Abstract

Abstract 2741

Cytogenetic analyses are essential for stratification and prognosis in childhood AML. We analysed the frequency of chromosomal aberrations and the outcome according to the cytogenetic findings in 386 patients with data (92%) out of the total group of 422 German patients in study AML-BFM 2004. The aim was to evaluate the prognostic impact of specific chromosomal aberrations in a large cohort of patients treated according to this BFM protocol.

Patients were <18 years of age and were diagnosed between 2004 and 2009. According to the AML-BFM risk criteria based on morphology, genetics and response on day 15 of therapy, patients were assigned to a high-risk (HR) and a standard risk (SR) group.

Cytogenetic and FISH analyses-as well as RT-PCR if indicated-were performed according to standard protocols on bone marrow or peripheral blood prior to therapy.

Results:

the number of patients in different karyotypic groups and their outcome are given in the table below:

Cytogenetic aberration Patients n (%) 5-year pEFS (SE) % p-value (Logrank)* 5-year pOS (SE) % p-value (Logrank)* CIR (SE) p-value (Gray)* 
Patients without cytogenetic data 36 42 (9) 0.14 66 (9) 0.49 31 (9) 0.86 
Total no. of patients with cytogenetic data 386 (100) 55 (3) 0.14 74 (3) 0.49 30 (3) 0.86 
normal karyotype 85 (22) 51 (6) 0.34 69 (6) 0.26 34 (6) 0.256 
t(8;21) or AML1/ETO 48 (12) 66 (7) 0.13 84 (6) 0.091 26 (7) 0.59 
t(15;17) or PML/RARα 24 (6) 92 (6) 0.0025 92 (6) 0.12 0 (0) 0.003 
inversion 16, t(16;16) or CBFβ/MYH11 36 (9) 66 (13) 0.025 100 0.004 31 (13) 0.336 
MLL-rearrangements 97 (25) 55 (4) 0.30 75 (5) 0.52 33 (6) 0.189 
t(10;11)(p12;q23) or MLL/AF10 13 (4) 23 (13) 0.011 59 (14) 0.037 62 (17) 0.005 
trisomy 21** 14 (4) 55 (14) 0.81 67 (14) 0.47 38 (14) 0.31 
trisomy 8** 36 (9) 39 (10) 0.06 71 (9) 0.40 38 (11) 0.37 
aberrations involving 12p 10 (3) 30 (14) 0.0063 70 (14) 0.38 30 (16) 0.645 
complex karyotypes*** 19 (5) 38 (12) 0.048 56 (13) 0.12 51 (13) 0.007 
other cytogenetic aberrations 35 (9) 55 (3) 0.46 54 (14) 0.18 25 (9) 0.215 
very-high-risk group**** 16 (4) 30 (12) 0.0011 50 (16) 0.051 26 (12) 0.997 
Cytogenetic aberration Patients n (%) 5-year pEFS (SE) % p-value (Logrank)* 5-year pOS (SE) % p-value (Logrank)* CIR (SE) p-value (Gray)* 
Patients without cytogenetic data 36 42 (9) 0.14 66 (9) 0.49 31 (9) 0.86 
Total no. of patients with cytogenetic data 386 (100) 55 (3) 0.14 74 (3) 0.49 30 (3) 0.86 
normal karyotype 85 (22) 51 (6) 0.34 69 (6) 0.26 34 (6) 0.256 
t(8;21) or AML1/ETO 48 (12) 66 (7) 0.13 84 (6) 0.091 26 (7) 0.59 
t(15;17) or PML/RARα 24 (6) 92 (6) 0.0025 92 (6) 0.12 0 (0) 0.003 
inversion 16, t(16;16) or CBFβ/MYH11 36 (9) 66 (13) 0.025 100 0.004 31 (13) 0.336 
MLL-rearrangements 97 (25) 55 (4) 0.30 75 (5) 0.52 33 (6) 0.189 
t(10;11)(p12;q23) or MLL/AF10 13 (4) 23 (13) 0.011 59 (14) 0.037 62 (17) 0.005 
trisomy 21** 14 (4) 55 (14) 0.81 67 (14) 0.47 38 (14) 0.31 
trisomy 8** 36 (9) 39 (10) 0.06 71 (9) 0.40 38 (11) 0.37 
aberrations involving 12p 10 (3) 30 (14) 0.0063 70 (14) 0.38 30 (16) 0.645 
complex karyotypes*** 19 (5) 38 (12) 0.048 56 (13) 0.12 51 (13) 0.007 
other cytogenetic aberrations 35 (9) 55 (3) 0.46 54 (14) 0.18 25 (9) 0.215 
very-high-risk group**** 16 (4) 30 (12) 0.0011 50 (16) 0.051 26 (12) 0.997 
*

in comparison to the total group,

**

without favorable genetics,

***

3 or more aberrations, at least one structural aberration; without favorable genetics; without MLL rearrangement,

****

definition: patients without favourable cytogenetics and at least one of the following aberration: t(9;22)(q34;q11), t(7;12)(q36;p13), t(4;11)(q21;q23), t(6;11)(q27;q23), t(6;9)(p23,q24), t(8;16)(p11;q13), -7, -12p.

SE = standard error, pOS = probability of overall survival, pEFS = probability of event-free survival, CIR = cumulative incidence of relapse at 5 years

All patients with t(15;17) and/or PML/RARα fusion gene are surviving disease free, except for two patients who died during the first two weeks of treatment. It is noteworthy that all children with inv(16) and/or CBFβ/MYH11 fusion gene are surviving (pOS=100%).

Compared to the results of study AML BFM 98, outcome of patients with MLL-rearrangements was significantly higher in study AML BFM 2004 (pEFS 35%, SE 5%, vs. pEFS 55%, SE4%) which may be due to more intensive treatment with liposomal daunorubicin (L-DNR) and 2-chlorodeoxyadenosine (2-CDA). Patients with the translocation t(9;11)(p22;q23) and/or the MLL/AF9 fusion gene [n=43] had a pEFS of 60% (SE 9%) and a pOS of 80% (SE 6%), whereas patients with translocation t(10;11)(p12;q23) and or the MLL/AF10 fusion gene [n=13] showed a poor outcome with a pEFS of 23% (SE 13%) and a pOS of 59% (SE 14%). Based on a literature review we defined a very-high-risk group (see definition in the table) which showed a very poor outcome both in study AML BFM 2004 (n=16, pEFS 30%, SE12%) and AML BFM 98 (n=22, pEFS 14%, SE 7%). In this very high risk group 25 patients of both studies achieved first complete remission (1st CR); 11 of them underwent allogeneic stem cell transplantation (SCT) (pEFS 52%, SE16%), 14 patients did not (pEFS of the 12 patients who had an EFS of at least 0.44 years: 13%, SE 11%), Mantel-Byar p=0.17).

Conclusion:

Our results confirm the favourable prognosis for patients showing the rearrangements t(8;21), t(15;17) and inv(16) and the unfavourable prognosis for those with complex karyotypes (3 or more chromosomal aberrations), deletions in 12p and t(10;11)(p12;q23). According to these results stratification of patients in further AML BFM studies will be even more differentiated, and patients of a genetically defined very high-risk group will have an indication for SCT in 1.CR.

Disclosure:

No relevant conflicts of interest to declare.

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Author notes

*

Asterisk with author names denotes non-ASH members.