B-Cell Lymphomas Treatment Regimens: Follicular Lymphoma (Grade 1-2)

B-Cell Lymphomas Treatment Regimens: Follicular Lymphoma (Grade 1-2)

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies.


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These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Note: All recommendations are category 2A unless otherwise indicated.

▶First Line Therapy1,a

REGIMEN

DOSING

Preferred Regimensb

Bendamustine + Obinutuzumab2-5,c-d

Day 1-2: Bendamustine 90mg/m2 IV over 10-30 minutes

Days 1,8,15 (Cycle 1): Obinutuzumab 1000mg IV, followed by:

Day 1 (Cycles 2-6): Obinutuzumab 1000mg IV.

Repeat cycle every 4 weeks for 6 cycles, followed by maintenance therapy with:

Day 1: Obinutuzumab 1000mg IV.

Repeat cycle every 8 weeks for a maximum of 2 years.

Bendamustine + Rituximab2,6-8,d-f

Days 1-2: Bendamustine 90mg/m2 IV over 10-30 minutes

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) + Obinutuzumab3,9-13,c,g-j

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally once daily

Days 1,8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1(Cycles 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 3 weeks for 6 cycles.

CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) + Rituximab6,9-12,14,15,f-j

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally once daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6-8 cycles.

CVP (Cyclophosphamide, Vincristine, Prednisone) + Obinutuzumab3,9-13,c,g-i

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes

Day 1: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally once daily

Days 1,8,15 (Cycle 1): Obinutuzumab 1000mg IV, followed by:

Day 1 (Cycles 2-6): Obinutuzumab 1000mg IV.

Repeat cycle every 3 weeks for 8 cycles.

CVP (Cyclophosphamide, Vincristine, Prednisone) + Rituximab6,9-12,16-18,f-i

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes OR

Day 1: Cyclophosphamide 1,000mg/m2 IV over 30 minutes.

Day 1: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally once daily

Day 1: Rituximab 375mg/m2 IV.

Repeat every 3 weeks for 6-8 cycles.

Lenalidomide + Rituximab6,19-22,f,k

Days 2-22: Lenalidomide 20mg orally once daily

Days 1,8,15,22 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycles 2-6): Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles, conditionally followed by:

Days 1-28: Lenalidomide 10mg once daily (for patients achieving a complete response [CR]).

Repeat cycle every 4 weeks for 12 cycles, with:

Day 1: Rituximab 375 mg/m2 IV.

Repeat cycle every 8 weeks for 6 cycles.

OR

Days 2-22: Lenalidomide 20mg orally once daily

Days 1,8,15,22 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycles 2-6): Rituximab 375mg/m2 IV

Repeat cycle every 4 weeks for 6 cycles, conditionally followed by:

Days 1-28: Lenalidomide 20mg orally once daily (for patients achieving a partial response [PR] until CR is achieved), followed by:

Days 1-28: Lenalidomide 10mg orally once daily to complete a total of 12 cycles.

Repeat cycle every 4 weeks for 3-6 cycles until complete clinical response followed by 6-9 cycles after CR achieved, with:

Day 1: Rituximab 375mg/m2 IV.

Repeat every 8 weeks for 6 cycles.

Other Recommended Regimens

Lenalidomide + Obinutuzumab (Category 2B)3,19,23,24,c,k

Days 1-21 (Cycles 1-6): Lenalidomide 20mg orally once daily

Days 1,8,15 (Cycle 1): Obinutuzumab 1000mg IV, followed by:

Day 1 (Cycles 2-6): Obinutuzumab 1000mg IV.

Repeat cycle every 4 weeks for 6 cycles, followed by:

Days 1-21 (Cycles 7-18): Lenalidomide 10mg orally once daily

Day 1 (odd numbered cycles beginning with Cycle 7): Obinutuzumab 1000mg IV.

Repeat cycle every 4 weeks for a maximum of 12 cycles, followed by:

Day 1: Obinutuzumab 1000mg IV.

Repeat cycle every 8 weeks for 6 cycles.

Rituximab (consider for low tumor burden)6,25-27,f

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle.

▶First-Line Therapy for Elderly or Infirm (if none of the above regimens are expected to be tolerable in the opinion of the treating physician)1,a

Preferred Regimens

Rituximab6, 25-27,f

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle.

Other Recommended Regimens

Chlorambucil28-30,l

Days 1-28: Chlorambucil 0.1mg/kg orally once daily.

Repeat cycle every 4 weeks.

OR

Day 1: Chlorambucil 40mg/m2 orally once daily.

Repeat cycle every 4 weeks.

Chlorambucil + Rituximab6,28,31,32,f,l

Days 1,8,15,22: Rituximab 375mg/m2 IV, with:

Day 1-42: Chlorambucil 6mg/m2 IV orally once daily.

Administer for one 6-week cycle, conditionally followed by consolidation therapy with:

Day 1: Rituximab 375mg/m2 IV, with:

Days 1-14: Chlorambucil 6mg/m2 IV orally once daily.

Repeat cycle every 4 weeks for 4 cycles (for patients who have had a response after first cycle).

Cyclophosphamide9,33,i

Days 1-28: Cyclophosphamide 50-100mg/m2 orally once daily.

Repeat cycle every 4 weeks.

Cyclophosphamide + Rituximab6,9,33,f,i

Day 1: Rituximab 375mg/m2 IV

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes OR

Day 1: Cyclophosphamide 1000mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks for 6-8 cycles.

Ibritumomab tiuxetan (Category 2B)34,35,m

See NCCN B-Cell Lymphoma guidelines (Follicular Lymphoma [grade 1-2])1

▶First-Line Consolidation or Extended Dosing (optional)1,a

Preferred Regimens Following Chemoimmunotherapy

Rituximab Maintenance (Category 1; for patients initially presenting with high tumor burden)6,36-38,f

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 8-12 weeks for 2 years.

Obinutuzumab Maintenance3-5,c

Day 1: Obinutuzumab 1000mg IV.

Repeat cycle every 8 weeks for 12 doses.

Other Recommended Regimens

Rituximab Consollidation (if initially treated with single-agent Rituximab)6,36-38,f

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 8 weeks for 4 cycles.

Ibritumomab tiuxetan (Category 2B)34,35,m

See NCCN B-Cell Lymphoma guidelines (Follicular Lymphoma [grade 1-2])1

▶Second-Line and Subsequent Therapy1,a

Preferred Regimensb

Bendamustine + Obinutuzumab (not recommended for patients treated with prior Bendamustine)2-5,c-e,n

Day 1-2: Bendamustine 90mg/m2 IV over 10-30 minutes

Days 1,8,15 (Cycle 1): Obinutuzumab 1000mg IV, followed by:

Day 1 (Cycles 2-6): Obinutuzumab 1000mg IV.

Repeat cycle every 4 weeks for 6 cycles, followed by maintenance therapy with:

Day 1: Obinutuzumab 1000mg IV.

Repeat cycle every 8 weeks for a maximum of 2 years.

Bendamustine + Rituximab (not recommended for patients treated with prior Bendamustine)2,6-8,d-f

Days 1-2: Bendamustine 90mg/m2 IV over 10-30 minutes

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) + Obinutuzumab3,9-13,c,g-j,n

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally once daily

Days 1,8,15 (Cycle 1): Obinutuzumab 1,000mg IV, followed by:

Day 1 (Cycles 2-6): Obinutuzumab 1,000mg IV.

Repeat cycle every 3 weeks for 6 cycles.

CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) + Rituximab6,9-12,14,15,f-j

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally once daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6-8 cycles.

CVP (Cyclophosphamide, Vincristine, Prednisone) + Obinutuzumab3,9-13,c,g-I,n

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes

Day 1: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally once daily

Days 1,8,15 (Cycle 1): Obinutuzumab 1000mg IV, followed by:

Day 1 (Cycles 2-6): Obinutuzumab 1000mg IV.

Repeat cycle every 3 weeks for 8 cycles.

CVP (Cyclophosphamide, Vincristine, Prednisone) + Rituximab6,9-12,16-18,f-i

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes OR

Day 1: Cyclophosphamide 1,000mg/m2 IV over 30 minutes

Day 1: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally once daily.

Day 1: Rituximab 375mg/m2 IV.

Repeat every 3 weeks for 6-8 cycles.

Lenalidomide + Rituximab6,19,39,f,k

Days 1-21 (Cycles 1-12): Lenalidomide 20mg orally once daily.

Day 1,8,15,22 (Cycle 1): Rituximab 375mg/m2 IV, followed by:

Day 1 (Cycles 2-5): Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 12 cycles.

Other Recommended Regimenso

Ibritumomab tiuxetan34,40,41,m

See NCCN B-Cell Lymphoma guidelines (Follicular Lymphoma [grade 1-2])1

Lenalidomide (if not a candidate for anti-CD20 monoclonal antibody therapy)19,42,k

Days 1-21: Lenalidomide 25mg orally once daily.

Repeat cycle every 4 weeks for 12 cycles.

Lenalidomide + Obinutuzumab3,19,23,24,c,k

Days 1-21 (Cycles 1-6): Lenalidomide 20mg orally once daily.

Days 1,8,15 (Cycle 1): Obinutuzumab 1000mg IV, followed by:

Day 1 (Cycles 2-6): Obinutuzumab 1000mg IV.

Repeat cycle every 4 weeks for 6 cycles, followed by:

Days 1-21 (Cycles 7-18): Lenalidomide 10mg orally once daily

Day 1 (odd numbered cycles beginning with Cycle 7): Obinutuzumab 1000mg IV.

Repeat cycle every 4 weeks for a maximum of 12 cycles, followed by:

Day 1: Obinutuzumab 1000mg IV.

Repeat cycle every 8 weeks for 6 cycles.

Obinutuzumab3,43,c

Days 1,8,15,22: Obinutuzumab 1000mg IV.

Administer for one 4-week cycle, conditionally followed by:

Day 1: Obinutuzumab 1,000mg IV.

Repeat cycle every 8 weeks for a maximum of 12 cycles (stable disease or objective response to therapy).

Rituximab6,25-27,f

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle.

▶Second-Line and Subsequent Therapy for Elderly or Infirm (if none of the above regimens are expected to be tolerable in the opinion of the treating physician)1,a

Preferred Regimens

Rituximab6,25-27,f

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle.

Other Recommended Regimens

Chlorambucil28-30,l

Days 1-28: Chlorambucil 0.1mg/kg orally once daily.

Repeat cycle every 4 weeks.

OR

Day 1: Chlorambucil 40mg/m2 orally once daily.

Repeat cycle every 4 weeks.

Chlorambucil + Rituximab6,28,31,32,f,l

Days 1,8,15,22: Rituximab 375mg/m2 IV, with:

Day 1-42: Chlorambucil 6mg/m2 IV orally once daily.

Administer for one 6-week cycle, followed by consolidation therapy with:

Day 1: Rituximab 375mg/m2 IV

Days 1-14: Chlorambucil 6mg/m2 IV orally once daily.

Repeat cycle every 4 weeks for 4 cycles (for patients who have had a response after first cycle).

Cyclophosphamide9,33,i

Days 1-28: Cyclophosphamide 50-100mg/m2 orally once daily.

Repeat cycle every 4 weeks.

Cyclophosphamide + Rituximab6,9,33,f,i

Day 1: Rituximab 375mg/m2 IV

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes OR

Day 1: Cyclophosphamide 1000mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks for 6-8 cycles.

Ibritumomab tiuxetan (Category 2B)34,40,41,m

See NCCN B-Cell Lymphoma guidelines (Follicular Lymphoma [grade 1-2])1

▶Second-Line Consolidation or Extended Dosing (optional)1,a

Preferred Regimens

Rituximab Maintenance (Category 1)6,36-38,f

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 12 weeks for 2 years.

Obinutuzumab Maintenance (for Rituximab-refractory disease)3-5,c

Day 1: Obinutuzumab 1000mg IV.

Repeat cycle every 8 weeks for 12 doses.

Other Recommended Regimens

• High-dose therapy with autologous stem cell rescue

• Allogeneic hematopoietic cell transplant for highly selected patients

▶Third-Line and Subsequent Therapy1,a

Preferred Regimens

Copanlisib (Relapsed/refractory after 2 prior therapies)44-46,p

Days 1,8,15: Copanlisib 60mg IV over 60 minutes.

Repeat cycle every 4 weeks.

Duvelisib (Relapsed/refractory after 2 prior therapies)47,48,q

Days 1-28: Duvelisib 25mg orally twice daily.

Repeat cycle every 4 weeks.

Idelalisib (Relapsed/refractory after 2 prior therapies)49-51,r

Days 1-28: Idelalisib 150mg orally twice daily.

Repeat cycle every 4 weeks.

Umbralisib (Relapsed/refractory after 3 prior therapies)52,53,s

Day 1: Umbralisib 800mg orally once daily.

Repeat every 4 weeks.

Tazemetostat (EZH2 mutation positive relapsed/refractory disease after 2 prior therapies; EZH2 wild type or unknown relapsed/refractory disease in patients who have no satisfactory alternative treatment options)54,55,t

Day 1: Tazemetostat 800mg orally twice daily.

Repeat cycle every 4 weeks.

Axicabtagene ciloleucel56-59

See NCCN B-Cell Lymphomas guidelines (Follicular Lymphoma [grade 1-2])1

▶Third-Line and Subsequent Therapy for Elderly or Infirm1,a

Preferred Regimens

Umbralisib (Relapsed/refractory after 3 prior regimens)52,53,s

Day 1: Umbralisib 800mg orally once daily.

Repeat cycle every 4 weeks.

▶Histologic Transformation to Diffuse Large B-Cell Lymphoma (DLBCL)1,a

Axicabtagene ciloleucel (only after ≥2 prior chemoimmunotherapy regimens)57-59,u,v

See NCCN B-Cell Lymphomas guidelines (Follicular Lymphoma [grade 1-2])1

Lisocabtagene maraleucel (only after ≥2 prior chemoimmunotherapy regimens)60,61,u,v

See NCCN B-Cell Lymphomas guidelines (Follicular Lymphoma [grade 1-2])1

Tisagenlecleucel (only after ≥2 prior chemoimmunotherapy regimens)62,63,u,v

See NCCN B-Cell Lymphomas guidelines (Follicular Lymphoma [grade 1-2])1

  a The choice of therapy requires consideration of many factors, including age, comorbidities, and future treatment possibilities (eg, HDT [high-dose therapy] with ASCR [autologous stem cell rescue]). Therefore, treatment selection is highly individualized.

  b Generally, a first-line treatment is not repeated

  c Obinutuzumab requires premedication with diphenhydramine, acetaminophen, and a corticosteroid.

  d This regimen may be associated with a risk of tumor lysis syndrome in patients with high-risk features, including extensive disease or underlying renal insufficiency.

  e Secondary malignancies have been associated with Bendamustine

  f Rituximab requires premedication with diphenhydramine and acetaminophen. Rituximab and hyaluronidase human injection for subcutaneous use may be substituted for Rituximab after patients have received the first full dose of Rituximab by intravenous infusion. The substitution cannot be made with used in combination with ibritumomab tiuxetan.

  g Myeloid growth factor therapy may be considered as primary prophylaxis based on the febrile neutropenia risk of the regimen

  h Vincristine is for intravenous use only and usually results in death or serious neurological damage if given via other routes.

  i Cyclophosphamide has been associated with secondary malignancies.

  j Doxorubicin has been associated with secondary malignancies.

  k Lenalidomide can be taken with or without food. Secondary malignancies have been associated with Lenalidomide. Participation in the risk evaluation and mitigation strategy (REMS) program is required for Lenalidomide.

  l Chlorambucil should be taken on an empty stomach. Secondary malignancies have been associated with Chlorambucil.

  m Selection of patients requires adequate marrow cellularity >15% and <25% involvement of lymphoma in bone marrow, and platelets >100000. In patients with prior autologous stem cell rescue, referral to a tertiary care center is highly recommended for ibritumomab tiuxetan.

  n Obinutuzumab is preferred in patients with Rituximab refractory disease, which includes disease progressing on or within 6 months of prior Rituximab therapy.

  o See second-line therapy for diffuse large b-cell lymphoma without regard to transplantability.

  p Copanlisib has multiple potential drug-drug and/or drug-food interactions. Review patient medical profile and drug package insert for specific drug and food interactions and recommendations.

  q Duvelisib has multiple potential drug-drug and/or drug-food interactions. Review patient medical profile and drug package insert for specific drug and food interactions and recommendations.

  r Idelalisib can be taken with or without food. Idelalisib has multiple potential drug-drug and/or drug-food interactions.

  s Umbralisib should be taken with food. Swallow tablet whole. Do not crush, break, cut, or chew tablets.

  t Tazemetostat can be taken with or without food. Tazemetostat has multiple potential drug-drug and/or drug-food interactions.

  u In patients intended to receive CAR T-cell therapy, Bendamustine should be used with caution unless after leukapheresis prior to CAR T-cell therapy, since it could impact the success of the patient’s T-cell collection.

  v Patients should have received at least one anthracycline or anthracenedione-based regimen, unless contraindicated.

References

1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for B-Cell Lymphomas V4.2021. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdff. Accessed July 25, 2021.

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5. Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): a randomised, controlled, open-label, multicentre, phase 3 trial. Lancet Oncol. 2016;17(8):1081-1093.

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21. Martin P, Jung SH, Pitcher B, et al. A phase II trial of lenalidomide plus rituximab in previously untreated follicular non-Hodgkin’s lymphoma (NHL): CALGB 50803 (Alliance). Ann Oncol. 2017;28(11):2806-2812.

22. Morschhauser F, Fowler NH, Feugier P, et al. Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N Engl J Med. 2018;379(10):934-947.

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24. Nastoupil LJ, Westin JR, Hagemeister FB, et al. Results of a phase II study of obinutuzumab in combination with lenalidomide in previously untreated, high tumor burden follicular lymphoma (FL). Blood. 2019;134 (Supplement_1):125.

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26. Martinelli G, Schmitz SFH, Utiger U et al. Long-term follow-up of patients with follicular lymphoma receiving single-agent rituximab at two different schedules in trial SAKK 35/98. J Clin Oncol. 2010;28(29):4480-4.

27. McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998;16(8):2825-2833.

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30. Rai KR, Peterson BL, Appelbaum FR, et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000;343(24):1750-1757.

31. Martinelli G, Laszlo D, Bertonlini F, et al. Chlorambucil in combination with induction and maintenance rituximab is feasible and active in indolent non-Hodgkin’s lymphoma. Br J Haematol. 2003;123(2):271-277.

32. Martinelli G, Montoro J, Vanazzi A, et al. Chlorambucil-rituximab as first-line therapy in patients affected by follicular non-Hodgkin’s lymphoma: a retrospective single-centre study. Hematol Oncol. 2015;33(4):129-135.

33. Peterson BA, Petroni GA, Frizzera G, et al. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol. 2003;21(1):5-15.

34. Ibritumomab tiuxetan (Zevalin) [package insert]. East Windsor, NJ. Acrotech Biopharma LLC; September 2019.

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Revised 8/21; NCCN B-Cell Lymphoma Guidelines (Follicular Lymphoma [grade 1-2]) © 2021 by Haymarket Media, Inc.

This article originally appeared on Cancer Therapy Advisor