http://informahealthcare.com/plt ISSN: 0953-7104 (print), 1369-1635 (electronic) Platelets, Early Online: 1–3 ! 2015 Informa UK Ltd. DOI: 10.3109/09537104.2015.1049138
CASE REPORT
Gastrointestinal bleeding in a chronic myeloid leukaemia patient precipitated by dasatinib-induced platelet dysfunction: Case report Louise Kostos, Kate Burbury, Gaurav Srivastava, & H. Miles Prince
Platelets Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
Division of Cancer, Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
Abstract
Keywords
Bleeding in patients with chronic myeloid leukaemia (CML) receiving the second-line tyrosine kinase inhibitor (TKI) dasatinib is a well-documented side effect, occurring in up to 24% of patients. In most cases, it is attributed directly to a secondary grade 3 or 4 thrombocytopaenia. Platelet dysfunction precipitated by dasatinib has been demonstrated in multiple in vitro and in vivo studies; however, there is currently no correlative data that definitively associates this with clinically significant bleeding. In this case, we report a patient with chronic-phase CML receiving dasatinib who developed significant gastrointestinal bleeding secondary to angiodysplasia in the absence of a severe thrombocytopaenia or coagulopathy. Platelet function testing on the PFA-100 assay and formal platelet aggregometry demonstrated impaired platelet aggregation, however, upon cessation of dasatinib, platelet function normalised and the bleeding resolved without further intervention. This case demonstrates that dasatinib-induced platelet dysfunction can cause clinically significant bleeding and highlights the need for physicians to be aware of this adverse effect.
Bleeding, chronic myeloid leukaemia, dasatinib, platelet-dysfunction History Received 3 March 2015 Revised 24 April 2015 Accepted 4 May 2015 Published online 1 June 2015
Introduction
Case report
Chronic myeloid leukaemia (CML) accounts for 15–20% of adult leukaemia [1]. The majority (85%) present in chronic phase (CPCML); however, prior to the tyrosine kinase inhibitor (TKI) era, disease progression to blast crisis was a common and often fatal occurrence. Since the introduction of highly effective TKI therapy, the 10-year overall survival now exceeds 90% and the prevalence of patients receiving long-term TKI therapy has substantially increased. As such, the focus has now shifted to the awareness and management of the off-target effects of these drugs and the tolerability of long-term therapy [2]. The introduction of TKIs in 2001, initially imatinib, has revolutionised the management of this disease [3, 4]. Imatinib resistance and/or intolerance, however, led to the development and approval of more potent second generation TKIs, dasatinib and nilotinib, which induce faster and deeper molecular response rates and are now in widespread use in CML front-line therapy [5–7]. Longer-term follow-up of these agents demonstrate the emergence of adverse events, some of which are not observed with over 10 years of experience with imatinib. Of particular relevance for dasatinib is the potential for bleeding complications [8]. Here, we report the case of an adult patient with CP-CML receiving dasatinib who developed gastrointestinal bleeding secondary to angiodysplasia. This was in the presence of impaired platelet function, which resolved, along with the bleeding, after cessation of dasatinib.
An 84-year-old female with CP-CML, first diagnosed in 2001 with good prognostic features (Sokal score 0.82, Hasford score 667), was initially treated with imatinib (300–400 mg daily). She continued on this for 11 years, achieving complete cytogenetic remission and a major molecular response (BCR-ABL 50.006%), but was ceased in April 2012 due to intolerable nausea. While off TKI therapy, BCR-ABL transcripts escalated to 0.150% on repeat testing, without a detectable mutation. Due to the prior intolerance of imatinib, dasatinib (100 mg daily) was commenced (September 2012), and a major molecular response (BCR-ABL 0.010%) was achieved by three months. Six months later the patient developed a clinically significant pleural effusion, a welldocumented side-effect of dasatinib. A transthoracic echocardiogram was performed at this time which demonstrated preserved systolic function (left ventricular ejection fraction 68%), normal pulmonary artery pressure (RVSP 29 mmHg) and impaired left ventricular relaxation (E/E’ ratio 24, DT 343 ms). The pleural effusion was refractory to medical management and thus dasatinib was ceased and the patient commenced nilotinib (300 mg BD). Unfortunately this was also poorly tolerated due to severe, clinically morbid scalp dermatitis and was discontinued. Due to rising BCR-ABL transcripts (0.100% August 2013) re-commencement of TKI therapy was indicated. The patient was reluctant to re-trial imatinib due to her previous struggle with nausea and thus in October 2013 the patient re-commenced dasatinib (100 mg daily), without re-emergence of the prior pulmonary toxicity. In February 2014, the patient presented with severe enterococcal sepsis, with streptococcal faecalis identified in a stool specimen. As such, the patient underwent a gastroscopy and colonoscopy which demonstrated normal macroscopic and
Correspondence: Dr. Kate Burbury, MBBS (Hons) FRACP FRCPA DPhil, Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia. Tel: +61 3 96561700 – page 7398. Fax: +61 3 96561408. E-mail: [email protected]
Platelets Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
2
L. Kostos et al.
histological appearance of the gastric and colonic mucosa, apart from two colonic polyps, which were resected and confirmed as benign tubular adenomas. Following the procedure, the patient developed melaena, associated with a significant drop in haemoglobin (105–88 g/L). Platelet count was 80 109/L on admission and remained stable throughout the inpatient stay. Coagulation profile was within normal limits (INR 1.1, APTT 26 s). The patient was not on any active antithrombotic or antiplatelet therapy, nor was she taking any medications that inhibit activity of CYP3A4 (a major enzyme responsible for the metabolism of dasatinib). Melaena was ongoing over the next fortnight with the patient requiring transfusion of five units of packed red cells and four units of platelets. CT angiogram did not demonstrate a definitive source of bleeding. Endoscopic examination of her colon reported a superficial ulcerated area with associated erythema at the junction of the caecum and the ascending colon, concordant with the polypectomy sites. Given the large volume of bleeding, these superficial erosions were not thought to be the source, and hence the patient proceeded to have a capsule endoscopy which identified an active bleeding site associated with angioectactic lesions in the proximal jejunem. The dasatinib had been continued throughout the admission and subsequent platelet function testing with the PFA-100 assay (Siemens, Malvern, Australia) demonstrated impaired platelet aggregation with a collagen/epinephrine closure time of 4300 s (normal range 82–150 s) and a collagen/ADP closure time of 155 s (normal range 62–110 s). Formal platelet aggregometry demonstrated a normal response with ristocetin, weak responses with ADP and arachidonic acid but no platelet aggregation to stimulation with collagen or epinephrine. Dasatinib was subsequently ceased and the melaena resolved without further surgical or medical intervention. One week later, the PFA-100 assay was repeated with near restoration of closure times: collagen/epinephrine 176 s and collagen/ADP 131 s. The patient had no further gastrointestinal bleeding and was discharged from hospital two days later. The patient recommenced low-dose imatinib (200 mg daily). Six weeks post-cessation of the dasatinib, mild thrombocytopenia persisted but remained stable (platelet count 90 109/L) and the patient suffered no further gastrointestinal bleeding.
Discussion Dasatinib is a potent second-generation TKI, along with bosutinib and nilotinib, used to treat patients with CML. These ATPcompetitive inhibitors share potent inhibition of BCR-ABL, which is responsible for malignant transformation in CML – with dasatinib being 325 times more potent than imatinib. Dasatinib also causes inhibition of other kinases including c-Kit, platelet-derived growth factor receptor (PDGF-R), and SRC family kinases (SFK). This is in contrast to imatinib and nilotinib which also target c-Kit and PDGF-R but not SFKs, and bosutinib which is a dual inhibitor of BCR-ABL and SFKs [2, 3, 9]. Although generally well tolerated, dasatinib therapy is not completely devoid of side effects, which are largely attributed to its broad spectrum of kinase inhibition. The most common toxicities include cytopenias, gastrointestinal symptoms, and fluid retention [10]. The incidence of bleeding complications in dasatinib studies range from 8% to 24% [8] and is well documented in multiple case reports, with gastrointestinal and central nervous system (CNS) bleeding being the most common sites. However, many of these reports cite grade 3 or 4 thrombocytopenia as the cause of the bleeding, which was not present in the case outlined in this report [11–14]. Two reports postulate that spontaneous bleeding in CML patients receiving
Platelets, Early Online: 1–3
dasatinib is secondary to platelet dysfunction [15, 16]; however, there is no available data on platelet function of these patients. Proteins targeted by TKIs, particularly dasatinib, are common to many cell types and are implicated in the highly dynamic processes of platelet activation, likely contributing to the bleeding diathesis seen with dasatinib use. The principle function of platelets is to form haemostatic thrombi at sites of vascular injury to maintain vascular integrity; processes which involve platelet signal transduction [17, 18]. Upon vascular injury, the interaction of platelets and its receptors (GPVI and integrin a2b1) with exposed extracellular matrix components including von Willebrand factor (vWF) and type I collagen initiate the platelet adhesion process. Platelet adhesion activates signalling pathways mediated by protein tyrosine kinase (PTK) receptors and G-protein-coupled receptors (GPCRs) that lead to secretion of a-granules and dense granules [3]. PTK phosphorylation (PTP) is an essential signalling pathway and is mediated by PTK which catalyses the transfer of the terminal phosphate of ATP to tyrosine residues on protein substrates [19, 20]. PTKs include receptor-TK, such as PDGF-R, vascular endothelial growth factor receptor (VEGFR) and c-Kit, and non-receptor-TK, such as SFK, Abl, and spleen tyrosine kinase (Syk). PTKs generate platelet signal transduction through many distinct signalling pathways, including immunoreceptor tyrosine-based activatory motif (ITAM) or growth factor receptor. Most of the key pathways recruit and activate SFK and as such are all potential targets of TKIs. Dasatinib is an effective reversible inhibitor of ITAM-mediated signalling pathways in platelets, particularly FcgRIIa and collagen GPVI/FcR which involves tyrosine phosphorylation, PI3-kinase activation and PLC/DAG kinase activation [21]. In addition, dasatinib targets SFKs, which are functionally involved in initiating platelet activation and aggregation in ITAM-mediated signalling pathways. In a 2009 study by Quinta´s-Cardama et al. [22], 91 patients with CP-CML either off therapy or receiving various first- and second-generation TKIs were evaluated with platelet aggregometry testing. Impaired platelet aggregation on stimulation of arachidonic acid, epinephrine, or both was observed in 70%, 85%, and 59% of patients on dasatinib, respectively. Dasatinib use also resulted in marked prolongation of closure time to collagen/ epinephrine on the PFA-100 system. Of note, imatinib use resulted in decreased aggregation in response to arachidonic acid only, while the majority of patients receiving nilotinib and bosutinib had preserved platelet aggregation to all agonists. Interestingly, two patients receiving dasatinib who demonstrated abnormal platelet aggregation on stimulation with epinephrine, normalised their platelet aggregation upon ceasing dasatinib and commencing bosutinib therapy – suggesting that the platelet dysfunction is unique to dasatinib and possibly independent of BCR-ABL1 or SFK inhibition, which dasatinib and bosutinib both share. A subsequent in vitro study demonstrated that dasatinib significantly inhibited platelet aggregation in response to collagen, with dasatinib 50 nM resulting in impaired platelet aggregation at all concentrations of collagen assessed (2.5 mg/ml, 5 mg/ml). In this study, ADP-induced platelet aggregation was not significantly impaired by dasatinib. Other experimental data has also demonstrated the rapid and reversible effect of dasatinib on bleeding time. Mice treated with differing doses of dasatinib experienced significantly longer tail bleeding times than the control group in a dose-dependent manner. This effect was evident merely 4 h after administration of the medication; however, 24 h following this bleeding times were decreased and, by 48 h, the dasatinib level was no longer detectable demonstrating its reversible effect on haemostasis. In keeping with the impact on haemostasis, dasatinib was shown to affect thrombus formation under physiologic arterial flow ex vivo
Dasatinib: Bleeding due to platelet dysfunction
Platelets Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
DOI: 10.3109/09537104.2015.1049138
in a dose-dependent manner when compared with both a control group and imatinib treatment. Whole human blood was perfused over a collagen matrix over 2 min, with the dasatinib and imatinib administered 4 h prior to blood collection. Both the surface covered by platelet aggregates and the thrombi volume were significantly reduced in the blood treated with dasatinib. Patients treated with imatinib also showed a decrease in thrombus volume; however, the effect was far more pronounced with dasatinib treatment [21]. Furthermore, dasatinib can impact thrombopoiesis, promoting megakaryocyte differentiation within the bone marrow but impairing the ability of megakaryocytes to migrate and form into proplatelets [23]. Therefore, the thrombocytopenia often observed in dasatinib therapy is the result of an impairment of megakaryocyte migration and maturation rather than a defect in megakaryocyte growth or an increase in platelet consumption. A growing body of experimental and clinical data demonstrate that dasatinib can impact platelet function in patients with CML, contributing to both impaired thrombopoiesis and more importantly, impaired adhesion and aggregation. Our report demonstrates both the clinical significance of the bleeding, which has the potential to be severe and life threatening, but with the impaired platelet function reversible upon cessation of the drug. Physicians should be aware of the importance of this adverse effect, with caution in clinical situations for CML patients on dasatinib that may warrant additional antithrombotic therapy and consider appropriate screening in patients receiving dasatinib who are at moderate to high risk of bleeding.
8.
9.
10.
11.
12.
13.
14.
Acknowledgements L. Kostos and K. Burbury wrote the article, G. Srivastava provided clinical information, H. M. Prince chose the patient, provided clinical information and edited the article.
Declaration of interest
15.
The authors report that they have no conflicts of interest.
References 1. Cagnetta A, Garuti A, Marani C, Cea M, Miglino M, Rocco I, Palermo C, Fugazza G, Cirmena G, Colombo N, et al. Evaluating treatment response of chronic myeloid leukemia: Emerging science and technology. Curr Cancer Drug Targets 2013;13:779–790. 2. Joske D. Chronic myeloid leukaemia: The evolution of gene targeted therapy. MJA 2008;189:277–281. 3. Lhermusier T, Van Rothem J, Garcia C, Gratacap MP, Payrastre B. Targeted drug therapy: The platelet side. Platelets 2011;22:479–484. 4. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, Niederwieser D, Resta D, Capdeville R, Zoellner U, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346:645–652. 5. Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, Cervantes F, Deininger M, Gratwohl A, Guilhot F, et al. Chronic myeloid leukaemia: An update of concepts and management recommendations of European LeukaemiaNet. J Clin Oncol 2009; 27:6041–6051. 6. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399–401. 7. Talpaz M, Silver RT, Druker BJ, Goldman JM, GambacortiPasserini C, Guilhot F, Schiffer CA, Fischer T, Deininger MW,
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Lennard AL, et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a phase 2 study. Blood 2002;99: 1928–1937. Quinta´s-Cardama A, Kantarjian H, Ravandi F, O’Brien S, Thomas D, Vidal-Senmache G, Wierda W, Kornblau S, Cortes J. Bleeding diasthesis in patients with chronic myelogenous leukaemia receiving dasatinib therapy. Cancer 2009;115:2482–2490. Rix U, Hantschel O, Durnberger G, Remsing Rix LL, Planyavsky M, Fernbach NV, Kaupe I, Bennett KL, Valent P, Colinge J, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood 2007;110:4055–4063. Grave M, Goodman V, Kaminskas E, Farrell A, Timmer W, Pope S, Harapanhalli R, Saber H, Morse D, Bullock J, et al. Sprycel for chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res 2008;14:352–359. Ishida Y, Terasako K, Oshima K, Sakamoto K, Ashizawa M, Sato M, Kikuchi M, Kimura S, Nakasone H, Okuda S, et al. Dasatinib followed by second allogeneic hematopoietic stem cell transplantation for relapse of Philadelphia chromosome-positive acute lymphoblastic leukemia after the first transplantation. Int J Hematol 2010;92:542–546. Ono Y, Mori T, Kato J, Yamane A, Yajima T, Iwao Y, Hibi T, Okamoto S. Hemorrhagic colonic ulcers caused by dasatinib for chronic myelogenous leukemia. Int J Hematol 2010;92:556–558. Yhim HY, Kim HS, Lee NR, Song EK, Kwak JY, Yim CY. Bilateral subdural hemorrhage as a serious adverse event of dasatinib in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol 2012;95:585–587. Sartor C, Papayannidis C, Chiara Abbenante M, Iacobucci I, Broccoli A, Venturi C, Testoni N, Ferrari A, Martinelli G. Recurrent gastrointestinal hemorrhage in treatment with dasatinib in a patient showing SMAD4 mutation with acute lymphoblastic leukemia Philadelphia positive and juvenile polyposis hereditary hemorrhagic telangiectasia syndrome. Hematol Rep 2013;5: 26–27. Chen J, Zheng Z, Shen J, Zhou Y. The combination of thymosin and methylprednisolone for the treatment of a patient with colonic ulcers, subcutaneous nodules, and pleural effusion after dasatinib treatment for chronic myeloid leukemia. Leuk Lymphoma 2010;51: 941–943. Mustafa Ali MK, Sabha MM, Al-Rabi KH. Spontaneous subdural hematoma in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia with normal platelet count after dasatinib treatment. Platelets 2014;15:1–4. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324:71–86. Michelson AD. Antiplatelet therapies for the treatment of cardiovascular disease. Nat Rev Drug Discov 2010;9:154–169. Broos K, De Meyer SF, Feys HB, Vanhoorelbeke K, Deckmyn H. Blood platelet biochemistry. Thromb Res 2012;129:245–249. Jackson SP. The growing complexity of platelet aggregation. Blood 2007;109:5087–5095. Gratacap M, Martin V, Valera M, Allart S, Garcia C, Sie´ P, Recher C, Payrastre B. The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo. Blood 2009;114:1884–1892. Quinta´s-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukaemia. Blood 2009;114:261–263. Mazharian A, Ghevaert C, Zhang L, Massberg S, Watson S. Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation. Blood 2011;117:5198–5206.
CASE REPORT
Gastrointestinal bleeding in a chronic myeloid leukaemia patient precipitated by dasatinib-induced platelet dysfunction: Case report Louise Kostos, Kate Burbury, Gaurav Srivastava, & H. Miles Prince
Platelets Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
Division of Cancer, Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
Abstract
Keywords
Bleeding in patients with chronic myeloid leukaemia (CML) receiving the second-line tyrosine kinase inhibitor (TKI) dasatinib is a well-documented side effect, occurring in up to 24% of patients. In most cases, it is attributed directly to a secondary grade 3 or 4 thrombocytopaenia. Platelet dysfunction precipitated by dasatinib has been demonstrated in multiple in vitro and in vivo studies; however, there is currently no correlative data that definitively associates this with clinically significant bleeding. In this case, we report a patient with chronic-phase CML receiving dasatinib who developed significant gastrointestinal bleeding secondary to angiodysplasia in the absence of a severe thrombocytopaenia or coagulopathy. Platelet function testing on the PFA-100 assay and formal platelet aggregometry demonstrated impaired platelet aggregation, however, upon cessation of dasatinib, platelet function normalised and the bleeding resolved without further intervention. This case demonstrates that dasatinib-induced platelet dysfunction can cause clinically significant bleeding and highlights the need for physicians to be aware of this adverse effect.
Bleeding, chronic myeloid leukaemia, dasatinib, platelet-dysfunction History Received 3 March 2015 Revised 24 April 2015 Accepted 4 May 2015 Published online 1 June 2015
Introduction
Case report
Chronic myeloid leukaemia (CML) accounts for 15–20% of adult leukaemia [1]. The majority (85%) present in chronic phase (CPCML); however, prior to the tyrosine kinase inhibitor (TKI) era, disease progression to blast crisis was a common and often fatal occurrence. Since the introduction of highly effective TKI therapy, the 10-year overall survival now exceeds 90% and the prevalence of patients receiving long-term TKI therapy has substantially increased. As such, the focus has now shifted to the awareness and management of the off-target effects of these drugs and the tolerability of long-term therapy [2]. The introduction of TKIs in 2001, initially imatinib, has revolutionised the management of this disease [3, 4]. Imatinib resistance and/or intolerance, however, led to the development and approval of more potent second generation TKIs, dasatinib and nilotinib, which induce faster and deeper molecular response rates and are now in widespread use in CML front-line therapy [5–7]. Longer-term follow-up of these agents demonstrate the emergence of adverse events, some of which are not observed with over 10 years of experience with imatinib. Of particular relevance for dasatinib is the potential for bleeding complications [8]. Here, we report the case of an adult patient with CP-CML receiving dasatinib who developed gastrointestinal bleeding secondary to angiodysplasia. This was in the presence of impaired platelet function, which resolved, along with the bleeding, after cessation of dasatinib.
An 84-year-old female with CP-CML, first diagnosed in 2001 with good prognostic features (Sokal score 0.82, Hasford score 667), was initially treated with imatinib (300–400 mg daily). She continued on this for 11 years, achieving complete cytogenetic remission and a major molecular response (BCR-ABL 50.006%), but was ceased in April 2012 due to intolerable nausea. While off TKI therapy, BCR-ABL transcripts escalated to 0.150% on repeat testing, without a detectable mutation. Due to the prior intolerance of imatinib, dasatinib (100 mg daily) was commenced (September 2012), and a major molecular response (BCR-ABL 0.010%) was achieved by three months. Six months later the patient developed a clinically significant pleural effusion, a welldocumented side-effect of dasatinib. A transthoracic echocardiogram was performed at this time which demonstrated preserved systolic function (left ventricular ejection fraction 68%), normal pulmonary artery pressure (RVSP 29 mmHg) and impaired left ventricular relaxation (E/E’ ratio 24, DT 343 ms). The pleural effusion was refractory to medical management and thus dasatinib was ceased and the patient commenced nilotinib (300 mg BD). Unfortunately this was also poorly tolerated due to severe, clinically morbid scalp dermatitis and was discontinued. Due to rising BCR-ABL transcripts (0.100% August 2013) re-commencement of TKI therapy was indicated. The patient was reluctant to re-trial imatinib due to her previous struggle with nausea and thus in October 2013 the patient re-commenced dasatinib (100 mg daily), without re-emergence of the prior pulmonary toxicity. In February 2014, the patient presented with severe enterococcal sepsis, with streptococcal faecalis identified in a stool specimen. As such, the patient underwent a gastroscopy and colonoscopy which demonstrated normal macroscopic and
Correspondence: Dr. Kate Burbury, MBBS (Hons) FRACP FRCPA DPhil, Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia. Tel: +61 3 96561700 – page 7398. Fax: +61 3 96561408. E-mail: [email protected]
Platelets Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
2
L. Kostos et al.
histological appearance of the gastric and colonic mucosa, apart from two colonic polyps, which were resected and confirmed as benign tubular adenomas. Following the procedure, the patient developed melaena, associated with a significant drop in haemoglobin (105–88 g/L). Platelet count was 80 109/L on admission and remained stable throughout the inpatient stay. Coagulation profile was within normal limits (INR 1.1, APTT 26 s). The patient was not on any active antithrombotic or antiplatelet therapy, nor was she taking any medications that inhibit activity of CYP3A4 (a major enzyme responsible for the metabolism of dasatinib). Melaena was ongoing over the next fortnight with the patient requiring transfusion of five units of packed red cells and four units of platelets. CT angiogram did not demonstrate a definitive source of bleeding. Endoscopic examination of her colon reported a superficial ulcerated area with associated erythema at the junction of the caecum and the ascending colon, concordant with the polypectomy sites. Given the large volume of bleeding, these superficial erosions were not thought to be the source, and hence the patient proceeded to have a capsule endoscopy which identified an active bleeding site associated with angioectactic lesions in the proximal jejunem. The dasatinib had been continued throughout the admission and subsequent platelet function testing with the PFA-100 assay (Siemens, Malvern, Australia) demonstrated impaired platelet aggregation with a collagen/epinephrine closure time of 4300 s (normal range 82–150 s) and a collagen/ADP closure time of 155 s (normal range 62–110 s). Formal platelet aggregometry demonstrated a normal response with ristocetin, weak responses with ADP and arachidonic acid but no platelet aggregation to stimulation with collagen or epinephrine. Dasatinib was subsequently ceased and the melaena resolved without further surgical or medical intervention. One week later, the PFA-100 assay was repeated with near restoration of closure times: collagen/epinephrine 176 s and collagen/ADP 131 s. The patient had no further gastrointestinal bleeding and was discharged from hospital two days later. The patient recommenced low-dose imatinib (200 mg daily). Six weeks post-cessation of the dasatinib, mild thrombocytopenia persisted but remained stable (platelet count 90 109/L) and the patient suffered no further gastrointestinal bleeding.
Discussion Dasatinib is a potent second-generation TKI, along with bosutinib and nilotinib, used to treat patients with CML. These ATPcompetitive inhibitors share potent inhibition of BCR-ABL, which is responsible for malignant transformation in CML – with dasatinib being 325 times more potent than imatinib. Dasatinib also causes inhibition of other kinases including c-Kit, platelet-derived growth factor receptor (PDGF-R), and SRC family kinases (SFK). This is in contrast to imatinib and nilotinib which also target c-Kit and PDGF-R but not SFKs, and bosutinib which is a dual inhibitor of BCR-ABL and SFKs [2, 3, 9]. Although generally well tolerated, dasatinib therapy is not completely devoid of side effects, which are largely attributed to its broad spectrum of kinase inhibition. The most common toxicities include cytopenias, gastrointestinal symptoms, and fluid retention [10]. The incidence of bleeding complications in dasatinib studies range from 8% to 24% [8] and is well documented in multiple case reports, with gastrointestinal and central nervous system (CNS) bleeding being the most common sites. However, many of these reports cite grade 3 or 4 thrombocytopenia as the cause of the bleeding, which was not present in the case outlined in this report [11–14]. Two reports postulate that spontaneous bleeding in CML patients receiving
Platelets, Early Online: 1–3
dasatinib is secondary to platelet dysfunction [15, 16]; however, there is no available data on platelet function of these patients. Proteins targeted by TKIs, particularly dasatinib, are common to many cell types and are implicated in the highly dynamic processes of platelet activation, likely contributing to the bleeding diathesis seen with dasatinib use. The principle function of platelets is to form haemostatic thrombi at sites of vascular injury to maintain vascular integrity; processes which involve platelet signal transduction [17, 18]. Upon vascular injury, the interaction of platelets and its receptors (GPVI and integrin a2b1) with exposed extracellular matrix components including von Willebrand factor (vWF) and type I collagen initiate the platelet adhesion process. Platelet adhesion activates signalling pathways mediated by protein tyrosine kinase (PTK) receptors and G-protein-coupled receptors (GPCRs) that lead to secretion of a-granules and dense granules [3]. PTK phosphorylation (PTP) is an essential signalling pathway and is mediated by PTK which catalyses the transfer of the terminal phosphate of ATP to tyrosine residues on protein substrates [19, 20]. PTKs include receptor-TK, such as PDGF-R, vascular endothelial growth factor receptor (VEGFR) and c-Kit, and non-receptor-TK, such as SFK, Abl, and spleen tyrosine kinase (Syk). PTKs generate platelet signal transduction through many distinct signalling pathways, including immunoreceptor tyrosine-based activatory motif (ITAM) or growth factor receptor. Most of the key pathways recruit and activate SFK and as such are all potential targets of TKIs. Dasatinib is an effective reversible inhibitor of ITAM-mediated signalling pathways in platelets, particularly FcgRIIa and collagen GPVI/FcR which involves tyrosine phosphorylation, PI3-kinase activation and PLC/DAG kinase activation [21]. In addition, dasatinib targets SFKs, which are functionally involved in initiating platelet activation and aggregation in ITAM-mediated signalling pathways. In a 2009 study by Quinta´s-Cardama et al. [22], 91 patients with CP-CML either off therapy or receiving various first- and second-generation TKIs were evaluated with platelet aggregometry testing. Impaired platelet aggregation on stimulation of arachidonic acid, epinephrine, or both was observed in 70%, 85%, and 59% of patients on dasatinib, respectively. Dasatinib use also resulted in marked prolongation of closure time to collagen/ epinephrine on the PFA-100 system. Of note, imatinib use resulted in decreased aggregation in response to arachidonic acid only, while the majority of patients receiving nilotinib and bosutinib had preserved platelet aggregation to all agonists. Interestingly, two patients receiving dasatinib who demonstrated abnormal platelet aggregation on stimulation with epinephrine, normalised their platelet aggregation upon ceasing dasatinib and commencing bosutinib therapy – suggesting that the platelet dysfunction is unique to dasatinib and possibly independent of BCR-ABL1 or SFK inhibition, which dasatinib and bosutinib both share. A subsequent in vitro study demonstrated that dasatinib significantly inhibited platelet aggregation in response to collagen, with dasatinib 50 nM resulting in impaired platelet aggregation at all concentrations of collagen assessed (2.5 mg/ml, 5 mg/ml). In this study, ADP-induced platelet aggregation was not significantly impaired by dasatinib. Other experimental data has also demonstrated the rapid and reversible effect of dasatinib on bleeding time. Mice treated with differing doses of dasatinib experienced significantly longer tail bleeding times than the control group in a dose-dependent manner. This effect was evident merely 4 h after administration of the medication; however, 24 h following this bleeding times were decreased and, by 48 h, the dasatinib level was no longer detectable demonstrating its reversible effect on haemostasis. In keeping with the impact on haemostasis, dasatinib was shown to affect thrombus formation under physiologic arterial flow ex vivo
Dasatinib: Bleeding due to platelet dysfunction
Platelets Downloaded from informahealthcare.com by Nyu Medical Center on 06/07/15 For personal use only.
DOI: 10.3109/09537104.2015.1049138
in a dose-dependent manner when compared with both a control group and imatinib treatment. Whole human blood was perfused over a collagen matrix over 2 min, with the dasatinib and imatinib administered 4 h prior to blood collection. Both the surface covered by platelet aggregates and the thrombi volume were significantly reduced in the blood treated with dasatinib. Patients treated with imatinib also showed a decrease in thrombus volume; however, the effect was far more pronounced with dasatinib treatment [21]. Furthermore, dasatinib can impact thrombopoiesis, promoting megakaryocyte differentiation within the bone marrow but impairing the ability of megakaryocytes to migrate and form into proplatelets [23]. Therefore, the thrombocytopenia often observed in dasatinib therapy is the result of an impairment of megakaryocyte migration and maturation rather than a defect in megakaryocyte growth or an increase in platelet consumption. A growing body of experimental and clinical data demonstrate that dasatinib can impact platelet function in patients with CML, contributing to both impaired thrombopoiesis and more importantly, impaired adhesion and aggregation. Our report demonstrates both the clinical significance of the bleeding, which has the potential to be severe and life threatening, but with the impaired platelet function reversible upon cessation of the drug. Physicians should be aware of the importance of this adverse effect, with caution in clinical situations for CML patients on dasatinib that may warrant additional antithrombotic therapy and consider appropriate screening in patients receiving dasatinib who are at moderate to high risk of bleeding.
8.
9.
10.
11.
12.
13.
14.
Acknowledgements L. Kostos and K. Burbury wrote the article, G. Srivastava provided clinical information, H. M. Prince chose the patient, provided clinical information and edited the article.
Declaration of interest
15.
The authors report that they have no conflicts of interest.
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