April 24, 2022

Jason Harris

Abatacept significantly reduced steroid-refractory chronic graft versus host disease and the use of prednisone following allogeneic hematopoietic stem cell transplantation.

Abatacept (Orencia) significantly reduced steroid-refractory chronic graft versus host disease (cGVHD) and the use of prednisone following allogeneic hematopoietic stem cell transplantation (HCT), according to phase 2 findings (NCT01954979) presented at the 2022 Tandem Meetings.1

“Abatacept was associated with a 58% overall response rate in steroid-refractory cGVHD,” said lead author Anita G. Koshy, MD, a clinical fellow in medicine at Beth Israel Deaconess Medical Center. “There was a durable reduction in prednisone dosing over time, severe infections were uncommon, and the infusions were well tolerated. Correlative immune studies are ongoing to better understand the mechanism of action of abatacept and chronic GVHD.”

Investigators defined steroid-refractory cGVHD as persistent signs and symptoms of cGVHD despite the use of 0.5 mg/kg daily prednisone for at least 4 weeks.

Thirty-nine patients who had undergone HCT a median of 43 months prior to the study received abatacept and 36 were evaluable for overall response rate (ORR). Eighteen patients had moderate cGVHD at baseline and 21 had severe cGVHD. Patients received a median of 5 (range, 1-11) previous treatments for cGVHD.

Investigators administered 10 mg/kg abatacept every 2 weeks for 3 doses. One month after administration of the third dose, patients received 3 additional doses every 4 weeks. One month later, patients received the sixth dose of abatacept.

Koshy and her colleagues assessed patients for response 1 month after administration of the sixth dose and observed an ORR of 58%. All responses were partial.

Patients who completed 6 doses of abatacept and continued to demonstrate response were eligible to receive up to 12 additional doses.

At baseline, skin (84%) was the most common site of cGVHD, followed by joints (82%), eyes (72%), lung (56%), mouth (44%), liver (23%), and gastrointestinal (GI) tract (15%).

“The most improved organ sites included the skin in 22% of patients, the mouth in 22% of patients, the eyes in 25% of patients, lung in 36% of patients, and joints in 22% of patients,” Koshy said. “Progression of disease occurred in 33% of patients and included organs such as the skin, mouth, eyes, liver, lung, and joints.”

Rate of cGVHD declined to 8% in patients with GI involvement.

Koshy added that abatacept led to a durable reduction in prednisone use. At baseline, the median daily dose of prednisone 20 mg per day. “There was a 27.5% reduction in the prednisone dose to 14.5 mg by the 1 month follow up time point,” she said.

At the 4-month follow-up, prednisone dose further declined to 10 mg per day.

Eligible patients had received allogeneic bone marrow or stem cell transplantation with myeloablative or reduced intensity conditioning regimens. They had to be at least 100 days removed from transplantation or donor lymphocyte infusion to enroll.

Patients were not allowed to change immunosuppressive medications for at least 4 weeks prior to enrollment and had to be on a stable immunosuppressive regimen for 2 weeks prior to enrollment.

The median patient age was 62 years (range, 25-77) and most patients were female (53.8%). The majority of patients had an ECOG performance score of 1 (69.2%) or 2 (28.2%). The most common sites of primary disease were acute myeloid leukemia (46.2%), myelodysplastic syndrome (20.5%), and acute lymphoblastic leukemia (12.8%).

The majority of patients (89.7%) received peripheral blood stem cell transplantation. The remainder underwent bone marrow transplant.

For conditioning intensity, 61.5% of patients received myeloablative conditioning while 35.9% received nonmyeloablative.

Just over half (56.4%) of patients received matched unrelated human leukocyte antigens (HLA) and 38.4% received matched related HLA. One (2.6%) patient each received mismatched related and mismatched unrelated HLA.

The most common grade 3/4 adverse event possibly related to abatacept treatment was neutropenia in 4 patients. Investigators observed serious grade 3/4 lung infections in 3 patients. One patient experienced grade 4 hemolysis, respiratory failure, and hepatic failure, and eventually died of concurrent HSV hepatitis while on treatment.

“Immune correlative studies are ongoing to help us better understand the mechanism by which abatacept may work in the treatment of cGVHD,” Koshy said in conclusion. “Thus far, T cell polarization assessments by flow cytometry have shown no difference in [interleukin] 10 and interferon gamma expression by CD4-positive T cells before and after treatment in our clinical responders. However, cytokine profiling of patient plasma and single cell RNA sequencing are currently underway to help us to better understand changes to the immune microenvironment potentially caused by abatacept.”

Reference

  1. Koshy AG, Kim HT, Stroopinksy D, et al. Phase II clinical trial of abatacept for steroid-refractory chronic graft versus host disease. Presented at: the 2022 Transplantation & Cellular Therapy Meetings; Salt Lake City, UT; April 23-26, 2022. Abstract 32.

December 14, 2021

Jessica Hergert

As second-line treatment, tisagenlecleucel failed to demonstrate an event-free survival advantage compared with standard of care platinum-based chemotherapy followed by autologous stem cell transplant or additional chemotherapy in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma.

As second-line treatment, tisagenlecleucel (Kymriah) failed to demonstrate an event-free survival (EFS) advantage compared with standard of care (SOC) platinum-based chemotherapy followed by autologous stem cell transplant (ASCT) or additional chemotherapy in patients with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma (NHL), according to findings from an analysis of the phase 3 BELINDA trial (NCT03570892) that were presented during a press briefing at the 2021 ASH Annual Meeting.1

“EFS was identical between the 2 arms,” said lead study author Michael R. Bishop, MD, a professor of medicine and director of the Hematopoietic Stem Cell Transplantation Program at the University of Chicago Medicine, during the press briefing.

“[Therefore], unfortunately, BELINDA did not meet its primary end point of improved EFS with tisagenlecleucel and the therapy was not found to be better than current available SOC,” Bishop added.

Approximately two-thirds of patients with B-cell NHL are essentially cured with frontline chemoimmunotherapy; however, a subset of patients who do not respond to initial therapy or relapse within 12 months following frontline therapy have poor outcomes and an expected survival of less than 12 months, Bishop explained.

In this subset, SOC options include platinum-based chemotherapy followed by ASCT in patients with chemotherapy-sensitive disease. However, more than half of these patients will not receive ASCT because of inadequate responses to second-line therapy.

Tisagenlecleucel, a CD19-directed CAR T-cell therapy, was FDA approved on May 1, 2018 for the treatment of adult patients with relapsed/refractory large B-cell lymphoma after at least 2 lines of prior systemic therapy.2 The regulatory indication included patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOC), high grade B-cell lymphoma (HGBL), and DLBCL arising from follicular lymphoma.

As tisagenlecleucel is an autologous CAR T-cell therapy, patients undergo leukapheresis to remove their T cells, which are then modified to effectively target the cancer. The modified cells are then infused back into the patient.

“Our hypothesis was that based upon the results in more advanced DLBCL that moving tisagenlecleucel treatment into up-front therapy for this poor-risk group of patients would result in improved outcomes, specifically EFS,” Bishop said.

The BELINDA trial randomized patients with confirmed relapsed/refractory aggressive NHL who recurred within 12 months following induction chemoimmunotherapy to tisagenlecleucel vs standard of care platinum-based chemotherapy followed by ASCT.

Overall, 396 patients were included in the screened set, but 74 patients did not complete screening to go onto leukapheresis. Therefore, 322 patients were included in the full analysis and safety sets. These patients were randomized 1:1 to tisagenlecleucel (n = 162; Arm A) or SOC (n = 160; Arm B). Ultimately, the tisagenlecleucel infused patient set included 236 patients comprised of 155 who were randomized to tisagenlecleucel and 81 who crossed over from Arm B.

In Arm A, 6 patients (3.7%) discontinued treatment without undergoing tisagenlecleucel infusion for reasons including physician decision (n = 2; 1.2%), progressive disease (PD; n = 2; 1.2%), manufacturing issue (n = 1; 0.6%), and patient decision (n = 1; 0.6%). In Arm B, 102 patients discontinued treatment without undergoing ASCT for reasons including progressive disease (n = 76; 47.5%), physician decision (n = 14; 8.8%), death (n = 7; 4.4%), patient decision (n = 2; 1.3%), technical problems (n = 2; 1.3%), and protocol deviation (n = 1; 0.6%).

Patients who received tisagenlecleucel underwent optimal bridging therapy with investigator’s choice of protocol-defined platinum-based chemotherapy regimens followed by lymphodepletion with, generally, 25 mg/m2 of daily fludarabine plus 250 mg/m2 of daily cyclophosphamide for 3 days. A single infusion of tisagenlecleucel was then given at a dose of 0.6 to 6 x 108 CAR T cells.

Patients who received SOC received investigator’s choice of platinum-based chemotherapy followed by ASCT in responders or a second platinum-based chemotherapy regimen in nonresponders.

The primary end point of the study was EFS, defined as the time from randomization to stable disease (SD) or PD at or after assessment at 12 weeks or death at any time. Moreover, SD or PD at 6 weeks was not considered an EFS event; however, the 6-week assessment evaluated disease burden before tisagenlecleucel infusion and after bridging therapy in patients enrolled to Arm A and determined whether patients enrolled to Arm B had a sufficient response to platinum-based chemotherapy to undergo ASCT.

Disease assessment was performed at 6 and 12 weeks; additional assessments were planned for every 3 months in the year following therapy and every 6 months in the second year following therapy.

Patients were stratified by first-line duration of response, International Prognostic Index (IPI), and geographic region.

Regarding baseline patient characteristics, disease subtypes in the tisagenlecleucel arm vs SOC arm, respectively, included DLBCL-NOS (62.3% vs 70%), HGBL with MYC and BCL2 and/or BCL6 (19.8% vs 11.9%), primary mediastinal large B-cell lymphoma (7.4% vs 8.1%), HGBL-NOS (4.3% vs 5%), grade 3B follicular lymphoma (3.1% vs 0.6%), and other (3.1% vs 4.4%). DLBCL cell of origin in the tisagenlecleucel arm vs SOC arm, respectively, was germinal center B-cell like (GCB; 28.4% vs 39.4%), non-GCB/activated B-cell (32.1% vs 26.3%), or unclassified/missing (1.9% vs 4.4%).

Remission durations in the tisagenlecleucel arm showed that 66% of patients were refractory, 18.5% relapsed less than 6 months following frontline treatment, and 15.4% of patients relapsed within 6 to 12 months. In the SOC arm, these rates were 66.9%, 20%, and 13.1%, respectively.

Most patients across arms were not based in the United States (70.5%), male (62.5%), younger than 65 years of age (68.9%), had IPI scores of at least 2 (61.5%), and had stage IV disease at the time of study entry (47.2%). Additionally, 43.2% of patients who received tisagenlecleucel vs 40.6% of patients who received SOC had an ECOG performance status of 1.

Most patients in both arms received 1 prior line of therapy for current lymphoma (98.8%) and did not have transformation of prior lymphoma (84.8%).

The median time since initial diagnosis was 8.4 months with tisagenlecleucel (Q1-Q3, 6.8-11.1) vs 8.2 months with SOC (Q1-Q3, 5.9-11.4). The median time since most recent relapse or PD was 1.4 months (Q1-Q3, 0.9-2.2) vs 1.1 months (Q1-Q3, 0.8-1.8), respectively.

The median time to randomization was 92 days (range, 61-158), and the median follow-up was 10 months (range, 2.9-23.2).

The safety profile of tisagenlecleucel was consistent with previously reported studies evaluating the therapy.

“We hope that the results of this study will be used to help design further trials in patients with DLBCL,” said Bishop.

Further details of the study will be published in the New England Journal of Medicine, Bishop concluded.

References

  1. Bishop MR, Dickinson M, Purtill D, et al. Tisagenlecleucel vs standard of care as second-line therapy of primary refractory or relapsed aggressive B-cell non-Hodgkin lymphoma: analysis of the phase III BELINDA study. Presented at: 2021 ASH Annual Meeting; December 9-14, 2021; Atlanta, GA. Abstract LBA-6.

  2. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. News release. FDA. May 1, 2018. Accessed December 13, 2021. https://bit.ly/3E0sxg5