Leukaemias and Malignant Lymphomas

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Leukaemias and Malignant Lymphomas

• Szabolcs Modok
• Dentists, 4th year, Internal medicine

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Acute leukaemias

• Presentation
• Bleeding
• Infection
• Fatigue
• Leukaemic blood smear or hiatus leukaemicus
• Pancytopenia

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Acute myeloid vs lymphoid leukaemia

• Myeloid
• Elderly
• MPO, CD34, etc
• Sudan black stain
• DIC
• Karyotypes (good)
• t(812)
• t(1517)
• inv(16)

• Lymphoid
• Younger age
• T cell (CD3, CD4)
• B cell (CD10,19,20)
• Lymphadenomegaly
• Karyotypes (bad)
• t(922)

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AML clinical subtypes

• De novo AML
• Secondary after MDS or myeloproliferative
  disease
• Treatment related ( 5 years after chemo- or
  radiotherapy)

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Acute Myeloid Leukaemia treatment

• Remission INDUCTION
• 73, i.e. cytarabine anthracycline
• CONSOLIDATION
• high dose cytarabine (3 courses)
• AML M3/promyelocytic ATRA, AsO3
• New agents anti-CD33 antibody, clofarabine
• Allogeneic stem cell transplantation

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Acute lymphoid leukaemia treatment

• Induction consolidation reinduction
  maintenance 2 years
• Drugs vincristine, anthracyclines, steroid,
  cytarabine
• CNS prophylaxis
• t(922) imatinib early SCT

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WHO classification of myeloproliferatív diseases

• Atypical
• Molecularly defined
• PDGFRA (Eo/mastocytosis)
• PDGFRB (Eo/CMMoL)
• c-KitD816V (SM), etc
• Clinico-pathological definition(Bcr/abl-
  rare JAK2V617F)
• Chr. neutrophil leukaemia
• Chr. Eosinophil leukaemia
• Hypereosinophil syndrome
• Chr. basophil leukaemia
• Chr. myelomonocytaer leukaemia, etc

• Classic
• Molecularly defined
• CML (Bcr/abl)
• Clinico-pathological definition(Bcr/abl- és
  gyakori a JAK2V617F)
• Polycythaemia vera (100)
• Essential thrombocythaemia (50)
• Myelofibrosis (50)

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Bcr/abl és imatinib
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Imatinib milestone in the treatment of CML
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Malignant Lymphomas

• Definition uncontrolled proliferation of
  lymphoid cells
• Classification Hodgkins Lymphomas
  Non-Hodgkin Lymphomas

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Facts about lymphomas (ACC, 2006 estimates)

• Hodgkins lymphoma
• stable incidence over last 20 years
• Survival1 year 93 5 years 85 10 years 80

• Non-Hodgkins lymphoma
• incidence doubled since early 1970s
• Survival1 year 78 5 years 60 10 years 49

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Hodgkins lymphoma
Incidence 2/100000 Mortality 0.7/100000 WHO
classification

• Nodular lymphocyte-predominant Hodgkins
  lymphoma (LPHD)
• Classical Hodgkins lymphoma 65 Nodular
  sclerosis Hodgkins lymphoma 5 Lymphocyte-rich
  classical Hodgkins lymphoma 25
  Mixed-cellularity Hodgkins lymphoma 5
  Lymphocyte-depleted Hodgkins lymphoma

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Hodgkins lymphoma

• Diagnosis lymph node excision, i.e. histology
• Staging prognosis Chest and abdominal CT
  scans Bone marrow biopsy Full blood count, ESR,
  CRP, Alb, ALP, LDH Clinical staging (CS)
  according to Ann Arbor (bulky disease, spleen
  and extranodal involvement)

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Ann Arbor clinical staging

1. One lymph node region
2. Two or more regionon the same side of the
   diaphragm
3. Multiple lymph node regionson both sides of the
   diaphragm
4. Extra-lymphatic organ involvement

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B symptoms Risk assessment

• Weight loss gt 10 of bodyweight in 6 months
• Night swets
• Fever (unexplained) gt 38.5 C

B symptoms

• Limited stage
• CS I II without risk factors
• Intermediate stage
• CS I II with one or more of the following risk
  factors
• large mediastinal mass (gt1/3 of thoracic width on
  chest X-ray or gt 7.5 cm on CT scan)
• extranodal involvement
• massive involvement of the spleen (diffuse
  enlargement or gt 5 nodules)
• elevated ESR (gt 30 mm/h for B-stages and gt 50
  mm/h for A-stages)
• extensive lymph node involvement (gt 3 lymph node
  areas)
• older age (gt 60 years)
• Advanced stage
• CS III IV

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Hodgkins lymphoma - LPHD

• Stage I involved field irradiation (30 Gy)
• Recurrent disease avoid aggressive treatment,
  because it is indolent
• Rituximab

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Hodgkins lymphoma - Classic

• Limited stage 2 - 4 cycles of ABVD with involved
  field irradiation (30 36 Gy)
• Intermediate stage 4 cycles of ABVD with
  involved field irradiation (30 36 Gy)
• Advanced stage 8 cycles of ABVD (or BEACOPP)
  with involved field irradiation to bulky tumours
  (gt 7.5 cm 30 36 Gy) or to residual tumour mass
  after chemotherapy.

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Hodgkins lymphoma Response evaluation

• Physical examination, blood tests and CT scans
  after the 4th and the last cycle of
  chemo/radiotherapy
• Biopsy
• Repeated radiology scans
• PET CT (negative predictive value)

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Hodgkins lymphoma Follow up

• History and physical examination every 3 months
  for a year, every 6 months for 3 years, then once
  a year
• Laboratory analysis and chest X-ray at 6, 12 and
  24 months
• CT scans once to confirm remission status
• Thyroid function after neck irradiation after 1,
  2 and 5 years
• After chest irradiation for premenopausal, and
  especially at an age below 25 years, women should
  be screened for secondary breast cancer
  clinically, and after the age of 40 -50, by
  mammography

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Hodgkins lymphoma Relapse

• DHAP, Dexa-BEAM, EPOCH SCT for chemosensitive
  patients with good performance status
• Experimental treatments, low intensity chemo or
  local radiotherapy for others

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Non-Hodgkins lymphomas (WHO classification)

• B-cell neoplasms
• Precursor B-cell neoplasm
• precursor B-acute lymphoblastic
  leukemia/lymphoblastic lymphoma (LBL)
• Peripheral B-cell neoplasms
• B-cell chronic lymphocytic leukemia/small
  lymphocytic lymphoma
• B-cell prolymphocytic leukemia
• Lymphoplasmacytic lymphoma/immunocytoma
• Mantle cell lymphoma
• Follicular lymphoma
• Extranodal marginal zone B-cell lymphoma of
  mucosa-associated lymphatic tissue (MALT) type
• Nodal marginal zone B-cell lymphoma ( monocytoid
  B-cells)
• Splenic marginal zone lymphoma ( villous
  lymphocytes)
• Hairy cell leukemia
• Plasmacytoma/plasma cell myeloma
• Diffuse large B-cell lymphoma
• Burkitt's lymphoma

• T-cell and putative NK-cell neoplasms
• Precursor T-cell neoplasm
• precursor T-acute lymphoblastic leukemia/LBL
• Peripheral T-cell and NK-cell neoplasms
• T-cell chronic lymphocytic leukemia/prolymphocytic
  leukemia
• T-cell granular lymphocytic leukemia
• Mycosis fungoides/Sézary syndrome
• Peripheral T-cell lymphoma, not otherwise
  characterized
• Hepatosplenic gamma/delta T-cell lymphoma
• Subcutaneous panniculitis-like T-cell lymphoma
• Angioimmunoblastic T-cell lymphoma
• Extranodal T-/NK-cell lymphoma, nasal type
• Enteropathy-type intestinal T-cell lymphoma
• Adult T-cell lymphoma/leukemia (human
  T-lymphotrophic virus HTLV 1)
• Anaplastic large cell lymphoma, primary systemic
  type
• Anaplastic large cell lymphoma, primary cutaneous
  type
• Aggressive NK-cell leukemia

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Chronic Lymphocytic Leukaemia (CLL)

• Incidence 3/100000
• Diagnosis gt 5109/L lymphocytes in blood CD19
  CD5/23, CD20 bone marrow infiltration gt 30
  lymph node histology
• Immunodeficiency (infection/second tumour)
• Autoimmune phenotypes

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CLL Modified Rai Staging
Hazard () Pathological stage Overall survival
Low risk (30) 0. Lymphocytosis gt 10 years
Intermediate risk (60) I. lymphadenomegaly 7 years
Intermediate risk (60) II. hepato/splenomegaly 7 years
High risk (10) III. anaemia (lt110 g/L) 1.5 years
High risk (10) IV. thrombopenia(lt100 G/L) 1.5 years
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CLL - Treatment

• Watch wait in stable limited disease
• Curative intent in selected cases (lt 60 years,
  allogen SCT)
• Palliative therapy in most cases chlorambucil cy
  clophosphamide fludarabine alemtuzumab
• Glucocorticosteroids/azathioprin
• Cyclosporin A
• Immunoglobulins
• Pneumovax 23

combinations
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Diffuse Large B-Cell Lymphoma (DLBCL)

• Incidence 3 - 4/100000
• Subtypes1. primary mediastinal2.
  intravascular3. T-cel/histiocyte rich 4.
  lymphomatoid granulosis like5. primary effusion

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ECOG performance score

• 0 no symptoms
• 1 symptomatic, out patient
• 2 symptomatic, lt 50 in bed
• 3 symptomatic, gt 50 in bed
• 4 bedridden, inpatient care is necessary

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Age adjusted international prognostic index
(aaIPI)

• Stage III IV
• serum LDH ?
• ECOG 2

Low risk aaIPI score 0-1 High risk aaIPI score
2-3

• Morphologic variants with bad prognosis
• Immunoblastic
• Plasmablastic
• CD5
• Intravascular

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DLBCL - Treatment
Localised disease 6 x R-CHOP (21)
Widespread disease

• gt 60 years of age
• 8 x R-CHOP (21)

• lt 60 years of age
• Low risk6 x R-CHOP (21)
• High risk8 x R-CHOP (14)HDCT SCT

LP and IT chemotherapy for high CNS risk patients
Salvage R-DHAP/R-IME/R-ICE SCT
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Follicular lymphoma (FL)

• Incidence 5 - 7/100000 (rising)
• Bcl2 overexpression due to t(1418) or t(1822)
• CD20/CD19/CD10 CD5

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FL WHO grades

• I Centrocytes lt 5 centroblast per large
  viewfield
• II Centrocytes 6 -15 centroblast per large
  viewfield
• III/A lt 15 centroblast per large viewfield with
  centrocytes
• III/B gt 15 centroblast per large viewfield
  without centrocytes

I, II III/A indolent lymphoma III/B
aggressive lymphoma
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FL prognosis FLIPI

• Risk factors
• gt 60 years of age
• Stage III IV (75 80 )
• gt 4 lymph node areas
• Serum LDH ?

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FL Treatment

• Stage I extended field irradiation with curative
  intent
• Stage II IV 15 20 spontaneous
  regression treatment is only indicated for
  progressive disease fludarabine chlorambucil
  rituximab CHOP remission maintenance or
  consolidation IFN a rituximab radioimmunot
  herapy, HDCT SCT

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Multiple myeloma (MM)

• Incidence 6/100000
• Diagnosis
• M protein in urine and/or plasma immunofixation
• plasma cells in the bone marrow ()
• lytic bone lesions

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MM Durie Salmon staging
Parameter Stage I Stage II Stage III
All criteria One or more One or more
Haemoglobin (g/dL) gt 10 8.5 10 lt 8.5
Serum Calcium (mM) lt 3.0 3.0 gt 3.0
M protein IgA (g/L) lt 30 30 - 50 gt 50
M protein IgG (g/L) lt 50 50 - 70 gt 70
Urine light chain (g/24h) 4 4 12 gt 12
Bone X-ray None Minor Advanced
Subclassification A Creat lt 177 ?M
B Creat ? 177 ?M
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MM MRI/PET staging
Stage MRI/PET scan
MGUS No activity
IA smouldering myeloma Single plasmocytoma and/or limited disease
IB lt 5 focal lesions, mild diffuse disease
II A B 5 20 focal lesions, moderate diffuse disease
III A B gt 20 focal lesions
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MM International Prognostic Index (IPI)
I II III
Albumin (g/L) gt 35 lt 35 any
?2M (mg/L) lt 3.5 3.5 5.5 gt 5.5
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MM - Treatment

• Watch wait in indolent disease
• Standard melphalan (9mg/m2/day 4 days) and
  prednisone (30mg/m2/day 4 days) repeated every 4
  6 weeks until stable disease
• INF - ? prolongs plateau phase (3 MU/m2 sc 3 x
  weekly)
• Bisphosphonates
• HD melphalan (200 mg/m2 iv) APBSCT (lt 65 years,
  no renal impairment) after VAD induction

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Indications for autologous SCT

• Agressive lymphoma (chemosensitive relapse)
• Follicular lymphoma (transformation to agressive
  lymphoma)
• Multiple myeloma (chemosensitive disease)
• Hodgkin lymphoma (chemosensitive relapse)

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Allogeneic SCT

• AML (intermediate or poor prognosis
• in remission)
• Adult ALL (remission)
• Aplastic anemia
• CML (special situations)