Voxelotor use in adults with sickle cell disease in a <scp>real‐world</scp> setting
Authors: Susanna A. Curtis, Jaime Betancourt, Niharika Kottapalli, Sean Campbell, Caterina Minniti
Journal: American Journal of Hematology (2021)

To the Editor: In 2019, voxelotor was approved by the United States Food and Drug Administration for the treatment of sickle cell disease (SCD) in patients ≥16 years. The HOPE trial showed that treatment with voxelotor reduced hemolysis and improved anemia and rates of adverse and serious adverse events were no different between high dose, low dose, and placebo groups.1 However, clinical trials do not provide all the information required for physicians to know how well the drug works in clinical practice. Postapproval real-world studies can identify barriers to use as well as risks and benefits not recognized in the initial clinical studies. We sought to examine voxelotor use in a real-world cohort of patients followed at a comprehensive urban sickle cell center. We hypothesized that economic and social barriers could prevent some patients from being able to obtain voxelotor, medication adherence may not be optimal, and that adverse events or side effects might result in fewer clinical and hematological benefits than those seen in the HOPE study. Data were obtained retrospectively from electronic medical records (EMRs) at our center. Patients with SCD who had been prescribed voxelotor from November 25, 2019 to December 31, 2020 were included in this analysis. Use of hydroxyurea and erythropoiesis-stimulating agents (ESA) were defined by the presence of active prescription in the EMR. Demographics, clinical outcomes, and SCD-related morbidities were abstracted from the EMR. Voxelotor therapy group included patients who verbally confirmed obtaining and starting the medication (VOX+), all others were defined as Vox−. Laboratory test results were obtained prior to ordering voxelotor, at steady state, defined as a visit with no acute complaints and at least 14 days from last episode of hospital or emergency room (ED) utilization. For VOX+ patients a second set of labs was obtained at least 14 days after starting voxelotor. Presence of voxelotor in patients' plasma was determined by changes in capillary zone electrophoresis based on methodology described in prior studies.2-4 Episodes which resulted in a visit to the ED or admission to our hospital and number of packed red blood cell transfusions were noted for the 3 months prior to, and the 3 months post therapy initiation. Data on side effects, dose modifications, reasons for terminal discontinuation were collected. Demographics, medications used, SCD-related morbidity, baseline ED visits, admissions, transfusion data, and baseline labs were compared between VOX+ and VOX− groups using a Mann Whitney U test for continuous variables and a Fisher's exact test for categorical variables. Baseline labs, ED visits, admissions and transfusions were compared to labs, ED visits, admissions, and transfusions post voxelotor using the Mann Whitney U test. Correlation of side effects with drug discontinuation and dose modification was examined using Fisher's exact test. Analyses were carried out using Stata software (version 15). Between November 2019 and December 2020, 65 adults with HbSS/HbSβ0 were prescribed voxelotor; 57% female; mean age 40.7 ± 12.2 years old, 58% on hydroxyurea, 14% had received at least one red blood cell transfusion in the previous 3 months and 19% were on an ESA. Of the 65, 43 (66%) patients started the medication during the time of this study, at a mean of 48.4 days (SD 53.2 days) after it was prescribed (VOX+), while 22 (34%) never started (VOX−). The most common reason for not starting (VOX−) was the inability to complete the application process for the drug, as it was dispensed from few specialty pharmacies with the assistance of Global Blood Therapeutics (GBT) care coordination staff (9/22, 41%). Other causes included lack of insurance approval (4/22, 18%), high copay (1/22, 5%), lost to follow-up (4/22, 18%), patient refusing therapy (1/22, 5%), decision to pursue an alternative therapy (2/22, 9%), and patient death (1/22, 5%). Of the 43 VOX+ patients, 39 were started on a dose of 1500 mg, 3 were started at 1000 mg, and 1 was started at 500 mg. VOX− pts were more likely to have a known alpha thalassemia mutation, while VOX+ pts were more likely to have a history of lower extremity ulcers and higher baseline aspartate aminotransferase. All other characteristics were similar between VOX+ and Vox− patients (Table S1). The median increase in hemoglobin was 1.5 g/dL and 22/33 (66%) showed an increase of 1 g/dL or more (Table 1, Figure S1). Laboratory data demonstrated a decrease in %HbF (p = .0018) but no change in total HbF (p = .35). This suggests the change in percent F is likely dilutional due to hemoglobin S surviving longer in circulation due to the reduction in hemolysis. A statistically significant increase in ALT (p = .0021) was observed, which had not been reported in the Hope trial. While none of the patients in this cohort required a dose modification for this, three recently seen patients developed Grade 2 (2) and Grade 3 (1) ALT abnormalities within 2 weeks after starting drug, all improved after either dose reduction or discontinuation. We therefore recommend monitoring liver function tests, and to expect a slight reduction in percent hemoglobin F after starting voxelotor. Voxelotor was detected in the plasma of 78% of patient who reported taking it. No change was seen in frequency of transfusions (p = .4), ED visits (p = .79) or admissions (p = .32). At the time of this review, patients had been on voxelotor an average of 48 weeks. Of those 29/43 (67%) noted at least one side effect and 14/43(33%) noted multiple side effects. Of those who experienced side effects: 8/29 (28%) chose to discontinue drug, 4/29 (14%) modified their dose from 1500 to 1000 mg and then discontinued, 9/29 (31%) reduced the dose to 1000 mg and continued and 2/29 (7%) reduced the dose to 500 mg and continued. At the end of the study, of the 31 patients still taking the medication 3 (10%) were taking 500 mg, 9 (29%) were taking 1000 mg, and 19 (61%) were taking 1500 mg. No single reported side effect was correlated with drug termination. However, those who noted either nausea/vomiting/diarrhea were more likely to reduce their dose (4/5 vs. 12/38 p = .04, 9/13 vs. 7/30 p = .004, respectively). We identified in a real-world cohort of adult patients several barriers to initiation of therapy, confirmed the hematological response, and expanded the range of side effects for voxelotor. Of the 65 patients prescribed voxelotor, 22 never started, and 12 discontinued due to side effects, leaving less than half of the patients prescribed voxelotor taking it a year later, and of those 12/31 were taking reduced doses. We have since developed recommendations to enable more patients to receive medication and to reduce side effect related discontinuation, such as discussing common side effects with each patient before starting the medication, recommending taking the medication with food, using Tylenol or NSAIDs for headaches, and using loperamide and discontinuing stool softeners to treat diarrhea. Many patients noted abdominal complaints resolved entirely after 2 weeks and some were able to increase their dose back to 1500 mg after this. The most common barrier to starting was that to receive the medication patients must fill out a Patient Authorization and Consent form with GBT. Patients struggled to fill this form out at home, felt uncomfortable signing paperwork, and were reluctant to respond to follow up phone calls from GBT. We began filling out the form in clinic and advised patients to put GBT contact information into their phones so they would be less hesitant to respond to calls from unknown telephone numbers. While we were able to help many patients by coordinating the process in clinic, it must be recognized that filling out all forms with the patients in clinic and addressing insurance refusals and applying for financial assistance represents a significant burden on both patients and providers. Patients who started voxelotor had a hematologic response similar to that of the HOPE trial despite 14% having received transfusions in the past 3 months and 23% receiving an ESA,1 both exclusion criteria for enrollment in the Hope trial. Though all of our VOX+ patients confirmed taking voxelotor in the EMR, only 78% of those with a capillary hemoglobin electrophoresis showed splitting of the A2 or F peaks, or the presence of a shoulder on the S peak characteristic of voxelotor use.2 Voxelotor has a short half-life of 35.5 h, so missing one or two doses could be sufficient to lose the effect on capillary electrophoresis.5 Also, the studies showing the effects of voxelotor on capillary electrophoresis were in vitro studies; sensitivity and specificity of these studies in the clinical setting is unknown.2 This study has several limitations: it took place at a single SCD center and may not be representative of other regions and care models. The study was retrospective via review of EMR. This study of voxelotor prescription and use in a cohort of patients with SCD revealed barriers to obtaining medication, changes in laboratory values previously not reported, and high rates of discontinuation and dose modification due to side effects. As voxelotor use becomes more widespread, we can expect to learn more about how to use it to obtain the most benefits for people living with SCD. Susanna Curtis is supported by a K23 from the NHLBI: 1 K23 HL151884-01A1. The authors have no interests to declare or disclose and no competing financial interest. All authors were involved in the clinical management of the reported patient, and contributed to the writing of the manuscript and approved the final version. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Table S1. Baseline demographics and laboratory makers. Figure S1. Waterfall plot of hemoglobin changes after starting voxelotor, each bar represents one patient. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.