Originally published as JCO Early Release 10.1200/JCO.2005.06.079 on November 30 2004

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Imatinib-Induced Regression of AIDS-Related Kaposi's Sarcoma

Henry B. Koon, Glenn J. Bubley, Liron Pantanowitz, David Masiello, Brad Smith, Katherine Crosby, JoAnn Proper, Will Weeden, Thomas E. Miller, Pamela Chatis, Merrill J. Egorin, Steven R. Tahan, Bruce J. Dezube

From the Beth Israel Deaconess Medical Center; PerkinElmer Life Sciences, Boston; Cell Signaling Technology, Beverly, MA; and University of Pittsburgh Cancer Institute, Pittsburgh, PA

Address reprint requests to Bruce J. Dezube, MD, Beth Israel Deaconess Medical Center, 330 Brookline Ave, CC-913, Boston, MA 02215; e-mail: bdezube{at}caregroup.harvard.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Activation of the platelet-derived growth factor (PDGF) and c-kit receptors has been proposed as important in mediating the growth of AIDS-related Kaposi's sarcoma (KS). We investigated the response of KS to the PDGF receptor (PDGFR)/c-kit inhibitor, imatinib mesylate, and investigated the effect of this therapy on critical signal transduction intermediates.

PATIENTS AND METHODS: Ten male patients with AIDS-related cutaneous KS, which progressed despite chemotherapy and/or highly active antiretroviral therapy, received imatinib mesylate administered orally, 300 mg twice daily. Clinical response was determined by serial tumor measurements. To determine biologic and histologic response, skin lesion biopsies were obtained at baseline and following 4 weeks of therapy.

RESULTS: Five of 10 participants had a partial response by tumor measurements. Biopsies after 4 weeks of therapy demonstrated histologic regression in four of six patients. Four patients' tumor biopsies were assessable for immunohistochemistry end points pre- and post-therapy. These demonstrated inhibition of PDGFR and its downstream effector, extracellular receptor kinase, which is a member of the mitogen-activated protein kinase family. The most common adverse event was diarrhea, which led to dose reduction in six patients.

CONCLUSION: Imatinib mesylate administered orally twice daily for AIDS-related KS results in clinical and histologic regression of cutaneous KS lesions within 4 weeks. These promising results demonstrate that inhibition of the c-kit and/or PDGF receptors may represent an effective strategy for treating KS.

	INTRODUCTION

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AIDS-related Kaposi's sarcoma (KS) is a multifocal, vascular, proliferative disease associated with HIV and KS herpes virus (KSHV)/human herpes virus-8 co-infection.¹ KS predominantly involves the skin, but may effect the mucosa and viscera.² Histologically, KS plaque and nodular lesions are made up of clusters of spindle-shaped cells (KS spindle cells), slit-like vessels, and a variable inflammatory infiltrate.³ A number of cytokines and growth factors have been implicated in KS progression, but the critical factors for growth in vivo are not known.^4-10

Both in vivo and in vitro studies have suggested platelet-derived growth factor (PDGF) signaling has a role in KS formation. KS spindle cells have been shown by in situ hybridization and immunohistochemistry to express both and ß PDGF receptors (PDGFRs).⁸ PDGF, the ligand for PDGFR, is expressed by a distinct subpopulation of KS spindle cells.^8,10 Studies have demonstrated that the growth of KS spindle cells can be arrested by placing them in PDGF-depleted medium.¹¹ This arrest can be mitigated by the addition of recombinant PDGF.⁸ Additionally, PDGF has been shown to induce the expression of vascular endothelial growth factor (VEGF) by KS spindle cells.⁹ These data suggest that the PDGFR is involved in two critical pathways in KS development: (1) induction of KS spindle cell growth and (2) induction of angiogenesis through VEGF.

In addition to PDGFR, another receptor tyrosine kinase that has been implicated in KS formation is c-kit. KSHV infection of dermal microvasculature endothelial cells (DMVEC) results in the upregulation of the c-kit receptor.¹² Furthermore, KSHV-infected DMVEC proliferate in response to c-kit ligand (stem-cell factor), which is constitutively expressed by DMVEC.¹² Expression of c-kit in HIV-related KS in vivo has been demonstrated by immunohistochemistry.¹³ Activating mutations of c-kit have not been reported in KS lesions. These observations suggest that c-kit may play an important role in the development of KS.

Activated PDGFR and c-kit stimulate multiple signaling pathways through downstream effectors. Both receptors have been shown to activate the serine/threonine kinase AKT via phosphoinositide 3-kinase (PI3K).^14,15 AKT may mediate cell cycle progression via cyclin D and block apoptosis through pathways that induce Bcl-XL, an anti-apoptotic Bcl-2 family member, as well as phosphorylate and inhibit Bad, a pro-apoptotic Bcl-2 family member.^16-18 PDGFR and c-kit may also activate the serine/threonine kinase extracellular receptor kinase (ERK), which is a member of the mitogen-activated protein kinase family.^19,20 ERK plays a critical role in the regulation of a number of transcription factors associated with cell proliferation. ERK, in conjunction with AKT signaling, activates nuclear factor kappa B, a transcription factor that has proliferative as well as anti-apoptotic effects on cells.²¹ ERK can also influence the cell cycle by regulating Kip1/p27 and cyclin D.²² Activation of these pro-growth and/or anti-apoptotic pathways by PDGFR and c-kit via AKT and/or ERK could contribute to the development of the KS lesion.

Imatinib mesylate (Gleevec; Novartis Pharma AG, Basel, Switzerland) selectively inhibits the tyrosine kinases Abl and c-kit, which result in its activity in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors, respectively.^23,24 Imatinib has been used successfully to treat dermatofibrosarcoma protuberans and hypereosinophilic syndrome, which are dependent on the PDGF pathway.^25,26 Because of the role of PDGFR and c-kit in KS, we investigated the response of AIDS-related KS to imatinib. In CML, the recommended imatinib dose is 400 to 600 mg per day for chronic phase and 600 to 800 mg per day for accelerated phase. Based on these data we chose a dose of 600 mg per day to optimize the chance for response. We also investigated the effect of therapy on the activation of the PDGFR and c-kit receptors; their downstream signaling intermediates, ERK and AKT; as well as the effect on plasma VEGF concentrations.

	PATIENTS AND METHODS

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Patients
Ten male patients with biopsy-proven AIDS-related KS were enrolled at Beth Israel Deaconess Medical Center (Boston, MA). All patients provided written informed consent in accordance with human experimentation guidelines of the Human Investigations Committee at Beth Israel Deaconess Medical Center. Patients were required to have KS involving the skin, and no pulmonary involvement, symptomatic gastrointestinal involvement, or tumor-associated edema. Additional eligibility criteria included documentation of HIV infection, a Karnofsky performance status 60%, and the following laboratory parameters: hemoglobin 8.0 gm/dL, absolute neutrophil count 1,000 cells/µL, platelet count 75,000/µL, serum creatinine 1.5 mg/dL (or measured creatinine clearance > 60 mL/min), AST/ALT 3 times the upper limit of normal, and a normal total serum bilirubin. HIV infection was documented by a positive enzyme-linked immunosorbent assay or Western Blot. Exclusion criteria included concurrent active opportunistic infection and symptomatic visceral KS requiring cytotoxic therapy. Patients could not have received treatment for KS within 4 weeks of study entry. Antiretroviral therapy was permitted but not required. Patients taking antiretroviral therapy could not have had a medication change within 4 weeks of study entry. No blood products were permitted within 4 weeks of study entry. Granulocyte colony-stimulating factor and erythropoietin were not permitted within 2 weeks of study entry to limit potential confounding causes if hematologic toxicity were to occur.

Study Design
In this open-label pilot study, imatinib was administered orally at a dose of 300 mg twice daily (600 mg/d) for 4 weeks. At the end of the 4-week period, patients without evidence of progression were allowed to continue on the drug until there was evidence of disease progression. Imatinib was provided by Novartis Pharma AG and was formulated as 100-mg hard gelatin capsules.

For grade 3/4 toxicity, imatinib was withheld until the toxicity resolved to grade 1. However, for grade 3/4 hematologic toxicity, defined as an absolute neutrophil count < 1,000/µL, or a platelet count < 50,000/µL, imatinib was withheld until the toxicity had resolved to grade 2. After resolution, the dose of imatinib was reduced to 200 mg twice daily. If the grade 3/4 toxicity recurred, imatinib was held until the toxicity resolved to grade 1 ( grade 2 for neutropenia and thrombocytopenia), and the daily dose of imatinib was reduced to 100 mg twice daily. If the grade 3/4 toxicity recurred yet again, therapy was discontinued. No dose reductions were performed for grade 1 to 4 anemia. Once on study, patients could be transfused packed red blood cells at the discretion of the investigators.

Schedule of Events
Clinical assessments, including a history and physical examination that focused on HIV- and KS-related signs and symptoms, evaluation of KS lesions, a complete blood count with differential, serum electrolytes, renal and liver function tests, amylase, lactate dehydrogenase, total protein, and albumin were performed on days 1, 8, 15, and 29 and then every 4 weeks after therapy was initiated. A 4-mm punch biopsy of a representative KS lesion at baseline and at 4 weeks was performed on all patients who consented and when the biopsy would not interfere with measuring tumor response. Plasma samples for cytokine concentrations were collected before imatinib administration and then 4 weeks after treatment was started. KS tumor assessments were based on measurement of cutaneous marker lesions and on the overall number and characteristics of cutaneous lesions. For patients with 50 total skin and oral lesions, all lesions were evaluated for flattening and change in number. For patients with > 50 lesions, three representative anatomic areas were chosen for ongoing evaluation of lesion number and characteristics.

Plasma Imatinib Concentrations
Blood samples were collected for pharmacokinetic analysis before imatinib administration and then 4 weeks after the first dose. Samples were collected in heparinized tubes and centrifuged at 2,400 xg for 5 minutes. Plasma was aliquoted and stored at –80°C until the time of analysis. Plasma concentrations of imatinib and its main metabolite (CGP-74588) were determined with a previously described and validated liquid chromatographic-mass spectrometric assay.²⁷

KS Biopsy/Immunohistochemistry
Tumor biopsies were immediately placed in formalin for fixation. After paraffin embedding, tissue sections of 5-µm thickness were prepared and stained using the antibodies anti-PDGFR, anti-c-kit, anti-phosphorylated (phospho)-PDGFR (tyrosine 751), anti-phospho-AKT (serine 473), and anti-phospho-ERK (threonine 202/tyrosine 204; Cell Signaling, Beverly, MA). Slides were de-paraffinized in xylene and ethanol. Antigen retrieval was performed by boiling the slides for 10 min in pH 6 citrate buffer. The slides stained for phospho-AKT and phospho-ERK were cooled for 30 minutes. The slides stained for phospho-PDGFR were cooled for 15 minutes in 1mM EDTA, pH 8.0. After 10 minutes in 3% H₂O₂, slides were incubated overnight with the primary antibody at a 1/250 dilution for phospho-AKT, 1/100 dilution for phospho-ERK, and 1/50 dilution for phospho-PDGFR at 4°C. This was followed by a 30-minute incubation with 100 µL of biotinylated anti-rabbit secondary antibody, then 30 minutes with ABC avidin/biotin (Vector Labs, Burlingame, CA). Slides were incubated in ethanol and xylene before mounting coverslips. Immunohistochemistry stains were then scored on a scale of 0 to 4+ by a dermatopathologist (S.R.T.).

VEGF Concentrations
The PerkinElmer Cytokine Chip (PerkinElmer, Cambridge, MA) was used to analyze VEGF concentrations. The assays rely on "sandwich" fluorescent detection, employing two antibodies per cytokine. A capture antibody that was specific for each cytokine was spotted in quadruplicate (one time in each subarray, four subarrays per gel pad) on the HydroGel-coated slide (PerkinElmer). The sample (75 µL) was pipetted onto one of the pads on the HydroGel-coated slide and allowed to incubate for 2 hours, during which time any cytokine present bound to its capture antibody. Unbound material was washed away and a biotinylated detector antibody mixture (75 µL) was added and incubated for 1 hour. This mixture contained detector antibodies that were specific for each cytokine and bound to the cytokine that had been retained by the appropriate capture antibody, thus forming a sandwich. The detector antibody, in turn, was bound by cyanine 3–conjugated streptavidin (75 µL for 30 min). The intensity of the fluorescent signal was proportional to the amount of cytokine protein in the sample.

After running the assay, slides were imaged using a ScanArray Confocal Laser Scanner (PerkinElmer). After imaging, the resulting tif files were quantitated using QuantArray software (PerkinElmer). Replicate spots were averaged and tested for outliers using the extreme studentized deviate method (n = 4; critical Z value, 1.48). Four-point standard curves were used to estimate the concentration of each cytokine in the samples. Standards were analyzed by point-to-point linear regression, and concentrations of experimental samples were estimated from these standards.

Statistics and Response Criteria
Complete response was defined as the absence of any detectable residual disease persisting for at least 4 weeks. Partial response was defined as either a 50% decrease in the number of all previously existing lesions or complete flattening of at least 50% of all previously raised lesions, or a 50% decrease in the sum of the products of the largest perpendicular diameters of the marker lesions. A partial response was required to persist for at least 4 weeks without the development of new lesions, new visceral sites of involvement, or increased tumor-associated edema or effusions. Progressive disease was defined by any of the following: 25% increase in the sum of the perpendicular diameters of the indicator lesions; 25% increase in the total lesion count; 25% increase in the number of raised lesions; new visceral sites of involvement; and development of new tumor-associated edema or effusion that lasted at least 1 week and interfered with normal activities. Stable disease was defined as any response not meeting the criteria for complete response, partial response, or progressive disease.²⁸

	RESULTS

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Patient Characteristics
Seven patients reported prior chemotherapy for KS, including single-agent chemotherapy with liposomal doxorubicin (n = 4), paclitaxel (n = 5), and liposomal daunorubicin (n = 2; Table 1). At the time of study entry, all patients were receiving highly active antiretroviral therapy (HAART) consisting of nucleoside/nucleotide reverse transcriptase inhibitors (NRTI) in combination with a protease inhibitor and/or non-NRTI. Although the protocol required that patients be on a stable antiretroviral regimen for a minimum of 28 days before study entry, eight of these 10 patients had been on the same regimen for > 22 weeks. The median time between initiation of the stable HAART regimen to study entry was 37.5 weeks (range, 4 to 52 weeks). Only patient 3, who had been on HAART for 4 weeks before study entry, had a significant increase in his CD4 count while on study.

Antitumor Effects
Five of 10 patients had a partial response by tumor measurement after only 4 weeks of imatinib therapy (Table 1). The remaining five patients, who had been developing new lesions before therapy, had stable disease at 4 weeks. Three of the patients with stable disease had biopsies after 4 weeks of therapy. Two of the three biopsies demonstrated histologic regression by the criteria previously described (Fig 1).¹³

View larger version (98K): [in this window] [in a new window]   Fig 1. Histologic regression of AIDS-related cutaneous Kaposi's sarcoma (KS) lesions. (A) Pretreatment plaque stage KS (at baseline); (B) Regressed KS lesion showing loss of spindle cells and a residual perivascular inflammatory infiltrate (at 4 weeks).

View larger version (127K): [in this window] [in a new window]   Fig 2. Kaposi's sarcoma skin lesions obtained at baseline demonstrate expression of (A) platelet-derived growth factor receptor and (B) c-kit.

View larger version (123K): [in this window] [in a new window]   Fig 3. Baseline and 4 weeks post-therapy immunohistochemistry of Kaposi's sarcoma spindle cells using antibodies directed against specific phosphorylation (activation) sites demonstrating (A) decreased platelet-derived growth factor receptor phosphorylation after treatment; (B) decreased extracellular receptor kinase phosphorylation after treatment; and (C) minimal AKT phosphorylation at baseline and no change after treatment.

	DISCUSSION

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Both the PDGFR and c-kit pathways have been implicated in the development of KS.^7-10,12 However, it is not known if in vitro models accurately represent the biology of the human disease. The availability of the PDGFR/c-kit inhibitor imatinib allowed us to investigate the importance of these pathways in AIDS-related KS in the clinic.

Imatinib, administered 300 mg orally twice daily to patients with AIDS-related KS and receiving HAART, was poorly tolerated. The incidence of diarrhea was higher than in trials with CML patients treated at the same dose. In those trials, 24% of the patients had grade 1/2 diarrhea and none had grade 3/4 diarrhea.^23,30 One possible explanation for the increased frequency and severity of the diarrhea is a drug interaction with the medications involved in the HAART regimen. Imatinib is a substrate for the cytochrome p450 isoforms, CYP3A4 and CYP2D6. All of the protease inhibitors approved at the time of the study, which included amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, are CYP3A4 inhibitors, with ritonavir inhibiting CYP2D6 to a lesser extent. Diarrhea is a side effect common to all of the protease inhibitors. The other class of antiretrovirals shown to affect the p450 system is non-nucleoside reverse transcriptase inhibitors. Delavirdine is a CYP3A inhibitor, while nevirapine is a CYP3A inducer, and efavirenz is a mixed CYP3A inducer/inhibitor. No correlation between any specific antiretroviral regimen and the incidence of diarrhea was observed. There was no obvious increase in plasma steady-state concentrations of imatinib or its metabolite. Although these data suggest there was no inhibition of imatinib metabolism, the imatinib concentrations may not be truly representative of the steady-state concentration. Samples were randomly obtained on day 28 and by that time, all patients with diarrhea had developed symptoms. The presence of the diarrhea could have affected the absorption of imatinib as well as patient adherence with the therapy. Unfortunately, plasma concentrations of the antiretrovirals were not measured. It is plausible that the observed toxicities may be due to imatinib inhibition of antiretroviral metabolism because imatinib is a substrate of the CYP3A4 and CYP2D6 pathways. Investigation into the mechanisms of imatinib toxicity is the subject of a future trial.

In this pilot study, imatinib was shown to induce clinical regression in five of 10 patients within 4 weeks of therapy. Patient 3, who had only been on HAART for 4 weeks before beginning therapy, had an increase in his CD4 count after 4 weeks of therapy. This raises the question of whether his response was to imatinib or was a delayed response to HAART. Although we cannot determine the reason for his response from our limited data, it is notable that he had been developing new lesions the week before he started imatinib.

In order to elucidate which signaling pathways may have been critical to imatinib-induced response, we examined tumor biopsies for evidence of decreased phosphorylation (ie, inhibition) of PDGFR and c-kit, as well as their downstream effectors AKT and ERK. Four patients had tumor biopsies that were assessable at baseline and at 4 weeks by immunohistochemistry with phosphospecific antibodies. After 4 weeks of therapy, three of these biopsies demonstrated a decrease of phosphorylation (activation) of the PDGFR and ERK pathways when compared to baseline. The fourth biopsy (patient 10) demonstrated +3 immunoreactivity for phospho-PDGFR and phospho-ERK at baseline and after 4 weeks of therapy. Interestingly, patient 10 had stable disease after 4 weeks on imatinib therapy and had low concentrations on imatinib and its metabolite at the time of biopsy. In contrast, there was minimal or no activation of AKT in pretreatment tumor specimens. Because the phospho-c-kit antibody recognized the phosphorylation of the activation motif on both PDGFR and c-kit, we were unable to determine conclusively the phosphorylation status of c-kit. Post-treatment biopsies demonstrated dramatic reduction in ERK and PDGFR phosphorylation in three patient specimens. These observations suggest that the ERK pathway, in contrast to the AKT pathway, may be critical for proliferation of KS lesions. This is of interest, as signaling from PDGFR in other cell systems is often transmitted through AKT.³¹

VEGF concentrations were measured in nine patients at baseline and after 4 weeks of therapy. In this study, no difference was seen in VEGF concentrations between responders and nonresponders. Although in vitro evidence suggested that inhibition of the PDGF pathway would decrease VEGF concentrations, our data would suggest that either PDGF regulation of VEGF is not the primary pathway in vivo, or there are parallel pathways that are able to compensate for PDGFR inhibition.

In conclusion, we demonstrated that imatinib may be an effective form of therapy in patients with AIDS-related KS. Unfortunately, imatinib administered at a dose of 600 mg daily was poorly tolerated in some patients. Therefore, a follow-up study planned by the AIDS Malignancy Clinical Trial Consortium is being performed at a dose of 400 mg per day. The reason for the increased toxicity in HIV patients on HAART is unclear and the mechanism of toxicity will be investigated in a follow-up study. This is the first study to demonstrate that inhibition of PDGFR and ERK correlates with regression of KS. Our findings support the need for further evaluation of imatinib as a single agent in patients with KS that is refractory to standard therapies.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Merrill Egorin, Novartis. Performed contract work within the last 2 years: Merrill Egorin, Novartis.

	Acknowledgment

 
We thank Jerome Groopman for his support during this project.

	NOTES

 
Supported by the AIDS Oncology Clinical Scientist Development Program (H.B.K., grant No. K12CA077846-03).

H.B.K. and G.J.B contributed equally to this work.

Funding for this study was provided by Novartis Pharma AG, Basel, Switzerland.

Presented in part at the International AIDS Malignancy Conference, Bethesda, MD, April 28-29, 2003, and 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted June 14, 2004; accepted October 13, 2004.

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