New drug development in non-hodgkin lymphomas

  • Bruce D. Cheson


The non-Hodgkin lymphomas (NHL) are characterized by initial responsiveness to a variety of chemotherapeutic regimens. Nevertheless, most patients progress and die from their disease. A number of new agents with unique mechanisms of action are in clinical development. Agents that are currently considered to be the most promising include those that induce apoptosis; those that interfere with cell cycling, tumor-associated angiogenesis, farnesylation of the Ras gene, and histone deacetylase; and those that inhibit the proteasome, among others. Increasing insights into the differences between tumors and among patients will lead to more individualized therapeutic strategies using agents directed at specific genetic and immunologic targets. More rapid accrual to high-quality clinical studies will facilitate dissemination of new agents to patients and lead to an increased cure rate for NHL.

References and Recommended Reading

  1. 1.
    Germann N, S B, Rotarski M, et al.: Preliminary results on the activity of oxaliplatin (L-OHP) in refractory/recurrent non-Hodgkin’s lymphoma patients. Ann Oncol 1999, 10:351–354.PubMedCrossRefGoogle Scholar
  2. 2.
    Younes A: Paclitaxel-based treatment of lymphoma. Semin Oncol 1999, 26:123–128. The use of the taxanes has been controversial in NHL; some studies suggest limited activity, whereas others see taxanes as sufficiently promising to explore in combination regimens. The activity appears to vary with histology and amount of and responsiveness to prior therapy.PubMedGoogle Scholar
  3. 3.
    O’Brien S, Kantarjian H, Ellis A, et al.: Topotecan in chronic lymphocytic leukemia. Cancer 1995, 75:1104–1108.PubMedCrossRefGoogle Scholar
  4. 4.
    Wilson WH, Little R, Pearson D, et al.: A phase II and dose escalation + G-CSF study of 9-aminocamptothecin in relapsed and refractory lymphomas. J Clin Oncol 1998, 16:2345–2351.PubMedGoogle Scholar
  5. 5.
    Cabanillas F: The role of topoisomerase-I inhibitors in the treatment of non-Hodgkin’s lymphoma. Semin Hematol 1999, 36:11–15. The authors review the variable results attained with topotecan and other TPI inhibitors in NHL and discuss the rationale for combination regimens.PubMedGoogle Scholar
  6. 6.
    Cheson BD: New chemotherapeutic strategies for the treatment of indolent lymphoid malignancies. Semin Hematol 1999, 36:26–33.PubMedGoogle Scholar
  7. 7.
    Foran JM, Oscier D, Orchard J, et al.: Pharmacokinetic study of single doses of oral fludarabine phosphate. J Clin Oncol 1999, 17:1574–1579. This phase I trial noted approximately 55% bioavailability of oral fludarabine with activity in CLL and NHL that was comparable with what had been reported with the intravenous preparation in previous studies in similar patients.PubMedGoogle Scholar
  8. 8.
    Fossa A, Santoro A, Hiddemann W, et al.: Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol 1999, 17:3786–3792. Although more than 50% of relapsed and refractory Hodgkin’s disease patients will respond to gemcitabine, this agent has limited activity in aggressive NHL.PubMedGoogle Scholar
  9. 9.
    Kurtzberg J, Keating MJ, Plunkett W, et al.: Compound 506 (2-amino-6-methoxypurine arabinoside) is active against resistant T-cell malignancies: preliminary results of an ongoing phase I trial [abstract]. J Clin Oncol 1996, 14:1750.Google Scholar
  10. 10.
    Gandhi V, Keating M, O’Brien S, et al.: Compound GW506U78 in refractory hematologic malignancies: relationship between cellular pharmacokinetics and clinical response. J Clin Oncol 1998, 16:3607–3615. The authors describe the activity of this new nucleoside analogue in patients with various hematologic malignancies and demonstrate a correlation between activity and intracellular drug levels.PubMedGoogle Scholar
  11. 11.
    Schwänen C, Karakas T, Begmann L: Bendamustine in the treatment of low-grade non-Hodgkin’s lymphomas. Onkologie 2000, 23:318–324.CrossRefGoogle Scholar
  12. 12.
    Kozuch P, Ibrahim N, Khuri F, et al.: Phase I clinical and pharmacological study of clofarabine [abstract]. Blood 1999, 94:127a.Google Scholar
  13. 13.
    Zhang P, Wang ZY, Hu XH, et al.: Arsenic trioxide treated 72 cases of acute promyelocytic leukaemia. Chin J Haematol 1996, 17:58–60.Google Scholar
  14. 14.
    Soignet SL, Maslak P, Wang ZG, et al.: Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 1998, 339:1341–1348.PubMedCrossRefGoogle Scholar
  15. 15.
    König A, Wrazel L, Warrell RP Jr, et al.: Comparative activity of melarsoprol and arsenic trioxide in chronic B-cell leukemia lines. Blood 1997, 90:562–570.PubMedGoogle Scholar
  16. 16.
    Soignet SL, Tong WP, Hirschfeld S, et al.: Clinical study of an organic arsenical, melarsoprol, in patients with advanced leukemia. Cancer Chemother Pharmacol 1999, 44:417–421.PubMedCrossRefGoogle Scholar
  17. 17.
    Zhang W, Ohnishi K, Shigeno K, et al.: The induction of apoptosis and cell cycle arrest by arsenic trioxide in lymphoid neoplasms. Leukemia 1998, 12:1383–1391.PubMedCrossRefGoogle Scholar
  18. 18.
    Varterasian ML, Mohammad RM, Eilender DS, et al.: Phase I study of bryostatin 1 in patients with relapsed non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. J Clin Oncol 1998, 16:56–62.PubMedGoogle Scholar
  19. 19.
    Vrana JA, Wang Z, Rao AS, et al.: Induction of apoptosis and differentiation by fludarabine in human leukemia cells (U937) with the macrocyclic lactone bryostatin 1. Leukemia 1999, 13:1046–1055.PubMedCrossRefGoogle Scholar
  20. 20.
    Beckwith M, Urba WJ, Longo DL: Growth inhibition of human lymphoma cell lines by the marine products, dolastatins 10 and 15. J Natl Cancer Inst 1993, 85:483–488.PubMedCrossRefGoogle Scholar
  21. 21.
    Maki A, Diwakaran H, Redman B, et al.: The bcl-2 and p53 oncoproteins can be modulated by bryostatin 1 and dolostatins in human diffuse large cell lymphoma. Anticancer Drugs 1995, 6:392–397.PubMedCrossRefGoogle Scholar
  22. 22.
    Al-Katib A, Mohammed RM, Dan M, et al.: Bryostatin 1-induced hairy cell features on chronic lymphocytic leukemia cells in vitro. Exp Hematol 1993, 21:61–65.PubMedGoogle Scholar
  23. 23.
    Bai R, Pettit GR, Hamel E: Dolastatin 10, a powerful cytostatic peptide derived from a marine animal: inhibition of tubulin polymerization mediated through the vinca alkaloid binding domain. Biochem Pharmacol 1990, 39:1941–1949.PubMedCrossRefGoogle Scholar
  24. 24.
    Verdier-Pinard P, Kepler JA, Pettit GR, et al.: Sustained intracellular retention of dolastatin 10 causes its potent antimitotic activity. Mol Pharmacol 2000, 57:180–187.PubMedGoogle Scholar
  25. 25.
    Takahashi I, Kobayashi E, Asano K, et al.: UCN-01, a selective inhibitor of protein kinase C from Streptomycesi. J Antibiot 1987, 40:1782–1784.PubMedGoogle Scholar
  26. 26.
    Tamaoki T: Use and specificity of staurosporine, UCN-01, and calphostin C as protein kinase inhibitors. Methods Enzymol 1991, 201:340–347.PubMedCrossRefGoogle Scholar
  27. 27.
    Shao RG, Shimizu T, Pommier Y: 7-Hydroxystaurosporine (UCN-01) induces apoptosis in human colon carcinoma and leukemia cells independently of p53. Exp Cell Res 1997, 234:388–397.PubMedCrossRefGoogle Scholar
  28. 28.
    Monks A, Harris E, Connelly J, et al.: Enhancement of fludarabine and gemcitabine toxicity by UCN-01 in a variety of tumor cell lines [abstract]. Proc AACR 1999, 40:45.Google Scholar
  29. 29.
    Wang S, Vrana JA, Bartimole TM, et al.: Agents that downregulate or inhibit protein kinase C circumvent resistance to 1-beta-D-arabinofuranosylcytosine-induced apoptosis in human leukemia cells that overexpress Bcl-2. Mol Pharmcol 1997, 52:1000–1009.Google Scholar
  30. 30.
    Sausville EA, Lush RD, Headlee D, et al.: Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models. Cancer Chemother Pharmacol 1998, 42:S54-S58.PubMedCrossRefGoogle Scholar
  31. 31.
    Senderowicz A, Headlee D, Lush R, et al.: Phase I trial of infusional UCN-01, a novel protein kinase inhibitor, in patients with refractory neoplasms [abstract]. Proc ASCO 1999, 18:159a.Google Scholar
  32. 32.
    Willis C, Byrd JC, Shinn C, et al.: UCN-01 chemosensitizes human B-chronic lymphocytic leukemia (B-CLL) cells to the effects of fludarabine. Blood 1999, 94:127a.Google Scholar
  33. 33.
    König A, Schwartz G, Mohammed RM, et al.: The novel cyclin-dependent kinase inhibitor flavopiridol downregulates bcl-2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines. Blood 1997, 90:4307–4312.PubMedGoogle Scholar
  34. 34.
    Parker BW, Kaur G, Nieves-Niera W, et al.: Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood 1998, 91:458–465.PubMedGoogle Scholar
  35. 35.
    Byrd JC, Shinn C, Waselenko JK, et al.: Flavopiridol induces apoptosis in chronic lymphocytic leukemia cells via activation of caspase-3 without evidence of bcl-2 modulation or dependence on functional p53. Blood 1998, 92:3804–3816.PubMedGoogle Scholar
  36. 36.
    Nave BT, Ouwens M, Withers DJ, et al.: Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J 1999, 344:427–431.PubMedCrossRefGoogle Scholar
  37. 37.
    Gibbons JJ, Discafani C, Peterson R, et al.: The effect of CCI-779, a novel macrolide anti-tumor agent, on the growth of human tumor cells in vitro and in nude mouse xenografts in vivo [abstract]. Proc AACR 1999, 40:2000.Google Scholar
  38. 38.
    Seufferlein T, Rozengurt E: Rapamycin inhibits constitutive p70s6k phosphorylation, cell proliferation, and colony formation in small cell lung cancer cells. Cancer Res 1996, 56:3895–3897.PubMedGoogle Scholar
  39. 39.
    Hosoi H, Dilling MB, Shikata T, et al.: Rapamycin causes poorly reversible inhibition of mTOR and induces p53-independent apoptosis of human rhabdomyosarcoma cells. Cancer Res 1999, 59:886–894.PubMedGoogle Scholar
  40. 40.
    Alexandre J, Raymond E, Depenbrock H, et al.: CCI-779, a new rapamycin analog, has antitumor activity at doses inducing only mild cutaneous effects and mucositis: early results of an ongoing phase I study. AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics, Washington, DC, November 16–19,1999 (7).Google Scholar
  41. 41.
    Ueda H, Nakajima H, Hori Y, et al.: Action of FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968, on Ha-ras transformed NIH3T3 cells. Biosci Biotech Biochem 1994, 58:1579–1583.CrossRefGoogle Scholar
  42. 42.
    Byrd JC, Shinn C, Ravi R, et al.: Depsipeptide (FR901228): a novel therapeutic agent with selective, in vitro activity against human B-cell chronic lymphocytic leukemia cells. Blood 1999, 94:1401–1408.PubMedGoogle Scholar
  43. 43.
    Lancet J, Rosenblatt J, Liesveld JL, et al.: Use of farnesyl transferase inhibitor R115777 in relapsed and refractory acute leukemias: preliminary results of a phase I study [abstract]. Proc ASCO 2000, 19:3d.Google Scholar
  44. 44.
    Menzel T, Rahman Z, Calleja E, et al.: Elevated intracellular level of basic fibroblast growth factor correlates with stage of chronic lymphocytic leukemia and is associated with resistance to fludarabine. Blood 1996, 87:1056–1063.PubMedGoogle Scholar
  45. 45.
    König A, Menzel T, Lynen S, et al.: Basic fibroblast growth factor (bFGF) upregulates the expression of bcl-2 in B cell chronic lymphocytic leukemia cell lines resulting in delaying apoptosis. Leukemia 1997, 11:258–265.PubMedCrossRefGoogle Scholar
  46. 46.
    Singhal S, Mehta J, Desikan R, et al.: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999, 341:1565–1571. This paper provides the first clinical data establishing efficacy of an anti-angiogenesis agent, thalidomide, in patients with a refractory lymphoid malignancy. This agent is now being widely studied in lymphomas as well.PubMedCrossRefGoogle Scholar
  47. 47.
    Adams J, Palombella VJ, Sausville EA, et al.: Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 1999, 59:2615–2622. The proteasome inhibitors have a unique mechanism of action, resulting in increased sensitivity to chemotherapy agents and induction of apoptosis.PubMedGoogle Scholar
  48. 48.
    Orlowski RZ, Eswara JR, Larond-Walker A, et al.: Tumor growth inhibition induced in a murine model of human Burkitt’s lymphoma by a proteasome inhibitor. Cancer Res 1998, 58:4342–4348.PubMedGoogle Scholar
  49. 49.
    Alizadeh AA, Eisen MB, Davis RE, et al.: Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000, 403:503–511. The authors present the first evidence that, using DNA microarrays, it is possible to identify clinically meaningful subgroups of patients. They believe that this technology will provide a molecular classification of tumors, including both those previously clinically detected and those that are undetected.PubMedCrossRefGoogle Scholar
  50. 50.
    Cheson BD, Horning SJ, Coiffier B, et al.: Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 1999, 17:1244–1253. In the past, comparison of clinical data among studies was problematic because of major differences in response criteria. This international group of physicians with expertise in NHL standardized response criteria that are now being widely used and should facilitate interpretation of clinical trials.PubMedGoogle Scholar

Copyright information

© Current Science Inc 2001

Authors and Affiliations

  • Bruce D. Cheson
    • 1
  1. 1.National Cancer InstituteBethesdaUSA

Personalised recommendations