Phase 2 study of oral panobinostat (LBH589) with or without erythropoietin in heavily transfusion-dependent IPSS low or int-1 MDS patients

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Patients with myelodysplastic syndromes (MDS) often display anemia for which currently available treatment options are limited. In fact, red blood cell (RBC) transfusions remain a crucial therapy although their use is linked to decreased survival. In lower-risk MDS, there is no licensed treatment option available throughout Europe, at present, although erythropoietin receptor stimulating agents (ESA) are active in a well-defined subset of patients with low transfusion burden and low endogenous erythropoietin (EPO) levels.1 Although the mechanism is not clearly defined, EPO-dependent signaling is impaired in the majority of anemic MDS patients. Recent findings suggest that mutations in epigenetic regulators contribute to the pathophysiology of MDS.2, 3 Targeting histone deacetylation (HDAC) with single agent valproic acid (VPA) has been shown to achieve substantial erythroid improvements, especially in IPSS lower-risk patients.4 Panobinostat (LBH589), an oral pan class I/II histone deacetylase inhibitor (HDACi), has shown promising anti-tumor activity in preclinical models and in leukemia patients through inhibiting cellular proliferation and inducing apoptosis.5, 6

Within a phase 2 trial (GEPARD study by the German MDS study group) we investigated the single agent activity of orally administered LBH589 in RBC transfusion-dependent low or intermediate-1 risk MDS patients who were either ESA refractory or had a low probability of response according to the Hellström-Lindberg score1, 7 ( identifier: NCT01034657). Transfusion dependence was defined as 4 units of blood within an 8-week period. The design of the study is shown in Figure 1. The primary objective of the trial was to evaluate the rate of erythroid improvement (HI-E) using modified International MDS Working Group (IWG) criteria8 after completion of the first part of the study (‘core phase’; 16 weeks).

Figure 1

Study design and efficacy outcome. After screening, all patients received LBH589 orally at a starting dose of 40 mg (n=30) or 30 mg (n=4) on Monday, Wednesday and Friday every week until week 16, when the response was evaluated (‘core phase’). In case of erythroid improvement (HI-E), patients continued on LBH589 until week 52, whereas patients with disease progression discontinued study treatment (dotted line). At the final visit of the core phase, 20 patients were evaluable for the assessment of primary efficacy variables. Only 14 patients with stable disease for transfusion needs were evaluable and met the criteria for randomization. Owing to drop out of 7 patients before randomization, 13 patients were eligible for the second part of the study (‘randomized phase’). Twelve patients were randomized to one of the two arms in equal parts and treated with either LBH589 alone (n=6) or LBH589+Epoetin Alfa HEXAL (ESA, 30 000 IU/week subcutaneously; n=6) for further 16 weeks. Both groups were evaluated after 32 weeks and continued treatment until week 52 only in case of HI-E or stable disease. Total responses for all patients were evaluated after 52 weeks of treatment (end of study, EOS). * one patient who was eligible for randomization was not randomized and continued with LBH589 single agent treatment; # two patients were lost to EOS assessment due to the occurrence of serious adverse events.

After the core phase, patients with stable disease regarding transfusion needs were randomized either to receive further treatment with LBH589 alone or LBH589 plus ESA (‘randomized phase’). This was done in an attempt to investigate whether HDACi mediated by LBH589 might overcome resistance to erythropoiesis-stimulating agents, like recently shown for all-trans retinoic acid.9 Per amendment 2, the study was terminated prematurely due to a lack of an observed response in the 34 patients treated thus far. Results presented are based on the full analysis set population. The study was conducted according to the Declaration of Helsinki, and all patients provided written informed consent.

Median age of the patient population was 66 years (range 51–81), and IPSS categories were low (n=11) or int-1 (n=23) with less than 5% bone marrow blast infiltration in all patients. The majority of patients (n=20) displayed no cytogenetic abnormalities, while deletion in chromosome 5 [del(5q)] was the most common abnormality observed in seven patients. At baseline, the average pretreatment number of transfusion units in the previous 8 weeks was 6.1.

Initially, 30 patients (88.2%) started treatment with 40 mg/day three times weekly every week, whereas subsequent patients (4; 11.8%) started with a lower dose of 30 mg/day within the first amendment. The starting dose was reduced to minimize the frequency of study drug interruptions necessary to manage side effects. During the core phase, patients received LBH589 for a median of 90.5 days (range 5–135 days). Twenty (58.8%) patients completed the 16 weeks’ treatment period, 14 patients stopped LBH589 prematurely, and 28 patients had dose reductions primarily due to adverse events (AEs). The most common reasons for premature discontinuation within the core phase included AEs (n=8; 23.5%), unsatisfactory therapeutic effect (n=2; 5.9%) and protocol violation (n=2; 5.9%). The treatment duration of the total population (n=34) until the first dose reduction/interruption occurred, amounts to a median of 24.5 days ranging from 3 to 239 days.

During the core phase, all 34 treated patients developed AEs with suspected drug relation. A total of 410 AEs were reported within the core phase. The most frequently reported AEs were diarrhea (n=46), thrombocytopenia (n=42), fatigue (n=30), neutropenia (n=26) and nausea (n=22). Within the total patient population, the most frequent (more than 15% of the patients) non-hematologic AEs were gastrointestinal in nature, including diarrhea (n=25), nausea (n=20), fatigue (n=17) followed by anorexia (n=10), asthenia (n=7) and hypothyroidism (n=6). The majority of gastrointestinal AEs were mild (grades 1 and 2; 86.6%). Most frequently reported hematologic AEs (incidence 5%) were thrombocytopenia (n=15), neutropenia (n=12), leukopenia (n=4) and anemia (n=4). In particular, grade 3–4 AEs occurred mostly as thrombocytopenia (n=11) and neutropenia (n=10) compared to leukopenia and anemia where 4 and 2 patients were reported, respectively. Discontinuation due to hematologic AEs was rare (n=3; 8.8%). Between the two cohorts starting with different doses (40 or 30 mg), the type and occurrence of the measured AEs were comparable. Thirteen patients (38%) experienced AEs that led to permanent discontinuation of the study treatment, suggesting that caution is advised especially in elderly patients undergoing LBH589 treatment within subsequent clinical trials. A total of 12 patients experienced serious adverse events during both phases of the study, 11 during the core phase and one additional patient during the randomized phase. Twenty-two AEs in the core phase and nine in the randomized phase were considered as serious. Two deaths were reported in this study. Both fatal events occurred during the follow-up period and were considered to be unrelated to the treatment by the investigator.

Myelosuppression, characterized by a reduction in platelet and neutrophil counts, as well as in decreased hemoglobin levels and decreased absolute lymphocyte count, remains the most prominent of laboratory abnormalities reported with oral LBH589.10 In fact, thrombocytopenia was the most evident hematologic side effect in this study followed by neutropenia and anemia. Comparing the median baseline values of 218 × 109/l platelets and 1.94 × 109/l neutrophils, the cell counts significantly decreased to 133.5 × 109/l and 1.1 × 109/l, respectively, in a treatment-dependent manner during the core phase (Figure 2). Lately, in preclinical models, it was shown that LBH589-induced thrombocytopenia is transient and that platelet counts recover rapidly after treatment is stopped.11 So far, our data obtained in this study are in accordance with the known potential antiproliferative properties of the HDACi LBH589 mainly on platelet maturation. In agreement with other studies, the most common drug-related non-hematological AEs were gastrointestinal side effects like diarrhea, nausea and fatigue.10 Altogether, the safety data collected in our trial are consistent with those in other HDACi studies.12

Figure 2

Treatment-dependent decline of patients’ platelet and neutrophil counts during core phase. The median and the interquartile range of the absolute numbers of platelets (a) and neutrophils (b) at each study visit during the core phase (week 0.1—week 16) were shown for all evaluable patients (n20).

Of the 20 patients evaluable for response at week 16, no patient achieved an erythroid response or RBC improvement. Rather, the mean transfusion need increased compared to baseline, from 6.1 to 8.2 in a period of 8 weeks. There was one patient (5.0%) with a del(5q) who had a partial cytogenetic response. Only 13 patients continued into the second study phase. Of these, six patients underwent combination treatment with LBH589+EPO, but again no response was observed after a median time of 75.5 days of combined therapy. In four patients (20.0%), a disease progression to a higher IPSS stage was reported.

The efficacy of VPA, a known HDAC2-specific inhibitor, especially in low-risk MDS4 prompted the exploration of a pan-HDACi LBH589 treatment effects in this disease. In fact, in this study 29% of patients with low- and Int-I risk profile achieved independence from RBC transfusions due to VPA alone. For the low-risk patients, the response rate was 50%. In strong contrast, a recent phase II study with a different HDACi, belinostat, in MDS patients showed no complete response (CR) or partial response (PR) and only one confirmed hematologic improvement in neutrophil counts and was stopped prematurely.13 In addition, none of the patients treated with LBH589 in this study achieved a CR or PR, while a total of 14 patients (70.0%) demonstrated stable disease after 4 months as best response. These different findings led us to the assumption that VPA might have a different mode of action compared to panobinostat or belinostat. Furthermore, HDACi are probably more effective in combination with DNA hypomethylating agents like azacytidine.14, 15

Taken together, these data demonstrate the absence of a meaningful clinical activity of LBH589 in lower-risk MDS patients. The significant toxicity seen in our older patient population within this study needs to be taken into consideration when further exploring this class of drugs in MDS patients.


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Correspondence to U Platzbecker.

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UP and AG had received speakers honoraria from Novartis Pharma GmbH. All other authors declare no conflict of interest.

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Platzbecker, U., Al-Ali, H., Gattermann, N. et al. Phase 2 study of oral panobinostat (LBH589) with or without erythropoietin in heavily transfusion-dependent IPSS low or int-1 MDS patients. Leukemia 28, 696–698 (2014) doi:10.1038/leu.2013.325

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