Key Reflections from ASH 2023

The 65th Annual Meeting & Exposition in Haematology (ASH) took place last month in California, and provided insight into the latest advances across haematology and haem-oncology. 

Here are the key highlights from the conference, industry breakthroughs and trends that will define the landscape in the years to come. Let’s dive into these trends below.

Approaching new milestones in haematology.

In benign haematology, there continues to be changes and advances in options across a range of clinical settings. Excitement was high at ASH 2023, following the US Food and Drug Administration’s (FDA) approval of two milestone treatments during the meeting: Casgevy and Lyfgenia. These represent the first cell-based gene therapies for the treatment of sickle cell disease in patients 12 years and older. There continues to be advances in severe haemophilia A with a novel monoclonal antibody that neutralises tissue factor pathway inhibitor, offering a new route to managing patients with haemophilia. Also for patients undergoing haematopoetic cell transplantation, Phase II data for an investigational monoclonal antibody targeting CSF-1R as a potential treatment for graft-versus-host disease (GVHD) was presented. Patients who failed prior approved therapy were treated and over 75% demonstrated response, which potentially offers new hope for patients with chronic GVHD. There was also new research presented on the role of the microbiome in GVHD, giving new routes of exploration regarding the role of microbiota in affecting T-cell response in GVHD. 

Advancements and updates in haem-oncology.

The haem-oncology space continues to make huge leaps in the development of new technologies, and integration from trials to the clinic. Here we summarise the key take-home developments across the main pillars of haem-oncology, including leukaemia, lymphoma and multiple myeloma:

1. Leukaemia: The rise of menin inhibitors. Following the approval of 11 new drugs in the last six years in the acute leukaemia space, there remains much promise of new agents that are anticipated to become available in 2024. The menin inhibitor revumenib took the spotlight in recent developments. The inhibitor was shown in a late breaking abstract to provide high rates of efficacy in relapsed refractory KMT2Ar acute leukemia when given as monotherapy. It may provide a promising avenue to allow more patients to proceed to a stem cell transplant, the only known curative treatment for aggressive and hard-to-treat KMT2Ar cancers. Targeting the menin protein is likely to be a significant focus of research for leukemia in the coming years, especially given the oral administration and potential role in combination approaches. In the chronic lymphocytic leukemia space, experts are increasingly optimistic about the possibility of moving from a continuous therapy approach to using minimal residual disease-guided fixed duration therapy. This opportunity for treatment breaks will bring relief to patients who currently suffer from a high treatment burden.
2. Lymphoma: A chemotherapy-free future? There is great optimism in seeing the lymphoma space move towards reduced chemotherapy and chemotherapy-free treatment strategies. The area is now increasingly directed by targeted therapy and immunotherapies, including CAR-T, checkpoint inhibitors, and bispecifics. Data of particular significance in this area was presented from the Phase III SYMPATICO trial in relapsed mantle cell lymphoma. This late breaking abstract showed that ibrutinib combined with venetoclax significantly improved progression-free survival (PFS) compared with ibrutinib alone. The authors highlighted a plateau in time to next treatment (TTNT).
   The median was not reached with the combination after nearly 5 years of follow-up, suggesting that some patients were functionally cured with this chemotherapy-free strategy.
3. Multiple myeloma: A booming landscape. The myeloma space was dominated by data from two Phase III studies that cemented the role of quadruplet therapy as induction for newly diagnosed multiple myeloma. IsKia (Isatuximab-carfilzomib-lenalidomidedexamethasone) and PERSEUS (Daratumumabbortezomib- lenalidomide-dexamethasone) both met their primary endpoints, with D-VRd likely to be approved globally in 2024. While both studies included maintenance within their design, further follow up is needed to understand the role of doublet therapy with anti-CD38 mAbs and lenalidomide in this setting. In the smouldering myeloma space, a small Phase I study Immuno-PRISM provided the first evidence of bispecifics in an early setting and proof of concept that this new generation of therapies may have an important role to play in the upfront treatment of high-risk myeloma. In the relapsed space there is much excitement around the future of personalised medicine, notably the role of BCL2 inhibitors for patients with t (11;14).
   There is also interest in the early development of CAR-T therapy targeted towards GPRC5D, which has demonstrated good response and safety in Phase I studies, especially in challenging populations such as extramedullary disease (EMD).
4. Reflections on the FDA CAR-T warning. In late November, the FDA announced an investigation of a serious risk of T-cell malignancy following CAR-T therapy. While data are still limited in length of follow-up, clinicians did not feel that this investigation was of major concern, and would not prohibit them from continuing to use CAR-T therapy. They cited the risk-benefit profile to still be favourable, with other safety aspects of CAR-T therapy such as CRS and ICANS of greater concern.

Looking to the future

As the landscape changes rapidly, the question of sequencing and resistance mechanisms is naturally becoming more complex. Interesting research into the loss of B-cell maturation antigen (BCMA) has suggested that there are two primary mechanisms: a double knockout leading to no expression of the BCMA antigen; or more commonly, a mutation in the extracellular domain that reduces binding of BCMA-targeted therapies. These reports suggest that mutations are highly specific to individual compounds, and therefore rechallenging with alternative BCMA-targeted therapies may be viable in later lines.

So… what’s next?

Bioscript Group’s specialist oncology and rare disease networks continually keep abreast of the latest developments across the space. If you want to discuss any key takeaways from this event, drop us a message with the word ‘ASH’ at https://bioscriptgroup.com/contact/ and our specialists will be happy to help in any way possible.