By Dr Zoe Drymoussi
During the 9-12th December 2022, the FLF team attended, in person, for the biggest events of the year in the world of haematology – the American Society of Hematology (ASH) annual meeting. More than 25,000 delegates, showcasing 3000+ abstracts, took over the city of New Orleans, Louisiana, with the aim to share and discuss all the latest research in haematology and blood cancer, including FL.
Whilst there the FLF team attended sessions, had a booth in the exhibition hall, established new relationships, and most importantly shared our latest updates about the CURE FL Awards research grant programme and the Precision Medicine Programme (PMP).
It was a fantastic few days, where we were able to engage with the very best academics, researchers, clinicians and experts from across academia and the life sciences – building relationships and fostering potential collaborations in the future, to help us achieve our mission.
Research summary and key take-outs
ASH 2022 provided a real treasure trove of developments in lymphoma research. Keep reading to learn about our clinical and research highlights for FL:
“WATCH AND WAIT” vs Rituximab – which option gives the best results long term?
For patients who have low tumour burden, the first option is often to undergo active surveillance also known as “WATCH AND WAIT” – whereby no treatment is given, and patients are monitored on a regular basis. A group at University College Hospital in London, UK, presented results from their “WATCH AND WAIT” international phase 3 trial. Looking at time to initiation of new treatment (TTNT), patients on watch and wait were compared to those on Rituximab (immunotherapy against CD20) with or without maintenance and followed for around 12 years.
The results showed that the Rituximab group (especially those on a maintenance regime) was less likely to relapse within the time-period tested. At 10 years, around half of Rituximab-treated patients had not started a new treatment (actually their 2nd therapy), compared to around 30% of those on watch and wait (their 1st therapy). However, when looking at transformation-free survival and overall survival, there was no difference between the groups. The investigators emphasised that patient preference plays an important role – watch and wait is still a valid strategy, as it has been shown that some patients will never need treatment.
An interesting group to study further will be those patients who remain on active surveillance for many years, and either require minimal or no treatment throughout their lifespan. Unlocking the molecular characteristics of these patients will prove to be important in deepening our understanding of FL biology.
CAR T-Cell treatment is showing longer response, though not yet curative
Longer follow-up of CAR-T (patient’s own T cells engineered to attack B cells) trials in the 2nd and 3rd line setting showed durable responses in patients, although further research is needed to improve outcomes and toxicity profiles.
Updated data in the phase 2 ELARA trial showed almost 90% of relapsed/ refractory FL patients continued to respond well to Tisagenlecleucel, remaining in remission after 2 years.
Looking at axicabtagene ciloleucel (axi-cel) in relapsed/refractory FL patients, 3-year data from the ZUMA-5 trial was compared to external standard of care control data from the SCHOLAR-5 cohort. Patients in both groups were balanced for characteristics that would affect their prognosis, such as being high-risk, the treatments previously received, tumour burden, and age. Investigators demonstrated that relapsed/ refractory FL patients had an overall response rate of almost 95% when treated with axi-cel, compared to only 54% in the SCHOLAR-5 group of patients. Progression-free survival was also much longer for axi-cel treated patients (3.3 years), compared to the SCHOLAR-5 cohort (13 months).
How can we improve CAR T-Cell treatments?
Important challenges remain around the logistics of administering the treatment in a community setting, and the high cost being hundreds of thousands of dollars – both of which mean that many patients may be missing out on this treatment. There is a big focus now on improving our understanding of why certain patients respond and others do not, what are the mechanisms of resistance, and identifying useful markers to better predict which patients will respond most favourably.
One mechanism that may be the reason some patients relapse after CAR-T therapy is T-cell exhaustion (when T-cells start to be dysfunctional, after many chronic infections and cancer). Therefore, there is an effort to understand this mechanism better, and define the targets that may be responsible. Using anti-PD-1 or PD-L1 (markers found to be increased during T-cell exhaustion) antibodies have not shown favourable results.
With regards to finding the best sequence of treatments, a small observational study in France, pulling from the DESCAR-T registry suggested that CAR-T treatment may still be effective in patients who have relapsed from previous bispecific antibody treatment. The FL patients in this case were progression-free by the end of the study (1 year follow-up). This means that further work to fine-tune the best order of treatments for patients is still very much needed.
The tumour microenvironment (all the cells, blood vessels, immune cells, signalling molecules and other structural proteins in the vicinity of the tumour) is proving to be hugely important in how a tumour develops and behaves to treatment. Researchers are increasingly demonstrating how tumour microenvironment characteristics may be predictive of prognosis for FL patients, and how it could be manipulated to improve therapies such as CAR-T. For example, patients with high levels of IRF4 (a protein important for full B-cell development) may be indicative of a less favourable prognosis. Blocking IRF4 may protect against T-cell exhaustion, thereby improving treatment outcomes.
Several bispecific antibody treatments on the horizon for FL
A number of bispecific antibodies (designed to bind and bring together both the lymphoma B cells and the lymphoma-killing T cells), have been in development in recent years, with Mosunetuzumab the first to be approved for the use in relapsed/ refractory FL: by the EMA (European Medicines Agency) in summer 2022, and now also by the FDA (US Food and Drug Administration) in December 2022.
The main advantage of these agents is that they overcome the logistical (and financial to an extent) challenges of administering CAR-T, since bispecific antibodies are “off-the-shelf” and therefore easier to deliver in the community setting. The encouraging data also means that we can expect to see more studies on using bispecific antibodies in earlier lines of treatment.
One new agent Odronextamab in the ELM-2 trial, showed promising response rates in relapsed/ refractory FL patients of 81% lasting 20.5 months, with a manageable side effect profile.
Others new agents such as Glofitamab, Epcoritamab (now extending to a phase 3 EPCORE FL-1 trial), and Blinatumomab, are gaining momentum in several early-phase studies, within a range of Non-Hodgkin Lymphoma (NHL) subtypes, including relapsed/ refractory FL patients. It will be very interesting to follow developments within this category of treatments over the coming months and years as data that is FL-specific with longer follow-up, as well as various novel combinations, matures.
The future of combination therapies
There were several examples where investigators are taking treatments that are already available and looking at new ways to use them – especially in new combinations of therapies.
An intriguing example is combining Polatuzumab Vedotin (an antibody drug conjugate, where the cytotoxic drug is brought into contact with the tumour cell), Obinutuzumab (anti-CD20 immunotherapy like Rituximab), and Lenalidomide (an immunomodulator, i.e. it uses the immune system to kill the tumour cells). This early-phase combination trial looked at patients who had undergone at least 3 prior lines of therapy, and around a quarter of patients were in the POD24 group (usually with worst prognosis as they progress within 24 months of diagnosis). The response rates were similar to some of the bispecific trials, with around 80% of patients responding after a follow of around 3.5 years.
Further trials comparing the triplet combination to R2 (Rituximab and Lenalidomide) will be interesting to follow, as will further developments in the VIPOR study – where 5 therapies were combined though for a shorter length of therapy. Understandably, one of the biggest concerns in this area is the cumulative toxicities that may arise. However, it is encouraging to see creative ways of optimising what is currently available to be used in a new way.
Biomarkers: To better understand FL biology and to better predict prognosis
Diagnosing high-risk patients is still very much an unmet need in FL. This is particularly true as we try to understand mechanisms of resistance in FL patients with multiple relapses or transformation.
Researchers are using biomarkers to improve the design of their trials, as well as to gain a deeper understanding of the underlying biological mechanisms – all helpful to making treatment decisions in the clinic. Three such examples were presented for CAR-T and bispecific antibody trials in the relapsed/ refractory setting:
Another important study described an improved model to better predict high-risk FL patients – the FLIPI24 model (FL International Prognostic Index model, for risk of event within 24 months of starting immunochemotherapy). Using data from across Europe, North America and Australia, researchers showed the FLIPI24 model performed better than current standard models in predicting the high-risk group of FL patients (those who relapse within 24 months of treatment), as well as predicting Overall Survival. This improved model promises to enhance clinical and research strategies, especially for detecting high-risk patients earlier.
Advanced technologies where genetic information can be analysed faster, on a larger scale, and at greater detail have helped to open up opportunities for laboratory investigations. Several insights into how tumour B-cells interact and respond to their microenvironment may help to identify FL patients most likely to transform. Three examples were presented, using single cell RNA and DNA sequencing on FL samples, alternative single cell sequencing technologies (whole transcriptome and genome), and bulk RNA sequencing on blood samples.
To conclude…
ASH 2022 was a truly amazing conference, and we continue to consider the incredible wealth of information, data, updates and exciting new developments in the field of lymphoma and FL in particular. Research in FL is certainly gaining momentum and the FLF are looking forward to what 2023 will bring – each study is one step closer to a cure for FL.
Feel free to share your comments or feedback on any part that caught your attention, by email on info@theflf.org – we’d love to hear from you.
