Document G69ojKDY4383N4ODe1pVEN3p4

dy of Chromosome #1 ve CML. 11. Prognostic Asp H. FINLEY aloblastic Leukemia (AML-M ty in Acute Lymphocytic Le d D. CATOVSKY Atient: Cytogenetic. I m m u n o l q ,2- lsevier Science Publishing Co., hc nada should add $28.00 for air diail. $48.00 for air delivery to&'-E I a i m s for missing issues can be h& r foreign addresses. Duplicate copier* tifv Elsevier of change of address, Cytogenetics. Elsevier Science Pub claims for missing issues to J o u r n bR Vanderbilt Ave.. New York. NY 10017. its in this journal to Journals Advebilt Ave.. New York; NY 10017. wved. Second class postage paid at -Ym been registered with the Copyright C k ersonol or internal use. or for the puww he condition that the copier pay !hm ?e of each article for copying beyond I& an article. the author has not given brov -ectly from the author This consent &a stribution. resale. advertising and p m / gan&d Chromosome Analysis in Patients ,qith Treatment-Associated Acute ,only- rnphocytic Leukemia I i),aneC. Arthur and Clara D.Bloomfield ,3 r , R . \ ~ ~ : It'e har.e analyzed G-banded metaphase chromosomes from 20 patients with treatment,,;oriated acute nonlymphocytic leukemia [t-ANLL). Nine patients were previously treated y r hematologic malignancies and 11 for solid tumors. The interval from initial therapy to t.\.YLL ranged from 35 to 182 mo (median 75.5 mo). Median age at diagnosis of t-A,VLL was ;.j.s years. Clonal chromosome abnormalities were found in 19 patients (95/,).Loss or partial ,ieietion of the long arm of chromosomes #5 and/or #7 were most common, occurring in nine :u!ients. These abnormalities were associated with hypodiploid complex karyotypes. Other random abnormalities recurring among karyotypes with abnormalities of chromosome #5 Juded loss of one #18. partial deletion of the long arm of chromosome #2, ring chromoes. and a Philadelphia (Ph'l chromosome. \Ye also identified a group of five patients .'. ?cse only karyot!.pic abnormality was addition of whole chromosomes. The remaining .five ;:gtients had other kanot!.pic abnormalities. the most common of which were structural rear:::ngements in a pseudodiploid clone. Combined data from our study and the three previously :.ub!ished large series of patients with t-ANLL studied with banding suggest a relationship iceen kar,.ot!.pe and intensity of prior therapy. with abnormalities of chromosomes #5 and x ? occurring more often in the intensively treated patients. \ rRODLTTION .is more patients with malignant diseases have been successfully treated with radiation and or chemotherapy, there have been increasing numbers of reports of secondary dysmyelopoietic syndromes and acute nonlymphocytic leukemia (ANLL) occurring among these treated patients [I-i]. Relatively few of these patients have had cytogenetic studies done when they developed cytopenias or ANLL [S-161.To date. amly three sizable series of banded chromosome studies of such patients have been .?ublished [:a. 17-19]. Clonal chromosome abnormalities were found in nearly all ijes. ij-ith hy-podipio~dkaryotypes and loss of part or all of chromosomes #5 and: :r it+; :being m a t common. Sirniiar abnormalities of chromosomes # 5 and #7 have &n reported in patients with de m v o "INLL who had prior exposure to carcinogens [20.211. Thus. it was postulated that these specific chromosome abnormalities may occur as a result of the exposures. In this article. we report the results of G-banded chromosome analyses of 20 From the 'i)epar.ments oi Laboratory Medicine and Pathology. Pediatrics. and Medicine. L'niversity of \:innesota Health Sciences Center and the Masonic Cancer Center. Minneapolis. \lK, Address requests for reprints to Dr. Diane C. Arthur. L'niversity of Minnesota Hospitals. OX 1 5 1 , kJq.0 Building. 420 Delaware Street S.E.. Minneapolis. %IN55.155. Received Ala!. 31. 1983: accepted July 1.1, 1983. 189 Cancer Genetic5 and C? togenetics 12. 189-199 (19114) 0165-4608 84 S03.00 'I L +- =1 J -.-n -0 I m mca .YU- I 8 0 +d U --u mE a .U- e.C- I c 01 I cc I e L? .? f -0003 *N N N N 2- c NC C.ahl - - - -- - e - - 1 '1 >I N ~. I Ye ,u- u -4. ti I hrn .N ?.I 2 191 -_ i 192 D. C. Arthur and C. D. B! -!I patients who developed ANLL folloiving therapy for a primary malignant!-. compare and contrast these results with those previously reported in the ii*t>rat,! The data suggest that there are specific recurring karyotypic abnormalitie. an-, patients with treatment associated ASLL (t-Ah'LL1and that these abnormal!::+ I:, correlate with the intensity of prior therapy. MATERIALS AND METHODS The study included 70 patients on the Medical Oncology seri.ice at the I'.::. t+ of Minnesota Hospitals who developed t-ANLL between October 1973 and .' ber 1982. A diagnosis of ANLL was made on the basis of cytology and cytoc.!i-mi staining of a bone marrow aspirate and biopsy. Cases were classified acr,lsr\iinc the FAB system 122) whenever possible: however. many were characteri;;ri 0.. panmyelosis [23) and were difficult to precisely classify within the FAB si !.:enti Heparinized bone marrow cells were received for cytogenetic analysis ::mi 20 patients prior to treatment of :heir .\SLL. Direct preparations and uns;!::!uL: short-term cultures were done in all cases. hletaphase chromosomes were h-.r~:+' according to the method of Tiio and LVhang [24] prior to 1978, and accordir;? t c method of Hozier and Lindquist 1231 from 1978 to date. G-banding was doiir u the Wright's technique of Sanchez et al. (261. Heparinized peripheral blooc! .. .:< received from four of the patients. Direct preparations and short-term C U l t t i i r performed. and the chromosomes were harvested and G-banded using :hr s:[' methods as for bone marrow. hietaphases were photographed on high-:in:: SO113 film, and photokaryotypes prepared in the usual fashion. RESULTS The clinical and cytogenetic data are summarized in Table 1.There M' and 8 males. ranging in age from 2 2 to 76 years (median 58.5 years) at diagnosis of t-ASLL. Kine patients had been previously treated For malignancies, including Hodgkin's disease (four patients), non-Ho phoma (two patients), Waldenstrom's macroglobulinemia [one patient]. myeloma [one patient), and chronic lymphocytic leukemia (one pat maining 11 patients had had nonhematologic solid tumors, including three .''% carcinomas, three breast carcinomas. and one each of renal cell carcinom::. t w ; metrial carcinoma. seminoma. basal cell carcinoma, and oat cell carcinon:.i I.' patients were treated previously with radiotherapy only, and six patients 15, !:h 9 !. motherapy only. Both radiation and chemotherapy was used in treating :!I:, ten patients. All 16 patients who were treated with chemotherapy receiI.+d kylating agent, either alone (eight patients) or in combination tvith othe: .l!2t'! ' The interval from initial therapy to . I S L L ranged from 35 to 182 mo, urith J :w' of 75.5 mo. Analyzable metaphase chromosomes were present in bone marrow s from all except one patient (no. 1). and in this case. mitoses wrere found i era1 blood. Peripheral blood chromosome analysis yielded information not from marrow alone in patient 9 and confirmed the results from bone 11 patients no. 15 and 17. Fifteen or more metaphases were present for anal! -.. 'I! ! patients. The remaining three patients had 10-13 analyzable metaphases. ... All normal metaphases (SS maining 19 patients (93?0)had ) were found in only one patient one or more abnormal clones. a (no. 201 s define, ! !! . I t ' , I. Second International LVorkshop on 'Chromosomes in Leukemia [ ~ T .JA .~i!:\.:~'~!' abnormal and normal ('Vi) metaphases was found in 13 patients. and l;;!lclr" metaphases (AI]only were found in the remaining six patients. Fourtee!! ;'.i:'t'' Chromosome Anal had a single abno tient had three ai hypodiploid 136'~ (36*0). The abnormal L malities of chror somes only. and # i were found I had more than u were hypodiplolc typic abnormalit] Loss of one iti patients 3-6. a I M'ith G-banding and q33) rather mosonle # 5 . tlv! two of patient 2 abnormal clo11e among these p ~ i mosome in fou deletion of the A representati1 Abnorma:iti# Figure 1 G-bal curring abnormal interstitial deletic ring chromosome 13 14 at a: \9 20 Interpretat the Unive 475 and Decap; Jdcayctoccohred-i&ng y racterized$,,t FL4Bs c h e N " , + $ialysis from d unstimul;i14il were ham- *tccording to was done us 4I blood was ab m cultures 4 using the w- n high-con- were 12 f e h i)at the tiwrd [or h e m a t o l d .-I in's lylp tit- .,, multih atient). The ~b ig three o v h trcinoma, en& arcinoma. Fopt tients with cb, eating the 0th~ received an & th other agenb. 8 . with a medLi, rrow specimena ound in pen& on not available jone marrow in )r analqsis in 17 hases. no. 20). Them defined by th 7). i\ mixture d ,. and a b n o d ourteen patieoh j1'3ci a single abnormal clone. four patients had two abnormal clones. and one patient had three abnormal clones. Of the 75 abnormal clones defined. nine were i,,.podiploid (36Ob), seven were pseudodiploid ( 2 8 O b ) , and nine were hyperdiploid 3 6"* I. The abnormal karyotypes can be divided into three subgroups: those with abnor:lldlities of chromosomes #3 and or 4 7 . those with additions of whole chromo;,)mes only, and a miscellaneous group. Abnormalities of chromosomes #5 and/or =; were found in nine patients (no. 1-9 in Table 1).Four of these nine patients jldd more than one abnormal clone. A majority of the abnormal clones (8 of 14) ..:.ere hypodiploid. and all but two (patient 8) were characterized by multiple karyo:vpic abnormalities. Loss of one #5 chromosome was found in both clones of patients 1 and 2 . In patients 3-6, a large portion of the long arm of one chromosome # 5 was deleted. {,.\'ithG-banding, this deletion appeared to be interstitial (breakpoints in bands q13 and q33) rather than terminal. Of the six patients who had abnormalities of chronlosome #5, two also had abnormalities of chromosome # 7 : a missing #7 in clone :]YO of patient 2 and a translocation involving the short arm of one #7 in the three ,ibnormal clones of patient 4. It is of interest that other abnormalities recurred xnong these patients with abnormalities of chromosome #5: loss of one #18 chronosome in four patients and a Ph' chromosome, ring chromosomes, and partial deletion of the long arm of one # 2 (breakpoint in band q31) in two patients each. .\ representative karyotype is shown in Figure 1. .Abnormalities of chromosome #7 were found in three additional patients. Pa- Figure l G-banded karyotype of one metaphase from patient 5 showing several of the re,-urring abnormalities seen in t-;ZSLL. including partial deletion of the long arm of one %2. !n!c.rstitial deletion of the long arm of one # 3 . loss of one #18. a Ph* chromosome, and four ring chromosomes. I 23 45 'E 7 8 9 IO It 12 X 13 14 15 rr'1 0 1 ,zl6 17 '18 a6 21 22 Y interpretation: 49,XX,-18,del(Z)(q31) ,del (5)(q13q33) ,16q+,del(17j ( ~ 1 1 ) . del ( 2 2 ) (q 11 ) ,t ( 11 ;12 ) ( 4 2 1;p13) ,+4r I ! 194 D. C. Arthur and C. D. Bl,r )inti. d Chromosome An i i ! I tients 7 and 8 had loss of one # i chromosome. Patient 7 also had an abn-78)' nicl. of chromosome # 5 but, in this case, most of the long arm was duplicated rdt: than deleted. Patient 9 had only one normal #7 chromosome, however, the sk arm of the second #7 was present in a marker chromosome composed ot the si! arm of one #i and the long arm of one #1 (Figure 2). Although our numbers are very small, there does not appear to be a correla!. between the type of first cancer and abnormalities of chromosomes #j or 3 ; . 'I group of six patients with loss of part or all of chromosome #j include? tour : tients with solid tumors of three different types and two patients with t!itfr-, hematologic malignancies. The patient who had loss of both chromosome2 +j <: #7 (no. 2) had had Waldenstrom's macroglobulinemia. Likewise, the three pdtir: with abnormalities of chromosome #i included two with different solid tun; and one with Hodgkin's disease. There is a suggestion, however, that abnormali* of chromosomes #5 or #7 tend to occur in patients with intensive prior t i + d t i i i r . Among these nine patients. seven had received either combination chemo:her<i: which included three or more agents. or radiotherapy plus chemotherap! , iyhr:. only two patients (no. 2 and 6) had received single-agent chemotherapy. Five of our patients (no. 10-14 in Table 1) had whole chromosome adt-ii:iontheir only karyotypic abnormality, and each of them had only one abnormdl 1 identified. The most commonly ,added were chromosomes #3. #8. #9. a n d f All five patients had had prior hematologic malignancies, including three 'X Hodgkin's disease, one with non-Hodgkin's lymphoma, and one with mu!tip]e 1: eloma. Three of these patients had received intensive prior therapy with r;dh: and combination chemotherapy. One patient received single-agent chenic!hrronly and one patient radiotherapy only. Figure 2 G-banded karyotype of one metaphase from patient 9 showing loss of the 'an< of one #7 chromosome. the short arm of which is preserved in the marker chrornosir::le il 23 45 I( 7 4 8 9 IO II 12 X ti 14 15 w 44 #@ 20 21 22 Y Interpretation: 46,XX,-7;del(l) (q2J) ,del (11)(q14) ,+mar(7 p t e ~ c e n::ce'-!"'' The last five I similar in that ai were pseudodip translocatlon th t(15;17)(q22:q21 with this translc primary malign< Gc- intensive singlr 2 I8~ J S S I O N 3 With improven? @ the study of ch! are found to h2 2 sis, and specifit phologic subgrl with t-ANLL h only three siza studies have sh ities. Hypodip] #5 and #i (i.k chromosomes) ring abnormali ANLL. We have an ANLL, and our with the literat malities; howe partial deletior ported. abnorri hypodiploid cc among the kar. de1(22)(q11), find the distal been two 133. chromosome ii one had an e> extra #18 [351 abnormality o mosomes, and Paris series [ I ai. [ l a ] found that there ma or partial dele A new finc whose only h most commoi Prior hemat o1 phoma. and disease, becat initial malign mLL than I! ur and C. D.Bloo ilso had an abno ,I lowever, the + cumposed of &e 195 The last five patients (no. 15-19) had other karyotypic abnormalities. They were ,imilar in that all had structural rearrangements and four of the six abnormal clones \\'ere pseudodiploid. Patient 19 was the only one in this study who had a specific translocation that is known to recur among patients with de novo ANLL. He had a t i 15:17)(q22:qZI) and also the 113 morphology that is characteristically associated lvith this translocation [27]. Four of these five patients had had solid tumors as their primary malignancy. Of interest also is the fact that four patients had received less Intensive single-modality therapy. 'wise, the three lromosome additions R d y one abnormal dj #3. #a7 #9, and i t ~ as, including three d& d one with multiple r therapy with r a d i a h igle-agent chemothemm lowing !OSS of the long*' marker chromosome. $3. <- ma 22 Y 7ptemcen: :cewlqt ,,,SCI.SSION \,\ith improvements in cytogenetic technology. rapid advances have been made in the study of chromosomes in cancer. Presently, most, if not all, patients with ANLL are found to have clonal chromosome abnormalities in the bone marrow at diagnosis. and specific abnormalities have been found to be associated with specific morphologic subgroups of A N L L and with prognosis [27-321. Relatively few patients Lvith t-ANLL have been studied with chromosome banding techniques. To date, only three sizable series of such patients have been published 110,17-19]. These studies have shown that most t-ASLL patients have clonal chromosome abnormalities. Hypodiploid complex karyotypes and specific abnormalities of chromosomes dj and # 7 (i.e., loss or partial deletion of the long arm of one or both of these chromosomes) have been found in a majority of these patients. The specific recurring abnormalities seen in de novo .INLL are uncommon among patients with t.ISLL. \Ye have analyzed G-banded metaphase chromosomes from 20 patients with t. \ I L L . and our data confirm and espand those previously published. In accordance ;vith ihe literature, all but one of our patients (95%) had clonal chromosome abnormalities: however, only 4 i o o of those with karyotypic abnormalities had loss or partial deletion of the long arm of chromosomes #5 andlor # i .As has been reported. abnormalities of chromosomes #5 and # 7 were commonly associated with hypodiploid complex karyotypes. il'e have also found other abnormalities recurring among the karyotypes with abnormalities of chromosome # 5 . A Ph' chromosome, de1(22)(qll),was found in two patients: however. in neither case were we able to find the distal long arm of the #22 translocated to another chromosome. There have been two 133. 3.11, and possibly a third [IS],previously reported cases of a Ph' chromosome in t-ASLL. Four of our patients had loss of one chromosome #18 and m e had an extra #18. Three cases with a missing #18 [ l o , 171 and one with an extra #18 1351 were previously reported. The latter case, however, did not have an abnormality of chromosomes #5 or X i . Finally, two of our patients had ring chroniosomes. and two had deletion of the distal long arm of one #2, de1(2)(q31).In the Paris series 1191, Berger et al. had one case with a ring chromosome, and Rowley et al. [181 found a de1('7)(q33)in one case studied with Q-banding. Thus, it appears that there may be other nonrandom karyotypic abnormalities associated with loss or partial deletion of chromosome d5 in t-ANLL. .I new finding among our cases of t-ANLL was a group of five patients [25yo) \;.hose only karyotypic abnormalities were additions of whole chromosomes, the most common being chromosomes # 3 . #8. #9, and #IO. All five patients had had prior hematologic malignancies. including Hodgkin's disease, non-Hodgkin's lymphoma. and multiple myeloma. It is unlikely that these karyotypes reflect prior disease. because the patients' prior diagnoses differed, there was no evidence of the initial malignancy at the time of t-.-\SLL. and these karyotypes are more typical of . \ s L L than lymphoma or myeloma. In reviewing the previous series of t-ANLL, an 7E- ! i I II . .L. ..,.. . ./ ..... ,, . 196 '/ ! ji ilI i' :i I !r d Chromosome .4n normalities of c [IO,181 and Fir Chicago and F1 whereas Berger and solid tum, received intenc plus chemothe et al. were mor Data from a the chromosor abnormality fo a correlation t: of patients wit were found to some addition nancies, wherl karyotypes or The correla found in t-ANI AcS andlor # 7 1 prior treatmen additions, and had received 1 The combi, ding thus sus and intensive patients with tah 3 Type of first (4 series = f 4r 1 'a 197 additional four cases with whole chromosome additions only [18,191 were found; the added chromosomes were #8, #9, and #21. The results from the three previously published large series of t-ANLL and our jtudy are summarized in Table 2. Only those cases analyzed by banding techniques ryere included (86 cases, total). Our data most closely resemble the results of Berger al. [19].In both. abnormalities of chromosomes #tj andlor #7 were seen in approximately 506 of the cases. Most of the remaining patients were divided among the whole chromosome additions and other chromosome abnormality groups. Abnormalities of chromosomes #tj and # i were much more prevalent in the Chicago , i o . 181 and Finsen [ I i ] studies. It can also be seen in Table 2 that the series from Chicago and Finsen included mostly patients who had had malignant lymphoma, ;\.hereas Berger et al. and we have studied more patients with polycythemia vera and solid tumors. A majority of patients in the Chicago and Finsen studies had received intensive prior therapy [combination chemotherapy (CCT) or radiotherapy plus chemotherapy (RT A CT]], while the patients in our series and that of Berger et al. were more evenly distributed among the treatment groups. Data from all four series regarding type of first cancer and prior therapy among the chromosome groups are given in Table 3. Although the type of chromosome &normality found in t-ANLL was not specific for a particular first cancer, there was d correlation between first cancer and chromosome group (p = 0.054). A majority of patients with hematologic malignancies, as well as nonhematologic solid tumors, ;$'ere found to have abnormalities of chromosomes #tj andlor Xi'. Whole chromosome additions were found only in patients who had had prior hematologic malignancies. whereas the remaining patients with solid tumors tended to have normal karyotypes or other chromosome abnormalities more frequently. The correlation between intensity of prior therapy and karyotypic abnormality found in t-ANLL was highly significant (p = 0.006).Abnormalities of chromosomes -45 and or # 7 were more likely to occur among patients who had received intensive prior treatment (CCT or RT CT), whereas normal karyotypes, whole chromosome ddditions, and other karyotypic abnormalities tended to occur among patients who had received less intensive {RTor CT) treatment. The combined data from four series of patients with t-ANLL studied with banding thus suggest a relationship between abnormalities of chromosomes #5 and # 7 and intensive prior treatment. Similar abnormalities of #5 and #7 were found in patients with de novo ASLL who had significant occupational exposures to carcin- rdbk 3 ~~ Type of first cancer and prior therapy among chromosome groups [4series = 86 patients) First cancer ~ ~~~~~~~~ ~~ ~ ~ ~~~ Prior therapy :'mo\ome groups Heme Son-heme (n = 63) ( n = 23) RT CT (n = 13) (n = 17) CCT (n = 16) RT + CT (n = 40) . .Abncrmalities 68" 61 46 41 75 80.0 .' ilf1C:l. :.nip 14 0 15 18 6 7.5 '._+.',r.dt::: ,rmalities ..a, 13 3 22 31 29 6 7.5 17 8 12 13 5.0 '.I1 I00 100 100 100 100 100.0 ' C-:::dtologic malignancies: Son-heme. nonhematologic solid tumors: RT. radiotherapy only: CT.chemotherapy - 1y.r'- . CCT. combination chemotherapy ( 2 3 drugs): RT + CT. both radiotherapy and chemotherapy. ?an::, ':5 are percents. i.e.. 6 W 0 of patients with hematologic malignancies as first cancer had abnormalities of -I?'. 7::. tj and or R i in :-.+SLL. .:_-. . -.&. 198 D. C. Arthur and C. D. Blocinfir. ogens ['O. 211. Taken together. these data provide evidence to suggest that certd regions on the long arms of chromosomes #5 and # i are particularly susceptlii . to damage by mutagenic carcinogenic agents and that defects of genes induced these regions may be important in the etiology of the resultant leukemia. We are grateful to Leanna Lindquist and Sharla Aaseng for their expert technical assistanrr doing the cytogenetic studies. and :o Vivian Schultz for her help with preparatio:! oi :: manuscript. Supported in part by the Coleman Leukemia Research Fund. REFERENCES 1. Coleman CS. iVilliams CJ. Flint .\. Glatstein EJ, Rosenberg SA. Kaplan HS (1977:. Herr. tologic neoplasia in patients treated for Hodgkin's disease. S Engl J Xled 297:1249-1?5- 2. Reimer RR. Hoover R. Fraumeni IF Jr. Young RC (1977):Acute leukemia after agent therapy of ovarian cancer. S Engl 1 bled 297:171-181. --3. Rosner F. Carey RIV. 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