CNS lymphoma

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42 regimens on this page 60 variants on this page

Untreated

EORTC-BTG Protocol 26952

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Regimen

Phase II

Induction phase

• Methotrexate (MTX) 1000 mg/m2 IV once on days 1, 10, 20
• Lomustine (Ceenu) 40 mg/m2 PO once on day 1
• Procarbazine (Matulane) 60 mg/m2 PO once per day on days 1 to 7
• Methylprednisolone (Solumedrol) 120 mg/m2 PO/IV every other day from days 1 to 20, and 60 mg/m2 days 20 to 45

Intrathecal component:

• Methotrexate (MTX) 15 mg IT (admixed with Cytarabine (Cytosar)) once on days 1, 5, 10, 15
• Cytarabine (Cytosar) 40 mg IT (admixed with Methotrexate (MTX)) once on days 1, 5, 10, 15

Supportive medications:

• 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 days, those with PR or CR proceed to:

Maintenance phase

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

Intrathecal component:

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

Supportive medications:

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

6-week cycles x 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; European Organization for Research and Treatment of Cancer 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 Organization for Research and Treatment of Cancer Brain Tumor Group. J Clin Oncol. 2003 Jul 15;21(14):2726-31. link to original article contains verified protocol PubMed

High-Dose Methotrexate

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Regimen #1

Study	Evidence	Comparator	Efficacy
Ferreri et al. 2009	Randomized Phase II, >20 per arm	High-dose MTX & Cytarabine	Seems to have inferior CRR

• Methotrexate (MTX) 3500 mg/m2 IV once on day 1: first 500 mg/m2 given over 15 minutes, remaining 3000 mg/m2 given over 3 hours

21-day cycles x 4 cycles

Followed within 4 weeks by whole brain irradiation.

Regimen #2

Study	Evidence
Thiel et al. 2010 (G-PCNSL-SG-1)	Nonrandomized

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

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

14-day cycle x 6 cycles

Patients with a complete response were randomized to whole-brain irradiation versus no further treatment. Patients with less than a complete response were randomized to salvage whole-brain irradiation versus salvage HiDAC.

Regimen #3

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

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

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

14-day cycles x 6 cycles

Patients intolerant of MTX or not achieving CR after 6 cycles were randomized to WBRT or PCV; see article for details.

Regimen #4

Study	Evidence
Batchelor et al. 2003	Phase II

The full dose of 8000 mg/m2 was only given if CrCl was at least 100. For CrCl less than 100, the dose was reduced by the percentage reduction below 100. For example, a CrCl of 50 would mandate a 50% dose reduction.

Induction phase

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

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

Patients achieving CR proceeded to consolidation:

Consolidation

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

14-day cycles x 2 cycles, then:

Maintenance

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

28-day cycles x 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 verified protocol PubMed
2. 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 verified protocol PubMed content property of HemOnc.org
3. 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 (IELSG). 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 verified protocol PubMed
4. 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 verified protocol PubMed
   1. Update: Abstract: Agnieszka Korfel, Eckhard Thiel, Peter Martus, Robert Moehle, Frank Griesinger, Michael Rauch, Alexander Roeth, Bernd Hertenstein, Thomas Fischer, Thomas Hundsberger, Hans-Guenther Mergenthaler, Christian Junghanss, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Naegele, Torsten Pietsch, Michael Weller. G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up. J Clin Oncol 32:5s, 2014 (suppl; abstr 8527) link to abstract

High-Dose Methotrexate & Cytarabine

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Regimen, Ferreri et al. 2009

Study	Evidence	Comparator	Efficacy
Ferreri et al. 2009	Randomized Phase II, >20 per arm	High-dose MTX	Seems to have superior CRR

• Methotrexate (MTX) 3500 mg/m2 IV once on day 1: first 500 mg/m2 given over 15 minutes, remaining 3000 mg/m2 given over 3 hours
• Cytarabine (Cytosar) 2000 mg/m2 IV bid on days 2 & 3

21-day cycles x 4 cycles

Followed within 4 weeks by whole brain irradiation.

References

1. 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 (IELSG). 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 verified protocol PubMed

High-Dose Methotrexate -> Cytarabine & Thiotepa

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Regimen #1

Study	Evidence
Illerhaus et al. 2006	Phase II

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

Supportive medications:

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

One course

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

• Cytarabine (Cytosar) 3 g/m2 IV over 3 hours once per day on days 30 & 31
• Thiotepa (Thioplex) 40 mg/m2 (route not specified) once on day 31

One course

This was for stem cell mobilization and was followed by autologous stem cell transplant.

Regimen #2

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

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

Supportive medications:

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

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

• Cytarabine (Cytosar) 3 g/m2 IV once per day on days 1 & 2
• Thiotepa (Thioplex) 40 mg/m2 (route not specified) once on day 2

21-day cycle x 2 cycles

Stem cells are mobilized and collected after the first cycle; this part was followed by autologous 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 verified protocol 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 verified protocol PubMed

High-Dose Methotrexate & Ifosfamide

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Regimen

Study	Evidence
Thiel et al. 2010 (G-PCNSL-SG-1)	Nonrandomized

All patients received the same induction regimen; however, the induction regimen was high-dose MTX until 2006.

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

14-day cycle x 6 cycles

Patients with a complete response were randomized to whole-brain irradiation versus no further treatment. Patients with less than a complete response were randomized to salvage whole-brain irradiation versus salvage HiDAC.

References

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 verified protocol PubMed
   1. Update: Abstract: Agnieszka Korfel, Eckhard Thiel, Peter Martus, Robert Moehle, Frank Griesinger, Michael Rauch, Alexander Roeth, Bernd Hertenstein, Thomas Fischer, Thomas Hundsberger, Hans-Guenther Mergenthaler, Christian Junghanss, Tobias Birnbaum, Lars Fischer, Kristoph Jahnke, Ulrich Herrlinger, Ludwig Plasswilm, Thomas Naegele, Torsten Pietsch, Michael Weller. G-PCNSL-SG-1 randomized phase III trial of high-dose methotrexate with or without whole brain radiotherapy for primary central nervous system lymphoma: Long-term follow-up. J Clin Oncol 32:5s, 2014 (suppl; abstr 8527) link to abstract

MPV

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MPV: Methotrexate, Procarbazine, Vincristine

Regimen, DeAngelis et al. 2002 (RTOG 93-10)

Phase II

• Methotrexate (MTX) 2500 mg/m2 IV once over 2 to 3 hours on day 1
• Procarbazine (Matulane) 100 mg/m2 PO once per day on days 1 to 7 of odd cycles (1, 3, 5)
• Vincristine (Oncovin) 1.4 mg/m2 (capped at 2.8 mg) IV on day 1

Intrathecal component:

• Methotrexate (MTX) 12 mg IT (via Ommaya) once one week after IV Methotrexate (MTX) administration
• Folinic acid (Leucovorin) 10 mg PO every 6 hours x 8 doses, beginning the evening of IT Methotrexate (MTX) administration

Supportive medications:

• Folinic acid (Leucovorin) 20 mg PO every 6 hours x 12 doses, beginning 24 hours after IV Methotrexate (MTX) administration
• Dexamethasone (Decadron) 16 mg PO once per day x 7 days, then 12 mg PO once per day x 7 days, then 8 mg PO once per day x 7 days, then 6 mg PO once per day x 7 days, then 4 mg PO once per day x 7 days, then 2 mg PO once per day x 7 days (starts with first cycle)

14-day cycles x 5 cycles, followed by:

• Whole-brain irradiation to 45 Gy in 1.80-Gy fractions or to 36 Gy in 1.20-Gy twice-daily fractions

References

1. DeAngelis LM, Seiferheld W, Schold SC, Fisher B, Schultz CJ; Radiation Therapy Oncology Group Study 93-10. 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 verified protocol PubMed

MT-R

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MT-R: Methotrexate, Temozolomide, Rituximab

Regimen, Rubenstein et al. 2013 (CALGB 50202)

Phase II

Induction phase

• Methotrexate (MTX) 8000 mg/m2 IV once over 4 hours on day 1
  • Given for a total of 7 doses.
• Temozolomide (Temodar) 150 mg/m2 PO once per day on days 7 to 11 (odd cycles only)
• Rituximab (Rituxan) 375 mg/m2 IV once on day 3
  • Rituximab omitted for T-cell PCNSL and given for a total of 6 doses in all others.

Supportive medications:

• Folinic acid (Leucovorin) 100 mg/m2 IV every 6 hours, start on day 2, continue until MTX level <0.05

14-day cycles x 8 cycles

Patients achieving CR or CRu were given one additional cycle of methotrexate & temozolomide, followed by consolidation therapy:

Consolidation

• Etoposide (Vepesid) 40 mg/kg IV continuous infusion over 96 hours, days 1 to 4
• Cytarabine (Cytosar) 2 gm/m2 IV Q12H over 2 hours × 8 doses, days 1 to 4

One course

References

1. 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 verified protocol PubMed

R-MPV

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R-MPV: Rituximab, Methotrexate, Procarbazine, Vincristine

Regimen

Study	Evidence
Shah et al. 2007	Phase II
Omuro et al. 2015	Phase II

• Rituximab (Rituxan) 500 mg/m2 IV once over 5 hours on day 1
• Methotrexate (MTX) 3500 mg/m2 IV once over 2 hours on day 2
• Procarbazine (Matulane) 100 mg/m2 PO once per day on days 1 to 7 of odd cycles
• Vincristine (Oncovin) 1.4 mg/m2 (capped at 2.8 mg) IV on day 2

Intrathecal component (only described in the Shah et al. 2007 trial):

• Methotrexate (MTX) 12 mg IT (via Ommaya) once sometime between day 5 and 12 (for patients with positive CSF cytology)

Supportive medications:

• Folinic acid (Leucovorin) 20 to 25 mg every 6 hours for at least 72 hours or until serum MTX level < 1e-8 mg/dL, beginning 24 hours after IV Methotrexate (MTX) administration

14-day cycles x 5 to 7 cycles

In Shah et al. 2007, followed in 3 to 5 weeks by whole-brain irradiation. In Omuro et al. 2015, patients proceeded to autologous stem cell transplant, after 5 cycles if CR achieved, or after 7 cycles for PR/CR at that time.

References

1. 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 verified protocol PubMed
   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 PubMed
2. 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 Jan 7. [Epub ahead of print] link to original article contains verified protocol PubMed

Consolidation and/or maintenance after upfront therapy

Autologous stem cell transplant

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Regimen #1

Study	Evidence
Omuro et al. 2015	Phase II

Treatment preceded by R-MPV.

• Thiotepa (Thioplex) 250 mg/m2 IV once per day on days −9, −8, and −7
• Busulfan (Myleran) 3.2 mg/kg IV once per day on days −6, −5, and −4
• Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days −3 and −2

Stem cell re-infusion occurs on day 0

Regimen #2

Study	Evidence
Illerhaus et al. 2006	Phase II

Treatment preceded by HD-MTX -> Ara-C & Thiotepa. Note that the day count starts from the very beginning of treatment.

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

Supportive medications:

• Granulocyte colony-stimulating factor starting on day 61, continued until WBC > 1x10^9/L for 3 days
• "Standard supportive measures were taken according to institutional guidelines."

Stem cells re-infused on day 56

Followed by whole-brain irradiation.

Regimen #3

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

Treatment preceded by HD-MTX -> Ara-C & Thiotepa.

• Carmustine (BiCNU) 400 mg/m2 IV once on day 1
• Thiotepa (Thioplex) 5 mg/kg (route not specified) BID 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 verified protocol PubMed
2. 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 Jan 7. [Epub ahead of print] link to original article contains verified protocol PubMed

Whole brain irradiation

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Regimen #1

Study	Evidence
Ferreri et al. 2009	Nonrandomized

Treatment preceded by high-dose MTX x 4 verus high-dose MTX & cytarabine x4.

• Any responders: Whole-brain irradiation to 36 Gy plus 9 Gy boost to the tumor bed
• Stable or progressive disease: Whole-brain irradiation to 40 Gy plus 9 Gy boost to the tumor bed

Regimen #2

Study	Evidence
Shah et al. 2007	Phase II

Treatment preceded by R-MPV.

• Complete responders: Whole-brain irradiation to 23.4 Gy in 1.80-Gy fractions
• All others: Whole-brain irradiation to 45 Gy in 1.80-Gy fractions

Regimen #3

Study	Evidence
Illerhaus et al. 2006	Phase II

Treatment preceded by autologous stem cell transplant. Note that the day count starts from the very beginning of treatment.

• Complete responders: Whole-brain irradiation to 45 Gy in 1-Gy fractions, starting on day 90
• Partial responders: Whole-brain irradiation to 50 Gy in 1-Gy fractions, starting on day 90

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 verified protocol PubMed
2. 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 verified protocol PubMed
   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 PubMed
3. 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 (IELSG). 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 verified protocol PubMed

Relapsed/refractory

High-dose Methotrexate & Ifosfamide

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Regimen

Retrospective

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

Supportive medications:

• 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 creatinine clearances <100 mL/min according to the following formula:

• Dose of methotrexate = (creatinine clearance/100) x 4000 mg/m2; the paper did not specify what method was used for calculating creatinine clearance. Patients with creatinine clearance <50 mL/min were excluded from the study.

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

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

References

1. 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 verified protocol PubMed

Whole brain irradiation

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Regimen

Study	Evidence
Nguyen et al. 2005	Phase II

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

• 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 verified protocol PubMed