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ANAPLASTIC LARGE CELL LYMPHOMA:- a clinico-pathological perspective

ANAPLASTIC LARGE CELL LYMPHOMA:- a clinico-pathological perspective. Lymphoma Meeting – The Alfred Hospital Monday 14 th April, 2008 Dr Andrew Guirguis Clinical Haematology Registrar. Outline of presentation. Classification Features (including immunophenotype)

JasminFlorian
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ANAPLASTIC LARGE CELL LYMPHOMA:- a clinico-pathological perspective

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  1. ANAPLASTIC LARGE CELL LYMPHOMA:- a clinico-pathological perspective Lymphoma Meeting – The Alfred Hospital Monday 14th 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

  5. 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

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

  7. 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*

  8. 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

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

  10. Re-classification:- • 1’ systemic ALK +ve • 1’ systemic ALK –ve • 1’ cutaneous ALK -ve Haematology 2001 – T cell and NK cell disorders

  11. Haematology 2001 – T cell and NK cell disorders

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

  13. 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

  14. 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

  15. Haematology 2001 – T cell and NK cell disorders

  16. 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!!

  17. 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.

  18. 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

  19. 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

  20. 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

  21. 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

  22. 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*

  23. Autologous hematopoietic SCT in peripheral T cell lymphoma using uniform high dose regimen – Smith 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)

  24. 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

  25. 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

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

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

  28. 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

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