LentiGlobin Is Highly Unlikely Cause of AML in SCD Patient


The lentiviral vector used to create LentiGlobin was deemed a very unlikely cause of AML in a patient with sickle cell disease.

The lentiviral vector BB305, which is used to create LentiGlobin (bb-1111), was deemed a "very unlikely" cause of acute myelogenous leukemia (AML) in a patient with sickle cell disease, according to a statement from bluebird bio, the company developing the gene therapy.

AML was diagnosed in a patient who received LentiGlobin approximately 6 years ago in a phase 1/2 study. The diagnosis of AML led to the suspension of clinical studies of LentiGlobin on February 16. Subsequently, the company announced preliminary findings indicating a number of classical causes of AML as the likely culprit.

In the initial assessment, which was announced on February 25, bluebird discovered monosomy 7, partial loss of chromosome 11, and mutations in RUNX1 and PTPN11, which are classical drivers of AML. Following additional findings from independent analyses on vector binding sites within AML cells and further genetic information, bluebird has confirmed that the vector is a highly unlikely cause of cancer. The company has initiated conversations with regulators to resume clinical studies for sickle cell disease and β-thalassemia.

“In addition to our earlier findings of several well-known genetic mutations and gross chromosomal abnormalities commonly observed in AML in this patient, our latest analyses identified the integration site for the vector within a gene called VAMP4," Philip Gregory, DPhil, chief scientific officer, bluebird bio, said in a statement. "VAMP4 has no known association with the development of AML nor with processes such as cellular proliferation or genome stability. Moreover, we see no significant gene misregulation attributable to the insertion event.”

The company indicated that BB305 was found in the AML blast cells; however, further assessment by independent parties identified the vector solely in the VAMP4 gene, which is not associated with oncogenesis. Despite the vector inserting into the VAMP4 gene, investigators could not find any disruption in the gene expression or regulation, which further ruled out its role in the development of AML.

“In totality, the data from our assessments provide important evidence demonstrating that it is very unlikely our BB305 lentiviral vector played a role in this case and we have shared with the FDA that we believe these results support lifting the clinical holds on our β-thalassemia and sickle cell disease programs,” said Gregory.

In addition to the patient with AML, another individual was diagnosed with a suspected case of myelodysplastic syndrome (MDS). This patient had prolonged anemia with trisomy 8 in a small fraction of bone marrow cells. The patient, however, did not meet the classical definition of MDS, as there were not blasts or dysplastic cells found in the bone marrow. The company had not yet reached a conclusion on this patient's case, and it is still investigating the clinical findings.

In addition to halting studies for LentiGlobin, bluebird bio also suspended clinical studies and the marketing of betibeglogene autotemcel (Zyntelgo), which is approved for transfusion-dependent β-thalassemia. This gene therapy is manufactured using the same lentiviral vector. The company is in conversations to resume all studies and marketing of the agent. There have been no hematologic malignancies diagnosed in studies of betibeglogene autotemcel.

Related Videos
Brian Van Tine, MD, PhD, on Looking Ahead on Cell Therapy for Sarcomas
J. Andrew Livingston, MD, on Forging Forward With Novel Sarcoma Trials
Farah Sheikh, PhD, on Continuing Gene Therapy Research Into Arrhythmias, Cardiac Dysfunction
Binod Dhakal, MD, on Benefit of Cilta-Cel in Earlier Lines of Multiple Myeloma Treatment
Thomas Povsic, MD, PhD, on EXACT Clinical Trial: Investigating Gene Therapy for Refractory Angina
Joseph Fraietta, PhD, on Achieving a Deeper Understanding of CAR T-Cell Therapy
Jacob Appelbaum, MD, PhD, on Investigating SC-DARIC33 and IL-15 for AML
Jonathan Yen, PhD, on Continuing Research With Prime Editing for Sickle Cell Disease
Related Content
© 2023 MJH Life Sciences

All rights reserved.