Complete resolution of oral Kaposi’s sarcoma achieved by changing immunosuppression: a case report

Abstract

A 38-year-old Afro-Caribbean woman, who was pre-dialysis with polycystic kidney disease, received a live-donor kidney transplant from her 55-year-old mother. This study documents her imunosuppression therapy including resolution of an oral Kaposi’s sarcoma and explores the many underlying problems with converting to an mTOR inhibitor.

Case history

A 38-year-old Afro-Caribbean woman, who was pre-dialysis with polycystic kidney disease, received a live-donor kidney transplant from her 55-year-old mother. They were a haplotype match and both tested positive for cytomegalo-virus antibody screening. Other virology (HIV, hepatitis) was negative in both individuals. Immunosuppression with basiliximab induction and tacrolimus-based triple maintenance therapy (trough levels 5–15 ng/ml, prednisolone 20 mg OD and Mycophenolate Mofetil 500 mg BD) was administered. At 3 months post transplantation, she underwent a surveillance biopsy which revealed an essentially normal kidney (all Banff scores 0). Following this biopsy, she was allocated to the control arm of an in-house, randomised, control trial comparing CNI minimisation to conversion to sirolimus at 3 months. Her immunosuppressive regimen was changed to Myfortic^® (Novartis Pharmaceuticals, NJ, USA) 720 mg BD and her tacrolimus target trough levels were lowered to 5–8 ng/ml. She began a 3-month schedule of steroid minimisation (5 mg reduction per month). Eight months post engraftment, she presented with three fungating mouth lesions. Incisional biopsies revealed Kaposi’s sarcoma staining positive for human herpes virus 8. A computerised tomography scan revealed wide-spread pulmonary metastasis.

Her 24-h urinary protein excretion, at the time of presentation, was 300 mg and her estimated glomerular filtration rate was 46 ml/min (Modified Diet in Renal Disease method). The patient underwent abrupt conversion to the immuno-suppressant Sirolimus 14 days later. Her tacrolimus was stopped and she received 10 mg of Sirolimus for 2 days and then 5 mg OD with dose adjustment for target levels of 10–15 ng/ml. Her Myfortic^® was reduced to 360 mg BD and she was planned for steroid withdrawal.

She underwent an 11-month surveillance biopsy when her eGFR was 48 ml/min (1 month post conversion to Sirolimus) which revealed a Banff 1A subclinical rejection. After joint discussion between the transplant and oncological teams, it was decided that treatment with pulsed methylprednisolone was not appropriate. Instead, sirolimus trough levels were increased to 15 ng/ml and a supporting prednisolone dose of 5 mg once daily with Myfortic^® (360 mg BD) was chosen to balance the risks of graft loss versus remitting malignancy.

She underwent a repeat biopsy 1 month later, which showed that the rejection had resolved. Figure 1 illustrates that her oral disease completely regressed 4 months later and a repeat CT thorax revealed regression of her pulmonary metastasis. She is now more than a year post diagnosis and in full-time employment. Her renal function remains excellent: Her estimated glomerular filtration rates at –3, 0, 3, 6, 9, 12 and 15 months post conversion are 41, 36, 48, 46, 49, 52 and 53 ml/min, respectively). However, she is intolerant of statin medication due to muscle cramps and has developed hypercholesterolaemia – a well-recognised side effect of sirolimus. She currently takes a full dose fibrate and her latest cholesterol level is 5.9 mmol/ml, 13 months post conversion.

Figure 1.

The left-sided images illustrate the Kaposi’s sarcoma whereas the right-sided pictures reveal complete regression of the lesions 4 months after conversion to rapamune.

Discussion

Renal transplant recipients are 10–20 times more likely to suffer a malignancy some time post transplantation compared to the normal population.¹ In fact, 10–15% of post-transplantation deaths are malignancy related and more than 50% of patients will develop a malignancy 15 years post engraftment. The pro-malignant effect of calcineurin inhibitors (such as tacrolimus and cyclosporine) is well recognised both in the clinical and molecular arenas.² Conversely, the mammalian target of rapamycin inhibitors (such as sirolimus) block the P13K–AKT–mTOR pathway which is frequently involved in malignancy.¹ Data from the UNOS registry reveal that renal transplant recipients treated with sirolimus develop significantly lower rates of malignancy.³ Prior to the option of converting to mTOR inhibitors, the only treatment plan for patients with post-transplant malignancy was to partially or fully withdraw immunosuppression and administer standard anti-cancer treatment such as surgery, chemotherapy or radiotherapy. In these cases, rapid graft loss was almost inevitable and regression of these lesions was not guaranteed. Expert opinion suggests that many patients would risk the consequences of malignancy and self-administer non-prescribed calcineurin inhibitors rather than return to dialysis.⁵

Retrospective, single-arm evidence demonstrates that Kaposi’s sarcoma in particular appears to respond very well to conversion to mTOR inhibitors.⁵ Sirolimus does, however, have many side effects and some clinicians feel that its use should be restricted until less toxic compounds are developed.

This case explores many underlying problems with converting to an mTOR inhibitor. An immunologically high-risk recipient suffered a subclinical rejection episode 1 month post conversion to sirolimus. No studies have so far reported on surveillance renal transplant biopsies performed so quickly post switching immunosuppressive agent. In this case, the histological signs of rejection resolved over a month and it is impossible to say whether this was due to the higher sirolimus levels or simply part of the change in immunological response associated with modulating immunosuppression.

This case report does demonstrate that, in this scenario, her eGFR 1 year post conversion remained unchanged. The associated problem of her hypercholesterolaemia is a critical issue, especially given her young age. A long-term level of 5.9 mmol/dl may pose significant risk to her cardiovascular status. Would it be safest for her to have her sirolimus withdrawn and be left with high-dose Myfortic^® after an appropriate time period? The risk of rejection associated with mycophenolate/steroid dual therapy may be higher than usual in Afro-Caribbean patients, so it was decided not to withdraw her sirolimus and observe her closely.