Tabelecleucel Shows High Response Rates in Patients with EBV-Associated Posttransplant Lymphoma Refractory to Rituximab

October 2018, Vol 8, No 10

Patients with Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorders (PTLD) who do not respond to first-line rituximab (Rituxan) therapy are extremely difficult to manage, said Susan E. Prockop, MD, Pediatric Oncologist, Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York City, at the 2018 European Hematology Association Congress.

However, a clinical trial with tabelecleucel showed that this “off-the-shelf” allogeneic T-cell therapy produced high overall response rates (ORRs) and durable responses in patients with EBV-PTLD who did not respond to rituximab treatment after allogeneic hematopoietic stem-cell transplant (HSCT) or solid-­organ transplant.

Promising Immunotherapy

Dr Prockop noted that tabelecleucel is bioengineered from donors with healthy immune function and does not require pretreatment. The tabelecleucel EBV-targeted T-cells, which are collected according to specific human leukocyte antigen (HLA) restrictions, are stocked in varieties that cover 90% of patients with EBV-PTLD. Once introduced to the patient’s body, the tabelecleucel T-cells proliferate in response to the HLA, which drives sustained responses that initiate cytotoxicity against EBV-expressing tumor cells.

EBV infection is widespread, lifelong, and generally asymptomatic; however, this infection is implicated in a wide variety of lymphoproliferative disorders, including lymphomas.

“In immunocompromised patients, including those undergoing allogeneic hematopoietic-cell transplant or solid-organ transplant, EBV-PTLD is really an infectious complication of immune suppression. It is a life-threatening condition,” said Dr Prockop in an interview at the meeting.

In patients who do not respond to first-line rituximab treatment after allogeneic HSCT, the median overall survival (OS) is 16 to 56 days. After solid-organ transplant in this population and nonresponse to ri­tuximab therapy, chemotherapy-induced treatment-related mortality is higher than for other patients with lymphoma (36% and 0% at 1 and 2 years, respectively).

Results From 2 Studies

Dr Prockop presented data from 49 patients with EBV-PTLD who had not responded to or whose disease relapsed after receiving rituximab. They were enrolled in 2 studies and had undergone allogeneic HSCT (N = 35; median age, 28 years) or solid-organ transplant (N = 14; median age, 18 years).

The ORRs (ie, complete responses plus partial responses) after a median follow-up of 23.3 months were 68.8% and 50.0% in the HSCT and solid-organ transplant groups, respectively, with complete responses in 57.1% and 14.3%, respectively. Responder analyses revealed a 2-year OS rate of 83% in patients who had HSCT and 86% in patients who had solid-organ transplant. None of the patients responding to tabelecleucel died from EBV-PTLD.

Patients who did not achieve a complete or partial response to tabelecleucel had short OS (median of 1.7 months after allogeneic HSCT vs 1.2 months after solid-­organ transplant). Most of the patients died from progression of the PTLD itself.

In this population of “quite ill” patients with multiple comorbidities, tabelecleucel was well-tolerated and no treatment-emergent adverse events were definitively attributed to tabelecleucel.

“Tabelecleucel elicits high overall response rates in subjects with difficult-to-treat Epstein-Barr virus–associated posttransplant lymphoproliferative disorder following allogeneic hematopoietic-cell transplant or ­solid-organ transplant for whom ­rituximab treatment has failed,” Dr Prockop added.

She noted that further research will seek means to sensitize nonresponding tumors to T-cells. Treating patients with tabelecleucel in earlier disease states may also improve responses.

Impressive Data

“Lymphoma that arises after transplantation, either solid-organ or hematopoietic stem-cell, is notoriously difficult to treat,” said Ran Reshef, MD, MSc, Director, Translational Research, Blood and Marrow Transplantation, Columbia University Medical Center, New York City, in an interview. Dr Reshef is an investigator in the 2 currently active clinical trials with tabelecleucel.

“This is usually driven by the fact that these patients do not have an intact immune system, because they are receiving immunosuppressive medications. Many have been through multiple medical procedures, or, among children, many are on dialysis and present a huge treatment challenge,” Dr Reshef said.

“So, to have a therapy with a very good safety and tolerability profile is a major breakthrough. These are extremely strong data showing how potent this type of therapy can be,” he added.

He underscored that the “off-the-shelf” feature offers a large advantage over autologous approaches that require 3 to 5 weeks of turnaround to harvest cells and put them through a manufacturing process, during which time disease progression can occur.

Tabelecleucel is currently being investigated in 2 phase 3 clinical trials of patients with PTLD, one for patients who had undergone allogeneic HSCT (NCT03392142) and one for patients who had undergone solid-­organ transplant (NCT03394365).

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