Emerging therapies and developments in the field of bone marrow failure

by Shreyans Gandhi, Clinical Research Fellow at King’s College Hospital

Greetings again from Kings, and yet again, what a privilege this is, to be able to report back from the seminal ASH meeting, the 60th one held in the beautiful city of Atlanta.

A 11 year retrospective study (2005-16) reported by Dr.Rice et al from Kings, reviewing stem cell transplant (SCT) outcomes from the international bone marrow registry database in a cohort of patients aged greater than 50 years with aplastic anaemia (AA), has confirmed a sentiment we have long held – SCT is a very feasible option in a good proportion of patients who might be elderly, but are otherwise fit and healthy.  Treatment guidelines for older patients with AA are incompletely developed, and SCT often remains a second line of therapy for patients either non-responsive or refractory to standard immune-suppressive treatment (IST). What this study underscores, is the ‘wellness’ of a person and it’s correlation to SCT outcomes. It further confirms, that Campath (an antibody directed against the active immune cells from the donor) is associated with less morbidity from one of the significant complications of SCT, namely Graft versus Host Disease (GvHD). A seminal research paper, published by Prof. Judith Marsh and her group from King’s, had previously shown that Campath based conditioning treatments in SCT, lead to significantly lower complications from GvHD, is safely tolerated, making this an attractive option. As transplant outcomes get better, a Campath based conditioning treatment for SCT in patients with AA, as frontline therapy, even in patients greater than 50 years, needs to be systematically studied and holds promise for patients.

Interestingly, patients aged 65-78 years had outcomes similar to those aged between 50-64 years, so long as the ‘wellness’ of a person was matched between the two groups.

Paroxysmal Nocturnal Haemoglobinuria (PNH) remains a complication seen in up to a half of patients with AA, especially after treatment with IST. This results from complement (an arm of the immune system) mediated destruction of the red blood cells. Anti-complement therapy (Eculizumab) has revolutionised the treatment of PNH, offering freedom from blood transfusion and independence to a majority of these patients. However, this requires 2 weekly infusions of the drug. Longer derivatives of this drug, have been trialled in phase 1 and 2 studies, ALXN 1210-PNH-103 and 201 study, examining a treatment naïve group of patients with PNH. Preliminary evidence from these studies show that the effect at complement blockade was rapid and sustained. The drug was safely tolerated and did not result in any significant side effects resulting in discontinuation. Furthermore, efficacy was seen with an improvement in blood parameters as well as an improvement in the FACIT-fatigue score (patient reported fatigue scoring system). This holds promise, as results from this study have led to the initiation of phase 3 trials, so watch this space.

Eltrombopag (a thrombomimetic agent is one which stimulates or boosts the production and maturation of blood cells, from the precursor blood making cells within the bone marrow) received FDA approval in 2014 as a drug of use in the setting of refractory AA. Reports from the extended study with the use of Eltrombopag from National Institute of Health (NIH) by Dunbar and colleagues, have shown that extended use of this drug, for upto 6 months at a fixed dose of 150 mg/day could speed and improve the response rates. Data from this extended study shared at ASH 2017, showed responses in upto a half of these patients, when they were given the larger dose of 150 mg/day and for an extended period of 6 months. Nearly 2/3rd of patients who had a robust response after a median duration of 12 months, could discontinue treatment. Of the 3 patients who had disease relapse, after discontinuation of the drug, response was restored on re-initiation of treatment. However, clonal evolution remains a concern and is seen in nearly 15% of patients at 6 months interval. No factor can reliably predict at this point in time, as to who is likely to progress with clonal evolution. This remains a story in development, undoubtedly with the promise of response in patients especially who have been refractory to IST previously, but with the caveat of careful monitoring.

T regulatory cells (Tregs) are a type of immunomodulatory cells within the immune system, that bring acceptance of self antigens, and prevent self directed attacks of the immune system against our own tissues and organs. They are pivotal at preventing auto-immune diseases and often a lot of auto-immune conditions have either dysfunctional or deficient Tregs, at the heart of it. AA is a quintessential auto-immune disorder, where the immune system clears the stem cells (the queen bee cell within the bone marrow making all the different type of blood cells) within the bone marrow. This results in a deficiency of the blood making cells and the consequent downstream effects of low blood counts, in all lineages. Immune suppression through IST have been the cornerstone of treatments in AA, to stall and prevent the immune attack on the stem cells. Research studies from our centre have previously shown that Tregs are not only deficient, but also dysfunctional in AA. This important finding, raises the spectre of harnessing the usefulness of these Tregs at suppressing the immune system and restoring the balance in the blood making factory within the bone marrow. Allogeneic Tregs (Tregs isolated and procured from other healthy donors) have been previously deployed at treating other ‘immune mediated conditions’ such as GvHD and inflammatory bowel disease, as part of a research study, where they have been safely administered and tolerated.

We wish to study and explore the utility of Allogeneic Tregs (Tregs isolated and procured from the cord blood cells from the placenta, cultured and expanded under appropriate conditions in the laboratory and stored for therapeutic use) in the treatment of AA as a phase 1 research study at King’s college Hospital. I am sure, in time to come, there will be more updates on this, so watch this space.