Immunosuppressive therapy (IST) is effective treatment for severe aplastic anemia (SAA); however data on the quality of that survival for pediatric patients are limited. To investigate the clinical features and outcomes of children with SAA treated with IST, NAPAAC conducted a retrospective study of patients aged 1 to 20 years (yrs) treated with IST at 25 member institutions between 1/1/2002 and 6/30/2014 with a minimum of 24 months (mos) of follow-up.

A total of 314 patients were treated with IST for SAA defined as a hypocellular marrow with at least two cytopenias: 1) absolute neutrophil count <500/uL, 2) platelet count <20,000/uL, and/or 3) hemoglobin <8 g/dL. The median age at diagnosis was 9.7 yrs and 51.6% were male. Patients were racially diverse with 58.3% white (15.9% overall Latino ethnicity), 16.6% Black, 7.3% Asian, and 17.8% mixed/other. A history of hepatitis was reported in 43 (13.7%) patients. Mean red cell volume (MCV) was elevated ≥100 fL in 54 of 272 pts (19.9%), median 89.1fL. Absolute lymphocyte count was <1,000/uL in 110 of 260 pts (42.3%). Lymphocyte telomere length was <1st percentile for age in 6 of 92 pts (6.5%). A granulocyte PNH clone was detectable in 55 of 140 pts (39.3%), all with a small clone size (75th quartile 0.12%).

IST regimens included: horse ATG and cyclosporine (hATG/CSA; n=263), horse ATG/ tacrolimus (n=15), rabbit ATG/CSA (n=14), rabbit ATG/tacrolimus (n=1), cyclophosphamide (n=19) and sequential horse/rabbit ATG (n=2). Median time from diagnosis to IST was 24 days, with 168 (54.2%) treated within 4 weeks (wks).

Response to IST was defined as follows:

  • Complete Response (CR): Hgb ≥ 10 g/dl, ANC ≥1,000/uL, Plts ≥100,000/uL

  • Very Good Partial Response (VGPR): Hgb ≥ 8 g/dl, ANC ≥ 500/uL, Plts ≥ 50,000/uL

  • Partial Response (PR): Hgb ≥ 8 g/dl, ANC ≥ 500/uL, Plts ≥ 20,000/uL

  • No Response (NR): Hgb < 8 g/dl, ANC < 500/uL, Plts < 20K/uL

Patients receiving PRBCs within 6 wks, platelets or G- or GM-CSF within 2 wks of a timed endpoint were deemed to have no response.

At a median follow-up of 61.5 mos post IST, 30 of 314 pts (9.6%) had died. Best response at any time after IST of 301 evaluable patients was CR (192; 61.1%), VGPR (25; 8%), PR (10; 3.2%) and NR (74; 23.6%). The median time to best response was 6 mos (range 3-48 mos), and did not differ with time between diagnosis and IST. Of the 227 pts with a CR, VGPR or PR at any time, 47 (20.7%) ultimately died or required additional therapy (IST and/or HSCT). Overall survival was 98% at 6 mos, 95% (95% CI: 92-97) at 24 mos, and 93% (95% CI: 90-96) at 60 mos. Survival did not differ between patients treated <4 vs ≥4 wks from diagnosis (p=0.533) with 24 mos estimate of 96% vs 94%. Survival without a subsequent therapy was 84% (95% CI: 80-88) at 6 mos, 68% (95% CI: 63-73) at 24 mos, and 58% (95% CI: 52-64) at 60 mos. Of the 261 evaluable pts treated with hATG/CSA, 21 pts (8.1%) died, overall survival was 94% (95% CI: 91-97) and one-third required at least one additional therapy.

Cytogenetics were available at diagnosis for 271 of 314 (86.3%) pts, and 8 (3%) had clonal abnormalities. Of 171 patients with cytogenetics after IST, 13 (7.6%) additional patients developed clonal abnormalities at a median time of 28.5 mos (range: 4.3-143 mos). Monosomy 7, del 7q, and del 13q were the most common abnormalities. Only 4 patients with clonal abnormalities developed MDS, with one each progressing to ALL and AML. The other two patients received a HSCT soon after the MDS diagnosis. There was no significant association between hepatitis, cytogenetic abnormalities, short telomeres, or PNH clone at diagnosis with response to IST.

In conclusion, we report a large multicenter retrospective analysis of ethnically diverse North American IST treated pediatric SAA patients. Acquisition of clonal abnormalities and progression to MDS/leukemia was rare. Outcomes included 69.1% of pts with a CR or VGPR and overall survival of 93%. Among the 314 patients, event-free survival was 58% at 60 mos with 130 (41%) having died or required subsequent therapies. Unexpectedly, neither clonal abnormalities at diagnosis or time between diagnosis and IST affected response. Clinical and laboratory features associated with survival, quality, and durability of response to IST are currently being ascertained. These data support the need for new approaches to treatment of pediatric SAA.


Rogers: Terumo BCT: Consultancy; Pfizer: Research Funding. Rothman: Agios Pharmaceuticals: Honoraria; Pfizer: Consultancy. Thompson: Celgene: Consultancy, Research Funding; Baxalta: Research Funding; Novartis: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding. Glader: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Huang: Baxter: Research Funding; Biogen: Research Funding; Bio Products Laboratory: Other: Study investigator; Novartis: Other: support to attend meeting. Shimamura: TransCellular Therapeutics: Other: Spouse is majority shareholder .

Author notes


Asterisk with author names denotes non-ASH members.