August 19th, 2022 marked an exciting day for haematologists and transfusion-dependent thalassaemia (TDT) patients alike. bluebird bio’s Zynteglo, a one-time therapy for TDT, became the first ever FDA-approved cell-based gene-therapy. But is Zynteglo really safe?
Seemingly destined for failure, the potentially curative therapy just couldn’t catch a break on the tumultuous path to FDA approval. Trials halted over reports of cancer, relatively small trial numbers and limited follow-up time have left some haematologists wondering, ‘is it worth the risk to my patients?’
The first warning sign came when Zynteglo trials were paused after cases of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) came to light in other bluebird bio gene-therapy trials.[1] Then, the UK’s National Institute for Health and Care Excellence (NICE) rejected Zynteglo, citing small trials and limited follow-up time as the reason for their decision.[2] The final blow came when bluebird bio was forced to leave Europe following failed marked access attributed to high upfront costs, as well as uncertainty surrounding long-term efficacy and safety of the therapy.[3]
Despite this cloud of uncertainty, efficacy and safety data from the two pivotal Phase 3 trials are promising. Haematologists may indeed be able to offer suitable patients a pain- and fatigue- free future. Of the 41 patients enrolled in the trials, 89% achieved transfusion independence after receiving Zynteglo.[4] The drug was generally well-tolerated, with the majority of adverse events consistent with known side effects of the procedure.[4] But what about cases of cancer reported in other trials?
Lenti-viral-based gene therapy products carry an inherent risk of insertional oncogenesis. Insertional oncogenesis occurs when lentiviral vectors (LVVs) integrate into the DNA of target cells and affect the expression of nearby oncogenes and tumour suppressor genes. This results in a predominant clone, clonal expansion and, ultimately, malignancy.[5] bluebird bio uses two different LVV to produce three different products (table 1). A simple tallying of the numbers reveals 5 cases of haematologic malignancies across all trials. However, a deeper dive into the data tells a more alarming story.
Table 1: bluebird bio gene-therapy products
Among 50 sickle cell disease (SCD) patients treated with lovo-cel, two developed AML. Insertional oncogenesis, which occurs when a LVV integrates into the DNA of target cells and affects the expression of nearby oncogenes and tumour suppressor genes, was ruled out in both cases. Peripheral blood analysis in one such patient revealed that blast cells contained a predominant site for BB305 LVV integration within the vesicle-associated membrane protein (VAMP4) gene.[6] Given that VAMP4 has no known role in cell proliferation or oncogenesis, it is unlikely to be driving the oncogenesis.
Furthermore, a VAMP4 insertion site was present in 71% of participants, none of whom presented with AML. Known driver mutations of AML, including RUNX1 and PTPN11, were detected in blast cells of both patients. This suggests that proliferative stress caused by the engraftment process lead to the development of somatic mutations.[6] Two additional SCD subjects were evaluated for suspected MDS, although MDS was later excluded.[1]
So, where does this leave the TDT patients? To date, the BB305 LVV has been exonerated in all reports of cancer. One might ask if none of the patients in the TDT trials developed malignancies, perhaps it is simply that SCD patients are at greater risk?
However, TDT subjects weren’t free of troubling reports, suggesting that they, too, may be susceptible to cancer. Three met the threshold for oligoclonality, of which two cases could be classified as stable oligoclonality. Both such patients had concerning cytopenia’s and insertion sites that fell in known proto-oncogenes. In all three patients with oligoclonality, there was a delay in platelet reconstitution. Whether these patients will ultimately develop a malignancy remains to be seen.
It doesn’t end there. In other TDT patients who exhibited delayed platelet engraftment and slow platelet recovery, there were several concerning reports of bone marrow pathology. These reports include evidence of ring sideroblasts and emergent dysplastic megakaryocytes.[1] Although it is true that no malignancies have been reported in TDT patients receiving Zynteglo, it does seem that it is only a matter of time.
If all these findings leave you with the ominous feeling that the benefit-risk profile of Zynteglo has not been completely characterised, you are justified.
In response to such doubt, the FDA and bluebird bio have put safeguards in place to monitor patients receiving Zynteglo for malignancies and further assess risk. All patients who were previously enrolled in a TDT bluebird trial can register for an observational long-term efficacy and safety follow-up study.[7]
Furthermore, in patients receiving Zyntego in the real-world setting, complete blood counts are performed at months 6 and 12, as well as at least annually for 15 years following treatment. Integration site analysis will also be performed at months 6 and 12, should it be deemed necessary.[4]
All things considered, many would argue that in a patient group with such a poor quality of life, Zynteglo is worth the risk. And yet, it is undeniably the haematologist’s duty to ensure that, in the post-approval environment, the long-term benefit and safety of Zynteglo is truly assessed.
Visit mybluebirdsupport.com to receive educational support and review the treatment guidelines for Zynteglo.
References
1. bluebird bio, Inc. FDA Briefing Document Cellular, Tissue, and Gene Therapies Advisory Committee Meeting. Available from: https://www.fda.gov/advisory-committees/advisory-committee-calendar/cellular-tissue-and-gene-therapies-advisory-committee-june-9-10-2022-meeting-announcement-06092022#event-materials. (2022).
2. NICE Draft Guidance Rejects Zynteglo for Transfusion-dependent Beta-thalassaemia. Available from https://www.eversana.com/2021/02/12/nice-draft-guidance-rejects-zynteglo-for-transfusion-dependent-beta-thalassaemia/. EVERSANA (2021).
3. Cohen, J. Bluebird Bio’s exiting the European market signals problems for cell and gene therapy market access. Available from https://lyfegen.com/bluebird-bios/. Lyfegen HealthTech AG (2021).
4. Zynteglo [Package Insert]. U.S. Food and Drug Administration website. https://www.fda.gov/vaccines-blood-biologics/zynteglo. Revised 17/08/2022. Accessed September 2022.
5. Ranzani, M., Annunziato, S., Adams, D. J. & Montini, E. Cancer gene discovery: exploiting insertional mutagenesis. Mol. Cancer Res. MCR11, 10.1158/1541-7786.MCR-13–0244 (2013).
6. Goyal, S. et al. Acute Myeloid Leukemia Case after Gene Therapy for Sickle Cell Disease. N. Engl. J. Med. 386, 138–147 (2022).
7. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Longterm Follow-up of Subjects With Transfusion-Dependent β-Thalassemia Treated With Ex Vivo Gene Therapy. Identifier: NCT02633943. Accessed September 2022. Available from: https://clinicaltrials.gov/ct2/show/NCT02633943.
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