https://orcid.org/0000-0003-1051-2555
In this issue of Blood Advances, Kelkar et al1 highlight a significant challenge that now faces hematology providers caring for patients with hemoglobinopathies: how to ethically allocate gene therapies for sickle cell disease (SCD) and transfusion-dependent thalassemia (TDT).
When the US Food and Drug Administration granted approvals for gene therapies for TDT (2022, 2024) and SCD (2023), there was hesitancy to open the flood gates and refer any patient with an eligible diagnosis for gene therapy. Make no mistake, the overdue attention to long-neglected diseases and the new hope for underserved populations were heartily embraced. At the time of approval, the clinical trials for gene therapy products for SCD and TDT had been extensively presented and discussed, with peer-reviewed publications eagerly anticipated.2-5 But, as providers waited for final approval, reality bit. The daunting chore of insurance and contract negotiations was apparent early on. Many hematologists realized that the availability of the resources required to bring a patient to, and through, gene therapy would quickly outpace demand, even if some patients elected not to be early adopters of the new treatment. Ultimately, our excitement for a breakthrough therapeutic option quickly collided with the prospect of operationalizing the complex processes of patient selection and prioritization. We, the community of hematology providers, were faced with the task of defining value structures to guide deployment of this resource. The answer, emphatically and skillfully delineated by Kelkar et al, is that our highest priority is to do no further harm to this already disadvantaged population of patients.
Transformative therapies for SCD and TDT have long been available but underused because of barriers including various limits to health care access and insufficient donor options. For persons with SCD, matched related donor transplantation remains the most common approach because of superior outcomes but is limited by lack of suitable family donors.6 For patients pursuing matched unrelated donor transplant, the National Marrow Donor Registry reports the odds of finding a matched unrelated donor as 29% for African-American patients and 47% for Asian/Pacific Islander patients, which accounts for most patients with SCD and TDT, respectively. More recently, improved outcomes for haploidentical transplants have expanded treatment options for adults with SCD.7,8 Despite these advances, the gap between these options and a cure available to all (geography notwithstanding) remains substantial. Gene therapy serves as a bridge across that gap but presents distinct obstacles. Having eliminated the donor challenge, gene therapy introduces new challenges including defining eligibility; patient prioritization; and, potentially, competition between diseases.
To avoid further harm, each center providing gene therapy must place the highest value on delineating a process to ensure ethical, systematic allocation. Developing an allocation process for the scarce and precious resource that is gene therapy for hemoglobin disorders will require deep planning and consideration. In the article by Kelkar et al, hematologists and stem cell transplant teams now have a robust road map from which to start their own deliberations. Hematologists must also learn from the history of others, including the solid organ transplant community, which has refined an approach to donation, procurement, and distribution that has evolved over decades.
For solid organ transplants, there are shared approaches to patient selection and organ allocation. Kelkar et al stop short of immediately calling for a national approach to gene therapy allocation, but the hematology community would do well to venerate a standardized approach. In 1984, the US Congress passed the National Organ Transplant Act to improve the process of organ matching and distribution, including bone marrow.9 The act called for the US Department of Health and Human Services to guide the allocation of solid organ transplants through the Organ Procurement and Transplantation Network in partnership with the United Network for Organ Sharing. This national approach acknowledged the singular pipeline of available organs. Beyond allocation, prioritization for solid organ transplant involves eligibility determined by each center based upon guidance from professional organizations. Similarly, although each gene therapy program may establish some specific local guidelines, we must also acknowledge the possibility that the availability of manufacturing slots could represent a similar narrow pipeline upon which all programs will converge. Our professional organizations and experts in the field should lead the effort to establish standardized essential eligibility criteria. The eligibility criteria outlined by Kelkar et al are sound but may benefit from additional consensus review led by a similarly multidisciplinary group, also accounting for regional variation. Furthermore, any eligibility criteria established today would be enhanced from regular review as we learn more about factors that influence patient outcomes after gene therapy. Although we should start with center-specific approaches, there should be priority placed on supporting the infrastructure to gather data on patient outcomes that evolve from varied prioritization schemes and eligibility criteria and, in short order, establish a national framework.
We live in an era in which innovative technologies outpace the infrastructure to support them. If more individuals with SCD had access to comprehensive care, then there would be a natural gateway for specialized treatments, and many access challenges would be resolved. If gene therapy centers were distributed in alignment with patient density, then we would worry less about “gamesmanship by more well-resourced patients.” When there is a consensus eligibility score, then lack of clarity or consistency cannot erode the focus on prioritization based on patient-related factors. When there is a national framework, the manufacturing pipeline can ethically allocate slots in the same way local centers must prioritize patient referrals. These goals are far beyond the scope of the work of Kelkar et al. For now, they have empowered hematologists to respond to the bite of reality with a clear acknowledgment of the value of balancing what is most important to patients, providers, and health care systems as we seek to cure 2 devastating diseases with gene therapy.
Conflict-of-interest disclosure: V.N.T. and T.A.F. have no competing financial interests relevant to this article.
