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Imatinib mesylate- and dasatinib-induced eosinophilia in a patient with chronic myelocytic leukemia
Ann Allergy Asthma Immunol xxx (2017) 1e2
Contents lists available at ScienceDirect
Letter
Imatinib mesylate- and dasatinib-induced eosinophilia in a patient with chronic myelocytic leukemia We present a case of a woman being treated for chronic myelocytic leukemia (CML) who developed eosinophilia without systemic involvement from imatinib mesylate (imatinib) confirmed by rechallenge with imatinib followed by eosinophilia recrudescence from dasatinib. Medications are a frequent cause of eosinophilia, especially in areas with a low prevalence of parasitic infections. Drug-induced eosinophilia can be asymptomatic or can lead to organ-specific complications.1 In the absence of other systemic involvement, this generally constitutes a benign drug effect caused by innumerable classes of medications. The cause might be a direct physiologic effect of certain cytokine therapies (interleukin [IL]-2 or granulocyteemacrophage colony-stimulating factor) or secondary clonal expansion of IL5eproducing T cells; however, mechanisms underlying most instances of drug-induced eosinophilia have not been determined.2 Eosinophilia without systemic involvement has not been reported from imatinib or dasatinib (OVID and PubMed search from 2000 through the first quarter of 2017). Imatinib is actively used as a therapy of choice for the management of hypereosinophilic syndrome with PDGFRA or PDGFRB rearrangement as an eosinophil-lowering agent and dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1-PDGFRa.3,4 A 65-year-old woman presented to the allergy-immunology clinic in 2015 complaining of 3 months of severe pruritus without corresponding skin lesions. Her medical history was notable for chronic idiopathic urticaria with dermatographism 3 years previously. Her examination findings were within normal limits except for urticaria at skin examination and areas of normal skin associated with the complaint of pruritus. Laboratory tests to screen for underlying illness were significant for thrombocytosis (602 K/mL) and basophilia (0.6 K/mL), with no eosinophilia (0.1 K/mL) and mildly increased alanine aminotransferase (53 U/L) and alkaline phosphatase (108 U/L). She was treated with 5 mg/d of levocetirizine plus 180 mg of fexofenadine twice daily with a prednisone taper starting at 30 mg/ d for 1 week and then 30 mg on alternate days. At her 2-week follow up appointment, she noted a “90%” improvement in the level of itching (“itching spells”) and fewer urticarial lesions. Hematology-oncology service was consulted because of persistent thrombocytosis and basophilia. CML was diagnosed based on fluorescence in situ hybridization and bone marrow biopsy examination, with conventional cytogenetics confirming the presence of the Philadelphia chromosome (46,XX, t[9; 22] [q34; q11.2]). After discussing first-line options, treatment was initiated with 400 mg/ d of imatinib with close clinical and laboratory monitoring. Her
Disclosures: Authors have nothing to disclose.
early clinical course was complicated by nausea, anorexia, and dizziness not necessitating discontinuation of imatinib. After 3 months of imatinib therapy, routine laboratory monitoring showed an increasing total eosinophil count over 4 weeks (maximum 1.9 K/mL). Laboratory test results to evaluate for other causes of eosinophilia included increased total serum immunoglobulin E (464 IU/mL), normal comprehensive chemistry panel, negative strongyloides immunoglobulin G antibody, normal tryptase (<1 ng/mL), and negative CKIT/KIT 816V mutational analysis. There was no evidence of T-cell clonality based on flow cytometric immunophenotyping. Thrombocytosis and basophilia had resolved after 3 weeks of imatinib therapy. Further, she met criteria for an early molecular response, with a BCR-ABL1 less than 10% on the international scale (BCR-ABL/ABL 0.158%), suggesting a favorable response to imatinib therapy. Imatinib was held, which was associated with a decrease in absolute eosinophil count (1.2 K/mL). Although other tyrosine kinase inhibitors (TKIs) are available, each carries a unique adverse event profile, and it was decided that imatinib therapy should resume. Again, a robust eosinophilia ensued (2.0 K/mL). Imatinib was discontinued and substituted with 100 mg/d of dasatinib. Nine days later, the patient complained of generalized itching, skin rash, and facial burning with redness. Examination showed skin excoriations on the arms, chest, and back, without rash or urticaria. Laboratory testing was significant for eosinophilia (0.9 K/mL). Concern arose over possible recrudescence of imatinib-induced eosinophilia, cross-reactivity (cross-intolerance) between imatinib and dasatinib, and CML treatment limited to nilotinib. Recrudescence of imatinib-induced eosinophilia was the impression of choice, which was treated with a slow prednisone taper with resolution of eosinophilia and continuation of dasatinib. However, 9 days after prednisone was discontinued, eosinophilia recurred at 1.4 K/mL associated with skin pruritus. The possibility arose that eosinophilia could complicate any TKI available to her and a joint decision between the allergy-immunology and hematology-oncology services was to treat the eosinophilia with 10 mg/d of prednisone and possibly a subsequent lower dose. The clinical course was control of eosinophilia and pruritus (aided by phototherapy), with her CML in molecular remission (at 16 months, BCR-ABL1 was not detected by polymerase chain reaction). Fluctuating transaminitis predating her CML was under evaluation by hepatology and anxiety with depression was controlled with 30 mg/d of paroxetine. Dyspnea, attributed to a dasatinib-induced pleural effusion (pleuracentesis: noninfectious, noneosinophilic, 94% lymphocytes) and ground-glass opacities on computerized tomography of her chest, occurred while on 100 mg/d of dasatinib. Dyspnea and computerized tomographic findings resolved after initially decreasing the dose of dasatinib to 80 mg/d and then holding dasatinib for 8 weeks and resuming at 20 mg/d.
http://dx.doi.org/10.1016/j.anai.2017.04.022 1081-1206/Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
2
Letter / Ann Allergy Asthma Immunol xxx (2017) 1e2
suggesting diverse mechanisms of action of these drugs, beyond solely directed at cellular antitumor targets.6,7 Such cross-intolerance was observed in this case after changing therapy from imatinib to an alternative TKI, dasatinib, retriggering eosinophilia without systemic involvement. However, this observed TKI cross-intolerance was successfully treated with lowdose prednisone, allowing continuation of dasatinib with no recurrence of the patient’s CML.
Figure 1. Patient’s absolute eosinophil count during imatinib and dasatinib therapy.
Medications and eosinophilia time course are illustrated in Figure 1. To our knowledge, this is the first report of imatinib- and dasatinib-induced eosinophilia without systemic involvement confirmed by rechallenge with imatinib, followed by eosinophilia recrudescence from dasatinib, and absence of laboratory markers of clonal eosinophilia or recurrence of the patient’s CML. A TKI class affect is suspected, with each drug likely inducing clonal T-cell subsets producing IL-5. In this case, IL-5 was not measured and there was no evidence of T-cell clonality based on flow cytometric immunophenotyping. Dasatinib has been associated with emergence of lymphocytosis with a natural killer or cytotoxic clonal T-cell phenotype; patients with this expansion can have a favorable response to therapy, despite the development of autoimmune complications, including fever, colitis, and pleural effusion.5 Previous reports of adverse cutaneous reactions without eosinophilia have been published, further supporting a cross-intolerance to imatinib, dasatinib, and nilotinib therapy,
Kris McGrath, MD* Brady Stein, MD, MHSy Lindsey Kalhagen, PA-Cy Lauren Leighton, PA-C* *Divisions of Allergy and Immunology and Hematology/Oncology Department of Medicine Northwestern University Chicago, Illinois [email protected]
References [1] Casey C, Ogbogu PU. Evaluation and differential diagnosis of persistent marked eosinophilia. Immunol Allergy Clin North Am. 2015;35:387e402. [2] Kuruvilla M, Khan DA. Eosinophilic drug allergy. Clin Rev Allergy Immunol. 2016; 50:228e239. [3] Roufosse F. Management of hypereosinophilic syndromes. Immunol Allergy Clin North Am. 2015;35:561e575. [4] Baumgartner C, Gleixner KV, Peter B, et al. Dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1PDGFRa. Exp Hematol. 2008;36:1244e1253. [5] Valent JN, Shiffer CA. Prevalence of large granular lymphocytosis in patients with chronic myelogenous leukemia (CML) treated with dasatinib. Leuk Res. 2011;35:e1ee3. [6] Novitizky-Basso I, Craddock C. Cross-Intolerance to imatinib, dasatinib, nilotinib therapy in a patient with chronic myeloid leukemia. Eur J Hematol. 2011;86: 548e549. [7] Amitay-Laish I, Stemmer SM, Lacouture ME. Adverse cutaneous reactions secondary to tyrosine kinase inhibitors including imatinib mesylate, nilotinib, and dasatinib. Dermatol Ther. 2011;24:386e395.
Contents lists available at ScienceDirect
Letter
Imatinib mesylate- and dasatinib-induced eosinophilia in a patient with chronic myelocytic leukemia We present a case of a woman being treated for chronic myelocytic leukemia (CML) who developed eosinophilia without systemic involvement from imatinib mesylate (imatinib) confirmed by rechallenge with imatinib followed by eosinophilia recrudescence from dasatinib. Medications are a frequent cause of eosinophilia, especially in areas with a low prevalence of parasitic infections. Drug-induced eosinophilia can be asymptomatic or can lead to organ-specific complications.1 In the absence of other systemic involvement, this generally constitutes a benign drug effect caused by innumerable classes of medications. The cause might be a direct physiologic effect of certain cytokine therapies (interleukin [IL]-2 or granulocyteemacrophage colony-stimulating factor) or secondary clonal expansion of IL5eproducing T cells; however, mechanisms underlying most instances of drug-induced eosinophilia have not been determined.2 Eosinophilia without systemic involvement has not been reported from imatinib or dasatinib (OVID and PubMed search from 2000 through the first quarter of 2017). Imatinib is actively used as a therapy of choice for the management of hypereosinophilic syndrome with PDGFRA or PDGFRB rearrangement as an eosinophil-lowering agent and dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1-PDGFRa.3,4 A 65-year-old woman presented to the allergy-immunology clinic in 2015 complaining of 3 months of severe pruritus without corresponding skin lesions. Her medical history was notable for chronic idiopathic urticaria with dermatographism 3 years previously. Her examination findings were within normal limits except for urticaria at skin examination and areas of normal skin associated with the complaint of pruritus. Laboratory tests to screen for underlying illness were significant for thrombocytosis (602 K/mL) and basophilia (0.6 K/mL), with no eosinophilia (0.1 K/mL) and mildly increased alanine aminotransferase (53 U/L) and alkaline phosphatase (108 U/L). She was treated with 5 mg/d of levocetirizine plus 180 mg of fexofenadine twice daily with a prednisone taper starting at 30 mg/ d for 1 week and then 30 mg on alternate days. At her 2-week follow up appointment, she noted a “90%” improvement in the level of itching (“itching spells”) and fewer urticarial lesions. Hematology-oncology service was consulted because of persistent thrombocytosis and basophilia. CML was diagnosed based on fluorescence in situ hybridization and bone marrow biopsy examination, with conventional cytogenetics confirming the presence of the Philadelphia chromosome (46,XX, t[9; 22] [q34; q11.2]). After discussing first-line options, treatment was initiated with 400 mg/ d of imatinib with close clinical and laboratory monitoring. Her
Disclosures: Authors have nothing to disclose.
early clinical course was complicated by nausea, anorexia, and dizziness not necessitating discontinuation of imatinib. After 3 months of imatinib therapy, routine laboratory monitoring showed an increasing total eosinophil count over 4 weeks (maximum 1.9 K/mL). Laboratory test results to evaluate for other causes of eosinophilia included increased total serum immunoglobulin E (464 IU/mL), normal comprehensive chemistry panel, negative strongyloides immunoglobulin G antibody, normal tryptase (<1 ng/mL), and negative CKIT/KIT 816V mutational analysis. There was no evidence of T-cell clonality based on flow cytometric immunophenotyping. Thrombocytosis and basophilia had resolved after 3 weeks of imatinib therapy. Further, she met criteria for an early molecular response, with a BCR-ABL1 less than 10% on the international scale (BCR-ABL/ABL 0.158%), suggesting a favorable response to imatinib therapy. Imatinib was held, which was associated with a decrease in absolute eosinophil count (1.2 K/mL). Although other tyrosine kinase inhibitors (TKIs) are available, each carries a unique adverse event profile, and it was decided that imatinib therapy should resume. Again, a robust eosinophilia ensued (2.0 K/mL). Imatinib was discontinued and substituted with 100 mg/d of dasatinib. Nine days later, the patient complained of generalized itching, skin rash, and facial burning with redness. Examination showed skin excoriations on the arms, chest, and back, without rash or urticaria. Laboratory testing was significant for eosinophilia (0.9 K/mL). Concern arose over possible recrudescence of imatinib-induced eosinophilia, cross-reactivity (cross-intolerance) between imatinib and dasatinib, and CML treatment limited to nilotinib. Recrudescence of imatinib-induced eosinophilia was the impression of choice, which was treated with a slow prednisone taper with resolution of eosinophilia and continuation of dasatinib. However, 9 days after prednisone was discontinued, eosinophilia recurred at 1.4 K/mL associated with skin pruritus. The possibility arose that eosinophilia could complicate any TKI available to her and a joint decision between the allergy-immunology and hematology-oncology services was to treat the eosinophilia with 10 mg/d of prednisone and possibly a subsequent lower dose. The clinical course was control of eosinophilia and pruritus (aided by phototherapy), with her CML in molecular remission (at 16 months, BCR-ABL1 was not detected by polymerase chain reaction). Fluctuating transaminitis predating her CML was under evaluation by hepatology and anxiety with depression was controlled with 30 mg/d of paroxetine. Dyspnea, attributed to a dasatinib-induced pleural effusion (pleuracentesis: noninfectious, noneosinophilic, 94% lymphocytes) and ground-glass opacities on computerized tomography of her chest, occurred while on 100 mg/d of dasatinib. Dyspnea and computerized tomographic findings resolved after initially decreasing the dose of dasatinib to 80 mg/d and then holding dasatinib for 8 weeks and resuming at 20 mg/d.
http://dx.doi.org/10.1016/j.anai.2017.04.022 1081-1206/Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
2
Letter / Ann Allergy Asthma Immunol xxx (2017) 1e2
suggesting diverse mechanisms of action of these drugs, beyond solely directed at cellular antitumor targets.6,7 Such cross-intolerance was observed in this case after changing therapy from imatinib to an alternative TKI, dasatinib, retriggering eosinophilia without systemic involvement. However, this observed TKI cross-intolerance was successfully treated with lowdose prednisone, allowing continuation of dasatinib with no recurrence of the patient’s CML.
Figure 1. Patient’s absolute eosinophil count during imatinib and dasatinib therapy.
Medications and eosinophilia time course are illustrated in Figure 1. To our knowledge, this is the first report of imatinib- and dasatinib-induced eosinophilia without systemic involvement confirmed by rechallenge with imatinib, followed by eosinophilia recrudescence from dasatinib, and absence of laboratory markers of clonal eosinophilia or recurrence of the patient’s CML. A TKI class affect is suspected, with each drug likely inducing clonal T-cell subsets producing IL-5. In this case, IL-5 was not measured and there was no evidence of T-cell clonality based on flow cytometric immunophenotyping. Dasatinib has been associated with emergence of lymphocytosis with a natural killer or cytotoxic clonal T-cell phenotype; patients with this expansion can have a favorable response to therapy, despite the development of autoimmune complications, including fever, colitis, and pleural effusion.5 Previous reports of adverse cutaneous reactions without eosinophilia have been published, further supporting a cross-intolerance to imatinib, dasatinib, and nilotinib therapy,
Kris McGrath, MD* Brady Stein, MD, MHSy Lindsey Kalhagen, PA-Cy Lauren Leighton, PA-C* *Divisions of Allergy and Immunology and Hematology/Oncology Department of Medicine Northwestern University Chicago, Illinois [email protected]
References [1] Casey C, Ogbogu PU. Evaluation and differential diagnosis of persistent marked eosinophilia. Immunol Allergy Clin North Am. 2015;35:387e402. [2] Kuruvilla M, Khan DA. Eosinophilic drug allergy. Clin Rev Allergy Immunol. 2016; 50:228e239. [3] Roufosse F. Management of hypereosinophilic syndromes. Immunol Allergy Clin North Am. 2015;35:561e575. [4] Baumgartner C, Gleixner KV, Peter B, et al. Dasatinib inhibits the growth and survival of neoplastic human eosinophils (EOL-1) through targeting of FIP1L1PDGFRa. Exp Hematol. 2008;36:1244e1253. [5] Valent JN, Shiffer CA. Prevalence of large granular lymphocytosis in patients with chronic myelogenous leukemia (CML) treated with dasatinib. Leuk Res. 2011;35:e1ee3. [6] Novitizky-Basso I, Craddock C. Cross-Intolerance to imatinib, dasatinib, nilotinib therapy in a patient with chronic myeloid leukemia. Eur J Hematol. 2011;86: 548e549. [7] Amitay-Laish I, Stemmer SM, Lacouture ME. Adverse cutaneous reactions secondary to tyrosine kinase inhibitors including imatinib mesylate, nilotinib, and dasatinib. Dermatol Ther. 2011;24:386e395.