Understanding the Ontogeny of Our Tiniest Patients With Leukemia

Infants with B-acute lymphoblastic leukemia (ALL) who are diagnosed at younger than 12 months experience extremely poor clinical outcomes with high rates of on-therapy relapse and event-free survival (EFS) less than 40 percent despite use of maximally intensive multiagent chemotherapy regimens.^1,2  The majority of infant ALL cases (~80 percent) are arrested at an early pro-B cell stage, harbor KMT2A rearrangements with one or more than 130 identified translocation partners, and are characterized by lymphoid/myeloid lineage plasticity.^3-5  Recent clinical studies have interestingly suggested that the clinical response of infants with KMT2A-rearranged ALL to induction chemotherapy, as assessed by the absence or presence of measurable residual disease (MRD), can stratify patients into two cohorts who better benefit from lymphoid-directed versus myeloid-directed postinduction therapy.⁶ 

A recent comprehensive meta-analysis of bulk transcriptomic data from more than 1,600 cases of childhood ALL and acute myeloid leukemia (AML) performed by Dr. Eleonora Khabirova and colleagues⁷  identified an early lymphocyte precursor (ELP) fetal-like state as the predominant signature within KMT2A-rearranged infant ALL cells. Despite the genetic heterogeneity within KMT2A-rearranged infant ALL, the ELP state appeared universal across all fusion partner subtypes assessed, with the strongest signature detected in the most common and worst prognosis KMT2A-AFF1 cohort. Interestingly, a major ELP state was also identified in KMT2A-rearranged ALL cases occurring in older children that tend to be associated with higher, but still inferior, EFS.⁸  More detailed single-cell RNA-sequencing analysis of KMT2A-rearranged and –non-rearranged infant ALL cases in comparison to normal fetal bone marrow cells confirmed ELP cells as the major signal at diagnosis and relapse within KMT2A-rearranged ALL cells, while more mature non-ELP signals comprised the majority of KMT2A– non-rearranged ALL cells. To elucidate the phylogenetic origin of infant ALL, and postulate based upon additional computational modeling that this primitive leukemogenesis occurs during early embryonic development prior to hematopoietic cell specification, the investigators also performed whole-genome DNA sequencing of ALL, AML, lineage-switch KMT2A-rearranged ALL-to-AML, and remission bone marrow cells. Finally, Dr. Khabirova and her team assessed differential gene expression of known and predicted cell surface antigens and identified numerous nonphysiologic target antigen pairings within infant ALL cells that may be amenable in future studies to immunotherapeutic targeting — an approach of great clinical interest given high rates of chemoresistance in this high-risk patient population.

A parallel single-cell multi-omics analysis of KMT2A-rearranged ALL reported by Dr. Changya Chen and colleagues⁹  also identified a critical primitive hematopoietic stem and progenitor cell–like signature within KMT2A-reararnged ALL cells. Using single-cell RNA-sequencing and chromatin accessibility assays, they detected significantly increased lineage plasticity with aberrant coexpression of B-lymphoid and myeloid genes in KMT2A-rearranged ALL cells from infants younger than six months at diagnosis. Interestingly, these patients’ ALL cells showed decreased expression of genes associated with steroid responsiveness, which likely contributes to higher rates of chemotherapy resistance and early relapse that may be associated with a lymphoid-to-myeloid lineage switch.¹⁰  Finally, the investigators identified immunosuppressive interferon-γ response signatures within primitive CD34+ CD19- KMT2A-rearranged cells that appear resistant to endogenous natural killer cell–mediated cytotoxicity and may contribute to failure of hematopoietic stem cell transplantation in patients.

Taken together, these two important studies provide a fine and detailed lens into the developmental origins of KMT2A-rearranged infant ALL and provide new understanding regarding its inherent biologic primitivity and plasticity that engenders conventional chemoresistance. Modern therapeutic approaches are already tailoring risk- and response-adapted chemotherapy strategies for infants with ALL and have recently shown superior benefit of myeloid-directed postinduction regimens for patients with MRD positivity after lymphoid-directed induction therapy.^6,11  Current and soon-to-open trials are further exploring the application of CD19-targeted immunotherapies, including blinatumomab and CD19 chimeric antigen receptor T cells (CAR-Ts), for infants with KMT2A-rearranged ALL.^12,13  Recent preclinical and clinical studies have also demonstrated encouraging activity of other precision medicine approaches such as FLT3 inhibitors, FLT3 bispecific antibodies, or FLT3 CAR-Ts (given known wild-type FLT3 overexpression in KMT2A-rearranged ALL), azacytidine and venetoclax, and menin inhibitors.^14-18  Although infants with ALL are small, their successful cure remains a mighty unmet medical need.