Childhood Secondary ALL after ALL Treatment.
Authors: Zuna Jan , Eckert Cornelia , Cavé Hélène , Meyer Claus , Schneider Björn , Fronkova Eva , Muzikova Katerina , Mendelova Denisa , Boutard Patrick , Schrauder André , Sterba Jaroslav , Marschalek Rolf , Stary Jan , Trka Jan 
Published: April 2020

Abstract
Data on secondary acute lymphoblastic leukaemia (sALL) following ALL treatment are very rare. To our knowledge only 8 such cases have been described so far - 6 and 2 with late developing t(9;22) and t(4;11), respectively. Recently, the extensive examination of immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements for the purposes of residual disease monitoring brought a new tool that can help in discrimination between real relapse and sALL clonally unrelated to the original disease. In our study we analysed 276 relapses of patients treated according to BFM-based protocols and examined in 3 centres (Prague, Berlin, Paris). We found 5 cases where the second malignancy is highly suspicious of being sALL rather than relapse. Our basal criteria for selection of the patients were (A) completely unrelated Ig/TCR rearrangements between presentation and relapse or (B) gain or loss of a leukaemo-specific fusion gene or (C) significant immunophenotypic switch. Basic patients characteristics are summarised in the table below. In two cases an MLL gene rearrangement appeared at the time of “relapse” with MLL/ENL and MAML2/MLL fusion genes, respectively. The MAML2 at 11q21 is a new fusion partner of the MLL gene not described previously. ALL is the most common childhood malignancy and thus it can be supposed that sALL after ALL treatment is more common than reported - sALLs without a significant lineage shift have been probably often automatically diagnosed as relapses. Based on the current knowledge on childhood ALL there are probably 3 types of disease recurrence: (1) genuine relapse from a resistant diagnostic (sub)clone, (2) secondary leukaemia arising from original pre-leukaemic clone (with some clonal markers maintained and some changed) and (3) pure sALL, clonally unrelated to the original leukaemia. In our study at least two patients (number 1 and 5) belong to the third category. This frequency (0,5–1%) is a minimal estimate as in some cases the differences could be subtler. In these “unquestionable” cases the adequate treatment strategy should be considered. Both “pure sALL” and “sALL from the same pre-leukaemic clone” cases should be also considered in discussions regarding an intensity of treatment strategies - some recurrences of ALL might, in fact, occur not because of low intensity of protocol but because of overtreatment. In our study we present a largest cohort of patients with possible sALL after ALL treatment analysed so far and, moreover, we describe a new fusion gene in ALL - MAML2/MLL.
Patients characteristics Patient 1 2 3 4 5 P=presentation; S=sALL; CR=remission preceding sALL; Ig/TCR: In each patient different letters stand for different and unrelated rearrangements Age at dg. [years] 5,8 3,1 3,0 5,5 5,1 Gender m m m m f Immunophenotype (P/S) BCP/T BCP/BCP preT/T BCP/BCP BCP/T Fusion genes (P/S) TEL-AML1/neg. TEL-AML1/TEL-AML1 neg./neg. neg./MLL-ENL neg./MAML2-MLL Ig/TCR (P/S) ABCD/EFGH ABCD/EFG AB/C A/A ABC/DE CR [years] 2,2 2,5 1,7 1,7 2,7