Contributions
Type: Publication Only
Background
Vorinostat, a histone deacetylase (HDAC) inhibitor has shown promise in a number of haematological malignancies including myeloma, lymphoma and myelodysplastic syndromes. Inhibition of histone deacetylases leads to arrest of tumor cell growth, differentiation and increased apoptotic cell death. The role of HDAC inhibitors in myeloproliferative neoplasms were described by Guerini et al (2008) who demonstrated the arrest of proliferation in polycythaemia vera (PV) and essential thrombocythaemia (ET) haemopoietic cells.
Aims
We describe our experience using Vorinostat as an alternative agent in therapy resistant ET.
Methods
A phase II study evaluating vorinostat in ET and PV reported early discontinuations due to adverse events, and poor tolerability (Andersen et al 2013). Two patients at our institution continued vorinostat in a compassionate use programme following this phase II study. We describe herein their on-going responses.
Results
Patient 1, a 54 years old male with CALR positive ET since 2001 complicated by a left internal capsule infarct, chronic kidney disease and leg ulcers whilst on hydroxycarbamide (HU). Despite dose escalation he was unresponsive to standard therapy with HU and anagrelide (ANA). On initiation of vorinostat 400 mg daily, his Haemoglobin (Hb) concentration was 103g/L (130 – 150g/L), leukocyte count 12.3 x 109/L (4.0 – 11.0 x 109/L), platelet count was 978 x 109/L (150-400 x 109/L), and creatinine was 151 umol/L (59-104 umol/L) (EGFR 42). Shortly following commencing on Vorinostat, there was a notable decline in his renal function to 201umol/L (EGFR to 29), thus a dose reduction to 300 mg daily was made with satisfactory control of platelet count. The only side effect he reported was dysgeusia, which did not impact on his activities of daily living. He has now been on Vorinostat for 51 months; over this time, the vorinostat dose was gradually reduced with overall stable platelet count control. His current maintenance dose is 100 mg/200 mg alternate days with a platelet count of 367 x109/L at last clinic visit. Renal function has remained stable throughout therapy; the most recent creatinine level was 171umol/L (EGFR 36).
The second patient, a 53 year old male also had CALR positive ET, diagnosed in 2004. He had a history of a previous cerebrovascular accident and was symptomatic from his ET; his main complaints were profound pruritus and fatigue. Both blood counts and symptoms were resistant to treatment with busulphan, HU, interferon and ANA. When vorinostat was initiated his Hb concentration was 128g/L, leukocyte count 5.3 x109/L and an unstable platelet count that ranged between 315 – 947 x109/L. To date the patient has been on vorinostat 52 months with minimal side effects. Vorinostat 300mg/400mg alternate days has reduced his symptom burden and maintained the platelet count below 800 x 109/L with no thrombotic or haemorrhagic events. Renal function has remained stable; creatinine level on commencing therapy was 77umol/L (EGFR 92) increasing to 104umol/L (EGFR 64) at last clinical visit.
Summary
Although displaying two contrasting clinical courses on vorinostat, both patients have demonstrated a prolonged clinical response with symptom and platelet count control. Therefore, we conclude that vorinostat may offer selected patients resistant to standard therapy an alternative agent in ET when options are often extremely limited.
Keyword(s): Essential Thrombocytemia, HDAC inhibitor, Resistance
Session topic: Publication Only
Type: Publication Only
Background
Vorinostat, a histone deacetylase (HDAC) inhibitor has shown promise in a number of haematological malignancies including myeloma, lymphoma and myelodysplastic syndromes. Inhibition of histone deacetylases leads to arrest of tumor cell growth, differentiation and increased apoptotic cell death. The role of HDAC inhibitors in myeloproliferative neoplasms were described by Guerini et al (2008) who demonstrated the arrest of proliferation in polycythaemia vera (PV) and essential thrombocythaemia (ET) haemopoietic cells.
Aims
We describe our experience using Vorinostat as an alternative agent in therapy resistant ET.
Methods
A phase II study evaluating vorinostat in ET and PV reported early discontinuations due to adverse events, and poor tolerability (Andersen et al 2013). Two patients at our institution continued vorinostat in a compassionate use programme following this phase II study. We describe herein their on-going responses.
Results
Patient 1, a 54 years old male with CALR positive ET since 2001 complicated by a left internal capsule infarct, chronic kidney disease and leg ulcers whilst on hydroxycarbamide (HU). Despite dose escalation he was unresponsive to standard therapy with HU and anagrelide (ANA). On initiation of vorinostat 400 mg daily, his Haemoglobin (Hb) concentration was 103g/L (130 – 150g/L), leukocyte count 12.3 x 109/L (4.0 – 11.0 x 109/L), platelet count was 978 x 109/L (150-400 x 109/L), and creatinine was 151 umol/L (59-104 umol/L) (EGFR 42). Shortly following commencing on Vorinostat, there was a notable decline in his renal function to 201umol/L (EGFR to 29), thus a dose reduction to 300 mg daily was made with satisfactory control of platelet count. The only side effect he reported was dysgeusia, which did not impact on his activities of daily living. He has now been on Vorinostat for 51 months; over this time, the vorinostat dose was gradually reduced with overall stable platelet count control. His current maintenance dose is 100 mg/200 mg alternate days with a platelet count of 367 x109/L at last clinic visit. Renal function has remained stable throughout therapy; the most recent creatinine level was 171umol/L (EGFR 36).
The second patient, a 53 year old male also had CALR positive ET, diagnosed in 2004. He had a history of a previous cerebrovascular accident and was symptomatic from his ET; his main complaints were profound pruritus and fatigue. Both blood counts and symptoms were resistant to treatment with busulphan, HU, interferon and ANA. When vorinostat was initiated his Hb concentration was 128g/L, leukocyte count 5.3 x109/L and an unstable platelet count that ranged between 315 – 947 x109/L. To date the patient has been on vorinostat 52 months with minimal side effects. Vorinostat 300mg/400mg alternate days has reduced his symptom burden and maintained the platelet count below 800 x 109/L with no thrombotic or haemorrhagic events. Renal function has remained stable; creatinine level on commencing therapy was 77umol/L (EGFR 92) increasing to 104umol/L (EGFR 64) at last clinical visit.
Summary
Although displaying two contrasting clinical courses on vorinostat, both patients have demonstrated a prolonged clinical response with symptom and platelet count control. Therefore, we conclude that vorinostat may offer selected patients resistant to standard therapy an alternative agent in ET when options are often extremely limited.
Keyword(s): Essential Thrombocytemia, HDAC inhibitor, Resistance
Session topic: Publication Only