CD371+ pediatric B-cell acute lymphoblastic leukemia: propensity to lineage switch and slow early response to treatment

: In the effort to improve immunophenotyping and minimal residual disease (MRD) assessment in acute lymphoblastic leukemia (ALL), the international Berlin-Frankfurt-Münster (iBFM) Flow Network introduced the myelomonocytic marker CD371 in 2014, for a large prospective characterization with a long follow-up. In the present study, we aimed to investigate the clinical and biological features of CD371-positive (CD371pos) pediatric BCP-ALL. From June 2014 to February 2017, 1812 pediatric patients with newly diagnosed BCP-ALLs enrolled in trial AIEOP-BFM ALL 2009 were evaluated as either screening (n=843, Italian centers) or validation cohort (n=969, other iBFM centers). Laboratory assessment at diagnosis consisted of morphological, immunophenotypic, and genetic analysis on bone marrow or peripheral blood samples. Response assessment relied on morphology, multiparametric flow-cytometry (MFC), and PCR-MRD. Overall, 160/1812 (8.8%) BCP-ALLs were CD371pos at diagnosis. This finding correlated with older age (p<0.001), lower ETV6::RUNX1 frequency (p<0.001), immunophenotypic immaturity (p<0.001), strong expression of CD34 and of CD45 (p<0.05). During induction therapy, CD371pos BCP-ALLs showed a transient myelomonocytic switch (mm-SW: up to 65.4% of samples at Day 15) and frequently an inferior response to chemotherapy [Slow Early Response by PCR-MRD, p<0.001]. However, the 5-year event-free survival was 88.3%. Among 420 patients from the validation cohort, 27/28 (96.4%) cases positive for DUX4-fusions were CD371pos. In conclusion, we comprehensively characterized CD371pos BCP-ALL in the largest pediatric cohort. CD371 is the most sensitive marker of transient mm-SW, whose recognition is essential for proper MFC-MRD assessment. CD371pos is associated to poor early-treatment response, although a good outcome can be reached after MRD-based ALL-related therapies.