As a provider taking care of patients with sickle cell disease (SCD), I’m always a little ambivalent about the state of the field. Part of me is in a perpetually celebratory mood about advances being made such as gene therapy, haplo-transplantation, new drugs, and expanded access to treatment in low-resource settings. The other part of me faces the growing data of how we are failing to provide equitable care and parity in outcomes with other genetic diseases like cystic fibrosis and hemophilia.
These seemingly opposed forces and emotions were apparently familiar to ancient Romans, as reflected and personified in their god Janus. Depicted as having two faces looking in opposite directions, Janus is the god of changes, transitions, passages — past and future. He fills a lot of roles evidently, and oral presentations in SCD struck me as, well, Janus-like. We heard talks describing some truly exciting research in curative therapies reflecting the optimistic future, but also important findings highlighting ongoing disparities. However, we are also reminded by our patients that with passage through a changing landscape comes personal transformation, and hopeful change at that.
Let’s start with the optimistic future. Some background may be helpful here. Recently, gene therapy trials in SCD were put on hold due to the occurrence of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).1 The occurring MDS and AML were shown to not be due to insertional events from the therapy itself (though not as certain in one case), but this has left the community concerned. Patients with SCD have an abnormal bone marrow and data show that there is a higher relative risk of MDS/AML at baseline in SCD. It has been recently proposed that the mechanism is stress hematopoiesis in the setting of what is essentially autologous transplantation, which may drive clonal expansion of these abnormal populations. Tracking clonal hematopoiesis pre– and post–gene therapy has been recently proposed as a necessary and potentially practice-changing step in the paradigm of curative therapy.1
Additionally, with concerns about gonadal failure, which is nearly universal in myeloablative regimens, and potential for busulfan conditioning contributing to morbidity, an antibody-based preparatory regimen is another major advancement that promises to change the risk-benefit calculus of curative therapies.
Two presentations happening Sunday, December 12 will substantially address these challenges in curative therapies. Dr. Alyssa Cull and colleagues will present data utilizing whole genome sequencing as a viable strategy to track mutation burdens pre– and post–gene therapy (abstract 559). Their data recapitulated previous findings of an excessive mutation burden in some patients pre–gene therapy. The method was also able to track excess mutations per hematopoietic stem and progenitor cells following autologous transplantation of the product. This is a promising strategy to risk stratify potential candidates for gene therapy.
In the same session, Dr. Naoya Uchida and colleagues will present data using a CD117 (c-kit) antibody-drug conjugate in a rhesus model for hematopoietic stem cell gene therapy (abstract 560). This model incidentally modified the BCL11A gene, relevant to one particular method of gene transduction being attempted in SCD. Robust engraftment of gene-modified CD34+ cells was observed with minimal toxicity as compared to busulfan conditioning. The feasibility of an antibody-based regimen demonstrated here has the potential to greatly improve the tolerability and safety profile of gene therapy for hemoglobinopathies.
The Education Program session “Curative Therapies and Considerations for Sickle Cell Disease” (with live Q&A virtual and in-person today at 9:30 a.m. Eastern time in Room C202-C204 of the Georgia World Congress Center) features an excellent discussion from panelists Drs. Lakshmanan Krishnamurti, Julie Kanter, and Sherif Badawy. Dr. Krishnamurti is discussing recent advances and evidence in haploidentical transplants and reduced intensity conditioning, including antibody-based, nonmyeloablative regimens. This presentation promises to be a thought-provoking addition to recent literature, with discussion of how these advances in haplo-transplantation open doors to curative therapies for many patients.2 Dr. Kanter is providing updates in current clinical trials for gene therapy in SCD. Especially helpful were the comparisons of various therapies under investigation. She will also address risk mitigation strategies for gene therapy, and I am very eager to hear her expert opinion. Dr. Badaway will discuss the challenges of engaging a historically marginalized and abused population in clinical studies. I found his discussion of patient-reported outcomes especially timely, and a piece that has been absent from too many trials in SCD. Don’t miss the live Q&A today!
Finally, to temper our enthusiasm, we have great presentations during the “Outcomes Research–Nonmalignant Conditions: Sickle Cell Disease Management and Outcomes Across the Lifespan” session. In a community that has been subject to inequity in access and outcomes, it is nonetheless just as encouraging to see work on this front as it is to see advances in curative therapies. In one of this session’s abstracts (abstract 489), Dr. Samantha Fisch and colleagues will report outcomes in pregnant women with SCD in a retrospective cohort in California. This important analysis showed higher rates of C-section, stillbirth, and maternal mortality. These data provide a much-needed, even if incomplete, picture of the inequity experienced by women with SCD and their babies. The dramatic differences in outcomes in these patients, while discouraging, provides valuable data for researchers wishing to focus efforts on peripartum management of SCD, where limited data currently exist to guide our management.
Another growing population with little data to guide management is older adults with SCD. Dr. Charity Oyedeji and colleagues will present interesting qualitative data on three main domains regarding the experience of patients with SCD living past life expectancy. These domains, or themes, were surprising to me and should be useful to any provider seeing patients with SCD. Describing her findings, I spoke in advance with Dr. Oyedeji, who shared with me, “My older patients can’t be offered curative therapy; they’re too sick. So my work is to see what we can do to improve their quality of life and functionality now.” In engaging a community long misunderstood by the medical establishment, these data can also inform how the research community might engage patients in scientific investigation.
So, while looking to the past and future, we can inhabit states of disappointment, change, and positivity, and allow those seemingly competing feelings to push us forward to better outcomes for patients with SCD.
- Jones RJ, DeBaun MR. Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both, or neither. Blood. 2021;138(11):942-947.
- Brodsky RA, DeBaun MR. Are genetic approaches still needed to cure sickle cell disease? J Clin Invest. 2020;130(1):7-9.
Dr. Ellsworth indicated no relevant conflicts of interest.
