Lineage switch in childhood acute leukemia: An unusual event with poor outcome

Abstract

Although rarely, switches between lymphoid and myeloid lineages may occur during treatment of acute leukemias (AL). Correct diagnosis relies upon confirmation by immunophenotyping of the lineage conversion and certification that the same cytogenetic/molecular alterations remain despite the phenotypic changes. From a total of 1,482 AL pediatric patients, we report nine cases of lineage conversion (0.6%), seven from lymphoid (four Pro-B, two Pre-B, one Common) to myelo-monocytic, and two from myeloid (bilineal, with myeloid predominance) to Pro-B. Eight patients were infants. Switches were suggested by morphology and confirmed with a median of 15 days (range: 8 days-6 months) from initiation of therapy. Of note, in five cases switches occurred before day 15. Stability of the clonal abnormalities was assessed by cytogenetic, RT-PCR/Ig-TCR rearrangement studies in all patients. Abnormalities in 11q23/MLL gene were detected in seven cases. Treatment schedules were ALL (two pts), Interfant-99 (five pts) and AML (two pts) protocols. Despite changing chemotherapy according to the new lineage, all patients died. Our findings support the association of lineage switches with MLL gene alterations and the involvement of a common lymphoid B-myeloid precursor. New therapies should be designed to address these rare cases. Possible mechanisms implicated are discussed. Am. J. Hematol. 87:890-897, 2012. V

Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy

“…10,11 Transition from a lymphoid to myeloid phenotype has been reported after intensive chemotherapy and HCT, but this study is the first to identify acquisition of a clonally related myeloid phenotype associated with CD19-negative escape after CD19 CAR-T-cell immunotherapy. Of the 7 patients who received CD19 CAR-T cell therapy for MLL-B-ALL, we identified 2 in whom the relapsed leukemia had lost expression of lymphoid B-lineage antigens, including CD19, and acquired expression of myeloid antigens.…”

The full transforming capacity of MLL-Af4 is interlinked with lymphoid lineage commitment

“…20 The ALL-to-AML switch can also be induced by chemotherapy and is usually associated with poor outcome. 5 Acquisition of additional genetic events enhancing the self-renewal program may give rise to the occasional MLL-Af4 AML in our model and t(4;11) AML in patients. Future investigation of our MLL-Af4 AML may help to identify critical cooperating factors driving the myeloid transition and potential therapeutic targets for this poor-outcome disease (or for preventing escape from CD19-directed therapy).…”

“…3,4 Lineage plasticity has been reported for MLL-fusion patients. 4,5 Understanding how MLL-fusion leukemia makes lineage decisions could improve disease treatment. Lineage association of MLL-fusion leukemia is influenced by the fusion partner.…”

Ostra białaczka o mieszanym fenotypie – jak rozpoznać, jak leczyć?

“…Zabieg ten należy planować również u pacjentów z lineage switch w trakcie intensywnego leczenia, którzy rokują najgorzej z całej grupy białaczek o niejednoznacznym fenotypie [34]. U dzieci z MPAL rekomenduje się zastosowanie megachemioterapii w przygotowaniu do allo-HSCT.…”