CAR T Cells Encouraging for Diffuse Large B-Cell Lymphoma

Nancy A. Melville

June 27, 2017

MADRID — Two investigational chimeric antigen receptor (CAR) modified T-cell therapies, both targeting CD19, have shown encouraging response rates in the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), with adverse events that raise concerns but so far appear manageable.

New findings with the two products were presented here at the European Hematology Association (EHA) 2017 Congress.

Gilles Salles, MD, head of the Department of Hematology at the Hospices Civils de Lyon, Université Claude Bernard, France, reported results from a global, pivotal phase 2 trial of CTL019 that he described as "impressive."

"This analysis of CTL019 in adults with relapsed or refractory DLBCL confirms the high response rates and durable responses observed in the previous single-center trial," Dr Salles said.

DLBCL, the most common type of lymphoma, accounts for approximately 30% of cases of non-Hodgkin's lymphoma. Relapsed or refractory DLBCL is especially aggressive, with very poor prognosis. Median overall survival in patients in whom second-line salvage therapy fails is only about 4.4 months, with a 1-year overall survival rate of just 23%.

CTL019 previously raised interest in a proof-of-concept study at the University of Pennsylvania, Philadelphia, that showed durable remissions with a single infusion of the therapy in 15 patients with relapsed or refractory DLBCL.

The overall response rate was 47% at months 3 and 6, and 20% and 40% of patients achieved complete responses at these time points, respectively. Another 27% and 7% had partial responses at months 3 and 6.

On the basis of these findings, the US Food and Drug Administration granted CTL019 breakthrough therapy status for the treatment of adult patients with relapsed and refractory DLBCL in whom two or more prior therapies have failed.

The new trial presented at the meeting was a phase 2 study, known as JULIET. This single-arm, open-label, multicenter trial took place at 27 sites around the world, Dr Salles commented. He reported a planned interim analysis from this trial, with results on 85 patients evaluated for safety and 51 evaluated for response. Data reflected a median time from infusion to cutoff of 3.7 months.

Patients had a median age of 56 years (range, 24 to 75 years), had relapsed or had progression after at least two lines of therapy, and were not candidates for stem cell transplant.

With a median dose of CTL019 3.1 × 108 (range, 0.1 to 6.0 × 108) cells, patients with 3 months or more of follow up or earlier discontinuation showed a best overall response rate of 59% (95% confidence interval, 44% - 72%; P < .0001); 43% had a complete response and 16% had a partial response, meeting the study's primary endpoint.

The complete and partial response rates at the 3-month time point were 37% and 8%, respectively, for an overall response rate of 45%.

The rate of relapse-free survival at 6 months was 79%, and all patients who achieved complete response at 3 months remained in that status until the data cutoff.

Efficacy did not differ in terms of prognostic subgroups, and no median duration of response was reached.

Among responders, CTL019 was detectable in peripheral blood for up to 355 days.

In terms of safety, cytokine release syndrome (CRS), which has been an issue in other CAR T-cell trials and has led to several deaths in other studies, occurred in 57% of patients, including grade 3 in 17% and grade 4 in 9%.

Dr Salles noted, however, that CRS was managed with the interleukin-6 antagonist tocilizumab (Actemra, Genentech) in 16% of patients, and there were no CRS-associated deaths.

He added that the grading scale used in the trial was more stringent than those used in other trials. In other words, patients with grade 2 or 3 in other trials would have been graded 3 or 4 in JULIET, he told Medscape Medical News.

"This is well reflected by the use of the main agent used in case of CRS, the anti-IL-6 [anti-interleukin-6] tocilizumab MoAb [monoclonal antibody] that was only necessary in 16% of the patients," Dr Salles said.

"And while 24% of the patients were admitted in an intensive care unit, only 8% of the patients were intubated."

Neurologic events occurred in 13% of patients, and all cases were managed with supportive care. In encouraging news, there were no cases of cerebral edema, which also has been a concern in CAR T-cell trials and have resulted in some deaths.

Grade 3 to 4 cytopenias lasting more than 28 days occurred in 21% of patients, and grade 3 to 4 febrile neutropenia occurred in 14% of patients.

Three patients died of disease within the first 30 days of infusion, but no deaths were attributed to CTL019.

"Adverse events in the trial were reversible and effectively managed by appropriately trained study site personnel," Dr Salles said.

He noted that another important aspect of the trial was the inclusion of older patients. Twenty percent in the trial were older than age 65 years, and the oldest patients were treated at age 75 years.

"While autologous transplant can be offered to fit patients of this range of age, this remains infrequent — particularly in Europe — and these patients are usually more exposed to short- and long-term toxicities," Dr Salles explained.

Furthermore, he said, if the standard salvage of autologous stem cell transplantation (ASCT) fails, patients have even fewer options.

"Hence, being able to develop active therapy in patients older than 65 and who may not be considered as standard candidates for ASCT or have failed ASCT represents [significant] progress for this group of patients, particularly since the median age of DLBCL at diagnosis is close to 62 years."

CAR T-cell therapy has gained interest not only for the encouraging early results but for the innovative, individualized therapeutic approach, in which patients' T cells are drawn and then reprogrammed in the lab to engage and eliminate the patient's cancer cells.

Dr Salles noted that the JULIET trial is the first global study of a CAR T-cell therapy in relapsed or refractory DLBCL with centralized manufacturing.

Axi-Cel Preliminary Results Also Encouraging

In the second anti-CD19 therapy showing encouraging results, Yi Lin, MD, from the Mayo Clinic in Rochester, Minnesota, presented findings from a primary analysis of the multicenter, phase 2 ZUMA-1 trial on axicabtagene ciloleucel (axi-cel).

The study involved 101 patients with relapsed or refractory DLBCL (n = 72) or refractory primary mediastinal B-cell lymphoma or transformed follicular lymphoma (n = 20), who were treated with axi-cel at a target dose of 2 × 106 cells/kg.

The study met its primary endpoint with an objective response rate of 82% in the first 92 patients who were dosed (P < .0001) and a complete response rate of 54%.

"The complete response rate of 54% is approximately seven-fold higher than the historic control rate of 8%," Dr Lin said.

At a median follow-up of 8.7 months, 44% of patients were in response and 39% were in complete response, she added.

In terms of safety, grade 3 or higher CRS occurred in 13% of patients and neurologic events occurred in 28%.

The most common grade 3 or higher treatment-emergent events were neutropenia (66%), leukopenia (44%), anemia (43%), febrile neutropenia (31%), and encephalopathy (21%).

Dr Lin noted that CRS and neurologic events were generally reversible, and the rates decreased over the course of the study.

"The incidences of severe CRS and neurologic events decreased over the course of the study, suggesting that the study teams at the participating sites have become more familiar with management of these side effects," Dr Lin told Medscape Medical News.

In addition, she noted that "the use of tocilizumab and steroid, drugs commonly given for management of these side effects, was not associated with decreased clinical response.

"This composite profile of clinical response and side effect makes axi-cel a paradigm-changing treatment option for patients with refractory non-Hodgkin lymphoma who have no curative options."

Dr Lin added that axi-cell had a 99% success rate in the manufacturing process of the cells in the study, successfully producing cells for 110 of 111 patients.

"As can be imagined, it would be nerve-wracking for patients to wait and wonder if CAR T is being successfully made or if they will need to come off the study and look at other treatments despite waiting," she explained.

"We can say with confidence, given the manufacturing success rate of the study, that we can almost always make axi-cel for the patient once we collect the blood cells."

The turnaround time for the process was also notably short, relative to the longer process with earlier CAR T therapies that put patients at risk for advancing cancer while they were awaiting the cell programming.

"In the ZUMA-1 trial, the average time between collection of a patient's blood cells and shipment back of axi-cel to the treatment site is only 17 days," Dr Lin noted.

"For the other trials, it is more in the range of 4 weeks. This can make a huge difference in patients with actively progressing lymphoma."

For CTL019, the median turnaround time for manufacturing cells was 29 days, from receipt of the frozen apheresis to the central manufacturing facility to product delivery, Dr Salles said.

CRS a Key Concern With CAR T-Cell Therapy

As CAR T-cell therapies advance, researchers have been noting the characteristics associated with an increased risk for CRS, including a study presented at the 2016 American Society of Hematology meeting showing distinct cytokine profiles in patients with tocilizumab-refractory CRS triggered by CAR T-cell therapy.

Such research is only beginning to provide some of the much-needed answers regarding CAR T-cell therapy, said Anton Hagenbeek, MD, PhD, professor of hematology in the Academic Medical Center at the University of Amsterdam, the Netherlands.

"Some cytokine profiles (linked to a CRS risk) are beginning to pop up, but the final word is not known yet," he told Medscape Medical News.

"With more patients enrolled in these kinds of studies, we will be able to better clarify the risk."

Dr Hagenbeek noted that while the reversibility of CRS in the two current studies is encouraging, the risk should be considered before a clinician attempts CAR T-cell therapy.

"Not a single patient has died in either study as a result of CRS due to the treatment. However, CRS is a very significant syndrome and only doctors who are experienced in treating that side effect should be allowed to provide CAR T-cell therapy," he said.

Emerging data should meanwhile also provide better answers on which patients, in general, will be the best candidates, Dr Hagenbeek said.

"We need more patients and more data to determine at which phase of the disease it will be most effective to treat with CAR T cells, but those at the highest risk, such as double-hit or triple-hit B-cell lymphomas are [possible candidates] because they fare very poorly with RCHOP [cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab]."

The CTL019 study was sponsored by Novartis Pharmaceuticals Corp, and the ZUMA-1 trial was sponsored by Kite Pharma Inc. Dr Salles has received compensation from Amgen, BMS, Celgene, Gilead, Janssen, Kite, Merck, MorphoSys, Novartis, Roche, and Servier. Dr Hagenbeek is involved in research in the ZUMA-1 trial in Europe but had no disclosures to report relating to the drugs discussed.

European Hematology Association (EHA) 2017 Congress. Abstracts LB2604 and S466. Presented June 25, 2017.

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