Rare recurring balanced chromosome abnormalities in therapy‐related myelodysplastic syndromes and acute leukemia: Report from an International Workshop†

Abstract

Seventy-seven patients were identified with Rare recurring (excluding 11q23, 21q22, inv(16), and t(15;17)) chromosome abnormalities among 511 patients with treatment-related myelodysplastic syndromes and acute leukemia accepted from centers in the United States, Europe, and Japan. The abnormality subsets included 3q21q26 (17 patients), 11p15 (17 patients), t(9;22)(q34;q11) (10 patients), 12p13 (9 patients), t(8;16)(p11;p13) (9 patients), and an "other" subset, which included t(6;9)(p23;q34) (3 patients), t(10;11)(p13;q13 approximately q21) (3 patients), t(1;17)(p36;q21) (2 patients), t(8;14)(q24;q32) (2 patients), t(11;19)(q13;q13) (2 patients), t(1;3)(p36;q21) (2 patients), and t(3;5)(q21;q31) (1 patient). Increased karyotypic complexity with additional balanced and unbalanced rearrangements was observed in 70% of cases. Among 54 cases with secondary abnormalities, chromosome 5 and/or 7 abnormalities were observed in 59%. The most frequent primary diseases were breast cancer (24 cases), Hodgkin disease (14 cases), non-Hodgkin lymphoma (10 cases), and de novo ALL (5 cases). Thirty-seven patients received alkylating agents plus topoisomerase II inhibitors with or without radiation therapy. The presenting diagnosis was t-AML in 47 cases, t-MDS in 23 cases (10 progressed to t-AML), and t-ALL in seven cases, five of whom had a t(9;22). The median latency time from initiation of original therapy to therapy-related disease diagnosis was quite long (69 months), and the overall median survival from the date of therapy-related disease diagnosis was very short (7 months). The 1-year survival rate was 34 +/- 7%, with no significant differences among subsets. Comparison with previously reported cases showed increased karyotypic complexity and adult presentation of pediatric-associated chromosome abnormalities.

High frequency of pro-B acute lymphoblastic leukemia in adults with secondary leukemia with 11q23 abnormalities

“…The current study and others, however, suggest that MLL abnormalities are involved in a higher percentage of t-ALL cases than t-AML cases, and t-ALL is usually associated with t(4;11). 8,9,[14][15][16] Andersen et al 8 recently reported two cases of MLL-positive, t-ALL and identified 21 other cases in the literature. All of those previously reported cases had received at least one topoisomerase II inhibitor.…”

Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they?

“…55 CBFb-MYH11 transgenic mice expressing the fusion protein under the control of the MRP8 promoter have been reported to develop dysgranulopoiesis 115 whereas the CBF-MYH11 KI mouse model develops AML. 56 Chromosomal translocations involving MLL, such as t(11;16)(MLL-CBP) 58,59 and t(11;19), 57 as well as MLL gene tandem duplications (MLL-PTD), 7 have been described in MDS and t-MDS, although frequencies are low. However, none of the MLL-AF9 mouse models, whether it be KI 61 or retroviral BM transduction/transplantation assay (rt/BMT) models, appear to develop MDS, and overt AML rapidly develops.…”

Therapy-related acute myeloid leukemia with chromosomal abnormalities involving t(9;22)(q34;q11) and t(3;21)(q26;q22) during chemotherapy for follicular lymphoma

“…In their study, patients mostly had non-hematological malignancies; in fact, only two cases had hematological malignancies, including one case of non-Hodgkin lymphoma. Block et al [9] analyzed 511 cases of t-MDS and t-AML that were registered into the international workshop (US, Europe, and Japan in 2002), including 10 cases with Ph chromosome, which comprised five cases of t-AML and five cases of therapy-related acute lymphoblastic leukemia (t-ALL). However, all cases with Ph chromosome occurred without preceding MDS, and only one case had both monosomy 5 and 7.…”

“…The emergence of such translocations in t-AML is associated with high aggressivity and very poor prognosis [9,15]. Thus, it is important to note the presence of these translocations in the early phase after chemotherapy and to consider more effective treatments, such as stem cell transplantation for eligible t-MN cases.…”