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Philadelphia chromosome-positive chronic myelogenous leukemia in treated Hodgkin's disease
Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia in Treated Hodgldn's Disease G. E. G. Verhoef, H. Demuynck, M. S. Stul, J. J. Cassiman, C. Mecucci, H. Van Den Berghe, and M. A. Boogaerts
ABSTRACT: A patient who developed Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) 8 years after successful treatment for Hodgkin's disease IHD) is reported. The Ph chromosome with a typical 9(221 translocation was identified by banding techniques in 80% of bone marrow (BM) cells. Southern blot analysis showed breakpoint cluster region (BCR) rearrangement as observed in classical CML. Until now, only three cases of Ph + CML have been reported after treatment for HD. At present, it is not clear whether development of CML after HD represents a therapy-induced complication, an increased susceptibility to secondary malignancies owing to the malignant process itself, a consequence of the immunological deficiencies in HD, or possibly a genetic susceptibility to malignancy. INTRODUCTION
I m p r o v e m e n t s in treatment of Hodgkin's disease (HD) in the past 25 years have allowed m a n y patients to experience long-term survival and cure. The most serious and life-threatening late c o m p l i c a t i o n of such anticancer treatment is occurrence of a s e c o n d a r y malignancy. Acute m y e l o i d leukemia (AML) as a second neoplasm in HD has been well d o c u m e n t e d [1, 2]. The cumulative risk of developing AML increases by 0 . 3 - 1 % a n n u a l l y beginning 1 - 2 years after diagnosis and treatment of HD, but may cause plateau after 10 years. There is also an increased risk of non-Hodgkin's l y m p h o m a (NHL) and solid tumors of various types [3, 4]. The P h i l a d e l p h i a (Ph) c h r o m o s o m e ( 2 2 q - ) , w h i c h is the result of a reciprocal translocation between c h r o m o s o m e s 9 and 22 t(9;22)(q34;q11) and is characteristic: of chronic m y e l o i d leukemia (CML), has seldom been reported in secondary hematologic malignancies [5]. We report a case of a patient who developed a classical Ph ÷ CML 8 years after successful treatment for HD. CASE REPORT
A p r e v i o u s l y healthy 49-year-old male patient was diagnosed as having HD, n o d u l a r sclerosing type, on b i o p s y of an inguinal l y m p h node in August 1981. The disease was subsequently staged as IIIB. Cytogenetic analysis of the bone marrow (BM) cells From the Department of Hematology a n d Center for H u m a n Genetics, University Hospital Gasthuisberg, Leuvem Belgium.
Address reprint requests to: Dr. G. E. G. Verhoef, Department of Hematology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven Belgium. Received December 27, 1989: accepted February 8. 1990.
171 '© 1990 Elsevier Science Publishing Co., Inc. 655 A v e n u e of the Americas. New York, NY 10010
Cancer Genet Cytogenet 4 9 : ] 7 ] 0165-4608/90/$03.50
17611990)
172
(;. E. (;. Verhoet e[ al.
showed a normal karyotype (46,XY). Combination chemotherapy with nitrogen mustard, vincristine, procarbazine, and prednisone was administered. He r e s p o n d e d well with a p p a r e n t l y complete remission at the end of 8 months of chemotherapy. A regular follow-up for a 7-year period did not show signs of relapse or hematologic abnormalities. In February 1989, leukocvtosis and thrombocytosis was detected at a routine follow-up examination. Physical examination was normal, without hepatos p l e n o m e g a l y or l y m p h nude enlargement. Peripheral blood counts showed red blood cells (RBC) 5.37 × 101e/L, hemoglobin 14.4 g/dl, hematocrit 0.44, reticulocytes 1.4%, mean c o r p u s c u l a r volume 82 fl, white blood cell (WBC) count 24 x 10'/L, and thrombocytes 510 × 10'/L. The differential WBC count showed 3% promyelucytes, 5% myelo(:ytes, 2% metamyeh~(:ytes, 6(1% neutrophils, 2% eosinophils, 4'!/,,basophils, 23% lymphocytes, and 1% mono(:vtes, Leucocyte alkaline phosphatase (LAP) score was 12 (normal, 14 1001. The serum vitamin 13~, level was 1,390 /zg/L (normal. 150-850). The BM aspiration was hyper(:elhflar with a i n y e l o i d : e r y t h r o i d ratio of 9:1 and contained 1% mveloblasts, 7% promyelo(:ytes, 26% myelocytes, 25% metamyelocytes, and 41% polymorphontlclear cells. Megakaryo(:ytes were numerous. There were no features of myelodysplasia. A Ph chromosome couht be identified in eight of 10 metaphases of BM (:ells. Therefore, a diagnosis of Ph ~ CML, 8 years after suc(:essful treatment for HD was established. The patient is still in chronic phase after a lO-month follow-up period. Cylogenetic Investigations Cytogenetic analvsis was performed on BM cells using short-terin (:ulture (24 hour) without mitogens. Chromosome preparations were processed for R banding and stained with acridine orange. At least 30 (:ells were analyzed, and 10 metaphases were karyotyped. At diagnosis (November 1981), all 10 metaphases examined showed a normal karyotype [46,XY). In February 1989, eight ()f the 10 karyotypes analyzed contained a Ph translocation [)etween chromosomes 9 and 22, t(9:22)(q34;q11), and two (:ells showed a normal karyotype (Fig. I). Molecular Studies DNA was digested with restriction endonucleases BglII, BamttI and HindlII, sizefractioned in a 0.7% agarose gel, and transferred onto a nylon membrane. The membrane was then hybridized to bcr probes :~XP-labeled by primer extension 161. The presence of bcr rearrangement was investigated by the universal bcr probe {bcr-u), provided by Dr. A. Hagelneijer {Rotterdam), encompassing the major breakpoint cluster region [MBCR). With a 1-kilobase (kb) lIindlII-EcoRI 3'bcr probe, provided by Mrs. 1,. Birge (Scottsdale, AZ) the site of the breakpoint can be localized inside this MBCR 171. Southern blot analysis showed hybridization of the bcr-u probe to the expected germline fragments and to rearranged fragments in BglIl, BamHI, a n d / / i n ( t I I l digests, respectively (Fig. 2). The rearranged fragments re(:ognized by the 3' bcr probe localize the breakpoint within the 3' segment of MBCIL DISCUSSION In our patient, the diagnosis of P h , bcr" CML 8 years after successful treatment for HD was made on the basis of clinical, morphological, cytogenetic, and molecular studies. Southern blot analysis in our patient indicated a bcr breakpoint within the MBCR as expected in typical CML ]8, 9l. Patients who have been treated for HD have an increased risk of developing secondary malignancy, including AML, NHL, and solid tumors of various types 11 4]. Translocation (9;22), or CML as a second neoplasm detected during the (:ourse of a
Ph-Positive CML in Treated HD
Figure 1
173
Karyotype of the bone marrow cells showing t(9;22)(q34;q11).
previous malignancy has seldom been reported. Swaim et al. [101 described a patient in w h o m CML d e v e l o p e d 8 years after the start of radiation therapy for HD. However, Swaim et al. [10] did not perform cytogenetic analysis. Dastugue et al. [111 reported a patient in w h o m a m y e l o d y s p l a s t i c syndrome developed 7 years after radiotherapy for a gastric l y m p h o m a . The initial m y e l o d y s p l a s t i c s y n d r o m e evolved to a myeloproliferative phase with transient polycythemia, progressive thrombocytosis, and hyperleukocytosis. Chromosome analysis performed in the terminal phase showed del(5) (q13q31) and t(9;22)(q34;q11). Teichmann et al. [12] reported six patients in w h o m Ph + CML d e v e l o p e d after chronic l y m p h o c y t i c leukemia (CLL). Whang-Peng et al. [131 reported the results of cytogenetic studies performed before and during development of secondary leukemia in patients with different types of neoplasia. Chronic myelogenous leukemia was observed in nine patients. Eight CML patients were Ph*. In two patients CML d e v e l o p e d after treatment for HD. The remaining patients had cancer of the breast (two patients), CLL (one patient), NHL [one patient), and acute l y m p h o b l a s t i c leukemia (two patients). The survival of the patients ranged from 7 to 34 inonths, a much shorter survival than for de novo CML. Three other cases of CML after radiation treatment for cancer of the uterus (two patients) and testicular carcinoma (one patient) have been described [14]. Michalski et al. [151 reported a patient with the Ph chromosome in whom preleukemia developed 5 years after treatment for HD: however, the clinical and hematologic findings of CML were absent. Three other patients had a therapy-related Ph + m y e l o d y s p l a s i a occurring after prolonged use of phenylbutazone, c y c l o p h o s p h a m i d e , and 6-mercaptopurine, respectively [16-18]. The Ph c h r o m o s o m e has also been reported in a variety of conditions other than CML and is a rather exceptional observation in primary m y e l o d y s p l a s t i c s y n d r o m e [19-22]. Only four cases have been described. Several explanations appear possible for the occurrence of CML in HD. First, the
174
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Figure 2 Arrangement of major breakpoint ~:luster region (MBCR) in patieIlt (P) and control (C) DNA. DNA was cut with the indicated restriction enzyme. The Southern filters were hybridized with probes bcr-n (u) and 3'her (3'). Germline bands apparent il~ lane C were derived from placenta DNA. White blood ~:ells were obtained from peripheral blood. Fragment sizes were determined by simultaneous ele~:trophoresis with a a DNA-HiIldlII/OX-174 RF DNA-HaeII[ digest and are given in kilobases.
cytostatic drugs used in treatment of HD may be directly involved in the pathogenesis of CML [23]. Second, the experience from studies of atomic bomb survivors and patients with ankylosing spondylitis confirmed the hypothesis that ionizing radiation plays an important role in secondary CML. Third, immunological deficiencies in HD patients as well as therapy-induced immunological abnormalities may contribute to the evolution of CML [24]. Fourth, HD patients may have an increased susceptibility to development of leukemic malignancies. In a previous study of 98 consecutive patients with HD, we found in 55 patients myelodysplastic features not related to therapy or stage [25]. These features persisted during the entire course of the disease irrespective of the occurrence of a remission of HD. These findings suggest a genetic susceptibility that plays a role in development of HD, de novo myelodysplasia, and Inyeloproliferative syndrome. Fifth, the neoplastic transformation of a progenitor, capable of differentiation into either lymphoid or myeloid cell lines might lead to the association of lymphoproliferative and myeloproliferative disorders. This case report implies that patients treated for HD require close follow-up for years after completing therapy.
P h - P o s i t i v e C M L in T r e a t e d HD
175
We thank Katrien Vandenbossche, Kathy Merckx. and Marie-Jos6 Mijten for expert technical assistance. This work was supported by the Inter-university Network for Fundamental research sponsored by the Belgian Government (1987-1991).
REFERENCES 1. Blayney DW. Longo DL, Young RC, Greene MH, Hubbard SM, Postal MG, De Vita V {1987): Decreasing risk of leukemia with prolonged follow-up after chemotherapy and radiotherapy for Hodgkin's disease. N Engl I Med 316:710-714. 2. Tucker MA, Coleman CN, Cox RS, Varghesa A, Rosenberg SA {1988): Risk of second cancers after treatment for Hodgkin's disease. N Engl I Med 318:76-81. 3. Krikorian JG, Burke JS, Rosenberg SA, Kaplan HS [1979): Occurrence of Non Hodgkin's lymphoma after therapy for Hodgkin's disease. N Engl J Med 300:452-458. 4. Boivin IF, O'Brien K (1988): Solid cancer risk after treatment of Hodgkin's disease. Cancer 61:2541 2546. 5. Rowley ]13 {19731: A new consistent chromosome abnormality in chronic myelogenous leukemia identified by quinacrine fluorescense and giemsa staining. Nature 243:29tl-293. 6. Feinberg A, Vogelstein B (1984): A technique for radiolabeling DNA restriction endonuclease fragments to high activity. Anal Biochem 137:266-267. 7. Mills KI, MacKenzy El), Birnie GD (1988): The site of breakpoint within the bcr is a prognostic factor in Philadelphia positive CML patients. Blood 72:1237-1241. 8. Groffen J, Stephenson IR, Heisterkamp N. de, Klein A, Bartram CR, Grosveld G (19841: Philadelphia chronmsomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36:93-99. 9. Collins SJ, Kubonishi I, Miyoshi I, Groudine MT (1984]: Altered transcription of c-abl oncogene in K562 and other chronic myelogenous leukemia cells. Science 225:72-74. 10. Swaim R, Windschitl HE, Doscherholmen A, Bankole RO, Bates HA (1971): Chronic myelogenous h;ukemia in Hodgkin's disease: hnnmnofluorescence of cells. Cancer 27:569-573. 11. Dastugue N, Demur C, Pris F, Bugat R, Attal M, Bourrouillou G, Colombies P (1988): Association of the Philadelphia chromosome aml 5q in secondary blood disorders. Cancer Genet Cytogenet 30:253-259. 12. Teichmann J, Sieber G, Ludwig WD, Karow J, Rnehl H (1986): Chronic myelocytic leukemia as a second neoplasia in the course of chronic lymphocytic leukemia. Leuk Res 10:361-368. 13. Whang-Peng J, Young RC, Lee EC, Longo DL, Schechter GP, DeVita VT (1988): (2ytogenetic studies in patients with secondary leukemia/dysmyelopoietic syndrome after different treatment modalities, Blood 71:403-414. 14. Philip P, Pedersen-Bjergard J (19881: Cytogenetic, clinical and cytological characteristics of radiotherapy-related leukmnias. Cancer Genet Cytogenet 31:227-236. 15. Michalski KA, Miles JH, Perry MC {1982): Unusual Ph' translocation in a preleukemia. Cam:er Genet Cytogenet 6:89-90. 16. Ohyashiki K. Ohyashiki JH, Raza A, Preisler HD, Sandberg AA (1987): Phenylbutazoneinduced myelodysplastic syndrome with Philadelphia translocation. Cancer Genet Cytogenet 26:213-216. 17. Wanders J, Wattendorff AR, Endtz LJ, den Hijs JJ, Leeksma CHW (1981): Chronic myeloid leukemia in myasthenia gravis after long-term treatment with 6-mercaptopurine. Acta Med S t a n d 210:235 239. 18. Ohyashiki K, Kocova M, Ryan DH, Rowe JM, Sandberg AA (1986): Secondary acute myeloblastic leukemia with a Ph translocation in a treated Wegener's granulomatosis. Cancer Genet Cytogenet 19:331-333. 19. Roth DG, Richman CM, Rowley JD (1980): Chronic myelodysplastic syndrome {preleukemia) with the Philadelphia chromosome. Blood 56:262-264. 20. Smadja N, Krulik M, Hagemeijer A, van der Plas DC, Canali GG, de Gramont A (1989): Cytogenetic and molecular studies of the Philadelphia translocation t(9;22) observed in a patient with myelodysplastic syndrome. Leukemia 3:236-238. 21. Berrebi A, Bruck R, Shtalrid M, Chemke C (1984): Philadelphia chromosome in idiopathic acquired sinderoblastic anemia. Acta Haematol 72:343-345.
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22. Canellos GP, Whang-Peng J {1972): Philadelphia chromosome-positive preleukemic state, Lancet 1:1227-1228, 23. Grunwald HW, Rosner F {1982): Acute myeloid leukemia following tre,atment of Hodgkin's disease. Cancer 50:t~76-683. 24. Levy R, Kaplan HS {1974): Unpaired lymphocyte function in untreated Hodgkin's disease, N Engl J Med 290:181-186. 25. Leeksma CW, Verhoef GEG, Haak HL, Kerkhofs H, Gerrits WBJ, Hermans J, te Velde J (1989): Myelodysplastic f~;atures, myelodysplastic syndrome and acute myeloid leukemia in Hodgkin's disease;. Br I Haematol 71:25.
ABSTRACT: A patient who developed Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) 8 years after successful treatment for Hodgkin's disease IHD) is reported. The Ph chromosome with a typical 9(221 translocation was identified by banding techniques in 80% of bone marrow (BM) cells. Southern blot analysis showed breakpoint cluster region (BCR) rearrangement as observed in classical CML. Until now, only three cases of Ph + CML have been reported after treatment for HD. At present, it is not clear whether development of CML after HD represents a therapy-induced complication, an increased susceptibility to secondary malignancies owing to the malignant process itself, a consequence of the immunological deficiencies in HD, or possibly a genetic susceptibility to malignancy. INTRODUCTION
I m p r o v e m e n t s in treatment of Hodgkin's disease (HD) in the past 25 years have allowed m a n y patients to experience long-term survival and cure. The most serious and life-threatening late c o m p l i c a t i o n of such anticancer treatment is occurrence of a s e c o n d a r y malignancy. Acute m y e l o i d leukemia (AML) as a second neoplasm in HD has been well d o c u m e n t e d [1, 2]. The cumulative risk of developing AML increases by 0 . 3 - 1 % a n n u a l l y beginning 1 - 2 years after diagnosis and treatment of HD, but may cause plateau after 10 years. There is also an increased risk of non-Hodgkin's l y m p h o m a (NHL) and solid tumors of various types [3, 4]. The P h i l a d e l p h i a (Ph) c h r o m o s o m e ( 2 2 q - ) , w h i c h is the result of a reciprocal translocation between c h r o m o s o m e s 9 and 22 t(9;22)(q34;q11) and is characteristic: of chronic m y e l o i d leukemia (CML), has seldom been reported in secondary hematologic malignancies [5]. We report a case of a patient who developed a classical Ph ÷ CML 8 years after successful treatment for HD. CASE REPORT
A p r e v i o u s l y healthy 49-year-old male patient was diagnosed as having HD, n o d u l a r sclerosing type, on b i o p s y of an inguinal l y m p h node in August 1981. The disease was subsequently staged as IIIB. Cytogenetic analysis of the bone marrow (BM) cells From the Department of Hematology a n d Center for H u m a n Genetics, University Hospital Gasthuisberg, Leuvem Belgium.
Address reprint requests to: Dr. G. E. G. Verhoef, Department of Hematology, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven Belgium. Received December 27, 1989: accepted February 8. 1990.
171 '© 1990 Elsevier Science Publishing Co., Inc. 655 A v e n u e of the Americas. New York, NY 10010
Cancer Genet Cytogenet 4 9 : ] 7 ] 0165-4608/90/$03.50
17611990)
172
(;. E. (;. Verhoet e[ al.
showed a normal karyotype (46,XY). Combination chemotherapy with nitrogen mustard, vincristine, procarbazine, and prednisone was administered. He r e s p o n d e d well with a p p a r e n t l y complete remission at the end of 8 months of chemotherapy. A regular follow-up for a 7-year period did not show signs of relapse or hematologic abnormalities. In February 1989, leukocvtosis and thrombocytosis was detected at a routine follow-up examination. Physical examination was normal, without hepatos p l e n o m e g a l y or l y m p h nude enlargement. Peripheral blood counts showed red blood cells (RBC) 5.37 × 101e/L, hemoglobin 14.4 g/dl, hematocrit 0.44, reticulocytes 1.4%, mean c o r p u s c u l a r volume 82 fl, white blood cell (WBC) count 24 x 10'/L, and thrombocytes 510 × 10'/L. The differential WBC count showed 3% promyelucytes, 5% myelo(:ytes, 2% metamyeh~(:ytes, 6(1% neutrophils, 2% eosinophils, 4'!/,,basophils, 23% lymphocytes, and 1% mono(:vtes, Leucocyte alkaline phosphatase (LAP) score was 12 (normal, 14 1001. The serum vitamin 13~, level was 1,390 /zg/L (normal. 150-850). The BM aspiration was hyper(:elhflar with a i n y e l o i d : e r y t h r o i d ratio of 9:1 and contained 1% mveloblasts, 7% promyelo(:ytes, 26% myelocytes, 25% metamyelocytes, and 41% polymorphontlclear cells. Megakaryo(:ytes were numerous. There were no features of myelodysplasia. A Ph chromosome couht be identified in eight of 10 metaphases of BM (:ells. Therefore, a diagnosis of Ph ~ CML, 8 years after suc(:essful treatment for HD was established. The patient is still in chronic phase after a lO-month follow-up period. Cylogenetic Investigations Cytogenetic analvsis was performed on BM cells using short-terin (:ulture (24 hour) without mitogens. Chromosome preparations were processed for R banding and stained with acridine orange. At least 30 (:ells were analyzed, and 10 metaphases were karyotyped. At diagnosis (November 1981), all 10 metaphases examined showed a normal karyotype [46,XY). In February 1989, eight ()f the 10 karyotypes analyzed contained a Ph translocation [)etween chromosomes 9 and 22, t(9:22)(q34;q11), and two (:ells showed a normal karyotype (Fig. I). Molecular Studies DNA was digested with restriction endonucleases BglII, BamttI and HindlII, sizefractioned in a 0.7% agarose gel, and transferred onto a nylon membrane. The membrane was then hybridized to bcr probes :~XP-labeled by primer extension 161. The presence of bcr rearrangement was investigated by the universal bcr probe {bcr-u), provided by Dr. A. Hagelneijer {Rotterdam), encompassing the major breakpoint cluster region [MBCR). With a 1-kilobase (kb) lIindlII-EcoRI 3'bcr probe, provided by Mrs. 1,. Birge (Scottsdale, AZ) the site of the breakpoint can be localized inside this MBCR 171. Southern blot analysis showed hybridization of the bcr-u probe to the expected germline fragments and to rearranged fragments in BglIl, BamHI, a n d / / i n ( t I I l digests, respectively (Fig. 2). The rearranged fragments re(:ognized by the 3' bcr probe localize the breakpoint within the 3' segment of MBCIL DISCUSSION In our patient, the diagnosis of P h , bcr" CML 8 years after successful treatment for HD was made on the basis of clinical, morphological, cytogenetic, and molecular studies. Southern blot analysis in our patient indicated a bcr breakpoint within the MBCR as expected in typical CML ]8, 9l. Patients who have been treated for HD have an increased risk of developing secondary malignancy, including AML, NHL, and solid tumors of various types 11 4]. Translocation (9;22), or CML as a second neoplasm detected during the (:ourse of a
Ph-Positive CML in Treated HD
Figure 1
173
Karyotype of the bone marrow cells showing t(9;22)(q34;q11).
previous malignancy has seldom been reported. Swaim et al. [101 described a patient in w h o m CML d e v e l o p e d 8 years after the start of radiation therapy for HD. However, Swaim et al. [10] did not perform cytogenetic analysis. Dastugue et al. [111 reported a patient in w h o m a m y e l o d y s p l a s t i c syndrome developed 7 years after radiotherapy for a gastric l y m p h o m a . The initial m y e l o d y s p l a s t i c s y n d r o m e evolved to a myeloproliferative phase with transient polycythemia, progressive thrombocytosis, and hyperleukocytosis. Chromosome analysis performed in the terminal phase showed del(5) (q13q31) and t(9;22)(q34;q11). Teichmann et al. [12] reported six patients in w h o m Ph + CML d e v e l o p e d after chronic l y m p h o c y t i c leukemia (CLL). Whang-Peng et al. [131 reported the results of cytogenetic studies performed before and during development of secondary leukemia in patients with different types of neoplasia. Chronic myelogenous leukemia was observed in nine patients. Eight CML patients were Ph*. In two patients CML d e v e l o p e d after treatment for HD. The remaining patients had cancer of the breast (two patients), CLL (one patient), NHL [one patient), and acute l y m p h o b l a s t i c leukemia (two patients). The survival of the patients ranged from 7 to 34 inonths, a much shorter survival than for de novo CML. Three other cases of CML after radiation treatment for cancer of the uterus (two patients) and testicular carcinoma (one patient) have been described [14]. Michalski et al. [151 reported a patient with the Ph chromosome in whom preleukemia developed 5 years after treatment for HD: however, the clinical and hematologic findings of CML were absent. Three other patients had a therapy-related Ph + m y e l o d y s p l a s i a occurring after prolonged use of phenylbutazone, c y c l o p h o s p h a m i d e , and 6-mercaptopurine, respectively [16-18]. The Ph c h r o m o s o m e has also been reported in a variety of conditions other than CML and is a rather exceptional observation in primary m y e l o d y s p l a s t i c s y n d r o m e [19-22]. Only four cases have been described. Several explanations appear possible for the occurrence of CML in HD. First, the
174
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Barn HI
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9.4 6.6
6.6
4.4
4.4
4.4
2.3 2.0
I .35
2.3
I .08
PROBE
u
3'
u
3'
u
3'
Figure 2 Arrangement of major breakpoint ~:luster region (MBCR) in patieIlt (P) and control (C) DNA. DNA was cut with the indicated restriction enzyme. The Southern filters were hybridized with probes bcr-n (u) and 3'her (3'). Germline bands apparent il~ lane C were derived from placenta DNA. White blood ~:ells were obtained from peripheral blood. Fragment sizes were determined by simultaneous ele~:trophoresis with a a DNA-HiIldlII/OX-174 RF DNA-HaeII[ digest and are given in kilobases.
cytostatic drugs used in treatment of HD may be directly involved in the pathogenesis of CML [23]. Second, the experience from studies of atomic bomb survivors and patients with ankylosing spondylitis confirmed the hypothesis that ionizing radiation plays an important role in secondary CML. Third, immunological deficiencies in HD patients as well as therapy-induced immunological abnormalities may contribute to the evolution of CML [24]. Fourth, HD patients may have an increased susceptibility to development of leukemic malignancies. In a previous study of 98 consecutive patients with HD, we found in 55 patients myelodysplastic features not related to therapy or stage [25]. These features persisted during the entire course of the disease irrespective of the occurrence of a remission of HD. These findings suggest a genetic susceptibility that plays a role in development of HD, de novo myelodysplasia, and Inyeloproliferative syndrome. Fifth, the neoplastic transformation of a progenitor, capable of differentiation into either lymphoid or myeloid cell lines might lead to the association of lymphoproliferative and myeloproliferative disorders. This case report implies that patients treated for HD require close follow-up for years after completing therapy.
P h - P o s i t i v e C M L in T r e a t e d HD
175
We thank Katrien Vandenbossche, Kathy Merckx. and Marie-Jos6 Mijten for expert technical assistance. This work was supported by the Inter-university Network for Fundamental research sponsored by the Belgian Government (1987-1991).
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