“The mind is not a vessel to be filled but a fire to be kindled.”
—Plutarch
About 30% to 40% of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) experience relapse, and 10% are refractory to the regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. Most relapses occur during the first 2 years.
At relapse, patients are categorized into one of two therapeutic groups: transplant-eligible or transplant-ineligible. Transplant-eligible patients who respond (at least a partial response) to platinum-based immunochemotherapy proceed with curative intent to high-dose chemotherapy and autologous hematopoietic transplantation (auto-HCT).1,2 This recommendation is based on the results of the PARMA trial1 (from 1995), in which 109 patients who had chemosensitive disease were randomly assigned to receive four cycles of chemotherapy with the regimen of dexamethasone, high-dose cytarabine, and cisplatin (n = 54) or high-dose chemotherapy with autologous hematopoietic cell rescue (n = 55). Radiotherapy was part of the transplantation protocol and was indicated at the sites of bulky (≥ 5 cm) disease.
Syed Ali Abutalib, MD
Miguel-Angel Perales, MD
Patients assigned to transplantation had superior overall survival of 53% vs 32% in the control arm. The overall response rate (84 vs 44%) and event-free survival rate (46% vs 12%) were also superior with auto-HCT. Certain disease characteristics, such as primary refractoriness, a high second-line age-adjusted International Prognostic Index (IPI), and double- or triple-hit genetic lesions in the tumor (rearrangement of MYC with BCL2 or BCL6 [or both]), have been associated with a lower likelihood of response to salvage therapy.
It is important to recognize that approximately half of transplant-eligible patients will not receive the intended auto-HCT owing to the failure of platinum-based immunochemotherapy. These subgroup patients are candidates for third-line therapies, including the U.S. Food and Drug Administration–approved chimeric antigen receptor (CAR) T-cell therapies.2-4
In the CORAL study,5 about 30% of patients who could not proceed to auto-HCT could still benefit from a third-line salvage chemotherapy regimen and received consolidation autologous transplantation, with a significant improvement in long-term survival. In this study, the overall survival was significantly improved in patients with lower tertiary IPI, patients responding to third-line treatment, and patients transplanted with a 1-year overall survival of 41.6% compared with 16.3% for those not transplanted (P < .0001).
The standard-of-care second-line therapy for transplant-ineligible patients is undefined, due to the lack of a curative therapy. The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®) include a long list of regimens or agents that can be administered with palliative intent.6
BELINDA Trial
ABSTRACT LBA-6: Tisagenlecleucel (n = 162) vs standard of care (n = 160; control arm) as second-line therapy of primary refractory or early (< 12 months) relapsed aggressive B-cell non-Hodgkin lymphoma (NHL; ClinicalTrials.gov identifier NCT03570892).7
Background: Tisagenlecleucel is an autologous anti-CD19 CAR T-cell therapy approved as a third-line treatment of relapsed or refractory DLBCL. In the JULIET study,2 a response occurred in 52% of patients with DLBCL who received tisagenlecleucel, and the 24-month progression-free survival was 33%.
Methods: The primary endpoint was event-free survival, which started from the time of randomization to less than a partial response or after 3 months’ assessment or death at any time.
Standard-of-Care Treatment Strategy: Investigator’s choice of four prespecified chemotherapy regimens (same as bridging therapy) followed, in patients having a response, by auto-HCT. In this group, 158 of 160 patients were assigned to platinum-based second-line therapy; 102 patients did not receive auto-HCT, including 76 with progressive disease. Of 62 patients who received auto-HCT, 10 received second-line salvage therapy, findings indicative of the aggressive disease characteristics in this population.
Crossover Allowed: Yes.
Bridging Chemotherapy in Tisagenlecleucel Arm: Yes; 47% received at least two cycles of platinum-based chemotherapy, 36% received one cycle, and 17% had no bridging therapy. More non-U.S. patients than U.S. patients received at least two cycles or regimens of bridging therapy (59% vs 21%), and less progressive disease before tisagenlecleucel infusion was observed in non-U.S. patients than in U.S. patients, despite a longer time to infusion.
Results: The median event-free survival in both groups was 3.0 months (hazard ratio [HR] for event or death in the tisagenlecleucel group = 1.07; 95% confidence interval [CI] = 0.82–1.40; P = .61). Ten patients in the tisagenlecleucel group and 13 in the standard-care group died of adverse events. At baseline, the percentage of patients with high-grade lymphomas was higher in the tisagenlecleucel group than in the standard-care group (24.1% vs 16.9%), as was the percentage with an IPI score of at least 2 (65.4% vs 57.5%).
Clinical Implications: Patients with aggressive relapsed or refractory B-cell NHL who were treated with tisagenlecleucel as second-line therapy did not have a higher protocol-defined event-free survival vs those given the standard of care. Interestingly, in the context of this trial, just 32.5% of patients received auto-HCT, a true comparator!
“At this point, it is unknown whether the overall survival of second-line chemotherapy responders who received high-dose chemotherapy and auto-HCT is inferior to that of those given CAR T-cell therapy.”— Syed Ali Abutalib, MD, and Miguel-Angel Perales, MD
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The possible contributing factors for a negative study include study design (primary endpoint, more than one salvage regimen allowed), delay of tisagenlecleucel infusion until after the week 6 assessment, imbalances in relevant patients’ characteristics, dose of lymphodepleting chemotherapy, and variability of the dose of tisagenlecleucel. Additional studies are needed to assess which patients may obtain the most benefit. The full report of the BELINDA study was published in The New England Journal of Medicine.8
TRANSFORM Trial
ABSTRACT 91: Lisocabtagene maraleucel (n = 90) vs standard of care (n = 91) with salvage chemotherapy followed by auto-HCT as second-line therapy in patients with refractory (including a complete response in up to 3 months) and relapsed (3–12 months) large B-cell lymphoma9 (NCT03575351).
Background: Lisocabtagene maraleucel is an autologous anti-CD19 CAR T-cell therapy approved as a third-line treatment of relapsed or refractory DLBCL. In the TRANSCEND NHL 001 study3 in patients with relapsed or refractory large B-cell lymphoma (at least three prior lines of therapy), lisocabtagene maraleucel treatment resulted in an overall response rate of 73%, with a complete response rate of 53%.
Methods: The primary endpoint is event-free survival, defined as the time from randomization to death from any cause; progressive disease; less than a partial response by 9 weeks after randomization (unlike BELINDA); or the start of new antineoplastic therapy (unlike BELINDA), whichever occurred first.
Standard-of-Care Treatment Strategy: Investigator’s choice of three prespecified chemotherapy regimens (same as bridging therapy) followed, in patients having a response, by auto-HCT.
Crossover Allowed: Yes, for patients with less than a partial response after three cycles of chemotherapy or not in complete remission after auto-HCT or demonstrating progressive disease at any time. A total of 50 patients crossed over to receive lisocabtagene maraleucel.
Bridging Chemotherapy: Yes, one cycle alone. A total of 58 patients (63%) received bridging therapy.
Secondary CNS Lymphoma: Yes, with four cases in three patients reported in the standard-of-care arm.
Results: The median event-free survival was 2.3 vs 10.1 months (HR = 0.349; P < .0001) with lisocabtagene maraleucel and the standard of care, respectively. Overall survival data were immature at the time of this interim analysis, with a median follow-up of 6.2 months.
Clinical Implications: In the prespecified interim analysis of the TRANSFORM study, at a median follow-up of 6.2 months, lisocabtagene maraleucel demonstrated statistically significant and clinically meaningful improvement in protocol-defined event-free survival compared with the standard of care. Of 91 patients in the control arm, 43 received auto-HCT, of whom 28 achieved complete remission with second-line chemotherapy. Safety results in the second-line setting were consistent with the lisocabtagene maraleucel safety profile in third-line or later large B-cell lymphoma.
ZUMA-7 Trial
ABSTRACT 2: Efficacy of axicabtagene ciloleucel (n = 180) compared with standard of care (n = 179) in patients with early relapsed (< 12 months) and refractory large B-cell lymphoma10 (NCT03391466).
Background: Axicabtagene ciloleucel is an autologous anti-CD19 CAR T-cell therapy approved as a third-line treatment of relapsed or refractory DLBCL. In ZUMA-1, the objective response rate was 82%, and the complete response rate was 54%.4
Methods: The primary endpoint was event-free survival, defined as the time from randomization to the earliest date of disease progression, the commencement of new therapy for lymphoma (unlike BELINDA7,8), death from any cause, or a best response of up to a partial response and including a response by the fifth month (day 150) assessment after randomization (unlike -BELINDA7,8 and TRANSFORM9) according to blinded central review.
Standard-of-Care Treatment Strategy: Patients received two to three cycles of an investigator-selected, protocol-defined, platinum-based chemoimmunotherapy regimen; patients with at least a partial response proceeded to auto-HCT. In this group, 168 of 179 patients received at least one dose of platinum-based second-line therapy; 56 and 27 patients had progressive and stable disease, respectively. Response to salvage chemotherapy was determined by the investigator.
Crossover Allowed: No. However, patients who did not have a response to standard therapy could receive axicabtagene ciloleucel outside the protocol (treatment switching). A total of 56% of patients in the standard-of-care group received subsequent CAR T-cell therapy.
Bridging Chemotherapy in the Axicabtagene Ciloleucel Arm: No. Optional bridging therapy was limited to glucocorticoids alone; 65 patients (36%) received bridging therapy with glucocorticoids. This strategy could have resulted in selection bias. Investigators agreed that “in the real world, however, bridging chemotherapy may sometimes need to be started urgently.”
Results: Median event-free survival was significantly longer with axicabtagene ciloleucel vs the standard of care (8.3 months [95% CI = 4.5–15.8 months] vs 2 months [95% CI = 1.6–2.8 months], respectively). Kaplan-Meier estimates of the 24-month event-free survival rates were significantly higher with axicabtagene ciloleucel (41% vs 16%, respectively).
Median overall survival, evaluated as a preplanned interim analysis, favored axicabtagene ciloleucel (94% received the infusion) vs the standard of care (62 of 179 patients received auto-HCT). However, it did not meet statistical significance (not reached vs 35.1 months, respectively; HR = 0.730; P = .027).
Grade ≥ 3 treatment-emergent adverse events occurred in 155 patients (91%) given axicabtagene ciloleucel and 140 patients (83%) given the standard of care. Treatment-related deaths occurred in one and two patients given axicabtagene ciloleucel and the standard of care, respectively.
Cytokine-Release Syndrome: Grade ≥ 3 occurred in 6%.
Neurotoxicity: Grade ≥ 3 occurred in 21% (high frequency compared with the BELINDA7,8 and TRANSFORM trials9).
No deaths related to cytokine-release syndrome or neurologic events occurred. Adverse events of grade 3 or higher occurred in 91% of patients who received axicabtagene ciloleucel and in 83% of those who received the standard of care.
Clinical Implications: ZUMA-7 with axicabtagene ciloleucel vs the standard of care in relapsed and refractory large B-cell lymphoma demonstrated a statistically significant and clinically meaningful improvement in protocol-defined event-free survival (HR = 0.398; P < .0001), with a trend toward overall survival improvement (HR = 0.730; P = .027) and an expected level of high-grade toxic effects. It is important to recognize the sobering fact that about 80 patients responded to the salvage regimen, but 62 patients received auto-HCT compared with 170 of 180 axicabtagene ciloleucel–assigned patients who received it. The investigators noted that in patients who received auto-HCT, the outcomes were not as poor. The full report of the ZUMA-7 study was published in The New England Journal of Medicine.11
Concluding Remarks
At this point, it is unknown whether the overall survival of second-line chemotherapy responders who received high-dose chemotherapy and auto-HCT is inferior to that with CAR T-cell therapy. It remains to be seen whether the results of the two positive trials will change practice.
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca. Dr. Perales has received honoraria from AbbVie, Astellas, Bristol Myers Squibb, Celgene, Equillium, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Novartis, Nektar Therapeutics, Omeros, OrcaBio, Takeda, and VectivBio AG, and Vor Biopharma; has served on data and safety monitoring boards for Cidara Therapeutics, Medigene, Sellas Life Sciences, and Servier; has been a member of the scientific advisory board of NexImmune; has ownership interests in NexImmune and Omeros; and has received research support from Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis.
REFERENCES
1. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 333:1540-1545, 1995.
2. Schuster SJ, Bishop MR, Tam CS, et al: Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 380:45-56, 2019.
3. Abramson JS, Palomba ML, Gordon LI, et al: Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet 396:839-852, 2020.
4. Locke FL, Miklos DB, Jacobson CA, et al: Axicabtagene ciloleucel as second-line therapy for large B-cell lymphoma. N Engl J Med. December 11, 2021 (early release online).
5. Van Den Neste E, Schmitz N, Mounier N, et al: Outcome of patients with relapsed diffuse large B-cell lymphoma who fail second-line salvage regimens in the International CORAL study. Bone Marrow Transplant 51:51-57, 2016.
6. Zelenetz AD, Gordon LI, Chang JE, et al: NCCN Guidelines® Insights: B-Cell Lymphomas, Version 5.2021 Available at https://jnccn.org/view/journals/jnccn/19/11/article-p1218.xml. Accessed on February 9, 2022.
7. Bishop MR, Dickinson M, Purtill D, et al: Tisagenlecleucel vs standard of care as second-line therapy of primary refractory or relapsed aggressive B-cell non-Hodgkin lymphoma: Analysis of the phase III BELINDA study. 2021 ASH Annual Meeting & Exposition. Abstract LBA-6. Presented December 14, 2021.
9. Kamdar M, Solomon SR, Arnason JE, et al: Lisocabtagene maraleucel, a CD19-directed chimeric antigen receptor T cell therapy, versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma: Results from the randomized phase 3 TRANSFORM study. 2021 ASH Annual Meeting & Exposition. Abstract 91. Presented December 11, 2021.
10. Locke FL, Miklos DB, Jacobson C, et al: Primary analysis of ZUMA‑7: A phase 3 randomized trial of axicabtagene ciloleucel versus standard‑of care therapy in patients with relapsed/refractory large B-cell lymphoma. 2021 ASH Annual Meeting & Exposition. Abstract 2. Presented December 12, 2021.
11. Neelapu SS, Locke FL, Bartlett NL, et al: Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531-2544, 2017.
Dr. Abutalib is Director, Hematology and BMT/Cellular Therapy Programs; Director, Clinical Apheresis Programs; Cancer Treatment Centers of America, Zion, Illinois; Associate Professor, Rosalind Franklin University of Medicine and Science; and Founder and Co-Editor of Advances in Cell and Gene Therapy. Dr. Perales is Chief, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, and Associate Professor of Medicine, Weill Cornell Medical College, New York.
