Page 79 - 2019_10 resto del Mondo_web

Introduction
Acquired severe aplastic anemia (SAA) is a rare disorder characterized by peripheral bi- or pancytopenia and bone marrow (BM) hypoplasia. Initial therapy for younger patients with SAA is a matched sibling hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST) if a matched sibling donor is not available.1 There is a paucity of data for children with SAA treated during the modern era from the ethnically and geographi- cally diverse population of North America. Pediatric stud- ies from the National Institutes of Health,2 the Japanese Childhood Aplastic Anemia Study Group,3-6 Brazil,7 and the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplant (SAAWP-EBMT)8,9 have been reported. However, diagnos- tic evaluation for constitutional disorders has been limit- ed, and duration of follow up has often been variable and short. Many published studies report outcomes with rab- bit anti-thymocyte globulin (rATG) due to the withdrawal of horse ATG (hATG) from some European and Asian markets in 2007; however, a large prospective study of upfront rATG versus hATG reported inferior response rates and lower survival with rATG.10 Thus, contemporary data to inform therapeutic decisions in pediatric patients treat- ed with IST in North America are of interest given inter- national differences in treatment regimens, recent advances in diagnosis of genetic marrow failure disorders, improvements in HSCT outcomes, and better supportive care.
To facilitate collaborative clinical studies of pediatric aplastic anemia, a consortium of 25 institutions (now numbering 39) across North America, named the North American Pediatric Aplastic Anemia Consortium (NAPAAC), was formed in 2014.11 The urgent need for evidence-based guidelines for patient management in pediatric SAA was highlighted by a NAPAAC survey of clinical practices of member institutions which revealed considerable variability in diagnostic evaluation and man- agement.11 Recognizing the challenges of performing a prospective trial to address these critical knowledge gaps, NAPAAC conducted a retrospective study of presentation and outcomes of pediatric patients diagnosed from 2002 to 2014 with SAA and treated with IST with a minimum of two years of follow up in member institutions. The objectives of the study were to determine the rates of response and survival following IST, to assess rates of clonal abnormalities, and to explore patient-specific fac- tors contributing to survival, refractory disease, relapse, and clonal progression following IST. This NAPAAC effort represents the first large study of pediatric SAA reflecting the racially diverse population of children afflicted by SAA across multiple centers in North America. These contem- porary data from a large number of pediatric patients will inform future studies of additional diagnostic or prognos- tic testing, and guide evidence-based clinical management.
Methods
Patients
A retrospective chart review was conducted by member institu- tions of all patients aged 1-20 years treated with IST as the first therapy for pediatric SAA between 1st January 2002 and 30th June 2014 for whom follow up was available for a minimum of 24
months or until death. This study was approved by the Institutional Review Board (IRB) at each participating institution or via a reliance agreement with the central study IRB at Boston Children’s Hospital. Each site abstracted data from the local med- ical record and entered them into a central Red Cap database. The data included demographics, disease characteristics at diagnosis, treatment, and outcomes. When available, the original anonymized written reports of specific studies including BM aspi- rate and biopsy, cytogenetics, fluorescence in situ hybridization (FISH), clonal analysis for paroxysmal nocturnal hemoglobinuria (PNH), telomere flow-FISH analysis, immunological analyses, and autopsies were uploaded for central review.
Submitted cases were included only if the diagnostic BM was reported as hypocellular and the patient had at least two peripher- al cytopenias: 1) absolute neutrophil count (ANC) < 0.5 x109/L; 2) platelet count (Plts) < 20x109/L; 3) hemoglobin (Hb) < 8 g/dL. Central review of diagnostic marrow slides was not feasible but marrow pathology reports were reviewed to confirm that the mar- row cellularity was <25% or hypocellularity was stated to be consistent with the diagnosis of SAA without a specified percent- age cellularity. Patients with a local diagnosis of an inherited BM failure syndrome were excluded from this study, as were subjects with an HLA-matched sibling who went to transplant upfront. Date of diagnosis was considered to be the date of the BM biopsy. Date of treatment was considered the first day of IST, and all out- comes were timed from the first day of treatment. Structured reporting of status and blood counts was required at initiation of IST, as well as at 3, 6, 12, 24, 36, 48, and 60 months, and at last fol- low up.
Definitions
Overall survival (OS) was measured from the time from first day of IST until death or date last known alive. Event-free survival (EFS) was measured from the time from start of IST until an event (death or start of a second therapy for SAA, either HSCT or a sec- ond course of IST) or the date last known to be without an event.
haematologica | 2019; 104(10)
Immunosuppressive therapy for pediatric aplastic anemia
Response12 was defined using hemoglobin (Hb), absolute neu- trophil count (ANC) and platelets (Plts). Complete response (CR), very good partial response (VGPR) and partial response (PR) required the indicated levels in all three lineages as noted below; no response (NR) was defined as failure in any lineage:
CR: Hb ≥10 g/dL and ANC ≥1x109/L and Plts ≥100x109/L VGPR: Hb ≥8 g/dL and ANC ≥0.5x109/L and Plts ≥50x109/L PR: Hb ≥8 g/dL and ANC ≥0.5x109/L and Plts ≥20x109/L
NR: Hb <8 g/dL or ANC <0.5x109/L or Plts <20x109/L
Patients receiving transfusions of packed red blood cells within
six weeks or platelets or granulocyte-colony stimulating factor (G- CSF)/granulocyte/macrophage-colony stimulating factor (GM- CSF) within two weeks of evaluation were deemed to have had NR at that time point. An objective response (OR) was defined as at least a PR (PR+VGPR+CR) and a deep response (DR) was defined as at least a VGPR (VGPR+CR). Duration of response (DOR) was defined as time from start of response to an event (death or start of a second therapy for SAA, either HSCT or a sec- ond course of IST).
Statistical analysis
Summary statistics included median and range for continuous variables and frequency and proportion for binary variables. Fisher's exact test and Wilcoxon rank sum test were used to com- pare proportions and medians, respectively. The proportion of subjects with an OR, DR, and CR were reported along with the exact binomial 95% confidence interval (95%CI). OS, EFS and DOR were estimated using the Kaplan-Meier method (log-log transformation for Confidence Interval) and compared using the
1975