Br J Haematol - 2022 - Cwynarski - Management of secondary central nervous system lymphoma

Management of Secondary Central Nervous System Lymphoma (SCNSL) British Journal of Haematology Good-Practice Paper, 2023;200:160-169 EXECUTIVE SUMMARY • SCNSL (= diffuse large B-cell lymphoma that involves the CNS at diagnosis or relapse) is uncommon, heterogeneous and carries poor prognosis if not treated intensively. • Three clinical situations are recognised: 1. Treatment-naïve synchronous systemic + CNS disease (TN-SCNSL) 2. Relapsed isolated CNS disease (RI-SCNSL) 3. Relapsed concomitant systemic + CNS disease (RC-SCNSL) • Best outcomes are obtained with high-dose methotrexate (HD-MTX)–containing induction followed by thiotepa/BCNU-based autologous stem-cell transplantation (ASCT). • The largest prospective study (MARIETTA, n = 75) showed 46 % 2-year overall survival (OS) in the intent-to-treat population and 71 % 2-year progression-free survival (PFS) in the TN-SCNSL subset. • Older, frailer patients and those with RC-SCNSL continue to have high unmet therapeutic needs. • The guidance provides graded, evidence-based recommendations for diagnosis, staging, treatment, response assessment, consolidation, radiotherapy, relapse management and palliation. KEY TOPICS AND MAIN POINTS 1. Diagnosis & Staging • Mandatory multimodality imaging: contrast MRI brain ± spine plus whole-body FDG-PET-CT. • Additional tests in men (testicular ultrasound), ophthalmology review, and lumbar puncture with CSF cytology/flow. • Tissue confirmation whenever feasible; exceptions allowed in defined circumstances. 2. Assessing Fitness • Neuro-cognitive deficit and poor performance status (PS) are common; frailty tools (CCI, G8) may help decide intensity. • Steroid “pre-phase” and single-agent HD-MTX (≥3 g/m²) can improve PS before multi-agent therapy. 3. Therapeutic Strategies • Intensive option of choice: MARIETTA protocol (MATRix ×3 → R-ICE ×3 + IT chemo) followed by BCNU/thiotepa ASCT. • Modified or less-intensive regimens (e.g., R-MTX-Ara-C ± R-ICE; R-CODOX-M/R-IVAC; R-CHOP + intercalated HD-MTX) for selected or older patients. • Consolidation with thiotepa-based ASCT is critical; dose-adjust for age >65 yr. • Whole-brain radiotherapy (WBRT) is reserved for selected settings (post-ASCT residual disease, failed stem-cell harvest, late isolated CNS relapse). 4. Response Assessment • MRI brain ± spine every two cycles; systemic imaging (CT/PET-CT) mid-treatment, pre-ASCT and end-therapy. 5. Relapse & Refractory Disease • RC-SCNSL has the worst outcome (MARIETTA 2-y PFS 14 %). • Options after HD-MTX failure: clinical trials, CAR-T cells, BTK or IMiD agents, WBRT, or best supportive care (BSC). 6. Novel / Emerging Therapies • CD19 CAR-T shows ~80 % initial responses but short median PFS (~3 m) in small SCNSL cohorts. • Ibrutinib, lenalidomide and other CNS-penetrating small molecules under study; access mainly via trials/compassionate use. IMPORTANT DATA & STATISTICS Population-based / Trial data • MARIETTA (IELSG42) – 75 pts (43 % TN, 20 % RI, 37 % RC): – Median age 58 yr (23-70), ECOG ≤3. – 2-y PFS 46 % (overall); 71 % (TN), 40 % (RI), 14 % (RC). – 49 % proceeded to ASCT; 2-y OS 46 %. • ASCT retrospective (n = 134): 2-y PFS 61 % (38 % TN, 62 % R/R). • MATRix real-world (PCNSL): high toxicity in pts >70 yr or PS 3-4; 76 % needed dose reduction; 11 % ICU admission. • R-CODOX-M/R-IVAC (DLBCL trial): 10 SCNSL pts – 2-y PFS 70 % (no ASCT). • CAR-T (TRANSCEND subset): 6 SCNSL pts, 3 CRs; separate cohort (n = 7) median PFS 83 days. Radiotherapy • Salvage WBRT median survival 24 m; 30 % durable remissions, but >50 % severe neurotoxicity in elderly. RECOMMENDATIONS (Organised by clinical pathway; original GRADE strength retained) A. Diagnosis & Imaging 1. Obtain pre-treatment contrast MRI brain (with diffusion) and whole-body FDG-PET-CT for all patients. (1A) 2. Add contrast MRI of the entire spine when symptoms or PET-CT findings suggest spinal disease. (1B) 3. Perform testicular ultrasound in all male patients. (1C) 4. Arrange slit-lamp examination to look for ocular (vitreo-retinal) involvement. (1B) 5. Avoid corticosteroids before biopsy whenever possible to preserve diagnostic accuracy. (1A) 6. Consider CNS biopsy in TN- or RC-SCNSL, but it is not obligatory if a systemic biopsy proves high-grade lymphoma and MRI features are typical. (1B) 7. Biopsy any previously un-sampled CNS lesion that is refractory to therapy to rule out alternative diagnoses. (1B) 8. Forgo biopsy in frail patients when care is purely palliative. (1B) 9. Aim to biopsy RI-SCNSL, especially if CNS relapse occurs >2 years after initial DLBCL; (1B) diagnosis without biopsy is acceptable if relapse occurs ≤2 years, MRI is typical and lesion inaccessible. (1B) 10. Perform lumbar puncture once imaging shows it is safe; positive cytology/flow is sufficient evidence of CNS disease. (1B) 11. Undertake vitreoretinal biopsy/vitrectomy when eye involvement is suspected, unless CNS lymphoma is already proven. (1B) 12. Discuss every confirmed SCNSL case in a specialist multidisciplinary team (MDT). (1A) B. Treatment Site & Trial Access 13. Refer/transfer patients to centres experienced in CNS lymphoma management. (1B) 14. Offer participation in clinical trials whenever available. (1A) C. Initial Measures & Conditioning for Therapy 15. A short steroid pre-phase can be used once diagnosis is secured. (2B) 16. In older patients or ECOG ≥ 2, start with rituximab + HD-MTX (≥3 g/m²) alone to improve PS before combining agents. (2B) D. Preferred Induction/Consolidation Regimens 17. Use the full MARIETTA protocol (MATRix ×3 → R-ICE ×3 + IT chemo) for fit patients <70 yr with TN- or RC-SCNSL who are candidates for ASCT. (1B) 18. If complete or good partial response is achieved after four cycles of immunochemotherapy, proceed directly to BCNU/thiotepa ASCT to reduce toxicity. (2B) 19. For RI-SCNSL <70 yr, give MARIETTA or alternatively four cycles of MATRix alone, followed by ASCT. (2B) 20. In TN-SCNSL, one-two cycles of R-CHOP may be given upfront when life-threatening systemic disease needs rapid control before MATRix. (3C) 21. In MATRix, reduce cytarabine by ≥25 % in cycle 1 for patients >60 yr or with poor PS, and cut doses in later cycles if severe infectious or haematologic toxicity occurs. (2B) 22. R-CODOX-M/R-IVAC is an alternative for TN-SCNSL patients <50 yr, PS < 2, wishing to avoid ASCT (limited data). (2B) 23. Offer R-MTX-Ara-C (± dose-adjusted R-ICE) to ASCT-eligible patients unsuitable for full-dose MATRix (e.g., selected >70 yr). (2C) 24. Consider R-CHOP with intercalated HD-MTX for TN-SCNSL unfit for MATRix modifications. (2C) 25. For TN-SCNSL with leptomeningeal—but not parenchymal—disease who cannot tolerate HD-MTX, give R-CHOP plus intrathecal chemotherapy. (2B) 26. Patients ineligible for intensive therapy should receive trials, best supportive care, or palliative regimens (IT chemo for leptomeningeal disease only, WBRT for symptomatic CNS disease, or BTK/IMiD agents where accessible). (2C) E. Response Assessment 27. TN- and RC-SCNSL: do brain (± spine) MRI every 2 cycles and systemic CT/PET-CT after 2-3 cycles; repeat both before ASCT and at end of treatment. (1B) 28. RI-SCNSL: do brain (± spine) MRI every 2 cycles; systemic imaging per local policy; repeat before ASCT and at therapy completion. (1B) F. Autologous Stem-Cell Transplantation 29. Re-evaluate ASCT suitability throughout treatment, weighing toxicity vs PS improvement. (2B) 30. Consolidate with BCNU/thiotepa ASCT when at least PR in CNS and partial or complete metabolic response systemically is achieved. (1B) 31. Harvest stem cells early, ideally after the second induction cycle. (1B) 32. In patients >65 yr, lower thiotepa from 20 mg/kg to 10 mg/kg. (2B) 33. Re-stage 2 months post-ASCT with MRI brain and whole-body PET-CT. (1B) G. Radiotherapy 34. For patients <60-65 yr with residual CNS disease but systemic CR after ASCT, consider consolidative WBRT. (2B) 35. Use WBRT instead of ASCT when stem-cell collection fails. (2B) 36. Consider WBRT for isolated CNS relapse after multiple systemic therapies. (2B) 37. Ensure that a radiotherapy specialist in CNS lymphoma participates in MDT decisions. (1B) H. Relapsed / Refractory or Unfit Patients 38. Offer radiotherapy or best supportive care (including corticosteroids) to unfit patients or those failing HD-MTX or multiple prior regimens. (2C) 39. Where feasible, consider CAR-T therapy, BTK inhibitors or IMiDs for progressive disease after intensive therapy or multiple relapses. (2C) CONCLUSIONS • Intensive HD-MTX–based induction followed by thiotepa-containing ASCT remains the cornerstone of potentially curative therapy for fit patients with SCNSL. • Outcomes are markedly better for TN- and RI-SCNSL than for RC-SCNSL, underscoring the need for earlier recognition and treatment. • Dose tailoring, alternative regimens and integration of novel agents/ CAR-T therapy are critical for elderly, frail or multiply relapsed patients. • Continued clinical-trial enrolment and collaborative research are essential to refine strategies and improve survival while minimising neurotoxicity.