October 12, 2023

Moniba Nazeef, MD

Sickle cell disease, a chronic debilitating disorder, is characterized by ongoing hemolytic anemia, vaso-occlusive events, and progressive organ damage.

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Sickle cell disease (SCD), a chronic debilitating disorder, is characterized by ongoing hemolytic anemia, vaso-occlusive events, and progressive organ damage. Chronic pain is a well-recognized complication, affecting more than 70% patients.¹ The average life expectancy of patients with SCD is shortened by more than 2 decades compared with the average American life span, with 50% lower quality adjusted life years despite multiple advances over the past decades.^2,3 Disparities and inequities faced by this patient population contribute to the morbidity and mortality associated with the disease.

Despite this, SCD is often not recognized as a condition of reduced quality of life and premature death. After the end of federal funding of SCD centers in 2008, health care systems and institutions have struggled to relegate proper resources to help manage this intensely complex patient population. Consequently, there has been less enthusiasm among hematologists and primary care physicians in caring for patients with SCD. Adult patients face extra challenges due to a lack of comprehensive care centers and programs in general.

Consequently, the burden of acute care use can increase significantly, which is of particular concern in the current health care climate.

SCD Therapeutic Landscape

Although SCD is a complex disorder with multiple facets of disease pathophysiology, acute and chronic pain is considered its hallmark. One of the essential aspects of management for the hematologist is to optimize the disease with available disease modifying therapies to reduce complication and crisis rates.

In 1997, the FDA approved hydroxyurea as the first disease modifying therapy for SCD based on a landmark study that demonstrated improvement in frequency of pain crises, hospitalizations, and acute chest syndrome.⁴ Twenty years later, 3 additional disease modifying medications— crizanlizum- ab-tmca (Adakveo), voxelotor (Oxbryta), and L-glutamine— have been approved to mitigate complications of the disease. Crizanlizumab is a P-selectin antibody aimed at inhibiting cellular adhesions and vaso-occlusion, thereby reducing frequency of pain crises.⁵ Voxelotor is a small molecule targeting inhibition of red cell polymerization and hemolysis, with improvement in hematocrit.⁶ L-glutamine reduces red cell oxidative stress and has been shown to modestly reduce the frequency of hospitalizations and crisis.⁷ These therapies can be used individually or in combination with each other based on the clinical picture, patient preferences, and SCD complications. Transfusions are preferred for patients who have significant organ comorbidities such as history of stroke, pulmonary hypertension, or recurrent acute chest syndrome; new therapies are still being investigated in this setting. Although issues with alloimmunization, iron overload, and need for large bore intrave- nous access remain challenging for this modality, transfusions can offer an objective way to optimize disease in challenging situations through reduction of hemoglobin S levels and hemolysis.

Additional strategies involving complement inhibitors, pyruvate kinase activators, and nitric oxide modulators are being investigated. These therapies target various pathophysiologic mechanisms such as hemolysis, red cell polymerization, and vasoconstriction.

Early emerging data in gene therapies using autologous stem cell source with techniques incorporating viral vectors and genome editing platforms for β-globin modification or HbF induction via BCL11A suppression are quite promising.^8-10 Results show significant reductions in vaso-occlusive crises and improvement in functioning hemoglobin concentrations that appear sustained in short-term follow-up. Long-term safety and practicality of this approach is being investigated and, if shown to be effective, might offer a huge paradigm shift in therapeutic options and approaches.

Comprehensive Programs

Institution of optimal disease modifying therapies and management of disease complications requires SCD expertise within comprehensive care management programs to improve long-term patient outcomes and acute care use. Implementation of such programs at strategic locations not only ensures access to adequate clinical care but also establishes pathways to clinical trials and curative therapies. These interventions can lead to significant health care cost savings, making a compelling case for a proactive approach by investing in strong clinical programs up front.

Every center or program requires key essential and optimal elements through dedicated staff support. Knowledgeable providers, patient navigators/coordinators, and social workers make up the backbone of this element. Sickle cell programs can follow several models of care, such as independent comprehensive or embedded centers in key locations that can also serve as regional hubs.¹¹ Resources needed by each center can vary depending on the patient population, staffing, and institutional structure. They may be coshared within larger frameworks, such as the cancer centers that house hematology care. Institutional support and key stakeholder buy-in is extremely important for the success of such programs and initiatives.

A multidisciplinary team approach that addresses the medical and psychosocial issues in SCD can be incorporated by programs through the following:

• Optimizing clinical management by implementation of evidence-based care using guidelines for SCD provided by the American Society of Hematology (ASH), the CDC, and the National Heart, Lung, and Blood Institute

• Partnering with key stakeholders in emergency departments, admitting services, pain/pallia- tive care specialists, and nursing to optimize inpatient management and use by implement- ing individualized care plans

• Implementing educational initiatives for train- ees, providers, nursing staff, and patients, with a focus on increasing knowledge and dispelling bias and stigma

• Collaborating with advanced subspecialties (eg, transfusion medicine, obstetrics/gynecol- ogy, nephrology, pulmonology, orthopedics, and bone marrow transplant)

• Offering psychosocial support, advocacy, outreach, and partnership with community-based organizations

• Creating optimal pediatrics to adult transitions pathways

• Creating networks with regional and national programs for research and interactive collab- oration among experts (eg, SCD Network sites and Extension for Community Health Outcomes programs)

Initiatives and Future Needs of SCD Centers

One of the several proposals by the ASH SCD initiative includes outlining a comprehensive framework for providers and their teams in establishing SCD programs and providing training through a series of workshops and mentorship. Improvement in patient care, expe- rience, and resource use are important metrics for the programs to assess their performance and should be incorporated in ongoing quality improvement and assurance processes. With upcoming disease modifying and gene therapies on the horizon, strong and sustainable clinical programs are urgently needed. As an example, the University of Wisconsin Sickle Cell and Hemoglobin Disorders Program outline that was established through this initiative to meet the needs of our patients and providers.

It is time for institutions, systems, and health policy makers to recognize that SCD care cannot be accomplished by providers alone. Appropriate funding and resources must be allocated to help clinics and programs provide compre- hensive and compassionate care and advance research initiatives. The Sickle Cell Disease Treatment Centers Act of 2022 is currently under congressional review.¹² This bill directs the Department of Health and Human Services to award grants for establishing SCD treatment centers that operate using a hub-and-spoke framework to provide integrated, longitudinal health care for individuals with SCD and trait. If passed, this will be an important and well-deserved step toward addressing the gaps created by health care disparities in sickle
cell management.

References

1. Drahos J, Boateng-Kuffour A, Calvert M, et al. Health-related quality of life, disease impacts, and health equity concerns in adults with sickle cell disease with recurrent vaso-occlusive crises: preliminary results from a global longitudinal survey. Blood. 2022;140(suppl 1):1387-1388. doi:10.1182/blood-2022-157818

2. Pleasants S. Epidemiology: a moving target. Nature. 2014;515(7526):S2-3. doi:10.1038/515S2a

3. Lubeck D, Agodoa I, Bhakta N, et al. Estimated life expectancy and income of patients with sickle cell disease compared with those without sickle cell disease. JAMA Netw Open. 2019;2(11):e1915374. doi:10.1001/jamanetworkopen.2019.15374

4. Charache S, Terrin ML, Moore RD, et al; Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med. 1995;332(20):1317-1322. doi:10.1056/ NEJM199505183322001

5. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the prevention of pain crises in sickle cell disease. N Engl J Med. 2017;376(5):429- 439. doi:10.1056/NEJMoa1611770

6. Vichinsky E, Hoppe CC, Ataga KI, et al; HOPE Trial Investigators. A phase 3 randomized trial of voxelotor in sickle cell disease. N Engl J Med. 2019;381(6):509-519. doi:10.1056/NEJMoa1903212

7. Niihara Y, Miller ST, Kanter J, et al; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A phase 3 trial of L-gluta- mine in sickle cell disease. N Engl J Med. 2018;379(3):226-235. doi:10.1056/NEJMoa1715971

8. Kanter J, Walters MC, Krishnamurti L, et al. Biologic and clini- cal efficacy of LentiGlobin for sickle cell disease. N Engl J Med. 2022;386(7):617-628. doi:10.1056/NEJMoa2117175

9. Esrick EB, Lehmann LE, Biffi A, et al. Post-transcriptional genetic silencing of BCL11A to treat sickle cell disease. N Engl J Med. 2021;384(3):205-215. doi:10.1056/NEJMoa2029392

10. Frangoul H, Altshuler D, Cappellini MD, et al. CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med. 2021;384(3):252-260. doi:10.1056/NEJMoa2031054

11. Kanter J, Smith WR, Desai PC, et al. Building access to care in adult sickle cell disease: defining models of care, essential compo- nents, and economic aspects. Blood Adv. 2020;4(16):3804-3813. doi:10.1182/bloodadvances.2020001743

12. Sickle Cell Disease Treatment Centers Act of 2022, HR 8855, 117th Cong (2022).