Advancements in gene therapies and stem cell transplantation have marked significant progress in hematology in 2024, offering new hope for patients with various blood disorders. However, challenges remain in patient uptake and managing treatment-related risks.
Regulatory Approvals Expand Treatment Options
In September, Health Canada authorized Vertex Pharmaceuticals and CRISPR Therapeutics' exagamglogene autotemcel (exa-cel), marketed as Casgevy, for sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT) in patients aged 12 and older. The approval was based on data from the CLIMB-121 and CLIMB-111 clinical trials. According to Kevin Kuo, MD, "Casgevy's approval is an exciting moment for 2 patient communities that have long awaited an innovative therapy that brings new hope and possibilities for those in need."
Pfizer Canada's gene therapy fidanacogene elaparvovec, branded as Beqvez, was approved in January for moderately severe to severe hemophilia B patients with congenital Factor IX (FIX) deficiency who are negative for neutralizing antibodies to variant adeno-associated virus (AAV) serotype Rh74. The approval was based on the BENEGENE-2 trial, which demonstrated noninferiority and superiority in annualized bleeding rates (ABR) compared to standard of care FIX therapy. Fréderic Lavoie stated, "Pfizer has more than 30 years of experience in developing and commercializing therapies for hematological disorders, and a deep understanding of the significant challenges that people living with hemophilia continually face. We are proud to introduce an innovative therapy for people living with hemophilia B in the form of gene therapy."
Challenges in Gene Therapy Uptake
Despite FDA approval in December 2023, the commercial uptake of gene therapies for SCD, including Casgevy and bluebird bio’s lovotibeglogene autotemcel (Lyfgenia), has been slow. As of August 2024, only 4 patients had begun treatment with Lyfgenia, while 20 had started with Casgevy. Andrew Obenshain, MBA, noted, "We are seeing clear evidence that our commercial launch is accelerating, with over 20 cell collections completed in SCD and TDT to date in 2024, and more than 40 additional patients already scheduled to initiate the treatment journey for a bluebird gene therapy by the end of this year."
Allogeneic Stem Cell Transplantation Shows Promise for Thalassemia
Data from a phase 4 trial in China (NCT04009525) suggest that allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be effective for TDT, particularly with matched sibling donors (MSDs). Rongrong Liu, MD, and colleagues reported, "We report excellent 2-year OS and EFS… Allo-HSCT with alternative donors can be considered as a frontline option for TDT patients lacking matched sibling donors. Patients receiving alternative donors will also benefit from an improved GvHD-prophylaxis strategy."
Safety Concerns Highlighted in Base-Editing Therapy Trial
A patient with SCD died from complications related to the busulfan-conditioning regimen required before administration of Beam Therapeutics’ BEAM-101, an investigational base-edited autologous hematopoietic stem cell (HSC) therapy. John Evans, MBA, commented, "This is a sad outcome and it really underscores the real risks of doing myeloablative transplant with chemotherapy. These risks are well known. This includes significant toxicities that are possible and the rare, but real, risk of mortality."
