Chromosomes and causation of human cancer and leukemia. L. Cytogenetics of leukemias complicating other diseases

Chromosomes and Causation of Human Cancer and Leukemia. L. Cytogenetics of Leukemias Complicating Other Diseases A. A. Sandberg, S. Abe,* J. R. Kowalczyk,* A. Zedgenidze,* J. Takeuchi, and S. Kakati

ABSTRACT: Complicating (secondary) leukemias in 20 patients, 18 of whom had various forms of neoplasia treated with chemotherapy and~or radiation, have been examined in regard to the karyotypic findings present in the leukemic cells of the marrow. In addition, the published cases of complicating leukemia have been tabulated. Based on the results of the present study and those in the literature it appears that chromosomes #3 and #17 should be stressed as being nonrandomly involved in complicating leukemia in addition to the previously stressed chromosomes #5 and #7. The results of the present study are discussed in relation to those reported in the literature, and stress put an the significance of cytogenetic changes in relation to possible causative factors of the complicating leukemia. The hypothesis is advanced that these nanrandom chromosome changes may reflect causative specificity of the complicating leukemia and that a concerted effort must be made to obtain more cogent information on the role of noxious agents in the causation of complicating leukemia. INTRODUCTION Leukemia, particularly of the acute form, complicating other diseases is being reported in an apparently increasing frequency. Most of the cases are related to chemotherapy (and possibly radiation therapy) used i n the treatment of various malign a n t states, ranging from l y m p h o m a [13,18,30,42,45,52,57,66,77,78,95] and multiple myeloma (MM) [12,50,62,70,92] to ovarian and breast cancer [14,47,65,71,99] and, rarely, even another form of leukemia [9,17,38,80]. Moreover, acute leukemia complicating therapy for n o n m a l i g n a n t disorders or in conditions with a changed immunologic milieu is being observed more and more frequently [14,75,89]. There is little doubt that the incidence of leukemia in the above-mentioned disorders has a higher frequency than w o u l d be seen u n d e r normal circumstances and is accelerating as a result of drug therapy; thus, complicating leukemia is an acute problem facing and perplexing oncologists and other clinicians involved in therapy for such

conditions. From RoswellPark MemorialInstitute, Buffalo,New York. *Present address: ChromosomeResearch Unit, Faculty of Science, Hokkaido University,North 8, West 5, Sapporo, Japan. tPresent address: Institute of Pediatrics, ul. Staszica 11, 20-081 Lublin,Poland. *Visitingscientist under the USA-USSRHealth CooperationProgram (Cancer). Present Address: Georgian Institute of Hemotologyand Blood Transfusion,PavlovStr. 22, Tblisi, USSR. Address requests for reprints to Avery A. Sandberg, M.D., Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY 14263. Received April 7, 1982; accepted May 13, 1982.

95 © Elsevier Science PublishingCo., Inc., 1982 52 VanderbiltAve., New York, NY 1 0 0 1 7

Cancer Geneticsand Cytogenetics7, 95-136 (1982) 0165-4608/82/100095-4252.75

96

A.A. Sandberg et al. In this paper we shall discuss the advantages and limitations of cytogenetic analysis in monitoring the development or establishing the diagnosis of complicating (secondary) leukemia, not only in disorders proven to have such a complication but also in conditions of a nonmalignant nature in which leukemia is increasingly becoming a serious complication [35,47,56,90]. In addition, the chromosome findings in published cases of complicating leukemia have been tabulated; the cases included in this tabulation are those associated with cancers of various organs, lymphomas, MM, nonmalignant conditions treated with cytotoxic drugs, and complicating leukemia in other forms of leukemia. Leukemias associated with such hematopoietic disorders as polycythemia vera (PV) and others have not been included, since they appear to be part of the integral progression of these diseases, unless the therapy used is known to be associated with a higher incidence of complicating leukemia. Since the number of patients with complicating leukemias involved in cytogenetic studies, particularly those based on banding analysis, is still relatively small, and since differences in treatment of the primary conditions differ among clinics, it is important to report the karyotypic findings on as many patients with complicating leukemias as are available, so that a clearer picture may be obtained on the development of such leukemias and possible factors leading to their evolution. The present report describes our experience with 20 patients with leukemia complicating other neoplastic and nonneoplastic diseases.

MATERIALS AND METHODS

The cytogenetic techniques used in analyzing the marrow samples of the patients have been described in detail elsewhere [83,84]. For more detailed analysis, G-, Q-, and C-banding methods were utilized, particularly in cases in which marker chromosomes were encountered. The case histories of two patients are presented in this paper in some detail, one describing a fairly typical course of the disease in a patient in whom a complicating acute leukemia developed following therapy for MM, and the other demonstrating the use of cytogenetic analysis in a case in which, though the cytogenetic findings revealed a definite abnormality, the clinical picture continued to be complicated. CASE REPORTS Case 9 (F.S.). A 52-year-old male with diabetes mellitus was diagnosed as having

MM of the IgA type in July 1974, at which time he received radiation to the spine. (An immunologic idiotype of this patient has been published [5], which incidentally indicated that the myeloma and erythroleukemia (EL) cells had separate clonal origins.) In October 1974, he was referred to Roswell Park Memorial Institute (RPMI) for further diagnostic and therapeutic procedures. At that time his blood IgG was found to be definitely elevated, his urine was shown to contain Bence-Jones protein, his hemoglobin level was 14 g/dl, his platelet count was 162,500/mm, ~ and his WBC count was 3500/mm 3 with a normal differential. The patient was given 1,3-bis(2chloroethyl)-l-nitrosourea therapy for 6 weeks (150 mg/m2), prednisone (0.8 mg/kg), and Diabina:e for his diabetes. Before therapy was started, the bone marrow was shown to contain 32% abnormal plasma cells compatible with those of MM. In July 1975, 20% such cells were seen in the marrow, at which time his hemoglobin level was 11.3 g/dl, his platelet count 257,000/mm 3, and his WBC count 5200/ram 3 with a normal differential. He was started on phenylalanine mustard (PAM) therapy (8 mg daily for 7 days) and prednisone (100 mg daily for 14 days), and after 14 days

Secondary Leukemia

97

the drug dosages were reduced. In October 1975, only 3.8% plasma cells were found in the marrow. The patient did fairly well, as indicated by the 9.6% plasma cells in the marrow in January 1976 accompanied by a WBC count of 3100/mm3; in March 1976 only 3% plasma cells were seen in the marrow. In May 1976 there was an increase in the number of lytic lesions of the bones, for which the patient did not require any further therapy, and in September of that year only 3% plasma cells were observed in the marrow; the patient had a fairly normal blood picture. In February 1977, the patient broke his finger as the result of a myeloma lesion and was restarted on PAM therapy which had to be discontinued because of severe pancytopenia. Radiation was given to the site of the fracture, and in May 1977 the patient was given intermittent intravenous PAM therapy as well as red cell and platelet transfusions. In June 1977 his WBC count was 3350/mm 3, his platelet count was 35,000/mm 3, his hemoglobin level was 8.7 g/dl, and only 4% plasma cells were found in the marrow. However, the patient developed a fever, probably because of a large abscess on the thigh. In August 1977, his platelet count was only 9500/ram 3, his WBC count was 200O/mm 3, and only 0.4% plasma cells were present in the marrow. The patient was started on cytoxan (cyclophosphamide), adriamycin, and prednisone. In September 1977 his hemoglobin level was 8.7 g/dl, hematocrit 27%, WBC count 6000/mm 3, and platelet count 2O,000/mm 3. The blood differential revealed the presence of 10% blasts, 3% promyelocytes, 4% myelocytes, 43% stabs, 7% lymphocytes, and 4% monocytes. A diagnosis of EL was established soon thereafter on the basis of the bone marrow cytology, which showed a definitely increased number of myeloblasts and promyelocytes accompanying megaloblastic hyperplasia. The patient died on November 1, 1977. Case 19 (D.J.). A 48-year-old male first developed symptoms in October 1977 consisting of pain in the left thigh, which he claimed was localized to the bone, fever (102-103°F), night sweats, and several episodes of herpes simplex infection. In November 1977, an enlarged lymph node was observed in the left neck region, which upon excision was shown to contain nonspecific lymphadenitis. On November 23, 1977, the spleen was found to be 3 cm below the costal margin, and a lymph node (2 cm in diameter) palpated in the left axillary region. An X ray of the chest revealed a small mediastinal mass. At that time the marrow was found to be hypocellular in nature, with a shift to the left in the granulocytic series. Cytogenetic analysis of the marrow revealed aneuploidy consisting primarily of an extra chromosome probably due to an isochromosome of the long arm of chromosome #12. During December 1977, the hemoglobin and platelet counts were found to be normal, whereas the WBC count of 16,000-24,000/mm 3, originally characterized by a normal blood differential, on December 23, 1977, showed 6% blasts, 1% promyelocytes, 5% myelocytes, and 2% nucleated red blood cells. The leukocyte alkaline phosphatase reaction was shown to be within the normal range. On December 23, 1977, X ray of the cheat revealed a mass in the right hilar area extending to the anterior mediastinum of the right side, which showed an increase in size from that observed about a month previously. On December 21, 1977, a thoracotomy was performed, and a biopsy of the mediastinal mass showed it to be teratocarcinoma. On January 3, 1978, the patient's WBC count was 50,000/mm 3, with a definite shift to the left. He was operated upon on January 10, 1978, and the mediastinal tumor removed; this was followed by radiation consisting of 4000 rads to the mediastinum. In early February 1978, the patient noticed a rather large (10.5 × 13 cm) mass in the right thigh, which upon biopsy was shown to be a teratocarcinoma. He received 3000 fads to the mass in April 1978 and was then started on chemotherapy [cis-diammine dichloroplatinum (DDP), bleomycin, and vinblastine]. A sonogram revealed a mass in the liver, and a tomogram nodules in the chest. The patient was

A. A. Sandberg et al.

98 Table 1 Patient's no. and initials

Clinical findings in patients with complicating leukemia in the present study a Age and Sex

2 H.B. 3 R.B.

77, M 25, M

4 M.B.

50, F

5 V.B.

51, M

6 E.L.

80, M

7 L.M.

43, M

8 R.B.

70, M

9 F.S. 10 S.S,

Therapy Diagnosis and date MM, April 1975 Lymphoma/ALL, Nov. 1977 Lung cancer/ andometria[ cancer, Feb. 1970 MPDc, Feb 1975 ITP, lymphoma?, May 1967 Lymphoma, April 1972

Drugs received b Alkaran, CCNU, P Cyt,P

Duration of AL

Oct. 1978 June 1978

Oct. 1978 June 1978

11 mo 1 mo 3 mo

--

April 1975

July 1978

Decadurablin, P,oxymetholone Imm, cyt,6MP, VC,P --

--

--

--

Cyt,adr,P

49, M 70, M

11 B.D,

45, F

HD, Sept. 1971

Cyt, proc,P,VC

12 D.F.

28, M

HD, March 1969

MM, Aug. 1967

3000 [1975) --

Date AL diagnosed

Adr, Proc,CCNU, cyt,MTX

Lymphoma, April 1975 MM, July 1974 MM, July 1973

13 H.McL.

X ray (rods)

Date of first BP hyperplasia

BCNU,PAM,P PAM, P

1967 >15,000 (19721973) --

Aug. 1972

Jan. 1978

5800 2400 (1974, 1977) 6000 [1971)

March 1977 April 1977

NM,BCNU, MOPP,P, bleo,proc Mel, VC, Cyt,P

6000 (1969, 1975)

May 1975

3600 (1973)

1973

1972

--

March 1975 Sept. 1979

2.5 yr

April 1978 Oct. 1977 July 1977

3 mo

Sept. 1978 March 1979

8 mo

3 me

7 mo 1 mo

7 mo

Nov. 1978

Aug. 1979 June 1980

3 mo 2 mo

Aug. 1979

Oct. 1979

1 mo

--

8 mo 9 mo

14 L.B.

77, F

HD, April 1975

15 M.C.

54, F

Ovarian cancer, Nov. 1967

NM,VC, proc,CCNU, P AMD,5FU, meI,MTX, cyt

16 M.Z.

18. M

HD, Oct. 1977

CCNU,VC, proc,P

8900? (1975, 1976, 1978) 12,0007 (1967, 1972, 1978, 1979} 2000 (1977)

17 T.R.

15, M

MTX,VC, cyt,6MP, P

4400 (1974~ 1980}

June 1980

18 H.L.

69, M

Cyt

No

Sept. 1979

Oct. 1979

1 mo

20 I.M.

48, M

Lymphoma, December 1973 Bladder cancer, July 1971 MM, Nov. 1975

Nov. 1979 June 1980

VC,PAM,P

3000 (1975)

June 1981

June 1981

10 too+

°Cases 1 a n d 19 are n o t i n c l u d e d i n t h i s table s i n c e n e i t h e r r e c e i v e d c h e m o t h e r a p y or r a d i a t i o n t h e r a p y for n e o p l a s i a . AL, A c u t e l e u k e m i a ; BP, b l a s t i c phase. bCCNU, 1 - ( 2 - ) - ( C h l o r o e t h y l ) - 3 - c y c l o h e x y l - l - n i t r o s o u r e a ; P, p r e d n i s o n e ; cyt, cytoxan; adr, a d r i a m y c i n ; proc, procarbazine; MTX, m e t h o t r e x a t e ; i m m , i m m u r a n ; GMP, 6 - m e r c a p t o p u r i n e ; VC, v i n c r i s t i n e ; BCNU, 1,3-bis(2c h l o r o e t h y l ) - l - n i t r o s o u r e a ; PAM, p h e n y l a l a n i n e m u s t a r d ; NM, n e o m y c i n ; MOPP. m u s t a r g e n , o n c o v i n , procarbazine, p r e d n i s o n e ; bleo, b l e o m y c i n ; mel, m e l p h a l a n ; AMD, a c t i n o m y c i n D; 5FU, 5-fluorouracil; allo, a l l o p u rinol; ara-C, c y t o s i n e a r a b i n o s i d e . CMPD, M y e l o p r o l i f e r a t i v e disorder.

maintained on the chemotherapy, though the dosage had to be adjusted because of severe thrombocytopenia observed in July 1978, at which time his platelet count dropped to 55,O00/mm 3, his WBC was 34,000/mm 3, and his hematocrit was 34%. The patient died on September 24, 1978. Autopsy revealed the presence of a metastatic teratocarcinoma and evidence of leukemia, probably subacute myeloid leukemia (SML). C o m m e n t s o n C a s e s 9 a n d 19

The two cases presented, though complicated and interesting, offered an opportunity for the cytogenetic studies to be of considerable, if not crucial, value in arriving at the exact diagnosis for the two patients. In case 9 karyotypic analysis of the

99

Secondary Leukemia

T i m e for d i a g n o s i s of o r i g i n a l d i s e a s e to

Date of

d e a t h (years) 3.3 0.75 8

--

T y p e of A L

T h e r a p y for A L b

Response

Date of first

death

Preleukemia

cytological study

---

---

AML AML

6MP,VC,AIIo A d r , A r a - C , VC,P

Good Poor

Aug. 1979 July 1978

AMMoL

VC,6MP, P

None

Nov. 1 9 7 8

Poor

M a y 1979

--

--

CMMoL -* AMMoL

8

AML

Ara-C,VC, 6 M P , P

Poor

J u l y 1977

Yes

1/21/72

6.5

AML

VC,P

Poor

Nov. 1979

Yes

--

3

AML

?

None

July 1979

--

4/11/78

3

EL

Cyt,adr,P

None

Nov. 1977

Yes

4

AML

VC,6MP,allo,P

None

A u g . 1977

Yes

4/5/77 8/1/77

7

AML

Thio,VC,P 5FU

None

M a y 1979

--

--

--

Nov, 1 9 7 9

--

--

None

Oct. 1 9 7 9

--

--

--

June 1980

Yes

--

Thymidine, 5-FU

None

Nov. 1 9 7 9

--

--

--

Nov, 1971

--

--

M a r c h 1991

--

--

Oct. 1979

No

9/19/79

Alive

Yes

10

EL

12

AML

5

--

VC,P

AML

--

12

EL

2.5

AML

--

6.5

ALL

AMD,ara-C, A d r

EL

None

--

AML

Ara-C

Partial

8 Alive

Poor

6/25/81

marrow revealed abnormal cells, undoubtedly leukemic, many weeks before there was a change in the bone marrow cell differential or clinical course of the disease. Unfortunately, at present the clinician is not in a position to decide upon an appropriate therapeutic course in patients with secondary acute leukemia, since he or she is faced not only with the problem of the primary disease and its therapeutic complications (e.g., bone marrow hypoplasia) but also that of whether preleukemia therapy is, in fact, indicated for the acute leukemia [usually acute myeloblastic leukemia (AML)]. In any case, there is little doubt that therapeutic approaches to the treatment of secondary acute leukemias will be established and that cytogenetic studies will be crucial, for they reveal the presence of acute leukemia at a much earlier stage than other histologic, laboratory, or clinical aspects. Case 19 presented a complex clinical picture in which the presence of a tumor with a possible leuke-

100

A.A. Sandberg et al. moid reaction was considered a distinct possibility. Chromosome studies on bone marrow cells revealed unequivocally the presence of karyotypic changes compatible with leukemia, since the chromosome constitution of blood lymphocytes was normal, excluding a congenital cytogenetic abnormality, and no tumor cells were encountered in the marrow.

CYTOGENETIC RESULTS Some of the clinical features, particularly as they relate to the development of secondary leukemia, of the various patients are shown in Table 1. Data for cases 1 and 19 are not shown in Table 1, since they were not treated with chemotherapy or radiation before the development of leukemia. However, both patients had considerable exposure to diagnostic radiation because of their lung lesions, and whether this did or did not play a part in the genesis of the complicating leukemia cannot be ruled out with certainty. In Table 2 are presented the major cytogenetic findings in these cases, and in Table 3a and b the chromosome counts for patients who had more than one cytogenetic analysis performed during the course of their disease. The development of leukemia following the original diagnosis ranged from 8 months to 12 years. The median was about 4 years. Of the 20 patients reported in this paper 5 had MM, 4 |ymphoma, and 4 Hodgkin's disease (HD). One of the patients had lung carcinoma followed by endometrial cancer, one had bladder cancer, one had a choriocarcinoma, and one had ovarian cancer. One patient suffered from a myeloproliferative disorder, one from tuberculosis (TB), and one from idiopathic thrombocytopenic purpura (ITP) complicated probably by lymphoma. All the patients (except for cases 1 and 19) had received some form of chemotherapy, directed toward either the neoplastic disease or other condition, before development of the acute leukemia. In addition, 8 of the patients had received radiation either before or in conjunction with chemotherapy. Almost all the patients developed a hypoplastic bone marrow either at the same time that leukemia was diagnosed or shortly before. Following the diagnosis of acute leukemia the patients lived from 1 to 11 months, withe the exception of one patient who lived for a little over 2 years. In the latter case the leukemia seemed to behave more like a subacute variety than an acute type. Six of the patients lived less than 3 months following the diagnosis, indicative that survival in complicating leukemia is much shorter than that seen in spontaneous types of leukemia. An interesting case is patient 17 who appeared to develop acute lymphoblastic leukemia (ALL) complicating a lymphoma. The morphology of the cells left little doubt as to the type of diagnosis, and thus this case appears to represent a rare form of ALL complicating another disease. The cytogenetic findings in the patients will be discussed in some detail, particularly for those patients for whom serial chromosome studies were available. Case 1 (F.A.). In this patient's marrow a mixture of normal (diploid) cells and hyperdiploid cells with trisomy 8 was found.

Case 2 (H.B.). Unfortunately, only one bone marrow specimen was available for this patient, who developed AML following treatment of MM. No karyotypic abnormalities could be ascertained. Case 3 (R.B.). The major clinical, cytologic, and immunologic findings of this case have been reported previously [40]. This patient's malignant.lymphoma was shown to be of the pre-T-cell type and terminated in AML. On 10/19/77, when the patient was seen for his lymphoma, bone marrow examination revealed a normal 46,XY

F F

F

M M M

M M

13 H . M c L . 14 L.B.

15 M.C.

16 M.Z. 17 T.R. 18 H.L.

19 D.J. 20 J.M.

Teratocarcinoma/SML Myeloma/AML

HD/AML Lymphoma/ALL Bladder cancer/EL

Ovarian cancer/EL

Myeloma/AML HD/AML

Myeloma/AML Lymphoma/ALL/AML Lung cancer/endometrial cancer/AML Myeloproliferative disorder/AML ITP/AML Lymphoma/EL Lymphosarcoma/AML Myeloma/AML Myeloma/AML HD/AML HD/EL

bdms = double m i n u t e chromosomes.

~Cells with nonclonal abnormalities,

M M M M M F M

E.L. L.M. R.N. F.S. S.S. B.D. D.F.

M

5 V.B.

6 7 8 9 10 11 12

M

M M F

1 F.A.

TB/AML

analysis

Sex

of chromosome

Original diagnosis a n d t y p e of l e u k e m i a

Results

2 H.B. 3 R.B. 4 M.B.

Patient's no. initials

Table 2

7/13/78

12/8/77 6/25/81

9/19/79

2/10/80

10/9/79 11/28/79

7/18/79 6/5/80

3

1

6

4

3 28 18 4 2

7/12/77 9/4/78

6/1/79

2 3 22 18

4

8/12/77 6/7/77 4/11/78 6/27/77

4/22/77

7/26/78

2

1 --

10/31/78 10/6/78

-<44

complicating

47

25

1

7

--3 6

--

2 20 3 4

22

5

1 2

45

12 1 --

24 8

7

--13 17

3

4 3 2 (2) a --

--

13 20 1 (1) ° 16

46

no.

3 __ 3 -5 ----

4 __ 6 2 12 -15 --

, + 15, + M

- Y / 4 4 , X , - Y, - 21

- 17, + 2 d m s b / 4 3 , X X , - 15, - 17, - 20, + 3 d m s 21, - 21, + 3 M 11,t(1;11},del(1)

47,XY, + i(12p) 45,XY,- 7

See text 4 4 , X X , - 15, 4 5 , X X , - 5, 46,XY,- 1,47,XY,+M 46,XY/45,X,

4 6 , X Y / 4 8 , X Y , + 7, + 8, + 8 , - 17 45,XY, - 7/46,XY 42,X,- Y,4q + ,- 8,- 16,17p +,- 21,- 22,+ Yp + 4 4 , X Y , - 2 , 3 p - , - 5 , - 6, - 17, - 20, + t ( 2 ; 6 ) , + t(5;6}, + t(17;20} 4 4 , X Y , - 7, - 16, - 19, - 21, - 22, + M1, + M2, + M J 4 6 , X Y 4 4 , X , - X, - 5 , t ( 3 ; 7 ) / 4 4 , X X , - 7, - 8 / 4 4 , X X , - 5, - 8 4 3 , X Y , - 3 , - 1 5 , - 15

13 ---1 ---

2 ---1 ---

- -

45,XY,- 7

4

, + 3p-

46,XY/47,XY, + 8

--

- -

1

m

-18

9

Clonal karyotype

46,XY 48,X,-Y,lp46,XX

- -

4 8 ~:

leukemia

47

No. of c e l l with chromosome

with

Date

in 20 cases

-3 2

Lymphoma EL EL

AML

.

complicating

4

3 30 19

----2

5 -2 (2) c

.

.

19 3 --

25 28 25 11 4

16 2 3 (21) c 2 3 (23) c

1 (1) ~

19

23

46

--1

----2

----

4

--

--

47

no.

leukemia

13

18

2

48_<

44,XY,+ t(2;6), 44,XY,+ t(2;6),

2,3p- ,+ t(5 ;6), + 2,3p - ,+ t(5;6), +

46,XY 46,XY,- 7/46,XY 45,XY, - 7 5 , - 6 , - 1 7 , - 20, t(17;20)/46,XY 5, - 6, - 1 7 , - 2 0 , t(17;20)

46,XY 46,XY 46,XY 46,XY 4 6 , X Y / 4 8 , X Y , + 7, + 8, + 8, - 1 7

46,XX 46,XX/46,XY,Ph ~ 46,XY,Ph 1

46,XY 46,XY 4 6 , X Y / 4 8 , X , - Y , l p - , + 3 p - , + 15, + M 4 8 , X , - Y , l p - , + 3 p - , + 15, + M

Clonal karyotype

~Cells with mate karyotype. N u m b e r s in p a r e n t h e s e s i n d i c a t e n u m b e r of cells w i t h P h L p o s i t i v e m a l e k a r y o t y p e .

~The patient received a bone m a r r o w transfusion f r o m a P h L p o s i t i v e male CML patient 2 d a y s before the study. At that time, a c h r o m o s o m e s t u d y w a s p e r f o r m e d on a peripheral blood culture (24 hr) w i t h o u t PHA.

18

.

----2

ITP ITP ITP ITP AML

Myeloma

2 2 (1) c --

--

1

1

--

2

45

--

-<44

with

N o . of c e l l s w i t h c h r o m o s o m e

in five patients

AML AML AML

changes

~Cell with nonclonal karyotypic abnormality~

6/27/77

F.S. ( c a s e 9) 4/5/77

6/7/77 9/13/77

2/19/75 6/3/76 8/12/77 L.M. ( c a s e 7) 3/30/73

12/7/74

9/30/78 b 10/2/78 E.L. ( c a s e 6) 1/21/72

7/26/78

M.B. ( c a s e 4)

AML

Lymphoma ALL AML?

R.B. ( c a s e 3) 10/19/77 4/1/78 6/9/78

7/13/78

Diagnosis

Serial karyotypic

Patient and date

Table 3a

['.o

Secondary Leukemia

Table 3b

103

Serial c h r o m o s o m e c o u n t s for t h r e e c a s e s w i t h c o m p l i c a t i n g l e u k e m i a Number of chromosomes

Patient and date M.C. (case 15) 10/9/79 10/23/79 10/29/79 11/8/79 H.McL. (case 13)

7/18/79 8/30/79 9/4/79 9/24/79 10/1/79 B.D. (case 11) 2/27/79 3/9/79 3/28/79

4/10/79

-<43

44

45

46

47

48

49 >

Poly

Total cells

4 2 5 4

4 2 7 8

4 7 1 3

1 7 9 6

1 6 -1

-2 -1

-1 ---

1 -2 --

15 27 24 23

5 4 3 6 1

9 4 3 4 3

14 3 1 6 3

2 3 5 8 13

-5 1 8 4

-4 2 4 3

-1 4 3 --

2 3 ----

32 27 19 39 27

6 14 7 6

17 7 14 12

5 1 1 3

-1

28 25 25 25

.

. 3 2 3

. . 1 --

. .

. .

---

. ---

k a r y o t y p e , a p i c t u r e t h a t w a s a g a i n o b t a i n e d i n A p r i l 1978. H o w e v e r , 2 m o n t h s l a t e r w h e n a s u s p i c i o n of A M L arose, 2 cells o u t of 23 w e r e s h o w n to h a v e t h e k a r y o t y p e 48,X,-Y,1p-, + 3 p - , + 15 p l u s e o n e m a r k e r (Fig. 1). T h i s k a r y o t y p e t h e n c h a r a c t e r i z e d a l m o s t all t h e c e l l s of t h e b o n e m a r r o w o b t a i n e d m o r e t h a n a m o n t h later, i n d i c a t i n g p r o g r e s s i v e i n v o l v e m e n t of t h e m a r r o w b y t h e l e u k e m i c p r o c e s s .

Case 4 (M.B.). T h i s p a t i e n t o r i g i n a l l y h a d h a d l u n g c a n c e r t r e a t e d n e a r l y t h r e e dec a d e s b e f o r e d e v e l o p i n g e n d o m e t r i a l c a n c e r . A M L s u p e r v e n e d f o l l o w i n g t h e r a p y for t h e latter, a n d t h e p a t i e n t u l t i m a t e l y d i e d of t h e l e u k e m i a . A t o n e p o i n t t h e p a t i e n t received bone marrow transfusions from a Phi-positive male with chronic myeloc y t i c l e u k e m i a (CML). T h i s t r a n s f u s i o n w a s g i v e n 2 d a y s b e f o r e t h e c y t o g e n e t i c s t u d i e s . T h u s , t h e p r e s e n c e of P h 1 i n t h e c e l l s of t h e s p e c i m e n o b t a i n e d is n o t surp r i s i n g . H o w e v e r , t h e k a r y o t y p e o b t a i n e d o n 7/26/78 (before t h e r a p y ) w a s f o u n d to b e t h a t of a n o r m a l female. Case 5 (V.B.). T h i s p a t i e n t , w h o h a d a m y e l o p r o l i f e r a t i v e d i s o r d e r , d e v e l o p e d A M L , a n d all b o n e m a r r o w cells w e r e s h o w n to h a v e m o n o s o m y 7. C a s e 6 (E.L.). D u r i n g a p e r i o d r a n g i n g f r o m J a n u a r y 1972 to J u n e 1976, w h e n t h e pat i e n t w a s t h o u g h t to h a v e ITP a n d p o s s i b l y l y m p h o m a , t h e k a r y o t y p e s of t h e b o n e m a r r o w w e r e a l w a y s t h o s e of a n o r m a l male. O n l y i n 1977, w h e n A M L s u p e r v e n e d , w a s t h e b o n e m a r r o w s h o w n to b e a b n o r m a l , c o n s i s t i n g m o s t l y of h y p e r d i p l o i d c e l l s w i t h t h e k a r y o t y p e 48,XY, + 7, + 8, + 8, - 17. T h i s p a t i e n t h a d a r a t h e r p r o t r a c t e d c o u r s e of dise a s e . a n d , i n fact, h i s l e u k e m i a l a s t e d 21/2 years, t h e l o n g e s t p e r i o d for a n y p a t i e n t i n t h e p r e s e n t series, s u g g e s t i n g t h a t h e m a y h a v e s u f f e r e d f r o m a r a t h e r a t y p i c a l f o r m of A M L r e s e m b l i n g C M L i n m a n y w a y s b u t w i t h o u t a P h 1.

Case 7 (L.M.). T h e b o n e m a r r o w e x a m i n e d i n 1973 w h e n t h e p a t i e n t h a d l y m p h o m a w a s s h o w n to b e t h a t of a n o r m a l m a l e ; w h e n t h e a c u t e l e u k e m i a s u p e r v e n e d i n 1977 (EL?), t h e m a r r o w w a s s h o w n to c o n t a i n a f e w d i p l o i d c e l l s b u t p r e p o n d e r -

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I

Ill

2

,/

3

4

I1 !1 1t In s.t It

5

12

i *t 0 ~ t. ~ ix,o ,d,, o,m

13 19

14 20

15

**

p**

21

22

X

M

Figure 1 Hyperdiploid karyotype of marrow from case 3 (R.B.) with l p - , + 3 p - , + 15 and a marker (M). The origin of the marker could not be ascertained. Arrows point to l p - and 3 p - , respectively. antly to consist of cells with the karyotype 4 5 , X Y , - 7, a picture that persisted during the next examination. Case 8 (R.N.). Only karyotypically abnormal cells were found in the bone marrow of this patient at the time that he developed AML. The karyotype was rather complicated but seemed basically to consist of 4 2 , X , - Y,4q + , - 8, - 16,17p + , - 2 1 , - 22, + Yp + (Fig. 2). Case 9 (F.S.). A bone marrow specimen, examined during a hypoplastic phase, was revealed to have an abnormal karyotype consisting of h y p o d i p l o i d y and a n u m b e r of translocations and other structural changes. The translocations involved chromosomes #2, #3, #5, #6, #17, and # 2 0 (Fig. 3). Some cells with diploid karyotypes were present. W h e n examined during the frank AML phase, the marrow was found to be totally aneuploid with the same karyotype as described above. At the time the AML developed the patient's bone marrow cells contained a rather complex karyotype consisting of 44,XY, - 2,3p - , - 5, - 6 , - 17, - 20, +t(2;6), +t(5;6),+t[17;20). In April 1977 a few normal cells were present, but they were absent from the marrow w h e n it was examined 2 months later, indicating that the leukemic cells had replaced the normal elements of the marrow.

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105

Figure 2 Hypodiploid karyotype of case 8 (R.N.) with 4 2 , X , - Y , 4 q + , - 8 , - 1 6 , 1 7 p + , - 2 1 , + Y p + . Yp + possibly consisted of the long arm of the Y (highly fluorescent portion) and most of the long arm of chromosome #10. Upward arrow points to 4q+, downward arrow to 17p+.

Case 10 (S.S.). Only one karyotypic examination was performed on this patient at the time that he developed AML. The bone marrow consisted of a mixture of abnormal and normal cells with the abnormal cells containing the karyotype 44,XY, - 7, - 16, - 19, - 21, - 22 and three markers (Fig. 4). The origin of the markers could not be ascertained. Case 11 (B.D.). The marrow of this patient consisted of a mixture of karyotypes, all abnormal in nature. All the cells were hypodiploid, some of them containing monosomy 5 and a translocation between chromosomes # 3 and #7, others having monosomies 7 and 8, and still others monosomies 5 and 8 (Fig. 5). Minor populations of cells contained monosomies 5 and 7 as well as a translocation between chromosomes #3 and # 7 and a marker, and those with 42 chromosomes i n c l u d e d - 5 , - 7 , - 1 4 , - 1 9 , and t(3;7). Thus, in this patient considerable karyotypic variety existed among the cells, though the majority of them appeared to have been characterized by monosomies 5 and 7 and t(3;7). These anomalies characterized the bone marrow that was examined over a period of nearly 6 weeks. The translocation t(3;7) was s h o w n to be due to (q13;p12).

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Figure 3 Hypodiploid karyotype from case 9 (F.S.) with 3p-,-5,-6,t(2;6),t(5;6),t(17;20),-20. Some variations on this karyotype occurred in the marrow ceils. The abnormalities probably involved an insertion of part of the short arm of chromosome #2 into the short arm of chromosome #6, translocation of the short arm and centromeric area of chromosome #5 to #6, and translocation of most of chromosome #20 to #17. Arrows point to 2p +, 3 p - , 6p +, and 17p *, respectively.

Case 12 (D.F.). All cells examined in this patient were karyotypically abnormal and had the karyotype 4 3 , X Y , - 3 , - 1 5 , - 15 (Fig. 6). Case 13 (H.McL.). The bone marrow of this patient during the acute leukemic phase, after m a n y years of treatment for MM, was examined over a period of nearly 3 months. The outstanding feature of the cytogenetic findings was the instability of the karyotype in the leukemic cells, with variations not only in the chromosome n u m b e r but also in karyotypes in cells containing the same n u m b e r of chromosomes (Fig. 7). W h e n the bone marrow was first examined on 7/18/79 and a suspicion of acute leukemia was entertained, only 1.8% blasts, 12.4% promyelocytes, and 7.6% plasma cells were present in the marrow.The chromosome n u m b e r ranged from 38 to 46, four cells being polyploid. The cells had a modal n u m b e r of 45 chromosomes, no two cells with this n u m b e r having identical karyotypes. Eight of the cells had double m i n u t e s (dms), their n u m b e r varying from one to eight per cell. Incidentally, the counts given in the tables are exclusive of the dms. Five cells were karyotyped in detail, and a few c o m m o n features noticed, consisting primarily of - 5 ,

F i g u r e 4 Hypodiploid karyotype with - 7 , - 1 6 , - 1 9 , - 2 1 , - 2 2 and three marker chromosomes (M1-M3) from case 10. M3 is a ring chromosome. The origin of the markers could not be established with certainty. F i g u r e 5 Hypodiploid karyotype of a bone marrow cells with - 5 , - 7 , 8 q - , t ( 3 ; 7 ) of case 11 (B.D.). Downward arrow points to 3q+ resulting from t(3;7), upward arrow to 8 q - .

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Figure 6 Hypodiploid karyotype from case 12 (D.F.) with 43 chromosomes as a result of loss of chromosomes in groups 3 and 15 ( - 3 , - 1 5 , - 1 5 ) .

- 1 1 , - 1 3 , - 1 8 , and - 2 1 . One c h r o m o s o m e #1 and one c h r o m o s o m e #17 were missing in three out of five cells. A c o m m o n marker chromosome, 11q+ (M1), was present in four out of the five cells k a r y o t y p e d (Fig. 7). The cells contained four to nine markers ranging from very small to very large, but w i t h variations from cell to cell. The second cytogenetic s t u d y performed on 8/30/79 revealed a pattern similar to the previous one, w i t h the c h r o m o s o m e counts ranging from 40 to 50 and two p o l y p l o i d cells. The karyotypes were very similar to the ones described above. During the next examinations the karyotype did not change significantly. For example, 12 karyotypes obtained from the sample of 9/24/79 revealed 3 to 11 markers per cell, each marker differing from the other in its origin. However, only one cell h a d the 11q+ described previously. Moreover, chromosomes # 5 and #13 were missing in 8 out of 12 cells karyotyped, whereas group 17 contained two c h r o m o s o m e s in 11 of 12 cells, a finding different from the previous one. It a p p e a r e d that, as the disease progressed, the karyotype became more unstable and no definite cytogenetic picture emerged. The last bone marrow s p e c i m e n from this patient, s t u d i e d on 10/ 1/79, again revealed variable karyotypes with a c h r o m o s o m e num]3er ranging from 42 to 48. None of the cells had a normal karyotype. Case 14 (L.B.). Examination of the bone marrow of this patient at the time w h e n she d e v e l o p e d AML revealed all the karyotypes to be abnormal. A l m o s t all the cells contained two dms, one of them p o s s i b l y being a small ring (Fig. 8). The karyotype was p r i m a r i l y 4 4 , X X , - 1 5 , - 17 plus 2 dms, the other cells being distributed evenly between the karyotype 4 3 , X X , - 1 5 , - 1 7 , - 2 0 plus three dins and a similar karyotype w i t h only two dms.

109

I

MI

Unidentified Markers

Figure 7 Marker M1 and unidentified marker chromosomes from case 13 (H.McL.), w h i c h was characterized by remarkable instability of and variations in the karyotypes during the course of the disease. M1 was due to 1 1 q + .

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Figure 8 Karyotype from case 14 (L.B.) with - 1 5 , - 1 7 , - 2 0 and two small marker chromosomes (M), the latter possibly being small ring chromosomes. Case 15 (M.C.). The bone marrow was examined on four different occasions during the m o n t h after the acute leukemia had been diagnosed. On 10/9/79 27 cells were examined, and the most c o m m o n abnormality noticed in 8 of these was - G and - B . Six of the cells had a small chromosome resembling a Ph I ( 2 2 q - ) and associated with a missing G. On 10/23/79 two of the cells with 46 chromosomes seemed to have a normal karyotype. G-Banding revealed c o m m o n features in the cells to be - 5 , - 2 1 , - 2 2 , and - X . Each cell had five to ten marker chromosomes whose origin could not be established with certainty (Fig. 9). However, M1 probably originated from chromosome #6, since it contained a part resembling the short arm of that chromosome; the origin of the phi-like chromosome could not be established with certainty. The karyotypic picture in the subsequent analysis did not differ from that described above. Case 16 (M.Z.). A total of ten cells were karyotyped with G-banding, none of the cells, i n c l u d i n g those with 46 chromosomes, having a normal karyotype. Two markers were present in all the cells. The most c o m m o n features of the karyotype of this patient's marrow cells were - 1 , - 1 1 , t(1;11)(q21;p15), and del(1)(p22) (Fig. 10). Case 17 (T.R.). The bone marrow of this patient was examined on two occasions. On 10/27/80 a totally normal male karyotype was obtained, whereas on 2/10/81 most

Secondary Leukemia

111

Mt Figure 9 Marker M1 of marrow cells from case 15 (M.C.); the marker possibly originated from a chromosome #6.

of the cells were h y p e r d i p l o i d w i t h the karyotype 47,XY plus one marker (Figs. 11 and 12). The cells with 46 c h r o m o s o m e s contained a normal male karyotype. Case 18 (H.L.). A b o u t two-thirds of the cells in the marrow of this patient had 45 c h r o m o s o m e s as a result of loss of the Y. Some of the cells also had - 2 1 (Fig. 13). This finding is not u n u s u a l in the marrow of normal elderly males [83]. Unfortunately, we d i d not have the o p p o r t u n i t y to examine the karyotype of his blood cells.

Case 19 (D.J.). The marrow of this patient was e x a m i n e d on four occasions. On 11/ 23/77 all the cells contained an abnormal chromosome, s h o w n to be i(12p) (Figs. 14 and 15). The c h r o m o s o m e n u m b e r was p r e p o n d e r a n t l y 47. Blood cells obtained on 12/8/77 were s h o w n to have a normal male karyotype w h e n stimulated w i t h phytohemagglutinin (PHA) and 47 c h r o m o s o m e s [including i(12)] w h e n unstimulated. On 12/29/77, 4/17/78, and 8/24/78 all the marrow cells contained i(12) and 47 chromosomes. Blood cells obtained on 12/29/77 and stimulated w i t h PHA had a p r e p o n derantly normal male karyotype (22 cells) and three cells with i(12p) (Fig. 16). Thus, the marrow of this patient consistently had cells with i(12p) and an otherwise normal karyotype. Case 20 (J.M.). The first cytogenetic e x a m i n a t i o n was performed on a blood sample on 6/25/81, at w h i c h time the patient had pancyt.openia resulting from chemotherapy [vincristine, melphalan, and prednisolone] for MM diagnosed in November 1975. Fifty cells were examined, of w h i c h 47 had the karyotype 4 5 , X Y , - 7 (Fig. 17), w i t h three metaphases having 44 c h r o m o s o m e s as a result of r a n d o m loss of chromosomes in a d d i t i o n to the - 7 . After 10 days of antileukemic c h e m o t h e r a p y (high doses of cytosine arabinoside), after w h i c h a partial remission was thought to have

112

A . A . Sandberg et al.

MI

M2

Figure 10 Markers M1 and M2 present in all the marrow cells of case 16 (M.Z.). The origin of these markers could not be established with certainty.

been obtained, cytogenetic e x a m i n a t i o n of the marrow on 8/29/81 revealed all 18 of the metaphases to be abnormal, i.e., 4 5 , X Y , - 7. The patient is still alive.

DISCUSSION The cytogenetic findings presented indicate that there is no consistent karyotypic change that characterizes leukemia complicating another disease, though some changes appear to occur more frequently than others. The karyotypic findings in

113

F i g u r e s 11 a n d 12 Hyperdiploid karyotypes containing 47 chromosomes with markers (M1 and M2} of different morphology in case 17 (T.R.). M1 is a metacentric chromosome, larger than the acrocentric M2. In some cells both markers were present.

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A.A. Sandberg et al.

Figure 13

Hypodiploid karyotype with - Y and -21 from case 18 (H.L.).

the cases of complicating leukemia published to date have been tabulated in Table 4, including some pertinent clinical information (age and sex of patient, time from diagnosis of original disease to leukemia development, survival following the diagnosis of leukemia, original diagnosis and therapy, and type of complicating leukemia). [In this paper no attempt has been made to list or refer to all cases of secondary leukemia following therapy of one type or another (or occurring spontaneously) as a complicating disease in malignant and nonmalignant conditions. Emphasis has been placed on more recent publications, particularly those containing karyotypic information, in which the reader will find ample references to some of the older literature.] Among these, morphologic changes and/or monosomies 5 and 7 have been stressed in the past [7,25,82,96], and the data of the present study (as well as those we have been able to collect from the literature; see Table 4) indicate that to these two chromosomes should be added involvement of chromosomes #3 and #17. Besides these nonrandom changes the karyotypic picture differed in other respects from case to case without two cases showing the same cytogenetic progression or evolvement. Another feature of the patients studied by us was the instability of the karyotypic pictures seen in the leukemic cells in at least three cases. Whether these changes represent clones or whether they are unique in their karyotypic instability and diversity is difficult to ascertain on the basis of presently available findings. That karyotypic progression occurs in acute leukemia developing as a complicating disease was evidenced by several patients in the present study in whom normal diploid findings were superseded by development of definite chromosomal changes which ultimately dominated the karyotypic picture in the marrow. A case in point is the patient (case 3) in whom only two abnormal cells were found in a preponderantly diploid marrow but in whom the karyotype characterizing these two cells ultimately became established in 100% of the marrow cells.

115

ii II !i I

2

it t|

3

4

5

I ) !I ¢! t t t i tt i ! 6

ii 13

19

7

8

9

20

II

12

i~i i . l !

li ii 14

I0

15

16

M

21

17

22

18

x

y

F i g u r e s 14 a n d 15 Hyperdiploid karyotypes from case 19 (D.J.) due to the presence of an extra chromosome (M), thought to be an i(12p). Figure 14 (top) is G-banded and Fig. 15 (bottom), Q-banded.

tt W0

19

1 |

20

i

e

8e

M

12

F i g u r e 16 Three partial karyotypes from case 19 (D.J.) showing the marker (M) and normal chromosomes #19, #20, and #12. F i g u r e 17

Hypodiploid karyotype with - 3 , - 7

from case 20 (J.M.).

Secondary Leukemia

117

In addition to nonrandom involvement of some chromosomes ( - 5 , - 7 , chromosomes #3 and #17), leukemia complicating other diseases, particularly that developing in patients with lymphoma or cancer treated with chemotherapy (and possibly radiation), may be characterized by chromosome instability, a shifting karyotypic picture, and possibly the ultimate establishment of a dominant clone [69,71,82,96]. Of the 18 cases reported in the present paper in which prior chemotherapy and/ or radiation was used and leukemia developed subsequently, involvement of chromosome #3 occurred in four cases, chromosome #5 in three cases, chromosome #7 in six cases (five with - 7 , one with +7), and chromosome #17 in four cases (three with - 1 7 , one with 17p+). Definite reciprocal translocations were established in two cases, but there is little doubt that other translocations, not readily identifiable, were present in other cases. Thus, in our material, involvement of chromosomes #7 and #17 was more frequent than that of chromosomes #3 and #5. Predominant involvement of chromosome #5 has characterized some series of cases and that of chromosome #7 others, though in almost all significant series of patients with complicating leukemia studied to date the four chromosomes mentioned above were preferentially involved, with the incidence varying from series to series. Preferential involvement of chromosome #5 (particularly monosomy 5) and chromosome #7 (monosomy 7) in complicating leukemia has been stressed by previous workers and, in fact, has been advanced as being rather characteristic of such leukemia. The data of the present study, as well as examination of the cases published in the literature, indicate to us that included among the chromosomes preferentially involved in complicating leukemia should be chromosomes #3 (particularly its short arm) and #17. Involvement of these chromosomes may range from 3 p - , to loss of chromosome #3, to similar involvement of chromosome #17. Thus, among the 206 cases mentioned in the present paper (Table 1 and 4), chromosome #7 was involved in 60 cases (29%), #5 in 38 (19%), #17 in 34 (17%), #3 in 24 (12%), #21 in 21 (10%), and #8 in 19 (9%). All other chromosomes were less frequently involved. It is possible that the cases of acute nonlymphocytic leukemia (ANLL) in which these four chromosomes (#3, #5, #7, and #17) are preferentially affected and which have been to date considered to be of spontaneous origin may, in fact, be leukemias caused by noxious and leukemogenic agents which, though hitherto unknown, should be rigorously looked for. Recently, considerable emphasis has been put on chromosome #3 as a participant in chromosomal changes observed in various hematopoietic conditions (for review see Ref. 85). Thus, the observation that involvement of chromosomes #3 in complicating leukemia is a rather preferential event is in keeping with the observations just mentioned. Admittedly, the group of patients with complicating (secondary) leukemia discussed in this paper is heterogeneous; however, the chromosome changes observed during the leukemic phase resembled those described in more homogeneous (e.g., lymphoma) groups of patients with such complications. Thus, it appears to us that the deciding parameter, at least as far as the chromosomal changes in complicating leukemia are concerned, is not the underlying disease per se but the agents used in therapy for the original condition and responsible for causing the appearance of the complicating leukemia. It is difficult not to come to this conclusion when it is apparent that similar karyotypic changes have accompanied acute leukemia developing in patients receiving chemotherapy (and radiation therapy) for ovarian or breast carcinoma, various forms of lymphoma, and diseases of a nonmalignant nature. As indicated elsewhere in this paper, since the changes observed in at least some of the patients resembled closely thse seen in so-called spontaneous ANLL, it is possible that the causes, at least in some of these spontaneous cases, may be related to

3 yr/4 mo 3 yr/3 mo 7.5 yr/3 mo 3.3 yr/ 1.5 yr~/? 0.6 yr~/? 2.5 yr/8 mo

3 yr/2 mo 10 yr/7 mo

2.5 yr/2 mo

3.5 yr/2 mo

3.25 yr/1 mo 3 yr/1 m o 2 yr/3 mo

F M M M F M M

67, 51, 20, 23, 19, 27, 50,

61, F 61, M

60, F

57, M

69, F 51, F 38,M

6 yr/4 mo 2 yr/5 mo . 8 yr/1.5yr ~ 15 yr/2 mo

9 yr/9 mo

F M M F

10 yr/4 mo

Time from original diagnosis and survival after leukemia onset

~ ~ ~ --~

AML EL CML AML

EL AML AML AML AMMoL AML AML

MM --~ AMMoL MM --~ RCL HD--~ AML

MM --~ AMMoL

MM -~ AMMoL

MM --~ AML P l a s m a c y t o m a --~ EL

MM ~ HD ~ HD ~ HD ~ HD--* HD ~ MM ~

HD --~ AML

HD HD HD HD

HD ~ EL

Original diagnosis and type of l e u k e m i a °

+ + + +

C+R C C+R

C+R

R R R R

+ R

C+R

C C

C R C C C C C

C + R

C + R R C + R C + R

C +R

T h e r a p y prior to leukemia b

G

45,XY, - 3, - B, + C?/ 44,XY,- B,- G,- 16,+C? 5 6 , + B , + 4 C , + D , + F , + 3M 42,XX, - 3D, - 17(18?), - F, + M 47,XY, + 14, - 17, + 18/48,XY, + 8, + 14, - 17, + 18/46,XY, - 8, + 14, - 17, + 18/46,XY, + 1 4 , - 17, + 18, -21

- 17(18?),-

Considerable s p r e a d in the h y p o d i p l o i d area, ranging from 34 to 45 w i t h p o l y p l o i d multiples; no c o n s i s t e n t a b n o r m a l i t y from cell to cell 4 6 , X X , - C , ( - 12?),+ D, + 1 6 , - G 47,XY, + C , - 1 6 , + M 46,XY,Ph 1 + 42-43 chromosomes; karyotyping difficult b e c a u s e of m o n o s o m i e s and trisomies A n e u p l o i d y w i t h o u t breaks, gaps, and deletions 43-44, - C c h r o m o s o m e s Partial deletion of D 44 (100%) 46,Ph 1 + (100%) 46/45, - C 45, - C/46 44,XY, - D, - E, r e a r r a n g e m e n t s in group C 46,XX, m u l t i p l e c h r o m a t i d breaks 4 5 - 4 8 (25%), 6 5 - 7 0 (25%), 30-35 (50%), 6 5 - 7 0 d o u b l e of the latter 44,XX, - B, - 17(18?)/43,XX, - B,

Karyotype of leukemic cells Ref.

L u n d h et al., 1975 [59]

Hossfeld et al., 1975 [43]

Hossfeld et al., 1975 [43]

Dahlke a n d Nowell, 1975 [23]

Canellos et al., 1975 [15]

Bennett, 1971 [6] W e i d e n et al., 1973 [94] Canellos, 1975 [16]

Steinberg et al., 1970 [91]

Ezdinli et al., 1969 [29]

D u r a n t and Tassoni, 1967 [26]

K a r y o t y p e s a n d s o m e c l i n i c a l i n f o r m a t i o n o n c a s e s of c o m p l i c a t i n g l e u k e m i a r e p o r t e d i n t h e l i t e r a t u r e

30, M

33, 72, 21, 36,

7, M

Age and sex

Table 4 O0

2.75 yr/8 m o 6 yrC/5 m o c

11 yr/8 mo

6.75 yr/2 m o

3.5 yr/3 m o 6.3 yr/3 m o 6 yr/1 m o

2.5 yr/2 m o

42, M 43, M

37, F

35, F

37, M

60, F

27, F 50, F

C+R C+R C+R R

HD --~ EL

C

HD --~ AML

HD --~ AML HD ---) p r e l e u k e m i a HD --> APL

C+R

HD --~ AML

C C

C C

MM --~ SA MM --) SA

3.5 yr/8 mo 3.5 yr/12 m o

62, M 85, F

MM --~ SA MM --~ SA

C÷R C+R C+R C+R C C C+R

HIg"---> AML HD -~ AML L y m p h o m a --~ ANLL L y m p h o m a ~ ANLL L y m p h o m a --~ ANLL MM --* AML MM ---) AML

3 yr/6 m o 2 yr/1 m o 13.25 yr/5 mo 8.8 yr/14 m o 5.5 yr/3 m o ~ 3 yr/8 m o 4.5 yr/4 m o

28, 27, 40, 43, 44, 78, 59,

M M M F M F M

C

MM --* AML

6 yr/3 m o

R

C+R C C+R

HD --* AML HD --* AML MM - . EL L y m p h o m a --* AML

61, M

mo me mo mo

C+R

yr/2 yr/3 yr/1 yr/2

L y m p h o m a -~ EL

2 5 9 5

4.5 yr/2 m o

F F F F

88, F

22, 57, 72, 59,

( q 2 2 ) , - 9, +M(9),t(1;9)(q22 or 23; p24)/48,XX,del(7)(q22) ,del(5) (q22;31--)33}/46,XX,t(2;3} (q31; q27),del(7)(q22),del(5} 46,XY, - 22, + M(22),t(11 ;22)(q13; p l l or 12) 46,XY,21q+ 47,XY, + 8, + 14, - 17, + 18, - 21 45 50, + M ( # 2 - like) 80-85 44-45, 15% p o l y p l o i d , 25% N 43-45, 15% polyploid, c h r o m o s o m e damage 4 5 , X Y , - C (80%)/, N (20%) 4 2 - 4 5 (50%)/47-51 (30%), 10% p s e u d o , 10% polyploid, c h r o m o s o m e damage 4 5 - 4 6 (25%)/46-47(70%) N (5%) 4 5 , X Y , - C, c h r o m o s o m e d a m a g e (breaks, dic) 4 4 , X X , - 5 , - 7 , - 16(177), - 1 8 , - 2M 4 8 , X X , - 5,t(8;?},t(15;?} (p11;?), - 16?, - 21, + 4M 46,XY,t(1;17)(p36;q21) 45,XX, - 7 45,XX, - 4, - 5, - 14,t(21;?)(q22;?), +2M 43?,XX, - B,del(6){q15 or 2 1 ) , - 7 , - 12, -?,+min

46,XX,del(7)(q22)/46,XX,del(7)

42,XX, - 5, - 1 2 , - 14, - 16, - 18, + M(16),t(12;16)(q11;q22--~ q24)

47,XX, + C/46,XX,-G, + F

" M i n o r degrees of a n e u p l o i d y " 48,XX

(continued)

Rowley et al., 1977 [82]

Gonzalez et al., 1977 [34]

Collins et al., 1977 [22]

Cavallin-St~hl et al., 1977 [20]

Meytes et al., 1976 [62] O s h i m u r a et al., 1976 [67]

Raich et al., 1975 [78]

5 yr/1 mo

4.6 yr/4 mo

1.75 yr/12 m o c

/4 mo 7.4 yr/2 mo d

5 yr/7 mo 6.5 yr/4 mo 4 yr/
57, F

51, F

22, M

64, M 37, F

41, 46, 33, 17,

3 yr/O.5 m o

2 yr/c 23 too/100 days 12.5 m/42 days 2 yr/4 mo

66, M

34, F 2V2, F

21/4, F 8, F

5 yrf

44, M

F F M F

4.25 yr/c 3 yr/3 mo

(continued)

31, M 51, F

Table 4

R a v i n d r a n a t h et al., 1978 [79]

45/46, ring, PC 45/46, 31 very large acrocentrics 45/46, 7 large s u b m e t a c e n t r i c s 45 w i t h any of the following; - D , -G,-E,-C 45 w i t h any of the following: - G, -C,-E 45 w i t h any of the following: - 5C, large acrocentric 45/46 p s e u d o d i p l o i d 46,XX,3p - ,11p + ,t(3;11)

C+R C+R C+R C+R

R R R C+R

S e m i n o m a --~ AMMoL

L y m p h o m a - * AML

Ca. breast --* CML ALL -~ JCML

ALL - * AML ALL --~ AML

C+R C

Secker Walker and Sandler, 1978 [861

Cleary et al., 1978 [21] Goh et al., 1978 [32]

46,XY 4 7 , 2 G - ,(Ph 1 + ?)

None C+R

R

C

46,XX,B(?4)p Originally fuzzy c h r o m o s o m e s w h i c h failed to band; half the cells h a d r e a r r a n g e m e n t s b u t no detectable clone - * 46,XX,deI(7)(q12)-~45,XX,- 7

Adler et al., 1978 [1]

Lymphoma -* preleukemia L y m p h o m a -~ preleukemia Renal t r a n s p l a n t - * CML MM --* AMMoL l y m p h o m a -~ BP of CML L y m p h o m a --~ AML MM --~ PCL W i l m s ' --~ ALL HD --~ AML

C+R

4 5 , X Y , - 5 , - 7 , - ? , + 2M 45,XX,t(1;?)(p36?;?),- 5 , - 7 , - 12, t(13;?)(q34?;?),del(14 - 15)(q24?), t(14?;?)(p17;?),- 17, - 22, + 3M, + rain 4 6 , X X , - 5,del(6)(q13), - 7,+8,-17,-2M 43,XX, - 5, - 13, - 18/44,XX, - 5,t(13;?) ( p 1 1 ; ? ) , - 18 46,XY,Ph 1 due to t(7;22)

C+R R

HD --~ AML L y m p h o m a -* preleukemia

bo

5 yr/1 m o

3.3 yr/3 yr 6 yr/5 m o 6 yr/16 m o

6 yr/7 m o 2.1 yr/2 m o

3.3 yr/9 m o 2.75 yr/6 m o 0.75 yr/2 m o 0.7 yr/4 m o 2.5 yr/4 m o

5 yr/1 m o

4.8 yr/4 m o

7.75 yr/2 m o 5 yr/1 mo

2.3 yr/0.5 m o 4.6 yr/5 m o 6.75 yr/?

4.25 yr/9 m o 8.2 yr/2 m o

5.9 yr/3 w k

45, M

56, M 53, M 21, M

63, F 18, M

3.5, F 3.5, F 23, M 52, M 69, F

63, F

62, F

28, M 62, M

57, M 65, F 24, M

48, M 74, F

22, F

C

Ca. ovary ~ AML

HI3 --~ APL

Lymphoma ~ CLL --~ AGL

AML

R+C R+C

L y m p h o m a --~ AML L y m p h o m a ~ ANLL L y m p h o m a ~ MPD

C+R

R

R

R

R+C R+C

L y m p h o m a --~ AML L y m p h o m a ~ AML

R

C+R C

MM --~ AML Ca. ovary ~ AML

L y m p h o m a ~ AML

C+R C+R C+R C C

ALL ~ AML L y m p h o m a --~ MPD ALL-AML ALL-AML MM --~ AML

C C+R

C+R C C

MM --~ AMMoL Renal t r a n s p l a n t --~ EL D r u g - i n d u c e d EL

D r u g - i n d u c e d EL L y m p h o m a --~ AML

C

L y m p h o m a ~ AML

H y p e r d i p l o i d y , large acrocentric a n d minute markers 46,XY - 5 , - 1 7 or - D , - 5 , 1 7 p + , - G 49,XY (extra c h r o m o s o m e s in g r o u p s C and G) 45,XX,-C 46,XY,t(1;20)(p31;q11),del(5) (p15),t(6;17)(q15?;p12}, del(7)(q34),del(15)(q24?), del(16)(q22?}/45,XY,- 18 46,XX 46,XX ( u n s t i m u l a t e d blood) -11,-17 Hyperdiploid? 45,XX,del(5)(q13),t(13;14) --->50,XX,plus + 1 , + 6 , + 8 , + 2 1 , - 7 4 5 , X X , - 7,t(3;9)(q29;p21) 48-50, + 6, + 9or + 8, + 1 0 , + 19, del(20q) ;t(11;12) 43-49,inv(1p), - 19, - 22, small fragments 43,XY, - 3, - 4C, + F, + min/44,XY, - 3, - 3C, + F, + min/42 (not analyzable) 45,XY, + M 46,XY,7p - ,7q - ,20q12 - / 4 7 , X Y , + E, 20q12 44,XY,5q - , - 7,12p - , - 22 46,XX,7q - / 4 5 , X X , - 7 45,XY, - 4C, + E, + 2M/ 4 4 , X Y , - 4 C , + E, + M 45,XY, - 7/46,XY, - F, + G 43,XX,-1,+3p+q-,4q+,-5,-5, - 7, + 9 , + 9,10p + , + 10, + 10, + 1Op- q-, + llp-,1 3 , - 15, - 16, - 17, - 1 8 , - 21/44,XX, as above but no - 18 46,XX, (one G small) (continued)

Wolf et al., 1979 [97]

W h a n g - P e n g et al., 1979 [96]

Patil et al., 1980 [71]

Liang et al., 1979 [58]

Kjeldsberg et al., 1979 [51]

Hurter et al., 1979 [44]

Harris et al., 1979 [39]

Ellerton et al., 1979 [27] Ellims et al., 1979 [28]

Casciato and Scott, 1979 [17]

4.9 yr/26 w k 7.1 yr/11 wk

7.7 yr/4 wk 11.8 yr/2 wk 5 yr/7 m o 1 yr/1 m e

1 y r / < l mo 0.75 yr/1 mo

5 yr/6 mo

4 yr/4 mo 0.5 yr/2 m o ~/2 m e

7 yr/5 m e

2.5 yr/1 m e

5 yr/1 mo 3 yr/12 m o 48 mo/12 m o c

5 yr/4 m o 11 mo/7 mo

F F F F

45, 28, 40, 37,

59, M 56, M

46, F

83, F 58, M 74, M

30, F

26, F

43, M 40, M 71, M

41, M 55, F

(continued)

24, F

Table 4 H y p e r d i p l o i d (48 - 49), + C, + E, + F Hypodiploid 43,-B,-B,+C,+C,+C, -D,-E,-E,-G/ 42,-B,-B,+C,+C, -D,-E,-E,-G 46,XX H y p o d i p l o i d 44, - C, - D/45, - C Hypodiploidy Hypodiploidy Phi-positive Hypodiploid Hypodiploid Hypodiploid Hypodiploid 4 4 - 4 5 , - 1 4 , - 1 6 , - 1 8 , - 19, + M, t(?;8)(qter;q13) (gain in C-group c h r o m o s o m e s ) 43 - 4 4 , - 5,del(5)(q13;q31 - 33), del(11)(q21), - 17, - 21,rings, m a r k e r s and fragments; congenital t(13;14), 15% p o l y p l o i d 4 0 - 4 4 , - 7, - 17, - 19, - 21, rings, m a r k e r s and fragments 47, + 21/46, - 1 7 , - 21 41-45 4 5 , X Y , - 5,17p +/45,XY, - 5,t(3;17) (p - ;p + ) / 4 4 , X Y , - 3, - 5,17p + 45,XX, - C 46,XX

C+R C+R

C+R C+R C+R C C C C+R C+R C None

C+R

C+R C+R C+R C C+R C

HD ~ AMMoL HD --~ AMMoL

HD --* AMMoL HD -~ EL Ca. ovary--* AMMoL Ca. colorectal --> AMMoL M e l a n o m a --~ AML Lymphoma -* AMMoL L y m p h o m a --* AMMoL L y m p h o m a --* EL L y m p h o m a --~ AML MM and AMMoL

HD --~ EL

HD ~ AML

HD --~ AMMoL HD --~ EL HD --~ ANLL

L y m p h o m a ~ AML L y m p h o m a --~ AMMoL

Kapadia et al., 1980 [48]

Gyger a n d Forest, 1980 [36]

Baccarini et al., 1980 [4]; Papa et al., 1979 [69]

A n n i n o et al., 1980 [2]

Zarrabi et al., 1979 [101]

Zarrabi and Rosner, 1979 [99]

b~

C+R C+R C C

HD -* preleukemia HD --~ A M L l i D --~ p r e l e u k e m i a L y m p h o m a --~ preleukemia

yr/12 mo c yr/3 m o yr/9 m o c yr/15 mo ~

F M F M

72, 33, 48, 61,

3.7 4.7 4.2 7.7

M

- C

45,XY,

- 7

4 6 , X Y , + 2, + 3, - B, - 3C, + 2E 46,XY 46,XX 4 6 , X X , - 4 , 5 q - , + 2C, - E 45,XY,- 1,-B,+ 2C,- 2E,+ M 45,XX, - C 45,XY,3p - ,5q- ,- 7 4 7 , X Y , - B , - B , + 3C, + D , - 2E, -F,+G,+M 45,XX, - 7 45,XY,5q-, - 7 45,XX,- 7

45,XX,

-7,5q-

C C+R C+R C C C+R C+R C+R C+R

H D ----> A M L HD ~ AML HD ~ AMMoL lid ~ AML H D ---~ A M L H D ---> A M L H D "-'* A M L HI:) --> A N L L HD ~ ANLL

3.5 yr/3 m o 9.75 yr/3 m o 1.6 y r / 3 6 m o ¢ 7 yr/18 mo c 7 yx/ 6 m o 11 yr/4 m o 10.1 yr/3 m o 2.6 y r / 1 6 m o 9.5 yr/3 m o

F M M F F M F M

58, 75, 25, 66, 57, 68, 25, 83, 68,

47,XX,+B 47,XY, + 8 4 7 , X Y , ; 8 / 4 8 , X Y , + 8, + 13 44,X, - X, - 7 , 5 q - / 4 4 , X , - X,

C C C C

5.2 yr/4 m o 2.7 yr/2 w k 4.2 yr/2 w k 6 yr/3 m o

F M M F

60, 50, 49, 23,

C+R C

Ca. o v a r y ~ A M L L y m p h o m a --~ AMMoL HD ~ AMMoL HD ~ AMMoL HI) ~ A M M o L H D --~ EL

4.7 yr/1 m o 5.5 yr/1 m o

47, F 84, F

C C+R C+R C

CLL - o A M M o L Ca. o v a r y --~ A M M o L Ca. b r e a s t - ~ A M L Rheumatoid arthritis --~ A M L

11 yr/4 m o 3.7 yr/3 w k 14 yr/1.5 m o 4.3 yr/2 m o

55, 51, 57, 50,

M F F F

M M ---* A M L

5 yr/1.5 m o

66, M

C+R C+R

45,XY,- D 44,XY, - 4, - 8/43,XY, - 4, - 17, - 18/44,XY, - 4 , 18/44,XY, - 4, + 13, - 17, - 1 8 / 4 3 , X Y , - 4, -17,-18 45,XY, - C/43,XY, - C, - D, - E/44, XY,+B,-C,-D,-E 47,XY, + C(8?), + C(117), - 16 47,XX,+C 45,XX, - C 4 8 , X X , + 8 , + 10, + 1 2 , - 5/ 46,XX, + 8 , - 5 / 45,XX, - 5 / 4 5 , X X , - 5,i(17q)/47,XX, + 8 , i ( 1 7 q ) / 4 8 , X X , + 9, + 1 0 , i ( 1 7 q ) / 44,XX, - 5, - 7 , i ( 1 7 q ) , d i c ( 3 q l l p ) / 48,XX, + 12, + 16/48,XX, + 17, + 20 4 5 , X X , - 16 47,XX,+ B

H D --* E L M M --~ EL

6 yr/3 w k 1.75 yr/5 m o

67, M

49, F

(continued)

P e d e r s e n - B j e r g a a r d et al., 1980, 1981 [72-74]

O9

45,XX, - 1, - 4 , 5 q - , 14q+,+4M 44,XX, - B , - C 44,-B,-C

C

C C

Ca. o v a r y - - ~ A M L Ca. u t e r u s --~ A M M o L Ca. u t e r u s --~ A M L Ca. o v a r y preleukemia Ca. o v a r y --~ preleukemia Ca. o v a r y --~ preleukemia Ca. o v a r y ~ A M L Ca. o v a r y preleukemia Ca. u t e r u s --~ A M L M e l a n o m a --~ A M L Ca. t e s t i s ~ A M L Ca. o v a r y ~ A M L L y m p h o m a --~ AMMoL HD ~ AMMoL L y m p h o m a --~ AMMoL HD ~ AMMoL

4 yr/2.5 m o 9.8 yr/0.5 m o 2.6 y r / l O m o 3.6 yr./2 m o

72, 57, 71, 39,

4 yr/1 m o c 2.5 yr/4 m o

2 yr/21 m o 4.2 yr/29 m o 1.7 yr/15 m o 7 y r 66 m o 8 yr/5 m o

45, F 58, F

63, 57, 40, 56,

4.7 yr/3 m o

4.2 yr/3 m o 4.2 yr/8 m o

4 yr/4 m o

70, F

F F M F

4.6 yr/6 m o

52, F

F F F F

4 6 , X Y , t ( 1 ; 1 7 ) , - 7, + r 45,XY,t(20;21) 46,XX,del(7)(q11),t(9;?)(p22;?)

C+R C+R C C+R C+R

R

C

R

46,XX 4 7 , X X , 5 q - , + G , 8 p - (?) 45,XY, - 7 46,XX 4 6 , X X , t ( 5 ; 1 2 ) , - 17, + M

C C+R

C

R

R

- 7, - 12, - 18,

40-45,-3,-B,-C

C C

H D --~ p r e l e u k e m i a M M --~ p r e l e u k e m i a

8.5 yr/2 m o c 3.75 yr/3 m o c

48, M

74, F

4 4 , X Y , - 3, + t(3;17), - 5, - 17, -20,+M 46,XY,5q4 5 , X X , - 7/48,XX, + t(1;7), - 7, +11,+13 45,XX, - B 46,XX 4 5 , X X , 5 q - , - 2C, + G 43,-B,-E,-2F,G,+ 2M

C+R

1.1 yr/1 m o

85, M

C

4 yr/3 m o

57, M

43,X,-Y,3 , 5 q - , - 7, - 1 0 , - 16, -22,+3M 44,XY, - 7,17p ÷, - 20,21q ÷

C

5.2 yr/3 m o

62, M

45,XX, - 7

C+R

L y m p h o m a --~ preleukemia L y m p h o m a --~ preleukemia L y m p h o m a --~ preleukemia H D --~ p r e l e u k e m i a

4 yr/22 m o c

(continued)

67, F

Table 4

A n d e r s o n e t al., 1981 [104]

C+R

C+R C+R?

E T --> EL ET --~ ANLL HD ---->AL L y m p h o m a -~ AML

Ca. breast -~, ANLL

Ca. breast --~ ANLL

3.5 yr/ 12 yr/ 6 yr/ 3yr/

4 2 5 4

M M F F M

F F M M

58, 42, 53, 55, 38,

52, 72, 30, 16,

C+R C

HD -~ EL HD -+ AML

4.2 yr/4 m o

3.75 yr/5 m o 3.8 yr/5 m o

32, F 47, F

5yr/

C C+R C

3 yr/1 m o

Ca. breast--~ ANLL L y m p h o m a -+ DMS HI3 -+ AML

7.5 mo/3 m o

72, F

C C

C C+R C+R C C

C+R C+R

61, F 52, M 60, M

1.25 yr! 2 m o

63, F

yr/ yr/ yr/ yr/13 m o

2yr/

HD -~ ANLL L y m p h o m a --~ AMMoL MM --~ AMMoL MM -~ AMMoL Ca. b r e a s t - * AMMoL Ca. breast -~ AMMoL Ca. c e c u m --~ ANLL

0.75 yr/ 4 yr/

73, M

69, M

C+R C+R

3.5 yr/ 7 yr/

20, F 29, M

C+R C+R

C

4 yr/2 0 m o 6 yr/

L y m p h o m a --~ AMMoL Ca. ovary ~ AMMoL HD ~ RA w i t h o u t blasts HD ~ ANLL HD ~ ANLL

38, M

8.5 yr/6 m o

4 6 , X Y , 7 q - ,(q34) 46,XY,t(11;17)(q13;q21), del(17)(q21)/46,XY,t(11;17) (q13;q21),del(17)(q21),t(4;4) (q21;q357) 4 5 , X X , - 3, - 2 C , - 17, - 18, - 21, + 1(17q), - 4 M / 8 6 - 8 8 44 - 46, - X, - 7, - F, + i(lq):, + M/ 45,XX, - B, - 7 , - 1 7 , - 20, + Bq (?4q), + ? 7 q - , + 18 or t(7p;17q) 1 cell 47, + C (no clones) 46,XY, - 5, + M 4 4 , X Y , - 5 , - 7 , - 17,del(3)(q13), + del(3)(p13),del(6)(q13) 47,XY, + 8 46,XX, - 7, - 17, - 21, + der(2;7) (cen;cen),del(2)(q33), del(11)(q22), + 11p + ,14p + , + t(21;21;21;16)(21q22; 21qllq22:21qllq22;16p13)

46,XY,t(13q;13q) (blood) 46,XY,7q - , - 21, + ?i(21q) (blood) 45,XX,- 7 46,XX, - 12, + ?21 45,XY, - 5, - 15, + r( - 7, i n c o n s i s t e n t ) 46,XX,17q+ 4 5 , X X , - 7 [blood)

4 6 , X X , 5 q - (blood) 44,XY, - B, - E, - F, + ?Bq (blood + PHA) 4 5 , X Y , - 7 (blood) 44,XY, - 7, + 20, - 21, - 22

46,XX 42, variable karyotype

46,XY,del(7)(p12),t(19;?)(q13 ;?)

(continued)

Rowley et al., 1981 [103]

N o w e l l et al., 1981 [65]

Davis et al., 1981 [25] Kaur et al., 1981 [102]

Berger et al., 1981 [7]

ol

1.75 yr/1 mo

7 yr/6 mo

3.8 y r / > l mo

3.33 yr/3 mo 2.2 yr/

5.7 yr/

6.8 yr/4 mo 3.8 yr/ 4 yr/1 mo

3.75 yr/1 m o 2 yr/12 mo c 4 yr/7 m o c

12 yr/2 mo

64, M

55, M

34, M

54, F 69, F

62, M

48, F 63, M 32, M

64, M 55, M 48, M

59, F

Ca. cervix --* AML Ca. lung --> DMS HD --* m y e l o d y s p l a s i a --> AML Ca. lung --* AMMoL Ca. colon --~ AMMoL Ca. p a n c r e a s --> AMMoL Ca. breast ---> AML

MM --~ EL

L y m p h o m a ~ DMS MM --~ DMS

HD --> AMMoL

HD --* AML

HD --~ AML

HD --~ DMS HD --* AML HD --~ AML

R

C + R C C

R C C

C + R

C C + R

C + R

R

C + R

C + R C + R C + R

46,XX

45,XY, - 7,12q + [?t(7;12)] 46,XY (not banded} 46,XX (not b a n d e d )

4 5 , X X , - 7,inv(1}(p36q13) 45,XY, - 7 44,XY, - 7, - 16,17p + ,20q - / 4 3 , X Y , - 5 , - 7 , - 1 2 , - 16,4p + ,17p + , 2 0 q - , + M/43,Xq + , etc. 45,XY, - 5, - 7,del(3)(p13), + der(5), t(5;17)(q11?;q11) 4 5 , X Y , - 7,del(5)(q13?)/45,XY,- 7, del(5)(q13?),t(12?;17?)(q13?;q12?) 4 4 , X Y , - 2 , - 3 , - 6 , - 1 2 , - 1 5 , - 21, - 22,?del(2)(p11),del(11)(?p14), t(14;?)(q32;?),t(17;?)(p13;?), del(22)(?q11), + 5 M / 4 3 , s a m e , - 7 46,XX? one X and one 10 atypical 4 5 , X X , - 7,t(3;9)(q29;p21}/ 44,same, - X 51,XY, + 1, + 2, + 6 , - 7, + 8 , - 14, +15,+21,+M 45,XX, - 7,ins(3;3)(q21;q21q26} 4 5 , X Y , - 7,t(2;3)(p21 - 23;q38} 45,XY, - 7

T a k e u c h i et al., 1981 [112]

Kross et al., 1981 [105] May e t a | . , 1981 [109] Joshi et al., 1981 [110]

eSimultaneous occurrence of MM and AL.

dSurvival after onset of BP of CML.

~Patient living at time of report.

bC. Chemotherapy; R, radiation.

aRCL, Reticutum cell leukemia; SA, sideroblastic anemia; BP, blastic phase; JCML, juvenile CML; PCL, plasma cell leukemia; MPD, myeloproliferative disorder; Ca., cancer; DMS, dysmyelopoietic syndrome.

8.33 yr/ 4 yr/1 mo 4 yr/
(continued)

55, M 28, M 25, M

Table 4

Secondary Leukemia

12 7

Table 5 Factors possibly active in the genesis of the karyotypic findings in complicating leukemia Disease background (malignant and nonmalignant conditions) Radiation Type Dose Location Duration Given with or without drugs Drug therapy Combination (with other drugs and/or radiation) Dose Duration Type Host factors Genome of the patient Metabolism (of given drugs, for example) Age and sex of the patient Past history Genetic background, particularly familial Environmental Exposure to toxins (e.g., petroleum products, insecticides, pesticides, chemical solvents, organic compounds) Geographic location (high risk areas?) Work environment

agents similar in nature to those used in chemotherapy or to a "triggering" mechanism akin to that observed in the patients in this and other series. Hypodiploidy in complicating leukemia appears to be twice as common as pseudodiploidy and hyperdiploidy combined. This was first pointed out by Rowley et al. [82] and later by other workers [7,96,72,73] and appears to be rather characteristic of complicating acute leukemia. In our series hypodiploidy was present in more than half of the patients studied (12 cases), only four cases being hyperdiploid. The same nonrandom changes occurred in diseases of varying background, e.g., - 5 in lymphoma and ovarian cancer. In general, spontaneous ANLL tends to have an almost even distribution between hypodiploidy and hyperdiploidy [83], and thus the findings in complicating leukemia appear to be rather unusual. For the series of patients with complicating leukemia (Table 4) and for ten cases of spontaneous ANLL, in the latter group Berger et al. [7] found chromosome #7 to be most frequently involved (in seven of ten of the cases), as it was in the complicating leukemias. It is interesting, though, that in the ten cases of spontaneous ANLL involvement of chromosomes #3 and #12 (combined) exceeded that of #5, i.e., six cases versus four cases. Chromosome #17 was involved in three of the cases. The rather frequent involvement of chromosome #17 was mentioned by Rowley and her co-workers [82], though it has not been discussed at length in any of the papers published to date. As indicated, stress has been put on involvement of chromosomes #5 and #7 [7,82,96]; we would like to add chromosomes #3 and #17, particularly the latter, to the list of chromosomes involved in a nonrandom fashion in secondary leukemia. Others have noted the complexity of chromosomal changes in secondary leukemia [34,69,96], indicating considerable instability of the karyotypic picture, as well as the complexity of the karyotypes themselves. Thus, it appears that the cytogenetic studies may have been performed at a stage of the disease during which clonal evolution was occurring without a stable karyotype character-

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A.A. Sandberg et al. izing a preponderant number of the cells. In other words, it is possible that secondary leukemia goes through a phase of considerable chromosomal variation with karyotypic instability but which may ultimately lead to the emergence of one stable clonal karyotype. Such a picture may also occur in spontaneous leukemia, but such a cytogenetically unstable phase is usually not seen because the disease probably manifests itself clinically in its late stages when karyotypic stability characterizes the leukemic cells. The types of leukemias that occurred in our cases are similar to those previously reported in the literature for various conditions (Table 4). The development of EL in two patients with HD and in the one patient with ovarian cancer is noteworthy, since it has been stressed that such a form of leukemia is rather rare in HD [26,33]. In a recently reported study Berger et al. [7] have correlated some of the cytologic features of the acute leukemias with the chromosome findings and have stressed the possible association of monosomy 7 ( - 7 ) with micromegakaryocytes and circulating giant platelets. Even though in a few of our patients with - 7 similar features were encountered, unfortunately we have no record regarding these features in the other two patients with this chromosome anomaly. Nevertheless, it appears that future studies should attempt to correlate similar features with the cytogenetic observations, since it is possible that some rather distinct syndromes may be uncovered in such a manner. To date, no cases of ANLL complicating another disease and characterized by t(8;21), t(15;17), or Ph 1 have been described. This might indicate that the causation of complicating leukemia versus that of the conditions associated with the cytogenetic characteristics just mentioned, e.g., acute promyelocytic leukemia (APL) with t(15;17), may be different. If this is true, cytogenetics would appear to offer a means of deciphering variable causations of ANLL. It is unfortunate that in the study by Zarrabi et al. [101], in which some of the patients were studied cytogenetically, the four patients with Auer bodies in their cells were not examined similarly, since these bodies tend to occur most commonly in patients with the M2 variety of AML, particularly those with the 8;21 translocation [87]. In the four patients with hypo° diploidy (no other cytogenetic data given) studied by these authors Auer bodies were present in the leukemic cells. As pointed out by others, complicating acute leukemia tends to be preceded by bone marrow hypoplasia of variable degree [88]. This hypoplasia, usually drug (and/ or radiation)-induced, can precede the leukemia for different periods of time. The same can be said for the intensity of the hypoplasia, which has also varied from one case to another. Acute leukemia induced by nonchemotherapeutic drugs (antibiotics, e.g., chloramphenicol) [7] also appears to go through a hypoplastic phase, possibly indicative that depression of the bone marrow plays a key role in secondary leukemia development. The role played by various forms of chemotherapy (and radiation therapy) in the development of complicating leukemia appears to have been somewhat clarified during recent years [31,48,81]. Patients with lymphoma, MM, and other neoplastic diseases who developed acute leukemia without treatment (cytotoxic drugs or radiation) have been reported in the past [21,49,51,55,99]. Such cases raise the possibility that therapy merely accelerates a process that might have taken place spontaneously or that patients are kept alive for sufficiently longer periods that allow them to develop leukemia as part of the disease complex. However, there are those who feel that the therapy given, particularly chemotherapy, plays a crucial role in the genesis of the complicating leukemia. In fact, some believe that alkylating agents of one type or another appear to be the major culprits in inducing complicating leukemia in patients with neoplastic diseases, though various forms of radiation used alone have also been shown to be associated with a higher incidence of such leukemias.

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Other forms of leukemia, besides those labeled ANLL [AML, EL, APL, and acute myelomonocytic leukemia (AMMoL)], complicating other diseases are rather rare. A few cases of Phi-positive CML complicating lymphoma have been described [1,29,32]; rarely, a secondary leukemia may assume the form of ALL [32,76,111]. Our case 17 developed complicating ALL of the null cell type (non-B, non-T) 2 years following chemotherapy for and 6.5 years after the diagnosis of lymphoma. The cytogenetic findings in the marrow were compatible with those seen in ALL rather than in lymphoma. Complicating ALL has been reported in five patients with breast cancer. Pizzolo et al. [76] stated that 87 cases of acute leukemia had been reported in breast cancer until 1979, 4 of which were ALL and the rest ANLL. In one case reported by these authors, the leukemic cells were characterized cytochemically and immunologically as those of ALL in a 46-year-old woman treated 2 years previously with chemotherapy and radiotherapy following a mastectomy for breast cancer. Of considerable interest also is the appearance of ANLL as a complicating leukemia following therapy for ALL [44,61,79]. Unfortunately, for the 11 such cases reported to date (see summary table in Ref. 61) the cytogenetic studies, in the few cases in whom they were performed, were done in the ANLL phase, so that we still do not know whether characteristic karyotypic findings for the ALL were superceded by those for the complicating AML. An exception is the case studied by Secker-Walker and Sandler [86], which involved an 8-year-old girl who developed AML following treatment of ALL. During the course of the disease, the patient's marrow and blood cells were studied cytogenetically. The marked contrast between the karyotypes and staining properties of the leukemic cells at diagnosis of ALL and those when AML emerged suggested that the leukemic myeloblasts were of an origin different from that of the preceding lymphoblasts. Of similar interest is the occurrence of ANLL in patients with chronic lymphocytic leukemia (CLL) [23]. An interesting case of untreated CLL was reported by Lawlor et al. [55], in which AML was diagnosed. More commonly acute leukemia develops in CLL patients who have received either radiation or chemotherapy. From a recent review of the literature [103] it appears that a total of 24 cases of CLL terminated in acute leukemia, all but 4 having been treated. An unusual case is that reported by Daneshvar-Alavi et al. [24]. The patient was a 50-year°old male with MM treated with radiation and melphalan. Three years after the diagnosis of MM, the patient was found to have complicating Phi-positive AML. The cytogenetic findings in the marrow were interesting: The preponderant number of cells were hypodiploid (32-45 chromosomes); however, diploid (5%) and hyperdiploid (12%) cells were also present. Regardless of the chromosome count, cells were either phi-negative or phi-positive, the latter being found in one-third of the cells. Even though banding was unsuccessful, the metaphases reported in the published article appear to contain Ph 1. The only other case of Phi-positive complicating leukemia was that observed at our institute and reported by Ezdinli et al. [29]. The patient was a 21-year-old male with HD treated with vincristine and radiation. The Phi-positive CML was diagnosed 8 years after the diagnosis of HD and a little over a year after the last radiation therapy. The cytological aspects of complicating acute leukemia, at least of the ANLL variety, appear to have features in common with so-called spontaneous acute leukemia. For example, in a relatively large number of cases of complicating AML, Auer bodies in the leukemic cells have been described [39,43,53,64,68,79,90,91]. It is unfortunate that in most of these cases karyotypic findings were not obtained, since AML with t(8;21) is almost invariably accompanied by Auer bodies, and yet to date no complicating AML with such a chromosomal anomaly has been described. One of the perplexing questions to be answered is why identical chemotherapy leads to the production of karyotypic changes of a different nature in patients treated

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A.A. Sandberg et al. with such drugs. Some of the factors that may be operative in this regard, as well as in the genesis of the complicating leukemia, have been listed in Table 5. It is possible that there is an interaction between the drug and the genetic makeup of the patient, and thus a hypothesis could be advanced that the drugs play a major role in leading to the nonrandom changes in chromosomes #3, #5, #7, and #17, with the effects of the host genome predominating in cases in which involvement of these chromosomes does not occur and other karyotypic changes are evident. To us it appears that, for any spontaneous leukemia in which involvement of the chromosomes just mentioned, particularly if they constitute a quadrirad, the suspicion should be raised that such a leukemia is not spontaneous in nature but possibly related to toxic agents of one type or another. Such an approach may ultimately lead to a subclassification of the various leukemias according to possible causative agents. A possible relationship between the causative agent (e.g., petroleum products, insecticides, etc.) and the karyotypic picture in ANLL has been the subject of interesting reports by Mitelman and his co-workers [107,108]. The data of the present study and some of the contentions promulgated in this paper support the concepts of Mitelman et al. and represent an extension of these concepts, respectively. It must be kept in mind, however, that the cases of complicating leukemia in which none of the more common karyotypic changes were observed (i.e., involvement of chromosomes #3, #5, #7, and #17), may reflect a causative background different from that of leukemias in which these chromosomes are involved, and thus it behooves all of us to continue searching for that possibility. At present, it is difficult to give an exact number for the incidence of complicating leukemia in various neoplastic and nonneoplastic diseases. What is clear is that the incidence of acute leukemia in patients receiving cytotoxic agents (and/or radiation?) is greatly increased over that observed in appropriate control groups or in the general population [3,66,93,96,101]. The largest series of cases that offer a reasonable figure involve HD and MM in which the incidence of complicating leukemia appears to range from a little over 1% to a little less than 5% [3,8,10,16,19,20,34,37,46,54,64,69]. The incidence in patients with solid tumors, with non-HD lymphoma (NHL), and in nonmalignant states appears to be similar [41,47,72,73,80,99]. A perplexing exception is the report by MacDougall et al. [60] of 630 cases of NHL seen between 1968 and 1978 at the Tumor Registry of Manitoba among which 35 cancers developed in 31 individuals (no significant difference in incidence in an age-matched control population) and no cases of acute leukemia were identified. Since the treatment of these cases probably did not differ basically from that in other reports, the absence of leukemic cases is striking. Of course, a number of factors affect the incidence of complicating leukemia, among them the type, intensity, and length of therapy used, the patients' survival [short survivals do not allow complicating leukemia to develop), the nature of the initial disease, and many other facets that can be evaluated only after an intensive attempt has been made to analyze the data on a large series of patients. What does appear certain at present is that complicating leukemia can appear following radiation therapy and/or chemotherapy and, rarely, in patients without therapy. It is difficult not to impute radiation and/or chemotherapy in increasing the incidence of secondary leukemia, though the possibility exists that by prolonging the life of the patient sufficient time is gained to allow the leukemogenic process to become evident. The interval between the diagnosis of HD and lymphoma and the appearance of the leukemia has been generally though to be, on the average, about 5 years [66,100,101]. This is supported by an average interval of about 4.7 years calculated

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on the basis of 11 cases in Table 1 and 184 cases in Table 4 for w h i c h data were available. The m e d i a n survival after l e u k e m i a d e v e l o p e d has been stated to be about 2-3 months, w i t h a range of a few days to over a year [3,66,96,100,101]. The m e d i a n values obtained for 17 of our cases (Table 1) and 159 cases in Table 4 were 2.9 months and 3.1 months, respectively. Thus, these data are in keeping w i t h those previously reported for acute leukemias complicating HD and l y m p h o m a . A m e d i a n interval of 2 years between cessation of therapy and the d e v e l o p m e n t of l e u k e m i a has been generally observed, though considerable variation occurs [106]. Some authors feel that differences exist between spontaneous and c o m p l i c a t i n g acute leukemia; e.g., in secondary leukemia the disease appears at a m u c h younger age, has a very poor response to antileukemic therapy, and is characterized by a relatively low male-to-female ratio (less than 1) [54,83]. W h e t h e r such differences will be borne out by further studies is difficult to ascertain at present, though data such as those of Larsen and Brincker [54], based on 201 consecutive cases of Hodgkin's disease treated between 1964 and 1975 with intensive radiation and/or chem o t h e r a p y in 3 of w h i c h AML was observed, are cogent. The observed n u m b e r of cases of acute l e u k e m i a was 75 times over the expected (p < 0.01). It appears to us that cytogenetics will probably play, as it has already, a key role in d e c i p h e r i n g m a n y of the features of complicating leukemia. This is related not only to some of the rather specific karyotypic changes observed but also to the possibility that such changes m a y predict the d e v e l o p m e n t of this complication. That cytogenetic approaches are not generally a p p r e c i a t e d is e v i d e n c e d by recent reviews on complicating leukemia, in one of w h i c h only a glib reference was m a d e to cytogenetic findings without even quoting the important paper published by Rowley et al. [82]; in the others no m e n t i o n is made of cytogenetic findings at all [3,10,11,54,93]. In our o p i n i o n only through a concerted effort in w h i c h all facets of the disease are a p p r e c i a t e d and encompassed, i n c l u d i n g the cytogenetic, will w e be able to learn more about the nature of factors leading to the d e v e l o p m e n t of leukemia complicating therapy for neoplastic and n o n n e o p l a s t i c conditions. Such approaches are particularly cogent and important in the c h e m o t h e r a p y of nonneoplastic conditions in w h i c h life expectancy is generally m u c h better than that following the d e v e l o p m e n t of acute leukemia. Thus, hopefully, criteria will emerge indicating the factors responsible for the d e v e l o p m e n t of the acute leukemia, particularly inklings as to subjects who m a y be the most susceptible to the d e v e l o p m e n t of secondary l e u k e m i a and further information on the type of t h e r a p y that m a y be useful in such c o m p l i c a t i n g leukemias. The failure to observe c h r o m o s o m a l changes in two of our cases has to be considered in light of recent indications that a search for c h r o m o s o m a l changes m a y have to be m a d e r e p e a t e d l y in order to establish rigorously w h e t h e r the l e u k e m i a is or is not d i p l o i d in character and the use of more optimal techniques for establishing the presence of c h r o m o s o m e anomalies in leukemia [11]. Even though every attempt was m a d e to search the marrows thoroughly in these two cases, no metaphases with abnormalities were encountered. Of course, we cannot rule out the possibility that the leukemic cells were not in mitosis, and hence w o u l d not be expected to yield abnormal metaphases, the d i p l o i d ones observed belonging to the n o n l e u k e m i c cells of the marrow. At the same time, there is no certainty that seco n d a r y l e u k e m i a is not d i p l o i d in character. Clinical research in the Department of Medical Oncology, Roswell Park Memorial Institute, was supported in part by Grants CA-2599 and CA-5834, and the cytogenetic studies by Grant CA-14555 from the National Cancer Institute. J.R.K. was supported by a Fogarty International Fellowship (1 F05 TW03009-01) from the National Cancer Institute. We wish to thank the staff of the Department of Medical Oncology for their cooperation.

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