Rabi Hanna:

Hi, my name is Rabi Hanna. I’m the chair of the Department of Pediatric Hematology Oncology at Cleveland Clinic Children’s. And I’m so happy to be here today at ASH 2023 with my dear colleague, Dr. Josu de la Fuente, the Professor of Practice at the Imperial College of Medicine in UK. Welcome to Sunny San Diego.

Josu de la Fuente:

Yes, it’s been a wonderful meeting, hasn’t it?

Rabi Hanna:

It has been great.

Josu de la Fuente:

So we’re going to focus on sickle cell disease, and I just wonder what have you seen that is new in relation to the natural history of the condition?

Rabi Hanna:

During this ASH 2023 there was a really important description of the natural history over the last four decades by the University of Cincinnati and Dr Kristine Karkoska, where she has described the improvement that has happened decades over decade in patients with sickle cell disease, but importantly highlighted how much we still have to do.

So for example, between 2000 to 2009, the median life expectancy was around 39 and between 2010 to 2019, now, the median life is 43 years of life, 44 for female, 41 for males. But she showed still significant increase in the mortality as we transition from pediatrics age 14 to 19 to 20 to 24 with now crude mortality in that age, it is 1.4 per hundred thousand of African Americans.

So we really have to do better in terms of access to healthcare, to adult hematologists. But again, I don’t want to take away that data shows continuous improvement probably due to some disease modifying agents. So what did we learn in ASH about any novel things in the pathophysiology of sickle cell disease and how could that relate to therapies?

Josu de la Fuente:

Very interestingly, ineffective erythropoiesis, which we thought it was the hallmark of thalassemia only, appears to have a significant contributory factor in sickle cell disease. And so Dr. Goddard from Marseilles was able to demonstrate the concept of ferroptosis, where iron uptake and accumulation in macrophages leads to increased ROS, lipid peroxidation and apoptosis, leading to ineffective red cell production.

The hope is that the novel second generation hemoglobin S polymerization inhibitors can actually address this. And Dr Hernandez of Emory was able to show in animal models in the Townes mice how this agent is able to reduce hypoxia endothelial damage, and reversal of the abnormal vascularization. More relevant for the patients who are expecting new agents to come to the clinic. What has been shown in ASH that will be coming to the treatment of patients soon?

Rabi Hanna:

Yeah, Agios really has shown now the data from their Phase II studies of a study called RISE UP, that it showed that this pyruvate kinase activator has in 79 patients with sickle cell disease continue to show improvement in both the 50 milligrams twice a day and the 100 milligrams twice a day. And it showed that improvement in the level of the hemoglobin. So more than 50% of the patients has more than 1.1 grams per deciliter increase.

But also in some of the markers of the health of red blood cells, continue to show improvement in the oxidative stress. But what it is clinically relevant, it was really the decrease in the hospitalization, which make us really excited and looking forward to see the result of their Phase III study. But if I can take a little bit from what we call it as a group disease modifying agents to some more exciting news during this ASH about cellular and gene therapy advances, what can you tell us, an update during this ASH 2023?

Josu de la Fuente:

So many patients, of course, are looking for a long-term permanent cure. And in the late breaking abstracts, Dr Adetola Kassim from Nashville from Vanderbilt University is presenting the 1507 trial with haploidentical transplantation and has been applied in a study fashion to adults with sickle cell disease with excellent outcomes.

However, as you are alluding to the big news that occurs during ASH was the FDA approval of two gene therapy agents, which removed the need of having a donor and makes in a way the transplant process a lot easier for the patient because there are no allo-reactive complications. So we had Dr Frangoul presenting the pivotal interim analysis data from the CLIMB-121 study in which 42 patients with sickle cell disease from the age of 12 to 35 were enrolled, had stem cell collections, which were then edited so that the BCL11A action was inhibited.

And this led to a 95% reduction in vaso-occlusive events with an 100% elimination of the hospitalizations for these patients due to vaso-occlusive crisis. Now, this has been backed up by quality-of-life data presented by Dr Akshay Sharma from St. Jude’s, in which across a variety of markers there have been not just biological improvement, reduction on crisis, but actually a significant difference to the life of these patients.

And importantly, Dr. Julie Kanter has been able to present more mature data of patient-reported outcomes in relation to lovo-cel, the gene addition product in which the patients themselves were able to identify reduction not just in pain, but in pain interference and fatigue that made a significant difference to the lives. But these are not the only approaches, although they are the initial approaches that have been approved by the regulators. And what other gene editing work have you seen at ASH?

Rabi Hanna:

I’m excited to present on the behalf of many of my collaborators, EDIT-301, RUBY study and also the EdiTHAL study. It’s another gene editing technique using a CRISPR and a novel endonuclease caspase-12. So the data we are presenting it is for 11 patients with sickle cell disease and six patients with thalassemia.

And the preliminary study show that this is similar safety profile to the myeloablative regimen using with other clinical trials and excitingly for many of these patients that they are going to look for other options too, that it’s showing preliminary results in terms of the efficacy. So these 11 patients, and I want to emphasize it’s still preliminary with some of the patients that are now 15 months, but the data show in all of these 11 patients zero pain crisis so far after the infusion of this novel autologous.

And for the thalassemia patients, we are also in the six patients, five of them are available right now because they’re beyond the one month’ we’re seeing transfusion independence. So I think this is exciting. What I consider more it is the involvement of many clinical researchers, many pharmaceutical companies to try to find better therapies for these patients with sickle cell disease that for many decades we didn’t pay attention to them. So that’s really the most exciting thing for me, Dr De la Fuente.

Josu de la Fuente:

And Dr Hanna, looking to the future, what have you seen that is likely to be a paradigmatic shift in the management of these patients?

Rabi Hanna:

I learned a lot during the ASH, but one of the plenary sessions that talks about the transcription factor for fetal hemoglobin and how for many decades we thought this is not being able to be targeted. And there was data presented by Dr Pamela Ting that it shows that the Wiz is potentially targeted in this preclinical data, which shows significant increase in the fetal hemoglobin. So this could be an additional hope and agent that we could achieve high level of fetal hemoglobin, similar to what we see in the persistent fetal hemoglobin that could make the phenotype much more milder for these patient and enable them to pursue all their potential in life.

Josu de la Fuente:

So all in all, an excellent ASH, and I think it’s very encouraging to see that red cell disorders in general are very well represented, but that sickle cell disease in particular is now a mainstay of the meeting and we really look forward to further advances in the coming years.

Rabi Hanna:

I 100% agree with you. This was exciting ASH 2023 and looking forward to next year with more advances in the field of non-malignant hematology.