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Clonal chromosome aberrations in Philadelphia-negative cells from chronic myelocytic leukemia patients treated with imatinib mesylate: report of two cases
Cancer Genetics and Cytogenetics 147 (2003) 78–80
Short communication
Clonal chromosome aberrations in Philadelphia-negative cells from chronic myelocytic leukemia patients treated with imatinib mesylate: report of two cases Christian Herensa,*, Fre´de´ric Baronb,1, Christiane Croisiauc, Francoise Tassind, Vincent Boursa a
Center for Human Genetics, University of Lie`ge, Lie`ge, Belgium Department of Medicine, Division of Haematology, University of Lie`ge, Lie`ge, Belgium c Department of Laboratory Haematology, Hoˆpital Saint Joseph, Lie`ge, Belgium d Division of Laboratory Hematology, Department of Clinical Biology, University of Lie`ge, Lie`ge, Belgium b
Received 10 March 2003; received in revised form 17 April 2003; accepted 25 April 2003
Abstract
Imatinib mesylate (tested as STI571), an abl kinase inhibitor, induces sustained, complete hematologic and cytogenetic responses in chronic myelocytic leukemia (CML) patients; however, emergence of clonal chromosomal aberrations in Philadelphia-negative (Ph⫺) cells during treatment has been reported. We describe two CML patients in chronic phase who presented with complete cytogenetic responses during imatinib mesylate therapy but developed new clonal chromosomal rearrangements in Ph⫺ cells. The first patient presented with a duplication of chromosome 1, dup(1)(q21q42), and the second showed two new clonal aberrations consisting of inv(1)(q12q32) and del(7)(q22) in the same clone. 쑖 2003 Elsevier Inc. All rights reserved.
1. Introduction The Philadelphia (Ph) chromosome is the hallmark of chronic myelocytic leukemia (CML) and results from the reciprocal t(9;22)(q34;q11) [1]. At the molecular level, the translocation juxtaposes 3′ DNA sequences of the ABL oncogene with 5′ DNA sequences of the BCR gene, resulting in the generation of a chimeric BCR–ABL fusion gene [2]. The bcr–abl tyrosine kinase protein has enhanced activity compared to the wild-type abl tyrosine kinase and is responsible for the pathogenesis of the disease [2]. Conventional therapies include α-interferon, hydroxyurea, and progenitor stem cell transplantation. Recently, a specific inhibitor of the tyrosine kinase domain of the bcr–abl protein, imatinib mesylate (trade name: Gleevec, Glivec; experimental name: STI571), has been shown to induce growth arrest or apoptosis in hematopoietic cells expressing BCR–ABL. Imatinib entered clinical trials in 1998 and has since been
shown to induce dramatic hematologic and cytogenetic responses [3,4]. While imatinib has remarkable clinical efficacy in CML, emergence of clonal chromosome aberrations in Ph-negative (Ph⫺) cells during treatment has been described [5–9]. We report here two additional cases of CML patients in chronic phase who developed new clonal cytogenetic anomalies in Ph⫺ cells during imatinib mesylate therapy.
2. Methods Conventional cytogenetic analyses were performed on 24-hour-cultured bone marrow cells, according to standard procedures. A minimum of 20 Q-banded karyotypes were established for each cytogenetic evaluation.
3. Case reports * Corresponding author. Center for Human Genetics, University of Lie`ge, CHU, Tour de Pathologie, B23, Sart Tilman, 4000 Lie`ge, Belgium. Tel.: ⫹32-43-66-25-60; fax: ⫹32-43-66-29-74. E-mail address: [email protected] (C. Herens). 1 The author is a Research Assistant of the National Fund for Scientific Research (FNRS, Belgium). 0165-4608/03/$ – see front matter 쑖 2003 Elsevier Inc. All rights reserved. doi: 10.1016/S0165-4608(03)00198-5
3.1. Case 1 A 64-year-old man with CML in chronic phase was diagnosed in May 2000. The karyotype at that time was 46,XY,t(9;22)(q34;q11)[19]/46,XY[1]. He underwent a nonmyeloablative stem cell transplantation from his sister in
C. Herens et al. / Cancer Genetics and Cytogenetics 147 (2003) 78–80
September 2000, but relapsed in July 2001 (accelerated phase). Imatinib treatment (600 mg/day) was initiated on August 23, 2001. The daily dose was reduced to 400 mg/ day on September 14, 2001, due to moderate anemia (hemoglobin: 12.2 g/dL; hematocrit: 38.7%) and thrombopenia (155 × 109/L). Complete cytogenetic response was observed 6 months after the beginning of imatinib treatment and persisted. A new abnormal clone appeared in May 2002. At that time, the karyotype was 46,XY,inv(1)(q12q32), del(7)(q22)[4]/46,XY[21]. The new abnormal clone emerged progressively and was observed in 16%, 33%, and 44% of metaphases at 9, 12, and 15 months, respectively.
79
Table 1 Chromosomes rearranged in the Ph-negative clones during imatinib mesylate treatment Chromosome
Aberrationa
No. of patients (%) n ⫽ 13
No. of clones (%) n ⫽ 17
8 7 1 5 13 Y
Trisomy[8] 7q⫺[3]/⫺7[1] inv[2]/dup[1] 5q⫺ 13q⫺ Extra copy
8 4 3 1 1 1
10 (59%) 4 (23.5%) 3 (17.6%) 1 (5.9%) 1 (5.9%) 1 (5.9%)
(61.5%) (30.8%) (23%) (7.7%) (7.7%) (7.7%)
a
Numbers in brackets represent the number of cases with the anomaly.
3.2. Case 2 CML in chronic phase with 97% Ph-positive (Ph+) bone marrow cells was diagnosed in March 1996 in a 59-year-old woman. Autograft marrow transplantation was performed in July 1997. She relapsed 6 months later. Interferon therapy was inefficient, 100% of the bone marrow metaphases being Ph⫹ in February 2001. Imatinib mesylate treatment (suppress protocol 113) was initiated in July 2001; the treatment was stopped at week 13 because of thrombopenia. The first cytogenetic evaluation after 3 months of treatment already evidenced a new abnormal clone in Ph⫺ cells. The karyotype was 46,XX,t(9;22)(q34;q11)[3]/46,XX,dup(1)(q21q42)[4]/ 46,XX[20]. Complete cytogenetic response was observed 6 months after the start of treatment and persisted. The new abnormal clone developed, however, and was observed in 13%, 33%, 44%, and 50% of metaphases at 6, 9, 12, and 15 months, respectively.
4. Discussion The development of new clonal aberrations in Ph⫺ cells of CML patients treated with imatinib mesylate appears to be a frequent phenomenon. Within a few years of the introduction of imatinib in clinical trials, 11 cases with new chromosomal abnormalities in Ph-negative clones have been
reported [5–9]; 13 cases, with our two included. According to this series, 4.6%–10.25% of treated patients show these anomalies. Trisomy 8 is by far the most common aberration, observed in 8 of 13 (61.5%) cases. Chromosomes 7 (4 cases) and 1 (3 cases) are also recurrently involved in rearrangements after imatinib therapy (Table 1). Three of 13 patients showed two chromosomal aberrations in the same clone, and 3/13 showed two or three distinct cytogenetic clones (Table 2). Several indicators suggest that the Ph⫺ abnormal cells probably are present in bone marrow before treatment. First, the delay between initiation of treatment and onset of new clonal chromosomal aberrations is rather short (3 and 9 months, in our two cases) (Table 2). Second, all but one of the patients with these new anomalies presented with major or complete cytogenetic responses (Table 2). The development of these new clones would be possible when hematopoiesis of Ph⫹ cells is efficiently inhibited, a common feature in imatinib-treated patients. In that way, the space created by the eradication of Ph⫹ cells could favor the development of Ph⫺ progenitors of cytogenetically abnormal cells. If this is the case, the same would be true for good responders to other treatments. Indeed, new clonal anomalies in Ph⫺ cells are reported in rare cases after busulfan or interferon therapy [9–15]. Such anomalies were observed in
Table 2 Review of the literature data of cases with Ph⫹ CML developing new Ph⫺ abnormal clones during imatinib mesylate treatment Reference
No. of patients
Frequency
Doses of imatinib (mg/day)
Cytogenetic response
Chromosomal anomaly(ies)
Delay (mo)
[5]
2/43
4.6%
[6]
3/36
8.3%
[7] [8]
1/16 3/30
6.25% 10%
[9]
2/19
10.25%
Our report
2/19
10.25%
? ? 600 600 400 400 400 600 600 300 500 400 600→400
MCR MCR MCR MCR MCR CCR CCR MCR CCR MCR NR CCR MCR
del(5)(q15q33) ⫹8 del(7)(q22) ⫹8 ⫹8 or del(7)(q22q32) ⫹8 ⫹8 or ⫺7 +8 or +8, +8 or +Y, ⫹8 Inv(1) and del(13) ⫹8 ⫹8 dup(1)(q21q42) inv(1)(q12q32) and del(7)(q22)
6 9 25 6 6 ? 6 and 9 10 ? 6 14 3 9
Abbreviations: CCR, complete cytogenetic response; MCR, major cytogenetic response; NR, no response.
80
C. Herens et al. / Cancer Genetics and Cytogenetics 147 (2003) 78–80
eight patients, six of whom presented with major or complete cytogenetic responses [9–15]. Finally, there are no documented data demonstrating a possible leukemogenic effect of imatinib mesylate, although four cases presented monosomy 7 or deletion 7q, both highly characteristic of therapy-related leukemias. We (unpublished data, 2002) and others [6] were unable, however, to demonstrate the existence of Ph⫺ abnormal clones before imatinib treatment, as assessed by fluorescence in situ hybridization (FISH). The pathological significance of the Ph⫺ abnormal clones remains to be elucidated, as follow-ups are very short. In our two cases, the new abnormal clones emerged progressively without any major clinical manifestations to date; however, moderate anemia (case 1) and thrombopenia (cases 1 and 2) were noted at the time of development of the new clone. In the literature, two patients with Ph⫺ abnormal clones developed acute myelocytic leukemia after interferon therapy and two others presented with refractory cytopenia or dysplastic changes consistent with myelodysplasia [8,12,13,15]. In the remaining cases, the new clones were observed during the chronic phase of CML. In conclusion, the onset of Ph⫺ abnormal clones appears to be a frequent phenomenon in good responders to imatinib mesylate; however, the origin and the clinical significance of such observation remain to be clarified. References [1] Rowley J. A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;43:290–3. [2] Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999;340: 1330–1340. [3] Druker BJ, Talpaz M, Resta DJ, Bin Peng RN, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCRABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–7. [4] Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B, Goldman J, O’Brien SG, Russell N, Fischer T, Ottmann O, Cony-Makhoul P, Facon T, Stone R, Miller C, Tallman M, Brown R, Schuster M, Loughran T, Gratwohl A, Mandelli F, Saglio G, Lazzarino M, Russo D, Baccarani M, Morra E. International STI571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645–52.
[5] Marktel S, Bua M, Marin D, Chase A, Udom C, Armstrong L, Apperley JF, Olavarria E, Goldman JM. Emergence of additional chromosomal abnormalities following treatment with STI571 (imatinib mesylate) for Philadelphia positive chronic myeloid leukemia in chronic phase [abstract]. Blood 2001;98:617a. [6] Gambacorti-Passeri C, Giudici G, Le Coutre P, Bungaro S, Pogliani EM, Kreuzer K-A, Tornaghi L, Alberti D, Corneo G, Biondi A. Nonrandom chromosomal abnormalities in Ph-negative bone marrow (BM) cells from CML patients achieving major cytogenetic responses (MCR) with STI571 (Gleevec) [abstract]. Blood 2001;98:257b. [7] Meunier V, Giraudier S, Van den Akker J, Perot C, Jouault H, CaronServan B, Robin V, Tulliez M, Imbert M. Treatment with STI571 (Novartis) in chronic myeloid leukemia (CML): unexpected hematological findings in a series of 26 patients [abstract]. Blood 2001; 98:263b. [8] Andersen MK, Pedersen-Bjergaard , Kjeldsen L, Dufva IH, BrondumNielsen K. Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia [letter]. 2002;16:1390–5. [9] Braziel RM, Launder TM, Druker BJ, Olson SB, Magenis RE, Mauro MJ, Sawyers CL, Paquette RL, O’Dwyer ME. Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 month’s experience. Blood 2002;200: 435–41. [10] Casali M, Truglio F, Milone G, Raimondo F, Parrinello G, Maserati E, Pasquali F. Trisomy 8 in Philadelphia chromosome (Ph1)-negative cells in the course of Ph1-positive chronic myelocytic leukemia. Genes Chromosomes Cancer 1992;4:269–70. [11] Bilhou-Nabera C, Marit G, Devianne I, Viard F, Salzes S, Montastruc M, Renoux M, Broustet A, Reiffers J, Bernard P. A second case of trisomy 8 in Philadelphia chromosome (Ph)-negative cells during the course of Ph-positive chronic myelocytic leukemia. Genes Chromosomes Cancer 1993;4:255–6. [12] Ariyama T, Inazawa J, Uemura Y, Kakazu N, Maekawa T, Urase F, Irimajiri K, Horiuchi A, Nakamura Y, Abe T. Clonal origin of Philadelphia chromosome negative cells with trisomy 8 appearing during the course of alpha-interferon therapy for Ph positive chronic myelocytic leukemia. Cancer Genet Cytogenet 1995;81:20–3. [13] Ohtsuka E, Kikuchi H, Abe Y, Moriyama K, Ohno E, Hirota K, Tezono K, Nasu M. Acute myeloblastic leukaemia without Philadelphia chromosome developing after interferon therapy for chronic myelocytic leukaemia with Philadelphia chromosome. Br J Cancer 1995;90:951–3. [14] Izumi T, Imagawa S, Hatake K, Miura Y, Ariyama T, Inazawa J, Abe T. Philadelphia chromosome-negative cells with trisomy 8 after busulfan and interferon treatment of Ph1-positive chronic myelogenous leukemia. Int J Hematol 1996;64:73–7. [15] Fayad L, Kantarjian H, O’Brien S, Seong D, Albitar M, Keating M, Talpaz M. Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases. Leukemia 1997; 11:767–71.
Short communication
Clonal chromosome aberrations in Philadelphia-negative cells from chronic myelocytic leukemia patients treated with imatinib mesylate: report of two cases Christian Herensa,*, Fre´de´ric Baronb,1, Christiane Croisiauc, Francoise Tassind, Vincent Boursa a
Center for Human Genetics, University of Lie`ge, Lie`ge, Belgium Department of Medicine, Division of Haematology, University of Lie`ge, Lie`ge, Belgium c Department of Laboratory Haematology, Hoˆpital Saint Joseph, Lie`ge, Belgium d Division of Laboratory Hematology, Department of Clinical Biology, University of Lie`ge, Lie`ge, Belgium b
Received 10 March 2003; received in revised form 17 April 2003; accepted 25 April 2003
Abstract
Imatinib mesylate (tested as STI571), an abl kinase inhibitor, induces sustained, complete hematologic and cytogenetic responses in chronic myelocytic leukemia (CML) patients; however, emergence of clonal chromosomal aberrations in Philadelphia-negative (Ph⫺) cells during treatment has been reported. We describe two CML patients in chronic phase who presented with complete cytogenetic responses during imatinib mesylate therapy but developed new clonal chromosomal rearrangements in Ph⫺ cells. The first patient presented with a duplication of chromosome 1, dup(1)(q21q42), and the second showed two new clonal aberrations consisting of inv(1)(q12q32) and del(7)(q22) in the same clone. 쑖 2003 Elsevier Inc. All rights reserved.
1. Introduction The Philadelphia (Ph) chromosome is the hallmark of chronic myelocytic leukemia (CML) and results from the reciprocal t(9;22)(q34;q11) [1]. At the molecular level, the translocation juxtaposes 3′ DNA sequences of the ABL oncogene with 5′ DNA sequences of the BCR gene, resulting in the generation of a chimeric BCR–ABL fusion gene [2]. The bcr–abl tyrosine kinase protein has enhanced activity compared to the wild-type abl tyrosine kinase and is responsible for the pathogenesis of the disease [2]. Conventional therapies include α-interferon, hydroxyurea, and progenitor stem cell transplantation. Recently, a specific inhibitor of the tyrosine kinase domain of the bcr–abl protein, imatinib mesylate (trade name: Gleevec, Glivec; experimental name: STI571), has been shown to induce growth arrest or apoptosis in hematopoietic cells expressing BCR–ABL. Imatinib entered clinical trials in 1998 and has since been
shown to induce dramatic hematologic and cytogenetic responses [3,4]. While imatinib has remarkable clinical efficacy in CML, emergence of clonal chromosome aberrations in Ph-negative (Ph⫺) cells during treatment has been described [5–9]. We report here two additional cases of CML patients in chronic phase who developed new clonal cytogenetic anomalies in Ph⫺ cells during imatinib mesylate therapy.
2. Methods Conventional cytogenetic analyses were performed on 24-hour-cultured bone marrow cells, according to standard procedures. A minimum of 20 Q-banded karyotypes were established for each cytogenetic evaluation.
3. Case reports * Corresponding author. Center for Human Genetics, University of Lie`ge, CHU, Tour de Pathologie, B23, Sart Tilman, 4000 Lie`ge, Belgium. Tel.: ⫹32-43-66-25-60; fax: ⫹32-43-66-29-74. E-mail address: [email protected] (C. Herens). 1 The author is a Research Assistant of the National Fund for Scientific Research (FNRS, Belgium). 0165-4608/03/$ – see front matter 쑖 2003 Elsevier Inc. All rights reserved. doi: 10.1016/S0165-4608(03)00198-5
3.1. Case 1 A 64-year-old man with CML in chronic phase was diagnosed in May 2000. The karyotype at that time was 46,XY,t(9;22)(q34;q11)[19]/46,XY[1]. He underwent a nonmyeloablative stem cell transplantation from his sister in
C. Herens et al. / Cancer Genetics and Cytogenetics 147 (2003) 78–80
September 2000, but relapsed in July 2001 (accelerated phase). Imatinib treatment (600 mg/day) was initiated on August 23, 2001. The daily dose was reduced to 400 mg/ day on September 14, 2001, due to moderate anemia (hemoglobin: 12.2 g/dL; hematocrit: 38.7%) and thrombopenia (155 × 109/L). Complete cytogenetic response was observed 6 months after the beginning of imatinib treatment and persisted. A new abnormal clone appeared in May 2002. At that time, the karyotype was 46,XY,inv(1)(q12q32), del(7)(q22)[4]/46,XY[21]. The new abnormal clone emerged progressively and was observed in 16%, 33%, and 44% of metaphases at 9, 12, and 15 months, respectively.
79
Table 1 Chromosomes rearranged in the Ph-negative clones during imatinib mesylate treatment Chromosome
Aberrationa
No. of patients (%) n ⫽ 13
No. of clones (%) n ⫽ 17
8 7 1 5 13 Y
Trisomy[8] 7q⫺[3]/⫺7[1] inv[2]/dup[1] 5q⫺ 13q⫺ Extra copy
8 4 3 1 1 1
10 (59%) 4 (23.5%) 3 (17.6%) 1 (5.9%) 1 (5.9%) 1 (5.9%)
(61.5%) (30.8%) (23%) (7.7%) (7.7%) (7.7%)
a
Numbers in brackets represent the number of cases with the anomaly.
3.2. Case 2 CML in chronic phase with 97% Ph-positive (Ph+) bone marrow cells was diagnosed in March 1996 in a 59-year-old woman. Autograft marrow transplantation was performed in July 1997. She relapsed 6 months later. Interferon therapy was inefficient, 100% of the bone marrow metaphases being Ph⫹ in February 2001. Imatinib mesylate treatment (suppress protocol 113) was initiated in July 2001; the treatment was stopped at week 13 because of thrombopenia. The first cytogenetic evaluation after 3 months of treatment already evidenced a new abnormal clone in Ph⫺ cells. The karyotype was 46,XX,t(9;22)(q34;q11)[3]/46,XX,dup(1)(q21q42)[4]/ 46,XX[20]. Complete cytogenetic response was observed 6 months after the start of treatment and persisted. The new abnormal clone developed, however, and was observed in 13%, 33%, 44%, and 50% of metaphases at 6, 9, 12, and 15 months, respectively.
4. Discussion The development of new clonal aberrations in Ph⫺ cells of CML patients treated with imatinib mesylate appears to be a frequent phenomenon. Within a few years of the introduction of imatinib in clinical trials, 11 cases with new chromosomal abnormalities in Ph-negative clones have been
reported [5–9]; 13 cases, with our two included. According to this series, 4.6%–10.25% of treated patients show these anomalies. Trisomy 8 is by far the most common aberration, observed in 8 of 13 (61.5%) cases. Chromosomes 7 (4 cases) and 1 (3 cases) are also recurrently involved in rearrangements after imatinib therapy (Table 1). Three of 13 patients showed two chromosomal aberrations in the same clone, and 3/13 showed two or three distinct cytogenetic clones (Table 2). Several indicators suggest that the Ph⫺ abnormal cells probably are present in bone marrow before treatment. First, the delay between initiation of treatment and onset of new clonal chromosomal aberrations is rather short (3 and 9 months, in our two cases) (Table 2). Second, all but one of the patients with these new anomalies presented with major or complete cytogenetic responses (Table 2). The development of these new clones would be possible when hematopoiesis of Ph⫹ cells is efficiently inhibited, a common feature in imatinib-treated patients. In that way, the space created by the eradication of Ph⫹ cells could favor the development of Ph⫺ progenitors of cytogenetically abnormal cells. If this is the case, the same would be true for good responders to other treatments. Indeed, new clonal anomalies in Ph⫺ cells are reported in rare cases after busulfan or interferon therapy [9–15]. Such anomalies were observed in
Table 2 Review of the literature data of cases with Ph⫹ CML developing new Ph⫺ abnormal clones during imatinib mesylate treatment Reference
No. of patients
Frequency
Doses of imatinib (mg/day)
Cytogenetic response
Chromosomal anomaly(ies)
Delay (mo)
[5]
2/43
4.6%
[6]
3/36
8.3%
[7] [8]
1/16 3/30
6.25% 10%
[9]
2/19
10.25%
Our report
2/19
10.25%
? ? 600 600 400 400 400 600 600 300 500 400 600→400
MCR MCR MCR MCR MCR CCR CCR MCR CCR MCR NR CCR MCR
del(5)(q15q33) ⫹8 del(7)(q22) ⫹8 ⫹8 or del(7)(q22q32) ⫹8 ⫹8 or ⫺7 +8 or +8, +8 or +Y, ⫹8 Inv(1) and del(13) ⫹8 ⫹8 dup(1)(q21q42) inv(1)(q12q32) and del(7)(q22)
6 9 25 6 6 ? 6 and 9 10 ? 6 14 3 9
Abbreviations: CCR, complete cytogenetic response; MCR, major cytogenetic response; NR, no response.
80
C. Herens et al. / Cancer Genetics and Cytogenetics 147 (2003) 78–80
eight patients, six of whom presented with major or complete cytogenetic responses [9–15]. Finally, there are no documented data demonstrating a possible leukemogenic effect of imatinib mesylate, although four cases presented monosomy 7 or deletion 7q, both highly characteristic of therapy-related leukemias. We (unpublished data, 2002) and others [6] were unable, however, to demonstrate the existence of Ph⫺ abnormal clones before imatinib treatment, as assessed by fluorescence in situ hybridization (FISH). The pathological significance of the Ph⫺ abnormal clones remains to be elucidated, as follow-ups are very short. In our two cases, the new abnormal clones emerged progressively without any major clinical manifestations to date; however, moderate anemia (case 1) and thrombopenia (cases 1 and 2) were noted at the time of development of the new clone. In the literature, two patients with Ph⫺ abnormal clones developed acute myelocytic leukemia after interferon therapy and two others presented with refractory cytopenia or dysplastic changes consistent with myelodysplasia [8,12,13,15]. In the remaining cases, the new clones were observed during the chronic phase of CML. In conclusion, the onset of Ph⫺ abnormal clones appears to be a frequent phenomenon in good responders to imatinib mesylate; however, the origin and the clinical significance of such observation remain to be clarified. References [1] Rowley J. A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973;43:290–3. [2] Sawyers CL. Chronic myeloid leukemia. N Engl J Med 1999;340: 1330–1340. [3] Druker BJ, Talpaz M, Resta DJ, Bin Peng RN, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL. Efficacy and safety of a specific inhibitor of the BCRABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–7. [4] Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, Talpaz M, Druker B, Goldman J, O’Brien SG, Russell N, Fischer T, Ottmann O, Cony-Makhoul P, Facon T, Stone R, Miller C, Tallman M, Brown R, Schuster M, Loughran T, Gratwohl A, Mandelli F, Saglio G, Lazzarino M, Russo D, Baccarani M, Morra E. International STI571 CML Study Group. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645–52.
[5] Marktel S, Bua M, Marin D, Chase A, Udom C, Armstrong L, Apperley JF, Olavarria E, Goldman JM. Emergence of additional chromosomal abnormalities following treatment with STI571 (imatinib mesylate) for Philadelphia positive chronic myeloid leukemia in chronic phase [abstract]. Blood 2001;98:617a. [6] Gambacorti-Passeri C, Giudici G, Le Coutre P, Bungaro S, Pogliani EM, Kreuzer K-A, Tornaghi L, Alberti D, Corneo G, Biondi A. Nonrandom chromosomal abnormalities in Ph-negative bone marrow (BM) cells from CML patients achieving major cytogenetic responses (MCR) with STI571 (Gleevec) [abstract]. Blood 2001;98:257b. [7] Meunier V, Giraudier S, Van den Akker J, Perot C, Jouault H, CaronServan B, Robin V, Tulliez M, Imbert M. Treatment with STI571 (Novartis) in chronic myeloid leukemia (CML): unexpected hematological findings in a series of 26 patients [abstract]. Blood 2001; 98:263b. [8] Andersen MK, Pedersen-Bjergaard , Kjeldsen L, Dufva IH, BrondumNielsen K. Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia [letter]. 2002;16:1390–5. [9] Braziel RM, Launder TM, Druker BJ, Olson SB, Magenis RE, Mauro MJ, Sawyers CL, Paquette RL, O’Dwyer ME. Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 month’s experience. Blood 2002;200: 435–41. [10] Casali M, Truglio F, Milone G, Raimondo F, Parrinello G, Maserati E, Pasquali F. Trisomy 8 in Philadelphia chromosome (Ph1)-negative cells in the course of Ph1-positive chronic myelocytic leukemia. Genes Chromosomes Cancer 1992;4:269–70. [11] Bilhou-Nabera C, Marit G, Devianne I, Viard F, Salzes S, Montastruc M, Renoux M, Broustet A, Reiffers J, Bernard P. A second case of trisomy 8 in Philadelphia chromosome (Ph)-negative cells during the course of Ph-positive chronic myelocytic leukemia. Genes Chromosomes Cancer 1993;4:255–6. [12] Ariyama T, Inazawa J, Uemura Y, Kakazu N, Maekawa T, Urase F, Irimajiri K, Horiuchi A, Nakamura Y, Abe T. Clonal origin of Philadelphia chromosome negative cells with trisomy 8 appearing during the course of alpha-interferon therapy for Ph positive chronic myelocytic leukemia. Cancer Genet Cytogenet 1995;81:20–3. [13] Ohtsuka E, Kikuchi H, Abe Y, Moriyama K, Ohno E, Hirota K, Tezono K, Nasu M. Acute myeloblastic leukaemia without Philadelphia chromosome developing after interferon therapy for chronic myelocytic leukaemia with Philadelphia chromosome. Br J Cancer 1995;90:951–3. [14] Izumi T, Imagawa S, Hatake K, Miura Y, Ariyama T, Inazawa J, Abe T. Philadelphia chromosome-negative cells with trisomy 8 after busulfan and interferon treatment of Ph1-positive chronic myelogenous leukemia. Int J Hematol 1996;64:73–7. [15] Fayad L, Kantarjian H, O’Brien S, Seong D, Albitar M, Keating M, Talpaz M. Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases. Leukemia 1997; 11:767–71.