ once per day on days 6 & 7, then on day 14 onwards until ANC >1,500/uL

3 consecutive cycles

Part 1: R-CODOX-M

• Rituximab (Rituxan) 500 mg/m2 IV once on days 0 & 8
• Cyclophosphamide (Cytoxan) 800 mg/m2 IV over 1 hour once on day 1; 200 mg/m2 IV over 1 hour once per day on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m2 (max dose of 2 mg) IV push once on days 1 & 8
• Doxorubicin liposomal (Doxil) 40 mg/m2 IV once "per protocol" on day 1
• Methotrexate (MTX) 300 mg/m2 IV over 1 hour, followed by 2700 mg/m2 IV over next 23 hours on day 10

CNS Prophylaxis:

• Cytarabine (Cytosar) 70 mg intrathecal once on days 1 & 3
• Methotrexate (MTX) 12 mg intrathecal (or 6 mg into Ommaya) once on day 15

Supportive medications:

• Folinic acid (Leucovorin) 200 mg/m2 IV once 36 hours after start of IV Methotrexate (MTX), then 15 mg/m2 IV Q6H until methotrexate level is <5 X 10-8
• Filgrastim (Neupogen) 5 mcg/kg SQ once per day on days 6 & 7, then on day 14 onwards until ANC >1,500/uL

Part 2: R-IVAC

• Rituximab (Rituxan) 375 mg/m2 IV on days 0 & 6 or 7 (2 doses per cycle)
• Ifosfamide (Ifex) 1500 mg/m2 IV over 3 hours once per day on days 1 to 5
• Etoposide (Vepesid) 60 mg/m2 IV over 1 hour once per day on days 1 to 5
• Cytarabine (Cytosar) 2 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses per cycle)

CNS Prophylaxis:

• Methotrexate (MTX) 15 mg intrathecal once on day 5

Supportive medications:

• Mesna (Mesnex) 500 mg/m2 mixed with first Ifosfamide (Ifex), then 1000 mg/m2/day IV continuous infusion on days 1 to 5
• Folinic acid (Leucovorin) 15 mg PO q6h x 4 doses, starting 24 hours after intrathecal Methotrexate (MTX)
• Filgrastim (Neupogen) 5 mcg/kg SQ once per day, starting on day 6 or 7 and continuing until ANC >1,500/uL

Four alternating cycles of R-CODOX-M & R-IVAC

References

1. 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 verified protocol PubMed

R-HCVAD/R-MA

R-HCVAD: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone
R-MA: Rituximab, Methotrexate, Ara-C (cytarabine)

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 per day on days 1 to 4, 11 to 14

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.

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 once per day 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

Dose modifications:

• 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)

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)

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.

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 once per day 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

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
• 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.

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

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