Priapism before and after hematopoietic stem cell therapy in individuals with sickle cell disease Open Access

TO THE EDITOR:

Priapism, defined as a persistent, painful erection with or without arousal, is a common complication of sickle cell disease (SCD) that affects children, adolescents, and adults. The prevalence of priapism in patients with SCD has been reported to be 32.6%¹ to 38%.² The comorbidities associated with priapism include permanent penile deformities, penile scarring, increased rates of sexual or erectile dysfunction, decreased overall sex life satisfaction, anxiety, sadness, depression, embarrassment, and fear.¹ Idris et al¹ demonstrated that as many as 50% of individuals with SCD never seek medical attention for their priapism events, indicating that the morbidity burden is likely higher than reported in the literature.

Recently, a phase 2 randomized controlled trial³ demonstrated that hydroxyurea (HU) combined with a placebo and hydroxyurea combined with tadalafil produced a 58.3% and 66.3% reduction in the incidence rate of priapism, respectively. This trial was the first to show an effective strategy to decrease the incidence of SCD-related priapism, Hematopoietic stem cell transplantation (HSCT) and gene therapy (ovotibeglogene autotemcel and ovotibeglogene autotemcel) are currently the only established curative therapies for SCD; however, the benefit of curative therapy in preventing further priapism episodes is not well defined. We conducted a multisite case series of individuals with SCD who had experienced priapism episodes before HSCT from 3 institutions to test our hypothesis, which was that HSCT significantly decreases the rate of priapism when compared with the period before HSCT in male patients with SCD.

We conducted a retrospective case series study of individuals with SCD at the Vanderbilt University Medical Center, the University of Illinois Chicago, and St. Jude Children’s Research Hospital. We included a manual electronic health record review to identify individuals with SCD who had experienced priapism episodes that required an inpatient, emergency and/or observation visit at the hospital and who then underwent HSCT. We extracted the age at HSCT, SCD phenotype, priapism events 36 months before HSCT, and priapism events 36 months after HSCT. Institutional review board approval at the Vanderbilt University Medical Center, the University of Chicago in Illinois, Chicago, and St. Jude Children’s Research Hospital was obtained, and the study was conducted in accordance with the Helsinki Declaration.

Descriptive statistics were used to describe the patients’ baseline characteristics and summarize the priapism rate before and after HSCT. A negative binomial regression was used to compare the priapism rate before and after HSCT given that the patients were not followed for the same time period before vs after the intervention. We also used a Wilcoxon signed-rank test as a conservative comparison of the priapism rates because of the small sample size. The MASS package in R Studio was used to perform the negative binomial regression. Statistical significance was defined as P < .05.

Based on our eligibility criteria, a total of 5 patients were identified across the 3 institutions (Table 1). All patients, except 1, were adults with a mean age of 22.2 years (range, 6-31). All patients had the hemoglobin SS or hemoglobin beta-thallasemia null phenotype. Three patients received an HLA-matched HSCT, and 2 patients received a haploidentical HSCT. All patients were followed for 36 months before and after the transplant, except for 1 patient, who was followed for 36 months before the transplant and only 24 months after the transplant. No patient received a shunt for priapism management before or after the transplant. Of the 5 patients, priapism was the main reason for transplant in only 1 patient, because of his high rate of priapism episodes (patient 4). In total, there were 31 priapism episodes before transplant (0.17 priapism episodes per person-month) and 2 episodes of priapism after transplant (0.01 priapism episodes per person-month). The incidence rate of priapism was significantly lower after HSCT; the incidence rate ratio (IRR) was 0.068, indicating that the rate following transplant was 6.8% of the rate before transplant (95% confidence interval [CI], 0.008-0.369; P = .0039). The 1/IRR value indicates that the rate before the transplant was 14.7 times higher than the rate after the transplant (95% CI, 2.71-125; P = .0039). The incidence rate reduction was 93.2% (0.631-0.992; P = .0039). Given the small sample size, a Wilcoxon signed-rank test was also used to compare the rates, which also found a lower rate after HSCT (P = .043).

HSCT restores normal hematopoiesis in individuals with SCD and significantly reduces SCD-related complications, like vaso-occlusive pain events.⁴ Leonard et al⁴ reported a significant decrease in vaso-occlusive events in the 12 to 24 months after HSCT. In this study, only patient 4 had episodes of priapism after HSCT with 2 priapism episodes in the 12 to 24-month period following HSCT. We were unable to determine the reason for these continued priapism episodes; no risk factors for priapism were revealed in this patient’s medical records other than SCD. We postulate the the patient may have other priapism risk factors that have not been documented, predisposing him to have repeat priapism episodes. To our knowledge, this is the first study to elucidate the role of HSCT in reducing priapism events in patients with SCD. This study demonstrated that HSCT effectively lowers the incidence of priapism, further supporting its role in decreasing acute vaso-occlusive pain and also in preventing future priapism events.

Studies have shown that a dysregulation in nitric oxide (NO) and phosphodiesterase 5 could be the primary mechanism of SCD-associated priapism by causing vascular dysfunction.⁵ Individuals with SCD have decreased NO levels because of free hemoglobin, an NO scavenger released by chronic hemolysis.⁶ HSCT restores normal hematopoiesis and, with full engraftment, eliminates chronic hemolysis, thereby potentially restoring normal NO/phosphodiesterase 5 regulation and reducing the frequency of priapism events in these individuals.

Our analysis, yielded wide confidence intervals for the IRR (95% CI, 0.008-0.369). Although the difference in rates before and after HSCT was large enough to address the small sample size, a cohort of 5 patients remains small and poses a significant limitation in our study. Achieving a larger sample size is quite challenging because SCD is a rare disease in the United States and the possibility of HSCT being a definitive treatment for recurrent priapism is only starting to emerge. Another limitation of our study was that we identified priapism episodes through electronic health records, thereby allowing only the identification of episodes that required an admission, emergency room visit, or outpatient visit, and not priapism episodes that occurred at home. We were also unable to include priapism comorbidities or risk factors associated with priapism. When priapism is an indication for curative therapy, then there is an opportunity to better address whether the comorbidities, including depression and anxiety associated with priapism, also subside.

In conclusion, our findings suggest that allogeneic HSCT not only alleviates common SCD morbidities, such as vaso-occlusive pain, but may also decrease the incidence of SCD-related priapism. Equally important, this case series demonstrated the feasibility of a multicenter before vs after transplant analysis to study rare indications for curative therapy. Our results should be viewed as hypothesis-generating. Additional studies are necessary to validate our findings that the incidence rate of priapism decreases after HSCT.

Acknowledgments: This research was supported by the National Heart, Lung, and Blood Institute (NHLBI), the Cooperative Study of Late Effects for SCD Curative Therapies (COALESCE, 1U01HL156620-01, NHLBI). This work was also supported by the American Society of Hematology Medical Student Physician-Scientist Award (J.A.M.-F.) and the Burroughs Wellcome Fund (M.R.D.).

Contribution: M.R.D. conceived of the study design; J.A.M.-F. wrote the first draft of the manuscript; M.R. performed statistical analysis; and all authors revised and edited the manuscript.

Conflict-of-interest disclosure: S.L.S. does not have conflicts of interested related to this manuscript but reports serving on advisory boards or as a consultant for Agios, BEAM Therapeutics, Novo Nordisk, Merck, Novartis, Pfizer, Chiesi, and Fulcrum. M.R.D. reports serving as the chair of the Novartis-sponsored single-arm clinical trial for secondary priapism prevention using US Food and Drug Administration–approved crizanlizumab. C.M.T. does not have conflicts of interest related to this manuscript but reports serving as a site principal investigator for the Novo Nordisk-sponsored trial for Etavopivat for SCD and Pfizer-sponsored trials for Voxelotor for SCD. The remaining authors declare no competing financial interests.

Correspondence: Michael R. DeBaun, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37203; email: m.debaun@vumc.org.