Seminars in Oncology
Volume 34, Supplement 5 , Pages S1-S2, December 2007

Introduction

  • Hagop M. Kantarjian (Guest Editor)

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Hagop M. Kantarjian, MD, Department of Leukemia, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 0428, Houston, TX 77030
    • Dr Kantarjian has received research grant support from Novartis, Bristol Myers Squibb, and MGI Pharma.

Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX.

Article Outline

 

Despite significant therapeutic advances in the management of lymphoproliferative disorders, more effective treatment options are still needed.1 Purine nucleoside phosphorylase (PNP) inhibitors are a promising new category of agents currently in clinical development for the treatment of patients with cutaneous T-cell lymphomas (CTCLs), T- and B-cell acute lymphoblastic leukemia (T-ALL, B-ALL), and chronic lymphocytic leukemia.

More than 30 years ago, the importance of PNP to the immune system became apparent when a child with a rare form of immunodeficiency was found to lack functional PNP.2 Low numbers of circulating T cells and normal or slightly reduced numbers of B cells are characteristic of individuals with this rare form of inherited immunodeficiency. PNP, a member of the purine salvage pathway enzymes, prevents an elevation in the levels of 2′-deoxyguanosine (dGuo) by catalyzing its conversion to guanine and 2′-deoxyribose-1-phosphate. In the absence of PNP, dGuo is phosphorylated to deoxyguanosine triphosphate (dGTP). In turn, high levels of intracellular dGTP alter the balance within the deoxynucleotide pool, ultimately leading to cellular apoptosis. It is notable that T cells have a high dGuo-phosphorylating capability and are particularly susceptible to a buildup of dGTP. Based on these considerations, it has been postulated that the inhibition of PNP activity could represent a viable approach for managing T cell-based and other lymphoproliferative disorders.

One of the challenges in developing clinically effective PNP inhibitors has been to achieve the necessary level of enzyme inhibition. In individuals with this detectable phenotype, the levels of PNP are generally less than 5%.2, 3 Parents of affected children and other individuals who are heterozygous for PNP mutations show ≤ 50% of the normal level of PNP activity, but are phenotypically normal.2 Thus, to achieve a clinical response, PNP inhibitors must reduce PNP activity below a very low threshold. A previously developed PNP inhibitor, BCX-34, did not provide statistically significant clinical responses in patients with psoriasis or CTCL, presumably because of its inability to achieve sufficient PNP inhibition.4

Forodesine (BCX-1777) is an active site-directed compound designed to bind to the transition state of PNP, and is therefore a more potent PNP inhibitor than those previously available.5, 6, 7, 8 Forodesine is the first PNP inhibitor to show clinical activity in lymphoproliferative disorders, including T-ALL, CTCL, and B-ALL. In 2003, results of a proof-of-concept study showed that forodesine treatment led to increased plasma dGuo levels and clinical activity in four of five patients with relapsed or refractory aggressive hematologic malignancies, including two of two patients with T-ALL and two of three patients with prolymphocytic leukemia.9, 10 More recently, interim results of a phase I/II study in patients with relapsed/refractory T-ALL showed that 11 (32.4%) of 34 patients achieved an objective response, including seven patients (20.6%) who showed a complete response.11 In one study of patients with refractory CTCL (stage IB or greater), 15 (53.6%) of 28 patients achieved an objective response, with two patients (7.1%) showing a complete response.12, 13 Interim results of a phase I/II study in patients with relapsed/refractory B-ALL showed that forodesine may benefit these patients as well.14, 15 Two patients, one relapsing after bone marrow transplantation and the other relapsing after one failed regimen, achieved complete response after 16 and 4 months of forodesine treatment, respectively. None of the other 10 patients in this study showed either a partial or complete response.14 In the course of these studies, forodesine has shown fewer drug-related adverse effects than have other commonly used nucleoside analogues, such as those used to treat patients with retroviral infections and hematologic malignancies.

Based on the interim results of the clinical studies with forodesine, PNP inhibition appears to be a viable approach to the management of T cell-based and other lymphoproliferative disorders. In this supplement to Seminars in Oncology, Dr Bruce Cheson reviews key issues in the clinical management of T-cell malignancies, including a discussion of novel emerging therapies. The biochemical mechanism of action of T cell-targeted therapies is analyzed in depth by Dr Varsha Gandhi. Dr Richard Larson compares the pharmacologic properties and clinical profile of forodesine with those of the nucleoside analogues nelarabine and clofarabine. Current information on the use of PNP inhibitors in CTCL and various lymphoid malignancies is summarized by Drs Madeleine Duvic and Francine Foss and by Dr Richard Furman and Prof Dieter Hoelzer, respectively. Finally, two interesting case studies of patients diagnosed with T-ALL, who relapsed following hematopoietic stem cell transplantation and were subsequently enrolled in a study in which they received forodesine, are presented by Dr Lia Gore.

It is hoped that the exciting and promising data with the PNP inhibitor forodesine summarized in this supplement will provide incentive for the further clinical evaluation of PNP inhibition in the treatment of patients with a variety of hematologic malignancies.

Back to Article Outline

References 

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  2. Giblett ER, Ammann AJ, Wara DW, et al. Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity. Lancet. 1975;1:1010–1013
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  11. Furman RR, Gore L, Ravandi F, et al. Forodesine IV (BCX-1777) is clinically active in relapsed/refractory T-cell leukemia: Results of a phase II study (interim report). Blood. 2006;108(suppl 1):524a;(abstr 1851)
  12. Duvic M, Forero-Torres A, Foss F. Oral forodesine (BCX-1777) is clinically active in refractory cutaneous T-cell lymphoma: Results of a phase I/II study. Blood. 2006;108(suppl 1):698a;(abstr 2467)
  13. Duvic M, Foss FM, Olsen EA, et al. Intravenous forodesine (BCX-1777), a novel purine nucleoside phosphorylase (PNP) inhibitor, demonstrates clinical activity in patients with refractory cutaneous T-cell lymphoma. Blood. 2004;104(suppl 1):683a;(abstr 2491)
  14. Ritchie E, Gore L, Roboz G, et al. Phase II study of forodesine, a PNP inhibitor, in patients with relapsed or refractory B-lineage acute lymphoblastic leukemia. Blood. 2006;108(suppl 1):533a;(abstr 1881)
  15. Furman RR, Gandhi VV, Bennett JC, et al. Intravenous forodesine (BCX-1777), a novel purine nucleoside phosphorylase (PNP) inhibitor, demonstrates clinical activity in phase I/II studies in patients with B-cell acute lymphoblastic leukemia. Blood. 2004;104(suppl 1):750a;(abstr 2743)

PII: S0093-7754(07)00226-6

doi:10.1053/j.seminoncol.2007.11.007

Seminars in Oncology
Volume 34, Supplement 5 , Pages S1-S2, December 2007

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