HIV-associated lymphoma

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J.C. Villasboas Bisneto, MD
Rochester, MN
19 regimens on this page
23 variants on this page

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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.

Upfront therapy

CHOP

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

Regimen

Study Evidence Comparator Efficacy
Kaplan et al. 2005 (AMC010) Phase III R-CHOP Seems not superior

Chemotherapy

Supportive medications

  • Combination antiretrovirals were required
  • G-CSF 5 mcg/kg SC once per day from days 4 to 13 or until ANC greater than 10k/uL.
  • 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

Radiation therapy

Patients with stage I, IE, or nonbulky stage II disease received "involved field radiotherapy to a total dose of at least 4000 cGy beginning 3 weeks after the third cycle of chemotherapy."

References

  1. 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 verified protocol link to PMC article PubMed

CODOX-M

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CODOX-M: Cyclophosphamide, Oncovin, DOXorubicin, Methotrexate

Regimen

Study Evidence
Magrath et al. 1996 (77-04) Phase II
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.

  • 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 prophylaxis

  • Cytarabine (Cytosar) 70 mg intrathecal once on day 1
    • Patients younger than 3 years old received "appropriately reduced doses"
  • Methotrexate (MTX) 12 mg intrathecal once on day 3
    • Patients younger than 3 years old received "appropriately reduced doses"

Supportive medications

  • Folinic acid (Leucovorin) 192 mg/m2 IV once on day 11, starting 36 hours after the start of the day 10 Methotrexate (MTX), 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/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

CODOX-M/IVAC

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

Regimen

Study Evidence
Magrath et al. 1996 (77-04) Phase II
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.

  • 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, Part A: CODOX-M

CNS prophylaxis

  • Cytarabine (Cytosar) 70 mg intrathecal once per day on days 1 & 3
    • Patients younger than 3 years old received "appropriately reduced doses"
  • Methotrexate (MTX) 12 mg intrathecal once 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

  • Folinic acid (Leucovorin) 192 mg/m2 IV once on day 11, starting 36 hours after the start of the day 10 Methotrexate (MTX), 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/uL

Chemotherapy, Part B: IVAC

CNS prophylaxis

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

Supportive medications

  • Mesna (Mesnex) 360 mg/m2 IV every 3 hours on days 1 to 5, given at same time as Ifosfamide (Ifex)
  • GM-CSF 7.5 mcg/kg SC once per day, starting on day 7 and continuing until ANC greater than 1000/uL

4 cycles (see note)

Note: 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/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 - Modified Magrath

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

Regimen

Study Evidence
Mead et al. 2008 (MRC/NCRI LY10) Non-randomized
  • 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) as follows:
    • Patients 65 years old or younger: 300 mg/m2 IV over 60 minutes on day 10, then 2700 mg/m2 IV over 23 hours on day 10 (total dose per cycle: 3000 mg/m2)
    • Patients older than 65 years old: 100 mg/m2 IV over 60 minutes on day 10, then 900 mg/m2 IV over 23 hours on day 10 (total dose per cycle: 1000 mg/m2)

CNS prophylaxis

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

Supportive medications

3 cycles (see note)

Note: Each cycle starts on the same day that the patient's ANC is greater than 1000/uL and unsupported (that is, without transfusion) platelet count greater than 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. Epub 2008 Jul 8. link to original article contains verified protocol link to PMC article PubMed

dmCODOX-M/IVAC - Modified Magrath

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

Regimen

Study Evidence
Mead et al. 2008 (MRC/NCRI LY10) Non-randomized
  • 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 high-risk patients.

Chemotherapy, Part A: dmCODOX-M

  • 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) as follows:
    • Patients 65 years old or younger: 300 mg/m2 IV over 60 minutes on day 10, then 2700 mg/m2 IV over 23 hours on day 10 (total dose per cycle: 3000 mg/m2)
    • Patients older than 65 years old: 100 mg/m2 IV over 60 minutes on day 10, then 900 mg/m2 IV over 23 hours on day 10 (total dose per cycle: 1000 mg/m2)

CNS prophylaxis

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

Supportive medications

Chemotherapy, Part B: IVAC

  • Ifosfamide (Ifex) as follows:
    • Patients 65 years old or younger: 1500 mg/m2 IV over 60 minutes once per day on days 1 to 5
    • Patients 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 (Cytosar) as follows:
    • Patients 65 years old or younger: 2000 mg/m2 IV over 3 hours every 12 hours on days 1 & 2 (total of 4 doses per cycle)
    • Patients older than 65 years old: 1000 mg/m2 IV over 3 hours every 12 hours on days 1 & 2 (total of 4 doses per cycle)

CNS prophylaxis

Supportive medications

  • Mesna (Mesnex) as follows:
    • Patients 65 years old or younger: 300 mg/m2 (mixed with Ifosfamide (Ifex)) IV over 60 minutes on days 1 to 5, then 300 mg/m2 IV every four hours x 2 doses on days 1 to 5
    • Patients older than 65 years old: 200 mg/m2 (mixed with Ifosfamide (Ifex)) IV over 60 minutes on days 1 to 5, then 200 mg/m2 IV every four hours x 2 doses on days 1 to 5
  • Folinic acid (Leucovorin) 15 mg PO once on day 6, 24 hours after intrathecal Methotrexate (MTX)
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 7 and continuing until ANC greater than 1000/uL

4 cycles (see note)

Note: 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/uL and unsupported (that is, without transfusion) platelet count greater than 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. Epub 2008 Jul 8. link to original article contains verified protocol link to PMC article PubMed

EPOCH, dose-escalated

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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 on days 1 to 4 (total dose per cycle: 200 mg/m2)
  • Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
  • Vincristine (Oncovin) 0.4 mg/m2/day IV continuous infusion on days 1 to 4 (total dose per cycle: 1.6 mg/m2)
  • Cyclophosphamide (Cytoxan) as follows:
    • CD4+ count less than 100/uL: 187 mg/m2 IV over 15 minutes once on day 5
    • CD4+ count greater than 100/uL: 375 mg/m2 IV over 15 minutes once on day 5
    • In each subsequent cycle, increase dose by 187 mg/m2 if the neutrophil nadir is greater than 500/uL and platelet nadir is greater than 25 x 109/L. Decrease dose by 187 mg/m2 if the neutrophil nadir is less than 500/uL or platelet nadir is less than 25 x 109/L.
  • Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion on days 1 to 4 (total dose per cycle: 40 mg/m2)

Supportive medications

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

21-day cycle for 6 cycles

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 verified protocol PubMed

GMALL-R

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

Regimen

Study Evidence
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

Chemotherapy, Cycle A

Supportive medications

Chemotherapy, Cycle B

Supportive medications

Chemotherapy, Cycle C

Supportive medications

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

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

LMB86

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To be completed

References

  1. 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 PubMed

m-BACOD

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

Variant #1, "low-dose"

Study Evidence Comparator Efficacy
Kaplan et al. 1997 Phase III Standard-dose m-BACOD Seems not superior

Note: this is of historical interest, only.

Chemotherapy

Supportive medications

  • GM-CSF 5 mcg/kg SC once per day on days 4 to 13 (as needed)

CNS prophylaxis

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

Variant #2, "standard-dose"

Study Evidence Comparator Efficacy
Kaplan et al. 1997 Phase III Low-dose m-BACOD Seems not superior

Note: this is of historical interest, only.

Chemotherapy

Supportive medications

  • GM-CSF 5 mcg/kg SC once per day on days 4 to 13

CNS prophylaxis

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

References

  1. 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 verified protocol PubMed

R-CDOP

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

Regimen

Study Evidence
Levine et al. 2012 (AMC047) Phase II

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once on day 1
  • Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
  • Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 IV once on day 1
  • Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
  • Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
  • "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."
  • Highly Active Antiretroviral Therapy (HAART) required; specific regimen left to physician discretion. Use of zidovudine was not allowed.

Supportive medications

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 verified protocol link to PMC article PubMed

R-CHOP

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

Variant #1, 3 cycles

Study Evidence Comparator Efficacy
Kaplan et al. 2005 (AMC010) Phase III CHOP Seems not superior

Intended for patients with stage I, IE, or nonbulky stage II disease.

Chemotherapy

Supportive medications

  • Combination antiretrovirals were required
  • G-CSF 5 mcg/kg SC once per day from days 4 to 13 or until ANC greater than 10k/uL.
  • 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

Variant #2, prednisone 100 mg

Study Evidence Comparator Efficacy
Kaplan et al. 2005 (AMC010) Phase III CHOP Seems not superior

Intended for patients with advanced disease.

Chemotherapy

Supportive medications

  • Combination antiretrovirals were required
  • G-CSF 5 mcg/kg SC once per day from days 4 to 13 or until ANC greater than 10k/uL.
  • PCP prophylaxis with ONE of the following:

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

Partial or complete responders received rituximab maintenane.

Variant #3, prednisone 40 mg/m2

Study Evidence
Ribera et al. 2007x Phase II

Chemotherapy

CNS prophylaxis

To be given with each cycle; day of administration not reported.

Supportive medications

  • 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

Patients with bulky disease or a residual mass received involved field radiotherapy (details not provided).

Variant #4

Study Evidence
Boué et al. 2006 Phase II

Chemotherapy

CNS prophylaxis

Decision was left to individual centers.

Supportive medications

  • Antiretrovirals were recommended
  • PCP prophylaxis was recommended with Cotrimoxazole (dose/schedule not specified)

21-day cycle for 6 cycles

References

  1. 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 verified protocol link to PMC article PubMed
  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 verified protocol 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 Groups. 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 verified protocol PubMed

R-CODOX-M

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

Regimen

Study Evidence
Noy et al. 2015 (AMC 048) Phase II

Intended for low-risk HIV-associated Burkitt lymphoma, and 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.

Chemotherapy

CNS prophylaxis

Supportive medications

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 verified protocol 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. 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 verified protocol link to PMC article PubMed

R-CODOX-M/R-IVAC

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

Regimen

Study Evidence
Noy et al. 2015 (AMC 048) Phase II

Intended for high-risk HIV-associated Burkitt lymphoma, and 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. 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.

Chemotherapy, Part A: R-CODOX-M

CNS prophylaxis

Supportive medications

Chemotherapy, Part B: R-IVAC

CNS prophylaxis

Supportive medications

4 alternating 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 verified protocol 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. 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 verified protocol link to PMC article PubMed

R-EPOCH, dose-escalated

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

Regimen

Study Evidence Comparator Efficacy
Sparano et al. 2010 (AMC034) Randomized Phase II EPOCH, then R Not reported (*)

Note: while this was a randomized trial, the primary efficacy endpoint was a historical control; see article for details.

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once "before each EPOCH cycle"
  • Etoposide (Vepesid) 50 mg/m2/day IV continuous infusion on days 1 to 4 (total dose per cycle: 200 mg/m2)
  • Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
  • Vincristine (Oncovin) 0.4 mg/m2/day IV continuous infusion on days 1 to 4 (total dose per cycle: 1.6 mg/m2)
  • Cyclophosphamide (Cytoxan) as follows:
    • CD4+ count less than 100/uL: 187 mg/m2 IV over 15 minutes once on day 5
    • CD4+ count greater than 100/uL: 375 mg/m2 IV over 15 minutes once on day 5
    • In each subsequent cycle, increase dose by 187 mg/m2 if the neutrophil nadir is greater than 500/uL and platelet nadir is greater than 25 x 109/L. Decrease dose by 187 mg/m2 if the neutrophil nadir is less than 500/uL or platelet nadir is less than 25 x 109/L.
  • Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion on days 1 to 4 (total dose per cycle: 40 mg/m2)

Supportive medications

21-day cycle for 6 to 8 cycles

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 link to PMC article PubMed

SC-EPOCH-RR

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

Regimen

Study Evidence
Dunleavy et al. 2010 Phase II
Dunleavy et al. 2013 Phase II, <20 pts in this arm

Dunleavy et al. 2010 reports on HIV+ DLBCL patients, whereas Dunleavy et al. 2013 reports on HIV+ Burkitt lymphoma patients. The regimen is the same.

Chemotherapy

CNS prophylaxis

Supportive medications

21-day cycles for one cycle beyond CR, minimum 3 and maximum of 6 cycles

Dose modifications

  • Cyclophosphamide (Cytoxan):
    • In the subsequent cycle, decrease dose by 187 mg/m2 if ANC was less than 500/uL 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/uL 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/uL and platelets were greater than 25 x 109/L for the entire cycle.

References

  1. 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 verified protocol link to PMC article PubMed
  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 link to PMC article PubMed

Stanford V

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Regimen

Study Evidence
Spina et al. 2002 Phase II

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

Chemotherapy

Supportive medications

12-week course

Subsequent treatment

  • PR: IFRT x 36 Gy
  • CR with initial bulky disease (5 cm or larger): IFRT x 36 Gy

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 verified protocol PubMed

Consolidation and/or maintenance after upfront therapy

Radiation therapy

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IFRT: Involved Field Radiation Therapy

Variant #1, 36 Gy of IFRT

Study Evidence
Spina et al. 2002 Phase II

Preceding treatment

Radiotherapy

4-week course

Variant #2, 40 Gy of IFRT

Study Evidence
Kaplan et al. 2005 (AMC010) Non-randomized portion of RCT

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 verified protocol 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 verified protocol link to PMC article PubMed

Rituximab monotherapy

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Regimen

Study Evidence
Kaplan et al. 2005 (AMC010) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

Monthly cycle for 3 cycles

References

  1. 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 verified protocol link to PMC article PubMed

Consolidation after salvage therapy

BEAM, then auto HSCT

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

Regimen

Study Evidence 1-year OS
Re et al. 2003 Phase II
Alvarnas et al. 2016 (BMT CTN 0803/AMC 071) Phase II 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. Erratum in: J Clin Oncol. 2004 Jan 15;22(2):386. Mazzuccato Maurizio [corrected to Mazzuccato Mauro]. link to original article PubMed
  2. 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 verified protocol link to PMC article PubMed