Anaplastic Large Cell Lymphoma:- a clinico
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Transcript 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
Classification
Features (including immunophenotype)
Clinical features (including prognostic features)
Rx modalities
Chemo
Role of transplantation
Novel therapies
Classification
One of the T cell lymphomas – nodal (-ve prognostic factor)
Haematology 2006 – Therapy of peripheral T/NK neoplasms
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
Primary systemic ALCL:-
Hallmark cellWarnke et al
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
Common type
Small cell variant
Lymphohistiocytic
Hodgkin’s disease like variant (? Nodular sclerosis)**
B cell specific activation protein
Reclassified by WHO
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*
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)
Occurs in 30s with M > F
Bimodal distribution
Extranodal involvement
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
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%.
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?
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
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
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
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
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*
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)
Results:
Limitations:
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.
For ALK+ve and high IPI – consider stem cell support.
ALK-ve pts – consider early SCT
Allogeneic transplants
Case reports in children
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