1. ANAPLASTIC LARGE CELL LYMPHOMA:- a clinico-pathological perspective Lymphoma Meeting – The Alfred Hospital Monday 14 th April, 2008 Dr Andrew Guirguis Clinical Haematology Registrar

2. Outline of presentation Classification Features (including immunophenotype) Clinical features (including prognostic features) Rx modalities Chemo Role of transplantation Novel therapies

3. Classification One of the T cell lymphomas – nodal (-ve prognostic factor) Haematology 2006 – Therapy of peripheral T/NK neoplasms

4. And yet many difficulties remain…. What comprises anaplastic large cell lymphoma? Much variation within studies Multiple variants in studies – small cell, large cell, histiocytic, Hodgkin’s like etc Expresses CD30 and EMA (epithelial membrane antigen) – Benharroch et al B-cell antigens – to be included or not to be?? 2 main types:- 1’ systemic* 1’ cutaneous Other:- HIV related, those with lymphomatoid papulosis, mycosis fungoides, Hodgkin’s etc

6. Primary systemic ALCL:- Large lymphoid cell neoplasm – pleomorphic nuclei with multiple nucleoli and abundant cytoplasm +ve for CD30 and T cell antigens Not limited to the skin Hallmark cell- Warnke et al

7. Variants Common type Small cell variant Lymphohistiocytic Hodgkin’s disease like variant (? Nodular sclerosis)** B cell specific activation protein Reclassified by WHO

8. Immunophenotype T cell markers – including HLA DR, CD25 60% - CD3 / CD 43 / CD45RO Cytogenetics – most have TCR rearrangement; not seen in 20-30% 2;5 translocation – anaplastic lymphoma kinase*

9. Translocation (2;5) Discovered in late 80s – 20-50% Results in fusion protein of NPM gene and anaplastic lymphoma kinase (ALK)** - activation of TK domain End result:- increased cell proliferation and reduced apoptosis Associated with better prognosis Highly specific to ALCL of T/null type. Rarely seen in other lymphoma types May be fused to other proteins other than NPM ALK protein – more common in children + young adults

11. JCO – Molecular Biology of ALCL (Ki +ve) – Kutok et al 2002

12. Re-classification:- a) 1’ systemic ALK +ve b) 1’ systemic ALK –ve c) 1’ cutaneous ALK -ve Haematology 2001 – T cell and NK cell disorders

14. Clinically speaking… 2% of all NHL (2 nd most common T-cell lymphoma) Occurs in 30s with M > F Bimodal distribution Extranodal involvement

15. Prognostic factors ALK CD56 +ve International prognostic index Survivin expression Inhibitor of apoptosis family – irrespective of ALK expression – Schlette et all (JCO 2003) High BCL2 expression Caspase 3 (component of pro-death pathways) - +ve

16. Rx options Much data looks at ALCL under the umbrella of T cell lymphomas Distinction is important Progress is impaired by rarity of the disease, chemoresistance of lymphoma other than ALCL ALK +ve and lack of RCT No clear consensus re optimal Rx

17. Haematology 2001 – T cell and NK cell disorders

19. 2. Risk stratification More well defined in children Not as clear in adults Studies in the adult population to date have not performed this step well !!

20. Specific Rx Much data in paediatric population:- Trials:- SFOP HM89/91; NHL-BFM90, UKCCSG, AIEOP, POG etc BFM (Berlin Frankfurt Munster) – excellent results using B-cell type Rx – EFS 5yrs of 76%. Cytoreductive phase then stratification according to stage. APO strategy – 70% EFS for advanced stage disease. Anthracycline containing. Induction phase then maintenance.

21. What about the big people? Usual Rx is multiagent anthracycline containing regimen (5ysr is 60-93% if ALK +ve vs 11-46% for ALK –ve disease) Outcome is inferior to children Poorer Px:- ALK –ve, High IPI, CD56 or survivin +ve

22. Prospective trial – non randomised (1991-97) N = 36 Rx:- MOPP / EBV / CAD hybrid scheme (mechlorethamine substituted by CCNU alternate cycles, vindesine, melphalan, PNL; then D8 – epidoxorubicin, vincristine + procarbazine; D15 – vinblastine + bleo Chemo each 28 days for 6 cycles +/- XRT Median f’up – 35mo. Max – 7.3yrs Remission rate 78% (CR) for CRT +/- XRT. At 74mo – 69%. No significant difference if XRT used or not! T phenotype treated with CRT + XRT – better survival than B-ALCL. Limitations:- Included B-cell ALCL?? (Haralambieva et al – BJH 2000) No distinction b/w ALK +ve and ALK -ve

23. What is becoming apparent… ALK+ve do better than ALK-ve (10yr follow-up 82% vs 28% - Falini et al). Of +ve pts – low-intermediate risk IPI vs high/intermediate risk

25. Primary Cutaneous ALCL Features:- limited to skin, no extracutaneous disease Histopathology:- large lymphoid cell neoplasm Immunophenotyping:- -ve ALK and EMA; CD30 +ve, CD4+ve Older adults* Solitary lesion or often localised Px favourable long term* Rx:- localised Important to rule out systemic disease with cutaneous spread – 5ysr 29-44% vs 90-100%. If ALK +ve – look for evidence of systemic disease

26. Should we transplant? Autologous transplant – role in first relapse is accepted as std of care (PARMA study – favour SCT over platinum based chemo) How about CR1? Controversial ? Transplant earlier in those with adverse prognostic factors Again data is difficult to assess – ALCL not looked at alone. PTCL often looked at as one entity*

27. Autologous hematopoietic SCT in peripheral T cell lymphoma using uniform high dose regimen – S mith et al – BMT 07 N=32 (PTCL unspecified 11 and ALCL 21). ASCT for 1’ refractory disease (no response to Rx or progression) or relapse 6 pts in CR1/PR1, 8 for 1’ refractory; 17 for relapsed, 1 uknown CR1/PR1 patients – all received anthracycline based chemo For relapse – salvage chemo given Transplant – busulfan (1mg/kg QID x 14), etoptoside (60mg/kg IV), cyclophos (60mg/kg IV for 2 days)

28. Results:- Median follow-up 30 mo 5ysr OS 34%; RFS 18% - very poor! No significant difference b/w OS and RFS – for ALCL and PTCL-us No significant difference b/w OS based on disease status at time of transplant. Limitations:- ? Too small ALK status not looked at. Fanin et al – 64 ALCL pts – inferior survival in those transplanted post relapse or refractory ALCL cf first remission. Again no’s too small and ? ALK status

29. Present recommendations? If ALK +ve – do not routinely transplant in CR1. If relapse – salvage chemo and SCT. Esp not recommended if IPI is low. For ALK+ve and high IPI – consider stem cell support. ALK-ve pts – consider early SCT

31. Allogeneic transplants Case reports in children Would expect fewer relapses Higher mortality rates during conditioning.

32. Newer agents ? ALK inhibitors (Blood 06) ? SGN30 – antiCD30 (JCO 07 – Ansell et al – Phase I/II studies)

33. References:- 1. Dx + Rx of childhood NHL – ASH 07 – Reiter 2. Should adolescents with NHL be treated as old children or young adults? Sandlund – ASH Haem 07 3. T cell and NK cell lymphoproliferative disorders – Haem 01 4. Therapy of peripheral T / NK neoplasm’s – Haem 06 5. Aggressive Peripheral T cell lymphomas – Haem 05 6. Auto hematopoietic SCT in peripheral T cell lymphoma using uniform high dose regimen – Smith et al – BMT 2007 7. Clinical characteristics, Rx outcome and survival of 36 adult pts with 1’ ALCL, Haematologica 1999 8. Phase I/II study of an anti-CD30 monoclonal antibody in HL + ALCL CD30 anaplastic large cell lymphoma:- a review of its histopathologic, genetic and clinical features. 9. 1’ systemic CD30+ve anaplastic LCL in the adult: sequential intensive Rx with F-MACHOP regimen +/- XRT and ABMT – Fanin et al – Blood 1996