Diagnosis and treatment of pediatric acquired aplastic anemia (AAA): An initial survey of the North American Pediatric Aplastic Anemia Consortium (NAPAAC)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106711/1/pbc24875.pd

L-leucine improves anemia and growth in patients with transfusion-dependent Diamond Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond Blackfan Anemia Registry

Background: Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, short stature, congenital anomalies, and cancer predisposition. Most cases are due to mutations in genes encoding ribosomal proteins (RP) leading to RP haploinsufficiency. Effective treatments for the anemia of DBA include chronic red cell transfusions, long-term corticosteroid therapy, or hematopoietic stem cell transplantation. In a small patient series and in animal models, there have been hematologic responses to L-leucine with amelioration of anemia. The study objectives of this clinical trial were to determine feasibility, safety, and efficacy of L-leucine in transfusion-dependent patients with DBA. Procedure: Patients ≥2 years of age received L-leucine 700 mg/m2 orally three times daily for nine months to determine a hematologic response and any improvement in growth (NCT01362595). Results: This multicenter, phase I/II study enrolled 55 subjects; 43 were evaluable. There were 21 males; the median age at enrollment was 10.4 years (range, 2.5-46.1 years). No significant adverse events were attributable to L-leucine. Two subjects had a complete erythroid response and five had a partial response. Nine of 25, and 11 of 25, subjects experienced a positive weight and height percentile change, respectively, at the end of therapy. Conclusions: L-leucine is safe, resulted in an erythroid response in 16% of subjects with DBA, and led to an increase in weight and linear growth velocity in 36% and 44% of evaluable subjects, respectively. Further studies will be critical to understand the role of L-leucine in the management of patients with DBA

Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease

We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease

Immunosuppressive therapy for pediatric aplastic anemia: a North American Pediatric Aplastic Anemia Consortium study

Quality of response to immunosuppressive therapy and long-term outcomes for pediatric severe aplastic anemia remain incompletely characterized. Contemporary evidence to inform treatment of relapsed or refractory severe aplastic anemia for pediatric patients is also limited. The clinical features and outcomes for 314 children treated from 2002 to 2014 with immunosuppressive therapy for acquired severe aplastic anemia were analyzed retrospectively from 25 institutions in the North American Pediatric Aplastic Anemia Consortium. The majority of subjects (n=264) received horse anti-thymocyte globulin (hATG) plus cyclosporine (CyA) with a median 61 months follow up. Following hATG/CyA, 71.2% (95%CI: 65.3,76.6) achieved an objective response. In contrast to adult studies, the quality of response achieved in pediatric patients was high, with 59.8% (95%CI: 53.7,65.8) complete response and 68.2% (95%CI: 62.2,73.8) achieving at least a very good partial response with a platelet count ≥50×109L. At five years post-hATG/CyA, overall survival was 93% (95%CI: 89,96), but event-free survival without subsequent treatment was only 64% (95%CI: 57,69) without a plateau. Twelve of 171 evaluable patients (7%) acquired clonal abnormalities after diagnosis after a median 25.2 months (range: 4.3-71 months) post treatment. Myelodysplastic syndrome or leukemia developed in 6 of 314 (1.9%). For relapsed/refractory disease, treatment with a hematopoietic stem cell transplant had a superior event-free survival compared to second immunosuppressive therapy treatment in a multivariate analysis (HR=0.19, 95%CI: 0.08,0.47; P=0.0003). This study highlights the need for improved therapies to achieve sustained high-quality remission for children with severe aplastic anemia

Laparoscopic splenectomy in childhood hematologic disorders

Laparoscopic splenectomy is a new technique that is being utilized in patients with a variety of mostly hematologic disorders. Its application in children has not been extensively documented. Between January 1994 and February 1995, 11 children less than 15 years of age underwent elective laparoscopic splenectomy. Data collected from this treatment group were compared to that from the ten most recent open splenectomy patients with comparable hematologic disorders. All procedures in both groups were successful in relief of symptoms, increase in platelet count, and/or increase in hematocrit. Operative times averaged 147 min in the laparoscopic group, compared to 112 min in the open group. Estimated blood loss was 32 ml in the laparoscopic group and 86 ml in the open group. Days to laparoscopic patient discharge were 3.6, compared to 5.3 days in the open group. There were no wound complications or need for perioperative platelet transfusions in the laparoscopic patients. Patient response has been uniformly positive in the laparoscopic group. Reusable access trocars are utilized for two of the four working ports. Stapling devices and special tissue morselizers are not required. There are no additional operating room or surgeon\u27s fees incurred in the laparoscopic procedures. This series demonstrates that laparoscopic splenectomy is a safe, cost-efficient alternative to open splenectomy in children with a variety of hematologic disorders

Prognostic significance of early vaso-occlusive complications in children with sickle cell anemia

Sickle cell anemia (SS) is highly phenotypically variable, and early predictors of outcome could guide clinical care. To determine whether early vaso-occlusive complications predicted subsequent adverse outcomes in the Dallas Newborn Cohort, we studied all members with SS or sickle-β(0)-thalassemia who presented in their first year of life and had 5 years or more of follow-up. We defined 3 potential early predictors: hospitalizations in the first 3 years of life for (1) painful events other than dactylitis, (2) dactylitis, and (3) acute chest syndrome (ACS). We studied the associations of these predictors with the following late adverse outcomes (occurring after the third birthday): death, first overt stroke, use of disease-modifying therapy, and hospitalizations for pain events and ACS. None of the early events predicted death or stroke. Early pain and ACS both predicted a modest, temporary increase in the number of later painful episodes, but early ACS strongly increased the odds of more frequent ACS throughout childhood. Dactylitis had limited utility as a predictor. Although we still lack a useful prognostic framework for young children with SS, those who experience early ACS might be candidates for higher risk interventions to mitigate or cure their disease

Long-term hydroxyurea therapy for infants with sickle cell anemia: the HUSOFT extension study

The long-term efficacy and toxicity of hydroxyurea for infants are undefined, and its role in preventing organ dysfunction is unknown. Short-term feasibility of hydroxyurea administration, toxicities, hematologic effects, and effect on spleen function in infants with sickle cell anemia (SCA) were reported (Hydroxyurea Safety and Organ Toxicity [HUSOFT] trial). These infants completing 2 years of hydroxyurea therapy (20 mg/kg/d) were offered study extension with dose escalation to 30 mg/kg/d. Patients were monitored with laboratory tests and biannual imaging studies. Hematologic indices were compared with predicted age-specific values and event rates compared with historic rates. All 21 subjects completing the original trial enrolled in the extension study: median age, 3.4 years old (range, 2.6 to 4.4 years); 12 females; 20 with Hb SS, 1 with Hb S/β0-thalassemia. Seventeen patients completed 4 years of hydroxyurea, and 11 completed 6 years. After 4 years, hydroxyurea was associated with increased hemoglobin concentration, percentage of fetal hemoglobin (Hb F), and mean corpuscular volume (MCV) and decreased reticulocytes, white blood cells (WBCs), and platelets (P < .01). Patients experienced 7.5 acute chest syndrome (ACS) events per 100 person-years, compared with 24.5 events per 100 person-years among historic controls (P = .001). Treated patients had better spleen function than expected and improved growth rates. Infants with SCA tolerate prolonged hydroxyurea therapy with sustained hematologic benefits, fewer ACS events, improved growth, and possibly preserved organ function