Ups and downs in the treatment of sickle cell disease

Despite promising early results, in this issue of Blood, Dampier et al¹ report the negative results of rivipansel, a predominantly E-selectin antagonist, in treating hospitalized vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD). Although these results are disappointing for patients and physicians, important lessons can nevertheless be learned.

SCD is a devastating disease with a huge global burden, affecting more than 100 000 patients in the United States as well as in Europe and millions in low-income countries. Its pathophysiology has emerged as an extremely complex one, involving not only hemoglobin polymerization as the primum movens but also a cascade of interrelated events including hemolysis; activation and adhesion of neutrophils, platelets, and endothelial cells; abnormal coagulation; sterile inflammation; vascular tone impairment; and nitric oxide functional deficit, among other downstream biological consequences.² Hydroxyurea, the main drug for the prevention of SCD complications, acts on almost all of these interlocking pieces, starting with antipolymerization effect through the reactivation of fetal hemoglobin, and its use has dramatically improved the prognosis of the disease in treated patients.³ Importantly, drugs in SCD, including hydroxyurea, have demonstrated benefits in reducing the incidence of related complications but not one single drug is yet available for treating acute VOC, which is the hallmark of SCD and its most frequent painful complication. Consequently, treatment of VOC still relies on symptomatic relief (of pain, inflammation, and anemia, notably), but none can effectively stop the process once it is triggered or accelerate resolution. New drugs that can effectively act on acute vaso-occlusion and/or synergistically address important facets of the pathophysiology of SCD are still urgently needed.

Among recently developed drugs in SCD, those that reduce the abnormal cell-cell interaction and particularly the adhesion of sickled erythrocytes and leukocytes on activated endothelial cells via selectin blockade were designed with the hope of interfering with the process of vaso-occlusion.⁴ Recently, crizanlizumab, an anti–P-selectin monoclonal antibody indeed showed effectiveness in reducing vaso-occlusive events in a phase 3 study.⁵ Based on promising early results of rivipansel in a phase 2 study,⁶ Dampier et al conducted a large, well-designed phase 3 clinical trial that compared the efficacy and safety of rivipansel with placebo administered intravenously in 345 randomized patients including 141 children ≥6 years of age, admitted in hospital for VOC requiring IV opioid analgesics. Results showed no significant benefit on a clinically relevant primary end point, namely the median time for readiness to discharge (ie, only oral pain medication required, acute complications of VOC resolved to the extent that they could be managed as an outpatient, IV hydration discontinued, IV antibiotics discontinued, and blood transfusions no longer required). However, in a post hoc analysis, the authors explored the timing of rivipansel administration after pain onset and suggested that the administration of the drug within 26.4 hours of VOC onset (earliest quartile) may be an important factor for reducing time for readiness to discharge, as well as time to discharge and time to discontinuation of IV opioids.

Time to treatment in general and analgesia in particular have long been recognized as central in the management of VOCs in patients with SCD.⁷ Likewise, duration of pain experienced at home before arriving for hospital-based management is an important factor in treatment efficacy. Patient-reported time of vaso-occlusive pain onset was a critical item captured in the study. Although it is a challenging parameter to collect given the subjective nature of pain, the possible progressive beginning, its multifactorial etiology, the notorious variability among subjects, the recall bias and subsequent arbitrary imputation, and individual differences in perception of pain onset, it is now clear that patient-reported outcomes are crucial to collect.⁸ Specifically for the vaso-occlusive process, it is likely that early intervention is required to intervene before the inflammatory storm subsequent to ischemia-reperfusion injury causes pain, particularly if the threshold for pain is low, as is the case in many patients with a history of recurrent pain. In fact, the authors point to a narrow time window for early administration of agents that target adhesion processes and suggest home-initiated therapy for best efficacy.

A series of disappointing results from well-conducted trials targeting better resolution of VOC has been published in recent years. Drugs such as poloxamer or sevuparin have failed to demonstrate efficacy.^9,10 Rivipansel will unfortunately be added to this list, and drugs for treating SCD can still be counted on one hand.

SCD is a tremendously challenging disease, including the design of clinical trials. Patient recruitment is difficult in high-income countries where most clinical trials are funded, not only because SCD is a rare disease and the pool of patients is small but also because of poor accrual. End points for efficacy are challenging and need to be refined with composite measures of the response of crisis to treatment, including patient-reported outcomes. Notwithstanding, there has never been such a large number of curative or disease-modifying drugs in the pipeline. Focus on and funding of SCD treatment are growing. Awareness for helping patients feel more engaged in clinical research is also increasing (https://www.hematology.org/about/apps-and-podcasts/scd-podcast-sign-up-form), and advocacy groups are becoming powerful worldwide. Until an affordable curative treatment is made available, there is still a long road ahead before we can offer a tailored and targeted multidrug home-based therapy to patients, but, finally, there is hope of such a therapy being available in the upcoming years.

Conflict-of-interest disclosure: The author declares no competing financial interests.