Post-Immunotherapy Lineage Switch in Acute Leukemia Free

The majority of acute leukemias are classified by their unique lineage, namely lymphoid or myeloid. Uncommonly, an acute leukemia cannot be assigned to a single lineage and is termed “acute leukemia of ambiguous lineage,” a category further subdivided as outlined in the figure. Definitions for lymphoid, myeloid, and ambiguous or mixed-lineage have evolved over time, with current definitions relying on flow cytometry.¹  Accurate lineage assignment by multiparametric flow cytometry requires appropriate assay development, validation by the flow cytometry laboratory, and sophisticated interpretation by pathologists. The two current classification systems (the fifth edition of the World Health Organization’s WHO Classification of Tumours: Haematolymphoid Tumours and The International Consensus Classification of Myeloid and Lymphoid Neoplasms) contain subtle but important differences in lineage marker interpretation.^2,3 

Transformation of an acute leukemia from one lineage to another while maintaining the cytogenetic and/or molecular markers of the original diagnosis, termed lineage switch, is rare. While reports of relapsed acute leukemia with lineage switch date back more than 40 years,⁴  increased immunotherapy use appears to be associated with increased lineage switch incidence. Lineage switch may be due to clonal evolution of leukemic progenitor cells with lineage plasticity, direct reprogramming or dedifferentiation of leukemic blasts, or expansion/emergence of a previously undetected different lineage clone.⁵ 

In a multicenter study led by National Institutes of Health investigators Sara K. Silbert, MD, MHSc, and Nirali N. Shah, MD, MHSc, 92 potential cases of lineage switch following antigen-targeted immunotherapy were submitted from 43 institutions/groups across eight countries. Of the submitted cases, 75 met study criteria for lineage switch, the majority involving patients with B-cell acute lymphoblastic leukemia (B-ALL) who experienced lineage switch to acute myeloid leukemia (AML, 53/75, 71%) or B-cell/myeloid mixed-phenotype acute leukemia (MPAL, 17/75, 23%) (Table). The remaining five cases represented rare lineage switch immunophenotypes (three cases of T-cell acute lymphoblastic leukemia to AML, one case of B-ALL to T-cell/myeloid MPAL, and one case of B-ALL to plasmablastic lymphoma).

Of those who experienced lineage switch from B-ALL to AML or B-cell/myeloid MPAL, KMT2A rearrangement was the most common B-ALL cytogenetic abnormality (64.3%), with the vast majority of patients (98.6%) receiving prior CD19 targeting and most cases (81.4%) presenting within six months of the most proximal immunotherapy. Treatment of the lineage switch was variable, most commonly constituting an AML-induction type chemotherapy-based regimen or the incorporation of gemtuzumab. Of the 69 patients with follow-up, 88% were deceased at last follow-up, with a 4.8-month median overall survival following lineage switch diagnosis. The most common cause of death was progressive/refractory lineage switch.