Hematological Malignancies Detected in Some Patients Treated With bluebird bio’s Active Cerebral Adrenoleukodystrophy Gene Therapy Eli-Cel

Seven of 67 patients treated with bluebird bio's elivaldogene autotemcel (eli-cel; marketed as Skysona), a gene therapy product comprised of engineered autologous CD34+ hematopoietic stem cells, for early, active cerebral adrenoleukodystrophy (CALD) across multiple clinical trials have developed hematologic malignancies, according to a study published in The New England Journal of Medicine.¹

The data comes from the phase 2/3 ALD-102 (NCT01896102), phase 2/3 ALD-104 (NCT03852498), and LTF-304 (NCT02698579) clinical trials. Notably, LTF-304 is an ongoing long-term follow-up study for patients treated in ALD-102 and ALD-104.

One of 32 patients treated in ALD-102 and 6 of 35 patients treated in ALD-104 were diagnosed with hematologic malignancies following treatment with eli-cel. One patient developed myelodysplastic syndrome (MDS) with unilineage dysplasia at 14 months posttreatment and another was diagnosed with the same at 26 months posttreatment. Another 3 patients were diagnosed with MDS with excess blasts at 28 months, 42 months, and 92 months posttreatment, respectively. Another patient was diagnosed with MDS at 36 months posttreatment. A single patient developed acute myeloid leukemia at 57 months posttreatment. Among the 7 patients, 6 remain alive, with 1 patient having died 49 months after treatment with eli-cel. This patient had received allogeneic hematopoietic stem-cell transplantation (HSCT) for treatment of their MDS, and their death 20 months after receiving HSCT was attributed to presumed graft-versus-host disease (GvHD).  

"The risk of oncogenesis with eli-cel must be weighed against the severity and natural history of CALD as well as the availability of other treatments and their risks, including allogeneic HSCT,” first author Christine N. Duncan, MD, the medical director of clinical research and clinical development for the Gene Therapy Program at Boston Children’s Hospital, and colleagues, wrote.¹ “Overall survival was 77.8% among patients who had undergone allogeneic HSCT 4 years previously in a matched cohort study; the cumulative incidence estimate for acute grade 2to 4 GvHD was 11.1%, and the estimate for GvHD overall was 17.2%. Moreover, the availability of HLA highly matched donors is limited and is a crucial determinant of outcomes in patients undergoing allogeneic HSCT. Most patients who received eli-cel in the ALD-102 and ALD-104 studies benefitted clinically, with 81% 4-year survival free of major functional disabilities and hematologic cancer, and without referral for allogeneic HSCT. Therefore, the probability and magnitude of benefit that gene therapy can offer in patients who do not have an appropriate donor must be considered. Because gene therapy is an evolving field, ongoing follow-up is critical to understanding the longer-term safety and efficacy of novel treatments like eli-cel.”

Eli-cel is 1 of 3 FDA-approved gene therapy products that bluebird bio has under its belt, with the other 2 being betibeglogeneautotemcel (beti-cel, Zynteglo), for transfusion dependent thalassemia (TDT), and lovotibeglogene autotemcel (lovo-cel; marketed as Lyfgenia), for sickle cell disease (SCD).^2,3 Notably, in September 2024, the company announced that it will be carrying out a restructuring with the intention of cutting costs, which will include letting go of around 25% of its employees.⁴ Patient use of lovo-cel, bluebird bio’s most recently approved gene therapy product, in the commercial setting has remained low.^2,3 The company noted that across its 3 gene therapy products, which also include Zynteglo and Skysona, 41 patent starts have been recorded thus far this year. Lovo-cel has a direct competitor in Vertex Pharmaceuticals' and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel; marketed as Casgevy), which is approved for both SCD and TDT. As of August 2024, 20 patients were reported to have begun treatment with exa-cel, although the breakdown of how many patients were being treated for SCD versus TDT was not clarified by the company.

REFERENCES
1. Duncan CN, Bledsoe JR, Grzywacz B, et al. Hematologic cancer after gene therapy for cerebral adrenoleukodystrophy. N Engl J Med. 2024;391(14):1287-1301. doi: 10.1056/NEJMoa2405541
2. bluebird bio reports second quarter 2024 results and highlights operational progress and 2024 guidance. News release. bluebird bio, Inc. August 14, 2024. Accessed October 15, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-reports-second-quarter-2024-results-and-highlights
3. Stock dive for bluebird as sickle cell gene therapy lags behind Vertex rival. News article. Anna Bratulic. FirstWord Pharma. August 14, 2024. Accessed October 15, 2024. https://firstwordpharma.com/story/5885598
4. bluebird bio Initiates Restructuring Intended to Optimize Cost Structure and Enable Quarterly Cash Flow Break-Even in the Second Half of 2025. News release. bluebird bio, Inc. September 24, 2024. Accessed October 15, 2024. https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-initiates-restructuring-intended-optimize-cost