The therapeutic landscape for patients with sickle cell disease (SCD) has recently expanded, and health care practitioners now have several options of disease-modifying drugs that are sickle cell specific. As of 2020, in the United States, there are 4 Food and Drug Administration (FDA)-approved drugs for patients living with SCD: hydroxyurea, L-glutamine,1 voxelotor,2 and crizanlizumab.3 Many more agents are currently being tested in phase II or III trials; therefore, we foresee that several new targeted therapies will be available by the end of the current decade. The treatment of individuals with SCD will become increasingly complex and, at the same time, mechanistically based, as a large number of these drugs are specifically being developed to affect and/or change the multifaceted pathophysiology of SCD.
Although hydroxyurea, also referred to as hydroxycarbamide, has been used by thousands of patients around the globe for >30 years4 and clinicians can rely on decades of clinical and laboratory data to inform and guide its use,5 fewer data exist for the 3 recently FDA-approved drugs—L-glutamine, voxelotor, and crizanlizumab. Therefore, many scientific and clinical questions remain about their mechanism of action, efficacy, effectiveness, and long-term safety profile. FDA-mandated postlicensing trials are planned or already under way to answer these remaining questions.
With increasing choices, clinicians who treat patients with SCD need to develop a systematic approach to evaluate and present different therapeutic options and, together with patients and their families, apply shared decision-making principles6 to make final recommendations and decisions. Practitioners need to take into consideration both the clinical characteristics of each patient, such as their age and disease phenotype, and their values and preferences. Social circumstances (eg, home environment, occupation) and the drug’s mechanism of action and route of administration should all be considered. Finally, insurance coverage and drug access need to be factored into the decision-making process. As with any disease, as newer drugs are developed, high costs may preclude drug access and become a substantial barrier, which creates and perpetuates inequity.
Although the new disease-modifying agents have not yet been compared to each other and have been given in combination with hydroxyurea in a very small subset of patients, some general guidance can be provided based on patients’ clinical characteristics (eg, venous access, disease phenotype), age, and preferences. In this chapter, we provide recommendations on how to incorporate the new disease-modifying agents in clinical practice, given the newest evidence for their efficacy and mode of utilization.
Considering Sickle Cell Phenotype in the Choice of Therapy
When clinically evident, the patient’s phenotype may be an important guide to therapy. Although on a spectrum and with substantial overlap, the phenotype in SCD can be divided into 2 main clinical subphenotypes: hemolytic and vaso-occlusive.7 The FDA-approved labels of the disease-modifying agents provide guidance in the decision process in relation to the ...