A woman with sickle cell disease (SCD) developed acute myeloid leukemia (AML) approximately 5.5 years after being treated with lovotibeglogene autotemcel (lovo-cel) as part of a clinical trial, but researchers believe the hematologic malignancy “was most likely independent of insertional oncogenesis,” according to a case study published in The New England Journal of Medicine.
Corresponding author Melissa Bonner, PhD, head of research at biotech company bluebird bio, explained that current management of SCD relies on lifelong use of acute and chronic treatments.
“Despite these therapies, patients continue to experience clinical symptoms, progressive organ damage, and other substantial morbidities, which contribute to decreased quality of life, sociopsychological challenges, significant health care resource utilization, and early mortality,” she said.
Allogeneic hematopoietic cell transplantation is currently the sole option with curative potential for SCD; however, this approach is only recommended for younger patients, and its use is limited by a need for donors and the risk of severe immunologic complications such as graft-versus-host disease, Dr. Bonner noted. In contrast to disease-modifying therapies approved to treat SCD symptoms, the investigational therapy lovo-cel is a “one-time treatment designed to address the root genetic cause of the disease,” she explained.
Dr. Bonner and researchers examined a case of AML in a patient from the phase I/II HGB-205 trial, which assessed the use of lovo-cel in patients with SCD. The investigators conducted integration site analysis and RNA sequencing to evaluate whether the hematologic malignancy was caused by insertional oncogenesis.
The investigators detected a total of 2,997 unique insertion sites in the patient. The insertion site found in the vesicle-associated membrane protein 4 gene (VAMP4) rose over time and reached a relative frequency of more than 60% in August 2020 and 98.6% in February 2021.
Based on findings from specific quantitative polymerase-chain-reaction analyses, the VAMP4 insertion site was observed in around 1% of peripheral blood cells (PBCs) at 54 months after treatment. By August 2020, this had increased to 7% of PBCs. The researchers noted that the increase occurred at the same time as an overall increase in the vector copy number in peripheral blood, which rose from around 0.05 copies per diploid genome to approximately 0.13 copies per diploid genome. Along with this increase, the researchers observed reductions in white cell and absolute neutrophil counts.
Ultimately, the researchers noted that vector was present in leukemic blast cells, suggesting that blast cells originated from a transduced hematopoietic stem cell and not from residual unablated host cells exposed to myelotoxic chemotherapy with busulfan. Likewise, the researchers indicate that the AML was not likely related to vector insertion, based on observations made on the location of the insertion site as well as the low transgene expression in blast cells and the absence of an impact on expression of surrounding genes.
Additionally, there were several somatic mutations present after diagnosis, which may have predisposed the patient to AML, suggesting that patients with SCD “are at increased risk for hematologic malignant conditions after transplantation, most likely because of a combination of risks associated with underlying [SCD], transplantation procedure, and inadequate disease control after treatment.”
Given the relatively short follow-up period of the study, Dr. Bonner and colleagues suggested longer-term follow-up is necessary to further evaluate the impact of transplant-mediated gene therapy in patients with SCD.
“As novel, one-time treatments like gene therapy and gene editing make their way to patients with SCD, longer follow-up will be required to assess the effects of these curative approaches,” Dr. Bonner said. A long-term safety and efficacy follow-up study, LTF-307, is seeking to do so. Dr. Bonner added that future research should also address the potential risk factors for the development of hematologic malignancies in communities affected by SCD.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Goyal S, Tisdale J, Schmidt M, et al. Acute myeloid leukemia case after gene therapy for sickle cell disease. N Engl J Med. 2022;386(2):138-147.
