Non-Hodgkin lymphoma

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Follicular lymphoma

Mantle cell lymphoma

BR

BR: Bendamustine, Rituximab

CALGB 59909

Regimen

Treatments 1-2, R-M-CHOP

Interval between treatment 1 & 2 based on count recovery. Median days between treatment 1 & 2 was 23 days, with a range of 16-41 days observed.

Supportive medications:

  • Filgrastim (Neupogen) 5 mcg/kg SC daily starting on day 4, to continue until ANC >10000 once or >5000 twice
  • Levofloxacin (Levaquin) 500 mg PO daily, starting on day 6, to continue until ANC ≥1500
  • Fluconazole (Diflucan) 200 mg PO daily, starting on day 6, to continue until ANC ≥1500

Patients with ≤15% involvement by disease in bone marrow biopsy after treatment 2 proceed to treatment 3. If bone marrow biopsy after treatment 2 has >15% involvement by disease, repeat treatment 2 (identified as "treatment 2.5"). Patients with >15% bone marrow involvement by disease after treatment 2.5 were removed from protocol.

Treatment 3, "EAR"

EAR: Etoposide, Ara-C, Rituximab
Treatment 3 begins 4 weeks after treatment 2, if ANC ≥1000, platelets ≥100,000/uL, Cr <2 mg/dL, total bilirubin <2x upper limit of normal, and AST <3x upper limit of normal.

Supportive medications:

  • Filgrastim (Neupogen) 10 mcg/kg SC daily starting on day 14, to continue until peripheral blood stem cell collection is complete
  • Levofloxacin (Levaquin) 500 mg PO daily, starting on day 7, to continue until ANC ≥500
  • Fluconazole (Diflucan) 200 mg PO daily, starting on day 6, to continue until ANC ≥500
  • Acyclovir (Zovirax) 200 mg PO TID, starting on day 6, to continue until 1 year after autologous stem cell transplant (ASCT)
  • Note: Text specified that Trimethoprim/Sulfamethoxazole (Bactrim DS) prophylaxis started during treatment 3 (see dose/schedule in treatment 4)--although table 1 did not list it--to continue until 3 months after ASCT.

Treatment 4, "CBV"

CBV: Cyclophosphamide, BiCNU, VP-16

Supportive medications:

  • Filgrastim (Neupogen) 5 mcg/kg SC daily starting on day +4, to continue until ANC >5000 once or >1500 twice
  • Levofloxacin (Levaquin) 500 mg PO daily, starting on day +2, to continue until ANC ≥500
  • Fluconazole (Diflucan) 200 mg PO daily, starting on day +1, to continue until ANC ≥500
  • Acyclovir (Zovirax) 200 mg PO TID, starting on day -2, to continue until 1 year after ASCT
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID on Saturday and Sunday, to continue until 3 months after ASCT

Treatment 5, Rituximab

Additional considerations

If cerebrospinal fluid (CSF) contained disease with CSF WBC ≤5 cells/uL:

  • Methotrexate (MTX) 12 mg intrathecal x 10 total doses during treatments 1-3; not given concurrently with intrathecal methotrexate or cytarabine

If CSF contained >5 cells/uL:

  • In addition to intrathecal chemotherapy above, patient also received 2 Gy x 12 fractions (total dose 24 Gy) cranial radiation

If any patient appeared to be experiencing carmustine-induced pneumonitis:

References

  1. Damon LE, Johnson JL, Niedzwiecki D, Cheson BD, Hurd DD, Bartlett NL, Lacasce AS, Blum KA, Byrd JC, Kelly M, Stock W, Linker CA, Canellos GP. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009 Dec 20;27(36):6101-8. Epub 2009 Nov 16. link to original article contains protocol PubMed

Hyper-CVAD & Rituximab (Rituxan)

CVAD: Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone

Regimen

Part A (cycles 1, 3, 5, 7):

  • Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 3 hours Q12H on days 2-4 (6 total doses)
  • Mesna (Mesnex) 600 mg/m2/day IV continuous infusion on days 2-4, starting 1 hour before cytoxan and completed 12 hours after the last dose of cytoxan
  • Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV piggyback on day 5, 12 hours after the last dose of cyclophosphamide, and on day 12
  • Doxorubicin (Adriamycin) 16.6-16.7 (note: reference had slightly different dosages in the text vs. table 1) mg/m2/day IV continuous infusion over 72 hours on days 5-7
  • Dexamethasone (Decadron) 40 mg PO/IV on days 2-5, 12-15
  • Rituximab (Rituxan) 375 mg/m2 IV on day 1
    • Patients with peripheral blood involvement could have the cycle 1 dose of rituximab delayed or omitted by clinician discretion

21-day cycles, alternating every 21 days with Part B, for a total of 4 cycles of Part A and 4 cycles of Part B

Part B (cycles 2, 4, 6, 8):

  • Methotrexate (MTX) 200 mg/m2 IV over 2 hours, then 800 mg/m2 IV over 22 hours on day 2
    • Patients with a Cr >1.5 mg/dL received a 50% reduced dose of methotrexate
  • Cytarabine (Cytosar) 3000 mg/m2 (1000 mg/m2 for patients >60 years old or with Cr >1.5) IV over 2 hours Q12H on days 3 & 4 (4 total doses)
  • Folinic acid (Leucovorin) 50 mg PO x1 12 hours after methotrexate is complete, then 15 mg PO Q6H x 8 doses. If serum methotrexate level at 24 hours is >1 umol/L or at 48 hours is >0.1 umol/L, dose of folinic acid is increased to 100 mg IV Q3H.
  • Rituximab (Rituxan) 375 mg/m2 IV on day 1
  • Urine alkalinized to pH of 6.8 or more prior to the start of methotrexate and kept within that range until methotrexate is cleared
  • Prednisolone 1% ophthalmic solution 2 drops in each eye 4 times per day on days 3-9was started on the day of the start of cytarabine infusion and was continued for 7 days to prevent chemical conjunctivitis.

21-day cycles, alternating every 21 days with Part A, for a total of 4 cycles of Part A and 4 cycles of Part B

Supportive medications (for both Part A and Part B):
All medications given for 10 days, starting 24-36 hours after doxorubicin infusion is complete

  • Filgrastim (Neupogen) 5 mcg/kg SC daily
  • Valacyclovir (Valtrex) 500 mg PO daily
  • Fluconazole (Diflucan) 100 mg PO daily
  • Levofloxacin (Levaquin) 500 mg PO daily or Ciprofloxacin (Cipro) (reference did not specify dose/frequency)
  • "Erythropoietin was permitted throughout therapy"

References

  1. Romaguera JE, Fayad L, Rodriguez MA, Broglio KR, Hagemeister FB, Pro B, McLaughlin P, Younes A, Samaniego F, Goy A, Sarris AH, Dang NH, Wang M, Beasley V, Medeiros LJ, Katz RL, Gagneja H, Samuels BI, Smith TL, Cabanillas FF. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005 Oct 1;23(28):7013-23. Epub 2005 Sep 6. link to original article contains protocol PubMed

Nordic regimen, maxi-CHOP, HiDAC, Rituximab (Rituxan)

CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
HiDAC: High Dose Ara-C

Regimen

Protocol originally started rituximab during cycle 4, but the protocol was amended to start it on cycle 2.
Cycle 1 uses maxi-CHOP, cycle 2 uses HiDAC, cycle 3 uses maxi-CHOP, etc.

  • Rituximab (Rituxan) 375 mg/m2 IV on day 1 of cycles 2-5, and 375 mg/m2 IV on days 1 & 9 of cycle 6

maxi-CHOP

21-day cycles, alternating with high-dose cytarabine, for a total of 3 cycles of maxi-CHOP and 3 cycles of high-dose cytarabine

HiDAC/HDAC, high-dose Cytarabine (Cytosar)

21-day cycles, alternating with maxi-CHOP, for a total of 3 cycles of maxi-CHOP and 3 cycles of high-dose cytarabine

Supportive medications:

  • Filgrastim (Neupogen) given during cycle 6 as part of stem cell mobilization, with at least 2 million CD34+ cells/kg harvested

High-dose chemotherapy with BEAM or BEAC started 1-2 weeks after completion of cycle 6, followed by stem cell transplant. If transplant was delayed, an additional 1-2 cycles of chemotherapy with maxi-CHOP or HiDAC could be given.

References

  1. Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Akerman M, Ehinger M, Sundström C, Langholm R, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008 Oct 1;112(7):2687-93. Epub 2008 Jul 14. link to original article PubMed

Marginal zone lymphoma (including MALT lymphomas)

Bortezomib monotherapy

Level of Evidence: Phase II

Regimen

21-day cycles x up to 6 cycles

Supportive medications:

  • No routine growth factors, antibiotic, or antiviral prophylaxis was given

References

  1. Conconi A, Martinelli G, Lopez-Guillermo A, Zinzani PL, Ferreri AJ, Rigacci L, Devizzi L, Vitolo U, Luminari S, Cavalli F, Zucca E; International Extranodal Lymphoma Study Group (IELSG). Clinical activity of bortezomib in relapsed/refractory MALT lymphomas: results of a phase II study of the International Extranodal Lymphoma Study Group (IELSG). Ann Oncol. 2011 Mar;22(3):689-95. link to original article contains verified protocol PubMed

Cladribine monotherapy

Level of Evidence: Phase II

Regimen

28-day cycles x 4 to 6 cycles

Dose reductions:

  • "In case of a persisting nadir of the WBCs ≤ 4.0 × 10^9/L (or neutrophils ≤ 1.5 × 10^9/L) and/or the platelets ≤ 100 × 10^9/L, the next treatment cycle was delayed by 1 week until achieving normal values and then treatment was administered at a reduced dose of 0.1 mg/kg body weight."

Supportive medications:

  • Not described

References

  1. Jäger G, Neumeister P, Brezinschek R, Hinterleitner T, Fiebiger W, Penz M, Neumann HJ, Mlineritsch B, DeSantis M, Quehenberger F, Chott A, Beham-Schmid C, Höfler G, Linkesch W, Raderer M. Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type with cladribine: a phase II study. J Clin Oncol. 2002 Sep 15;20(18):3872-7. link to original article contains verified protocol PubMed

Rituximab monotherapy

Level of Evidence: Phase II

Regimen

References

  1. Conconi A, Martinelli G, Thiéblemont C, Ferreri AJ, Devizzi L, Peccatori F, Ponzoni M, Pedrinis E, Dell'Oro S, Pruneri G, Filipazzi V, Dietrich PY, Gianni AM, Coiffier B, Cavalli F, Zucca E. Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT type. Blood. 2003 Oct 15;102(8):2741-5. link to orginal article contains protocol PubMed
  2. Martinelli G, Laszlo D, Ferreri AJ, Pruneri G, Ponzoni M, Conconi A, Crosta C, Pedrinis E, Bertoni F, Calabrese L, Zucca E. Clinical activity of rituximab in gastric marginal zone non-Hodgkin's lymphoma resistant to or not eligible for anti-Helicobacter pylori therapy. J Clin Oncol. 2005 Mar 20;23(9):1979-83. link to original article contains protocol PubMed

Aggressive lymphoma (primarily diffuse large B-cell lymphoma)

ACVBP-R

ACVBP-R: Adriamycin, Cyclophosphamide, Vindesine, Bleomycin, Prednisone, Rituximab

Synonyms: R-ACVBP

Structured Concept: none

Level of Evidence: Phase III Improved OS Increased toxicity

Induction Regimen

14-day cycles x 4 cycles

Supportive medications:

  • Filgrastim (Neupogen) 300 mcg (for patients <75 kg) or 480 mcg (for patients at least 75 kg) SC daily on days 6-13

Consolidation Regimen

Supportive medications:

14-day cycles x 2 cycles, beginning 4 weeks after completion of induction, then

14-day cycles x 4 cycles, beginning 2 weeks after completion of MTX, then

14-day cycles x 2 cycles, beginning 2 weeks after completion of REI

References

  1. Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains verified protocol PubMed

CHOP

CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Synonyms: CHOP-21, ACOP, CAVP, COPA, VACP, VCAP

Structured Concept: C9549 (NCI-T), C0055598 (NCI-MT/UMLS)

Regimen #1, Elias, et al. 1978; Jones, et al. 1979; Fisher, et al. 1993; Miller, et al. 1998

21-day cycles x 8 cycles

Regimen #2, Pfreundschuh, et al. 2004 & Verdonck, et al. 2007

21-day cycles x 6 cycles

Supportive medications (only listed in Pfreundschuh, et al. 2004):

  • At the discretion of ordering physician: Filgrastim (Neupogen) 300 mcg (for patients <75 kg) or 480 mcg (for patients at least 75 kg) SC daily on days 4-13

Regimen #3, Miller, et al. 1998 - CHOP-21 & radiation

21-day cycles x 3 cycles, then followed by radiation therapy

Radiation therapy, starting 3 weeks after cycle 3 of CHOP:

  • Involved field radiation therapy, 180-200 cGy fractions, total dose of 4000-5500 cGy. Total dose was often influenced by whether patients had clinical evidence of residual disease after 4000 cGy.

Regimen #4, Coiffier, et al. 2002 & 2010, Feugier, et al. 2005 - LNH-98.5

21-day cycles x 8 cycles

Supportive medications:

  • Filgrastim (Neupogen) used for later cycles if patients developed grade 4 neutropenia or febrile neutropenia

References

  1. Elias L, Portlock CS, Rosenberg SA. Combination chemotherapy of diffuse histiocytic lymphoma with cyclophosphamide, adriamycin, vincristine and prednisone (CHOP). Cancer. 1978 Oct;42(4):1705-10. contains verified protocol PubMed
  2. Jones SE, Grozea PN, Metz EN, Haut A, Stephens RL, Morrison FS, Butler JJ, Byrne GE Jr, Moon TE, Fisher R, Haskins CL, Coltman CA Jr. Superiority of adriamycin-containing combination chemotherapy in the treatment of diffuse lymphoma: a Southwest Oncology Group study. Cancer. 1979 Feb;43(2):417-25. contains verified protocol PubMed
  3. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993 Apr 8;328(14):1002-6. link to original article PubMed
  4. Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, LeBlanc M, Carlin S, Chase E, Fisher RI. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998 Jul 2;339(1):21-6. link to original article contains verified protocol PubMed
  5. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. link to original article contains verified protocol PubMed
  6. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D, Schmitz N, Glass B, Rübe C, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):626-33. Epub 2004 Feb 24. link to original article contains verified protocol PubMed
  7. Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20;23(18):4117-26. link to original article contains protocol PubMed
  8. Verdonck LF, Notenboom A, de Jong DD, MacKenzie MA, Verhoef GE, Kramer MH, Ossenkoppele GJ, Doorduijn JK, Sonneveld P, van Imhoff GW. Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: a phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Blood. 2007 Apr 1;109(7):2759-66. link to original article contains verified protocol PubMed
  9. Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Fermé C, Tilly H. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010 Sep 23;116(12):2040-5. link to original article contains verified protocol PubMed

CHOP Intensified

CHOP-DI: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone, Dose Intense
I-CHOP: Intensified Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Synonyms: CHOP-14, CHOP-DI, I-CHOP

Structured Concept: none

Regimen #1, Blayney, et al. 2003 - CHOP-DI, SWOG 9349

14-day cycles x up to 6 cycles

Supportive medications:

Regimen #2, Verdonck, et al. 2007 - I-CHOP

Level of Evidence: Phase III Equivalent OS Increased toxicity

14-day cycles x 6 cycles

Supportive medications:

Regimen #3, Pfreundschuh, et al. 2004 - CHOP-14

14-day cycles x 6 cycles

Supportive medications:

  • Filgrastim (Neupogen) 300 mcg (for patients <75 kg) or 480 mcg (for patients at least 75 kg) SC daily on days 4-13

References

  1. Blayney DW, LeBlanc ML, Grogan T, Gaynor ER, Chapman RA, Spiridonidis CH, Taylor SA, Bearman SI, Miller TP, Fisher RI; Southwest Oncology Group. Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349). J Clin Oncol. 2003 Jul 1;21(13):2466-73. link to original article contains verified protocol PubMed
  2. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D, Schmitz N, Glass B, Rübe C, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):626-33. Epub 2004 Feb 24. link to original article contains verified protocol PubMed
  3. Verdonck LF, Notenboom A, de Jong DD, MacKenzie MA, Verhoef GE, Kramer MH, Ossenkoppele GJ, Doorduijn JK, Sonneveld P, van Imhoff GW. Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: a phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Blood. 2007 Apr 1;109(7):2759-66. link to original article contains verified protocol PubMed

CHOPE

CHOPE: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone, Etoposide

Synonyms: CHOEP, VAC0P

Structured Concept: C9702 (NCI-T), C0212922(NCI-MT/UMLS)

Regimen

14 or 21-day cycles x 6 cycles, next cycle to start as long as WBC is >2.5 and platelets >80

  • CHOEP-14 uses 14-day cycles; CHOEP-21 uses 21-day cycles

Supportive medications:

  • For 14-day cycles: Filgrastim (Neupogen) 300 mcg (for patients <75 kg) or 480 mcg (for patients at least 75 kg) SC daily on days 4-13
  • Filgrastim (Neupogen) use for 21-day cycles is by discretion of ordering physician

References

  1. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D, Schmitz N, Glass B, Rübe C, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):626-33. Epub 2004 Feb 24. link to original article contains verified protocol PubMed

EPOCH

EPOCH: Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin

Synonyms: CHEOP, DA-EPOCH

Structured Concept: C63779 (NCI-T), C1880475 (NCI-MT/UMLS)

Regimen #1, dose-adjusted EPOCH (DA-EPOCH), Wilson, et al. 2002

Supportive medications:

21-day cycles x 6-8 cycles

Dose-adjustments for EPOCH protocol:

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

Regimen #2, original EPOCH protocol, Wilson, et al. 1993

Supportive medications:

21-day cycles x 6-8 cycles

References

  1. Wilson WH, Bryant G, Bates S, Fojo A, Wittes RE, Steinberg SM, Kohler DR, Jaffe ES, Herdt J, Cheson BD, et al. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. J Clin Oncol. 1993 Aug;11(8):1573-82 link to original article contains verified protocol PubMed
  2. Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N, Steinberg SM, Little RF, Janik J, Gutierrez M, Raffeld M, Staudt L, Cheson BD, Longo DL, Harris N, Jaffe ES, Chabner BA, Wittes R, Balis F. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood. 2002 Apr 15;99(8):2685-93. link to original article contains verified protocol PubMed

m-BACOD

m-BACOD: methotrexate (moderate dose), Bleomycin, Adriamycin (doxorubicin), Cyclophosphamide, Oncovin (vincristine), Dexamethasone

Structured Concept: C63458 (NCI-T), C1883662 (NCI-MT/UMLS)

Level of Evidence: Phase II

Regimen

Dose adjustments:

  • If nadir WBC <1,000 or nadir platelets <50,000: 50% of cyclophosphamide and doxorubicin
  • If WBC <1,000, platelets <50,000, or creatinine >50% of baseline on day of treatment, methotrexate was omitted

21-day cycles x 10 cycles

Supportive medications: none reported

References

  1. Shipp MA, Yeap BY, Harrington DP, Klatt MM, Pinkus GS, Jochelson MS, Rosenthal DS, Skarin AT, Canellos GP. The m-BACOD combination chemotherapy regimen in large-cell lymphoma: analysis of the completed trial and comparison with the M-BACOD regimen. J Clin Oncol. 1990 Jan;8(1):84-93. link to original article contains verified protocol PubMed
  2. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993 Apr 8;328(14):1002-6. link to original article PubMed

ProMACE-CytaBOM

ProMACE-CytaBOM: Prolix (prednisone), Methotrexate, Adriamycin (doxorubicin), Cyclophosphamide, Etoposide, Cytarabine, Bleomycin, Oncovin (vincristine), Methotrexate

Structured Concept: C63460 (NCI-T), C1882461 (NCI-MT/UMLS)

Regimen

Dose adjustments:

  • "If WBC is ≥4,000, use 100% doses of all drugs
  • If WBC count is 3,000 to 3,999, 100% prednisone, bleomycin, vincristine, cytarabine, and methotrexate; 75% cyclophosphamide, Adriamycin, and etoposide
  • If WBC count is 2,000 to 2,999, 100% prednisone, bleomycin, vincristine, and methotrexate; 75% etoposide, cytarabine; 50% cyclophosphamide, Adriamycin
  • If WBC count is 1,000 to 1,999, 100% prednisone, bleomycin, vincristine and methotrexate; 25% cyclophosphamide, Adriamycin, etoposide, and cytarabine
  • If WBC count is 0 to 999, 100% prednisone, vincristine, and bleomycin; 50% methotrexate, no other drugs
  • If platelet count is ≥100,000, use 100% doses of all drugs
  • If platelet count is 50,000 to 99,000, 100% prednisone, bleomycin, vincristine, and methotrexate; 50% etoposide and cytarabine; 25% cyclophosphamide and Adriamycin
  • If platelet count is 0 to 49,000, 100% prednisone, bleomycin, and vincristine; 50% methotrexate, no other drugs"

21-day cycles x 6 cycles or 2 cycles after maximum clinical response

Supportive medications:

References

  1. Longo DL, DeVita VT Jr, Duffey PL, Wesley MN, Ihde DC, Hubbard SM, Gilliom M, Jaffe ES, Cossman J, Fisher RI, et al. Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: results of a prospective randomized trial. J Clin Oncol. 1991 Jan;9(1):25-38. Erratum in: J Clin Oncol 1991 Apr;9(4):710. link to original article contains verified protocol PubMed
  2. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993 Apr 8;328(14):1002-6. link to original article PubMed

R-CHOP

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

Synonyms: R-CHOP-21, CHOP-R

Structured Concept: C9760 (NCI-T), C0393023 (NCI-MT/UMLS)

Regimen #1, Coiffier, et al. 2002 & 2010; Feugier, et al. 2005 - LNH-98.5

Level of Evidence: Phase III Mixed OS Similar toxicity

21-day cycles x 8 cycles

Supportive medications:

  • Filgrastim (Neupogen) used for later cycles if patients developed grade 4 neutropenia or febrile neutropenia

Regimen #2, Pfreundschuh, et al. 2006 & 2011 - MInT

Level of Evidence: Phase III Improved OS Similar toxicity

21-day cycles x 6 cycles

Supportive medications:

References

  1. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. link to original article contains verified protocol PubMed
  2. Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20;23(18):4117-26. link to original article contains protocol PubMed
  3. Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-91. link to original article contains verified protocol PubMed
  4. Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Fermé C, Tilly H. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010 Sep 23;116(12):2040-5. link to original article contains verified protocol PubMed
  5. Pfreundschuh M, Kuhnt E, Trümper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, Jaeger U, Zinzani PL, Shpilberg O, Kvaloy S, de Nully Brown P, Stahel R, Milpied N, López-Guillermo A, Poeschel V, Grass S, Loeffler M, Murawski N; MabThera International Trial (MInT) Group. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011 Oct;12(11):1013-22. link to original article contains protocol PubMed
  6. Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains verified protocol PubMed

R-CHOP Intensified

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

Synonyms: R-CHOP-14

Structured Concept: none

Regimen

Pre-phase

7-day course, then

Main regimen

14-day cycles x 6-8 cycles (8 doses of rituximab regardless of total # of cycles)

Supportive medications:

Radiation therapy (only for patients meeting criteria)

  • Radiation therapy, 36 Gy to areas of initial bulky disease (masses at least 7.5 cm in diameter) or extranodal involvement

References

  1. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008 Feb;9(2):105-16. link to original article contains verified protocol PubMed

R-CVP

R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Structured Concept: C63473 (NCI-T), C1882520 (NCI-MT/UMLS)

Regimen

21-day cycles x up to 8 cycles

References

See references for CVP

R-EPOCH

R-EPOCH: Rituximab, Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin

Synonyms: EPOCH-R, REPOCH

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

Regimen

21-day cycles x 6-8 cycles

Supportive medications:

  • Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 6 and continuing until ANC >5,000/uL past nadir
  • PCP prophylaxis with any one of the following:
  • Only in García-Suárez, et al. 2007: Darbepoetin alfa (Aranesp) 2.25 ug/kg SC when hemoglobin concentration was ≤100 g/l.

Dose-adjustments for EPOCH protocol:

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

21-day cycles x 6-8 cycles

Supportive medications:

  • EITHER Filgrastim (Neupogen) 5 mcg/kg SQ 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. Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N, Steinberg SM, Little RF, Janik J, Gutierrez M, Raffeld M, Staudt L, Cheson BD, Longo DL, Harris N, Jaffe ES, Chabner BA, Wittes R, Balis F. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood. 2002 Apr 15;99(8):2685-93. link to original article contains verified protocol PubMed
  2. García-Suárez J, Bañas H, Arribas I, De Miguel D, Pascual T, Burgaleta C. Dose-adjusted EPOCH plus rituximab is an effective regimen in patients with poor-prognostic untreated diffuse large B-cell lymphoma: results from a prospective observational study. Br J Haematol. 2007 Jan;136(2):276-85. link to original article contains verified protocol PubMed
  3. Wilson WH, Dunleavy K, Pittaluga S, Hegde U, Grant N, Steinberg SM, Raffeld M, Gutierrez M, Chabner BA, Staudt L, Jaffe ES, Janik JE. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008 Jun 1;26(16):2717-24. link to original article PubMed
  4. Wilson WH, Jung SH, Porcu P, Hurd D, Johnson J, Martin SE, Czuczman M, Lai R, Said J, Chadburn A, Jones D, Dunleavy K, Canellos G, Zelenetz AD, Cheson BD, Hsi ED; Cancer Leukemia Group B. A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica. 2012 May;97(5):758-65. Epub 2011 Dec 1. link to original article PubMed

HIV-associated lymphoma

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

CNS lymphoma, including prophylaxis

High-dose Methotrexate (MTX) & Ifosfamide

Regimen

  • Methotrexate (MTX) 4000 mg/m2 IV over 4 hours on day 1
  • Ifosfamide (Ifex) 1500-2000 mg/m2 IV over 3 hours on days 3-5
  • Mesna (Mesnex) for prophylaxis of hemorrhagic cystitis
  • Folinic acid (Leucovorin) rescue starting 24 hours after start of methotrexate infusion
  • Sodium bicarbonate via IV fluid or PO routes used for urine alkalinization to maintain urine pH of at least 8
  • Check methotrexate levels 24, 48, and 72 hours after completion of methotrexate infusion.

Methotrexate (MTX) dose adjusted for creatinine clearances <100 mL/min according to the following formula:

  • Dose of methotrexate = (creatinine clearance/100) x 4000 mg/m2; the paper did not specify what method was used for calculating creatinine clearance. Patients with creatinine clearance <50 mL/min were excluded from the study.

up to 8 cycles (reference did not list timing/criteria to be used for next cycle of therapy)

References

  1. Fischer L, Korfel A, Kiewe P, Neumann M, Jahnke K, Thiel E. Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma. Ann Hematol. 2009 Feb;88(2):133-9. Epub 2008 Aug 5. link to original article contains verified protocol PubMed
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