Investigation Continues but Preliminary Data May Clear LentiGlobin as Cause of AML in Patient With SCD

Preliminary evidence pinpoints classical causes for acute myelogenous leukemia (AML) in a patient with sickle cell disease (SCD) treated with LentiGlobin (bb-1111) in a phase 1/2 study.

The diagnosis of AML, plus another suspected case of myelodysplastic syndrome (MDS), led to the suspension of phase 1/2 and 3 studies of the gene therapy LentiGlobin on February 16. The updated findings from the 2 patients were reported at the 10th Annual SVB Leerink Global Healthcare Conference by executives from bluebird bio, the company developing the gene therapy. LentiGlobin utilizes a BB305 lentiviral vector, which was a suspected culprit in the malignant cases.

UPDATE: LentiGlobin Is Highly Unlikely Cause of AML in SCD Patient

"These mutations that we see are characteristics of AML and are seen in patients who have not participated in any gene therapy study. They're the classical drivers of AML," Philip Gregory, DPhil, chief scientific officer at bluebird, said during the presentation. "With respect to vector involvement, a vector integration event does not create a chromosomal abnormality of this scale. What you need to investigate is whether there was a step in between."

The company found several genetic abnormalities in the patient with SCD who had been diagnosed with AML, including monosomy 7, partial loss of chromosome 11, and mutations in RUNX1 and PTPN11, all of which are known drivers of AML oncogenesis. This diagnosis occurred approximately 6 years following treatment with LentiGlobin.

"These are all genes associated with AML, classical mutations associated with AML, as well as genomic rearrangements associated with AML, and provide an independent mechanism for which this AML occurred," said Gregory. "The patient had a relatively low VCN [vector copy number] of 0.55 for the drug product, this was a group A patient and preceded all of the improvements to manufacturing and changes we introduced in group C and investigations are underway on the role, if any, that the vector played in the AML."

The patient diagnosed with MDS was treated in group C. This patient had prolonged anemia with trisomy 8 and tetraploidy in a small fraction of 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. As with the patient with AML, this case continues to be explored.

"We're now in the process of identifying a strategy to determining whether the vector is present in the relevant cells and whether it has any role in the hematologic findings in this patient," said Gregory. "Most of our studies are focused on the vector and whether the vector played any specific role."

There are two main possibilities for the malignant cases identified in the study, Gregory noted. The first option is that the genetic drivers were already present in the genes of the patient prior to the initiation of LentiGlobin treatment. Secondly, that the vector may have disrupted expression of these genes, either transcriptionally or mechanistically, leading to the genomic changes responsible for oncogenesis; however, Gregory noted, "the lentiviral vector platform was designed to avoid potential mutational oncogenesis. Among our studies and all of those done in the clinic and academia, there have so far seen no confirmed cases of vector-based AML or MDS oncogenesis with a lentiviral vector."

Out of caution, bluebird bio also suspended marketing of betibeglogene autotemcel (Zyntelgo) for transfusion-dependent β-thalassemia, since it is manufactured with the same lentiviral vector. There have been no hematologic malignancies diagnosed in these studies.

"It is an important reminder that we're talking about two sickle patients. Two patients who have had sickle their entire lives, and very severe cases, and now on top it they are now dealing with these events of AML and MDS. That cannot be forgotten in how we engage in this and how we think about this," Nick Leschly, chief executive officer of bluebird bio, said during the presentation. "This is not only important for these 2 patients, and for bluebird therapies, but also for the field."

More information is expected on the AML case within the next couple of weeks, Gregory noted. The MDS case is earlier in the clinical evaluation and they could not provide a definitive timeline; however, they did expect more details in the next few weeks.