Bluebird bio sickle cell gene therapy trial halted on cancer worry

Recently I was going through a list I’m updating of regenerative medicine biotech companies including Bluebird bio. Now just a few days later the world seems turned upside down for the firm and maybe to some degree for other companies doing related work.

Bluebird bio blues: 2 trial participants get cancer

Bluebird Bio photo, gene therapy sickle cell
Bluebird Bio photo.

News broke today that Bluebird Bio had to halt its sickle cell clinical trial as 2 participants got blood cancers.

In a press release, the firm gave the details on the severe adverse events, termed “Suspected Unexpected Serious Adverse Reactions.”

The company suspended its Phase 1/2 and Phase 3 trials of LentiGlobin gene therapy for sickle cell disease.

One participant in the Phase 1/2 developed a form of leukemia called AML. Another participant in the same trial developed myelodysplastic syndrome (MDS). This is a type of blood disorder that is considered a form of cancer, although it initially manifests as abnormal blood cells like a pre-leukemia.

This second participant with an adverse event had received the gene therapy 5 years ago.

The LentiGlobin therapy works by making blood cells produce a tweaked functionally helpful form of globin. From the firm’s website:

“LentiGlobin for SCD was designed to add functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem cells (HSCs). Once patients have the βA-T87Q-globin gene, their red blood cells can produce anti-sickling hemoglobin (HbAT87Q) that decreases the proportion of HbS, with the goal of reducing sickled red blood cells, hemolysis and other complications.”

Since LentiGlobin is in part a virus (for therapeutic delivery), there is some possibility, at least theoretically, that it could activate proto-oncogenes in the genome or cause other issues, but the vector is specifically designed to minimize such risks. Today’s news brings the theoretical more into the realm of possible, but we just don’t know.

What does this mean? It’s complicated

Over at STAT News, Adam Feuerstein, who broke the story, has more details. It’s a complex situation and there’s not enough information to be sure what this means. Adam notes that a third earlier patient treated with the firm’s Lentiglobin gene therapy also developed MDS:

“In December 2018, Bluebird disclosed the diagnosis of myelodysplastic syndrome (MDS), a cancer-like disease of the bone marrow, in a sickle cell disease patient who had undergone treatment with its Lentiglobin gene therapy three years beforehand. At that time, Bluebird concluded that the chemotherapy administered to the patient to prepare for the gene therapy was likely the cause of the cancer, based on tests it conducted. The patient subsequently died last July.”

These three events are enough to warrant halting things where they are to try to figure out what is going on.

One complication is that beyond the gene therapy, participants also receive a chemo drug called busulfan to ablate their immune system. Feuerstein notes busulfan itself has on rare occasions led to MDS in patients who get it prior to a stem cell transplant. The drug is a powerful carcinogen in addition to killing blood stem cells. Therefore, at this point it’s unclear whether the adverse events might be related to busulfan, the globin gene therapy, or a combo of both.

The odds are unfortunately probably low that the cancer cases are totally unrelated to the clinical trial interventions.

Derek Lowe has some helpful thoughts on this news and more background.

Impact on approved Thalassemia product

As a precautionary measure, the firm is also halting sales of its approved  β-thalassemia drug (ZYNTEGLO) in Europe and the UK. From the PR:

“No cases of hematologic malignancy have been reported in any patient who has received treatment with betibeglogene autotemcel for transfusion-dependent β-thalassemia (licensed as ZYNTEGLOTM in the European Union and the United Kingdom), however because it is also manufactured using the same BB305 lentiviral vector used in LentiGlobin gene therapy for SCD, the company has decided to temporarily suspend marketing of ZYNTEGLO while the AML case is assessed.”

This seems like a wise move. You can learn more by watching the video below on this development.

Longer term impact, including on other gene therapy biotechs?

I can only imagine what the trial participants and their families are going through. My heart goes out to them.

There is likely going to be at least some temporary negative impact on clinical research more generally. Many firms are doing gene therapy work of various kinds so there’s concern over impact of this news on the sector.

Overall, the field needs much more data to make sense of this bad news, but it is definitely very concerning. I bet many of us are at least thinking back at least momentarily now about the case of Jesse Gelsinger, a gene therapy trial participant from many years ago who died afterwards. However, it’s too early to know how worried we should be about the new situation. It’s also unclear whether it’s comparable in any way to the outcomes for Gelsinger and other participants in gene therapy trials of decades past.

Maybe not. The field has come a long way.


  1. Bluebird suspends studies of sickle cell gene therapy following cancer diagnoses in two more treated patients. Adam Feuerstein, STAT News, February 16, 2021.
  2. Trial search for BlueBird bio listings related to sickle cell disease., conducted February 16, 2021.
  3. PubChem listing on Busulfan.

2 thoughts on “Bluebird bio sickle cell gene therapy trial halted on cancer worry”

  1. What’s the latest studies on MDS and Myelofibrosis. Does GHK-cu peptide have any positive affects since it activates stem cell growth and production?

  2. Gelsinger received gene therapy via adenoviral vectors, which lead to different problems because most people have pre-existing neutralizing antibodies against adenovirus type 5. In this particular study, they tried to overcome this (then unknown) fact by increasing the dose by logs at the time until they treated Jesse, who probably had no or a dramatically lower anti-Ad5 AB titer. So in fact he was overdosed, and that caused thrombocytopenia and multi-organ failure.

    The problem with retro and lentiviral vectors is that they randomly integrate, which can lead to oncogenesis. This fact is already known for almost 20 years (, and one wonders why randomly integrating vectors are still being used for stem cell gene therapy.

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