CASE 205 Denyo Adjoa Zakhia, MD Kristin Hunt Karner, MD Henry Ford Hospital, Detroit, MI

CLINICAL HISTORY 61 year-old Caucasian male Cough, night sweats, low-grade fever Complete blood count Hemoglobin – 9.4 gm/dl White blood cell count – 71.1 K/uL Platelet count – 135 K/uL Peripheral blood smear Leukocytosis with 79% blasts

BONE BIOPSY BONE MARROW ASPIRATE Cellularity ->95% Blasts-87% H&E CD1a

FLOW CYTOMETRY cyto CD3

FLOW CYTOMETRY SUMMARY Positive antigen panel Negative antigen panel cytoCD3 cytoTDT CD2 CD7 CD13 CD15 CD34 CD117 HLA-DR CD3 CD4 CD8 CD5 CD10 CD11b CD14 CD16 CD33 CD56 CD61 CD235a cytoCD79a cytoMPO

CHROMOSOMAL ANALYSIS OF BONE MARROW ASPIRATE 46,XY,del(16)(q13)[6]/46,XY[14] FISH ANALYSIS No genetic abnormalities involving: MYC(8q24) BCL6(3q27) IGH-BCL2(14:18) API2-MALT1(11:18) BCR-ABL(9:22) MLL (11q23) Inv 16

WHAT IS THE DIAGNOSIS? EGIL WHO

Mixed phenotype acute leukemia, favor T/myeloid EGIL T-lineage: Score 3.5 Myeloid: Score 2.5 Mixed phenotype acute leukemia, favor T/myeloid

Acute leukemia of T-cell Lineage with aberrant myeloid differentiation WHO table (criteria) Myeloid lineage Myeloperoxidase (flow cytometry, immunohistochemistry or cytochemistry) Or Monocytic differentiation (at least too of NSE, CD11c, CD14, CD64, lysozyme) T lineage Cytoplasmic CD3 or Surface CD3 B lineage Strong CD19 with at least one of the following strongly expressed (CD79a, cytoplasmic CD22, CD10) Or Weak CD19 with at least two of the following strongly expressed (CD79a, cytoplasmic CD22, CD10) Acute leukemia of T-cell Lineage with aberrant myeloid differentiation

PANEL CONSENSUS DIAGNOSIS INITIAL PROPOSED DIAGNOSIS Mixed phenotype acute leukemia, favor T/myeloid Acute leukemia of T-cell Lineage with aberrant myeloid differentiation PANEL CONSENSUS DIAGNOSIS EARLY T-CELL PRECURSOR ALL with MYELOID ANTIGEN EXPRESSION

NEED FOR A CONSENSUS IN THE CLASSIFICATION SYSTEM Provide appropriate treatment Provide appropriate prognostication

Treatment and Outcome Hyper CVAD therapy Matched unrelated donor stem cell transplant Complications DVT New diagnosis of Hepatitis C infection Clostridium difficile colitis Reactivation of EBV and BK virus Subdural hemorrhage Patient in remission at day 116+ s/p SCT

IMMUNOPHENOTYPE (Adapted from WHO 2008) CD7 CD1a CD2/CD5 CD3 Cytoplasmic | Surface CD4/CD8 CD4+ CD8+ Double + TdT T-ALL Mature T-ALL/LBL can be stratified into different stages of intra-thymic differentiation according to antigens co-expressed Pro T-ALL cCD3, CD7 + CD2-, CD1a-, cd34+/- Pre-T Ccd3+, cd7+, cd2+ Cd1a- Cd34+/- Cortical T Cd3+, cd7+, cd2+, cd1a+, Cd34- Medullary Cd3+, cd7+, cd2+, surface cd3+ Cd1a-, cd34-, Cd4 and cd8 double negative in pro and pre-T Cd4 and cd8 co-expression in cortical T Cd4/cd8 either expression in medullary Early

COMMON DIAGNOSTIC FEATURES OF EARLY T-CELL PRECURSOR ALL (ETP-ALL) Comprises 85-90% of all lymphoblastic lymphoma Adolescents > Younger children 15% pediatric ALL 25% adult ALL Presentation: Mediastinal mass with pleura effusions Bone marrow involvement if present <20% High peripheral blood blast counts

CLINICAL SIGNIFICANCE OF ETP-ALL Clinical, laboratory and biologic characteristics not useful in prognostication HIGH RISK INDUCTION FAILURE EARLY RELAPSE CNS RELAPSE Children treated as high risk 75% 5 yr-event free survival rate (similar to pre B-ALL/LBL) The presence of minimal residual disease following therapy is a strong adverse prognostic indicator.

DOES MYELOID ANTIGEN EXPRESSION OFFER ANY CLINICAL SIGNIFICANCE? Asnafi et al CD13 and CD33 most frequently expressed myeloid-associated antigens 15% of 91 cases reviewed MPO – negative or very rarely <3% CD13/Cd33 expression seen in 19 – 32 5 of T-ALL/LBL Presence of myeloid markers does not indicate MPAL or exclude diagnosis of T-ALL

Uckun et al Not an adverse prognostic factor in childhood ALL

Evaluated c-kit expression in 295 ALL patients and in 977 AML patients T- ALL, 5.4 % expressed c-kit In AML 84% expressed c-kit Concluded High c-kit expression is an independent predictor of Lower complete response in ALL Higher complete response in AML Not an independent predictor of disease free survival in ALL or AML T-ALL may benefit from AML type therapy

Improved survival rates Normal karyotype T(10:14)(q24:q11) HOX11:TCRα Overexpression of HOX11 gene

THANK YOU QUESTIONS???

REFERENCES Goldberg JM, Silverman LB, Levy DE, et al. Childhood T-cell acute lymphoblastic leukemia: the Dana- Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol. 2003;21:3616- 3622. Onciu M, Lai R, Vega F, et al. Precursor T-cell acute lymphoblastic leukemia in adults: age-related immunophenotypic, cytogenetic, and molecular subsets. Am J Clin Pathol. 2002;117:252-258. Brunning R, Borowitz M, Matutes E, et al. Precursor B-cell and T-cell neoplasms. In: Jaffe ES, Harris NL, Stein H, et al, eds. Pathology and Genetics of Tumors of Hematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2001:109-117. World Health Organization Classification of Tumors. Thalhammer-Scherrer R, Mitterbauer G, Simonitsch I, et al. The immunophenotype of 325 adult acute leukemias’: relationship to morphologic and molecular classification and proposal for a minimal screening program highly predictive for lineage discrimination. Am J Clin Pathol. 2002;117:380-389. Asnafi V, Beldjord K, Libura M, et al. Age-related phenotypic and oncogenic differences in T-cell acute lymphoblastic leukemias may reflect thymic atrophy. Blood. 2004;104:4173-4180. Asnafi V, Buzyn A, Thomas X, et al. Impact of TCR status and genotype on outcome in adult T-cell acute lymphoblastic leukemia: a LALA-94 study. Blood. 2005;105:3072-3078. Uckun FM, Sather HN, Gaynon PS, et al. Clinical feature and treatment outcome of children with myeloid antigen positive acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood. 1997;90:28-35. Tsao AS, Kantarjian H, Thomas D, et al. C-kit receptor expression in acute leukemias: association with patient and disease characteristics and with outcome. Leuk Res. 2004;28:373-378. Ferrando AA, Neuberg DS, Dodge RK, et al. Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia. Lancet. 2004;363:535-536. Schneider NR, Carroll AJ, Shuster JJ, et al. New recurring cytogenetic abnormalities and association of blast cell karyotypes with prognosis in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group report of 343 cases. Blood. 2000;96:2543-2549. X Han, CE Bueso-Ramos. Precursor T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma and acute biphenotypic leukemias. Am J of clin pathol 2007;127:528-544. Bene MC, Bernier RO, Casasnovas G, et al. The reliability and specificity of c-kit for the diagnosis of acute myeloid Leukemias and Undifferentiated leukemias. Blood 1998;15:596-599.