Prognostic Factors in CD10 Negative Precursor B-Cell Acute Lymphoblastic Leukemia in Children: Data from Three Consecutive Trials ALL-BFM 86, 90, and 95.
Authors: Möricke Anja , Ratei Richard , Ludwig Wolf-Dieter , Harbott Jochen , Borkhardt Arndt , Viehmann Susanne , Zimmermann Martin , Gadner Helmut , Riehm Hansjörg , Schrappe Martin 
Published: October 2019

The overall unfavorable prognosis of CD10 negative (CD10−) precursor B-cell acute lymphoblastic leukemia (BCP-ALL) is well known. We analyzed 4473 pediatric patients (pts) <18 years (y) with BCP-ALL and immunophenotyping of CD10 enrolled from 1986 to 2000 in three consecutive ALL-BFM trials to explore prognostic factors in the CD10− subset. CD10 negativity was defined by CD10 expression in <20% of blasts. 233 pts (5.2%) were CD10−. In comparison to CD10 positive (CD10+) BCP-ALL pts, CD10− pts comprised more infants (age <1y 34% vs. 1%, p(X2)<0.001), more cases with hyperleukocytosis (WBC ≥100/nl 43% vs. 6%, p<0.001), more CNS involvement (CNS positive 10% vs. 2%; p<0.001) and an impaired treatment response (prednisone poor response (PPR) 22% vs. 5%, p<0.001; induction failure 6% vs. 1%, p<0.001). Estimated probability of 5 years event free survival (5y-pEFS) was significantly lower in pts with CD10− as compared to CD10+ BCP-ALL (49±3% vs 81±0.6%, p(log-rank)<0.001). Cox regression analysis including age, WBC, prednisone response (PR) and MLL/AF4 status as covariables revealed CD10 negativity as independent prognostic factor (RR 1.5, 95% confidence interval (CI) 1.1–2.1, p=0.01). Further analyses were performed within the CD10− group: 83% of infants and 60% of pts ≥1y were successfully analyzed for MLL/AF4. MLL/AF4 was detected in 55% of pts <1y and 27% of pts ≥1y. The well known risk factors for BCP-ALL (sex, age, WBC, CNS involvement, MLL/AF4 and PPR) also had prognostic impact within the CD10− group:

n* 5y-pEFS* (%) SE (%) p (log-rank) *5 pts w/o reinduction were excluded sex female 109 55 5 0.022 male 119 40 5 age <1y 78 25 5 <0.001 ≥1y 150 62 4 WBC <100/nl 128 62 4 <0.001 ≥100/nl 100 33 5 CNS neg 181 54 4 0.011 pos 21 33 10 MLL/AF4 neg 95 53 5 0.001 pos 61 29 6 PR good 170 57 4 <0.001 poor 50 30 6

Out of a number of immunophenotypic markers, analyzed at different expression cut-off points, CD24 at missing or weak expression of <40% and CD65 at high expression of ≥40% were significantly correlated with unfavorable clinical characteristics and worse outcome within the CD10− group. Significant correlation with PR could only be demonstrated for expression of CD24, which is presumed to act as negative regulator in B-cell development through mediation of apoptosis.

age<1y* WBC ≥100/nl* MLL/AF4 pos* PPR# pEFS§ n/total (%) n/total (%) n/total (%) n/total (%) % ±SE * all p(X2)<0.01, #CD24 p=0.01, CD65 n.s., §all p(log-rank]<0.001 CD24 <40% 37/77 (48) 52/77 (68) 33/56 (59) 24/73 (33) 32 ±5 CD24 ≥40% 34/122 (28) 35/122 (29) 18/76 (24) 20/119 (17) 59 ±5 CD65 <40% 56/180 (31) 67/180 (37) 39/120 (33) 39/175 (22) 30 ±7 CD65 ≥40% 22/44 (50) 32/44 (73) 21/34 (62) 10/41 (24) 54 ±4

Including age, WBC, PR and MLL/AF4 status as covariables, out of the analyzed markers only CD65 proved to be an independent prognostic factor in CD10− BCP-ALL (Cox regression analysis: RR 1.5, 95% CI 1.1–2.9, p=0.018). The identification of additional prognosis associated immunophenotypic markers may contribute to further refinement of treatment strategies for CD10− BCP-ALL pts.