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Translocation (15;17) and trisomy 21 in the microgranular variant of acute promyelocytic leukemia
Cancer Genetics and Cytogenetics 132 (2002) 74–76
Short communication
Translocation (15;17) and trisomy 21 in the microgranular variant of acute promyelocytic leukemia Derrick W. Spella,*, Gopalrao V. N. Velagaletib, Dennie V. Jonesa, William S. Velasqueza a
Division of Hematology / Oncology, Department of Internal Medicine, 301 University Boulevard, Route 0565 Galveston, Texas 77555, USA b Division of Genetics, Department of Pediatrics, The University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, Texas 77555, USA Received 30 April 2001; received in revised form 12 June 2001; accepted 12 June 2001
Abstract
Cytogenetic abnormalities in acute myelogenous leukemia have been identified as one of the most important prognostic factors. Favorable chromosomal changes such as inv(16), t(8;21), and t(15;17) are associated with higher rates of complete remission and event-free survival. Translocation t(15;17) characterizes acute promyelocytic leukemia (APL) (French-American-British [FAB] class M3) in almost all patients. Secondary chromosomal abnormalities are also present in approximately one-third of patients with newly diagnosed APL. We present a 26-year-old Hispanic man diagnosed with the microgranular variant of APL (FAB class M3v) whose initial cytogenetics included t(15;17) and trisomy 21. The prognostic implications of trisomy 21 and other secondary cytogenetic aberrations in APL are reviewed. To our knowledge, this is the first reported case of trisomy 21 with t(15;17) in the microgranular variant of APL. © 2002 Elsevier Science Inc. All rights reserved.
1. Introduction Acute promyelocytic leukemia (APL) accounts for approximately 10–15% of acute myelogenous leukemia (AML) and is a very distinct subtype with regard to clinical, morphologic, and prognostic features. The median age of patients with APL is approximately 30 to 40 years and for unknown reasons a higher incidence is reported in Latinos [1]. Acute promyelocytic leukemia also has the highest frequency of hemorrhagic morbidity and mortality among all subtypes of AML, yet five-year overall survival rates of better than 75% are reported [2]. One of the reasons for the favorable prognosis in APL is the presence of translocation t(15;17) in almost all patients. Most patients with t(15;17) will respond to combination treatment with all trans-retinoic acid (ATRA) and cytarabine (Ara-C)/anthracycline-based chemotherapy [1]. Chromosomal abnormalities accompanying t(15;17) are reported in 23–39% of cases of APL in the literature [2–10]. Despite the common occurrence of secondary anomalies, their clinical significance has only recently been elucidated. We report a patient with newly diagnosed APL whose ini* Corresponding author. Tel.: 409-772-1164; fax: 409-772-3533. E-mail address: [email protected] (D.W. Spell).
tial cytogenetics demonstrated t(15;17) and trisomy 21. The prognostic implications of trisomy 21 and other secondary genetic aberrations associated with t(15;17) are also examined. 2. Case report A 26-year-old Hispanic man presented with increasing fatigue over one month, along with dyspnea on exertion and easy bruising for four to five days. Physical examination revealed petechiae of the mouth and lower extremities. A blood count showed a white cell count of 13.7103 /mL, hemoglobin of 5.7 gm/dL, and platelet count of 11103 / mL. Coagulation studies were unremarkable. Flow cytometry performed on bone marrow samples identified the presence of an abnormal population of CD13()/CD33()/ CD14()/DR() myeloid cells. Bone marrow examination revealed a marked increase in cellularity with sheets of immature myeloid cells most consistent with the microgranular variant of APL. The patient was treated with induction therapy consisting of three days of idarubicin, seven days of Ara-C, and daily ATRA. Repeat bone marrow examination on induction day 30 confirmed a complete remission. After completing two cycles of consolidation therapy with idarubicin and Ara-C, the patient remained in remission. The patient is currently
0165-4608/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S0165-4608(01)00 5 3 1 - 3
D.W. Spell et al. / Cancer Genetics and Cytogenetics 132 (2002) 74–76
receiving maintenance therapy with continuous 6-mercaptopurine, weekly methotrexate, and intermittent ATRA and remains without evidence of leukemia. 3. Cytogenetics Unstimulated short-term cultures were set up from the bone marrow aspirate obtained at diagnosis. Analysis of 20 metaphases showed clonal abnormalities. The modal count was 47 chromosomes, with the presence of an extra chromosome 21 and the characteristic reciprocal translocation involving a chromosome 15 and a chromosome 17. The karyotype was interpreted as 47,XY,t(15;17)(q22;q21), 21[20] (Fig. 1) [11]. Additional fluorescence in situ hybridization (FISH) studies with a dual color translocation probe for the PML locus at 15q22 and RAR locus at 17q21 (Vysis, Downers Grove, IL, USA) were carried out. Analysis of 303 interphase nuclei showed a hybridization pattern consistent with PML/RAR fusion in 270 (89.1%) nuclei. A second chromosome analysis of the bone marrow aspirate after completion of induction therapy showed a normal 46,XY karyotype in all 20 cells analyzed. Repeat FISH studies with a dual color PML/RAR translocation probe also showed a normal hybridization pattern in 196 of the 204 (96.1%) of the nuclei confirming the clinical remission.
75
The remaining 3.9% of the cells showed a signal pattern consistent with PML/RAR fusion; however, this amount of cells is considered background noise since the cutoff for positive fusion results established in our laboratory is greater than or equal to 12.2%. 4. Discussion Prior to 1996, only three reports catalogued secondary cytogenetic changes associated with APL [3–5]. The prognostic implications of additional cytogenetic abnormalities associated with APL have recently been examined in six studies [2,6–10]. Two of these reports found that secondary chromosomal anomalies did not confer a poor prognosis in APL [6,7]. In contrast, two other studies found that additional abnormalities did confer a worse prognosis in APL [8,9]. The conflicting results of these four reports can be attributed to relatively small sample sizes as well as varied or outdated treatment plans. In a much larger study, Grimwade et al. [10] evaluated the prognostic implications of numerous chromosomal abnormalities in AML. The authors discovered that additional cytogenetic changes did not alter the outcome of patients with favorable cytogenetic anomalies such as t(15;17). Even chromosomal abnormalities categorized in the adverse risk
Fig. 1. Karyotype at diagnosis: 47,XY,t(15;17)(q22;q21),21.
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D.W. Spell et al. / Cancer Genetics and Cytogenetics 132 (2002) 74–76
group, like monosomies 5 and 7, had no effect on response rates or overall survival in individuals with concurrent favorable cytogenetics. Furthermore, trisomy 21 was categorized in the intermediate risk group. This intermediate group contained cytogenetic abnormalities classified as neither favorable nor adverse and included patients with normal cytogenetics. In a comprehensive trial involving the largest cohort of patients with t(15;17) to date, de Botton et al. [2] also demonstrated that additional cytogenetic changes in patients with t(15;17) had no impact on prognosis. All patients in the study received ATRA in addition to Ara-C/anthracyclinebased chemotherapy. No significant difference was seen between patients with only t(15;17) and patients with t(15;17) in combination with other chromosomal abnormalities for complete remission rate, event-free survival at two years, and overall survival at two years. Only one report in the literature has exclusively addressed the prognostic importance of trisomy 21 in patients with AML. Cortes et al. [12] determined that response rates and survival were comparable for patients with favorable cytogenetics alone and patients with favorable cytogenetics associated with trisomy 21. Response rates and survival were also similar in patients with monosomy 5 or 7 and patients with monosomy 5 or 7 accompanying trisomy 21. The authors concluded that the prognosis of patients with trisomy 21 was most contingent on the prognosis of the associated chromosomal aberrations. Unlike children with constitutional trisomy 21 and AML [13], there is no convincing evidence that acquired trisomy 21 has any impact upon prognosis in APL. The two studies that reported an inferior prognosis in APL associated with secondary chromosomal abnormalities were less than ideal. [8,9] In the largest study evaluating the prognostic significance of cytogenetic changes in AML, patients with t(15;17) and additional chromosomal anomalies maintained a favorable outcome regardless of the additional cytogenetic change [10]. De Botton et al. [2] confirmed this observation in the only trial wherein all of the patients were treated with both ATRA and anthracyclinebased chemotherapy. In summary, APL is often associated with additional cytogenetic abnormalities. The majority of evidence currently supports the concept that patients with t(15;17) and trisomy 21, or any other additional abnormality, have the same favorable prognosis as patients with t(15;17) alone.
References [1] Avvisati G, Lo Coco F, Mandelli F. Acute promyelocytic leukemia: Clinical and morphological features and prognostic factors. Semin Hematol 2001;38:4–12. [2] de Botton S, Chevret S, Sanz M, Dombret H, Thomas X, Guerci A, Fey M, Rayon C, Huguet F, Sotto J, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, San Miguel J, Link H, Desablens B, Stamatoullas A, Deconinck E, Geiser K, Hess U, Maloisel F, Castaigne S, Preudhomme C, Chomienne C, Degos L, Fenaux P. Additional chromosomal abnormalities in patients with acute promyelocytic leukaemia (APL) do not confer poor prognosis: results of APL 93 trial. Br J Haematol 2000;111:801–6. [3] Heim S, Mitelman F. Secondary chromosome aberrations in the acute leukemias. Cancer Genet Cytogenet 1986;22:331–8. [4] Berger R, Le Coniat M, Derre J, Vecchione D, Jonveaux P. Cytogenetic studies in acute promyelocytic leukemia: A survey of secondary chromosomal abnormalities. Genes Chromosomes Cancer 1991;3:332–7. [5] Johansson B, Mertens F, Mitelman F. Secondary chromosomal abnormalities in acute leukemias. Leukemia 1994;8:953–62. [6] Schoch C, Haase D, Haferlach T, Freund M, Link H, Lengfelder E, Loffler H, Buchner T, Fonatsch C. Incidence and implication of additional chromosome aberrations in acute promyelocytic leukaemia with translocation t(15;17)(q22;q21): A report on 50 patients. Br J Haematol 1996;94:493–500. [7] Slack JL, Arthur DC, Lawrence D, Mrózek K, Mayer RJ, Davey FR, Tantravahi R, Pettenati MJ, Bigner S, Carroll AJ, Rao KW, Schiffer CA, Bloomfield CD. Secondary cytogenetic changes in acute promyelocytic leukemia—Prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: A Cancer and Leukemia Group B study. J Clin Oncol 1997;15:1786–95. [8] Hiorns LR, Swansbury GJ, Mehta J, Min T, Dainton MG, Treleaven J, Powles RL, Catovsky D. Additional chromosome abnormalities confer worse prognosis in acute promyelocytic leukaemia. Br J Haematol 1997;96:314–21. [9] Pantic M, Novak A, Marisavljevic D, Djordjevic V, Elezovic I, Vidovic A, Colovic M. Additional chromosome aberrations in acute promyelocytic leukemia: characteristics and prognostic influence. Med Oncol 2000;17:307–13. [10] Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A. The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial. Blood 1998;92:2322–33. [11] ISCN. An international system for human cytogenetic nomenclature. Mitelman F, editor. Basel: S. Karger, 1995. [12] Cortes JE, Kantarjian H, O’Brien S, Keating M, Pierce S, Freireich EJ, Estey E. Clinical and prognostic significance of trisomy 21 in adult patients with acute myelogenous leukemia and myelodysplastic syndromes. Leukemia 1995;9:115–7. [13] Taub JW, Huang X, Matherly LH, Stout ML, Buck SA, Massey GV, Becton DL, Chang MN, Weinstein RJ, Ravindranath Y. Expression of chromosome 21-localized genes in acute myeloid leukemia: differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin. Blood 1999;94:1393–400.
Short communication
Translocation (15;17) and trisomy 21 in the microgranular variant of acute promyelocytic leukemia Derrick W. Spella,*, Gopalrao V. N. Velagaletib, Dennie V. Jonesa, William S. Velasqueza a
Division of Hematology / Oncology, Department of Internal Medicine, 301 University Boulevard, Route 0565 Galveston, Texas 77555, USA b Division of Genetics, Department of Pediatrics, The University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, Texas 77555, USA Received 30 April 2001; received in revised form 12 June 2001; accepted 12 June 2001
Abstract
Cytogenetic abnormalities in acute myelogenous leukemia have been identified as one of the most important prognostic factors. Favorable chromosomal changes such as inv(16), t(8;21), and t(15;17) are associated with higher rates of complete remission and event-free survival. Translocation t(15;17) characterizes acute promyelocytic leukemia (APL) (French-American-British [FAB] class M3) in almost all patients. Secondary chromosomal abnormalities are also present in approximately one-third of patients with newly diagnosed APL. We present a 26-year-old Hispanic man diagnosed with the microgranular variant of APL (FAB class M3v) whose initial cytogenetics included t(15;17) and trisomy 21. The prognostic implications of trisomy 21 and other secondary cytogenetic aberrations in APL are reviewed. To our knowledge, this is the first reported case of trisomy 21 with t(15;17) in the microgranular variant of APL. © 2002 Elsevier Science Inc. All rights reserved.
1. Introduction Acute promyelocytic leukemia (APL) accounts for approximately 10–15% of acute myelogenous leukemia (AML) and is a very distinct subtype with regard to clinical, morphologic, and prognostic features. The median age of patients with APL is approximately 30 to 40 years and for unknown reasons a higher incidence is reported in Latinos [1]. Acute promyelocytic leukemia also has the highest frequency of hemorrhagic morbidity and mortality among all subtypes of AML, yet five-year overall survival rates of better than 75% are reported [2]. One of the reasons for the favorable prognosis in APL is the presence of translocation t(15;17) in almost all patients. Most patients with t(15;17) will respond to combination treatment with all trans-retinoic acid (ATRA) and cytarabine (Ara-C)/anthracycline-based chemotherapy [1]. Chromosomal abnormalities accompanying t(15;17) are reported in 23–39% of cases of APL in the literature [2–10]. Despite the common occurrence of secondary anomalies, their clinical significance has only recently been elucidated. We report a patient with newly diagnosed APL whose ini* Corresponding author. Tel.: 409-772-1164; fax: 409-772-3533. E-mail address: [email protected] (D.W. Spell).
tial cytogenetics demonstrated t(15;17) and trisomy 21. The prognostic implications of trisomy 21 and other secondary genetic aberrations associated with t(15;17) are also examined. 2. Case report A 26-year-old Hispanic man presented with increasing fatigue over one month, along with dyspnea on exertion and easy bruising for four to five days. Physical examination revealed petechiae of the mouth and lower extremities. A blood count showed a white cell count of 13.7103 /mL, hemoglobin of 5.7 gm/dL, and platelet count of 11103 / mL. Coagulation studies were unremarkable. Flow cytometry performed on bone marrow samples identified the presence of an abnormal population of CD13()/CD33()/ CD14()/DR() myeloid cells. Bone marrow examination revealed a marked increase in cellularity with sheets of immature myeloid cells most consistent with the microgranular variant of APL. The patient was treated with induction therapy consisting of three days of idarubicin, seven days of Ara-C, and daily ATRA. Repeat bone marrow examination on induction day 30 confirmed a complete remission. After completing two cycles of consolidation therapy with idarubicin and Ara-C, the patient remained in remission. The patient is currently
0165-4608/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S0165-4608(01)00 5 3 1 - 3
D.W. Spell et al. / Cancer Genetics and Cytogenetics 132 (2002) 74–76
receiving maintenance therapy with continuous 6-mercaptopurine, weekly methotrexate, and intermittent ATRA and remains without evidence of leukemia. 3. Cytogenetics Unstimulated short-term cultures were set up from the bone marrow aspirate obtained at diagnosis. Analysis of 20 metaphases showed clonal abnormalities. The modal count was 47 chromosomes, with the presence of an extra chromosome 21 and the characteristic reciprocal translocation involving a chromosome 15 and a chromosome 17. The karyotype was interpreted as 47,XY,t(15;17)(q22;q21), 21[20] (Fig. 1) [11]. Additional fluorescence in situ hybridization (FISH) studies with a dual color translocation probe for the PML locus at 15q22 and RAR locus at 17q21 (Vysis, Downers Grove, IL, USA) were carried out. Analysis of 303 interphase nuclei showed a hybridization pattern consistent with PML/RAR fusion in 270 (89.1%) nuclei. A second chromosome analysis of the bone marrow aspirate after completion of induction therapy showed a normal 46,XY karyotype in all 20 cells analyzed. Repeat FISH studies with a dual color PML/RAR translocation probe also showed a normal hybridization pattern in 196 of the 204 (96.1%) of the nuclei confirming the clinical remission.
75
The remaining 3.9% of the cells showed a signal pattern consistent with PML/RAR fusion; however, this amount of cells is considered background noise since the cutoff for positive fusion results established in our laboratory is greater than or equal to 12.2%. 4. Discussion Prior to 1996, only three reports catalogued secondary cytogenetic changes associated with APL [3–5]. The prognostic implications of additional cytogenetic abnormalities associated with APL have recently been examined in six studies [2,6–10]. Two of these reports found that secondary chromosomal anomalies did not confer a poor prognosis in APL [6,7]. In contrast, two other studies found that additional abnormalities did confer a worse prognosis in APL [8,9]. The conflicting results of these four reports can be attributed to relatively small sample sizes as well as varied or outdated treatment plans. In a much larger study, Grimwade et al. [10] evaluated the prognostic implications of numerous chromosomal abnormalities in AML. The authors discovered that additional cytogenetic changes did not alter the outcome of patients with favorable cytogenetic anomalies such as t(15;17). Even chromosomal abnormalities categorized in the adverse risk
Fig. 1. Karyotype at diagnosis: 47,XY,t(15;17)(q22;q21),21.
76
D.W. Spell et al. / Cancer Genetics and Cytogenetics 132 (2002) 74–76
group, like monosomies 5 and 7, had no effect on response rates or overall survival in individuals with concurrent favorable cytogenetics. Furthermore, trisomy 21 was categorized in the intermediate risk group. This intermediate group contained cytogenetic abnormalities classified as neither favorable nor adverse and included patients with normal cytogenetics. In a comprehensive trial involving the largest cohort of patients with t(15;17) to date, de Botton et al. [2] also demonstrated that additional cytogenetic changes in patients with t(15;17) had no impact on prognosis. All patients in the study received ATRA in addition to Ara-C/anthracyclinebased chemotherapy. No significant difference was seen between patients with only t(15;17) and patients with t(15;17) in combination with other chromosomal abnormalities for complete remission rate, event-free survival at two years, and overall survival at two years. Only one report in the literature has exclusively addressed the prognostic importance of trisomy 21 in patients with AML. Cortes et al. [12] determined that response rates and survival were comparable for patients with favorable cytogenetics alone and patients with favorable cytogenetics associated with trisomy 21. Response rates and survival were also similar in patients with monosomy 5 or 7 and patients with monosomy 5 or 7 accompanying trisomy 21. The authors concluded that the prognosis of patients with trisomy 21 was most contingent on the prognosis of the associated chromosomal aberrations. Unlike children with constitutional trisomy 21 and AML [13], there is no convincing evidence that acquired trisomy 21 has any impact upon prognosis in APL. The two studies that reported an inferior prognosis in APL associated with secondary chromosomal abnormalities were less than ideal. [8,9] In the largest study evaluating the prognostic significance of cytogenetic changes in AML, patients with t(15;17) and additional chromosomal anomalies maintained a favorable outcome regardless of the additional cytogenetic change [10]. De Botton et al. [2] confirmed this observation in the only trial wherein all of the patients were treated with both ATRA and anthracyclinebased chemotherapy. In summary, APL is often associated with additional cytogenetic abnormalities. The majority of evidence currently supports the concept that patients with t(15;17) and trisomy 21, or any other additional abnormality, have the same favorable prognosis as patients with t(15;17) alone.
References [1] Avvisati G, Lo Coco F, Mandelli F. Acute promyelocytic leukemia: Clinical and morphological features and prognostic factors. Semin Hematol 2001;38:4–12. [2] de Botton S, Chevret S, Sanz M, Dombret H, Thomas X, Guerci A, Fey M, Rayon C, Huguet F, Sotto J, Gardin C, Makhoul PC, Travade P, Solary E, Fegueux N, Bordessoule D, San Miguel J, Link H, Desablens B, Stamatoullas A, Deconinck E, Geiser K, Hess U, Maloisel F, Castaigne S, Preudhomme C, Chomienne C, Degos L, Fenaux P. Additional chromosomal abnormalities in patients with acute promyelocytic leukaemia (APL) do not confer poor prognosis: results of APL 93 trial. Br J Haematol 2000;111:801–6. [3] Heim S, Mitelman F. Secondary chromosome aberrations in the acute leukemias. Cancer Genet Cytogenet 1986;22:331–8. [4] Berger R, Le Coniat M, Derre J, Vecchione D, Jonveaux P. Cytogenetic studies in acute promyelocytic leukemia: A survey of secondary chromosomal abnormalities. Genes Chromosomes Cancer 1991;3:332–7. [5] Johansson B, Mertens F, Mitelman F. Secondary chromosomal abnormalities in acute leukemias. Leukemia 1994;8:953–62. [6] Schoch C, Haase D, Haferlach T, Freund M, Link H, Lengfelder E, Loffler H, Buchner T, Fonatsch C. Incidence and implication of additional chromosome aberrations in acute promyelocytic leukaemia with translocation t(15;17)(q22;q21): A report on 50 patients. Br J Haematol 1996;94:493–500. [7] Slack JL, Arthur DC, Lawrence D, Mrózek K, Mayer RJ, Davey FR, Tantravahi R, Pettenati MJ, Bigner S, Carroll AJ, Rao KW, Schiffer CA, Bloomfield CD. Secondary cytogenetic changes in acute promyelocytic leukemia—Prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: A Cancer and Leukemia Group B study. J Clin Oncol 1997;15:1786–95. [8] Hiorns LR, Swansbury GJ, Mehta J, Min T, Dainton MG, Treleaven J, Powles RL, Catovsky D. Additional chromosome abnormalities confer worse prognosis in acute promyelocytic leukaemia. Br J Haematol 1997;96:314–21. [9] Pantic M, Novak A, Marisavljevic D, Djordjevic V, Elezovic I, Vidovic A, Colovic M. Additional chromosome aberrations in acute promyelocytic leukemia: characteristics and prognostic influence. Med Oncol 2000;17:307–13. [10] Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A. The importance of diagnostic cytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRC AML 10 trial. Blood 1998;92:2322–33. [11] ISCN. An international system for human cytogenetic nomenclature. Mitelman F, editor. Basel: S. Karger, 1995. [12] Cortes JE, Kantarjian H, O’Brien S, Keating M, Pierce S, Freireich EJ, Estey E. Clinical and prognostic significance of trisomy 21 in adult patients with acute myelogenous leukemia and myelodysplastic syndromes. Leukemia 1995;9:115–7. [13] Taub JW, Huang X, Matherly LH, Stout ML, Buck SA, Massey GV, Becton DL, Chang MN, Weinstein RJ, Ravindranath Y. Expression of chromosome 21-localized genes in acute myeloid leukemia: differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin. Blood 1999;94:1393–400.