Corrigendum: The Spectrum of SPTA1-Associated Hereditary Spherocytosis.

[This corrects the article DOI: 10.3389/fphys.2019.00815.].

The Spectrum of SPTA1-Associated Hereditary Spherocytosis.

Hereditary spherocytosis (HS) is the most common red blood cell (RBC) membrane disorder causing hereditary hemolytic anemia. Patients with HS have defects in the genes coding for ankyrin (ANK1), band 3 (SLC4A1), protein 4.2 (EPB42), and α (SPTA1) or ß-spectrin (SPTB). Severe recessive HS is most commonly due to biallelic SPTA1 mutations. α-spectrin is produced in excess in normal erythroid cells, therefore SPTA1-associated HS ensues with mutations causing significant decrease of normal protein expression from both alleles. In this study, we systematically compared genetic, rheological, and protein expression data to the varying clinical presentation in eleven patients with SPTA1-associated HS. The phenotype of HS in this group of patients ranged from moderately severe to severe transfusion-dependent anemia and up to hydrops fetalis which is typically fatal if transfusions are not initiated before term delivery. The pathogenicity of the mutations could be corroborated by reduced SPTA1 mRNA expression in the patients' reticulocytes. The disease severity correlated to the level of α-spectrin protein in their RBC cytoskeleton but was also affected by other factors. Patients carrying the low expression αLEPRA allele in trans to a null SPTA1 mutation were not all transfusion dependent and their anemia improved or resolved with partial or total splenectomy, respectively. In contrast, patients with near-complete or complete α-spectrin deficiency have a history of having been salvaged from fatal hydrops fetalis, either because they were born prematurely and started transfusions early or because they had intrauterine transfusions. They have suboptimal reticulocytosis or reticulocytopenia and remain transfusion dependent even after splenectomy; these patients require either lifetime transfusions and iron chelation or stem cell transplant. Comprehensive genetic and phenotypic evaluation is critical to provide accurate diagnosis in patients with SPTA1-associated HS and guide toward appropriate management.

Spotlight on romiplostim in the treatment of children with chronic immune thrombocytopenia: design, development, and potential place in therapy.

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia. In approximately one-third of cases, the duration of thrombocytopenia will extend beyond 12 months consistent with a diagnosis of chronic ITP. Minor bleeding manifestations are common in chronic ITP while severe or life-threatening bleeding complications are uncommon. Moreover, spontaneous resolution occurs in the majority of children with chronic ITP necessitating treatment in only those children with ongoing bleeding manifestations or impairment in health-related quality of life (HRQOL). The characterization of thrombopoietin (TPO) and remarkable advancements in our understanding of the pathophysiology of ITP has led to the development of a new class of agents, the TPO-receptor agonists that have documented efficacy in the amelioration of thrombocytopenia and bleeding manifestations in chronic ITP. Romiplostim is a second-generation TPO-receptor agonist that has undergone limited evaluation in the treatment of chronic ITP in children. Evolving data suggest that romiplostim may be a safe and effective agent in the treatment of chronic ITP in children. Additional data are needed to confirm its ability to increase platelet counts, decrease bleeding manifestation, and improve the HRQOL of children and caregivers impacted by chronic ITP.

Successful treatment of secondary graft failure following unrelated cord blood transplant with hematopoietic growth factors in a pediatric patient with Fanconi anemia.

Graft failure following allogeneic HCT in Fanconi anemia is associated with significant mortality. Retransplantation may be considered; however, the limited toxicity profile of HGFs also makes them an option for the treatment of graft failure. We describe a five-yr-old female diagnosed with Fanconi anemia and marrow failure treated with HCT. The course was complicated by secondary graft failure treated successfully with HGFs including G-CSF, EPO, and romiplostim. The outcome could be related to the intervention, but could also be the natural course of recovery, including recovering from a recent CMV infection treated with ganciclovir. We found the use of HGFs to be an effective and safe alternative to the potential complications as well as morbidity and mortality associated with the use of retransplantation.

Long-term use of the thrombopoietin-mimetic romiplostim in children with severe chronic immune thrombocytopenia (ITP).

BACKGROUND: Treatment of chronic severe pediatric ITP is not well studied. In a phase 1/2 12-16-week study, 15/17 romiplostim-treated patients achieved platelet counts ≥50 × 109 /L, and romiplostim treatment was well tolerated. In a subsequent open-label extension (≤109 weeks), 20/22 patients received romiplostim; all achieved platelet counts >50 × 109 /L. Twelve patients continued in a second extension (≤127 weeks). Longitudinal data from start of romiplostim treatment through the two extensions were evaluated to investigate the safety and efficacy of long-term romiplostim treatment in chronic severe pediatric ITP. PROCEDURE: Patients received weekly subcutaneous romiplostim, adjusted by 1 µg/kg/week to maintain platelet counts (50-200 × 109 /L, maximum dose 10 µg/kg). Bone marrow examinations were not required. RESULTS: At baseline, patients were median age 10.0 years; median ITP duration 2.4 years; median platelet count 13 × 109 /L; 73% were male; and 36% had prior splenectomy. Median romiplostim treatment duration was 167 weeks (Q1, Q3: 78,227 weeks), and median average weekly dose was 5.4 µg/kg (Q1, Q3: 4.3, 8.0 µg/kg). Seven patients discontinued treatment: four withdrew consent, two were noncompliant, and one received alternative therapy. None withdrew because of adverse events (AEs). After the first 12 weeks, median platelet counts remained >50 × 109 /L. Eight (36.4%) patients received rescue medication, and 14 (63.6%) used concurrent ITP therapy. Seven patients (31.8%) reported serious AEs, and two (9.1%) reported life-threatening AEs (both thrombocytopenia); there were no serious AEs attributed to treatment and no fatalities. CONCLUSIONS: Long-term romiplostim treatment in this small cohort increased and maintained platelet counts for over 4 years in children with ITP with good tolerability and without significant toxicity. Pediatr Blood Cancer 2015;62:208-213. © 2014. The Authors. Pediatr Blood & Cancer published by Wiley Periodicals, Inc.

Successful treatment of post-transplant thrombocytopenia with romiplostim in a pediatric patient with X-linked chronic granulomatous disease.

Thrombocytopenia is a frequent complication following HSCT in pediatric patients. Romiplostim is a TPO receptor agonist that has been utilized successfully in the treatment of pediatric patients with immune thrombocytopenia. We describe a three-yr-old male with X-linked CGD treated with an unrelated donor bone marrow transplant. His course was complicated by the development of symptomatic thrombocytopenia. He was started on romiplostim with prompt improvement in his thrombocytopenia. We found the use of romiplostim to be an effective and safe alternative to the potential complications as well as morbidity and mortality associated with the use of immunosuppressive agents such as corticosteroids.

Thrombopoietic agents for the treatment of persistent and chronic immune thrombocytopenia in children.

OBJECTIVES: To determine the safety, tolerability, or efficacy of 2 licensed thrombopoietic agents in children with persistent and chronic immune thrombocytopenia (ITP). STUDY DESIGN: Retrospective analysis approved by the institutional review board of children with ITP not on-study who received thrombopoietin (TPO) therapy; 21 received romiplostim (11 at Children's Hospital of Orange County, 10 at Weill Cornell Medical Center) and 12 received eltrombopag (all at Weill Cornell Medical Center). Primary response measures were platelet counts ≥ 50 × 10(9)/L or ≥ 20 × 10(9)/L above baseline for 2 consecutive weeks and 50% of platelet counts ≥ 50 × 10(9)/L. Duration of treatment and adverse events, including bone marrow myelofibrosis (MF) consensus grades, were tabulated. RESULTS: Twenty-seven of 33 (82%) patients responded to TPO agents, 18 of 21 to romiplostim, and 9 of 12 to eltrombopag, after an average of 3.6 previous ITP therapies. These 27 patients had platelet counts ≥ 50 × 10(9)/L and ≥ 20 × 10(9)/L above baseline for 2 consecutive weeks; 26 had 50% of platelet counts ≥ 50 × 10(9)/L. Duration of romiplostim use ranged from 6 to 44 months (11/18 ongoing) and of eltrombopag 23 to 53 months (7/12 ongoing). One patient on eltrombopag experienced a provoked deep-vein thrombosis at site of ankle fracture. No other serious drug-related adverse events occurred. Among 24 bone marrows, 10 after greater than 2 years of therapy, 23 were normal (MF grades 0-1); 1 was MF-2. CONCLUSION: Retrospective analysis of off-study use of TPO agents in children with mainly chronic ITP showed increases in platelet counts in more than 4 of 5 children. The long-term use of TPO agents, up to 53 months, without tachyphylaxis supports their efficacy. These agents appear safe, effective, and tolerable in children with chronic ITP.

Successful cord blood transplantation in a patient with malignant infantile osteopetrosis and hemophilia.

MIOP is a congenital disorder of osteoclast differentiation or dysfunction. Inadequate bone resorption by osteoclasts results in a spectrum of complications including hypocalcemia, osteosclerosis, marrow failure, extramedullary hematopoiesis, hydrocephalus, visual deficits, and eventual mortality. Early diagnosis and timely HCT is a recommended treatment approach for select patients prior to the development of end-organ damage. A comorbid bleeding disorder presents a unique challenge in the setting of MIOP and cord blood HCT given the additional risk factors for bleeding including delayed engraftment, a high risk of developing sinusoidal obstruction syndrome, and potential need for emergent invasive procedures. To our knowledge, this is the first report of a patient with an autosomal recessive form of MIOP who successfully underwent a cord blood HCT complicated by the presence of mild hemophilia A and HCT-related complications including delayed engraftment, sinusoidal obstruction syndrome, and need for multiple invasive procedures (e.g., ventriculostomy, tracheostomy) without clinically significant bleeding. Given the underlying diagnosis of MIOP and need for HCT, the challenge of mitigating the significant risk of bleeding in a patient with a comorbid bleeding disorder is discussed.

Rare factor deficiencies.

PURPOSE OF REVIEW: By definition, rare factor deficiencies have a prevalence of less than 200,000 in the US population, or an incidence of less than one in 2000 in Europe. The very small numbers of patients with rare disorders present challenges in diagnosis, evaluation of bleeding risk and treatment. Use of new assays, full genome sequencing, and global clotting assays will significantly improve diagnosis of patients with rare bleeding disorders. RECENT FINDINGS: In addition to new assays available for monitoring patients, new therapy, both recombinant and plasma derived, is now available. Registries and clinical trials have demonstrated decreased bleeding and improved outcomes when patients are treated with these agents. Expanding international registries have been initiated to correlate genotype and bleeding phenotype in conjunction with global assays. SUMMARY: Ongoing research continues to expand our understanding of the pathophysiology of rare factor deficiencies. This work complements medical practice to incorporate early diagnosis and new treatment options for patients, resulting in safer and less sensitizing regimens and much improved clinical outcomes.

Unrelated hematopoietic stem cell transplantation in a patient with congenital dyserythropoietic anemia and iron overload.

CDA is a heterogeneous group of disorders that result in morphologically abnormal erythroid maturation and ineffective erythropoiesis. Curative therapy for CDA focuses on the use of HSCT using fully matched sibling donors. This is the first report of a Type II CDA patient with severe iron overload who was successfully treated with HSCT using a HLA-matched unrelated donor after aggressive chelation therapy. Given the challenges of HSCT in any patient with CDA and severe iron overload, the role of novel approaches to iron chelation and HSCT is discussed.

Inflammatory polyps following successful HLA-matched cord blood transplantation in a patient with X-linked lymphoproliferative syndrome.

Gastrointestinal complications following HSCT are numerous and include a variety of issues resulting in hepatic, biliary, pancreatic, and intestinal compromise. In the context of an underlying state of immune dysregulation, novel complications may arise including autoimmunity. To our knowledge, this is the first report of a patient with XLP who was successfully treated with HSCT using an HLA-matched unrelated cord blood unit that was complicated by the development of inflammatory polyps of the colon. Given the underlying diagnosis of XLP and its associated immune dysregulation, the challenge of understanding unique gastrointestinal manifestations of autoimmunity following HSCT is discussed.