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(R)-GEMOX chemotherapy for unfit patients with refractory or recurrent primary central nervous system lymphoma: a LOC study

  • A. Collignon
  • C. Houillier
  • G. Ahle
  • O. Chinot
  • S. Choquet
  • A. Schmitt
  • P. Agape
  • C. Soussain
  • K. Hoang-Xuan
  • Emeline Tabouret
Original Article
  • 18 Downloads

Abstract

Recurrent primary central nervous system lymphomas (PCNSL) have a very poor prognosis. For young and fit patients, intensive chemotherapy followed by autologous stem cell transplantation could be proposed at relapse. In the other cases (unfit or elderly patients), therapeutic options are limited with no consensual regimen. The poly-chemotherapy by (R)-GEMOX is associated with anti-tumor activity in systemic lymphomas and a favorable toxicity profile. Our objective was to evaluate the activity and tolerance of (R)-GEMOX in PCNSL patients enrolled in the French nation-wide LOC cohort. We retrospectively analyzed all refractory or recurrent patients included in the LOC network who benefited from (R)-GEMOX (rituximab 375 mg/m2, gemcitabine 1000 mg/m2, and oxaliplatine 100 mg/m2). Administration, tolerance, and efficacy data were analyzed. Thirteen patients, treated in five different institutions, benefited from the (R)-GEMOX regimen from February 2013 to August 2017. At the initiation of (R)-GEMOX, median age was 71.4 years old (range, 49.5–82.5) and median Karnofsky performance status (KPS) was 60 (range, 40–80). Seven patients were in second line of treatment whereas the six others were in third line or over. All patients had received methotrexate-based polychemotherapy as first-line treatment except one. Overall response rate was 38% with two complete responses and three partial responses. Median progression-free survival was 3.2 months (95%CI: 0.2–6.2), and median overall survival was 8.2 months (95%CI: 0.6–15.8). Toxicity was mainly hematological including grade ¾ neutropenia (38%), lymphopenia (23%), and thrombopenia (23%). Older age (p = 0.046) and low KPS (p = 0.054) tended to be associated with a worse prognosis. (R)-GEMOX is associated with substantial response rate and favorable toxicity profile in unfit patients with recurrent PCNSL. (R)-GEMOX could be considered to be an additional option in patients with recurrent/refractory PCNSL.

Keywords

Primary central nervous system lymphoma Recurrent Refractory Chemotherapy 

Notes

Acknowledgments

LOC Network, AP-HM tissue bank AC 2013-1786, ARTC-sudassociation.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

For this type of study, formal consent is not required.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ (2011) Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br J Cancer 105(9):1414–1418CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Rubenstein JL, Gupta NK, Mannis GN, LaMarre AK, Treseler P (2013) How I treat CNS lymphomas. Blood 122(14):2318–2330CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ferreri AJM, Blay J-Y, Reni M, Pasini F, Spina M, Ambrosetti A et al (2003) Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol Off J Am Soc Clin Oncol 21(2):266–272CrossRefGoogle Scholar
  4. 4.
    Abrey LE, Ben-Porat L, Panageas KS, Yahalom J, Berkey B, Curran W et al (2006) Primary central nervous system lymphoma: the Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol 24(36):5711–5715CrossRefPubMedGoogle Scholar
  5. 5.
    McAllister LD, Doolittle ND, Guastadisegni PE, Kraemer DF, Lacy CA, Crossen JR et al (2000) Cognitive outcomes and long-term follow-up results after enhanced chemotherapy delivery for primary central nervous system lymphoma. Neurosurgery 46(1):51–60 discussion 60-61CrossRefPubMedGoogle Scholar
  6. 6.
    Batchelor T, Carson K, O’Neill A, Grossman SA, Alavi J, New P et al (2003) Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96–07. J Clin Oncol Off J Am Soc Clin Oncol 21(6):1044–1049CrossRefGoogle Scholar
  7. 7.
    Roth P, Hoang-Xuan K (2014) Challenges in the treatment of elderly patients with primary central nervous system lymphoma. Curr Opin Neurol 27(6):697–701CrossRefPubMedGoogle Scholar
  8. 8.
    Zhu J-J, Gerstner ER, Engler DA, Mrugala MM, Nugent W, Nierenberg K, Hochberg FH, Betensky RA, Batchelor TT (2009) High-dose methotrexate for elderly patients with primary CNS lymphoma. Neuro-Oncol 11(2):211–215CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Ng S, Rosenthal MA, Ashley D, Cher L (2000) High-dose methotrexate for primary CNS lymphoma in the elderly. Neuro-Oncol 2(1):40–44CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Welch MR, Omuro A, Deangelis LM (2012) Outcomes of the oldest patients with primary CNS lymphoma treated at Memorial Sloan-Kettering Cancer Center. Neuro-Oncol 14(10):1304–1311CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Roth P, Martus P, Kiewe P, Möhle R, Klasen H, Rauch M et al (2012) Outcome of elderly patients with primary CNS lymphoma in the G-PCNSL-SG-1 trial. Neurology 79(9):890–896CrossRefPubMedGoogle Scholar
  12. 12.
    Langner-Lemercier S, Houillier C, Soussain C, Ghesquières H, Chinot O, Taillandier L, Soubeyran P, Lamy T, Morschhauser F, Benouaich-Amiel A, Ahle G, Moles-Moreau MP, Moluçon-Chabrot C, Bourquard P, Damaj G, Jardin F, Larrieu D, Gyan E, Gressin R, Jaccard A, Choquet S, Brion A, Casasnovas O, Colin P, Reman O, Tempescul A, Marolleau JP, Fabbro M, Naudet F, Hoang-Xuan K, Houot R (2016) Primary CNS lymphoma at first relapse/progression: characteristics, management, and outcome of 256 patients from the French LOC network. Neuro-Oncol 18(9):1297–1303CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Jahnke K, Thiel E, Martus P, Herrlinger U, Weller M, Fischer L, Korfel A, on behalf of the German Primary Central Nervous System Lymphoma Study Group (G-PCNSL-SG) (2006) Relapse of primary central nervous system lymphoma: clinical features, outcome and prognostic factors. J Neurooncol 80(2):159–165CrossRefPubMedGoogle Scholar
  14. 14.
    Soussain C, Hoang-Xuan K, Taillandier L, Fourme E, Choquet S, Witz F et al (2008) Intensive chemotherapy followed by hematopoietic stem-cell rescue for refractory and recurrent primary CNS and intraocular lymphoma: Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. J Clin Oncol Off J Am Soc Clin Oncol 26(15):2512–2518CrossRefGoogle Scholar
  15. 15.
    Plotkin SR, Betensky RA, Hochberg FH, Grossman SA, Lesser GJ, Nabors LB et al (2004) Treatment of relapsed central nervous system lymphoma with high-dose methotrexate. Clin Cancer Res Off J Am Assoc Cancer Res 10(17):5643–5646CrossRefGoogle Scholar
  16. 16.
    Pentsova E, Deangelis LM, Omuro A (2014) Methotrexate re-challenge for recurrent primary central nervous system lymphoma. J Neurooncol 117(1):161–165CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gaviani P, Simonetti G, Innocenti A, Lamperti E, Botturi A, Silvani A (2016) Safety and efficacy of primary central nervous system lymphoma treatment in elderly population. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiol 37(1):131–133Google Scholar
  18. 18.
    Grommes C, De-Angelis LM (2017) Primary CNS Lymphoma. J Clin Oncol 35(21):2410–2418CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hottinger AF, DeAngelis LM, Yahalom J, Abrey LE (2007) Salvage whole brain radiotherapy for recurrent or refractory primary CNS lymphoma. Neurology 69(11):1178–1182CrossRefPubMedGoogle Scholar
  20. 20.
    López A, Gutiérrez A, Palacios A, Blancas I, Navarrete M, Morey M et al (2008) GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study. Eur J Haematol 80(2):127–132CrossRefPubMedGoogle Scholar
  21. 21.
    Abrey LE, Batchelor TT, Ferreri AJM, Gospodarowicz M, Pulczynski EJ, Zucca E et al (2005) Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol Off J Am Soc Clin Oncol 23(22):5034–5043CrossRefGoogle Scholar
  22. 22.
    Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology. - PubMed - NCBI [Internet]. [cité 28 juin 2018]. Disponible sur: https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/?term=Diagnosis+and+treatment+of+primary+CNS+lymphoma+in+immunocompetent+patients%3A+guidelines+from+the+European+Association+for+Neuro-Oncology
  23. 23.
    Reni M, Zaja F, Mason W, Perry J, Mazza E, Spina M et al (2007) Temozolomide as salvage treatment in primary brain lymphomas. Br J Cancer 96(6):864–867CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Makino K, Nakamura H, Hide T-I, Kuratsu J-I (2012) Salvage treatment with temozolomide in refractory or relapsed primary central nervous system lymphoma and assessment of the MGMT status. J Neurooncol 106(1):155–160CrossRefPubMedGoogle Scholar
  25. 25.
    Enting RH, Demopoulos A, DeAngelis LM, Abrey LE (2004) Salvage therapy for primary CNS lymphoma with a combination of rituximab and temozolomide. Neurology 63(5):901–903CrossRefPubMedGoogle Scholar
  26. 26.
    Wong ET, Tishler R, Barron L, Wu JK (2004) Immunochemotherapy with rituximab and temozolomide for central nervous system lymphomas. Cancer 101(1):139–145CrossRefPubMedGoogle Scholar
  27. 27.
    Kim Y-J, Choe J-H, Park J-H, Hong Y-K (2015) Efficacy of Procarbazine, Lomustine, and vincristine chemotherapy for recurrent primary central nervous system lymphomas. Brain Tumor Res Treat 3(2):75–80CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Herrlinger U, Brugger W, Bamberg M, Küker W, Dichgans J, Weller M (2000) PCV salvage chemotherapy for recurrent primary CNS lymphoma. Neurology 54(8):1707–1708CrossRefPubMedGoogle Scholar
  29. 29.
    Choquet S, Grenier A, Houillier C, Soussain C, Moles MP, Gastinne T et al (2015) Very High Efficiency of ICE (Ifosfamide-Carboplatin-Etoposide) in Relapse/Refractory (R/R) Primary Central Nervous System (PCNSL) and Vitreo-Retinal (VRL) Non Hodgkin Lymphoma. a LOC Network Multicenter Retrospective Study on 58 Cases. Blood 126(23):1524–1524Google Scholar
  30. 30.
    Platine and cytarabine-based salvage treatment for primary central nervous system lymphoma. - PubMed - NCBI [Internet]. [cité 28 juin 2018]. Disponible sur: https://www-ncbi-nlm-nih-gov.gate2.inist.fr/pubmed/21656329
  31. 31.
    Illerhaus G, Schorb E, Kasenda B (2018) Novel agents for primary central nervous system lymphoma: evidence and perspectives. Blood 132(7):681–688PubMedGoogle Scholar
  32. 32.
    Ghesquieres H, Houillier C, Chinot O, Choquet S, Molucon-Chabrot C, Beauchene P, Gressin R, Morschhauser F, Schmitt A, Gyan E, Hoang-Xuan K, Nicolas-Virelizier E, Chevrier M, Savignoni A, Turbiez I, Veillas F, Soumelis V, Soussain C (2016) Rituximab-Lenalidomide (REVRI) in Relapse or Refractory Primary Central Nervous System (PCNSL) or Vitreo Retinal Lymphoma (PVRL): Results of a « Proof of Concept » Phase II Study of the French LOC Network. BloodGoogle Scholar
  33. 33.
    Rubenstein JL, Geng H, Fraser EJ, Formaker P, Chen L, Sharma J et al (2018) Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma. Blood Adv 2(13):1595–1607CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Chamoun K, Choquet S, Boyle E, Houillier C, Larrieu-Ciron D, Al Jijakli A et al (2017) Ibrutinib monotherapy in relapsed/refractory CNS lymphoma: a retrospective case series. Neurology 88(1):101–102CrossRefPubMedGoogle Scholar
  35. 35.
    Grommes C, Pastore A, Palaskas N, Tang SS, Campos C, Schartz D, Codega P, Nichol D, Clark O, Hsieh WY, Rohle D, Rosenblum M, Viale A, Tabar VS, Brennan CW, Gavrilovic IT, Kaley TJ, Nolan CP, Omuro A, Pentsova E, Thomas AA, Tsyvkin E, Noy A, Palomba ML, Hamlin P, Sauter CS, Moskowitz CH, Wolfe J, Dogan A, Won M, Glass J, Peak S, Lallana EC, Hatzoglou V, Reiner AS, Gutin PH, Huse JT, Panageas KS, Graeber TG, Schultz N, DeAngelis LM, Mellinghoff IK (2017) Ibrutinib unmasks critical role of Bruton tyrosine kinase in primary CNS lymphoma. Cancer Discov 7(9):1018–1029CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Choquet S, Houllier C, Bijou F et al (2016) Ibrutinib monotherapy in relapse or refractory primary CNS lymphoma (PCNSL) and primary vitreoretinal lymphoma (PVRL). Result of the interim analysis of the iLOC phase II Study from the Lysa and the French LOC Network [abstract]. BloodGoogle Scholar
  37. 37.
    Chapuy B, Roemer MGM, Stewart C, Tan Y, Abo RP, Zhang L et al (2016) Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 127(7):869–881CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Nayak L, Iwamoto FM, LaCasce A, Mukundan S, Roemer MGM, Chapuy B et al (2017) PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood 129(23):3071–3073CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Graber J, Plato B, Moore D, Mawad R (2018) Two cases of Pembrolizumab therapy for CNS lymphoma (P6.136). Neurology 90(15 supplement) Disponible sur: http://n.neurology.org/content/90/15_Supplement/P6.136.abstract
  40. 40.
    Corazzelli G, Capobianco G, Arcamone M, Ballerini PF, Iannitto E, Russo F, Frigeri F, Becchimanzi C, Marcacci G, de Chiara A, Pinto A (2009) Long-term results of gemcitabine plus oxaliplatin with and without rituximab as salvage treatment for transplant-ineligible patients with refractory/relapsing B-cell lymphoma. Cancer Chemother Pharmacol 64(5):907–916CrossRefPubMedGoogle Scholar
  41. 41.
    Mounier N, El Gnaoui T, Tilly H, Canioni D, Sebban C, Casasnovas R-O et al (2013) Rituximab plus gemcitabine and oxaliplatin in patients with refractory/relapsed diffuse large B-cell lymphoma who are not candidates for high-dose therapy. A phase II Lymphoma Study Association trial. Haematologica nov 98(11):1726–1731CrossRefGoogle Scholar
  42. 42.
    Faivre S, Raymond E, Woynarowski JM, Cvitkovic E (1999) Supraadditive effect of 2′,2′-difluorodeoxycytidine (gemcitabine) in combination with oxaliplatin in human cancer cell lines. Cancer Chemother Pharmacol 44(2):117–123CrossRefPubMedGoogle Scholar
  43. 43.
    Smith MR, Joshi I, Jin F, Obasaju C (2005) Enhanced efficacy of gemcitabine in combination with anti-CD20 monoclonal antibody against CD20+ non-Hodgkin’s lymphoma cell lines in vitro and in scid mice. BMC Cancer 5:103CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Jacobs S, McCully CL, Murphy RF, Bacher J, Balis FM, Fox E (2010) Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates. Cancer Chemother Pharmacol 65(5):817–824CrossRefPubMedGoogle Scholar
  45. 45.
    Stukov AN, Filatova LV, Latipova DK, Bespalov VG, Belyaeva OA, Kireeva GS et al (2015) Therapeutic activity of gemcitabine in intracranial tumors. Vopr Onkol 61(2):274–279PubMedGoogle Scholar
  46. 46.
    Petereit HF, Rubbert-Roth A (2009) Rituximab levels in cerebrospinal fluid of patients with neurological autoimmune disorders. Mult Scler Houndmills Basingstoke Engl 15(2):189–192CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.APHM, service de Neuro-OncologieTimone Hospital, CHU TimoneMarseilleFrance
  2. 2.Aix-Marseille UniversitéMarseilleFrance
  3. 3.APHP, UPMC Univ Paris 06, Service de neurologie Mazarin, Groupe Hospitalier Pitié-SalpêtrièreSorbonne UniversitésParisFrance
  4. 4.Service de NeurologieHôpitaux Civils de ColmarColmarFrance
  5. 5.Service d’HématologieGroupe Hospitalier Pitié-SalpêtrièreParisFrance
  6. 6.Service d’oncologie médicale, Unité d’hématologieInstitut BergonieBordeauxFrance
  7. 7.Unité d’hématologieCentre Hospitalier Départemental Felix GuyonSaint DenisFrance
  8. 8.Service d’HématologieInstitut Curie-René HugueninSaint-CloudFrance

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