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Z.R. Rogers et al.
OS for either the entire cohort (HR=1.0, 95%CI: 0.98,1.02; P=0.76) or the hATG/CyA group (HR=0.99, 95%CI: 0.98,1.03; P=0.69). EFS is shown in Figure 4B. Among all subjects receiving second-line treatment (n=110), 49 (44.6%) failed with a median time to failure of 88.5 months (95%CI: 45.6,131.5). Among the 92 subjects from the hATG/CyA group receiving second-line treatment, 43 (46.7%) failed with a median time to failure of 64.4 months (95%CI: 44.2,131.5)
Outcomes of second-line treatment with HSCT versus IST were compared for all subjects and for the hATG/CyA treatment group. Among all subjects receiving subsequent treatment (n=110), 45 received HSCT and 65 received IST. Among the hATG/CyA group receiving second-line treat- ment (n=92), 38 received HSCT and 54 received a second course of IST. Due to the significantly longer follow up with second-line IST as compared to bone marrow trans- plantation for both the entire cohort (69 vs. 36 months; log rank, P=0.05) and the hATG/CyA group (74 vs. 36 months; log rank, P=0.026), the data were censored at 36 months in the analysis to minimize the impact of differen- tial follow up. The analysis shows that EFS is significantly longer with the second-line treatment of HSCT compared with IST (log rank, P≤0.011) (Figure 4C); this effect remains after adjusting for other variables (Online Supplementary Figure S1).
Discussion
We report a multi-institutional study of the presentation and outcomes of 314 North American pediatric SAA patients treated with IST. Although retrospective studies are limited by potential confounding factors and data availability, this multicenter study provides a contempo- rary analysis of the diagnostic evaluation and treatment outcomes for pediatric SAA. Since the natural history, risks, benefits, and outcomes of treatments are not identi- cal between children versus adults with SAA, the study of rare diseases such as pediatric SAA requires collaborative effort through large consortia with the goal of improving diagnosis and treatment. As with any rare disease, nation- al registries would greatly advance the prospective study of pediatric aplastic anemia.
Although traditionally reticulocytopenia has been used as a diagnostic criterion for SAA, in this large study, retic- ulocytopenia with an ARC <60x109/L did not correlate with a Hb <8 g/dL in a subset of patients. We found that the majority of clinicians were using clinically significant anemia and need for transfusion, rather than the ARC, to inform diagnosis and initiation of therapy. Indeed, in the setting of severe anemia without BM failure, the reticulo- cyte count would be expected to be markedly higher, so even an ARC within the normal range may be a sign of impaired erythropoiesis.
Red cell macrocytosis may be indicative of the time frame from evolution of reduced hematopoietic stem cell numbers and clinically significant cytopenias. In addition, red cell macrocytosis may be associated with dysplastic processes. However, no association between macrocytosis and likelihood of hematologic response or survival was observed. Lymphopenia in pediatric patients with other cytopenias may be seen with primary immunological dis- orders; however, no association with response was
observed. Development of cytogenetically abnormal clones or overt hematologic clonal disease was rare, although post-treatment marrow surveillance was not uni- formly conducted or captured due to the retrospective nature of this analysis.
A correlation between short leukocyte telomere length at diagnosis, measured by quantitative polymerase chain reaction, with increased risk of relapse, clonal evolution, and reduced survival has been reported.21 Since current clinically available telomere length testing utilizes flow- FISH,13 we explored whether the results of this clinical telomere length assay correlated with outcomes. We did not detect a correlation between telomere lengths less than either the 1st or 10th percentile for age with response to IST.
We observed some notable differences from reported outcomes for adult SAA patients treated with hATG/CyA. Since the magnitude of blood count recovery is especially important to support normal growth and activity in chil- dren, we examined the quality of response to IST. Of those pediatric patients who responded to hATG/CyA, the quality of response was high, with 59.8% achieving a CR and 68.2% achieving a DR. In contrast, typical rates of CR cited for adults is 10%.12 In addition, a lower rate of clonal progression was noted for children in comparison to the 10-15% clonal progression reported in adults, although this observation is potentially limited by the ret- rospective nature of this study and short follow-up time.22,23 However, EFS was low, with events continuing to accrue well past five years post IST without an apparent plateau. EFS is of particular concern for pediatric patients given their long future lifespan. Accordingly, both clinical decisions and evaluation of new therapies should be based on pediatric data whenever possible, rather than on extrapolation of data from adult cohorts. For patients with refractory or relapsed disease, EFS was superior for patients receiving second-line treatment with HSCT com- pared with IST even after adjusting for age, gender, time from initial IST to second treatment, and lymphocytope- nia. A prospective study of 21 pediatric SAA patients receiving a second course of IST for refractory disease reported anaphylaxis in three patients and a trilineage response in only two (11%) of the remaining 18 patients, with a 5-year failure-free survival of only 9% at five years post second-line therapy.6 Together with the excellent contemporary outcomes of MUD transplantation,24-26 these data strongly suggest that allogeneic transplantation with a MUD is a superior second-line therapy for relapsed or refractory SAA after IST for pediatric patients. In addi- tion, these data suggest a potential role for MUD HSCT as upfront therapy in young patients. A randomized pilot and feasibility trial comparing hATG/CyA versus MUD HSCT in newly diagnosed SAA patients lacking an HLA- matched family donor is currently underway.
Acknowledgments
The authors are grateful to Susan Kornetsky for her guidance and expertise. We also thank Tim Colby, Brian Sheehan, and Melissa Rose for their assistance with this project.
Funding
This project was supported by the Copeman Fund, Julian’s Dinosaur Guild, and an NIH R24 DK 099808 to AS and DAW, the Rauch Family Foundation to TDC, the Campini Foundation to JNH and U54 DK106857 to GMK.
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haematologica | 2019; 104(10)