Shields J

Introduction: Systemic mastocytosis (SM) is a rare myeloid neoplasm that is caused by accumulation of abnormal mast cells in the bone marrow, liver, spleen, and skin. The KIT D816V mutation encodes a constitutively activated receptor tyrosine kinase that drives disease pathogenesis. We present a case of systemic mastocytosis with associated clonal hematological non-mast cell disease (SM-AHNMD).

Background: A 71-year-old man presented with anemia, thrombocytopenia, absolute monocyte count of 2,000-4,000 and weight loss in August 2016. A CT showed splenomegaly and lymphadenopathy. Bone marrow biopsy revealed positive CD117 mast cells, CD34 myeloblasts and reticulin fibrosis consistent with SM. Immunohistochemistry confirmed the neoplastic cells were positive for CD25, but negative for CD2. PCR analysis revealed KIT D816V point mutation. Serum tryptase was 295 ug/L (normal 2.2-13.2). He was started on imatinib mesylate. However, his anemia, thrombocytopenia and splenomegaly worsened. He developed bilateral femoral neck fractures in April 2017. Imatinib was discontinued. He underwent bilateral hip hemiarthroplasty. Histology was consistent with SM (positive CD25 and CD117) with dysplastic megakaryocytes and increased monocytosis. By WHO classification he has SM-AHNMD with chronic myelomonocytic leukemia. He was started on cladribine for 4 cycles with good response in splenomegaly, anemia and thrombocytopenia, but he developed leukocytosis. Serum tryptase initially decreased to 141 but then rose to 243. Midostaurin 100 mg orally twice a day was initiated in December 2017. His cytopenia and splenomegaly improved. In March 2018 he was admitted for sigmoid colon obstruction due to inflammation or mass and underwent diverting loop ileostomy. Biopsy could not be performed. His serum tryptase decreased to 178 but increased to 275 in June 2018. He continues on midostaurin.

Discussion: SM-AHNMD constitutes approximately 40% of all SM with poor prognosis. SM is resistance to imatinib because of KIT D816V mutation. Cladribine has some activity. Midostaurin inhibits non-mutant and mutant KIT D816V with 58% response rate and median overall survival of 20 months. Our patient has a good response to both drugs.

Conclusions: Clinicians should be able to diagnose and treat SM. Cladribine and midostaurin are active drugs for SM.

Introduction: Systemic mastocytosis (SM) is a rare myeloid neoplasm that is caused by accumulation of abnormal mast cells in the bone marrow, liver, spleen, and skin. The KIT D816V mutation encodes a constitutively activated receptor tyrosine kinase that drives disease pathogenesis. We present a case of systemic mastocytosis with associated clonal hematological non-mast cell disease (SM-AHNMD).

Background: A 71-year-old man presented with anemia, thrombocytopenia, absolute monocyte count of 2,000-4,000 and weight loss in August 2016. A CT showed splenomegaly and lymphadenopathy. Bone marrow biopsy revealed positive CD117 mast cells, CD34 myeloblasts and reticulin fibrosis consistent with SM. Immunohistochemistry confirmed the neoplastic cells were positive for CD25, but negative for CD2. PCR analysis revealed KIT D816V point mutation. Serum tryptase was 295 ug/L (normal 2.2-13.2). He was started on imatinib mesylate. However, his anemia, thrombocytopenia and splenomegaly worsened. He developed bilateral femoral neck fractures in April 2017. Imatinib was discontinued. He underwent bilateral hip hemiarthroplasty. Histology was consistent with SM (positive CD25 and CD117) with dysplastic megakaryocytes and increased monocytosis. By WHO classification he has SM-AHNMD with chronic myelomonocytic leukemia. He was started on cladribine for 4 cycles with good response in splenomegaly, anemia and thrombocytopenia, but he developed leukocytosis. Serum tryptase initially decreased to 141 but then rose to 243. Midostaurin 100 mg orally twice a day was initiated in December 2017. His cytopenia and splenomegaly improved. In March 2018 he was admitted for sigmoid colon obstruction due to inflammation or mass and underwent diverting loop ileostomy. Biopsy could not be performed. His serum tryptase decreased to 178 but increased to 275 in June 2018. He continues on midostaurin.

Discussion: SM-AHNMD constitutes approximately 40% of all SM with poor prognosis. SM is resistance to imatinib because of KIT D816V mutation. Cladribine has some activity. Midostaurin inhibits non-mutant and mutant KIT D816V with 58% response rate and median overall survival of 20 months. Our patient has a good response to both drugs.

Conclusions: Clinicians should be able to diagnose and treat SM. Cladribine and midostaurin are active drugs for SM.

Introduction: Systemic mastocytosis (SM) is a rare myeloid neoplasm that is caused by accumulation of abnormal mast cells in the bone marrow, liver, spleen, and skin. The KIT D816V mutation encodes a constitutively activated receptor tyrosine kinase that drives disease pathogenesis. We present a case of systemic mastocytosis with associated clonal hematological non-mast cell disease (SM-AHNMD).

Background: A 71-year-old man presented with anemia, thrombocytopenia, absolute monocyte count of 2,000-4,000 and weight loss in August 2016. A CT showed splenomegaly and lymphadenopathy. Bone marrow biopsy revealed positive CD117 mast cells, CD34 myeloblasts and reticulin fibrosis consistent with SM. Immunohistochemistry confirmed the neoplastic cells were positive for CD25, but negative for CD2. PCR analysis revealed KIT D816V point mutation. Serum tryptase was 295 ug/L (normal 2.2-13.2). He was started on imatinib mesylate. However, his anemia, thrombocytopenia and splenomegaly worsened. He developed bilateral femoral neck fractures in April 2017. Imatinib was discontinued. He underwent bilateral hip hemiarthroplasty. Histology was consistent with SM (positive CD25 and CD117) with dysplastic megakaryocytes and increased monocytosis. By WHO classification he has SM-AHNMD with chronic myelomonocytic leukemia. He was started on cladribine for 4 cycles with good response in splenomegaly, anemia and thrombocytopenia, but he developed leukocytosis. Serum tryptase initially decreased to 141 but then rose to 243. Midostaurin 100 mg orally twice a day was initiated in December 2017. His cytopenia and splenomegaly improved. In March 2018 he was admitted for sigmoid colon obstruction due to inflammation or mass and underwent diverting loop ileostomy. Biopsy could not be performed. His serum tryptase decreased to 178 but increased to 275 in June 2018. He continues on midostaurin.

Discussion: SM-AHNMD constitutes approximately 40% of all SM with poor prognosis. SM is resistance to imatinib because of KIT D816V mutation. Cladribine has some activity. Midostaurin inhibits non-mutant and mutant KIT D816V with 58% response rate and median overall survival of 20 months. Our patient has a good response to both drugs.

Conclusions: Clinicians should be able to diagnose and treat SM. Cladribine and midostaurin are active drugs for SM.

Purpose: Unresectable hepatocellular carcinoma (HCC) is often treated with sorafenib or transarterial chemoembolization (TACE) for palliation. Cancer patients on aspirin or clopidogrel see improved survival. Addition of antiplatelet therapy can improve outcomes as seen in this case series of patients with liver cancer.

HCC develops from platelet mediated cytotoxic T lymphocyte liver damage. Sorafenib, aspirin and clopidogrel act via depletion of platelets and also reduce carcinogenic intrahepatic cytotoxic T lymphocytes. Mean progression free survival on treatment is dismal; sorafenib (5.5 mo), TACE (3.9 mo). and TACE plus sorafenib (6.3 mo.). Median overall survival on sorafenib, TACE, and TACE + sorafenib are 10.7, 19-20 mo, and 12 mo, respectively.

Background: 5 male HCC patients were treated with sorafenib and/or TACE and aspirin, clopidogrel, or both. They all underwent triphasic CT scans. Case 1: Age 55 years, male, 2x2 cm lesion; received sorafenib 200 mg twice daily, 81 mg aspirin, and 75 mg clopidogrel. The patient achieved complete remission twice and was alive at 7 years 2 mo. Case 2: Age 69 years, male, 5x5 cm HCC; received TACE once and took 81 mg aspirin daily. He achieved radiographic complete remission and was alive at 43 mo 9 days. Case 3: Age 67 years, male, 6 x 6 cm HCC; had TACE once and 81 mg aspirin daily. Patient had complete remission at 32 mo and 16 days. Case 4: Age 72, male, 2 x 2 cm HCC; had TACE and 81 mg aspirin. He achieved complete remission at 14 months. Case 5: Age 68 years, male, 8 x 5 cm HCC; previously failed TACE and sorafenib. The patient presented with weight loss, class Child C cirrhosis, large volume ascites; alpha-fetoprotein (AFP) 208,960 ng/mL. He started on baby aspirin, diuretics and hospice care. A month later, his ascites decreased and he began sorafenib 200 mg twice daily. 3 months later the AFP dropped to 83,000 ng/mL. 5 months later, AFP 5950 ng/mL, tumor 3x2 cm; no ascites. 13 mo later: AFP 34,620 ng/mL, alive, asymptomatic.

Conclusion: These cases achieved progression free survival and overall survival significantly better (3-4x) than historical controls. Childs C cases might also benefit from adding aspirin or clopidogrel to sorafenib. Antiplatelet medication merits further study in hepatocellular cancer treated with sorafenib or TACE.

Purpose: Unresectable hepatocellular carcinoma (HCC) is often treated with sorafenib or transarterial chemoembolization (TACE) for palliation. Cancer patients on aspirin or clopidogrel see improved survival. Addition of antiplatelet therapy can improve outcomes as seen in this case series of patients with liver cancer.

HCC develops from platelet mediated cytotoxic T lymphocyte liver damage. Sorafenib, aspirin and clopidogrel act via depletion of platelets and also reduce carcinogenic intrahepatic cytotoxic T lymphocytes. Mean progression free survival on treatment is dismal; sorafenib (5.5 mo), TACE (3.9 mo). and TACE plus sorafenib (6.3 mo.). Median overall survival on sorafenib, TACE, and TACE + sorafenib are 10.7, 19-20 mo, and 12 mo, respectively.

Background: 5 male HCC patients were treated with sorafenib and/or TACE and aspirin, clopidogrel, or both. They all underwent triphasic CT scans. Case 1: Age 55 years, male, 2x2 cm lesion; received sorafenib 200 mg twice daily, 81 mg aspirin, and 75 mg clopidogrel. The patient achieved complete remission twice and was alive at 7 years 2 mo. Case 2: Age 69 years, male, 5x5 cm HCC; received TACE once and took 81 mg aspirin daily. He achieved radiographic complete remission and was alive at 43 mo 9 days. Case 3: Age 67 years, male, 6 x 6 cm HCC; had TACE once and 81 mg aspirin daily. Patient had complete remission at 32 mo and 16 days. Case 4: Age 72, male, 2 x 2 cm HCC; had TACE and 81 mg aspirin. He achieved complete remission at 14 months. Case 5: Age 68 years, male, 8 x 5 cm HCC; previously failed TACE and sorafenib. The patient presented with weight loss, class Child C cirrhosis, large volume ascites; alpha-fetoprotein (AFP) 208,960 ng/mL. He started on baby aspirin, diuretics and hospice care. A month later, his ascites decreased and he began sorafenib 200 mg twice daily. 3 months later the AFP dropped to 83,000 ng/mL. 5 months later, AFP 5950 ng/mL, tumor 3x2 cm; no ascites. 13 mo later: AFP 34,620 ng/mL, alive, asymptomatic.

Conclusion: These cases achieved progression free survival and overall survival significantly better (3-4x) than historical controls. Childs C cases might also benefit from adding aspirin or clopidogrel to sorafenib. Antiplatelet medication merits further study in hepatocellular cancer treated with sorafenib or TACE.

Purpose: Unresectable hepatocellular carcinoma (HCC) is often treated with sorafenib or transarterial chemoembolization (TACE) for palliation. Cancer patients on aspirin or clopidogrel see improved survival. Addition of antiplatelet therapy can improve outcomes as seen in this case series of patients with liver cancer.

HCC develops from platelet mediated cytotoxic T lymphocyte liver damage. Sorafenib, aspirin and clopidogrel act via depletion of platelets and also reduce carcinogenic intrahepatic cytotoxic T lymphocytes. Mean progression free survival on treatment is dismal; sorafenib (5.5 mo), TACE (3.9 mo). and TACE plus sorafenib (6.3 mo.). Median overall survival on sorafenib, TACE, and TACE + sorafenib are 10.7, 19-20 mo, and 12 mo, respectively.

Background: 5 male HCC patients were treated with sorafenib and/or TACE and aspirin, clopidogrel, or both. They all underwent triphasic CT scans. Case 1: Age 55 years, male, 2x2 cm lesion; received sorafenib 200 mg twice daily, 81 mg aspirin, and 75 mg clopidogrel. The patient achieved complete remission twice and was alive at 7 years 2 mo. Case 2: Age 69 years, male, 5x5 cm HCC; received TACE once and took 81 mg aspirin daily. He achieved radiographic complete remission and was alive at 43 mo 9 days. Case 3: Age 67 years, male, 6 x 6 cm HCC; had TACE once and 81 mg aspirin daily. Patient had complete remission at 32 mo and 16 days. Case 4: Age 72, male, 2 x 2 cm HCC; had TACE and 81 mg aspirin. He achieved complete remission at 14 months. Case 5: Age 68 years, male, 8 x 5 cm HCC; previously failed TACE and sorafenib. The patient presented with weight loss, class Child C cirrhosis, large volume ascites; alpha-fetoprotein (AFP) 208,960 ng/mL. He started on baby aspirin, diuretics and hospice care. A month later, his ascites decreased and he began sorafenib 200 mg twice daily. 3 months later the AFP dropped to 83,000 ng/mL. 5 months later, AFP 5950 ng/mL, tumor 3x2 cm; no ascites. 13 mo later: AFP 34,620 ng/mL, alive, asymptomatic.

Conclusion: These cases achieved progression free survival and overall survival significantly better (3-4x) than historical controls. Childs C cases might also benefit from adding aspirin or clopidogrel to sorafenib. Antiplatelet medication merits further study in hepatocellular cancer treated with sorafenib or TACE.

Background: Sunitinib is one of the most commonly used first line treatments for metastatic renal cell carcinoma (mRCC). While toxicities are common, rhabdomyolysis is rare. The case presented here describes the quick and severe nature of this toxicity.

Case: The patient is a 71-year-old white male with mRCC admitted on 3/29/17 due to muscle weakness, fatigue, poor oral intake, and difficulty swallowing for 2 weeks. He was diagnosed with RCC and had a right nephrectomy in 2014. He developed biopsy proven lung metastasis, and sunitinib was started in May 2016. Sunitinib dose at that time was 37.5 mg per oral daily x 4 weeks every 6 weeks. On admission, he had a platelet count of 13,000, serum creatinine 2.23 mg/dL, total bilirubin 4 mg/dL, AST/ALT > 2,000 U/L, INR 2.9, calcium 7.5, creatinine kinase > 5,000 U/L, uric acid 12 mg/dL, and severe global hypokinesia with LVEF 30-35%. He quickly developed lactic acidosis and ARDS. In ICU he received bicarbonate, oxygen, furosemide, and treatment for hyperkalemia. Despite all treatment support he continued to decline. His family chose to deescalate care, and he died on 4/1/17.

Discussion: Sunitinib induced rhabdomyolysis has been reported in 2 patients with metastatic RCC. The proposed mechanism suggests sunitinib could interfere with fatty acid b-oxidation and glycogenolysis. Under these conditions AMP-kinase activity usually acts as a rescue pathway. Sunitinib inhibits AMP-Kinase thus causing decline in intracellular ATP and elevation in myoplasmic Ca2+. Sufficient ATP supply by mitochondrial respiratory chain fails and extrusion of Ca2+ to the extracellular space is reduced. Long-lasting Ca2+ elevations leads to myoplasmic Ca2+ overload and activate calpain proteases. The skeletal muscle specific calpain 3 protease may cause destruction of the myofibrils. Increase in creatinine kinase is the main clinical presentation.

Conclusions: Sunitinib-induced rhabdomyolysis is a very rare occurrence. Our case will be the third reported case in literature. Initial recognition of this toxicity is very important to ensure timely care.

References: (1) Ruggeri EM, Cecere FL, Moscetti L, Doni L, Padalino D, Di Costanzo F. Severe rhabdomyolysis during sunitinib treatment of metastatic renal cell carcinoma. A report of two cases. Ann Oncol. 2010;21(9):1926-1927. (2) Hohenegger M. Drug induced rhabdomyolysis. Curr Opin Pharmacol. 2012;12(3):335-339.

Background: Sunitinib is one of the most commonly used first line treatments for metastatic renal cell carcinoma (mRCC). While toxicities are common, rhabdomyolysis is rare. The case presented here describes the quick and severe nature of this toxicity.

Case: The patient is a 71-year-old white male with mRCC admitted on 3/29/17 due to muscle weakness, fatigue, poor oral intake, and difficulty swallowing for 2 weeks. He was diagnosed with RCC and had a right nephrectomy in 2014. He developed biopsy proven lung metastasis, and sunitinib was started in May 2016. Sunitinib dose at that time was 37.5 mg per oral daily x 4 weeks every 6 weeks. On admission, he had a platelet count of 13,000, serum creatinine 2.23 mg/dL, total bilirubin 4 mg/dL, AST/ALT > 2,000 U/L, INR 2.9, calcium 7.5, creatinine kinase > 5,000 U/L, uric acid 12 mg/dL, and severe global hypokinesia with LVEF 30-35%. He quickly developed lactic acidosis and ARDS. In ICU he received bicarbonate, oxygen, furosemide, and treatment for hyperkalemia. Despite all treatment support he continued to decline. His family chose to deescalate care, and he died on 4/1/17.

Discussion: Sunitinib induced rhabdomyolysis has been reported in 2 patients with metastatic RCC. The proposed mechanism suggests sunitinib could interfere with fatty acid b-oxidation and glycogenolysis. Under these conditions AMP-kinase activity usually acts as a rescue pathway. Sunitinib inhibits AMP-Kinase thus causing decline in intracellular ATP and elevation in myoplasmic Ca2+. Sufficient ATP supply by mitochondrial respiratory chain fails and extrusion of Ca2+ to the extracellular space is reduced. Long-lasting Ca2+ elevations leads to myoplasmic Ca2+ overload and activate calpain proteases. The skeletal muscle specific calpain 3 protease may cause destruction of the myofibrils. Increase in creatinine kinase is the main clinical presentation.

Conclusions: Sunitinib-induced rhabdomyolysis is a very rare occurrence. Our case will be the third reported case in literature. Initial recognition of this toxicity is very important to ensure timely care.

References: (1) Ruggeri EM, Cecere FL, Moscetti L, Doni L, Padalino D, Di Costanzo F. Severe rhabdomyolysis during sunitinib treatment of metastatic renal cell carcinoma. A report of two cases. Ann Oncol. 2010;21(9):1926-1927. (2) Hohenegger M. Drug induced rhabdomyolysis. Curr Opin Pharmacol. 2012;12(3):335-339.

Background: Sunitinib is one of the most commonly used first line treatments for metastatic renal cell carcinoma (mRCC). While toxicities are common, rhabdomyolysis is rare. The case presented here describes the quick and severe nature of this toxicity.

Case: The patient is a 71-year-old white male with mRCC admitted on 3/29/17 due to muscle weakness, fatigue, poor oral intake, and difficulty swallowing for 2 weeks. He was diagnosed with RCC and had a right nephrectomy in 2014. He developed biopsy proven lung metastasis, and sunitinib was started in May 2016. Sunitinib dose at that time was 37.5 mg per oral daily x 4 weeks every 6 weeks. On admission, he had a platelet count of 13,000, serum creatinine 2.23 mg/dL, total bilirubin 4 mg/dL, AST/ALT > 2,000 U/L, INR 2.9, calcium 7.5, creatinine kinase > 5,000 U/L, uric acid 12 mg/dL, and severe global hypokinesia with LVEF 30-35%. He quickly developed lactic acidosis and ARDS. In ICU he received bicarbonate, oxygen, furosemide, and treatment for hyperkalemia. Despite all treatment support he continued to decline. His family chose to deescalate care, and he died on 4/1/17.

Discussion: Sunitinib induced rhabdomyolysis has been reported in 2 patients with metastatic RCC. The proposed mechanism suggests sunitinib could interfere with fatty acid b-oxidation and glycogenolysis. Under these conditions AMP-kinase activity usually acts as a rescue pathway. Sunitinib inhibits AMP-Kinase thus causing decline in intracellular ATP and elevation in myoplasmic Ca2+. Sufficient ATP supply by mitochondrial respiratory chain fails and extrusion of Ca2+ to the extracellular space is reduced. Long-lasting Ca2+ elevations leads to myoplasmic Ca2+ overload and activate calpain proteases. The skeletal muscle specific calpain 3 protease may cause destruction of the myofibrils. Increase in creatinine kinase is the main clinical presentation.

Conclusions: Sunitinib-induced rhabdomyolysis is a very rare occurrence. Our case will be the third reported case in literature. Initial recognition of this toxicity is very important to ensure timely care.

References: (1) Ruggeri EM, Cecere FL, Moscetti L, Doni L, Padalino D, Di Costanzo F. Severe rhabdomyolysis during sunitinib treatment of metastatic renal cell carcinoma. A report of two cases. Ann Oncol. 2010;21(9):1926-1927. (2) Hohenegger M. Drug induced rhabdomyolysis. Curr Opin Pharmacol. 2012;12(3):335-339.