HIV-associated lymphoma

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CODOX-M/IVAC

CODOX-M: Cyclophosphamide, Oncovin, DOXorubicin, M ethotrexate
IVAC: Ifosfamide, Vepesid (etoposide), AC 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:

• Cytarabine (Cytosar) 70 mg intrathecal on day 5 (in addition to doses above)
• Methotrexate (MTX) 12 mg intrathecal on day 17 (in addition to dose above)

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

• Ifosfamide (Ifex) 1500 mg/m2 IV on days 1-5
• Mesna (Mesnex) 360 mg/m2 IV every 3 hours on days 1-5, given at same time as ifosfamide
• Etoposide (Vepesid) 60 mg/m2 IV on days 1-5
• Cytarabine (Cytosar) 2000 mg/m2 IV every 12 hours on days 1 & 2 (total of 4 doses per cycle)
• Methotrexate (MTX) 12 mg intrathecal on day 5

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

• Cytarabine (Cytosar) 70 mg intrathecal on days 7 & 9
• Methotrexate (MTX) 12 mg intrathecal on day 17 (in addition to dose above)

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 content property of HemOnc.org
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

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:

• Filgrastim (Neupogen) OR Pegfilgrastim (Neulasta) OR Sargramostim (Leukine) starting on day 3, to continue until beyond nadir of blood counts
• Erythropoietin (e.g. Epoetin alfa (Procrit) or Darbepoetin alfa (Aranesp)) at physician discretion
• PCP prophylaxis required
• Oral quinolone if CD4 cell count ≤100 and absolute neutrophil count (ANC) <500/uL at entry or during treatment

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-CODOX-M/IVAC

R-CODOX-M: Rituximab, Cyclophosphamide, Oncovin, DOXorubicin, M ethotrexate
IVAC: Ifosfamide, Vepesid (etoposide), AC 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:
    • Normal LDH
    • WHO performance status of 0 or 1
    • Ann Arbor stage I or II
    • 0 or 1 extranodal sites of disease
  • Any patients which do not meet low-risk criteria are classified as high-risk

Part A: CODOX-M (modified)

• Cyclophosphamide (Cytoxan) 800 mg/m2 IV on day 1; 200 mg/m2 IV on days 2-5
• Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg per cycle) IV on days 1 & 8
• Doxorubicin (Adriamycin) 40 mg/m2 IV on day 1
• Cytarabine (Cytosar) 70 mg intrathecal on days 1 & 3
• Methotrexate (MTX) dose according to age:
  • Patients 65 years old or younger: Methotrexate (MTX) 300 mg/m2 IV over 1 hour on day 10; then 2700 mg/m2 IV over 23 hours on day 10; total dose on day 10 is 3000 mg/m2
  • Patients older than 65 years old: Methotrexate (MTX) 100 mg/m2 IV over 1 hour on day 10; then 900 mg/m2 IV over 23 hours on day 10; total dose on day 10 is 1000 mg/m2
• Folinic acid (Leucovorin) 15 mg/m2 IV every 3 hours x 5 doses on day 11, starting 36 hours after start of the day 10 methotrexate; then Folinic acid (Leucovorin) 15 mg/m2 IV every 6 hours until methotrexate level is <5 x 10^-8
• Methotrexate (MTX) 12 mg intrathecal on day 15
• Folinic acid (Leucovorin) 15 mg PO once on day 16, 24 hours after intrathecal methotrexate

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 13 and continuing until ANC >1,000/uL

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:

• Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 7 and continuing until ANC >1,000/uL

High-risk patients receive Part A: CODOX-M (modified) 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 (modified) 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
2. 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

• Rituximab (Rituxan) 375 mg/m2 IV "before each EPOCH cycle"
• Etoposide (Vepesid) 50 mg/m2/day (total dose of 200 mg/m2) IV continuous infusion on days 1-4
• Prednisone (Sterapred) 60 mg/m2 PO BID on days 1-5
• Vincristine (Oncovin) 0.4 mg/m2/day (total dose of 1.6 mg/m2) IV continuous infusion on days 1-4
• Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1-4
• Cyclophosphamide (Cytoxan) 187 mg/m2 (if CD4 count <100/uL) or 375 mg/m2 (if CD4 count >100/uL) IV over 15 minutes on day 5
  • In each subsequent cycle, increase dose of Cyclophosphamide (Cytoxan) by 187 mg/m2 if the neutrophil nadir is >500/μL and platelet nadir is >25/μL. Decrease dose of Cyclophosphamide (Cytoxan) by 187 mg/m2 if the neutrophil nadir is <500/μL or platelet nadir is <25/μL.

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