Annals of Oncology Advance Access published online on June 10, 2009
Annals of Oncology, doi:10.1093/annonc/mdn792
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HDAC inhibitor-based therapies and haematological malignancy
Laboratory of Cancer Biology, Department of Clinical Pharmacology, University of Oxford, Oxford, UK
* Correspondence to: Prof. N. B. La Thangue; Laboratory of Cancer Biology, Department of Clinical Pharmacology, Old Road Campus Research Building, Old Road Campus, Oxford OX3 7DQ, UK. Tel: +44-1865-617090; Fax: +44-1865-617092; E-mail: nick.lathangue{at}ndcls.ox.ac.uk
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abstract |
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 Top abstract introductionthe histone deacetylase familyclinical evaluation of HDAC...conclusionsfundingacknowledgementsreferences |
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Reversible acetylation mediated by histone deacetylase (HDAC) influences a broad repertoire of physiological processes, many of which are aberrantly controlled in tumour cells. Since HDAC inhibition prompts tumour cells to enter apoptosis, small-molecule HDAC inhibitors have been developed as a new class of mechanism-based anticancer agent, many of which have entered clinical trials. While the clinical picture is evolving and the precise utility of HDAC inhibitors remains to be determined, it is noteworthy that certain tumour types undergo a favourable response, in particular haematological malignancies. Vorinostat (suberoylanilide hydroxamic acid) has been approved for treating cutaneous T-cell lymphoma in patients with progressive, persistent or recurrent disease. Here, we discuss developments in our understanding of molecular events that underlie the anticancer effects of HDAC inhibitors and relate this information to the emerging clinical picture for the application of HDAC inhibitors in haematological malignancies.
cancer, clinical, haematological malignancy, HDAC, inhibitor, therapy
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introduction |
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Topabstractintroductionthe histone deacetylase familyclinical evaluation of HDAC...conclusionsfundingacknowledgementsreferences |
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The recognition that aberrant epigenetic control is an important determinant in attaining the malignant phenotype has stimulated intense efforts to develop mechanism-based drugs that reinstate normal epigenesis in tumour cells [1]. One of the most rapidly progressing and promising areas has been in the development of small-molecule inhibitors of histone deacetylase (HDAC) enzymes [2]. In cell-based studies, HDAC inhibitors are potent antiproliferative agents, where treatment causes a variety of outcomes including cell-cycle arrest, apoptosis, cell differentiation and in some cases autophagy [3–5]. HDAC inhibitors have a striking effect on tumour cell proliferation compared with their normal cellular counterparts, implying that a therapeutic window might exist that could be exploited in delivering an efficacious dose in the clinical setting. Consequently, an expanding portfolio of HDAC inhibitors has entered clinical studies. While the outcome of HDAC inhibitor-based therapies is complex and often difficult to predict, it is significant that certain types of tumours are already known to undergo a favourable response. Haematological malignancies seem to be particularly sensitive to HDAC inhibitors, and in this respect, vorinostat (ZolinzaTM, Merck, NJ; also called suberoylanilide hydroxamic acid) has been approved by the Food and Drug Administration (FDA) (http://www.fda.gov/Cder/Offices/OODP/whatsnew/vorinostat.htm) for treating cutaneous T-cell lymphoma (CTCL) [6]. There do, however, remain significant gaps in our understanding as to how HDAC inhibitors exert therapeutic benefit and their clinical utility in other malignancies is currently not clear. Here, we discuss recent developments in our understanding of the molecular events that underlie the antitumour activity of HDAC inhibitors, with a particular focus on the emerging clinical picture in haematological malignancy.
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the histone deacetylase family |
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Topabstractintroductionthe histone deacetylase familyclinical evaluation of HDAC...conclusionsfundingacknowledgementsreferences |
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Histone proteins are responsible for assembling the vast amounts of genomic DNA into a size and structure that can be easily accommodated in the eukaryotic nucleus. Histones receive a rich repertoire of post-translational modifications, frequently referred to as the ‘histone code’, which impacts on both their intrinsic properties and interactions with chromatin-associated proteins and has significant consequences on the level of gene activity [7, 8].
Acetylation is regulated by two groups of enzymes with opposite activities. Histone acetyltransferases catalyse the transfer of acetyl groups on to the side chain of lysine residues in target proteins [9]. HDAC provides the counter-balancing activity through deacetylating lysine residues. The HDAC family is divided into Zn2+-dependent (class I, II and IV), of which there are 11 enzymes, and Zn2+-independent, nicotinamide–adenine dinucleotide-dependent (class III) enzymes (Table 1) [2]. Most inhibitors being developed as anticancer agents target class I, II and IV enzymes, which will be the focus of our discussion, although interest in the class III sirtuin family is increasing [10].
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It is the Zn2+ dependency of HDAC enzymes that provides the basis for the inhibitory effect of many HDAC inhibitors. The naturally occurring antifungal antibiotic trichostatin A (TSA; Figure 1) was one of the first high-affinity inhibitors to be identified [11] and since then has proven to be an invaluable chemical tool for dissecting HDACs and their role in cellular proliferation. TSA is a hydroxamic acid-based compound that docks into the active site of the enzyme, where the hydroxyl group chelates the coordinating Zn2+ ion, resulting in enzyme inhibition in the low nanomolar range [12]. Several HDAC inhibitors in development reflect a similar pharmacophoric template and mechanism of action, including vorinostat, PXD101, LAQ824, LBH589 and ITF2357 (Figure 1 and Table 2).
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In the cell, HDAC enzymes mediate their effects on chromatin as components of large protein complexes and frequently in association with corepressor proteins like Sin3A, NCoR and SMRT [1]. HDACs interact with and repress diverse transcription factors, so it is somewhat surprising that genome-wide transcript profiling by microarray has indicated that a relatively small percentage of genes (between 2% and 5%) is influenced by HDAC inhibition [13–15]. It is likely therefore that mechanisms in addition to altered transcription contribute to cell killing. In fact, the increasing array of non-histone targets, some with importance in tumour cell growth and proliferation, supports this idea (Figure 2 and Table 3) [16, 17].
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The HDAC subunits have subfamily- and subunit-specific roles. Class I HDACs are ubiquitously expressed in all cells and may be more significant in regulating proliferation [18], and HDAC2 has been shown to suppress apoptosis in tumour cells [19]. Other HDAC subunits carry out specific roles that frequently involve different cellular targets. HDAC6, located in the cytoplasm where it acts as an
-tubulin deacetylase [20], may participate in regulating cell viability in response to misfolded proteins [21]. HDAC6 also has the capacity to bind directly to ubiquitinated proteins through a ubiquitin-binding domain and target cargo proteins for subsequent processing [22]. Class II HDACs meanwhile have a key role in tissue-specific events, in particular differentiation. HDAC9 has been implicated in cardiomyocyte differentiation as shown in HDAC9–/– knockout mice, which exhibit increased cardiac growth [23]. HDAC4 acts as a repressor of chondrocyte hypertrophy through interacting with the myocyte-specific enhancer factor 2C transcription factor [24, 25], and HDAC7 functions in the negative regulation and apoptosis of T cells reflecting its interaction with the orphan nuclear receptor Nur77 [26]. Overall, the diverse roles of HDAC suggest that the mechanism of cell death resulting from HDAC inhibitor-based therapies is likely to be multifactorial and will not be straightforward to predict in any given cell type or disease situation. In recent years, research has progressed to clearly demonstrate that HDACs regulate an array of proteins through controlling the level of acetylation, and it has become very clear that HDAC activity is not restricted to the control of chromatin. The precise constellation of HDAC subunits expressed in the tumour cell, the genetic alterations that have occurred in growth-regulating pathways and the extent of epigenetic reprogramming during progression to the neoplastic state represent some of the confounding factors that influence the cellular outcome of HDAC inhibition.
As a consequence of the complexity of the cellular function of HDAC enzymes, it is currently unclear as to whether pan-HDAC or specific HDAC inhibitors will provide the most clinical benefit to patients, while minimising toxic effects. However, for now perhaps a more important question in order for these mechanism-based anticancer agents to be most beneficial is how can we identify and stratify patients into a population that will respond to HDAC inhibitors? One strategy to answer this question is to identify predictive and prognostic biomarkers, i.e. measurable molecular, cellular or genetic parameter that can indicate biological or pathological processes or a pharmacological response to a therapeutic agent (FDA, www.fda.gov). To date, examples of putative HDAC inhibitor biomarkers include measuring HDAC enzyme levels, assessing histone acetylation and also identifying a gene signature of HDAC inhibitor response by DNA microarray [27]. Recently, a functionally relevant and predictive biomarker was identified for HDAC inhibitors [28]. The identification of such biomarkers will help in predicting which tumours respond favourably to HDAC inhibitors and ultimately patient stratification into groups that will gain most clinical benefit.
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clinical evaluation of HDAC inhibitors |
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Topabstractintroductionthe histone deacetylase familyclinical evaluation of HDAC...conclusionsfundingacknowledgementsreferences |
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HDAC inhibitors that are undergoing extensive clinical evaluation include the pan-HDAC inhibitors, such as vorinostat and panobinostat, and more selective inhibitors, such as romidepsin and MS-275 (Table 3). Of these, vorinostat is the most advanced drug, which was approved in October 2006 by the FDA for the treatment of advanced forms of CTCL that have failed multiple other systemic treatment options [29]. We now review the clinical progress of vorinostat and other HDAC inhibitors with respect to haematological malignancies.
cutaneous T-cell lymphoma
CTCLs are extranodal non-Hodgkin’s lymphomas (NHLs) of malignant, clonal T lymphocytes presenting in the skin. In the United States, there are 
1100 new cases of CTCL diagnosed per year. The World Health Organisation–European Organisation for Research and Treatment of Cancer (EORTC) classification of CTCL lists 13 different types, classifying them according to behaviour [29, 30]. The most common form of CTCL is mycosis fungoides (MF), which constitutes approximately half of all cases [31], and the more aggressive form of CTCL is Sezary syndrome (SS), which comprises 4% of new cases and is a leukaemic variant consisting of the triad of generalised pruritic erythroderma, leukaemia and lymphadenopathy [31, 32]. The EORTC has recently published consensus recommendations on the treatment of MF and SS. Generally, early-stage disease is treated by skin-directed therapies including topical corticosteroids, psoralen and UVA treatment, topical chemotherapy with nitrogen mustard, topical retinoids (bexarotene gel) and total skin electron beam radiation. More advanced disease is treated by systemic therapies including chemotherapy, photopheresis, oral retinoids (bexarotene), interferon and denileukin diftitox. Despite reasonable response rates, especially with combination treatments, durable responses are seldom seen and there is a need for more effective and less toxic therapies.
vorinostat
Vorinostat was well tolerated in phase I trials in both oral and i.v. formulations demonstrating a broad range of antitumour activity in both solid and haematological malignancies. Adverse effects were generally not serious and included thrombocytopaenia, fatigue, dehydration and gastrointestinal side-effects.
In the phase II setting, two important trials have reported response rates of 30% in MF. This is comparable with the response rates seen with other agents used in advanced disease such as bexarotene and denileukin diftitox. The first of these trials involved 33 patients (one-third of whom had SS). Most patients had received at least one prior chemotherapy regimen. Eight patients had a partial response (PR) with no complete responses (CR) observed. Time to progression (TTP) was 30.2 weeks in responders compared with 12.1 weeks in nonresponders. The overall response rate (ORR) was 24% but over half the patients with baseline pruritis derived symptomatic relief and the overall clinical benefit rate was determined to be 58% [33].
In the second trial, 74 patients with advanced MF or SS were treated with vorinostat and the objective RR was 29.7% (36.4% RR in SS patients). The median TTP was 4.9 months overall, but in responders, this was not reached at the time of publication. Pruritis relief was observed in 32% of patients, including those who did not meet objective response criteria [34]. A post hoc subset analysis of patients involved in this trial who had received vorinostat for >2 years has also recently been reported [35]. There were six patients in this group including five responders (one CR, four PR) and one with stable disease (SD). Although there were a number of adverse events experienced by most of the patients, namely diarrhoea, nausea, fatigue and alopecia, the only serious adverse event was pulmonary embolism from which the patient fully recovered. The authors concluded that there was evidence of prolonged safety and clinical benefit in these patients with advanced CTCL.
romidepsin
There have been a number of phase I and II trials with romidepsin (also known as FK228 and depsipeptide) in CTCL. The drug has been generally well tolerated, and encouraging results from a phase I trial identified significant activity with three PRs in CTCL and one CR in peripheral T-cell lymphomas (PTCLs) [36]. In a phase II trial in relapsed and refractory CTCL and PTCL, interim results from 42 enrolled patients have shown an ORR in CTCL of 31% (three CRs, 10 PRs). There was also an increase in histone acetylation in normal and malignant blood cells. The main toxic effects reported included fatigue, nausea, vomiting, anorexia and transient granulocytopenia and thrombocytopaenia [37].
Final results from one further phase II trial of romidepsin comprising 96 patients with treatment refractory CTCL have recently been presented [38]. Of the 72 assessable patients, the ORR was 42% with a median time to response of 1.9 months. Pruritis relief rate was 92%. The most commonly reported adverse events included fatigue and pyrexia. Electrocardiogram abnormalities were noted in most of these trials and their clinical relevance remains under investigation. Romidepsin received orphan drug designation from the FDA for the treatment of non-Hodgkin’s T-cell lymphomas, including CTCL and PTCL, and orphan status from the European Medicines Agency (EMEA) for the treatment of CTCL and PTCL.
panobinostat (LBH589)
In a trial of 11 patients with CTCL treated with panobinostat, two achieved CRs and four attained PRs indicating an ORR of 60%. Panabinostat is currently in phase II/III clinical development in patients with CTCL. A recent report on a phase II trial that has enrolled 95 patients so far has demonstrated encouraging clinical activity [39]. Two groups of patients are being treated: group one has had prior bexarotene treatment and group two is bexarotene naive. In the former, 11 of 62 patients have had confirmed skin responses including two CRs. In the latter, 4 of 33 patients have had confirmed skin responses. Toxic effects have been manageable with the commonest being diarrhoea, thrombocytopaenia, nausea and fatigue. Panobinostat has received orphan drug designation by the FDA and EMEA for the treatment of CTCL.
belinostat (PXD101)
Phase I and II trials are ongoing in CTCL as well as in several other tumour types, both as a single agent and in combination with agents including bortezomib, 5-fluorouracil, 5-azacytidine, carboplatin, paclitaxel and isotretinoin [40].
peripheral T-cell lymphoma
PTCLs are a biologically diverse and uncommon group of diseases. PTCL, so called because of their post-thymic origin, involves malignant T lymphocytes and represents 12% to 15% of all NHLs in Western populations. Approximately 5000 cases of PTCL and other T-cell NHLs are diagnosed annually in the United States. Compared with their B-cell counterparts, PTCLs remain largely unexplored and the optimal treatment is not well defined due to disease rarity and biological heterogeneity. Patients with PTCL may have a durable remission after they achieve a CR with standard chemotherapy, with an overall survival rate of 25% at 5 years [41]. However, most patients experience relapse and have a poor response to further treatment.
romidepsin
Following a small phase I trial of romidepsin, three patients with CTCL had a PR and one patient with PTCL had a CR. These encouraging results prompted the initiation of phase II clinical studies [36]. Of the 17 PTCL patients enrolled in one phase II trial, four patients (24%) achieved a PR lasting 9 and 12 months in two cases and remained ongoing over 4 months in the other two patients. Overall, the drug was well tolerated with observed toxic effects including nausea, vomiting, fatigue, neutropenia, thrombocytopaenia and hypocalcaemia [42]. An ongoing multi-institutional phase II study of romidepsin in relapsed and refractory PTCL reported both CR and PR in patients with various subtypes of PTCL, including one CR ongoing for >34 months. The RR for 36 patients with PTCL was 31%, with three patients (8%) achieving a CR and eight patients (22%) achieving a PR. Thus, romidepsin has significant single-agent activity in PTCL. Similar to CTCL trials, the principal toxic effects reported in all the enrolled patients included fatigue, nausea, vomiting, anorexia and transient granulocytopenia and thrombocytopaenia.
A phase II trial evaluating the efficacy and safety of romidepsin in patients with PTCL that has progressed or become refractory following systemic treatment has recently been initiated. This open-label, single-arm, multinational trial will be conducted at 35 sites in the United States and Europe [43]. Finally, the interim analysis of a continuing phase II study using belinostat reported two CRs and five cases of SD in 11 patients with PTCL including a CR in one patient. The best response remains to be determined in two patients with treatment ongoing [44].
Hodgkin’s lymphoma
Hodgkin’s lymphoma (HL) is characterised by the disruption of normal lymph node architecture and the presence of a minority of malignant Hodgkin/Reed–Sternberg cells amid a background of non-neoplastic cell populations comprising T and B lymphocytes and other cell types [45]. Approximately 150 000 cases of HL exist in the United States, and an estimated 8000 new cases of HL will be diagnosed this year [46]. Many HL patients are cured with initial therapy, although a portion of patients will experience primary induction failure or disease relapse.
vorinostat
A phase I dose-escalation trial compared i.v. with oral formulations of vorinostat in patients with a variety of pretreated haematological malignancies, including HL [47]. Of the five patients with HL, one achieved a PR that lasted 9 months and two had SD with some disease reduction. The patient who achieved a PR discontinued study participation, re-enrolled to receive oral vorinostat upon disease progression and achieved a second PR that lasted 10 months. Another patient with refractory HL had an 15% reduction in thoracic/lung tumour burden but developed an infection and was removed from the study.
MGCD0103
MGCD0103 is a subunit-selective HDAC inhibitor, currently in multiple phase I–II clinical trials as a single agent or in combination with various chemotherapeutic agents including 5-azacytidine and gemcitabine [48]. Preliminary data from a phase II monotherapy clinical trial in 20 patients with relapsed or refractory disease produced a PR rate of 40% and a 45% disease control rate (CR + PR + SD for more than six cycles) [49]. An open-label phase II trial is also currently ongoing using MGCD0103 in patients with relapsed/refractory HL [50]. Among 23 patients, two had CR and six had PR for an ORR of 38%. The two patients with CR had progression-free survival lasting >270 and >420 days with both responses ongoing. A phase II combination trial with MGCD0103 and 5-azacytidine has recently started recruiting patients with relapsed or refractory HL or non-HL. MGCD0103 has been granted orphan drug designation by the FDA for the treatment of HL [51]. However, enrolment into MGCD0103 clinical trials was recently put on partial clinical hold because pericardial effusion was observed in some patients [52].
multiple myeloma
Multiple myeloma (MM) is characterised by excessive numbers of abnormal plasma cells in the bone marrow and the overproduction of abnormal immunoglobulins. As a result, patients may develop bone lesions, anaemia, hypercalcaemia, renal damage and immunosuppression [53]. The American Cancer Society has estimated that 20 000 new cases of MM will be diagnosed in 2007, making it the second most common haematological cancer in the United States. Despite the availability of treatments for MM, there is currently no cure for the disease, highlighting the requirement for more effective therapies.
The first clinical trial of HDAC inhibition specifically in MM patients used romidepsin [54], although several other HDAC inhibitors have also been investigated.
romidepsin
In a phase II trial, patients were generally heavily pretreated with an average of three prior treatments and mean disease duration of 6.3 years. Twelve patients were treated at the same dose used successfully to treat CTCL and PTCL [48]. Two patients were withdrawn after the first cycle with SD, six patients progressed during the first two cycles, four patients remained stable after two to seven cycles and no PRs were observed. Romidepsin was well tolerated with fatigue, nausea and transient thrombocytopaenia being the major adverse events. A phase I trial of oral vorinostat was conducted in MM but the maximum tolerated doses (MTD) were not determined as the study was prematurely terminated [55]. Drug-related adverse effects included fatigue, anorexia, dehydration, diarrhoea and nausea and were mostly grade 1 or 2. Of the 10 assessable patients, one had a minor response (MR) and nine had SD, demonstrating modest single-agent activity.
ITF2357
This HDAC inhibitor is an orally effective hydroxamic acid with in vivo activity against MM cells [56]. A recent phase II study treated 16 MM patients with a median of three prior therapies. The most common grade 3–4 toxic effects were gastrointestinal side-effects, neutropenia and thrombocytopaenia, while five patients achieved SD and one achieved a PR [57].
vorinostat
A phase I trial examined two regimens for vorinostat in MM [55]. Assessable patients were given 200, 250 or 300 mg, twice daily for 5 days/week over a 4-week cycle, or 200, 300 or 400 mg, twice daily for 14 days on a 3-week cycle. Thirteen patients were recruited and of the 10 assessable, there was one minimal response and nine SD. Only one patient had a dose-limiting toxicity of fatigue, although other toxic effects observed included fatigue, anorexia, dehydration, diarrhoea and nausea.
panobinostat
Panobinostat is also currently being evaluated in phase I and II studies in MM. In an ongoing phase I study of seven assessable patients, three heavily pretreated patients had SD, with additional improvements in disease symptoms [58]. These studies demonstrated that HDAC inhibitors are well tolerated as single agents and clinical trials are now being carried out in combination with bortezomib which demonstrated that such combinations are tolerable with promising response rates [59–62].
belinostat
The activity of belinostat alone or with dexamethasone (standard care for MM patients) was assessed in a phase II trial in patients who had failed at least two prior therapies [63]. In 12 patients on monotherapy for two cycles, there were six SD (duration 6–12 weeks) and six PD. The short duration of SD in belinostat monotherapy was attributed to patient withdrawal or moving to dexamethasone addition in spite of disease stabilisation. All six patients receiving belinostat and dexamethasone had previously received at least two dexamethasone-containing regimens. One patient had a PR (duration 6 weeks); five patients had SD which lasted for 15 and 35 weeks in two cases. In 69 cycles of treatment, there were seven grade 3–4 adverse events, including anaemia, infection, respiratory distress, hyperglycaemia, thrombocytopaenia and fatigue.
Finally, combination therapy of HDAC inhibitors with standard chemotherapeutic agents such as liposomal doxorubicin and melphalan [64] as well as lenalidomide combination therapy also looks promising in the preclinical setting [65].
diffuse large B-cell lymphoma
Diffuse large B-cell lymphomas (DLBCLs) are the most common subgroup of NHLs, accounting 30% of lymphomas. These tumours are fast growing and aggressive with a tendency to metastasise. DLBCLs are most commonly diagnosed in middle-aged and elderly individuals, with 16 000 new cases per year in the United States [66]. Chemotherapy is considered to be the standard treatment regimen for patients with DLBCLs, but the 5-year progression-free survival rate remains <50%.
vorinostat
In a phase I trial, antitumour activity was observed in DLBCL patients treated with oral vorinostat, as three of the seven patients achieved a clinical response [65, 67]. These patients had transformed DLBCLs, and one achieved a CR lasting >1 year. The preliminary results prompted a phase II trial to further evaluate the efficacy and safety of oral vorinostat in patients with relapsed DLBCLs [68]. Eighteen patients who had received two or more systemic therapies with a median age of 66 years were enrolled. Seven received 300 mg for 14 days every 3 weeks, but four had grade 3 or 4 toxicity. The schedule was amended to 300 mg for 3 days every week which was well tolerated. One achieved a CR after 85 days which lasted for >468 days in total and one had SD for 301 days. However, 16 discontinued due to PD, with the median TTP being 44 days. Common drug-related adverse experiences (mostly grade 1–2) were diarrhoea, fatigue, nausea, anaemia and vomiting. Despite vorinostat being well tolerated, it has been shown to have limited activity against relapsed DLBCLs.
MGCD0103
The HDAC inhibitor MGCD0103 was tested in a phase II trial as a monotherapy for the treatment of relapsed or refractory follicular lymphoma (FL) and DLBCL [69]. Oral MGCD0103 was administered to a total of 38 patients (19 FLs and 19 DLBCLs). At the time of re-examination after treatment, 19 of 24 patients who had computed tomography scans showed a reduction in tumour volume; 12 (50%) showed >30% reduction and seven (29%) showed >40% reduction. To date, one CR and one PR have been observed in FL patients and two PR were observed in patients with DLBCLs. Common toxic effects observed included fatigue, nausea, diarrhoea, anorexia and decreased appetite; however, no grade 4 toxic effects were observed.
myelodysplastic syndrome and acute myeloid leukaemia
Myelodysplastic syndrome (MDS) refers to a group of clonal stem-cell disorders characterised by ineffective haematopoiesis in one or more lineages of the bone marrow that generally follow a path of cytopaenia to myeloid leukaemia. MDS may arise both de novo and as a consequence of chemo- or radiotherapy. However, as MDS is more prevalent with increasing age, it may arise due to genetic damage caused by hazardous exposure or inherited susceptibility. Current treatment of MDS includes DNA methylation inhibitors (5'-azacytidine and decitabine) as well as the immunomodulatory inhibitor, lenalidomide. Cytokines and agents that block cytokine receptors have also shown efficacy. The annual incidence of MDS ranges from 2 to 12 cases per 100 000, but increases to 50 cases per 100 000 among people aged 
70 years [70].
Acute myeloid leukaemias (AMLs) arise from the proliferation of immature myeloid precursor cells. Several variants of AMLs are known to exist, many of which are associated with specific fusion proteins. For example, acute promyelocytic leukaemia (APML) arises when promyelocytes proliferate rather than differentiating. Over 90% of patients diagnosed with APML exhibit a chromosomal translocation that results in the PML–RAR t(15:17) fusion protein containing the promyelocytic leukaemia protein and the retinoic acid receptor alpha isoform. APML variants also exist with chromosomal translocation t(11:17), where the RAR gene fuses with the promyelocytic leukaemia zinc finger protein (PLZF) gene. Pathologically, however, these two forms of APML are indistinguishable. Non-APMLs also exhibit fusion proteins such as AML–ETO1 t(8:21). Generally, however, all acute leukaemias regardless of genetic signature present with signs and symptoms of pancytopenia (anaemia, neutropenia and thrombocytopaenia) causing weakness, fatigue and infections.
vorinostat
A phase I trial of oral vorinostat was conducted in 41 patients [31 AMLs, three chronic lymphocytic leukaemias (CLLs) and three MDS] [71]. An MTD of 200 mg twice daily or 250 mg thrice daily was established. Observed toxic effects included fatigue, thrombocytopaenia, nausea and vomiting as well as diarrhoea. Overall, seven patients had improved tumour responses; two CR and two CR with incomplete blood count recovery.
MS-275
A phase I trial of oral MS-275 was conducted in 38 patients with advanced acute lymphoblastic leukaemias [72]. The MTD was 8 mg/m2 weekly for 4 weeks every 6 weeks. Common toxic effects included DLTs of infections and neurological toxicity and non-DLTs of fatigue, anorexia, nausea and vomiting, hypoalbuminemia and hypocalcaemia. No responses to classical criteria were observed, although alteration in acetylated histone H3 was observed, demonstrating inhibition of HDAC enzymes in vivo.
MGCD0103
In a phase I trial administering MGCD0103 orally for 3 weeks, 29 patients were recruited (76% AMLs and 24% MDS). Of these patients, 24 had received previous treatments. An MTD was established due to toxic effects including fatigue, nausea and vomiting and diarrhoea. Three patients achieved a complete bone marrow response (blasts <5%) [73].
sodium phenylbutyrate
Thirteen patients were given a continuous i.v. infusion of sodium phenylbutyrate for either seven consecutive days of 14 or 21 consecutive days of 28. Sodium phenylbutyrate was well tolerated despite prolonged infusions and in two patients on the 21 of 28 regimen, haematological improvement was observed [74].
valproic acid
Normal pharmacological intervention involves administering ‘all-trans’ retinoic acid (ATRA); however, patients can develop resistance easily. Studies have therefore been carried out to identify whether HDAC inhibitors have potential as an adjuvant to ATRA. A phase II trial in patients with AMLs and MDS using valproic acid (VPA) as both monotherapy and in combination with ATRA has been carried out. In total, 58 patients were recruited, of which 31 received VPA as a single agent. However, ATRA was administered to 13 of these patients who showed no response or relapsed. The remaining 27 patients received VPA–ATRA for the duration of the trial. The trial reported results for 23 patients with a peripheral blood count >5% and indicated that five patients showed a complete peripheral blast clearance while six patients showed a diminished blast count. The VPA was also well tolerated in most cases, although side-effects did include fatigue, tremor and thrombocytopaenia [75]. A previous phase II trial combining VPA and ATRA in AMLs and MDS patients has also shown an ORR of 35% (7 of 23 patients). Generally, these trials have shown VPA to have beneficial effects in AMLs, as a combination therapy [76].
A third VPA–ATRA combination trial conducted on 26 patients also produced similar findings to these two trials. Nineteen patients completed 4 weeks of VPA–ATRA treatment. The remaining seven patients were removed due to rapid disease progression (n = 3) or unacceptable side-effects (n = 4). In total, one PR and one MR were observed. All 19 patients were removed from the trial after 4 weeks of treatment, however, due to disease progression. The VPA–ATRA combination was considered to be well tolerated; however, observed toxic effects included fatigue, petechiae, vasculitis, conjunctivitis, dyspnoea and electrolyte imbalance [77].
romidepsin
A total of 20 patients (10 AMLs and 10 CLLs) were recruited for a trial to examine romidepsin. Romidepsin (13 mg/kg/m2) was administered on days 1, 8 and 15 every 28 days. Overall, no CR or PR responses were observed; however, the CLL patients did have a more evident antileukaemic response (7 of 10 patients with elevated leukocyte counts showed a significant reduction). As described in other romidepsin trials, the major toxic effects observed were nausea, fatigue, emesis, anorexia and hypocalcaemia [78].
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conclusions |
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Topabstractintroductionthe histone deacetylase familyclinical evaluation of HDAC...conclusionsfundingacknowledgementsreferences |
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HDAC inhibitors are potent antiproliferative agents with relatively little effect on normal tissues. The mechanism by which this antitumour activity is mediated remains unclear, although numerous mechanisms have been proposed [14]. A large number of clinical trials are ongoing in both haematological and solid malignancies using a wide variety of HDAC inhibitors.
In contrast to many solid tumours, some haematological malignancies are very sensitive to conventional cytotoxic agents as well as some newer agents such as bortezomib. However, there remains a significant therapeutic need for more efficacious and less toxic agents especially for relapsed and treatment-resistant disease. Despite recent advances, the duration of response to standard cytotoxic treatments in CTCL, PTCL, MM and DLBCL remains disappointing. Furthermore, better therapies are urgently needed for relapsed Hodgkin’s disease.
A number of clinical trials have been completed and many others are ongoing using HDAC inhibitors as single agents and in combination for the treatment of various haematological malignancies with some promising early results. Perhaps, the most hopeful of these have been in advanced CTCL and consequently, vorinostat is now a licensed treatment in the United States for advanced cases. Significant single-agent activity for romidepsin has been demonstrated in PTCL and encouraging results have also been seen in HL with MGCD0103. From the trials conducted, it is also clear that a major clinical advantage is that HDAC inhibitors are very well tolerated in the majority of patients.
The future of HDAC inhibitor therapies in haematological malignancy is likely to lie in designing biologically rational combination therapies with other agents that can be predicted to have synergistic or additive effects. For example, in APML, the PML–RAR fusion protein causes resistance to physiological levels of retinoic acid and this resistance can be overcome with HDAC inhibitors. Preclinical studies have demonstrated synergistic interactions with bortezomib and HDAC inhibitors in causing apoptosis of tumour cells and consequently, trials combining these two agents are ongoing in MM.
Finally, predictive biomarkers that may assist in identifying patient or tumour groups that are more sensitive to HDAC inhibitors are being sought. The search for these biomarkers will be greatly aided by elucidation of the mechanism through which HDAC inhibitors exert their effects and this in turn should enable malignant disease to be stratified into groups that are likely to undergo clinical benefit.
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funding |
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Cancer Research UK, Medical Research Council, Association of International Cancer Research, Leukaemia Research Fund and European Union.
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We thank Rosemary Williams for help in preparing the manuscript.
Received for publication October 2, 2008. Revision received December 18, 2008. Accepted for publication December 19, 2008.
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references |
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