Acute myeloid leukemia is a type of cancer that involves stem cell precursors of the myeloid lineage cells, platelets, and white blood cells, with the exception of B and T cells. It is mainly driven by genetic variations that cause neoplastic changes and clonal proliferation. A small percentage of cases can be traced to chemotherapy or certain chemical exposures.

“Patients with [acute myeloid leukemia] will initially present in a myriad of ways. Some cases of disease will be discovered on routine blood work while others may present with symptomatic complications such as infection, bleeding or disseminated intravascular coagulation,” Pelcovits and Niroula wrote in Updates in Hematology/Oncology. 

Sickle cell disease is characterized by chronic hemolytic anemia, vasculopathy, and recurring episodes of vaso-occlusive crises. It is a genetic disease caused by mutations in the β-globin gene. The only potentially curative treatment is allogeneic hematopoietic stem-cell transplantation, which many patients do not qualify for due to immunological complications and the inherent risk of major surgery. Gene therapy has also been proposed as a treatment option. 

“Gene therapy with LentiGlobin for sickle cell disease consists of autologous transplantation of the patients’ own hematopoietic stem cells transduced with the BB305 lentiviral vector encoding the βA-T87Q-globin gene, which is designed to produce antisickling hemoglobin,” Goyal and colleagues wrote in The New England Journal of Medicine. 

The use of autologous hematopoietic stem cells may circumvent the risk associated with allogeneic hematopoietic stem cell transplantation; however, the efficacy and safety of LentiGlobin is still under investigation. 

Goyal et al presented the case study of a patient who received LentiGlobin for SCD and developed acute myeloid leukemia after 5.5 years. This case study opens up a debate on whether the development of acute myeloid leukemia in this patient was vector-mediated. 

The case study details a 31-year-old woman who had recurrent vaso-occlusive crises that required frequent hospital stays. In August 2015 as part of a clinical study, she received LentiGlobin produced from hematopoietic stem cells harvested from the bone marrow.

At day 16, she received granulocyte colony-stimulating factor due to fever. She then received neutrophil and platelet engraftment at days 19 and 31.

“At 6 months after treatment, the vector copy number in peripheral blood was 0.05 copies per diploid genome and the level of gene therapy–derived hemoglobin (HBAT87Q) was 4.33% of total non-transfused hemoglobin, findings that suggest low engraftment of gene-modified cells and low transgene expression with minimal clinical benefit, because the pretransplantation sickle cell disease phenotype persisted and led to the need for hydroxyurea therapy and packed red-cell transfusions,” the authors of the study wrote. 

In 2020, she was found to have 2% blast cells in peripheral blood, thought to be related to post-infection recovery. In 2021, she developed neutropenia. Acute myeloid leukemia was diagnosed upon the detection of 22% to 50% blast cells in the bone marrow and 29% blast cells in peripheral blood. 

Read about SCD complications 

The patient’s physicians proceeded to investigate any possible relationships between acute myeloid leukemia and the gene therapy she received. After an extensive investigation, they determined that the leukemia could possibly be related to the gene therapy. 

The patient underwent chemotherapy and a human leukocyte antigen-haploidentical peripheral-blood stem-cell transplantation. Ninety days after transplantation, she suffered from a relapse with the re-emergence of circulating blast cells, which prompted her physicians to prescribe additional rounds of chemotherapy. She eventually died from complications of progressive acute myeloid leukemia. 

Heightened Risk in Patients With SCD

The patient in this case was the only one out of 7 study participants treated with LentiGlobin to develop acute myeloid leukemia. In this patient, vectors were present in leukemic blast cells, which indicates that the blast cells originated from transfused hematopoietic stem cells as opposed to residual unablated host cells exposed to busulfan. 

“Longer follow-up is required to assess the effect of transplant-mediated gene therapy for patients with sickle cell disease,” Goyal et al wrote. 

Read more about SCD prognosis 

Notwithstanding the patient findings reported in this case study, studies have shown that patients with SCD are 2 to 11 times more likely to develop hematologic malignant conditions. Studies suggest this could be due to chronic hypoxia, endothelial and vascular damage, erythropoietin stress, chronic inflammation, and damage to hematopoietic stem cell compartments in the bone marrow. This means that any decision to proceed with transplant-mediated gene therapy for patients with SCD should be made with great care. 

“Studies provide at least preliminary evidence to support a prospective registry of malignancy in children and adults with SCD pre-and post-curative therapy,” Jones and DeBaun wrote in Blood. 

This case study demonstrates the complexities of initiating new forms of therapy that can be initially viewed as promising. As always, further research into this subject will yield more definite answers and strengthen the decision-making process between physicians and their patients. 


Pelcovits A, Niroula R. Acute myeloid leukemia: a reviewR I Med J (2013). 2020;103(3):38-40.

Goyal S, Tisdale J, Schmidt M, et al. Acute myeloid leukemia case after gene therapy for sickle cell diseaseN Engl J Med. 2022;386(2):138-147. doi:10.1056/NEJMoa2109167

Jones RJ, DeBaun MR. Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both, or neitherBlood. 2021;138(11):942-947. doi:10.1182/blood.2021011488