Comparing the Safety and Efficacy of L-Glutamine, Voxelotor, and Crizanlizumab for Reducing the Frequency of Vaso-Occlusive Crisis in Sickle Cell Disease: A Systematic Review

Abstract

Sickle cell disease (SCD) is a group of inherited red blood cell disorders affecting millions worldwide. The median life expectancy of someone with SCD remains significantly low despite improvements in standards of care and the implementation of hydroxyurea therapy. Notably, a 20-year interval existed (after the implementation of hydroxyurea therapy) prior to the approval of other sickle cell medications, namely, l-glutamine, voxelotor, and crizanlizumab. In this systematic review, these new medications' impact on the occurrences of vaso-occlusive crisis (VOC) events were analyzed and the adverse events of each were noted. Further, a secondary analysis was conducted to determine the effect of combination therapies, whether synergistic, antagonistic, or additive. The systematic review was conducted following the PRISMA 2020 guidelines. The effect-based and dose-effect-based approaches were utilized to determine the combined drugs combination index based on the recommended dosage to achieve an efficacy of 50%. L-glutamine and crizanlizumab were effective in reducing the frequency of VOC (p= 0.0216 and p = 0.02). Voxelotor effect on the reduction of VOC occurrences was not significant, however, its effect on increasing hemoglobin levels was significant (p= <0.001). In all three therapies, pain was the most common adverse event reported by participants. The analysis of combination therapies revealed that voxelotor plus l-glutamine was synergistic, voxelotor plus crizanlizumab was antagonistic, and l-glutamine plus crizanlizumab was additive. Thus, voxelotor plus l-glutamine combination therapy may be more beneficial to sickle cell disease patients. As such, robust combination drug studies for approved therapies used in SCD should be initiated with a specific focus on voxelotor plus l-glutamine. Additionally, the development of medications that lessen the pain burden in sickle cell disease patients should also be prioritized.

Keywords: combination therapy; crizanlizumab; l-glutamine; sickle cell; vaso-occlusive crisis; voxelotor.

Figure 1. Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2). Risk of bias assessment: Low risk (+), Some Concerns (!), High Risk (-). This Figure contains information on the Cochrane Risk-of-Bias Tool for randomized trials to assess the quality and bias of the RCTs used in the systematic review.

Figure 2. JBI Critical Appraisal Checklist for Case Series. Risk of bias assessment: Yes (√), No (X), Unclear (?), Not applicable (NA). This figure contains information on the JBI checklist for the case series included in the systematic review. The JBI checklist is a set of questions for case series to assess the quality of the studies.

Figure 3. JBI Critical Appraisal Checklist for Case Reports. Risk of bias assessment: Yes (√), No (X), Unclear (?), Not applicable (NA). This figure is a summary of the JBI Critical Appraisal Checklist for Case Reports used to evaluate the quality and bias of the studies employed in the systematic review.

Figure 4. PRISMA flow diagram outlining the process used to identify and screen articles obtained from PubMed, PMC, Medline, Cochrane Library, and Clinicaltrials.gov and the subsequent selection of twelve articles included in the systematic review.

From: Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews [17]. For more information, visit: http://www.prisma-statement.org/

Figure 5. A Venn Diagram of the benefits of the SCD therapies from the articles used in the systematic review. Similar effects between the drugs are included.

The adverse events reported in the randomized controlled trials are denoted in black text whilst the adverse events reported in the case series and case reports are denoted in colored text. ACS- acute chest syndrome, RBC- red blood cell, SCD- sickle cell disease, VOC- vaso-occlusive crisis.

Figure 6. A summary of voxelotor, crizanlizumab, and l-glutamine adverse effects from the 12 eligible articles used in the systematic review.

The adverse events reported in the randomized controlled trials are denoted in black text whilst the adverse events reported in the case series and case reports are denoted in colored text. Major adverse events are denoted in bold text. ACS- Acute Chest Syndrome, AKI- acute kidney injury, DRESS- drug reaction with eosinophilia and systemic symptoms, n- the number of cases, rash- (generalized, erythematous, urticaria, papular, macular, maculopapular, vesicular, pruritic), sC5b-9- soluble Complement 5b-9, URTI- upper respiratory tract infection, UTI- urinary tract infection.

Figure 7. A Venn Diagram of the adverse events (of named drugs) reported in the 12 eligible articles used in the systematic review.

The adverse events reported in the randomized controlled trials are denoted in black text whilst the adverse events reported in the case series and case reports are denoted in colored text. Major adverse events are denoted in bold text. ACS- Acute Chest Syndrome, AKI- acute kidney injury, c- major adverse event associated with crizanlizumab, DRESS- drug reaction with eosinophilia and systemic symptoms, l- major adverse event associated with l-glutamine, rash- (generalized, erythematous, urticaria, papular, macular, maculopapular, vesicular, pruritic), sC5b-9- soluble Complement 5b-9, URTI- upper respiratory tract infection, UTI- urinary tract infection, v- major adverse event associated with voxelotor.