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severe ulcerative colitis: data from the United Kingdom inflammatory bowel disease audit. Aliment Pharmacol Ther 2013; 38: 935–45. 25 Sjoberg M, Walch A, Meshkat M, Gustavsson A, Jarnerot G, Vogelsang H et al. Infliximab or cyclosporine as rescue therapy in hospitalized patients with steroid-refractory ulcerative colitis:
a retrospective observational study. Inflamm Bowel Dis 2012; 18: 212–18. 26 Mocciaro F, Renna S, Orlando A, Rizzuto G, Sinagra E, Orlando E et al. Cyclosporine or infliximab as rescue therapy in severe refractory ulcerative colitis: early and long-term data from a retrospective observational study. J Crohns Colitis 2012; 6: 681–6.
27 Naves JE, Llao J, Ruiz-Cerulla A, Romero C, Manosa M, Lobaton T et al. Long-term comparative efficacy of cyclosporine- or infliximab-based strategies for the management of steroid-refractory ulcerative colitis attacks. Inflamm Bowel Dis 2014; 20: 1375–81.
B R I E F C O M M U N I C AT I O N S
Resolution of paraneoplastic immune thrombocytopenia following everolimus treatment for metastatic renal cell carcinoma S. Zheng,1 H. Chan,2 R. J. Epstein2,3 and J. E. Joseph1,3 Departments of 1Haematology and 2Oncology, St Vincent’s Hospital, New South Wales and 3Faculty of Medicine, St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, Australia
Key words paraneoplastic thrombocytopenia, renal cell carcinoma, everolimus. Correspondence Shiying Zheng, Department of Haematology, St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, NSW 2010, Australia. Email: [email protected] Received 21 October 2014; accepted 13 February 2015.
Abstract Autoimmune thrombocytopenia is an uncommon but reported paraneoplastic manifestation of renal cell carcinoma (RCC). Treatment usually involves management of the underlying malignancy; however, steroids have shown a benefit in published case reports. Here, we describe a patient with profound thrombocytopenia secondary to metastatic RCC. It was refractory to steroid and intravenous immunoglobulin, but the platelet count improved markedly following initiation of everolimus. The possible explanation includes immunomodulation, tumour lysis or a combination of both effects. This is the first reported case of everolimus used in paraneoplastic thrombocytopenia from RCC. More studies are needed for further investigation of its potential use in secondary immune thrombocytopenia from RCC and perhaps other malignancies.
doi:10.1111/imj.12779
Paraneoplastic syndromes presenting as immunemediated haematological disorders are rare, but have occasionally been reported in renal cancer.1 Such syndromes often resolve with treatment of the underlying malignancy. Case reports have also documented benefit with the use of steroids for paraneoplastic autoimmune thrombocytopenia.2 Here, we report a patient with metastatic renal cell carcinoma (RCC) who developed secondary immune thrombocytopenic purpura (ITP) which proved refractory to steroids but responded to a Funding: None. Conflict of interest: None.
second-line therapy for renal clear cell carcinoma, everolimus. A 65-year-old Caucasian man from rural Australia presented with a 2-day history of gross haematuria and oral mucosal bleeding. He had a background of metastatic renal clear cell carcinoma with extensive lymphadenopathy, multiple pulmonary nodules in the right lung and infiltrative skeletal disease. His cancer had initially been treated with a partial right nephrectomy; after recurrence, the patient was commenced on a tyrosine kinase inhibitor, pazopanib. The latter medication had been ceased by the patient 4 weeks prior to the current presentation due to severe fatigue. His general © 2015 Royal Australasian College of Physicians
666
Brief Communications
medical history included hypertension, hypothyroidism, prostatomegaly and renal calculi of the right kidney. No risk factor of human immunodeficiency virus infection was identified. He had no known drug allergy and was on esomeprazole 20 mg daily, thyroxine 50 mcg mane, amlodipine 5 mg daily and irbesartan 300 mg combined with hydrochlorothiazide 12.5 mg daily. Both of the antihypertensives were ceased 2 weeks prior to admission due to hypotension. Norfloxacin 400 mg twice daily was started by the patient’s general practitioner for a suspected urinary tract infection based on his haematuria. On examination, the patient had perioral bleeding, petechiae and presence of gross macroscopic haematuria. Full blood examination showed marked anaemia with haemoglobin at 68 g/L, reduced mean cell volume of 77 fl and mean cell haemoglobin of 25.0 pg as well as severe thrombocytopenia at 4 × 109/L. The total leucocyte count was 5.6 × 109/L with the following differential counts: neutrophils 4.1 × 109/L, lymphocytes 0.7 × 109/L, monocyte 0.7 × 109/L. The blood film showed anisocytosis, polychromasia and rouleaux. Red cell fragmentation was not seen on the blood film. Iron studies were consistent with anaemia of chronic disease. A disseminated intravascular coagulation screen was negative. Peripheral blood lymphocyte immunophenotyping showed no evidence of a clonal lymphoid population. Two weeks prior to presentation, the platelet count was elevated at 545 × 109/L. The provisional diagnosis was ITP, either secondary to recent introduction of norfloxacin, idiopathic in nature or paraneoplastic. Due to ongoing haematuria causing symptomatic anaemia, prednisone 1 mg/kg and 0.4 g/kg of intravenous immunoglobulin (IVIG) were administered, together with one pool of platelet concentrates. Full blood count at 1 h after platelet infusion confirmed no
platelet increment. The patient had ongoing significant haematuria and developed epistaxis on day 4 of admission, necessitating further red cell transfusion, the use of tranexamic acid 1 g sixth hourly and cauterisation of the right nostril. Bone marrow biopsy was performed, which showed plentiful numbers of normal megakaryocytes with no evidence of metastatic carcinoma involving the marrow or myelodysplastic syndrome. IVIG was then increased to 1 g/kg for further 2 days and pulse methylprednisolone 1 g intravenously was given without success. The patient developed steroid-induced diabetes requiring insulin therapy. On day 11 of admission, platelet count remained at 3 × 109/L. In view of the underlying RCC and the known dual effects of mammalian target of rapamycin (mTOR) inhibitors on immunomodulation and tumour lysis, everolimus 10 mg daily was initiated. This was subsequent to a discussion with the patient about the potential marrow suppressive side effects including more profound thrombocytopenia. On day 14, which was 3 days after commencement of everolimus, the platelet count rose to 9 × 109/L. His platelet count continued to rise to 124 × 109/L on discharge (day 22 of admission) (Fig. 1). On follow up, 4 weeks post discharge, the platelet count was 578 × 109/L. Despite continuing on the everolimus, his RCC later progressed and he was managed with supportive measures only. Paraneoplastic syndromes are a heterogeneous group of disorders related to malignancy that cannot be explained by the direct local or metastatic effects of the cancer. Paraneoplastic autoimmune thrombocytopenia in solid tumours is a rare but well-reported phenomenon.3 It is most common in patients with lung and breast cancers, very rare in prostate cancer, but relatively common in renal cell and ovarian cancers.2 Although an autoantibody directly related to this form of
Figure 1 Relationship of platelet counts, days of admission and treatment administered. © 2015 Royal Australasian College of Physicians
667
Brief Communications
paraneoplastic autoimmunity has not been identified, it is thought that immune dysregulation secondary to malignancy results in the destruction of platelets.4 There have been reported cases of clinical improvement after tumour resection,5–7 chemotherapy8 or radiation together with hormonal therapy,9 without immunosuppression for ITP, although some of the response was short lived, presumably due to residual metastasis or recurrence. In other cases, immunotherapy prior to surgery was used.10,11 Danazol, an attenuated androgen, has been successfully used in a recent case report to correct RCC-related thrombocytopenia after 2 months of treatment, prior to curative partial nephrectomy.12 Nevertheless, response occurs slowly (typically 3–4 months13) and its use is contraindicated in patients with known prostate disease. Therefore, we did not consider danazol given the patient’s concurrent comorbidity of prostatomegaly and the bleeding complication of secondary ITP requiring transfusion. Aggressive immunosuppression has been used to control the aberrant immune response. There are case reports demonstrating response in patients where standard therapy for primary ITP was utilised.2 However, as manifested in our patient, clinical presentations can be more severe and refractory to regular therapy than the non-malignant counterpart. This has also been observed in other paraneoplastic autoimmune diseases.4 In our case, after failing oral steroid, regular dose IVIG, high dose IVIG and pulse methylprednisolone, we used everolimus, which is known to possess both immunomodulatory and antineoplastic effects. It is a derivative of sirolimus and through oral admission acts as an inhibitor of the mTOR. The mTOR is an important component of the intracellular signalling pathway that regulates cell function. By inhibiting mTOR, it hinders interleukin-2-driven T-cell proliferation.14,15 Hence, its immunosuppressive activity is widely used in the transplant setting. However, there has been no report of its use in ITP. MTOR is also important in cell growth, angiogenesis and metabolism. It is acknowledged that abnormal functioning of signalling pathways in RCC, including activa-
References 1 Kim HL, Belldegrun AS, Freitas DG, Bui MH, Han KR, Dorey FJ et al. Paraneoplastic signs and symptoms of renal cell carcinoma: implications for prognosis. J Urol 2003; 170: 1742–6. 2 Krauth MT, Puthenparambil J, Lechner K. Paraneoplastic autoimmune
tion of mTOR, together with loss of the Von Hippel– Lindau tumour suppressor gene lead to increased expression of hypoxia-inducible factor 1 (HIF-1). This results in overexpression of the HIF-1 target gene products, such as vascular endothelial growth factor (VEGF), and induces tumour angiogenesis, growth and progression of RCC.16 The RECORD Trial was a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with progressive metastatic RCC despite VEGF-targeted therapy. It showed a 4.9 months improvement in progression-free survival.16 Everolimus has gained both US Food and Drug Administration and European Society for Medical Oncology indication as second-line therapy for RCC. It is most commonly used after a tyrosine kinase inhibitor, such as pazopanib and sunitinib. Our patient had a dramatic and sustained improvement of the platelet count after treatment using everolimus. Despite the concern of worsening thrombocytopenia due to the inhibitory effect of everolimus on growth factor-dependent proliferation in haemopoietic cells,14 such adverse reaction was not observed in this case. In the RECORD trial, thrombocytopenia was observed to be more common in everolimus-treated arm (55 patients, 20% in the treatment arm, vs three patients, 2% in the placebo arm). However, only two patients (
severe ulcerative colitis: data from the United Kingdom inflammatory bowel disease audit. Aliment Pharmacol Ther 2013; 38: 935–45. 25 Sjoberg M, Walch A, Meshkat M, Gustavsson A, Jarnerot G, Vogelsang H et al. Infliximab or cyclosporine as rescue therapy in hospitalized patients with steroid-refractory ulcerative colitis:
a retrospective observational study. Inflamm Bowel Dis 2012; 18: 212–18. 26 Mocciaro F, Renna S, Orlando A, Rizzuto G, Sinagra E, Orlando E et al. Cyclosporine or infliximab as rescue therapy in severe refractory ulcerative colitis: early and long-term data from a retrospective observational study. J Crohns Colitis 2012; 6: 681–6.
27 Naves JE, Llao J, Ruiz-Cerulla A, Romero C, Manosa M, Lobaton T et al. Long-term comparative efficacy of cyclosporine- or infliximab-based strategies for the management of steroid-refractory ulcerative colitis attacks. Inflamm Bowel Dis 2014; 20: 1375–81.
B R I E F C O M M U N I C AT I O N S
Resolution of paraneoplastic immune thrombocytopenia following everolimus treatment for metastatic renal cell carcinoma S. Zheng,1 H. Chan,2 R. J. Epstein2,3 and J. E. Joseph1,3 Departments of 1Haematology and 2Oncology, St Vincent’s Hospital, New South Wales and 3Faculty of Medicine, St Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, Australia
Key words paraneoplastic thrombocytopenia, renal cell carcinoma, everolimus. Correspondence Shiying Zheng, Department of Haematology, St Vincent’s Hospital, 390 Victoria Street, Darlinghurst, NSW 2010, Australia. Email: [email protected] Received 21 October 2014; accepted 13 February 2015.
Abstract Autoimmune thrombocytopenia is an uncommon but reported paraneoplastic manifestation of renal cell carcinoma (RCC). Treatment usually involves management of the underlying malignancy; however, steroids have shown a benefit in published case reports. Here, we describe a patient with profound thrombocytopenia secondary to metastatic RCC. It was refractory to steroid and intravenous immunoglobulin, but the platelet count improved markedly following initiation of everolimus. The possible explanation includes immunomodulation, tumour lysis or a combination of both effects. This is the first reported case of everolimus used in paraneoplastic thrombocytopenia from RCC. More studies are needed for further investigation of its potential use in secondary immune thrombocytopenia from RCC and perhaps other malignancies.
doi:10.1111/imj.12779
Paraneoplastic syndromes presenting as immunemediated haematological disorders are rare, but have occasionally been reported in renal cancer.1 Such syndromes often resolve with treatment of the underlying malignancy. Case reports have also documented benefit with the use of steroids for paraneoplastic autoimmune thrombocytopenia.2 Here, we report a patient with metastatic renal cell carcinoma (RCC) who developed secondary immune thrombocytopenic purpura (ITP) which proved refractory to steroids but responded to a Funding: None. Conflict of interest: None.
second-line therapy for renal clear cell carcinoma, everolimus. A 65-year-old Caucasian man from rural Australia presented with a 2-day history of gross haematuria and oral mucosal bleeding. He had a background of metastatic renal clear cell carcinoma with extensive lymphadenopathy, multiple pulmonary nodules in the right lung and infiltrative skeletal disease. His cancer had initially been treated with a partial right nephrectomy; after recurrence, the patient was commenced on a tyrosine kinase inhibitor, pazopanib. The latter medication had been ceased by the patient 4 weeks prior to the current presentation due to severe fatigue. His general © 2015 Royal Australasian College of Physicians
666
Brief Communications
medical history included hypertension, hypothyroidism, prostatomegaly and renal calculi of the right kidney. No risk factor of human immunodeficiency virus infection was identified. He had no known drug allergy and was on esomeprazole 20 mg daily, thyroxine 50 mcg mane, amlodipine 5 mg daily and irbesartan 300 mg combined with hydrochlorothiazide 12.5 mg daily. Both of the antihypertensives were ceased 2 weeks prior to admission due to hypotension. Norfloxacin 400 mg twice daily was started by the patient’s general practitioner for a suspected urinary tract infection based on his haematuria. On examination, the patient had perioral bleeding, petechiae and presence of gross macroscopic haematuria. Full blood examination showed marked anaemia with haemoglobin at 68 g/L, reduced mean cell volume of 77 fl and mean cell haemoglobin of 25.0 pg as well as severe thrombocytopenia at 4 × 109/L. The total leucocyte count was 5.6 × 109/L with the following differential counts: neutrophils 4.1 × 109/L, lymphocytes 0.7 × 109/L, monocyte 0.7 × 109/L. The blood film showed anisocytosis, polychromasia and rouleaux. Red cell fragmentation was not seen on the blood film. Iron studies were consistent with anaemia of chronic disease. A disseminated intravascular coagulation screen was negative. Peripheral blood lymphocyte immunophenotyping showed no evidence of a clonal lymphoid population. Two weeks prior to presentation, the platelet count was elevated at 545 × 109/L. The provisional diagnosis was ITP, either secondary to recent introduction of norfloxacin, idiopathic in nature or paraneoplastic. Due to ongoing haematuria causing symptomatic anaemia, prednisone 1 mg/kg and 0.4 g/kg of intravenous immunoglobulin (IVIG) were administered, together with one pool of platelet concentrates. Full blood count at 1 h after platelet infusion confirmed no
platelet increment. The patient had ongoing significant haematuria and developed epistaxis on day 4 of admission, necessitating further red cell transfusion, the use of tranexamic acid 1 g sixth hourly and cauterisation of the right nostril. Bone marrow biopsy was performed, which showed plentiful numbers of normal megakaryocytes with no evidence of metastatic carcinoma involving the marrow or myelodysplastic syndrome. IVIG was then increased to 1 g/kg for further 2 days and pulse methylprednisolone 1 g intravenously was given without success. The patient developed steroid-induced diabetes requiring insulin therapy. On day 11 of admission, platelet count remained at 3 × 109/L. In view of the underlying RCC and the known dual effects of mammalian target of rapamycin (mTOR) inhibitors on immunomodulation and tumour lysis, everolimus 10 mg daily was initiated. This was subsequent to a discussion with the patient about the potential marrow suppressive side effects including more profound thrombocytopenia. On day 14, which was 3 days after commencement of everolimus, the platelet count rose to 9 × 109/L. His platelet count continued to rise to 124 × 109/L on discharge (day 22 of admission) (Fig. 1). On follow up, 4 weeks post discharge, the platelet count was 578 × 109/L. Despite continuing on the everolimus, his RCC later progressed and he was managed with supportive measures only. Paraneoplastic syndromes are a heterogeneous group of disorders related to malignancy that cannot be explained by the direct local or metastatic effects of the cancer. Paraneoplastic autoimmune thrombocytopenia in solid tumours is a rare but well-reported phenomenon.3 It is most common in patients with lung and breast cancers, very rare in prostate cancer, but relatively common in renal cell and ovarian cancers.2 Although an autoantibody directly related to this form of
Figure 1 Relationship of platelet counts, days of admission and treatment administered. © 2015 Royal Australasian College of Physicians
667
Brief Communications
paraneoplastic autoimmunity has not been identified, it is thought that immune dysregulation secondary to malignancy results in the destruction of platelets.4 There have been reported cases of clinical improvement after tumour resection,5–7 chemotherapy8 or radiation together with hormonal therapy,9 without immunosuppression for ITP, although some of the response was short lived, presumably due to residual metastasis or recurrence. In other cases, immunotherapy prior to surgery was used.10,11 Danazol, an attenuated androgen, has been successfully used in a recent case report to correct RCC-related thrombocytopenia after 2 months of treatment, prior to curative partial nephrectomy.12 Nevertheless, response occurs slowly (typically 3–4 months13) and its use is contraindicated in patients with known prostate disease. Therefore, we did not consider danazol given the patient’s concurrent comorbidity of prostatomegaly and the bleeding complication of secondary ITP requiring transfusion. Aggressive immunosuppression has been used to control the aberrant immune response. There are case reports demonstrating response in patients where standard therapy for primary ITP was utilised.2 However, as manifested in our patient, clinical presentations can be more severe and refractory to regular therapy than the non-malignant counterpart. This has also been observed in other paraneoplastic autoimmune diseases.4 In our case, after failing oral steroid, regular dose IVIG, high dose IVIG and pulse methylprednisolone, we used everolimus, which is known to possess both immunomodulatory and antineoplastic effects. It is a derivative of sirolimus and through oral admission acts as an inhibitor of the mTOR. The mTOR is an important component of the intracellular signalling pathway that regulates cell function. By inhibiting mTOR, it hinders interleukin-2-driven T-cell proliferation.14,15 Hence, its immunosuppressive activity is widely used in the transplant setting. However, there has been no report of its use in ITP. MTOR is also important in cell growth, angiogenesis and metabolism. It is acknowledged that abnormal functioning of signalling pathways in RCC, including activa-
References 1 Kim HL, Belldegrun AS, Freitas DG, Bui MH, Han KR, Dorey FJ et al. Paraneoplastic signs and symptoms of renal cell carcinoma: implications for prognosis. J Urol 2003; 170: 1742–6. 2 Krauth MT, Puthenparambil J, Lechner K. Paraneoplastic autoimmune
tion of mTOR, together with loss of the Von Hippel– Lindau tumour suppressor gene lead to increased expression of hypoxia-inducible factor 1 (HIF-1). This results in overexpression of the HIF-1 target gene products, such as vascular endothelial growth factor (VEGF), and induces tumour angiogenesis, growth and progression of RCC.16 The RECORD Trial was a phase III, randomised, double-blind, placebo-controlled trial of everolimus in patients with progressive metastatic RCC despite VEGF-targeted therapy. It showed a 4.9 months improvement in progression-free survival.16 Everolimus has gained both US Food and Drug Administration and European Society for Medical Oncology indication as second-line therapy for RCC. It is most commonly used after a tyrosine kinase inhibitor, such as pazopanib and sunitinib. Our patient had a dramatic and sustained improvement of the platelet count after treatment using everolimus. Despite the concern of worsening thrombocytopenia due to the inhibitory effect of everolimus on growth factor-dependent proliferation in haemopoietic cells,14 such adverse reaction was not observed in this case. In the RECORD trial, thrombocytopenia was observed to be more common in everolimus-treated arm (55 patients, 20% in the treatment arm, vs three patients, 2% in the placebo arm). However, only two patients (
