NCCN Guidelines® Insights: B-Cell Lymphomas, Version 5.2021

Featured Updates to the NCCN Guidelines

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  • 1 Memorial Sloan Kettering Cancer Center;
  • | 2 Robert H. Lurie Comprehensive Cancer Center of Northwestern University;
  • | 3 University of Wisconsin Carbone Cancer Center;
  • | 4 The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute;
  • | 5 Massachusetts General Hospital Cancer Center;
  • | 6 Stanford Cancer Institute;
  • | 7 Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;
  • | 8 City of Hope National Medical Center;
  • | 9 Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;
  • | 10 UCLA Jonsson Comprehensive Cancer Center;
  • | 11 Vanderbilt-Ingram Cancer Center;
  • | 12 UCSF Helen Diller Family Comprehensive Cancer Center;
  • | 13 The University of Texas MD Anderson Cancer Center;
  • | 14 Huntsman Cancer Institute at the University of Utah;
  • | 15 Mayo Clinic Cancer Center;
  • | 16 Roswell Park Comprehensive Cancer Center;
  • | 17 University of Michigan Rogel Cancer Center;
  • | 18 Duke Cancer Institute;
  • | 19 Fox Chase Cancer Center;
  • | 20 Consultant;
  • | 21 Dana-Farber/Brigham and Women’s Cancer Center;
  • | 22 Abramson Cancer Center at the University of Pennsylvania;
  • | 23 O'Neal Comprehensive Cancer Center at UAB;
  • | 24 University of Colorado Cancer Center;
  • | 25 UT Southwestern Simmons Comprehensive Cancer Center;
  • | 26 UC San Diego Moores Cancer Center;
  • | 27 Yale Cancer Center/Smilow Cancer Hospital;
  • | 28 Moffitt Cancer Center;
  • | 29 Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;
  • | 30 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;
  • | 31 UC Davis Comprehensive Cancer Center;
  • | 32 Fred & Pamela Buffett Cancer Center; and
  • | 33 National Comprehensive Cancer Network.

In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody–drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1–mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

NCCN: Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Medicine (ACCME): NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nursing (ANCC): NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacy (ACPE): NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-21-014-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/90850; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail education@nccn.org.

Release date: November 10, 2021; Expiration date: November 10, 2022

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to the NCCN Guidelines for B-Cell Lymphomas

  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for B-Cell Lymphomas

Disclosure of Relevant Financial Relationships

The NCCN staff listed below discloses no relevant financial relationships:

Kerrin M. Rosenthal, MA; Kimberly Callan, MS; Genevieve Emberger Hartzman, MA; Erin Hesler; Kristina M. Gregory, RN, MSN, OCN; Rashmi Kumar, PhD; Karen Kanefield; and Kathy Smith.

Individuals Who Provided Content Development and/or Authorship Assistance:

Andrew D. Zelenetz, MD, PhD, Panel Chair, has disclosed receiving consulting fees from AbbVie, Inc., Amgen Inc., AstraZeneca Pharmaceuticals LP, BeiGene, Celgene Corporation, Genentech, Inc., Janssen Pharmaceutica Products, LP, MorphoSys AG, Novartis Pharmaceuticals Corporation, and Adaptive Biotech; serving as a scientific advisor for BeiGene and Bristol-Myers Squibb/Celgene/Juno; and receiving grant/research support from BeiGene, MEI Pharma Inc., and Roche Laboratories, Inc.

Leo I. Gordon, MD, Panel Vice Chair, has disclosed no relevant financial relationships.

Julie E. Chang, MD, Panel Member, has disclosed no relevant financial relationships.

Beth Christian, MD, Panel Member, has disclosed receiving grant/research support from Acerta Pharma, Celgene Corporation, Genentech, Inc., Genentech, Inc., Immunomedics, Inc., Janssen Pharmaceutica Products, LP, Merck & Co., Inc., Millennium Pharmaceuticals, Inc., Triphase, Seattle Genetics, Inc., and Teva Pharmaceutical Industries Ltd; receiving consulting fees from AstraZeneca Pharmaceuticals LP, Genentech, Inc., MorphoSys AG, Verastem Oncology, and Seattle Genetics, Inc.

Boyu Hu, MD, Panel Member, has disclosed receiving grant/research support from Celgene Corporation, Genentech, Inc., and CRISPR Therapeutics; and consulting fees from TG Therapeutics.

Megan Lim, MD, PhD, Panel Member, has disclosed receiving consulting fees from EUSA and Thermofisher, Inc.; and honoraria from Seattle Genetics, Inc.

Stephen D. Smith, MD, Panel Member, has disclosed receiving grant/research support from Acerta Pharma, AstraZeneca Pharmaceuticals LP, Bayer HealthCare, BeiGene, Genentech, Inc., Incyte Corporation, Merck & Co., Inc., Denovo Biopharma, Pharmacyclics, and Portola Pharmaceuticals, Inc.; receiving consulting fees from AstraZeneca Pharmaceuticals LP, Genentech, Inc., Karyopharm Therapeutics, Kite Pharma, and Millennium Pharmaceuticals, Inc.; and serving as a scientific advisor for BeiGene and ADC Therapeutics. Their spouse receives grant/research support from Bristol-Myers Squibb, Ayala, and Ignyta; and consulting fees from Bristol-Myers Squibb and Ayala.

Mary A. Dwyer, MS, CGC, Director, Guidelines Operations, NCCN, has disclosed that she has no relevant financial relationships.

Hema Sundar, PhD, Manager, Global Clinical Content, NCCN, has disclosed no relevant financial relationships.

To view all of the conflicts of interest for the NCCN Guidelines Panel, go to https://www.nccn.org/guidelines/guidelines-panels-and-disclosure

This activity is supported by educational grants from Agios Pharmaceuticals; AstraZeneca; Clovis Oncology, Inc.; Daiichi Sankyo; Eisai; Epizyme Inc.; Novartis; and Pharmacyclics LLC, an AbbVie Company and Janssen Biotech, Inc., administered by Janssen Scientific Affairs, LLC. This activity is supported by an independent medical education grant from Bristol-Myers Squibb, and Regeneron Pharmaceuticals, Inc. and Sanofi Genzyme. This activity is supported by an independent medical educational grant from Mylan Inc. This activity is supported by a medical education grant from Karyopharm Therapeutics. This activity is supported by an independent educational grant from AbbVie.

Overview

B-cell non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders characterized by a diverse clinical course, ranging from indolent to highly aggressive. Diffuse large B-cell lymphoma (DLBCL; 32%), follicular lymphoma (FL; 17%), marginal zone lymphoma (MZL; 8%), and mantle cell lymphoma (MCL; 4%) constitute the majority of B-cell lymphoma subtypes.1,2

In recent years, a variety of targeted therapies, such as BTK inhibitors, PI3K inhibitors, EZH2 inhibitors, antibody–drug conjugates, anti-CD19 CAR T-cell therapies, and other CD19-directed targeted therapies, have emerged as effective treatment options for relapsed/refractory (R/R) disease in various subtypes of B-cell lymphomas. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for B-Cell Lymphomas for the treatment of R/R disease.

Follicular Lymphoma

FL is the most common subtype of B-cell NHL and approximately 90% of patients have a t(14;18) translocation. FL is divided into 3 grades (FL1-2, FL3A, and FL3B).3 FL1-2 is managed according to the treatment recommendations outlined for FL. FL3B is commonly treated as DLBCL. The management of FL3A is controversial and treatment should be individualized. Frequently, patients with disease relapse or progression of disease (POD) after first-line therapy will benefit from a second period of observation. Systemic therapy options for patients with FL at first relapse with high tumor burden or symptomatic disease include alternate non–cross-resistant anti-CD20 monoclonal antibody (mAb)–based chemoimmunotherapy or a combination of lenalidomide and rituximab.4 Rituximab monotherapy may be appropriate for patients with late relapse, particularly if disease burden is low.5 However, until recently no FDA-approved treatment options were available specifically for R/R FL in the third-line setting and beyond.6

POD within ≤24 months of diagnosis (POD24) and failure to achieve event-free survival at 12 months (EFS12) after initial treatment with chemoimmunotherapy have been identified as poor prognostic indicators of overall survival (OS).79 Patients with POD24 after first-line therapy should be considered for treatment with lenalidomide-based regimens, novel approaches including clinical trials, or referral for consideration of autologous hematopoietic cell transplant (HCT).1012

PI3K Inhibitors

Copanlisib (PI3K-α/δ), duvelisib (PI3K-γ/δ), and idelalisib (PI3K-δ) are the FDA-approved PI3K inhibitors for R/R FL after 2 prior therapies. The dual PI3K-δ/CK1-ε inhibitor umbralisib was recently FDA-approved for R/R FL after 3 prior therapies.

In phase II studies, copanlisib, duvelisib, and idelalisib have resulted in overall response rates (ORRs) of 59%, 42%, and 56%, respectively (Table 1).1316 Idelalisib and copanlisib have also been shown to be effective for high-risk patients with disease relapse ≤2 years after first-line therapy. Infections, diarrhea, colitis, hepatotoxicity, and transient cytopenias are common treatment-emergent adverse events (TEAEs), and the various PI3K inhibitors exhibit differences in their toxicity profiles (Table 2), depending on the PI3K isoform inhibition. For example, copanlisib is also associated with hyperglycemia and hypertension but a lower incidence of diarrhea.

Table 1.

PI3K Inhibitors in R/R FL and MZL: Efficacy Data From Phase II Trials

Table 1.
Table 2.

PI3K Inhibitors in R/R FL and MZL: Safety Data From Phase II Trials

Table 2.

In a multicenter phase IIb study (UNITY-NHL) of 208 patients with R/R indolent NHL (MZL, n=69; FL, n=117; small lymphocytic lymphoma, n=22) with a median follow-up of 27.5 months, umbralisib resulted in an overall response rate of 45% (5% complete response [CR] and 40% partial response [PR]) among patients with FL.17 All patients had received ≥2 prior lines of therapy including anti-CD20 mAb and an alkylating agent. The median progression-free survival (PFS) was 11 months and the estimated 2-year PFS rate was 18%.

Umbralisib at a dose of 800 mg once daily has a relatively favorable toxicity profile among PI3K inhibitors and was also associated with a lower incidence of treatment discontinuations related to TEAEs. Grade ≥3 TEAEs, including neutropenia, diarrhea, and increased levels of alanine transaminase and aspartate aminotransferase, were reported in 12%, 10%, 6.7%, and 7.2% of the patients, respectively (Table 2). In comparison with the other 3 available PI3K inhibitors, umbralisib had a better toxicity profile and was also associated with a lower incidence of treatment discontinuations due to TEAEs. In the UNITY-NHL trial, discontinuations related to TEAEs occurred in 15% of patients compared with 21%, 31%, and 28% discontinuation rates reported with copanlisib, duvelisib, and idelalisib, respectively.

Copanlisib, duvelisib, and idelalisib are included as options for R/R FL after ≥2 prior therapies in fit patients (FOLL-B, 3 of 5, opposite page). Umbralisib is included as an option for R/R FL after ≥3 prior therapies in fit as well as elderly or infirm patients (FOLL-B, 3 of 5, opposite page).

Tazemetostat

Tazemetostat, an EZH2 inhibitor, is FDA-approved for EZH2 mutation–positive R/R FL after ≥2 prior systemic therapies, and for those with R/R FL who have no satisfactory alternative treatment options.

In a phase II trial of 99 patients with R/R FL (45 patients with EZH2-mutated [EZH2mut] FL; 54 patients with wild-type EZH2 (EZH2wt) after ≥2 systemic therapies, including PI3K inhibitor or an immunomodulatory drug, tazemetostat resulted in an ORR of 69% (13% CR; 56% PR; 29% stable disease) in the EZH2mut cohort (median follow-up was 22 months) and 35% (4% CR; 31% PR; 33% stable disease) in the EZH2wt cohort.18 With a median follow-up of 36 months, the median PFS was 14 months and 11 months for EZH2mut and EZH2wt cohorts, respectively. The median OS was not reached in either cohort. The ORR was higher for patients with EZH2mut FL than those with EZH2wt FL in all subgroups: POD24 (63% vs 25%), double-refractory disease (no objective response to rituximab-based regimen and relapse within 6 months or refractory to alkylating agent–based chemotherapy; 78% vs 27%), and refractory to rituximab (no objective response to rituximab-based regimens or progressive disease within 6 months of completion of rituximab-based therapy; 59% vs 31%). Notably, this study was not designed to compare the outcomes based on the EZH2 mutation status.

Tazemetostat had a favorable toxicity profile, with thrombocytopenia (3%), neutropenia (3%), and anemia (2%) being the most common grade ≥3 adverse events and serious TEAEs reported in only 4% of patients.

Tazemetostat is included as an option for third-line and subsequent therapy for patients with EZH2mut R/R FL (FOLL-B, 3 of 5, page 1220). Testing for EZH2 mutation status is feasible using paraffin-embedded tissue, and should be performed by an approved sequencing assay. Tazemetostat is also recommended as an option for R/R FL (EZH2wt or unknown) in patients who have no satisfactory alternative treatment options (FOLL-B, 3 of 5, page 1220).

CAR T-Cell Therapy

Axicabtagene ciloleucel was FDA-approved for the treatment of R/R FL following ≥2 lines of systemic therapy based on the results of the ZUMA-5 trial.

ZUMA-5 was a phase II trial evaluating the efficacy of axicabtagene ciloleucel in 146 patients with R/R indolent lymphoma (FL, n=124; MZL, n=22) after ≥2 prior lines of systemic therapy.19 Treatment with axicabtagene ciloleucel resulted in an ORR of 92% (76% CR) among the 104 patients with indolent lymphoma evaluable for efficacy. The ORR was 94% (80% CR) among the 84 patients with FL (median age was 61 years [range, 34–79 years]; 38% of patients had an ECOG performance status of 1; 86% of patients had stage III/IV disease).19 With a median follow-up of 18 months, the median PFS and OS were not reached for all patients on study. The estimated 12-month PFS and OS were 74% and 93%, respectively. In an updated analysis that stratified patients with FL based on the presence or absence of POD24, treatment with axicabtagene ciloleucel resulted in similar ORR in the 2 cohorts (92%) with a CR rate of 75% in patients with POD24 and 86% in patients without POD24.20 With a median follow-up of 23 months, the median PFS and OS were not reached in both groups. The estimated 18-month PFS rates were 55% and 84% for patients with and without POD24, respectively. The corresponding OS rates were 85% and 94%, respectively.

Neutropenia and anemia were the most common grade ≥3 adverse events, reported in 33% and 23% of patients, respectively. Grade ≥3 cytokine release syndrome (CRS) and neurologic events were reported in 6% and 15% of patients, respectively. Notably, 3 deaths occurred in the study, with 1 due to CRS related to treatment with axicabtagene ciloleucel and the other 2 due to aortic dissection and coccidiomycosis infection unrelated to treatment with axicabtagene ciloleucel.

Axicabtagene ciloleucel is included as an option for third-line and subsequent therapy for R/R FL in fit patients (FOLL-B, 3 of 5, page 1220).

Marginal Zone Lymphomas

MZLs originate in the marginal zone of lymphoid follicles found in the mucosa-associated lymphoid tissues (MALT), spleen, and lymph nodes. Extranodal MZLs of MALT (MALT lymphomas), nodal MZL (NMZL), and splenic MZL (SMZL) are the 3 distinct subtypes of MZLs. MZLs represent a clinical challenge in that the heterogeneity and relative rarity of individual subtypes has largely precluded the use of conventional treatment approach across all subtypes. Alternate non–cross-resistant chemoimmunotherapy regimens, rituximab monotherapy, and ibritumomab tiuxetan are included as options for R/R disease in patients with indications for treatment. In recent years, improved understanding of the complex pathobiology of MZLs has resulted in the development of novel treatment options for R/R disease.

BTK Inhibitors

Ibrutinib and zanubrutinib are the 2 FDA-approved BTK inhibitors for the treatment of R/R MZL.21,22

In a multicenter phase II study of 60 patients with R/R MZL (after prior therapy with an anti–CD20-mAb–based regimen), ibrutinib resulted in an ORR of 48% (50% for extranodal MZL, 54% for splenic MZL, and 41% for nodal MZL).21 After a median follow-up of 19 months, the median PFS was 14 months. The median PFS by subtype was 14 months for extranodal MZL, 19 months for SMZL, and 8 months for NMZL. The median OS has not been reached and the 18-month estimated OS rate was 81%. Infections (19%), anemia (14%), pneumonia (8%), and fatigue (6%) were the most common grade ≥3 adverse events. Bleeding events (all were grades 1–2) were reported in 59% of patients, and major bleeding (grade 5) occurred only in 2% of patients.

Zanubrutinib was recently FDA-approved for the treatment of R/R MZL after at least one prior anti–CD20-mAB–based regimen, based on the results of the MAGNOLIA trial. The phase II multicenter MAGNOLIA trial included 68 patients with R/R MZL after ≥1 line of therapy (including ≥1 anti–CD20-mAb–based regimen).22 At a median follow-up of 16 months, zanubrutinib resulted in an ORR of 68% (as assessed by independent review committee; 26% CR) among the 65 patients evaluable for efficacy. The median PFS was not reached and the PFS rate was 83% at both 12 and 15 months. Responses were observed in all subtypes with an ORR of 64% (40% CR), 76% (20% CR), 67% (8% CR), and 50% (25% CR) in extranodal, nodal, splenic, and indeterminate subtypes, respectively. Infections (46%), diarrhea (22%), neutropenia (13%), thrombocytopenia (13%), atrial fibrillation/flutter (3%), and hypertension (3%) were the most common all-grade adverse events. Bleeding events were reported in 37% of patients, but there were no events of major hemorrhages. Grade ≥3 neutropenia and infections were reported in 10% and 16% of patients, respectively.

Ibrutinib and zanubrutinib are included as options for preferred regimens for second-line and subsequent therapy in fit as well as elderly or infirm patients with R/R MZL (MZL-A, 2 of 4, page 1221). Zanubrutinib may be considered as an option for patients with R/R MZL with contraindications or intolerance to ibrutinib.23,24

PI3K Inhibitors

Umbralisib is the only PI3K inhibitor that is FDA-approved for MZL. In the UNITY-NHL trial described earlier that included 69 patients with relapsed/refractory indolent MZL after ≥1 prior line of therapy with anti-CD20 mAb based regimen, umbralisib resulted in an ORR of 49% (16% CR; 33% PR).17 The ORRs were comparable across all subtypes (45% for both MALT lymphoma and splenic MZL; 60% for nodal MZL). With a median follow-up of 28 months, median PFS was not reached and the estimated 2-year PFS rate was 51%. Umbralisib was also associated with better toxicity profile than the other 3 available PI3K inhibitors (Table 2) and it was associated with a low incidence of discontinuations related to TEAEs (as described earlier).

Umbralisib is included as an option for second-line and subsequent therapy in fit as well as elderly or infirm patients with R/R MZL after at least one prior anti–CD20-mAB–based regimen (MZL-A, 2 of 4, page 1221).

Other P13K inhibitors (copanlisib, duvelisib, and idelalisib) have demonstrated activity in R/R MZL resulting in ORRs of 78%, 39%, and 47%, respectively (Table 1) and are included as options for third-line therapy in fit patients with R/R MZL after 2 prior therapies (MZL-A, 2 of 4, page 1221).14,16,25 However, these are not FDA-approved for the treatment of R/R MZL.

Mantle Cell Lymphoma

MCL is characterized by the reciprocal chromosomal translocation t(11;14) and is thought to possess the unfavorable characteristics of both indolent and aggressive B-cell NHL subtypes owing to the incurability of disease with conventional chemoimmunotherapy and a typically more aggressive disease course compared with indolent lymphomas.26 Aggressive induction with a cytarabine-based chemoimmunotherapy followed by consolidation with autologous HCT and rituximab maintenance is recommended for fit younger patients with MCL who are eligible for transplant. Rituximab maintenance after autologous HCT is associated with survival benefit in patients who achieve a CR or a very good PR (≥75% disease reduction) after induction chemoimmunotherapy.2729 The presence of TP53 mutation, however, is associated with poor prognosis in younger patients (inferior responses to both induction chemotherapy and high-dose chemotherapy followed by HCT), and patients with TP53 mutation should be considered for clinical trials investigating novel agents.30 Rituximab maintenance following less aggressive induction chemoimmunotherapy (eg, R-CHOP or modified R-HyperCVAD) is recommended for patients not eligible for transplant.31,32 Data from a prospective, randomized phase II trial suggest that there is no benefit to rituximab maintenance after induction therapy with the bendamustine-based regimen,33 whereas rituximab maintenance following bortezomib-based regimens has not been evaluated in clinical trials.

BTK inhibitors (acalabrutinib, ibrutinib, or zanubrutinib; all 3 are FDA-approved for the treatment of R/R MCL),3438 lenalidomide + rituximab,39 bortezomib ± rituximab,40,41 and bendamustine-based regimens (bendamustine + rituximab or RBAC [rituximab/bendamustine/cytarabine])42,43 are appropriate options for R/R MCL. Results from clinical studies also suggest that the use of ibrutinib-based combination regimens (ibrutinib + rituximab, ibrutinib + venetoclax, ibrutinib + lenalidomide + rituximab) may be better than ibrutinib monotherapy.4446

Early treatment failure after first-line therapy (disease relapse and initiation of second-line therapy within 12 months after up-front autologous HCT) and POD24 are associated with a poor prognosis. Additionally, patients with POD after ≥2 lines of therapy are considered a high-risk group with a shortened median time to subsequent relapse.4749 In the MANTLE-FIRST study that evaluated the clinical outcomes of patients with R/R MCL following cytarabine-based induction chemoimmunotherapy, ibrutinib was particularly effective for refractory disease to induction chemoimmunotherapy or early POD, and bendamustine-based regimens had similar efficacy to ibrutinib for late POD.50 However, longer follow-up is needed to confirm these findings from this retrospective study. Limited data from retrospective studies suggest that venetoclax monotherapy and the RBAC regimen result in favorable response rates in patients with R/R MCL after BTK inhibitor therapy.43,5153 However, the optimal second-line therapy for management of R/R MCL after BTK inhibitor therapy has not been established in prospective studies.48,54,55

Allogeneic HCT is a potentially curative option for eligible patients with R/R disease that is in remission following second-line therapy.56 However, with the recent approval of CAR T-cell therapy for R/R MCL, in most NCCN Member Institutions allogeneic HCT has been deferred to disease relapse following multiple prior therapies (including disease relapse following CAR T-cell therapy). Data on the outcomes of allogeneic HCT following CAR T-cell therapy are not yet available.

CAR T-Cell Therapy

Brexucabtagene autoleucel was recently FDA-approved for the treatment of R/R MCL after chemoimmunotherapy and BTK inhibitor therapy based on the results of the ZUMA-2 trial.57

ZUMA-2 included 74 patients with R/R MCL who had been treated with up to 5 prior lines of therapy, including anthracycline-based or bendamustine-based chemotherapy, anti-CD20 mAb, and BTK inhibitor. Brexucabtagene autoleucel resulted in an ORR of 85% (59% CR).57 The ORRs were consistently higher among patients with poor prognostic features, including pleomorphic or blastoid morphology, TP53 mutation, or Ki-67 index ≥50%. With a median follow-up of 12 months, the estimated 12-month PFS and OS rates were 61% and 83%, respectively.

Grade ≥3 cytopenias and infections were the most common adverse events, reported in 94% and 32% of patients, respectively. Grade ≥3 CRS and neurologic events occurred in 15% and 31% of patients, respectively.

Brexucabtagene autoleucel is included as an option for third-line therapy for fit patients with R/R MCL after prior treatment with chemoimmunotherapy and BTK inhibitor (MANT-A, 2 of 4, page 1222).

Diffuse Large B-Cell Lymphoma

DLBCL is the most common subtype of mature B-cell NHL. Gene expression profiling has identified distinct subtypes within DLBCL based on cell of origin: germinal center B-cell (GCB) subtype and activated B-cell (ABC) subtype.3,58 GCB DLBCL is associated with an improved outcome compared with ABC DLBCL in patients treated with conventional chemoimmunotherapy with R-CHOP. Currently, the up-front treatment approach remains the same for both GCB and ABC subtypes. Chemoimmunotherapy followed by high-dose therapy with autologous stem cell rescue (HDT/ASCR) is the appropriate treatment for R/R DLBCL that is chemotherapy-sensitive at relapse, in patients who are candidates for transplant, and outcomes differ based on the response to initial therapy, timing of relapse, and opportunity to undergo HDT/ASCR.59 Optimal management for patients who are not candidates for transplant has not been established, and therefore enrollment in a clinical trial is preferred for these patients. Gemcitabine and oxaliplatin (± rituximab)60 and polatuzumab vedotin (monotherapy or in combination with bendamustine ± rituximab)61,62 are appropriate chemoimmunotherapy treatment options for R/R disease in patients who are not candidates for transplant. Other appropriate nonchemotherapy options for transplant-ineligible patients include lenalidomide (± rituximab)63,64 and ibrutinib65 (particularly for patients with non-GCB DLBCL) or tafasitamab (anti-CD19 mAb).66 Brentuximab vedotin can be considered as an option for patients with CD30-positive DLBCL.67

The prognosis, however, remains poor for patients with refractory disease after ≥2 second-line therapy regimens.68,69 Anti-CD19 CAR T-cell therapy has emerged as an effective treatment option for this group of patients. Axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel are the 3 anti-CD19 CAR T-cell therapies that are FDA-approved for R/R DLBCL (after ≥2 prior systemic therapy regimens, regardless of eligibility for transplant).7072 More recently, tafasitamab (anti-CD19 mAb) + lenalidomide, loncastuximab tesirine (anti-CD19 antibody–drug conjugate), polatuzumab vedotin (anti-CD79B antibody–drug conjugate) in combination with bendamustine and rituximab, and selinexor (selective small molecule inhibitor of XPO1-mediated nuclear export) have been FDA-approved for R/R DLBCL.61,62,66,73,74 Recent clinical trial data support the use of tafasitamab + lenalidomide as the preferred treatment option for transplant-ineligible patients with R/R DLBCL.

Tafasitamab + Lenalidomide

In a multicenter, single-arm phase II trial (L-MIND) of 156 patients with R/R DLBCL after at least one prior systemic therapy (but no more than 3 lines of prior therapy) and ineligible for transplant, the combination of tafasitamab + lenalidomide (12 cycles followed by tafasitamab monotherapy for patients with stable disease given until POD) resulted in an ORR of 60% (43% CR; 18% PR).66 At a median follow-up of 17 months, the median PFS was 12 months. The estimated 12- and 18-month PFS rates were 50% and 46%, respectively. At a median follow-up of 20 months, the median OS was not reached. The estimated 12- and 18-month OS rates were 64% and 38%, respectively. Tafasitamab + lenalidomide also resulted in promising response rates in patients with GCB-DLBCL, suggesting activity for this combination that was irrespective of the cell of origin, in contrast to previous data of lenalidomide monotherapy for the treatment of relapsed/refractory DLBCL.64 However, a more definitive interpretation was not possible, because 27% of patients had undetermined cell of origin or the gene-expression profiling results were unevaluable in 60% of patients. Notably, patients with DLBCL refractory to first-line treatment were excluded from this study.

Neutropenia (48%), thrombocytopenia (17%), and febrile neutropenia (12%) were the most common grade ≥3 hematologic toxicities. Most nonhematologic adverse events were grade 1–2, with diarrhea (32%) and rash (27%) being the most common. The incidence and severity of treatment-related adverse events decreased upon discontinuation of lenalidomide after 12 cycles as per study protocol.

Tafasitamab in combination with lenalidomide is included as an option for second-line subsequent therapy for R/R DLBCL in patients who are not candidates for transplant (BCEL-C, 2 of 5, page 1223).

Loncastuximab Tesirine

In a multicenter, single-arm, phase II trial (LOTIS-2) of 145 patients with R/R DLBCL after ≥2 multiagent systemic therapy regimens (including high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements and primary mediastinal B-cell lymphoma), loncastuximab tesirine resulted in an ORR of 48% (24% CR; 24% PR).73 The median PFS, OS, and relapse-free survival were 5, 10, and 13 months, respectively. A subgroup of patients (10%) achieved an ORR of 47% (40% CR) to subsequent CD19-directed CAR T-cell therapy, and the results of another small study also showed that CD19 antigen loss after loncastuximab tesirine is not common.75 These findings suggest that the use of loncastuximab tesirine does not preclude subsequent responses to CD19-directed CAR T-cell therapy. However, these preliminary results need to be confirmed in a larger cohort of patients, and at this time it is unclear whether loncastuximab tesirine or any other CD19-directed therapy (eg, tafasitamab) would have a negative impact on the efficacy of subsequent anti-CD19 CAR T-cell therapy.

Neutropenia (26%) and thrombocytopenia (18%) were the most common grade ≥3 hematologic toxicities. Most nonhematologic adverse events were grade 1–2, with fatigue (26%), nausea (23%), cough (21%), and peripheral edema (19%) being the most common. Elevated levels of gamma-glutamyl transferase (24%), alkaline phosphatase (19%), aspartate aminotransferase (15%), and alanine aminotransferase (13%) were the most common grade 1–2 biochemical treatment-emergent adverse events, with elevated gamma-glutamyl transferase being the most common treatment-related adverse event leading to treatment discontinuation in 10% of patients.

Loncastuximab tesirine is included as an option for third-line subsequent therapy for R/R DLBCL, regardless of eligibility for transplant (BCEL-C, 2 of 5, page 1223).

Selinexor

In a multicenter, phase IIb study (SADAL) of heavily pretreated R/R DLBCL (2–5 lines of previous therapies and POD after autologous HCT or were not candidates for autologous HCT), selinexor resulted in an ORR of 29% (12% CR; 17% PR).74 In this study, 267 patients were randomly assigned, with 175 assigned to the 60-mg group and 92 assigned to the 100-mg group, which was discontinued due to the improved therapeutic window observed with 60 mg in a prespecified interim analysis (which included highly selected patients with refractory DLBCL who had to be off-treatment for at least 3 months since the end of their last therapy). The primary analysis included 127 of 175 the patients assigned to the 60-mg group. The median follow-up was 11 months. The median OS for all patients was 9 months (median OS not reached in patients with PR or better, and 18 months in patients with stable disease). In a subgroup analysis, selinexor resulted in an ORR of 34% (14% CR) in GCB-DLBCL compared with an ORR of 21% (10% CR) in the non-GCB DLBCL.

Thrombocytopenia (46%), neutropenia (25%), anemia (22%), fatigue (11%), hyponatremia (8%), and nausea (6%) were the most common grade 3–4 adverse events.

Selinexor is included as a third-line and subsequent therapy option for R/R DLBCL after ≥2 lines of systemic therapy, including in patients with POD after transplant or CAR T-cell therapy (BCEL-C, 2 of 5, page 1223).

Summary

The advent of novel targeted therapies represents a major paradigm shift in the management of patients with R/R B-cell lymphomas. Accurate diagnosis of the B-cell lymphoma subtype, appropriate patient selection, and effective management of unique spectrum of adverse events associated with targeted therapies should be an integral part of the management of patients with R/R disease. Referral of appropriate patients for participation in well-designed prospective clinical trials should be considered to facilitate the development novel chemotherapy-free treatment options.

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NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel's discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in anyway.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© National Comprehensive Cancer Network, Inc. 2021.

All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

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