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Molecularly targeted therapy for Kaposi's sarcoma in a kidney transplant patient: case report, "what worked and what did not"
© Volkow et al; licensee BioMed Central Ltd. 2007
Received: 09 August 2006
Accepted: 27 March 2007
Published: 27 March 2007
Imatinib is a tyrosine-kinase inhibitor; for which there is limited information regarding its effects on AIDS Kaposi's sarcoma and none in patients with transplant-associated Kaposi's sarcoma. Sirolimus, an immunosuppressive drug used for kidney transplant, exhibits antiangiogenic activity related to impaired production of VEGF (vascular endothelial growth factor), clinical benefit has been reported in Kaposi's sarcoma associated with renal graft.
Here we report a case of an 80 year old male, who developed Kaposi's Sarcoma nine months after receiving a living non-related donor kidney transplant at age 74. Three years after treatment with different chemotherapeutic agents for progressive cutaneous Kaposi's Sarcoma with no visceral involvement, he was prescribed Imatinib (200 mg/day for two weeks followed by 400 mg/day) after four weeks of treatment he developed anasarca, further progression of KS and agranulocytosis. Imatinib was discontinued and there was significant clinical recovery. One year later his immunosuppressive therapy was changed to Sirolimus and regression of the Kaposi's sarcoma occurred.
The lack of benefit and severe toxicity associated with the use of Imatinib in this patient should alert clinicians of potentially adverse consequence of its use in patients with transplant associated Kaposi's sarcoma. On the other hand the positive response seen in this patient to Sirolimus even after a long evolution of Kaposi's sarcoma, multiple chemotherapy regimens and extensive cutaneous disease further suggest it therapeutical utility for transplant associated Kaposi's sarcoma.
Since the identification of Human Herpes 8 (HHV-8) in 1994, [1, 2] there have been great advances in the understanding of the pathogenesis of Kaposi's sarcoma (KS). The better understanding of autocrine and paracrine factors in the proliferation and differentiation of KS cells  has provided a potential benefit derived from targeted therapy, a therapeutic field which has achieved an enormous development over the last decade. There are few reports regarding novel treatment options for KS, this includes the use of Imatinib in AIDS KS  and the use of Sirolimus in renal transplant KS patients .
Imatinib is a tyrosine-kinase inhibitor that induces apoptosis in Bcr-Abl positive cell lines, platelet-derived growth factor positive cells and c-kit positive gastrointestinal stromal cells. Limited information exists regarding its effects on KS cells . Though the drug safety profile is good it can induce severe adverse events . Because Imatinib is metabolized through the CYP3A3 enzyme it can result in adverse drugs interaction. Its safety in patients with renal-insufficiency or kidney graft is unknown.
HHV-8 up-regulates the vascular endothelial growth factor (VEGF) receptor Flk-1/KDR in endothelial cells. In vitro infection of human primary endothelial cells with HHV-8 causes long-term proliferation and survival of cells. Blocking the interaction between VEGF and Flk-1/KDR can abolish VEGF induced proliferation. Sirolimus an immunosuppressive drug used in kidney transplantation , exhibits antiangiogenic activity related to impaired production of VEGF and limited proliferative response of endothelial cells to stimulation by VEGF, therefore inhibiting KS progression.
End stage renal disease started on hemodyalisis (79 years old male).
Living non-related donor kidney transplant.
Diagnosed with Kaposi's Sarcoma.
Three year chemotherapy (vincristine-belomycin) (liposomal adriamycin)
Agranulocitosis, anasarca increase in creatinine.
Placitaxel (developed allergic rash).
Change immunosuppressive therapy for Sirolimus.
Persistent Kaposi's Sarcoma regression, still on Sirolimus.
The patient is an 80 year old male with diabetes mellitus and hypertension, who at age 74 (March 2001) had received a living non-related donor kidney transplant. At that time he was discharged with a double immunosuppressive therapy consisting of prednisone 20 mg/day and mophetil mycophenolate 1.5 gr/day. No calcineurin inhibitor was administered. His prednisone dose was further decreased to 5 mg/day and mophetil mycophenolate doses sustained. In November 2001 he developed cutaneous purple elevated lesions in his lower limbs that were diagnosed as KS by skin biopsy. He received 19 administrations of vincristine (1 mg) and bleomycin (15 mg) weekly that resulted in flattening and fading of the lesions. Treatment was discontinued for two months, and KS recurred, with pain and edema in both legs.
On July 2002, with an almost 100% involvement of his lower limbs skin with KS but no visceral involvement he received 50 mg of liposomal-adriamycin. In addition, he was then prescribed valganciclovir 450 mg BID (corrected for creatinine clearance)  and three additional administrations of liposomal-adriamycin, up to December 2002. He showed 40% response again with early relapse. On January 2003 the patient developed disseminated herpes zoster, which was treated with IV acyclovir.
KS is a proliferative disease, cytokine mediated, where the presence of the Human Herpes virus 8 is essential for the process, and immunesuppression is a necessary fact . The disease is insidious and with an unpredictable course; when there is no visceral involvement, it is usually not life threatening. 
It has been recognized that glucocorticoids have a major role in KS development, [9–11] and their withdrawal may induce regression of KS lesions [12, 13]. In vitro they have a synergistic effect with oncostatin, an autocrine element involved in KS-cells proliferation.
A wide variety of therapies have been used for KS, including interferon [14, 15] and different chemotherapeutic regimens . Recently Imatinib has been used in KS AIDS patients with short periods of observation . In addition, a recent study demonstrated that Siroliumus inhibited progression of dermal KS in kidney transplanted patients with an outstanding clinical outcome .
There is currently no evidence of imatinib effectiveness in transplant associated-KS patients; and there is therefore no basis for its prescription in this group of patients. Moreover, in the case we are reporting, Imatinib not only had no clinical benefit but resulted in life threatening toxicity. In contrast in this patient Sirolimus treatment was associated with extensive regression of severe cutaneous KS even after a long-standing and extended disease, and multiple previous chemotherapy treatments (Table 1). Sirolimus exhibits antiangiogenic activity related to impaired production of VEGF and limiting proliferative response of endothelial cells to stimulation by VEGF, limiting the progression of KS. The KS regression in this case cannot be solely attributed to prednisone withdrawal, since he had been on very low doses of prednisone (2.5 mg qd) months before Sirolimus was initiated. Our results corroborate therapeutic benefit of Sirolimus in kidney graft recipients[5, 17, 18] both as an immunosuppressant to prevent graft rejection and to induce long standing KS regression.
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