Newly emerged isolated Del(7q) in patients with prior cytotoxic therapies may not always be associated with therapy-related myeloid neoplasms

Abstract

Deletion 7q is a common chromosomal abnormality in myeloid neoplasms. Detection of del(7q) in patients following cytotoxic therapies is highly suggestive of an emerging therapy-related myeloid neoplasm. In this study, we describe 39 patients who acquired del(7q) as a sole abnormality in their bone marrow following cytotoxic therapies for malignant neoplasms. The median interval from cytotoxic therapies to detection of del(7q) was 40 months (range, 4-190 months). Twenty-eight patients showed an interstitial and 11 showed a terminal 7q deletion. Fifteen patients (38%) had del(7q) as a large clone and 24 (62%) as a small clone. With a median followup of 21 months (range, 1-135 months), 18 (46%) patients developed therapy-related myeloid neoplasms, including all 15 patients with a large del(7q) clone and 3/24 (12.5%) with a small clone. Of the remaining 21 patients with a small del(7q) clone, 16 showed no evidence of therapy-related myeloid neoplasms and 5 had an inconclusive pathological diagnosis. We conclude that isolated del(7q) emerging in patients after cytotoxic therapy may not always be associated with therapy-related myeloid neoplasms in about half of patients. The clone size of del(7q) is critical; a large clone is almost always associated with therapy-related myeloid neoplasms, whereas a small clone can be a clinically indolent or transient finding. Abnormalities of chromosome 7, either monosomy (−7) or deletion of the long arm (del(7q)), are the most common cytogenetic abnormalities detected in acute myeloid leukemia and myelodysplastic syndromes. 1-3 Del(7q)/ − 7 occurs in~8% of de novo acute myeloid leukemia and~10% of de novo myelodysplastic syndromes. 1,4 Del(7q) has been classified as the intermediate-II risk group in de novo acute myeloid leukemia 5 and the intermediate risk group in de novo myelodysplastic syndromes, respectively. 6 Therapy-related myeloid neoplasm is a late complication of cytotoxic therapies for primary malignant and non-malignant diseases. Cytogenetic abnormalities can be detected in more than 90% of patients with therapy-related myeloid neoplasms, and more than half of these patients have a complex karyotype. 7 Del(7q)/ − 7 presents in~50% of patients with therapy-related myeloid neoplasms and are often associated with prior exposure to alkylating agents or ionizing radiation. 1,[8][9][10][11][12][13] Any newly emerged cytogenetic abnormalities in patients with a prior history of cytotoxic therapies often raises the concern of development of therapy-related myeloid neoplasms, especially when the abnormalities include del(7q)/ − 7.In our practice, we have observed that some patients develop isolated del(7q) in their bone marrow following cytotoxic therapies, yet never develop therapy-related myeloid neoplasms with close follow-up. In order to better understand the

How I investigate Clonal cytogenetic abnormalities of undetermined significance

“…Of note, 13 of 15 (87%) patients with persistent del(7q) were either diagnosed with t‐MDS at the time of del(7q) detection or developed t‐MDS during the follow‐up. In contrast, 11 of 12 patients with transient del(7q) did not show BM disease during the follow‐up interval, and the exception was a patient in whom del(7q) was no longer detectable, but who subsequently acquired an unrelated CCA and was diagnosed with t‐MDS . In the study of del(20q) as a sole abnormality following cytotoxic therapies, del(20q) was persistently or intermittently detected in 46 patients and transient in 15 patients.…”

“…Some CCA can be a transient finding, especially when the CCA emerges during or immediately following cytotoxic therapies (including chemotherapy and SCT); these transient CCAs are unlikely associated with t‐MDS/AML In a case series of acquired isolated del(7q) following cytotoxic therapies, among 27 patients who had at least 1 follow‐up cytogenetics study, del(7q) was persistent in 15 patients and was transient in 12 patients. Of note, 13 of 15 (87%) patients with persistent del(7q) were either diagnosed with t‐MDS at the time of del(7q) detection or developed t‐MDS during the follow‐up.…”

“…To date, most CCAUS reported have been single isolated abnormalities, including a chromosomal gain such as +8, +Y, +15; or a partial loss of a chromosome like del(20q), del(5q), del(7q), del(11q); or balanced rearrangements including t(11q23;v), t(1;16)(p37;q21), inv(5)(p15.1q11.2), t(5;19)(p15.3;q11.1), t(1;10)(q12;q26.2), and t(9;17)(q34;q21) . None of the CCAUS falls into the poor‐ or very poor‐risk IPSS groups .…”

“…Del(7q) occurs in 5%‐10% of de novo AML and MDS, and in ~50% of patients with t‐MDS/AML . In a study that included 39 patients who acquired del(7q) as a sole abnormality following cytotoxic therapies, 18 (46%) patients had a diagnosis of t‐MDS or t‐AML, 5 patients had an unclear diagnosis due to inadequate follow‐up, and 16 patients showed no evidence of t‐MDS/AML with a median follow‐up of 21 months.…”

“…A diagnosis of CCAUS is often challenging for the following reasons: (i) Almost all clonal cytogenetic abnormalities observed in CCAUS also can be observed in MDS/AML; (ii) clonal cytogenetic abnormalities in MDS can start with a small clone at the first time of detection, similar to CCAUS, but this clone gains a proliferative advantage over time eventually becoming the dominant clone in BM; (iii) a clonal cytogenetic abnormality may be detected initially as an isolated abnormality that is consistent with CCAUS, but might facilitate the gain of additional abnormalities (clonal evolution) or development of a new clone, by contributing to genome instability or altering the BM microenvironment; and it is well known in patients with MDS that detection of a clonal cytogenetic abnormality can precede the morphologic dysplasia by 1 month to about 3 years …”