Lymphoma: Update on Frontline Management

Educational Objectives

The goal of this program is to improve the diagnosis and management of lymphoma. After hearing and assimilating this program, the clinician will be better able to:

1. Assess the effectiveness and safety of various treatment options for lymphoma.
2. Devise evidence-based treatment plans for patients with different lymphoma subtypes while considering individual patient factors and risk stratification.
3. Evaluate the role of central nervous system prophylaxis in patients with diffuse large B-cell lymphoma.

Summary

Hodgkin lymphoma: patients with early-stage favorable disease are treated with doxorubicin hydrochloride (Adriamycin), bleomycin sulfate, vinblastine sulfate, and dacarbazine (ABVD)-based chemotherapy with or without radiotherapy depending on risk factors and interim disease response; patients with early-stage unfavorable risk disease are treated with 6 cycles of chemotherapy; bleomycin is omitted (ie, AVD) if the patient shows favorable response after 2 cycles; radiotherapy is considered in patients with a suboptimal response; patients with advanced-stage lymphoma are treated with antibody drug conjugate, brentuximab vedotin and AVD

Evidence: the ECHELON-1 trial (Straus et al [2022]) demonstrated improvement in progression-free survival (PFS) in patients taking brentuximab vedotin plus AVD vs ABVD; at 6-yr follow-up, significant improvement in overall survival (OS) was observed with brentuximab vedotin plus AVD

Checkpoint inhibitors: nivolumab and pembrolizumab is recommended for patients with relapsed refractory Hodgkin lymphoma; SWOG S1826 trial (Herrara et al [2024]) — demonstrated that nivolumab plus AVD significantly improved PFS compared with brentuximab vedotin plus AVD across various patient subgroups; established nivolumab plus AVD as the new standard of care for advanced-stage Hodgkin lymphoma

Aggressive B-cell lymphoma (BCL): chemotherapy often yields inadequate outcomes in patients with double-hit lymphomas (genetic abnormalities in BCL2 and MYC) vs standard rituximab (RIX), cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP); dose-adjusted etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride with RIX (R-EPOCH) regimen has demonstrated improved outcomes in this high-risk subgroup and is currently considered the standard of care; treatment options for early-stage double-hit lymphoma include R-CHOP or R-CHOP with RIX plus polatuzumab vedotin (POLA; R-CHOP-21); choosing between regimens often depends on the patient’s International Prognostic Index (IPI) score, which helps assess their individual risk for disease progression; patients with advanced disease are treated with R-CHOP or R-CHOP-21 followed by autologous stem cell transplantation (ASCT)

Treatment algorithm: patients with a low IPI score (0 or 1) and no high-risk features (eg, lactate dehydrogenase [LDH], bulky disease) may be eligible for short course of 4 cycles of R-CHOP chemotherapy, provided they achieve a complete response after the first 3 cycles as assessed by positron emission tomography; patients with low IPI but with elevated LDH or bulky disease receive 6 cycles of R-CHOP; those with an intermediate or high IPI score (2-5) are treated with R-CHOP-21

Evidence: several clinical trials have attempted to replace R-CHOP as the standard of care for aggressive large BCL (LBCL); many of these trials either failed to demonstrate a significant improvement in outcomes or showed only marginal benefits in specific patient subgroups; this landscape shifted with the emergence of POLA, an antibody-drug conjugate initially approved for relapsed or refractory disease; POLARIX trial (Tilly et al [2022]) — evaluated the efficacy of POLA in combination with a modified R-CHOP regimen (CHP-21) vs standard R-CHOP in patients with diffuse LBCL (DLBCL) and an IPI score of 2 to 5; vincristine was omitted from the R-CHOP regimen in the POLA-CHP-21 arm to minimize the risk of overlapping neurotoxicity; results of the study demonstrated a statistically significant improvement in PFS for patients treated with POLA-CHP-21 vs R-CHOP; no difference was observed in OS; the question of whether this regimen might be adequate for patients with the high-risk double-hit rearrangements was not addressed in this study

Central nervous system (CNS) prophylaxis: traditional practice was to use prophylactic intrathecal chemotherapy or high-dose methotrexate (MTX) to prevent CNS relapses in patients with DLBCL; the International CNS Lymphoma Study Group (Lewis et al [2023]) found no difference in CNS disease progression between patients who did vs did not receive CNS prophylaxis; a meta-analysis by Ho et al (2021) demonstrated no meaningful impact of CNS prophylaxis on the risk for CNS relapse in DLBCL; current recommendations discourage the use of routine CNS prophylaxis; high-dose MTX with leucovorin rescue is considered for patients with primary testicular DLBCL

Mantle cell lymphoma (MCL): key developments include the incorporation of RIX into frontline therapy, which demonstrated a substantial improvement in treatment outcomes; the inclusion of cytarabine and the implementation of alternating chemotherapy regimens (eg, Nordic regimen and cyclophosphamide, vincristine sulfate, Adriamycin, MTX, and cytarabine [hyper-CVAD]) further enhanced treatment efficacy; the widespread adoption of upfront ASCT as consolidation therapy for younger, fit patients with MCL contributed to improved long-term outcomes; treatment algorithm — patients with low-risk asymptomatic MCL can be managed with watchful waiting; young, fit individuals are typically candidates for intensive treatment regimens, eg, bendamustine-RIX (BR), followed by RIX with high-dose cytarabine, and subsequently, high-dose chemotherapy with ASCT; for patients who are not suitable candidates for intensive therapies, 6 cycles of BR followed by long-term RIX maintenance therapy (≤6 yr) has demonstrated favorable outcomes

Evidence: TRIANGLE trial (Dreyling et al [2024]) — patients with MCL were randomized to receive either standard therapy with R-CHOP (6 cycles) and RIX, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP) with ASCT consolidation vs standard therapy plus ibrutinib with ASCT consolidation vs standard therapy plus ibrutinib with no ASCT consolidation, with or without RIX maintenance in all 3 arms; results of the study demonstrated an improvement in failure-free survival and OS in patients who received standard therapy plus ibrutinib, with or without ASCT; Eastern Cooperative Oncology Group-American College of Radiology Imaging Network 4151 trial — evaluated the contribution of ASCT to long-term outcomes in patients who achieved minimal residual disease (MRD)-negative remission who were eligible for ASCT; criteria included a clonal immunoglobulin rearrangement detectable by polymerase chain reaction for MRD testing; patients were randomized to receive ASCT followed by RIX maintenance vs RIX maintenance therapy without ASCT; there was no statistically significant difference in OS between the 2 groups

Care strategy: standard of care is upfront consolidation with ASCT for patients who are medically fit; a covalent Bruton tyrosine kinase inhibitor (BTKi) may be integrated into frontline treatment for the younger and medically fit patients; older and less medically fit patients receive 6 cycles of BR and RIX maintenance; patients with TP53 mutations have poor prognosis and may require cytotoxic chemotherapy, eg, acalabrutinib

Chronic lymphocytic leukemia (CLL): choosing between indefinite therapy and a time-limited therapy involves a shared decision-making process between the physician and the patient, considering individual factors; for patients receiving indefinite therapy, treatment options typically include ibrutinib with or without venetoclax or zanubrutinib; patients who are candidates for time-limited therapy may receive a defined course of chemotherapy, eg, BR, potentially followed by a consolidation with a BTKi; the treatment landscape for CLL has moved away from traditional cytotoxic chemotherapy regimens (eg, fludarabine-cyclophosphamide-RIX [FCR], BR) towards novel targeted therapies

GAIA-CLL trial (Eicchorst et al [2023]): evaluated the efficacy of venetoclax (BCL2 inhibitor) combined with obinutuzumab vs traditional chemotherapy regimens (FCR in younger patients and BR in older patients); the trial also explored the addition of ibrutinib (a BTKi) to the venetoclax-obinutuzumab (VO) combination; rates of MRD negativity were significantly higher in patients receiving VO, both alone and in combination with ibrutinib, compared with those receiving chemotherapy; both venetoclax-based regimens, with and without ibrutinib, demonstrated superior PFS vs control groups; in patients with low-risk disease (defined by specific genetic and clinical factors), chemoimmunotherapy appeared to be equally effective, if not superior, to the venetoclax-based regimens; MRD status at the completion of treatment did not significantly influence OS; this may be attributed to the long natural history of CLL and the availability of highly effective subsequent treatment options

Burkitt lymphoma: traditional management included intensive chemotherapy regimens, eg, the McGrath regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone, MTX, cytarabine, and RIX) or hyper-CVAD, alternating with high-dose MTX and cytarabine; intensive regimens were reserved for younger, medically fit patients; for older or less fit patients, R-EPOCH has been considered a viable alternative; in the HOVON/SAKK 127 study, Löwenberg et al (2021) aimed to compare the McGrath regimen to R-EPOCH in patients with Burkitt lymphoma; however, due to slow accrual, the trial was prematurely closed after an interim analysis; the interim analysis demonstrated that R-EPOCH achieved outcomes comparable to the McGrath regimen (similar PFS and OS)

Readings

Bobillo S, Joffe E, Sermer D, et al. Prophylaxis with intrathecal or high-dose methotrexate in diffuse large B-cell lymphoma and high risk of CNS relapse. Blood Cancer J. 2021;11(6):113. Published 2021 Jun 16. doi:10.1038/s41408-021-00506-3; Dreyling M, Doorduijn J, Giné E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024;403(10441):2293-2306. doi:10.1016/S0140-6736(24)00184-3; Eichhorst B, Niemann CU, Kater AP, et al. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754. doi:10.1056/NEJMoa2213093; Ho G, Tan C, de Mel S, et al. Central nervous system (CNS) prophylaxis in antiCD20-CHOP treated DLBCL at intermediate to high risk for CNS relapse: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2021;167:103507. doi:10.1016/j.critrevonc.2021.103507; Lewis KL, Jakobsen LH, Villa D, et al. High-dose methotrexate as CNS prophylaxis in high-risk aggressive B-cell lymphoma. J Clin Oncol. 2023;41(35):5376-5387. doi:10.1200/JCO.23.00365; Löwenberg B, Pabst T, Maertens J, et al. Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial. Blood Adv. 2021;5(4):1110-1121. doi:10.1182/bloodadvances.2020003855; Straus DJ, Długosz-Danecka M, Connors JM, et al. Brentuximab vedotin with chemotherapy for stage III or IV classical Hodgkin lymphoma (ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial [published correction appears in Lancet Haematol. 2022 Feb;9(2):e91. doi: 10.1016/S2352-3026(22)00009-6]. Lancet Haematol. 2021;8(6):e410-e421. doi:10.1016/S2352-3026(21)00102-2; Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Dean was recorded at the Cleveland Clinic Cancer Conference: Innovations in Multidisciplinary Care, held November 1-3, 2024, in Hollywood, FL, and presented by Cleveland Clinic. For information on upcoming CME activities from this presenter, please visit clevelandclinicmeded.com. Audio Digest thanks the speakers and Cleveland Clinic for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

Lecture ID:

ON160501

Qualifies for:

ABIM MOC, Clinical Pharmacology

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.