Seminars in Hematology
Volume 43, Issue 4 , Pages 251-261 , October 2006

New Drugs for the Treatment of Advanced-Stage Diffuse Large Cell Lymphomas

  • Owen A. O’Connor

      Affiliations

    • Laboratory of Experimental Therapeutics for the Lymphoproliferative Malignancies, Memorial Sloan-Kettering Cancer Center, New York, NY.
    • Department of Medicine, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY.
    • Corresponding Author InformationAddress correspondence to Owen A. O’Connor, MD, PhD, Department of Medicine, Lymphoma and Developmental Chemotherapy Services, Box 329, 1275 York Ave, New York, NY 10021.
    • O.A.O. is the recipient of the Leukemia and Lymphoma Society Scholar in Research Award. O.A.O. is supported by the The Werner and Elaine Dannheisser Fund for Research on the Biology of Aging of the Lymphoma Foundation.
  • ,
  • Paul Hamlin

      Affiliations

    • Department of Medicine, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, NY.

References 

  1. Ye BH, Lista F, Lo Coco F, et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science. 1993;262:747–750
  2. Ye BH, Rao PH, Chaganti RS, et al. Cloning of bcl-6, the locus involved in chromosome translocations affecting band 3q27 in B-cell lymphoma. Cancer Res. 1993;53:2732–2735
  3. Ye BH, Chaganti S, Chang CC, et al. Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. EMBO J. 1995;14:6209–62017
  4. Dent AL, Shaffer AL, Yu X, et al. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science. 1997;276:589–592
  5. Shaffer AL, Yu X, He Y, et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity. 2000;13:199–212
  6. Pasqualucci L, Bereschenko O, Niu H, et al. Molecular pathogenesis of non-Hodgkin’s lymphoma: The role of Bcl-6. Leuk Lymphoma. 2003;44(suppl 3):S5–S12
  7. Capello D, Vitolo U, Pasqualucci L, et al. Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia. Blood. 2000;95:651–659
  8. Bereshchenko OR, Gu W, Dalla-Favera R. Acetylation inactivates the transcriptional repressor BCL6. Nat Genet. 2002;32:606–613
  9. Luo J, Nikolaev AY, Imai S, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001;107:137–148
  10. Vaziri H, Dessain SK, Ng Eaton E, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 2001;107:149–159
  11. Imai S, Armstrong CM, Kaeberlein M, et al. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature. 2000;403:795–800
  12. Kelly WK, O’Connor OA, Marks PA. Histone deacetylase inhibitors: from target to clinical trials. Expert Opin Investig Drugs. 2002;11:1695–1713
  13. Kelly WK, Richon VM, O’Connor O, et al. Phase I clinical trial of histone deacetylase inhibitor: Suberoylanilide hydroxamic acid administered intravenously. Clin Cancer Res. 2003;9:3578–3588
  14. O’Connor OA, Heaney ML, Schwartz L, et al. Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies. J Clin Oncol. 2006;24:166–173
  15. Kelly WK, O’Connor OA, Krug LM, et al. Phase I study of an oral histone deacetylase inhibitor, suberoylanilide hydroxamic acid, in patients with advanced cancer. J Clin Oncol. 2005;23:3923–3931
  16. Piekarz RL, Robey RW, Zhan Z, et al. T-cell lymphoma as a model for the use of histone deacetylase inhibitors in cancer therapy: impact of depsipeptide on molecular markers, therapeutic targets, and mechanisms of resistance. Blood. 2004;103:4636–4643
  17. Piekarz RL, Robey R, Sandor V, et al. Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: A case report. Blood. 2001;98:2865–2868
  18. Duvic MTR, Zhang C, Goy A, Richon V, Frankel S. Phase II trial of oral suberoylanilide hydroxamic acid (SAHA) for cutaneous T-cell lymphoma (CTCL) unresponsive to conventional therapy. J Clin Oncol. 2005;23:16S;(abstr 6571)
  19. Ryan QC, Headlee D, Acharya M, et al. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol. 2005;23:3912–3922
  20. Prive GG, Melnick A, Ahmad KF, Licht JD. The BTB domain zinc finger proteins. In:  Iuchi S,  Kuldell N editor. Zinc Finger Proteins: From Atomic Contact to Cellular Function. Austin, TX: Landes Bioscience; 2005;
  21. Polo JM, Dell’Oso T, Ranuncolo SM, et al. Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Nat Med. 2004;10:1329–1335
  22. Reed JC. Dysregulation of apoptosis in cancer. J Clin Oncol. 1999;17:2941–2953
  23. Reed JC. Bcl-2 and the regulation of programmed cell death. J Cell Biol. 1994;124:1–6
  24. Cleary ML, Smith SD, Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell. 1986;47:19–28
  25. Tsujimoto Y, Gorham J, Cossman J, et al. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science. 1985;229:1390–1393
  26. Tsujimoto Y, Croce CM. Analysis of the structure, transcripts, and protein products of bcl-2, the gene involved in human follicular lymphoma. Proc Natl Acad Sci U S A. 1986;83:5214–5218
  27. Yang J, Liu X, Bhalla K, et al. Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science. 1997;275:1129–1132
  28. Kluck RM, Bossy-Wetzel E, Green DR, et al. The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science. 1997;275:1132–1136
  29. Rai K, Wallace P, Soho C, Landrigan B, Meyn P, Wei T, et al. Efficacy and safety of the combination of genasense fludarabine and rituximab in previously treated and untreated subjects with chronic lymphocytic leukemia. Blood. 2005;106:(abstr 2129)
  30. O’Brien SM, Cunningham CC, Golenkov AK, et al. Phase I to II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in patients with advanced chronic lymphocytic leukemia. J Clin Oncol. 2005;23:7697–7702
  31. O’Connor OA, Smith EA, Toner LE, et al. The combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide. Clin Cancer Res. 2006;12:2902–2911
  32. Wu D. An overview of the clinical pharmacology and therapeutic potential of gossypol as a male contraceptive agent and in gynaecological disease. Drugs. 1989;38:333–341
  33. Tuszynski GP, Cossu G. Differential cytotoxic effect of gossypol on human melanoma, colon carcinoma, and other tissue culture cell lines. Cancer Res. 1984;44:768–771
  34. Coyle T, Levante S, Shetler M, et al. In vitro and in vivo cytotoxicity of gossypol against central nervous system tumor cell lines. J Neurooncol. 1994;19:25–35
  35. Gilbert NE, O’Reilly JE, Chang CJ, et al. Antiproliferative activity of gossypol and gossypolone on human breast cancer cells. Life Sci. 1995;57:61–67
  36. Wang X, Wang J, Wong SC, et al. Cytotoxic effect of gossypol on colon carcinoma cells. Life Sci. 2000;67:2663–2671
  37. Flack MR, Pyle RG, Mullen NM, et al. Oral gossypol in the treatment of metastatic adrenal cancer. J Clin Endocrinol Metab. 1993;76:1019–1024
  38. Van Poznak C, Seidman AD, Reidenberg MM, et al. Oral gossypol in the treatment of patients with refractory metastatic breast cancer: A phase I/II clinical trial. Breast Cancer Res Treat. 2001;66:239–248
  39. Bushunow P, Reidenberg MM, Wasenko J, et al. Gossypol treatment of recurrent adult malignant gliomas. J Neurooncol. 1999;43:79–86
  40. Liu S, Kulp SK, Sugimoto Y, et al. The (−)-enantiomer of gossypol possesses higher anticancer potency than racemic gossypol in human breast cancer. Anticancer Res. 2002;22:33–38
  41. Oliver CL, Bauer JA, Wolter KG, et al. In vitro effects of the BH3 mimetic, (−)-gossypol, on head and neck squamous cell carcinoma cells. Clin Cancer Res. 2004;10:7757–7763
  42. Paoluzzi L, Gonen M, Toner L, Smith E, Yang D, Holmund J, et al. Targeting antiapoptotic BcL-2 family members with AT-101 in pre-clinical models of aggressive lymphoma in combination with cyclophosphamide (C) and rituximab (R) produces a marked improvement in therapeutic efficacy. Blood. 2005;106:(abstr 926)
  43. Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005;435:677–681
  44. Petros AM, Dinges J, Augeri DJ, et al. Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. J Med Chem. 2006;49:656–663
  45. Sirotnak FM, DeGraw JI, Moccio DM, et al. New folate analogs of the 10-deaza-aminopterin series (Basis for structural design and biochemical and pharmacologic properties). Cancer Chemother Pharmacol. 1984;12:18–25
  46. Wang ES, O’Connor O, She Y, et al. Activity of a novel anti-folate (PDX, 10-propargyl 10-deazaaminopterin) against human lymphoma is superior to methotrexate and correlates with tumor RFC-1 gene expression. Leuk Lymphoma. 2003;44:1027–1035
  47. Sirotnak FM, DeGraw JI, Chello PL, et al. Biochemical and pharmacologic properties of a new folate analog, 10-deaza-aminopterin, in mice. Cancer Treat Rep. 1982;66:351–358
  48. Sirotnak FM. Obligate genetic expression in tumor cells of a fetal membrane property mediating “folate” transport: Biological significance and implications for improved therapy of human cancer. Cancer Res. 1985;45:3992–4000
  49. Chiao JH, Roy K, Tolner B, et al. RFC-1 gene expression regulates folate absorption in mouse small intestine. J Biol Chem. 1997;272:11165–11170
  50. DeGraw JI, Colwell WT, Piper JR, et al. Synthesis and antitumor activity of 10-propargyl-10-deazaaminopterin. J Med Chem. 1993;36:2228–2231
  51. O’Connor OA, Hamlin P, Neylon E, Moskowitz C, Portlock C, Straus D, et al. Pralatrexate (10-Propargyl-10-Deazaaminopterin(PRX)), a novel antifolate, effects durable complete remissions (CR) in patients with a diversity of drug resistant T-cell lymphomas with minimal toxicity. Blood. 2005;106:(abstr 2678)
  52. Mackay F, Woodcock SA, Lawton P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999;190:1697–1710
  53. Do RK, Hatada E, Lee H, et al. Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. J Exp Med. 2000;192:953–964
  54. Khare SD, Sarosi I, Xia XZ, et al. Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci U S A. 2000;97:3370–3375
  55. Novak AJ, Grote DM, Ziesmer SC, et al. Elevated serum B-lymphocyte stimulator levels in patients with familial lymphoproliferative disorders. J Clin Oncol. 2006;24:983–987
  56. Elsawa SF, Novak AJ, Grote DM, et al. B-lymphocyte stimulator (BLyS) stimulates immunoglobulin production and malignant B-cell growth in Waldenstrom macroglobulinemia. Blood. 2006;107:2882–2888
  57. Dillon SR, Gross JA, Ansell SM, et al. An APRIL to remember: Novel TNF ligands as therapeutic targets. Nat Rev Drug Discov. 2006;5:235–246
  58. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235–242
  59. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: A study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23:4117–4126
  60. Habermann TWE, Morrison VA, Cassileth PA, Cohn J, Dakhil S, Gascoyne RD, et al. Rituximab-CHOP versus CHOP with or without maintenance rituximab in patients 60 years of age or older with diffuse large B-cell lymphoma (DLBCL). Blood. 2004;104:40a;(abstr)
  61. Pfreundschuh M, Trumper L, Osterborg A, et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006;7:379–391
  62. Skvortsova I, Popper BA, Skvortsov S, et al. Pretreatment with rituximab enhances radiosensitivity of non-Hodgkin’s lymphoma cells. J Radiat Res (Tokyo). 2005;46:241–248
  63. Witzig TE, White CA, Wiseman GA, et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 1999;17:3793–3803
  64. Zelenetz A, Salen M, Vose J, Younes A, Kaminski M. Patients with transformed low grade lymphoma attain durable responses following out-patient radioimmunotherapy with tositumomab and iodine I 131 tositumomab. Blood. 2002;100:357;(abstr 1384)
  65. Morschhauser F, Huglo D, Martinelli G. Yttrium-90 ibrituomomab tiuxetan (Zevalin) for patients with relapsed/refractory diffuse large b-cell lymphoma not appropriate for autologous stem cell transplantation: results of an open-label phase II trial. Blood. 2004;104:41a;(abstr)
  66. Hamlin P, Moskowitz CH, Wegner B. Early safety and efficacy analysis of a phase II study of sequential R-CHOP and yttrium-90 ibritumomab tiuxetan (Zevalin) for elderly high risk patients with untreated DLBCL. Blood. 2005;106:(abstr 926)
  67. Gopal A, Rajendran J, Gooley TA, Pagel J, Fisher D, Petersdorf S, et al. A phase II study of myeloablative I-131-anti-CD20 (tositumomab) radioimmunotherapy (RIT) and autologous hematopoietic stem cell transplantation (ASCT) for adults ≥ 60 years of age with high-risk, relapsed, or refractory B-cell lymphoma. Blood. 2005;106:(abstr 487)
  68. Pervan Milena JC, Matso D, et al. Active combination therapy of bortezomib (Velcade) and ibritumomab tiuxetan (Zevalin) in an in vivo diffuse large B-cell lymphoma model. Blood. 2005;

PII: S0037-1963(06)00150-8

doi: 10.1053/j.seminhematol.2006.07.002

Seminars in Hematology
Volume 43, Issue 4 , Pages 251-261 , October 2006