Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous t-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome)

R. Dummer, M. Duvic, J. Scarisbrick, E. A. Olsen, Sima Rozati, N. Eggmann, S. M. Goldinger, K. Hutchinson, L. Geskin, T. M. Illidge, E. Giuliano, J. Elder, Y. H. Kim

Research output: Contribution to journalArticle

Abstract

Background: Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL). Patients and methods: In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients. Results: All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3-15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure. Conclusion: Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.

Original languageEnglish (US)
Article numbermdu231
Pages (from-to)1807-1812
Number of pages6
JournalAnnals of Oncology
Volume25
Issue number9
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

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Purine-Nucleoside Phosphorylase
Mycosis Fungoides
Lymphoma
Skin
Safety
Population
Skin Manifestations
Cutaneous T-Cell Lymphoma
Second Primary Neoplasms
Social Responsibility
Liver Failure
Sleep Initiation and Maintenance Disorders
Pruritus
Esophageal Neoplasms
forodesine
Nausea
Fatigue
Headache
Disease Progression
Diarrhea

Keywords

  • Cutaneous T-cell lymphomas
  • Forodesine
  • Mycosis fungoides
  • Purine nucleoside phosphorylase inhibitor
  • Sézary syndrome

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous t-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome). / Dummer, R.; Duvic, M.; Scarisbrick, J.; Olsen, E. A.; Rozati, Sima; Eggmann, N.; Goldinger, S. M.; Hutchinson, K.; Geskin, L.; Illidge, T. M.; Giuliano, E.; Elder, J.; Kim, Y. H.

In: Annals of Oncology, Vol. 25, No. 9, mdu231, 01.01.2014, p. 1807-1812.

Research output: Contribution to journalArticle

Dummer, R, Duvic, M, Scarisbrick, J, Olsen, EA, Rozati, S, Eggmann, N, Goldinger, SM, Hutchinson, K, Geskin, L, Illidge, TM, Giuliano, E, Elder, J & Kim, YH 2014, 'Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous t-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome)', Annals of Oncology, vol. 25, no. 9, mdu231, pp. 1807-1812. https://doi.org/10.1093/annonc/mdu231
Dummer, R. ; Duvic, M. ; Scarisbrick, J. ; Olsen, E. A. ; Rozati, Sima ; Eggmann, N. ; Goldinger, S. M. ; Hutchinson, K. ; Geskin, L. ; Illidge, T. M. ; Giuliano, E. ; Elder, J. ; Kim, Y. H. / Final results of a multicenter phase II study of the purine nucleoside phosphorylase (PNP) inhibitor forodesine in patients with advanced cutaneous t-cell lymphomas (CTCL) (Mycosis fungoides and Sézary syndrome). In: Annals of Oncology. 2014 ; Vol. 25, No. 9. pp. 1807-1812.
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abstract = "Background: Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL). Patients and methods: In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients. Results: All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3-15). No complete remissions were observed. In the efficacy group of patients, 11{\%} achieved partial remission and 50{\%} had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96{\%} of all treated patients reported one or more adverse events (AEs) and 33{\%} reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10{\%}) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure. Conclusion: Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.",
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AU - Dummer, R.

AU - Duvic, M.

AU - Scarisbrick, J.

AU - Olsen, E. A.

AU - Rozati, Sima

AU - Eggmann, N.

AU - Goldinger, S. M.

AU - Hutchinson, K.

AU - Geskin, L.

AU - Illidge, T. M.

AU - Giuliano, E.

AU - Elder, J.

AU - Kim, Y. H.

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N2 - Background: Forodesine is a potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to intracellular accumulation of deoxyguanosine triphosphate (dGTP) in T and B cells, resulting in apoptosis. Forodesine has demonstrated impressive antitumor activity in early phase clinical trials in cutaneous T-cell lymphoma (CTCL). Patients and methods: In this phase II study, patients with CTCL who had already failed three or more systemic therapies were recruited. We investigated the response rate, safety and tolerability of oral forodesine treatment in subjects with cutaneous manifestations of CTCL, stages IB, IIA, IIB, III and IVA. The safety population encompassing all stages was used for analysis of accountability, demographics and safety. The efficacy population differed from the safety population by exclusion of stage IB and IIA patients. Results: All 144 patients had performance status 0-2. The median duration of CTCL from diagnosis was 53 months (5-516 months). The median number of pretreatments was 4 (range: 3-15). No complete remissions were observed. In the efficacy group of patients, 11% achieved partial remission and 50% had stable disease. The median time to response was 56 days and the median duration of response was 191 days. A total of 96% of all treated patients reported one or more adverse events (AEs) and 33% reported a serious AE. The majority of AEs were classified as mild or moderate in severity. The most commonly reported AEs (>10%) were peripheral edema, fatigue, insomnia, pruritus, diarrhea, headache and nausea. Overall eight patients died during the study: five due to sepsis and infections, one due to a second malignancy (esophageal cancer), one due to disease progression and one due to liver failure. Conclusion: Oral forodesine at a dose of 200 mg daily is feasible and shows partial efficacy in this highly selected CTCL population and some durable responses.

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KW - Sézary syndrome

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