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Pharmacy Practice in Focus: Oncology
Relapsed treatment has evolved with CAR T, bispecific antibodies, and immunotherapies.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma and accounts for approximately 30% of newly diagnosed cases each year globally.1 Frontline chemoimmunotherapy leads to cures in about 50% to 60% of patients with DLBCL. However, historically, relapsed DLBCL was associated with poor outcomes, especially in patients who are chemotherapy resistant.2
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Over the past decade, the treatment landscape for relapsed/refractory (R/R) DLBCL has significantly changed due to FDA approvals of a number of immunotherapies and bispecific antibodies, as well as use of chimeric antigen receptor (CAR) T-cell therapies in earlier lines. In R/R DLBCL, the treatment algorithm is broadly categorized based on whether the disease is primary refractory, relapsed within 12 months of primary therapy, or relapsed after 12 months (Figure). Treatment options for R/R DLBCL have expanded to include novel agents in the third line and beyond. With numerous preferred treatments available, decisions are guided by careful consideration of the potential benefits weighed against the associated toxicities.
Salvage therapy followed by autologous stem cell transplantation (ASCT) is the standard of care for patients with relapsed DLBCL occurring at least 12 months after initial treatment and the goal of ASCT in this setting is cure. ASCT is superior to the alternative of chemotherapy alone and can cure approximately 20% to 50% of patients with relapsed DLBCL.3,4 The most significant determinant of successful cure after ASCT is the disease status at time of transplant. Patients with DLBCL who are transplanted with a PET-negative complete response (CR) have excellent disease-free survival (DFS) rates of approximately 80%, while those transplanted with residual PET-positive disease have DFS rates of 35% to 43%.5 Table 1 lists evidence for the most commonly used salvage chemoimmunotherapy regimens before ASCT.4,6 Rituximab (Rituxan; Biogen and Genentech) plus dexamethasone, cytarabine, and cisplatin (R-DHAP) tends to have a higher risk of severe toxicities compared with rituximab plus ifosfamide (Ifex; Baxter Healthcare), carboplatin, and etoposide phosphate (R-ICE) and rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP), as demonstrated in both the CORAL (NCT00137995) and NCIC-CTG LY.12 (NCT02910063) trials.4,6 This makes toxicity management a key factor in choosing the appropriate salvage regimen for individual patients.4,6
PFS, progression-free survival; R-ICE, rituximab, ifosfamide, carboplatin, etoposide phosphate; R-DHAP, rituximab, dexamethasone, cytarabine, cisplatin; R-GDP, rituximab, gemcitabine, dexamethasone, cisplatin.
CAR T cells targeting CD19, which is expressed on malignant B cells, were found to have potent activity in clinical trials involving patients with R/R DLBCL, leading to approvals of 3 commercial CAR T-cell products after 2 lines of therapy (Table 2).7-9 Long-term follow-up data of these landmark trials show durable responses and offer a potential cure in a subset of patients. Patients may often require bridging therapy, if ongoing progression and/or impending organ damage before or after leukapheresis. Bendamustine should be avoided before leukapheresis because of its prolonged lymphotoxic effect.10
AE, adverse effect; CRS, cytokine release syndrome; ORR, overall response rate; OS, overall survival.
In patients with relapse within 12 months or refractory disease, results of the ZUMA-7 trial (NCT03391466) showed that axicabtagene ciloleucel (Y escarta; Kite Pharma) improved event-free survival (EFS) to 8.3 months compared with 2 months with standard of care (salvage chemotherapy followed by ASCT), whereas results of the TRANSFORM trial (NCT03575351) demonstrated that lisocabtagene maraleucel (liso-cel, Breyanzi; Juno Therapeutics) improved EFS to 10.1 months compared with 2.3 months with standard of care, respectively. Both trials demonstrated the significant benefit of CAR T-cell therapies in transplant-eligible patients and led to FDA approval in this population.11,12 However, ASCT can also be pursued in patients who achieve a PET-negative CR after bridging therapy.13 Liso-cel is also approved by the FDA for patients not eligible for hematopoietic stem cell transplantation due to comorbidities or age based on the results of the PILOT trial (NCT04359784).14
Results of several recent trials have shown promising efficacy of targeting other B-cell markers with either antibody-drug conjugate (ADC) or naked antibodies. These can be used in patients who are ineligible for transplant or CAR T-cell therapy, as well as with subsequent relapses. Knowledge about ideal sequencing of these therapies is lacking. These regimens are reviewed in Table 3.15-17 The L-MIND trial (NCT02399085) evaluated the combination of tafasitamab (Monjuvi; Incyte), a naked CD19 antibody, with lenalidomide, an immunomodulator, and reported that for patients enrolled in the trial, the most common reason for transplant ineligibility was age over 70 (46%).15 However, in the trial published by Sehn et al evaluating polatuzumab vedotin (Polivy; Genentech), a CD79b-targeted ADC delivering monomethyl auristatin E, a microtubule inhibitor, in combination with bendamustine and rituximab, the most common reasons identified as deeming a patient to be transplant ineligible were age (32.5%) and insuf ficient response to salvage therapy (30%).16 There are other key differences in patient considerations including dosing schedule, route of administration, and Risk Evaluation and Mitigation Strategy programs. The tafasitamab plus lenalidomide (Revlimid; Bristol Myers Squibb) regimen is a combination of intravenous (IV) therapy tafasitamab with the oral therapy lenalidomide. The dosing schedule for this regimen is completed on a 28-day cycle and starts with lenalidomide daily for 21 days, followed by 7 days off in combination for the first 12 cycles of therapy with weekly tafasitamab for the first 3 cycles (the first cycle also has a day 4 dose), followed by twice-weekly tafasitamab.15 The polatuzumab vedotin plus bendamustine and rituximab regimen is administered IV on a 21-day cycle with treatment on days 1 and 2 of each cycle.16
AE, adverse event; BR, bendamustine and rituximab; CR, complete response; GGT, gamma-glutamyl transferase; OR, objective response; ORR, overall response rate.
In the subsequent therapy setting, the LOTIS-2 trial (NCT03589469) demonstrated the utility of loncastuximab tesirine, a CD19-targeted ADC, in multiple R/R DLBCL. The dosing schedule for this regimen was 1 dose of loncastuximab tesirine IV on day 1 of each 21-day cycle.17 As this drug can cause pronounced photosensitivity rash, patients should receive a recommendation to avoid prolonged sunlight exposure.
The advent of using bispecific antibodies for the treatment of multiple R/R DLBCL has expanded the therapies available to these patients. These regimens are reviewed in Table 4.18,19 Patients receiving glofitamab (Columvi; Genentech) are to receive obinutuzumab 1000 mg IV 7 days before the first dose of glofitamab, a CD20×CD3 bispecific monoclonal antibody, aimed to debulk the tumor, followed by step-up dosing in cycle 1 before proceeding to full treatment dose of glofitamab IV on day 1 of a 21-day cycle.18 Epcoritamab (Epkinly; AbbVie and Genmab), a CD20×CD3 bispecific monoclonal antibody, also requires the use of step-up dosing in the first cycle, followed by subcutaneous doses on days 1 and 15 of each 28-day cycle moving forward.19 Of note, both glofitamab and epcoritamab have recommendations for hospitalization during the step-up dose period with observation for at least 24 hours post dose to monitor for the development of cytokine release syndrome. Patients receiving epcoritamab do not receive obinutuzumab as a lead-in to starting therapy as do those starting glofitamab.
AE, adverse event; CR, complete response; CRS, cytokine release syndrome; NR, not reached; ORR, overall response rate.
Jessica M. Lewis-Gonzalez, PharmD, BCOP, is a clinical hematology-oncology and cell therapy pharmacist at the University of New Mexico (UNM) Comprehensive Cancer Center in Albuquerque, New Mexico.
Shashank R. Cingam, MD, is a hematology-oncology and cell therapy physician at UNM Comprehensive Cancer Center in Albuquerque, New Mexico.
There are many considerations when selecting the best regimen for a patient with R/R DLBCL. The primary consideration is if they are considered chemo resistant (relapsed < 12 months from frontline therapy, refractory disease, or not achieving CR after salvage therapy); for such patients, CAR T-cell therapy may be a preferred choice over ASCT. For patients relapsing after CAR T-cell therapy or ASCT, treatment must be personalized and informed by patient- and disease-specific factors, including prior therapy, disease biology, T-cell fitness, access to treatments, as well as comorbidities. For patients deemed to be ineligible for ASCT, considerations should focus on patient- and disease-specific factors, including prior therapy, disease biology, comorbidities, and dosing schedule. Participation in clinical trials should also be encouraged in patients with R/R DLBCL when available.
Disclosures: Shashank R. Cingam, MD, is on the advisory board of Janssen and receives research funding from Pfizer.
