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Philadelphia-positive T-acute lymphoblastic leukemia
Philadelphia-Positive T-Acute Lymphoblastic Leukemia Andries Louwagie, Arnold Criel, C. M. Verfaillie, Y. J. Valcke, H. Lamberts, M. Hidajat, Cristina Mecucci, and Herman Van Den Berghe
A case of typical T-acute lymphoblastic leukemia (T-ALL) is reported in which, at diagnosis, 100% of bane m a r r o w metaphases showed a Philadelphia (Ph) translocation, t(9;22). These cells completely disappeared following chemotherapy. The significance of the Ph chromosome in T a n d B leukemic cells is d i s c u s s e d .
ABSTRACT:
INTRODUCTION A Philadelphia chromosome (Ph) has been observed in approximately 15%-20% of adults with acute lymphoblastic leukemia (ALL) [1]. The immunologic phenotype is that of common ALL and, on further analysis, the proliferating cells are of pre-B origin. To our knowledge, two cases of Ph-positive T-ALL have been reported [2, 3]. Recently, Miller et al. [4] reported a late appearance of a Ph in a T-cell ALL. The present report concerns a 50-yr-old man with Ph-positive T-ALL, with apparent complete disappearance of the Ph during remission.
CASE REPORT
Patient H. L., born on 4/12/33, was hospitalized on the 4/1/83 complaining of fatigue and malaise for about 6 wk. Clinical examination revealed pallor, easy bruising, and marked splenomegaly. Chest x-ray showed a huge mediastinal mass due to lymph node hyperplasia. Relevant peripheral blood data were: hemoglobin 7.2 g/dl; red blood cells, 2.5 x 1012/L; reticulocytes, 4/1000; leukocytes, 221 x 109/L with 1% neutrophils and 99% predominantly undifferentiated lymphocytic blast cells; platelet count, 58 x 109/L; fibrinogen, 0.58 g/L; fibrinogen degradation products, 0.58 g/L. Bone marrow examination revealed a hypercellular bone marrow with the presence of 99% highly undifferentiated blast cells, with an increased cytoplasm/nucleus ratio and often a cleaved to reniform nucleus.
From the Department of Hematology (A.L., A.C., C.M.V., Y.J.V., H.L., M.H.), St. Jansziekenhuis, Brugge, Belgium and the Center for Human Genetics (H.V.D.B., C.M.), University of Leuven, Belgium
Address requests for reprints to Dr. Herman Van Den Berghe, Center for Human Genetics, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium, Received June 26, 1984; accepted August 4, 1984
297 © 1985 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York, NY 10017
Cancer Genetics and Cytogenetics 16, 297-300 (1985) 0165-4608/85/$03.30
298
Louwagie et al.
On cytochemical examination the malignant ceils were periodic acid-Schiff stain-, peroxydase-, S u d a n black, and a l p h a - n a p h t y l acetate esterase-negative. Acid p h o s p h a t a s e staining s h o w e d a strong, dot-like positivity, not resistant to preincubation with tartrate. Immunologic p h e n o t y p i n g of the blast cells was consistent with T-ALL. The data are s u m m a r i z e d in Table 1. Cytogenetic analysis was performed prior to any treatment on u n s t i m u l a t e d bone marrow cells cultivated for 48 hr. Acridine-orange R-banding was used. A Ph chromosome was found in all 28 cells examined. The karyotype was 46,XY,t(9;22)(q34;q11). No other anomalies were detected. A diagnosis of Ph-positive T-cell ALL, thus, was m a d e on the basis of the morphology of the blasts, the cytochemistry, and the i m m u n o l o g i c phenotype. Treatment was initiated in A p r i l 1983. Induction treatment consisted of w e e k l y administration of a d r i a m y c i n e 45 mg/m 2, Vincristine 3mg/m 2, and p r e d n i s o n e 25 mg/m2. During i n d u c t i o n the patient d e v e l o p e d meningeal invasion, w h i c h was treated with cranial irradiation (2400 R) and intrathecal methotrexate (12 mg i.t. every 2 days × 6). After a 3-wk course with adriamycin, vincristine and predinisone, remission was not obtained, and treatment was reinforced with adriamycin, 45 mg/m 2 (day 1); Vincristin, 2 mg/m 2 (day 1); L-asparaginase (Crasnitin), 200 U/kg (day 1 - d a y 7); and p r e d n i s o n e 25 mg/m 2 (day 1 - d a y 7). Complete remission was obtained in May 1983. Cytogenetic investigation done on 25 metaphases showed that the Ph c h r o m o s o m e a p p a r e n t l y had d i s a p p e a r e d from the bone marrow. Consolidation therapy was started on the 5/10/83 with Methotrexate i.v., 15 mg/m 2 2/wk × 2; methotrexate i.t., 12 mg i.v. 1/wk × 4; 5-thioguanine, 1 mg/kg/day. Maintenance t h e r a p y consisted of 6-Thioguanine 1-2 mg/kg day and methotrexate i.t., 12 mg 1/mo. Intermittent r e i n d u c t i o n courses were given with 12 w k interval. They consisted of Vincristine, 1.4 mg/m 2 (day 1 and day 8); prednisone, 40 mg {day 1 - d a y 14); methotrexate i.v., 15 mg/m 2 x 2 (wk 3); methotrexate i.t., 12 mg × 2 (wk 4); and methotrexate i.v., 15 mg/m 2 × 2 (wk 5). The patient has been in complete remission for more than 13 mo. Three further cytogenetic analyses of bone marrow aspirated during remission only s h o w e d normal karyotypes in 30 metaphases examined each time. The abnormal clone, thus, was no longer detectable.
Table 1
E Rosettes OKT3 OKT4 OKT8 OKT10 Ia C-ALL s-lg BA-1 BA-3 Leu 9 Tdt
Immunologic typing of the blast cells 50% 1% 39% 79% 92% 1% 12% 6% 2% 0% 96% 9O%
Ph-Positive T-ALL
299
DISCUSSION There can be no doubt about the T-cell nature of the Ph-positive ALL in this adult patient. First, the clinical findings of splenomegaly and the marked m e d i a s t i n a l enlargement due to l y m p h node h y p e r p l a s i a are consistent with this diagnosis. Second, the blood examination showed a high leukocyte count with almost 99% undifferentiated blast cells, strong dot-like acid phosphatase positivity, and sometimes with a cleaved to reniform nucleus. The same blasts also were a b u n d a n t l y present in the bone marrow. Finally, the diagnosis of T-ALL was further confirmed by immunologic typing: E + , T d t + , O K T 1 0 + , OKT8 + , and Leu 9 positivity. Chromosome analysis revealed the presence of a Ph chromosome w i t h o u t additional chromosomal abnormalities in all of the bone marrow metaphases. Complete disappearance of the c h r o m o s o m a l l y abnormal cell p o p u l a t i o n was noted during remission. Ph-positive ALL, both in children and in adults, is n o w recognized universally [5-7]. In most instances, the Ph abnormality is not found in all cells but in about 5 % - 3 0 % of the cells. The vast majority, however, were ALL of the null-cell type and could be further identified as pre-B cells, using m o n o c l o n a l antibodies. To our knowledge, only two cases of T-ALL with Ph c h r o m o s o m e at diagnosis have been documented. The present observation adds further evidence to the occurrence of a Ph in cells of the T-lineage. Hence, the Ph c h r o m o s o m e appears to occur in the granulocytic series of chronic granulocytic leukemia, in the precursors of the erythrocytic, megakaryocytic and monocytic lineages [8], and in the B-cell lineage of chronic m y e l o i d leukemia in chronic phase [9]. This already i n d i c a t e d the origin of the B-cell lineage to be close to the p l u r i p o t e n t h e m o p o i e t i c stem cell. Further evidence for a c o m m o n origin of the B-cell lineage and the p r i m a r y hemopoietic stem cell was given by Greaves et al. [10] and Lebien et al. [11], w h o demonstrated the presence of early progenitors of the B-lineage in chronic granulocytic leukemia (CGL) patients in l y m p h o i d blast transformation and by Van Den Berghe et al., who were the first to describe a Ph chromosome in p l a s m a cells [12]. Recently, Hernandez et al. [13], Herrman et al. [14], Griffin et al. [15], and Janossy (personal communication) observed cases of T l y m p h o i d CGL blastic crises. The observation of T- and B-cell crisis in CGL, and of Ph positivity in B-ALL and T-ALL point to the existence of man of a c o m m o n stem cell for the hemo- and i m m u n o poietic system.
REFERENCES 1. Third International Workshop on Chromosomes in Leukemia, 1980 (1981): Chromosomal abnormalities in acute lymphoblastic leukemia: Structural and numerical changes in 234 cases. Cancer Genet Cytogenet 4:101-110. 2. Roozendaal KJ, Van Der Reijden HJ, Geraedts JPM (1981): Philadelphia chromosome positive acute lymphoblastic leukemia with T-cell characteristics. Br J Haematol 47:145-147. 3. Dankbaar H, Willemze R, Spaander PJ, Geraedts JPM (1982): Philadelphia chromosome positive T-ALL. Br J Haematol 50:543. 4. Miller BA, Reid MM, Nell M, Lipton JM, Sallan SE, Nathan DG Tantravahi R (1984): Tcell acute lymphoblastic leukemia with late developing Philadelphia chromosome. Br J Haematol 56:139-146. 5. Chessels JM, Janossy G, Lawler SD, Secker Walker LM (1979): The Phl chromosome in childhood leukemia. Br J Haematol 41:25-41. 6. Bloomfield CD, Peterson LC, Yunis JJ, Brunning RD (1977): The Philadelphia chromosome (Ph 2) in adults presenting with acute leukemia; a comparison of Ph 1+ and Ph 1- patients. Br 1 Haematol 36:347-358.
300
L o u w a g i e et al.
7. Swansbury GL, Secker-Walker LM, Lawler SD et al (1981): Chromosomal findings in acute lymphoblastic leukemia of childhood: An independent prognostic factor. Lancet ii:249250. 8. Goldman JM, Dao-Peiker (1982): New approaches in chronic granulocytic leukemia--Origin, prognosis and treatment. Semin Hem 19:241-256. 9. Martin PJ, Najfeld V, Hansen [A et al (1980): Involvement of the B-lymphoid system in chronic myelogenous leukemia. Nature 287:49-50. 10. Greaves MF, Verbi W, Reeves R, Hoffbrand A, Drysdale HC, Jones L, Sacker LS. Samaraturuga (1979): "Pre-B" phenotypes in blast crisis of P h l positive CML: Evidence for a pluripotential stem cell "target." Leuk Res 3:181-191. 11. Lebien TW, Hozier J, Minowada J, Kersey JH (1979): Origin of chronic myelocytic leukemia in a precursor of pre-B lymphocytes. N Engl J Med 301:144-147. 12. Van Den Berghe H, Louwagie A, Broeckaert-Van Orshoven A, David G, Verwilghen R, Michaux JL, Sokal G (1979): Philadelphia chromosome in h u m a n multiple myeloma. J Natl Cancer Inst 63:11-16. 13. Hernandez P, Carnot J, Cruz C (1982): Chronic myeloid leukemia blast crisis with T-cell features (Letter). Br J Haematol 51:175-177. 14. Herrinan E, Ludwig WD, Kolecki (1984): Blast crisis in CML showing early T-lymphobtastic transformation. Br J Haematol 56:175-176. 15. Griffin JD, Tantzavahi R, Canellos GP, Wisch FS, Reinherz EL, Sherwood G, Beveridge Rp, Daley JF, Lane H, Schlossman SF (1983): T-cell surface antigens in a patient with blast crisis of chronic mveloid leukemia. Blood 61:640-644.
A case of typical T-acute lymphoblastic leukemia (T-ALL) is reported in which, at diagnosis, 100% of bane m a r r o w metaphases showed a Philadelphia (Ph) translocation, t(9;22). These cells completely disappeared following chemotherapy. The significance of the Ph chromosome in T a n d B leukemic cells is d i s c u s s e d .
ABSTRACT:
INTRODUCTION A Philadelphia chromosome (Ph) has been observed in approximately 15%-20% of adults with acute lymphoblastic leukemia (ALL) [1]. The immunologic phenotype is that of common ALL and, on further analysis, the proliferating cells are of pre-B origin. To our knowledge, two cases of Ph-positive T-ALL have been reported [2, 3]. Recently, Miller et al. [4] reported a late appearance of a Ph in a T-cell ALL. The present report concerns a 50-yr-old man with Ph-positive T-ALL, with apparent complete disappearance of the Ph during remission.
CASE REPORT
Patient H. L., born on 4/12/33, was hospitalized on the 4/1/83 complaining of fatigue and malaise for about 6 wk. Clinical examination revealed pallor, easy bruising, and marked splenomegaly. Chest x-ray showed a huge mediastinal mass due to lymph node hyperplasia. Relevant peripheral blood data were: hemoglobin 7.2 g/dl; red blood cells, 2.5 x 1012/L; reticulocytes, 4/1000; leukocytes, 221 x 109/L with 1% neutrophils and 99% predominantly undifferentiated lymphocytic blast cells; platelet count, 58 x 109/L; fibrinogen, 0.58 g/L; fibrinogen degradation products, 0.58 g/L. Bone marrow examination revealed a hypercellular bone marrow with the presence of 99% highly undifferentiated blast cells, with an increased cytoplasm/nucleus ratio and often a cleaved to reniform nucleus.
From the Department of Hematology (A.L., A.C., C.M.V., Y.J.V., H.L., M.H.), St. Jansziekenhuis, Brugge, Belgium and the Center for Human Genetics (H.V.D.B., C.M.), University of Leuven, Belgium
Address requests for reprints to Dr. Herman Van Den Berghe, Center for Human Genetics, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium, Received June 26, 1984; accepted August 4, 1984
297 © 1985 Elsevier Science Publishing Co., Inc. 52 Vanderbilt Ave., New York, NY 10017
Cancer Genetics and Cytogenetics 16, 297-300 (1985) 0165-4608/85/$03.30
298
Louwagie et al.
On cytochemical examination the malignant ceils were periodic acid-Schiff stain-, peroxydase-, S u d a n black, and a l p h a - n a p h t y l acetate esterase-negative. Acid p h o s p h a t a s e staining s h o w e d a strong, dot-like positivity, not resistant to preincubation with tartrate. Immunologic p h e n o t y p i n g of the blast cells was consistent with T-ALL. The data are s u m m a r i z e d in Table 1. Cytogenetic analysis was performed prior to any treatment on u n s t i m u l a t e d bone marrow cells cultivated for 48 hr. Acridine-orange R-banding was used. A Ph chromosome was found in all 28 cells examined. The karyotype was 46,XY,t(9;22)(q34;q11). No other anomalies were detected. A diagnosis of Ph-positive T-cell ALL, thus, was m a d e on the basis of the morphology of the blasts, the cytochemistry, and the i m m u n o l o g i c phenotype. Treatment was initiated in A p r i l 1983. Induction treatment consisted of w e e k l y administration of a d r i a m y c i n e 45 mg/m 2, Vincristine 3mg/m 2, and p r e d n i s o n e 25 mg/m2. During i n d u c t i o n the patient d e v e l o p e d meningeal invasion, w h i c h was treated with cranial irradiation (2400 R) and intrathecal methotrexate (12 mg i.t. every 2 days × 6). After a 3-wk course with adriamycin, vincristine and predinisone, remission was not obtained, and treatment was reinforced with adriamycin, 45 mg/m 2 (day 1); Vincristin, 2 mg/m 2 (day 1); L-asparaginase (Crasnitin), 200 U/kg (day 1 - d a y 7); and p r e d n i s o n e 25 mg/m 2 (day 1 - d a y 7). Complete remission was obtained in May 1983. Cytogenetic investigation done on 25 metaphases showed that the Ph c h r o m o s o m e a p p a r e n t l y had d i s a p p e a r e d from the bone marrow. Consolidation therapy was started on the 5/10/83 with Methotrexate i.v., 15 mg/m 2 2/wk × 2; methotrexate i.t., 12 mg i.v. 1/wk × 4; 5-thioguanine, 1 mg/kg/day. Maintenance t h e r a p y consisted of 6-Thioguanine 1-2 mg/kg day and methotrexate i.t., 12 mg 1/mo. Intermittent r e i n d u c t i o n courses were given with 12 w k interval. They consisted of Vincristine, 1.4 mg/m 2 (day 1 and day 8); prednisone, 40 mg {day 1 - d a y 14); methotrexate i.v., 15 mg/m 2 x 2 (wk 3); methotrexate i.t., 12 mg × 2 (wk 4); and methotrexate i.v., 15 mg/m 2 × 2 (wk 5). The patient has been in complete remission for more than 13 mo. Three further cytogenetic analyses of bone marrow aspirated during remission only s h o w e d normal karyotypes in 30 metaphases examined each time. The abnormal clone, thus, was no longer detectable.
Table 1
E Rosettes OKT3 OKT4 OKT8 OKT10 Ia C-ALL s-lg BA-1 BA-3 Leu 9 Tdt
Immunologic typing of the blast cells 50% 1% 39% 79% 92% 1% 12% 6% 2% 0% 96% 9O%
Ph-Positive T-ALL
299
DISCUSSION There can be no doubt about the T-cell nature of the Ph-positive ALL in this adult patient. First, the clinical findings of splenomegaly and the marked m e d i a s t i n a l enlargement due to l y m p h node h y p e r p l a s i a are consistent with this diagnosis. Second, the blood examination showed a high leukocyte count with almost 99% undifferentiated blast cells, strong dot-like acid phosphatase positivity, and sometimes with a cleaved to reniform nucleus. The same blasts also were a b u n d a n t l y present in the bone marrow. Finally, the diagnosis of T-ALL was further confirmed by immunologic typing: E + , T d t + , O K T 1 0 + , OKT8 + , and Leu 9 positivity. Chromosome analysis revealed the presence of a Ph chromosome w i t h o u t additional chromosomal abnormalities in all of the bone marrow metaphases. Complete disappearance of the c h r o m o s o m a l l y abnormal cell p o p u l a t i o n was noted during remission. Ph-positive ALL, both in children and in adults, is n o w recognized universally [5-7]. In most instances, the Ph abnormality is not found in all cells but in about 5 % - 3 0 % of the cells. The vast majority, however, were ALL of the null-cell type and could be further identified as pre-B cells, using m o n o c l o n a l antibodies. To our knowledge, only two cases of T-ALL with Ph c h r o m o s o m e at diagnosis have been documented. The present observation adds further evidence to the occurrence of a Ph in cells of the T-lineage. Hence, the Ph c h r o m o s o m e appears to occur in the granulocytic series of chronic granulocytic leukemia, in the precursors of the erythrocytic, megakaryocytic and monocytic lineages [8], and in the B-cell lineage of chronic m y e l o i d leukemia in chronic phase [9]. This already i n d i c a t e d the origin of the B-cell lineage to be close to the p l u r i p o t e n t h e m o p o i e t i c stem cell. Further evidence for a c o m m o n origin of the B-cell lineage and the p r i m a r y hemopoietic stem cell was given by Greaves et al. [10] and Lebien et al. [11], w h o demonstrated the presence of early progenitors of the B-lineage in chronic granulocytic leukemia (CGL) patients in l y m p h o i d blast transformation and by Van Den Berghe et al., who were the first to describe a Ph chromosome in p l a s m a cells [12]. Recently, Hernandez et al. [13], Herrman et al. [14], Griffin et al. [15], and Janossy (personal communication) observed cases of T l y m p h o i d CGL blastic crises. The observation of T- and B-cell crisis in CGL, and of Ph positivity in B-ALL and T-ALL point to the existence of man of a c o m m o n stem cell for the hemo- and i m m u n o poietic system.
REFERENCES 1. Third International Workshop on Chromosomes in Leukemia, 1980 (1981): Chromosomal abnormalities in acute lymphoblastic leukemia: Structural and numerical changes in 234 cases. Cancer Genet Cytogenet 4:101-110. 2. Roozendaal KJ, Van Der Reijden HJ, Geraedts JPM (1981): Philadelphia chromosome positive acute lymphoblastic leukemia with T-cell characteristics. Br J Haematol 47:145-147. 3. Dankbaar H, Willemze R, Spaander PJ, Geraedts JPM (1982): Philadelphia chromosome positive T-ALL. Br J Haematol 50:543. 4. Miller BA, Reid MM, Nell M, Lipton JM, Sallan SE, Nathan DG Tantravahi R (1984): Tcell acute lymphoblastic leukemia with late developing Philadelphia chromosome. Br J Haematol 56:139-146. 5. Chessels JM, Janossy G, Lawler SD, Secker Walker LM (1979): The Phl chromosome in childhood leukemia. Br J Haematol 41:25-41. 6. Bloomfield CD, Peterson LC, Yunis JJ, Brunning RD (1977): The Philadelphia chromosome (Ph 2) in adults presenting with acute leukemia; a comparison of Ph 1+ and Ph 1- patients. Br 1 Haematol 36:347-358.
300
L o u w a g i e et al.
7. Swansbury GL, Secker-Walker LM, Lawler SD et al (1981): Chromosomal findings in acute lymphoblastic leukemia of childhood: An independent prognostic factor. Lancet ii:249250. 8. Goldman JM, Dao-Peiker (1982): New approaches in chronic granulocytic leukemia--Origin, prognosis and treatment. Semin Hem 19:241-256. 9. Martin PJ, Najfeld V, Hansen [A et al (1980): Involvement of the B-lymphoid system in chronic myelogenous leukemia. Nature 287:49-50. 10. Greaves MF, Verbi W, Reeves R, Hoffbrand A, Drysdale HC, Jones L, Sacker LS. Samaraturuga (1979): "Pre-B" phenotypes in blast crisis of P h l positive CML: Evidence for a pluripotential stem cell "target." Leuk Res 3:181-191. 11. Lebien TW, Hozier J, Minowada J, Kersey JH (1979): Origin of chronic myelocytic leukemia in a precursor of pre-B lymphocytes. N Engl J Med 301:144-147. 12. Van Den Berghe H, Louwagie A, Broeckaert-Van Orshoven A, David G, Verwilghen R, Michaux JL, Sokal G (1979): Philadelphia chromosome in h u m a n multiple myeloma. J Natl Cancer Inst 63:11-16. 13. Hernandez P, Carnot J, Cruz C (1982): Chronic myeloid leukemia blast crisis with T-cell features (Letter). Br J Haematol 51:175-177. 14. Herrinan E, Ludwig WD, Kolecki (1984): Blast crisis in CML showing early T-lymphobtastic transformation. Br J Haematol 56:175-176. 15. Griffin JD, Tantzavahi R, Canellos GP, Wisch FS, Reinherz EL, Sherwood G, Beveridge Rp, Daley JF, Lane H, Schlossman SF (1983): T-cell surface antigens in a patient with blast crisis of chronic mveloid leukemia. Blood 61:640-644.