See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/279914879
Panobinostat in combination with bortezomib in patients with relapsed or refractory
peripheral T-cell...
Article · July 2015
DOI: 10.1016/S2352-3026(15)00097-6
CITATIONS
4
READS
127
14 authors, including:
Some of the authors of this publication are also working on these related projects:
LymphomaView project
Hematology OncologyView project Daryl Tan
Raffles Medical Group
74PUBLICATIONS 901CITATIONS
SEE PROFILE
Colin Phipps
Singapore General Hospital 46PUBLICATIONS 76CITATIONS
SEE PROFILE
William Hwang
Duke-NUS Medical School 121PUBLICATIONS 1,389CITATIONS
SEE PROFILE
Won Seog Kim
Samsung Medical Center
650PUBLICATIONS 11,748CITATIONS
SEE PROFILE
All content following this page was uploaded by Daryl Tan on 09 July 2015.
The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the original document
Lancet Haematol 2015 Published Online July 8, 2015
http://dx.doi.org/10.1016/
S2352-3026(15)00097-6 See Online/Comment http://dx.doi.org/10.1016/
S2352-3026(15)00116-7 Department of Hematology, Singapore General Hospital, Singapore (D Tan MRCP, C Phipps FRCPath,
W Y C K Hwang FRCP, H Yeap BSc, Y S Lee FRCPath,
S G Kumar FRCPath, Y T Goh MBBS); Raffl es Cancer Centre, Raffl es Hospital, Singapore (D Tan); Department of Pathology, Singapore General Hospital, Singapore (S Y Tan FRCPath); Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (Y H Chan PhD);Medical Oncology, National Cancer Centre of Singapore, Singapore (K Tay MD, S T Lim MRCP); Sime Darby Medical Centre, Selangor, Malaysia (S C Ng FRCP); Hospital Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia (Prof S Fadilah PhD);
and Samsung Medical Centre, Seoul, South Korea (W S Kim MD) Correspondence to:
Dr Yeow Tee Goh, Department of Haematology, Singapore General Hospital, Singapore 169608, Republic of Singapore [email protected]
Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma:
an open-label, multicentre phase 2 trial
Daryl Tan, Colin Phipps, William Y K Hwang, Soo Yong Tan, Chun Hsien Yeap, Yiong Huak Chan, Kevin Tay, Soon Thye Lim, Yuh Shan Lee, Sathish Gopalakrishnan Kumar, Soo Chin Ng, S Fadilah, Won Seog Kim, Yeow Tee Goh , for the SGH651 investigators
Summary
Background Patients with relapsed or refractory peripheral T-cell lymphoma have a poor prognosis after conventional chemotherapy. Approved novel agents have only modest single-agent activity in most subtypes of peripheral T-cell lymphoma. Panobinostat is a potent oral pan-deacetylase inhibitor. Findings of many preclinical studies have shown synergistic antilymphoma activity when panobinostat is combined with the proteasome inhibitor bortezomib. We aimed to study the e ect of panobinostat and bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma.
Methods In this open-label, multicentre phase 2 trial, we recruited patients aged 21 years or older with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy from fi ve tertiary hospitals in Singapore, Malaysia, and South Korea. Patients received 20 mg oral panobinostat three times a week and 1·3 mg/m² intravenous bortezomib two times a week, both for 2 of 3 weeks for up to eight cycles. The primary endpoint was the proportion of patients who achieved an objective response in accordance with the International Working Group revised response criteria; analyses were by intention to treat. The study is completed and is registered with ClinicalTrials.gov, number NCT00901147.
Findings Between Nov 9, 2009, and Nov 26, 2013, we enrolled 25 patients with various histological subtypes of peripheral T-cell lymphoma. Of 23 patients assessable for responses, ten (43%, 95% CI 23–63) patients had an objective response, of which fi ve were complete responses. Serious adverse events were reported in ten (40%) of 25 patients. Common treatment-related grade 3–4 adverse events included thrombocytopenia (17 [68%]), neutropenia (ten [40%]), diarrhoea (fi ve [20%]), and asthenia or fatigue (two [8%]). We recorded peripheral neuropathy of any grade in ten (40%) patients.
Interpretation Combined proteasome and histone deacetylase inhibition is safe and feasible and shows encouraging activity for patients with peripheral T-cell lymphoma. Our fi ndings validate those of preclinical studies showing synergism in the combination and represent a rational way forward in harnessing the full potential of novel agents in peripheral T-cell lymphoma.
Funding Novartis Pharmaceuticals, Janssen Pharmaceuticals, and Singhealth Foundation.
Introduction
Peripheral T-cell lymphomas constitute a biologically heterogeneous group of aggressive cancers derived from mature (post-thymic) T cells and natural killer cells.
These lymphomas are uncommon and account for 10–15% of all non-Hodgkin lymphomas worldwide.1 However, a geographical variation in the incidence of peripheral T-cell lymphomas is well documented and in some parts of Asia, incidences as high as 20–25% have been reported.2,3 This disparity might be caused by a higher geographical susceptibility to specifi c pathogenic viruses in Asian countries, such as Epstein-Barr virus and human T-cell leukaemia virus-1 (HTLV-1). With the exception of ALK-positive anaplastic large-cell lymphoma, peripheral T-cell lymphomas are associated with a poor prognosis with estimated 5-year overall survival of 10–20%.4,5 In the absence of a consensus on the optimum standard fi rst-line treatment for peripheral T-cell
lymphoma, most newly diagnosed patients are treated like di use large B-cell lymphoma with CHOP-like chemotherapy (cyclophosphamide, vincristine, doxoru- bicin, and prednisolone), with younger patients having the option of consolidation with upfront high-dose therapy with autologous stem-cell transplantation.
Despite 50–60% of patients responding to this treatment, relapses are common and outcomes of patients with relapsed or refractory disease after failing such conventional chemotherapies have been poor.5
Of late, several novel agents have been approved by the US Food and Drug Administration (FDA) for patients with relapsed or refractory peripheral T-cell lymphomas.
Although the objective response rate of 86% shown with brentuximab vedotin in systemic anaplastic large-cell lymphoma is remarkable, the e cacy of pralatrexate, romidepsin, and belinostat with objective response rates ranging between 25% and 29% is modest for other forms
Articles
of peripheral T-cell lymphoma.6–9 Therefore, more e ective treatments are needed to improve on these single agents in this setting.
Panobinostat is a pan-deacetylase inhibitor with potent activity against class I, II, and IV deacetylases.10–12 Inhibition of deacetylases induces the acetylation of both histone and other non-histone proteins, resulting in antitumour activity via increased tumour suppressor gene transcription, growth inhibition, cell cycle regulation, and apoptosis.13,14 Proteasome inhibitors such as bortezomib are clinically e ective in multiple myeloma and mantle cell lymphoma. Potential mechanisms of action include inhibition of tumour growth by cell cycle arrest and induction of cell death. This process includes the inhibition of the nuclear factor B (NF B), which could be upregulated in some types of peripheral T-cell lymphoma and confer resistance to apoptosis.15–18 Although both panobinostat and bortezomib have only modest single-agent activities in patients with peripheral T-cell lymphoma, preclinical data suggest that the combination of the two drugs is highly synergistic.11,12,19–21
One hypothesis for synergy is through the accumulation of polyubiquitinated proteins by concurrent targeting of the proteasome with bortezomib and the aggresome pathway via histone deacetylase 6 inhibition, and this leads to increased cell stress and apoptosis.22,23 Collectively, these data and the unmet need for more novel approaches
in patients with relapsed or refractory peripheral T-cell lymphomas provide a strong rationale for the clinical testing of this combination. In our multi-institutional phase 2 trial, we aimed to study the activity of this novel combination in patients with peripheral T-cell lymphoma.
Methods
Study objectives, design, and patients
In this open label, single-arm, phase 2 study done at fi ve tertiary hospitals in Singapore, Malaysia, and South Korea, we recruited patients with relapsed or refractory peripheral T-cell lymphoma who had received at least one previous line of systemic therapy. The following histological subtypes of peripheral T-cell lymphoma as defi ned by WHO and confi rmed by local pathologists were included for enrolment: peripheral T-cell lymphoma not otherwise specifi ed, angioimmunoblastic T-cell lym- phoma, extranodal natural killer (NK) T-cell lymphoma, nasal type, enteropathy-type T-cell lymphoma, sub- cutaneous panniculitis-like T-cell lymphoma, cutaneous gamma or delta T-cell lymphoma, transformed mycosis fungoides, hepatosplenic T-cell lymphoma, ALK-negative anaplastic large-cell lymphoma, and ALK-positive anaplastic large-cell lymphoma that had relapsed after autologous stem-cell transplant.24
Other eligibility criteria included age of 21 years or older, measurable disease according to International Research in context
Evidence before this study
Relapsed or refractory peripheral T-cell lymphoma after conventional chemotherapy is associated with a very poor prognosis and there is currently no recommendation on the standard approach to helping these patients.Between January, 2010, and January, 2015, we searched PubMed and abstracts from all major oncology and haematology congresses including the annual meetings of the American Society of Clinical Oncology, the American Society of Haematology, the European Haematology Association, and the International Conference on Malignant Lymphoma, to identify publications in English on novel targeted treatments for relapsed or refractory peripheral T-cell lymphoma. We used the search terms “T-cell lymphoma”,
“novel agents”, “histone deacetylase inhibitor”, “proteasome inhibitor”, and “anti-folate”, and restricted our search to novel compounds that are in more advanced stages of clinical testing (phase 2 or 3 studies). We identifi ed several full publications and congress abstracts describing the results of phase 2 studies on romidepsin, pralatrexate, belinostat, brentuximab vedotin, denileukin diftitox, bendamustine, bortezomib, and lenalidomide in relapsed or refractory peripheral T-cell lymphoma. No clinical study reported on the use of novel combination of targeted agents. The respective studies on romidepsin, pralatrexate, belinostat, and brentuximab vedotin led to their approvals by the US Food and Drug Administration (FDA). With the exception of the remarkable effi cacy of
brentuximab vedotin in systemic anaplastic large cell lymphoma (86% of patients responding to treatment), the effi cacy of romidepsin, pralatrexate, and belinostat in relapsed or refractory peripheral T-cell lymphoma is only modest with objective response rates between 25% and 29%.
Added value of this study
For patients with relapsed or refractory peripheral T-cell lymphoma, there is an unmet need to improve the eff ectiveness of currently approved novel agents to induce remission and reduce disease burden to enable stem-cell transplantation. Our data compare favourably with the modest single-agent activities of novel targeted compounds and ours is the fi rst study to show that the combination of two novel agents (proteasome and histone deacetylase inhibition) is safe, feasible, and promising in peripheral T-cell lymphoma. Our fi ndings validate data from abundant preclinical studies suggesting that a combination approach is synergistic.
Implications of all the available evidence
Because peripheral T-cell lymphoma is clinically heterogeneous and associated with a very poor prognosis, the identifi cation of synergistic novel combinations preclinically and the translation to clinical studies represents the most rational way forward in harnessing the full potential of novel agents in peripheral T-cell lymphoma. This approach will certainly fi ll the emergent need for improved treatment strategies in these patients.
Workshop Criteria (IWC),25 and measurable cutaneous disease, Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and adequate bone marrow and organ function: absolute neutrophil count of 1·0 × 10 cells per L or higher; platelet count of 50 × 10 platelets per L or higher, or 30 × 10 platelets per L or higher if bone marrow involvement was recorded;
total bilirubin, aspartate aminotransferase and alanine aminotransferase two times or lower than the upper limit of normal; and serum creatinine two times or lower than the upper limit of normal. Major exclusion criteria included the concomitant use of any other anticancer treatment, therapeutic warfarin, and drugs that could prolong the corrected QT (QTc) interval or inhibitors of CYP3A4.
Additionally, patients were ineligible if they had received previous treatment with a deacetylase inhibitor or bortezomib, or had treatment with chemotherapy or immunotherapy within 3 weeks before the start of study.
Patients were not eligible if they had any known cardiac abnormalities such as congenital long QT syndrome, QTcF interval less than 480 ms, a myocardial infarction within 12 months of study entry, substantial electro- cardiogram abnormalities, congestive heart failure, left ventricular ejection fraction below normal, known history of sustained ventricular tachycardia, ventricular fi brillation, torsade de pointes, hypertrophic cardio- myopathy or restrictive cardiomyopathy, or any cardiac arrhythmia requiring anti-arrhythmic drugs. We also excluded any patients with coexisting peripheral neuropathy or neuropathic pain of grade 2 or worse severity or any clinically signifi cant active infection such as HIV or clinically active hepatitis B and C.
Written informed consent was obtained from all patients and the protocol was approved by the institu- tional review boards of all participating institutions. The study was done in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.
Procedures
Patients received 20 mg oral panobinostat three times per week and 1·3 mg/m² intravenous bortezomib twice per week (on days 1, 4, 8, and 11), both for 2 of 3 weeks for up to six to eight 21-day cycles or until the onset of unacceptable toxic e ects or disease progression. Per protocol, extension of therapy beyond eight cycles was not allowed, even for responding patients. The dosages of the study drugs were based on the maximum tolerated dose of both drugs derived from the phase 1b component of the panobinostat or placebo with bortezomib and dexamethasone in patients with relapsed multiple myeloma (PANORAMA [NCT01023308]) study that assessed the same combination in patients with relapsed or refractory multiple myeloma.26
Dose delays and reductions were allowed for grade 3 or worse non-haematological toxic e ects, absolute neutrophil count 0·5 × 10 cells per L or lower, or platelet
count 25 × 10 platelets per L or lower. Panobinostat doses were reduced from 20 mg to 15 mg (one dose level reduction), or 15 mg to 10 mg (two dose levels reduction).
Bortezomib doses were reduced from 1·3 mg/m² to 1·0 mg/m² (one dose level reduction) and 1·0 mg/m² to 0·7 mg/m² (two dose levels reduction). Patients who could not tolerate both panobinostat and bortezomib were required to permanently discontinue treatment, but were still followed up for disease assessment and survival. We used the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).
Patients had electrocardiogram monitoring done in triplicate on days 1 and 5 of cycle one and on day 8 of cycles two to eight. Data were reviewed locally and centrally. E cacy and safety data were reviewed by an independent data monitoring committee.
Outcomes
The primary endpoint was the proportion of patients with an objective response according to the Revised Response Criteria in eligible patients given the com- bination of bortezomib and panobinostat.24 Secondary endpoints were progression-free survival, overall survival, time to response, duration of response, and safety and tolerability of the treatment combination.
We assessed responses for activity with CT or
¹ F-fl uorodeoxyglucose–PET (FDG-PET) scans after every two cycles at weeks 6, 12, 18, and 24 in accordance
Patients (n=25)
Age (years) 59 (35–79)
Sex
Men 16 (64%)
Women 9 (36%)
ECOG performance status
0 9 (36%)
1 15 (60%)
2 1 (4%)
Time from diagnosis (months) 12 (4–85)
Stage at enrolment
II 4 (16%)
III 11 (44%)
IV 10 (40%)
Previous lines of treatment 2 (1–4)
Previous high-dose therapy 7 (28%)
Lymphoma subtype
Peripheral T-cell lymphoma, not otherwise specifi ed 9 (36%) Angioimmunoblastic T-cell lymphoma 8 (32%) ALK-positive anaplastic large cell lymphoma 1 (4%) ALK-negative anaplastic large cell lymphoma 4 (16%) Natural killer/T-cell lymphoma, nasal type 2 (8%) Subcutaneous panniculitis-like 1 (4%) Data are median (range) or n (%). ECOG=Eastern Cooperative Oncology Group.
Table 1: Patient characteristics at study baseline
Articles
with the Revised Response Criteria.24 Clinical response was established both by investigators and by an independent central review committee. Complete response required clearing of known sites of disease and partial response required recorded response in a ected areas. The key secondary endpoint was progression-free
survival, which was defi ned as the time from the date of start of treatment to the date of event defi ned as the fi rst documented progression or death due to any cause.
Other secondary endpoints included the overall survival, defi ned as the time from date of treatment to the date of death due to any cause, the time to response, defi ned as the time from the date of the start of treatment to the date of fi rst documented response (complete response or partial response) and the duration of response, defi ned as the time from the date of fi rst documented response (complete response or partial response) to the date of event as defi ned for the progression-free survival. The data cuto for this report was Nov 1, 2014.
Statistical analysis
To establish the sample size needed, we assumed that 20–50% of patients would respond to the combination.
The Gehan’s two stage optimum design required a response in one of 11 patients in stage 1 of the study to accrue the full cohort of 25 patients to target a response rate of 25% or better with a power of 95%, and to rule out a lower than 25% response rate, with 10% probabilities of accepting a poor study regimen and of rejecting a good one.27We used the Kaplan-Meier method to determine duration of response, progression-free survival, and overall survival. Response durations were censored at the time of fi rst disease recurrence. The interim analysis was planned after the last patient enrolled in stage one had undergone the fi rst response evaluation. All descriptive statistical analyses were done with SPSS software (version 21.0). The study is registered with ClinicalTrials.
gov, number NCT00901147.
Role of the funding source
The funders of the study collaborated with the study steering committee (DT, YTG, YHC, SCN, and WSK) in the study design and data collection. They were not involved in data analysis, data interpretation, and preparation of the report. All authors had full access to all the data in the study and the corresponding author had fi nal responsibility for the decision to submit for publication.
Results
We enrolled 25 patients between Nov 9, 2009, and Nov 26, 2013. Table 1 shows patient demographic and baseline characteristics. Several di erent histological subtypes were accrued, with the most common being peripheral T-cell lymphoma not otherwise specifi ed (36%), followed by angioimmunoblastic T-cell lymphoma (32%). Most patients (88%) had stage III or IV disease at study entry. The median time from peripheral T-cell lymphoma diagnosis to study entry was 12 months, and the median number of previous systemic therapies was two (range one to four) with seven (28%) patients having undergone previous autologous stem-cell transplantation.
Assessable patients (n)
Objective response rate (%)
Complete response
Partial response
Stable disease
Progressive disease
All patients 23 10 (43%) 5 5 5 8
Peripheral T-cell lymphoma, not
otherwise specifi ed 7 2 (22%) 1 1 2 3
Angioimmunoblastic T-cell
lymphoma 8 4 (50%) 2 2 1 3
ALK-positive anaplastic large cell
lymphoma 1 1 (100%) 1 0 0 0
ALK-negative anaplastic large cell lymphoma
4 1 (25%) 0 1 1 2
Natural killer/T-cell lymphoma, nasal type
2 1 (50%) 0 1 1 0
Subcutaneous panniculitis-like
T-cell lymphoma 1 1 (100%) 1 0 0 0
Data are n or n (%).
Table 2: Responses by peripheral T-cell lymphoma subtype Figure 1: Waterfall plot
Shows percentage change from baseline for all assessable patients.
–100 –75 –50 –25 0 25 50 75 100
Progressive disease
Tumour size (% change from baseline)
Stable disease Patients (n=23)
Partial remission Complete remission Angioimmunoblastic T-cell lymphoma Peripheral T-cell lymphoma, not otherwise specified ALK-positive anaplastic large cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Extranodal natural killer/T-cell lymphoma ALK-negative anaplastic large cell lymphoma Best clinical response
At the time of data cuto , all patients had discontinued treatment. As a standard in most participating centres, most patients were assessed by FDG-PET. Six of 11 patients (55%) enrolled in stage one of the study showed a response by central review and this allowed the full recruitment of 25 patients for the study. Two patients enrolled in stage two of the study withdrew consent during cycle 1 of treatment before completion of the treatment cycle and before any e cacy assessment could be made and were therefore excluded from overall response assessment. Otherwise, all enrolled patients were included for all other analyses.
Median follow-up duration was 15·3 months (range 0·3–40·0, IQR 5·3–33·4). Ojective responses were noted in ten (43%, 95% CI 23–63) of 23 assessable patients, of whom fi ve (22%) had complete responses. Five (22%) patients had stable disease whereas eight (35%) developed progressive disease during the study. Figure 1 shows details of individual responses. The study regimen showed activity across di erent peripheral T-cell lymphoma subtypes (table 2). Patients with angioimmunoblastic T-cell lymphoma had the greatest response with four (50%) of eight patients responding. The median time to response was 39·5 days (range 33–127, IQR 42–84) and the median duration of response was 5·6 months (range 2–33, IQR 1·25–27·5). The median duration of treat ment was 54 days (range 10–208, IQR 28–116).
Ten (40%) patients were treated for at least four cycles, and six (24%) patients received six to eight cycles of treatment.
All seven patients who had progressive disease had rapid disease progression soon after study enrolment and none received more than two cycles of treatment. Five patients had a subsequent stem-cell transplant.
Median progression-free survival was 2·59 months (95% CI 0·01–5·42; fi gure 2A) whereas median overall survival was 9·90 months (3·52–16·26; fi gure 2B) after a median follow-up duration of 15·3 months (IQR 5·3–33·4).
Eight of the enrolled 25 patients remained alive at the time of data lock. Five patients who completed all treatment cycles successfully went on to receive sequential allogeneic stem-cell transplantation. The primary reasons for discontinuing treatment were progressive disease (ten [40%]), adverse events (four [16%]), withdrawal of consent (four [16%]), and death (one [4%]).
Table 3 shows toxic e ect data. Common non- haematological adverse events of any grade included diarrhoea, peripheral neuropathy, fatigue or asthenia, and vomiting. The most common haematological adverse events of any grade were thrombocytopenia, neutropenia, and anaemia. The most common grade 3 and 4 adverse events recorded were thrombocytopenia, neutropenia, and diarrhoea. However, febrile neutro- penia occurred in only three (12%) patients and platelet concentrations typically returned to baseline levels at the beginning of the subsequent cycle. Grade 1 and 2 adverse events occurring in 10% or more of patients were diarrhoea, peripheral neuropathy, fatigue, vomiting, and decreased appetite.
We noted a higher incidence of grade 3 to 4 thrombo- cytopenia and neutropenia in patients who had received previous autologous stem-cell transplantation (seven [100%] of seven patients with previous autologous stem- cell transplantation vs six [32%] of 18 without previous autologous stem-cell transplantation), suggesting that previous treatment might be an important contributing cause. Both thrombocytopenia and neutropenia were managed with dose interruptions and modifi cations. No patients discontinued the study due to haematological toxic e ects and we recorded no major haemorrhagic complication. We noted no signifi cant study drug-related cardiac abnormalities. Although ten (40%) patients had treatment-emergent peripheral neuropathy, events were generally mild, with only two (8%) grade 3 or 4 events in which patients had to discontinue study even after dose
Figure 2: Progression-free survival (A) and overall survival (B) Lighter green lines show 95% CI.
Number at risk 0 25
5 8
10 4
15 2
20 2
25 2
30 2
35 2
40 0 Time (months)
Progression-free survival (%)
0 20 40 60 80 100
A
Number at risk 0 25
5 19
10 13
15 10
20
8 9 9
25
5 30
2 4 35
0
40 45 50 55
Time (months)
Overall survival (%)
0 20 40 60 80 100
B
Articles
interruptions and dose modifi cations. A patient who had a previous cardiac history developed acute coronary syndrome that led to cardiogenic shock and had to be taken o the study. This event was deemed to be non- study drugs related. One patient died while on study during treatment cycle two and the reported cause of death was progressive disease. Overall, the major adverse events leading to study treatment discontinuation were peripheral neuropathy (two), diar rhoea (one), and acute coronary syndrome (one). There were ten reported serious adverse events judged to be possibly related to treatment; the events were infection (two), thrombo- cytopenia (three), peripheral neuropathy (two), diarrhoea (one), constipation (one), and rash (one).
The median relative dose intensity was 80·8% for bortezomib and 89·2% for panobinostat. Dose reductions were needed for 21 patients (84%) because of adverse events. Eight patients (32%) had dose reductions for both bortezomib and panobinostat. 22 (88%) patients required dose interruptions of both or either drugs due to adverse events. Seven (28%) patients had their treatment cycles delayed more than 7 days, six (24%) because of adverse events, and one (4%) because of other reasons.
Discussion
In this phase 2 study, we recorded encouraging objective responses, including complete responses in a fi fth of patients with the combination of panobinostat with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma, many of whom had been heavily pre-treated. Although a validation study might be essential to confi rm our fi ndings, the proportion of patients who responded compares favourably with the
modest activity of novel single-agents that were recently approved by the FDA for use in this same setting.7–9 However, the median duration of response of 5 6 months is short compared with the duration of responses of 17 months recorded with romidepsin and 13·6 months with belinostat.8,9 This fi nding might be attributable to the limitation of treatment cycles to eight rather than the allowance for extended treatment until disease progression even in responding patients. As a result, some patients with no alternative sequential treatment like stem-cell transplantation developed progressive disease shortly after completion of treatment. Notwith- standing the duration of response, our study combin- ation could serve as an important bridge to allogeneic stem-cell transplantation in which disease control is a prerequisite. To our knowledge, this study is the fi rst to show that epigenetic modulation via pan-deacetylase- inhibitor-based treatment in combination with proteasome inhibition is feasible and potentially synergistic in peripheral T-cell lymphoma. A combination of bortezomib with either romidepsin or belinostat would have been regarded as a more logical sequential study approach after the phase 2 studies of both drugs.
However, when we initiated this study, there was no access to belinostat in Asia and we excluded romidepsin because it is a selective class 1 deacetylase inhibitor and does not inhibit the aggresome pathway, which is dependent on histone deacetylase 6 activity. Additionally, the FDA had also recently issued guidance in support of the co-development of two or more investigational drugs in combination if the disease or disorder studied was serious and there was a strong biological rationale for use of the combination.
Although peripheral T-cell lymphoma is clinically heterogeneous, we recorded activity of the combination across the di erent subtypes. Because the numbers are small, no meaningful statistical correlation can be made.
An objective response rate of close to 50% has been reported with belinostat, another pan-deacetylase inhibitor in angioimmunoblastic T-cell lymphoma.9 This fi nding was not shown with the use of romidepsin.6,28 Whether the e ect of deacetylase inhibitors on angio immunoblastic T-cell lymphoma is class dependent deserves further exploration. The complete response reported in the patient with subcutaneous panniculitits-like T-cell lymphoma corroborates similar fi ndings of complete response with the use of romidepsin in this rare entity.29 A patient with nasal type NK/T-cell lymphoma responded very well whereas another had disease stabilisation. In view of the highly aggressive nature of this entity in the relapsed or refractory setting and the reliance of Epstein-Barr virus on the NF B and other anti-apoptotic pathways in lympho- magenesis, further exploration of this combination is warranted in patients with nasal type NK/T-cell lymphoma.
Because distinct oncogenic pathways might be associated with the di erent peripheral T-cell lymphoma entities, the study regimen might have di erent mechanisms of action
All grades
(%) Grades
1–2 (%) Grades 3
(%) Grade 4
(%) Non-haematological toxic eff ects
Diarrhoea 12 (48%) 7 (28%) 5 (20%) 0 (0%)
Peripheral neuropathy 10 (40%) 8 (32%) 1 (4%) 1 (4%) Fatigue or asthenia 9 (36%) 7 (28%) 2 (8%) 0 (0%)
Vomiting 7 (28%) 5 (20%) 2 (8%) 0 (0%)
Decreased appetite 3 (12%) 3 (12%) 0 (0%) 0 (0%)
Pyrexia 3 (12%) 2 (8%) 1 (4%) 0 (0%)
Peripheral oedema 1 (4%) 0 (0%) 1 (4%) 0 (0%)
Constipation 1 (4%) 1 (0%) 1 (4%) 0 (0%)
Rash 2 (8%) 1 (4%) 1 (4%) 0 (0%)
Erythema 1 (4%) 1 (4%) 0 (0%) 0 (0%)
Anorexia 2 (8%) 2 (8%) 0 (0%) 0 (0%)
Others 4 (16%) 4 (16%) 0 (0%) 0 (0%)
Haematological toxic eff ects
Thrombocytopenia 17 (68%) 0 (0%) 6 (24%) 11 (44%) Neutropenia 11 (44%) 1 (4%) 7 (28%) 3 (12%)
Anaemia 6 (24%) 4 (16%) 2 (8%) 0 (0%)
Leucopenia 3 (12%) 1 (4%) 1 (4%) 1 (4%)
Table 3: Incidences of non-haematological and haematological toxic eff ects
in the various entities. Hence, our continuing biomarker correlative studies are designed to establish whether the study regimen is more active in entities with upregulation of NF B activity or transcription factors or co-regulators modifi ed by acetylation, and hopefully this will help further elucidate the best way forward in the treatment of each subtype.
Common grade 3–4 adverse events and haematological toxic e ects with incidence of 20% or more included thrombocytopenia, neutropenia, anaemia, and diarrhoea.
These data partly refl ect the overlapping toxic e ect profi les of panobinostat and bortezomib. Although more than two-thirds of patients in the panobinostat group had grade 3–4 thrombocytopenia, no patient discontinued study because of thrombocytopenia. In addition to the e ects of the drugs on platelet concentrations, the high incidence is also attributable to the lower platelet entry criterion of 50 × 10 platelets per L or more for study enrolment. This study was designed to allow better recruitment of patients with peripheral T-cell lymphoma who frequently have disease involvement in marrow and had previous myelosuppressive chemotherapeutic treat- ments and hence, tend to have lower baseline platelet con centrations. Generally, thrombocytopenia was manage able and reversible, with platelet concentrations typically recovering to baseline at the end of each treatment cycle. This is consistent with the understanding that bortezomib and histone deacetylase inhibitors cause thrombocytopenia by reversibly inhibiting the function and maturation of megakaryocytes and the related release of pro-platelets rather than a direct cytotoxic e ect on the megakaryocytes or their progenitors. Hence, the resultant thrombocytopenia is non-cumulative and would rapidly resolve upon treatment interruption.30–33
Diarrhoea could be managed supportively and with dose interruptions and modifi cations. Treatment-emergent peripheral neuropathy and fatigue or asthenia were two other adverse events with an incidence of 30% or higher.
Most events were grade 1 or 2. Peripheral neuropathy is a common toxic e ect associated with the use of bortezomib.
Because the standard of care for administration of bortezomib at the time of study inception was via the intravenous route, the high incidence of peripheral neuropathy was anticipated. With the shift in clinical practice toward subcutaneous bortezomib, on the basis of a more favourable safety profi le, a switch to subcutaneous bortezomib in combination with panobinostat could lead to improved tolerability and a longer treatment duration with the combination and perhaps, improved outcomes.34 The incidences of toxic e ects recorded in this phase 2 study were similar to those reported in the major phase 3 PANORAMA1 study.35 The on-treatment deaths and drop- outs due to progressive disease were within the range of what can be anticipated for patients with relapsed or relapsed peripheral T-cell lymphoma.
In summary, our study is the fi rst to show that combined proteasome and histone deacetylase inhibition
is safe, feasible, and promising in patients with peripheral T-cell lymphoma. Our fi ndings validate abundant preclinical studies suggesting that a combination approach is synergistic and represents a rational way forward that harnesses the full potential of novel agents in peripheral T-cell lymphoma.
Contributors
DT, YTG, CP, and CHY researched the scientifi c literature. DT, YTG, and CHY contributed to study design. DT, CP, WYKH, SYT, CHY, KT, STL, YSL, SGK, SCN, SF, WSK, and YTG collected data. DT, CP, CHY, YHC, and YTG analysed and interpreted data. All authors participated in drafting or reviewing of the report and all authors approved the submitted version.
Declaration of interests
DT reports grants from Janssen and Novartis during the conduct of the study; personal fees from Janssen and Celgene. YTG reports grants from Novartis and Janssen during the conduct of the study; personal fees from Janssen, BMS, Novartis, Sanofi , Roche, Celgene, and Gilead Sciences. CP, WYKH, SYT, CHY, YHC, KT, STL, YSL, SGK, SCN, SF, and WSK declare no competing interests.
Acknowledgments
We thank Novartis and Janssen pharmaceuticals for their funding support and the provision of the study drugs; Singhealth Foundation for funds for the biomarker analysis component of the study; and our patients and their caregivers for their time and support for the trial.
References
1 Non-Hodgkin’s Lymphoma Classifi cation Project. A clinical evaluation of the International Lymphoma Study Group classifi cation of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classifi cation Project. Blood 1997; 89: 3909–18.
2 Anderson JR, Armitage JO, Weisenburger DD. Epidemiology of the non-Hodgkin’s lymphomas: distributions of the major subtypes di er by geographic locations. Non-Hodgkin’s Lymphoma Classifi cation Project. Ann Oncol 1998; 9: 717–20.
3 Au WY, Ma SY, Chim CS, et al. Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classifi cation scheme: a single center experience of 10 years.
Ann Oncol 2005; 16: 206–14.
4 Vose J, Armitage J, Weisenburger D, and the International T-cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology fi ndings and clinical outcomes. J Clin Oncol 2008; 26: 4124–30.
5 Mak V, Hamm J, Chhanabhai M, et al. Survival of patients with peripheral T-cell lymphoma after fi rst relapse or progression:
spectrum of disease and rare long-term survivors. J Clin Oncol 2013;
31: 1970–76.
6 Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol 2012;
30: 2190–96.
7 O’Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. J Clin Oncol 2011; 29: 1182–89.
8 Coi er B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy.
J Clin Oncol 2012; 30: 631–36.
9 O’Connor O, Masszi T, Savage KJ, et al. Belinostat, a novel pan- histone deacetylase inhibitor (HDACi), in relapsed or refractory peripheral T-cell lymphoma (R/R PTCL): results from the BELIEF trial. American Society of Clinical Oncology Annual Meeting;
Chicago, IL, USA; May 31–June 4, 2013. Abstr 8507.
10 Atadja P. Development of the pan-DAC inhibitor panobinostat (LBH589): successes and challenges. Cancer Lett 2009;
280: 233–41.
11 Ottmann OG, Spencer A, Prince HM, et al. Phase IA/II study of oral panobinostat (LBH589), a novel pan-deacetylase inhibitor (DACi) demonstrating e cacy in patients with advanced hematologic malignancies. 50th American Society of Hematology Annual Meeting; San Francisco, CA, USA; Dec 6–9, 2008. Abstr 958.
Articles
8 www.thelancet.com/haematology Published online July 8, 2015 http://dx.doi.org/10.1016/S2352-3026(15)00097-6
12 Ellis L, Pan Y, Smyth GK, et al. Histone deacetylase inhibitor panobinostat induces clinical responses with associated alterations in gene expression profi les in cutaneous T-cell lymphoma.
Clin Cancer Res 2008; 14: 4500–10.
13 Peart MJ, Smyth GK, van Laar RK, et al. Identifi cation and functional signifi cance of genes regulated by structurally di erent histone deacetylase inhibitors. Proc Natl Acad Sci USA 2005;
102: 3697–702.
14 Johnstone RW, Licht JD. Histone deacetylase inhibitors in cancer therapy: is transcription the primary target? Cancer Cell 2003;
4: 13–18.
15 Martinez-Delgado B, Meléndez B, Cuadros M, et al. Expression profi ling of T-cell lymphomas di erentiates peripheral and lymphoblastic lymphomas and defi nes survival related genes.
Clin Cancer Res 2004; 10: 4971–82.
16 Nasr R, El-Sabban ME, Karam JA, et al. E cacy and mechanism of action of the proteasome inhibitor PS-341 in T-cell lymphomas and HTLV-I associated adult T-cell leukemia/lymphoma. Oncogene 2005;
24: 419–30.
17 Sors A, Jean-Louis F, Pellet C, et al. Down-regulating constitutive activation of the NF-kappaB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis. Blood 2006;
107: 2354–63.
18 Iqbal J, Wright G, Wang C, et al, and the Lymphoma Leukemia Molecular Profi ling Project and the International Peripheral T-cell Lymphoma Project. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood 2014; 123: 2915–23.
19 Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 2007; 25: 4293–97.
20 Paoluzzi L, Scotto L, Marchi E, Zain J, Seshan VE, O’Connor OA.
Romidepsin and belinostat synergize the antineoplastic e ect of bortezomib in mantle cell lymphoma. Clin Cancer Res 2010;
16: 554–65.
21 Bhalla S, David K, Mauro L, et al. Histone deacetylase inhibitor (HDACi) PCI-24781 and bortezomib result in synergistic apoptosis in Hodgkin lymphoma (HL) and non-Hodgkin’s lymphoma (NHL) cell lines: investigation of cell death and NFKB-mediated pathways. 50th American Society of Hematology 49th American Society of Hematology Annual Meeting; Atlanta, GA, USA;
Dec 8–11, 2007. Abstr 3589.
22 Ocio EM, Vilanova D, Atadja P, et al. In vitro and in vivo rationale for the triple combination of panobinostat (LBH589) and dexamethasone with either bortezomib or lenalidomide in multiple myeloma. Haematologica 2010; 95: 794–803.
23 Hideshima T, Bradner JE, Wong J, et al. Small-molecule inhibition of proteasome and aggresome function induces synergistic antitumor activity in multiple myeloma. Proc Natl Acad Sci USA 2005; 102: 8567–72.
24 Swerdlow SH, Campo E, Harris NL, et al. WHO Classifi cation of tumours of the haematopoietic and lymphoid tissues. 4th edn.
Lyon: IARC, 2008.
25 Cheson BD, Pfi stner B, Juweid ME, et al, and the International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25: 579–86.
26 San-Miguel JF, Richardson PG, Günther A, et al. Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma. J Clin Oncol 2013; 31: 3696–703.
27 Gehan EA. Update on planning of phase II clinical trials.
Drugs Exp Clin Res 1986; 12: 43–50.
28 Piekarz RL, Frye R, Prince HM, et al. Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 2011; 117: 5827–34.
29 Bashey S, Krathen M, Abdulla F, Sundram U, Kim YH. Romidepsin is e ective in subcutaneous panniculitis-like T-cell lymphoma.
J Clin Oncol 2012; 30: e221–25.
30 Lonial S, Waller EK, Richardson PG, et al, and the SUMMIT/
CREST Investigators. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 2005; 106: 3777–84.
31 Giver CR, Jaye DL, Waller EK, Kaufman JL, Lonial S. Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound e ect of bone marrow megakaryocytes.
Leukemia 2011; 25: 362–65.
32 Bishton MJ, Harrison SJ, Martin BP, et al. Deciphering the molecular and biologic processes that mediate histone deacetylase inhibitor-induced thrombocytopenia. Blood 2011; 117: 3658–68.
33 Evens AM, Rosen ST, Helenowski I, et al. A phase I/II trial of bortezomib combined concurrently with gemcitabine for relapsed or refractory DLBCL and peripheral T-cell lymphomas.
Br J Haematol 2013; 163: 55–61.
34 Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study.
Lancet Oncol 2011; 12: 431–40.
35 San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol 2014; 15: 1195–206.
