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Journal of Cancer Research and Clinical Oncology

, Volume 145, Issue 1, pp 129–136 | Cite as

Trofosfamide in the treatment of elderly or frail patients with diffuse large B-cell lymphoma

  • Hanno M. WitteEmail author
  • Armin Riecke
  • Thomas Mayer
  • Tobias Bartscht
  • Dirk Rades
  • Hendrik Lehnert
  • Hartmut Merz
  • Sebastian Fetscher
  • Harald Biersack
  • Niklas Gebauer
Original Article – Cancer Research

Abstract

Purpose

The introduction of immunochemotherapy has led to a significant improvement in treatment results and prognosis of diffuse large B-cell non-Hodgkins lymphoma (DLBCL) both at initial diagnosis and in relapse. Trofosfamide, an oxazaphosphorine derivative, has been utilized as alternative treatment option for patients with lymphoproliferative diseases unsuitable for conventional chemotherapy agents and protocols because of age, comorbidity, or poor performance score. While data on the activity and safety of single-agent trofosfamide have been published, the potential value of this agent in immunochemotherapy in combination with anti-CD20 antibodies such as rituximab has not been investigated to our knowledge.

Methods

Safety and therapeutic effectiveness of trofosfamide given orally at a dose of 50 mg twice daily alone, or in combination with standard-dose rituximab, was investigated in a cohort of elderly and/or highly comorbid patients with histologically confirmed primary or secondary DLBCL.

Results

Treatment with trofosfamide in this combination setting was generally well tolerated with no treatment-related deaths and manageable side effects, most of which were WHO class I–II; the most clinically relevant toxicity was cytopenia. 19 of 21 examined patients responded to therapy with 11 of 21 (52.4%) achieving a complete remission (CR). Median overall and progression-free survival (OS and PFS) in the CR-group was 14 and 9 months, respectively. In the subgroup with trofosfamide-based first-line therapy, 7 of 10 (70%) achieved CR and median PFS was not reached.

Conclusions

Immunochemotherapy with rituximab and trofosfamide (RT) is safe and effective in elderly and poor-performance patients with DLBCL. Response rates are comparable to most commonly used primary and salvage treatment protocols. The potential value of TR regimen in both first-line and relapsed/refractory DLCBL merits further investigation and is probably underestimated.

Keywords

Trofosfamide Diffuse large B-cell lymphoma Elderly Prognosis 

Notes

Acknowledgements

The authors would like to thank Svenja Kopelke and Rudina Marx for their administrative support.

Author contributions

Study design and drafting of manuscript: NG, HW, HB and DR. Data collection and analysis, revision of manuscript: HW, NG, HL, HM and SF. Revision and final approval of manuscript: all authors.

Funding

The authors declare no funding source for this study.

Compliance with ethical standards

Ethical approval

This study was approved by the ethics committee of the University of Luebeck (Reference no: 17-266) and was conducted in accordance with the Declaration of Helsinki and internationally accepted ethical guidelines.

Informed consent

Upon hospital admission, all participants gave their written informed consent for the storage of personal data and the use of data for research purposes.

Availability of data and materials

Data supporting the conclusions of this article are included in the article.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

432_2018_2772_MOESM1_ESM.docx (34 kb)
Supplementary material 1 (DOCX 34 KB)

References

  1. Blomqvist C, Wiklund T, Pajunen M, Virolainen M, Elomaa I (1995) Oral trofosfamide: an active drug in the treatment of soft-tissue sarcoma. Cancer Chemother Pharmacol 36:263–265CrossRefGoogle Scholar
  2. Boos J, Kupker F, Blaschke G, Jurgens H (1993) Trofosfamide metabolism in different species-ifosfamide is the predominant metabolite. Cancer Chemother Pharmacol 33:71–76CrossRefGoogle Scholar
  3. Brinker A, Kisro J, Letsch C, Bruggemann SK, Wagner T (2002) New insights into the clinical pharmacokinetics of trofosfamide. Int J Clin Pharmacol Ther 40:376–381CrossRefGoogle Scholar
  4. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-Lopez A, Hagenbeek A et al (1999) Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17:1244CrossRefGoogle Scholar
  5. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P et al (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242CrossRefGoogle Scholar
  6. Gunsilius E, Gierlich T, Mross K, Gastl G, Unger C (2001) Palliative chemotherapy in pretreated patients with advanced cancer: oral trofosfamide is effective in ovarian carcinoma. Cancer Invest 19:808–811CrossRefGoogle Scholar
  7. Hans CP, Weisenburger DD, Greiner TC et al (2004) Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103:275–282CrossRefGoogle Scholar
  8. Hempel G, Krumpelmann S, May-Manke A, Hohenlochter B, Blaschke G, Jurgens H, Boos J (1997) Pharmacokinetics of trofosfamide and its dechloroethylated metabolites. Cancer Chemother Pharmacol 40:45–50CrossRefGoogle Scholar
  9. Jahnke K, Wagner T, Bechrakis NE, Willerding G, Coupland SE, Fischer L, Thiel E, Korfel A (2005) Pharmacokinetics and efficacy of ifosfamide or trofosfamide in patients with intraocular lymphoma. Ann Oncol 16:1974–1978CrossRefGoogle Scholar
  10. Kanemasa Y, Shimoyama T, Sasaki Y, Tamura M, Sawada T, Omuro Y, Hishima T, Maeda Y (2017) The impacts of initial and relative dose intensity of R-CHOP on outcomes of elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma 58:736–739CrossRefGoogle Scholar
  11. Kasper B, Ho AD, Egerer G (2005) A new therapeutic approach in patients with advanced sarcoma. Int J Clin Oncol 10:438–440CrossRefGoogle Scholar
  12. Kouroukis CT, Browman GP, Esmail R, Meyer RM (2002) Chemotherapy for older patients with newly diagnosed, advanced-stage, aggressive-histology non-Hodgkin lymphoma: a systematic review. Ann Intern Med 136:144–152CrossRefGoogle Scholar
  13. Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman CA, Tubiana M (1989) Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds meeting. J Clin Oncol 7:1630–1636CrossRefGoogle Scholar
  14. Ohmachi K, Niitsu N, Uchida T, Kim SJ, Ando K, Takahashi N, Takahashi N, Uike N, Eom HS, Chae YS et al (2013) Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol 31:2103–2109CrossRefGoogle Scholar
  15. Park SI, Grover NS, Olajide O, Asch AS, Wall JG, Richards KL, Sobol AL, Deal AM, Ivanova A, Foster MC et al (2016) A phase II trial of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma. Br J Haematol 175:281–289CrossRefGoogle Scholar
  16. Peters FP, Fickers MM, Erdkamp FL, Wals J, Wils JA, Schouten HC (2001) The effect of optimal treatment on elderly patients with aggressive non-Hodgkin’s lymphoma: more patients treated with unaffected response rates. Ann Hematol 80:406–410CrossRefGoogle Scholar
  17. Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile JF, Castaigne S, Coiffier B, Haioun C, Bologna S, Fitoussi O et al (2011) Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol 12:460–468CrossRefGoogle Scholar
  18. Pfreundschuh M (2010) How I treat elderly patients with diffuse large B-cell lymphoma. Blood 116:5103–5110CrossRefGoogle Scholar
  19. Potzi P, Aiginger P, Kuhbock J (1979) [Ixoten therapy in malignant lymphomas]. Acta Med Austriaca 6:247–249Google Scholar
  20. Reichardt P, Pink D, Tilgner J, Kretzschmar A, Thuss-Patience PC, Dorken B (2002) Oral trofosfamide: an active and well-tolerated maintenance therapy for adult patients with advanced bone and soft tissue sarcomas. Results of a retrospective analysis. Onkologie 25:541–546Google Scholar
  21. Reichle A, Bross K, Vogt T, Bataille F, Wild P, Berand A, Krause SW, Andreesen R (2004) Pioglitazone and rofecoxib combined with angiostatically scheduled trofosfamide in the treatment of far-advanced melanoma and soft tissue sarcoma. Cancer 101:2247–2256CrossRefGoogle Scholar
  22. Reissig A, Walther M (2013) Old wine in new pipes? Treatment of advanced non-small cell lung cancer with trofosfamide. Onkologie 36:409–413CrossRefGoogle Scholar
  23. Rituximab Package Insert. Biogen Idec Inc., and Genentech, Inc. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/103705s5344lbl.pdf. Accessed 02 Apr 2018
  24. Salminen E, Nikkanen V, Lindholm L (1995) Trofosfamide is effective in refractory non-Hodgkin’s lymphoma. Eur J Cancer 31A:2419–2420CrossRefGoogle Scholar
  25. Salminen E, Nikkanen V, Lindholm L (1997) Palliative chemotherapy in non-Hodgkin’s lymphoma. Oncology 54:108–111CrossRefGoogle Scholar
  26. Sehn LH, Donaldson J, Chhanabhai M, Fitzgerald C, Gill K, Klasa R, MacPherson N, O’Reilly S, Spinelli JJ, Sutherland J et al (2005) Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol 23:5027–5033CrossRefGoogle Scholar
  27. Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, Klasa R, Savage KJ, Shenkier T, Sutherland J et al (2007) The revised International prognostic index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood 109:1857–1861CrossRefGoogle Scholar
  28. Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani R, Ghielmini M, Salles GA, Zelenetz AD, Jaffe ES (2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127:2375–2390CrossRefGoogle Scholar
  29. Wist E, Risberg T (1991) Trofosfamide in non-Hodgkin’s lymphoma. A phase II study. Acta Oncol 30:819–821CrossRefGoogle Scholar
  30. Wolff JE, Molenkamp G, Westphal S, Pietsch T, Gnekow A, Kortmann RD, Kuehl J (2000) Oral trofosfamide and etoposide in pediatric patients with glioblastoma multiforme. Cancer 89:2131–2137CrossRefGoogle Scholar
  31. Zhang J, Tian Q, Yung Chan S, Chuen Li S, Zhou S, Duan W, Zhu YZ (2005) Metabolism and transport of oxazaphosphorines and the clinical implications. Drug Metab Rev 37:611–703CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Hanno M. Witte
    • 1
    • 2
    Email author
  • Armin Riecke
    • 2
  • Thomas Mayer
    • 2
  • Tobias Bartscht
    • 1
  • Dirk Rades
    • 3
  • Hendrik Lehnert
    • 4
  • Hartmut Merz
    • 5
  • Sebastian Fetscher
    • 6
  • Harald Biersack
    • 1
  • Niklas Gebauer
    • 1
  1. 1.Department of Haematology and OncologyUniversity Hospital of Schleswig-Holstein (UKSH)LübeckGermany
  2. 2.Department of Haematology and OncologyGerman Armed Forces Hospital UlmUlmGermany
  3. 3.Department of Radiation OncologyUniversity Hospital of Schleswig-HolsteinLübeckGermany
  4. 4.Department of Internal Medicine IUniversity Hospital of Schleswig-HolsteinLübeckGermany
  5. 5.Reference Center for Lymph Node Pathology and HaematopathologyLübeckGermany
  6. 6.Department of Haematology and OncologySana HospitalsLübeckGermany

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