CD10⁻ Pre-B Acute Lymphoblastic Leukemia (ALL): A Distinct High-Risk Subgroup of Adult ALL.

Introduction: Immunological subtyping and molecular genetic analysis enable risk-adapted treatment of acute lymphoblastic leukemia (ALL). Translocations involving the mixed lingeage leukemia (MLL) gene characterize one poor-prognosis subtype of adult B-lineage precursor ALL correlating with a CD19⁺/CD10⁻/cytoplasmic (cy) IgM⁻ immunophenotype (pro-B ALL).

Patients and Methods: Immunophenotyping was performed on 2,408 newly diagnosed ALL specimens indentifying pro-B ALL, TdT⁺/CD19⁺/CD10⁻/cyIgM⁻/surface(S)Ig⁻; c-ALL, TdT⁺/CD19⁺/CD10⁺/cyIgM⁻/SIg⁻; and pre-B ALL, TdT⁺/CD19⁺/CD10⁺/cyIgM⁺/SIg⁻. Ambiguous cases of CD10-positivity (5–15% CD10-positivity) were rechecked by a second antibody. BCR-ABL RT-PCR and cytogenetics were performed. CD10-negative blasts also underwent MLL-AF4 RT-PCR. FISH using directly labelled probes for MLL was done in selected cases. Patients were treated according the German Multicenter Adult ALL trials (GMALL) with MLL-rearrangement positive patients treated in the high-risk arm.

Results: Immunophenotyping identified 70 CD10-negative pre-B ALL specimens (TdT⁺CD19⁺cyIgM⁺). Fifty-six of these 70 CD10-negative pre-B ALL specimens contained a sufficient amount of blasts for molecular analysis. A total of 46/56 CD10-negative pre-B ALL were assigned to MLL-rearrangement positivity, revealing either MLL-AF4 fusion by RT-PCR (n = 38) or an 11q23/MLL translocation by cytogenetics (n = 4) or FISH (n = 4).

Looking at clinical characteristics, MLL-rearrangement-positive patients were characterized by a higher median white blood cell count (P = .0002) and their blasts showed frequently neuroglial antigen 2 chondroitin sulfate proteoglycan (P = .02).

Forty CD10⁻ pre-B ALL patients with molecular genetic and/or cytogenetic data were evaluable for the treatment response and outcome. A complete remission (CR) was achieved in 6 of 7 (86%) MLL-rearrangement-negative and in 27 of 33 (82%) MLL-rearrangement-positive patients (P = .06). CR was maintained by 2 of 6 (33.3%) MLL-rearrangement-negative and 7 of 27 (26%) MLL-rearrangement-positive patients. The probability of remission duration after 3 years was 0.37 (± 0.29 SE) in MLL-rearrangement-negative versus 0.28 (± 0.13 SE) in MLL-rearrangement-positive patients contributing essentially to the overall survival at 3 years after diagnosis of 0.15 (± 0.06 SE) in patients with CD10-negative pre-B ALL.

Conclusion: Our data identify CD10⁻ cytoplasmic Ig-positive pre-B ALL as a rare (2.2%) but distinct immunosubtype of adult ALL that is characterized by a high MLL rearrangement rate and a worse outcome with conventional intensified treatment strategies.