Complications of stem cell transplants

Created in the 1950s, the field of allogeneic hematopoietic cell transplantation has had significant clinical advances over the seven decades since its inception. However, graft‐versus‐host disease (GVHD), the second leading cause of transplantation‐related mortality¹, remains a significant obstacle due to high morbidity and mortality.

Similarly, thrombolytic microangiopathy (TMA) has been identified as an important and potentially life-threatening complication of hematopoietic cell transplantation (HCT). This condition, if not diagnosed and treated quickly, can lead to significant morbidity or mortality².

The severity of GVHD and TMA has produced a great need for effective and safe treatments for transplant organ rejection. Currently, there are a number of treatments available and in trials for the treatment of these conditions.

Thrombolytic microangiopathy

Approximately 20,000 HCT procedures are performed in the U.S. annually, and TMA is reported to occur in about 10 to 25 percent of HCT patients.

OMS 721 (narsoplimab), a monoclonal antibody from Omeros Corp, is currently in phase III trials for hematopoietic stem cell transplant-associated thrombotic microangiopathy but was accepted for rolling submission by the FDA in 2019. In trials, 54 per cent of patients receiving at least one dose of narsoplimab achieved complete responder status (met full set of FDA-agreed response criteria) and 65 percent of patients who received the protocol-specified narsoplimab treatment of at least 4 weeks of dosing achieved complete responder status. The 100-day survival (defined as survival from the day of HSCT-TMA diagnosis) is 68 per cent in all treated patients. OMS 721 is expected to be filed with the EU in 2020/21.

Tepadina from Adrienne SRI and in the US from Amneal BioScience was approved in the EU and US in 2013 to reduce the risk of graft rejection when used with older drug combination busulfan plus cyclophosamide as a regimen for allogeneic haematopoietic stem cell transplantation in pediatric patients with class 3 Beta thalassemia. There is a generic version on the market.

Graft versus host disease

GvHD is a common complication following an allogeneic tissue transplant. It is commonly associated with stem cell transplant, but the term also applies to other forms of tissue graft. GVHD occurs in 30-70% of patients who undergo a medical procedure of allogeneic hematopoietic stem cell transplantation.

In 2017, the FDA approved Imbruvica (ibrutinib) from AbbVie for the treatment of adult patients with chronic GVHD after failure of one or more lines of systemic therapy. With this approval, Imbruvica became the first and only therapy specifically approved for adults with cGVHD.  A Phase II study found ibrutinib demonstrated efficacy, sustained responses and reduced symptom severity, with an overall response rate (ORR) of 67%. Imbruvica remains in phase III studies in the EU.

More recently, in 2019 the FDA approved Jakafi (ruxolitinib) from Incyte Corp for the treatment of steroid-refractory acute GVHD in adult and paediatric patients 12 years and older. Data from the Phase III REACH2 study show Jakavi improves outcomes across a range of efficacy measures compared to best available therapy (BAT). REACH2 was the first Phase III study in acute GvHD to have met its primary endpoint. Incyte Corp also has itacitinib in phase III trials but it failed to meet primary endpoint in latest study.

Ryoncil/Prochymal from Mesoblast Ltd was approved in Canada, Japan and New Zealand, and filed with the FDA in January 2020 for steroid-refractory GvHD. Ryoncil / Prochymal, is a mesenchymal stem cell treatment. In recent phase III trials day 28 Overall Response in those receiving remestemcel-L was achieved in 70% and Day 100 survival was 75%.

Glassia (alpha1-proteinase inhibitor) (Alpha1-PI) from Shire Takeda was in a Phase II/III trial but it appears that it is terminated.

In May 2020, Kadmon Holdings reported positive results from Phase III ROCK star pivotal trial of KD 025 (belumosudil) in patients with chronic GvHD disease. This trial reported an overall response rate of 73% with 200 mg once daily and 74% with 200 mg twice daily. Kadmon Holdings has submitted an NDA to the FDA due for completion in Q4 2020.These trial benefits are comparable to Imbruvica and superior in safety.

There is a risk of mismatched unrelated donor transplants including an increase in treatment related morbidity. Orencia (abatacept) from BMS has demonstrated potential efficacy in this class of patients in a successful Phase II trial of GvHD where the drug reduced the occurrence of acute GvHD from 32 to 3 % in paediatric and adult patients who underwent mismatched unrelated donor stem cell transplants.

Other drugs in phase III trials include Leukotac (inolimomab) from Elsalys Biotech is a monoclonal antibody directed at the IL-2 receptor. It is also in phase III trials for acute steroid-resistant GvHD. Trial data shows Inolimomab reduces by 43% the relative risk of death and overall survival endpoint was reached by 30.6% versus 19.6% for conventional treatment. Elsalys was acquired by Mediolanum Farmaceutici SpA in May 2020.