Lineage switch from acute myeloid leukemia to T cell/myeloid mixed phenotype acute leukemia: First report of an adult case
Authors: Brian P. Hanley, Eva Yebra‐Fernandez, Renuka Palanicawandar, Eduardo Olavarria, Kikkeri N. Naresh
Journal: American Journal of Hematology (2018)

Lineage switching in acute leukemia is rare. Majority of cases represent a lineage switch from acute lymphoblastic leukemia (ALL) to acute myeloid leukemia (AML) and tend to occur in children.1 A switch from AML to ALL is very rare, with only a few cases reported in the English literature, all of which are in children.2 A lineage switch from AML to a mixed phenotype acute leukemia (MPAL) is exceptionally rare.3 We report, what we believe is first reported case of a lineage switch from AML to a biphenotypic T cell/myeloid MPAL and the first case of an AML to MPAL switch in an adult patient. At presentation, diagnosis of AML was made on a 52 year old man on peripheral blood and bone marrow examination. He had a white blood cell count (WCC) 17.1 × 109/L with a blast count of 2.6 × 109/L. Bone marrow showed replacement by atypical blastic cells amounting to >80% of the marrow cellularity. Flow cytometry of the bone marrow aspirate showed two abnormal subsets of myeloid immature cells; one was positive for CD34, myeloperoxidase, CD13, CD117, HLADR, CD38, and CD71 (weak) with aberrant expression of CD7 and CD56. The second was CD34 negative and showed partial monocytic differentiation (CD36, CD14, CD64, and CD300e) with a highly asynchronous maturation pattern. The latter population showed CD56 and dim CD33 expression. On the bone marrow trephine biopsy, blasts expressed CD34 (>30%), CD117, myeloperoxidase, CD68R and HLADR (Figure 1). Cytogenetics showed a 46XY karyotype with no KMT2A (11q2;3 probe; Kreatech Diagnostics) rearrangement. There was evidence of mono-allelic CEBPA mutation and no evidence of FLT3 or NPM1 mutations. The diagnosis of acute monoblastic leukemia with a normal karyotype was made. He was treated with the local AML protocol consisting of Cytarabibe 200 mg/m2 × 10 days and Daunorubicin 60 mg/m2 × 3 days and achieved complete remission. He received consolidation with a second course of Cytarbine plus Daunorubicne (8 + 3) and two cycles of high dose Cytarabine (2 g/m2 every 12 h for six doses). After 9 months the patient represented with lethargy and low WCC. Bone marrow biopsy showed relapse of acute leukemia with >30% blasts. On immunophenotyping, blasts expressed CD34, myeloperoxidase, TdT (55%), cyCD3 (55%), CD7, and CD99. There were negative for smCD3, CD5, CD1a, CD19, and CD79a. On immunohistochemistry on the bone marrow trephine biopsy, blasts expressed CD34, CD117, CD3 (>50%), CD7, myeloperoxidase, HLA-DR, WT1 (focally), and TdT. They were negative for PAX5, CD5, TCR-beta, CD2, CD10, and CD68R (Figure 1). There was no evidence of FLT3 or NPM1 mutations. A diagnosis of relapse with mixed phenotype acute leukemia (T cell/myeloid) was made. MPALs account for 2%-4% of acute leukemia depending on the diagnostic criteria used and confer a poorer prognosis as compared to AML or ALL.4 The World health organization (WHO) criteria require expression of lineage specific markers of at least two lineages.4 The WHO classifies two distinct types of MPAL on the basis of genetic signatures; BCR-ABL fusion MPAL and KMT2A translocation MPAL, however recent analyses suggests that MPAL is extremely genetically heterogeneous.5 To our knowledge, this is the first reported case of a lineage switch from AML to MPAL with T cell/myeloid differentiation. Lineage switching is seen in 6%-9% of acute leukemia's at relapse.1 The time to relapse is significantly shortened in patients undergo lineage switching and this is associated with a poor event free survival.1 The question of whether lineage switching represents a recurrence of a highly plastic original clone or the emergence of a new clone/subclone remains unanswered.1 The mechanisms underlying class switching in acute leukemia are incompletely understood, however several hypotheses exist. The first is that the original clone, which is already committed to one lineage, is highly plastic and undergoes an alteration in cell phenotype with or without a change in genotype.1 This could occur directly through a lineage swap or through reactivation of a stem cell programme (transdifferentiation or dedifferentiation respectively).1 The redirection of cell lineage in this case may be established at the level of the individual cell through epigenetic factors or changes in transcription factors and at the level of the cellular environment where changes in transcription factor activity may be induced by extracellular signals.1 Another possible mechanism is that tumors retain oligopotential progenitors (common progenitor model).1 Leukemic transformation may occur in these early progenitors and be influenced by intracellular and extracellular cues.2 The microenvironment of the tumor cells is also likely to play a role, with mouse models of leukemia showing that in vivo manipulation of the cytokine levels influences lineage-restricted and multipotent cells.6Clonal selection is another potential explanation, whereby there may have been multiple neoplastic populations at the index diagnosis and the chemotherapeutic used eradicated the clone that was diagnosed originally, thus allowing the expansion of a subclone with different phenotype. The precise mechanism is incompletely understood and it may be that multiple factors act in unison.