ANAPLASTIC LARGE CELL LYMPHOMA:- a clinico-pathological perspective

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ANAPLASTIC LARGE CELL LYMPHOMA- a
clinico-pathological perspective

• Lymphoma Meeting The Alfred Hospital
• Monday 14th April, 2008
• Dr Andrew Guirguis
• Clinical Haematology Registrar

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Outline of presentation

• Classification
• Features (including immunophenotype)
• Clinical features (including prognostic features)
• Rx modalities
• Chemo
• Role of transplantation
• Novel therapies

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Classification

• One of the T cell lymphomas nodal (-ve
  prognostic factor)

Haematology 2006 Therapy of peripheral T/NK
neoplasms
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And yet many difficulties remain.

• What comprises anaplastic large cell lymphoma?
• Much variation within studies
• Multiple variants in studies small cell, large
  cell, histiocytic, Hodgkins 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, Hodgkins etc

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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
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Variants

• Common type
• Small cell variant
• Lymphohistiocytic
• Hodgkins disease like variant (? Nodular
  sclerosis)
• B cell specific activation protein
• Reclassified by WHO

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Immunophenotype

• T cell markers including HLA DR, CD25
• 60 - CD3 / CD 43 / CD45RO
• Cytogenetics most have TCR rearrangement not
  seen in 20-30
• 25 translocation anaplastic lymphoma kinase

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Translocation (25)

• 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

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• JCO Molecular Biology of ALCL (Ki ve) Kutok
  et al 2002

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• Re-classification-
• 1 systemic ALK ve
• 1 systemic ALK ve
• 1 cutaneous ALK -ve

Haematology 2001 T cell and NK cell disorders
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Haematology 2001 T cell and NK cell disorders
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Clinically speaking

• 2 of all NHL (2nd most common T-cell lymphoma)
• Occurs in 30s with M gt F
• Bimodal distribution
• Extranodal involvement

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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

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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

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Haematology 2001 T cell and NK cell disorders
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• 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!!

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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.

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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

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• 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 fup 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

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What is becoming apparent

• ALKve 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

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Primary Cutaneous ALCL

• Features- limited to skin, no extracutaneous
  disease
• Histopathology- large lymphoid cell neoplasm
• Immunophenotyping- -ve ALK and EMA CD30 ve,
  CD4ve
• 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

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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

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Autologous hematopoietic SCT in peripheral T cell
lymphoma using uniform high dose regimen Smith
et al BMT 07

• N32 (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)

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• 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 nos too small and
  ? ALK status

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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 ALKve and high IPI consider stem cell
  support.
• ALK-ve pts consider early SCT

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Allogeneic transplants

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

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Newer agents
? ALK inhibitors (Blood 06) ? SGN30 antiCD30
(JCO 07 Ansell et al Phase I/II studies)
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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 neoplasms 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 CD30ve anaplastic LCL
in the adult sequential intensive Rx with
F-MACHOP regimen /- XRT and ABMT Fanin et al
Blood 1996