Platelets
ISSN: 0953-7104 (Print) 1369-1635 (Online) Journal homepage: http://www.tandfonline.com/loi/iplt20
Spontaneous subdural hematoma in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia with normal platelet count after dasatinib treatment Moaath K. Mustafa Ali, Marwa M. Sabha & Kamal H. Al-Rabi To cite this article: Moaath K. Mustafa Ali, Marwa M. Sabha & Kamal H. Al-Rabi (2015) Spontaneous subdural hematoma in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia with normal platelet count after dasatinib treatment, Platelets, 26:5, 491-494 To link to this article: http://dx.doi.org/10.3109/09537104.2014.935316
Published online: 15 Jul 2014.
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Date: 15 September 2015, At: 02:10
http://informahealthcare.com/plt ISSN: 0953-7104 (print), 1369-1635 (electronic) Platelets, 2015; 26(5): 491–494 ! 2014 Informa UK Ltd. DOI: 10.3109/09537104.2014.935316
CASE REPORT
Spontaneous subdural hematoma in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia with normal platelet count after dasatinib treatment Moaath K. Mustafa Ali1, Marwa M. Sabha2, & Kamal H. Al-Rabi1 Division of Hematology and Oncology, Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan, and 2Division of Hematology and Oncology, Department of Pediatrics, King Hussein Cancer Center, Amman, Jordan
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1
Abstract
Keywords
Dasatinib, which is an inhibitor of BCR-ABL and SRC family tyrosine kinases, is used for the treatment of patients with Philadelphia chromosome (Ph) positive leukemia, especially for those who develop resistance or who are intolerant to imatinib. The most common adverse effects attributed to its use are: myelosuppression, nausea, diarrhea, and peripheral edema. Hemorrhage, which could be gastrointestinal, genitourinary or central nervous system, is a less frequent adverse effect. In this case, we report a patient affected by precursor B-cell acute lymphoblastic leukemia (ALL) positive for the Ph chromosome translocation treated with the tyrosine kinase inhibitor (TKI) dasatinib. During the treatment with dasatinib the patient developed subdural hematoma (SDH). She did not have any head trauma, thrombocytopenia, coagulopathy or meningeal involvement, making dasatinib-induced platelet dysfunction the most likely cause of SDH.
Acute lymphoblastic leukemia, dasatinib, Philadelphia chromosome, subdural hematoma
Introduction Dasatinib, which is a second generation BCR-ABL tyrosine kinase inhibitor (TKI), has been approved for the treatment of Philadelphia chromosome (Ph)-positive malignancies such as acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) [1, 2]. Dasatinib targets most imatinib-resistant BCR-ABL mutations by distinctly binding to active and inactive ABL-kinase. This inhibition blocks proliferation of leukemia cells. Dasatinib has also been shown to inhibit SRC family (including SRC, LKC, YES, FYN); c-KIT, EPHA2 and platelet derived growth factor receptor (PDGFRb) [3, 4]. In vitro, dasatinib has 325-fold greater potency than imatinib mesylate (IM) for inhibiting BCR-ABL [4]. Several adverse reactions have been encountered with dasatinib use, including: headache, fatigue, skin rash, diarrhea, abdominal pain, nausea, vomiting, pleural effusion, myelosuppression and hemorrhage. Hemorrhage has been reported in 9–40% of patients using dasatinib [5, 6]. Bleeding can be: gastrointestinal, genitourinary, soft tissue hematoma and central nervous system (CNS) bleeding. In this case, we describe a patient who developed spontaneous SDH after dasatinib treatment. The patient did not have any risk factors for SDH, making dasatinib induced-platelet dysfunction the most likely cause.
Case Report A 29-year-old woman was diagnosed with Ph-positive precursor B-cell ALL in July 2012. The patient was treated with Correspondence: Moaath K. Mustafa Ali, MD, Division of Hematology and Oncology, King Hussein Cancer Center, P.O Box 1269, Amman 11941, Jordan. Tel: 00962799109555. Fax: 0096265353001. E-mail: [email protected].
History Received 8 May 2014 Revised 28 May 2014 Accepted 12 June 2014 Published online 14 July 2014
Hyper-CVAD/methotrexate-cytarabine chemotherapy regimen for 8 cycles. Initially, she was treated with Imatinib Mesylate (IM) at a daily dose of 400 mg for 2 weeks in the first 4 cycles, and then it was substituted with Dasatinib 70 mg twice daily for 2 weeks in the last 4 cycles because of inadequate response. She completed the 8th cycle in February 2013. Repeated cerebrospinal fluid (CSF) cytologic exam failed to reveal any leukemic cells. She achieved complete cytogenetic remission and partial molecular remission. Two months later, she underwent allogenic peripheral blood stem cell transplant (PBSCT) from a matched related donor. One month later she achieved molecular remission. Two months later, the patient relapsed. Consequently, she was started on salvage dasatinib and dexamethasone. In February 2014, the patient had complete remission and underwent donor lymphocyte infusion. On 28 February 2014, the patient presented to the emergency department with 10 days history of frontal headache that she never experienced before. She denied any history of head trauma or bleeding. Review of system, family history and social history was unremarkable. She was on the following medications: dasatinib 140 mg P.O QD, valaciclovir 500 mg P.O BID, co-trimoxazole 80 mg P.O QD, refresh eye drops TID, lansoprazole 15 mg P.O QD, and prophylactic amoxicillin 1 g P.O BID. On physical examination, her pulse rate was: 93 and blood pressure was: 113/ 68 mmHg. Head, neck, chest and abdomen examination was unremarkable. The Glasgow Comma Scale was 15/15 and her neurologic exam was normal. Laboratory testing was the following: RBC: 3 170 000/ml (normal range (NR): 4–5.5 106/ml); hemoglobin: 11.4 g/dl (NR: 12–16 g/dl); WBC: 6900/ml (NR: 4– 11 103/ml); platelets: 230 103/ml (NR: 150–400 103/ml); PT: 13.3 seconds (secs) (NR: 12.6–13.5 secs); INR: 1.04 (NR: 0.85– 1.25); and aPTT: 38.2 secs (NR: 29–37 seconds). Liver function test and kidney function test were all normal. Brain CT scan
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imaging with contrast showed an acute mixed attenuation left hemispheric subdural hematoma associated with mass effect on the surrounding structures, right subfalcine herniation and right lateral ventricle obstructive hydrocephalus (Figure 1). The patient was given mannitol to decrease intracranial pressure. The neurosurgery team was consulted and the patient underwent left SDH evacuation with two burr holes and subdural drain. Dasatinib was discontinued because a relationship between dasatinib and SDH is possible. Over the following days, her headache subsided and her neurologic exam was stable. She was discharged home after 5 days without having any complication and she was scheduled for follow-up visit after 4 days at the neurosurgical
Figure 1. An axial computed tomography scan of the head revealed a subdural hematoma.
clinic. Multidisciplinary clinic was held later and the patient was started on nilotinib.
Discussion We present a patient with Ph-positive ALL who developed SDH during treatment with Dasatinib. The most common causes of SDH are trauma and aneurysmal hemorrhages [7]. Our patient did not have any history of head trauma, and brain imaging study did not show any evidence of vascular aneurysms. It is noteworthy to mention that the patient did not have diffuse cerebral atrophy, significant retching, significant emesis, or other apparent precipitating event. This patient was not taking any medications with anti-platelet or anti-coagulant effect. The occurrence of SDH in patients with Ph-positive ALL could be attributed to several causes; leptomeningeal invasion by leukemic cells is a possible cause of SDH in patients with ALL [8]. However, both CSF cytology and previous gadoliniumenhanced MRI were negative in our patient. Other important predisposing factors to SDH are thrombocytopenia and coagulopathy, both of which were not present in our patient. The use of TKI such as imatinib and dasatinib are also risk factors to develop SDH in patients with leukemia [9–12]. The use of dasatinib increases the risk of both gastrointestinal hemorrhage and central nervous system hemorrhage (Table I). Tyrosine kinase inhibitors (TKI) can cause thrombocytopenia which is a risk factor for SDH. Dasatinib was found to cause mild thrombocytopenia in mice without altering platelet half-life, suggesting that it inhibits platelet formation [24]. Dasatinib is known to cause broad spectrum inhibition of kinases, including: BCR-ABL, SRC family kinases, KIT, PDGFR-b, and ephrin receptor tyrosine kinases [3]. PDGFR-b, a receptor expressed in pericytes, is known to play an important role in angiogenesis and vessel wall formation [25]. Thus, inhibition of PDGFR-b by dasatinib could induce mechanical instability of the capillary wall which has been shown in PDGFR-b-deficient mouse embryo [25]. Tyrosine kinase inhibitors (TKI) can cause altered platelet function, which predisposes patient to SDH. Several studies investigated the mechanisms by which dasatinib causes platelet dysfunction (Table II). However, the platelet function was not tested in this patient because this was a retrospective report.
Table I. Summary of case reports of different types of bleeding in ALL or CML patients following dasatinib treatment. Reference
Type of leukemia
Type of bleeding
Proposed mechanism of dasatinib induced bleeding
Shimokaze et al. [13]
ALL
GI
Erkut et al. [14] Ishida et al. [15]
CML ALL
GI GI
Ono et al. [16] Chen et al. [17] Sunami et al. [18]
CML CML CML
GI GI GI
Yhim et al. [9]
ALL
Patodi et al. [19] Sartor et al. [20]
CML ALL
Bilateral subdural hematoma GI GI
Kmira et al. [21] Chisti et al. [22]
CML CML blast crisis with ALL CML
Colitis associated with lymphocytic infiltrate of the lamina propriax. Acute colitisx. After the second HSCT; bleeding was secondary to the conditioning regimen used, gastrointestinal acute GVHD and dasatinib induced thrombocytopenia (30 103/ml). Colonic ulcers and thrombocytopenia (21 103/ml). Acute lymphocytic colitis and platelets dysfunctionx. Bleeding was secondary to CMV-colitis and dasatinib induced CD8-positive lymphocytic colitis. Thrombocytopenia (platelets count were kept 20 103/ml by transfusion). Acute colitisx. The patient had juvenile polyposis and hereditary hemorrhagic telangiectasia; bleeding was attributed to dasatinib induced thrombocytopenia (17 103/ml) and his genetic background. Acute colitisx. Acute lymphoplasmacytic colitis and mild thrombocytopenia (90 103/ml). CD8-positive lymphocytic colitisx.
Saito et al. [23]
GI GI GI
xPatient had normal platelet count. ALL, acute lymphoblastic leukemia; GI, gastrointestinal; HSCT, hematopoietic stem cell transplantation; GVHD, graft versus host disease, CML, chronic myelogenous leukemia; CMV, cytomegalovirus.
Subdural hematoma/dasatinib
DOI: 10.3109/09537104.2014.935316
Table II. Studies investigating the mechanisms by which dasatinib induces altered platelet function.
Author Lombardo LJ et al. [3]
Quinta´s-Cardama et al. [26]
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Gratacap MP et al. [27]
Ezumi Y et al.¥ [28], Quek LS et al.¥ [29] and Inoue O et al.¥[30]
Proposed mechanism of dasatinib-induced platelet dysfunction Broad spectrum inhibition of kinases, including: BCR-ABL, SRC family kinases, KIT, PDGFR-b, and ephrin receptor tyrosine kinases Impaired platelet activation: reduced epinephrine-induced platelet aggregation and reduced arachidonic acid induced platelet aggregation. Impaired platelet activation by thrombin or adenosine diphosphate. Inhibition of platelet signaling and functions initiated by collagen or FcgRIIA cross-linking, which require SRC family kinase (SFK) phosphorylation of immunoreceptor tyrosinebased activation motifs. Altered platelet aggregation by inhibiting key kinases (SFKs LYN and FYN) which play critical roles in early platelet activation by glycoprotein VI, upstream of SYK and PLCg2, and by integrin a2b1
3.
4.
5.
6.
7.
¥Studies invistigated the role of different kinases in platlet activation. 8.
Because the patient did not have any trauma, thrombocytopenia, coagulopathy or meningeal involvement, dasatinib-induced platelet dysfunction was most likely the cause of SDH. We discontinued dasatinib because of the life-threatening bleeding. It is not clear whether dasatinib can be readministered to patients with bleeding complications. Thus, further studies are needed to test for the safety of re-challenging patients who had lifethreatening bleeding with dasatinib. This case reports a patient with life threatening central nervous system hemorrhage after dasatinib treatment without evidence of obvious risk factors; such finding should keep physicians alert to this atypical cause of headache in patients taking dasatinib. In summary, we reported the rare but serious adverse event of SDH in a patient receiving dasatinib and with normal platelet count. Physicians should be alert to this kind of bleeding complication in patients with advanced stage CML or Ph-positive ALL receiving dasatinib.
Acknowledgment
9.
10.
11.
12.
13.
14.
The authors thank Dr. Alaa I. Saleh for the help she provided in the preparation of the case report. 15.
Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. No funding was received for this study.
16.
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acute lymphoblastic leukemia with resistance or intolerance to imatinib. interim results of a phase 2 study. Blood 2007;110: 2309–2315. Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LA, Das J, Doweyko AM, et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004;47: 6658–6661. O’Hare T, Walters DK, Stoffregen EP, Jia T, Manley PW, Mestan J, Cowan-Jacob SW, Lee FY, Heinrich MC, Deininger MW, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005;65:4500–4505. Kantarjian H, Cortes J, Kim DW, Dorlhiac-Llacer P, Pasquini R, DiPersio J, Muller MC, Radich JP, Khoury HJ, Khoroshko N, et al. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib. 15-month median follow-up. Blood 2009;113:6322–6329. Brave 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 leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant to or intolerant of imatinib mesylate. Clin Cancer Res 2008;14:352–359. Bullock MR, Chesnut R, Ghajar J, Gordon D, Hartl R, Newell DW, Servadei F, Walters BC, Wilberger JE. Surgical management of acute subdural hematomas. Neurosurgery 2006;58:S16–S24 (discussion Si-iv). Pitner SE, Johnson WW. Chronic subdural hematoma in childhood acute leukemia. Cancer 1973;32:185–190. 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. Patel SB, Gojo I, Tidwell ML, Sausville EA, Baer MR. Subdural hematomas in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy. Leuk Lymphoma 2011; 52:1211–1214. Song KW, Rifkind J, Al-Beirouti B, Yee K, McCrae J, Messner HA, Keating A, Lipton JH. Subdural hematomas during CML therapy with imatinib mesylate. Leuk Lymphoma 2004;45:1633–1636. Kim MS, Lee DH, Lee YR, Kim DK, Bae SH, Hwang JY, Kwon KA, Lee S, Han JY, Kim KU, et al. A case of subdural hematoma in patient with chronic myeloid leukemia treated with high-dose imatinib mesylate. Korean J Hematol 2010;45:73–75. Shimokaze T, Mitsui T, Takeda H, Kawakami T, Arai T, Ito M, Iwaba A, Izumino H, Takahashi N, Kanno M, et al. Severe hemorrhagic colitis caused by dasatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia. Pediatr Hematol Oncol 2009;26:448–453. Erkut M, Erkut N, Ersoz S, Arslan M, Sonmez M. A case of acute colitis with severe rectal bleeding in a patient with chronic myeloid leukemia after dasatinib use. Acta Haematol 2010;123:205–206. 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. 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. Sunami Y, Sato E, Ichikawa K, Yasuda H, Komatsu N. Hemorrhagic colitis caused by dasatinib following cytomegalovirus enterocolitis in a patient with chronic myelogenous leukemia in the second chronic phase. Rinsho Ketsueki 2011;52:282–286.
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19. Patodi N, Sagar N, Rudzki Z, Langman G, Sharma N. Haemorrhagic colitis caused by dasatinib. Case Rep Hematol 2012;2012:417106. 20. 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. 21. Kmira Z, Nesrine BS, Houneida Z, Wafa BF, Aida S, Yosra BY, Monia Z, Sriha B, Abderrahim K. Severe hemorrhagic colitis in a patient with chronic myeloid leukemia in the blastic phase after dasatinib use. World J Gastrointest Pathophysiol 2013;4:59–62. 22. Chisti MM, Khachani A, Brahmanday GR, Klamerus J. Dasatinibinduced haemorrhagic colitis in chronic myeloid leukaemia (CML) in blast crisis. BMJ Case Rep 2013;2013; doi: 10.1136/bcr-2013200610. 23. Saito M, Izumiyama K, Mori A, Irie T, Tanaka M, Morioka M, Saga A, Musashi M, Kato T, Meguro T, et al. Intestinal bleeding in patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors. Rinsho Ketsueki 2014;55:130–132. 24. Mazharian A, Ghevaert C, Zhang L, Massberg S, Watson SP. Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation. Blood 2011;117:5198–5206.
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25. Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 1997; 277:242–245. 26. Quintas-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood 2009;114:261–263. 27. Gratacap MP, Martin V, Valera MC, 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. 28. Ezumi Y, Shindoh K, Tsuji M, Takayama H. Physical and functional association of the Src family kinases Fyn and Lyn with the collagen receptor glycoprotein VI-Fc receptor gamma chain complex on human platelets. J Exp Med 1998;188:267–276. 29. Quek LS, Pasquet JM, Hers I, Cornall R, Knight G, Barnes M, Hibbs ML, Dunn AR, Lowell CA, Watson SP. Fyn and Lyn phosphorylate the Fc receptor gamma chain downstream of glycoprotein VI in murine platelets, and Lyn regulates a novel feedback pathway. Blood 2000;96:4246–4253. 30. Inoue O, Suzuki-Inoue K, Dean WL, Frampton J, Watson SP. Integrin alpha2beta1 mediates outside-in regulation of platelet spreading on collagen through activation of Src kinases and PLCgamma2. J Cell Biol 2003;160:769–780.
ISSN: 0953-7104 (Print) 1369-1635 (Online) Journal homepage: http://www.tandfonline.com/loi/iplt20
Spontaneous subdural hematoma in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia with normal platelet count after dasatinib treatment Moaath K. Mustafa Ali, Marwa M. Sabha & Kamal H. Al-Rabi To cite this article: Moaath K. Mustafa Ali, Marwa M. Sabha & Kamal H. Al-Rabi (2015) Spontaneous subdural hematoma in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia with normal platelet count after dasatinib treatment, Platelets, 26:5, 491-494 To link to this article: http://dx.doi.org/10.3109/09537104.2014.935316
Published online: 15 Jul 2014.
Submit your article to this journal
Article views: 67
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=iplt20 Download by: [UNSW Library]
Date: 15 September 2015, At: 02:10
http://informahealthcare.com/plt ISSN: 0953-7104 (print), 1369-1635 (electronic) Platelets, 2015; 26(5): 491–494 ! 2014 Informa UK Ltd. DOI: 10.3109/09537104.2014.935316
CASE REPORT
Spontaneous subdural hematoma in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia with normal platelet count after dasatinib treatment Moaath K. Mustafa Ali1, Marwa M. Sabha2, & Kamal H. Al-Rabi1 Division of Hematology and Oncology, Department of Internal Medicine, King Hussein Cancer Center, Amman, Jordan, and 2Division of Hematology and Oncology, Department of Pediatrics, King Hussein Cancer Center, Amman, Jordan
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1
Abstract
Keywords
Dasatinib, which is an inhibitor of BCR-ABL and SRC family tyrosine kinases, is used for the treatment of patients with Philadelphia chromosome (Ph) positive leukemia, especially for those who develop resistance or who are intolerant to imatinib. The most common adverse effects attributed to its use are: myelosuppression, nausea, diarrhea, and peripheral edema. Hemorrhage, which could be gastrointestinal, genitourinary or central nervous system, is a less frequent adverse effect. In this case, we report a patient affected by precursor B-cell acute lymphoblastic leukemia (ALL) positive for the Ph chromosome translocation treated with the tyrosine kinase inhibitor (TKI) dasatinib. During the treatment with dasatinib the patient developed subdural hematoma (SDH). She did not have any head trauma, thrombocytopenia, coagulopathy or meningeal involvement, making dasatinib-induced platelet dysfunction the most likely cause of SDH.
Acute lymphoblastic leukemia, dasatinib, Philadelphia chromosome, subdural hematoma
Introduction Dasatinib, which is a second generation BCR-ABL tyrosine kinase inhibitor (TKI), has been approved for the treatment of Philadelphia chromosome (Ph)-positive malignancies such as acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) [1, 2]. Dasatinib targets most imatinib-resistant BCR-ABL mutations by distinctly binding to active and inactive ABL-kinase. This inhibition blocks proliferation of leukemia cells. Dasatinib has also been shown to inhibit SRC family (including SRC, LKC, YES, FYN); c-KIT, EPHA2 and platelet derived growth factor receptor (PDGFRb) [3, 4]. In vitro, dasatinib has 325-fold greater potency than imatinib mesylate (IM) for inhibiting BCR-ABL [4]. Several adverse reactions have been encountered with dasatinib use, including: headache, fatigue, skin rash, diarrhea, abdominal pain, nausea, vomiting, pleural effusion, myelosuppression and hemorrhage. Hemorrhage has been reported in 9–40% of patients using dasatinib [5, 6]. Bleeding can be: gastrointestinal, genitourinary, soft tissue hematoma and central nervous system (CNS) bleeding. In this case, we describe a patient who developed spontaneous SDH after dasatinib treatment. The patient did not have any risk factors for SDH, making dasatinib induced-platelet dysfunction the most likely cause.
Case Report A 29-year-old woman was diagnosed with Ph-positive precursor B-cell ALL in July 2012. The patient was treated with Correspondence: Moaath K. Mustafa Ali, MD, Division of Hematology and Oncology, King Hussein Cancer Center, P.O Box 1269, Amman 11941, Jordan. Tel: 00962799109555. Fax: 0096265353001. E-mail: [email protected].
History Received 8 May 2014 Revised 28 May 2014 Accepted 12 June 2014 Published online 14 July 2014
Hyper-CVAD/methotrexate-cytarabine chemotherapy regimen for 8 cycles. Initially, she was treated with Imatinib Mesylate (IM) at a daily dose of 400 mg for 2 weeks in the first 4 cycles, and then it was substituted with Dasatinib 70 mg twice daily for 2 weeks in the last 4 cycles because of inadequate response. She completed the 8th cycle in February 2013. Repeated cerebrospinal fluid (CSF) cytologic exam failed to reveal any leukemic cells. She achieved complete cytogenetic remission and partial molecular remission. Two months later, she underwent allogenic peripheral blood stem cell transplant (PBSCT) from a matched related donor. One month later she achieved molecular remission. Two months later, the patient relapsed. Consequently, she was started on salvage dasatinib and dexamethasone. In February 2014, the patient had complete remission and underwent donor lymphocyte infusion. On 28 February 2014, the patient presented to the emergency department with 10 days history of frontal headache that she never experienced before. She denied any history of head trauma or bleeding. Review of system, family history and social history was unremarkable. She was on the following medications: dasatinib 140 mg P.O QD, valaciclovir 500 mg P.O BID, co-trimoxazole 80 mg P.O QD, refresh eye drops TID, lansoprazole 15 mg P.O QD, and prophylactic amoxicillin 1 g P.O BID. On physical examination, her pulse rate was: 93 and blood pressure was: 113/ 68 mmHg. Head, neck, chest and abdomen examination was unremarkable. The Glasgow Comma Scale was 15/15 and her neurologic exam was normal. Laboratory testing was the following: RBC: 3 170 000/ml (normal range (NR): 4–5.5 106/ml); hemoglobin: 11.4 g/dl (NR: 12–16 g/dl); WBC: 6900/ml (NR: 4– 11 103/ml); platelets: 230 103/ml (NR: 150–400 103/ml); PT: 13.3 seconds (secs) (NR: 12.6–13.5 secs); INR: 1.04 (NR: 0.85– 1.25); and aPTT: 38.2 secs (NR: 29–37 seconds). Liver function test and kidney function test were all normal. Brain CT scan
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imaging with contrast showed an acute mixed attenuation left hemispheric subdural hematoma associated with mass effect on the surrounding structures, right subfalcine herniation and right lateral ventricle obstructive hydrocephalus (Figure 1). The patient was given mannitol to decrease intracranial pressure. The neurosurgery team was consulted and the patient underwent left SDH evacuation with two burr holes and subdural drain. Dasatinib was discontinued because a relationship between dasatinib and SDH is possible. Over the following days, her headache subsided and her neurologic exam was stable. She was discharged home after 5 days without having any complication and she was scheduled for follow-up visit after 4 days at the neurosurgical
Figure 1. An axial computed tomography scan of the head revealed a subdural hematoma.
clinic. Multidisciplinary clinic was held later and the patient was started on nilotinib.
Discussion We present a patient with Ph-positive ALL who developed SDH during treatment with Dasatinib. The most common causes of SDH are trauma and aneurysmal hemorrhages [7]. Our patient did not have any history of head trauma, and brain imaging study did not show any evidence of vascular aneurysms. It is noteworthy to mention that the patient did not have diffuse cerebral atrophy, significant retching, significant emesis, or other apparent precipitating event. This patient was not taking any medications with anti-platelet or anti-coagulant effect. The occurrence of SDH in patients with Ph-positive ALL could be attributed to several causes; leptomeningeal invasion by leukemic cells is a possible cause of SDH in patients with ALL [8]. However, both CSF cytology and previous gadoliniumenhanced MRI were negative in our patient. Other important predisposing factors to SDH are thrombocytopenia and coagulopathy, both of which were not present in our patient. The use of TKI such as imatinib and dasatinib are also risk factors to develop SDH in patients with leukemia [9–12]. The use of dasatinib increases the risk of both gastrointestinal hemorrhage and central nervous system hemorrhage (Table I). Tyrosine kinase inhibitors (TKI) can cause thrombocytopenia which is a risk factor for SDH. Dasatinib was found to cause mild thrombocytopenia in mice without altering platelet half-life, suggesting that it inhibits platelet formation [24]. Dasatinib is known to cause broad spectrum inhibition of kinases, including: BCR-ABL, SRC family kinases, KIT, PDGFR-b, and ephrin receptor tyrosine kinases [3]. PDGFR-b, a receptor expressed in pericytes, is known to play an important role in angiogenesis and vessel wall formation [25]. Thus, inhibition of PDGFR-b by dasatinib could induce mechanical instability of the capillary wall which has been shown in PDGFR-b-deficient mouse embryo [25]. Tyrosine kinase inhibitors (TKI) can cause altered platelet function, which predisposes patient to SDH. Several studies investigated the mechanisms by which dasatinib causes platelet dysfunction (Table II). However, the platelet function was not tested in this patient because this was a retrospective report.
Table I. Summary of case reports of different types of bleeding in ALL or CML patients following dasatinib treatment. Reference
Type of leukemia
Type of bleeding
Proposed mechanism of dasatinib induced bleeding
Shimokaze et al. [13]
ALL
GI
Erkut et al. [14] Ishida et al. [15]
CML ALL
GI GI
Ono et al. [16] Chen et al. [17] Sunami et al. [18]
CML CML CML
GI GI GI
Yhim et al. [9]
ALL
Patodi et al. [19] Sartor et al. [20]
CML ALL
Bilateral subdural hematoma GI GI
Kmira et al. [21] Chisti et al. [22]
CML CML blast crisis with ALL CML
Colitis associated with lymphocytic infiltrate of the lamina propriax. Acute colitisx. After the second HSCT; bleeding was secondary to the conditioning regimen used, gastrointestinal acute GVHD and dasatinib induced thrombocytopenia (30 103/ml). Colonic ulcers and thrombocytopenia (21 103/ml). Acute lymphocytic colitis and platelets dysfunctionx. Bleeding was secondary to CMV-colitis and dasatinib induced CD8-positive lymphocytic colitis. Thrombocytopenia (platelets count were kept 20 103/ml by transfusion). Acute colitisx. The patient had juvenile polyposis and hereditary hemorrhagic telangiectasia; bleeding was attributed to dasatinib induced thrombocytopenia (17 103/ml) and his genetic background. Acute colitisx. Acute lymphoplasmacytic colitis and mild thrombocytopenia (90 103/ml). CD8-positive lymphocytic colitisx.
Saito et al. [23]
GI GI GI
xPatient had normal platelet count. ALL, acute lymphoblastic leukemia; GI, gastrointestinal; HSCT, hematopoietic stem cell transplantation; GVHD, graft versus host disease, CML, chronic myelogenous leukemia; CMV, cytomegalovirus.
Subdural hematoma/dasatinib
DOI: 10.3109/09537104.2014.935316
Table II. Studies investigating the mechanisms by which dasatinib induces altered platelet function.
Author Lombardo LJ et al. [3]
Quinta´s-Cardama et al. [26]
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Gratacap MP et al. [27]
Ezumi Y et al.¥ [28], Quek LS et al.¥ [29] and Inoue O et al.¥[30]
Proposed mechanism of dasatinib-induced platelet dysfunction Broad spectrum inhibition of kinases, including: BCR-ABL, SRC family kinases, KIT, PDGFR-b, and ephrin receptor tyrosine kinases Impaired platelet activation: reduced epinephrine-induced platelet aggregation and reduced arachidonic acid induced platelet aggregation. Impaired platelet activation by thrombin or adenosine diphosphate. Inhibition of platelet signaling and functions initiated by collagen or FcgRIIA cross-linking, which require SRC family kinase (SFK) phosphorylation of immunoreceptor tyrosinebased activation motifs. Altered platelet aggregation by inhibiting key kinases (SFKs LYN and FYN) which play critical roles in early platelet activation by glycoprotein VI, upstream of SYK and PLCg2, and by integrin a2b1
3.
4.
5.
6.
7.
¥Studies invistigated the role of different kinases in platlet activation. 8.
Because the patient did not have any trauma, thrombocytopenia, coagulopathy or meningeal involvement, dasatinib-induced platelet dysfunction was most likely the cause of SDH. We discontinued dasatinib because of the life-threatening bleeding. It is not clear whether dasatinib can be readministered to patients with bleeding complications. Thus, further studies are needed to test for the safety of re-challenging patients who had lifethreatening bleeding with dasatinib. This case reports a patient with life threatening central nervous system hemorrhage after dasatinib treatment without evidence of obvious risk factors; such finding should keep physicians alert to this atypical cause of headache in patients taking dasatinib. In summary, we reported the rare but serious adverse event of SDH in a patient receiving dasatinib and with normal platelet count. Physicians should be alert to this kind of bleeding complication in patients with advanced stage CML or Ph-positive ALL receiving dasatinib.
Acknowledgment
9.
10.
11.
12.
13.
14.
The authors thank Dr. Alaa I. Saleh for the help she provided in the preparation of the case report. 15.
Declaration of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. No funding was received for this study.
16.
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