dale, V. Valentine, and C. Nowak for technical assistance, J. Gilbert. For personal use .... Evans WE, Rodman J, Relling MV, Crom WR, Rivera GK,. Crist WM, Pui ...
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1993 82: 576-580
Cytogenetically different leukemic clones at relapse of childhood acute lymphoblastic leukemia SC Raimondi, CH Pui, DR Head, GK Rivera and FG Behm
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Cytogenetically Different Leukemic Clones at Relapse of Childhood Acute Lymphoblastic Leukemia By Susana C. Raimondi, Ching-Hon Pui, David R. Head, Gaston K. Rivera, and Frederick G. Behm Sequential analysis of blast cell chromosomes in 9 8 cases of acute lymphoblastic leukemia (ALL) disclosed entirely different karyotypes for nine patients at the time of relapse. The presenting clinical, immunophenotypic, and cytogenetic features of this subgroup were similar to those of the 89 patients without major karyotypic shifts. The median length of initial remissionsin these nine patients, all of whom received intensive multiagent therapy, was 24 months (range, 6 to 35); responses to subsequent treatment have been uniformly poor. Prominent cytogenetic
changes included a gain of modal chromosome numbers in five cases, a loss of chromosomes in two, and the acquisition of an 11q23 rearrangement in three. We propose several different mechanisms to account for these findings. In one, the presence of an entirely different ALL karyotype at relapse may represent induction of secondary leukemia analogous to the well-described entity of epipodophyllotoxin-related secondary acute myeloid leukemia (AML). 0 1993 by The American Society of Hematology.
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present (but undetected) at diagnosis or arose later through evolution of a preleukemic stem cell or through malignant transformation of normal lymphoid progenitors by intensive chemotherapy including DNA-topoisomerase I1 inhibitors.
EASSESSMENT OF lymphoblast biologic features at the time of relapse has contributed importantly to our understanding of leukemia pathophysiology. Earlier studies claimed only minor phenotypic variations between cases studied at diagnosis and relapse,’4 but with wider use of intensive chemotherapy and comprehensive assays for lymphoid and myeloid cell markers, reports of major phenotypic shifts in acute lymphoblastic leukemia (ALL) have a~peared.~-” The most disturbing of these observations has been the diagnosis of acute myeloid leukemia (AML) in patients treated for ALL. Initially, such cases were thought to arise from clonal selection and overgrowth of rare transformed myeloid cells within the leukemic blast population (so-called lineage switch).* More recent studies have linked secondary AML to the genetic effects of DNA-topoisomerase I1 inhibitors, such as the epipodophyllotoxins and anthracyclines.’”’’ ALL occurs much more frequently than AML as an initial hematologic malignancy in children, yet only rarely is it reported as a second malignant neoplasm. Hunger et alZ0 recently summarized the published case histories of secondary ALL, concluding that this complication is more frequent than previously thought. Here, we report complete karyotypic shifts in nine of 98 cases of ALL that were successfully banded at diagnosis and relapse. The evidence suggests the emergence of new leukemic clones that were either
From the Departments of Pathology and Laboratory Medicine, and Hematology-Oncology, St Jude Children S Research Hospital, Memphis; and the Department of Pathology and Pediatrics, University of Tennessee, Memphis, College of Medicine, Memphis, TN. Submitted October 13, 1992; accepted March 2, 1993. Supported in part by Leukemia Program Project Grant No. CA20180, Cancer Center Support (CORE) Grant No. CA-21765from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC). Address reprint requests to Susana C. Raimondi, PhD, Department of Pathology and Laboratory Medicine, St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. section I734 solely to indicate this fact. 0 I993 by The American Society of Hematology. 0006-4971/93/8202-0035$3.00/0 576
MATERIALS AND METHODS
From December 1979 to December 1991,98 patients with ALL had successful cytogenetic studies of their leukemic cells both at diagnosis and at relapse. The diagnosis of ALL was based on morphologic and cytochemical criteria of the French-American-British (FAB) Cooperative Group.21Thus, by definition, all cases lacked a myeloid phenotype (90%).35 A more likely reason would be the use of intensive multiagent chemotherapy for both higher- and lower-risk patients at our i n ~ t i t u t i o n . * ~ - ~ ~ Intensified treatment could contribute to the development of cytogenetically different leukemic clones by any of several mechanisms. First, the stem line detected at relapse might have been present at diagnosis but at a level too low to be detected by standard methods. Effective treatment could then have eradicated the dominant line, allowing the minor (drug-resistant) clone to expand. In this regard, we have shown that ALL cases occasionally possess two cytogenetically independent blast cell populations at diagnosis, apparently derived from a common ~ r o g e n i t o r . Second, ~~ treatment might have abolished an overtly leukemic, cytogenetically abnormal clone but not a preleukemic stem cell, which eventually could have given rise to a new leukemic clone. This hypothesis is supported by studies of G6PD heterozygotes with AML in clonal remi~sion.~' We have no compelling findings that would distinguish between these two alternatives. A third possibility is the secondary induction of ALL by transformation of a normal lymphoid precursor. Thus, it may be important that the lymphoblasts in three of our cases studied at relapse (no. 4 through 6) were characterized by the acquisition ofan 1 lq23 rearrangement, an abnormality often implicated in topoisomerase I1 inhibitor-induced secondary AML,I2-I9as well as secondary ALL arising after treatment for solid In this regard, patients no. 4 and 5 were treated with teniposide on a twice-weekly schedule that has been associated with a greatly increased risk of secondary AML." These observations suggest that DNAtopoisomerase I1 inhibitors have the potential to transform lymphoid, as well as myeloid progenit01-s.~~ The outcome of standard retrieval chemotherapy in this group of patients has been discouraging, indicating the need for effective alternatives (eg, bone marrow transplantation). Finally, routine study of ALL with sequential cytogenetic and molecular analyses is needed to pinpoint the mechanism(s) giving rise to new leukemic clones. ACKNOWLEDGMENT
The authors thank A. Fuchs, P. Mardis, T. Huddleston, S. Ragsdale, V. Valentine, and C. Nowak for technical assistance,J. Gilbert
From bloodjournal.hematologylibrary.org by guest on July 13, 2011. For personal use only. DIFFERENT CLONE AT RELAPSE OF ALL
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