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Overview of the Updated NCCN Guidelines on B-Cell Lymphomas
B-cell lymphomas are a subtype of non-Hodgkin Lymphoma (NHL) that affect B lymphocytes, a part of the immune system also known as B cells. These cancers can be either indolent or aggressive and represent up to 85% of NHL diagnoses in the United States.1 Some of the most common types of B-cell lymphomas include the following:
- diffuse large B-cell lymphoma (DLBCL);
- follicular lymphoma (FL);
- mantle cell lymphoma (MCL);
- and marginal zone lymphoma (MZL).
First-line treatment for these cancer types is often chemotherapy combined with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Although cure rates are high, up to 30% of patients with NHL may experience relapse. Chemotherapy with R-CHOP can be modified for patients with NHL undergoing stem cell transplantation, which allows patients to tolerate higher doses of chemotherapy.2 Other treatment options include immunotherapies such as chimeric antigen receptor (CAR) T-cell therapy, which modifies a patient’s own T-cells to better combat cancer cells, or immune checkpoint inhibitors that block specific proteins from binding with partner proteins.
Diffuse Large B-Cell Lymphoma
DLBCL represents approximately 24% of NHL diagnoses per year and is the most common aggressive NHL that originates from the germinal center.3 It can affect patients at any age but primarily occurs among adults aged 60 years or older and is fast growing.1 Patients diagnosed with DLBCL typically require immediate treatment due to lymphadenopathy and constitutional symptoms. Chemoimmunotherapy with R-CHOP can lead to cure in up to 60% of patients.3 High-dose chemotherapy or autologous stem cell transplant are options for patients who do not respond to R-CHOP; however, only a minority of patients who receive these therapies achieve long-term remission.3
Follicular Lymphoma
FL is a slow growing type of NHL that is found more frequently in older adults and is characterized by diffuse swelling of the lymph nodes, bone marrow involvement, and an enlarged spleen.4 Due to its indolence, FL typically is considered more of a chronic disease rather than curable disease; however, the disease can progress to a more aggressive form of lymphoma. Treatment is often delayed until symptoms become problematic. Asymptomatic patients with FL may only require observation. Treatment for more advanced cases could include chemoimmunotherapy, rituximab, lenalidomide, kinase inhibitors, or stem cell transplantation.4 In more serious cases and over time, some FLs can turn into fast-growing DLBCL.1
Mantle Cell Lymphoma
An aggressive lymphoma, MCL usually requires treatment with immunochemotherapy at the time of diagnosis.5 Named for the origin of the tumor cells in the “mantle zone” of the lymph node, MCL usually is widespread in patients at diagnosis and can involve the lymph nodes, spleen, blood, and bone marrow.1
Due to its aggressive nature, there is not a single standard of care and patients often relapse after aggressive chemoimmunotherapy regimens that could include rituximab, cytarabine, and stem cell transplantation.5 As such, median overall survival at time of diagnosis is 4 to 5 years.6
Marginal Zone Lymphomas
An indolent subtype of NHL, MZL originates in marginal zone B cells and can lead to increased abnormal growth of B cells. The cancer is more common in men than women, and median age at diagnosis is 67 years.7 MZL represents between 5% and 10% of all NHL diagnoses.7
There are 3 subtypes of MZL: extranodal MZL or mucosa-associated lymphoid tissue, nodal MZL, and splenic MZL.1 Treatment options are dependent on the type and include antibiotics combined with proton pump inhibitors, radiation therapy, chemotherapy, immunotherapy, or splenectomy.
MZL has also been linked to hepatitis C infection and data show treating hepatitis C may also prove beneficial treating this lymphoma.1
National Comprehensive Cancer Network Guidelines
The National Comprehensive Cancer Network (NCCN) represents a group of 32 cancer centers. The organization offers free Clinical Practice Guidelines in Oncology that provide recommendations for the prevention, diagnosis, and management of malignancies. NCCN offers Guidelines for 97% of cancers and are frequently updated to reflect advances across the cancer care continuum.8
To develop these Guidelines,8 NCCN organizes a panel of experts who evaluate treatment options and make evidence-based recommendations with the insight of clinical expertise. The panel reviews and discusses all recommendations and changes to current recommendations, then agrees as a group whether or not to make any additions, deletions, or changes.
A stated goal8 of the NCCN Guidelines is to “represent the breadth of appropriate recommendations for a given clinical situation. As such, they provide a range of options to allow individual clinicians the latitude to select the most appropriate intervention for each patient.”
NCCN Guidelines for B-Cell Lymphomas: 2022 Updates
The NCCN Guidelines for B-Cell Lymphomas have been updated multiple times in 2022 with the most recent iteration, Version 4.2022, published on June 9, 2022, following a bulk of updates from Versions 1.2022, 2.2022, and 3.2022.9
Guideline Changes to Therapies
Recent global changes to the Guidelines9 included updates to suggested treatment regimens and revisions to the recommendation for allogeneic hematopoietic cell transplant, changing it to “Allogeneic hematopoietic cell transplant in selected cases” and adding a footnote to define selected cases, which include mobilization failures and persistent bone marrow involvement.
Axicabtagene ciloleucel: The Version 1.2022 update9 added axicabtagene ciloleucel as a third-line and subsequent therapy option for MZL (if not previously given). For patients with DLBCL and relapsed disease <12 months prior or primary refractory disease, axicabtagene ciloleucel with bridging therapy as clinically indicated was added as a category 1 recommendation for patients with intention to proceed to CAR T-cell therapy. It also modified guidance for treatment of patients with CAR T-cell therapy, adding “Axicabtagene is also indicated for patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy” to the first sub-bullet under patient selection.9
The updated recommendation for FL and MZL came from the phase 2 ZUMA-5 trial,10 which assessed axicabtagene ciloleucel in patients with relapsed/refractory FL or MZL. The primary end point was overall response rate (ORR). Of 153 patients enrolled, 148 received an infusion of axicabtagene ciloleucel. The median follow-up was 17.5 months. Among 104 patients eligible for the primary analysis,10 the ORR was 92% (n=96) and the complete response rate (CRR) was 74% (n=77). Based on results from the ZUMA-5 trial, axicabtagene ciloleucel had previously received accelerated FDA approval to treat relapsed/refractory FL following ≥2 lines of systemic therapy.11
The recommendation for relapsed/refractory DLBCL came from the phase 2 ZUMA-1 trial.12 This trial evaluated axicabtagene ciloleucel in patients with refractory DLBCL (n=81), transformed FL (n=30), or primary mediastinal B-cell lymphoma (n=8). The primary analysis12 included 101 patients that were evaluated 6 months after infusion. The ORR was 82%. After a median follow-up of 15 months, the estimated progression-free survival (PFS) and overall survival (OS) were 41% and 52%, respectively. Follow-up data13 after 2 years confirmed these initial findings. After a median follow-up of 27 months, 39% of patients remained in ongoing remission and 51% remained alive.13
On April 1, 2022, the FDA approved axicabtagene ciloleucel for the second-line treatment of large B-cell lymphoma based on data from the ZUMA-7 trial.14 ZUMA-7, which examined 359 patients with primary refractory or relapse large B-cell lymphoma within 12 months following completion of first-line therapy, reported that patients treated with axicabtagene ciloleucel (n=180) exhibited event-free survival (EFS) of 8.3 months compared with 2 months for patients treated with standard care options (n=179).15 Furthermore, the study also showed 24-month EFS of 41% in the group of patients taking axicabtagene ciloleucel and 16% in the group of patients treated with standard care.15
Brentuximab vedotin: The Version 2.2022 update9 added a footnote to the sections covering DLBCL and FL emphasizing that brentuximab vedotin and ibrutinib are not options for second-line therapy for FL; however, brentuximab vedotin remains listed as useful in certain situations as a second-line therapy for CD30+ disease. Both therapies remain listed as useful in certain circumstances for treatment of DLBCL.
Duvelisib: The Version 1.2022 update9 removed the PI3K inhibitor duvelisib from other recommended regimens for MZL. The drug also was removed from the section covering special considerations for the use of small-molecule inhibitors.
Ibritumomab tiuxetan: The Version 1.2022 update9 removed ibritumomab tiuxetan from other recommended regimens for the first-line therapy of elderly or infirm patients with FL. In addition, ibritumomab tiuxetan was removed from other recommended regimens for first-line therapy of MZL, along with footnote: “Selection of patients requires adequate marrow cellularity >15% and <25% involvement of lymphoma in bone marrow, and platelets >100,000.... As of 2010, updates suggest a trend towards an increased risk of MDS [myelodysplastic syndromes] with RIT [radioimmunotherapy]. Cytogenetics/FISH assessment for MDS markers is recommended for patients receiving RIT.”
Ibritumomab tiuxetan remains a recommended option for first-line consolidation in FL and second-line or subsequent therapy for FL and MZL, but footnotes strongly suggest referral to tertiary care center for patients taking ibritumomab tiuxetan.9
Idelalisib: The Version 1.2022 update9 removed idelalisib as a third-line and subsequent therapy option for FL and MZL based on its withdrawal of FDA indication.
Rituximab, dexamethasone, cytarabine (RDHA) + platinum: The Version 1.2022 update9 revised RDHA + platinum to include carboplatin (if not previously given), useful in certain circumstances, for second-line and subsequent therapy for patients with MCL.
A phase 3 trial16 evaluated the role of rituximab maintenance after high-dose therapy/autologous stem cell transplantation among patients with MCL aged <66 years at diagnosis. A total of 299 patients were enrolled and randomly assigned to rituximab maintenance or observation after transplantation. Induction chemoimmunotherapy with RDHA + platinum (carboplatin, cisplatin, or oxaliplatin) resulted in an ORR of 89% with 77% experiencing a complete response.16
A subsequent analysis17 evaluated the prognostic impact of carboplatin, cisplatin, or oxaliplatin on survival. PFS and OS were identical for all 3 regimens, though a trend toward improved PFS and OS with RDHA + oxaliplatin was noted. In the intent-to-treat population, the 4-year PFS and OS rates were 87% and 92% for RDHA + oxaliplatin compared to 65% and 76%, respectively, for the combined cohort of RDHA + carboplatin and RDHA + cisplatin.17
Tazemetostat: The Version 1.2022 update9 added tazemetostat as a category 2A recommendation for second-line therapy in older or infirm patients with EZH2 wild type or unknown relapsed/refractory disease.
This change came from an open-label, single-arm, phase 2 trial,18 which investigated tazemetostat in patients with FL. The trial was conducted at 38 clinics or hospitals throughout the world and included 99 patients who were categorized by EZH2 status: mutant (n=45) or wild type (n=54). The primary end point was ORR.
The median follow-up was 22 months in the EZH2 mutant arm and 35.9 months in the wild type arm. The ORR was 69% (95% CI, 53-82; n=31) and 35% (95% CI, 23-49; n=19), respectively. The median duration of response was 10.9 months (95% CI, 7.2–not estimable [NE]) in the mutant arm and 13 months (95% CI, 5.6–NE) in the wild type arm. Median PFS was 13.8 months (95% CI, 10.7–22) and 11.1 months (95% CI, 3.7–14.6), respectively.18
Tisagenlecleucel: The most recent update9 to the Guidelines, Version 4.2022, added anti-CD-19 CAR T-cell therapy, tisagenlecleucel, as a category 2A recommendation for the third-line and subsequent treatment of patients with FL. It also modified guidance for treatment of patients with CAR T-cell therapy, adding “Tisagenlecleucel is also indicated for patients with relapsed or refractory FL after two or more lines of systemic therapy,” to the first sub-bullet under patient selection.
This change came from the phase 2 ELARA trial19 which evaluated tisagenlecleucel in adult patients with relapsed/refractory FL after ≥2 lines of therapy or who relapsed after autologous stem cell transplantation. The primary end point was CRR and ORR was a secondary end point.
The trial19 enrolled 98 patients, 97 of whom received tisagenlecleucel. Of 94 patients evaluable for efficacy, the CRR rate was 69.1% (95% CI, 77.5–92.4) and ORR was 86.2% (95% CI, 77.5–92.4).19
Umbralisib: The Version 3.2022 update9 included changes concerning umbralisib within the sections covering for FL, MZL, and special considerations for the use of small molecule inhibitors. The drug had been under FDA investigation into whether treatment led to an increased risk of death. The investigation focused on results of the phase 3 UNITYCLL trial and culminated in the FDA withdrawing its approval of umbralisib on June 1, 2022, to treat FL and MZL, after previously granting the drug accelerated approval in 2021.20
Venetoclax: The Version 1.2022 update9 changed the combination of venetoclax + ibrutinib from a category 2B to a category 2A recommended regimen, useful in certain circumstances, for second-line and subsequent therapy in MCL. In addition, venetoclax on its own was added a category 2B recommendation, useful in certain circumstances, for the second-line treatment of patients with MCL.
A phase 2 study21 examined daily oral ibrutinib + venetoclax in 24 patients with either relapsed or refractory MCL (n=23) or previously untreated MCL (n=1). The primary end point was CRR at week 16. The CRR according to computed tomography at week 16 was 42%, which was higher than the historical CRR of 9% with ibrutinib alone (P <.001). Overall, the study found that 78% of patients who experienced a response to venetoclax + ibrutinib were estimated to have an ongoing response at 15 months.21
The addition of venetoclax as a category 2B recommendation came from a study22 of 106 patients that demonstrated safety and efficacy of venetoclax in relapsed or refractory NHL. Findings from this phase 1 study22 showed that venetoclax achieved responses across all NHL subtypes, with an ORR of 44% and median PFS of 5.4 months (95% CI, 3.5-8.4). For patients with MCL, these results were higher, with an ORR of 75% and median PFS of 14 months. The estimated overall survival at 12 months was 70% for all patients and 82% for patients with MCL.22
Guidelines also note that patients with MCL face a high risk of tumor lysis syndrome (TLS), and clinicians should monitor dosage given to reduce the risk of TLS.9
Conclusion
Due to the variability in severity of subtypes, B-cell lymphomas remain a challenge to treat effectively. The NCCN Guidelines are a valuable addition to a clinician’s toolbox and help ensure patients receive the safest and most effective treatments available. NCCN maintains all Guidelines on its website, which includes a section on recently updated Guidelines.23,24
Due the ongoing changing nature of science and rapidly growing literature, it is crucial that those tasked with treating patients remain current on best practices and approved or newly recommended treatment plans.
References
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2. Zahid U, Akbar F, Amaraneni A, et al. A review of autologous stem cell transplantation in lymphoma. Curr Hematol Malig Rep. 2017;12(3):217-226. doi:10.1007/s11899-017-0382-1
3. Liu Y, Barta SK. Diffuse large B-cell lymphoma: 2019 update on diagnosis, risk stratification, and treatment. Am J Hematol. 2019;94(5):604-616. doi:10.1002/ajh.25460
4. Freedman A, Jacobsen E. Follicular lymphoma: 2020 update on diagnosis and management. Am J Hematol. 2020;95(3):316-327. doi:10.1002/ajh.25696
5. Maddocks K. Update on mantle cell lymphoma. Blood. 2018;132(16):1647-1656. doi:10.1182/blood-2018-03-791392
6. Vose JM. Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management [published correction appears in Am J Hematol. 2018 May;93(5):E134]. Am J Hematol. 2017;92(8):806-813. doi:10.1002/ajh.24797
7. Lymphoma Research Foundation. Understanding lymphoma: marginal zone lymphoma. Accessed June 8, 2022. https://lymphoma.org/wp-content/uploads/2022/05/LRF_Marginal_Zone_Lymphoma_Fact_Sheet.pdf
8. National Comprehensive Cancer Network. Development and update of guidelines. Accessed June 8, 2022. https://www.nccn.org/guidelines/guidelines-process/development-and-update-of-guidelines
9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): B-Cell Lymphomas. Accessed June 8, 2022. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
10. Jacobson CA, Chavez JC, Sehgal AR, et al. Axicabtagene ciloleucel in relapsed or refractory indolent non-Hodgkin lymphoma (ZUMA-5): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2022;23(1):91-103. doi:10.1016/S1470-2045(21)00591-X
11. US Food and Drug Administration. FDA grants accelerated approval to axicabtagene ciloleucel for relapsed or refractory follicular lymphoma. March 8, 2021. Accessed June 8, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-axicabtagene-ciloleucel-relapsedor-refractory-follicular-lymphoma
12. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017 Dec 28;377(26):2531-2544. doi: 10.1056/NEJMoa1707447
13. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1–2 trial. Lancet Oncol. 2019 Jan;20(1):31-42. doi:10.1016/S1470-2045(18)30864-7
14 US Food and Drug Administration. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. April 1, 2022. Accessed June 8, 2022. https://www.fda.gov/drugs/resources-information-approved-drugs/fdaapproves-axicabtagene-ciloleucel-second-line-treatment-large-b-cell-lymphoma
15. Locke FL, Miklos DB, Jacobson CA, et al; All Zuma-7 Investigators and Contributing Kite Members. Axicabtagene ciloleucel as second-line therapy for large b-cell lymphoma. N Engl J Med. 2022;386(7):640-654. doi:10.1056/NEJMoa2116133
16. Le Gouill S, Thieblemont C, Oberic L, et al; LYSA Group. Rituximab after autologous stem-Cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017;377(13):1250-1260. doi:10.1056/NEJMoa1701769
17. Guile SL, Thieblemont C, Oberic L, et al. R-DHA-oxaliplatin before autologous stem cell transplantation prolongs PFS and OS as compared to R-DHA-carboplatin and R-DHA-cisplatin in patients with mantle cell lymphoma, a subgroup analysis of the LyMa trial. Blood. 2017;130(suppl 1): 1496. doi:10.1182/blood.V130.Suppl_1.1496.1496
18. Morschhauser F, Tilly H, Chaidos A, et al. Tazemetostat for patients with relapsed or refractory follicular lymphoma: an open-label, single-arm, multicentre, phase 2 trial. Lancet Oncol. 2020;21(11):1433-1442. doi:10.1016/S1470-2045(20)30441-1
19. Fowler NH, Dickinson M, Dreyling M, et al. Tisagenlecleucel in adult relapsed or refractory follicular lymphoma: the phase 2 ELARA trial. Nat Med. 2022 Feb;28(2):325-332. doi:10.1038/s41591-021-01622-0
20. US Food and Drug Administration. FDA approval of lymphoma medicine Ukoniq (umbralisib) is withdrawn due to safety concerns. June 1, 2022. Accessed June 8, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/fda-approvallymphoma-medicine-ukoniq-umbralisib-withdrawn-due-safety-concerns
21. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211-1223. doi:10.1056/NEJMoa1715519
22. Davids MS, Roberts AW, Seymour JF, et al. Phase I First-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35(8):826-833. doi:10.1200/JCO.2016.70.4320
23. National Comprehensive Cancer Network. NCCN Guidelines: treatment by cancer type. Accessed June 8, 2022. https://www.nccn.org/guidelines/category_1
24. National Comprehensive Cancer Network. Recently updated guidelines. Accessed June 8, 2022. https://www.nccn.org/guidelines/recently-publishedguidelines
