BACKGROUND: Mixed phenotype acute leukemia (MPAL) represents a diagnostic and therapeutic dilemma. The European Group for the Immunological Classification of Leukemias (EGIL) scoring system unambiguously defines MPAL expressing aberrant lineage markers. Discussions surrounding it have focused on scoring details, and information is limited regarding its biological, clinical and prognostic significance. The recent World Health Organization classification is simpler and could replace the EGIL scoring system after transformation into unambiguous guidelines. DESIGN AND METHODS: Simple immunophenotypic criteria were used to classify all cases of childhood acute leukemia in order to provide therapy directed against acute lymphoblastic leukemia or acute myeloid leukemia. Prognosis, genotype and immunoglobulin/T-cell receptor gene rearrangement status were analyzed. RESULTS: The incidences of MPAL were 28/582 and 4/107 for children treated with acute lymphoblastic leukemia and acute myeloid leukemia regimens, respectively. In immunophenotypic principal component analysis, MPAL treated as T-cell acute lymphoblastic leukemia clustered between cases of non-mixed T-cell acute lymphoblastic leukemia and acute myeloid leukemia, while other MPAL cases were included in the respective non-mixed B-cell progenitor acute lymphoblastic leukemia or acute myeloid leukemia clusters. Analogously, immunoglobulin/T-cell receptor gene rearrangements followed the expected pattern in patients treated as having acute myeloid leukemia (non-rearranged, 4/4) or as having B-cell progenitor acute lymphoblastic leukemia (rearranged, 20/20), but were missing in 3/5 analyzed cases of MPAL treated as having T-cell acute lymphobastic leukemia. In patients who received acute lymphoblastic leukemia treatment, the 5-year event-free survival of the MPAL cases was worse than that of the non-mixed cases (53+/-10% and 76+/-2% at 5 years, respectively, P=0.0075), with a more pronounced difference among B lineage cases. The small numbers of MPAL cases treated as T-cell acute lymphoblastic leukemia or as acute myeloid leukemia hampered separate statistics. We compared prognosis of all subsets with the prognosis of previously published cohorts. CONCLUSIONS: Simple immunophenotypic criteria are useful for therapy decisions in MPAL. In B lineage leukemia, MPAL confers poorer prognosis. However, our data do not justify a preferential use of current acute myeloid leukemia-based therapy in MPAL.

CLIP Childhood Leukemia Investigation Prague Department of Pediatric Hematology and Oncology Charles University 2ndFaculty of Medicine and University Hospital Motol Prague Czech Republic

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Rubnitz JE, Onciu M, Pounds S, Shurtleff S, Cao X, Raimondi SC, et al. Acute mixed lineage leukemia in children: the experience of St. Jude Children's Research Hospital. Blood. 2009;113(21):5083–9. PubMed PMC

Weir EG, Ali Ansari-Lari M, Batista DA, Griffin CA, Fuller S, Smith BD, et al. Acute bilineal leukemia: a rare disease with poor outcome. Leukemia. 2007;21(11):2264–70. PubMed

Bierings M, Szczepanski T, van Wering ER, Willemse MJ, Langerak AW, Revesz T, et al. Two consecutive immunophenotypic switches in a child with immunogenotypically stable acute leukaemia. Br J Haematol. 2001;113(3):757–62. PubMed

Krawczuk-Rybak M, Zak J, Jaworowska B. A lineage switch from AML to ALL with persistent translocation t(4;11) in congenital leukemia. Med Pediatr Oncol. 2003;41(1):95–6. PubMed

Killick S, Matutes E, Powles RL, Hamblin M, Swansbury J, Treleaven JG, et al. Outcome of biphenotypic acute leukemia. Haematologica. 1999;84(8):699–706. PubMed

Matutes E, Morilla R, Farahat N, Carbonell F, Swansbury J, Dyer M, et al. Definition of acute biphenotypic leukemia. Haematologica. 1997;82(1):64–6. PubMed

Owaidah TM, Al Beihany A, Iqbal MA, Elkum N, Roberts GT. Cytogenetics, molecular and ultrastructural characteristics of biphenotypic acute leukemia identified by the EGIL scoring system. Leukemia. 2006;20(4):620–6. PubMed

Lo Coco F. Hybrid phenotypes and lineage promiscuity in acute leukemia. Haematologica. 1991;76(3):215–25. PubMed

Hrusak O, Porwit-MacDonald A. Antigen expression patterns reflecting genotype of acute leukemias. Leukemia. 2002;16(7):1233–58. PubMed

Mejstrikova E, Kalina T, Trka J, Stary J, Hrusak O. Correlation of CD33 with poorer prognosis in childhood ALL implicates a potential of anti-CD33 frontline therapy. Leukemia. 2005;19(6):1092–4. PubMed

Kalina T, Vaskova M, Mejstrikova E, Madzo J, Trka J, Stary J, et al. Myeloid antigens in childhood lymphoblastic leukemia: clinical data point to regulation of CD66c distinct from other myeloid antigens. BMC Cancer. 2005;5(1):38. PubMed PMC

Bene MC, Bernier M, Casasnovas RO, Castoldi G, Knapp W, Lanza F, et al. The reliability and specificity of c-kit for the diagnosis of acute myeloid leukemias and undifferentiated leukemias. The European Group for the Immunological Classification of Leukemias (EGIL) Blood. 1998;92(2):596–9. PubMed

Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A, et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL) Leukemia. 1995;9(10):1783–6. PubMed

Campana D, Behm FG. Immunophenotyping of leukemia. J Immunol Methods. 2000;243(1–2):59–75. PubMed

Borowitz MJ, Chan JKC. T lymphoblastic leukemia/lymphoma. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Geneva: WHO Press; 2008. pp. 176–8.

Borowitz MJ, Chan JKC. B lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Geneva: WHO Press; 2008. pp. 171–5.

Borowitz MJ, Chan JKC. B lymphoblastic leukaemia/lymphoma, not otherwise specified. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Geneva: WHO Press; 2008. pp. 168–70.

Borowitz MJ, Béné M-C, Harris NL, Porwit A, Matutes E. Acute leukemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., editors. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Geneva: WHO Press; 2008. pp. 150–1.

Szczepanski T, Beishuizen A, Pongers-Willemse MJ, Hahlen K, Van Wering ER, Wijkhuijs AJ, et al. Cross-lineage T cell receptor gene rearrangements occur in more than ninety percent of childhood precursor-B acute lymphoblastic leukemias: alternative PCR targets for detection of minimal residual disease. Leukemia. 1999;13(2):196–205. PubMed

Wright S, Chucrallah A, Chong YY, Kantarjian H, Keating M, Albitar M. Acute lymphoblastic leukemia with myeloperoxidase activity. Am J Hematol. 1996;51(2):147–51. PubMed

Rytting ME, Kantarjian H, Albitar M. Acute lymphoblastic leukemia with Burkittlike morphologic features and high myeloperoxidase activity. Am J Clin Pathol. 2009;132(2):182–5. quiz 306. PubMed

Krejci O, Prouzova Z, Horvath O, Trka J, Hrusak O. Cutting edge: TCR delta gene is frequently rearranged in adult B lymphocytes. J Immunol. 2003;171(2):524–7. PubMed

Fronkova E, Krejci O, Kalina T, Horvath O, Trka J, Hrusak O. Lymphoid differentiation pathways can be traced by TCR delta rearrangements. J Immunol. 2005;175(4):2495–500. PubMed

Zuna J, Krejci O, Madzo J, Fronkova E, Sramkova L, Hrusak O, et al. TEL/AML1 and immunoreceptor gene rearrangements-which comes first? Leuk Res. 2005;29(6):633–9. PubMed

Boeckx N, Willemse MJ, Szczepanski T, van der Velden VH, Langerak AW, Vandekerckhove P, et al. Fusion gene transcripts and Ig/TCR gene rearrangements are complementary but infrequent targets for PCR-based detection of minimal residual disease in acute myeloid leukemia. Leukemia. 2002;16(3):368–75. PubMed

Szczepanski T, van der Velden VH, Raff T, Jacobs DC, van Wering ER, Bruggemann M, et al. Comparative analysis of T-cell receptor gene rearrangements at diagnosis and relapse of T-cell acute lymphoblastic leukemia (T-ALL) shows high stability of clonal markers for monitoring of minimal residual disease and reveals the occurrence of second T-ALL. Leukemia. 2003;17(11):2149–56. PubMed

Paietta E, Ferrando AA, Neuberg D, Bennett JM, Racevskis J, Lazarus H, et al. Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. Blood. 2004;104(2):558–60. PubMed

Van Vlierberghe P, Meijerink JP, Stam RW, van der Smissen W, van Wering ER, Beverloo HB, et al. Activating FLT3 mutations in CD4+/CD8- pediatric T-cell acute lymphoblastic leukemias. Blood. 2005;106 (13):4414–5. PubMed

Wakabayashi Y, Watanabe H, Inoue J, Takeda N, Sakata J, Mishima Y, et al. Bcl11b is required for differentiation and survival of alphabeta T lymphocytes. Nat Immunol. 2003;4(6):533–9. PubMed

MacLeod RA, Nagel S, Drexler HG. BCL11B rearrangements probably target T-cell neoplasia rather than acute myelocytic leukemia. Cancer Genet Cytogenet. 2004;153(1):88–9. PubMed

Strehl S, Nebral K, Konig M, Harbott J, Strobl H, Ratei R, et al. ETV6-NCOA2: a novel fusion gene in acute leukemia associated with coexpression of T-lymphoid and myeloid markers and frequent NOTCH1 mutations. Clin Cancer Res. 2008;14(4):977–83. PubMed

Nachman J. Apples and oranges: mixed lineage acute leukemia. Blood. 2009;113(21):5036. PubMed

Baruchel A, Cayuela JM, Ballerini P, Landman-Parker J, Cezard V, Firat H, et al. The majority of myeloid-antigen-positive (My+) childhood B-cell precursor acute lymphoblastic leukaemias express TEL-AML1 fusion transcripts. Br J Haematol. 1997;99(1):101–6. PubMed

Stams WA, Beverloo HB, den Boer ML, de Menezes RX, Stigter RL, van Drunen E, et al. Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome. Leukemia. 2006;20(3):410–6. PubMed

Loh ML, Goldwasser MA, Silverman LB, Poon WM, Vattikuti S, Cardoso A, et al. Prospective analysis of TEL/AML1-positive patients treated on Dana-Farber Cancer Institute Consortium Protocol 95–01. Blood. 2006;107(11):4508–13. PubMed PMC

Xu XQ, Wang JM, Lu SQ, Chen L, Yang JM, Zhang WP, et al. Clinical and biological characteristics of adult biphenotypic acute leukemia in comparison with that of acute myeloid leukemia and acute lymphoblastic leukemia: a case series of a Chinese population. Haematologica. 2009;94(7):919–27. PubMed PMC

Mejstrikova E, Fronkova E, Kalina T, Omelka M, Batinic D, Dubravcic K, et al. Detection of residual B precursor lymphoblastic leukemia by uniform gating flow cytometry. Pediatr Blood Cancer. 2010;54(1):62–70. PubMed

Behm FG. Immunophenotyping. In: Pui CH, editor. Childhood Leukemias. Cambridge: Cambridge University Press; 2006. pp. 150–209.

Hasle H. Myelodysplastic and myeloproliferative disorders in children. Curr Opin Pediatr. 2007;19(1):1–8. PubMed

DUX4r, ZNF384r and PAX5-P80R mutated B-cell precursor acute lymphoblastic leukemia frequently undergo monocytic switch

Automated identification of leukocyte subsets improves standardization of database-guided expert-supervised diagnostic orientation in acute leukemia: a EuroFlow study

Automated database-guided expert-supervised orientation for immunophenotypic diagnosis and classification of acute leukemia

CEBPE-Mutant Specific Granule Deficiency Correlates With Aberrant Granule Organization and Substantial Proteome Alterations in Neutrophils

Recent advances in the management of pediatric acute lymphoblastic leukemia

High-resolution Antibody Array Analysis of Childhood Acute Leukemia Cells

CD2-positive B-cell precursor acute lymphoblastic leukemia with an early switch to the monocytic lineage