Non-Hodgkin lymphoma

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Follicular lymphoma

BR

BR: Bendamustine, Rituximab

Regimen #1, Rummel, et al. 2005

• Rituximab (Rituxan) 375 mg/m2 IV on day 1

Cycle 1 is started 7 days after the first dose of rituximab

• Bendamustine (Treanda) 90 mg/m2 IV over 30 minutes on days 1 & 2 of cycles 1-4
• Rituximab (Rituxan) 375 mg/m2 IV on day 1 of cycles 1-5

28-day cycles x 5 cycles

Regimen #2, Rummel, et al. 2012 - StiL NHL1

• Bendamustine (Treanda) 90 mg/m2 IV on days 1 & 2
• Rituximab (Rituxan) 375 mg/m2 IV on day 1

28-day cycles x up to 6 cycles

References

1. Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, Josten KM, Dürk H, Rost A, Neise M, von Grünhagen U, Chow KU, Hansmann ML, Hoelzer D, Mitrou PS. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005 May 20;23(15):3383-9. link to original article contains protocol PubMed
2. Mathias J. Rummel, Norbert Niederle, Georg Maschmeyer, Andre G. Banat, Ulrich von Gruenhagen, Christoph Losem, Dorothea Kofahl-Krause, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz A. Duerk, Harald Ballo, Martina Stauch, Juergen Barth, Axel Hinke, Wolfram Brugger, Study Group Indolent Lymphomas (StiL). Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study. 2012 ASCO Annual Meeting abstract 3. link to abstract ASCO Post article ASCO plenary session video

BVR

BVR: Bendamustine, Velcade, Rituximab

Regimen (Friedberg, et al. 2011)

• Bendamustine (Treanda) 90 mg/m2 IV over 30-60 minutes on days 1 & 4, given last
• Bortezomib (Velcade) 1.3 mg/m2 IV push on days 1, 4, 8, 11, given first
• Rituximab (Rituxan) 375 mg/m2 IV on day 1, given after bortezomib and before bendamustine

28-day cycles x 6 cycles

Supportive medications:

• Premedications, antiemetic therapy, and growth factor support per institutional guidelines
• No routine antibiotic or antiviral prophylaxis was given

Alternate regimen (Fowler, et al. 2011)

• Bendamustine (Treanda) 50-90 mg/m2 IV over 60 minutes on days 1 & 2, given after bortezomib and before rituximab
• Bortezomib (Velcade) 1.6 mg/m2 IV on days 1, 8, 15, 22, given first
• Rituximab (Rituxan) 375 mg/m2 IV on days 1, 8, 15, 22 of cycle 1, then 375 mg/m2 IV on day 1 of cycles 2-5; given last

35-day cycles x 5 cycles

Supportive medications:

• Antiviral prophylaxis at physician discretion

References

1. Friedberg JW, Vose JM, Kelly JL, Young F, Bernstein SH, Peterson D, Rich L, Blumel S, Proia NK, Liesveld J, Fisher RI, Armitage JO, Grant S, Leonard JP. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood. 2011 Mar 10;117(10):2807-12. Epub 2011 Jan 14. link to original article contains protocol PubMed
2. Fowler N, Kahl BS, Lee P, Matous JV, Cashen AF, Jacobs SA, Letzer J, Amin B, Williams ME, Smith S, Saleh A, Rosen P, Shi H, Parasuraman S, Cheson BD. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: the phase II VERTICAL study. J Clin Oncol. 2011 Sep 1;29(25):3389-95. Epub 2011 Aug 1. link to original article contains protocol PubMed

Cyclophosphamide (Cytoxan)

Regimen

• Cyclophosphamide (Cytoxan) 100 mg/m2 PO daily, with dose modifications according to WBC and platelet count as listed in table 1 of Peterson, et al. 2003

References

1. Peterson BA, Petroni GR, Frizzera G, Barcos M, Bloomfield CD, Nissen NI, Hurd DD, Henderson ES, Sartiano GP, Johnson JL, Holland JF, Gottlieb AJ. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol. 2003 Jan 1;21(1):5-15. link to original article contains protocol PubMed

CHOP -> Tositumomab & I-131 (Bexxar)

CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Regimen

CHOP

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 100 mg PO on days 1-5

21-day cycles x 6 cycles

Supportive medications:

• Allopurinol (Aloprim) 300 mg PO daily for patients with bulky disease

Tositumomab & I-131 (Bexxar) dosimetric step

• On Day 0, infusions of:
  • Tositumomab 450 mg IV over 1 hour
  • Tositumomab 35 mg labeled with 5 mCi of Iodine-131 IV over 20 minutes
  • First scan of whole body dosimetry & redistribution
• Day 2, 3, or 4: Second scan of whole body dosimetry & redistribution
• Day 6 or 7: Third scan of whole body dosimetry & redistribution

Tositumomab & I-131 (Bexxar) therapeutic step

• Any day from day 7-14, infusions of:
  • Tositumomab 450 mg IV over 1 hour
  • Tositumomab 35 mg labeled with an individually calculated dose of Iodine-131 that will provide 75 cGy of radiation to the total body IV over 20 minutes
    • 65 cGy total body dose used for patients with platelet counts of 100-150,000/mm3

Calculated dose of I-131 is based on information from serial total-body gamma-camera counts

Supportive medications:

• Acetaminophen (Tylenol) 650 mg PO as premedication for tositumomab
• Diphenhydramine (Benadryl) 50 mg PO as premedication for tositumomab
• Potassium iodide 4 drops PO TID, Lugol solution 20 drops PO TID, or potassium iodide tablets 130 mg PO daily starting at least 24 hours before the dosimetric step and continuing for 14 days after the therapeutic infusion

References

1. Press OW, Unger JM, Braziel RM, Maloney DG, Miller TP, LeBlanc M, Gaynor ER, Rivkin SE, Fisher RI. A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood. 2003 Sep 1;102(5):1606-12. Epub 2003 May 8. link to original article contains protocol PubMed
2. Press OW, Unger JM, Braziel RM, Maloney DG, Miller TP, Leblanc M, Fisher RI; Southwest Oncology Group. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin's lymphoma: five-year follow-up of Southwest Oncology Group Protocol S9911. J Clin Oncol. 2006 Sep 1;24(25):4143-9. Epub 2006 Aug 8. link to original article PubMed

FCMR

FCMR: Fludarabine, Cyclophosphamide, Mitoxantrone, Rituximab

Regimen

• Fludarabine (Fludara) 25 mg/m2 IV over 30 minutes on days 1-3
• Cyclophosphamide (Cytoxan) 200 mg/m2 IV over 4 hours on days 1-3
• Mitoxantrone (Novantrone) 8 mg/m2 IV over 30 minutes on day 1
• Rituximab (Rituxan) 375 mg/m2 IV on day 0

28-day cycles x 4 cycles

References

1. Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. link to original article contains protocol PubMed

Fludarabine (Fludara) & Rituximab (Rituxan)

Regimen

• Rituximab (Rituxan) 375 mg/m2 IV on days 1 & 4

Cycle 1 begins 72 hours after the second dose of rituximab

• Fludarabine (Fludara) 25 mg/m2 IV on days 1-5 of cycles 1-6
• Rituximab (Rituxan) 375 mg/m2 IV given 72 hours before cycle 2 day 1, 72 hours before cycle 4 day 1, and 72 hours before cycle 6 day 1
• Rituximab (Rituxan) 375 mg/m2 IV on days 1 & 4 of cycle 7

28-day cycles x 7 cycles

References

1. Czuczman MS, Koryzna A, Mohr A, Stewart C, Donohue K, Blumenson L, Bernstein ZP, McCarthy P, Alam A, Hernandez-Ilizaliturri F, Skipper M, Brown K, Chanan-Khan A, Klippenstein D, Loud P, Rock MK, Benyunes M, Grillo-Lopez A, Bernstein SH. Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol. 2005 Feb 1;23(4):694-704. link to original article contains protocol PubMed

Rituximab (Rituxan), Ibritumomab tiuxetan & Yttrium-90 (Zevalin)

Regimen

Consolidation therapy for patients in complete or partial remission after first-line therapy

• Rituximab (Rituxan) 250 mg/m2 IV on days 1 & 8
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 14.8 MBq/kg (maximum dose of 1184 MBq) IV slow push over 10 minutes on day 8 immediately following rituximab

8-day course of therapy

Alternate regimen #1 (Witzig, et al. Aug 2002)

For patients with rituximab-refractory disease

• Rituximab (Rituxan) 250 mg/m2 IV on days 1 & 8
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (15 MBq/kg) (maximum dose of 32 mCi/1.2 GBq) IV over 10 minutes on day 8 immediately following rituximab

8-day course of therapy

Alternate regimen #2 (Witzig, et al. May 2002)

For patients with relapsed or refractory disease

• Rituximab (Rituxan) 250 mg/m2 IV on days 1 & 8
• Ibritumomab tiuxetan 1.6 mg & Indium-111 5 mCi IV over 10 minutes on day 1
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (15 MBq/kg) (maximum dose of 32 mCi/1.2 GBq) IV over 10 minutes on day 8 immediately following rituximab

8-day course of therapy

References

1. Witzig TE, Gordon LI, Cabanillas F, Czuczman MS, Emmanouilides C, Joyce R, Pohlman BL, Bartlett NL, Wiseman GA, Padre N, Grillo-López AJ, Multani P, White CA. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. J Clin Oncol. 2002 May 15;20(10):2453-63. link to original article contains protocol PubMed
2. Witzig TE, Flinn IW, Gordon LI, Emmanouilides C, Czuczman MS, Saleh MN, Cripe L, Wiseman G, Olejnik T, Multani PS, White CA. Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin's lymphoma. J Clin Oncol. 2002 Aug 1;20(15):3262-9. link to original article contains protocol PubMed
3. Morschhauser F, Radford J, Van Hoof A, Vitolo U, Soubeyran P, Tilly H, Huijgens PC, Kolstad A, d'Amore F, Gonzalez Diaz M, Petrini M, Sebban C, Zinzani PL, van Oers MH, van Putten W, Bischof-Delaloye A, Rohatiner A, Salles G, Kuhlmann J, Hagenbeek A. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol. 2008 Nov 10;26(32):5156-64. Epub 2008 Oct 14. link to original article contains protocol PubMed

R-CHOP

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

Regimen (Hiddemann, et al. 2005)

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 100 mg/m2 PO on days 1-5
• Rituximab (Rituxan) 375 mg/m2 IV on day 0

21-day cycles x 6-8 cycles

Alternate regimen (Czuczman, et al. 1999)

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 100 mg/m2 PO on days 1-5
• Rituximab (Rituxan) doses given by the following schedule:
  • Rituximab (Rituxan) 375 mg/m2 IV on days -6 & -1 of cycle 1 (7 and 2 days before cycle 1 day 1)
  • Rituximab (Rituxan) 375 mg/m2 IV 2 days before cycle 3 day 1 and 2 days before cycle 5 day 1
  • Rituximab (Rituxan) 375 mg/m2 IV 8 days and 15 days after completion of cycle 6 (i.e. what would be cycle 7 days 8 & 15)

21-day cycles x 6 cycles

References

1. Czuczman MS, Grillo-López AJ, White CA, Saleh M, Gordon L, LoBuglio AF, Jonas C, Klippenstein D, Dallaire B, Varns C. Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol. 1999 Jan;17(1):268-76. link to original article contains protocol PubMed
2. Czuczman MS, Weaver R, Alkuzweny B, Berlfein J, Grillo-López AJ. Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin's lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up. J Clin Oncol. 2004 Dec 1;22(23):4711-6. Epub 2004 Oct 13. link to original article PubMed
3. Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, Reiser M, Metzner B, Harder H, Hegewisch-Becker S, Fischer T, Kropff M, Reis HE, Freund M, Wörmann B, Fuchs R, Planker M, Schimke J, Eimermacher H, Trümper L, Aldaoud A, Parwaresch R, Unterhalt M. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2005 Dec 1;106(12):3725-32. Epub 2005 Aug 25. link to original article contains protocol PubMed

R-CVP

R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 40 mg/m2 PO on days 1-5
• Rituximab (Rituxan) 375 mg/m2 IV on day 1

21-day cycles x up to 8 cycles

References

1. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, Solal-Celigny P, Offner F, Walewski J, Raposo J, Jack A, Smith P. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005 Feb 15;105(4):1417-23. link to original article contains protocol PubMed
2. Marcus R, Imrie K, Solal-Celigny P, Catalano JV, Dmoszynska A, Raposo JC, Offner FC, Gomez-Codina J, Belch A, Cunningham D, Wassner-Fritsch E, Stein G. Phase III study of R-CVP compared with cyclophosphamide, vincristine, and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol. 2008 Oct 1;26(28):4579-86. Epub 2008 Jul 28. link to original article PubMed

R-FND

R-FND: Rituximab, Fludarabine, Novantrone, Dexamethasone

Regimen

Primary reference was not able to be obtained to verify this regimen

• Fludarabine (Fludara) 25 mg/m2 IV on days 1-3
• Mitoxantrone (Novantrone) 10 mg/m2 IV on day 1
• Dexamethasone (Decadron) 20 mg PO/IV on days 1-5
• Rituximab (Rituxan) 375 mg/m2 IV on day 1

28-day cycles x up to 8 cycles

Supportive medications:

• Prophylactic trimethoprim/sulfamethoxazole, acyclovir, and fluconazole

References

1. McLaughlin P, Hagemeister FB, Rodriguez MA, Sarris AH, Pate O, Younes A, Lee MS, Dang NH, Romaguera JE, Preti AH, McAda N, Cabanillas F. Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. Semin Oncol. 2000 Dec;27(6 Suppl 12):37-41. PubMed
2. P. McLaughlin, M. A. Rodriguez, F. B. Hagemeister, J. Romaguera, A. H. Sarris, A. Younes, N. H. Dang, A. Goy, F. Samaniego, M. Hess, et al. Stage IV indolent lymphoma: A randomized study of concurrent vs. sequential use of FND chemotherapy (fludarabine, mitoxantrone, dexamethasone) and rituximab (R) monoclonal antibody therapy, with interferon maintenance. 2003 ASCO Annual Meeting Abstract 2269. link to abstract
3. Hagemeister F, Cabanillas F, Coleman M, Gregory SA, Zinzani PL. The role of mitoxantrone in the treatment of indolent lymphomas. Oncologist. 2005 Feb;10(2):150-9. link to original article PubMed
4. Liu Q, Fayad L, Cabanillas F, Hagemeister FB, Ayers GD, Hess M, Romaguera J, Rodriguez MA, Tsimberidou AM, Verstovsek S, Younes A, Pro B, Lee MS, Ayala A, McLaughlin P. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. J Clin Oncol. 2006 Apr 1;24(10):1582-9. link to original article PubMed
5. G. E. Manoukian, F. B. Hagemeister, P. McLaughlin, L. Fayad, F. Samaniego, A. Goy, J. E. Romaguera, B. Pro, F. Cabanillas, M. A. Rodriguez. Rituximab, fludarabine, mitoxantrone, and dexamethasone (R-FND) for patients with relapsed indolent B-cell lymphoma (RIL). 2010 ASCO Annual Meeting Abstract 8078. link to abstract

Rituximab (Rituxan)

Regimen

• Rituximab (Rituxan) 375mg/m2 IV weekly x 4 weeks; initial infusion rate of 50 mg/H, then increased as tolerated by 50 mg/H every 30 minutes, to a maximum rate of 300 mg/H

4-week course

Supportive medications:

• Acetaminophen (Tylenol) 650 mg PO 30 minutes prior to each dose of rituximab
• Diphenhydramine (Benadryl) 50 mg PO 30 minutes prior to each dose of rituximab

Maintenance regimen (Salles, et al. 2011)

Starts 8 weeks after the last induction treatment

• Rituximab (Rituxan) 375mg/m2 IV on day 1

8-week cycles x 12 cycles

References

1. Colombat P, Salles G, Brousse N, Eftekhari P, Soubeyran P, Delwail V, Deconinck E, Haïoun C, Foussard C, Sebban C, Stamatoullas A, Milpied N, Boué F, Taillan B, Lederlin P, Najman A, Thièblemont C, Montestruc F, Mathieu-Boué A, Benzohra A, Solal-Céligny P. Rituximab (anti-CD20 monoclonal antibody) as single first-line therapy for patients with follicular lymphoma with a low tumor burden: clinical and molecular evaluation. Blood. 2001 Jan 1;97(1):101-6. link to original article contains protocol PubMed
2. Hainsworth JD, Litchy S, Burris HA 3rd, Scullin DC Jr, Corso SW, Yardley DA, Morrissey L, Greco FA. Rituximab as first-line and maintenance therapy for patients with indolent non-hodgkin's lymphoma. J Clin Oncol. 2002 Oct 15;20(20):4261-7. link to original article contains protocol PubMed
3. Salles G, Seymour JF, Offner F, López-Guillermo A, Belada D, Xerri L, Feugier P, Bouabdallah R, Catalano JV, Brice P, Caballero D, Haioun C, Pedersen LM, Delmer A, Simpson D, Leppa S, Soubeyran P, Hagenbeek A, Casasnovas O, Intragumtornchai T, Fermé C, da Silva MG, Sebban C, Lister A, Estell JA, Milone G, Sonet A, Mendila M, Coiffier B, Tilly H. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet. 2011 Jan 1;377(9759):42-51. Epub 2010 Dec 20. link to original article contains protocol PubMed

Tositumomab & I-131 (Bexxar)

Regimen

Dosimetric step

• On Day 0, infusions of:
  • Tositumomab 450 mg IV over 1 hour
  • Tositumomab 35 mg labeled with 5 mCi of Iodine-131 IV over 20 minutes
  • First scan of whole body dosimetry & redistribution
• Day 2, 3, or 4: Second scan of whole body dosimetry & redistribution
• Day 6 or 7: Third scan of whole body dosimetry & redistribution

Therapeutic step

• Any day from day 7-14, infusions of:
  • Tositumomab 450 mg IV over 1 hour
  • Tositumomab 35 mg labeled with an individually calculated dose of Iodine-131 that will provide 75 cGy of radiation to the total body IV over 20 minutes
    • 65 cGy total body dose used for patients with platelet counts of 100-150,000/mm3

Calculated dose of I-131 is based on information from serial total-body gamma-camera counts

Supportive medications:

• Acetaminophen (Tylenol) 650 mg PO as premedication for tositumomab
• Diphenhydramine (Benadryl) 50 mg PO as premedication for tositumomab
• Potassium iodide 2 drops PO TID starting at least 24 hours before the dosimetric step and continuing for 14 days after the therapeutic infusion; may also use Lugol’s solution or potassium iodide tablets

References

1. Kaminski MS, Zelenetz AD, Press OW, Saleh M, Leonard J, Fehrenbacher L, Lister TA, Stagg RJ, Tidmarsh GF, Kroll S, Wahl RL, Knox SJ, Vose JM. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol. 2001 Oct 1;19(19):3918-28. link to original article contains protocol PubMed
2. Kaminski MS, Tuck M, Estes J, Kolstad A, Ross CW, Zasadny K, Regan D, Kison P, Fisher S, Kroll S, Wahl RL. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med. 2005 Feb 3;352(5):441-9. link to original article contains protocol PubMed
3. Fisher RI, Kaminski MS, Wahl RL, Knox SJ, Zelenetz AD, Vose JM, Leonard JP, Kroll S, Goldsmith SJ, Coleman M. Tositumomab and iodine-131 tositumomab produces durable complete remissions in a subset of heavily pretreated patients with low-grade and transformed non-Hodgkin's lymphomas. J Clin Oncol. 2005 Oct 20;23(30):7565-73. Epub 2005 Sep 26. link to original article PubMed
4. Tositumomab and I-131 (Bexxar) package insert

Mantle cell lymphoma

BR

BR: Bendamustine, Rituximab

• Regimen is the same as BR in follicular lymphoma, Regimen #2, Rummel, et al. 2012 - StiL NH1

CALGB 59909

Regimen

Treatments 1-2, R-M-CHOP

• Rituximab (Rituxan) 375 mg/m2 IV on day 1 (rituximab withheld if circulating mantle cells are >10,000 cells/uL)
• Methotrexate (MTX) 300 mg/m2 IV over 4 hours on day 2
• Folinic acid (Leucovorin) 50 mg/m2 IV every 6 hours x 3 doses, starting 24 hours after completion of methotrexate, then 10 mg/m2 IV/PO every 6 hours until serum methotrexate level <0.05 uM
• Cyclophosphamide (Cytoxan) 2000 mg/m2 IV over 2 hours on day 3
• Doxorubicin (Adriamycin) 50 mg/m2 IV on day 3
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg for patients >40 years old) IV on day 3
• Prednisone (Sterapred) 100 mg/m2 PO on days 3-7

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.

• Etoposide (Vepesid) 10 mg/kg/day (40 mg/kg total dose) IV continuous infusion over 96 hours on days 1-4
• Cytarabine (Cytosar) 2000 mg/m2 IV over 2 hours BID on days 1-4 (8 total doses)
• Rituximab (Rituxan) 375 mg/m2 IV on days 6 & 13
• Daily leukapheresis to start when WBC ≥5000/uL

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

• Carmustine (BiCNU) 15 mg/kg (maximum dose of 550 mg/m2) IV over 1 hour on day -6
• Etoposide (Vepesid) 60 mg/kg IV over 4 hours on day -4
• Cyclophosphamide (Cytoxan) 100 mg/kg IV over 2 hours on day -2
• Autologous blood stem cells infused on day 0.

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

• Rituximab (Rituxan) 375 mg/m2 IV weekly x 2 doses, 6 and 7 weeks after ASCT

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:

• Prednisone (Sterapred) 0.5 mg/kg PO BID x 2 weeks, then tapered over 4 weeks

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 2mg 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)

Regimen

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

• Cyclophosphamide (Cytoxan) 1200 mg/m2 IV on day 1
• Doxorubicin (Adriamycin) 75 mg/m2 IV on day 1
• Vincristine (Oncovin) 2 mg IV on day 1
• Prednisone (Sterapred) 100 mg PO on days 1-5

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)

• Cytarabine (Cytosar) 3000 mg/m2 IV over 3 hours Q12H on days 1 & 2 (4 total doses)
  • Patients >60 years old received Cytarabine (Cytosar) 2000 mg/m2 IV over 3 hours Q12H on days 1 & 2 (4 total doses)

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

Aggressive lymphoma (primarily diffuse large B-cell lymphoma)

ACVBP-R (R-ACVBP)

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

Induction Regimen

• Cyclophosphamide (Cytoxan) 1200 mg/m2 IV on day 1
• Doxorubicin (Adriamycin) 75 mg/m2 IV on day 1
• Vindesine (Eldisine) 2 mg/m2 IV on days 1 & 5
• Bleomycin (Blenoxane) 10 units IV on days 1 & 5
• Prednisone (Sterapred) 60 mg/m2 PO on days 1-5
• Rituximab (Rituxan) 375 mg/m2 IV on day 1
• Methotrexate (MTX) 15 mg intrathecal on day 1 for CNS prophylaxis

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

• Methotrexate (MTX) 3000 mg/m2 IV on day 1

Supportive medications:

• Calcium folinate - Folinic acid (Leucovorin) rescue

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

• Rituximab (Rituxan) 375 mg/m2 IV on day 1
• Etoposide (Vepesid) 300 mg/m2 IV on day 1
• Ifosfamide (Ifex) 1500 mg/m2 IV on day 1

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

• Cytarabine (Cytosar) 100 mg/m2 SC on days 1-4

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

CHOEP

CHOEP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Etoposide, Prednisone

Regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV on day 1
• Vincristine (Oncovin) 2 mg IV on day 1
• Etoposide (Vepesid) 100 mg/m2 IV on days days 1-3
• Prednisone (Sterapred) 100 mg PO on days 1-5
• Patients with initial bulky disease (mass conglomerate at least 7.5 cm) received 36 Gy radiation therapy and to extranodal sites of disease when possible

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

• Example orders for CHOEP in lymphoma

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

CHOP-21

CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 100 mg PO on days 1-5

21-day cycles x 6-8 cycles

Supportive medications (varies depending on reference):

• 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

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
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

R-CHOP-21 (CHOP-R)

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

Regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 100 mg PO on days 1-5
• Rituximab (Rituxan) 375mg/m2 IV on day 1

21-day cycles x 6-8 cycles

• Example orders for R-CHOP in lymphoma

Supportive medications (varies depending on reference):

• 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

CVP

CVP: Cyclophosphamide, Vincristine, Prednisone

Regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 40 mg/m2 PO on days 1-5

21-day cycles x up to 8 cycles

References

1. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J, Solal-Celigny P, Offner F, Walewski J, Raposo J, Jack A, Smith P. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood. 2005 Feb 15;105(4):1417-23. link to original article contains protocol PubMed

R-CVP

R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2mg per cycle) IV on day 1
• Prednisone (Sterapred) 40 mg/m2 PO on days 1-5
• Rituximab (Rituxan) 375mg/m2 IV on day 1

21-day cycles x up to 8 cycles

References

See references for CVP

EPOCH

EPOCH: Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin

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

• Etoposide (Vepesid) 50 mg/m2/day (total dose of 200 mg/m2) IV continuous infusion on days 1-4
• Prednisone (Sterapred) 60 mg/m2 PO BID on days 1-5
• Vincristine (Oncovin) 0.4 mg/m2/day (total dose of 1.6 mg/m2) IV continuous infusion on days 1-4
• Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1-4
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 5

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:
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID 3 days per week
  • Atovaquone (Mepron) 1500 mg PO daily
  • Pentamidine (Nebupent) 300 mg nebulized every 28 days

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

• Etoposide (Vepesid) 50 mg/m2/day (total dose of 200 mg/m2) IV continuous infusion on days 1-4
• Prednisone (Sterapred) 60 mg/m2 PO on days 1-6
• Vincristine (Oncovin) 0.4 mg/m2/day (total dose of 1.6 mg/m2) IV continuous infusion on days 1-4
• Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1-4
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 6

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:
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID 3 days per week
  • Atovaquone (Mepron) 1500 mg PO daily
  • Pentamidine (Nebupent) 300 mg nebulized every 28 days

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

R-EPOCH (EPOCH-R)

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

Regimen

• Rituximab (Rituxan) 375 mg/m2 IV once per cycle or day 1 before the start of EPOCH (depending on reference)
• Etoposide (Vepesid) 50 mg/m2/day (total dose of 200 mg/m2) IV continuous infusion on days 1-4
• Prednisone (Sterapred) 60 mg/m2 PO BID on days 1-5
• Vincristine (Oncovin) 0.4 mg/m2/day (total dose of 1.6 mg/m2) IV continuous infusion on days 1-4
• Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1-4
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 5

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:
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID 3 days per week
    • Alternative used only in García-Suárez, et al. 2007: cotrimoxazole 480 mg PO BID 3 days per week
  • Atovaquone (Mepron) 1500 mg PO daily
  • Pentamidine (Nebupent) 300 mg nebulized every 28 days
• 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

1. 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

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)

• Example orders for High-dose Methotrexate (MTX) & Ifosfamide in lymphoma

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

HIV-associated lymphoma

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

Regimen

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

21-day cycles x 6-8 cycles

Supportive medications:

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

References

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