Difference between revisions of "Follicular lymphoma"
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Revision as of 15:37, 15 July 2013
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Untreated
BR
BR: Bendamustine, Rituximab
Regimen, Mathias et al. 2012 (StiL NHL1)
Level of Evidence: Phase III
- Bendamustine (Treanda) 90 mg/m2 IV over 30 to 60 minutes once on days 1 & 2
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycles x up to 6 cycles
Supportive medications:
- "Standard antiemetic prophylaxis"
- No prophylactic antibiotics
- Prophylactic use of G-CSF allowed according ASCO guidelines (2006)
References
- 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
- Ian Flinn et al. An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study. 2012 ASH Annual Meeting abstract 902. link to abstract
- Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; on behalf of the Study group indolent Lymphomas (StiL). Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Feb 19. pii: S0140-6736(12)61763-2. doi: 10.1016/S0140-6736(12)61763-2. [Epub ahead of print] link to original article contains verified protocol PubMed
Cyclophosphamide (Cytoxan)
Regimen
Level of Evidence: Phase III
- 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
- 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 verified protocol PubMed
CF
CF: Cyclophosphamide, Fludarabine
Regimen
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
- Fludarabine (Fludara) 20 mg/m2 IV once per day on days 1 to 5
28-day cycles, number not specified (regimen was notable for excess mortality)
References
- Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. doi: 10.1200/JCO.2008.17.1561. Epub 2009 Mar 2. link to original article contains verified protocol PubMed
CHOP
CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
Regimen #1, Hiddemann et al. 2005
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once daily on days 1 to 5
21-day cycles x 6 to 8 cycles
Regimen #2, Zinzani et al. 2004
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
- Prednisone (Sterapred) 100 mg PO once daily on days 1 to 5
21-day cycles x 6 cycles; patients with PR or CR with detectable bcl-2/IgH fusion by PCR received:
- Rituximab (Rituxan) 375 mg/m2 IV once weekly on days 1, 8, 15, 22
References
- Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, Storti S, Lauta VM, Guardigni L, Gentilini P, Tucci A, Molinari AL, Gobbi M, Falini B, Fattori PP, Ciccone F, Alinari L, Martelli M, Pileri S, Tura S, Baccarani M. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol. 2004 Jul 1;22(13):2654-61. Epub 2004 May 24. link to original article contains verified protocol PubMed
- 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 verified protocol PubMed
- Nickenig C, Dreyling M, Hoster E, Pfreundschuh M, Trumper L, Reiser M, Wandt H, Lengfelder E, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. Combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) improves response rates but not survival and has lower hematologic toxicity compared with combined mitoxantrone, chlorambucil, and prednisone (MCP) in follicular and mantle cell lymphomas: results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group. Cancer. 2006 Sep 1;107(5):1014-22. link to original article contains verified protocol PubMed
CHOP -> 131Iodine-Tositumomab (Bexxar)
CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
CHOP-RIT: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone RadioImmunoTherapy
Regimen, Press, et al. 2003 (SWOG S9911) & Press, et al. 2013 (SWOG S0016)
Level of Evidence: Phase III
CHOP
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg PO once daily on days 1 to 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 1, 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 within 1 hour of finishing dosimetric dose on day 1
- Day 2, 3, or 4: Second scan of whole body dosimetry & redistribution
- Day 6 or 7: Third scan of whole body dosimetry & redistribution
Supportive medications:
- Acetaminophen (Tylenol) 650 mg PO as premedication for tositumomab
- Diphenhydramine (Benadryl) 50 mg PO as premedication for tositumomab
- Potassium iodide (SSKI, saturated solution of 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
Tositumomab & I-131 (Bexxar) therapeutic step
- Any one day 7-14 days after dosimetric infusion, infusions of:
- Tositumomab 450 mg IV over 1 hour, given first
- 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 (SSKI, saturated solution of 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
- 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 verified protocol PubMed
- Update: 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
- Press OW, Unger JM, Rimsza LM, Friedberg JW, Leblanc M, Czuczman MS, Kaminski M, Braziel RM, Spier C, Gopal AK, Maloney DG, Cheson BD, Dakhil SR, Miller TP, Fisher RI. Phase III Randomized Intergroup Trial of CHOP Plus Rituximab Compared With CHOP Chemotherapy Plus 131Iodine-Tositumomab for Previously Untreated Follicular Non-Hodgkin Lymphoma: SWOG S0016. J Clin Oncol. 2013 Jan 20;31(3):314-20. doi: 10.1200/JCO.2012.42.4101. Epub 2012 Dec 10. link to original article contains partial protocol PubMed
CVP
CVP: Cyclophosphamide, Vincristine, Prednisone
Synonyms: COP, COP protocol 2, VCP
Structured Concept: C9573 (NCI-T), C0056633 (NCI-MT/UMLS)
Regimen #1, Marcus, et al. 2005
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once daily on days 1 to 5
21-day cycles x up to 8 cycles
Regimen #2, Hochster, et al. 2009 (ECOG1496)
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once daily on days 1 to 5
21-day cycles x 6 to 8 cycles
Patients were then randomized to maintenance rituximab or observation.
References
- 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
- Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. doi: 10.1200/JCO.2008.17.1561. Epub 2009 Mar 2. link to original article contains verified protocol PubMed
CVP -> 131Iodine-Tositumomab (Bexxar)
CVP: Cyclophosphamide, Vincristine, Prednisone
Regimen
Level of Evidence: Phase II
CVP
- Cyclophosphamide (Cytoxan) 400 mg/m2 PO once daily on days 1 to 5
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once daily on days 1 to 5
21-day cycles x 6 cycles, followed within 56 days by:
Tositumomab & I-131 (Bexxar) dosimetric step
- On Day 1, 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 within 1 hour of finishing dosimetric dose on day 1
- Day 2, 3, or 4: Second scan of whole body dosimetry & redistribution
- Day 6 or 7: Third scan of whole body dosimetry & redistribution
Supportive medications:
- Acetaminophen (Tylenol) 650 mg PO as premedication for tositumomab
- Diphenhydramine (Benadryl) 50 mg PO as premedication for tositumomab
- Potassium iodide (SSKI, saturated solution of 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
Tositumomab & I-131 (Bexxar) therapeutic step
- Any one day 7-14 days after dosimetric infusion, infusions of:
- Tositumomab 450 mg IV over 1 hour, given first
- 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 (SSKI, saturated solution of 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
- Link BK, Martin P, Kaminski MS, Goldsmith SJ, Coleman M, Leonard JP. Cyclophosphamide, vincristine, and prednisone followed by tositumomab and iodine-131-tositumomab in patients with untreated low-grade follicular lymphoma: eight-year follow-up of a multicenter phase II study. J Clin Oncol. 2010 Jun 20;28(18):3035-41. doi: 10.1200/JCO.2009.27.8325. Epub 2010 May 10. link to original article PubMed .
Fludarabine -> 131Iodine-Tositumomab (Bexxar)
Regimen
Level of Evidence: Phase II
- Fludarabine (Fludara) 25 mg/m2 IV once daily on days 1 to 5
5-week cycles x 3 cycles, followed by:
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
References
- Leonard JP, Coleman M, Kostakoglu L, Chadburn A, Cesarman E, Furman RR, Schuster MW, Niesvizky R, Muss D, Fiore J, Kroll S, Tidmarsh G, Vallabhajosula S, Goldsmith SJ. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol. 2005 Aug 20;23(24):5696-704. link to original article contains verified protocol PubMed
Fludarabine & Rituximab
Regimen
Level of Evidence: Phase II
- Rituximab (Rituxan) 375 mg/m2 IV once on days 1 & 4
Cycle 1 begins 72 hours after the second dose of rituximab
- Fludarabine (Fludara) 25 mg/m2 IV once daily on days 1 to 5 of cycles 1 to 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 once on days 1 & 4 of cycle 7
28-day cycles x 7 cycles
References
- 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
FLUMIZ
FLUMIZ: FLUdarabine, MItoxantrone, Zevalin
Level of Evidence: Phase II
Regimen
- Fludarabine (Fludara) 40 mg/m2 PO daily on days 1 to 3
- Mitoxantrone (Novantrone) 10 mg/m2 IV once on day 1
28-day cycles x 6 cycles
Supportive medications:
- Allopurinol (Aloprim) 300 mg PO daily for patients with bulky disease
- No prophylactic use of G-CSF, but patients with grade 3 or 4 neutropenia or delayed neutropenic fever could be given growth factors for later cycles at physician discretion
Patients were restaged 4-6 weeks after finishing cycle 6. People with at least a partial response (PR), neutrophil count >1.5 x 109/L, platelet count >100 x 109/L, and less than 25% bone marrow involvement were eligible for consolidation therapy with Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 6 to 10 weeks after the end of cycle 6.
Consolidation therapy
- Rituximab (Rituxan) 250 mg/m2 IV once on day 1 and another single dose on day 7, 8, or 9 (total dose of rituximab is 500 mg/m2)
- Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 14.8 MBq/kg (maximum dose of 1184 MBq) IV slow push over 10 minutes immediately following second dose of rituximab
- Patients with platelet count of 100-149 x 109/L received a reduced dose of Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 11.1 MBq/kg (maximum dose of 1184 MBq) IV slow push over 10 minutes immediately following second dose of rituximab
References
- Zinzani PL, Tani M, Pulsoni A, Gobbi M, Perotti A, De Luca S, Fabbri A, Zaccaria A, Voso MT, Fattori P, Guardigni L, Ronconi S, Cabras MG, Rigacci L, De Renzo A, Marchi E, Stefoni V, Fina M, Pellegrini C, Musuraca G, Derenzini E, Pileri S, Fanti S, Piccaluga PP, Baccarani M. Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ). Lancet Oncol. 2008 Apr;9(4):352-8. doi: 10.1016/S1470-2045(08)70039-1. Epub 2008 Mar 14. link to original article contains verified protocol PubMed
FM
FM: Fludarabine, Mitoxantrone
Regimen
Level of Evidence: Phase III
- Fludarabine (Fludara) 25 mg/m2 IV daily on days 1 to 3
- Mitoxantrone (Novantrone) 10 mg/m2 IV once on day 1
21-day cycles x 6 cycles; patients with PR or CR with detectable bcl-2/IgH fusion by PCR received:
- Rituximab (Rituxan) 375 mg/m2 IV once weekly on days 1, 8, 15, 22
References
- Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, Storti S, Lauta VM, Guardigni L, Gentilini P, Tucci A, Molinari AL, Gobbi M, Falini B, Fattori PP, Ciccone F, Alinari L, Martelli M, Pileri S, Tura S, Baccarani M. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol. 2004 Jul 1;22(13):2654-61. Epub 2004 May 24. link to original article contains verified protocol PubMed
FMR
FMR: Fludarabine, Mitoxantrone, Rituximab
Regimen
Level of Evidence: Phase III
- Fludarabine (Fludara) 25 mg/m2 IV daily on days 1 to 3
- Mitoxantrone (Novantrone) 10 mg/m2 IV once on day 1
21-day cycles x 6 cycles; patients with PR or CR with detectable bcl-2/IgH fusion by PCR received:
- Rituximab (Rituxan) 375 mg/m2 IV once weekly on days 1, 8, 15, 22
References
- Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, Storti S, Lauta VM, Guardigni L, Gentilini P, Tucci A, Molinari AL, Gobbi M, Falini B, Fattori PP, Ciccone F, Alinari L, Martelli M, Pileri S, Tura S, Baccarani M. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol. 2004 Jul 1;22(13):2654-61. Epub 2004 May 24. link to original article contains verified protocol PubMed
FMR-Z
FMR-Z: Fludarabine, Mitoxantrone, Rituximab, Zevalin
Regimen
Level of Evidence: Phase II
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Fludarabine (Fludara) 25 mg/m2 IV daily on days 2 to 4
- Mitoxantrone (Novantrone) 10 mg/m2 IV once on day 2
28-day cycles x 4 cycles
Supportive medications:
- No prophylactic use of G-CSF, but patients with grade 3 or 4 neutropenia or delayed neutropenic fever could be given growth factors for later cycles at physician discretion
Patients were restaged 2 to 3 weeks after finishing cycle 4. People with at least a partial response (PR), neutrophil count >1.5 x 109/L, platelet count >100 x 109/L, and less than 25% bone marrow involvement were eligible for consolidation therapy with Ibritumomab tiuxetan & Yttrium-90 (Zevalin) given within 12 weeks (paper does not specify "within 12 weeks" of what).
Consolidation therapy
- Rituximab (Rituxan) 250 mg/m2 IV once on day 1 and another single dose on day 7, 8, or 9 (total dose of rituximab is 500 mg/m2)
- Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 14.8 MBq/kg (maximum dose of 1184 MBq) IV slow push over 10 minutes immediately following second dose of rituximab
- Patients with platelet count of 100-149 x 109/L received a reduced dose of Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 11.1 MBq/kg (maximum dose of 1184 MBq) IV slow push over 10 minutes immediately following second dose of rituximab
References
- Zinzani PL, Tani M, Pulsoni A, De Renzo A, Stefoni V, Broccoli A, Montini GC, Fina M, Pellegrini C, Gandolfi L, Cavalieri E, Torelli F, Scopinaro F, Argnani L, Quirini F, Derenzini E, Rossi M, Pileri S, Fanti S, Baccarani M. A phase II trial of short course fludarabine, mitoxantrone, rituximab followed by ⁹⁰Y-ibritumomab tiuxetan in untreated intermediate/high-risk follicular lymphoma. Ann Oncol. 2012 Feb;23(2):415-20. doi: 10.1093/annonc/mdr145. Epub 2011 May 2. link to original article contains verified protocol PubMed
131Iodine-Tositumomab (Bexxar)
Regimen
Level of Evidence: Phase II
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
References
- 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 verified protocol PubMed
MCP
MCP: Mitoxantrone, Chlorambucil, Prednisolone
Regimen
Level of Evidence: Phase III
- Mitoxantrone (Novantrone) 8 mg/m2 IV once on days 1 & 2
- Chlorambucil (Leukeran) 3 mg/m2 PO TID (written in the reference as "3 x 3 mg/m2"; total daily dose is 9 mg/m2) on days 1 to 5
- Prednisolone (Millipred) 25 mg/m2 PO once daily on days 1 to 5
28-day cycles x up to 8 cycles
References
- Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer A, Dölken G, Naumann R, Knauf W, Freund M, Rohrberg R, Höffken K, Franke A, Ittel T, Kettner E, Haak U, Mey U, Klinkenstein C, Assmann M, von Grünhagen U; East German Study Group Hematology and Oncology Study. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol. 2007 May 20;25(15):1986-92. Epub 2007 Apr 9. link to original article contains verified protocol PubMed
O-CHOP
O-CHOP: Ofatumumab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
Level of Evidence: Phase II
Regimen, Czuczman, et al. 2012 (409 Study)
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 3
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 3
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 3
- Prednisone (Sterapred) 100 mg PO once daily on days 3 to 7
- Ofatumumab (Arzerra) 300 mg IV once on cycle 1 day 1; 1000 mg IV once on day 1 of cycles 2 to 6
- Both 500 and 1000 mg doses were tested, but since there was no increase in toxicity in patients receiving the 1000 mg dose, the 1000 mg dose was chosen for future ofatumumab trials "to avoid underdosing patients"
21-day cycles x 6 cycles
Supportive medications:
- Acetaminophen (Tylenol) 1000 mg (no route specified) before each dose of ofatumumab
- Cetirizine (Zyrtec) 10 mg (or equivalent) PO before each dose of ofatumumab
- Prednisolone (Millipred) (or equivalent) 100 mg before dose 1 and 2 of ofatumumab
References
- Czuczman MS, Hess G, Gadeberg OV, Pedersen LM, Goldstein N, Gupta I, Jewell RC, Lin TS, Lisby S, Strange C, Windfeld K, Viardot A; 409 Study Investigators. Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma. Br J Haematol. 2012 May;157(4):438-45. doi: 10.1111/j.1365-2141.2012.09086.x. Epub 2012 Mar 13. link to original article contains verified protocol PubMed
R-CHOP
R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
Regimen #1, Hiddemann, et al. 2005
Level of Evidence: Phase III Improved OS Increased toxicity
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once daily on days 1 to 5
- Rituximab (Rituxan) 375 mg/m2 IV once on day -1
21-day cycles x 6 to 8 cycles
Regimen #2, Czuczman, et al. 1999 & Press, et al. 2013 (SWOG S0016)
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once daily on days 1 to 5
- Rituximab (Rituxan) doses given by the following schedule:
- Rituximab (Rituxan) 375 mg/m2 IV once on days -7 & -2 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
Regimen #3, Watanabe, et al. 2011 (JCOG 0203)
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg PO once daily on days 1 to 5
- Rituximab (Rituxan) 375 mg/m2 IV once on day -2 of cycles 1, 2, 4, 6 (total of 4 doses, each one given 2 days before those cycles)
21-day cycles x 6 cycles
Supportive medications:
- G-CSF "according to the [2000] American Society of Clinical Oncology guidelines," i.e. generally no routine use except for patients at high risk (>40%) for febrile neutropenia due to special circumstances
Regimen #4, Federico, et al. 2013 (FOLL05)
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once daily on days 1 to 5
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
21-day cycles x 6 cycles, with two additional cycles of rituximab alone
Regimen #5, Zinzani et al. 2004
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
- Prednisone (Sterapred) 100 mg PO once daily on days 1 to 5
21-day cycles x 6 cycles; patients with PR or CR with detectable bcl-2/IgH fusion by PCR received:
- Rituximab (Rituxan) 375 mg/m2 IV once weekly on days 1, 8, 15, 22
References
- 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
- Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, Storti S, Lauta VM, Guardigni L, Gentilini P, Tucci A, Molinari AL, Gobbi M, Falini B, Fattori PP, Ciccone F, Alinari L, Martelli M, Pileri S, Tura S, Baccarani M. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol. 2004 Jul 1;22(13):2654-61. Epub 2004 May 24. link to original article contains verified protocol PubMed
- Update: 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 to 6. Epub 2004 Oct 13. link to original article PubMed
- 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
- Watanabe T, Tobinai K, Shibata T, Tsukasaki K, Morishima Y, Maseki N, Kinoshita T, Suzuki T, Yamaguchi M, Ando K, Ogura M, Taniwaki M, Uike N, Takeuchi K, Nawano S, Terauchi T, Hotta T. Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial. J Clin Oncol. 2011 Oct 20;29(30):3990-8. doi:10.1200/JCO.2011.34.8508. Epub 2011 Sep 19. link to original article contains verified protocol PubMed
- Ian Flinn et al. An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study. 2012 ASH Annual Meeting abstract 902. link to abstract
- Press OW, Unger JM, Rimsza LM, Friedberg JW, Leblanc M, Czuczman MS, Kaminski M, Braziel RM, Spier C, Gopal AK, Maloney DG, Cheson BD, Dakhil SR, Miller TP, Fisher RI. Phase III Randomized Intergroup Trial of CHOP Plus Rituximab Compared With CHOP Chemotherapy Plus 131Iodine-Tositumomab for Previously Untreated Follicular Non-Hodgkin Lymphoma: SWOG S0016. J Clin Oncol. 2013 Jan 20;31(3):314-20. doi: 10.1200/JCO.2012.42.4101. Epub 2012 Dec 10. link to original article PubMed
- Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, Di Raimondo F, Carella AM, Pulsoni A, Merli F, Arcaini L, Angrilli F, Stelitano C, Gaidano G, Dell'olio M, Marcheselli L, Franco V, Galimberti S, Sacchi S, Brugiatelli M. R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Follicular Lymphoma: Results of the FOLL05 Trial Conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Mar 25. [Epub ahead of print] link to original article contains verified protocol PubMed
R-CHOP -> 90Yttrium-Ibritumomab-Tiuxetan (Zevalin)
Regimen #1, Hainsworth et al. 2009
Level of Evidence: Phase II
- Rituximab (Rituxan) 375 mg/m2 IV once weekly
Four week course, followed by:
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg PO daily on days 1 to 5
21-day cycles x 3 cycles, followed in 4 weeks by:
- Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (dose reduced to 0.3 mCi/kg if platelet count 100-149k)
See text for further information about Zevalin eligbility criteria. If patient did not meet criteria within 7 weeks after final R-CHOP, Zevalin was omitted.
Regimen #2, Jacobs et al. 2008
Level of Evidence: Phase II
R-CHOP given as per standard ECOG dosing, except that rituximab is given on day 1 of each cycle:
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose per cycle: 2 mg) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once daily on days 1 to 5
Supportive medications:
- Filgrastim (Neupogen) "recommended according to guidelines"
21-day cycles x 3 cycles, followed by Zevalin:
Interval between R-CHOP and Zevalin is not specified in the paper
- Rituximab (Rituxan) 250 mg/m2 IV once 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 once on day 8 immediately following rituximab
8-day course of therapy, followed in 1 to 2 weeks by:
- Rituximab (Rituxan) 375 mg/m2 IV once weekly
Four week course
References
- Jacobs SA, Swerdlow SH, Kant J, Foon KA, Jankowitz R, Land SR, DeMonaco N, Joyce J, Osborn JL, Evans TL, Schaefer PM, Luong TM. Phase II trial of short-course CHOP-R followed by 90Y-ibritumomab tiuxetan and extended rituximab in previously untreated follicular lymphoma. Clin Cancer Res. 2008 Nov 1;14(21):7088-94. doi: 10.1158/1078-0432.CCR-08-0529. link to original article contains verified protocol PubMed
- Hainsworth JD, Spigel DR, Markus TM, Shipley D, Thompson D, Rotman R, Dannaher C, Greco FA. Rituximab plus short-duration chemotherapy followed by Yttrium-90 Ibritumomab tiuxetan as first-line treatment for patients with follicular non-Hodgkin lymphoma: a phase II trial of the Sarah Cannon Oncology Research Consortium. Clin Lymphoma Myeloma. 2009 Jun;9(3):223-8. doi: 10.3816/CLM.2009.n.044. link to original article contains verified protocol PubMed
R-CHVP+I
R-CHVP+I: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, VP-16 (etoposide), Prednisolone, Interferon-α2a
Regimen
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
- Etoposide (Vepesid) 100 mg/m2 IV once on day 1
- Prednisolone (Millipred) 40 mg/m2 PO once daily on days 1 through 5
- Rituximab (Rituxan) 375 mg/m2 IV once on days 1 and 8 of cycles 3 and 4; once on day 1 of cycles 5 and 6 (6 total doses)
28-day cycles x 6 cycles, then
- Interferon alfa-2a (Roferon-A) 4.5 million units SC TIW (patients younger than 70 years) or 3 million units SC TIW (patients older than 70 years)
Continuously for 18 months
References
- Salles G, Mounier N, de Guibert S, Morschhauser F, Doyen C, Rossi JF, Haioun C, Brice P, Mahé B, Bouabdallah R, Audhuy B, Ferme C, Dartigeas C, Feugier P, Sebban C, Xerri L, Foussard C. Rituximab combined with chemotherapy and interferon in follicular lymphoma patients: results of the GELA-GOELAMS FL2000 study. Blood. 2008 Dec 15;112(13):4824-31. doi: 10.1182/blood-2008-04-153189. Epub 2008 Sep 17. link to original article contains verified protocol PubMed
R-CVP
R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone
Level of Evidence: Phase III Improved OS Similar toxicity
Regimen
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once daily on days 1 through 5
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
21-day cycles x up to 8 cycles
References
- 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
- 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
- Ian Flinn et al. An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study. 2012 ASH Annual Meeting abstract 902. link to abstract
- Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, Di Raimondo F, Carella AM, Pulsoni A, Merli F, Arcaini L, Angrilli F, Stelitano C, Gaidano G, Dell'olio M, Marcheselli L, Franco V, Galimberti S, Sacchi S, Brugiatelli M. R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Follicular Lymphoma: Results of the FOLL05 Trial Conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Mar 25. [Epub ahead of print] link to original article contains verified protocol PubMed
R-FM
R-FM: Rituximab, Fludarabine, Mitoxantrone
Regimen, Federico et al. 2013 (FOLL05)
Level of Evidence: Phase III
- Fludarabine (Fludara) 25 mg/m2 IV once daily on days 1 through 3
- Mitoxantrone (Novantrone) 10 mg/m2 IV once on day 1
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
21-day cycles x 6 cycles, with 2 additional cycles of rituximab alone
References
- Federico M, Luminari S, Dondi A, Tucci A, Vitolo U, Rigacci L, Di Raimondo F, Carella AM, Pulsoni A, Merli F, Arcaini L, Angrilli F, Stelitano C, Gaidano G, Dell'olio M, Marcheselli L, Franco V, Galimberti S, Sacchi S, Brugiatelli M. R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Follicular Lymphoma: Results of the FOLL05 Trial Conducted by the Fondazione Italiana Linfomi. J Clin Oncol. 2013 Mar 25. [Epub ahead of print] link to original article contains verified protocol PubMed
R-MCP
R-MCP: Rituximab, Mitoxantrone, Chlorambucil, Prednisolone
Regimen
Level of Evidence: Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Mitoxantrone (Novantrone) 8 mg/m2 IV once on days 3 & 4
- Chlorambucil (Leukeran) 3 mg/m2 PO TID (written in the reference as "3 x 3 mg/m2"; total daily dose is 9 mg/m2) on days 3 to 7
- Prednisolone (Millipred) 25 mg/m2 PO once daily on days 3 to 7
28-day cycles x up to 8 cycles
References
- Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer A, Dölken G, Naumann R, Knauf W, Freund M, Rohrberg R, Höffken K, Franke A, Ittel T, Kettner E, Haak U, Mey U, Klinkenstein C, Assmann M, von Grünhagen U; East German Study Group Hematology and Oncology Study. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol. 2007 May 20;25(15):1986-92. Epub 2007 Apr 9. link to original article contains verified protocol PubMed
Rituximab monotherapy
Regimen
Level of Evidence: Phase II
- Rituximab (Rituxan) 375 mg/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
Patients with response or stable disease at 12 weeks in Ghielmini et al, 2004 were randomized to maintenance rituximab or no further treatment.
References
- 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 to 6. link to original article contains protocol PubMed
- 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
- Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article contains protocol PubMed
- Meta-analysis: Vidal L, Gafter-Gvili A, Leibovici L, Dreyling M, Ghielmini M, Hsu Schmitz SF, Cohen A, Shpilberg O. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009 Feb 18;101(4):248-55. Epub 2009 Feb 10. PubMed
Rituximab & Lenalidomide
Regimen
Level of Evidence: Phase II
- Lenalidomide (Revlimid) 20 mg PO daily on days 1 to 21
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycles up to 6 cycles
References
- N. H. Fowler, P. McLaughlin, F. B. Hagemeister, L. W. Kwak, M. A. Fanale, S. S. Neelapu, L. Fayad, R. Z. Orlowski, M. Wang, F. Samaniego. Complete response rates with lenalidomide plus rituximab for untreated indolent B-cell non-Hodgkin's lymphoma. J Clin Oncol 28:15s, 2010 (suppl; abstr 8036). 2010 ASCO Annual Meeting abstract 8036. link to abstract
90Yttrium-Ibritumomab-Tiuxetan (Zevalin)
Regimen
Level of Evidence: Phase II
Recruitment was limited to patients at least 50 years old due to radiation safety concerns
- Rituximab (Rituxan) 250 mg/m2 IV once on day 1, then another single dose on day 8 or 9
- Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 15 MBq/kg (maximum dose of 1200 MBq) IV once on day 8 or 9, given after rituximab
8 to 9-day course of therapy
References
- Scholz CW, Pinto A, Linkesch W, Lindén O, Viardot A, Keller U, Hess G, Lastoria S, Lerch K, Frigeri F, Arcamone M, Stroux A, Frericks B, Pott C, Pezzutto A. 90Yttrium-Ibritumomab-Tiuxetan as First-Line Treatment for Follicular Lymphoma: 30 Months of Follow-Up Data From an International Multicenter Phase II Clinical Trial. J Clin Oncol. 2013 Jan 20;31(3):308-13. doi:10.1200/JCO.2011.41.1553. Epub 2012 Dec 10. link to original article contains verified protocol PubMed
Consolidation and/or maintenance
Observation
Regimen
Level of Evidence: Phase III
No treatment; used as a comparator arm and here for reference purposes only.
References
- Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. doi: 10.1200/JCO.2008.17.1561. Epub 2009 Mar 2. link to original article contains verified protocol PubMed
Rituximab monotherapy
Regimen #1, van Oers, et al. 2006 (EORTC 20981)
Level of Evidence: Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
3-month cycles until relapse or for a maximum of 2 years
Regimen #2, Salles, et al. 2011 (PRIMA)
Level of Evidence: Phase III
Starts 8 weeks after the last induction treatment
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
8-week cycles x 12 cycles
Regimen #3, Hainsworth et al. 2002
Level of Evidence: Phase II
- Rituximab (Rituxan) 375 mg/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
Regimen #4, Ghielmini, et al. 2004 (SAKK)
Level of Evidence: Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once at week 12, months 5, 7, 9 (8 total doses, including the initial treatment)
Total treatment course of 9 months
Regimen #5, Forstpointner, et al. 2004 (GLSG)
Level of Evidence: Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
Two courses at 3 and 9 months after completion of salvage therapy (8 total doses)
Regimen #6, Hochster, et al. 2009 (ECOG1496)
Level of Evidence: Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
Four courses, every 6 months (16 total doses)
References
- 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
- Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article contains protocol PubMed
- 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 verified protocol PubMed
- van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301. Epub 2006 Jul 27. link to original article contains verified protocol PubMed
- Update: Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group (GLSG). Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. link to original article contains verified protocol PubMed
- Meta-analysis: Vidal L, Gafter-Gvili A, Leibovici L, Dreyling M, Ghielmini M, Hsu Schmitz SF, Cohen A, Shpilberg O. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009 Feb 18;101(4):248-55. Epub 2009 Feb 10. PubMed
- Hochster H, Weller E, Gascoyne RD, Habermann TM, Gordon LI, Ryan T, Zhang L, Colocci N, Frankel S, Horning SJ. Maintenance rituximab after cyclophosphamide, vincristine, and prednisone prolongs progression-free survival in advanced indolent lymphoma: results of the randomized phase III ECOG1496 Study. J Clin Oncol. 2009 Apr 1;27(10):1607-14. doi: 10.1200/JCO.2008.17.1561. Epub 2009 Mar 2. link to original article contains verified protocol PubMed
- Update: van Oers MH, Van Glabbeke M, Giurgea L, Klasa R, Marcus RE, Wolf M, Kimby E, van t Veer M, Vranovsky A, Holte H, Hagenbeek A. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010 Jun 10;28(17):2853-8. Epub 2010 May 3. link to original article contains verified protocol PubMed
- 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
90Yttrium-Ibritumomab-Tiuxetan (Zevalin)
Regimen
Level of Evidence: Phase III
Consolidation therapy for patients in complete or partial remission after first-line therapy
- Rituximab (Rituxan) 250 mg/m2 IV once on days 1 & 8
- Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 14.8 MBq/kg (maximum dose of 1184 MBq) IV slow push over 10 minutes once on day 8 immediately following rituximab
8-day course of therapy
References
- 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
- Update: Morschhauser F, Radford J, Van Hoof A, Botto B, Rohatiner AZ, Salles G, Soubeyran P, Tilly H, Bischof-Delaloye A, van Putten WL, Kylstra JW, Hagenbeek A. 90Yttrium-Ibritumomab Tiuxetan Consolidation of First Remission in Advanced-Stage Follicular Non-Hodgkin Lymphoma: Updated Results After a Median Follow-Up of 7.3 Years From the International, Randomized, Phase III First-Line Indolent Trial. J Clin Oncol. 2013 Apr 1. [Epub ahead of print] link to original article contains protocol PubMed
Relapsed/refractory
BR
BR: Bendamustine, Rituximab
Regimen #1, Rummel, et al. 2005
Level of Evidence: Phase II
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
Cycle 1 is started 7 days after the first dose of rituximab
- Bendamustine (Treanda) 90 mg/m2 IV over 30 minutes once on days 1 & 2 of cycles 1 to 4
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1 of cycles 1 to 5
28-day cycles x 5 cycles
Regimen #2, Robinson, et al. 2008
Level of Evidence: Phase II
- Rituximab (Rituxan) 375 mg/m2 IV once
Cycle 1 is started 7 days after the first dose of rituximab:
- Bendamustine (Treanda) 90 mg/m2 IV over 30 to 60 minutes once on days 2 & 3
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycles x 4 cycles; however, the paper also said that people "could receive up to six cycles if disease regression was evident between the second and fourth cycles"
One more dose of rituximab 28 days after the fourth cycle:
- Rituximab (Rituxan) 375 mg/m2 IV once
References
- 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
- Robinson KS, Williams ME, van der Jagt RH, Cohen P, Herst JA, Tulpule A, Schwartzberg LS, Lemieux B, Cheson BD. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008 Sep 20;26(27):4473-9. Epub 2008 Jul 14. link to original article contains verified protocol PubMed
BVR
BVR: Bendamustine, Velcade, Rituximab
Regimen #1, Friedberg, et al. 2011
Level of Evidence: Phase II
- Bendamustine (Treanda) 90 mg/m2 IV over 30 to 60 minutes once 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 once 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
Regimen #2, Fowler, et al. 2011 (VERTICAL)
Level of Evidence: Phase II
- Bendamustine (Treanda) 50-90 mg/m2 IV over 60 minutes once on days 1 & 2, given after bortezomib and before rituximab
- Bortezomib (Velcade) 1.6 mg/m2 IV once on days 1, 8, 15, 22, given first
- Rituximab (Rituxan) 375 mg/m2 IV once on days 1, 8, 15, 22 of cycle 1, then 375 mg/m2 IV once on day 1 of cycles 2 to 5; given last
35-day cycles x 5 cycles
Supportive medications:
- Antiviral prophylaxis at physician discretion
References
- 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
- 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
CHOP
CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
Regimen, Van Oers, et al. 2006 (EORTC 20981)
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg PO once daily on days 1 to 5
21-day cycles x 6 cycles
Responders (PR or CR) were randomized to maintenance rituximab or no further treatment.
References
- van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301. Epub 2006 Jul 27. link to original article contains verified protocol PubMed
- Update: van Oers MH, Van Glabbeke M, Giurgea L, Klasa R, Marcus RE, Wolf M, Kimby E, van t Veer M, Vranovsky A, Holte H, Hagenbeek A. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010 Jun 10;28(17):2853-8. Epub 2010 May 3. link to original article contains verified protocol PubMed
FCM
FCM: Fludarabine, Cyclophosphamide, Mitoxantrone
Regimen
Level of Evidence: Phase III
- Fludarabine (Fludara) 25 mg/m2 IV over 30 minutes once daily on days 1 to 3
- Cyclophosphamide (Cytoxan) 200 mg/m2 IV over 4 hours on days 1 to 3
- Mitoxantrone (Novantrone) 8 mg/m2 IV over 30 minutes once on day 1
28-day cycles x 4 cycles
Responders (PR or CR) were randomized to maintenance rituximab or no further treatment.
References
- 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 verified protocol PubMed
- Update: Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group (GLSG). Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. link to original article contains verified protocol PubMed
Fludarabine & Rituximab
Regimen
Level of Evidence: Phase II
- Rituximab (Rituxan) 375 mg/m2 IV once on days 1 & 4
Cycle 1 begins 72 hours after the second dose of rituximab
- Fludarabine (Fludara) 25 mg/m2 IV once daily on days 1 to 5 of cycles 1 to 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 once on days 1 & 4 of cycle 7
28-day cycles x 7 cycles
References
- 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
131Iodine-Tositumomab (Bexxar)
Regimen
Level of Evidence: Phase II
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 7-15, 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 (SSKI, saturated solution of 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
- 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 verified protocol PubMed
- 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
Ofatumumab monotherapy
Regimen, Czucman, et al. 2012 (405 Study)
Level of Evidence: Phase II
- Ofatumumab (Arzerra) 300 mg IV once on week 1 (dose 1); then 1000 mg IV every week thereafter (doses 2 to 8)
8-week total course
Supportive medications:
- Acetaminophen (Tylenol) 1000 mg (no route specified) before each dose of ofatumumab
- Cetirizine (Zyrtec) 10 mg (or equivalent) PO before each dose of ofatumumab
- Prednisolone (Millipred) (or equivalent) 100 mg before dose 1 and 2 of ofatumumab
References
- Czuczman MS, Fayad L, Delwail V, Cartron G, Jacobsen E, Kuliczkowski K, Link BK, Pinter-Brown L, Radford J, Hellmann A, Gallop-Evans E, DiRienzo CG, Goldstein N, Gupta I, Jewell RC, Lin TS, Lisby S, Schultz M, Russell CA, Hagenbeek A; 405 Study Investigators. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood. 2012 Apr 19;119(16):3698-704. Epub 2012 Mar 2. link to original article contains verified protocol PubMed
PEP-C
PEP-C: Prednisone, Etoposide, Procarbazine, Cyclophosphamide
Regimen
Level of Evidence: Phase II
Induction phase
- Prednisone (Sterapred) 20 mg PO once daily after breakfast
- Cyclophosphamide (Cytoxan) 50 mg PO once daily after lunch
- Etoposide (Vepesid) 50 mg PO once daily after dinner
- Procarbazine (Matulane) 50 mg PO once daily at bedtime
Supportive medication:
- Ondansetron (dose not specified) with each procarbazine dose
Continue until WBC <3 x 109/L, hold until WBC recovery, then titrate in maintenance phase per paper (see publication for details)
Maintenance phase
- Same medications and doses given per day as used in the induction phase, but the number of days per week they are used is titrated to maintain a WBC of at least 3; for example, 5 out of 7 days, every other day, once per week, etc.
References
- Coleman M, Martin P, Ruan J, Furman R, Niesvizky R, Elstrom R, George P, Kaufman TP, Leonard JP. Prednisone, etoposide, procarbazine, and cyclophosphamide (PEP-C) oral combination chemotherapy regimen for recurring/refractory lymphoma: low-dose metronomic, multidrug therapy. Cancer. 2008 May 15;112(10):2228-32. doi:10.1002/cncr.23422. link to original article contains verified protocol PubMed
- Coleman M, Ruan G, Elstrom RL, Martin P, Leonard JP. Metronomic therapy for refractory/relapsed lymphoma: the PEP-C low-dose oral combination chemotherapy regimen. Hematology. 2012 Apr;17 Suppl 1:S90-2. doi:10.1179/102453312X13336169155970. PubMed
R-CHOP
R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
Regimen #1, Czuczman, et al. 1999
Level of Evidence: Phase II
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once daily on days 1 to 5
- Rituximab (Rituxan) doses given by the following schedule:
- Rituximab (Rituxan) 375 mg/m2 IV once 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
Regimen #2, Van Oers, et al. 2006 (EORTC 20981)
Level of Evidence: Phase III
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg PO once daily on days 1 to 5
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
21-day cycles x 6 cycles
Responders (PR or CR) were randomized to maintenance rituximab or no further treatment.
References
- 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
- Update: 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 to 6. Epub 2004 Oct 13. link to original article PubMed
- van Oers MH, Klasa R, Marcus RE, Wolf M, Kimby E, Gascoyne RD, Jack A, Van't Veer M, Vranovsky A, Holte H, van Glabbeke M, Teodorovic I, Rozewicz C, Hagenbeek A. Rituximab maintenance improves clinical outcome of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood. 2006 Nov 15;108(10):3295-301. Epub 2006 Jul 27. link to original article contains verified protocol PubMed
- Update: van Oers MH, Van Glabbeke M, Giurgea L, Klasa R, Marcus RE, Wolf M, Kimby E, van t Veer M, Vranovsky A, Holte H, Hagenbeek A. Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin's lymphoma: long-term outcome of the EORTC 20981 phase III randomized intergroup study. J Clin Oncol. 2010 Jun 10;28(17):2853-8. Epub 2010 May 3. link to original article contains verified protocol PubMed
R-FCM
R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone
Regimen
Level of Evidence: Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once on day -1 (the day before FCM)
- Fludarabine (Fludara) 25 mg/m2 IV over 30 minutes once daily on days 1 to 3
- Cyclophosphamide (Cytoxan) 200 mg/m2 IV over 4 hours on days 1 to 3
- Mitoxantrone (Novantrone) 8 mg/m2 IV over 30 minutes once on day 1
28-day cycles x 4 cycles
Responders (PR or CR) were randomized to maintenance rituximab or no further treatment.
References
- 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 verified protocol PubMed
- Update: Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group (GLSG). Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. link to original article contains verified protocol PubMed
R-FND
R-FND: Rituximab, Fludarabine, Novantrone, Dexamethasone
Regimen
- Fludarabine (Fludara) 25 mg/m2 IV once daily on days 1 to 3
- Mitoxantrone (Novantrone) 10 mg/m2 IV once on day 1
- Dexamethasone (Decadron) 20 mg PO/IV once daily on days 1 to 5
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycles x up to 8 cycles
References
- 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
- 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 contains verified dosages
- 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 content property of HemOnc.org
- 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
- 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 contains verified dosages
Rituximab monotherapy
Regimen #1, Witzig et al. 2002; Ghielmini et al. 2004
Level of Evidence: Phase III
- Rituximab (Rituxan) 375 mg/m2 IV weekly x 4 weeks
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
Patients with response or stable disease at 12 weeks in Ghielmini et al. 2004 were randomized to maintenance rituximab or no further treatment.
Regimen #2, Coiffier et al. 2011 (LYM-3001)
Level of Evidence: Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22 on cycle 1; once on day 1 of subsequent cycles
5-week cycles x 6 cycles
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
References
- 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 verified protocol PubMed
- Ghielmini M, Schmitz SF, Cogliatti SB, Pichert G, Hummerjohann J, Waltzer U, Fey MF, Betticher DC, Martinelli G, Peccatori F, Hess U, Zucca E, Stupp R, Kovacsovics T, Helg C, Lohri A, Bargetzi M, Vorobiof D, Cerny T. Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly x 4 schedule. Blood. 2004 Jun 15;103(12):4416-23. Epub 2004 Feb 19. link to original article contains protocol PubMed
- Coiffier B, Osmanov EA, Hong X, Scheliga A, Mayer J, Offner F, Rule S, Teixeira A, Walewski J, de Vos S, Crump M, Shpilberg O, Esseltine DL, Zhu E, Enny C, Theocharous P, van de Velde H, Elsayed YA, Zinzani PL; LYM-3001 study investigators. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011 Aug;12(8):773-84. Epub 2011 Jul 1. link to original article contains verified protocol PubMed
- Zinzani PL, Khuageva NK, Wang H, Garicochea B, Walewski J, Van Hoof A, Soubeyran P, Caballero D, Buckstein R, Esseltine DL, Theocharous P, Enny C, Zhu E, Elsayed YA, Coiffier B. Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial. J Hematol Oncol. 2012 Oct 22;5:67. doi: 10.1186/1756-8722-5-67. link to original article PubMed
Temsirolimus (Torisel)
Regimen
Level of Evidence: Phase II
- Temsirolimus (Torisel) 25 mg IV over 30 minutes once per week
28-day cycles x minimum of 2 cycles
References
- Smith SM, van Besien K, Karrison T, Dancey J, McLaughlin P, Younes A, Smith S, Stiff P, Lester E, Modi S, Doyle LA, Vokes EE, Pro B. Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol. 2010 Nov 1;28(31):4740-6. doi: 10.1200/JCO.2010.29.2813. Epub 2010 Sep 13. link to original article contains verified protocol PubMed
VR
VR: Velcade, Rituximab
Regimen #1, Coiffier, et al. 2011 (LYM-3001)
Level of Evidence: Phase III
- Bortezomib (Velcade) 1.6 mg/m2 IV push over 3 to 5 seconds once on days 1, 8, 15, 22
- Rituximab (Rituxan) 375 mg/m2 IV once on days 1, 8, 15, 22 of cycle 1 only; then 375 mg/m2 IV once on day 1 of cycles 2 to 5
35-day cycles x 5 cycles
Supportive medications:
- No routine antiviral prophylaxis was mandated
Regimen #2, de Vos, et al. 2009
Level of Evidence: Phase II
- Bortezomib (Velcade) 1.6 mg/m2 IV once on days 1, 8, 15, 22
- Rituximab (Rituxan) 375 mg/m2 IV once on days 1, 8, 15, 22 of cycle 1 only
35-day cycles x 3 cycles
Regimen #3, Agathocleous, et al. 2010
Level of Evidence: Phase II
- Bortezomib (Velcade) 1.6 mg/m2 IV once on days 1, 8, 15, 22
- Rituximab (Rituxan) 375 mg/m2 IV once on days 1, 8, 15, 22 of cycles 1 & 4 only (total of 8 doses)
35-day cycles x up to 6 cycles
References
- de Vos S, Goy A, Dakhil SR, Saleh MN, McLaughlin P, Belt R, Flowers CR, Knapp M, Hart L, Patel-Donnelly D, Glenn M, Gregory SA, Holladay C, Zhang T, Boral AL. Multicenter randomized phase II study of weekly or twice-weekly bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal-zone B-cell lymphoma. J Clin Oncol. 2009 Oct 20;27(30):5023-30. doi:10.1200/JCO.2008.17.7980. Epub 2009 Sep 21. link to original article contains verified protocol PubMed
- Agathocleous A, Rohatiner A, Rule S, Hunter H, Kerr JP, Neeson SM, Matthews J, Strauss S, Montoto S, Johnson P, Radford J, Lister A. Weekly versus twice weekly bortezomib given in conjunction with rituximab, in patients with recurrent follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinaemia. Br J Haematol. 2010 Nov;151(4):346-53. doi: 10.1111/j.1365-2141.2010.08340.x. Epub 2010 Sep 29. link to original article contains verified protocol PubMed
- Coiffier B, Osmanov EA, Hong X, Scheliga A, Mayer J, Offner F, Rule S, Teixeira A, Walewski J, de Vos S, Crump M, Shpilberg O, Esseltine DL, Zhu E, Enny C, Theocharous P, van de Velde H, Elsayed YA, Zinzani PL; LYM-3001 study investigators. Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial. Lancet Oncol. 2011 Aug;12(8):773-84. Epub 2011 Jul 1. link to original article contains verified protocol PubMed
- Zinzani PL, Khuageva NK, Wang H, Garicochea B, Walewski J, Van Hoof A, Soubeyran P, Caballero D, Buckstein R, Esseltine DL, Theocharous P, Enny C, Zhu E, Elsayed YA, Coiffier B. Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naïve or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial. J Hematol Oncol. 2012 Oct 22;5:67. doi: 10.1186/1756-8722-5-67. link to original article PubMed
90Yttrium-Ibritumomab-Tiuxetan (Zevalin)
Regimen #1, Witzig, et al. May 2002 - Yttrium-90 and Indium-111
Level of Evidence: Phase III
For patients with relapsed or refractory disease
- Rituximab (Rituxan) 250 mg/m2 IV once on days 1 & 8
- Ibritumomab tiuxetan 1.6 mg & Indium-111 5 mCi IV over 10 minutes once 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 once on day 8 immediately following rituximab
8-day course of therapy
Regimen #2, Witzig, et al. Aug 2002 - Yttrium-90 only
Level of Evidence: Phase II
For patients with rituximab-refractory disease
- Rituximab (Rituxan) 250 mg/m2 IV once 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 once on day 8 immediately following rituximab
8-day course of therapy
References
- Witzig TE, White CA, Wiseman GA, Gordon LI, Emmanouilides C, Raubitschek A, Janakiraman N, Gutheil J, Schilder RJ, Spies S, Silverman DH, Parker E, Grillo-López AJ. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma. J Clin Oncol. 1999 Dec;17(12):3793-803. link to original article contains verified protocol PubMed
- 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 verified protocol PubMed
- 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 verified protocol PubMed