21q22 balanced chromosome aberrations in therapy‐related hematopoietic disorders: Report from an International Workshop†

Abstract

The International Workshop on the relationship between prior therapy and balanced chromosome aberrations in therapy-related myelodysplastic syndromes (t-MDS) and therapy-related acute leukemia (t-AL) identified 79 of 511 (15.5%) patients with balanced 21q22 translocations. Patients were treated for their primary disease, including solid tumors (56%), hematologic malignancy (43%), and juvenile rheumatoid arthritis (single case), by radiation therapy (5 patients), chemotherapy (36 patients), or combined-modality therapy (38 patients). 21q translocations involved common partner chromosomes in 81% of cases: t(8;21) (n = 44; 56%), t(3;21) (n = 16; 20%), and t(16;21) (n = 4; 5%). Translocations involving 15 other partner chromosomes were also documented with involvement of AML1(CBFA2/RUNX1), identifying a total of 23 different 21q22/AML1 translocations. The data analysis was carried out on the basis of five subsets of 21q22 cases, that is, t(8;21) with and without additional aberrations, t(3;21), t(16;21), and other 21q22 translocations. Dysplastic features were present in all 21q22 cases. Therapy-related acute myeloid leukemia (t-AML) at presentation was highest in t(8;21) (82%) and lowest in t(3;21) (37.5%) patients. Cumulative drug dose exposure scores for alkylating agents (AAs) and topoisomerase II inhibitors indicated that t(3;21) patients received the most intensive therapy among the five 21q22 subsets, and the median AA score for patients with secondary chromosome 7 aberrations was double the AA score for the entire 21q22 group. All five patients who received only radiation therapy had t(8;21) t-AML. The median latency and overall survival (OS) for 21q22 patients were 39 and 14 months (mo), compared to 26 and 8 mo for 11q23 patients, 22 and 28 mo for inv(16), 69 and 7 mo for Rare recurring aberrations, and 59 and 7 mo for Unique (nonrecurring) balanced aberration (latency P < or = 0.016 for all pairwise comparisons; OS, P < or = 0.018 for all pairwise comparisons). The percentages of 21q22 patients surviving 1 year, 2 years, and 5 years were 58%, 33%, and 18%, respectively. Noticeable differences were observed in median OS between 21q22 patients (n = 7) receiving transplant (BMT) (31 mo) compared to 21q22 patients who received intensive non-BMT therapy (n = 46) (17 mo); however, this was nonsignificant because of the small sample size (log-rank, P = 0.33). t-MDS/t-AML with balanced 21q22 aberrations was associated with prior exposure to radiation, epipodophyllotoxins, and anthracyclines, dysplastic morphologic features, multiple partner chromosomes, and longer latency periods when compared to 11q23 and inv(16) t-MDS/AML Workshop subgroups. In general, patients could be divided into two prognostic risk groups, those with t(8;21) (median OS, 19 mo) and those without t(8;21) (median OS, 7 mo) leukemia (log-rank, P = 0.0007).

Alternative genetic pathways and cooperating genetic abnormalities in the pathogenesis of therapy-related myelodysplasia and acute myeloid leukemia

“…Interestingly, 7qÀ/ À7 was in the International Workshop Study of t-MDS and t-AML the most common secondary cytogenetic abnormality in patients with balanced translocations to chromosome band 21q22. 33 We have observed defects of chromosme 7 in five of nine patients with translocations to 21q22 and rearranged AML1. Thus, abnormalities of AML1 of two types, point mutations as observed in pathway I, and chimeric gene fusions as observed in pathway IV, are both associated with defects of chromosome arm 7q.…”

“…Also these abnormalities have been associated with previous therapy with topoisomerase II inhibitors, most often anthracyclines. [31][32][33] Seven of our 10 patients in this pathway had received topoisomerase II inhibitors. Whereas patients with t(3;21)(q26;q22) and rearrangement between the EVI1 and AML1 genes often present as t-MDS, most other patients belonging to pathway IV present as overt t-AML ( Figure 1).…”

Karyotype is an independent prognostic parameter in therapy-related acute myeloid leukemia (t-AML): an analysis of 93 patients with t-AML in comparison to 1091 patients with de novo AML

“…1): 273a; abstract) cannot explain the worse outcome, as a study on 44 cases with t-AML and t (8;21) showed no difference in outcome between cases with and without additional karyotype aberrations. 44 In 48 cases with t-AML and inv(16) and 44 t-AML with t(15;17) also, no prognostic impact of secondary chromosome aberrations was observed. 45 t-AMLs are often excluded from therapeutic trials and therefore are treated on a more individual basis that might be less intensive, although in this study treatment within a clinical trial did not influence outcome in patients with favorable karyotype.…”

“…The median OS of t-AML cases with t(8;21) as the sole abnormality and for cases with t(8;21) and additional chromosome aberrations was comparable (17.0 and 30.9 months, NS) as reported from the International Workshop on balanced translocations in t-AML. 44 The respective data from de novo clinical trials show a median OS of 61 months 31 and an overall survival rate at 5 years of 52 and 59%, respectively. 31,32 Overall, t-AMLs with favorable cytogenetics show an inferior outcome compared to their de novo counterparts.…”

Etiology and Management of Therapy-Related Myeloid Leukemia

“…29 Their median survival was 14 months, and 18% were alive after 5 years. Patients with t(8;21) had a more favorable outcome than those with other 21q22 rearrangements (P = .014).…”