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The current treatment of sickle cell disease relies on lifelong use of palliative short-term and long-term treatments
.
Allogeneic hematopoietic stem cell transplantation is the only accepted and potential treatment option for patients with sickle cell disease; however, its use suffers from the lack of matched donors, immune complications, and the inherent risks of transplant-related morbidity and mortality.
Before receiving LentiGlobin gene therapy, the patient had sickle cell disease (βS/βS genotype) with recurrent vascular occlusive crisis.
Despite long-term hydroxyurea treatment, it still resulted in frequent hospitalizations
.
In February 2021, at the age of 31, she was diagnosed with acute myeloid leukemia
The total dose of CD34+ cells in patients administered with the drug is 2.
6×10 6 cells per kilogram of body weight (including 1.
5×10 6 cells per kilogram of CD34hi long-term regenerated hematopoietic stem and progenitor cells [hspc]), each of the diploid genome The carrier copy number is 0.
57 copies
.
On the 16th day after LentiGlobin treatment, the patient was treated with granulocyte colony stimulating factor due to fever, followed by neutrophil and platelet engraftment on the 19th and 31st days after treatment
CD34 + cells to the patient's total dose of drug administration × 10 2.
Figure 1: Researchers performed an integration site analysis to evaluate the role of vector insertion in the development of acute myeloid leukemia
Figure 2: It was investigated whether the insertion site of VAMP4 affects the gene expression of the 10-megabase region flanking VAMP4
.
These population-level data indicate that the gene expression levels near the VAMP4 site in CD34+ bone marrow cells of patients are similar to those of CD34+ mobilized peripheral blood cells in healthy donors
Figure 2: It was investigated whether the insertion site of VAMP4 affects the gene expression of the 10-megabase region flanking VAMP4
After the diagnosis of acute myeloid leukemia, the patient received 3 cycles of induction chemotherapy, and as a result, the morphological remission appeared.
In June 2021, she received the same peripheral blood stem cell transplantation with human leukocyte antigen-haploid, but there was minimal residual The disease is still positive
.
The patient relapsed 90 days after transplantation, reappeared circulating blasts, and received additional chemotherapy; however, she later died of complications from progressive acute myeloid leukemia
Analysis of the patient’s peripheral blood samples revealed that the mother cell contained a BB305 lentiviral vector insertion site
.
The results of the causality investigation showed that, considering the location of the insertion site, the low expression of the transgene in the mother cell, and the lack of influence on the expression of surrounding genes, leukemia is unlikely to be related to the vector insertion
Researchers believe that understanding the underlying risk factors for the development of hematological malignancies is important for communities affected by sickle cell disease and people considering gene therapy
.
Unlike the case of acute myeloid leukemia diagnosed in 2018, the current patient's case shows the presence of vectors in leukemic blasts, which indicates that the blasts are derived from transduced stellate cells, not from non-degraded host cells exposed to Busuvan
.
The possible factors leading to the development of acute myeloid leukemia are proposed, such as the use of hydroxyurea, transplantation procedures, including the use of a cleansing agent, such as Bushufan
.
In addition, after bone marrow ablation, the bone marrow niche has experienced extensive proliferation of hematopoietic stem cells and heat shock stem cells, resulting in proliferative stress, which may lead to the increase and accumulation of mutations
.
However, a higher proportion of transgene expressing cells may eliminate many of them, which requires longer follow-up to evaluate the effect of transplant-mediated gene therapy on patients with sickle cell disease
.
The possible factors leading to the development of acute myeloid leukemia are proposed, such as the use of hydroxyurea, transplantation procedures, including the use of a cleansing agent, such as Bushufan
.
In addition, after bone marrow ablation, the bone marrow niche has experienced extensive proliferation of hematopoietic stem cells and heat shock stem cells, resulting in proliferative stress, which may lead to the increase and accumulation of mutations
.
However, a higher proportion of transgene expressing cells may eliminate many of them, which requires longer follow-up to evaluate the effect of transplant-mediated gene therapy on patients with sickle cell disease
.
Original source:
Goyal S, Tisdale J, Schmidt M, Kanter J, Jaroscak J, Whitney D, Bitter H, Gregory PD, Parsons G, Foos M, Yeri A, Gioia M, Voytek SB, Miller A, Lynch J, Colvin RA, Bonner M .
Acute Myeloid Leukemia Case after Gene Therapy for Sickle Cell Disease.
N Engl J Med.
2021 Dec 12.
doi: 10.
1056/NEJMoa2109167.
Epub ahead of print.
PMID: 34898140.
Acute Myeloid Leukemia Case after Gene Therapy for Sickle Cell Disease.
N Engl J Med.
2021 Dec 12.
doi: 10.
1056/NEJMoa2109167.
Epub ahead of print.
PMID: 34898140.
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