Chimeric antigen receptor (CAR) T-cell therapy has made great strides in treating patients with relapsed or refractory diffuse large-B cell lymphoma (DLBCL) and refractory mantle cell lymphoma (MCL), but there may be newer strategies that can produce equivalent outcomes, and not all patients with relapsed or refractory disease may need to be treated with CAR T cells, explained Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, who spoke at the National Comprehensive Cancer Network® (NCCN®) 2020 Virtual Congress: Hematologic Malignancies.1
CAR T cells are manufactured from each patient’s individual T cells, which are leukopheresed, isolated, transduced with CAR, expanded and purified, and then reintroduced into the patient after cytoreductive chemotherapy. Manufacturing CAR T-cell therapy is a time-consuming, expensive, laborious process, and once the CAR T cells are reinfused, the therapy is associated with serious toxicity. That said, CAR T-cell therapy can be life-saving for patients who have run out of other treatment options.
“Updated ZUMA-1 data show a plateau in progression-free survival and overall survival. We would expect a long-term survival plateau in the range of 5% to 10%, but it is approximately 40%.”— Andrew D. Zelenetz, MD, PhD
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The first two CAR T-cell products approved by the U.S. Food and Drug Administration for the treatment of pediatric acute lymphoblastic leukemia (ALL) and adult DLBCL were axicabtagene ciloleucel and tisagenlecleucel. Axicabtagene ciloleucel is also approved for the treatment of MCL. Brexucabtagene autoleucel was recently approved for patients with MCL that does not respond to other treatments or has recurred. And a CD19-directed CAR T-cell therapy, lisocabtagene maraleucel, is close to approval.
Complications of CAR T-Cell Therapy
Two major toxicities associated with CAR T-cell therapy are cytokine-release syndrome and immune cell–associated neurologic syndrome.
Cytokine-release syndrome is characterized by a so-called cytokine storm, which can involve hemodynamic changes, decreased protein and albumin, coagulopathy, cardiac arrhythmia, elevated risk of hepatic and renal dysfunction, and elevated serum cytokines. With experience, researchers found that cytokine-release syndrome could be treated with tocilizumab with or without corticosteroids.
CAR T-cell–associated neurologic syndrome can manifest with neurologic signs and symptoms that include an inability to find words, confusion, progression to coma, cerebral edema, and seizures. “[Immune cell–associated neurologic syndrome] can be severe. It generally occurs 2 to 4 days after cytokine-release syndrome. Most often it is reversible, but there have been fatalities, and it is not clear what treatments are effective,” Dr. Zelenetz told listeners.
Criteria have been developed for grading cytokine-release syndrome and for treating it. “The big questions have been: Are vasopressors necessary? Is there a need for high-flow oxygen?” he said.
The American Society for Transplantation and Cellular Therapy (ASTCT) grading system states that grade 3 or 4 cytokine-release syndrome requires vasopressors; grade 3 also requires high-flow nasal cannula, and grade 4 requires positive pressure, intubation, and mechanical ventilation.2
In addition, the ASTCT has developed consensus guidelines for grading immune cell–associated neurologic syndrome, from grades 1 through 4. The severity of symptoms is categorized as mild to moderate for grades 1 and 2 vs more severe symptoms for grades 3 and 4.2
“The ASTCT criteria are only one set of guidelines. There are other guidelines, and data may be conflicting, depending on the criteria used in different studies,” he explained.
Clinical Trials of CAR T Cells
“For patients with DLBCL in second relapse after high-dose chemotherapy and stem cell transplant rescue who do not achieve remission with second-line therapy, the median survival is about 6 months,” Dr. Zelenetz explained. “This was the setting for the ZUMA-1 trial.”
“Studies show that all three CAR T-cell agents represent a new treatment for relapsed or refractory DLBCL. This includes transformed follicular lymphoma and transformed marginal zone lymphoma.”— Andrew D. Zelenetz, MD, PhD
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ZUMA-1 was a phase I (n = 7) and phase II (n = 101) trial that enrolled a total of 108 patients with refractory DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma in two cohorts: cohort 1 included patients with DLBCL and cohort 2 included all others.3 Overall, 77 patients had DLBCL and 24 had transformed follicular lymphoma.
“These patients were in bad shape. About 26% had primary refractory disease and 53% were refractory to two prior lines of therapy. Almost 70% had received at least three prior lines of therapy,” Dr. Zelenetz emphasized.
Nearly all patients experienced an adverse event. Approximately 81% had cytokine-release syndrome. Grade 3 or 4 neurologic events were reported in 30%.
More than half the patients (54%) achieved a complete response, and 20% had a partial response. At a median follow-up of 27.1 months, the median duration of response was 11 months; median progression-free survival was 5.9 months and median overall survival was not reached.
“Updated ZUMA-1 data show a plateau in progression-free survival and overall survival. We would expect a long-term survival plateau in the range of 5% to 10%, but it is approximately 40%,” he said.
“There was some predictability. Better expansion of T cells after infusion predicted for a more likely ongoing response,” Dr. Zelenetz noted.
The JULIET trial enrolled 111 patients with relapsed or refractory DLBCL treated with tisagenlecleucel.4 The population had baseline characteristics similar to those enrolled in ZUMA-1. About 52% had been exposed to three or more prior lines of therapy.
At 1 year, the overall response rate was 52% (40% complete response, 12% partial response). One year after response, 65% of responders were relapse-free.
Every patient experienced adverse events, and 65% had serious adverse events. Adverse events of grade 3 or 4 included cytokine-release syndrome (22%), neurologic effects (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (12%).
“This therapy was somewhat better tolerated than axicabtagene ciloleucel, with less neurologic toxicity. And it was effective in all subgroups. The survival plateau was similar to what we saw in ZUMA-1, but around 30% to 35%,” he said.
Lisocabtagene maraleucel was studied in the TRANSCEND trial in patients with relapsed or refractory DLBCL.5 More than 50% of patients had received three or more prior lines of therapy. Unlike the previous two trials, toxicity was mild, and the rates of grade 3 or 4 cytokine-release syndrome (2%) and neurologic toxicity (10%) were relatively low.
The overall response rate in TRANSCEND was 73%, with activity across all subgroups. The survival plateau is approximately 40%.
“Lisocabtagene appears to be the safest of the three CAR T-cell products,” Dr. Zelenetz commented. “Studies show that all three CAR T-cell agents represent a new treatment for relapsed or refractory DLBCL. This includes transformed follicular lymphoma and transformed marginal zone lymphoma.”
Are CAR T Cells Absolutely Required?
“Some patients achieve a partial response from high-dose chemotherapy and stem cell transplant. The thinking now is that if the patient is not in complete response, you can go on to CAR T cells,” he explained.
A study that included 67 patients with DLBCL and early (< 12 months) or late (≥ 12 months) chemoimmunotherapy failure evaluated outcomes in patients who were positron-emission tomography (PET)-positive and in partial response after second-line chemotherapy and went on to autologous hematopoietic cell transplant (HCT).6 Nonrelapse mortality was low. Disease progression was reported in about half the patients. The progression-free/overall survival plateau was around 45%, which is similar to results in third-line therapy with CAR T cells.
“This raises the question of whether you have to go on to CAR T-cell therapy, or can you continue with high-dose chemotherapy and stem cell transplant,” he said. “A randomized trial is needed to compare CAR T-cell therapy with autologous HCT before CAR T-cell therapy replaces transplant.”
Mantle Cell Lymphoma
“MCL is a bit more of a challenge than DLBCL. Frequently, patients with this disease have circulating tumor cells,” Dr. Zelenetz said.
The ZUMA-2 trial enrolled 74 patients with refractory MCL treated with brexucabtagene autoleucel (formerly KTE-X19), a CAR T-cell product that eliminates MCL cells.7 After leukapheresis, patients had the option of bridging therapy, then conditioning chemotherapy, and then infusion of brexucabtagene autoleucel. All patients had previous treatment with a Bruton’s tyrosine kinase inhibitor.
“This was a population with unfavorable disease characteristics. About 82% had Ki67 proliferation; 17% had TP53 mutations,” he said.
After CAR T-cell treatment, nearly 91% had any-grade cytokine-release syndrome, and grade 2 or higher cytokine-release syndrome was reported in 15%. About 61% had a neurologic event; grade 3 or higher neurologic toxicity was seen in 31%. None of these toxicities were fatal.
Brexucabtagene autoleucel had broad activity in this population. The response rate was above 90%, and activity was seen across all subgroups, including those with or without TP53 mutations.
“In patients with chemorefractory disease, CAR T-cell therapy represents a major step forward. It can provide durable complete responses in a portion of patients. However, there is room for improvement.”— Andrew D. Zelenetz, MD, PhD
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Data are not as mature as those from ZUMA-1 and JULIET, but the survival plateau is around 50%. “These data are exciting, but we need longer-term follow-up,” Dr. Zelenetz said. “Classically, we see late responses. We will see additional trials of CAR T-cell therapy in MCL.”
CAR T-cell therapy is now included in the NCCN algorithm for relapsed/refractory MCL.
Concluding Remarks
“In patients with chemorefractory disease, CAR T-cell therapy represents a major step forward. It can provide durable complete responses in a portion of patients. However, there is room for improvement,” Dr. Zelenetz said.
“For chemosensitive patients, it’s not clear that CAR T-cell therapy is clearly superior to high-dose chemotherapy and stem cell transplant if the patient is PET-positive after chemotherapy. Additional randomized trials are needed, and they are ongoing as we speak,” he added.
DISCLOSURE: Dr. Zelenetz holds stock or other ownership interests in Adaptive Biotechnologies; has received honoraria from Clinical Care Options, NCCN, Oncology Information Group, and PER; has served in a consulting or advisory role for Amgen, AstraZeneca, BeiGene, Cancer Support Community, Celgene, DAVA Oncology, Genentech/Roche, Gilead Sciences, Janssen, Karyopharm Therapeutics, Medscape, MEI Pharma, MorphoSys, Novartis, Pfizer, Pharmacyclics, Prime Education, TRM Oncology, Vaniam Group, and Verastem; and has received research funding from BeiGene, Genentech/Roche, Gilead Sciences, and MEI Pharma.
REFERENCES
1. Zelenetz A: Is it time to consider CAR-T for all patients with relapsed/refractory diffuse large B-cell lymphoma and mantle cell lymphoma? NCCN 2020 Virtual Congress: Hematologic Malignancies. Presented October 9, 2020.
2. Lee DW, Santomasso BD, Locke FL, et al: ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant 25:625-638, 2020.
3. Neelapu S, Locke FL, Bartlett NL, et al: Axicabtagene ciloleucel CAR-T therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531-2544, 2017.
4. Schuster SJ, Bishop MR, Tam CS, et al: Tisagenlecleucel in adult relapsed or refractory large B-cell lymphoma. N Engl J Med 380:45-56, 2019.
5. Abramson JS, Palomba ML, Gordon LJ, et al: Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 100): A multicenter seamless design study. Lancet 396:838-852, 2020.
6. Shah NN, Ahn KW, Litovich C, et al: Is autologous transplantation in relapsed diffuse large B-cell lymphoma patients achieving only a PET/CT positive partial remission appropriate in the CAR-T era? ASCO20 Virtual Scientific Program. Abstract 8000.
7. Wang M, Munoz J, Locke FL, et al: KTE-X19 CAR-T-cell therapy in relapsed or refractory mantle cell lymphoma. N Engl J Med 382:1331-1342, 2020.
