Clinically meaningful improvements in patient-reported outcomes in mitapivat-treated patients with pyruvate kinase deficiency.

Clinically meaningful benefits in the signs, symptoms, and impacts of #PKDeficiency as assessed by disease-specific patient-reported outcome measures were observed in mitapivat-treated adult patients in two phase 3 clinical trials.

2022 Review of the 2019 American Society of Hematology Guidelines on Immune Thrombocytopenia.

The 2019 ASH guidelines for immune thrombocytopenia (ITP) included recommendations on management of adults (recommendations 1-9) and children (recommendations 10-21) with primary ITP (1). We describe here results of a review of the 2019 guidelines by a working group of experts requested by ASH to inform decision-making about the need for and timing of a guideline revision. An updated Medline and Embase search applied the same search terms as in the 2019 ASH guidelines, limited to systematic reviews and clinical trials, from May 2017 to July 2022. There were 193 studies identified, 102 underwent abstract review and 54 full review. Each study was assessed based on relevance to the previous recommendation with regards to the population, prioritized outcomes, new outcomes, and study design. Reviewers assessed if the data would change the strength or the directionality of the existing recommendation or merit development of a new recommendation. Based on this review, the ASH Committee on Quality endorsed a focused update on second-line management for adults with ITP. In addition, there will be continued annual monitoring and reviewing of the 2019 ASH guidelines on ITP in full to evaluate when there is sufficient new evidence to warrant additional revisions.

Integrating circulating T follicular memory cells and autoantibody repertoires for characterization of autoimmune disorders.

Introduction: Autoimmune diseases are heterogeneous and often lack specific or sensitive diagnostic tests. Increased percentages of CD4+CXCR5+PD1+ circulating T follicular helper (cTfh) cells and skewed distributions of cTfh subtypes have been associated with autoimmunity. However, cTfh cell percentages can normalize with immunomodulatory treatment despite persistent disease activity, indicating the need for identifying additional cellular and/or serologic features correlating with autoimmunity. Methods: The cohort included 50 controls and 56 patients with autoimmune cytopenias, gastrointestinal, pulmonary, and/or neurologic autoimmune disease. Flow cytometry was used to measure CD4+CXCR5+ T cell subsets expressing the chemokine receptors CXCR3 and/or CCR6: CXCR3+CCR6- Type 1, CXCR3-CCR6- Type 2, CXCR3+CCR6+ Type 1/17, and CXCR3- CCR6+ Type 17 T cells. IgG and IgA autoantibodies were quantified using a microarray featuring 1616 full-length, conformationally intact protein antigens. The 97.5th percentile in the control cohort defined normal limits for T cell subset percentages and total number (burden) of autoantibodies. Results: This study focused on CD4+CXCR5+ T cells because CXCR5 upregulation occurs after cognate T-B cell interactions characteristic of autoimmune diseases. We refer to these cells as circulating T follicular memory (cTfm) cells to acknowledge the dynamic nature of antigen-experienced CXCR5+ T cells, which encompass progenitors of cTfh or Tfh cells as well as early effector memory T cells that have not yet lost CXCR5. Compared to controls, 57.1% of patients had increased CXCR5+CXCR3+CCR6+ cTfm1/17 and 25% had increased CXCR5+CXCR3-CCR6+ cTfm17 cell percentages. Patients had significantly more diverse IgG and IgA autoantibodies than controls and 44.6% had an increased burden of autoantibodies of either isotype. Unsupervised autoantibody clustering identified three clusters of patients with IgG autoantibody profiles distinct from those of controls, enriched for patients with active autoimmunity and monogenic diseases. An increased percentage of cTfm17 cells was most closely associated with an increased burden of high-titer IgG and IgA autoantibodies. A composite measure integrating increased cTfm1/17, cTfm17, and high-titer IgG and/or IgA autoantibodies had 91.1% sensitivity and 90.9% specificity for identifying patients with autoimmunity. Percentages of cTfm1/17 and cTfm17 percentages and numbers of high-titer autoantibodies in patients receiving immunomodulatory treatment did not differ from those in untreated patients, thus suggesting that measurements of cTfm can complement measurements of other cellular markers affected by treatment. Conclusions: This study highlights two new approaches for assessing autoimmunity: measuring CD4+CXCR5+ cTfm subsets as well as total burden of autoantibodies. Our findings suggest that these approaches are particularly relevant to patients with rare autoimmune disorders for whom target antigens and prognosis are often unknown.

Mitapivat improves ineffective erythropoiesis and iron overload in adult patients with pyruvate kinase deficiency.

ABSTRACT: Pyruvate kinase (PK) deficiency is a rare, hereditary disease characterized by chronic hemolytic anemia. Iron overload is a common complication regardless of age, genotype, or transfusion history. Mitapivat, an oral, allosteric PK activator, improves anemia and hemolysis in adult patients with PK deficiency. Mitapivat's impact on iron overload and ineffective erythropoiesis was evaluated in adults with PK deficiency who were not regularly transfused in the phase 3 ACTIVATE trial and long-term extension (LTE) (#NCT03548220/#NCT03853798). Patients in the LTE received mitapivat throughout ACTIVATE/LTE (baseline to week 96; mitapivat-to-mitapivat [M/M] arm) or switched from placebo (baseline to week 24) to mitapivat (week 24 to week 96; placebo-to-mitapivat [P/M] arm). Changes from baseline in markers of iron overload and erythropoiesis were assessed to week 96. Improvements in hepcidin (mean, 4770.0 ng/L; 95% confidence interval [CI], -1532.3 to 11 072.3), erythroferrone (mean, -9834.9 ng/L; 95% CI, -14 328.4 to -5341.3), soluble transferrin receptor (mean, -56.0 nmol/L; 95% CI, -84.8 to -27.2), and erythropoietin (mean, -32.85 IU/L; 95% CI, -54.65 to -11.06) were observed in the M/M arm (n = 40) from baseline to week 24, sustained to week 96. No improvements were observed in the P/M arm (n = 40) to week 24; however, upon transitioning to mitapivat, improvements similar to those observed in the M/M arm were seen. Mean changes from baseline in liver iron concentration by magnetic resonance imaging at week 96 in the M/M arm and the P/M arm were -2.0 mg Fe/g dry weight (dw; 95% CI, -4.8 to -0.8) and -1.8 mg Fe/g dw (95% CI, -4.4 to 0.80), respectively. Mitapivat is the first disease-modifying pharmacotherapy shown to have beneficial effects on iron overload and ineffective erythropoiesis in patients with PK deficiency. This trial was registered at www.ClinicalTrials.gov as #NCT03548220 (ACTIVATE) and #NCT03853798 (LTE).

Diagnosis and management of pyruvate kinase deficiency: international expert guidelines.

Pyruvate kinase (PK) deficiency is the most common cause of chronic congenital non-spherocytic haemolytic anaemia worldwide, with an estimated prevalence of one in 100 000 to one in 300 000 people. PK deficiency results in chronic haemolytic anaemia, with wide ranging and serious consequences affecting health, quality of life, and mortality. The goal of the International Guidelines for the Diagnosis and Management of Pyruvate Kinase Deficiency was to develop evidence-based guidelines for the clinical care of patients with PK deficiency. These clinical guidelines were developed by use of GRADE methodology and the AGREE II framework. Experts were invited after consideration of area of expertise, scholarly contributions in PK deficiency, and country of practice for global representation. The expert panel included 29 expert physicians (including adult and paediatric haematologists and other subspecialists), geneticists, laboratory specialists, nurses, a guidelines methodologist, patients with PK deficiency, and caregivers from ten countries. Five key topic areas were identified, the panel prioritised key questions, and a systematic literature search was done to generate evidence summaries that were used in the development of draft recommendations. The expert panel then met in person to finalise and vote on recommendations according to a structured consensus procedure. Agreement of greater than or equal to 67% among the expert panel was required for inclusion of a recommendation in the final guideline. The expert panel agreed on 31 total recommendations across five key topics: diagnosis and genetics, monitoring and management of chronic complications, standard management of anaemia, targeted and advanced therapies, and special populations. These new guidelines should facilitate best practices and evidence-based PK deficiency care into clinical practice.

Pyruvate kinase activators for treatment of pyruvate kinase deficiency.

Pyruvate kinase (PK) deficiency is a congenital hemolytic anemia with wide-ranging clinical symptoms and complications associated with significant morbidity and reduced health-related quality of life in both children and adults. The management of patients with PK deficiency has been historically challenging due to difficulties in the diagnostic evaluation, heterogeneity of clinical manifestations, and treatment options limited to supportive care with transfusions and splenectomy. An oral allosteric PK activator, mitapivat, is now a clinically available disease-modifying treatment for adults with PK deficiency. Phase 2 and 3 clinical trials of mitapivat have demonstrated sustained improvements in hemolytic anemia, hematopoiesis, and quality of life in many adults with PK deficiency and a generally reassuring safety profile with continued dosing. Additional long-term benefits include rapid and ongoing reduction in iron overload and potential stabilization of bone health. Clinical trials of treatment with mitapivat in children with PK deficiency are ongoing. In addition to disease-modifying treatment with PK activators, gene therapy is a potentially curative treatment currently under evaluation in clinical trials. With the availability of disease-targeted therapies, accurately diagnosing PK deficiency in patients with chronic hemolytic anemia is critical. PK activation and gene therapy have the potential to change the natural history of PK deficiency by improving clinical manifestations and patient quality of life and decreasing the risk of long-term complications.

Psychometric validation of the Pyruvate Kinase Deficiency Diary and Pyruvate Kinase Deficiency Impact Assessment in adults in the phase 3 ACTIVATE trial.

BACKGROUND: Pyruvate kinase (PK) deficiency is a rare hereditary disorder characterized by chronic hemolytic anemia and serious sequalae which negatively affect patient quality of life. This study aimed to psychometrically validate the first disease-specific patient-reported outcome (PRO) instruments: the 7-item PK Deficiency Diary (PKDD) and 12-item PK Deficiency Impact Assessment (PKDIA), designed to assess signs, symptoms, and impacts of PK deficiency in patients enrolled in the ACTIVATE global phase 3 study of mitapivat versus placebo (NCT03548220). METHODS: All validation analyses for the PKDD and PKDIA were performed on blinded data, with analyses on item integrity, scoring, reliability, and validity conducted on data from screening and baseline. Completion rates and baseline response distributions were characterized using descriptive statistics. Item response modelling was used to inform a weighted scoring system. Reliability was assessed by internal consistency and test-retest reliability; and validity by convergent and known-groups analyses. RESULTS: Of the 80 adults enrolled, baseline data were available for 77 (96.3%) and 78 (97.5%) patients for the PKDD and PKDIA, respectively. Item responses skewed right, indicating that mean values exceeded median values, especially for items utilizing a 0-10 numeric scale, which were subsequently recoded to a 0-4 scale; 4 items were removed from the PKDIA due to redundancy or low relevance to the trial population. Both the PKDD and PKDIA demonstrated high internal consistency (McDonald's coefficient ω = 0.86 and 0.90, respectively), test-retest reliability (intra-class coefficients of 0.94 and 0.87, respectively), and convergent validity with other PROs (linear correlation coefficients [|r|] between 0.30-0.73 and 0.50-0.82, respectively). CONCLUSIONS: The findings provide evidence of validity and reliability for the PKDD and PKDIA, the first disease-specific PRO measures for PK deficiency, and can therefore increase understanding of, and more accurately capture, the wider impact of PK deficiency on health-related quality of life. Trial registration ClinicalTrials.gov, NCT03548220. Registered June 07, 2018; https://www. CLINICALTRIALS: gov/ct2/show/NCT03548220 .

Pyruvate kinase (PK) deficiency is a rare genetic blood disorder with a wide range of signs and symptoms that may have a negative impact on patients' quality of life. Patient-reported outcome (PRO) instruments are tools that assess how a disease affects a patient from the patient's perspective. These instruments must go through a validation process to make sure they truly capture the patient's experience with their condition or its treatment. This study aimed to validate two new PRO instruments in adult patients enrolled in the ACTIVATE clinical trial (NCT03548220), where patients with PK deficiency received the drug mitapivat or a placebo. These two new PRO instruments are the first to be developed specifically for PK deficiency: the PK Deficiency Diary (PKDD), a daily diary that asks 7 questions to measure the core signs and symptoms of PK deficiency, and the PK Deficiency Impact Assessment (PKDIA), a weekly questionnaire with 12 questions to assess the impact of PK deficiency on a patient's life. The results of this study showed that the PKDD and PKDIA properly and reliably measured the signs, symptoms, and impacts of PK deficiency that they aimed to capture. These findings indicate that the PKDD and PKDIA are the first validated PROs specifically for PK deficiency and can help improve the understanding of the impact of PK deficiency on patients' quality of life.

HLA antibodies in fetal and neonatal alloimmune thrombocytopenia.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is caused by antibodies against human platelet antigens (HPA). However, in many cases that meet clinical criteria for the condition, maternal sera do not have HPA antibodies. In studies examining whether human leukocyte antigen (HLA) antibodies cause FNAIT, the results are limited and inconclusive. This study sought to examine whether clinically suspected FNAIT cases with absent maternal HPA antibodies had different HLA antibody strength and specificity compared to controls. STUDY DESIGN AND METHODS: A retrospective case-control study assessed class I HLA antibody strength and specificity in cases submitted for testing to Versiti, Wisconsin. There were 813 cases that met initial screening criteria, but written consent could only be obtained for 50. After review of medical records and expert panel review, 31 cases with clinical criteria of FNAIT and maternal HLA but not HPA antibodies were included. Each case was matched for maternal age, gestational age at delivery, parity, and race/ethnicity to two controls from unaffected pregnancies that had maternal serum HLA antibodies. RESULTS: FNAIT cases were found to have both significantly higher HLA antibody strength, measured by mean fluorescence index (MFI), and broader HLA antibody specificity at antigen epitope level, compared to matched controls (p < .001). p-values remained significant after controlling for parity and gestational age at delivery. DISCUSSION: Additional studies are needed to further examine whether the strong HLA antibodies identified in HPA-antibody-negative cases directly cause neonatal thrombocytopenia and whether prenatal treatment may be warranted in select cases to prevent recurrence.

Updates and advances in pyruvate kinase deficiency.

Mutations in the PKLR gene lead to pyruvate kinase (PK) deficiency, causing chronic hemolytic anemia secondary to reduced red cell energy, which is crucial for maintenance of the red cell membrane and function. Heterogeneous clinical manifestations can result in significant morbidity and reduced health-related quality of life. Treatment options have historically been limited to supportive care, including red cell transfusions and splenectomy. Current disease-modifying treatment considerations include an oral allosteric PK activator, mitapivat, which was recently approved for adults with PK deficiency, and gene therapy, which is currently undergoing clinical trials. Studies evaluating the role of PK activators in other congenital hemolytic anemias are ongoing. The long-term effect of treatment with disease-modifying therapy in PK deficiency will require continued evaluation.

The Pyruvate Kinase Deficiency Global Longitudinal (Peak) Registry: rationale and study design.

INTRODUCTION: Pyruvate kinase (PK) deficiency is a rare, under-recognised, hereditary condition that leads to chronic haemolytic anaemia and potentially serious secondary complications, such as iron overload, cholecystitis, pulmonary hypertension and extramedullary haematopoiesis. It is an autosomal recessive disease caused by homozygous or compound heterozygous mutations in the PKLR gene. Due to its rarity and clinical heterogeneity, information on the natural history and long-term clinical course of PK deficiency is limited, presenting major challenges to patient management, the development of new therapies and establishing disease-specific treatment recommendations. The Pyruvate Kinase Deficiency Global Longitudinal (Peak) Registry is an initiative to address the gaps in the knowledge of PK deficiency. This manuscript describes the objectives, study design and methodology for the Peak Registry. METHODS AND ANALYSIS: The Peak Registry is an observational, longitudinal, global registry of adult and paediatric patients with a genetically confirmed diagnosis of PK deficiency. The Peak Steering Committee is composed of 11 clinicians and researchers with experience in the diagnosis and management of PK deficiency from 10 countries, a patient representative and representatives from the sponsor (Agios Pharmaceuticals). The registry objective is to foster an understanding of the longitudinal clinical implications of PK deficiency, including its natural history, treatments and outcomes, and variability in clinical care. The aim is to enrol up to 500 participants from approximately 60 study centres across 20 countries over 7 years, with between 2 and 9 years of follow-up. Data will include demographics, diagnosis history, genotyping, transfusion history, relevant clinical events, medications, emergency room visits and hospitalisations. ETHICS AND DISSEMINATION: Registry protocol and informed consent forms are approved by institutional review boards/independent ethics committees at each study site. The study is being conducted in accordance with the Declaration of Helsinki. Registry data will be published in peer-reviewed journal articles and conference publications. TRIAL REGISTRATION NUMBER: NCT03481738.

Utilization of an ITP quality improvement pathway improves adherence to management guidelines.

Despite availability of epidemiologic studies and national guidelines for the management of newly diagnosed pediatric immune thrombocytopenia (ITP), practice variation exists among and within hematology practices. We previously described the development of an ITP pathway guiding management based on bleeding symptoms. Over an 8-year period, integration of this iterative ITP pathway into management of newly diagnosed ITP increased observation rates in children with no or mild bleeding symptoms and improved consistency of laboratory evaluation and treatment strategies without increasing adverse outcomes. This quality improvement initiative has been sustainable, acceptable to providers, and increased adherence to guidelines.

Pediatric refractory immune thrombocytopenia: A systematic review.

Pediatric immune thrombocytopenia (ITP) is an acquired disorder associated with autoimmune destruction and impairment of platelet production in children. Some children exhibit poor or transient response to ITP-directed treatments and are referred to as having refractory ITP (rITP). There is currently no consensus on the definition of rITP, nor evidence-based treatment guidelines for patients with rITP. After a survey of pediatric ITP experts demonstrated lack of consensus on pediatric rITP, we pursued a systematic review to examine the reported clinical phenotypes and treatment outcomes in pediatric rITP. The search identified 253 relevant manuscripts; following review, 11 studies proposed a definition for pediatric rITP with no consensus amongst them. Most definitions included suboptimal response to medical management, while some outlined specific platelet thresholds to define this suboptimal response. Common attributes identified in this study should be used to propose a comprehensive definition, which will facilitate outcome comparisons of future rITP studies.

Diagnosis, monitoring, and management of pyruvate kinase deficiency in children.

Pyruvate kinase (PK) deficiency is a rare, congenital red blood cell disorder caused by a single gene defect. The spectrum of genotypes, variants, and phenotypes are broad, commonly requiring a multimodal approach including enzyme and genetic testing for accurate and reliable diagnosis. Similarly, management of primary and secondary sequelae of PK deficiency varies, mainly including supportive care with transfusions and surgical interventions to improve symptoms and quality of life. Given the risk of acute and long-term complications of PK deficiency and its treatment, regular monitoring and management of iron burden and organ dysfunction is critical. Therefore, all children and adolescents with PK deficiency should receive regular hematology care with visits at least every 6 months regardless of transfusion status. We continue to learn more about the spectrum of symptoms and complications of PK deficiency and best practice for monitoring and management through registry efforts (NCT03481738). The treatment of PK deficiency has made strides over the last few years with newer disease-modifying therapies being developed and studied, with the potential to change the course of disease in childhood and beyond.

Mitapivat versus Placebo for Pyruvate Kinase Deficiency.

BACKGROUND: Pyruvate kinase deficiency is a rare, hereditary, chronic condition that is associated with hemolytic anemia. In a phase 2 study, mitapivat, an oral, first-in-class activator of erythrocyte pyruvate kinase, increased the hemoglobin level in patients with pyruvate kinase deficiency. METHODS: In this global, phase 3, randomized, placebo-controlled trial, we evaluated the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency who were not receiving regular red-cell transfusions. The patients were assigned to receive either mitapivat (5 mg twice daily, with potential escalation to 20 or 50 mg twice daily) or placebo for 24 weeks. The primary end point was a hemoglobin response (an increase from baseline of ≥1.5 g per deciliter in the hemoglobin level) that was sustained at two or more scheduled assessments at weeks 16, 20, and 24. Secondary efficacy end points were the average change from baseline in the hemoglobin level, markers of hemolysis and hematopoiesis, and the change from baseline at week 24 in two pyruvate kinase deficiency-specific patient-reported outcome measures. RESULTS: Sixteen of the 40 patients (40%) in the mitapivat group had a hemoglobin response, as compared with none of the 40 patients in the placebo group (adjusted difference, 39.3 percentage points; 95% confidence interval, 24.1 to 54.6; two-sided P<0.001). Patients who received mitapivat had a greater response than those who received placebo with respect to each secondary end point, including the average change from baseline in the hemoglobin level. The most common adverse events were nausea (in 7 patients [18%] in the mitapivat group and 9 patients [23%] in the placebo group) and headache (in 6 patients [15%] and 13 patients [33%], respectively). Adverse events of grade 3 or higher occurred in 10 patients (25%) who received mitapivat and 5 patients (13%) who received placebo. CONCLUSIONS: In patients with pyruvate kinase deficiency, mitapivat significantly increased the hemoglobin level, decreased hemolysis, and improved patient-reported outcomes. No new safety signals were identified in the patients who received mitapivat. (Funded by Agios Pharmaceuticals; ACTIVATE ClinicalTrials.gov number, NCT03548220.).

Thrombopoietin receptor agonists and rituximab for treatment of pediatric immune thrombocytopenia: A systematic review and meta-analysis of prospective clinical trials.

BACKGROUND: Children with immune thrombocytopenia (ITP) may require second-line ITP therapies. The high remission rate in pediatric patients, need for extended-duration use of thrombopoietin receptor agonists (TPO-RAs), drug adherence, potential side effects, monitoring, and cost effectiveness are factors that should be considered in decision-making about second-line therapies. Rituximab (RTX) has been used off-label for years to treat ITP but there are limited studies about its efficacy and safety in children. To date, no studies have directly compared TPO-RAs with RTX for the treatment of childhood ITP. METHODS: This systematic review analyzed the overall platelet response, durability of treatment effect, and safety for RTX use in comparison to TPO-RAs in pediatric ITP. MEDLINE/PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched through December 2020 and meta-analysis was conducted using proportions of success/failure for each intervention in the selected studies. RESULTS: The proportion of participants achieving the primary endpoint of a platelet response above 50,000 was similar for TPO-RAs (proportion = 0.71, 95% CI: 0.63-0.78) and RTX (proportion = 0.68, 95% CI: 0.53-0.82). However, considerable variation was found between the two groups with regards to the sustainability of the response and other secondary outcomes such as need for rescue and adverse events. RTX was associated with higher rates of rescue therapy. CONCLUSIONS: In this analysis of prospective pediatric ITP studies, RTX and TPO-RAs had similar rates of overall platelet response but differed in other important measures. Prospective comparative studies are needed to better characterize second-line treatments for pediatric ITP.

Health-related quality of life and fatigue in children and adults with pyruvate kinase deficiency.

Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic hemolytic anemia. Although recognition of the disease spectrum has recently expanded, data describing its impact on health-related quality of life (HRQoL) are limited. In this prospective international cohort of 254 patients (131 adults and 123 children) with PKD, we used validated measures to assess the impact of disease on HRQoL (EuroQol 5-Dimension Questionnaire, Pediatric Quality of Life Inventory Generic Core Scale version 4.0, and Functional Assessment of Cancer Therapy-Anemia) and fatigue (Patient Reported Outcomes Measurement Information System Fatigue and Pediatric Functional Assessment of Chronic Illness Therapy-Fatigue). Significant variability in HRQoL and fatigue was reported for adults and children, although individual scores were stable over a 2-year interval. Although adults who were regularly transfused reported worse HRQoL and fatigue compared with those who were not (EuroQol-visual analog scale, 58 vs 80; P = .01), this difference was not seen in children. Regularly transfused adults reported lower physical, emotional, and functional well-being and more anemia symptoms. HRQoL and fatigue significantly differed in children by genotype, with the worst scores in those with 2 severe PKLR mutations; this difference was not seen in adults. However, iron chelation was associated with significantly worse HRQoL scores in children and adults. Pulmonary hypertension was also associated with significantly worse HRQoL. Additionally, 59% of adults and 35% of children reported that their jaundice upset them, identifying this as an important symptom for consideration. Although current treatments for PKD are limited to supportive care, new therapies are in clinical trials. Understanding the impact of PKD on HRQoL is important to assess the utility of these treatments. This trial was registered at www.clinicaltrials.gov as #NCT02053480.