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Open Access 01-12-2019 | Lymphoma | Research article

HDMTX-based induction therapy followed by consolidation with conventional systemic chemotherapy and intraventricular therapy (modified Bonn protocol) in primary CNS lymphoma: a monocentric retrospective analysis

Authors: Sabine Seidel, Agnieszka Korfel, Thomas Kowalski, Michelle Margold, Fatme Ismail, Roland Schroers, Alexander Baraniskin, Hendrik Pels, Peter Martus, Uwe Schlegel

Published in: Neurological Research and Practice | Issue 1/2019

Abstract

Background

To evaluate outcome and toxicity of High-dose methotrexate (HDMTX)-based induction therapy followed by consolidation with conventional systemic chemotherapy and facultative intraventricular therapy (modified Bonn protocol) in patients with primary CNS lymphoma (PCNSL).

Methods

Between 01/2005 and 12/2013 113 patients with newly diagnosed PCNSL presented at our center; 98 of those qualified for HDMTX based chemotherapy, received a modified Bonn protocol and were included in the analysis. The treatment regimen was based on the “Bonn protocol”, but modified by omission of systemic drugs not able to cross the intact blood brain barrier. Intraventricular therapy was postponed until completion of three induction chemotherapy cycles or was replaced by intrathecal liposomal AraC and rituximab was added to induction from 2010 onwards.

Results

Median patient age was 67 years (range 38–83). Complete response/complete response unconfirmed (CR/CRu) was achieved in 59/98 patients (60%), partial response (PR) in 9/98 patients (9%). Twenty-four patients (23%) had progressive disease (PD), 6 (6%) died on therapy. Median progression-free survival (PFS) for all patients was 11.4 months, median overall survival (OS) 29.1 months. A trend to better outcome for intraventricular therapy versus intrathecal liposomal AraC was found in patients < 65 years (HR 0.53 [0.19–1.47] for OS and 0.46 [0.21–1.02] for PFS. Ommaya reservoir infection occurred in 3/33 patients (9%).

Conclusions

The data of this single center experience suggest that the outcome with a modified Bonn protocol was comparable to that of the previous regimen, showed fewer Ommaya reservoir infections and may have a trend for better outcome with intraventricular therapy.

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Ostrom, Q. T., Gittleman, H., Liao, P., Rouse, C., Chen, Y., Dowling, J., Wolinsky, Y., Kruchko, C., & Barnholtz-Sloan, J. (2014). CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro-Oncology, 16(Suppl 4), iv1–i63. https://doi.org/10.1093/neuonc/nou223.CrossRefPubMedPubMedCentral

Korfel, A., & Schlegel, U. (2013). Diagnosis and treatment of primary CNS lymphoma. Nature Reviews Neurology, 9(6), 317–327. https://doi.org/10.1038/nrneurol.2013.83.CrossRefPubMed

Nelson, D. F. (1999). Radiotherapy in the treatment of primary central nervous system lymphoma (PCNSL). Journal of Neuro-Oncology, 43, 241–247.CrossRefPubMed

Abrey, L. E., Yahalom, J., & DeAngelis, L. M. (2000). Treatment for primary CNS lymphoma: The next step. Journal of Clinical Oncology, 18, 519–526.CrossRef

Thiel, E., Korfel, A., Martus, P., Kanz, L., Griesinger, F., Rauch, M., Röth, A., Hertenstein, B., von Toll, T., Hundsberger, T., Mergenthaler, H. G., Leithäuser, M., Birnbaum, T., Fischer, L., Jahnke, K., Herrlinger, U., Plasswilm, L., Nägele, T., Pietsch, T., Bamberg, M., & Weller, M. (2010). High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial. Lancet Oncology, 11(11), 1036–1047. https://doi.org/10.1016/S1470-2045(10)70229-1.CrossRefPubMed

Pels, H., Schmidt-Wolf, I. G., Glasmacher, A., Schulz, H., Engert, A., Diehl, V., Zellner, A., Schackert, G., Reichmann, H., Kroschinsky, F., Vogt-Schaden, M., Egerer, G., Bode, U., Schaller, C., Deckert, M., Fimmers, R., Helmstaedter, C., Atasoy, A., Klockgether, T., & Schlegel, U. (2003). Primary central nervous system lymphoma: Results of a pilot and phase II study of systemic and intraventricular chemotherapy with deferred radiotherapy. Journal of Clinical Oncology, 21, 4489–4495.CrossRefPubMed

DeAngelis, L. M. (2003). Primary central nervous system lymphoma: a curable brain tumor. Journal of Clinical Oncology, 21(24), 4471–4473.CrossRefPubMed

Juergens, A., Pels, H., Rogowski, S., Fliessbach, K., Glasmacher, A., Engert, A., Reiser, M., Diehl, V., Vogt-Schaden, M., Egerer, G., Schackert, G., Reichmann, H., Kroschinsky, F., Bode, U., Herrlinger, U., Linnebank, M., Deckert, M., Fimmers, R., Schmidt-Wolf, I. G., & Schlegel, U. (2010). Long-term survival with favorable cognitive outcome after chemotherapy in primary central nervous system lymphoma. Annals of Neurology, 67, 182–189. https://doi.org/10.1002/ana.21824.CrossRefPubMed

Pels, H., Juergens, A., Glasmacher, A., Schulz, H., Engert, A., Linnebank, M., Schackert, G., Reichmann, H., Kroschinsky, F., Vogt-Schaden, M., Egerer, G., Bode, U., Schaller, C., Lamprecht, M., Hau, P., Deckert, M., Fimmers, R., Bangard, C., Schmidt-Wolf, I. G., & Schlegel, U. (2009). Early relapses in primary CNS lymphoma after response to polychemotherapy without intraventricular treatment: Results of a phase II study. Journal of Neuro-Oncology, 91(3), 299–305. https://doi.org/10.1007/s11060-008-9712-4.CrossRefPubMed

10.

Rubinstein, J. L., His, E. D., Johnson, J. L., Jung, S. H., Nakashima, M. O., Grant, B., Cheson, B. D., & Kaplan, L. D. (2013). Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). Journal of Clinical Oncology, 31(25), 3061–3068. https://doi.org/10.1200/JCO.2012.46.9957.CrossRef

11.

Illerhaus, G., Kasenda, B., Ihorst, G., Egerer, G., Lamprecht, M., Keller, U., Wolf, H. H., Hirt, C., Stilgenbauer, S., Binder, M., Hau, P., Edinger, M., Frickhofen, N., Bentz, M., Möhle, R., Röth, A., Pfreundschuh, M., von Baumgarten, L., Deckert, M., Hader, C., Fricker, H., Valk, E., Schorb, E., Fritsch, K., & Finke, J. (2016). High-dose chemotherapy with autologous haematopoietic stem cell transplantation for newly diagnosed primary CNS lymphoma: A prospective, single-arm, phase 2 trial. Lancet Haematology, 3(8), e388–e397. https://doi.org/10.1016/S2352-3026(16)30050-3.CrossRefPubMed

12.

Morris, P. G., Correa, D. D., Yahalom, J., Raizer, J. J., Schiff, D., Grant, B., Grimm, S., Lai, R. K., Reiner, A. S., Panageas, K., Karimi, S., Curry, R., Shah, G., Abrey, L. E., DeAngelis, L. M., & Omuro, A. (2013). Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: final results and long-term outcome. Journal of Clinical Oncology, 31(31), 3971–3979. https://doi.org/10.1200/JCO.2013.50.4910.CrossRefPubMedPubMedCentral

13.

Ferreri, A. J. M., Cwynarski, K., Pulczynski, E., Fox, C. P., Schorb, E., La Rosée, P., Binder, M., Fabbri, A., Torri, V., Minacapelli, E., Falautano, M., Ilariucci, F., Ambrosetti, A., Roth, A., Hemmaway, C., Johnson, P., Linton, K. M., Pukrop, T., Sønderskov Gørløv, J., Balzarotti, M., Hess, G., Keller, U., Stilgenbauer, S., Panse, J., Tucci, A., Orsucci, L., Pisani, F., Levis, A., Krause, S. W., Schmoll, H. J., Hertenstein, B., Rummel, M., Smith, J., Pfreundschuh, M., Cabras, G., Angrilli, F., Ponzoni, M., Deckert, M., Politi, L. S., Finke, J., Reni, M., Cavalli, F., Zucca, E., & Illerhaus, G. (2017). Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematology, 4(11), e510–e523. https://doi.org/10.1016/S2352-3026(17)30174-6.CrossRefPubMed

14.

Houillier, C., Taillandier, L., Lamy, T., Chinot, O., Molucon-Chabrot, C., Soubeyran, P., Gressin, R., Choquet, S., Damaj, G., Thyss, A., Jaccard, A., Delwail, V., Gyan, E., Sanhes, L., Cornillon, J., Garidi, R., Delmer, A., Savignoni, A., Jijakli, A., Morel, P., Bourquard, P., Moles, M., Deconinck, E., Morel, P., Gastinne, T., Constans, J., Langer, A., Lacomblez, L., Delgadillo, D., Dureau, S., Turbiez, I., Plissonnier, A., Cassoux, N., Touitou, V., Ricard, D., Hoang-Xuan, K., & Soussain, C. (2016). Whole brain radiotherapy (WBRT) versus intensive chemotherapy with Haematopoietic stem cell rescue (IC + HCR) for primary central nervous system lymphoma (PCNSL) in young patients: An intergroup Anocef-Goelams randomized phase II trial (PRECIS). Blood, 128(22), 782.

15.

Yule, S. M., Price, L., Pearson, A. D., & Boddy, A. V. (1997). Cyclophosphamide and ifosfamide metabolites in the cerebrospinal fluid of children. Clinical Cancer Research, 3(11), 1985–1992.PubMed

16.

Ferreri, A. J., 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. British Journal of Cancer, 90(2), 353–358.CrossRefPubMedPubMedCentral

17.

Birnbaum, T., Stadler, E. A., von Baumgarten, L., & Straube, A. (2012). Rituximab significantly improves complete response rate in patients with primary CNS lymphoma. Journal of Neuro-Oncology, 109(2), 285–291. https://doi.org/10.1007/s11060-012-0891-7.CrossRefPubMed

18.

Holdhoff, M., Ambady, P., Abdelaziz, A., Sarai, G., Bonekamp, D., Blakeley, J., Grossman, S. A., & Ye, X. (2014). High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma. Neurology, 83(3), 235–239. https://doi.org/10.1212/WNL.0000000000000593.CrossRefPubMedPubMedCentral

19.

Rubinstein, J. L., Fridlyand, J., Abrey, L., Shen, A., Karch, J., Wang, E., Issa, S., Damon, L., Prados, M., McDermott, M., O'Brien, J., Haqq, C., & Shuman, M. (2007). Phase 1 study of intraventricular administration of rituximab in patients with recurrent CNS and intraocular lymphoma. Journal of Clinical Oncology, 25(11), 1350–1356.CrossRef

20.

Ott, R. J., Brada, M., Flower, M. A., Babich, J. W., Cherry, S. R., & Deehan, B. J. (1991). Measurements of blood-brain barrier permeability in patients undergoing radiotherapy and chemotherapy for primary cerebral lymphoma. European Journal of Cancer, 27(11), 1356–1361.CrossRefPubMed

21.

Pulczynski, E. J., Kuittinen, O., Erlanson, M., Hagberg, H., Fosså, A., Eriksson, M., Nordstrøm, M., Østenstad, B., Fluge, Ø., Leppä, S., Fiirgaard, B., Bersvendsen, H., & Fagerli, U. M. (2015). Successful change of treatment strategy in elderly patients with primary central nervous system lymphoma by de-escalating induction and introducing temozolomide maintenance: results from a phase II study by the Nordic Lymphoma Group. Haematologica, 100(4), 534–540. https://doi.org/10.3324/haematol.2014.108472.CrossRefPubMedPubMedCentral

22.

Glantz, M. J., Cole, B. F., Recht, L., Akerley, W., Mills, P., Saris, S., Hochberg, F., Calabresi, P., & Egorin, M. J. (1998). High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: Is intrathecal chemotherapy necessary? Journal of Clinical Oncology, 16(4), 1561–1567.CrossRefPubMed

23.

Bleyer, W. A., Poplack, D. G., & Simon, R. M. (1978). "Concentration x time" methotrexate via a subcutaneous reservoir: a less toxic regimen for intraventricular chemotherapy of central nervous system neoplasms. Blood, 51(5), 835–842.PubMed

24.

Küker, W., Nägele, T., Thiel, E., Weller, M., & Herrlinger, U. (2005). Primary central nervous system lymphomas (PCNSL): MRI response criteria revised. Neurology, 65(7), 1129–1131.CrossRefPubMed

25.

World Health Organization. (1979) WHO Handbook for Reporting Results of Cancer Treatment. WHO offset publication no. 48 Geneva, Switzerland.

26.

DeAngelis, L. M., Seiferheld, W., Schold, S. C., Fisher, B., & Schultz, C. J. (2002). Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation therapy oncology group study 93-10. Journal of Clinical Oncology, 20(24), 4643–4648.CrossRefPubMed

27.

Poortmans, P. M., Kluin-Nelemans, H. C., 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. Journal of Clinical Oncology, 21(24), 4483–4488.CrossRefPubMed

28.

Ferreri, A. J., Reni, M., Foppoli, M., Martelli, M., Pangalis, G. A., Frezzato, M., Cabras, M. G., Fabbri, A., Corazzelli, G., Ilariucci, F., Rossi, G., Soffietti, R., Stelitano, C., Vallisa, D., Zaja, F., Zoppegno, L., Aondio, G. M., Avvisati, G., Balzarotti, M., Brandes, A. A., 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. https://doi.org/10.1016/S0140-6736(09)61416-1.CrossRefPubMed

29.

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, M. S., Gonzalez-Aguilar, A., Houillier, C., Delgadillo, D., Lacomblez, L., Tanguy, M. L., & 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 Haematology, 2(6), e251–e259. https://doi.org/10.1016/S2352-3026(15)00074-5.CrossRefPubMed

30.

Doolittle, N. D., Korfel, A., Lubow, M. A., Schorb, E., Schlegel, U., Rogowski, S., Fu, R., Dósa, E., Illerhaus, G., Kraemer, D. F., Muldoon, L. L., Calabrese, P., Hedrick, N., Tyson, R. M., Jahnke, K., Maron, L. M., Butler, R. W., & Neuwelt, E. A. (2013). Long-term cognitive function, neuroimaging, and quality of life in primary CNS lymphoma. Neurology, 81(1), 84–92. https://doi.org/10.1212/WNL.0b013e318297eeba.CrossRefPubMedPubMedCentral

31.

Roth, P., Martus, P., Kiewe, P., Möhle, R., Klasen, H., Rauch, M., Röth, A., Kaun, S., Thiel, E., Korfel, A., & Weller, M. (2012). Outcome of elderly patients with primary CNS lymphoma in the G-PCNSL-SG-1 trial. Neurology 2012, 79(9), 890–896. https://doi.org/10.1212/WNL.0b013e318266fcb2.CrossRef

32.

Fritsch, K., Kasenda, B., Schorb, E., Hau, P., Bloehdorn, J., Möhle, R., Löw, S., Binder, M., Atta, J., Keller, U., Wolf, H. H., Krause, S. W., 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(4), 846–852. https://doi.org/10.1038/leu.2016.334.CrossRefPubMed

33.

Mendez, J. S., Ostrom, Q. T., Gittleman, H., Kruchko, C., DeAngelis, L. M., Barnholtz-Sloan, J. S., & Grommes, C. (2018). The elderly left behind-changes in survival trends of primary central nervous system lymphoma over the past 4 decades. Neuro-Oncology, 20(5), 687–694. https://doi.org/10.1093/neuonc/nox187.CrossRefPubMed

Title: HDMTX-based induction therapy followed by consolidation with conventional systemic chemotherapy and intraventricular therapy (modified Bonn protocol) in primary CNS lymphoma: a monocentric retrospective analysis
Authors: Sabine Seidel
Agnieszka Korfel
Thomas Kowalski
Michelle Margold
Fatme Ismail
Roland Schroers
Alexander Baraniskin
Hendrik Pels
Peter Martus
Uwe Schlegel
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Lymphoma
Rituximab
Methotrexate
Methotrexate
Rituximab
Cytostatic Therapy
Published in: Neurological Research and Practice / Issue 1/2019
Electronic ISSN: 2524-3489
DOI: https://doi.org/10.1186/s42466-019-0024-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

HDMTX-based induction therapy followed by consolidation with conventional systemic chemotherapy and intraventricular therapy (modified Bonn protocol) in primary CNS lymphoma: a monocentric retrospective analysis

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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