Due to disease rarity, our knowledge regarding t-ALL is limited. Unlike t-MNs, t-ALL is not currently defined by the WHO as a sole disease entity. Some reports have analyzed t-ALL regardless of how the primary malignancy was treated,7,8 and other studies have focused on patients who received chemotherapy or radiotherapy.4,5 Focusing on the effects of chemotherapy and radiotherapy that might have caused genomic instability, our study investigated t-ALL patients who underwent chemotherapy or radiotherapy.
Previous studies have reported that KMT2A rearrangement is a common abnormality in t-ALL.4,6 KMT2A rearrangement is the prototypical cytogenetic finding among t-AML patients exposed to topoisomerase II inhibitors, and the incidence of KMT2A rearrangement is higher in t-ALL compared to dn-ALL.4,6 We studied one t-ALL patient with KMT2A-EPS15 rearrangement (P116). The patient had a history of alkylating therapy along with topoisomerase II inhibitor treatment. In our study, the t-ALL group showed a higher prevalence of KMT2A rearrangement than the dn ALL group (11.1% vs. 3.1%), but statistical significance was not reached (p = 0.302). Future study with a larger number of t-ALL patients is necessary to fully investigate the relationship between KMT2A rearrangement and t-ALL.
In this study, we identified a total of 71 adult ALL cases with available genetic mutation information (assessed by NGS), including 54 dn-BLL and 8 t-BLL patients who were previously diagnosed with a malignancy. The mutational burden was low in both groups; although dn-BLL cases tended to have a higher number of variants (median, 2.0; range, 0.25–3.0) than t-BLL cases, the difference was not statistically significant.
A notable observation of our study is that TP53 and RB1 alterations were more frequent in t-BLL than in dn-BLL patients. The role of TP53 in development of t-MNs after exposure to topoisomerase II inhibitor and alkylating agent has been well described.1 Frequent TP53 alteration, including copy number alteration in t-MN9 and t-BLL, has been reported.6 Somatic TP53 alteration is suggested to influence defects in the DNA damage response in t-MN9 as well as development of t-BLL.6 RB1, a cell cycle regulator, is altered recurrently in t-MN10 and ALL.11 There have been no previous reports demonstrating frequent RB1 mutation in t-ALL. However, higher frequency of TP53/RB1 tumor suppressor pathway mutations in our t-ALL cohort suggests overlapping features in high-risk genetic subtypes, as reported in high-risk BLL.12 However, the sample size is limited, and the results need to be verified.
Of all investigated t-ALL patients, 33.3% had a family history of cancer, but only somatic mutations were found in our study. The possible involvement of cancer-predisposing genes not included in our target panel cannot be ruled out, but germline mutation was not found in our gene panel including common oncogenes BRCA1, BRCA2, TP53, DDX41, RUNX1, ANKRD26, and ETV6. Recent study reported a t-ALL case in Li-Fraumeni syndrome patient.6 In a study by Churpek et al., the cancer susceptibility gene was screened in patients with t-ALL among the breast cancer survivors, and TP53 mutation was found in two of the four t-ALL patients who underwent the test.5 Since very few studies have previously investigated germline presentation genes in t-ALL patients, future study with large series is required for identifying the exact frequency of germline mutations among t-ALL patients.
According to previous studies, t-ALL has a poorer prognosis than dn-ALL.4,13 In our study, t-ALL showed a trend of shorter OS than dn-ALL, but we could not demonstrate statistical significance due to the small number of patients. As previously demonstrated by other studies, t-ALL patients were older than dn-ALL patients at diagnosis, and this might be explained by the 6.4-year median time from diagnosis of prior malignancy to ALL diagnosis in our study. This duration was similar to that reported by other groups.5,14
Breast cancer was one of the most common prior malignancies in our study, in concordance with other reports, possibly due to its relatively superior prognosis to other cancers and frequent use of topoisomerase II inhibitors and alkylating agents for its treatment. Another common prior cancer was osteosarcoma. This might be due to the usage of doxorubicin in its treatment regimen, which is also a topoisomerase II inhibitor. In addition, most osteosarcomas occur in children or young adults aged 10 to 30 years.
Eight of 9 t-ALL patients showed NED for prior malignancy, and the median OS was significantly higher in patients with NED at t-ALL diagnosis. The prior cancer can worsen during t-ALL treatment, and even after CR, progression to allo-HSCT might not be possible due to the presence of residual primary tumor.
Previous reports have suggested the promising role of allo-HSCT in t-ALL treatment.13,14 Our analysis corroborated these findings regarding allo-HSCT as a favorable t-ALL treatment to improve OS.
The limitations of this study are mainly related to its retrospective nature and small sample size. Since data collection was performed from patients diagnosed in a period of 12 years, rapidly changing therapeutic options for prior malignancies and ALL might have caused bias. Also, although we conducted additional cytogenetic studies and mutational analysis with available samples, minimal residual disease (MRD) data are lacking from the earlier patients. Multi-center, prospective studies with NGS and MRD monitoring data are needed to gather a sufficient number of patients for statistically significant, minimally biased results. In this way, the emerging roles of bispecific antibodies and chimeric antigen receptor therapy in t-ALL are promising directions for future study.
In conclusion, our study outlines t-ALL as a rare but distinct disease entity with a genetic profile similar to t-MNs and poor survival outcomes. t-ALL patients with remaining prior malignancy show especially poor prognosis. Though further analysis is needed for validation, t-ALL patients seem to benefit from allo-HSCT. Multi-center, prospective studies with a large number of patients are necessary.