Characteristics of Thrombocytopenia in Patients Treated with Oral Panobinostat (LBH589).

Panobinostat (LBH589), a hydroxamic acid derivative, is a potent pan-deacetylase inhibitor (DACi) with anti-tumor activity in a wide variety of preclinical cancer models and promising clinical activity in Phase I/II trials. In preclinical toxicity studies, the hematopoietic and lymphatic systems were identified as primary target organs; panobinostat has demonstrated reversible myelosuppression, including decreased platelet release, which may be due to a delay in maturation of megakaryocytes. Hematology parameters are closely monitored in clinical trials, especially when panobinostat is combined with concomitant medications associated with myelosuppression. Thrombocytopenia is the most common adverse event (AE) associated with panobinostat treatment in the clinic. This analysis represents the first clinical characterization of thrombocytopenia in patients treated with oral, single-agent panobinostat in Phase I and II studies.

Analysis was performed on pooled data from eight completed or ongoing Phase I and II studies in patients with advanced hematologic malignancies or solid tumors. The following doses and 28-day cycle dosing schedules were analyzed: doses ranging from 20 to 60 mg/dose (administered on Days 1, 3 and 5 [TIW every week]) or 30 to 60 mg/dose (TIW every other week). Patients with a baseline and at least one post-baseline platelet count value were included in the dataset. Patients were counted only once based on the worst post-baseline value.

The pooled analysis included data from 308 patients (120 female/188 male) with a median age of 59 years (range: 16–87), with solid tumors/lymphomas/myeloma (receiving panobinostat weekly [n=84] or every other week [n=19]) or with other hematologic malignancies, especially with acute myeloid leukemia or myelodysplastic syndrome (receiving panobinostat weekly [n=175] or every other week [n=30]). Newly occurring or worsening thrombocytopenia was the most common lab abnormality of any grade and of Grade 3/4 (88% any grade, 64% Grade 3/4) with weekly dosing. Frequency of Grade 3/4 thrombocytopenia correlated with increasing weekly doses, occurring in 38% of patients at 20 mg, 63% at 30 mg, 85% at 40 mg and 95% at 60 mg/dose. With every-other-week dosing, Grade 3/4 thrombocytopenia was observed in 67% of patients across doses (67% of patients at 30 mg, 63% at 45 mg and 70% at 60 mg/dose). Median time to thrombocytopenia, for patients with solid tumors/lymphomas/myeloma or with other hematologic malignancies, respectively, was 15 and 30 days on the weekly schedule (n=84 and 175 pts), and 64 and 8 days on the every-other-week schedule (n=19 and 30 pts). Thrombocytopenia was the most common reason for dose adjustments or discontinuation. Incidence of at least one dose reduction due to AE or lab abnormality for patients with either solid tumors/lymphomas/myeloma or with other hematologic malignancies, respectively, was 45% and 29% on the weekly schedule vs 37% and 10% on the every-other-week schedule. Consequently, median exposure to panobinostat was variable for patients with solid tumors and hematologic malignancies, respectively, on the weekly schedule (56.5 days and 33 days) vs every other week (117 days and 45 days), suggesting a trend favoring the every-other-week schedule. Separate time-to-event analysis revealed other hematologic malignancy, lower platelet count at baseline and lower body surface area as potential risk factors for thrombocytopenia. The event was generally effectively managed by dose interruption or dose reduction and platelet transfusion predominantly in patients with acute myeloid leukemia or myelodysplastic syndrome.

Thrombocytopenia is commonly observed with panobinostat but is generally predictable, manageable and reversible. Every-other-week (TIW) dosing schedules of oral panobinostat may effectively reduce the incidence and severity of thrombocytopenia and the number of dose reductions or interruptions or need for transfusions. Results of this pooled analysis suggest that every-other-week dosing schedules of oral panobinostat may be better tolerated with regard to thrombocytopenia. This finding warrants further investigation in ongoing, planned Phase II and III studies.

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