Efficacy and tolerability of the histone deacetylase inhibitor panobinostat in clinical practice

Abstract

The histone deacetylase inhibitor panobinostat has shown efficacy in phase-II and phase-III trials for multiple myeloma and has recently received market approval in combination with bortezomib and dexamethasone. Here, we retrospectively report our single center experience with panobinostat/bortezomib/dexamethasone (FVD) in a heavily pretreated patient population (n = 24) with a high degree of refractoriness to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Median age was 67 years (range 49-87) and the median number of prior therapies was 5 (range 2-17). Fourteen patients (58%) had high-risk cytogenetic aberrations. Thirteen (54%) and 21 (88%) patients were refractory to PIs and IMiDs, respectively. Twelve patients (50%) were refractory to bortezomib and 7 (29%) to carfilzomib; 6 patients (25%) were refractory to both bortezomib and carfilzomib. In 21 patients evaluable for response, overall response rate (ORR; ≥PR) was 33% (7/21) and 81% (17/21) achieved at least stable disease. Median progression-free survival (PFS) and overall survival were 3.5 and 9.8 months, respectively. Significant differences between bortezomib-sensitive and -refractory patients were observed. In bortezomib-sensitive patients, median PFS was 6.3 months compared to 2.3 months in bortezomib-refractory patients (P < .001). Median overall survival was not reached vs 4.8 months (P = .046) in bortezomib-sensitive and bortezomib-refractory patients, respectively. The only patient refractory to carfilzomib but sensitive to bortezomib achieved very good partial remission and PFS of 6.3 months, suggesting discrete mechanisms of resistance to different PIs. As expected, thrombocytopenia and fatigue/asthenia occurred in nearly all patients (96% and 83%, respectively). Diarrhea was observed in only 19% of patients which compares favorably with the high rates of diarrhea reported in the PANORAMA trials. With panobinostat dose reductions in 67% of patients, FVD was tolerated by the majority of patients. In conclusion, FVD showed efficacy in a heavily pretreated, high-risk multiple myeloma population with a high degree of patients refractory to novel agents including PIs.

Comparison of the antifibrotic effects of the pan-histone deacetylase-inhibitor panobinostat versus the IPF-drug pirfenidone in fibroblasts from patients with idiopathic pulmonary fibrosis

“…Although LBH589 is reported to be selectively cytotoxic towards ‘abnormal’ tumor cells whereas normal healthy cells are relatively unaffected [ 34 , 39 ], patients with multiple myeloma receiving LBH589 indicated significant adverse effects [ 35 , 36 ]. LBH589 (Farydak ® ) was recently approved in the US and EU in combination with bortezomib (BTZ) and dexamethasone (Dex), for the treatment of patients with relapsed and/or refractory multiple myeloma who have received at least two prior treatment regimens including bortezomib and an immunomodulatory drug [ 36 ].…”

Sunlight‐ or UVA‐Light‐Mediated Synthesis of Hydroxamic Acids from Carboxylic Acids

“…The aim of our work was to study in detail the coupling of carboxylic acids with Oprotected hydroxylamines under light-mediated conditions, using a protocol employing a CTC, derived from DMAP (halogen bond acceptor) and three different halogen bond donors (BrCCl 3 or CCl 4 or CBr 4 ). Commercially available O-benzylhydroxylamine (5), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (6), Otritylhydroxylamine (7) and O-trimethylsilylhydroxylamine (8) were used in the present study. For the optimization studies, 8oxo-8-(phenylamino)octanoic acid (9) was employed as a model carboxylic acid, because it leads to the drug Vorinostat.…”

“…The most important property of hydroxamic acids is their ability to inhibit histone deacetylases (HDACs) and exhibit potent activity as anticancer agents [2] . In more detail, three hydroxamic acids, namely Vorinostat ( 1 ), [3] Belinostat ( 2 ) [4] and Panobinostat ( 3 ) [5] (Figure 1), are approved drugs for the treatment of primary cutaneous T‐cell lymphoma, peripheral T‐cell lymphoma and multiple myeloma, respectively. In addition, Bufexamac ( 4 , Figure 1) is a non‐steroidal anti‐inflammatory drug used to treat skin conditions, such as atopic eczema and inflammatory dermatoses, [6] which has been identified as a class IIb (HDAC6, HDAC10) HDAC inhibitor [7] .…”

Efficacy and toxicity of histone deacetylase inhibitors in relapsed/refractory multiple myeloma: Systematic review and meta‑analysis of clinical trials

“…A total of 19 clinical trials with 2,193 evaluable participants treated with one of three HDACis (panobinostat, ricolinostat and vorinostat) were included in the present study. In terms of study design, there was one real-world study (15), 2 phase III studies (11,16), 4 phase II studies (17–20), 5 phase I/II studies (21–25) and 7 phase I studies (26–32). Baseline information of the included study characteristics and prior therapies are presented in Tables I and II.…”