Life after sickle cell disease, is it really UHURU?

Sickle cell disease (SCD) is a common genetic disease that affects millions of individuals worldwide. The disease is associated with relentless end-organ injury, episodic emergencies, and early mortality. Deficiencies in SCD diagnosis, clinical care, treatment, and research are well-recognized global health disparities. Unfortunately, we see emerging evidence that increased use of curative therapies do not eliminate these disparities, and paradoxically may illuminate them.

At present, curing SCD requires exposing individuals to preparative regimens with short- and long-term toxicities. These regimens include chemotherapy, always an alkylating agent, and sometimes radiation. Unlike in cancer care, there are no standardized descriptions of preparative regimens to cure SCD. A recent study highlighted that some “reduced intensity” preparative regimens for SCD cure have higher cyclophosphamide equivalent doses than myeloablative conditioning regimens¹. Despite the need for late effect monitoring with these exposures, long term follow-up care for individuals with SCD exposed to curative therapies is not assured and is neither standardized nor well studied. However, gene therapy may soon become a standard treatment option for SCD, bringing needed attention to this neglected concern. We need to know: What long-term care is needed for people exposed to therapies intended to cure SCD, and who will care for the cured?

Sickle cell disease, its medical treatment, and curative therapy all present potential sequelae that require clinical monitoring. Some require treatment for graft-versus-host disease and sequelae of immunosuppression, including viral reactivation and post-transplant lymphoproliferative disease. Even when curative therapy is successful, permanent SCD injury can persist. For many people cured of SCD, especially those cured in adulthood, chronic pain will be a fact of life, and treatment will be ongoing. Clinicians who are unfamiliar with SCD generally, such as those who work in acute care settings, may continue to manage pain as acute events. Some clinicians familiar with SCD, but unfamiliar with curative therapies may continue similar patterns out of inertia or clinical uncertainty. We have seen cases of patients who, despite full engraftment, have been treated as if having repeated SCD painful crises, including with exposure to high-dose opioids or hydroxyurea. Transplant specialists may lack expertise in managing SCD end-organ complications, some of which are halted but not reversed by curative therapies. Chronic pain management, particularly with respect to chronic opioid therapy, may require separate expertise. Other SCD complications also do not necessarily resolve with curative therapies. Cognitive impairment may be permanent. Psychiatric comorbidities, including suicidal ideation, can emerge during curative treatment^2,3. In addition, preparative regimens for cure pose risks of malignancy, end-organ damage, and infertility^2,4–6.

Patient experiences in the US and Nigeria underscore that use of curative therapies for SCD does not eliminate care inequities. In fact, patients treated with curative therapies need a medical home for ongoing multidisciplinary care, for all the reasons noted previously. However, this care may become more difficult to access after curative therapies. Both children and adults cured of SCD at distant centres are returning home without access to medical professionals to provide specialized care. In some cases, long-term follow-up of children cured of SCD may be available in paediatric settings and subsequently interrupted in young adulthood because of limited adult specialists.

Despite over 30 years of experience with allogeneic hematopoietic cell transplant for SCD, survivorship care is not standardized. Yet in the time since transplant was first used to cure SCD, survivorship care for cancer has become a firmly established, multidisciplinary field of care and research⁷. People with SCD exposed to curative therapies need a survivorship model that is developed with expert input, and that must be improved through iterative quality improvement efforts and collaborative research. As in cancer, specialists with integrated expertise in SCD, SCD cures and late effects of treatment are needed to provide lifespan care.

The few post-transplant clinics for SCD spotlight care opportunities and knowledge gaps. Where such clinics exist, some have managed to assemble multidisciplinary teams of transplant and SCD experts. In some of these clinics, multiple experts see patients during the same clinic visit to minimize travel time and improve access. However, these endeavours are ad hoc, depend upon local availability of scarce resources, and little evidence exists to define best practice. Emerging guidance to inform care relies on expert input, not evidence⁸. Post-HCT end-organ function, pain trajectories, and other patient-reported outcomes are only now under systematic investigation (COALESCE NCT05153967, STELLAR). These data are needed to help standardize the multidisciplinary team, the dimensions of post-HCT care, and outcome reporting. All are lacking, as illustrated in a recent systematic review⁵. However, some needs are immediately evident. Counselling, monitoring, and treatment for late effects of therapy, complex chronic pain, mental health, and social determinants of health are required (Figure).

A multidisciplinary care model for people exposed to therapies intended to cure sickle cell disease accounts for possible persistent sickle cell disease and sickle cell disease treatment sequelae along with monitoring for sequelae of curative therapies. Ideal teams to provide lifespan care will have integrated medical expertise in SCD, transplant and mental healthcare in collaboration with advanced practice clinicians and physical rehabilitation and social support.

While expert- and evidence-informed guideline are needed to define adequate care for people exposed to SCD cures, it will only work if structures exist to provide it. In much of the world, including high-income settings such as the US and low-income settings like Nigeria, creating essential clinical infrastructure is among the many equity concerns raised by expanding access to curative therapies for SCD. Existing SCD care centres cannot take on this responsibility without further support. These centres are already overwhelmed and under-resourced. There are not enough specialists to care for people with SCD. The majority of SCD care teams do not have all necessary expertise to care for a curative therapy-exposed patient population.

Erratic care for people exposed to curative therapies for SCD could result in increased acute care utilization and perpetuate or even exacerbate pre-existing, irreversible end organ damage (e.g. osteonecrosis or restrictive lung disease). This possibility threatens the hope that gene therapy will reduce SCD-associated healthcare costs. In the US, outcomes-based payment models are being considered for highly anticipated, and enormously expensive, gene therapy⁹. In the US, the Centers for Medicare and Medicaid Services is considering how – or if – it will ensure access to future FDA-approved gene therapy to individuals with SCD. This requires attending to both the upfront costs and life-long care systems required for people who have been exposed to preparative regimens, and who may have chronic sequelae of SCD or endure relapse when curative therapies fail. If the clinical benefits of gene therapy are evident, and access is restricted due to costs associated with disorganized care after treatment, it will perpetuate systemic injustice against an already marginalized patient population¹⁰.

Collaborations, standardization, and adequate resources to support people exposed to curative therapies for SCD are urgently needed. The absence of resources compounds disturbing and entrenched SCD care inequities. Care systems can be developed even as data to inform care emerges. Global health, federal agencies, and non-governmental institutions need to ensure that investments are made to (1) ensure systematic data collection that identifies disease-modifying therapy and preparative regimen exposure and long-term outcomes, and (2) develop multidisciplinary specialty clinics to care for people exposed to curative regimens for SCD. These agencies must also ensure that resources are not diverted from existing, under-resourced SCD care infrastructure. Cure without care jeopardizes the uptake, success, and long-term outcomes of curative therapies. Ultimately, this will risk exacerbating rather than alleviating the SCD care crisis.