Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes

279

234

Section: Discussionsupporting

confidence: 62%

PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma

Richardson

Schlossman

Alsina

et al. 2013

279

234

“…Our results are consistent with observations made by Giver et al, who reported similar reductions in platelet number with the administration of panobinostat to BALB/c mice, along with an increase in TPO levels and megakaryocyte number. 36 Another group also reported that oral administration of a novel HDACI, FR235225, to Lewis rats over 1 week resulted in a dose-dependent TCP and an increase in megakaryocyte number. 37 This group went on to demonstrate the effects of this and 2 other novel HDACIs not used in clinical practice on a human erythroleukemic cell line.…”

Section: Discussionmentioning

confidence: 99%

“…36 Another group also reported that oral administration of a novel HDACI, FR235225, to Lewis rats over 1 week resulted in a dose-dependent TCP and an increase in megakaryocyte number. 37 This group went on to demonstrate the effects of this and 2 other novel HDACIs not used in clinical practice on a human erythroleukemic cell line.…”

Section: Discussionmentioning

confidence: 99%

Deciphering the molecular and biologic processes that mediate histone deacetylase inhibitor–induced thrombocytopenia

Bishton

Harrison

Martin

et al. 2011

131

Histone deacetylase inhibitor (HDACI)-induced thrombocytopenia (TCP) is a major dose-limiting toxicity of this new class of drugs. Using preclinical models to study the molecular and biologic events that underpin this effect of HDACI, we found that C57BL/6 mice treated with both the HDAC1/ 2-selective HDACI romidepsin and the pan-HDACI panobinostat developed significant TCP. HDACI-induced TCP was not due to myelosuppression or reduced platelet lifespan, but to decreased platelet release from megakaryocytes. Cultured primary murine megakaryocytes showed reductions in proplatelet extensions after HDACI exposure and a dose-dependent increase in the phosphorylation of myosin light chain 2 (MLC2). Phosphorylation of MLC to phospho-MLC (pMLC) and subsequent proplatelet formation in megakaryocytes is regulated by the Rho-GTPase proteins Rac1, CDC42, and RhoA. Primary mouse megakaryocytes and the human megakaryoblastic cell line Meg-01 showed reductions in Rac1, CDC42, and RhoA protein levels after treatment with HDACIs. We were able to overcome HDACIinduced TCP by administering the mousespecific thrombopoietin (TPO) mimetic AMP-4, which improved platelet numbers to levels similar to untreated controls. Our report provides the first detailed account of the molecular and biologic processes involved in HDACI-mediated TCP. Moreover, our preclinical studies provide evidence that dose-limiting TCP induced by HDACIs may be circumvented using a TPO mimetic. (Blood. 2011;117(13):3658-3668) IntroductionCovalent posttranslational modifications to specific sites within histone proteins, including acetylation, methylation, and phosphorylation, are able to affect gene transcription in cells. 1 Increased acetylation of histones is associated with open DNA and increased transcription, whereas deacetylation is associated with transcriptional repression. 2 Disruption of this balance is associated with cancer onset and progression. 3 The histone deacetylase (HDAC) enzymes control the structural conformation of chromatin via deacetylation of core nucleosomal histones. To date, a total of 18 HDACs have been described and are divided into 4 general classes. Class I HDACs are thought to be located within the cell nucleus only, whereas class II and class IV HDACs shuttle between the cell cytoplasm and the nucleus. Class III HDACs comprise the NAD ϩ -dependent sirtuin family proteins. 4 HDAC inhibitors (HDACIs) are structurally diverse antineoplastic agents distinguished both by their chemical structure and by their target specificity. 5 HDACIs induce chromatin remodeling and altered gene expression, and the function of nonhistone proteins may also be affected by direct acetylation. 6,7 Panobinostat is a cinnamic hydroxamic acid with inhibitory effects against all class I, II, and IV HDAC enzymes and marked antitumor activity across a broad range of hematologic cancers, including Hodgkin lymphoma. [8][9][10] Romidepsin is a bicyclic tetrapeptide that preferentially interacts with class I enzymes, and has activity in cutaneous T-cell lymphoma, ...

“…Overall, these results suggest that, in general, the safety profile remains consistent regardless of prior treatment and adverse events are manageable with dose interruptions or reductions and supportive measures for key toxicities (eg, loperamide for diarrhea and platelet transfusion for thrombocytopenia). 19,20 In the overall PANORAMA 1 study population, there were slightly more on-treatment deaths in the PAN-BTZ-Dex arm vs the Pbo-BTZ-Dex arm (n 5 30 [8%] vs n 5 18 [5%], respectively). The proportions of on-treatment deaths were similar among the subgroup of patients who received $2 prior regimens including bortezomib and an IMiD (PAN-BTZ-Dex, n 5 5 [6.9%]; Pbo-BTZ-Dex, n 5 5 [6.8%]).…”

mentioning

confidence: 99%

Panobinostat plus bortezomib and dexamethasone in previously treated multiple myeloma: outcomes by prior treatment

Richardson

Hungria

Yoon

et al. 2016

122

104

Key Points• Benefit from panobinostatdexamethasone-bortezomib was greatest in patients who received $2 prior regimens including bortezomib and IMiDs.Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3 PANORAMA 1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n 5 485), prior bortezomib plus an IMiD (n 5 193), and ‡2 prior regimens including bortezomib and an IMiD (n 5 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and ‡2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/ fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received ‡2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01023308. (Blood. 2016;127(6):713-721)