Antitumor activity of nivolumab on hemodialysis after renal allograft rejection
A 63 year-old female with longstanding type-1 diabetes mellitus and hypertension developed chronic renal failure in 2002 and underwent a pre-emptive renal allograft transplant from her donor husband in 2004 without requiring prior dialysis. Both the donor and recipient were cytomegalovirus-negative. She received basiliximab 20 mg prior to her transplant surgery and another 20 mg on day 4 post-transplant. Following transplantation she was immunosuppressed with mycophenolate mofetil, prednisone and tacrolimus. She had longstanding stable kidney function following transplantation with a baseline GFR of 84 mL/min and a creatinine of 80 micromol/L. Her past medical history was remarkable for iatrogenic hypothyroidism following parathyroidectomy for primary hyperparathyroidism, and she had no prior history of malignancy.
In April 2015, after ten years of immunosupression, she developed an irregular hyperpigmented and evolving lesion on her left upper back which was resected in May 2015. The biopsy of the left scapular site revealed a superficial spreading invasive melanoma with a maximum Breslow thickness of 2.59 mm, Clark level of IV, with, mitoses of 5/mm2. No ulceration was identified, but tumor infiltrating lymphocytes and tumor regression were present. Peripheral margins were uninvolved, but deep margin was involved by a satellite nodule and microsatellitosis was also present. Wide-local excision and bilateral axillary lymph node biopsies were performed July 2015, as lymphoscintigraphy had identified drainage of each of the lesion to the contralateral axilla when injected with technetium 99 sulfur colloid. Three right axillary lymph nodes were removed and were negative for malignancy, but 1 left axillary lymph node was removed and pathology revealed an 8.5 mm × 7.5 mm melanoma deposit with extranodal extension. As a result, the patient required a wide local excision with a 2 cm margin and pathology demonstrated residual disease and microsatellites, with negative margins. A second lesion was excised at the time of surgery in the right scapula, again consistent with superficial spreading invasive melanoma, Breslow thickness 1 mm, Clark level II, without ulceration, no mitoses and clear margins (pT1a). Completion lymph-node dissection August 2015 retrieved 22 lymph nodes, all of which were negative for melanoma, with final American Joint Committee on Cancer (AJCC) pathological staging of pT3aN2c.
Staging CT in July 2015 showed a non-specific 6.5 mm non-calcified right lower lobe (RLL) lung nodule, not previously present. BRAF mutation test of the with real-time PCR assay using the Qiagen BRAF RGQ kit was BRAF wild-type. The patient was not offered adjuvant radiotherapy and declined high-dose adjuvant interferon.
Follow-up CT imaging in October 2015 demonstrated increase in size of the RLL lung nodule and the appearance of at least eight new subcentimeter bilateral pulmonary nodules, along with increased mediastinal and left hilar lymphadenopathy (12 mm). The patient was asymptomatic. A follow-up 2-deoxy-2[F-18] fluoro-D-glucose (FDG) PET-CT scan in December 2015 demonstrated an intensely hypermetabolic (SUV max 9.9) left hilar lymph node enlarging to 16 mm, along with non-FDG avid pulmonary nodules. An endobronchial ultrasound-guided biopsy of the hilar lymph node (station 11 L) demonstrated atypical cells reactive for S100/melanA, confirming metastatic melanoma. Her case was discussed at the multidisciplinary tumor board and renal transplantation team, and a recommendation for anti-PD-1 treatment was made, based on available safety data and high risk of cancer-related mortality. Full discussion with patient and her husband regarding the risks and benefits of treatment were had and the patient wished to proceed with treatment including unknown risks of allograft rejection. Immunosuppressive medications were titrated off and she was left on 10 mg of prednisone daily, with no deterioration in renal function prior to nivolumab administration.
The patient received her first treatment of nivolumab (anti-PD-1 treatment for metastatic melanoma, single intravenous dose of 324 mg) on January 7th, 2016. She reported no subjective toxicities within the first week of treatment, but on day 8 the patient developed lethargy, abdominal pain, nausea, vomiting and loose stools (4 times per day), malaise, anorexia and fatigue. Physical examination demonstrated signs of uremia and concurrent tenderness in the lower abdomen at the site of allograft implantation without peritoneal signs. Laboratory investigations showed a creatinine rise to 577 micromol/L without any change in electrolytes. The ultrasound Doppler of her kidney showed markedly abnormal appearance of the transplant kidney with findings suggestive of acute medical renal disease, poor perfusion and elevated resistive indices concerning for transplant dysfunction. She received a pulse of corticosteroids (methylprednisolone 500 mg IV × 1), and developed diabetic ketoacidosis requiring insulin infusion and initiation of hemodialysis. She had a second pulse of steroids with close endocrinologic monitoring and insulin sliding scale, after which prednisone was tapered down. Renal allograft function did not return and she was discharged home on hemodialysis. Nivolumab was withheld and the patient was observed.
Restaging CT thorax on February 2016 demonstrated a partial resolution of bilateral pulmonary nodules, hilar lymph nodes and mediastinal lymph nodes but right lower pleural thickening was noted. However, the patient had subsequent clinical deterioration 6 weeks later in March 2016 with dyspnea, cough and hypoxia with CT thorax showing significant progression of lung parenchymal disease and multiple new lung nodules. Infection was ruled out by bronchoscopic examination, and empiric treatment with piperacillin/tazobactam. After careful consideration and multidisciplinary review, the patient was re-administered nivolumab starting April 2016, with both ongoing clinical and radiographic response. Restaging 12-week CT thorax June 2016 on nivolumab shows almost total resolution of previously noted multiple bilateral pulmonary nodules and consolidations (Fig. 1), but some slight increase in size of mediastinal and hilar lymph nodes not meeting criteria for progression by immune-related response criteria (irRC) in solid tumors [11]. At the time of publication the patient has an ongoing (8-month) response in lung metastases and stable mediastinal/hilar lymph nodes, but slight growth of a single axillary lymph node.
Radiographic response to nivolumab on hemodialysis; CT chest exams performed at baseline and 12 weeks after re-initiation of therapy demonstrates resolution of lung nodules (indicated by the yellow arrows). The hilar lymph node indicated by the red arrow is stable