Annals of Hematology

, Volume 97, Issue 12, pp 2391–2401 | Cite as

Impact of front line relative dose intensity for methotrexate and comorbidities in immunocompetent elderly patients with primary central nervous system lymphoma

  • Jonathan FarhiEmail author
  • Kamel Laribi
  • Corentin Orvain
  • Jean-François Hamel
  • Mélanie Mercier
  • Aurélien Sutra Del Galy
  • Aline Clavert
  • Marie-Christine Rousselet
  • Aline Tanguy-Schmidt
  • Mathilde Hunault-Berger
  • Marie-Pierre Moles-Moreau
Original Article


Primary central nervous system lymphomas (PCNSL) are non-Hodgkin lymphomas strictly localized to the CNS, occurring mainly in elderly patients with comorbidities. Current treatment in fit patients relies on high-dose methotrexate and high-dose cytarabine. The aim of this study was to evaluate the efficacy and feasibility of this treatment in elderly patients and to assess potential prognostic factors associated with survival. We conducted a retrospective study in two centers between January 2008 and September 2015 including 35 elderly immunocompetent patients who received first-line treatment with high-dose methotrexate. With a median follow-up of 19.8 months (range: 1.7–73.4 months), median overall survival (OS) was 39.5 months (95% confidence interval (95% CI): 18.3–60.7) and median progression-free survival (PFS) was 25.8 months (95% CI: 5.2–46.4). In univariate analysis, administration of high-dose cytarabine and achieving a relative dose intensity for methotrexate > 75% were associated with increased OS (p = 0.006 and p = 0.003, respectively) and PFS (p = 0.003 and p = 0.04, respectively) whereas comorbidities, defined by a CIRS-G score ≥ 8, were associated with decreased OS and PFS (p = 0.02 and p = 0.04, respectively). A high MSKCC score was associated with decreased OS (p = 0.02). In multivariate analysis, administration of high-dose cytarabine was associated with increased OS and PFS (p = 0.02 and p = 0.007, respectively). Comorbidities and relative dose intensity for methotrexate are important for the prognosis of elderly patients with PCNSL. These results must be confirmed in prospective trials.


Primary central nervous system lymphoma Elderly patients High-dose methotrexate High-dose cytarabine Relative dose intensity Comorbidities 


Compliance with ethical standards

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Hoang-Xuan K, Bessell E, Bromberg J, Hottinger AF, Preusser M, Rudà R, Schlegel U, Siegal T, Soussain C, Abacioglu U, Cassoux N, Deckert M, Dirven CMF, Ferreri AJM, Graus F, Henriksson R, Herrlinger U, Taphoorn M, Soffietti R, Weller M (2015) Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology. Lancet Oncol 16:e322–e332CrossRefGoogle Scholar
  2. 2.
    O’Neill BP, Decker PA, Tieu C, Cerhan JR (2013) The changing incidence of primary central nervous system lymphoma is driven primarily by the changing incidence in young and middle-aged men and differs from time trends in systemic diffuse large B-cell non-Hodgkin’s lymphoma. Am J Hematol 88:997–1000. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Deckert M, Engert A, Brück W, Ferreri AJM, Finke J, Illerhaus G, Klapper W, Korfel A, Küppers R, Maarouf M, Montesinos-Rongen M, Paulus W, Schlegel U, Lassmann H, Wiestler OD, Siebert R, DeAngelis LM (2011) Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma. Leukemia 25:1797–1807. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Camilleri-Broët S, Crinière E, Broët P et al (2006) A uniform activated B-cell-like immunophenotype might explain the poor prognosis of primary central nervous system lymphomas: analysis of 83 cases. Blood 107:190–196. CrossRefGoogle Scholar
  5. 5.
    Kasenda B, Ferreri AJM, Marturano E, Forst D, Bromberg J, Ghesquieres H, Ferlay C, Blay JY, Hoang-Xuan K, Pulczynski EJ, Fosså A, Okoshi Y, Chiba S, Fritsch K, Omuro A, O'Neill BP, Bairey O, Schandelmaier S, Gloy V, Bhatnagar N, Haug S, Rahner S, Batchelor TT, Illerhaus G, Briel M (2015) First-line treatment and outcome of elderly patients with primary central nervous system lymphoma (PCNSL)--a systematic review and individual patient data meta-analysis. Ann Oncol 26:1305–1313. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Roth P, Hoang-Xuan K (2014) Challenges in the treatment of elderly patients with primary central nervous system lymphoma. Curr Opin Neurol 27:697–701. CrossRefGoogle Scholar
  7. 7.
    Ferreri AJM, Blay J-Y, Reni M, Pasini F, Spina M, Ambrosetti A, Calderoni A, Rossi A, Vavassori V, Conconi A, Devizzi L, Berger F, Ponzoni M, Borisch B, Tinguely M, Cerati M, Milani M, Orvieto E, Sanchez J, Chevreau C, Dell’Oro S, Zucca E, Cavalli F (2003) Prognostic scoring system for primary CNS lymphomas: the international extranodal lymphoma study group experience. J Clin Oncol 21:266–272CrossRefGoogle Scholar
  8. 8.
    Abrey LE, Ben-Porat L, Panageas KS, Yahalom J, Berkey B, Curran W, Schultz C, Leibel S, Nelson D, Mehta M, DeAngelis LM (2006) Primary central nervous system lymphoma: the Memorial Sloan-Kettering Cancer Center prognostic model. J Clin Oncol 24:5711–5715. CrossRefGoogle Scholar
  9. 9.
    Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373–383CrossRefGoogle Scholar
  10. 10.
    Miller MD, Paradis CF, Houck PR, Mazumdar S, Stack JA, Rifai AH, Mulsant B, Reynolds CF III (1992) Rating chronic medical illness burden in geropsychiatric practice and research: application of the Cumulative Illness Rating Scale. Psychiatry Res 41:237–248CrossRefGoogle Scholar
  11. 11.
    Salvi F, Miller MD, Grilli A, Giorgi R, Towers AL, Morichi V, Spazzafumo L, Mancinelli L, Espinosa E, Rappelli A, DessÃ-Fulgheri P (2008) A manual of guidelines to score the modified cumulative illness rating scale and its validation in acute hospitalized elderly patients. J Am Geriatr Soc 56:1926–1931. CrossRefGoogle Scholar
  12. 12.
    Bellera CA, Rainfray M, Mathoulin-Pélissier S et al (2012) Screening older cancer patients: first evaluation of the G-8 geriatric screening tool. Ann Oncol 23:2166–2172. CrossRefGoogle Scholar
  13. 13.
    Hryniuk WM, Goodyear M (1990) The calculation of received dose intensity. J Clin Oncol 8:1935–1937CrossRefGoogle Scholar
  14. 14.
    Fridrik MA, Greil R, Hausmaninger H et al (1997) Randomized open label phase III trial of CEOP/IMVP-Dexa alternating chemotherapy and filgrastim versus CEOP/IMVP-Dexa alternating chemotherapy for aggressive non-Hodgkin’s lymphoma (NHL). A multicenter trial by the Austrian Working Group for Medical Tumor Therapy. Ann Hematol 75:135–140CrossRefGoogle Scholar
  15. 15.
    Abrey LE (2005) Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma. J Clin Oncol 23:5034–5043. CrossRefGoogle Scholar
  16. 16.
    National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 Published: May 28, 2009 (v4.03: June 14, 2010)Google Scholar
  17. 17.
    Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE (2006) Long-term follow-up of high-dose methotrexate-based therapy with and without whole brain irradiation for newly diagnosed primary CNS lymphoma. J Clin Oncol 24:4570–4574. CrossRefGoogle Scholar
  18. 18.
    Desablens B, Gardembas M, Delwail V et al (1999) Primary CNS lymphomas: long term results of the GOELAMS LCP88 trial with a focus on neurological complications among 152 patients. Ann Oncol 10(Suppl 3):40 (abstract)Google Scholar
  19. 19.
    Poortmans PMP, Kluin-Nelemans HC, Haaxma-Reiche H, van’t Veer M, Hansen M, Soubeyran P, Taphoorn M, Thomas J, van den Bent M, Fickers M, van Imhoff G, Rozewicz C, Teodorovic I, van Glabbeke M (2003) High-dose methotrexate-based chemotherapy followed by consolidating radiotherapy in non-AIDS-related primary central nervous system lymphoma: European Organization for Research and Treatment of Cancer Lymphoma Group Phase II Trial 20962. J Clin Oncol 21:4483–4488. CrossRefGoogle Scholar
  20. 20.
    Lyman GH, Crawford J, Tomita D, Whittaker S, Dale DC (2015) Changing patterns of chemotherapy relative dose intensity and supportive care for aggressive B-cell non-Hodgkin lymphoma. Leuk Lymphoma 57:1–8. CrossRefGoogle Scholar
  21. 21.
    Olivier G, Clavert A, Lacotte-Thierry L, Gardembas M, Escoffre-Barbe M, Brion A, Cumin I, Legouffe E, Solal-Celigny P, Chabin M, Ingrand P, Colombat P, Delwail V (2014) A phase 1 dose escalation study of idarubicin combined with methotrexate, vindesine, and prednisolone for untreated elderly patients with primary central nervous system lymphoma. The GOELAMS LCP 99 trial. Am J Hematol 89:1024–1029. CrossRefGoogle Scholar
  22. 22.
    Omuro A, Chinot O, Taillandier L, Ghesquieres H, Soussain C, Delwail V, Lamy T, Gressin R, Choquet S, Soubeyran P, Huchet A, Benouaich-Amiel A, Lebouvier-Sadot S, Gyan E, Touitou V, Barrié M, del Rio MS, Gonzalez-Aguilar A, Houillier C, Delgadillo D, Lacomblez L, Tanguy ML, Hoang-Xuan K (2015) Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial. Lancet Haematol 2:e251–e259CrossRefGoogle Scholar
  23. 23.
    Fritsch K, Kasenda B, Schorb E, Hau P, Bloehdorn J, Möhle R, Löw S, Binder M, Atta J, Keller U, Wolf HH, Krause SW, Heß G, Naumann R, Sasse S, Hirt C, Lamprecht M, Martens U, Morgner A, Panse J, Frickhofen N, Röth A, Hader C, Deckert M, Fricker H, Ihorst G, Finke J, Illerhaus G (2017) High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia 31:846–852. CrossRefGoogle Scholar
  24. 24.
    Wildiers H, Reiser M (2011) Relative dose intensity of chemotherapy and its impact on outcomes in patients with early breast cancer or aggressive lymphoma. Crit Rev Oncol Hematol 77:221–240. CrossRefGoogle Scholar
  25. 25.
    Joerger M, Huitema ADR, Illerhaus G, Ferreri AJM (2012) Rational administration schedule for high-dose methotrexate in patients with primary central nervous system lymphoma. Leuk Lymphoma 53:1867–1875. CrossRefGoogle Scholar
  26. 26.
    Ferreri AJM, Guerra E, Regazzi M, Pasini F, Ambrosetti A, Pivnik A, Gubkin A, Calderoni A, Spina M, Brandes A, Ferrarese F, Rognone A, Govi S, Dell'Oro S, Locatelli M, Villa E, Reni M (2004) Area under the curve of methotrexate and creatinine clearance are outcome-determining factors in primary CNS lymphomas. Br J Cancer 90:353–358. CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ferreri AJM, Reni M, Foppoli M, Martelli M, Pangalis GA, Frezzato M, Cabras MG, Fabbri A, Corazzelli G, Ilariucci F, Rossi G, Soffietti R, Stelitano C, Vallisa D, Zaja F, Zoppegno L, Aondio GM, Avvisati G, Balzarotti M, Brandes AA, Fajardo J, Gomez H, Guarini A, Pinotti G, Rigacci L, Uhlmann C, Picozzi P, Vezzulli P, Ponzoni M, Zucca E, Caligaris-Cappio F, Cavalli F (2009) High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 374:1512–1520. CrossRefGoogle Scholar
  28. 28.
    Coiffier B, Lepage E, Briere J et al (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242. CrossRefGoogle Scholar
  29. 29.
    Siegal T (2014) Primary central nervous system lymphoma: current state of anti-CD20 therapy and appraisal of reported response criteria. J Clin Neurosci 21:709–715. CrossRefGoogle Scholar
  30. 30.
    Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D, LaRocca R, Grant B, DeAngelis LM, Abrey LE (2007) Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 25:4730–4735. CrossRefGoogle Scholar
  31. 31.
    Birnbaum T, Stadler EA, von Baumgarten L, Straube A (2012) Rituximab significantly improves complete response rate in patients with primary CNS lymphoma. J Neuro-Oncol 109:285–291. CrossRefGoogle Scholar
  32. 32.
    Gregory G, Arumugaswamy A, Leung T, Chan KL, Abikhair M, Tam C, Bajel A, Cher L, Grigg A, Ritchie D, Opat S (2013) Rituximab is associated with improved survival for aggressive B cell CNS lymphoma. Neuro-Oncology 15:1068–1073. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kansara R, Shenkier TN, Connors JM, Sehn LH, Savage KJ, Gerrie AS, Villa D (2015) Rituximab with high-dose methotrexate in primary central nervous system lymphoma. Am J Hematol 90:1149–1154. CrossRefGoogle Scholar
  34. 34.
    Holdhoff M, Ambady P, Abdelaziz A, Sarai G, Bonekamp D, Blakeley J, Grossman SA, Ye X (2014) High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. Neurology 83:235–239CrossRefGoogle Scholar
  35. 35.
    Madle M, Krämer I, Lehners N, Schwarzbich M, Wuchter P, Herfarth K, Egerer G, Ho AD, Witzens-Harig M (2015) The influence of rituximab, high-dose therapy followed by autologous stem cell transplantation, and age in patients with primary CNS lymphoma. Ann Hematol 94:1853–1857. CrossRefGoogle Scholar
  36. 36.
    Chamberlain MC, Johnston SK (2010) High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma. Neuro-Oncology 12:736–744. CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Fritsch K, Kasenda B, Hader C, Nikkhah G, Prinz M, Haug V, Haug S, Ihorst G, Finke J, Illerhaus G (2011) Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly. Ann Oncol 22:2080–2085. CrossRefGoogle Scholar
  38. 38.
    Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD, Kaplan LD (2013) Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 31:3061–3068. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ferreri AJM, Cwynarski K, Pulczynski E, Ponzoni M, Deckert M, Politi LS, Torri V, Fox CP, Rosée PL, Schorb E, Ambrosetti A, Roth A, Hemmaway C, Ferrari A, Linton KM, Rudà R, Binder M, Pukrop T, Balzarotti M, Fabbri A, Johnson P, Gørløv JS, Hess G, Panse J, Pisani F, Tucci A, Stilgenbauer S, Hertenstein B, Keller U, Krause SW, Levis A, Schmoll HJ, Cavalli F, Finke J, Reni M, Zucca E, Illerhaus G (2016) Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol 3:e217–e227. CrossRefGoogle Scholar
  40. 40.
    Bromberg J, Issa S, Bukanina K et al (2017) Effect of rituximab in primary central nervous system lymphoma - results of the Randomized Phase III HOVON 105/ALLG NHL 24 Study. Blood 130:582–582Google Scholar
  41. 41.
    Song Y, Wen Y, Xue W, Zhang Y, Zhang M (2017) Effect of rituximab on primary central nervous system lymphoma: a meta-analysis. Int J Hematol 106:612–621. CrossRefGoogle Scholar
  42. 42.
    Terret C, Albrand G, Rainfray M, Soubeyran P (2015) Impact of comorbidities on the treatment of non-Hodgkin’s lymphoma: a systematic review. Expert Rev Hematol 8:329–341. CrossRefGoogle Scholar
  43. 43.
    Extermann M, Boler I, Reich RR, Lyman GH, Brown RH, DeFelice J, Levine RM, Lubiner ET, Reyes P, Schreiber FJ III, Balducci L (2012) Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer 118:3377–3386. CrossRefGoogle Scholar
  44. 44.
    Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, Lichtman SM, Gajra A, Bhatia S, Katheria V, Klapper S, Hansen K, Ramani R, Lachs M, Wong FL, Tew WP (2011) Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol 29:3457–3465. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Aaldriks AA, Maartense E, le Cessie S, Giltay EJ, Verlaan HACM, van der Geest LGM, Kloosterman-Boele WM, Peters-Dijkshoorn MT, Blansjaar BA, van Schaick HW, Nortier JWR (2011) Predictive value of geriatric assessment for patients older than 70 years, treated with chemotherapy. Crit Rev Oncol Hematol 79:205–212. CrossRefGoogle Scholar
  46. 46.
    Kanesvaran R, Li H, Koo K-N, Poon D (2011) Analysis of prognostic factors of comprehensive geriatric assessment and development of a clinical scoring system in elderly Asian patients with cancer. J Clin Oncol 29:3620–3627. CrossRefGoogle Scholar
  47. 47.
    Soubeyran P, Bellera C, Goyard J, Heitz D, Curé H, Rousselot H, Albrand G, Servent V, Jean OS, van Praagh I, Kurtz JE, Périn S, Verhaeghe JL, Terret C, Desauw C, Girre V, Mertens C, Mathoulin-Pélissier S, Rainfray M (2014) Screening for vulnerability in older cancer patients: the ONCODAGE Prospective Multicenter Cohort Study. PLoS One 9:e115060. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Decoster L, Van Puyvelde K, Mohile S et al (2015) Screening tools for multidimensional health problems warranting a geriatric assessment in older cancer patients: an update on SIOG recommendations†. Ann Oncol 26:288–300. CrossRefGoogle Scholar
  49. 49.
    Dubruille S, Libert Y, Roos M, Vandenbossche S, Collard A, Meuleman N, Maerevoet M, Etienne AM, Reynaert C, Razavi D, Bron D (2015) Identification of clinical parameters predictive of one-year survival using two geriatric tools in clinically fit older patients with hematological malignancies: major impact of cognition. J Geriatr Oncol 6:362–369. CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Jonathan Farhi
    • 1
    • 2
    Email author
  • Kamel Laribi
    • 2
  • Corentin Orvain
    • 1
  • Jean-François Hamel
    • 3
  • Mélanie Mercier
    • 1
  • Aurélien Sutra Del Galy
    • 1
  • Aline Clavert
    • 1
  • Marie-Christine Rousselet
    • 4
  • Aline Tanguy-Schmidt
    • 1
  • Mathilde Hunault-Berger
    • 1
  • Marie-Pierre Moles-Moreau
    • 1
  1. 1.Service des Maladies du SangCHU AngersAngers Cedex 9France
  2. 2.Service d’Hématologie CliniqueCH Le MansLe MansFrance
  3. 3.Service de Méthodologie et BiostatistiquesCHU AngersAngersFrance
  4. 4.Département de Pathologie Cellulaire et TissulaireCHU AngersAngersFrance

Personalised recommendations