Mantle cell lymphoma overview and management

Mantle cell lymphoma overview

1. MANTLE CELL LYMPHOMA

2. INTRODUCTION Uncommon B cell lymphoma A mixed bag of subtypes Characterized by heterogenous behavior – course ranging from indolent to highly aggressive with poor prognosis High rate of extra nodal involvement – bone marrow (53% –82%), blood(50%), liver ( 25% ) & the gastro-intestinal tract (20 – 60 %)

3. Epidemiology Median age of diagnosis – mid 60s – 70s, in Asian countries median age ~ 60yrs Striking male predominance - > 70 % cases Strong tendency to present with advance stage – most present in stage III/IV Peculiar tendency to invade GI tract – Lymphomatous polyposis Median OS 3-5yrs, with treatment > 10yrs

4. Pathogenesis

5. VARIANTS - INDOLENT Mantle cell neoplasia in situ Cyclin D 1 + ve cells in mantle zone without nodal architecture disruption Low rate of disease progression Leukemic non nodal 10-20 % Derived from post germinal center antigen exposed B cell IGHV mutated & SOX11 neg Typically present with peripheral blood monoclonal lymphocytosis and splenomegaly without significant LNpathy

6. VARIANTS – AGGRESSIVE Classical 80-90 % cases Nodal / extranodal diseased B Symptoms Splenomegaly TP53 mutated Blastoid morphology High proliferation index & high MIPI score Resistance to induction therapy Poor prognosis – median OS ~ 1.8yrs

7. Diagnosis Excision biopsy or bone marrow aspiration and biopsy Immunophenotype: CD 5 + , CD 43 + , CD 20 + , Cyclin D1 + , FMC7 + , SOX11 +/- CD 10 - , CD 23 - Hallmark translocation t(11:14) – By karyotyping or FISH

8. STAGING

9. PROGNOSTIC FACTORS Performance status Advance age High MIPI Bulky disease ( node > 5cm, spleen > 20cm) Blastoid / pleomorphic morphology Ki 67 >30% SOX 11 + ve on IHC TP 53 mutation or del 17p Early relapse (POD < 24)

10. PROGNOSTIC SCORES

11. PROGNOSTIC SCORES

12. MANAGEMENT Induction Consolidation – Auto SCT Maintenance

13. MANAGEMENT – INDUCTION REGIMENS Timothy s Fenske

14. MANAGEMENT – INDUCTION REGIMENS – (NCCN)

15. MANAGEMENT – INDUCTION REGIMENS R – Hyper CVAD / R- MA ( MTx + High dose ARA C) Median FFS: 4.8 yrs Death from acute toxicity: 5.2% 2 nd malignancy ( AML & MDS): 6.2 % Nordic MCL 2 ( R Maxi CHOP / R– ara C f/b Auto SCT) 9 % developed 2 nd malignancy on long term follow up

16. MANAGEMENT – INDUCTION REGIMENS R - CHOP / R - DHAP Age < 65 yrs R– CHOP f/b ASCT vs R - CHOP / R – DHAP f/b ASCT 2.4 % secondary leukemia and 4.3% other cancer in ara -C group

17. MANAGEMENT – INDUCTION REGIMENS Retrospective analysis of LyMA trial ( R – DHAP X 4 # f/b ASCT f/b Rituximab maintenance) compared Cisplatin vs Carboplatin vs Oxaliplatin 4 yr PFS: 65 % vs 65 % vs 86.5 % 4 yr OS: 75.9% vs 75.9 % vs 92 %

18. MANAGEMENT – INDUCTION REGIMENS BR/R- HiDAC f/b Auto SCT N = 87 ORR: 97 %, CR: 90% 92 % completed induction and 84% auto ASCT 3 yrs PFS: 83 % , 3 yr OS: 92 % Gr 3-4 AEs: Thrombocytopenia 85%, Neutropenia: 83%, FN: 15 %

19. MANAGEMENT Timothy s Fenske

20. MANAGEMENT – INDUCTION REGIMENS (NCCN)

21. MANAGEMENT – INDUCTION REGIMENS

22. MANAGEMENT – INDUCTION REGIMENS

23. MANAGEMENT – INDUCTION REGIMENS R-BAC 500 Phase II, n: 57, Italian Median age: 71yrs Rituximab 375mg/m 2 (Day 1) Bendamustin 70mg/m 2 (Day 2-3), ara C 500 mg/m 2 (Day 2-4) ORR: 91%, CR: 91 %, Gr 3-4 AEs: Neutropenia 49%, thrombocytopenia 52%, dose reduction: 72%

24. MANAGEMENT – INDUCTION REGIMENS BR + Ibrutinib (SHINE Trial) Phase III, double blind n: 523 Age > 65yrs BR + Ibrutinib vs BR + Placebo f/b Rituximab +/- Ibrutinib maintenance x 12 doses

25. ASCT CONSOLIDATION

26. PFS post CR PFS post PR OS

27. Conclusion Only PFS benefit, no OS benefit Improved OS: High MIPI Received CHOP like induction Blastoid or pleomorphic histology Did not receive cytrabine in induction

28. TRIANGLE TRIAL

29. MAINTENANCE

30. NORDIC MCL n = 112 ( Transplanted) Rituximab maintenance vs Observation 5 yr PFS: 73% vs 68 %, HR: 0.36(95 % CI 0.20 – 0.84) OS: 78 % both arms

31. StiL MAINTAIN TRIAL n = 120 Median age: 71yrs Stage II bulky ( > 7cm ), III and IV BR X 6 cycles f/b R q2 months x 2 yrs (n = 59) vs Observation (n = 61) PFS: NR vs 54.7 months, HR: 0.64 ( 95% CI 0.36 – 1.14) p=0.13 OS: 69.6 months vs NR, HR: 1.53 ( 95% CI 0.73 – 3.32) p=0.27

32. Ongoing trial ECOG ACRIN 4151 Any induction MRD Neg CR – ASCT + 3 yr maintenance Rituximab vs 3 yr maintenance Rituximab

33. MAINTENANCE

34. How will I treat

35. THANK YOU