Reference: August 2024 | Issue 8 | Vol 10 | Page 39
Encouraging new data for CD19 CAR-T candidate GLPG5101 in NHL
Dr Marie José Kersten, Professor of Haematology at Amsterdam University Medical Centres, Netherlands, presented promising findings from the ongoing phase 1/2 ATALANTA-1 study of CD19 chimeric antigen receptor (CAR)-T candidate GLPG5101 in relapsed/refractory non-Hodgkin lymphoma (R/R NHL) at the annual European Haematological Association (EHA) 2024 Congress.
The oral presentation included updated safety and efficacy data for GLPG5101 in patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL), as well as durability and cellular kinetics data. Treatment with GLPG5101 led to high complete response rates (CRR) in heavily pretreated patients with R/R NHL, and the data suggest that a decentralised manufactured autologous CAR T-cell candidate is a viable approach for this cohort.
GLPG5101 is a second generation anti-CD19/41BB CAR-T product candidate, which is administered as a single fixed intravenous dose. The primary objective of the phase 1 part of the study is to evaluate the safety and preliminary efficacy to determine the recommended dose for the phase 2 part of the study.
The primary objective of phase 2 is to evaluate the objective response rate (ORR), while the secondary objectives include CRR, duration of response, progression free and overall survival, safety, pharmacokinetic profile, and the feasibility of decentralised manufacturing.
According to the researchers, complex logistics result in several negative outcomes, including limited access to commercially available products; longer vein-to-vein times; and patient drop-out. Therefore, an “innovative, decentralised, and automated point-of-care manufacturing model” was developed to allow administration of a fresh autologous CAR T-cell product within one week
of apheresis.
As of the data cut-off date of December 20, 2023, 34 patients (17 in phase 1 and 17 in phase 2) received GLPG5101 with a median vein-to-vein time of seven days. Overall, safety results were available for 33 patients and efficacy results were available for 31. GLPG5101 showed an encouraging safety profile, with mostly low-grade treatment emergent adverse events. Two cases of cytokine release syndrome grade 3 were observed in phase 1 and one case of immune effector cell-associated neurotoxicity syndrome (grade 3) was observed in phase 2.
In phase 1, 14 of 16 efficacy-evaluable patients responded to treatment (ORR 87.5 per cent), with 12 patients achieving a complete response (CRR 75 per cent). In phase 2, 14 of 15 efficacy-evaluable patients responded to treatment (ORR 93.3 per cent), and all responders achieved a complete response (CRR 93.3 per cent).
High ORR and CRR were observed in the pooled phase 1 and phase 2 efficacy analysis set. In patients with DLBCL, seven of nine efficacy-evaluable patients responded to treatment (ORR 78 per cent), with five patients achieving a complete response (CRR 56 per cent). In patients with FL or MZL, objective and complete responses were observed in 16 of 17 efficacy evaluable patients (ORR and CRR 94 per cent). In patients with MCL, all five of the five efficacy-evaluable patients responded to treatment (ORR and CRR 100 per cent). Durable responses were observed in the majority of responding patients, with 71 per cent and 100 per cent of patients in the phase 1 and 2 portions of the research, respectively, displaying an ongoing response at the data cut-off point.
Dr Kersten said the results show “that it’s feasible to decentralise CAR T-cell manufacturing, and with a fresh-out/fresh-in procedure, you can have a very short vein-to-vein time.”
CAR-T benefits patients aged 75 years and older with LBCL
Data from a real-world study of adults with relapsed/refractory large B-cell lymphoma (R/R LBCL) has shown that CD19 chimeric antigen receptor (CAR) T-cell therapy is “feasible in a population of patients aged 75 years and older”.
Senior author Dr Pierre Bories, Institute for Cancer Strasbourg Europe, France, delivered the findings during an oral presentation at the EHA 2024 Congress, and said that he and his colleagues found no significant difference in terms of efficacy, safety, or survival for older patients when compared with younger populations receiving the treatment. The research was conducted in response to an under-representation of this cohort in real-life studies and clinical trials.
The retrospective analysis included 1,524 patients in the French DESCAR-T registry who had at least two previous infusions of CAR-T cell therapy. The primary endpoint was overall survival, and secondary endpoints included progression-free survival (PFS), best objective response rate (ORR), complete response rates (CRR), and non-relapse mortality.
A total of 70 per cent were treated with axicabtagene ciloleucel, and the remaining 30 per cent received tisagenlecleucel. The cohort consisted of 125 people who were 75 years old or older (median age of 76) and 1,399 who were under the age of 75 (median age of 62). Compared with patients aged 75 or younger, those who were 75 years or older had a higher hematopoietic cell transplantation-specific comorbidity index score, had fewer prior transplants than those under 75, and more commonly received tisagenlecleucel CAR-T cell therapy.
No significant differences in terms of characteristics including gender, LBCL subset, number of prior lines of therapy, performance status, age-adjusted International Prognostic Index, rate of patients receiving a bridging therapy, response to the bridging therapy, and LDH were noted at the time of infusion. The median follow-up period was 12.7 months.
Results demonstrated no significant differences in terms of ORR, CRR, or estimated median PFS, and median overall survival was 18.3 months in the older group and 24 months in the under-75 group.
Although no differences in cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, ICU admissions, or the need for mechanical ventilation were recorded, rates of non-relapse mortality were notably more common in the 75 years and older group, which warrants further investigation, according to Dr Bories.
“Our findings show a higher non-relapse mortality in this older population, which mainly relied on late infectious events, occurring after 28 days…. I think this deserves special attention and we have to be more careful with frail patients.”
Machine learning to transform iron deficiency screening
Novel full blood count (FBC) measurements with machine learning (ML) can improve detection of iron deficiency (ID), according to Mr Daniel Kreuter, a PhD student in applied mathematics at Cambridge University, UK, who presented findings from a recent study at the EHA 2024 Congress.
Researchers analysed data from 48,000 blood donors from the randomised controlled INTERVAL trial – which was designed to determine the effects of frequent blood donation on the donors – and 250,000 outpatients from Cambridge University Hospitals to investigate the sensitivity of current ID screening on a larger scale than is published currently, and to optimise screening performance using modern ML-based techniques trained on a novel ‘high-dimensional’ FBC.
During a general FBC analysis, only around 20 of the available 500 summary values, or dimensions, are reported to healthcare teams, while the remaining data are generally discarded.
However, these “high-dimensional data are exactly ideal for a pattern recognition algorithm”, said Mr Kreuter, who described the steps taken during the ML training process. He also said that when the researchers combined the currently used FBC parameters, such as mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), and red cell distribution width (RDW), sensitivity for ID was poor and over half of ID cases were missed.
The researchers also found that ferritin studies under-diagnose ID and “perform particularly poorly in medically vulnerable groups who stand to benefit most from diagnosis”.
Researchers used two ID definitions, the first being 15mcg/L, based on which conventional measures identified ID 18.8 per cent of the time. Using a definition of a fall in haemoglobin of 10g/L over two years, conventional measures identified ID 44.5 per cent of the time. The novel ML model identified iron deficiency about 75 per cent of the time under both definitions, Mr Kreuter said.
Overall, the model displayed improved cost-effectiveness and notably better ID detection than current standard practices. The researchers are now validating the ML with a second, more ethnically diverse donor population and exploring advanced approaches.
Positive results for menin-MLL inhibitor DSP-5336 in early trials for leukaemia with certain genetic markers
DSP-5336 – an investigational small molecule inhibitor of the menin and mixed-lineage leukaemia (MLL) protein interaction – delivered favourable results in an ongoing, first-in-human, phase 1/2 study, particularly for acute leukaemia patients with certain genetic markers, the EHA 2024 Congress heard. The molecule plays key roles in biological pathways, including cell growth regulation, cell cycle control, genomic stability, bone development, and haematopoiesis.
According to the researchers, menin inhibitors are an important new class of agents for patients with acute leukaemias. Dr Naval Daver, Director at Leukaemia Research Alliance Programme and Professor in the Department of Leukaemia at The University of Texas MD Anderson Cancer Centre, US, told delegates that acute myeloid leukaemia (AML) with nucleophosmin 1 (NPM1) mutations (NPM1c) and MLL rearrangements (KMT2Ar) are particularly sensitive to the novel treatment. Around 30 per cent of AML patients have NPM1 mutations and 5-to-10 per cent of AML patients have KMT2A (MLL) rearrangements.
Building on preliminary phase 1 data presented at the 2023 American Society of Haematology (ASH) Annual Meeting, which assessed the safety and tolerability of the treatment, Dr Daver presented updated data from the open-label, ongoing dose escalation and optimisation portion of the phase 1/2 study.
A total of 57 patients were included in the research, who received oral DSP-5336 in repeating 28-day cycles at doses ranging from 40-to-300mg twice-daily. The median age of participants was 63 years, almost 60 per cent were female, and 93 per cent had AML. KMT2Ar or NPM1c was detected in 26 patients and 14 patients, respectively.
Optimal results were observed at doses of 140mg twice daily or higher, particularly in those with either an NPM1 mutation or KMT2A rearrangement. Over half (57 per cent) of the patients responded to treatment, including 5 (24 per cent) who had complete remission or complete remission with partial haematologic recovery. Overall, DSP-5336 displayed no dose limiting toxicity and an acceptable safety and tolerability profile. The most commonly reported adverse effects were gastrointestinal, primarily vomiting (17.5 per cent) and nausea (12.3 per cent).
Differentiation syndrome occurred in three participants, but did not case death or result in treatment cessation. Severe Q3 prolongation was documented in two patients. Patients responded to treatment within an average duration of 1.4 months. Research to identify the recommended dose of DSP-5336 for the phase II part of the study is on-going and evaluation of DSP-5336 in combination with other standard AML treatment is being planned.
“The response in patients previously untreated with menin inhibitors is encouraging, and competitive, with greater than 50 per cent objective response rate alongside a favourable safety profile in patients with relapsed or refractory acute leukaemia,” said Dr Daver.
“Menin inhibitors have tremendous potential to improve the outcomes of certain types of acute leukaemia, as they reverse the leukemogenic activity of MLL fusion and mutated NPM1 proteins. In addition to promising clinical activity, the safety profile of DSP-5336 has been especially encouraging and may differentiate it from other menin inhibitors.”
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