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 S. Abdul Wahid, Won Seog Kim, Yeow Tee Goh

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Abstract

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 effect 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 five 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 five 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 (five [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 findings 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.

Original languageEnglish
Pages (from-to)e326-e333
JournalThe Lancet Haematology
Volume2
Issue number8
DOIs
Publication statusPublished - 2015

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Peripheral T-Cell Lymphoma
panobinostat
Bortezomib
Asthenia
Republic of Korea
Proteasome Inhibitors
Intention to Treat Analysis
Histone Deacetylases
Malaysia
Singapore
Peripheral Nervous System Diseases
Proteasome Endopeptidase Complex
Neutropenia
Tertiary Care Centers
Thrombocytopenia
Pharmaceutical Preparations
Fatigue
Diarrhea

ASJC Scopus subject areas

  • Hematology

Cite this

Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma : An open-label, multicentre phase 2 trial. / Tan, Daryl; Phipps, Colin; Hwang, William Y K; Tan, Soo Yong; Yeap, Chun Hsien; Chan, Yiong Huak; Tay, Kevin; Lim, Soon Thye; Lee, Yuh Shan; Kumar, Sathish Gopalakrishnan; Ng, Soo Chin; S. Abdul Wahid, S Fadilah; Kim, Won Seog; Goh, Yeow Tee.

In: The Lancet Haematology, Vol. 2, No. 8, 2015, p. e326-e333.

Research output: Contribution to journalArticle

Tan, D, Phipps, C, Hwang, WYK, Tan, SY, Yeap, CH, Chan, YH, Tay, K, Lim, ST, Lee, YS, Kumar, SG, Ng, SC, S. Abdul Wahid, SF, Kim, WS & Goh, YT 2015, 'Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma: An open-label, multicentre phase 2 trial', The Lancet Haematology, vol. 2, no. 8, pp. e326-e333. https://doi.org/10.1016/S2352-3026(15)00097-6
Tan, Daryl ; Phipps, Colin ; Hwang, William Y K ; Tan, Soo Yong ; Yeap, Chun Hsien ; Chan, Yiong Huak ; Tay, Kevin ; Lim, Soon Thye ; Lee, Yuh Shan ; Kumar, Sathish Gopalakrishnan ; Ng, Soo Chin ; S. Abdul Wahid, S Fadilah ; Kim, Won Seog ; Goh, Yeow Tee. / Panobinostat in combination with bortezomib in patients with relapsed or refractory peripheral T-cell lymphoma : An open-label, multicentre phase 2 trial. In: The Lancet Haematology. 2015 ; Vol. 2, No. 8. pp. e326-e333.
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T2 - An open-label, multicentre phase 2 trial

AU - Tan, Daryl

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AU - Hwang, William Y K

AU - Tan, Soo Yong

AU - Yeap, Chun Hsien

AU - Chan, Yiong Huak

AU - Tay, Kevin

AU - Lim, Soon Thye

AU - Lee, Yuh Shan

AU - Kumar, Sathish Gopalakrishnan

AU - Ng, Soo Chin

AU - S. Abdul Wahid, S Fadilah

AU - Kim, Won Seog

AU - Goh, Yeow Tee

PY - 2015

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N2 - 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 effect 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 five 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 five 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 (five [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 findings 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.

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