Download Anaplastic Large Cell Lymphoma:- a clinico

ANAPLASTIC LARGE CELL
LYMPHOMA:a clinico-pathological perspective
Lymphoma Meeting – The Alfred Hospital
Monday 14th April, 2008
Dr Andrew Guirguis
Clinical Haematology Registrar
Outline of presentation
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Classification

Features (including immunophenotype)
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Clinical features (including prognostic features)
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Rx modalities
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Chemo
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Role of transplantation
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Novel therapies
Classification
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One of the T cell lymphomas – nodal (-ve prognostic factor)
Haematology 2006 – Therapy of peripheral T/NK neoplasms
And yet many difficulties
remain….
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What comprises anaplastic large cell lymphoma?
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Much variation within studies
Multiple variants in studies – small cell, large cell, histiocytic, Hodgkin’s like etc
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Expresses CD30 and EMA (epithelial membrane antigen) – Benharroch et al
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B-cell antigens – to be included or not to be??
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2 main types:
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1’ systemic*
1’ cutaneous
Other:- HIV related, those with lymphomatoid papulosis, mycosis fungoides, Hodgkin’s
etc
Primary systemic ALCL:-
Hallmark cellWarnke et al
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Large lymphoid cell neoplasm –
pleomorphic nuclei with multiple nucleoli
and abundant cytoplasm

+ve for CD30 and T cell antigens

Not limited to the skin
Variants
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Common type
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Small cell variant
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Lymphohistiocytic
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Hodgkin’s disease like variant (? Nodular sclerosis)**
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B cell specific activation protein
Reclassified by WHO
Immunophenotype
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T cell markers – including HLA DR, CD25
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60% - CD3 / CD 43 / CD45RO
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Cytogenetics – most have TCR rearrangement; not seen in 20-30%
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2;5 translocation – anaplastic lymphoma kinase*
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
JCO – Molecular Biology of ALCL (Ki +ve) – Kutok et al 2002
Re-classification:-
Haematology 2001 – T cell and NK cell disorders
a)
1’ systemic ALK +ve
b)
1’ systemic ALK –ve
c)
1’ cutaneous ALK -ve
Haematology 2001 – T cell and NK cell disorders
Clinically speaking…

2% of all NHL (2nd most common T-cell lymphoma)
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Occurs in 30s with M > F
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Bimodal distribution
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Extranodal involvement
Prognostic factors
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ALK
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CD56 +ve
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International prognostic index
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Survivin expression
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Inhibitor of apoptosis family – irrespective of ALK
expression – Schlette et all (JCO 2003)
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High BCL2 expression
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Caspase 3 (component of pro-death pathways) - +ve
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
Haematology 2001 – T cell and NK cell disorders

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!!
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%.
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
Cytoreductive phase then stratification according to stage.
APO strategy – 70% EFS for advanced stage disease. Anthracycline
containing. Induction phase then maintenance.
What about the big people?
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Usual Rx is multiagent anthracycline containing regimen
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(5ysr is 60-93% if ALK +ve vs 11-46% for ALK –ve disease)
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Outcome is inferior to children
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Poorer Px:- ALK –ve, High IPI, CD56 or survivin +ve
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Prospective trial – non randomised (1991-97)
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N = 36
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Rx:- MOPP / EBV / CAD hybrid scheme (mechlorethamine substituted by CCNU alternate cycles, vindesine,
melphalan, PNL; then D8 – epidoxorubicin, vincristine + procarbazine; D15 – vinblastine + bleo
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Chemo each 28 days for 6 cycles +/- XRT
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Median f ’up – 35mo. Max – 7.3yrs
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Remission rate 78% (CR) for CRT +/- XRT. At 74mo – 69%. No significant difference if XRT
used or not!
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T phenotype treated with CRT + XRT – better survival than B-ALCL.
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Limitations:
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Included B-cell ALCL?? (Haralambieva et al – BJH 2000)
No distinction b/w ALK +ve and ALK -ve
What is becoming apparent…
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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
Primary Cutaneous ALCL

Features:- limited to skin, no extracutaneous disease
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Histopathology:- large lymphoid cell neoplasm
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Immunophenotyping:- -ve ALK and EMA; CD30 +ve, CD4+ve
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Older adults*
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Solitary lesion or often localised
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Px favourable long term*
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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
Should we transplant?
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Autologous transplant – role in first relapse is accepted as std of care
(PARMA study – favour SCT over platinum based chemo)
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How about CR1?

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Controversial
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? 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*
Autologous hematopoietic SCT in peripheral T cell
lymphoma using uniform high dose regimen – Smith et al –
BMT 07
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N=32 (PTCL unspecified 11 and ALCL 21).

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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

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CR1/PR1 patients – all received anthracycline based chemo
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For relapse – salvage chemo given
Transplant – busulfan (1mg/kg QID x 14), etoptoside (60mg/kg IV),
cyclophos (60mg/kg IV for 2 days)
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Results:
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

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Limitations:
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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.
? 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
Present recommendations?

If ALK +ve – do not routinely transplant in CR1. If relapse –
salvage chemo and SCT. Esp not recommended if IPI is low.
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For ALK+ve and high IPI – consider stem cell support.
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ALK-ve pts – consider early SCT
Allogeneic transplants
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Case reports in children
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Would expect fewer relapses

Higher mortality rates during conditioning.
Newer agents
? ALK inhibitors (Blood 06)
? SGN30 – antiCD30 (JCO 07 –
Ansell et al – Phase I/II studies)
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