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JCAR017 Shows Promising Activity, Mild Toxicity in CD19+ Lymphoma

Silas Inman @silasinman
Published: Thursday, Dec 08, 2016

Dr Jeremy S. Abramson

Jeremy S. Abramson, MD

The CD19-directed CAR T-cell therapy JCAR017 demonstrated a 60% complete response (CR) rate in patients with relapsed or refractory CD19-positive non-Hodgkin lymphoma (NHL), according to findings from the multicenter, phase I TRANSCEND study presented at the 2016 ASH Annual Meeting.

The study administered JCAR017 at various doses to patients with diffuse large B-cell lymphoma (DLBCL), grade 3b follicular lymphoma, and mantle cell lymphoma (MCL). The overall response rate (ORR) with the lowest dose of the therapy was 80%. CRs were seen in patients with double- and triple-hit lymphoma and for 1 patient with CNS disease. After 3 months of follow-up, 42% of assessable patients remained in response.

"Thus far, JCAR017 is producing encouraging overall and complete response rates in highly chemotherapy-refractory diffuse large B-cell lymphoma, for which no current standard therapy exists," said lead investigator Jeremy S. Abramson, MD, from Massachusetts General Hospital Cancer Center. "More time is needed to see how durable these remissions prove, but thus far a number of responding patients continue in ongoing remission at limited follow-up."

There were fewer adverse events (AEs) seen with JCAR017 compared with other CD19-targeted CAR T-cell therapies. None of the enrolled patients experienced severe cytokine release syndrome (CRS). Thirty-six percent of patients had grade 1/2 CRS and just 1 participant required treatment with tocilizumab. Additionally, 5 patients (14%) had severe neurotoxicity, all of which resolved with treatment.

"The toxicity profile has been notable for low rates of both cytokine release syndrome and neurotoxicity, with no cases of severe cytokine release syndrome observed to date, and all cases of CRS and neurotoxicity being reversible," Abramson noted.

In the phase I study, patients underwent leukapheresis at study entry for the manufacturing of the CAR T cells. Prior to JCAR017 infusion, patients received lymphodepleting chemotherapy with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2) daily for 3 days. A modified continual reassessment method was utilized to determine CAR T cell dose level (DL), to avoid potential AEs. Three DLs were utilized: 5 x 107 cells (DL1), 1 x 108 cells (DL2), and 1.5 x 108 cells (DL3).

The median age of patients was 63 years, and NHL subtypes included DLBCL (n = 15), transformed DLBCL (n = 10), MCL (n = 2), and follicular grade 3b (n = 1). Eighty-six percent of patients were refractory to their last therapy and 82% were chemorefractory. Patients had ECOG performance statuses of 0 (50%), 1 (36%), and 2 (14%).

Patients had received a median of 4 prior therapies (range, 1-8), and a quarter had received ≥5 prior lines of therapy. Overall, 57% of patients received stem cell transplants, which were allogeneic (14%) and autologous (46%).

In 27 efficacy evaluable patients treated across doses, the ORR was 78%, with a CR rate of 52%. Those with chemorefractory DLBCL (n = 16) had an ORR of 75%, which included a CR rate of 56%. Overall, 2 patients had double-hit, 3 had triple-hit, and 4 had double-expresser DLBCL. Within this group of 9 patients with aggressive subtypes, there were 7 CRs and 2 PRs. 

In a small cohort of patients with DLBCL treated with a double dose at DL1 (n = 3), the ORR was 67%. One of 2 patients with MCL responded to a single-dose of DL1. Additionally, 2 patients received a single dose of DL2, which elicited a CR rate of 100%. Furthermore, assessment of safety with DL2 did not reveal severe CRS or grade 3/4 neurotoxicity.

The most common all-grade treatment-emergent AEs across all patients and dose (N = 28) were fatigue (39%), CRS (36%), decreased appetite (29%), constipation (25%), vomiting (25%), diarrhea (21%), dizziness (21%), headache (18%), hypertension (18%), nausea (18%), and peripheral edema (18%). There was 1 grade 5 respiratory failure in a patient with MCL who progressed on JCAR017 and had begun subsequent therapy. This was deemed to be potentially related to JCAR017.

Four patients required treatment with dexamethasone and 1 received tocilizumab. No patients were treated with vasopressors and anti-epileptics were initiated for 1 patients with CNS lymphoma and for 5 experiencing neurotoxicity symptoms.

In addition to JCAR017, Juno Therapeutics, the developer of the medication, is also exploring the CD19-targeted CAR T-cell therapy JCAR015. The phase II ROCKET study assessing JCAR015 for relapsed or refractory B cell acute lymphoblastic leukemia was placed on hold, following several cases of cerebral edema. However, given its more mild toxicity profile, the JCAR015 setback should not impact JCAR017, as the 2 therapies are different, Abramson noted.

"Currently the other JCAR therapy in multicenter clinical trials is JCAR015, which is being studied in acute lymphoblastic leukemia," he said. "The primary difference between the products is that JCAR017 uses 41BB as the co-stimulatory domain, while JCAR015 uses CD28. Of course, the patient populations between these two studies are quite different as well."

The TRANSCEND trial continues to recruit patients with NHL, with a target enrollment of 144 (NCT02631044). A phase II study will be opened soon to continue to assess JCAR017 for patients with relapse/refractory DLBCL.
Abramson JS, Palomba L, Gordon  LI, et al. Transcend NHL 001: Immunotherapy with the CD19-Directed CAR T-Cell Product JCAR017 Results in High Complete Response Rates in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 4192.

 



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