CNS lymphoma

Section editors
	Seema Nagpal, MD Stanford University Palo Alto, CA		Tarsheen Sethi, MD, MSCI Yale University New Haven, CT tarsheen2

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42 regimens on this page 60 variants on this page

Guidelines

BSH

• 2018: Fox et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma

EANO

• 2015: Hoang-Xuan et al. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology

ESH

• 2019: Fox et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma

ESMO

• 2016: Vitolo et al. Extranodal diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

GEL/TAMO

• 2016: Peñalver et al. Guidelines for diagnosis, prevention and management of central nervous system involvement in diffuse large B-cell lymphoma patients by the Spanish Lymphoma Group (GELTAMO)

NCCN

• NCCN Guidelines - Central Nervous System Cancers

CNS prophylaxis, systemic therapy

High-dose Cytarabine monotherapy (HiDAC)

HiDAC: High Dose Ara-C (Cytarabine)

Regimen

Study	Evidence
Holte et al. 2013 (NLG LBC-04)	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

• R-CHOEP-14 x 8

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

• HD-MTX

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 NCT01502982

Methotrexate monotherapy

Regimen

Study	Evidence
Holte et al. 2013 (NLG LBC-04)	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

• HiDAC

Chemotherapy

• Methotrexate (MTX) 3000 mg/m² IV continuous infusion over 24 hours, started on day 1

Supportive therapy

• Folinic acid (Leucovorin) (dose/frequency not specified) starting at 36 hours

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 NCT01502982

CNS treatment, local therapy

IT Cytarabine monotherapy

Regimen

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

CNS therapy, treatment

• Cytarabine (Ara-C) 50 mg IT once per day on days 1, 4, 8, 11, 15, 18, 22, 25

4-week course

Subsequent treatment

• 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	Years 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

• Cytarabine liposomal (DepoCyt) 50 mg IT once on day 1

14-day cycle for 2 cycles

Subsequent treatment

• 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	Years 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 (MTX)
  • 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

• IELSG20: Whole brain irradiation, within 4 weeks
• IELSG32: Whole brain irradiation versus Carmustine & Thiotepa with auto HSCT

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 NCT00210314
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 NCT01011920

Cytarabine, Methotrexate, Rituximab

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

Regimen

Study	Years 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

• SCNSL1: R-CHOP x 1

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

• Rituximab (Rituxan) 375 mg/m² IV once per day on days -5 & 0

CNS therapy

• SCNSL1: Cytarabine liposomal (DepoCyt)

Supportive therapy

• Levoleucovorin (Fusilev) 15 mg/m² IV every 6 hours for 12 doses, beginning 24 hours after the start of Methotrexate (MTX)
  • 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

• SCNSL1: Intensification phase (see paper for details)
• IELSG 32: Whole brain irradiation versus Carmustine & Thiotepa with auto HSCT

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 NCT00801216
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 NCT01011920

MATRix

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

Regimen

Study	Years 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

• 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)
• Cytarabine (Ara-C) 2000 mg/m² IV over 60 minutes every 12 hours on days 2 & 3
• Thiotepa (Thioplex) 30 mg/m² IV over 30 minutes once on day 4

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days -5 & 0

Supportive therapy

• Levoleucovorin (Fusilev) 15 mg/m² IV every 6 hours for 12 doses, beginning 24 hours after the start of Methotrexate (MTX)
  • 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

• Whole brain irradiation versus Carmustine & Thiotepa with auto HSCT

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 NCT01011920

MBVP

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

Regimen

Study	Years 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

• Methotrexate (MTX) 3000 mg/m² IV once per day on days 1 & 15
• Carmustine (BCNU) 100 mg/m² IV once on day 4
• Teniposide (Vumon) 100 mg/m² IV once per day on days 2 & 3

Glucocorticoid therapy

• Prednisone (Sterapred) 60 mg/m² PO once per day on days 1 to 5

28-day cycle for 2 cycles

Subsequent treatment

• Responders, all ages: HiDAC consolidation
  • Patients younger than 60 also received: 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	Years 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

• Whole brain irradiation, within 4 weeks

Regimen variant #2, 4000 mg/m²

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

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

Chemotherapy

• Methotrexate (MTX) 4000 mg/m² IV over 4 hours once on day 1

14-day cycle for 6 cycles

Subsequent treatment

• Patients with CR: whole-brain irradiation versus no further treatment
• Patients with less than CR in the WB-XRT arm: Salvage whole-brain irradiation
• Patients with less than CR in the no-WB-XRT: Salvage HiDAC

Regimen variant #3, 8000 mg/m²

Study	Evidence
Herrlinger et al. 2005 (NOA-03)	Phase 2

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

Chemotherapy

• Methotrexate (MTX) 8000 mg/m² IV over 4 hours once on day 1

14-day cycle for 6 cycles

Subsequent treatment

• 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	Evidence
Batchelor et al. 2003 (NABTT 96-07)	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

• Patients achieving CR: HD-MTX x 2, then methotrexate maintenance

Regimen variant #5, 20-day course

Study	Evidence
Montemurro et al. 2007 (OSHO-53)	Phase 2

Chemotherapy

• Methotrexate (MTX) by the following age-based critera:
  • 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

• Responders (CR or PR): Bu/TT, then autologous hematopoietic stem cell transplant

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 NCT00210314
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 NCT00153530
   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	Evidence
Illerhaus et al. 2008a	Phase 2

Chemotherapy

• Lomustine (CCNU) 110 mg/m² PO once on day 1
• Methotrexate (MTX) 3000 mg/m² IV over 4 hours once per day on days 1, 15, 30
• Procarbazine (Matulane) 60 mg/m² PO once per day on days 1 to 10

Supportive therapy

• Folinic acid (Leucovorin) 15 mg/m² (route not specified) every 6 hours beginning 24 hours after start of Methotrexate (MTX) 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	Evidence
Hoang-Xuan et al. 2003 (EORTC 26952)	Phase 2

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

Chemotherapy

• Methotrexate (MTX) 1000 mg/m² IV once per day on days 1, 10, 20
• Lomustine (CCNU) 40 mg/m² PO once on day 1
• Procarbazine (Matulane) 60 mg/m² PO once per day on days 1 to 7

Glucocorticoid therapy

• Methylprednisolone (Solumedrol) as follows:
  • Days 1 to 20: 120 mg/m² IV or PO every other day
  • Days 20 to 45: 60 mg/m² IV or PO every other day

CNS therapy

• Methotrexate (MTX) 15 mg IT (admixed with Cytarabine (Ara-C)) once per day on days 1, 5, 10, 15
• Cytarabine (Ara-C) 40 mg IT (admixed with Methotrexate (MTX)) once per day on days 1, 5, 10, 15

Supportive therapy

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

45-day course

Subsequent treatment

• Patients achieving PR or CR: Lomustine, methotrexate, procarbazine maintenance

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	Evidence
Abrey et al. 2003	Phase 2

Chemotherapy, part 1

• Methotrexate (MTX) 3500 mg/m² (maximum dose of 7000 mg) IV over 2 hours once on day 1

Supportive therapy

• Folinic acid (Leucovorin) 25 mg PO every 6 hours, beginning 24 hours after start of Methotrexate (MTX), continued for 12 doses or until serum MTX level less than 100 nmol/L

14-day cycle for 5 cycles Patients proceed to part two 72 hours after 5th dose of MTX or once the 5th dose MTX level has cleared:

Chemotherapy, part 2

• Cytarabine (Ara-C) 3000 mg/m² IV once per day on days 1 & 2

Supportive therapy

• Filgrastim (Neupogen) as follows:
  • Cycle 1: 10 mcg/kg SC once per day, starting on day 4 and continued until stem cell collection complete
  • Cycle 2: 5 mcg/kg SC once per day continued for 2 weeks or until ANC greater than 3000/uL

1-month cycle for 2 cycles (Stem cell collection took place after the first cycle)

Subsequent treatment

• BEAM, then autologous hematopoietic stem cell transplant

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

Chemotherapy, part 1

• Methotrexate (MTX) 8000 mg/m² IV over 4 hours once per day on days 1, 10, 20

Supportive therapy

• Folinic acid (Leucovorin) 15 mg/m² every 6 hours, beginning 24 hours after start of Methotrexate (MTX), continuing until clearance

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

Chemotherapy, stem cell mobilization

• Cytarabine (Ara-C) 3000 mg/m² IV over 3 hours once per day on days 2 & 3
• Thiotepa (Thioplex) 40 mg/m² (route not specified) once on day 3

20-day course

Subsequent treatment

• BCNU/TT, then autologous hematopoietic stem cell transplant

Protocol variant #2

Study	Evidence
Illerhaus et al. 2008	Pilot, <20 patients

Chemotherapy, part 1

• Methotrexate (MTX) 8000 mg/m² IV over 4 hours once on day 1

Supportive therapy

• Folinic acid (Leucovorin) 15 mg/m² every 6 hours, beginning 24 hours after start of Methotrexate (MTX), continuing until clearance

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

Chemotherapy, part 2

• Cytarabine (Ara-C) 3000 mg/m² IV once per day on days 1 & 2
• Thiotepa (Thioplex) 40 mg/m² (route not specified) once on day 2

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

Subsequent treatment

• BCNU/TT, then autologous hematopoietic stem cell transplant

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	Evidence
Chamberlain et al. 2010	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

• Rituximab (Rituxan) 375 mg/m² IV once on day 8

14-day cycle for 4 to 6 cycles

Subsequent treatment

• Patients with PR/CR: High-dose methotrexate consolidation

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

Chemotherapy

• Methotrexate (MTX) 2500 mg/m² IV over 2 to 3 hours once on day 1
• Procarbazine (Matulane) as follows:
  • Cycles 1, 3, 5: 100 mg/m² PO once per day on days 1 to 7
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2.8 mg) IV once on day 1

CNS therapy

• Methotrexate (MTX) 12 mg IT once on day 8 (via Ommaya reservoir)

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 (MTX) administration
  • Days 8 & 9: 10 mg PO every 6 hours for 8 doses, beginning on the evening of IT Methotrexate (MTX) 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

• Whole-brain irradiation

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	Evidence
Glass et al. 2016 (RTOG 0227)	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

• Methotrexate (MTX) 3500 mg/m² IV once on day 1
• Temozolomide (Temodar) as follows:
  • Cycles 2 & 4: 100 mg/m² PO once per day on days 8 to 12

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once, 3 days prior to first dose of MTX

Supportive therapy

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

14-day cycle for 5 cycles

Subsequent treatment

• WB-XRT consolidation

Regimen variant #2

Study	Evidence
Rubenstein et al. 2013 (CALGB 50202)	Phase 2

Chemotherapy

• Methotrexate (MTX) 8000 mg/m² IV over 4 hours once on day 1
• Temozolomide (Temodar) as follows:
  • Cycles 1, 3, 5, 7: 150 mg/m² PO once per day on days 7 to 11

Targeted therapy

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

Supportive therapy

• Folinic acid (Leucovorin) 100 mg/m² IV every 6 hours, start on day 2, continue until MTX level less than 50 nmol/L

14-day cycle for 7 cycles

Subsequent treatment

• Patients achieving CR or CRu: Methotrexate & Temozolomide x 1, then CYVE consolidation

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 NCT00098774
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 NCT00068250

MVBP

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

Regimen

Study	Evidence
Colombat et al. 2006	Phase 2

Chemotherapy

• Methotrexate (MTX) 3000 mg/m² IV once per day on days 1 & 15
• Etoposide (Vepesid) 100 mg/m² IV once on day 2
• Carmustine (BCNU) 100 mg/m² IV once on day 3

Glucocorticoid therapy

• Methylprednisolone (Solumedrol) 60 mg/m² (route not specified) once per day on days 1 to 5

Supportive therapy

• Folinic acid (Leucovorin) details not specified

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

CNS therapy

• Methotrexate (MTX) 20 mg IT (admixed with Cytarabine (Ara-C) and Methylprednisolone (Solumedrol))
• Cytarabine (Ara-C) 50 mg IT (admixed with Methotrexate (MTX) and Methylprednisolone (Solumedrol))
• Methylprednisolone (Solumedrol) 40 mg IT (admixed with Cytarabine (Ara-C) and Methotrexate (MTX))

6 doses total (timing not specified)

Subsequent treatment

• Responding patients (CR or PR): cytarabine & ifosfamide for stem cell mobilization, then BEAM, then autologous hematopoietic stem cell transplant
• Non-responders: Salvage CYVE

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

Eligibility criteria

• Age 66-75 years

Targeted therapy, A cycles

• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once on day 1

Chemotherapy, A cycles

• Methotrexate (MTX) as follows:
  • Cycles 1 & 4: 3000 mg/m² IV once on day 1
• Ifosfamide (Ifex) as follows:
  • Cycle 1: 800 mg/m² IV once per day on days 2 to 5

Glucocorticoid therapy, A cycles

• Dexamethasone (Decadron) as follows:
  • Cycles 1 & 4: 10 mg/m²/day PO on days 2 to 5

CNS therapy, A cycles

• Cytarabine liposomal (DepoCyt) as follows:
  • Cycles 1 & 4: 50 mg IT once on day 2

Chemotherapy, B cycles

• Methotrexate (MTX) as follows:
  • Cycles 2 & 5: 5000 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 2 & 5: 150 mg/m² IV once per day on days 2 to 6

Glucocorticoid therapy, B cycles

• Dexamethasone (Decadron) as follows:
  • Cycles 2 & 5: 10 mg/m²/day PO on days 2 to 5

CNS therapy, B cycles

• Cytarabine liposomal (DepoCyt) as follows:
  • Cycles 2 & 5: 50 mg IT once on day 2

Glucocorticoid therapy, C cycles

• Dexamethasone (Decadron) as follows:
  • Cycles 3 & 6: 20 mg/m²/day PO on days 3 to 7

Chemotherapy, C cycles

• Cytarabine (Ara-C) as follows:
  • Cycles 3 & 6: 1000 mg/m² IV every 12 hours on days 1 & 2
• Vindesine (Eldisine) as follows:
  • Cycles 3 & 6: 5 mg IV once on day 1

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

Subsequent treatment

• Temozolomide maintenance

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 NCT01458730

Nordic Regimen, younger patients

Protocol

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

Eligibility criteria

• Age 18 to 65 years

Targeted therapy, A cycles

• Rituximab (Rituxan) as follows:
  • Cycle A1: 375 mg/m² IV once on day 1

Chemotherapy, A cycles

• Methotrexate (MTX) 5000 mg/m² IV once on day 1
• Ifosfamide (Ifex) 800 mg/m² IV once per day on days 2 to 5

Glucocorticoid therapy, A cycles

• Dexamethasone (Decadron) 10 mg/m²/day PO on days 2 to 5

CNS therapy, A cycles

• Cytarabine liposomal (DepoCyt) 50 mg IT once on day 2

Chemotherapy, B cycles

• Methotrexate (MTX) 5000 mg/m² IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1
• Cyclophosphamide (Cytoxan) 200 mg/m² IV once per day on days 2 to 5

Glucocorticoid therapy, B cycles

• Dexamethasone (Decadron) 10 mg/m²/day PO on days 2 to 5

CNS therapy, B cycles

• Cytarabine liposomal (DepoCyt) 50 mg IT once on day 2

Glucocorticoid therapy, C cycles

• Dexamethasone (Decadron) 20 mg/m²/day PO on days 3 to 7

Chemotherapy, C cycles

• Cytarabine (Ara-C) 1500 mg/m² IV every 12 hours on days 1 & 2
• Vindesine (Eldisine) 5 mg IV once on day 1

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 NCT01458730

R-MCP (CCNU)

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

Regimen

Study	Evidence
Fritsch et al. 2011	Phase 2

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

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV over 90 minutes once per day on days -6, 1, 15, 29

Chemotherapy

• Methotrexate (MTX) 3000 mg/m² IV over 4 hours once per day on days 2, 16, 30
• Lomustine (CCNU) 110 mg/m² PO once on day 2
• Procarbazine (Matulane) 60 mg/m² PO once per day on days 2 to 11

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	Evidence
Fritsch et al. 2016 (PRIMAIN)	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

• Methotrexate (MTX) 3000 mg/m² IV over 4 hours once per day on days 2, 16, 30
• Procarbazine (Matulane) 60 mg/m² PO once per day on days 2 to 11

42-day cycle for 3 cycles

Subsequent treatment

• Procarbazine maintenance

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 NCT00989352

R-MPV

R-MPV: Rituximab, Methotrexate, Procarbazine, Vincristine

Regimen

Study	Years 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

• Rituximab (Rituxan) 500 mg/m² IV over 5 hours once on day 1

Chemotherapy

• Methotrexate (MTX) 3500 mg/m² IV over 2 hours once on day 2
• Procarbazine (Matulane) as follows:
  • Odd cycles: 100 mg/m² PO once per day on days 1 to 7
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2.8 mg) IV once on day 2

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 (MTX) administration

14-day cycle for 5 to 7 cycles

Subsequent treatment

• MSK 01-146: followed in 3 to 5 weeks by whole-brain irradiation
• MSK 04-129: Bu/TT/Cy, then autologous hematopoietic stem cell transplant, after 5 cycles if CR achieved, or after 7 cycles for PR/CR at that time

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 NCT00594815
   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 NCT00596154

Consolidation and/or maintenance after upfront therapy

BCNU/TT, then auto HSCT

BCNU/TT: BCNU (Carmustine), ThioTepa

Regimen variant #1

Study	Years 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

• High-dose methotrexate, then Ara-C & Thiotepa

Chemotherapy

• Carmustine (BCNU) 400 mg/m² IV once on day 50
• Thiotepa (Thioplex) 5 mg/kg (route not specified) once per day on days 51 & 52

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

• Whole-brain irradiation

Regimen variant #2

Study	Evidence
Illerhaus et al. 2008	Pilot, <20 patients

Preceding treatment

• High-dose methotrexate, then Ara-C & Thiotepa

Chemotherapy

• Carmustine (BCNU) 400 mg/m² IV once on day 1
• Thiotepa (Thioplex) 5 mg/kg (route not specified) twice per day on days 2 & 3

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 NCT01011920
   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	Evidence
Colombat et al. 2006	Phase 2

Preceding treatment

• MVBP x 2

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day 1
• Etoposide (Vepesid) 200 mg/m² IV once per day on days 2 to 5
• Cytarabine (Ara-C) 100 mg/m² IV every 12 hours on days 2 to 5
• Melphalan (Alkeran) 140 mg/m² IV once on day 6

Day of transplant is not specified

Subsequent treatment

• Whole-brain irradiation

Regimen variant #2

Study	Evidence
Abrey et al. 2003	Phase 2

Preceding treatment

• Methotrexate, then Cytarabine

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day -7
• Etoposide (Vepesid) 100 mg/m² IV every 12 hours on days -6 to -3
• Cytarabine (Ara-C) 200 mg/m² IV every 12 hours on days -6 to -3
• Melphalan (Alkeran) 140 mg/m² IV once on day -2

Supportive therapy

• Filgrastim (Neupogen) 5 mcg/kg SC every 12 hours, starting on day +1 and continued until ANC greater than 1000/uL for 3 days or greater than 10,000/uL 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	Evidence
Montemurro et al. 2007 (OSHO-53)	Phase 2

Preceding treatment

• High-dose methotrexate x 2

Chemotherapy

• Busulfan (Myleran) 4 mg/kg PO four times per day on days -8 to -5
• Thiotepa (Thioplex) 5 mg/kg IV once per day on days -4 & -3

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	Evidence
Omuro et al. 2015 (MSK 04-129)	Phase 2

Preceding treatment

• R-MPV

Chemotherapy

• Busulfan (Myleran) 3.2 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 and -2

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 NCT00596154

High-dose Cytarabine monotherapy (HiDAC)

HiDAC: High Dose Ara-C (Cytarabine)

Regimen

Study	Years 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

• Whole-brain irradiation x 45 Gy

Chemotherapy

• Cytarabine (Ara-C) 3000 mg/m² IV over 3 hours once per day on days 1 & 2

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	Evidence
Rubenstein et al. 2013 (CALGB 50202)	Phase 2

Preceding treatment

• MT-R induction

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 NCT00098774

Lomustine, Methotrexate, Procarbazine

Regimen

Study	Evidence
Hoang-Xuan et al. 2003 (EORTC 26952)	Phase 2

Preceding treatment

• Lomustine, Methotrexate, Procarbazine, Methylprednisolone induction

Chemotherapy

• Methotrexate (MTX) 1000 mg/m² IV once on day 1
• Lomustine (CCNU) 40 mg/m² PO once on day 1
• Procarbazine (Matulane) 60 mg/m² PO once per day on days 1 to 7

CNS therapy

• Methotrexate (MTX) 15 mg IT (admixed with Cytarabine (Ara-C)) once on day 1
• Cytarabine (Ara-C) 40 mg IT (admixed with Methotrexate (MTX)) once on day 1

Supportive therapy

• Folinic acid (Leucovorin) 25 mg PO every 6 hours for 3 days, initiated 24 hours after IV Methotrexate (MTX) administration

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	Evidence
Chamberlain et al. 2010	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

• High-dose methotrexate & Rituximab

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	Evidence
Batchelor et al. 2003 (NABTT 96-07)	Phase 2

Preceding treatment

• High-dose methotrexate induction

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	Evidence
Fritsch et al. 2016 (PRIMAIN)	Phase 2

Preceding treatment

• R-MP x 3

Chemotherapy

• Procarbazine (Matulane) 100 mg PO once per day on days 1 to 5

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 NCT00989352

Temozolomide monotherapy

Regimen variant #1

Study	Evidence
Glass et al. 2016 (RTOG 0227)	Phase 1/2

Preceding treatment

• WB-XRT consolidation

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	Evidence
Pulczynski et al. 2015 (NLGPCNSL)	Phase 2

Preceding treatment

• Nordic Regimen for older patients

Chemotherapy

• Temozolomide (Temodar) 150 mg/m²/day PO on days 1 to 5

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 NCT01458730
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 NCT00068250

Whole brain irradiation

WBRT: Whole-Brain Radiation Therapy

Regimen variant #1, 23.4 Gy

Study	Years 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

• Whole-brain irradiation to 23.4 Gy in 1.80 Gy fractions

Regimen variant #2, 30 Gy

Study	Evidence
Colombat et al. 2006	Phase 2

Preceding treatment

• BEAM, then autologous hematopoietic stem cell transplant, with complete response

Radiotherapy

• Whole-brain irradiation to 30 Gy in 1.80 Gy fractions

Regimen variant #3, 30 Gy + 10 Gy boost

Study	Evidence
Colombat et al. 2006	Phase 2

Preceding treatment

• BEAM, then autologous hematopoietic stem cell transplant, with partial response

Radiotherapy

• Whole-brain irradiation to 30 Gy in 1.80 Gy fractions plus 10 Gy boost to the tumor bed

Regimen variant #4, 36 Gy

Study	Years 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

• RTOG 0227: MT-R induction
• IELSG32: CYM versus Cytarabine, MTX, Rituximab versus MATRix induction, with complete response

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

• RTOG 0227: Temozolomide consolidation

Regimen variant #5, 36 Gy + 9 Gy boost

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ferreri et al. 2009 (IELSG20)	2004-2007	Non-randomized portion 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

• IELSG20: High-dose methotrexate x 4 versus High-dose CYM x 4, with any response
• IELSG32: CYM versus Cytarabine, MTX, Rituximab versus MATRix induction, with partial response

Radiotherapy

• Whole-brain irradiation to 36 Gy in 1.80 Gy fractions plus 9 Gy boost to the tumor bed

Regimen variant #6, 40 Gy + 9 Gy boost

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

Preceding treatment

• High-dose methotrexate x 4 versus High-dose CYM x 4, with stable or progressive disease

Radiotherapy

• Whole-brain irradiation to 40 Gy in 1.80 Gy fractions plus 9 Gy boost to the tumor bed

Regimen variant #7, 45 Gy

Study	Years 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

• Abrey et al. 2000 & RTOG 93-10: MPV x 5
• Illerhaus et al. 2006: BCNU/TT, then autologous hematopoietic stem cell transplant, with complete response
• Shaw et al. 2007: R-MPV x 5 to 7 cycles, without complete response
• G-PCNSL-SG-1, before 2006: High-dose methotrexate x 6
• G-PCNSL-SG-1, after 2006: High-dose methotrexate & ifosfamide x 6

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, Shaw et al. 2007: 1.80 Gy fractions

Subsequent treatment

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

Regimen variant #8, 50 Gy

Study	Years 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

• BCNU/TT, then autologous hematopoietic stem cell transplant, with partial response

Radiotherapy

• Whole-brain irradiation to 50 Gy in 1 Gy fractions, starting on day 90

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 NCT00594815
   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 NCT00210314
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 NCT00153530
   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 NCT00068250
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 NCT01011920
   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

Relapsed or refractory, salvage therapy

High-dose Cytarabine monotherapy (HiDAC)

HiDAC: High Dose Ara-C (Cytarabine)

Regimen

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

Preceding treatment

• Before 2006: Non-response to High-dose methotrexate
• After 2006: Non-response to Methotrexate & Ifosfamide

Chemotherapy

• Cytarabine (Ara-C) 3000 mg/m² IV over 3 hours every 12 hours on days 1 & 2

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 NCT00153530
   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	Evidence
Soussain et al. 2001	Pilot, >20 pts
Soussain et al. 2008	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

• Responders: Bu/TT/Cy, then autologous hematopoietic stem cell transplant

Regimen variant #2

Study	Evidence
Colombat et al. 2006	Phase 2

Preceding treatment

• Non-response to MVBP x 2

Chemotherapy

• Cytarabine (Ara-C) 1000 mg/m² IV every 12 hours on days 1 & 2
• Etoposide (Vepesid) 150 mg/m² IV once per day on days 1 & 2

2 cycles (length not specified)

Subsequent treatment

• Whole-brain irradiation

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

• Example orders for High-dose Methotrexate (MTX) & Ifosfamide in lymphoma

Regimen

Study	Evidence
Fischer et al. 2008	Retrospective

Chemotherapy

• Ifosfamide (Ifex) 1500 to 2000 mg/m² IV over 3 hours once per day on days 3 to 5
• Methotrexate (MTX) 4000 mg/m² IV over 4 hours once on day 1

Supportive therapy

• Mesna (Mesnex) for prophylaxis of hemorrhagic cystitis
• Folinic acid (Leucovorin) rescue starting 24 hours after start of Methotrexate (MTX) infusion
• Sodium bicarbonate via IV fluid or PO routes 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.

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.

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

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

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

Preceding treatment

• Before 2006: Non-response to high-dose MTX x 6
• After 2006: Non-response to High-dose methotrexate & ifosfamide x 6

Radiotherapy

• Whole-brain irradiation to 45 Gy in 1.5 Gy fractions

Regimen variant #2

Study	Evidence
Colombat et al. 2006	Phase 2

Preceding treatment

• CYVE salvage

Radiotherapy

• Whole-brain irradiation to 30 Gy in 1.8 Gy fractions plus 10 Gy boost to the tumor bed

Regimen variant #3

Study	Evidence
Nguyen et al. 2005	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

• Whole-brain irradiation with median dose:
  • Patients not receiving a boost: 36 Gy (range 28 to 45 Gy)
  • Patients receiving a boost: 36 Gy (range 19.6 to 40 Gy) + 10 Gy (range 10 to 21.6 Gy)

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 NCT00153530
   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	Evidence
Soussain et al. 2001	Pilot, >20 pts
Soussain et al. 2008	Phase 2

Preceding treatment

• CYVE salvage x 2

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

• Clonazepam (Klonopin) 2 mg/day IV from the first day of Busulfan (Myleran) until completion of Busulfan (Myleran)

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

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22

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 NCT00072449

Temozolomide monotherapy

Regimen

Study	Evidence
Reni et al. 2007	Phase 2

Chemotherapy

• Temozolomide (Temodar) 150 mg/m² PO once per day on days 1 to 5

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	Evidence
Korfel et al. 2016 (TemPCNSL)	Phase 2

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

Targeted therapy

• Temsirolimus (Torisel) 75 mg IV once per day on days 1, 8, 15, 22

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 NCT00942747

Topotecan monotherapy

Regimen

Study	Evidence
Fischer et al. 2006	Phase 2
Voloschin et al. 2008	Phase 2, <20 pts

Chemotherapy

• Topotecan (Hycamtin) 1.5 mg/m² IV over 30 minutes once per day on days 1 to 5

Supportive therapy

• Voloschin et al. 2008: Ondansetron (Zofran) (dose/route not specified) prior to Topotecan (Hycamtin)

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