Near-Tetraploidy in Childhood Acute Lymphoblastic Leukemias Does Not Adversely Affect Prognosis: An EGIL Retrospective Study On 36 Cases Petr Lemez, Andishe Attarbaschi, Marie-Christine Bene, Yves Bertrand, Gian-Luigi Castoldi, Erik Forestier, Richard Garand, Oskar A. Haas, Emmanuelle Homolle, Sandrine Kagialis-Girard, Wolf-Dieter Ludwig, Estella Matutes, Marie-Pierre Pages, Winfried Pickl, Anna Porwit, Alberto Orfao, Jan Stary, Herbert Strobl, Pascaline Talmant, Mars B. Van't Veer, Zuzana Zemanova, for the European Group for the Immunological Characterization of Leukaemias (EGIL). (Introduced by Jaroslav Jelinek) Dept. of Hematology, Hosp. Jihlava, Jihlava, Czech Rep.
Authors: Lemez Petr 
Published: October 2019

Abstract
Abstract 1585
Poster Board I-611
The first larger study on near-tetraploid (metaphases with 80∼104 chromosomes) acute lymphoblastic leukemias (NT-ALL) described 20 children: 9 of the T-lineage (T-ALL) and 11 of the B-cell precursors (BCP-ALL), and concluded that: “NT-ALL represented a unique subgroup of ALL, characterized by preponderance of T-cell immunophenotype, specific morphologic features, and possibly a poorer prognosis” (Pui et al, Blood 1990;76:590). The aim of our study was to enlarge the limited knowledge on these rarely occurring NT-ALL. The EGIL collected retrospectively laboratory and clinical data of 36 children (under the age of 18 years) with NT-ALL from 6 European countries diagnosed and treated in international studies between 1992 and 2008. Bone marrow blasts of all 36 children were negative for peroxidase. Immunophenotyping of leukemic blasts showed that 10 cases were diagnosed as T-ALL and 26 cases as BCP-ALL. In 4 cases aberrant near-diploid metaphases were simultaneously present. At least a single normal metaphase was found in 27 cases. Leukemic blasts of all patients were BCR/ABL1 negative. T-ALL was diagnosed in 7 boys and three girls of a median age 11.9 (3.6 – 17.5) years. CNS infiltration was found in one child. Heterogeneity of NT-T-ALL cases was apparent with immunophenotyping because they belonged to all 4 EGIL categories: TI or TII were each diagnosed in two cases; TIII or TIV each in three cases. Their blasts were negative for HLA-DR in all 10 cases and for CD34 in all 6 examined cases. Cytogenetic examinations revealed different structural abnormalities in 6 cases. All 10 cases achieved complete remission (CR) after induction chemotherapy and 8 are remaining in the 1st CR, exhibiting event-free survival (EFS) 80 % with a median follow-up of 37+ months. One case died of septic shock in pancytopenia after his 3rd consolidation therapy and survived only 7 months. Another case relapsed in the bone marrow and maxilla after 25 months. He reached the 2nd CR with chemotherapy and is alive after unrelated HLA-identical stem cell transplantation (SCT) for 14 months. Survival of NT-T-ALL cases has been favorable - 90 % with a median of 41 (7-120) months. NT-BCP-ALL was further divided according to the cytogenetic and molecular results into 4 categories. ETV6/RUNX1 positive BCP-ALL was diagnosed in 7 boys and 5 girls with a median age of 7.0 (3.3-15.5) years. Immunophenotyping of bone marrow blasts lead to the diagnosis of EGIL categories BII in 10 cases and BIII in two. Blasts from all cases were positive for HLA-DR and for CD34 in 8 of 9 cases. All these 12 cases have achieved CR after induction chemotherapy and are alive in the 1st CR for 18-147 (median 65) months. Twelve cases of ETV6/RUNX1 negative BCP-ALL fall to at least two categories: two cases exhibited simultaneously hypodiploid metaphases with NT ones, 10 cases had only NT metaphases. These 10 cases were 6 boys and 4 girls with a median age of 9.5 (4.4-14.5) years and WBC 0.9-13.0 × 109/l. Immunophenotyping of blasts established the diagnosis of BII in 9 cases and BIII in one. All tested cases were positive for HLA-DR and CD34, three expressed CD2 antigen. All these cases reached CR after induction chemotherapy and are remaining in the 1st CR for 12-155 (median 73) months. Hypodiploid ETV6/RUNX1 negative BII BCP-ALL was diagnosed in two girls. One with a karyotype of 44 chromosomes relapsed after 37 months and died of infection in the 2nd CR after unrelated allogeneic SCT. The other with 45 chromosomes reached CR and is remaining in CR for 7 months. Leukemic blasts of two boys, 9.5 year-old, with BII NT-BCP-ALL were not examined for ETV6/RUNX1. One is in the 1st CR for 82 months. Another relapsed twice after 6 and 11 years. He underwent cord blood SCT in the 3rd CR and died 2.5 months later of cerebral toxoplasmosis. In summary, our data show immunophenotypic, cytogenetic, and molecular heterogeneity of childhood NT-ALL. In contrast to previous reports, we observed favorable prognosis of NT-ALL patients after current more intensive induction and consolidation chemotherapy. Near-tetraploidy did not deteriorate prognosis of childhood NT-ALL cases across different immunophenotypic, cytogenetic and molecular ALL types.
Supported by grants MSM0021620813, MZOVFN2005.

Disclosures
No relevant conflicts of interest to declare.