Key Clinical Summary: Evolving the Treatment Paradigm for Sickle Cell Disease

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Introduction:

This summary outlines the evolving treatment paradigm for Sickle Cell Disease (SCD), shifting from historically supportive care to an era with multiple disease-modifying and curative therapies. A key theme is the necessity of a multimodal and individualized approach to patient management, integrating new pharmacologic agents, considering curative options like hematopoietic stem cell transplant (HSCT) and gene therapy, and employing comprehensive pain management strategies. Special attention is also required for the growing population of older adults with SCD, who have distinct clinical needs.

The Foundational and Targeted Pharmacologic Therapies

A strategic, layered approach to pharmacotherapy is recommended, starting with a foundational treatment and adding agents based on the patient's specific disease manifestations (e.g., vaso-occlusive crises vs. anemia).

Hydroxyurea: Considered the standard of care, it's the first disease-modifying therapy approved and is indicated for children over 9 months and adults with three or more crises per year. It has been shown to reduce pain crises by 44% and also decreases ACS and transfusion needs. Ongoing monitoring of blood counts is essential.
L-Glutamine: An option for patients aged 5 and older with recurrent VOCs, particularly those who are intolerant to or have an inadequate response to hydroxyurea. It can reduce pain and ACS. Considerations include potential GI side effects and the need for twice-daily dosing of a powder formulation.
Crizanlizumab: A P-selectin inhibitor indicated for patients 16 and older with at least two pain crises in the past year. It reduces pain crises by approximately 45% but is administered as a monthly IV infusion, which carries a risk of infusion reactions.

Patient Selection for Curative Therapies: HSCT and Gene Therapy

For patients with severe SCD, discussions about curative options should begin early. Careful patient selection is critical for both HSCT and gene therapy.

Eligibility Criteria: Key factors for consideration include a severe SCD phenotype, assessment of end-organ damage, psychosocial stability, and age. Age Limits: HSCT is typically considered for patients under 50, while the oldest patients in gene therapy trials were in their mid-40s.
HSCT: Matched sibling donor (MSD) HSCT is the most established curative option, with approximately 95% survival rates. Other options like haploidentical HSCT are expanding access. A major consideration is the risk of Graft-versus-Host Disease (GVHD).
Gene Therapy: Two recently approved approaches, Lovo-cel (gene addition) and Exa-cel (gene editing), offer a significant >90% reduction in VOCs and avoid the risk of GVHD. Long-term follow-up data is currently limited to a few years. Counseling: Essential discussions must cover individualized risk-benefit analysis, fertility preservation before chemotherapy, and the logistical requirements of post-procedure care.

Multimodal Pain Management: A Balanced Approach

A significant challenge in SCD is balancing effective pain control with opioid stewardship. An

individualized pain action plan is crucial for both acute and chronic pain.

Acute VOC Management: Strategies include rapid opioid titration, adjuvant NSAIDs (if not contraindicated), ketamine for opioid-refractory pain, and regional anesthesia for localized pain.
Chronic Pain Management: This requires a broader approach, including structured opioid management plans, agents for neuropathic pain (e.g., SNRIs), and psychological interventions like Cognitive Behavioral Therapy (CBT).
Non-Pharmacologic Interventions: These are often underutilized but highly beneficial. Interventions such as physical therapy, TENS units, heat therapy, and mindfulness can reduce opioid requirements by 30-40% while improving quality of life.

Special Considerations for an Aging SCD Population

With median survival now exceeding 50 years in high-income countries, a growing population of older adults with SCD presents unique management challenges.

Clinical Adaptations: Clinicians must make pharmacologic dose adjustments for age-related renal and hepatic insufficiency and perform systematic screening for progressing end-organ damage.
Functional Assessment: Regular evaluation of daily living activities is important, as older SCD patients experience greater functional limitations.
The Evidence Gap: It is critical to recognize that older adults have been systematically excluded from most major clinical trials, including recent gene therapy studies, creating an evidence gap that complicates treatment decisions. Care should blend geriatric principles with SCD-specific knowledge.