Leukemia & Lymphoma
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Dasatinib-induced immunosuppression and recurrent respiratory tract infections Faruk Obut, Nicole Randall, Jo-Anne H. Young, Peter Valent & Celalettin Ustun To cite this article: Faruk Obut, Nicole Randall, Jo-Anne H. Young, Peter Valent & Celalettin Ustun (2015) Dasatinib-induced immunosuppression and recurrent respiratory tract infections, Leukemia & Lymphoma, 56:8, 2484-2485, DOI: 10.3109/10428194.2014.994179 To link to this article: http://dx.doi.org/10.3109/10428194.2014.994179
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Accepted author version posted online: 11 Dec 2014. Published online: 21 Jan 2015. Submit your article to this journal
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ilal20 Download by: [Central Michigan University]
Date: 05 November 2015, At: 22:25
Leukemia & Lymphoma, August 2015; 56(8): 2484–2485 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.994179
SHORT COMMUNICATION
Dasatinib-induced immunosuppression and recurrent respiratory tract infections Faruk Obut1, Nicole Randall1, Jo-Anne H. Young2, Peter Valent3 & Celalettin Ustun1 1Division of Hematology-Oncology and Transplantation and 2Division of Infectious Disease, Department of Medicine,
Downloaded by [Central Michigan University] at 22:25 05 November 2015
University of Minnesota, Minneapolis, MN, USA and 3Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
We read the study by Alsobhi et al. with great interest [1], and agree that tyrosine kinase inhibitors (TKIs) have revolutionized therapy for patients with chronic myelogenous leukemia (CML) in the chronic phase (CP) [2]. As the authors reported, neutropenia is the most common side effect of TKI therapy [3]. In a larger study comparing dasatinib (n ⫽ 259 patients) with imatinib (n ⫽ 259), infections occurred in 10.5% of patients with CP-CML receiving dasatinib, in part due to neutropenia (24%), and 2% of these patients died of infections [3]. The case we discuss here underscores a lesser-known side effect of TKIs: suppression of the immune system. A 55-year-old male (healthy other than Alzheimer disease) was diagnosed with Philadelphia chromosome positive CP-CML in July 2010. Imatinib was started (400 mg/day), but replaced by dasatinib (100 mg/day) after 22 months. In July 2012 and April 2013, BCR/ABL1 transcripts became undetectable in the peripheral blood and bone marrow, respectively. However, the patient developed a productive cough and dyspnea while taking dasatinib in February 2013. A chest computed tomography (CT) scan showed patchy areas of airspace in the lung bases, likely due to infection. These episodes were treated empirically as acute bronchitis or atypical pneumonia. Despite antibiotic therapy, respiratory symptoms recurred on a monthly basis, and the patient was admitted to hospital in July 2013 with fever, hypoxia and neutrophilia (absolute neutrophil count of 12 ⫻ 108/L) while receiving cefuroxime. Chest CT showed consolidation in the left lung and pleural effusion. Thoracentesis revealed a high white blood cell count (3696 ⫻ 109/L) composed mainly of lymphocytes (82%) in the pleural effusion, as seen with dasatinib-induced pleural effusions [4]. An echocardiogram revealed a normal left ventricular ejection fraction. Cytomegalovirus in blood and common respiratory viruses in a nasal swab were undetectable by polymerase chain reaction (PCR). The patient was treated with a 14-day course of intravenous (IV) piperacillin–tazobactam, levofloxacin and
vancomycin for health-care associated pneumonia, but the treatment course was complicated by acute kidney injury (creatinine increased to 5 mg/dL). Renal failure was considered to be due to acute tubular necrosis from prolonged dehydration; however, interstitial nephritis from vancomycin and dasatinib could not be excluded. Serum immunoglobulin G (IgG), IgA and IgM levels were all decreased: 312 mg/ dL (normal, 695–1620 mg/dL), 67 mg/dL (normal, 70–380 mg/dL) and 26 mg/dL (normal, 60–265 mg/dL), respectively. Serum protein electrophoresis (SPEP) showed hypogammaglobulinemia (gamma fraction was 0.3 g/dL, normal, 0.7–1.6 g/dL). Absolute CD3⫹, CD4 ⫹ and CD8 ⫹ T-cell counts in blood were 0.39 ⫻ 109/L, 0.29 ⫻ 109/L and 0.1 ⫻ 109/L, respectively. Intravenous immunoglobulin (IVIG) replacement therapy was not tolerated by the patient because of an allergic reaction. Dasatinib was replaced with omacetaxine at maintenance dosing (1.25 mg/m2 twice a day subcutaneously). Although omacetaxine use was complicated by severe pancytopenia and cytogenetic relapse, Ig levels (IgG 913 mg/dL, IgA 137 mg/dL and IgM 89 mg/dL), gamma fraction in SPEP (0.9 g/dL) and kidney function all returned to normal levels within 2 months. When cytogenetic relapse was detected in November 2013, omacetaxine was replaced with bosutinib (500 mg/day). The patient again achieved a complete cytogenetic and molecular response. Since discontinuation of dasatinib (for a year), IgG levels have been normal, and the patient has had no further respiratory infections; however, absolute T-cell counts have remained similarly low. Opportunistic infections are uncommon without neutropenia in patients with CP-CML, although they have been reported [5]. The effects of TKIs on the immune system have been evaluated. In patients with CML, IgA and IgG levels were decreased with imatinib, IgM levels were decreased with dasatinib (from 0.86 g/L to 0.39 g/L in 12 months) and no significant changes in immunoglobulin levels were observed with nilotinib as compared to healthy volunteers
Correspondence: Celalettin Ustun, MD, Associate Professor of Medicine, 14-142 PWB, 516 Delaware Street SE, Minneapolis, MN 55455, USA. Tel: (612)6240123. Fax: (612)625-6919. E-mail: [email protected] Received 9 September 2014; revised 19 November 2014; accepted 22 November 2014
2484
Downloaded by [Central Michigan University] at 22:25 05 November 2015
Dasatinib-induced immunosuppression and recurrent respiratory tract infections 2485 and pre-treatment levels [6]. Another study showed decreased numbers of B cells but normal serum immunoglobulin levels with dasatinib [5]. Dasatinib-treated patients had significantly lower median B-cell proportions in peripheral blood and bone marrow when compared to imatinib-treated patients or healthy controls [7]. As compared to healthy volunteers, patients with CML had an impaired response to pneumococcal vaccination owing to lower levels of blood IgM memory B cells and impaired B cell signaling after treatment with TKIs [8]. With respect to the cellular immune system, dasatinib inhibited T cell activation, proliferation, cytokine production and degranulation in a dose-dependent manner in vitro [9,10]. These effects of dasatinib were more prominent in CD4 ⫹ cells than in CD8 ⫹ cells and more prominent in naive T cells than in memory T cell subsets [9]. However, in vivo, absolute lymphocyte counts, CD8 ⫹ cells and γδ T cell counts in peripheral blood increased significantly during dasatinib therapy in patients with CML [7]. It has been shown that dasatinib inhibits TCR signaling through Srcfamily kinase LCK, which is important for the suppression of T-cell function [10–12]. Dasatinib also affects the innate immune system. The proportions and absolute counts of natural killer (NK) cells (in peripheral blood) [7] and monocytes (in peripheral blood and bone marrow) were increased in patients on dasatinib therapy when compared to healthy controls or imatinib-treated patients [7]. NK cell activity was increased with dasatinib therapy in patients with CML [13]. In vitro, dasatinib induced transient suppression of IgE-dependent activation of blood basophils [5]. TKIs affect different parts of the immune system; however, these effects vary significantly between in vivo and in vitro conditions and commonly used TKIs. In our patient, both humoral and cellular immune systems (in particular CD8 ⫹ cells) were suppressed during dasatinib therapy, although relevant values at the time of diagnosis were unknown. Switching dasatinib to a non-TKI drug and then to bosutinib (another Src family kinase inhibitor) was associated with improvement in the humoral immune system and no recurrence of respiratory infections. It can be speculated that this might be a result of bosutinib, in contrast to dasatinib, which does not inhibit neutrophil Bruton’s tyrosine kinase (Btk) family members important to neutrophil activation [14]. Because no microorganism was identified in the patient, one can argue that the patient in fact had experienced dasatinib-induced pulmonary toxicity mimicking lung infection, as reported in another patient [15]. On the other hand, prior antibiotic use most likely caused the false-negative cultures in our patient, who had clinical signs of pneumonia (fevers, neutrophilia and consolidation in the lung). In conclusion, it is not recommended (i.e. not costeffective) to check humoral or cellular immunity in all
patients with CP-CML in routine clinical practice, but it might be warranted in those with recurrent infections without neutropenia (because it may have an impact on supportive therapy, IVIG replacement, etc.). It is also important to remember that these patients’ response to vaccination may be suboptimal, and that dasatinib-induced lung toxicity can mimic infections.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Alsobhi E, Abrar MB, Abdelaal M, et al. Response to imatinib therapy in adult patients with chronic myeloid leukemia in Saudi population: a single-center study. Leuk Lymphoma 2014 Aug 4. [Epub ahead of print] [2] Bhamidipati PK, Jabbour E. Frontline therapy. Chronic myeloid leukemia: from daily management to complicated issues. New York: Nova Group; 2014. pp 107–128. [3] Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012;120:2454–2465. [4] Quintas-Cardama A , Kantarjian H, O’Brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol 2007;25:3908–3914. [5] Sillaber C, Herrmann H, Bennett K, et al. Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily. Eur J Clin Invest 2009;39:1098–1109. [6] Koskela H, Stromberg A , Richter J, et al. Tyrosine kinase inhibitor therapy induced changes in humoral immunity in patients with chronic myeloid leukemia. Blood 2011;118:740–740. [7] Rohon P, Porkka K, Mustjoki S. Immunoprofiling of patients with chronic myeloid leukemia at diagnosis and during tyrosine kinase inhibitor therapy. Eur J Haematol 2010;85:387–398. [8] de Lavallade H, Khoder A , Hart M, et al. Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling. Blood 2013;122:227–238. [9] Weichsel R, Dix C, Wooldridge L, et al. Profound inhibition of antigen-specific T-cell effector functions by dasatinib. Clin Cancer Res 2008;14:2484–2491. [10] Blake S, Hughes TP, Mayrhofer G, et al. The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro. Clin Immunol 2008;127:330–339. [11] Chen JZ. Inhibition of immune responses by dasatinib may account for its different effects on neuroblastoma between in vitro and in vivo. Int J Cancer 2010;127:1249–1250. [12] Schade AE, Schieven GL, Townsend R, et al. Dasatinib, a smallmolecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood 2008;111:1366–1377. [13] Hayashi Y, Nakamae H, Katayama T, et al. Different immunoprofiles in patients with chronic myeloid leukemia treated with imatinib, nilotinib or dasatinib. Leuk Lymphoma 2012;53:1084–1089. [14] Futosi K, Nemeth T, Pick R, et al. Dasatinib inhibits proinflammatory functions of mature human neutrophils. Blood 2012;119:4981–4991. [15] Jasielec JK , Larson RA . Dasatinib-related pulmonary toxicity mimicking an atypical infection. J Clin Oncol 2014 Jun 23. [Epub ahead of print]
ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
Dasatinib-induced immunosuppression and recurrent respiratory tract infections Faruk Obut, Nicole Randall, Jo-Anne H. Young, Peter Valent & Celalettin Ustun To cite this article: Faruk Obut, Nicole Randall, Jo-Anne H. Young, Peter Valent & Celalettin Ustun (2015) Dasatinib-induced immunosuppression and recurrent respiratory tract infections, Leukemia & Lymphoma, 56:8, 2484-2485, DOI: 10.3109/10428194.2014.994179 To link to this article: http://dx.doi.org/10.3109/10428194.2014.994179
View supplementary material
Accepted author version posted online: 11 Dec 2014. Published online: 21 Jan 2015. Submit your article to this journal
Article views: 110
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ilal20 Download by: [Central Michigan University]
Date: 05 November 2015, At: 22:25
Leukemia & Lymphoma, August 2015; 56(8): 2484–2485 © 2015 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.994179
SHORT COMMUNICATION
Dasatinib-induced immunosuppression and recurrent respiratory tract infections Faruk Obut1, Nicole Randall1, Jo-Anne H. Young2, Peter Valent3 & Celalettin Ustun1 1Division of Hematology-Oncology and Transplantation and 2Division of Infectious Disease, Department of Medicine,
Downloaded by [Central Michigan University] at 22:25 05 November 2015
University of Minnesota, Minneapolis, MN, USA and 3Division of Hematology and Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
We read the study by Alsobhi et al. with great interest [1], and agree that tyrosine kinase inhibitors (TKIs) have revolutionized therapy for patients with chronic myelogenous leukemia (CML) in the chronic phase (CP) [2]. As the authors reported, neutropenia is the most common side effect of TKI therapy [3]. In a larger study comparing dasatinib (n ⫽ 259 patients) with imatinib (n ⫽ 259), infections occurred in 10.5% of patients with CP-CML receiving dasatinib, in part due to neutropenia (24%), and 2% of these patients died of infections [3]. The case we discuss here underscores a lesser-known side effect of TKIs: suppression of the immune system. A 55-year-old male (healthy other than Alzheimer disease) was diagnosed with Philadelphia chromosome positive CP-CML in July 2010. Imatinib was started (400 mg/day), but replaced by dasatinib (100 mg/day) after 22 months. In July 2012 and April 2013, BCR/ABL1 transcripts became undetectable in the peripheral blood and bone marrow, respectively. However, the patient developed a productive cough and dyspnea while taking dasatinib in February 2013. A chest computed tomography (CT) scan showed patchy areas of airspace in the lung bases, likely due to infection. These episodes were treated empirically as acute bronchitis or atypical pneumonia. Despite antibiotic therapy, respiratory symptoms recurred on a monthly basis, and the patient was admitted to hospital in July 2013 with fever, hypoxia and neutrophilia (absolute neutrophil count of 12 ⫻ 108/L) while receiving cefuroxime. Chest CT showed consolidation in the left lung and pleural effusion. Thoracentesis revealed a high white blood cell count (3696 ⫻ 109/L) composed mainly of lymphocytes (82%) in the pleural effusion, as seen with dasatinib-induced pleural effusions [4]. An echocardiogram revealed a normal left ventricular ejection fraction. Cytomegalovirus in blood and common respiratory viruses in a nasal swab were undetectable by polymerase chain reaction (PCR). The patient was treated with a 14-day course of intravenous (IV) piperacillin–tazobactam, levofloxacin and
vancomycin for health-care associated pneumonia, but the treatment course was complicated by acute kidney injury (creatinine increased to 5 mg/dL). Renal failure was considered to be due to acute tubular necrosis from prolonged dehydration; however, interstitial nephritis from vancomycin and dasatinib could not be excluded. Serum immunoglobulin G (IgG), IgA and IgM levels were all decreased: 312 mg/ dL (normal, 695–1620 mg/dL), 67 mg/dL (normal, 70–380 mg/dL) and 26 mg/dL (normal, 60–265 mg/dL), respectively. Serum protein electrophoresis (SPEP) showed hypogammaglobulinemia (gamma fraction was 0.3 g/dL, normal, 0.7–1.6 g/dL). Absolute CD3⫹, CD4 ⫹ and CD8 ⫹ T-cell counts in blood were 0.39 ⫻ 109/L, 0.29 ⫻ 109/L and 0.1 ⫻ 109/L, respectively. Intravenous immunoglobulin (IVIG) replacement therapy was not tolerated by the patient because of an allergic reaction. Dasatinib was replaced with omacetaxine at maintenance dosing (1.25 mg/m2 twice a day subcutaneously). Although omacetaxine use was complicated by severe pancytopenia and cytogenetic relapse, Ig levels (IgG 913 mg/dL, IgA 137 mg/dL and IgM 89 mg/dL), gamma fraction in SPEP (0.9 g/dL) and kidney function all returned to normal levels within 2 months. When cytogenetic relapse was detected in November 2013, omacetaxine was replaced with bosutinib (500 mg/day). The patient again achieved a complete cytogenetic and molecular response. Since discontinuation of dasatinib (for a year), IgG levels have been normal, and the patient has had no further respiratory infections; however, absolute T-cell counts have remained similarly low. Opportunistic infections are uncommon without neutropenia in patients with CP-CML, although they have been reported [5]. The effects of TKIs on the immune system have been evaluated. In patients with CML, IgA and IgG levels were decreased with imatinib, IgM levels were decreased with dasatinib (from 0.86 g/L to 0.39 g/L in 12 months) and no significant changes in immunoglobulin levels were observed with nilotinib as compared to healthy volunteers
Correspondence: Celalettin Ustun, MD, Associate Professor of Medicine, 14-142 PWB, 516 Delaware Street SE, Minneapolis, MN 55455, USA. Tel: (612)6240123. Fax: (612)625-6919. E-mail: [email protected] Received 9 September 2014; revised 19 November 2014; accepted 22 November 2014
2484
Downloaded by [Central Michigan University] at 22:25 05 November 2015
Dasatinib-induced immunosuppression and recurrent respiratory tract infections 2485 and pre-treatment levels [6]. Another study showed decreased numbers of B cells but normal serum immunoglobulin levels with dasatinib [5]. Dasatinib-treated patients had significantly lower median B-cell proportions in peripheral blood and bone marrow when compared to imatinib-treated patients or healthy controls [7]. As compared to healthy volunteers, patients with CML had an impaired response to pneumococcal vaccination owing to lower levels of blood IgM memory B cells and impaired B cell signaling after treatment with TKIs [8]. With respect to the cellular immune system, dasatinib inhibited T cell activation, proliferation, cytokine production and degranulation in a dose-dependent manner in vitro [9,10]. These effects of dasatinib were more prominent in CD4 ⫹ cells than in CD8 ⫹ cells and more prominent in naive T cells than in memory T cell subsets [9]. However, in vivo, absolute lymphocyte counts, CD8 ⫹ cells and γδ T cell counts in peripheral blood increased significantly during dasatinib therapy in patients with CML [7]. It has been shown that dasatinib inhibits TCR signaling through Srcfamily kinase LCK, which is important for the suppression of T-cell function [10–12]. Dasatinib also affects the innate immune system. The proportions and absolute counts of natural killer (NK) cells (in peripheral blood) [7] and monocytes (in peripheral blood and bone marrow) were increased in patients on dasatinib therapy when compared to healthy controls or imatinib-treated patients [7]. NK cell activity was increased with dasatinib therapy in patients with CML [13]. In vitro, dasatinib induced transient suppression of IgE-dependent activation of blood basophils [5]. TKIs affect different parts of the immune system; however, these effects vary significantly between in vivo and in vitro conditions and commonly used TKIs. In our patient, both humoral and cellular immune systems (in particular CD8 ⫹ cells) were suppressed during dasatinib therapy, although relevant values at the time of diagnosis were unknown. Switching dasatinib to a non-TKI drug and then to bosutinib (another Src family kinase inhibitor) was associated with improvement in the humoral immune system and no recurrence of respiratory infections. It can be speculated that this might be a result of bosutinib, in contrast to dasatinib, which does not inhibit neutrophil Bruton’s tyrosine kinase (Btk) family members important to neutrophil activation [14]. Because no microorganism was identified in the patient, one can argue that the patient in fact had experienced dasatinib-induced pulmonary toxicity mimicking lung infection, as reported in another patient [15]. On the other hand, prior antibiotic use most likely caused the false-negative cultures in our patient, who had clinical signs of pneumonia (fevers, neutrophilia and consolidation in the lung). In conclusion, it is not recommended (i.e. not costeffective) to check humoral or cellular immunity in all
patients with CP-CML in routine clinical practice, but it might be warranted in those with recurrent infections without neutropenia (because it may have an impact on supportive therapy, IVIG replacement, etc.). It is also important to remember that these patients’ response to vaccination may be suboptimal, and that dasatinib-induced lung toxicity can mimic infections.
Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Alsobhi E, Abrar MB, Abdelaal M, et al. Response to imatinib therapy in adult patients with chronic myeloid leukemia in Saudi population: a single-center study. Leuk Lymphoma 2014 Aug 4. [Epub ahead of print] [2] Bhamidipati PK, Jabbour E. Frontline therapy. Chronic myeloid leukemia: from daily management to complicated issues. New York: Nova Group; 2014. pp 107–128. [3] Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012;120:2454–2465. [4] Quintas-Cardama A , Kantarjian H, O’Brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol 2007;25:3908–3914. [5] Sillaber C, Herrmann H, Bennett K, et al. Immunosuppression and atypical infections in CML patients treated with dasatinib at 140 mg daily. Eur J Clin Invest 2009;39:1098–1109. [6] Koskela H, Stromberg A , Richter J, et al. Tyrosine kinase inhibitor therapy induced changes in humoral immunity in patients with chronic myeloid leukemia. Blood 2011;118:740–740. [7] Rohon P, Porkka K, Mustjoki S. Immunoprofiling of patients with chronic myeloid leukemia at diagnosis and during tyrosine kinase inhibitor therapy. Eur J Haematol 2010;85:387–398. [8] de Lavallade H, Khoder A , Hart M, et al. Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling. Blood 2013;122:227–238. [9] Weichsel R, Dix C, Wooldridge L, et al. Profound inhibition of antigen-specific T-cell effector functions by dasatinib. Clin Cancer Res 2008;14:2484–2491. [10] Blake S, Hughes TP, Mayrhofer G, et al. The Src/ABL kinase inhibitor dasatinib (BMS-354825) inhibits function of normal human T-lymphocytes in vitro. Clin Immunol 2008;127:330–339. [11] Chen JZ. Inhibition of immune responses by dasatinib may account for its different effects on neuroblastoma between in vitro and in vivo. Int J Cancer 2010;127:1249–1250. [12] Schade AE, Schieven GL, Townsend R, et al. Dasatinib, a smallmolecule protein tyrosine kinase inhibitor, inhibits T-cell activation and proliferation. Blood 2008;111:1366–1377. [13] Hayashi Y, Nakamae H, Katayama T, et al. Different immunoprofiles in patients with chronic myeloid leukemia treated with imatinib, nilotinib or dasatinib. Leuk Lymphoma 2012;53:1084–1089. [14] Futosi K, Nemeth T, Pick R, et al. Dasatinib inhibits proinflammatory functions of mature human neutrophils. Blood 2012;119:4981–4991. [15] Jasielec JK , Larson RA . Dasatinib-related pulmonary toxicity mimicking an atypical infection. J Clin Oncol 2014 Jun 23. [Epub ahead of print]
