Cytogenetic aberrations in adult acute lymphoblastic leukemia—A population‐based study

Abstract Cytogenetic aberrations are recognized as important prognostic factors in adult acute lymphoblastic leukemia (ALL), but studies seldom include elderly patients. From the population‐based Swedish ALL Registry, we identified 728 patients aged 18–95 years, who were diagnosed with ALL 1997–2015 and had cytogenetic information. Registry data were complemented with original cytogenetic reports. BCR‐ABL1 was the most recurrent aberration, with a frequency of 26%, with additional cytogenetic alterations in 64%. KTM2A rearrangement was the second most frequent aberration found in 7%. Low hypodiploidy‐near triploidy and complex karyotype had negative impact, while t(1;19);TCF3‐PBX1 showed positive impact on overall survival. However, after correction for age only complex karyotype remained significant.


INTRODUCTION
Information regarding cytogenetic aberrations has been recognized as important for prognosis in acute lymphoblastic leukemia (ALL) for decades [1,2]. Thus, to genetically characterize ALL at diagnosis is mandatory and has implications for choice of treatment [3]. Still, genetic reference studies in adult ALL are infrequent and often derived from clinical trials with a corresponding selection bias excluding or not completely representing elderly ALL patients. In 2010, Moorman et al.

RESULTS
The median age of the 933 patients reported to the registry was 53 years (range 18-95). Details regarding immunophenotype and treatment are described in the previous registry publication [5]. Additional cytogenetic aberrations (ACA) to BCR-ABL1 were frequent and found in 64% of the patients, 19% had no ACA, and 17% were not examined with anything but a targeted investigation or had a normal karyotype with ≥20 metaphases (n = 6). The most common ACA was an additional Philadelphia chromosome +der(22)(t(9;22) (n = 32), followed by -7 (n = 14) and +8 (n = 11). Of these, eight had a combination of +der (22) and +8 being most common, as previously reported [6]. The impact of ACA reported in some studies [7][8][9][10] was not confirmed here, or in the study by Moorman et al. [6].
KTM2A-r is commonly recognized as a negative prognostic factor [11], but the negative impact on prognosis is not always retained in multiple variable analysis correcting for other factors [6,12]. We did not find a difference in outcome for patients with KTM2A-r compared to those with normal karyotype, nor was there a difference in outcome for patients with different KTM2A-r subtypes. In Sweden, the chemotherapy regimen has included high-dose cytarabine, which is suggested beneficial for KTM2A-r in children [13]. In addition, allogeneic hematopoietic stem cell transplantation has been recommended for fit patients for the main part of the period, which might have influenced outcome. Yet, the relatively low number of patients could also have hampered the analyses.
HeH is well known as a favorable prognostic factor for children with ALL, but few data are available for adults. In our study, there was a trend toward younger age and lower WBC, but when correcting for age, HeH was not a favorable factor in adult ALL, confirming previous reports [6,11,14]. Atypical chromosome gains compared to classical pediatric HeH [11] and the presence of two or more additional structural abnormalities [14] has previously been correlated to adverse sur- Abbreviations: HeH, high hyperdiploidy; Ho-Tr, low hypodiploidy-near triploidy; NOS, not otherwise specified; WBC, white blood cell count.  [6] showed inferior survival, later confirmed by some [12] but not all study groups [11,15]. One possible explanation could be specific alterations such as loss of p53; however, the frequency was too low to solely explain the impact of complex karyotype on prognosis. Complex karyotype has not been considered a high risk factor in Sweden, and thereby allografting has not been recommended upfront in cases with good initial response. In this material, it was done as upfront treatment for only eight of the 22 patients harboring a complex karyotype.
The strength of our study is that we report the frequency of genetic alterations found in adult ALL in a population-based manner with no upper age limit. The weakness is associated with the limited details concerning clinical data in the registry. Also, diagnostic procedures have rapidly evolved and cytogenetic diagnostics have reached standards that were not available for patients in the early part of the study period.
We conclude that complex karyotype is a previously debated negative prognostic factor in adult ALL. With treatment according to national guidelines, no other aberration including BCR-ABL1, KTM2Ar, or HeH impacted survival. Incorporating complex karyotype in future risk stratification should therefore be considered.

ACKNOWLEDGMENTS
We would like to thank the Swedish Adult ALL group and the ALL team at the Regional Cancer Center in Lund. We would also express our