Universal Journal of Medicine and Dentistry(ISSN:2277-0992) Vol. 1(7) pp. 079-085, October, 2012 Available online http://www.universalresearchjournals.

org/ujmd Copyright 2012 Transnational Research Journals

Review Research paper

Rare oral manifestation of chronic myelogenous leukemia and its targeted therapy: A case report and literature review
John A .Loudona, Hedley G. Colemanb, Carl M. Allenc, Mark Schifterd, Thomas Nge, George Al-Horanif
Syd; Cert Oral Path. FAAOMP (Ohio): Wetherill Park Medical Centre, Suite 101, Stockland Mall, Wetherill Park, Sydney, NSW, 2164, Australia. b Department of Oral Pathology, Faculty of Dentistry, The University of Sydney, ICPMR, Westmead Hospital C-24, Westmead, Sydney, NSW, 2145, Australia c th Department of Oral Pathology, College of Dentistry, The Ohio State University, 305W. 12 Ave., Columbus, OH, 43210, United States of America d Department of Oral Medicine, Oral Pathology and Special Needs Dentistry, Level 3, Westmead Centre for Oral Health, Westmead Hospital Dental Clinical School, Westmead Hospital, Darcy Rd., Westmead, Sydney, NSW, 2145, Australia e Sydney Medical School, C-24, The University of Sydney, Westmead Hospital, Sydney NSW, 2145, Australia f Wetherill Park Medical Centre, Suite 101, Stockland Mall, Polding St., Wetherill Park, Sydney, NSW, 2164, Australia
Accepted 20 September, 2012
a

In this paper, a case of diffuse slate-grey pigmentation of the palate is presented. The patient was a middle aged man who was diagnosed previously with chronic myelogenous leukemia. He has been receiving imatinib mesylate (Gleevec) therapy for management of his leukemia for several years. The observation of extensive palatal pigmentation coupled with other sites intraorally such as buccal mucosa and extraoral sites such as left shoulder prompted detailed investigation. The only lesion the patient knew about was the shoulder lesion which had developed over the last several years. Representative lesional biopsy of the palate demonstrated extensive iron deposition coupled with interspersed melanin. Literature reviews indicated only one similar report, published very recently, with such a similar clinical and histopathological appearance. Plausible mechanisms to explain the observation of pigmentation are outlined along with special tests performed to rule out multiple differential diagnostic possibilities. This report highlights the need for clinicians to be aware of this type of presentation when examining patients being treated for chronic myelogenous leukemia. Keywords: deposition. INTRODUCTION Oral manifestations of systemic disease are becoming increasingly significant for dental surgeons. Thus as clinicians it is so important to be observant with the patients we treat and to be attentive to follow-up on anything unusual we may notice. This point was made recently (Shah et al., 2011). More often nowadays we are called upon to see patients with significant chronic
*Corresponding author Email: jon.uk1515@gmail.com; Tel; 61-2-9756-3636,

chronic myelogenous leukemia; Gleevec; intraoral pigmentation; iron deposition; melanin

disease being managed medically. One of these chronic diseases is leukemia and the presenting mouth-related findings have been reviewed (Neville et al., 2008). Leukemias represent a varied group of malignancies of hematopoietic stem cell origin. A subgroup of these malignancies is represented by the myeloid leukemias which generally affect adults. Another subgroup is represented by the lymphoid leukemias which span a broad age range from children (acute lymphoblastic leukemia) to the elderly (chronic lymphocytic leukemia). In terms of myeloid leukemias, chronic myelogenous

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leukemia (CML) peaks in the third to fourth decades. Signs and symptoms of CML are reflected in the reduction of red blood cells and raised WBC count. Thrombocytopenia that results in easy bruising and bleeding can occur and is due to lack of platelets. In this respect, petechial hemorrhages of the posterior hard palate and soft palate can be seen. Other mouth related findings secondary to leukemia include ulceration due to an impaired immune defense. Additionally, oral candidiasis, herpetic ulcers, gingival enlargement and periodontal bony loss secondary to immune alteration and infiltration by leukemic cells may be presenting features. The following demonstrates a case of significant intraoral iron deposition with closely associated melanin accumulation in a patient with CML being treated with Gleevec. CASE A 62-year old gentleman of Asian background presented for routine clinical dental care. A striking slate-grey, relatively well defined, lesion was seen on the hard palate extending down the midline onto the soft palate area (Figure 1). This image was taken approximately three months post-biopsy and shows the elliptical area of healed biopsy wound as appearing normally pigmented. Orthopantomogram findings were unremarkable. The patient reported no previous symptoms of the lesion and in fact was unaware of its presence. He was however aware of an area of pigmentation that had developed over the last few years on the skin of the left clavicular region (Figure 2). The patients medical history was significant for CML diagnosed in 2001 and is presently successfully in remission as maintained by Gleevec commenced soon after diagnosis. He is presently a nonsmoker (having stopped smoking 25 years ago) and social drinker only and does not participate in any habits such as chewing tobacco or betel quid. Notably also the patient has not had any environmental exposure to heavy metals during his working career. An area suggestive of a similar type of nevus to the palate was seen involving the left posterior buccal mucosa. Biopsy was performed of the palatal lesion in August 2011 and the patient has been followed up since. The biopsy area healing was uneventful and retained a light pink mucosal appearance after 10 months post surgery. No change to the size or texture of the presenting lesions was ascertained in 10 months follow-up. The patient is continuing to have regular medical assessments for the management of his leukemia. Sections show pigment deposition in the submucosa of the palate (Figure 3a). Staining by Perls iron stain demonstrated extensive granular iron deposits (Figure 3b).

In order to show melanin deposition a sensitive PanMelanin staining protocol was followed (Figure 3c). The specificity of the staining protocols was examined by performing a melanin bleaching reaction which removed a significant proportion of the pigment (Figure 3d). Histopathology A biopsy was performed by taking an elliptical section of representative lesional mucosa, 10 x 4 mm with a variable depth measuring 2-4 mm from the left hard palate (Figure 1). Routine hematoxylin and eosin stained sections were performed (Figure 3a) and in addition, Perls iron stain was employed (Figure 3b) as well as panmelanin (Figure 3c) and melanin bleaching (Figure 3d). Microscopic exam shows squamous mucosa and underlying tissue containing minor salivary gland in the submucosa. The mucosa appears unremarkable with no basal hyperplasia, junctional activity or increase in basal melanocytes. There are scattered pigment laden cells in the superficial submucosa. A number are stained positive for iron with Perl stain. (Figure 3b).There is no evidence of dysplasia or malignancy. Immunohistochemistry with panmelanin stain is negative in the pigmented cells. Panmelanin stain combines the use of markers: melan A, tyrosinase and S-100 which offers a sensitive and specific melanocytic stain. This reaction detected melanin in a variety of other closely associated cells (Figure 3c). To confirm that there was a significant deposition of iron a melanin bleach was performed which confirmed the remaining stained cells to be iron pigment laden (Figure 3d). DISCUSSION CML may result in increased susceptibility to infections in addition to anemia and thrombocytopenia. Of clinical importance is that this particular disease process has been linked to a clear genetic abnormality viz: a chromosomal translocation known as the Philadelphia chromosome. The result is that a section of the BCR (Breakpoint Cluster Region) of chromosome 22 is fused to ABL gene (a protooncogene encoding a cytoplasmic and nuclear protein tyrosine kinase implicated in cell division) on chromosome 9. The resulting abnormal fusion gene product generates a novel protein with constitutive tyrosine kinase signaling activity which acts as a driver for this cancer (Faderl et al., 1999; Hehlmann et al., 2007). Contemporary recommendations for treatment of CML is with the use of imatinib mesylate (Gleevec). Gleevec received the U.S. Food and Drug Administration approval in May 2001 for use as an anticancer drug and was touted on the front page cover of TIME magazine in the

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Figure 1. View of hard palate post-biopsy. Patients left side is to the right of the image. Elliptical area of biopsy wound healing site is demonstrated.

Figure 2. Image taken of left shoulder at time of palatal biopsy

Figure 3a. Routine hematoxylin and eosin staining of representative palatal biopsy specimen

Figure 3b. Perls iron stain of representative section of palatal biopsy.

Figure 3c. PanMelanin staining of representative section of palatal biopsy.

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Figure 3d. Melanin bleaching of representative palatal biopsy specimen.

Table I. Skin and mucosal side effects of Gleevec therapy

Location Intraoral - palate Intraoral - palate intraoral - palate intraoral - palate extraoral - skin extraoral - skin extraoral - skin extraoral - skin extraoral skin

Finding Literature hyperpigmentation; Wong et al., 2011 melanin deposition hyperpigmentation; Mattsson et al., 2011 melanin deposition hyperpigmentation; Li et al., 2012 melanin and iron deposition hyperpigmentation; Resende et al.,2011 reactive melanosis Alexandrescu et al.,2008 hypopigmentation Tsao et al., 2003 hyperpigmentation Balagula et al., 2011 hyperpigmentation; iron deposition Belasco and Miller, 2007 hyperpigmentation Resende et al.,2011

same month as being a magic bullet for cancer. It acts via specific (targeted) inhibition of a signaling factor (tyrosine kinase). This is produced by the fusion protein product created by the Philadelphia chromosome translocation in CML as discussed above. Gleevec has been recently reported to produce as a potential oral side effect a diffuse hyperpigmentation of the palate. This presents with positive melanin staining but negative for iron (Wong et al., 2011). A reactive melanosis of the dermis has also been reported for patients managed by Gleevec (Alexandrescu et al., 2008). A number of the intraoral and extraoral pigmentary side-effects of Gleevec therapy are presented in Table I. Pigment deposition in the oral mucosa may reflect many different processes and is a challenging situation to diagnose accurately (Neville et al., 2008). Included in this differential diagnosis is: racial pigmentation, amalgam tattoo, melanotic macule, smokers melanosis, melanocytic nevus, melanoacanthoma and pigmentation secondary to injection of certain medications such as minocycline. Other examples can be cited such as systemic diseases like Addisons hypoadrenocorticism and finally of course, malignant melanoma. Physiological pigmentation may appear alarming with biopsy of the

relevant area being required to place the clinicians as well as patients mind at ease (Chandra et al., 2010). An excellent summary of these detailed differential diagnoses is presented by Resende et al., (2011). Various diagnostic considerations may be ruled out by the taking of a suitable medical history, yet, in other instances, a biopsy is certainly warranted to rule out possible intraoral melanoma as the main diagnostic concern. Drug induced palatal pigment changes in particular have been associated with a number of medications including Gleevec (Mattsson et al., 2011). This report makes the point that not only may hyperpigmentary changes be associated with Gleevec but also hypopigmentation (Table I; Tsao et al., 2003). The patients examined in the recent Mattsson et al., (2011) study had been on Gleevec for 5-6 years and presented with blue-brown pigmentations of the hard palate. Extensive melanin deposition in the lamina propria was observed. Another very recent report (Li et al., 2012) discusses Gleevec causing palatal diffuse pigmentary grey-blue painless alterations. The patients discussed had been on Gleevec for several years and histopathologically there was deposition of fine dark

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brown spherical granules in the submucosal tissues. No hemorrhage or inflammation nor melanocytic hyperplasia was seen. The granules were positive for both iron and melanin. It was commented that much like minocycline and anti-malarial medications producing an intraoral pigment change that Gleevec also led to putative deposition of a drug metabolite. In this case containing both melanin and iron. Another study (Wong et al., 2011), mentioned above, demonstrates the finding of melanin build-up in the palatal lamina propria in a patient taking Gleevec therapy for CML. Prussian blue staining for iron was negative. Mechanisms to explain the presence of melanin in the oral tissues include alterations in the c-Kit receptor tyrosine kinase. This receptor controls melanogenesis and melanocyte homeostasis and can be a target for Gleevec. Interestingly, Gleevec induced dermal hyperpigmentation is uncommon compared to its other more recognized side-effect, that of hypopigmentation (Balagula et al., 2011). This phenomenon as suggested above may be linked to alterations in c-kit signaling pathway (Wong et al., 2011; Alexandrescu et al., 2008). Therefore the observation of dermal pigmentation on the shoulder (Figure 2) is remarkable if this too is associated with Gleevec. The fact that the patient indicates it has come on in the last few years appears consistent with the notion that dermal involvement with Gleevec is also occurring in our case. No biopsy of the shoulder lesion was performed. It is certainly feasible that the shoulder lesion could well represent a pigmentary alteration secondary to Gleevec therapy, perhaps via the c-kit mechanism. Alternatively, the shoulder lesion may represent a deposition of drug complexes with melanin and iron consistent with the palatal findings. As mentioned, definitive proof rests on further special tests. Another interesting, though rather rare lesion is that of nevus of Ito and Ota. The nevus of Ito affects the shoulder area and may associate with nevus of Ota which itself is a blue or gray patch on the face. This may be acquired during life and within the distribution of the first or second division of the trigeminal nerve. It may be bilateral and involve oral sites or ocular and is a melanocytic lesion (Kannan, 2003). Asians are more commonly affected. The fact that in our present case the lesional tissues demonstrated a significant deposit of iron tends to mitigate against the combined nevus of Ito and Ota as a diagnosis. Due to the significant amount of iron deposition seen on biopsy of the palatal submucosa, hemochromatosis was also entertained in the diagnosis. Hemochromatosis is a genetic disorder of autosomal recessive pattern and the gene responsible is the HFE gene on chromosome 6 (Pietrangelo, 2010). Indeed this condition may lead to skin pigmentation by iron (Camaschella and Merlini, 2005). Secondary causes of iron accumulation such as

multiple blood transfusion and excess dietary iron and severe chronic hemolysis were ruled out from medical history. Diagnostically, in respect to iron disorders of metabolism, serum ferritin assay is the standard minimally invasive screening protocol. This however has non-specific complications as it is raised in infection, inflammation, fever and with liver and renal disease. These conditions can be ruled out by appropriate medical tests. It was found that in the present case serum ferritin levels were within normal limits ruling out iron metabolic disorders. Other systemic iron assays too such as transferrin were normal. With these findings and in the context of the patients medical background the only plausible conclusion is that our current observations are related to CML and/or his Gleevec therapy. It is understood that leukemias may result in thrombocytopenia, or a decrease in the number of circulating platelets (Neville et al., 2008). This can lead to focal dermal and/or mucosal ecchymoses or bruises which upon resolution would leave a residue of iron from exsanguinated red blood cells. This iron is in turn normally engulfed by resident tissue macrophages and becomes hemosiderin deposits within the tissues which can be detected by Perls staining. The platelet count for the patient has been regularly monitored during his Gleevec therapy and no major or significant persistent deviations from normal levels have been indicated. This does not rule out minor fluctuations occurring in-between blood assays that could in theory lead to focal hemorrhages with associated resultant iron deposition. Gleevec therapy in itself also contributes to a platelet decrease (Paul et al., 2010). This could potentially lead to dermatological effects such as focal ecchymoses with secondary localized iron accumulations. A case of altered dermal iron metabolism, or dermal hemosiderosis secondary to Gleevec therapy for CML, presented as reactive slate-grey patches on the skin developing over a several year period (Belasco and Miller, 2007). These patches were markedly positive for iron. It remains a potential possibility that the shoulder lesion in our case is related to this type of Gleevec-induced dermal hemosiderosis. Another possibility is that, as mentioned above, undetected thrombocytopenic episodes secondary to CML may lead to focal iron deposition. In order to shine further light on these suggestions a shoulder lesion biopsy is required. In the investigation of Resende et al. (2011) Gleevec associated hyperpigmentation of the palate of a 38 yr old man with CML diagnosed in 2005 is presented. He commenced Gleevec therapy that year along with receiving hematopoietic stem cell transplantation therapy and associated immunotherapy. In 2010 a diffuse blue hyperpigmentation of the hard palate was noted clinically yet the patient was unaware of its presence. A blue hyperpigmentation was also noted on the nose and ears. A provisional diagnosis of drug induced

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hyperpigmentation was made. No biopsy was done. As stated in this paper, pigmentation of the oral mucosa can reflect many conditions. These include racial pigmentation, melanotic macules, melanoma, blue nevi as well as exogenous pigmentations. In addition, systemic disorders leading to a pigmentary alteration such as Addisons disease and fibrous dysplasia and Nelson syndrome (rare today as this is secondary to bilateral removal of the adrenal glands) can be entertained in the differential diagnosis. Endogenous pigmentation via iron deposition can occur in focal hemorrhage within the mucosa secondary to, for example, a bleeding diathesis as well as drug induced changes. In this context it ought to be reminded that CML may result in a secondary episodic thrombocytopenia as mentioned above which in turn leads to a reactive diathesis with focal hemorrhages. This could certainly in itself result in iron deposits within tissues in addition to any direct drug-induced effects. The article concludes by saying the mouth related alterations secondary to Gleevec therapy are very rare. More cases are required to understand this relatively new lesion. In our present case, melanin and iron deposition is seen in close proximity (Figure 3). It has been postulated of late that joint complex formation of iron and melanin and a drug metabolite of Gleevec can occur (Li et al., 2012). Other drugs such as antimalarial medications may lead to deposition of iron and melanin (Kleinegger et al., 2000), This latter article discusses multifocal oral and facial pigmentation in an individual taking the antimalarial drug quinacrine. Macrophages bearing iron and melanin deposits were noted in the lamina propria tissues. With chloroquine antimalarial drug therapy hyperpigmentation of the oral mucosa is seen (Moraes et al., 2011) - usually affecting the palate. On microscopic exam, melanin incontinence is present and no iron is observed. It is certainly possible that in the above outlined studies a drug metabolite has complexed with iron and/or melanin to result in the features observed. Antimalarials and a listing of other medications leading to mouth pigment changes via deposition of melanin and drug metabolites has been adequately presented (Neville et al., 2008). A central aspect of the importance of arriving at a defined diagnosis in the case of pigmented oral lesions is to rule out cancerous activity. Melanotic pigmentation of the palate can represent a precursor to malignant melanoma (Meleti et al., 2010). Also, Auluck et al. (2008) highlight the importance of biopsy and periodic follow-up for patients with unusual focal pigmented lesions of the mouth. Additionally to Gleevec, other drugs are being developed to specifically target the genetic lesion in CML. In patients demonstrating a resistance to Gleevec, second generation tyrosine kinase inhibitors are indicated (San Jose-Eneriz et al., 2009). Such second

generation targeting agents are Nilotinib (Breccia and Alimena, 2010) and Dasatinib (Olivieri and Manzione, 2007). The question is will these novel drugs lead to intraoral side effects as has been implied from the literature for Gleevec? Dasatinib certainly appears to have depigmentation capabilities (Sun A. et al., 2009) yet little appears to be known in this regard for Nilotinib. As usage with these relatively new drugs spreads then answers to this question will be forthcoming. In terms of management of pigmented lesions treatment may be indicated to electively remove an area of melanin pigmentation via CO2 laser (Esen et al., 2004). Removal of iron related stains may be more difficult and is not routinely performed. CONCLUSION Our present case adds to the body of literature outlining the rare side-effects of CML and its targeted therapy. The deposition of iron and melanin suggests a reaction to a drug metabolite of Gleevec. We cannot also rule out the focal build up of iron in tissues chronically traumatized in patients with CML as a secondary feature to subclinical/undetected episodes of thrombocytopenia. Followup of the biopsy site for about 10 months showed that the healing mucosa remains normal in coloration. This in itself suggests that the pigment deposition is not only exogenous but also slow to occur. The shoulder lesion was not biopsied but certainly it is tempting to suggest that it too is associated with the same process as noted for the palatal pigmentation. Further examination/special tests would be required to shed light on that aspect. Other intraoral sites of pigmentation were noted but not biopsied yet in all likelihood represent a similar process to that of the palate. Future studies examining the precise nature of any associated drug metabolites of Gleevec deposited in the tissues are needed. Whether these metabolites directly chelate to iron and/or melanin will shine more light on how this pigmentation arises. Other designed targeted therapies ought to be closely followed for this potential side-effect as well. Finally, as more and more longer term survivors of CML are being seen in the dental office as well as in general medical practice clinicians ought to be aware of the type of presentation that may occur clinically in such patients. Our article aims to educate and demonstrate this particular interesting presentation.
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