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.
Physicians: 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.
Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.
Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-23-011-H01-P
PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until November 10, 2024. PAs should only claim credit commensurate with the extent of their participation.
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/92947; 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 email education@nccn.org.
Release date: November 10, 2023; Expiration date: November 10, 2024
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
None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
Individuals Who Provided Content Development and/or Authorship Assistance:
The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.
Leo I. Gordon, MD, Panel Vice Chair
Mary A. Dwyer, MS, CGC, Senior Director, Guidelines Coordinator, NCCN
Hema Sundar, PhD, Senior Director, Global Clinical Content, NCCN
The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.
Andrew D. Zelenetz, MD, PhD, Panel Chair, has disclosed serving as a consultant for AbbVie, Inc., Amgen Inc., Arvinas, AstraZeneca Pharmaceuticals LP, BeiGene, Bristol Myers Squibb, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Janssen Pharmaceutica Products, LP,MEI Pharma Inc.,MorphoSys AG, Novartis Pharmaceuticals Corporation, and Roche Laboratories, Inc.; serving as a scientific advisor for Adaptive Biotechnologies, ADC Therapeutics, Arvinas, and Eli Lilly and Company; and receiving grant/research support from BeiGene, Genentech, Inc., MEI Pharma Inc., and Roche Laboratories, Inc.
L. Elizabeth Budde, MD, PhD, Panel Member, has disclosed serving as a consultant for AbbVie, Inc., ADC Therapeutics, AstraZeneca Pharmaceuticals LP, Kite Pharma, and Roche Laboratories, Inc.; and receiving grant/research support from Amgen Inc., AstraZeneca Pharmaceuticals LP, Merck & Co., Inc., and Mustang Bio, Inc.
Boyu Hu, MD, Panel Member, has disclosed receiving grant/research support from Artiva Biotherapeutics, AstraZeneca Pharmaceuticals LP, Caribou Biosciences, Celgene Corporation, CRISPR Therapeutics, Genentech, Inc., MorphoSys AG, Newave Pharmaceutical Inc., and Repare Therapeutics Inc.; and serving as a consultant for ADC Therapeutics, Bristol Myers Squibb, Eli Lilly and Company, GenMab, ImmPACT Bio, Novartis Pharmaceuticals Corporation, and SeaGen.
Ann S. LaCasce, MD, MMSc, Panel Member, has disclosed serving as a consultant for Kite Pharma and SeaGen.
Praveen Ramakrishnan, MD, MS, Panel Member, has disclosed serving as a consultant for ADC Therapeutics, Bristol Myers Squibb, Cellectar Biosciences, Inc., Ipsen, Kite Pharma, Ono Pharmaceutical Co., Ltd., Pharmacyclics, and Rafael Pharmaceuticals, Inc./Cornerstone Pharmaceuticals; and receiving honoraria from ADC Therapeutics, Cellectar Biosciences, Ipsen, Ono Pharmaceutical Co., Ltd., and Pharmacyclics.
Erin Reid, MD, Panel Member, has disclosed receiving grant/research support from ADC Therapeutics, Aptose Biosciences Inc., and Millennium Pharmaceuticals, Inc.
Stephen D. Smith, MD, Panel Member, has received grant/research support from ADC Therapeutics, AstraZeneca Pharmaceuticals LP, Bayer HealthCare, BeiGene, Bristol Myers Squibb, DeNovo Biopharma, Enterome, Genentech, Inc., Incyte Corporation, Kymera Therapeutics,Merck & Co., Inc.,MorphoSys AG, Nanjing Pharmaceuticals, and Viracta Therapeutics; and serving as a consultant for AbbVie, Inc.,ADC Therapeutics,AstraZeneca Pharmaceuticals LP, BeiGene,Genentech, Inc., Incyte Corporation, KaryopharmTherapeutics, Kite Pharma, andNumab Therapeutics.
Jakub Svoboda, MD, Panel Member, has disclosed receiving grant/research support from Adaptive Biotechnologies, AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb, Incyte Corporation, Merck & Co., Inc., Pharmacyclics, and TG Therapeutics, Inc.; and served as a consultant for Adaptive Biotechnologies, AstraZeneca Pharmaceuticals LP, Atara Biotherapeutics, Bristol Myers Squibb, Incyte Corporation, and Pharmacyclics.
Lode J. Swinnen, MB, ChB, Panel Member, has disclosed receiving grant/research support from AbbVie, Inc.
Joseph Tuscano, MD, Panel Member, has disclosed receiving grant/research support fromAbbVie, Inc.,ADCTherapeutics, BristolMyers Squibb,Genentech, Inc., Pharmacyclics, and SeaGen.
Julie M. Vose, MD, MBA, Panel Member, has disclosed receiving honoraria from AbbVie, Inc., AstraZeneca Pharmaceuticals LP, Eli Lilly and Company, and MEI Pharma Inc.
To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels
This activity is supported by educational grants from AstraZeneca; Exact Sciences; Novartis; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Daiichi Sankyo. This activity is supported by independent medical education grants from Illumina, Inc. and Regeneron Pharmaceuticals, Inc.
Updates in the Treatment of Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is a heterogenous subtype of B-cell non-Hodgkin lymphoma. The 2022 WHO Classification of Haematolymphoid Tumours (WHO-HAEM5) and International Consensus Classification (ICC) reflect the heterogeneity of this entity and recognize the 3 subtypes of MCL with different clinicopathologic and molecular features: classic MCL (nodal or extranodal); leukemic and nonnodal MCL; and in situ mantle cell neoplasia (ISMCN).1,2 Classic MCL is SOX11-positive and immunoglobulin heavy chain variable gene (IGHV)–unmutated with a generally aggressive clinical course.3,4 The leukemic and nonnodal subtype is typically SOX11-negative and IGHV-mutated and has an indolent disease course.3,5,6
Genetic aberrations involving the TP53 gene are associated with poor prognosis. In younger patients, TP53 mutation is associated with inferior responses to both induction chemoimmunotherapy and high-dose therapy with autologous stem cell rescue [HDT/ASCR]).7–9 Therefore, TP53 sequencing is an essential prognostic test to identify classic MCL with TP53 mutation, and aids in the selection of appropriate treatment, particularly if up-front HDT/ASCR is anticipated.10
These NCCN Guidelines Insights discuss recent updates to the management of newly diagnosed and relapsed/refractory disease in the NCCN Clinical Practice Guidelines in Oncology for B-Cell Lymphomas.
Induction Therapy
Aggressive induction therapy with cytarabine-based chemoimmunotherapy followed by HDT/ASCR and rituximab maintenance has been the standard treatment approach for classic wild-type MCL in patients eligible for transplant.11–13 Less aggressive induction therapy followed by rituximab maintenance is recommended for patients who are not candidates for transplant.14
Induction therapy with alternating RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and RDHAP (rituximab, dexamethasone, cytarabine, and platinum [carboplatin, cisplatin, or oxaliplatin]) followed by HDT/ASCR was associated with significantly improved time to treatment failure (TTF) and overall survival (OS) compared with RCHOP followed by HDT/ASCR in younger patients with advanced-stage MCL.15
The TRIANGLE study, a 3-arm phase III randomized trial of ibrutinib-based induction and maintenance therapy, showed acceptable safety and efficacy in using ibrutinib as part of induction therapy in younger, transplant-eligible patients.16 A total of 870 patients aged <66 years with previously untreated stage II–IV MCL were randomized to 3 treatment arms (1:1:1). Rituximab maintenance was included in all 3 arms:
• Arm A: alternating RCHOP/RDHAP followed by HDT/ASCR and observation (n=288);
• Arm A+I: alternating RCHOP + ibrutinib/RDHAP followed by HDT/ASCR and 2-year maintenance therapy with ibrutinib (n=292); and
• Arm I: alternating RCHOP + ibrutinib/RDHAP followed by 2-year maintenance therapy with ibrutinib (n=290).
The overall responses rates (ORRs) were 94% (36% complete response [CR]) for arm A and 98% (45% CR) for the combined arms A+I/I. With a median follow-up of 31 months, the 3-year failure-free survival (FFS) rates were significantly higher for arm A+I and arm I than for arm A (88% and 86% vs 72%, respectively; P=.0008 for A+I vs A; P=.9979 for I vs A). The median OS was not reached in all 3 arms and the 3-year OS rates were 91%, 92%, and 86% for A+I, I, and A, respectively. The subgroup analyses demonstrated an FFS benefit with the addition of ibrutinib to induction and maintenance therapy in patients with p53 overexpression, but the impact of ibrutinib in patients with TP53 mutation was not reported. The addition of ibrutinib did not result in FFS benefit in patients with high Ki-67 proliferation index and blastoid variant. The toxicity profile of alternating RCHOP + ibrutinib/RDHAP was same as that of alternating RCHOP/RDHAP, with anemia (61% vs 59%), neutropenia (49% vs 47%), and thrombocytopenia (61% vs 59%) being the most common grade 3–5 hematologic toxicities.16
Based on the preliminary results of this study, alternating RCHOP + ibrutinib/RDHA + platinum (carboplatin, cisplatin, or oxaliplatin) is included as an option for aggressive induction therapy for patients with classical TP53-mutated MCL (MANT-3, page 1122) and classical TP53 wild-type MCL (MANT-4, page 1123). Long-term follow-up is needed to confirm the preliminary results. Head-to-head clinical trials in other B-cell malignancies have demonstrated a more favorable toxicity profile for acalabrutinib and zanubrutinib compared with ibrutinib, without compromising efficacy.17,18 Therefore, the substitution of ibrutinib with another covalent BTK inhibitor (acalabrutinib or zanubrutinib) in the induction phase of the TRIANGLE regimen is included with a category 2B recommendation (MANT-A 1 of 4, page 1126). However, acalabrutinib and zanubrutinib were not specifically evaluated in the TRIANGLE study.
The randomized phase III SHINE study compared ibrutinib in combination with bendamustine + rituximab (BR) and rituximab maintenance (n=261) versus BR and rituximab maintenance (n=262) in patients aged >65 years with previously untreated MCL.19 At a median follow-up of 85 months, the median PFS was superior for ibrutinib + BR compared with BR (81 vs 53 months; P=.01). Although this study met the primary end point of superior progression-free survival (PFS) in the ibrutinib arm, the OS was not different in the 2 treatment arms, specifically due to more deaths related to adverse events in the ibrutinib group compared with the placebo group (11% vs 6%). Based on these results, the panel consensus did not support the inclusion of ibrutinib + BR as an option for less aggressive induction therapy.
Maintenance Therapy With or Without HDT/ASCR
In the TRIANGLE study, at a median follow-up of 31 months, induction therapy with alternating RCHOP + ibrutinib/RDHAP followed by maintenance therapy with ibrutinib + rituximab resulted in superior FFS compared with induction therapy with alternating RCHOP/RDHAP followed by HDT/ASCR.16 Both of the ibrutinib-containing arms (A+I and I) were associated with superior FFS compared with transplant alone. FFS rates were not significantly different between the 2 ibrutinib-containing arms (A+I vs I). Grade 3–5 neutropenia was higher with A+I (44%) compared with ibrutinib (23%) or A alone (17%). However, this did not translate into a higher rate of infections in the A+I arm.
The results of the TRIANGLE study suggest that alternating RCHOP + ibrutinib/RDHAP followed by maintenance therapy with ibrutinib + rituximab is an effective induction therapy for patients aged <66 years, and consolidation therapy with HDT/ASCR could be avoided in this group of patients. Based on the preliminary results of this study, the NCCN Guidelines recommend maintenance therapy with ibrutinib + rituximab for patients with a CR following aggressive induction therapy (MANT-4, opposite page).16 It should be noted that the TRIANGLE study confirmed the benefit of ibrutinib maintenance after alternating RCHOP + ibrutinib/RDHAP, and that the value of ibrutinib maintenance after other aggressive induction therapy regimens has not been established. As with the induction phase, the substitution of ibrutinib with another covalent BTK inhibitor (acalabrutinib or zanubrutinib) in the maintenance phase of the TRIANGLE regimen is included with a category 2B recommendation (MANT-A 1 of 4, page 1126).
HDT/ASCR as first-line consolidation has demonstrated promising outcomes in a number of studies and is considered as an appropriate option for consolidation therapy in some NCCN Member Institutions.20–26 HDT/ASCR followed by maintenance therapy with ibrutinib + rituximab is also included as an option for patients with a CR following aggressive induction therapy (MANT-4, above).
Relapsed/Refractory Disease
Covalent BTK inhibitors (acalabrutinib and zanubrutinib) and lenalidomide + rituximab are the preferred treatment options for second-line therapy.27–30
Acalabrutinib and zanubrutinib are the 2 covalent BTK inhibitors that currently have an FDA-approved indication for treatment of relapsed or refractory (R/R) MCL. Ibrutinib received accelerated approval for R/R MCL in November 2013 based on the ORR from the phase II clinical trial.31 In April 2023, the accelerated approval status of ibrutinib for the treatment of R/R MCL was withdrawn following the results of the confirmatory phase III SHINE study.19 Although the panel acknowledged the change in the regulatory status of ibrutinib, the consensus was to continue listing ibrutinib monotherapy or ibrutinib in combination with rituximab as an option for second-line and subsequent therapy based on the safety and efficacy results from earlier phase II and III studies in R/R MCL.32–34 The panel consensus was to move ibrutinib ± rituximab to other recommended regimens based on the data from head-to-head clinical trials in other B-cell malignancies that have demonstrated a more favorable toxicity profile for acalabrutinib and zanubrutinib compared with ibrutinib without compromising efficacy.17,18
Limited data from retrospective studies suggest that RBAC500 (rituximab, bendamustine, and cytarabine) and venetoclax monotherapy result in favorable response rates in patients with R/R MCL after BTK inhibitor therapy.35–37 Acalabrutinib and zanubrutinib were shown to be effective in the treatment of patients with B-cell malignancies with intolerance to ibrutinib.38–40 However, they are not effective for ibrutinib-refractory MCL with BTK C481S mutations, because their mechanisms of resistance to acalabrutinib and zanubrutinib are similar to that of ibrutinib. Prior to the approval of CAR T-cell therapy (brexucabtagene autoleucel),41 the optimal treatment approach for R/R MCL after BTK inhibitor therapy had not been established in prospective studies, with many of the studies reporting poor outcomes for R/R MCL after prior BTK inhibitor therapy.42–44
Pirtobrutinib (a highly selective noncovalent BTK inhibitor of wild-type and C481S mutant BTK) received accelerated FDA approval for the treatment of R/R MCL based on the results of the multicenter, single-arm BRUIN trial that demonstrated the safety and efficacy of pirtobrutinib in patients with intolerance or disease that is refractory to prior covalent BTK inhibitors.45 In the extended follow-up of this study evaluating 90 patients with previously treated MCL (74 patients had discontinued prior BTK inhibitor therapy due to disease progression), the ORR as determined by the independent review committee (IRC) was 58% (20% CR).46 At a median follow-up of 12 months, the median duration of response was 22 months for the 52 patients with responding disease. The 12-month and estimated 18-month response rates were 57% and 52%, respectively. Grade ≥3 neutropenia was the most common treatment-related adverse event for the entire cohort of this study, which included 725 patients with various B-cell malignancies. Pirtobrutinib was also associated low rates of grade ≥3 hypertension (3%), hemorrhage (2%), and atrial fibrillation or flutter (1%).
The NCCN Guidelines recommend pirtobrutinib as an option for patients with MCL that is refractory to or progressing on second-line therapy (covalent BTK inhibitor-based regimens or fixed-duration regimens) and also for patients experiencing a partial response (PR) to second-line fixed-duration treatment regimens (MANT-6 and MANT-A 2 of 4, pages 1125 and 1127, respectively).
Consolidation with allogeneic hematopoietic cell transplant (HCT) is recommended in selected patients with R/R MCL that is in remission following second-line therapy with fixed-duration regimens (MANT-6, opposite page). Some of the panel members also felt that consolidation therapy with HDT/ASCR (if not previously received as part of induction therapy) is a reasonable treatment option for selected patients with classical TP53 wild-type MCL who have experienced a CR to second-line therapy with fixed-duration regimens (MANT-6, opposite page).47 Allogeneic HCT is also included as an option for patients with MCL that is refractory to or progressing on second-line and subsequent therapy (covalent BTK inhibitor-based regimens or fixed-duration regimens) and for disease relapse following CAR T-cell therapy, particularly if the disease is responsive to additional therapy (CR or PR to alternative second-line therapy) (MANT-6, opposite page).
Updates in the Treatment of R/R Follicular Lymphoma and Diffuse Large B-Cell Lymphoma
Follicular lymphoma (FL) is characterized by a variable remitting/relapsing disease course (indolent disease that can be observed until there are indications for treatment vs aggressive disease with indications for treatment requiring multiple lines of therapy). Alternate non–cross-resistant anti-CD20 monoclonal antibody (mAb)–based chemoimmunotherapy or a combination of lenalidomide and rituximab are the recommended second-line therapy options for FL at first relapse with high tumor burden or symptomatic disease.
Axicabtagene ciloleucel and tisagenlecleucel are the 2 anti-CD19 CAR T-cell therapies that are FDA approved for R/R FL after ≥2 prior systemic therapy regimens.48,49 Tazemetostat (EZH2 inhibitor) is FDA‐approved for R/R FL after ≥2 prior systemic therapies.50 Copanlisib is the only PI3K inhibitor that is FDA-approved for the treatment of R/R indolent lymphomas.51 Copanlisib and tazemetostat are also effective for patients with disease relapse ≤2 years after first-line therapy, and both are appropriate third-line treatment options for patients who are not eligible for CAR T-cell therapy.
Other PI3K inhibitors, including duvelisib, idelalisib, and umbralisib, had previously received accelerated FDA approval for R/R FL based on the improved ORR and PFS, as shown in preliminary clinical trials.52–55 However, there was later a voluntary withdrawal of this FDA indication for duvelisib, idelalisib, and umbralisib based on the substantial toxicity of PI3K inhibitors having a detrimental impact on OS in recent clinical trials; therefore, these agents are not recommended for the treatment of R/R FL.56
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with an aggressive clinical course. Chemoimmunotherapy followed by HDT/ASCR is the appropriate treatment for R/R DLBCL that is chemotherapy-sensitive in patients who are candidates for transplant.57–63
Antibody–drug conjugates (polatuzumab vedotin [anti-CD79b antibody–drug conjugate] in combination with BR and loncastuximab tesirine [anti-CD19 antibody–drug conjugate]), tafasitamab (anti-CD19 monoclonal antibody) in combination with lenalidomide, and selinexor (selective small molecule inhibitor of XPO1-mediated nuclear export) are FDA-approved for R/R DLBCL after ≥2 prior lines of therapies, and these are appropriate options for patients with R/R disease who are not candidates for transplant.64–67
However, the prognosis remains poor for patients with refractory disease after ≥2 second-line therapy regimens.68 In addition, primary refractory disease or early relapse within 12 months from the completion of first-line therapy are associated with extremely poor outcomes after second-line therapies.69,70 Although 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, only axicabtagene ciloleucel and lisocabtagene maraleucel are approved as second-line therapy for patients with primary refractory disease or relapsed disease within 12 months after first-line therapy.71–76
Bispecific T-Cell Engagers for R/R Disease
Relapse following CAR T-cell therapy occurs in approximately 60% of patients, and treatment options are very limited for this group of patients.77,78 Bispecific T-cell engagers are a novel class of immunotherapies that have shown promising efficacy for the treatment of heavily pretreated FL and DLBCL, including disease relapse following CAR T-cell therapy. Mosunetuzumab, epcoritamab, and glofitamab are the 3 FDA-approved anti-CD20/CD3 bispecific T-cell engagers. Mosunetuzumab is approved for R/R FL. Epcoritamab and glofitamab are approved for R/R DLBCL.
Evidence from clinical trials supporting the use of bispecific T-cell engagers for R/R FL and DLBCL are discussed in the following sections.
R/R Follicular Lymphoma
In a single-arm, multicenter phase II study (n=90), mosunetuzumab resulted in high response rates and durable remissions in patients with R/R FL after ≥2 lines of therapy, including an anti-CD20 mAb and an alkylating agent.79 The ORR assessed by the IRC was 80% (60% CR). Patients experiencing a CR after 8 cycles completed treatment with no additional cycles, whereas those with a PR or stable disease received a total of 17 cycles.
Mosunetuzumab resulted in favorable response rates across all subgroups, including those with high-risk disease and EZH2-mutated FL. At the median follow-up of 18 months, the median PFS was 18 months, as assessed by IRC. The estimated event-free survival and OS rates were 61% and 90%, respectively. The updated follow-up data also confirmed durability of responses and the safety profile of mosunetuzumab.80 In addition, the efficacy of mosunetuzumab was also better compared with the patient’s last prior therapy. After a median follow-up of 27 months, the investigator-assessed ORR was 78% (60% CR) compared with 56% (36% CR) for the last prior therapy. The median PFS was not reached for mosunetuzumab compared with 13 months for last prior therapy. The estimated 24-months PFS rates were 51% and 24% for mosunetuzumab and last prior therapy, respectively.
Mosunetuzumab (intravenous; fixed-duration treatment) is recommended as an option for R/R FL after ≥2 prior lines of therapy (FOLL-5 and FOLL-B 3 of 5, pages 1120 and 1121, respectively).
R/R Diffuse Large B-cell Lymphoma
Epcoritamab and glofitamab are recommended as options for third-line therapy for patients with R/R DLBCL, including those with disease progression after transplant or CAR T-cell therapy (BCEL-10 and BCEL-C 3 of 6, pages 1128 and 1129, respectively).
Epcoritamab
The phase I/II, single-arm multicenter study (EPCORE NHL-1) evaluated subcutaneous epcoritamab in patients (n=157) with R/R DLBCL (including transformed indolent lymphomas, high-grade B-cell lymphomas [HGBL], or primary mediastinal large B-cell lymphoma [PMBL]) after ≥2 lines of therapy (including an anti-CD20 mAb-based regimen, prior failure and ineligibility for HDT/ASCR, and prior CAR T-cell therapy [≥30 days since last treatment]).81 Median follow-up was 11 months, and the ORR (assessed by the IRC) was 63% (39% CR). The median PFS was 4 months (not reached in patients who achieved CR) and the 6-month PFS rate was 44%; median OS was not reached. Among the prespecified subgroups, the ORR was 55% (30% CR) for patients with primary refractory disease and 54% (34% CR) for patients who had received prior CAR T-cell therapy. The ORR was higher in the subgroup of patients who had not received prior CAR T-cell therapy (69%; 42% CR).
Epcoritamab is given as continuous treatment until disease progression and further studies are needed to determine the optimal duration of treatment in patients experiencing CR.
Glofitamab
Intravenous glofitamab (fixed-duration treatment for 12 cycles) was evaluated in a phase II study for patients (n=154) with R/R DLBCL (including transformed FL, HGBL, or PMBL) after ≥2 lines of therapy (including an anti-CD20 mAb-based or an anthracycline-based regimen, prior failure of HDT/ASCR, or CAR T-cell therapy).82 Pretreatment with one dose of obinutuzumab was given for all patients to mitigate cytokine-release syndrome (CRS). At a median follow-up of 13 months, 52% of patients had an objective response (39% CR) as assessed by IRC; median PFS was 5 months. The estimated 12-month PFS and OS rates were 37% and 50%, respectively. In the prespecified subgroup analysis, there was a trend toward a higher CR rate among patients with relapsed disease compared with those with disease that was refractory to the patient’s last line of therapy. The CR rate was 35% for patients who had received prior CAR T-cell therapy and 42% for those who had not. After a median follow-up of 18 months, the OS rate was 41% for the entire study population, and the PFS and OS rates were 80% and 94%, respectively, for patients with a CR at the end of treatment.83
Safety Profile of Bispecific T-Cell Engagers
CRS (mostly grade 1–2) was the most common adverse event of special interest associated with all 3 bispecific T-cell engagers, and immune effector cell–associated neurotoxicity syndrome (ICANS) was less common. CRS and ICANS were graded using the American Society for Transplantation and Cellular Therapy (ASTCT) criteria.84
Mosunetuzumab
CRS (42%), fatigue (37%), headache (30%), and pyrexia (28%) were the most common grade 1–2 events. Grade 3–4 neutropenia was reported in 13% of patients.80 CRS (grade 1–2) was predominantly confined to cycle 1 of step-up dosing. Among the 42% of patients who developed CRS, grade 3 was reported in 2% and resolved in all patients. Corticosteroids or tocilizumab were used for the management of CRS in 15% and 8% of patients, respectively, and a combination of both was used in 10% of patients. ICANS were very rare and all low grade (grade 1–2 confusion rate was reported in 3% of patients with no incidences of aphasia, seizures, encephalopathy, or cerebral edema). The safety profile enables outpatient administration of mosunetuzumab.
Epcoritamab
Any-grade CRS was reported in 50% of patients with epcoritamab (grade ≥3: 3%). CRS occurred after administration of the first full dose and prophylactic high-dose steroids were given to mitigate CRS during the initial 4 weeks of step-up dosing. Tocilizumab was used for the management of CRS in 28% of patients.81 ICANS (any grade) was reported in 6% of patients (grade ≥3: 3%). Pyrexia (24%), fatigue (23%), neutropenia (22%), diarrhea (20%), and nausea (20%) were the other common adverse events of any grade.
Glofitamab
CRS (any grade) was reported in 63% of patients, and most of the CRS events were associated with the first 3 doses during the step-up cycle.82 Obinutuzumab was given prior to the infusion of glofitamab for all patients to mitigate CRS, and symptoms of CRS occurring after the infusion of glofitamab were mainly controlled with corticosteroids and tocilizumab. ICANS (any grade) was reported in 8% of patients (grade ≥3: 3%). All of the events associated with ICANS (dysphonia, confusional state, and disorientation) were mainly grade 1–2. Infections (38%), neutropenia (38%), anemia (31%), and thrombocytopenia (25%) were the other common adverse events of any grade.
Available data as previously discussed suggest that the overall safety profile of bispecific T-cell engagers is better than that of CAR T-cell therapies. In addition to CRS and ICANS, severe and prolonged cytopenias are a very common toxicity of CAR T-cell therapy, which may be associated with the use of bridging chemotherapy (required for disease control) or with the use of lymphodepleting chemotherapy prior to CAR T-cell administration, or it may be an immune-mediated effect of the CARs.85,86 The presence of rapidly progressing disease and lack of access to a certified CAR T-cell therapy center will also limit the use of CAR T-cell therapy in many patients.
Bispecific T-cell engagers are “off-the-shelf” immunotherapies (more readily available than CAR T-cells), thus obviating the need for bridging or lymphodepleting chemotherapy. However, a step-up dosing schedule (over a period of time before reaching the effective target dose) to mitigate the risk of CRS is required for all 3 bispecific T-cell engagers, which can be challenging in patients with rapidly progressing disease. Additional clinical trials to optimize the step-up dosing and long-term follow-up data from ongoing clinical trials are needed to confirm the preliminary findings regarding the safety and efficacy of bispecific T-cell engagers.
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