chromosome banding patterns in patients with chronic myelocytic leukemia

Chromosome Banding Patterns in Patients with Chronic Myelocytic Leukemia

Felix Carbonell, Javier Benitez, Felix Prieto, Lurdes Badia, and Jos6 S nchez-Fayos

ABSTRACT: One hundred and nine patients with Phi-positive chronic myelocytic leukemia were cytogenetically studied with banding methods. Seventy-eight patients were studied in the chronic phase and 39 patients in the blastic phase. The standard translocation was present in 107 cases. Two patients showed complex translocations involving chromosomes No. 6, 9, 22, 11 and No. 9, 22, 11, respectively. PhLnegative cells were detected in S cases (7%). Chromo- some aberrations in addition to the Ph 1 chromosome were observed in 6 cases (8%) during the chronic phase. The karyotypic findings during the blastic phase were similar to those reported in the past [trisomy 8, iso(17q), and a second Phi]. The significance of PhLnegative cells, the geographic heterogeneity of the chromosomal aberrations, the effect of chemotherapy on the appearance of new clones, and the importance of the materials and methods used for the comparison of cytogenetic patterns at different laboratories are discussed.

INTRODUCTION

The chromosomal abnormal i t ies associated wi th the classical type of chronic myelocytic l eukemia (CML) have been wel l defined in both the chronic and blast ic phases [1-3]. However, observations on variant Ph 1 translocat ions, the presence of res idual normal cells, the significance of new translocat ions in addi t ion to the Ph ~ chromosome, the effect of t reatment on chromosomes, and analyses of geographic differences require further amplif icat ion. In order to e lucidate certain controversial points, it is helpful to report new cytogenetic data. The present s tudy describes our experience wi th the cytogenetic analysis of pat ients wi th PhLposi t ive CML and discusses the significance of our findings.

MATERIALS AND METHODS

The pat ients in the present s tudy inc luded 109 ind iv idua ls wi th Phi-posi t ive CML (65 males and 44 females) who were seen between September 1977 and December 1980. Cytogenetic analyses were performed on direct bone marrow prepara t ions and/or after short- term (48 hr) b lood cultures wi thout s t imula t ion or wi th s t imula- t ion by human p lacenta-condi t ioned medium.

From the Department of Clinical Physiology, University of Ulm, West Germany; the Departments of Genetics and Hematology, Fundaci6n Jim6nez Dfaz, Madrid; and the Department of Hematology, CSSS La Fe, Valencia, Spain.

Address request for reprints to Dr. Felix Carbonell, Department of Clinical Physiology, University of Ulm, Oberer Eselsberg, D-7900 Ulm, West Germany.

Received February 24, 1982; accepted April 21, 1982.

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© Elsevier Science Publishing Co., Inc., 1982 Cancer Genetics and Cytogenetics 7, 287-297 (1982) 52 Vanderbilt Ave., New York, NY 1 0 0 1 7 0165-4608/82/120287-11502.75

288

Table 1 Cytogenetics of patients in the chronic phase

Material and Case method Karyotype

1-4 BMD Normal/Ph ~ 5-6 PB + Normal/Ph ~ 7-56 BMD Ph ~

57-65 PB + Ph ~ 66 BMD Normal/Ph~/Ph ~, + Ph ~ 67 BMD Ph~/Ph 1, + P h ~ 68 PB + t(6;9;22;11)(p21;q34;q11;q13) 69 PB + Ph 1, - Y 70 BMD PhVPh ~, + 21

Ph 1, t(9;22)(q34;q11); + Ph 1, + 22q-; BMD, bone marrow direct preparation; PB +, blood culture (48 hr) with human placenta- conditioned medium.

T a b l e 2 C y t o g e n e t i c s of t h e p a t i e n t s a n a l y z e d in b o t h p h a s e s a

Material and Case Date Phase method Karyotype

71 10/30/78 C BMD Ph ~ 5/03/79 C BMD Ph ~ 7/06/79 B BMD Ph ~

72 3/03/79 C BMD Ph ~ 2/28/80 B BMD Ph ~

73 1/31/76 C BMD Ph ~ 2/19/79 B BMD PhVPh~,i(17q), + 8

74 7/14/77 C BMD Ph ~ 3/13/78 C BMD Phl/Ph ~, + 21 9/15/78 B BMD Ph ~, + 21

11/01/78 B BMD Ph 1, + 21/Ph ~, + 21, + 21fPh ~, + 8, + 9, + 21, + 21/

75 12/15/76 C BMD 1/15/79 B BMD

76 3/31/80 C BMD 6/15/80 B BM -

7/16/60 R BMD 77 12/07/78 C BMD

1/11/80 B BMD 78 11/13/73 b C BMD

4/O3/79 C BMD 4/01/80 B BMD

Phi, + 8 ,+ 12,+C, + 19, + 21,+ 21 ph 1 Phl/Ph*,18q + ph ~ Ph 1, + Ph~,r(19)/Ph ~, + Ph ~, + 17/

Ph ~, + Ph 1, + 8, + 17/ Ph *, + Ph ", + 8, + 17, + r(19)/ p h l , + p h * , + 8 ,+ 17,1q+

ph * ph * ph l /ph 1, + 8

Phl/Ph 1, - D

PhVPh ~, - 13fPh ~, - 13, - 20, + mar Ph~/Ph 1, - 13/Ph ~, - 13, - 20, + mar

°C, Chronic phase; B, blast phase; R, remission; BMD, bone marrow direct preparation; BM-, bone marrow culture (48 hr) without stimulation.

~Unbanded.

Chromosome Banding Patterns in CML 289

Banding studies were carried out using the t ryps in -Giemsa technique [4]. The nomencla ture used in descr ibing the chromosome abnormal i t ies is that recom- mended by the Paris Conference. For cytogenetic evaluat ion we used the cri teria p roposed at the First Internat ional Workshop on Chromosomes in Leukemia [5]. An average of 35 metaphases were analyzed per examinat ion.

RESULTS

Patients Studied in the Chronic Phase

Seventy-eight pat ients were s tudied in the chronic phase of the disease (Tables 1 and 2). The Ph 1 chromosome was der ived from the s tandard t ranslocat ion in 77 cases. Case 68 was character ized by a complex t ranslocat ion involving chromosomes No. 6, 9, 22, and 11 [6]. Normal metaphases were found in 7 pat ients (9%), the Phi-negative cells varying between 2% and 25% of the total number of cells examined.

Aberrat ions in addi t ion to the Ph ~ chromosome were observed in a total of six cases (8%). Tr isomy 21 was found in two cases, a second Ph ~ was found in two cases, and the Y chromosome was missing in one patient. Case 78 showed three clones character ized by Ph ~, monosomies 13 and 20, and one dicentr ic marker chromosome (Fig. 1).

Patients Studied in the Blastic Phase

Of the 39 pat ients s tudied in the blastic phase (Tables 2 and 3), 38 had a Ph 1 chromosome due to the s tandard translocation. Case 83 had a complex t rans locat ion involving chromosomes No. 9, 22, and 11 (Fig. 2). Only 4 out of 39 cases had Ph 1 as the only abnormal i ty (10%). Twelve cases showed pseudod ip lo id clones (31%),

Figure 1 Partial karyotype from case 78 showing the standard Ph I translocation, loss of chromosome No. 13, and a dicentric chromosome (13;20).

q ~ A

a t t t

9 22 13 14 15 19 20

290 F. Carbonell et al.

ill & t

N

9 II 2 2

Figure 2 Partial karyotype from patient 83. Complex Ph 1 translocation involving chromosomes No. 9, 11, and 22.

20 patients deve loped hype rd ip lo id clones (51%), and 3 cases were character ized by hypod ip lo id clones (8%). The most frequently observed abnormali t ies were trisomy 8 (16 cases), i sochromosome 17q or t r isomy 17 (14 cases), and a second Ph 2 (8 cases).

Aberrat ions in chromosome No. 1 were found in four pat ients (cases 76, 102, 104, 109). In case 76 a l q + chromosome was observed (Fig. 3) in 2 out of the 43 metaphases analyzed. Pat ient 104 showed a metaphase wi th a t ranslocat ion between chromosomes No. 1 and 14 in 1 out of 50 cells (Fig. 4). The other two patients were character ized by abnormali t ies in the short arm of chromosome No. 1 in the majori ty of the metaphases (Figs. 5 and 6).

Aberrat ions in chromosome No. 3 were found in two patients: Case 84, wi th ins(3;3)(q26;q21q26), had been previous ly repor ted [7]; the other case, 103, showed a t ranslocat ion between chromosomes No. 3 and 20 (Fig. 7).

DISCUSSION

The results obtained in the present series are very s imilar to those repor ted by other laboratories [8-20]. The chronic phase is character ized by a relat ive uni formity of results, in which only the Ph I chromosome was seen as the p redominan t disorder.

C h r o m o s o m e Band ing Pat te rns in CML

Tab le 3 Cytogene t ics of the pa t ien ts in the acute phase

291

Material and Case method ° Karyotype

79 PB - 8 0 PB +

81 PB - 8 2 BMD 83 PB + 84 PB +

85 BMD 86 PB - 8 7 BMD 88 BM

89-90 PB + 91 PB +

92 BMD 93 BMD 94 BMD

95-96 PB + 97 PB + 98 PB + 99 PB +

IO0 PB + 101 PB + 102 BMD 103 PB + 104 PB + 105 BMD 106 BMD 107 BMD

108 PB+ BMD

109

ph 1

ph 1 Phl,21q + PhVPh ~,20q + t(9;22;ll)(q34;q11;q13) Ph~,ins(3;3)(q26;q2 lq26) PhVPh 1, + mar Phl/Ph 1, - 8 Phl/Ph 1, + 8 Phi ,+8 Phl/Ph ~,i(17q) Phl,i(17q) Ph~,i(17q) Ph~,i(17q),- 7 Ph ~, + Ph 1 Ph~/Phl,i(17q]/Ph~,i(17q), + 8 Phi,i(17q)/Ph~,i(17q), + 8 PhVPh 1,i(17q), + 8/Ph 1, + Ph ~,i(17q), + 8 PhVPh~,inv(7)/Ph~,i(17q), + 8 Ph ~,6q-/Ph ~,6q- ,i(17q) Ph 1,i(17q + ),19p - , + 8 PhVPh z,lp +, - 7, + marl/Ph~,lp + ,8q +, - 7, + mar2 PhVPhl,t(3;20) PhVPh 1, + PhVPh ~, + Ph ~,2 lq +, + 8/Ph 1, + Ph ~, + Ph ~,2 lq + , + 8,t(14;?1) Normal/PhVPh ~, + Phl/Ph ~, + Ph 1, + 8, + 9 PhVPh ~, + 21 Ph~/Ph ~, + Ph ~, + 8/Ph ~, + Ph 1, + 8, + 13, + 19, + 21/

Ph ~, + Ph ~, + 8, + 8, + 13, + 19, + 21/Ph ~, + Ph ~, + 8, + 8, + 13, + 14, + 19, + 21 PhVPh 1, + Ph ~, + 17, + 19/Ph ~, + Ph ~, + 8, + 17, + 19/Ph ~,

+ P h i , + 8 , + 9 , + 17,+19 Ph ~, + Ph ~,lp + plus multiple aberrations

°BMD, Bone marrow direct preparation; PB-, blood culture (24 hr) without stimulation; PB +, blood culture (48 hr) with human placenta-conditioned medium stimulation.

In contrast , there is a b road e v o l u t i o n of the karyotype in the acute phase . At this stage of the disease, t r i somy 8, i s o c h r o m o s o m e 17q, and a second Ph 1 c h r o m o s o m e are the mos t charac te r i s t ic add i t iona l aberra t ions observed.

U n u s u a l t r ans loca t ions were no t seen in the p re sen t series. Howeve r , two com- p l ex t rans loca t ions were observed . In the first case c h r o m o s o m e s No. 6, 9, 22, and 11 were affected. The second case s h o w e d a t r ans loca t ion a m o n g c h r o m o s o m e s No. 9, 22, and 11. In bo th cases the breaks were loca l i zed speci f ica l ly at bands 6p21, 9q34, 22q11, and 11q13. These break po in t s have been desc r ibed in o ther c o m p l e x and u n u s u a l t rans loca t ions [21]. These f indings suggest that a specia l p r ed i l e c t i on may exis t for breaks at cer ta in c h r o m o s o m e po in t s and that the rup tu res are no t a r a n d o m p h e n o m e n o n . As far as the c l in ica l m e a n i n g of the u n u s u a l and c o m p l e x t rans loca t ions is conce rned , we are in ag reemen t w i t h Sandberg [21] in the sense that these pa t ien ts do not differ c l in ica l ly f rom those w i t h the s tandard t rans loca- t ion. The surv iva l of our pa t ien ts was longer than 33 m o n t h s in the first case w i t h t(6;9;22;11) and 26 m o n t h s in the s econd case w i t h t(9;22;11). In bo th cases the c l in ica l p i c tu re and e v o l u t i o n w e r e typ ica l of CML.

The p re sence of Ph i -nega t ive me taphases was de tec ted in 8 (7%) of our pat ients .


h

6

!¢ 13

i I

19

7 8 9

14

20

Figure 3

15 16

Ii " "" I

21 22 Y

G-Banded karyotype of a ceil from case 76 in the b]astJc phase contaJnJn 8 an

abnormal chromosome No. 1 (lq + ), trisomies 8 and 17, and two Ph 1 chromosomes.

This finding is in agreement with those reported by Whang-Peng [22] and lower than that reported by Cunningham and Sokal [23,24]. The Phi-negative cells were detected at the beginning of the disease. Only one patient in the acute phase (patient 105) showed a small clone with normal metaphases. On the other hand, the progressive disappearance of the Phi-negative mitoses could be observed in the cases where a sequential study was carried out. At present, our patients have not been followed long enough to draw any conclusions about the prognostic value of this finding. In this regard it is important to note that Sokal [24], from a study based on 195 cases and 16 years of observation, reported that the presence of Phi-negative metaphases in the marrow was not associated with a better prognosis. On the other hand, failure to detect Ph2-negative cells with current cytogenetic methods does not preclude the existence of "depressed" normal cells in these patients, as has been suggested by the cytogenetic studies carried out on myeloid and erythroid colonies grown in vitro [25-27] and in patients after radical chemotherapy [23].

In contrast to other reports [13,18,19], we did not observe trisomy 8 or isochro- mosome 17q in the chronic phase. Both disorders were observed only in the acute and transitional phases. We observed a second Ph 1 chromosome during the chronic phase in two cases. In case No. 67 it represented only 2 of the 50 metaphase analyzed; the observation time for this patient is 30 months, and he is still doing well. In the other case, case 66, the cells with a second Ph ~ chromosome represented half of the mitoses analyzed. This patient had refractory anemia and showed a poor response to treatment with busulfan and hydroxyurea. Unfortunately, the survival period could not be established because the patient went back to his native country.

In the acute phase, it is important to note the presence of a great polymorphism


6

13 14 I1~ 15 ~6 t7 "18

I I

19

1 ! im 4 - . - | 20 21 22 Y

Figure 4 G-Banded karyotype from patient 104 with the standard Ph 1 translocafion, trisomy 8, two other Ph 1 chromosomes and, in addition, an abnormally large marker chromosome due to a translocation (14;?1).

in the chromosome aberrations in addition to the classical alterations. Of special interest are four cases (cases 76, 102, 104, and 109) with changes in chromosome No. 1. Recently, Alimena et al. [8] have proposed that a possible relationship may exist between the treatment carried out during the chronic phase and additional structural rearrangement in chromosome No. 1. In their series, aberrations in chromosome No. 1 were seen only in patients treated with intensive chemotherapy during the chronic phase. However, our observations are not consistent with this finding. All our patients were treated only with busulfan during the chronic phase. Of interest was the observation that the rearrangement in the long arm was limited to a small number of cells. In contrast, in the two cases with rearrangement in the short arm (cases 102 and 109), the majority of the metaphases were involved. The fact that these disorders were observed in patients with multiple chromosome aberrations and with different types of chemotherapy suggests that the treatment during the chronic phase should not be considered the only etiological factor.

A second point of interest is the geographic distribution of the chromosome aberrations. Mitelman and Levan [1] found different chromosome patterns in human neoplasmas in different countries. An interesting explanation for this observation has been postulated, in the sense that the geographic variations may be due to different causal agents. Previous studies have already shown that the frequency of abnormal metaphases can be amplified by the method of marrow culture used [28- 30]. The employment of different methods may influence the degree of correlation between the karyotype pattern reported by different laboratories.

Another point to stress is the material used to perform the cytogenetic analysis. Some studies, in which different hemopoietic organs were cytogenetically analyzed,


Figure 5 G-Banded karyotype from patient 109 containing the standard Ph 1 translocation and an abnormal chromosome No. 1 (lp +).

have demonst ra ted that new abnormal clones can be detected in the spleen and/or lymph nodes but not in the bone marrow [31-33]. These results suggest that the origin of acute t ransformation may be extramedul lary. We have analyzed s imulta- neous ly bone marrow and blood cells in different patients. We detected an isochro- mosome 17q in the blood cul ture in two cases and, at this t ime, the marrow cul ture under the same condi t ions showed only cells wi th the Ph 1 chromosome as the only aberrat ion (Carbonell et al., unpub l i shed data). These results are consis tent wi th the hypothes is of an ex t ramedul la ry local izat ion of the new clones. The observat ion may be expla ined if one considers the myelo id cells in b lood as a "poo l" of cells that have originated at different bone marrow sites and in other hemopoie t ic organs. The cul ture of these cells together wi th the s tudy of a large number of metaphases [34] can offer informat ion about new clones that is not p rovided by use of the direct method only in pat ients in t ransi t ion or in the acute phase of CML.

This work was supported in part by the Deutsche Forschungsgemeinschaft (SFB 112). We wish to thank Drs. H. Heimpel and M. L. Marty and the Stiddeutsche H/imoblastose-

Gruppe for clinical and hematological data, Dr. J. D. Rowley for critically reviewing the cytogenetic data, and Dr. E. B. Harriss for constructive comments on the manuscript. We also acknowledge the valuable technical assistance of Mrs. E. Kratt and Mrs. K. Neuhaus.

It All e R 6

~ ,c O

A " qp

1 7 8 9 2 2 mar

Figure 6 Partial karyotypes from patient 102 showing a complex rearrangement involving chromosomes No. 1, 7, and 8. A standard type of Ph 1 chromosome was present.

F igure 7 G-Banded karyotype from patient 103 showing the standard Ph 1 translocation, del(3), monosomy 20, and an abnormally large marker chromosome probably due to a translocation (3;20).

2 9 5

296 F. Carbonell et el.

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chromosome banding patterns in patients with chronic myelocytic leukemia

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