Policy for Central Nervous System [CNS] Prophylaxis in Lymphoid Malignancies UNCONTROLLED WHEN PRINTED Note: NOSCAN Haematology MCN has approved the information contained within this document to guide the management of adult patients with a Lymphoid Malignancy only: any patients who have been entered in a clinical trial should be managed according to the appropriate trial protocols Document control Prepared by NOSCAN Haematology MCN Approved by NOSCAN Haematology MCN Issue date May 2016 Review date May 2017 Version V2.0 [April 2016] NOSCAN Policy for CNS Prophylaxis in Lymphoid Malignancies V2.0 [April 2016] Page 1 of 7
The following definitions are used throughout this document: Abbreviation ATLL BCSH HAART HIV IT IV FISH LDH MALT lymphoma MTX MYC NHL NOS PTCL R-CHOP R-CVP Definition Adult T-cell Leukaemia/Lymphoma British Committee for Standards in Haematology Highly Aactive Antiretroviral Therapy Human Immunodeficiency Virus Intrathecal Intravenous Fluorescence In Situ Hybridization Lactate DeHydrogenase Mucosa-associated Lymphoid Tissue lymphoma Methotrexate Myelocytomatosis/ a regulator gene Non-Hodgkin Lymphoma Not Other Specified Peripheral T-Cell Lymphoma Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone Rituximab, Cyclophosphamide, Vincristine, Prednisolone NOSCAN Policy for CNS Prophylaxis in Lymphoid Malignancies V2.0 [April 2016] Page 2 of 7
Policy for CNS Prophylaxis in Lymphoid Malignancies Background CNS relapse is rare in most tumour types but conveys very poor prognosis when it occurs. The risk of CNS relapse is dependent on a number of factors including histological subtype, site of primary disease and other factors eg LDH. Some patients will have CNS disease at diagnosis, which is outside the scope of this document. CNS disease usually occurs early with a median of 5-12 months from diagnosis with ~33% of cases occurring during primary therapy [1-3]. Disease can be either parenchymal or leptomeningeal, therefore prophylaxis must adequately treat both. Recent BCSH guidelines recommend intrathecal therapy (IT) but acknowledge the weaknesses in the evidence for IT prophylaxis.[3] Systemic therapy with high dose methotrexate (MTX) is suggested as a possible alternative. Risk Stratification Burkitt s Lymphoma, Lymphoblastic Lymphoma & ATLL All cases high risk (>20%) CNS prophylaxis incorporated in standard treatment schedules Diffuse Large B Cell Lymphoma overall risk 5% [4, 5] High Risk Subgroups Disease sites testes [6, 7], breast [8], paraspinal masses, intravascular lymphoma [9], epidural space [10], paranasal sinuses MYC +ve (MYC translocation demonstrable by FISH) [11] High LDH and >1 extranodal sites [12, 13] Isolated renal and marrow involvement are rare and the reported high incidence of CNS relapse is confounded by other better established high risk features (eg high LDH, multiple extranodal sites) [3, 14] Mantle Cell Lymphoma 4-9% [15] CNS relapse usually seen with systemic relapse Insufficient evidence for routine prophylaxis Intensive treatment includes high dose Cytarabine which will penetrate CNS Peripheral T Cell Lymphoma- <4% [16] No published studies specifically address risk of CNS relapse in PTCL Retrospective analyses found no cases in patients with Angioimmunoblastic T cell Lymphoma, Hepatosplenic T cell Lymphoma or Enteropathy associated T cell Lymphoma Suggested for PTCL, NOS with risk factors cf DLBCL Anaplastic NHL 1-3% Insufficient data for primary prophylaxis Follicular Lymphoma - <1% CNS relapse mainly seen with high grade transformation NOSCAN Policy for CNS Prophylaxis in Lymphoid Malignancies V2.0 [April 2016] Page 3 of 7
No rationale for routine prophylaxis Small lymphocytic lymphoma - <1% MALT lymphoma - <1% Hodgkin s lymphoma - <0.5% No rationale for routine prophylaxis HIV related lymphoma Increase in Primary CNS Lymphoma and CNS involvement in systemic NHL (17-23%) CNS prophylaxis recommended for all patients [17] Due to concerns about toxicity and interactions with HAART IT MTX is preferred over IV MTX for this specific situation Indications for CNS prophylaxis In view of the above the following should ALWAYS receive CNS prophylaxis unless they are too unfit: Burkitt s lymphoma Lymphoblastic lymphoma ATLL DLBCL & PTCL (NOS) if: 1. High LDH with >1 extranodal site 2. Involvement of testes, breast, epidural space, paraspinal mass, paranasal sinuses or intravascular lymphoma 3. MYC +ve 4. HIV +ve Patients not falling into the above categories should be considered on an individual basis at the local MDT. CNS prophylaxis regimen CNS prophylaxis is included in standard protocols for Burkitt s lymphoma, Lymphoblastic lymphoma and ATLL DLBCL or PTCL (NOS): IT MTX has been most commonly used historically however 2 large randomised controlled trials have failed to show any protective benefit [1, 2]. Additionally, a recent study in patients treated with chemoimmunotherapy also failed to demonstrate benefit of IT MTX [18]. Furthermore, studies that have demonstrated a benefit of CNS prophylaxis have combined IT MTX with High Dose MTX [13, 19]. A retrospective study of DLBCL has shown that High Dose MTX can be safely delivered with R-CHOP and is associated with a low risk (2 out of 65 high risk patients) of CNS relapse [20]. NOSCAN Policy for CNS Prophylaxis in Lymphoid Malignancies V2.0 [April 2016] Page 4 of 7
Recommendation (Also see page 7) Published evidence suggests that lower doses will be ineffective [1, 12, 21, 22]. If 3g/m 2 cannot be safely delivered due to liver or renal impairment or concerns about tolerability due to comorbidity/frailty then prophylaxis with IT MTX 12.5mg for 3 doses with cycles 2-4 of R-CHOP may be considered in line with current BCSH Guidelines [3]. References 1. Bernstein, S.H., et al., Natural history of CNS relapse in patients with aggressive non-hodgkin's lymphoma: a 20-year follow-up analysis of SWOG 8516 -- the Southwest Oncology Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2009. 27(1): p. 114-9. 2. Boehme, V., et al., CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood, 2009. 113(17): p. 3896-902. 3. McMillan, A., et al., Guideline on the prevention of secondary central nervous system lymphoma: British Committee for Standards in Haematology. British journal of haematology, 2013. 163(2): p. 168-81. 4. Hill, Q.A. and R.G. Owen, CNS prophylaxis in lymphoma: who to target and what therapy to use. Blood reviews, 2006. 20(6): p. 319-32. 5. McMillan, A., Central nervous system-directed preventative therapy in adults with lymphoma. British journal of haematology, 2005. 131(1): p. 13-21. 6. Fonseca, R., et al., Testicular lymphoma is associated with a high incidence of extranodal recurrence. Cancer, 2000. 88(1): p. 154-61. 7. Zucca, E., et al., Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2003. 21(1): p. 20-7. 8. Gholam, D., et al., Primary breast lymphoma. Leukemia & lymphoma, 2003. 44(7): p. 1173-8. 9. Shimada, K., et al., Central nervous system involvement in intravascular large B- cell lymphoma: a retrospective analysis of 109 patients. Cancer science, 2010. 101(6): p. 1480-6. 10. MacKintosh, F.R., et al., Central nervous system involvement in non-hodgkin's lymphoma: an analysis of 105 cases. Cancer, 1982. 49(3): p. 586-95. 11. Savage, K.J., et al., MYC gene rearrangements are associated with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP chemotherapy. Blood, 2009. 114(17): p. 3533-7. 12. van Besien, K., et al., Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood, 1998. 91(4): p. 1178-84. NOSCAN Policy for CNS Prophylaxis in Lymphoid Malignancies V2.0 [April 2016] Page 5 of 7
13. Haioun, C., et al., Incidence and risk factors of central nervous system relapse in histologically aggressive non-hodgkin's lymphoma uniformly treated and receiving intrathecal central nervous system prophylaxis: a GELA study on 974 patients. Groupe d'etudes des Lymphomes de l'adulte. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2000. 11(6): p. 685-90. 14. Villa, D., et al., Diffuse large B-cell lymphoma with involvement of the kidney: outcome and risk of central nervous system relapse. Haematologica, 2011. 96(7): p. 1002-7. 15. Ghielmini, M. and E. Zucca, How I treat mantle cell lymphoma. Blood, 2009. 114(8): p. 1469-76. 16. Pro, B. and G. Perini, Central nervous system prophylaxis in peripheral T-cell lymphoma. Blood, 2010. 115(26): p. 5427. 17. Dunleavy, K. and W.H. Wilson, How I treat HIV-associated lymphoma. Blood, 2012. 119(14): p. 3245-55. 18. Schmitz, N., et al., CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO, 2012. 23(5): p. 1267-73. 19. Tilly, H., et al., Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-hodgkin lymphoma. Blood, 2003. 102(13): p. 4284-9. 20. Abramson, J.S., et al., Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer, 2010. 116(18): p. 4283-90. 21. Evans, W.E., et al., Methotrexate cerebrospinal fluid and serum concentrations after intermediate-dose methotrexate infusion. Clinical pharmacology and therapeutics, 1983. 33(3): p. 301-7. 22. Perez-Soler, R., T.L. Smith, and F. Cabanillas, Central nervous system prophylaxis with combined intravenous and intrathecal methotrexate in diffuse lymphoma of aggressive histologic type. Cancer, 1986. 57(5): p. 971-7. NOSCAN Policy for CNS Prophylaxis in Lymphoid Malignancies V2.0 [April 2016] Page 6 of 7
Appendix 1 - Systemic Anti Cancer Therapy NOSCAN Haematology MCN has agreed the maximum routine starting doses and treatment durations in the management of Lymphoid Malignancies across the North of Scotland as follows Note: Where available, Clinical Trials should be considered the preferred option for eligible patients Methotrexate (MTX) Clinical Indications: for CNS Prophylaxis in Lymphoid Malignancies Methotrexate 3.5mg/m² IV infusion (3 hrs duration) on Day 8 Day 4 of cycle 2 RCHOP only. Rituximab + Cyclophosphamide + Doxorubicin + Vincristine + Prednisolone (R- CHOP) Clinical Intent: Curative and/or Disease Control Rituximab 375mg/m² IV infusion (1 hour duration) on Day 1 Cyclophosphamide 750mg/m² IV infusion (bolus) on Day 1 Doxorubicin 50 g/m² IV infusion (bolus) on Day 1 Vincristine 1.4m g/m² (2mg cap) IV infusion (10 minute duration) on Day 1 Prednisolone 100mg orally (once daily) on Days 1-5 only Repeat every 3 weeks/21 days Continue for up to 6 cycles Rituximab + Cyclophosphamide + Vincristine + Prednisolone (R-CVP) Clinical Intent: Curative and/or Disease Control Rituximab 375mg/m² IV infusion (1 hour duration) on Day 1 Cyclophosphamide 750mg/m² IV infusion (bolus) on Day 1 Vincristine 1.4m g/m² (2mg cap) IV infusion (10 minute duration) on Day 1 Prednisolone 100mg orally (once daily) on Days 1-5 Repeat every 3 weeks/21 days Continue for up to 6 cycles NOSCAN Policy for CNS Prophylaxis in Lymphoid Malignancies V2.0 [April 2016] Page 7 of 7