Efficacy and Safety of Voxelotor in Sickle Cell Disease: A Systematic Review

Introduction: Sickle cell disease (SCD) is caused by mutation of beta-globin chain alleles, with the involvement of at least one sickle mutation. Sickling of red cells leads to hemolytic anemia, vaso-occlusions, and inflammation. Voxelotor (GBT440) is a hemoglobin modulator that prevents polymerization by increasing the affinity of hemoglobin with oxygen. We performed a systematic review to evaluate the efficacy and safety of voxelotor in SCD patients. Methods: PRISMA guidelines were followed to perform the literature search and selection of articles for this systematic review. A search was performed using databases including PubMed, Cochrane, Web of Science, Embase, and clinicaltrials.gov. We used the following keywords, "Voxelotor" OR "Benzaldehydes" OR "GBT440" AND "Sickle Cell Anemia" from the inception of literature till 04/25/2020. Out of 475 articles, we screened and included three clinical trials and a case series measuring the efficacy (i-e, change in Hemoglobin (Hb), Hb modification, etc.) and safety (adverse events) in clinical terms (N=359). We excluded case reports, pre-clinical studies, review articles, and meta-analysis. RESULTS: We included data on 359 patients, with 12-67 years of age. In Blyden et al. 2018, authors presented a case series of 7 patients with advanced SCD treated with 700 mg-1500 mg voxelotor. With treatment, vaso-occlusive episodes related hospitalizations decreased by 67%, hemoglobin levels, and markers of hemolysis improved in all patients. Authors in Hutchaleelaha et al. 2019 randomly assigned 24 participants to a once-daily dose of 900 mg, 600 mg, 300 mg voxelotor, and placebo for 15 days. With treatment, hemoglobin modification was maximum in the 900 mg voxelotor group. Headache and diarrhea were the only adverse events related to voxelotor treatment. No grade 3 adverse events were reported. In phase I/II trial by Howard et al. 2019, (n=54) 38 patients were followed for 28 days, and 16 patients were followed for >90 days. The compliance for study drug was 91%. In the 28-day cohort, treatment with 1000 mg of voxelotor showed maximum improvement in hemoglobin level, reticulocyte count, and unconjugated bilirubin. In >90-day cohort, the improvement in hemoglobin, unconjugated bilirubin, and reticulocyte count were statistically significant in favor of 900 mg voxelotor treatment as compared to placebo (p<0.05). LDH showed variability with treatment. Vaso-occlusive episodes seen in voxelotor groups were reported when the treatment was on hold or after the last dose. No grade ≥3 adverse events were reported. In a randomized placebo-controlled phase III clinical trial by Vichinsky et al. 2019, two doses of voxelotor 1500 mg (N=90) and 900 mg (N=92) were compared with placebo (N=92). 12-65 years old SCD patients were followed for 24 weeks. After treatment, improvement in hemoglobin was statistically significant in favor of 1500 mg voxelotor vs. placebo. Moreover, markers of hemolysis, reticulocyte count, and indirect bilirubin levels were also significantly improved in favor of 1500mg voxelotor treatment vs. placebo. The incidence of vaso-occlusive crisis episodes was similar in 1500 mg, 700 mg, and placebo groups (p>0.05). Treatment-related adverse events were seen in 94%, 93%, and 89% of participants in 1500mg, 700mg, and placebo groups, respectively. (Table 1) There are 6 ongoing clinical trials registered on clinicaltrials.gov (n=665) to determine the efficacy and safety of high doses of voxelotor and its use in children below 12 years. (Table 2) Conclusion: Voxelotor has an acceptable safety profile in sickle cell disease patients of 12 years or older. Voxelotor has shown a dose-dependent improvement in hemoglobin levels and markers of hemolysis, which is associated with a reduction in end-organ damage. Moreover, the increase in hemoglobin was not associated with an increase in vaso-occlusive crisis episodes, in contrast to the other hemoglobin modulator (senicapoc). Additional large prospective multicenter randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

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Adverse Events in Sickle Cell Patients with Nocturnal Hypoxia.

Blood ◽

10.1182/blood.v106.11.3793.3793 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3793-3793

Author(s):

Andrew D. Campbell ◽

Megumi Okumura ◽

Ndidi Unaka ◽

Sally Hutchinson ◽

Onyinye Onyekwere

Keyword(s):

Obstructive Sleep Apnea ◽

Sleep Apnea ◽

Sickle Cell Disease ◽

Adverse Events ◽

Sickle Cell ◽

Case Series ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Obstructive Sleep ◽

The Relationship

Abstract The relationship between hemoglobin dexoygenation and sickling is well known. However, the relationship between hypoxia and severity of disease in sickle cell patients has not been well established. Recently, nocturnal hypoxemia has been associated with higher incidence of CNS events including strokes, and elevated TCDs. We present our case series on 13 patients(12 SS, 1 SC) with sickle cell disease (SCD) who have nocturnal hypoxia. Approximately 75 patients were screened at the University of Michigan Sickle Cell clinic for nocturnal hypoxia either by symptoms of obstructive sleep apnea or by longitudinal baseline clinic 02 saturations (02 Sat <92%). Of the 13 hypoxic pts, median baseline O2 Sat 90%(n=13, mean 90) and the median nocturnal O2sat (Nctnl 02 sat) 84%(n=13, mean 80%) with 10/13 with moderate-severe nocturnal hypoxia (O2sats<85%)based on sleep studies. Multiple adverse events noted in the cohort were pulmonary hypertension (PHTN TRJV>2.5, n=9, median 2.74/mean 2.74,) frequent pain episodes(>3visits to ER or hospitalizations/year, n=7, with 5 pts >5/year ), recurrent acute chest syndrome( ≥ 3 episodes, n= 10), CNS events (n=3 silent infarcts, vascular stenosis), priapism( (n=4, among 6 males ). Also reported were possible causes of the underlying hypoxia including obstructive sleep apnea(OSA)(n=7 of 11 pts), asthma(n= 10 of 13 pts), and chronic lung disease( n=8). In conclusion, the persistence of nocturnal hypoxia in pediatric sickle cell disease could possibly contribute to the development of severe complications of sickle cell disease. Treatment of underlying hypoxia (ie nighttime oxygen, maximize asthma treatment, T&A for OSA)may help prevent complications and lead to the improvement clinical symptoms. Further, chronic nocturnal hypoxia may complicate pulmonary disease and accelerated the development of PHTN. More studies are needed to clarify the mechanism of hypoxia in SCD. Table I. Clinical &Demographic Data of 13 SCD Patients with Nocturnal Hypoxia. Age:(6–22y/o, mean 15) Sex: M=6 F=7 Clinical: Total Mild Mod Sev. Genotype: SS=12, SC=1 Mean Range Nctnl Hypoxia(<%) 13 3 5(<85) 5(<80) Baseline O2 Sat(%) 90 +3.0 86–97 Obstr Sleep Apnea 7 3 3 1 Nctnl 02 sat (%) 80+8.4 59–87 Pulm HTN 9 4 4 1 Total #Apneic Events(11) 65.6+80 6–256 Rest. Lung Ds. 8 2 5 1 Obstr. Apneic Events(7) 27+68.5 0–221 # of Episodes <3 3–4 >4 Hypopneic Events(9) 32.5+38 0–132 ACS 2 5 5 TRJet Velocity 2.74+.42 2–3.5 Severe Pain Crises/yr 1 2 5

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Direct Oral Anticoagulants in Sickle Cell Disease, Where We Stand and Where We Are Heading: A Systematic Review

Blood ◽

10.1182/blood-2021-144694 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4188-4188

Author(s):

Waail Rozi Kashgary ◽

Elrazi Awadelkarim Awadelkarim Hamid Ali ◽

Alaa Rahhal ◽

Abdulrahman F Al-Mashdali ◽

Yousef Hailan ◽

...

Keyword(s):

Systematic Review ◽

Clinical Practice ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Observational Studies ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Case Series ◽

Cell Disease ◽

Bleeding Events

Abstract Introduction: Sickle Cell Disease (SCD) is a hemolytic disorder with an increased risk of venous thromboembolism (VTE). By the age of 40 years around 11-12% of sickle cell disease patients will have at least one episode of VTE. VTE among patients with SCD is associated with a two to four times increase in mortality compared to SCD patients without VTE. Nevertheless, the evidence guiding VTE management in SCD, specifically in terms of anticoagulant choice, is scarce. Therefore, we conducted a systematic review that evaluates the effectiveness and safety of direct oral anticoagulants (DOACs) in SCD with VTE. Methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the English literature (PubMed, SCOPUS, and Google Scholar) for randomized controlled trials, observational studies, reviews, case series, and case reports for patients with SCD treated with DOAC for thromboembolic disease. We used the terms in combination: "Sickle cell disease" or "Sickle cell anemia", and "DOAC", "rivaroxaban", "apixaban", "dabigatran" "edoxaban". The search included all articles published up to 20th April 2021. Quality and risk of bias assessment were done by two independent authors for each included study. Results: A total of 7 articles were included; four observational studies, and three case series addressing this matter. Patel A et al. found that the use of DOACs, including rivaroxaban, dabigatran, and apixaban in comparison to vitamin K antagonists (VKAs) and low molecular weight heparin (LMWH) for the treatment of VTE in SCD among adults was associated with similar VTE recurrence rate and a better safety profile in terms of a significant reduction in major bleeding events. Similarly, Roberts MZ et al. reported that the use of DOACs for VTE treatment in SCD compared to VKAs resulted in similar effectiveness in terms of VTE recurrence, but the use of DOACs was associated with a similar safety in comparison to VKAs in contrary to the results reported by Patel A et al. in their retrospective study. With regards to the risk of major hemorrhagic events associated with the use of non-VKAs, Gupta VK et al. showed that among 55 patients with SCD treated with VKAs, DOACs, or injectable anticoagulants, only patients treated with VKAs had major bleeding events. Discussion: The current data demonstrated that the use of DOACs for VTE in SCD has similar effectiveness in the prevention of VTE recurrence in comparison to other anticoagulants, including VKAs and injectable anticoagulants with a better safety profile. However, given the absence of clinical practice guidelines for the treatment of VTE among patients with SCD, the clinical practice guidelines recommendations for VTE treatment can be applied to patients with SCD. According to the latest CHEST guidelines (2016) for the treatment of VTE, the use of DOACs is recommended in patients with VTE over VKAs. Similarly, the latest American Society of Hematology (2020) guidelines for VTE suggest the use of DOACs over VKAs, except among patients with renal insufficiency (creatinine clearance less than 30 mL/min), moderate to severe liver disease, or those with antiphospholipid syndrome. Conclusion: In view of the current evidence and based on the results observed; using DOACs was associated with lesser bleeding incidence and fewer complications comparing to VKAs. We think it is rational to use DOACs for VTE treatment among patients with SCD rather than use VKAs. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Efficacy and Safety of Regimens Used for the Treatment of POEMS Syndrome- a Systematic Review

Blood ◽

10.1182/blood-2020-141078 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-7

Author(s):

Unaiza Faizan ◽

Muhammad Saad Farooqi ◽

Hassaan Imtiaz ◽

Muhammad Yasir Anwar ◽

Muhammad Khawar Sana ◽

...

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Clinical Studies ◽

Case Series ◽

Poems Syndrome ◽

Efficacy And Safety ◽

Phase I Clinical Trials ◽

Myeloma Protein ◽

Neurological Response ◽

Grade 3

Introduction: POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy/edema, myeloma protein, skin changes) is a rare disorder associated with plasma cell neoplasia where an overproduction of proinflammatory cytokines such as vascular endothelial growth factor (VEGF) upregulates vasculogenesis and increases vascular permeability resulting in multiple symptoms of the disease e.g. edema and hemangioma. Although the limited-stage disease can be treated with radiotherapy, treatment for the more advanced disease remains unclear. Here we offer a systematic review of the efficacy and safety of treatment regimens used to treat POEMS syndrome in the adult population. Methods: Databases i.e. PubMed, Embase, Web of Science, and clinicaltrials.gov were searched since inception through May 15th, 2020, following the PRISMA guidelines. Out of 421 studies, 8 articles (5 prospective clinical trials, and 3 retrospective studies) were included. Phase I clinical trials, abstracts, case reports, case series, and review articles were excluded. Results: A total of 171 patients (21-79 years of age) were evaluated in 8 clinical studies. Immunomodulator Based Regimens: In the 5 clinical studies (N=96) where lenalidomide (Len) plus dexamethasone (Dex) were used, the hematological (heme) complete response (CR) ranged from 20% to 46%. Heme CR was defined as the absence of monoclonal immunoglobulins in serum or urine. VEGF CR defined as normalization of serum VEGF levels ranged from 35% to 80%. Neurological response defined as the improvement in the overall neuropathy limitations scale (ONLS) by at least one score ranged from 0% to 95%. These studies reported 2-3 year progression-free survival (PFS) and overall survival (OS) of 59% to 92% and 90% to 100%, respectively. In the study by Suichi et al. (N=5), VEGF CR was reported to be 80%. However, no neurological improvement was seen in these patients. Proteasome Inhibitor Based Regimens: In the study by He et al. (N=20) bortezomib in combination with cyclophosphamide and Dex yielded heme, VEGF, and neurological responses in 76%, 88%, and 95% of the patients, respectively. No grade ≥3 treatment-related adverse effects (TRAE) were seen. Conventional Chemotherapy Based Regimens: In the phase II trial conducted by Misawa et al. (N=25) the reduction in serum VEGF levels, as well as clinical response as measured by improvement in muscle strength, was higher in the thalidomide arm as compared to the placebo arm. Grade ≥3 TRAE reported in the treatment arm were cardiac arrest, heart failure, and dehydration in 1 (8%) patient each. In the study by Li et al. (N=31) melphalan (Mel) in combination with Dex achieved heme, VEGF, and neurological response rates of 81%, 100%, and 100%, respectively. Twenty percent of the patients experienced grade ≥3 TRAE. Conclusion: Immunomodulator and chemotherapy based regimens appear to have a reasonable safety and efficacy profile. Lenalidomide and melphalan based therapies were most effective. Proteasome inhibitors based regimens yielded efficacious results without significant toxicity. More studies with existing and newer combinations with autologous stem cell transplantation are warranted. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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The Role of Hydroxyurea to Prevent Silent Stroke in Sickle Cell Disease: Systematic Review and Meta-Analysis

Blood ◽

10.1182/blood-2018-99-112290 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2373-2373

Author(s):

Carla Hasson ◽

Lisa Veling ◽

Juan Felipe Rico ◽

Rahul Mhaskar

Keyword(s):

Systematic Review ◽

Sickle Cell Disease ◽

Adverse Events ◽

Sickle Cell ◽

Observational Studies ◽

Assessment Tool ◽

Conflicts Of Interest ◽

Meta Analysis ◽

Blood Transfusions ◽

Cell Disease

Abstract Chronic blood transfusions are standard of care for stroke prevention in sickle cell disease. We evaluated hydroxyurea's efficacy in preventing silent stroke. We searched for randomized controlled trials (RCTs) and observational studies on Pubmed, CENTRAL, Embase, and Web of Science without using language/time limits. Eligible studies compared hydroxyurea with transfusions or observation to prevent silent stroke. This systematic review adheres to the Cochrane guidelines. Data were pooled using random effects model using STATA to perform meta-analysis. Methodological quality of RCTs was investigated using the Cochrane risk of bias assessment tool, while observational studies were assessed using the Downs & Black Checklist for Study Quality. One RCT enrolling 121 participants was included. There were no strokes, silent strokes, or deaths reported in either arm. There was no difference between hydroxyurea versus chronic blood transfusions (RR 1.52, 95% CI 0.57 to 4.02, P = 0.39) for adverse events. We included 10 observational studies, with 361 participants receiving hydroxyurea. There were no deaths attributed to hydroxyurea. Approximately 1% (I2 = 48.67%, 95% CI 0.0 to 0.05, 314 participants, seven comparisons) of patients receiving hydroxyurea had stroke. Approximately 18% (I2 = 91.37%, 95% CI 0.03 to 0.4, 266 participants, six comparisons) of the hydroxyurea patients had silent stroke. Approximately 24% (I2 = 88.54%, 95% CI 0.02 to 0.57, 91 participants, four comparisons) of the hydroxyurea patients had adverse events attributed to hydroxyurea. Our findings suggest that hydroxyurea is safe and may prevent silent stroke and stroke. More high-quality studies are needed. Disclosures No relevant conflicts of interest to declare.

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Manifestations of HbSE sickle cell disease: a systematic review

Journal of Translational Medicine ◽

10.1186/s12967-021-02931-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Ibrahim Khamees ◽

Fateen Ata ◽

Hassan Choudry ◽

Ashraf T. Soliman ◽

Vincenzo De Sanctis ◽

...

Keyword(s):

Systematic Review ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Case Series ◽

Causative Mutation ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Number Of Patients ◽

The Mean ◽

Marrow Embolism

Abstract Background Sickle cell disease (SCD) is commonly encountered in Africa and Middle Eastern countries. The causative mutation in the gene encoding the hemoglobin subunit β (HBB) leads to various genotypic variants of the disease. This results in varied phenotypes, with a spectrum of complications, from benign to fatal. Hemoglobin SS (HBSS) genotype is associated with most of these complications; hence, it is a severe form of SCD. On the other hand, rare genotypes such as hemoglobin SE (HBSE) are considered benign. There is limited literature about the clinical manifestations and characteristics of patients with HBSE. We pooled all available data describing the phenotypic manifestations of HBSE heterozygote worldwide to perform a systematic review. Methods We performed a systematic review according to PRISMA guidelines using PubMed, SCOPUS, and Google Scholar databases. Two independent reviewers (FA and IK) evaluated studies for eligibility and extracted data. We synthesized data on demographics, manifestations, and management of HBSE disease. PROSPERO Registration Number: CRD42021229877. Results We found 68 HBSE patients reported in the literature. 24 cases were extracted from case reports whereas 44 cases from case series and retrospective studies. Turkey reported the highest number of patients (n = 22). 32 (47%) of the patients were males. The mean age was 20.9 ± 18.26 years. The mean HBS and HBE percentages were 61.1% ± 7.25% and 32.3% ± 5.06%, respectively, whereas the mean hemoglobin was 11.64 ± 1.73 g/dl. Reported manifestations of HBSE disease included acute vaso-occlusive pain crisis (n = 22, 32.3%), splenomegaly (n = 11, 16.1%), hemolytic anemia (n = 10, 14.7%), infections (n = 8. 11.7%), bone infarction (n = 4, 5.8%), gallstones (n = 3, 4.4%), venous thromboembolism (VTE) (n = 2, 2.9%) and stroke (n = 2, 2.9%), and hematuria (n = 2, 2.9%). Death due to HBSE complications was reported in three patients. Conclusion HBSE is a rare genotypic variant of SCD. It has been considered a benign form; however, there are multiple reports of severe complications. Severe complications observed in HBSE disease include vaso-occlusive crisis, acute chest syndrome, stroke, bone marrow embolism, and death.

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Surgical Revascularization for Pediatric Patients with Sickle Cell Disease and Moyamoya Disease in the Prevention of Ischemic Strokes: A Single-Center Case Series and a Systematic Review

World Neurosurgery ◽

10.1016/j.wneu.2018.11.157 ◽

2019 ◽

Vol 123 ◽

pp. 435-442.e8 ◽

Cited By ~ 3

Author(s):

Pedro Aguilar-Salinas ◽

Kelsey Hayward ◽

Roberta Santos ◽

Vibhuti Agarwal ◽

Eric Sauvageau ◽

...

Keyword(s):

Systematic Review ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Moyamoya Disease ◽

Pediatric Patients ◽

Case Series ◽

Single Center ◽

Cell Disease ◽

Surgical Revascularization

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Efficacy and safety of recently approved drugs for sickle cell disease: a review of clinical trials

Experimental Hematology ◽

10.1016/j.exphem.2020.08.008 ◽

2020 ◽

Vol 92 ◽

pp. 11-18.e1 ◽

Cited By ~ 2

Author(s):

Muhammad Ashar Ali ◽

Asrar Ahmad ◽

Hafsa Chaudry ◽

Wajeeha Aiman ◽

Sobia Aamir ◽

...

Keyword(s):

Clinical Trials ◽

Sickle Cell Disease ◽

Sickle Cell ◽

Efficacy And Safety ◽

Cell Disease ◽

Approved Drugs

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Crizotinib Versus Chemotherapy on ALK-positive NSCLC: A Systematic Review of Efficacy and Safety

Current Cancer Drug Targets ◽

10.2174/1568009617666170623115846 ◽

2018 ◽

Vol 19 (1) ◽

pp. 41-49 ◽

Cited By ~ 2

Author(s):

Mingxia Wang ◽

Guanqi Wang ◽

Haiyan Ma ◽

Baoen Shan

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Adverse Events ◽

Objective Response Rate ◽

Retrospective Studies ◽

Response Rate ◽

Objective Response ◽

Treated Group ◽

Efficacy And Safety ◽

Alk Positive

Introduction: Crizotinib was approved to treat anaplastic lymphoma kinase (ALK)- positive non-small cell lung cancer (NSCLC) by the Food and Drug Administration in 2011.We conducted a systematic review of clinical trials and retrospective studies to compare the efficacy and safety of crizotinib with chemotherapy. </P><P> Methods: We searched electronic databases from inception to Dec. 2016. Clinical trials and retrospective studies regarding crizotinib and crizotinib versus chemotherapy in treatment of NSCLC were eligible. The primary outcomes were the objective response rate (ORR) and disease control rate (DCR). Results: Nine studies (five clinical trials and four retrospective studies) including 729 patients met the inclusion criteria. Crizotinib treatment revealed 1-year OS of 77.1% and PFS of 9.17 months. And crizotinib had a better performance than chemotherapy in ORR (OR: 4.97, 95%CI: 3.16 to 7.83, P<0.00001, I2=35%). DCR revealed superiority with crizotinib than chemotherapy (OR: 3.42, 95% CI: 2.33 to 5.01, P<0.00001, I2=0%). PR (partial response) were significant superior to that of chemotherapy through direct systematic review. No statistically significant difference in CR (complete response) was found between crizotinib-treated group and chemotherapy-treated group. Regarding SD (stable disease), chemotherapy-treated group had a better performance than crizotinib-treated group. Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, nausea, and hematologic toxicity. This systematic review revealed improved objective response rate and increased disease control rate in crizotinib group comparing with chemotherapy group. Crizotinib treatment would be a favorable treatment option for patients with ALK-positive NSCLC. ALK inhibitors may have future potential applications in other cancers driven by ALK or c-MET gene mutations.

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