HIV-associated lymphoma

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CODOX-M/IVAC

CODOX-M: Cyclophosphamide, Oncovin, DOXorubicin, Methotrexate
IVAC: Ifosfamide, Vepesid (etoposide), Ara-C (cytarabine)

Regimen, Magrath, et al. 1996 & Wang, et al. 2003

  • Patients are stratified into high and low risk:
    • Low risk patients must fulfill all of the following criteria:
      • Serum LDH within the institution's normal range (for the NCI, this was <350 IU/L)
      • Single extraabdominal mass or completely resected abdominal disease
    • Any patients which do not meet low risk criteria are classified as high risk

Part A: CODOX-M for high risk patients

  • Cyclophosphamide (Cytoxan) 800 mg/m2 IV on day 1; cyclophosphamide 200 mg/m2 IV on days 2-5
  • Vincristine (Oncovin) 1.5 mg/m2 (no maximum dose) IV on days 1 & 8 of cycle 1; vincristine 1.5 mg/m2 (no maximum dose) IV on days 1, 8, 15 of cycle 3
  • Doxorubicin (Adriamycin) 40 mg/m2 IV on day 1
  • Methotrexate (MTX) 1200 mg/m2 IV over 1 hour on day 10; then 240 mg/m2/hour IV over 23 hours on day 10; total dose on day 10 is 6720 mg/m2
  • Folinic acid (Leucovorin) 192 mg/m2 IV on day 11, starting 36 hours after the start of the day 10 methotrexate, then 12 mg/m2 IV every 6 hours thereafter until serum methotrexate level is <5 x 10-8 mol/L
  • Cytarabine (Cytosar) 70 mg intrathecal on days 1 & 3
    • Patients younger than 3 years old received "appropriately reduced doses"
  • Methotrexate (MTX) 12 mg intrathecal on day 15
    • Patients younger than 3 years old received "appropriately reduced doses"

Patients with CNS disease at presentation received the following extra doses of intrathecal chemotherapy during cycle 1:

Supportive medications:

  • GM-CSF 7.5 mcg/kg SQ daily, starting on day 13 and continuing until ANC >1,000/uL

Part A: CODOX-M for low risk patients

  • Cyclophosphamide (Cytoxan) 800 mg/m2 IV on day 1; cyclophosphamide 200 mg/m2 IV on days 2-5
  • Vincristine (Oncovin) 1.5 mg/m2 (no maximum dose) IV on days 1 & 8
  • Doxorubicin (Adriamycin) 40 mg/m2 IV on day 1
  • Methotrexate (MTX) 1200 mg/m2 IV over 1 hour on day 10; then 240 mg/m2/hour IV over 23 hours on day 10; total dose on day 10 is 6720 mg/m2
  • Folinic acid (Leucovorin) 192 mg/m2 IV on day 11, starting 36 hours after the start of the day 10 methotrexate, then 12 mg/m2 IV every 6 hours thereafter until serum methotrexate level is <5 x 10-8 mol/L
  • Cytarabine (Cytosar) 70 mg intrathecal on day 1
    • Patients younger than 3 years old received "appropriately reduced doses"
  • Methotrexate (MTX) 12 mg intrathecal on day 3
    • Patients younger than 3 years old received "appropriately reduced doses"

Supportive medications:

  • No GM-CSF used for low risk patients

Part B: IVAC for high risk patients

Patients with CNS disease at presentation received the following extra doses of intrathecal chemotherapy during cycle 2:

Supportive medications:

  • GM-CSF 7.5 mcg/kg SQ daily, starting on day 7 and continuing until ANC >1,000/uL

High risk patients receive Part A: CODOX-M and Part B: IVAC given in an alternating fashion x total of 4 cycles (A, B, A, B). Low risk patients receive Part A: CODOX-M x 3 cycles only. Each cycle starts on the same day that the patient's ANC is >1,000/uL.

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. Wang ES, Straus DJ, Teruya-Feldstein J, Qin J, Portlock C, Moskowitz C, Goy A, Hedrick E, Zelenetz AD, Noy A. Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma. Cancer. 2003 Sep 15;98(6):1196-205. link to original article contains verified protocol PubMed

dmCODOX-M/IVAC - Modified Magrath

dmCODOX-M: dose-modified Cyclophosphamide, Oncovin, DOXorubicin, Methotrexate
IVAC: Ifosfamide, Vepesid (etoposide), Ara-C (cytarabine)

Regimen, Mead, et al. 2008 - MRC/NCRI LY10 trial

  • Patients are stratified into high and low risk:
    • Low risk patients must fulfill at least 3 of the following criteria:
    • Any patients which do not meet low risk criteria are classified as high risk

Part A: dmCODOX-M

Patients with CNS disease at presentation received the following extra doses of intrathecal chemotherapy:

Supportive medications:

  • Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 13 and continuing until ANC >1,000/uL
  • Allopurinol (Aloprim) PO and/or rasburicase (Elitek) prior to starting chemotherapy

Part B: IVAC

  • Ifosfamide (Ifex) dose according to age:
    • Patients 65 years old or younger: Ifosfamide (Ifex) 1500 mg/m2 IV over 1 hour on days 1-5
    • Patients older than 65 years old: Ifosfamide (Ifex) 1000 mg/m2 IV over 1 hour on days 1-5
  • Mesna (Mesnex) dose according to age:
    • Patients 65 years old or younger: Mesna (Mesnex) 300 mg/m2 (mixed with ifosfamide) IV over 1 hour on days 1-5; then 300 mg/m2 IV every four hours x 2 doses on days 1-5
    • Patients older than 65 years old: Mesna (Mesnex) 200 mg/m2 (mixed with ifosfamide) IV over 1 hour on days 1-5; then 200 mg/m2 IV every four hours x 2 doses on days 1-5
  • Etoposide (Vepesid) 60 mg/m2 IV over 1 hour on days 1-5
  • Cytarabine (Cytosar) dose according to age:
    • Patients 65 years old or younger: Cytarabine (Cytosar) 2000 mg/m2 IV over 3 hours every 12 hours x 4 doses on days 1 & 2 (total of 4 doses per cycle)
    • Patients older than 65 years old: Cytarabine (Cytosar) 1000 mg/m2 IV over 3 hours every 12 hours x 4 doses on days 1 & 2 (total of 4 doses per cycle)
  • Methotrexate (MTX) 12 mg intrathecal on day 5
  • Folinic acid (Leucovorin) 15 mg PO once on day 6, 24 hours after intrathecal methotrexate

Supportive medications:

High risk patients receive Part A: dmCODOX-M and Part B: IVAC given in an alternating fashion x total of 4 cycles (A, B, A, B). Low risk patients receive Part A: dmCODOX-M x 3 cycles only. Each cycle starts on the same day that the patient's ANC is >1,000/uL and unsupported (that is, without transfusion) platelet count >75 x 109/L

References

  1. 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. doi: 10.1182/blood-2008-03-145128. Epub 2008 Jul 8. link to original article contains verified protocol PubMed

DR-COP

DR-COP: Doxil (pegylated liposomal doxorubicin), Rituximab, Cyclophosphamide, Oncovin, Prednisone

Levels of Evidence: Phase II

Regimen

  • Doxorubicin liposomal (Doxil) 40 mg/m2 IV on day 1
  • Rituximab (Rituxan) 375 mg/m2 IV on day 1
  • Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
  • Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV on day 1
  • Prednisone (Sterapred) 100 mg PO daily on days 1-5
  • "CNS prophylaxis was mandated in patients with involvement of bone marrow, testis, sinuses, or epidural regions and with stage IV and/or ≥ two extranodal sites, with specific regimen left to physician discretion."
  • Highly Active Antiretroviral Therapy (HAART) required; specific regimen left to physician discretion. Use of zidovudine was not allowed.

21-28 day cycles x up to 6 cycles

Supportive medications:

References

  1. Levine AM, Noy A, Lee JY, Tam W, Ramos JC, Henry DH, Parekh S, Reid EG, Mitsuyasu R, Cooley T, Dezube BJ, Ratner L, Cesarman E, Tulpule A. Pegylated Liposomal Doxorubicin, Rituximab, Cyclophosphamide, Vincristine, and Prednisone in AIDS-Related Lymphoma: AIDS Malignancy Consortium Study 047. J Clin Oncol. 2012 Nov 19. [Epub ahead of print] link to original article contains verified protocol PubMed

R-dmCODOX-M/IVAC

R-dmCODOX-M: Rituximab, dose-modified Cyclophosphamide, Oncovin, DOXorubicin, Methotrexate
IVAC: Ifosfamide, Vepesid (etoposide), Ara-C (cytarabine)

Regimen #1, Mead, et al. 2008 & Kassam, et al. 2012

Kassam, et al. 2012 is a retrospective analysis that includes analysis of the use of rituximab with dose-modified CODOX-M/IVAC, and it lists Mead, et al. 2008 as its reference for this. However, since Mead, et al. 2008 did not include the use of rituximab, and Kassam, et al. 2012 did not describe exactly how rituximab was used in addition to that cited regimen, rituximab will not be included in this summary of the regimen. If one were to speculate, one would presume the dosage & schedule would be Rituximab (Rituxan) 375 mg/m2 IV once per cycle.

  • Patients are stratified into high and low risk:
    • Low risk patients must fulfill at least 3 of the following criteria:
    • Any patients which do not meet low risk criteria are classified as high risk

Part A: dmCODOX-M

Patients with CNS disease at presentation received the following extra doses of intrathecal chemotherapy:

Supportive medications:

  • Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 13 and continuing until ANC >1,000/uL
  • Allopurinol (Aloprim) PO and/or rasburicase (Elitek) prior to starting chemotherapy

Part B: IVAC

  • Ifosfamide (Ifex) dose according to age:
    • Patients 65 years old or younger: Ifosfamide (Ifex) 1500 mg/m2 IV over 1 hour on days 1-5
    • Patients older than 65 years old: Ifosfamide (Ifex) 1000 mg/m2 IV over 1 hour on days 1-5
  • Mesna (Mesnex) dose according to age:
    • Patients 65 years old or younger: Mesna (Mesnex) 300 mg/m2 (mixed with ifosfamide) IV over 1 hour on days 1-5; then 300 mg/m2 IV every four hours x 2 doses on days 1-5
    • Patients older than 65 years old: Mesna (Mesnex) 200 mg/m2 (mixed with ifosfamide) IV over 1 hour on days 1-5; then 200 mg/m2 IV every four hours x 2 doses on days 1-5
  • Etoposide (Vepesid) 60 mg/m2 IV over 1 hour on days 1-5
  • Cytarabine (Cytosar) dose according to age:
    • Patients 65 years old or younger: Cytarabine (Cytosar) 2000 mg/m2 IV over 3 hours every 12 hours x 4 doses on days 1 & 2 (total of 4 doses per cycle)
    • Patients older than 65 years old: Cytarabine (Cytosar) 1000 mg/m2 IV over 3 hours every 12 hours x 4 doses on days 1 & 2 (total of 4 doses per cycle)
  • Methotrexate (MTX) 12 mg intrathecal on day 5
  • Folinic acid (Leucovorin) 15 mg PO once on day 6, 24 hours after intrathecal methotrexate

Supportive medications:

High risk patients receive Part A: dmCODOX-M and Part B: IVAC given in an alternating fashion x total of 4 cycles (A, B, A, B). Low risk patients receive Part A: dmCODOX-M x 3 cycles only. Each cycle starts on the same day that the patient's ANC is >1,000/uL and unsupported (that is, without transfusion) platelet count >75 x 109/L

Regimen #2, Lacasce, et al. 2004 & Barnes, et al. 2011 - modified Magrath

Lacasce, et al. 2004 describes this particular modified Magrath regimen, and Barnes, et al. 2011 references it as the foundation for its R-CODOX-M/IVAC regimen. There were several vague details/errors in Lacasce, et al. 2004 that limit one's ability to confidently use this regimen.

  • Patients are stratified into high and low risk:
    • Low risk patients must fulfill both of the following criteria:
      • Normal LDH
      • Single focus of disease measuring <10 cm in greatest diameter
    • Any patients which do not meet low risk criteria are classified as high risk

Part A: R-CODOX-M

  • Rituximab (Rituxan) 375 mg/m2 IV once per cycle (no day specified by Barnes, et al. 2011)
  • Cyclophosphamide (Cytoxan) 800 mg/m2 IV on days 1 & 2
  • Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV on days 1 & 10
  • Doxorubicin (Adriamycin) 50 mg/m2 IV on day 1
  • Methotrexate (MTX) 3000 mg/m2 IV (no duration of infusion given) on day 10
    • Note: Lacasce, et al. 2004 says that methotrexate is given after urine is alkalinzied to a pH <7; this is almost certainly a typo, and it was probably intended to say "alkalinzied to a pH >7"
  • Folinic acid (Leucovorin) 200 mg/m2 IV on day 11, starting 24 hours after the start of the day 10 methotrexate, then 15 mg/m2 IV every 6 hours thereafter until serum methotrexate level is <0.1 x 10-6 M
  • Cytarabine (Cytosar) 50 mg intrathecal on days 1 & 3
    • Day 3 dose is not given to low risk patients
    • Hydrocortisone 50 mg intrathecal administered with all doses of intrathecal chemotherapy
  • Methotrexate (MTX) 12 mg intrathecal on day 1, admixed with day 1 cytarabine
    • Hydrocortisone 50 mg intrathecal administered with all doses of intrathecal chemotherapy

Patients with CNS disease at presentation received the following extra doses of intrathecal chemotherapy during cycle 1:

  • Cytarabine (Cytosar) 50 mg intrathecal on day 5 (in addition to doses above)
  • Methotrexate (MTX) 12 mg intrathecal on day 10 (in addition to dose above)
  • Hydrocortisone 50 mg intrathecal administered with all doses of intrathecal chemotherapy

Supportive medications:

  • G-CSF (no dose specified) on days 3-8
    • Note: Lacasce, et al. 2004 says that "G-CSF was restarted therafter if ANC > 1000"; this is believed to be a typo. The authors probably intended to say "G-CSF was restarted therafter if ANC <1000." Additionally, figure 1 contradicts the body text and indicates that G-CSF is given on days 1-6, and restarted on day 12: "ANC <1000 on day 12, restart G-CSF."

Part B: R-IVAC

Patients with CNS disease at presentation received the following extra doses of intrathecal chemotherapy during the first cycle of IVAC (cycle 2 overall):

  • Cytarabine (Cytosar) 50 mg intrathecal on days 3 & 5
  • Methotrexate (MTX) 12 mg intrathecal on day 5
    • Note: Lacasce, et al. 2004 said that these are additional doses, but there is already a dose of methotrexate 12 mg intrathecal regularly scheduled to be given on day 5. Therefore, it is unclear whether a second dose of methotrexate 12 mg is to be given.
  • Hydrocortisone 50 mg intrathecal administered with all doses of intrathecal chemotherapy

Supportive medications:

High risk patients receive Part A: CODOX-M and Part B: IVAC given in an alternating fashion x total of 4 cycles (A, B, A, B). Low risk patients receive Part A: CODOX-M x 3 cycles only. Each cycle starts on the same day that the patient's ANC is >1,000/uL.

References

  1. 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
  2. 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. doi: 10.1182/blood-2008-03-145128. Epub 2008 Jul 8. link to original article contains verified protocol PubMed
  3. 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. doi: 10.1093/annonc/mdq677. Epub 2011 Feb 21. link to original article contains partial protocol PubMed content property of HemOnc.org
  4. Kassam S, Bower M, Lee SM, de Vos J, Fields P, Gandhi S, Nelson M, Montoto S, Tenant-Flowers M, Burns F, Marcus R, Edwards SG, Cwynarski K. A retrospective, multi-center analysis of treatment intensification for HIV-positive patients with high-risk diffuse large B-cell lymphoma. Leuk Lymphoma. 2012 Dec 3. [Epub ahead of print] link to original article PubMed

R-EPOCH, dose-escalated (EPOCH-R)

Regimen

21-day cycles x 6-8 cycles

Supportive medications:

  • EITHER Filgrastim (Neupogen) 5 mcg/kg SC daily, starting 24 hours after EPOCH is completed and continuing until "neutrophil recovery"—no absolute count specified
  • OR Pegfilgrastim (Neulasta) 6 mg SC x1 24 hours after EPOCH is completed
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3x per week (e.g. Monday, Wednesday, Friday)
  • Fluconazole (Diflucan) 100 mg PO daily
  • Ciprofloxacin (Cipro) 500 mg PO BID, starting on day 8 and to continue to at least day 15 or postnadir ANC of at least 1000
    • Other fluoroquinolone can be used at discretion of physician

References

  1. Sparano JA, Lee JY, Kaplan LD, Levine AM, Ramos JC, Ambinder RF, Wachsman W, Aboulafia D, Noy A, Henry DH, Von Roenn J, Dezube BJ, Remick SC, Shah MH, Leichman L, Ratner L, Cesarman E, Chadburn A, Mitsuyasu R; AIDS Malignancy Consortium. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood. 2010 Apr 15;115(15):3008-16. Epub 2009 Dec 18. link to original article contains verified protocol PubMed
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