- Email: [email protected]
Imatinib-induced apoptosis in the eosinophils of patients with a hypereosinophilic syndrome: A surrogate marker of response?
Letters to the Editor / Leukemia Research 31 (2007) 719–726
follow-up period support the hypothesis of a possible association of del(13) with a favorable outcome in patients with CML-BP. However, given the paucity of analyses in this field, the clinical consequences as well as the influence on the disease outcome resulting from the occurrence of del(13) in CML-BP remain unresolved. Finally, we therefore believe that reports from centers and health facilities regarding different aspects of this intriguing disease should be stimulated.
Acknowledgements This study was carried out in the Hospital PIO XII of S˜ao Jos´e dos Campos supported by the Servic¸o de Hematologia e Hemoterapia de S˜ao Jos´e dos Campos. No potential conflict of interest relevant to this article was reported. Contributions. Dr. Evandro Secchi Rosa is on the staff of Servic¸o de Hematologia e Hemoterapia de S˜ao Jos´e dos Campos and contributed with the diagnosis and treatment components of the study. Dr. Carla Cec´ılia Mulin is on the staff of Servic¸o de Hematologia e Hemoterapia de S˜ao Jos´e dos Campos and contributed with the laboratorial components (cytogenetic and molecular assays) of the study.
References [1] Anastasi J, Feng J, Le Beau MM, Larson RA, Rowley JD, Vardiman JW. The relationship between secondary chromosomal abnormalities and blast transformation in chronic myelogenous leukemia. Leukemia 1995;9(4):628–33. [2] Merzianu M, Medeiros LJ, Cortes J, Yin C, Lin P, Jones D, et al. Inv(16)(p13q22) in chronic myelogenous leukemia in blast phase: a clinicopathologic, cytogenetic, and molecular study of five cases. Am J Clin Pathol 2005;124(5):807–14. [3] Patel BB, Mohamed AN, Schiffer A. “Acute myelogenous leukemia like” translocations in CML blast crisis: two new cases of inv(16)/t(16;16) and a review of the literature. Leukemia Res 2006;30(2): 225–32. [4] Yin CC, Medeiros LJ, Glassman AB, Lin P. t(8;21)(q22;q22) in blast phase of chronic myelogenous leukemia. Am J Clin Pathol 2004;121(6):836–42. [5] Storlazzi CT, Anelli L, Surace C, Rocchi M, Albano F, Pastore D, et al. Molecular cytogenetic characterization of a novel additional chromosomal aberration in blast crisis of a Ph-positive chronic myeloid leukemia. Cancer Genet Cytogenet 2002;134(2):109–13. [6] Adeyinka A, Dewald GW. Cytogenetics of chronic myeloproliferative disorders and related myelodysplastic syndromes. Hematol Oncol Clin N Am 2003;17(5):1129–49. [7] Mauritzson N, Albin M, Rylander L, Billstrom R, Ahlgren T, Mikoczy Z, et al. Pooled analysis of clinical and cytogenetic features in treatmentrelated and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analysed 1976–1993 and on 5098 unselected cases reported in the literature. Leukemia 2002;16(12):2366–78. [8] Moravcova J, Zmekova V, Klamova H, Voglova J, Faber E, Michalova K, et al. Differences and similarities in kinetics of BCR-ABL transcript levels in CML patients treated with imatinib mesylate for chronic or accelerated disease phase. Leukemia Res 2004;28(4):415–9.
725
Fernando Callera ∗ Evandro Secchi Rosa 1 Carla Cecilia Mulin 1 Servi¸co de Hematologia e Hemoterapia de S˜ao Jos´e dos Campos, Rua Antonio Sais, 425, S˜ao Jos´e Dos Campos, S˜ao Paulo 12210-040, Brazil ∗ Corresponding
author. Tel.: +55 12 3921 3766; fax: +55 12 3921 3766. E-mail address: [email protected] (F. Callera) 1 Tel.: +55 12 3921 3766; fax: +55 12 3921 3766. 15 June 2006 Available online 21 August 2006 doi: 10.1016/j.leukres.2006.06.026
Imatinib-induced apoptosis in the eosinophils of patients with a hypereosinophilic syndrome: A surrogate marker of response? In their recent article Pardanani et al. [1] have argued that the association of the phenotypic spectrum with the FIP1L1-PDGFRA mutations is quite close and may be largely restricted to Eosinophilia associated Systemic Mast Cell Disease, even if, in reality, their patients did not meet the criteria for systemic mastocytosis. Although this is an interesting intellectual argument, however, it has little relevance because patients with FIP1L1-PDGFRA fusion responded to Imatinib. The identification of additional patients who lack the fusion gene but who respond to Imatinib [2] as also experienced by us is more important. The identification of responsive patients to Imatinib would be significantly facilitated by quantitative surrogate pharmacodynamic markers that can be used by clinicians who do not have access to the techniques necessary to carry out a molecular diagnosis. Herein we propose such a validation by showing a striking correlation between Imatinib-induced apoptosis in eosinophils and the response to therapy. Briefly, a common feature observed in responsive patients, is a typically very rapid response to therapy. Eosinophil cytoreduction occurs in a few days and is generally achieved with a 100 mg daily dose of Imatinib [3]. In vitro, the data have shown that Imatinib not only inhibits phosphorilation of the FIP1L1-PDGFRA (F/P) fusion protein, but also strongly induces the apoptosis of cells expressing this protein [4]. Surprisingly in a clinical setting there have been no reports, to our knowledge, of induced eosinophil apoptosis by Imatinib. So, could this feature be predictive of response? By utilizing the flow cytometric analysis after the staining of eosinophils with Annexin V fluorescein and propidium iodide in combination with light and electron microscopy, we studied eosinophil apoptosis in the peripheral blood of hypereosinophilic patients, before and during treatment with Imatinib. Our study included five patients with FIP1L1-PDGFRA
726
Letters to the Editor / Leukemia Research 31 (2007) 719–726
fusion and seven hypereosinophilic patients without an F/P fusion. Their median age was 48 years and all patients were males. The median eosinophil count at the baseline was 22,500 mm−3 (range 8965–58,000 mm−3 ) and all patients were symptomatic with current evidence or history of tissue involvement, mostly cardiovascular or neurologic. Patients were started at a dose of 100 mg Imatinib taken orally once a day with food; if no response was observed after 1 week of treatment, patients were treated at 400 mg/day. At 0 h all patients showed a low degree of eosinophil apoptotic cells with a mean value of 4.1 ± 0.9%; at 96 h after treatment, the percentages of apoptotic cells showed a peak with a mean value of 68.1 ± 3.2% in six patients; 7.2 ± 1.1% in the others (p = 0.000), while the six patients (5 F/P+, 1 F/P−) with an elevated apoptosis at 96 h achieved a sustained complete response with Imatinib Mesylate therapy while the others did not. In non-responding patients Imatinib was escalated to 400 mg/day without a response. Our data suggest that a significant elevated apoptosis of eosinophils in hypereosinophilic syndrome patients after a 96 h Imatinib therapy can be predictive of response to treatment not only in patients with FIP1L1-PDGFRA fusion but also in the subset of patients without a detectable gene fusion. These remarks could be useful for clinicians who do not have access to the techniques necessary to carry out a molecular diagnosis.
routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature. Leuk Res 2006;30:965–70. [2] Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201–14. [3] Pardanani A, Reeder T, Porrata LF, Li CY, Tazelaar HD, Baxter EJ, et al. Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. Blood 2003;101:3391–7. [4] Cools J, Quentmeier H, Huntly BJ, Marynen P, Griffin JD, Drexler HG, et al. The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood 2004;103:2802–5.
Vincenzo Pitini∗ Carmela Arrigo Giuseppe Altavilla Claudia Naro Department of Medical Oncology, University of Messina, Via Consolare Valeria 98125, Messina, Italy Maria Righi Department of Human Pathology, University of Messina, Via Consolare Valeria 98125, Messina, Italy ∗ Corresponding
author. Tel.: +39 090 2213241; fax: +39 090 2213231. E-mail address: [email protected] (V. Pitini)
28 June 2006 Available online 15 September 2006 References doi: 10.1016/j.leukres.2006.07.011 [1] Pardanani A, Ketterling RP, Li C-Y, Patnaik MM, Wolanskyj AP, Elliott MA, et al. FIP1L1-PDGFRA in eosinophilic disorders: prevalence in
follow-up period support the hypothesis of a possible association of del(13) with a favorable outcome in patients with CML-BP. However, given the paucity of analyses in this field, the clinical consequences as well as the influence on the disease outcome resulting from the occurrence of del(13) in CML-BP remain unresolved. Finally, we therefore believe that reports from centers and health facilities regarding different aspects of this intriguing disease should be stimulated.
Acknowledgements This study was carried out in the Hospital PIO XII of S˜ao Jos´e dos Campos supported by the Servic¸o de Hematologia e Hemoterapia de S˜ao Jos´e dos Campos. No potential conflict of interest relevant to this article was reported. Contributions. Dr. Evandro Secchi Rosa is on the staff of Servic¸o de Hematologia e Hemoterapia de S˜ao Jos´e dos Campos and contributed with the diagnosis and treatment components of the study. Dr. Carla Cec´ılia Mulin is on the staff of Servic¸o de Hematologia e Hemoterapia de S˜ao Jos´e dos Campos and contributed with the laboratorial components (cytogenetic and molecular assays) of the study.
References [1] Anastasi J, Feng J, Le Beau MM, Larson RA, Rowley JD, Vardiman JW. The relationship between secondary chromosomal abnormalities and blast transformation in chronic myelogenous leukemia. Leukemia 1995;9(4):628–33. [2] Merzianu M, Medeiros LJ, Cortes J, Yin C, Lin P, Jones D, et al. Inv(16)(p13q22) in chronic myelogenous leukemia in blast phase: a clinicopathologic, cytogenetic, and molecular study of five cases. Am J Clin Pathol 2005;124(5):807–14. [3] Patel BB, Mohamed AN, Schiffer A. “Acute myelogenous leukemia like” translocations in CML blast crisis: two new cases of inv(16)/t(16;16) and a review of the literature. Leukemia Res 2006;30(2): 225–32. [4] Yin CC, Medeiros LJ, Glassman AB, Lin P. t(8;21)(q22;q22) in blast phase of chronic myelogenous leukemia. Am J Clin Pathol 2004;121(6):836–42. [5] Storlazzi CT, Anelli L, Surace C, Rocchi M, Albano F, Pastore D, et al. Molecular cytogenetic characterization of a novel additional chromosomal aberration in blast crisis of a Ph-positive chronic myeloid leukemia. Cancer Genet Cytogenet 2002;134(2):109–13. [6] Adeyinka A, Dewald GW. Cytogenetics of chronic myeloproliferative disorders and related myelodysplastic syndromes. Hematol Oncol Clin N Am 2003;17(5):1129–49. [7] Mauritzson N, Albin M, Rylander L, Billstrom R, Ahlgren T, Mikoczy Z, et al. Pooled analysis of clinical and cytogenetic features in treatmentrelated and de novo adult acute myeloid leukemia and myelodysplastic syndromes based on a consecutive series of 761 patients analysed 1976–1993 and on 5098 unselected cases reported in the literature. Leukemia 2002;16(12):2366–78. [8] Moravcova J, Zmekova V, Klamova H, Voglova J, Faber E, Michalova K, et al. Differences and similarities in kinetics of BCR-ABL transcript levels in CML patients treated with imatinib mesylate for chronic or accelerated disease phase. Leukemia Res 2004;28(4):415–9.
725
Fernando Callera ∗ Evandro Secchi Rosa 1 Carla Cecilia Mulin 1 Servi¸co de Hematologia e Hemoterapia de S˜ao Jos´e dos Campos, Rua Antonio Sais, 425, S˜ao Jos´e Dos Campos, S˜ao Paulo 12210-040, Brazil ∗ Corresponding
author. Tel.: +55 12 3921 3766; fax: +55 12 3921 3766. E-mail address: [email protected] (F. Callera) 1 Tel.: +55 12 3921 3766; fax: +55 12 3921 3766. 15 June 2006 Available online 21 August 2006 doi: 10.1016/j.leukres.2006.06.026
Imatinib-induced apoptosis in the eosinophils of patients with a hypereosinophilic syndrome: A surrogate marker of response? In their recent article Pardanani et al. [1] have argued that the association of the phenotypic spectrum with the FIP1L1-PDGFRA mutations is quite close and may be largely restricted to Eosinophilia associated Systemic Mast Cell Disease, even if, in reality, their patients did not meet the criteria for systemic mastocytosis. Although this is an interesting intellectual argument, however, it has little relevance because patients with FIP1L1-PDGFRA fusion responded to Imatinib. The identification of additional patients who lack the fusion gene but who respond to Imatinib [2] as also experienced by us is more important. The identification of responsive patients to Imatinib would be significantly facilitated by quantitative surrogate pharmacodynamic markers that can be used by clinicians who do not have access to the techniques necessary to carry out a molecular diagnosis. Herein we propose such a validation by showing a striking correlation between Imatinib-induced apoptosis in eosinophils and the response to therapy. Briefly, a common feature observed in responsive patients, is a typically very rapid response to therapy. Eosinophil cytoreduction occurs in a few days and is generally achieved with a 100 mg daily dose of Imatinib [3]. In vitro, the data have shown that Imatinib not only inhibits phosphorilation of the FIP1L1-PDGFRA (F/P) fusion protein, but also strongly induces the apoptosis of cells expressing this protein [4]. Surprisingly in a clinical setting there have been no reports, to our knowledge, of induced eosinophil apoptosis by Imatinib. So, could this feature be predictive of response? By utilizing the flow cytometric analysis after the staining of eosinophils with Annexin V fluorescein and propidium iodide in combination with light and electron microscopy, we studied eosinophil apoptosis in the peripheral blood of hypereosinophilic patients, before and during treatment with Imatinib. Our study included five patients with FIP1L1-PDGFRA
726
Letters to the Editor / Leukemia Research 31 (2007) 719–726
fusion and seven hypereosinophilic patients without an F/P fusion. Their median age was 48 years and all patients were males. The median eosinophil count at the baseline was 22,500 mm−3 (range 8965–58,000 mm−3 ) and all patients were symptomatic with current evidence or history of tissue involvement, mostly cardiovascular or neurologic. Patients were started at a dose of 100 mg Imatinib taken orally once a day with food; if no response was observed after 1 week of treatment, patients were treated at 400 mg/day. At 0 h all patients showed a low degree of eosinophil apoptotic cells with a mean value of 4.1 ± 0.9%; at 96 h after treatment, the percentages of apoptotic cells showed a peak with a mean value of 68.1 ± 3.2% in six patients; 7.2 ± 1.1% in the others (p = 0.000), while the six patients (5 F/P+, 1 F/P−) with an elevated apoptosis at 96 h achieved a sustained complete response with Imatinib Mesylate therapy while the others did not. In non-responding patients Imatinib was escalated to 400 mg/day without a response. Our data suggest that a significant elevated apoptosis of eosinophils in hypereosinophilic syndrome patients after a 96 h Imatinib therapy can be predictive of response to treatment not only in patients with FIP1L1-PDGFRA fusion but also in the subset of patients without a detectable gene fusion. These remarks could be useful for clinicians who do not have access to the techniques necessary to carry out a molecular diagnosis.
routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature. Leuk Res 2006;30:965–70. [2] Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, et al. A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 2003;348:1201–14. [3] Pardanani A, Reeder T, Porrata LF, Li CY, Tazelaar HD, Baxter EJ, et al. Imatinib therapy for hypereosinophilic syndrome and other eosinophilic disorders. Blood 2003;101:3391–7. [4] Cools J, Quentmeier H, Huntly BJ, Marynen P, Griffin JD, Drexler HG, et al. The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. Blood 2004;103:2802–5.
Vincenzo Pitini∗ Carmela Arrigo Giuseppe Altavilla Claudia Naro Department of Medical Oncology, University of Messina, Via Consolare Valeria 98125, Messina, Italy Maria Righi Department of Human Pathology, University of Messina, Via Consolare Valeria 98125, Messina, Italy ∗ Corresponding
author. Tel.: +39 090 2213241; fax: +39 090 2213231. E-mail address: [email protected] (V. Pitini)
28 June 2006 Available online 15 September 2006 References doi: 10.1016/j.leukres.2006.07.011 [1] Pardanani A, Ketterling RP, Li C-Y, Patnaik MM, Wolanskyj AP, Elliott MA, et al. FIP1L1-PDGFRA in eosinophilic disorders: prevalence in