- Email: [email protected]
Emergence of clonal chromosomal abnormalities in Philadelphia negative hematopoiesis in chronic myeloid leukemia patients treated with nilotinib after failure of imatinib therapy
Leukemia Research 33 (2009) e218–e220
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor
Emergence of clonal chromosomal abnormalities in Philadelphia negative hematopoiesis in chronic myeloid leukemia patients treated with nilotinib after failure of imatinib therapy Clonal cytogenetic abnormalities (CAs) in Philadelphia negative (Ph−) metaphases have been widely observed during imatinib treatment in patients with chronic myeloid leukemia (CML) [1,2]. Recently, the appearance of such abnormalities in some CML patients, treated with dasatinib after imatinib failure, has been described [3,4]. To the best of our knowledge, only one patient has been reported to develop a cytogenetic abnormality in Ph− clone during nilotinib treatment, following imatinib [5]. The incidence and consequences of CAs in Ph− cells during treatment with second generation tyrosine kinase inhibitors (TKIs) should be extensively investigated; this issue, deserves a particular attention, since these new drugs put a far higher pressure on the leukemic and the residual normal hematopoiesis than imatinib. At our institute we analyzed 30 late chronic phase (CP) CML patients treated with nilotinib after imatinib failure by conventional cytogenetic (CC) and fluorescence in situ hybridization (FISH). Cytogenetic analysis of bone marrow (BM) was performed at diagnosis, during imatinib treatment, before starting nilotinib and every 3–6 months during the first year of nilotinib therapy; thereafter every 12 months or in case of disease progression. FISH was performed using DNA commercial probes. At diagnosis LSI Dual Color Dual Fusion BCR-ABL DNA probe (Vysis, Downers Grove, IL, USA) was used to characterize BCR-ABL rearrangement. The subsequent analysis was performed using appropriate probes, depending on the results of CC. The patients were 18 females and 12 males, median age was 51 years (range 18–77). The median time of imatinib therapy was 34 months (range 7–71). Fourteen patients received only imatinib as previous therapy, whereas 16 patients were treated with additional therapies, such as: hydroxyurea, interferon-␣, cytosinearabinoside, busulphan. During nilotinib therapy 18 (60%) patients achieved a complete cytogenetic response (CCyR), within a median time of 4.7 months (range 1–10). Patients were followed for a median time of 18 months (range 4–42) after commencing nilotinib therapy (Table 1). Three out of 30 patients (10%) developed CAs in Ph− cells, namely: trisomy 8, del(20)(q11q13) and t(3;5)(p12;p13). There were 2 males and 1 female, aged between 31 and 58 years. Del(20q)(q11q13) (no.1) and trisomy 8 (no.2) persisted for 12 and 18 months, respectively, and were still present at the last cytogenetic study (21 and 24 months, respectively), whereas t(3;5)(p12;p13) (no.3) was transient: it appeared after 6 months of therapy and disappeared within 2 months. Patients’ characteristics are summarized in Table 2. Retrospective FISH analysis performed on stored BM specimens of patients no.1 and no.2 failed to detect the above reported aberrations before nilotinib therapy. After a median follow-up of 19 months (range 0145-2126/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2009.05.010
Table 1 Clinical features of 30 patients treated with nilotinib. Patients characteristics Median age at start of nilotinib, years (range) Sex (F/M) Median follow-up on imatinib, mo (range) Median follow-up on nilotinib, mo (range) Median time from diagnosis to nilotinib, mo (range) Imatinib alone as previous therapy, n (%)
51(18–77) 18/12 34(7–71) 18(4–42) 57.5(6–260) 14(46.7)
Best cytogenetic response to nilotinib, n. Complete CyR Partial CyR Minor CyR No response
18 2 2 8
CyR, cytogenetic response.
12–24) of nilotinib treatment, all patients were alive: 2 patients (no.1 and no.2) were in CCyR and continued nilotinib treatment, while the last patient (no.3) lost CCyR after 12 months from the first detection of del(20)(q11q13) and therefore discontinued nilotinib. At time of reporting, he was treated with bosutinib (Table 2). The incidence and type of abnormalities after nilotinib are similar to those reported in patients treated with imatinib [1,2]. Although these alterations are similar to those seen in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemias (AML), they are rarely reported to evolve to MDS or AML [1–4]. Zeidan et al. [5] described a patient with monosomy 7 in Ph− cells, who showed dysplastic changes in BM and therefore was taken off nilotinib. None of our 3 patients developed myelodysplastic features in concomitance with the emergence of cytogenetic abnormalities. On the basis of published data, patients with chromosome 7 abnormalities seem to have a greater risk to develop MDS/AML [6]. Several hypothesis have been proposed to explain the origin of these abnormalities; it has been suggested that CAs provide an evidence of a two-step process of CML pathogenesis, in which the acquisition of BCR-ABL rearrangement is a secondary event and arises in a pre-existent Ph− clone. This notion is supported by the recent observation that specific cytogenetic abnormalities were present in both Philadelphia positive and negative cells of patients responding to imatinib [7]. A closely related explanation is that either Ph positive or other abnormal clones arose from a genetically unstable progenitor, with the Ph− abnormalities revealed only by TKIs induced suppression of Ph positive clone. Because of an association between CAs in Ph− cells and previous treatments with cytarabine or idarubicin [1], it has been speculated that prior exposure to cytotoxic drugs is a risk for the development of CAs. However, none of our 3 patients has been previously exposed to these kind of drugs; therefore the role of previous therapy in the pathogenesis of CAs in Ph− cells can be relevant in some but
A, CCyR 6 Cytogenetic resistance Imatinib 3
CAs, clonal abnormalities; Ph−, Philadelphia negative; MDS, myelodysplastic syndrome; IFN-␣, interferon-alpha; CCyR, complete cytogenetic response; A, alive; PCyR, partial cytogenetic response. a Karyotype before starting nilotinib. b Time between start of nilotinib treatment and first appearance of Ph− clone. c Karyotype with the highest percentage of abnormal cells in Ph− clone.
12 46,XY[30] No 46,XY,t(9;22) (q34;q11)[6] 46,XY,t(3;5) (p12;p13)[2] 46,XY[22]
CCyR No 6 Imatinib 2
Cytogenetic resistance
46,XY,t(9;22) (q34;q11)[28]/46,XY[2] 46,XX,t(9;22) (q34;q11)[21]/46,XX[4]
47,XX, +8[16]/46,XX[14]
CCyR
A, CCyR 24
A, PCyR 21
47,XY, +8,t(9;22) (q32;q11)[15] 46,XY,del(20) (q11q13)[9] 46,XY[6] 47,XX, +8[8]/46,XX[22] CCyR No 46,XY,del(20) (q11q13)[14] 46,XY[16] 9 IFN-␣ imatinib 1
Intolerance
47,XY, +8,t(9;22) (q34;q11)[30]
MDS Karyotype with CAc Time to CA (mo)b Baseline karyotypea Cause of imatinib failure Previous treatment Pt. no.
Table 2 Clinical characteristics and karyotypes of patients with clonal CAs in Ph− cells.
Best response to nilotinib
Last karyotype
Follow-up on nilotinib (mo)
Outcome
Letter to the Editor / Leukemia Research 33 (2009) e218–e220
e219
not in all patients. Another hypothesis is that nilotinib treatment itself induced or favoured the acquisition of additional abnormalities. This theory has been suggested by recent in vitro studies where nilotinib and imatinib induced chromosome, centrosome and spindle defects in human fibroblast cells [8]. The molecular mechanism of the effects of nilotinib on centrosome and chromosomal stability may be due to ABL permanent inhibition. This could lead to the accumulation of new genetic damages, since ABL interacts with different proteins involved in the response to DNA damage and DNA repair such as p73, DNA-PK, ATM and RAD51 [9,10]. These effects may be particularly significant when the hematopoiesis must be restored from a limited pool of Ph− stem cells, which are under enormous stress to maintain cellular output. In this scenario, not only the stem cells could acquire more genetic damages than usual but also the acquired random karyotypic changes, which would normally be repaired or forced towards apoptosis, survive and proliferate when the ABL protein is inactivated. Our data confirm that clonal Ph− hematopoiesis is a general phenomenon associated with TKIs-induced suppression of BCR-ABL positive cells. The prognosis of patients with CAs in Ph− cells does not seem to be affected by the appearance of such abnormalities, however a larger cohort of patients as well as a longer follow-up are needed to evaluate the clinical significance of these abnormalities. This phenomenon in late CP CML patients treated with nilotinib is worth of close attention, in view of the introduction of nilotinib, as first-line therapy, in early CP CML patients [11]. To date, cytogenetic analysis is the only technique for identifying the presence and/or the development of clonal abnormalities in Ph− hematopoiesis during TKIs therapy. Conflict of interest statement Gianantonio Rosti: Grant and speaker bureau (Novartis); Speaker bureau (BMS). Michele Baccarani: Research grants and honoraries as speaker and consultant from Novartis. Acknowledgments This study was supported by grants from University of Bologna (RFO), Fondazione del Monte di Bologna e Ravenna, Italian MIUR PRIN 2005 (to NT) and AIL. Contributions: CB designed the study and prepared the manuscript. SL, GM, CG and MS performed molecular and cytogenetics studies. FP, FC collected clinical data. MB, GR were involved in revising the manuscript. NT gave final approval for submission. References [1] Bumm T, Müller C, Al-Ali HK, Krohn K, Shepherd P, Schmidt E, et al. Emergence of clonal cytogenetic abnormalities in Ph− cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003;101:1941–9. [2] Deininger MW, Cortes J, Paquette R, Park B, Hocchaus A, Baccarani M, et al. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells. Cancer 2007;110(7):1509–19. [3] Fabarius A, Haferlach C, Müller MC, Erben P, Lahaye T, Giehl M, et al. Dynamics of cytogenetic aberrations in Philadelphia chromosome positive and negative hematopoiesis during dasatinib therapy of chronic myeloid leukemia patients after imatinib failure. Haematologica 2007;92:834–7. [4] De Melo VA, Milojkovic D, Khorashad JS, Marin D, Goldman JM, Apperley JF, et al. Philadelphia negative clonal hematopoiesis is a significant feature of dasatinib therapy for chronic myeloid leukemia. Blood 2007;110:3086– 7. [5] Zeidan A, Kakati S, Anderson B, Barcos M, Wetzler M. Monosomy 7 in t(9;22)negative cells during nilotinib therapy in an imatinib-resistant chronic myeloid leukemia case. Cancer Genetics and Cytogenetics 2007;176:169–71. [6] Kovitz C, Kantarjian HM, Garcia-Manero G, Abruzzo LV, Cortes J. Myelodysplastic syndrome and acute leukemia after imatinib mesylate therapy for chronic myeloid leukemia. Blood 2006;108:2811–3.
e220
Letter to the Editor / Leukemia Research 33 (2009) e218–e220
[7] Zaccaria A, Valenti AM, Donti E, Gozzetti A, Ronconi S, Spedicato F. Persistence of chromosomal abnormalities additional to the Philadelphia chromosome after Philadelphia chromosome disappearance during imatinib therapy for chronic myeloid leukemia. Haematologica 2007;92:564– 5. [8] Fabarius A, Giehl M, Frank O, Spiess B, Zheng C, Müller MC, et al. Centrosome aberrations after nilotinib and imatinib treatment in vitro are associated with mitotic spindle defects and genetic instability. British Journal of Haematology 2007;138:369–73. [9] Kharbanda S, Yuan ZM, Weichselbaum R, Kufe D. Determination of cell fate by C-Abl activation in response to DNA damage. Oncogene 1998;17: 3309–18. [10] Yuan ZM, Huang Y, Ishiko T, Nakada S, Utsugisawa T, Kharbanda S, et al. Regulation of Rad51 by c-Abl in response to DNA damage. The Journal of Biological Chemistry 1998;273:3799–802. [11] Rosti G, Castagnetti F, Palandri F, Breccia M, Levato L, Capucci A, et al. Nilotinib 800 Mg daily as first line treatment of chronic myeloid leukemia in early chronic phase: result of a phase 2 trial of the GIMEMA CML. Working Party Haematologica 2008;93(sp1). Abstract [0404].
Carmen Baldazzi ∗ , Simona Luatti, Giulia Marzocchi, Monica Stacchini, Carla Gamberini, Fausto Castagnetti, Francesca Palandri, Gianantonio Rosti, Michele Baccarani, Nicoletta Testoni Institute of Hematology “Lorenzo e Ariosto Seràgnoli”, Sant’Orsola-Malpighi Hospital-University of Bologna, Via Massarenti 9, 40138 Bologna, Italy ∗ Corresponding
author. Tel.: +39 0516363793; fax: +39 0516364037. E-mail address: [email protected] (C. Baldazzi) 7 May 2009 Available online 13 June 2009
Contents lists available at ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Letter to the Editor
Emergence of clonal chromosomal abnormalities in Philadelphia negative hematopoiesis in chronic myeloid leukemia patients treated with nilotinib after failure of imatinib therapy Clonal cytogenetic abnormalities (CAs) in Philadelphia negative (Ph−) metaphases have been widely observed during imatinib treatment in patients with chronic myeloid leukemia (CML) [1,2]. Recently, the appearance of such abnormalities in some CML patients, treated with dasatinib after imatinib failure, has been described [3,4]. To the best of our knowledge, only one patient has been reported to develop a cytogenetic abnormality in Ph− clone during nilotinib treatment, following imatinib [5]. The incidence and consequences of CAs in Ph− cells during treatment with second generation tyrosine kinase inhibitors (TKIs) should be extensively investigated; this issue, deserves a particular attention, since these new drugs put a far higher pressure on the leukemic and the residual normal hematopoiesis than imatinib. At our institute we analyzed 30 late chronic phase (CP) CML patients treated with nilotinib after imatinib failure by conventional cytogenetic (CC) and fluorescence in situ hybridization (FISH). Cytogenetic analysis of bone marrow (BM) was performed at diagnosis, during imatinib treatment, before starting nilotinib and every 3–6 months during the first year of nilotinib therapy; thereafter every 12 months or in case of disease progression. FISH was performed using DNA commercial probes. At diagnosis LSI Dual Color Dual Fusion BCR-ABL DNA probe (Vysis, Downers Grove, IL, USA) was used to characterize BCR-ABL rearrangement. The subsequent analysis was performed using appropriate probes, depending on the results of CC. The patients were 18 females and 12 males, median age was 51 years (range 18–77). The median time of imatinib therapy was 34 months (range 7–71). Fourteen patients received only imatinib as previous therapy, whereas 16 patients were treated with additional therapies, such as: hydroxyurea, interferon-␣, cytosinearabinoside, busulphan. During nilotinib therapy 18 (60%) patients achieved a complete cytogenetic response (CCyR), within a median time of 4.7 months (range 1–10). Patients were followed for a median time of 18 months (range 4–42) after commencing nilotinib therapy (Table 1). Three out of 30 patients (10%) developed CAs in Ph− cells, namely: trisomy 8, del(20)(q11q13) and t(3;5)(p12;p13). There were 2 males and 1 female, aged between 31 and 58 years. Del(20q)(q11q13) (no.1) and trisomy 8 (no.2) persisted for 12 and 18 months, respectively, and were still present at the last cytogenetic study (21 and 24 months, respectively), whereas t(3;5)(p12;p13) (no.3) was transient: it appeared after 6 months of therapy and disappeared within 2 months. Patients’ characteristics are summarized in Table 2. Retrospective FISH analysis performed on stored BM specimens of patients no.1 and no.2 failed to detect the above reported aberrations before nilotinib therapy. After a median follow-up of 19 months (range 0145-2126/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2009.05.010
Table 1 Clinical features of 30 patients treated with nilotinib. Patients characteristics Median age at start of nilotinib, years (range) Sex (F/M) Median follow-up on imatinib, mo (range) Median follow-up on nilotinib, mo (range) Median time from diagnosis to nilotinib, mo (range) Imatinib alone as previous therapy, n (%)
51(18–77) 18/12 34(7–71) 18(4–42) 57.5(6–260) 14(46.7)
Best cytogenetic response to nilotinib, n. Complete CyR Partial CyR Minor CyR No response
18 2 2 8
CyR, cytogenetic response.
12–24) of nilotinib treatment, all patients were alive: 2 patients (no.1 and no.2) were in CCyR and continued nilotinib treatment, while the last patient (no.3) lost CCyR after 12 months from the first detection of del(20)(q11q13) and therefore discontinued nilotinib. At time of reporting, he was treated with bosutinib (Table 2). The incidence and type of abnormalities after nilotinib are similar to those reported in patients treated with imatinib [1,2]. Although these alterations are similar to those seen in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemias (AML), they are rarely reported to evolve to MDS or AML [1–4]. Zeidan et al. [5] described a patient with monosomy 7 in Ph− cells, who showed dysplastic changes in BM and therefore was taken off nilotinib. None of our 3 patients developed myelodysplastic features in concomitance with the emergence of cytogenetic abnormalities. On the basis of published data, patients with chromosome 7 abnormalities seem to have a greater risk to develop MDS/AML [6]. Several hypothesis have been proposed to explain the origin of these abnormalities; it has been suggested that CAs provide an evidence of a two-step process of CML pathogenesis, in which the acquisition of BCR-ABL rearrangement is a secondary event and arises in a pre-existent Ph− clone. This notion is supported by the recent observation that specific cytogenetic abnormalities were present in both Philadelphia positive and negative cells of patients responding to imatinib [7]. A closely related explanation is that either Ph positive or other abnormal clones arose from a genetically unstable progenitor, with the Ph− abnormalities revealed only by TKIs induced suppression of Ph positive clone. Because of an association between CAs in Ph− cells and previous treatments with cytarabine or idarubicin [1], it has been speculated that prior exposure to cytotoxic drugs is a risk for the development of CAs. However, none of our 3 patients has been previously exposed to these kind of drugs; therefore the role of previous therapy in the pathogenesis of CAs in Ph− cells can be relevant in some but
A, CCyR 6 Cytogenetic resistance Imatinib 3
CAs, clonal abnormalities; Ph−, Philadelphia negative; MDS, myelodysplastic syndrome; IFN-␣, interferon-alpha; CCyR, complete cytogenetic response; A, alive; PCyR, partial cytogenetic response. a Karyotype before starting nilotinib. b Time between start of nilotinib treatment and first appearance of Ph− clone. c Karyotype with the highest percentage of abnormal cells in Ph− clone.
12 46,XY[30] No 46,XY,t(9;22) (q34;q11)[6] 46,XY,t(3;5) (p12;p13)[2] 46,XY[22]
CCyR No 6 Imatinib 2
Cytogenetic resistance
46,XY,t(9;22) (q34;q11)[28]/46,XY[2] 46,XX,t(9;22) (q34;q11)[21]/46,XX[4]
47,XX, +8[16]/46,XX[14]
CCyR
A, CCyR 24
A, PCyR 21
47,XY, +8,t(9;22) (q32;q11)[15] 46,XY,del(20) (q11q13)[9] 46,XY[6] 47,XX, +8[8]/46,XX[22] CCyR No 46,XY,del(20) (q11q13)[14] 46,XY[16] 9 IFN-␣ imatinib 1
Intolerance
47,XY, +8,t(9;22) (q34;q11)[30]
MDS Karyotype with CAc Time to CA (mo)b Baseline karyotypea Cause of imatinib failure Previous treatment Pt. no.
Table 2 Clinical characteristics and karyotypes of patients with clonal CAs in Ph− cells.
Best response to nilotinib
Last karyotype
Follow-up on nilotinib (mo)
Outcome
Letter to the Editor / Leukemia Research 33 (2009) e218–e220
e219
not in all patients. Another hypothesis is that nilotinib treatment itself induced or favoured the acquisition of additional abnormalities. This theory has been suggested by recent in vitro studies where nilotinib and imatinib induced chromosome, centrosome and spindle defects in human fibroblast cells [8]. The molecular mechanism of the effects of nilotinib on centrosome and chromosomal stability may be due to ABL permanent inhibition. This could lead to the accumulation of new genetic damages, since ABL interacts with different proteins involved in the response to DNA damage and DNA repair such as p73, DNA-PK, ATM and RAD51 [9,10]. These effects may be particularly significant when the hematopoiesis must be restored from a limited pool of Ph− stem cells, which are under enormous stress to maintain cellular output. In this scenario, not only the stem cells could acquire more genetic damages than usual but also the acquired random karyotypic changes, which would normally be repaired or forced towards apoptosis, survive and proliferate when the ABL protein is inactivated. Our data confirm that clonal Ph− hematopoiesis is a general phenomenon associated with TKIs-induced suppression of BCR-ABL positive cells. The prognosis of patients with CAs in Ph− cells does not seem to be affected by the appearance of such abnormalities, however a larger cohort of patients as well as a longer follow-up are needed to evaluate the clinical significance of these abnormalities. This phenomenon in late CP CML patients treated with nilotinib is worth of close attention, in view of the introduction of nilotinib, as first-line therapy, in early CP CML patients [11]. To date, cytogenetic analysis is the only technique for identifying the presence and/or the development of clonal abnormalities in Ph− hematopoiesis during TKIs therapy. Conflict of interest statement Gianantonio Rosti: Grant and speaker bureau (Novartis); Speaker bureau (BMS). Michele Baccarani: Research grants and honoraries as speaker and consultant from Novartis. Acknowledgments This study was supported by grants from University of Bologna (RFO), Fondazione del Monte di Bologna e Ravenna, Italian MIUR PRIN 2005 (to NT) and AIL. Contributions: CB designed the study and prepared the manuscript. SL, GM, CG and MS performed molecular and cytogenetics studies. FP, FC collected clinical data. MB, GR were involved in revising the manuscript. NT gave final approval for submission. References [1] Bumm T, Müller C, Al-Ali HK, Krohn K, Shepherd P, Schmidt E, et al. Emergence of clonal cytogenetic abnormalities in Ph− cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003;101:1941–9. [2] Deininger MW, Cortes J, Paquette R, Park B, Hocchaus A, Baccarani M, et al. The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells. Cancer 2007;110(7):1509–19. [3] Fabarius A, Haferlach C, Müller MC, Erben P, Lahaye T, Giehl M, et al. Dynamics of cytogenetic aberrations in Philadelphia chromosome positive and negative hematopoiesis during dasatinib therapy of chronic myeloid leukemia patients after imatinib failure. Haematologica 2007;92:834–7. [4] De Melo VA, Milojkovic D, Khorashad JS, Marin D, Goldman JM, Apperley JF, et al. Philadelphia negative clonal hematopoiesis is a significant feature of dasatinib therapy for chronic myeloid leukemia. Blood 2007;110:3086– 7. [5] Zeidan A, Kakati S, Anderson B, Barcos M, Wetzler M. Monosomy 7 in t(9;22)negative cells during nilotinib therapy in an imatinib-resistant chronic myeloid leukemia case. Cancer Genetics and Cytogenetics 2007;176:169–71. [6] Kovitz C, Kantarjian HM, Garcia-Manero G, Abruzzo LV, Cortes J. Myelodysplastic syndrome and acute leukemia after imatinib mesylate therapy for chronic myeloid leukemia. Blood 2006;108:2811–3.
e220
Letter to the Editor / Leukemia Research 33 (2009) e218–e220
[7] Zaccaria A, Valenti AM, Donti E, Gozzetti A, Ronconi S, Spedicato F. Persistence of chromosomal abnormalities additional to the Philadelphia chromosome after Philadelphia chromosome disappearance during imatinib therapy for chronic myeloid leukemia. Haematologica 2007;92:564– 5. [8] Fabarius A, Giehl M, Frank O, Spiess B, Zheng C, Müller MC, et al. Centrosome aberrations after nilotinib and imatinib treatment in vitro are associated with mitotic spindle defects and genetic instability. British Journal of Haematology 2007;138:369–73. [9] Kharbanda S, Yuan ZM, Weichselbaum R, Kufe D. Determination of cell fate by C-Abl activation in response to DNA damage. Oncogene 1998;17: 3309–18. [10] Yuan ZM, Huang Y, Ishiko T, Nakada S, Utsugisawa T, Kharbanda S, et al. Regulation of Rad51 by c-Abl in response to DNA damage. The Journal of Biological Chemistry 1998;273:3799–802. [11] Rosti G, Castagnetti F, Palandri F, Breccia M, Levato L, Capucci A, et al. Nilotinib 800 Mg daily as first line treatment of chronic myeloid leukemia in early chronic phase: result of a phase 2 trial of the GIMEMA CML. Working Party Haematologica 2008;93(sp1). Abstract [0404].
Carmen Baldazzi ∗ , Simona Luatti, Giulia Marzocchi, Monica Stacchini, Carla Gamberini, Fausto Castagnetti, Francesca Palandri, Gianantonio Rosti, Michele Baccarani, Nicoletta Testoni Institute of Hematology “Lorenzo e Ariosto Seràgnoli”, Sant’Orsola-Malpighi Hospital-University of Bologna, Via Massarenti 9, 40138 Bologna, Italy ∗ Corresponding
author. Tel.: +39 0516363793; fax: +39 0516364037. E-mail address: [email protected] (C. Baldazzi) 7 May 2009 Available online 13 June 2009