HIV-associated lymphoma

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 Tarsheen Sethi, MD, MSCI
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The most common HIV-associated lymphomas are of DLBCL or Burkitt lymphoma histology; plasmablastic lymphoma and primary effusion lymphomas are also frequently seen in advanced-stage HIV/AIDS. In patients with a normal CD4+ T-cell count and well-controlled HIV, the lymphoma is typically treated as per the histologic subtype. For others, regimens specific to HIV-associated lymphoma have been developed and are included here.

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

Untreated, pre-phase

CVP

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

Regimen

Study Evidence
Galicier et al. 2007 (LMB86) Phase 2

Chemotherapy

Glucocorticoid therapy

Subsequent treatment

References

  1. LMB86: Galicier L, Fieschi C, Borie R, Meignin V, Daniel MT, Gérard L, Oksenhendler E. Intensive chemotherapy regimen (LMB86) for St Jude stage IV AIDS-related Burkitt lymphoma/leukemia: a prospective study. Blood. 2007 Oct 15;110(8):2846-54. Epub 2007 Jul 3. link to original article contains dosing details in manuscript PubMed

Upfront therapy

CHOP

CHOP: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
CHOP-21: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone every 21 days
ACOP
CAVP
COPA
VACP
VCAP

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kaplan et al. 2005 (AMC010) 1998-2002 Phase 3 (C) R-CHOP Did not meet primary endpoint of CR rate

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Combination antiretrovirals were required
  • G-CSF (type not specified) 5 mcg/kg SC once per day from days 4 to 13 or until ANC greater than 10k/μL.
  • PCP prophylaxis with ONE of the following:

21-day cycle for 3 cycles for early disease, or minimum of 6 cycles or 2 past CR for advanced disease

Subsequent treatment

  • AMC010, patients with stage I, IE, or nonbulky stage II disease: IFRT consolidation, beginning 3 weeks after the third cycle of chemotherapy

References

  1. AMC010: Kaplan LD, Lee JY, Ambinder RF, Sparano JA, Cesarman E, Chadburn A, Levine AM, Scadden DT. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood. 2005 Sep 1;106(5):1538-43. Epub 2005 May 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003595

CODOX-M

CODOX-M: Cyclophosphamide, Oncovin, DOXorubicin, Methotrexate

Regimen

Study Evidence
Wang et al. 2003 Retrospective

Note: Wang et al. 2003 retrospectively identified 8 HIV+ Burkitt lymphoma patients who had undergone treatment with CODOX-M/IVAC per the NCI 77-04 protocol.

  • 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 less than 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

This regimen is for low risk patients.

Chemotherapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) by the following age-based criteria:
    • 3 years old or older: 70 mg IT once on day 1
    • Younger than 3 years old: "appropriately reduced doses"
  • Methotrexate (MTX) by the following age-based criteria:
    • 3 years old or older: 12 mg IT once on day 3
    • Younger than 3 years old: "appropriately reduced doses"

Supportive therapy

  • Leucovorin (Folinic acid) 192 mg/m2 IV once 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 less than 50 nmol/L

3 cycles; each cycle starts on the same day that the patient's ANC is greater than 1000/μL

References

  1. Retrospective: 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 dosing details in manuscript PubMed

CODOX-M/IVAC

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

Regimen

Study Evidence
Magrath et al. 1996 (NCI 77-04) Phase 2
Wang et al. 2003 Retrospective

Note: the original protocol of Magrath et al. 1996 did not comment on HIV status. Wang et al. 2003 retrospectively identified 8 HIV+ Burkitt lymphoma patients who had undergone treatment with CODOX-M/IVAC. CODOX-M and IVAC are given in an alternating fashion for a total of 4 cycles (A, B, A, B). Each cycle starts on the same day that the patient's ANC is greater than 1000/μL.

  • 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 less than 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

This regimen is for high-risk patients.

Chemotherapy, CODOX-M portion (cycles 1 & 3; "Part A")

CNS prophylaxis, CODOX-M portion (cycles 1 & 3; "Part A")

  • Cytarabine (Ara-C) by the following age-based criteria:
    • 3 years old or older: 70 mg IT once per day on days 1 & 3
    • Younger than 3 years old: "appropriately reduced doses"
  • Methotrexate (MTX) by the following age-based criteria:
    • 3 years old or older: 12 mg IT once on day 15
    • Younger than 3 years old: "appropriately reduced doses"

CNS treatment, CODOX-M portion

  • Cytarabine (Ara-C) as follows:
    • Cycle 1: 70 mg IT once on day 5 (in addition to doses above)
  • Methotrexate (MTX) as follows:
    • Cycle 1: 12 mg IT once on day 17 (in addition to dose above)

Supportive therapy, CODOX-M portion (cycles 1 & 3; "Part A")

  • Leucovorin (Folinic acid) 192 mg/m2 IV once 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 less than 50 nmol/L
  • GM-CSF 7.5 mcg/kg SC once per day, starting on day 13 and continuing until ANC greater than 1000/μL

Chemotherapy, IVAC portion (cycles 2 & 4; "Part B")

CNS prophylaxis, IVAC portion (cycles 2 & 4; "Part B")

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

Supportive therapy, IVAC portion (cycles 2 & 4; "Part B")

  • Mesna (Mesnex) 360 mg/m2 IV every 3 hours on days 1 to 5, given with ifosfamide
  • GM-CSF 7.5 mcg/kg SC once per day, starting on day 7 and continuing until ANC greater than 1000/μL

4 cycles (see note)

References

  1. NCI 77-04: 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. Retrospective: 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 dosing details in manuscript PubMed

dmCODOX-M - Modified Magrath

dmCODOX-M: dose-modified Cyclophosphamide, Oncovin, DOXorubicin, Methotrexate

Regimen

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

This regimen is 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 (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) 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)

CNS therapy, prophylaxis

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

Supportive therapy

Supportive therapy

3 cycles (see note) Note: Each cycle starts on the same day that the patient's ANC is greater than 1000/μL and unsupported (that is, without transfusion) platelet count greater than 75 x 109/L.

References

  1. 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

dmCODOX-M/IVAC - Modified Magrath

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

Regimen

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

Note: This regimen is for high-risk patients. dmCODOX-M and IVAC are given in an alternating fashion for a total of 4 cycles (A, B, A, B). Each cycle starts on the same day that the patient's ANC is greater than 1000/μL and unsupported (that is, without transfusion) platelet count greater than 75 x 109/L.

  • 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

Chemotherapy, dmCODOX-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) 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)

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

CNS treatment, dmCODOX-M portion (cycles 1 & 3)

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

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

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 (mixed with ifosfamide) IV over 60 minutes once per day on days 1 to 5, then 300 mg/m2 IV every four hours for 2 doses on days 1 to 5
    • Older than 65 years old: 200 mg/m2 (mixed with ifosfamide) IV over 60 minutes once per day on days 1 to 5, then 200 mg/m2 IV every four hours for 2 doses on days 1 to 5
  • Leucovorin (Folinic acid) 15 mg PO once on day 6, 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)

4 cycles (see note)

References

  1. 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

EPOCH, dose-escalated

EPOCH: Etoposide, Prednisone, Oncovin (Vincristine), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin)

Regimen

Study Evidence
Little et al. 2003 Non-randomized

Note: the paper refers to this regimen as dose-adjusted EPOCH but to avoid confusion with the other version of dose-adjusted EPOCH, we refer to it as dose-escalated EPOCH, here.

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) by the following laboratory-based criteria:
    • CD4+ count less than 100/μL: 187 mg/m2 IV over 15 minutes once on day 5
    • CD4+ count more than 100/μL: 375 mg/m2 IV over 15 minutes 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

Supportive therapy

  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6 and continuing until ANC greater than 5000/μL past nadir

21-day cycle for 6 cycles

Dose and schedule modifications

    • In each subsequent cycle, increase cyclophosphamide dose by 187 mg/m2 (maximum dose 750 mg/m2) if the neutrophil nadir is greater than 500/μL and platelet nadir is greater than 25 x 109/L. Decrease dose by 187 mg/m2 if the neutrophil nadir is less than 500/μL or platelet nadir is less than 25 x 109/L.

References

  1. Little RF, Pittaluga S, Grant N, Steinberg SM, Kavlick MF, Mitsuya H, Franchini G, Gutierrez M, Raffeld M, Jaffe ES, Shearer G, Yarchoan R, Wilson WH. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood. 2003 Jun 15;101(12):4653-9. Epub 2003 Feb 27. link to original article contains dosing details in manuscript PubMed

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

Glucocorticoid therapy

5-day course, followed by:


Induction

Targeted therapy, A cycle

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

Supportive therapy, A cycle

Targeted therapy, B cycle

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

Supportive therapy, B cycle

Targeted therapy, C cycle

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

Supportive therapy, C cycle

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)

CNS therapy, prophylaxis

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

m-BACOD

m-BACOD: methotrexate (moderate dose), Bleomycin, Adriamycin (Doxorubicin), Cyclophosphamide, Oncovin (Vincristine), Dexamethasone

Regimen variant #1, "low-dose" #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kaplan et al. 1997 (ACTG 142) 1991-1994 Phase 3 (E-de-esc) m-BACOD; standard-dose Did not meet primary endpoint of OS

Note: this is of historical interest, only.

Chemotherapy

Glucocorticoid therapy

Supportive therapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) as follows:
    • Cycle 1: 50 mg IT once per day on days 1, 8, 15
    • Cycle 2: 50 mg IT once on day 1

21-day cycle for 2 cycles past complete remission (minimum of 4 cycles)


Regimen variant #2, "low-dose" #2

Study Evidence
Levine et al. 1991 Non-randomized

Note: this is of historical interest, only; the MTX dose is slightly higher than above.

Chemotherapy

Glucocorticoid therapy

Supportive therapy

CNS therapy, prophylaxis

4 to 6 cycles


Regimen variant #3, "standard-dose"

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kaplan et al. 1997 (ACTG 142) 1991-1994 Phase 3 (C) m-BACOD; low-dose Did not meet primary endpoint of OS

Note: this is of historical interest, only.

Chemotherapy

Glucocorticoid therapy

Supportive therapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) as follows:
    • Cycle 1: 50 mg IT once per day on days 1, 8, 15
    • Cycle 2: 50 mg IT once on day 1

21-day cycle for 2 cycles past complete remission (minimum of 4 cycles)

References

  1. Levine AM, Wernz JC, Kaplan L, Rodman N, Cohen P, Metroka C, Bennett JM, Rarick MU, Walsh C, Kahn J, Miles S, Ehmann WC, Feinberg J, Nathwani B, Gill PS, Mitsuyasu R. Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance in AIDS-related lymphoma: a prospective multi-institutional trial. JAMA. 1991 Jul 3;266(1):84-8. link to original article contains dosing details in abstract PubMed
  2. ACTG 142: Kaplan LD, Straus DJ, Testa MA, Von Roenn J, Dezube BJ, Cooley TP, Herndier B, Northfelt DW, Huang J, Tulpule A, Levine AM; National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin's lymphoma associated with human immunodeficiency virus infection. N Engl J Med. 1997 Jun 5;336(23):1641-8. link to original article contains dosing details in manuscript PubMed

R-CDOP

R-CDOP: Rituximab, Cyclophosphamide, Doxil (Pegylated liposomal doxorubicin), Oncovin (Vincristine), Prednisone
DR-COP: Doxil (pegylated liposomal doxorubicin), Rituximab, Cyclophosphamide, Oncovin, Prednisone

Regimen

Study Dates of enrollment Evidence
Levine et al. 2012 (AMC047) 2007-NR Phase 2

Targeted therapy

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

  • "CNS prophylaxis was mandated in patients with involvement of bone marrow, testis, sinuses, or epidural regions and with stage IV and/or at least two extranodal sites, with specific regimen left to physician discretion."

Supportive therapy

21- to 28-day cycle for up to 6 cycles

References

  1. AMC047: 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. 2013 Jan 1;31(1):58-64. Epub 2012 Nov 19. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00389818

R-CHOP

R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Regimen variant #1, 3 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kaplan et al. 2005 (AMC010) 1998-2002 Phase 3 (E-esc) CHOP Did not meet primary endpoint of CR rate

Note: This regimen variant was intended for patients with stage I, IE, or nonbulky stage II disease.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Combination antiretrovirals were required
  • G-CSF (type not specified) 5 mcg/kg SC once per day from days 4 to 13 or until ANC greater than 10k/μL.
  • PCP prophylaxis with ONE of the following:

21-day cycle for 3 cycles for early disease, or minimum of 6 cycles or 2 past CR for advanced disease

Subsequent treatment

  • IFRT consolidation x 4000 cGy


Regimen variant #2, prednisone 40 mg/m2

Study Dates of enrollment Evidence
Boué et al. 2006 NR Phase 2
Ribera et al. 2007x 2001-04 to 2006-04 Phase 2

Targeted therapy

  • Rituximab (Rituxan) 375 mg/m2 IV once on day 1
    • In Boué et al. 2006, first dose was given on day -1

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Supportive therapy

  • Combination antiretrovirals were required: one or two protease inhibitors and two nucleoside reverse transcriptase inhibitors
  • PCP prophylaxis with ONE of the following:

21-day cycle for 6 cycles

Subsequent treatment

  • Ribera et al. 2007x, patients with bulky disease or a residual mass: IFRT consolidation (details not provided)


Regimen variant #3, prednisone 100 mg

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kaplan et al. 2005 (AMC010) 1998-2002 Phase 3 (E-esc) CHOP Did not meet primary endpoint of CR rate

Note: This regimen variant was intended for patients with advanced disease.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Combination antiretrovirals were required
  • G-CSF (type not specified) 5 mcg/kg SC once per day from days 4 to 13 or until ANC greater than 10k/μL.
  • PCP prophylaxis with ONE of the following:

21-day cycle for a minimum of 6 cycles or 2 past CR

Subsequent treatment

References

  1. AMC010: Kaplan LD, Lee JY, Ambinder RF, Sparano JA, Cesarman E, Chadburn A, Levine AM, Scadden DT. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood. 2005 Sep 1;106(5):1538-43. Epub 2005 May 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003595
  2. Boué F, Gabarre J, Gisselbrecht C, Reynes J, Cheret A, Bonnet F, Billaud E, Raphael M, Lancar R, Costagliola D. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. J Clin Oncol. 2006 Sep 1;24(25):4123-8. Epub 2006 Aug 8. link to original article contains dosing details in manuscript PubMed
  3. Ribera JM, Oriol A, Morgades M, González-Barca E, Miralles P, López-Guillermo A, Gardella S, López A, Abella E, García M; PETHEMA; GELTAMO; GELCAB; GESIDA. Safety and efficacy of cyclophosphamide, adriamycin, vincristine, prednisone and rituximab in patients with human immunodeficiency virus-associated diffuse large B-cell lymphoma: results of a phase II trial. Br J Haematol. 2008 Feb;140(4):411-9. Epub 2007 Dec 19. link to original article contains dosing details in manuscript PubMed

R-CODOX-M

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

Regimen

Study Dates of enrollment Evidence
Noy et al. 2015 (AMC 048) 2007-2010 Phase 2

Note: This regimen was intended for low-risk HIV-associated Burkitt lymphoma, and was the first published prospective regimen to explicitly use rituximab. This is sometimes called modified Magrath but is in fact a second modification to the modified Magrath described by LaCasce et al. 2004.

Targeted therapy

Chemotherapy

CNS therapy, prophylaxis

Supportive therapy

  • Leucovorin (Folinic acid) 200 mg/m2 IV once 24 hours after methotrexate, then 25 mg/m2 IV every 6 hours until methotrexate level is less than 50 nmol/L
  • Pegfilgrastim (Neulasta) 6 mg SC once on day 3
  • Filgrastim (Neupogen) (dose not specified) SC once per day, starting once methotrexate level is less than 50 nmol/L (approximately day 18) and continuing until ANC greater than 1000/μL

21- to 28-day cycle for 3 cycles

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 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 contains partial protocol PubMed content property of HemOnc.org
  3. Retrospective: 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. 2013 Sep;54(9):1921-7. Epub 2013 Jan 4. link to original article PubMed
  4. AMC 048: Noy A, Lee JY, Cesarman E, Ambinder R, Baiocchi R, Reid E, Ratner L, Wagner-Johnston N, Kaplan L. AMC 048: modified CODOX-M/IVAC-rituximab is safe and effective for HIV-associated Burkitt lymphoma. Blood. 2015 Jul 9;126(2):160-6. Epub 2015 May 8. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00392834

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

Study Dates of enrollment Evidence
LaCasce et al. 2004 NR Phase 2, fewer than 20 pts
Noy et al. 2015 (AMC 048) 2007-2010 Phase 2

Note: This protocol was intended for high-risk HIV-associated Burkitt lymphoma, and was the first published prospective regimen to explicitly use rituximab. This is sometimes called modified Magrath but is in fact a second modification to the modified Magrath described in LaCasce et al. 2004. Note that the preferred sequence is A, B, A, B but the authors note that for patients with anasarca or other concerns for retaining MTX, the sequence can be B, A, B, A. Also note that the paper does not specify whether hydrocortisone is used with the day 3 IT chemo; the authors have clarified (December 31, 2017) that this is left to institutional policy.

Targeted therapy, both portions (cycles 1 to 4)

Chemotherapy, R-CODOX-M portion (cycles 1 & 3; "Part A")

Supportive therapy, R-CODOX-M portion (cycles 1 & 3; "Part A")

  • Leucovorin (Folinic acid) 200 mg/m2 IV once 24 hours after methotrexate, then 25 mg/m2 IV every 6 hours until methotrexate level is less than 50 nmol/L
  • Filgrastim (Neupogen) (dose not specified) SC once per day, starting once methotrexate level is less than 50 nmol/L (approximately day 18) and continuing until ANC greater than 1000/μL

CNS prophylaxis, R-CODOX-M portion (cycles 1 & 3; "Part A")

Chemotherapy, R-IVAC portion (cycles 2 & 4; "Part B")

  • Ifosfamide (Ifex) 1500 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 7500 mg/m2)
  • Etoposide (Vepesid) 60 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 300 mg/m2)
  • Cytarabine (Ara-C) 2000 mg/m2 IV every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m2)

Supportive therapy, R-IVAC portion (cycles 2 & 4; "Part B")

CNS prophylaxis, R-IVAC portion (cycles 2 & 4; "Part B")

4 cycles (see note)

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 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 contains partial protocol PubMed content property of HemOnc.org
  3. Retrospective: 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. 2013 Sep;54(9):1921-7. Epub 2013 Jan 4. link to original article PubMed
  4. AMC 048: Noy A, Lee JY, Cesarman E, Ambinder R, Baiocchi R, Reid E, Ratner L, Wagner-Johnston N, Kaplan L. AMC 048: modified CODOX-M/IVAC-rituximab is safe and effective for HIV-associated Burkitt lymphoma. Blood. 2015 Jul 9;126(2):160-6. Epub 2015 May 8. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00392834

R-EPOCH, dose-escalated

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sparano et al. 2010 (AMC034) 2002-2006 Randomized Phase 2 (E-switch-ic) EPOCH, then R Not reported1

1While this was a randomized trial, the primary efficacy endpoint was a historical control; see article for details.

Targeted therapy

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) by the following laboratory-based criteria:
    • CD4+ count less than 100/μL: 187 mg/m2 IV over 15 minutes once on day 5
    • CD4+ count more than 100/μL: 375 mg/m2 IV over 15 minutes 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

Supportive therapy

21-day cycle for 6 to 8 cycles

Dose and schedule modifications

    • In each subsequent cycle, increase cyclophosphamide dose by 187 mg/m2 if the neutrophil nadir is greater than 500/μL and platelet nadir is greater than 25 x 109/L. Decrease dose by 187 mg/m2 if the neutrophil nadir is less than 500/μL or platelet nadir is less than 25 x 109/L.

References

  1. AMC034: 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 dosing details in manuscript link to PMC article PubMed NCT00049036

SC-EPOCH-RR

SC-EPOCH-RR: Short Course Rituximab, Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin, with dose-dense Rituximab

Regimen

Study Dates of enrollment Evidence
Dunleavy et al. 2013 (NCI 93-C-0133HIV) 2000-11 to 2009-12 Phase 2, fewer than 20 pts in this arm
Dunleavy et al. 2010 (NCI 97-C-0040) 2001-06 to 2009-04 Phase 2

Note: NCI 97-C-0040 reported on HIV+ DLBCL patients, whereas NCI 93-C-0133 reported on HIV+ Burkitt lymphoma patients. The regimen is the same.

Targeted therapy

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Supportive therapy

21-day cycle for 3 to 6 cycles, one cycle beyond CR

Dose and schedule modifications

  • Cyclophosphamide (Cytoxan):
    • In the subsequent cycle, decrease dose by 187 mg/m2 if ANC was less than 500/μL for 2 to 4 days or platelets were less than 25 x 109/L for 2 to 4 days.
    • In the subsequent cycle, decrease dose by 375 mg/m2 if ANC was less than 500/μL for 5 or more days or platelets were less than 25 x 109/L for 5 or more days.
    • If dose-reduced in prior cycle, increase dose by 187 mg/m2, up to maximum of 750 mg/m2, if ANC was greater than 500/μL and platelets were greater than 25 x 109/L for the entire cycle.

References

  1. NCI 97-C-0040: Dunleavy K, Little RF, Pittaluga S, Grant N, Wayne AS, Carrasquillo JA, Steinberg SM, Yarchoan R, Jaffe ES, Wilson WH. The role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Blood. 2010 Apr 15;115(15):3017-24. Epub 2010 Feb 3. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00001563
  2. NCI 93-C-0133HIV: 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 dosing details in manuscript link to PMC article PubMed NCT00001337

Stanford V

Regimen

Study Dates of enrollment Evidence
Spina et al. 2002 1997-05 to 2001-10 Phase 2

Note: this regimen was for HIV-associated Hodgkin lymphoma, unfavorable stage I or advanced stage.

Chemotherapy

Glucocorticoid therapy

  • Prednisone (Sterapred) as follows:
    • Weeks 1 to 10: 40 mg/m2 PO every other day
    • Weeks 11 & 12: taper by 10 mg/m2 every other day until off

Supportive therapy

12-week course

Subsequent treatment

  • Spina et al. 2002, PR: IFRT consolidation x 3600 cGy
  • Spina et al. 2002, CR with initial bulky disease (5 cm or larger): IFRT consolidation x 3600 cGy

References

  1. Spina M, Gabarre J, Rossi G, Fasan M, Schiantarelli C, Nigra E, Mena M, Antinori A, Ammassari A, Talamini R, Vaccher E, di Gennaro G, Tirelli U. Stanford V regimen and concomitant HAART in 59 patients with Hodgkin disease and HIV infection. Blood. 2002 Sep 15;100(6):1984-8. link to original article contains dosing details in manuscript PubMed

Consolidation after upfront therapy

Radiation therapy

IFRT: Involved Field Radiation Therapy

Regimen variant #1, 3600 cGy of IFRT

Study Dates of enrollment Evidence
Spina et al. 2002 1997-05 to 2001-10 Phase 2

Preceding treatment

Radiotherapy

4-week course


Regimen variant #2, 4000 cGy of IFRT

Study Dates of enrollment Evidence
Kaplan et al. 2005 (AMC010) 1998-2002 Non-randomized part of phase 3 RCT

Note: This regimen variant was intended for patients with stage I, IE, or nonbulky stage II disease.

Preceding treatment

Radiotherapy

One course

Subsequent treatment

References

  1. Spina M, Gabarre J, Rossi G, Fasan M, Schiantarelli C, Nigra E, Mena M, Antinori A, Ammassari A, Talamini R, Vaccher E, di Gennaro G, Tirelli U. Stanford V regimen and concomitant HAART in 59 patients with Hodgkin disease and HIV infection. Blood. 2002 Sep 15;100(6):1984-8. link to original article contains dosing details in manuscript PubMed
  2. AMC010: Kaplan LD, Lee JY, Ambinder RF, Sparano JA, Cesarman E, Chadburn A, Levine AM, Scadden DT. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood. 2005 Sep 1;106(5):1538-43. Epub 2005 May 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003595

Rituximab monotherapy

Regimen

Study Dates of enrollment Evidence
Kaplan et al. 2005 (AMC010) 1998-2002 Non-randomized part of phase 3 RCT

Preceding treatment

  • AMC010, early disease: Definitive IFRT
  • AMC010, advanced disease: Induction R-CHOP

Targeted therapy

1-month cycle for 3 cycles

References

  1. AMC010: Kaplan LD, Lee JY, Ambinder RF, Sparano JA, Cesarman E, Chadburn A, Levine AM, Scadden DT. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood. 2005 Sep 1;106(5):1538-43. Epub 2005 May 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003595

Consolidation after salvage therapy

BEAM, then auto HSCT

BEAM: BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Regimen

Study Evidence Efficacy
Re et al. 2003 Phase 2
Alvarnas et al. 2016 (BMT CTN 0803/AMC 071) Phase 2 1-year OS: 87% (95% CI, 72-94.5)

Note: days of chemotherapy are slightly different in Re et al. 2003; see paper for details.

Chemotherapy

Hematopoietic stem cells are reinfused on day 0

References

  1. Re A, Cattaneo C, Michieli M, Casari S, Spina M, Rupolo M, Allione B, Nosari A, Schiantarelli C, Vigano M, Izzi I, Ferremi P, Lanfranchi A, Mazzuccato M, Carosi G, Tirelli U, Rossi G. High-dose therapy and autologous peripheral-blood stem-cell transplantation as salvage treatment for HIV-associated lymphoma in patients receiving highly active antiretroviral therapy. J Clin Oncol. 2003 Dec 1;21(23):4423-7. Epub 2003 Oct 27. link to original article PubMed
  2. BMT CTN 0803/AMC 071: Alvarnas JC, Le Rademacher J, Wang Y, Little RF, Akpek G, Ayala E, Devine S, Baiocchi R, Lozanski G, Kaplan L, Noy A, Popat U, Hsu J, Morris LE Jr, Thompson J, Horowitz MM, Mendizabal A, Levine A, Krishnan A, Forman SJ, Navarro WH, Ambinder R. Autologous hematopoietic cell transplantation for HIV-related lymphoma: results of the BMT CTN 0803/AMC 071 trial. Blood. 2016 Aug 25;128(8):1050-8. Epub 2016 Jun 13. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01141712
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