Session: 614. Acute Lymphoblastic Leukemias: Biomarkers, Molecular Markers, and Minimal Residual Disease in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research, Measurable Residual Disease
Methods: We performed Ig HTS (Adaptive ClonoSEQ) to define and compare the Ig rearrangement state of B-LLy with that of B-ALL using extracted gDNA from paraffin-embedded tumor slide preparations from 34 patients with B-LLy (N=15 SR; N=17 HR; N=2 stage unknown) from Children’s Oncology Group (COG) protocols APEC14B1 and AALL0932, and diagnostic BM from 283 patients with B-ALL from COG protocols AALL0331 (N=141; SR) and AALL0232 (N=142; HR). We also measured B-LLy MDD in 31 patients by tracking tumor-associated Ig rearrangements in pre-treatment BM and peripheral blood (PB).
Results: All 34 B-LLy and 281/283 B-ALL samples had dominant IgH and/or Ig light chain clone(s). We detected IgH clones in 91.1% of B-LLy, 86.7% of which reflected complete V(D)J rather than partial diversity (D)-joining (J) rearrangements (vs. 74.8% complete V(D)J in B-ALL). In contrast, patients with B-ALL had more incomplete DJ rearrangements (P=0.04) indicative of a transformation state prior to variable (V) gene recombination. B-ALL V(D)J clones were enriched for usage of the most D-proximal V genes, IGHV06-01 and IGHV01-02, consistent with data indicating preferential D-proximal V gene usage in immature lymphoid progenitors and leukemia. B-LLy did not share this preferential V gene usage and lacked representation of IGHV06-01, distinguishing it from B-ALL. Further, 82.4% of B-LLy (vs. 59.7% of B-ALL; P=0.017) had dominant Ig light chain clone(s), indicative of a more mature rearrangement state. Ig HTS data from the BM and/or PB were available for 31 patients: 80.6% were MDD+, including 69.2% (N=9 of 13) with localized/SR B-LLy. BM/PB MDD level did not significantly vary between patients with localized/SR (median 0.012%; range 0-88.13%) vs. disseminated/HR (median 0.052%; range 0-24.31%) clinical staging. There was also no significant difference in MDD level between the BM and PB among 16 patients with evaluable samples from both sites. While a low event rate limited association with outcome, 0 of 6 patients without measurable MDD experienced relapse/progression/death (vs. 3 of 25 MDD+ patients).
Conclusions: B-LLy Ig clonal composition reflects a more mature developmental state than B-ALL and a spectrum of BM/PB MDD across clinical stages. Developmentally ordered Ig rearrangement first involves IgH D-J recombination, followed by V gene rearrangement, and finally Ig light chain V-J rearrangement at kappa and then lambda loci. Thus, Ig clonal composition provides biologically informative data relevant to B cell maturation stage, which here supports classification of B-LLy as a distinct entity from B-ALL. Further, the spectrum of MDD observed in this cohort agnostic of clinical stage suggests that Ig HTS may have novel utility in refining currently limited B-LLy risk stratification by distinguishing select patients who lack measurable disease dissemination or for tracking treatment response via PB HTS. In sum, Ig HTS may have a role in informing therapeutic strategies based on the unique features of B-LLy and in characterizing it as a biologically distinct entity from B-ALL.
Disclosures: Lee: Adaptive Biotechnologies: Current Employment, Other: Equity/share-holder. Wood: Cellnomics LLC: Current equity holder in private company; Amgen: Consultancy. Rau: Servier: Other: Advisory board participation; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory board participation; Abbvie: Other: spouse currently employed. Angiolillo: Servier Pharmaceuticals: Current Employment. Teachey: Jazz: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; BEAM Therapeutics: Research Funding. Allen: Genentech: Research Funding; Electra: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. Hermiston: Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Kirsch: Adaptive Biotechnologies: Current Employment, Other: Equity/share-holder.