T cell biomarker predicts CAR T cell therapy response in relapsed lymphoma

27th January 2023

A T cell biomarker pre-transfusion is predictive of a favourable response to CAR T cell therapy in patients with relapsed/refractory lymphoma

A T cell biomarker, represented by low levels of differentiated CD3⁺CD27^–CD28^– T cells before leukapheresis could serve as a novel marker to predict an individual’s response to CAR T cell therapy in those with relapsed/refractory diffuse large B cell lymphoma (DLBCL), according to a study by researchers from the Medical University of Vienna, Austria.

Chimeric antigen receptor (CAR) T cell therapy produces a durable response in patients with either relapsed or refractory DLBCL. However, trying to identify which groups of patients are likely to respond to therapy is difficult and currently based on lactate dehydrogenase after lymphodepletion, tumour volume and Eastern Cooperative Oncology Group performance status. Nevertheless, each of these three measures does not relate to the immune system. In the current study, the Austrian team looked at a particular T cell biomarker and made use of a matched group of healthy control patients for comparative purposes.

T cell biomarker and CAR T treatment response

A total of 33 patients (mean age = 61.8 years, 42.4% female) with either relapsed or refractory DLBCL were matched with a health control group of 24 patients (median age = 60, 41.7% female).

When compared to healthy controls, DLBCL patients had significant lymphopenia and a higher frequency of differentiated CD3⁺CD27^–CD28^– T cells (28.7% vs 6.6%, p < 0.001). There were 26 patients infused with CAR T cell therapy and the overall response (OR) 3 months after the infusion was 57.7%, with a complete response (CR) seen in 42.3% of patients.

In regression analysis, the Austrian team found that low levels of differentiated CD3⁺CD27^–CD28^– T cells (23.3% vs 35.1%) were independently associated with an overall response. In fact, the association was even more evident when patients were stratified by either complete remission or non-complete remission (13.7% vs 37.7%, p = 0.001). Using a cut-off value of below 18% of CD3⁺CD27^–CD28^– T cells was highly predictive of a complete response at 12 months (67% vs 13%, p = 0.009).

The authors concluded that a low number of CD3⁺CD27^–CD28^– T cells at leukapheresis represented a novel, pre-infusion T cell biomarker that enabled prediction of a CAR T cell response in patients with relapsed or refractory DLBCL.

Citation
Worel N et al. The frequency of differentiated CD3⁺CD27^–CD28^– T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma. Front Immunol 2023

Glofitamab fast and effective in refractory mantle cell lymphoma

9th January 2023

Glofitamab therapy following obinutuzumab induced a fast and durable complete response rate in patients with refractory mantle cell lymphoma

Glofitamab therapy following obinutuzumab pre-treatment, led to a fast and durable complete response rate in patients with refractory or relapsed mantle cell lymphoma after the use of Bruton tyrosine kinase inhibitors according to a study presented at the American Society of Haematology (ASH) conference in in New Orleans, US.

Mantle cell lymphoma (MCL) is a rare, subtype of B-cell non-Hodgkin lymphomas characterised by a translocation resulting in over-expression of the cyclin D1 gene.  It develops from malignant B-lymphocytes within a region of a lymph node known as the mantle zone and largely affects men aged between 60 and 70 years of age, with around 1 in 200,000 diagnoses per year. The first-line treatment consists of intensive chemotherapy with autologous stem cell transplant for the fit or less intensive chemotherapy for less fit and transplant-ineligible individuals, although many eventually relapse with a progressive clinical course. Treatment with Bruton tyrosine kinase inhibitors such as ibrutinib is common although among ibrutinib-refractory MCL patients, there is a short survival. For example, one trial in 114 patients found that the median overall survival following cessation of ibrutinib was 2.9 months. 

Glofitamab is a T-cell-engaging bispecific antibody possessing a novel 2:1 structure with bivalency for CD20 on B cells and mono-valency for CD3 on T cells. In a phase 1 trial of patients with relapsed or refractory B-cell non-Hodgkin lymphoma, the drug showed favourable activity with frequent and durable complete responses and a predictable and manageable safety profile.

In the current study reported at ASH, patients were pre-treated with obinutuzumab 7 days prior to the first dose of glofitamab to mitigate the risk of cytokine release syndrome (CRS). Intravenous glofitamab step-up dosing was given on day 8 (2.5 mg) and 15 (10 mg) of the the first cycle, followed by a target dose of 16mg after 1000mg obinutuzumab or 30mg after 2000mg obinutuzumab, from the first day of the second cycle, then every 3 weeks for up to 12 cycles.

Glofitamab response rate

A total of 37 patients with a median age of 72 years (73% male) received glofitamab step-up dosing and of whom, 16 received pre-treatment with obinutuzumab 1000 mg. The majority (91.9%) had Stage III/IV disease and the median number of prior therapies was 3 with 64.9% having received a Bruton Kinase inhibitor. In addition, patients received glofitamab a median of 1.9 months after their last, treatment.

After a median follow-up of 8 months, overall response rate (ORR) and complete response (CR) rates were 83.8% and 73.0% respectively, across both obinutuzumab cohorts although the CR rate was higher with obinutuzumab 2000 mg (81% vs 62.5%). However, most impressive, was that across both cohorts, the median time to achieving a complete response was 51 days and an estimated 71.6% of patients with a CR remained in response at 9 months, with a median CR of 10 months.

In terms of safety, the most common adverse events were CRS (75.7%) and neutropenia (40.5%) although the CRS rates were lower with the higher dose of obinutuzumab (66.7% vs 87.5%). Neurologic adverse events occurred in 15.4% of all patients although none discontinued treatment due to adverse events.

The authors concluded that using a fixed-duration glofitamab monotherapy induced high and durable CR rates, the majority of which were achieved early, in heavily pretreated patients with MCL, most of whom had prior Bruton kinase inhibitor therapy and thus a particularly poor prognosis. 

Citation
Phillips TJ et al. Glofitamab Monotherapy Induces High Complete Response Rates in Patients with Heavily Pretreated Relapsed or Refractory Mantle Cell Lymphoma. Abstract No 74, ASH 2022

Tafasitamab shows best efficacy in refractory diffuse large B-cell lymphoma

21st December 2022

A systematic review and meta‐analysis found that tafasitamab showed the best efficacy in relapsed/refractory diffuse large B-cell lymphoma

According the findings of a systematic review and meta-analysis undertaken by Korean researchers and presented at the American Society of Haematology conference, 2022, tafasitamab showed a trend for best efficacy among failed autologous stem cell transplantation (ASCT) or ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients.

Diffuse large B cell lymphoma is the most common lymphoma, accounting for about 25% to 30% of all the non-Hodgkin lymphomas and which presents as a rapidly growing mass or enlarging lymph nodes in a nodal or extra-nodal site. Non-Hodgkin lymphomas account for about 80% of all lymphomas and while there are more than 30 subtypes, the common ones are diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Although 5-year survival rates range from 60% to 70%, up to 50% of patients become refractory to or relapse after treatment. Moreover, outcomes for refractory or relapsed patients are poor, with one study of 861 patients, 636 of whom had refractory disease, finding that the median overall survival was 6.3 months and that only 20% of patients were alive at 2 years. For patients with relapsed/refractory disease, there are several combination chemotherapy regimens available including tafasitamab-cxix, polatuzumab vedotin-piiq, bendamustine as well as CAR T cell therapies. Nevertheless, the most effective treatment remains to be determined.

In the present study, the Korean researchers performed a systematic review and meta‐analysis to identify prospective phase II or III clinical studies evaluating the efficacy of treatments for ASCT-failed or ineligible relapse/refractory DLBCL patients. They used random effects models to estimate one-year progression-free survival rate, complete remission rate, and subgroup differences. In addition, meta-regression models were performed with adjustment for relevant covariates, particularly the median number of previous lines of systemic therapy and CAR T cell therapy was used as a reference treatment in the meta-regression analysis.

Tafasitamab and one-year progression-free survival

The researchers identified 56 cohorts in 50 studies with 3,544 relapsed/refractory DLBCL patients. For the analysis, treatment regimens were divided into nine groups: CAR T cell therapy, chemotherapy, lenalidomide-based therapy, ibrutinib-based therapy, tafasitamab-based therapy, polatuzumab plus bendamustine and rituximab (pola-BR), loncastuximab, selinexor, and others.

The pooled one-year progression-free survival rate was 0.40 (95% CI 0.35 – 0.46) for CAR T cell therapy, 0.23 (95% CI 0.16 – 0.30) for chemotherapy, 0.28 (95% CI 0.19 – 0.37) for lenalidomide and 0.46 (95% CI 0.37 – 0.56) for tafasitamab.

Although CAR T cell treatment was significantly better than many of the others, in fact, loncastuximab, pola-BR, and tafasitamab were all shown to have no significant difference in efficacy to CAR T cell therapy after adjustment for the median number of prior lines of treatment in the meta-regression analysis.

The authors concluded that tafasitamab showed a trend of best efficacy and that CAR T cell therapy was no more effective than tafasitamab, loncastuximab or pola-BR. However, because of the high level of heterogeneity, the authors called for randomised controlled trials to confirm their findings.

Citation
Kim J et al. Comparison of Several Salvage Treatments of Relapsed/Refractory Large B-Cell Lymphoma Including Chimeric Antigen Receptor T-Cell Therapy: A Systematic Review and Meta‐Analysis. Abstract 2986 ASH conference 2022