In this issue of Blood Advances, Shenoy et al1 present a comprehensive list of long-term follow-up evaluations recommended after curative therapy for sickle cell disease (SCD). As experts in SCD and transplant for SCD, Shenoy et al provide organ- and outcome-specific evidence to support their long-term follow-up recommendations and highlight opportunities for further research.
This important article contextualizes the long-term follow-up priorities and needs for patients with SCD who undergo potentially curative therapy, a broad term that now includes multiple modalities. Although not yet considered curative by SCD experts, for the purposes of this article and that of Shenoy et al, gene therapy is intended to be curative. Allogeneic transplantation using a matched sibling donor is a well-established therapeutic option, with significant advances in alternative donor strategies in recent years.2 The US Food and Drug Administration's (FDA) approval of 2 genetic therapies for the treatment of SCD3 then begs the question if allogeneic transplant with its known/perceived limitations and morbidity is relevant in the new and upcoming era of gene therapy.4
The answer to this provocative question is, of course, yes. SCD experts consider gene therapy to be transformative and not yet curative given the limited long-term outcome data and lack of established durability. The median follow-up for the two FDA-approved therapies, lovotibeglogene autotemcel and exagamglogene autotemcel, is 41.9 months (range, 0.9-72.3)5 and 34.7 months (range, 4.5-63.8),6 respectively, for lovotibeglogene autotemcel and exagamglogene autotemcel. For a patient considering allogeneic transplant vs gene therapy (whether commercial or as part of a clinical trial), factors such as experience with allogeneic transplant, large numbers treated,7 known long-term follow-up, option for less toxic conditioning, cost, and access may outweigh the limited number of patients treated with gene therapy to date, lack of long-term data, and exorbitant costs associated with these novel autologous cellular therapies. Patients who undergo gene therapy in its current form (stem cell collection, ex vivo modification, and myeloablative conditioning) do so with an expectation of short-term vaso-occlusive event (VOE) reduction with hope of but uncertain long-term improvement.
The authors define cure as the restoration of physical and psychosocial quality of life similar to unaffected peers, correction of laboratory parameters, and abrogation of medical needs connected to the disease that is stable long-term, spanning a normal lifespan. To be able to consider gene therapy curative in the long term rather than transformative in the short term, organized registries are required to collect uniform data from all treated patients directly addressing the durability, changes to organ function, and patient-reported outcomes over time.
Although SCD is a growing global health disorder,8 only a fraction of individuals with SCD will pursue curative therapy, which is currently limited to high-income countries where the disease burden is lower but access to high-risk therapies exists. Studying small populations of patients constrains the ability to generate robust health outcome evidence. However, successful models recommended for SCD suggest that systematic surveillance data and a longitudinal registry can improve health care, enhance health outcomes, and advance understanding of diseases and treatments.9 Shenoy et al propose recommendations to establish the uniformity required to compare therapies, define expectations, provide insights into interventions posttherapy, and help patients and providers select the best approach.
The decision to seek a curative option for SCD is unique. Unlike in malignant conditions, allogeneic or autologous transplantation for SCD is not urgent. Patients face multiple complex decisions: to proceed or not, which therapy to pursue, and when to pursue it, if at all. Some decisions, such as the ability to tolerate myeloablation, may be decided for the patient. But for most, multiple strategies may be suitable. These complex decisions require informed consent and shared decision making to preserve a patient's control over his or her medical care. The current process requires providers to clearly explain the knowns and unknowns. In the case of gene therapy, VOEs are reduced, hemoglobin and hemolysis markers are normalized or improved, and quality of life is improved, all in the short-term. The evidence for long-term health outcomes, including the risk for secondary malignancy, and real-world outcomes outside of a clinical trial, will come from the uniform adoption of assessments, as proposed by Shenoy et al. When this is performed for all intended curative strategies and compared with longitudinal registry data, only then will patients be able to make truly informed decisions about which therapy may serve them best. Although acknowledgment of the uncertainties and lack of long-term data is necessary, it must be said that how a patient is counseled may be colored by that provider's biases and expectations for durability in the future. Speaking with multiple providers in an age of uncertainty is critical to combat any 1 provider’s unintentional sway that may impact shared decision-making. As suggested by the authors, clear long-term data will enable providers to more clearly predict and communicate advantages and disadvantages, and how they may vary among therapies and over a patient's lifespan. This communication fosters patient trust, historically lacking and recently worsened by the abrupt withdrawal of voxelotor, by reducing the uncertainties and better understanding these highly complex, high-risk, and high-reward therapies.
Gene therapy for the treatment of SCD requires coordinated and systematic patient follow-up before and after therapy. The expert recommendations provided by Shenoy et al create a framework for evidenced-based assessments, timing, and research priorities necessary to deliver high-quality curative therapies to patients living with SCD.
Conflict-of-interest disclosure: The author declares no competing financial interests.
