Morgan Drucker

Summary: Inotuzumab ozogamicin (InO) is approved by the U.S. Food and Drug Administration (FDA) for relapsed/refractory (R/R) B‐cell acute lymphoblastic leukaemia (B‐ALL), with a standard schedule of 1.8 mg/m ² fractionated into three doses for cycle 1. Alternative dosing with fewer doses or lower cumulative doses may be considered to minimize toxicity or expedite transition to consolidative therapy, though data on the efficacy and toxicity of this approach are limited. We conducted a multi‐institutional retrospective analysis of 72 paediatric, adolescent and young adult (AYA) patients receiving at least one InO dose; 41 with standard dosing and 31 with alternative dosing. Between the two approaches, standard dosing was associated with improved composite complete response (CRc); however, there was no difference in ability to proceed to consolidative cellular therapy, nor differences in 2‐year event‐free or overall survival. Ten per cent of patients experienced sinusoidal obstruction syndrome (SOS), all following haematopoietic stem cell transplant. Most cases occurred in patients receiving standard InO dosing; however, given the overall few cases, it is unclear if this is due to a difference in dosing regimen. In conclusion, this large real‐world study of InO use in the paediatric/AYA R/R B‐ALL population suggests using alternate InO dosing strategies can successfully bridge patients to consolidative therapy with no difference in outcomes compared with standard dosing.

Acute myeloid leukemia (AML) is a multiclonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single-cell molecular profiling and immunophenotyping on 43 samples from 32 patients with NPM1 (nucleophosmin 1)–mutated AML at different time points in disease progression. Here, we show that diagnosis and relapse AML samples display similar clonal architecture patterns, but signaling mutations drive increased clonal complexity, specifically at relapse, which correlates with overall survival. We uncovered unique genotype-immunophenotype relationships regardless of disease state, suggesting leukemic lineage trajectories can be hard-wired by the mutations present. Analysis of longitudinal samples from patients on front-line AML therapy identified dynamic clonal and immunophenotypic changes consistent with the genotype-immunophenotype relationships we identified.