CNS lymphoma

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 Seema Nagpal, MD
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 Tarsheen Sethi, MD, MSCI
Yale University
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41 regimens on this page
59 variants on this page


Guidelines

BSH

EANO

ESH

ESMO

GEL/TAMO

NCCN

CNS prophylaxis, systemic therapy

High-dose Cytarabine monotherapy (HiDAC)

HiDAC: High Dose Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence
Holte et al. 2013 (NLG LBC-04) 2004-2008 Phase 2

Note: IT treatment was not part of prophylaxis, except that Methotrexate (MTX) 15 mg IT was allowed at time of diagnostic LP.

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) by the following age-based criteria:
    • Younger than 60: 3000 mg/m2 IV twice per day on days 1 & 2 (total dose: 12,000 mg/m2)
    • 60 to 65 years: 2000 mg/m2 IV twice per day on days 1 & 2 (total dose: 8000 mg/m2)
    • Older than 65: not defined

21-day course

Subsequent treatment

References

  1. NLG LBC-04: Holte H, Leppä S, Björkholm M, Fluge O, Jyrkkiö S, Delabie J, Sundström C, Karjalainen-Lindsberg ML, Erlanson M, Kolstad A, Fosså A, Ostenstad B, Löfvenberg E, Nordström M, Janes R, Pedersen LM, Anderson H, Jerkeman M, Eriksson M; Nordic Lymphoma Group. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol. 2013 May;24(5):1385-92. Epub 2012 Dec 17. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry

Methotrexate monotherapy

Regimen

Study Dates of enrollment Evidence
Holte et al. 2013 (NLG LBC-04) 2004-2008 Phase 2

Note: IT treatment was not part of prophylaxis, except that Methotrexate (MTX) 15 mg IT was allowed at time of diagnostic LP.

Preceding treatment

Chemotherapy

Supportive therapy

One course

References

  1. NLG LBC-04: Holte H, Leppä S, Björkholm M, Fluge O, Jyrkkiö S, Delabie J, Sundström C, Karjalainen-Lindsberg ML, Erlanson M, Kolstad A, Fosså A, Ostenstad B, Löfvenberg E, Nordström M, Janes R, Pedersen LM, Anderson H, Jerkeman M, Eriksson M; Nordic Lymphoma Group. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol. 2013 May;24(5):1385-92. Epub 2012 Dec 17. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry

CNS treatment, local therapy

IT Cytarabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Glantz et al. 1999 1994-1998 Phase 3 (C) IT liposomal cytarabine Inferior ORR

CNS therapy, treatment

4-week course

Subsequent treatment

  • Glantz et al. 1999, responders: Further therapy was given to responders; see text for details

References

  1. Glantz MJ, LaFollette S, Jaeckle KA, Shapiro W, Swinnen L, Rozental JR, Phuphanich S, Rogers LR, Gutheil JC, Batchelor T, Lyter D, Chamberlain M, Maria BL, Schiffer C, Bashir R, Thomas D, Cowens W, Howell SB. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol. 1999 Oct;17(10):3110-6. link to original article contains dosing details in manuscript PubMed

IT Cytarabine liposomal monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Glantz et al. 1999 1994-1998 Phase 3 (E-RT-switch-ic) IT cytarabine Superior ORR

CNS therapy, treatment

14-day cycle for 2 cycles

Subsequent treatment

  • Glantz et al. 1999, responders: Further therapy was given to responders; see text for details

References

  1. Glantz MJ, LaFollette S, Jaeckle KA, Shapiro W, Swinnen L, Rozental JR, Phuphanich S, Rogers LR, Gutheil JC, Batchelor T, Lyter D, Chamberlain M, Maria BL, Schiffer C, Bashir R, Thomas D, Cowens W, Howell SB. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol. 1999 Oct;17(10):3110-6. link to original article contains dosing details in manuscript PubMed

Upfront therapy, randomized data

Cytarabine & Methotrexate (CYM)

CYM: CYtarabine & Methotrexate

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ferreri et al. 2009 (IELSG20) 2004-2007 Randomized Phase 2, >20 per arm (E-esc) High-dose MTX Seems to have superior CR rate
Ferreri et al. 2016 (IELSG32) 2010-2014 Randomized Phase 2 (C) 1. Cytarabine, Methotrexate, Rituximab Did not meet primary endpoint of CR rate
2. MATRix Inferior CR rate

Chemotherapy

  • Cytarabine (Ara-C) 2000 mg/m2 IV over 60 minutes every 12 hours on days 2 & 3
  • Methotrexate (MTX) 500 mg/m2 IV over 15 minutes, then 3000 mg/m2 IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m2)

Supportive therapy

  • As described in Ferreri et al. 2016:
  • Levoleucovorin (Fusilev) 15 mg/m2 IV every 6 hours for 12 doses, beginning 24 hours after the start of methotrexate
    • Modifications if MTX level is high 48 hours after the end of the infusion; see paper for details

21-day cycle for 4 cycles

Subsequent treatment

References

  1. IELSG20: Ferreri AJ, 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; International Extranodal Lymphoma Study Group. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009 Oct 31;374(9700):1512-20. Epub 2009 Sep 18. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
  2. IELSG32: Ferreri AJ, 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; International Extranodal Lymphoma Study Group. 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. 2016 May;3(5):e217-27. Epub 2016 Apr 6. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry

Cytarabine, Methotrexate, Rituximab

R-HD-MTX/ARA-C: Rituximab, High-Dose MethoTreXate, ARA-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ferreri et al. 2015 (SCNSL1) 2006-2013 Phase 2
Ferreri et al. 2016 (IELSG32) 2010-2014 Randomized Phase 2 (E-esc) 1. CYM Did not meet primary endpoint of CR rate
2. MATRix Seems to have inferior CR rate

Note: SCNSL1 was intended for secondary CNS lymphoma, whereas IELSG32 was intended for primary CNS lymphoma.

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 2000 mg/m2 IV over 60 minutes every 12 hours on days 2 & 3
  • Methotrexate (MTX) 500 mg/m2 IV over 15 minutes, then 3000 mg/m2 IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m2)

Targeted therapy

CNS therapy

Supportive therapy

  • Levoleucovorin (Fusilev) 15 mg/m2 IV every 6 hours for 12 doses, beginning 24 hours after the start of methotrexate
    • Modifications if MTX level is high 48 hours after the end of the infusion; see paper for details

21-day cycle for 4 cycles

Subsequent treatment

References

  1. SCNSL1: Ferreri AJ, Donadoni G, Cabras MG, Patti C, Mian M, Zambello R, Tarella C, Di Nicola M, D'Arco AM, Doa G, Bruno-Ventre M, Assanelli A, Foppoli M, Citterio G, Fanni A, Mulè A, Caligaris-Cappio F, Ciceri F. High doses of antimetabolites followed by high-dose sequential chemoimmunotherapy and autologous stem-cell transplantation in patients with systemic B-cell lymphoma and secondary CNS involvement: Final results of a multicenter phase II trial. J Clin Oncol. 2015 Nov 20;33(33):3903-10. Epub 2015 Aug 17. link to original article PubMed Clinical Trial Registry
  2. IELSG32: Ferreri AJ, 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; International Extranodal Lymphoma Study Group. 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. 2016 May;3(5):e217-27. Epub 2016 Apr 6. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry

MATRix

MATRix: Methotrexate, Ara-C (Cytarabine), Thiotepa, Rituximab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ferreri et al. 2016 (IELSG32) 2010-2014 Randomized Phase 2 (E-esc) 1. CYM Superior CR rate
2. Cytarabine, Methotrexate, Rituximab Seems to have superior CR rate

Chemotherapy

Targeted therapy

Supportive therapy

  • Levoleucovorin (Fusilev) 15 mg/m2 IV every 6 hours for 12 doses, beginning 24 hours after the start of methotrexate
    • Modifications if MTX level is high 48 hours after the end of the infusion; see paper for details

21-day cycle for 4 cycles

Subsequent treatment

References

  1. IELSG32: Ferreri AJ, 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; International Extranodal Lymphoma Study Group. 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. 2016 May;3(5):e217-27. Epub 2016 Apr 6. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry

MBVP

MBVP: Methotrexate, BCNU (Carmustine), Vumon (Teniposide), Prednisone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bromberg et al. 2019 (HOVON 105/ALLG NHL 24) 2010-2016 Phase 3 (C) R-MBVP Did not meet primary endpoint of EFS

Chemotherapy

Glucocorticoid therapy

28-day cycle for 2 cycles

Subsequent treatment

  • HOVON 105/ALLG NHL 24, responders 60 and older: HiDAC consolidation
  • HOVON 105/ALLG NHL 24, responders younger than 60: HiDAC consolidation, then low-dose WBRT

References

  1. HOVON 105/ALLG NHL 24: Bromberg JEC, Issa S, Bakunina K, Minnema MC, Seute T, Durian M, Cull G, Schouten HC, Stevens WBC, Zijlstra JM, Baars JW, Nijland M, Mason KD, Beeker A, van den Bent MJ, Beijert M, Gonzales M, de Jong D, Doorduijn JK; HOVON; ALLG. Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2019 Feb;20(2):216-228. Epub 2019 Jan 7. link to original article contains dosing details in abstract PubMed ACTRN12610000908033
    1. HRQoL analysis: van der Meulen M, Bakunina K, Nijland M, Minnema MC, Cull G, Stevens WBC, Baars JW, Mason KD, Beeker A, Beijert M, Taphoorn MJB, van den Bent MJ, Issa S, Doorduijn JK, Bromberg JEC, Dirven L. Health-related quality of life after chemotherapy with or without rituximab in primary central nervous system lymphoma patients: results from a randomised phase III study. Ann Oncol. 2020 Aug;31(8):1046-1055. Epub 2020 May 3. link to original article PubMed

Methotrexate monotherapy

Regimen variant #1, 3500 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ferreri et al. 2009 (IELSG20) 2004-2007 Randomized Phase 2 (C) CYM; high-dose Seems to have inferior CR rate

Chemotherapy

  • Methotrexate (MTX) 500 mg/m2 IV over 15 minutes, then 3000 mg/m2 IV over 3 hours once on day 1 (total dose per cycle: 3500 mg/m2)

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #2, 4000 mg/m2

Study Dates of enrollment Evidence
Thiel et al. 2010 (G-PCNSL-SG-1) 2000-2009 Non-randomized part of RCT

Note: All patients received the same induction regimen; however, the induction regimen was changed after 2006 to high-dose MTX & ifosfamide.

Chemotherapy

14-day cycle for 6 cycles

Subsequent treatment


Regimen variant #3, 8000 mg/m2

Study Dates of enrollment Evidence
Herrlinger et al. 2005 (NOA-03) 1998-05 to 2000-03 Phase 2

Note: This was considered a negative trial by the authors and is included here for historical purposes.

Chemotherapy

14-day cycle for 6 cycles

Subsequent treatment

  • NOA-03, patients intolerant of MTX or not achieving CR after 6 cycles: Salvage whole-brain irradiation versus PCV; see article for details


Regimen variant #4, 8000 mg/m2 with renal adjustment

Study Dates of enrollment Evidence
Batchelor et al. 2003 (NABTT 96-07) 1998-1999 Phase 2

Chemotherapy

  • Methotrexate (MTX) 8000 mg/m2 IV over 4 hours once on day 1
    • The full dose of 8000 mg/m2 was only given if CrCl was at least 100 mL/min/1.73m2. For CrCl less than 100 mL/min/1.73m2, the dose was reduced by the percentage reduction below 100. For example, a CrCl of 50 mL/min/1.73m2 would mandate a 50% dose reduction.

14-day cycle until CR or a maximum of 8 cycles

Subsequent treatment


Regimen variant #5, 20-day course

Study Dates of enrollment Evidence
Montemurro et al. 2007 (OSHO-53) 1999-2004 Phase 2

Chemotherapy

  • Methotrexate (MTX) by the following age-based criteria:
    • 60 or younger: 8000 mg/m2 IV over 4 hours once per day on days 1 & 10
    • Older than 60: 6000 mg/m2 IV over 4 hours once per day on days 1 & 10

20-day course

Subsequent treatment

References

  1. NABTT 96-07: Batchelor T, Carson K, O'Neill A, Grossman SA, Alavi J, New P, Hochberg F, Priet R. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003 Mar 15;21(6):1044-9. link to original article contains dosing details in manuscript PubMed
  2. NOA-03: Herrlinger U, Küker W, Uhl M, Blaicher HP, Karnath HO, Kanz L, Bamberg M, Weller M; Neuro-Oncology Working Group of the German Society. NOA-03 trial of high-dose methotrexate in primary central nervous system lymphoma: final report. Ann Neurol. 2005 Jun;57(6):843-7. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
  3. OSHO-53: Montemurro M, Kiefer T, Schüler F, Al-Ali HK, Wolf HH, Herbst R, Haas A, Helke K, Theilig A, Lotze C, Hirt C, Niederwieser D, Schwenke M, Krüger WH, Dölken G. Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation and response-adapted whole-brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hamato-Onkologie OSHO-53 phase II study. Ann Oncol. 2007 Apr;18(4):665-71. Epub 2006 Dec 21. link to original article contains dosing details in manuscript PubMed
  4. IELSG20: Ferreri AJ, 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; International Extranodal Lymphoma Study Group. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009 Oct 31;374(9700):1512-20. Epub 2009 Sep 18. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
  5. G-PCNSL-SG-1: Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithäuser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nägele T, Pietsch T, Bamberg M, Weller M. 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 Oncol. 2010 Nov;11(11):1036-47. Epub 2010 Oct 20. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Update: Korfel A, Thiel E, Martus P, Möhle R, Griesinger F, Rauch M, Röth A, Hertenstein B, Fischer T, Hundsberger T, Mergenthaler HG, Junghanß C, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Roth P, Bamberg M, Pietsch T, Weller M. Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology. 2015 Mar 24;84(12):1242-8. Epub 2015 Feb 25. link to original article PubMed

Upfront therapy, non-randomized or retrospective data

Lomustine, Methotrexate, Procarbazine

MCP: Methotrexate, CCNU (Lomustine), Procarbazine

Regimen

Study Dates of enrollment Evidence
Illerhaus et al. 2008a 1998-2004 Phase 2

Chemotherapy

Supportive therapy

  • Folinic acid (Leucovorin) 15 mg/m2 (route not specified) every 6 hours beginning 24 hours after start of methotrexate infusion, continued until clearance

45-day cycle for up to 3 cycles

References

  1. Illerhaus G, Marks R, Müller F, Ihorst G, Feuerhake F, Deckert M, Ostertag C, Finke J. High-dose methotrexate combined with procarbazine and CCNU for primary CNS lymphoma in the elderly: results of a prospective pilot and phase II study. Ann Oncol. 2009 Feb;20(2):319-25. Epub 2008 Oct 26. link to original article contains dosing details in manuscript PubMed

Lomustine, Methotrexate, Procarbazine, Methylprednisolone

Regimen

Study Dates of enrollment Evidence
Hoang-Xuan et al. 2003 (EORTC 26952) 1997-1999 Phase 2

Note: This was the first prospective phase 2 trial evaluating chemotherapy alone in older patients with PCNSL.

Chemotherapy

Glucocorticoid therapy

CNS therapy

Supportive therapy

  • Folinic acid (Leucovorin) 25 mg PO every 6 hours for 3 days, initiated 24 hours after IV methotrexate administrations, and 10 mg PO every 6 hours for 2 days after IT methotrexate administrations

45-day course

Subsequent treatment

References

  1. EORTC 26952: Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY, Baron B; EORTC Brain Tumor Group. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organisation for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003 Jul 15;21(14):2726-31. link to original article contains dosing details in manuscript PubMed

Methotrexate, then Cytarabine

Protocol

Study Dates of enrollment Evidence
Abrey et al. 2003 NR Phase 2

Note: Patients proceed to part two 72 hours after 5th dose of MTX or once the 5th dose MTX level has cleared.

Chemotherapy, part 1

  • Methotrexate (MTX) as follows:
    • Cycles 1 to 5: 3500 mg/m2 (maximum dose of 7000 mg) IV over 2 hours once on day 1

Supportive therapy, part 1

  • Folinic acid (Leucovorin) as follows:
    • Cycles 1 to 5: 25 mg PO every 6 hours, beginning 24 hours after start of methotrexate, continued for 12 doses or until serum MTX level less than 100 nmol/L

Chemotherapy, part 2

Supportive therapy, part 2

  • Filgrastim (Neupogen) as follows:
    • Cycle 6: 10 mcg/kg SC once per day, starting on day 4 and continued until stem cell collection complete
    • Cycle 7: 5 mcg/kg SC once per day continued for 2 weeks or until ANC greater than 3000/μL

14-day cycle for 5 cycles, then 1-month cycle for 2 cycles (stem cell collection took place between cycles 6 & 7)

Subsequent treatment

References

  1. Abrey LE, Moskowitz CH, Mason WP, Crump M, Stewart D, Forsyth P, Paleologos N, Correa DD, Anderson ND, Caron D, Zelenetz A, Nimer SD, DeAngelis LM. Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis. J Clin Oncol. 2003 Nov 15;21(22):4151-6. link to original article contains dosing details in manuscript PubMed

Methotrexate, then Cytarabine & Thiotepa

Protocol variant #1

Study Dates of enrollment Evidence
Illerhaus et al. 2006 1998-2003 Phase 2

Chemotherapy, part 1

Supportive therapy

28-day course Patients with CR, PR, or SD "with clinical improvement" after the 2nd dose of MTX proceeded to:

Chemotherapy, stem cell mobilization

20-day course

Subsequent treatment


Protocol variant #2

Study Dates of enrollment Evidence
Illerhaus et al. 2008 2003-2006 Pilot, <20 patients

Chemotherapy, part 1

Supportive therapy

10-day cycle for 2 to 4 cycles, followed by:

Chemotherapy, part 2

21-day cycle for 2 cycles (Stem cells are mobilized and collected after the first cycle)

Subsequent treatment

References

  1. Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C, Derigs G, Frickhofen N, Feuerhake F, Volk B, Finke J. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol. 2006 Aug 20;24(24):3865-70. Epub 2006 Jul 24. link to original article contains dosing details in manuscript PubMed
    1. Update: Kasenda B, Schorb E, Fritsch K, Finke J, Illerhaus G. Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. Ann Oncol. 2012 Oct;23(10):2670-5. Epub 2012 Apr 3. Erratum in: Ann Oncol. 2015 Mar;26(3):608-11. link to original article PubMed
  2. Illerhaus G, Müller F, Feuerhake F, Schäfer AO, Ostertag C, Finke J. High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system. Haematologica. 2008 Jan;93(1):147-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Kasenda B, Schorb E, Fritsch K, Finke J, Illerhaus G. Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. Ann Oncol. 2012 Oct;23(10):2670-5. Epub 2012 Apr 3. Erratum in: Ann Oncol. 2015 Mar;26(3):608-11. link to original article PubMed

Methotrexate & Rituximab

Regimen

Study Dates of enrollment Evidence
Chamberlain et al. 2010 2000-2007 Phase 2

Note: the bounds as described in the paper do not account for the situation where CrCl = 60 mL/min/1.73m2.

Chemotherapy

  • Methotrexate (MTX) by the following laboratory-based criteria:
    • CrCl greater than 60 mL/min/1.73m2: 8000 mg/m2 IV over 6 hours once on day 1
    • CrCl less than 60 mL/min/1.73m2: 4000 mg/m2 IV over 6 hours once on day 1

Targeted therapy

14-day cycle for 4 to 6 cycles

Subsequent treatment

References

  1. Chamberlain MC, Johnston SK. High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma. Neuro Oncol. 2010 Jul;12(7):736-44. link to original article contains dosing details in manuscript link to PMC article PubMed

MPV

MPV: Methotrexate, Procarbazine, Vincristine

Regimen

Study Dates of enrollment Evidence
Abrey et al. 2000 1992-1998 Non-randomized
DeAngelis et al. 2002 (RTOG 93-10) 1993-NR Phase 2

Chemotherapy

CNS therapy

Supportive therapy

  • Folinic acid (Leucovorin) as follows:
    • Days 2 to 4: 20 mg PO every 6 hours for 12 doses, beginning 24 hours after IV methotrexate administration
    • Days 8 & 9: 10 mg PO every 6 hours for 8 doses, beginning on the evening of IT methotrexate administration
  • Dexamethasone (Decadron) as follows:
    • Cycle 1: 16 mg PO once per day on days 1 to 7, then 12 mg PO once per day on days 8 to 14
    • Cycle 2: 8 mg PO once per day on days 1 to 7, then 6 mg PO once per day on days 8 to 14
    • Cycle 3: 4 mg PO once per day on days 1 to 7, then 2 mg PO once per day on days 8 to 14

14-day cycle for 5 cycles

Subsequent treatment

References

  1. Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000 Sep;18(17):3144-50. link to original article contains dosing details in manuscript PubMed
    1. Update: Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. 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. 2006 Oct 1;24(28):4570-4. link to original article PubMed
  2. RTOG 93-10: DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group; SWOG. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002 Dec 15;20(24):4643-8. link to original article contains dosing details in manuscript PubMed

MT-R

MT-R: Methotrexate, Temozolomide, Rituximab

Regimen variant #1

Study Dates of enrollment Evidence
Glass et al. 2016 (RTOG 0227) NR Phase 1/2

Note: This is the MTD of this phase 1/2 trial; it appears that only a single dose of rituximab was given.

Chemotherapy

Targeted therapy

Supportive therapy

  • Folinic acid (Leucovorin) 25 mg IV every 6 hours, starting 24 hours after methotrexate, continue until MTX level less than 100 nmol/L

14-day cycle for 5 cycles

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence
Rubenstein et al. 2013 (CALGB 50202) 2004-2009 Phase 2

Chemotherapy

Targeted therapy

  • Rituximab (Rituxan) by the following histology-specific criteria:
    • B-cell PCNSL, Cycles 1 to 6: 375 mg/m2 IV once on day 3

Supportive therapy

14-day cycle for 7 cycles

Subsequent treatment

References

  1. CALGB 50202: Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD, Kaplan LD. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013 Sep 1;31(25):3061-8. Epub 2013 Apr 8 link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
  2. RTOG 0227: Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, Werner-Wasik M, Fisher BJ, Liepman MK, Augspurger M, Bokstein F, Bovi JA, Solhjem MC, Mehta MP. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG Oncology RTOG 0227. J Clin Oncol. 2016 May 10;34(14):1620-5. Epub 2016 Mar 28. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry

MVBP

MVBP: Methotrexate, VP16 (Etoposide), BCNU (Carmustine), MethylPrednisolone

Regimen

Study Dates of enrollment Evidence
Colombat et al. 2006 1999-2001 Phase 2

Chemotherapy

Glucocorticoid therapy

Supportive therapy

2 courses (length not specified), separated by 21 days

CNS therapy

6 doses total (timing not specified)

Subsequent treatment

References

  1. Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, Berthou C, Bay JO, Delepine R, Desablens B, Camilleri-Broët S, Linassier C, Lamy T; GOELAMS. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant. 2006 Sep;38(6):417-20. link to original article contains dosing details in manuscript PubMed

Nordic Regimen, older patients

Regimen

Study Dates of enrollment Evidence
Pulczynski et al. 2015 (NLGPCNSL) 2007-2010 Phase 2

Eligibility criteria

  • Age 66-75 years

Targeted therapy, A cycles

Chemotherapy, A cycles

Glucocorticoid therapy, A cycles

CNS therapy, A cycles

Chemotherapy, B cycles

Glucocorticoid therapy, B cycles

CNS therapy, B cycles

Glucocorticoid therapy, C cycles

Chemotherapy, C cycles

21-day cycle for 6 cycles (A1, then B1, then C1, then A2, then B2, then C2)

Subsequent treatment

References

  1. NLGPCNSL: Pulczynski EJ, Kuittinen O, Erlanson M, Hagberg H, Fosså A, Eriksson M, Nordstrøm M, Østenstad B, Fluge Ø, Leppä S, Fiirgaard B, Bersvendsen H, Fagerli UM; Nordic Lymphoma Group. 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. 2015 Apr;100(4):534-40. Epub 2014 Dec 5. link to original article contains dosing details in manuscript in supplement link to PMC article PubMed Clinical Trial Registry

Nordic Regimen, younger patients

Protocol

Study Dates of enrollment Evidence
Pulczynski et al. 2015 (NLGPCNSL) 2007-2010 Phase 2

Eligibility criteria

  • Age 18 to 65 years

Targeted therapy, A cycles

Chemotherapy, A cycles

Glucocorticoid therapy, A cycles

CNS therapy, A cycles

Chemotherapy, B cycles

Glucocorticoid therapy, B cycles

CNS therapy, B cycles

Glucocorticoid therapy, C cycles

Chemotherapy, C cycles

21-day cycle for 6 cycles (A1, then B1, then C1, then A2, then B2, then C2)

References

  1. NLGPCNSL: Pulczynski EJ, Kuittinen O, Erlanson M, Hagberg H, Fosså A, Eriksson M, Nordstrøm M, Østenstad B, Fluge Ø, Leppä S, Fiirgaard B, Bersvendsen H, Fagerli UM; Nordic Lymphoma Group. 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. 2015 Apr;100(4):534-40. Epub 2014 Dec 5. link to original article contains dosing details in manuscript in supplement link to PMC article PubMed Clinical Trial Registry

R-MCP (CCNU)

R-MCP: Rituximab, Methotrexate, CCNU (Lomustine), Procarbazine

Regimen

Study Dates of enrollment Evidence
Fritsch et al. 2011 2005-2009 Phase 2

Note: this regimen should not be confused with the other R-MCP (rituximab, mitoxantrone, cyclophosphamide, prednisone) used in indolent lymphomas.

Targeted therapy

Chemotherapy

Supportive therapy

  • Folinic acid (Leucovorin) (dose/route not specified) every 6 hours beginning 24 hours after start of MTX infusion, continued for 3 days or until clearance

43-day cycle for up to 3 cycles

References

  1. Fritsch K, Kasenda B, Hader C, Nikkhah G, Prinz M, Haug V, Haug S, Ihorst G, Finke J, Illerhaus G. Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly. Ann Oncol. 2011 Sep;22(9):2080-5. Epub 2011 Feb 8. link to original article contains dosing details in manuscript PubMed

R-MP

R-MP: Rituximab, Methotrexate, Procarbazine

Regimen

Study Dates of enrollment Evidence
Fritsch et al. 2016 (PRIMAIN) 2009-2013 Phase 2

Targeted therapy

  • Rituximab (Rituxan) as follows:
    • Cycle 1: 375 mg/m2 IV over 90 minutes once per day on days -6, 1, 15, 29
    • Cycles 2 & 3: 375 mg/m2 IV over 90 minutes once per day on days 1, 15, 29

Chemotherapy

42-day cycle for 3 cycles

Subsequent treatment

References

  1. PRIMAIN: 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. High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 2017 Apr;31(4):846-852. Epub 2016 Nov 15. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry

R-MPV

R-MPV: Rituximab, Methotrexate, Procarbazine, Vincristine

Regimen

Study Dates of enrollment Evidence
Shah et al. 2007 (MSK 01-146) 2002-2005 Phase 2
Omuro et al. 2015 (MSK 04-129) 2005-2011 Phase 2

Targeted therapy

Chemotherapy

CNS therapy

  • (only described in MSK 01-146)
  • Methotrexate (MTX) 12 mg IT (via Ommaya) once sometime between day 5 and 12 (for patients with positive CSF cytology)

Supportive therapy

  • Folinic acid (Leucovorin) 20 to 25 mg every 6 hours for at least 72 hours or until serum MTX level less than 100 nmol/L, beginning 24 hours after IV methotrexate administration

14-day cycle for 5 to 7 cycles

Subsequent treatment

References

  1. MSK 01-146: Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D, LaRocca R, Grant B, DeAngelis LM, Abrey LE. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007 Oct 20;25(30):4730-5. Erratum in: J Clin Oncol. 2008 Jan 10;26(2):340. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Update: Morris PG, Correa DD, Yahalom J, Raizer JJ, Schiff D, Grant B, Grimm S, Lai RK, Reiner AS, Panageas K, Karimi S, Curry R, Shah G, Abrey LE, DeAngelis LM, Omuro A. 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. J Clin Oncol. 2013 Nov 1;31(31):3971-9. Epub 2013 Oct 7. link to original article link to PMC article PubMed
  2. MSK 04-129: Omuro A, Correa DD, DeAngelis LM, Moskowitz CH, Matasar MJ, Kaley TJ, Gavrilovic IT, Nolan C, Pentsova E, Grommes CC, Panageas KS, Baser RE, Faivre G, Abrey LE, Sauter CS. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood. 2015 Feb 26;125(9):1403-10. Epub 2015 Jan 7. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry

Consolidation after upfront therapy

BCNU/TT, then auto HSCT

BCNU/TT: BCNU (Carmustine), ThioTepa

Regimen variant #1

Study Dates of enrollment Evidence
Illerhaus et al. 2006 1998-2003 Phase 2

Note that the day count starts from the very beginning of treatment.

Preceding treatment

Chemotherapy

Supportive therapy

  • Granulocyte colony-stimulating factor starting on day 61, continued until WBC greater than 1 x 109/L for 3 days
  • "Standard supportive measures were taken according to institutional guidelines."

Stem cells re-infused on day 56

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence
Illerhaus et al. 2008 2003-2006 Pilot, <20 patients

Preceding treatment

Chemotherapy

Stem cells re-infused on day 7

References

  1. Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C, Derigs G, Frickhofen N, Feuerhake F, Volk B, Finke J. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol. 2006 Aug 20;24(24):3865-70. Epub 2006 Jul 24. link to original article contains dosing details in manuscript PubMed
    1. Update: Kasenda B, Schorb E, Fritsch K, Finke J, Illerhaus G. Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. Ann Oncol. 2012 Oct;23(10):2670-5. Epub 2012 Apr 3. Erratum in: Ann Oncol. 2015 Mar;26(3):608-11. link to original article PubMed
  2. Illerhaus G, Müller F, Feuerhake F, Schäfer AO, Ostertag C, Finke J. High-dose chemotherapy and autologous stem-cell transplantation without consolidating radiotherapy as first-line treatment for primary lymphoma of the central nervous system. Haematologica. 2008 Jan;93(1):147-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Kasenda B, Schorb E, Fritsch K, Finke J, Illerhaus G. Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. Ann Oncol. 2012 Oct;23(10):2670-5. Epub 2012 Apr 3. Erratum in: Ann Oncol. 2015 Mar;26(3):608-11. link to original article PubMed
  3. IELSG32: Ferreri AJ, 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; International Extranodal Lymphoma Study Group. 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. 2016 May;3(5):e217-27. Epub 2016 Apr 6. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Update: Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, 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 KM, Pukrop T, Sønderskov Gørløv J, Balzarotti M, Hess G, Keller U, Stilgenbauer S, Panse J, Tucci A, Orsucci L, Pisani F, Levis A, Krause SW, Schmoll HJ, Hertenstein B, Rummel M, Smith J, Pfreundschuh M, Cabras G, Angrilli F, Ponzoni M, Deckert M, Politi LS, Finke J, Reni M, Cavalli F, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group. 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 Haematol. 2017 Nov;4(11):e510-e523. Epub 2017 Oct 17. link to original article PubMed

BEAM, then auto HSCT

BEAM: BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Regimen variant #1

Study Dates of enrollment Evidence
Colombat et al. 2006 1999-2001 Phase 2

Preceding treatment

Chemotherapy

Day of transplant is not specified

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence
Abrey et al. 2003 NR Phase 2

Preceding treatment

Chemotherapy

Supportive therapy

  • Filgrastim (Neupogen) 5 mcg/kg SC every 12 hours, starting on day +1 and continued until ANC greater than 1000/μL for 3 days or greater than 10,000/μL for 1 day

Stem cells reinfused on day 0

References

  1. Abrey LE, Moskowitz CH, Mason WP, Crump M, Stewart D, Forsyth P, Paleologos N, Correa DD, Anderson ND, Caron D, Zelenetz A, Nimer SD, DeAngelis LM. Intensive methotrexate and cytarabine followed by high-dose chemotherapy with autologous stem-cell rescue in patients with newly diagnosed primary CNS lymphoma: an intent-to-treat analysis. J Clin Oncol. 2003 Nov 15;21(22):4151-6. link to original article contains dosing details in manuscript PubMed
  2. Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, Berthou C, Bay JO, Delepine R, Desablens B, Camilleri-Broët S, Linassier C, Lamy T; GOELAMS. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant. 2006 Sep;38(6):417-20. link to original article contains dosing details in manuscript PubMed

Bu/TT, then auto HSCT

Bu/TT: Busulfan, ThioTepa

Regimen

Study Dates of enrollment Evidence
Montemurro et al. 2007 (OSHO-53) 1999-2004 Phase 2

Preceding treatment

Chemotherapy

Stem cell re-infusion occurs on day 0

References

  1. OSHO-53: Montemurro M, Kiefer T, Schüler F, Al-Ali HK, Wolf HH, Herbst R, Haas A, Helke K, Theilig A, Lotze C, Hirt C, Niederwieser D, Schwenke M, Krüger WH, Dölken G. Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation and response-adapted whole-brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hamato-Onkologie OSHO-53 phase II study. Ann Oncol. 2007 Apr;18(4):665-71. Epub 2006 Dec 21. link to original article contains dosing details in manuscript PubMed

Bu/TT/Cy, then auto HSCT

Bu/TT/Cy: Busulfan, ThioTepa, Cyclophosphamide
TBC: Thiotepa, Busulfan, Cyclophosphamide

Regimen

Study Dates of enrollment Evidence
Omuro et al. 2015 (MSK 04-129) 2005-2011 Phase 2

Preceding treatment

Chemotherapy

Stem cell re-infusion occurs on day 0

References

  1. MSK 04-129: Omuro A, Correa DD, DeAngelis LM, Moskowitz CH, Matasar MJ, Kaley TJ, Gavrilovic IT, Nolan C, Pentsova E, Grommes CC, Panageas KS, Baser RE, Faivre G, Abrey LE, Sauter CS. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood. 2015 Feb 26;125(9):1403-10. Epub 2015 Jan 7. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry

High-dose Cytarabine monotherapy (HiDAC)

HiDAC: High Dose Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence
Abrey et al. 2000 1992-1998 Non-randomized
DeAngelis et al. 2002 (RTOG 93-10) 1993-NR Phase 2

Time interval of cycles is not explicitly described and is derived from Table 1 in DeAngelis et al. 2002.

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

References

  1. Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000 Sep;18(17):3144-50. link to original article contains dosing details in manuscript PubMed
    1. Update: Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. 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. 2006 Oct 1;24(28):4570-4. link to original article PubMed
  2. RTOG 93-10: DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group; SWOG. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002 Dec 15;20(24):4643-8. link to original article contains dosing details in manuscript PubMed

CYVE

CYVE: CYtarabine & VEpesid (Etoposide)
EA: Etoposide & Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence
Rubenstein et al. 2013 (CALGB 50202) 2004-2009 Phase 2

Preceding treatment

Chemotherapy

  • Cytarabine (Ara-C) 2000 mg/m2 IV over 2 hours every 12 hours on days 1 to 4 (total dose: 16,000 mg/m2)
  • Etoposide (Vepesid) 10 mg/kg/day IV continuous infusion over 96 hours, started on day 1 (total dose: 40 mg/kg)

4-day course

References

  1. CALGB 50202: Rubenstein JL, Hsi ED, Johnson JL, Jung SH, Nakashima MO, Grant B, Cheson BD, Kaplan LD. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol. 2013 Sep 1;31(25):3061-8. Epub 2013 Apr 8 link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry

Lomustine, Methotrexate, Procarbazine

Regimen

Study Dates of enrollment Evidence
Hoang-Xuan et al. 2003 (EORTC 26952) 1997-1999 Phase 2

Preceding treatment

Chemotherapy

CNS therapy

Supportive therapy

42-day cycle for 5 cycles

References

  1. Hoang-Xuan K, Taillandier L, Chinot O, Soubeyran P, Bogdhan U, Hildebrand J, Frenay M, De Beule N, Delattre JY, Baron B; EORTC Brain Tumor Group. Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organisation for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003 Jul 15;21(14):2726-31. link to original article contains dosing details in manuscript PubMed

Methotrexate monotherapy

Regimen variant #1

Study Dates of enrollment Evidence
Chamberlain et al. 2010 2000-2007 Phase 2

Note: the bounds as described in the paper do not account for the situation where CrCl = 60 mL/min/1.73m2.

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) by the following laboratory-based criteria:
    • CrCl greater than 60 mL/min/1.73m2: 8000 mg/m2 IV over 6 hours once on day 1
    • CrCl less than 60 mL/min/1.73m2: 4000 mg/m2 IV over 6 hours once on day 1

28-day cycle for 4 cycles


Regimen variant #2

Study Dates of enrollment Evidence
Batchelor et al. 2003 (NABTT 96-07) 1998-1999 Phase 2

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 8000 mg/m2 IV over 4 hours once on day 1
    • The full dose of 8000 mg/m2 was only given if CrCl was at least 100 mL/min/1.73m2. For CrCl less than 100 mL/min/1.73m2, the dose was reduced by the percentage reduction below 100. For example, a CrCl of 50 mL/min/1.73m2 would mandate a 50% dose reduction.

28-day cycle for 11 cycles

References

  1. Batchelor T, Carson K, O'Neill A, Grossman SA, Alavi J, New P, Hochberg F, Priet R. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003 Mar 15;21(6):1044-9. link to original article contains dosing details in manuscript PubMed
  2. Chamberlain MC, Johnston SK. High-dose methotrexate and rituximab with deferred radiotherapy for newly diagnosed primary B-cell CNS lymphoma. Neuro Oncol. 2010 Jul;12(7):736-44. link to original article contains dosing details in manuscript link to PMC article PubMed

Procarbazine monotherapy

Regimen

Study Dates of enrollment Evidence
Fritsch et al. 2016 (PRIMAIN) 2009-2013 Phase 2

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

  1. PRIMAIN: 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. High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study). Leukemia. 2017 Apr;31(4):846-852. Epub 2016 Nov 15. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry

Temozolomide monotherapy

Regimen variant #1

Study Dates of enrollment Evidence
Glass et al. 2016 (RTOG 0227) NR Phase 1/2

Preceding treatment

Chemotherapy

  • Temozolomide (Temodar) as follows:
    • Week 14: 200 mg/m2 PO once per day for 5 days (150 mg/m2 allowed)
    • Weeks 18, 22, 26, 30, 34, 38, 42, 46, 50: 200 mg/m2 PO once per day for 5 days


Regimen variant #2

Study Dates of enrollment Evidence
Pulczynski et al. 2015 (NLGPCNSL) 2007-2010 Phase 2

Preceding treatment

Chemotherapy

28-day cycle for up to 13 cycles (1 year)

References

  1. NLGPCNSL: Pulczynski EJ, Kuittinen O, Erlanson M, Hagberg H, Fosså A, Eriksson M, Nordstrøm M, Østenstad B, Fluge Ø, Leppä S, Fiirgaard B, Bersvendsen H, Fagerli UM; Nordic Lymphoma Group. 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. 2015 Apr;100(4):534-40. Epub 2014 Dec 5. link to original article contains dosing details in supplement link to supplement link to PMC article PubMed Clinical Trial Registry
  2. RTOG 0227: Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, Werner-Wasik M, Fisher BJ, Liepman MK, Augspurger M, Bokstein F, Bovi JA, Solhjem MC, Mehta MP. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG Oncology RTOG 0227. J Clin Oncol. 2016 May 10;34(14):1620-5. Epub 2016 Mar 28. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry

Whole brain irradiation

WBRT: Whole-Brain Radiation Therapy

Regimen variant #1, 23.4 Gy

Study Dates of enrollment Evidence
Shah et al. 2007 (MSK 01-146) 2002-2005 Phase 2

Preceding treatment

  • R-MPV x 5 to 7 cycles, with complete response

Radiotherapy


Regimen variant #2, 30 Gy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colombat et al. 2006 1999-2001 Phase 2
Mishima et al. 2023 (JCOG1114C) 2014-09-20 to 2018-08-24 Phase 3 (C) Temozolomide & WBRT Might have superior OS
OS24: 86.8% vs 71.4%
(HR 0.46, 95% CI 0.20-1.05)

Preceding treatment

Radiotherapy


Regimen variant #3, 30 Gy + 10 Gy boost

Study Dates of enrollment Evidence
Colombat et al. 2006 1999-2001 Phase 2

Preceding treatment

Radiotherapy


Regimen variant #4, 36 Gy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Glass et al. 2016 (RTOG 0227) NR Phase 1/2
Ferreri et al. 2016 (IELSG32) 2010-2014 Randomized Phase 2 (C) BCNU/TT, then auto HSCT Did not meet primary endpoint of PFS241

1Reported efficacy for IELSG32 is based on the 2017 update.

Preceding treatment

Radiotherapy

  • Whole-brain irradiation to 36 Gy by the following study-specific criteria:
    • RTOG 0227: 1.2 Gy twice per day fractions on weeks 11 to 13
    • IELSG32: 1.80 Gy fractions

Subsequent treatment


Regimen variant #5, 36 Gy + 9 Gy boost

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ferreri et al. 2009 (IELSG20) 2004-2007 Non-randomized part of phase 2 RCT
Ferreri et al. 2016 (IELSG32) 2010-2014 Randomized Phase 2 (C) BCNU/TT, then auto HSCT Did not meet primary endpoint of PFS241

1Reported efficacy for IELSG32 is based on the 2017 update.

Preceding treatment

Radiotherapy


Regimen variant #6, 40 Gy + 9 Gy boost

Study Dates of enrollment Evidence
Ferreri et al. 2009 (IELSG20) 2004-2007 Non-randomized part of phase 2 RCT

Preceding treatment

Radiotherapy


Regimen variant #7, 45 Gy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Abrey et al. 2000 1992-1998 Non-randomized
DeAngelis et al. 2002 (RTOG 93-10) 1993-NR Phase 2
Illerhaus et al. 2006 1998-2003 Phase 2
Thiel et al. 2010 (G-PCNSL-SG-1) 2000-2009 Phase 3 (E-esc) No further treatment Inconclusive whether non-inferior OS
Shah et al. 2007 (MSK 01-146) 2002-2005 Phase 2

Note that the day count in Illerhaus et al. 2006 starts from the very beginning of treatment.

Preceding treatment

Radiotherapy

  • Whole-brain irradiation to 45 Gy by the following study-specific criteria:
    • Illerhaus et al. 2006: 1 Gy fractions, starting on day 90
    • G-PCNSL-SG-1: 1.5 Gy fractions
    • Abrey et al. 2000, RTOG 93-10, MSK 01-146: 1.80 Gy fractions

Subsequent treatment

  • Abrey et al. 2000 & RTOG 93-10: HiDAC consolidation


Regimen variant #8, 50 Gy

Study Dates of enrollment Evidence
Illerhaus et al. 2006 1998-2003 Phase 2

Note that the day count starts from the very beginning of treatment.

Preceding treatment

Radiotherapy

References

  1. Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000 Sep;18(17):3144-50. link to original article contains dosing details in manuscript PubMed
    1. Update: Gavrilovic IT, Hormigo A, Yahalom J, DeAngelis LM, Abrey LE. 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. 2006 Oct 1;24(28):4570-4. link to original article PubMed
  2. RTOG 93-10: DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group; SWOG. Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol. 2002 Dec 15;20(24):4643-8. link to original article contains dosing details in manuscript PubMed
  3. Illerhaus G, Marks R, Ihorst G, Guttenberger R, Ostertag C, Derigs G, Frickhofen N, Feuerhake F, Volk B, Finke J. High-dose chemotherapy with autologous stem-cell transplantation and hyperfractionated radiotherapy as first-line treatment of primary CNS lymphoma. J Clin Oncol. 2006 Aug 20;24(24):3865-70. Epub 2006 Jul 24. link to original article contains dosing details in manuscript PubMed
    1. Update: Kasenda B, Schorb E, Fritsch K, Finke J, Illerhaus G. Prognosis after high-dose chemotherapy followed by autologous stem-cell transplantation as first-line treatment in primary CNS lymphoma--a long-term follow-up study. Ann Oncol. 2012 Oct;23(10):2670-5. Epub 2012 Apr 3. Erratum in: Ann Oncol. 2015 Mar;26(3):608-11. link to original article PubMed
  4. Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, Berthou C, Bay JO, Delepine R, Desablens B, Camilleri-Broët S, Linassier C, Lamy T; GOELAMS. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant. 2006 Sep;38(6):417-20. link to original article contains dosing details in manuscript PubMed
  5. Shah GD, Yahalom J, Correa DD, Lai RK, Raizer JJ, Schiff D, LaRocca R, Grant B, DeAngelis LM, Abrey LE. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol. 2007 Oct 20;25(30):4730-5. Erratum in: J Clin Oncol. 2008 Jan 10;26(2):340. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Update: Morris PG, Correa DD, Yahalom J, Raizer JJ, Schiff D, Grant B, Grimm S, Lai RK, Reiner AS, Panageas K, Karimi S, Curry R, Shah G, Abrey LE, DeAngelis LM, Omuro A. 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. J Clin Oncol. 2013 Nov 1;31(31):3971-9. Epub 2013 Oct 7. link to original article link to PMC article PubMed
  6. IELSG20: Ferreri AJ, 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; International Extranodal Lymphoma Study Group. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet. 2009 Oct 31;374(9700):1512-20. Epub 2009 Sep 18. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
  7. G-PCNSL-SG-1: Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithäuser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nägele T, Pietsch T, Bamberg M, Weller M. 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 Oncol. 2010 Nov;11(11):1036-47. Epub 2010 Oct 20. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Update: Korfel A, Thiel E, Martus P, Möhle R, Griesinger F, Rauch M, Röth A, Hertenstein B, Fischer T, Hundsberger T, Mergenthaler HG, Junghanß C, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Roth P, Bamberg M, Pietsch T, Weller M. Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology. 2015 Mar 24;84(12):1242-8. Epub 2015 Feb 25. link to original article PubMed
  8. RTOG 0227: Glass J, Won M, Schultz CJ, Brat D, Bartlett NL, Suh JH, Werner-Wasik M, Fisher BJ, Liepman MK, Augspurger M, Bokstein F, Bovi JA, Solhjem MC, Mehta MP. Phase I and II study of induction chemotherapy with methotrexate, rituximab, and temozolomide, followed by whole-brain radiotherapy and postirradiation temozolomide for primary CNS lymphoma: NRG Oncology RTOG 0227. J Clin Oncol. 2016 May 10;34(14):1620-5. Epub 2016 Mar 28. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry
  9. IELSG32: Ferreri AJ, 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; International Extranodal Lymphoma Study Group. 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. 2016 May;3(5):e217-27. Epub 2016 Apr 6. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Update: Ferreri AJM, Cwynarski K, Pulczynski E, Fox CP, 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 KM, Pukrop T, Sønderskov Gørløv J, Balzarotti M, Hess G, Keller U, Stilgenbauer S, Panse J, Tucci A, Orsucci L, Pisani F, Levis A, Krause SW, Schmoll HJ, Hertenstein B, Rummel M, Smith J, Pfreundschuh M, Cabras G, Angrilli F, Ponzoni M, Deckert M, Politi LS, Finke J, Reni M, Cavalli F, Zucca E, Illerhaus G; International Extranodal Lymphoma Study Group. 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 Haematol. 2017 Nov;4(11):e510-e523. Epub 2017 Oct 17. link to original article PubMed
  10. JCOG1114C: Mishima K, Nishikawa R, Narita Y, Mizusawa J, Sumi M, Koga T, Sasaki N, Kinoshita M, Nagane M, Arakawa Y, Yoshimoto K, Shibahara I, Shinojima N, Asano K, Tsurubuchi T, Sasaki H, Asai A, Sasayama T, Momii Y, Sasaki A, Nakamura S, Kojima M, Tamaru JI, Tsuchiya K, Gomyo M, Abe K, Natsumeda M, Yamasaki F, Katayama H, Fukuda H. Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C. Neuro Oncol. 2023 Apr 6;25(4):687-698. link to original article link to PMC article PubMed jRCTs031180207

Relapsed or refractory, salvage therapy

High-dose Cytarabine monotherapy (HiDAC)

HiDAC: High Dose Ara-C (Cytarabine)

Regimen

Study Dates of enrollment Evidence
Thiel et al. 2010 (G-PCNSL-SG-1) 2000-2009 Non-randomized part of RCT

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

  1. G-PCNSL-SG-1: Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithäuser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nägele T, Pietsch T, Bamberg M, Weller M. 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 Oncol. 2010 Nov;11(11):1036-47. Epub 2010 Oct 20. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Update: Korfel A, Thiel E, Martus P, Möhle R, Griesinger F, Rauch M, Röth A, Hertenstein B, Fischer T, Hundsberger T, Mergenthaler HG, Junghanß C, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Roth P, Bamberg M, Pietsch T, Weller M. Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology. 2015 Mar 24;84(12):1242-8. Epub 2015 Feb 25. link to original article PubMed

CYVE

CYVE: CYtarabine, VEpesid (Etoposide)

Regimen variant #1

Study Dates of enrollment Evidence
Soussain et al. 2001 1992-1995 Pilot, >20 pts
Soussain et al. 2008 2000-2005 Phase 2

Chemotherapy

  • Cytarabine (Ara-C) as follows:
    • 2000 mg/m2 IV over 3 hours once per day on days 2 to 5
    • 50 mg/m2 IV over 12 hours once per day on days 1 to 5
  • Etoposide (Vepesid) 200 mg/m2 IV over 2 hours once per day on days 2 to 5

2 cycles

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence
Colombat et al. 2006 1999-2001 Phase 2

Preceding treatment

  • Non-response to MVBP x 2

Chemotherapy

2 cycles (length not specified)

Subsequent treatment

References

  1. Soussain C, Suzan F, Hoang-Xuan K, Cassoux N, Levy V, Azar N, Belanger C, Achour E, Ribrag V, Gerber S, Delattre JY, Leblond V. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol. 2001 Feb 1;19(3):742-9. link to original article contains dosing details in manuscript PubMed
  2. Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, Berthou C, Bay JO, Delepine R, Desablens B, Camilleri-Broët S, Linassier C, Lamy T; GOELAMS. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant. 2006 Sep;38(6):417-20. link to original article contains dosing details in manuscript PubMed
  3. Soussain C, Hoang-Xuan K, Taillandier L, Fourme E, Choquet S, Witz F, Casasnovas O, Dupriez B, Souleau B, Taksin AL, Gisselbrecht C, Jaccard A, Omuro A, Sanson M, Janvier M, Kolb B, Zini JM, Leblond V; Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. 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. 2008 May 20;26(15):2512-8. Epub 2008 Apr 14. link to original article contains dosing details in manuscript PubMed

Ifosfamide & Methotrexate

Regimen

Study Evidence
Fischer et al. 2008 Retrospective

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) for prophylaxis of hemorrhagic cystitis
  • Folinic acid (Leucovorin) rescue starting 24 hours after start of methotrexate infusion
  • Sodium bicarbonate IV or PO used for urine alkalinization to maintain urine pH of at least 8
    • Check methotrexate levels 24, 48, and 72 hours after completion of methotrexate infusion.

Up to 8 cycles (reference did not list timing/criteria to be used for next cycle of therapy)

Dose modifications

  • Methotrexate (MTX) dose adjusted for CrCl less than 100 mL/min/1.73m2 according to the following formula:
  • Dose of methotrexate = (CrCl/100) x 4000 mg/m2; the paper did not specify what method was used for calculating CrCl. Patients with CrCl less than 50 mL/min/1.73m2 were excluded from the study.

References

  1. Retrospective: Fischer L, Korfel A, Kiewe P, Neumann M, Jahnke K, Thiel E. Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma. Ann Hematol. 2009 Feb;88(2):133-9. Epub 2008 Aug 5. link to original article contains dosing details in manuscript PubMed

Whole brain irradiation

Regimen variant #1, 30 Gy

Study Dates of enrollment Evidence
Colombat et al. 2006 1999-2001 Phase 2

Preceding treatment

Radiotherapy

One course


Regimen variant #2, 36 Gy

Study Dates of enrollment Evidence
Nguyen et al. 2005 1994-2003 Phase 2

Note: The authors do not clearly describe a pre-determined dosing protocol but report that the most common fraction size was 1.5 Gy.

Radiotherapy

One course


Regimen variant #3, 36 Gy + 10 Gy boost

Study Dates of enrollment Evidence
Nguyen et al. 2005 1994-2003 Phase 2

Note: The authors do not clearly describe a pre-determined dosing protocol but report that the most common fraction size was 1.5 Gy.

Radiotherapy

One course


Regimen variant #4, 45 Gy

Study Dates of enrollment Evidence
Thiel et al. 2010 (G-PCNSL-SG-1) 2000-2009 Non-randomized part of RCT

Preceding treatment

Radiotherapy

One course

References

  1. Nguyen PL, Chakravarti A, Finkelstein DM, Hochberg FH, Batchelor TT, Loeffler JS. Results of whole-brain radiation as salvage of methotrexate failure for immunocompetent patients with primary CNS lymphoma. J Clin Oncol. 2005 Mar 1;23(7):1507-13. link to original article contains dosing details in manuscript PubMed
  2. Colombat P, Lemevel A, Bertrand P, Delwail V, Rachieru P, Brion A, Berthou C, Bay JO, Delepine R, Desablens B, Camilleri-Broët S, Linassier C, Lamy T; GOELAMS. High-dose chemotherapy with autologous stem cell transplantation as first-line therapy for primary CNS lymphoma in patients younger than 60 years: a multicenter phase II study of the GOELAMS group. Bone Marrow Transplant. 2006 Sep;38(6):417-20. link to original article contains dosing details in manuscript PubMed
  3. G-PCNSL-SG-1: Thiel E, Korfel A, Martus P, Kanz L, Griesinger F, Rauch M, Röth A, Hertenstein B, von Toll T, Hundsberger T, Mergenthaler HG, Leithäuser M, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Plasswilm L, Nägele T, Pietsch T, Bamberg M, Weller M. 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 Oncol. 2010 Nov;11(11):1036-47. Epub 2010 Oct 20. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry
    1. Update: Korfel A, Thiel E, Martus P, Möhle R, Griesinger F, Rauch M, Röth A, Hertenstein B, Fischer T, Hundsberger T, Mergenthaler HG, Junghanß C, Birnbaum T, Fischer L, Jahnke K, Herrlinger U, Roth P, Bamberg M, Pietsch T, Weller M. Randomized phase III study of whole-brain radiotherapy for primary CNS lymphoma. Neurology. 2015 Mar 24;84(12):1242-8. Epub 2015 Feb 25. link to original article PubMed

Consolidation after salvage therapy

Bu/TT/Cy, then auto HSCT

Bu/TT/Cy: Busulfan, ThioTepa, Cyclophosphamide

Regimen

Study Dates of enrollment Evidence
Soussain et al. 2001 1992-1995 Pilot, >20 pts
Soussain et al. 2008 2000-2005 Phase 2

Preceding treatment

Chemotherapy

  • Busulfan (Myleran) by the following age-based criteria:
    • Up to 60 years old: 10 mg/kg PO or 8 mg/kg IV once per day on days -6, -5, and -4
    • 60 and older: 6 mg/kg PO or 4.8 mg/kg IV once per day on days -6, -5, and -4
  • Thiotepa (Thioplex) 250 mg/m2 IV once per day on days -9, -8, and -7
  • Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2

Supportive therapy

Stem cell re-infusion occurs on day 0

References

  1. Soussain C, Suzan F, Hoang-Xuan K, Cassoux N, Levy V, Azar N, Belanger C, Achour E, Ribrag V, Gerber S, Delattre JY, Leblond V. Results of intensive chemotherapy followed by hematopoietic stem-cell rescue in 22 patients with refractory or recurrent primary CNS lymphoma or intraocular lymphoma. J Clin Oncol. 2001 Feb 1;19(3):742-9. link to original article contains dosing details in manuscript PubMed
  2. Soussain C, Hoang-Xuan K, Taillandier L, Fourme E, Choquet S, Witz F, Casasnovas O, Dupriez B, Souleau B, Taksin AL, Gisselbrecht C, Jaccard A, Omuro A, Sanson M, Janvier M, Kolb B, Zini JM, Leblond V; Société Française de Greffe de Moëlle Osseuse-Thérapie Cellulaire. 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. 2008 May 20;26(15):2512-8. Epub 2008 Apr 14. link to original article contains dosing details in manuscript PubMed

Relapsed or refractory, subsequent lines of therapy

Rituximab monotherapy

Regimen

Study Dates of enrollment Evidence
Batchelor et al. 2011 (NABTT-2201) 2004-NR Pilot, <20 pts

Targeted therapy

28-day cycle for up to 2 cycles

References

  1. NABTT-2201: Batchelor TT, Grossman SA, Mikkelsen T, Ye for, Desideri S, Lesser GJ. Rituximab monotherapy for patients with recurrent primary CNS lymphoma. Neurology. 2011 Mar 8;76(10):929-30. link to original article contains dosing details in manuscript link to PMC article PubMed Clinical Trial Registry

Temozolomide monotherapy

Regimen

Study Dates of enrollment Evidence
Reni et al. 2007 2000-2005 Phase 2

Chemotherapy

28-day cycles

References

  1. Reni M, Zaja F, Mason W, Perry J, Mazza E, Spina M, Bordonaro R, Ilariucci F, Faedi M, Corazzelli G, Manno P, Franceschi E, Pace A, Candela M, Abbadessa A, Stelitano C, Latte G, Ferreri AJ. Temozolomide as salvage treatment in primary brain lymphomas. Br J Cancer. 2007 Mar 26;96(6):864-7. Epub 2007 Feb 27. link to original article contains dosing details in manuscript link to PMC article PubMed

Temsirolimus monotherapy

Regimen

Study Dates of enrollment Evidence
Korfel et al. 2016 (TemPCNSL) 2009-2014 Phase 2

Note: This is the dose used in stage 2 of this two-stage protocol.

Targeted therapy

28-day cycles

References

  1. TemPCNSL: Korfel A, Schlegel U, Herrlinger U, Dreyling M, Schmidt C, von Baumgarten L, Pezzutto A, Grobosch T, Kebir S, Thiel E, Martus P, Kiewe P. Phase II trial of temsirolimus for relapsed/refractory primary CNS lymphoma. J Clin Oncol. 2016 May 20;34(15):1757-63. Epub 2016 Mar 14. link to original article contains dosing details in manuscript PubMed Clinical Trial Registry

Topotecan monotherapy

Regimen

Study Dates of enrollment Evidence
Voloschin et al. 2008 1998-2002 Phase 2, <20 pts
Fischer et al. 2006 2000-2004 Phase 2

Chemotherapy

Supportive therapy

21-day cycle for 6 to 10 cycles

References

  1. Fischer L, Thiel E, Klasen HA, Birkmann J, Jahnke K, Martus P, Korfel A. Prospective trial on topotecan salvage therapy in primary CNS lymphoma. Ann Oncol. 2006 Jul;17(7):1141-5. Epub 2006 Apr 7. link to original article contains dosing details in manuscript PubMed
  2. Voloschin AD, Betensky R, Wen PY, Hochberg F, Batchelor T. Topotecan as salvage therapy for relapsed or refractory primary central nervous system lymphoma. J Neurooncol. 2008 Jan;86(2):211-5. Epub 2007 Sep 21. link to original article contains dosing details in manuscript PubMed

Prognosis

IELSG Prognostic Scoring System (2003)

  1. Ferreri AJ, Blay JY, 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. Prognostic scoring system for primary CNS lymphomas: the International Extranodal Lymphoma Study Group experience. J Clin Oncol. 2003 Jan 15;21(2):266-72. link to original article PubMed
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