For aggressive B-cell lymphomas, chimeric antigen receptor (CAR) T-cell therapy saves lives, but relapse remains common, and a second-line standard of care is lacking. During the 2021 Pan Pacific Lymphoma Conference, Grzegorz (Greg) S. Nowakowski, MD, Professor of Medicine and Oncology, Lymphoma Group, Mayo Clinic, Rochester, Minnesota, discussed newly approved agents and the evidence for their use in this setting.1
Grzegorz (Greg) S. Nowakowski, MD
Outcomes After CAR T-Cell Therapy
The expanding use of CAR T-cell therapy only increases the proportion of patients in need of effective therapies upon relapse after such treatment. A recent study found that 60% of responders were maintaining those responses 5 years later, but 57% of all patients had relapsed, mostly within 1 year of treatment.2 “We need to know how to address this population, and the data on these patients are limited,” he said.
Chow et al3 have reported outcomes for patients relapsing within and beyond 30 days of CAR T-cell therapy. Altogether, median overall survival was poor, at 5.4 months. For those relapsing later, it was better, 9.3 months, whereas it was poor for those relapsing early, 3.7 months (P = .042). “Maybe only about one in five patients survives beyond about 24 months, so clearly this is a huge unmet need,” Dr. Nowakowski commented.
Why Not Enroll in a Clinical Trial?
Informal research has suggested that participation in a clinical trial may be the optimal treatment after relapse, according to key opinion leaders, “myself included,” continued Dr. Nowakowski. Although this is understandable, since a standard of care is lacking, it is “problematic,” as there are multiple barriers to enrollment, such as prolonged cytopenia.
In designing trials, we need to focus on very different inclusion criteria [for patients who relapse after CAR T-cell therapy], especially with regard to hematologic recovery.— Grzegorz (Greg) S. Nowakowski, MD
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A study of 53 patients with aggressive B-cell lymphomas, presented during the 2021 Pan Pacific Lymphoma Conference, examined inclusion criteria for major trials leading to accelerated approval of four different agents.4 The study investigators found that 47% of patients would be excluded from enrollment for hematologic factors: absolute neutrophil count < 1,000 or 1,500 cells/mL or platelets < 75,000/mL. Patients who were ineligible for trials also had a significantly shorter time from CAR T-cell therapy to disease progression.
“These criteria were not very conservative, but despite that, nearly half the patients were excluded based on hematologic parameters at the time of relapse that are actually very reasonable for relapsed or refractory disease,” Dr. Nowakowski noted. “So, clinical trials, which we recommend, capture only about half our patients at the time of relapse after CAR T-cell therapy.”
Other reasons why patients are not eligible include poor performance status, central nervous system relapse, poor renal or liver function, and complications such as infections. “In designing trials, we need to focus on very different inclusion criteria, especially with regard to hematologic recovery,” he suggested.
Treatment Options for DLBCL After Relapse
“This is an exciting time in diffuse large B-cell lymphoma [DLBCL], as a number of new agents have been approved. But the question is how active are they after relapse from CAR T-cell therapy?” asked Dr. Nowakowski. He focused on four agents and the data supporting their use.
The CD79b-directed antibody-drug conjugate polatuzumab vedotin-piiq has been approved in combination with bendamustine and rituximab after two or more prior therapies. In the pivotal trial, the objective response rate was 45%, including complete responses in 40% of patients compared with 17.5% and 17.5% with bendamustine/rituximab alone.5 The median duration of response was 12.6 vs 7.7 months.
In a separate multicenter retrospective study of a similar population, 12 of 80 patients had failed to respond to CAR T-cell therapy before receiving polatuzumab vedotin as bridging treatment to allogeneic stem cell transplantation (allo-SCT) or palliative treatment and 7 responded. This represents a 64% improvement over bendamustine/rituximab (P < .001), though the duration of benefit was limited.6
Loncastuximab tesirine could be an important agent to consider in patients who still have CD19-positive disease.— Grzegorz (Greg) S. Nowakowski, MD
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“This is an indication that polatuzumab vedotin alone or in combination with bendamustine/rituximab could be active in this group of patients,” stated Dr. Nowakowski.
Oral selinexor, a selective inhibitor of nuclear transplant, also received accelerated approval for relapsed or refractory DLBCL after at least two lines of prior treatment. In a study of 127 patients with relapsed or refractory DLBCL, the objective response rate was 28%, of which only 12% were complete responses.7 The data are limited as to the drug’s benefit after CAR T-cell therapy, but there are case reports of efficacy, especially as a bridge to allo-SCT.8
The CD19-directed cytolytic antibody tafasitamab-cxix, given with lenalidomide, also recently received accelerated approval for patients with relapsed or refractory DLBCL who are not eligible for autologous transplant. “This antibody targeting CD19 is engineered to enhance antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Lenalidomide potentiates T-cell and natural killer cell activation/expansion and direct cell death, giving a rationale for its potential activity, according to Dr. Nowakowski.
Early studies have shown a response rate of 60% and a complete response rate of 42.5%. Of note, these responses appear to be durable, especially in patients with complete responses.9,10 “Real-world” data from the Mayo Clinic, Rochester, show a response rate of 67% with the combination.11
Lenalidomide also has shown activity after CAR T-cell therapy. In a study presented during the 2020 American Society of Hematology (ASH) Annual Meeting and Exposition, 41 patients received lenalidomide, including 10 as a single agent, 30 in combination with rituximab, and 1 in combination with obinutuzumab.12 The objective response rate was 27.1%, including complete responses in 21.1%. Median progression-free survival was 101 days, and median overall survival was 225 days. Response rates were higher for patients starting treatment within 15 days of CAR T-cell infusion (63.6% vs 18.8%; P = .006).
“There appears to be some activity for lenalidomide in these patients, which based on response rates is similar to what we see in relapsed or refractory DLBCL in previous phase II studies,” Dr. Nowakowski said. “Real-world” data from the Mayo Clinic, Rochester, showed a response rate of 34% with lenalidomide monotherapy.11
The most recent accelerated approval is for loncastuximab tesirine-lpyl, a CD19-directed antibody and alkylating agent conjugate, for DLBCL after at least two lines of therapy. In the LOTIS-2 trial of 145 patients, the response rate was 48.3%, with complete responses seen in 24.8%.13 The median duration of response for complete and partial responders alike was approximately 13 months. The study included 13 patients who experienced disease progression after CAR T-cell therapy, and 46.2% of them responded to loncastuximab tesirine. CD19 expression after CAR T-cell therapy was required for treatment.
“Loncastuximab tesirine could be an important agent to consider in patients who still have CD19-positive disease. After CAR T-cell therapy, 20% or so may no longer express CD19,” he commented.
We are going to need real-world data of results with sequential therapy in various clinical situations to know how best to sequence treatments.— Grzegorz (Greg) S. Nowakowski, MD
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Other Out-of-the-Box Options
Several other options can also be considered after CAR T-cell therapy. One is the use of radiation therapy, which with modern techniques can now be delivered precisely to the area of need. A series of 14 cases from Memorial Sloan Kettering has shown sustained benefit with irradiation for localized relapse, including for patients with disease that is refractory to chemotherapy or who have double-hit disease.14 Among 14 patients treated with salvage irradiation after disease progression on CAR T-cell therapy, the 6 patients with localized relapses responded. Median overall survival for all patients was 10 months. Three patients were bridged to allo-SCT, and all were alive at the time of analysis. The study concluded that radiotherapy may be integrated with novel agents or transplantation to attempt durable remissions.
PD-1 blockade initially elicited enthusiasm, though subsequent data have been somewhat discouraging; trials are ongoing. Retreatment with CAR T-cell therapy has not been particularly beneficial unless an antigen other than CD19 is targeted. Small molecules, including Bruton’s tyrosine kinase inhibitors, are attractive, given that cytopenias are not particularly a problem with them. Palliative chemotherapy may help some patients, Dr. Nowakowski said.
Perhaps the most enthusiasm is for bispecific antibodies, which were discussed in depth at the Pan Pacific Lymphoma Conference by Christopher Flowers, MD, MS, FASCO. Four agents in clinical trials for patients with DLBCL, some with prior CAR T-cell therapy, are mosunetuzumab, glofitamab, odronextamab, and epcoritamab. Complete response rates as high as 50% have been reported. (For a more detailed discussion of these novel agents, see the September 25, 2021, issue of The ASCO Post.)
“I think this approach could be extremely promising because the therapy is not myelosuppressive…. We expect bispecific antibodies to be approved,” Dr. Nowakowski commented.
A Therapeutic Bridge
“The key opinion leaders are right: The best treatment of relapse after CAR T-cell therapy is a clinical trial. But there are options outside of trials, including recently approved drugs…, and I think the most traction will be with agents with limited hematologic toxicity…. These therapies should be thought of as bridges, mostly to allo-SCT,” Dr. Nowakowski concluded. “We are going to need real-world data of results with sequential therapy in various clinical situations to know how best to sequence treatments.”
DISCLOSURE: Dr. Nowakowski has served as a paid consultant for Celgene, BMS, Seattle Genetics, Roche/Genentech, MorphoSys, Selvita, and Curis; and has received research funding from Celgene, BMS, Roche/Genentech, and MorphoSys.
REFERENCES
1. Nowakowski GS: Best management of relapsed and refractory high-grade B-cell lymphoma post-CAR T therapy. 2021 Pan Pacific Lymphoma Conference. Presented August 13, 2021.
2. Chong EA, Ruella M, Schuster SJ: Five-year outcomes for refractory B-cell lymphomas with CAR T-cell therapy. N Engl J Med 384:673-674, 2021.
3. Chow VA, Gopal AK, Maloney DG, et al: Outcomes of patients with large B-cell lymphomas and progressive disease following CD19-specific CAR T-cell therapy. Am J Hematol 94:E209-E213, 2019.
4. Bezerra ED, Maurer MJ, Khurana A, et al: Barriers to enrollment in clinical trials for aggressive B-cell lymphoma progressing after CAR T-cell therapy. 2021 Pan Pacific Lymphoma Conference. Presented August 9, 2021.
5. Sehn LH, Herrera AF, Flowers CR, et al: Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 38:155-165, 2020.
6. Liebers N, Duell J, Fitzgerald D, et al: Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas. Blood Adv 5:2707-2716, 2021.
7. Kalakonda N, Maerevoet M, Cavallo F, et al: Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): A single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol 7:e511-e522, 2020.
8. Horesh N, Weiler-Sagie M, Ringelstein-Harlev S: Single agent oral selinexor as a key to potential cure in refractory diffuse large B-cell lymphoma: Case report and literature review. Am J Blood Res 11:111-117, 2021.
9. Salles G, Duell J, González Barca E, et al: Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): A multicentre, prospective, single-arm, phase 2 study. Lancet Oncol 21:978-988, 2020.
10. Düll J, Maddocks KJ, Gonzalez-Barca E, et al: Long-term analyses from L-MIND, a phase II study of tafasitamab (MOR208) combined with lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. 2021 ASCO Annual Meeting. Abstract 7513. Presented June 4, 2021.
11. Nowakowski GS, Rodgers TD, Marino D, et al: RE-MIND study: A propensity score-based 1:1 matched comparison of tafasitamab + lenalidomide (L-MIND) versus lenalidomide monotherapy (real-world data) in transplant-ineligible patients with relapsed/refractory diffuse large B-cell lymphoma. 2020 ASCO Virtual Scientific Program. Abstract 8020. Presented May 29, 2020.
12. Thieblemont C, Chevret S, Allain V, et al: Lenalidomide enhances CAR T-cell response in patients with refractory/relapsed large B-cell lymphoma experiencing progression after infusion. 2020 ASH Annual Meeting & Exposition. Abstract 1115. Presented December 5, 2020.
13. Caimi PF, Ai WZ, Alderuccio JP, et al: Efficacy and safety of loncastuximab tesirine (ADCT-402) in relapsed/refractory diffuse large B-cell lymphoma. 2020 ASH Annual Meeting & Exposition. Abstract 1183. Presented December 5, 2020.
14. Imber BS, Sadelain M, DeSelm C, et al: Early experience using salvage radiotherapy for relapsed/refractory non-Hodgkin lymphomas after CD19 chimeric antigen receptor (CAR) T cell therapy. Br J Haematol 190:45-51, 2020.
