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Lineage switch and relapse in sanctuary site: Some lessons to learn about plasticity in KMT2Ar acute leukemia

To the Editor, Lineage switch is a rare event in childhood acute leukemia, often associated with KMT2A rearrangement (KMT2Ar),1 or occurring after anti-CD19 therapy.2 Lineage switch is characterizedbyan immunophenotypic change with persistence of the same molecular or cytogenetic abnormality. A 15-month-old male child was diagnosed with a nonhyperleukocytic B-cell precursor acute lymphoblastic leukemia (ALL), without central nervous system (CNS) involvement, of pro-B (B-I) immunophenotype (CD19, CD22, CD79a, CD10–, cμ–, sIg–) (Figure S1A,B) without myeloid markers. Cytogenetic analysis by fluorescence in situ hybridization (FISH) revealed an MLL (KMT2A) rearrangement in 61% of the nuclei with loss of the telomeric part of the 11q23-MLL probe. Intensive conventional chemotherapy (CAALLF01; ClinicalTrials.gov NCT02716233) resulted in complete remission, with undetectable minimal residual disease at the end of induction. During maintenance therapy with mercaptopurine and methotrexate, a cytological analysis of bone marrow (BM) aspirate performed because of persistent pancytopenia revealed hypoplasia and 67% ofmyeloblasts. Flow cytometry confirmed a myeloid immunophenotype (CD34–, CD117–, CD33, CD13, CD4, CD15, CD65) without B-lineage markers (Figure S1C,D). Cytogenetic analysis displayed a complex karyotype with the same KMT2Ar by FISH as observed at diagnosis and an 8q trisomy not present at diagnosis, suggesting clonal evolution. Molecular analysis revealed that the emergence of a frameshift mutation of PTEN also absent at diagnosis. Cerebrospinal fluid (CSF) analysis showed 180 blasts/mm3 (100% myeloblasts). Salvage therapy with one cycle of FLA-GO (fludarabine, cytarabine, and gemtuzumab-ozogamicin) led to a second complete remission. Intrathecal chemotherapy with methotrexate and cytarabine cleared CSF blasts. Threeweeks later,while the patientwas still in aplasia, he developed a subconjunctival hemorrhage (Figure 1A) followed by the appearance of a hyphema and divergent strabismus. Slit-lamp examination showed a bulging aspect of the iris in favor of an expansive process of the ciliary bodies associated with hematic liquid in the anterior chamber. This fluid contained myeloblasts (Figures 1B,C) co-expressing CD13 and CD33. Contemporary lumbar puncture and BM aspirate demonstrated a combined myeloid relapse. Molecular analysis retrieved the P-TEN mutation and showed the emergence of subclonal K-RAS and TP53 mutations. Salvage with azacitidine/venetoclax was planned. Unfortunately, the evolution was rapidly unfavorable with the appearance of cutaneous and intrabuccal lesions and the child died before treatment. Extramedullary relapse is common in pediatric ALL,3 involving gonads or the CNS. The latter is satisfactorily prevented by intrathecal chemotherapy and high-dose methotrexate.4 Historically, isolated extramedullary relapses were considered to have a better prognosis than medullary relapses, but recent data seem to challenge this paradigm.4–6 The literature on ophthalmic involvement in acute leukemia is scarce.7–9 However, it seems to be associated with a poor prognosis.8,9 Our case raises the question of a systematic ophthalmologic examination at diagnosis or during follow-up of high-risk AL. The reasons for the persistence of leukemic clones in these so-called “sanctuary” areas are complex and probably explained bymicroenvironmental factors and poor chemotherapy diffusion.10,11 KMT2Ar AL is now identified as a unique entity by the 2016 WHO classification with distinct pathological, immunohistochemical, and clinical features.12 KMT2Ar AL is very common in infants presenting with de novo AL and patients with treatment-related secondary myelodysplastic syndrome or acute myeloblastic leukemia (AML) after exposure to topoisomerase II inhibitors.13 Chromosomal rearrangements of KMT2A occur in 80% of infant ALL and 50% of infant AML.13 More than 100 different KMT2A rearrangements have been identified.14 Breakpoints located in KMT2A intron 11 are associated with infant ALL, whereas breakpoints in intron 9 predominate in older AML patients.15 In ALL, KMT2Ar is associated with CD10 negativity and coexpression of myeloid antigens, suggesting that these leukemias arise from very immature progenitors. In AML, KMT2Ar is frequently associated with monocytic differentiation. Indeed, in the case reported here, the myeloid blasts had lost CD34 and CD117 but expressed CD4, suggesting engagement in the monocytic lineage. More rarely, KMT2Ar may present with an ambiguous lineage, either due to a mixed phenotype or undifferentiated acute leukemia.16 Most KMT2Ar are associated with a poor prognosis in infant AL, while very few such as t(1;11)(q21;q23) KMT2A/MLLT11 have a good or intermediate outcome.15,17,18 In AML, the prognosis of KMT2Ar seems less unfavorable.17 Lineage switch is a rare event in the evolution of pediatric acute leukemia, which is known to be associated with a dismal prognosis.1 The pathophysiology of lineage switch remains unclear and several hypotheses have been formulated: therapeutic pressure leading to the selection of a subclone of a different lineage already present at diagnosis, reprogramming of a leukemic pluripotent stem cell, and