Haematological
malignancies
part 2
The lymphoid malignancies
Dr Yasmin Reyal
Consultant Haematologist
T-year Investigation of Disease
Overview
• Lymphoid development
• ALL
• NHL – high grade vs low grade
• Hodgkin lymphoma
• Myeloma
Learning objectives
• a) Understand the concept of haematological
malignancies
• b) Be able to differentiate them: MPD, MDS, myeloma,
leukaemias, and lymphomas
• c) General principles of diagnosis, staging and treatment
Classification of the
haematological malignancies
MYELOID LYMPHOID
ACUTE Acute myeloid leukaemia Acute lymphoblastic leukaemia
(aggressiv (AML) (ALL)
e)
CHRONIC Chronic myeloid leukaemia Chronic lymphocytic leukaemia
(indolent) (CML) (CLL)
Myeloproliferative Non Hodgkin Lymphoma
neoplasms (MPNs) (high grade vs low grade)
Myelodysplastic syndrome Hodgkin Lymphoma
(MDS) Myeloma
Lymphoid development
• B- and T-lymphocytes
• Humoral and cellular arms
of the adaptive immune
response
Acute lymphoblastic
leukaemia
• Accumulation of lymphoid blasts in BM and LNs
• Most common malignancy in childhood (peak age 3-7
years)
• Second peak after age 40 years
• Incidence 1/100000/year
• Male preponderance in T-ALL
• Clinical features – BM failure, organ infiltration, including
rarely testicular mass, mediastinal mass
ALL
laboratory features
Distinguished from AML by presence of lymphoid
markers, eg CD19, CD7, cCD3 rather than myeloid
markers, eg CD13, CD33 on flow cytometry
Cytogenetics
The t(9;22) translocation (Ph+) is found in 20-30%
of cases and is considered a poor risk feature.
Imatinib incorporated in treatment
ALL
Treatment and prognosis
1. Explain diagnosis/treatment & complications
2. Supportive care: blood products, antibiotics, antifungals, Hickman line, allopurinol, specialist unit
3. Chemotherapy:
- extended course 2-3 years, given in blocks of combination chemotherapy, including
intrathecal methotrexate
4. SCT for patients with ‘high risk disease’ – Ph+, high WCC, adverse cytogenetics, T-ALL
(age limit due to toxicity ie GVHD, infection)
5. CAR-T cellular therapy
Prognosis:
Curable in over 90% of children, but about 40% 5 year survival in adults
Prognosis in elderly inferior to young and fit patients. Prognosis also worse at relapse.
Chronic lymphocytic
leukaemia
• Persistent lymphocytosis with increased mature
lymphocytes
• Commonest leukaemia (1% of all cancers)
• Incidence 6/100000/year
• Peak incidence 60-80 years – disease of the elderly
• M:F 2:1
• Defects in apoptotic pathways important in aetiology
CLL
clinical features
• Often incidental finding on routine FBC - asymptomatic
• Lymphadenopathy
• Hepatosplenomegaly
• BM failure
• B-symptoms
• Diagnosed morphologically and with immunophenotyping – CLL score
• Cytogenetics – deletion or mutation of TP53 on chr 17p, associated with worse
outcome
• Features of haemolysis
• Paraprotein – usually IgM/IgG
• Staging Rai or Binet, based on no. LN areas, Hb, platelets
CLL blood film
CLL treatment
• Indolent, not curable
• Options include:
• Active surveillance
• Oral chemo
• Combination chemotherapy
• Monoclonal antibodies
• Anti-apoptotic pathway ,eg
ibrutinib, idelalisib, venetoclax
• Splenectomy
Most patients not fit for SCT
Richter’s transformation
Lymphoma
• Malignant proliferation of lymphocytes that usually
accumulate in lymph nodes.
• Can have leukaemic phase if ‘overflows’ to blood.
• Can infiltrate other organs.
Classification of lymphoma
Hodgkin Non-Hodgkin
lymphoma lymphoma (NHL)
High grade Low grade
lymphoma lymphoma
Over 50 entities in the WHO classification 2016
85% are B-cell lymphomas
Aetiology of lymphoma
• Viral – endemic – EBV, HTLV
• EBV implicated in endemic Burkitt’s, HL, PTLD
• Immune dysregulation – HIV, immunosuppression
• Familial association
• Chromosomal translocations (often involve IgH
rearrangements)
• Gene rearrangements / mutations
• Pro-proliferative (eg.c-Myc) or pro-apoptotic (eg. BCL2)
General clinical features of
lymphoma
• ‘B symptoms’
- Fever, night sweats, weight loss
• Malaise
• Painless lymphadenopathy
• Hepatosplenomegaly
• Mass
• Mass effects – eg hydronephrosis
Lymphadenopathy
• H HIV
• I Infective: Infective mononucleosis
CMV
Toxoplasmosis
Pyogenic infections
• L Lymphoma
• L’ Leukaemia esp. ALL and CLL
• S Sarcoidosis
• S Syphilis
• T Tuberculosis
• A All disseminated malignancy
• R Rheumatoid arthritis/CTD
• T oxicty e.g Phenytoin
Lymphoma diagnosis -
imaging
Lymphoma diagnosis -
histology
• Lymph node biopsy
- Excise whole node, not
core biopsy or FNA
• Biopsy of mass if no LNs
• Bone marrow biopsy
• Molecular studies on tissue,
eg c-myc, BCL2, BCL6
Lymphoma staging
“Ann Arbor”
• I 1 lymph node group
• II 2+ lymph node groups on the same side of the
diaphragm
• III Lymph nodes above and below the diaphragm
• IV Beyond the lymph nodes, including BM
A for no B symptoms, and B if B symptoms present
• E: involvement of a single, extranodal site, contiguous or
proximal to a known nodal site (stages I to III only; additional
extranodal involvement is stage IV)
• S: splenic involvement
• X: bulky nodal disease: nodal mass >1/3 of intrathoracic
diameter or 10 cm in dimension
Lymphoma prognosis
• Depends on type of lymphoma
• IN GENERAL:
• Hodgkin – aggressive, but usually curable
• High grade NHL – aggressive, but often curable
• Low grade NHL – indolent and usually treatable, but
rarely curable
General approach to
lymphoma treatment
DOES PATIENT REQUIRE TREATMENT?
ARE THEY FIT FOR TREATMENT?
• Chemotherapy
• Immunotherapy – monoclonal Ab, eg Rituximab (anti-CD20),
• Small molecule inhibitors
• Radiotherapy
• Cellular therapy – CAR-T
• Stem cell transplant
• Supportive care
• Palliative care
Surgery is NOT treatment of choice
Other prognostic factors
• Age
• Performance status (and co-morbidities)
• Stage
• Tumour burden
Hodgkin Lymphoma
• High grade lymphoma
• Histology demonstrates characteristic
Reed-Sternberg cells:
•EBV genome detected in 50% of cases
Hodgkin Lymphoma
Features
• Any age, bimodal peak
• Incidence 3/100000/year
• Male:Female 2:1
• Lymphadenopathy - painless,
‘rubbery’ asymmetrical
• Cervical > Axillary > Inguinal can
fluctuate.
• Usually contiguous
• Alcohol-induced pain
• Splenomegaly in 50%
• B-Symptoms in 35% & pruritus
Hodgkin Lymphoma
Treatment
• Chemotherapy: e.g ABVD (Adriamycin, Bleomycin, Vincristine,
Dacarbazine)
• Monoclonal antibodies – eg brentuximab (anti-CD30)
• Checkpoint inhibitors
• Radiotherapy: can be curative in early stages / adjunct to
chemotherapy
• Stem cell transplant considered in relapse – autologous and
allogeneic
• 5-year survival – 80-98% but depends on stage & grade
• Long-term side effects of treatment
Non-Hodgkins Lymphoma
• Low grade: Follicular lymphoma
SLL/CLL
Lymphoplasmacytoid lymphoma (aka
WaldenstromMacroglobulinaemia)
Marginal zone lymphoma (splenic marginal zone lymphoma
and MALT)
• Mantle Cell Lymphoma
• High grade: Diffuse large B-cell lymphoma (DLBCL)
Burkitt lymphoma
NHL - sub types
• Follicular Lymphoma Common NHL, a benign course for many years,
and so presents late. Can undergo high grade transformation.
• Marginal Zone lymphoma often related to underlying inflammation
e.g MALToma - H.pylori, Hepatitis C
• Mantle cell lymphoma lymphadenopathy often with BM involvement
and in peripheral blood. Prognosis is poor.
• DLBCL Common high grade lymphoma
• Burkitt’s Lymphoma very aggressive
• Endemic (African): in malaria areas; associated with EBV
infection. Often presents in children with massive jaw lymph
nodes
• Sporadic: not associated with EBV; occurs throughout the world.
NHL
Endemic Burkitt lymphoma
NHL treatment
• Low grade – active surveillance, treat if symptomatic
• As for high grade
• Can undergo high grade transformation
• Small molecule inhibitors – BTKi, PI3Ki, BCL2i
• High-grade
• Chemotherapy eg. CHOP (cyclophosphamide, vincristine,
adriamycin, prednisolone)
• Monoclonal antibodies eg. Rituximab (anti-CD20)
• Small molecule inhibitors
• Radiotherapy: adjunct, palliative
• Cellular therapy – CAR-T cells,
• Stem cell transplant: autologous, allogeneic
5 year survival very variable: 26-70%
T-cell lymphomas
• Rare
• Generally present with peripheral
lymphadenopathy.
• May occur in skin
e.g Mycosis Fungoides
• Adult T-cell leukaemia/lymphoma
associated with HTLV-1 infection.
Novel lymphoma therapies
• Immunotherapies:
• Monoclonal antibodies – antiCD20, anti-CD30, antiCD79
• CAR-T cells
• Bi-specific T-cell engager (BiTE)
• Immunomodulatory drugs - lenalidomide
• Immune checkpoint inhibitors – nivolumab, pembroluzimab
• Small molecule inhibitors:
• Bruton’s tyrosine kinase – ibrutinib, acalabrutinib,
zanubrutinib
• Bcl2 – venetoclax, navitoclax
• PI3K - idelalisib
Novel targeted therapies
CAR T-Cells
(chimeric antigen receptor)
Myeloma
B-cell lymphoid malignancy characterised by monoclonal
expansion and accumulation of abnormal plasma cells in
bone marrow
Myeloma
epidemiology
• 2% of all cancers
• Second most common haematological malignancy
• 4 per 100000 per year in UK
• Median age at diagnosis 65y
• 2x more common in Afro-Caribbean than white
population
Myeloma bone marrow
microenvironment
Osteoclast activating Bone
factors Osteoclast
Osteoblast
Growth
factors
Angiogenic factors
BM stromal cells
B-cell Maturation
• Bone marrow produces naïve B-cells
• Travel to lymph node and are exposed to an antigen by a
APC.
• Undergo somatic hypermutation of Ig genes
• Leave lymph node as plasma or ‘memory’ cells and
return to bone marrow.
Immunoglobulin
• Found in the gamma
region of the serum
electrophoresis
• Light chains can be
found in the urine as
Bence Jones proteins
• Can be:
Ig G - 65 %
Ig A - 30 % The rest of the Ig
Ig M, D or mixed in rare repertoire is suppressed
cases
Clinical Presentation
• Symptoms of bone disease
• Symptoms of renal impairment
• Anaemia \\\\\
• Hypercalcaemia
CRAB criteria
• Recurrent / persistent bacterial infection
• Hyperviscosity
• Cord compression
• Features suggestive of amyloidosis
• Incidental finding of persistent raised ESR
• Coagulopathy
Myeloma
Investigations
• FBC
• U&E, creatinine, urate, calcium, phosphate
• Liver function tests
• Immunoglobulins
• Serum protein electrophoresis & immunofixation
• Paraprotein quantification
• Serum Free light chain (SFLC) assay
• Beta-2 microglobulin, LDH
• Creatinine clearance
• 24 hour urinary protein excretion
• Urinary protein electrophoresis & immunofixation
• Quantification of Bence-Jones protein
Paraprotein or M
protein
Immunoglobulin produced by
single clone of plasma cells.
A monoclonal (M) band seen on
protein electrophoresis
Seen in:
• Myeloma
• MGUS
• Waldenstrom’s
macroglobulinaemia
• CLL
• Other low grade lymphomas
Myeloma Bone Disease
• Lytic lesions
• Pathological fractures
• Spinal cord compression
• Plain XR
• Cross-sectional imaging
– MRI, CT, PET CT
Histological diagnosis
• bone marrow aspirate
• bone marrow trephine
• Cytogenetics
• Flow cytometry
Diagnostic Criteria International
Myeloma Working
Group 2003
MGUS Asymptomati Symptomatic
c myeloma myeloma
Paraprotein <30g/l Paraprotein >30g/l Paraprotein in
serum +/- urine
BM plasma cells BM plasma Clonal PCs in BM
<10% cells>10% or biopsy proven
plasmacytoma
No myeloma- No myeloma- Any myeloma-
related organ or related organ or related organ or
tissue impairment. tissue impairment tissue impairment
No evidence of (including bone (including bone
other B-cell lesions) or lesions)
proliferative symptoms
disorders or light-
chain associated
amyloidosis.
Myeloma - complications
• Anaemia/bone marrow failure
• Myeloma bone disease
-pain, pathological fractures, spinal cord
compression
• Renal failure
• Hypercalcaemia
• Hyperviscosity syndrome
• Infections
• Amyloidosis
• Bleeding
Renal Failure in Myeloma
• Immunoglobulin deposition causing acute tubular
necrosis
• Iatrogenic: NSAIDs for bone pain, chemotherapy
• Pyelonephritis
• Hypercalcaemia
• Hyperuricaemia
• Amyloid
Myeloma Treatment
• Indolent, incurable, relapsing/remitting course
• Asymptomatic – active surveillance
• Steroids
• Targeted therapies
• proteasome inhibitors (bortezomib, carfilzomib, ixazomib)
• immunomodulatory agents (thalidomide, lenalidomide, pomalidomide)
• histone deacetylase (panobinostat)
• monoclonal antibodies (daratumamab, elotuzomab)
• Chemotherapy
• Radiotherapy
• Supportive care – analgesia, EPO, transfusion, dialysis
• Kyphoplasty
Asymptomatic/smouldering
myeloma
• No organ damage
• Median TTP 2-3years
• Mayo risk score based on plasma cells >20%, paraprotein
>20g/l and SFLC ratio >20
• No benefit in starting treatment early
• Active surveillance
• Signs of disease progression is indication to start
treatment
• CRAB-SLiM criteria (60% PCs, SFLCr>100, focal lesions on MRI) – additional
biomarkers for those at high risk of progression (Rajkumar et al Lancet Oncol 2014)
Bisphosphonates
• Inhibit osteoclast activity by preventing osteoclast
differentiation
• Also induce apoptosis in myeloma cells in vitro
• Zolendronic acid
• Reduce skeleton related events
• Patients without overt bony disease benefit most
• May extend survival in some patients with advanced
disease
Myeloma - prognosis
Palumbo et al JCO 2015
ISS is the International Staging System based on albumin and B2microglobulin level
Overall median survival 5-7 years
30% will live >10 years (younger standard risk patient) (ONS data 2019)
Summary
Summary
MYELOID LYMPHOID
ACUTE Acute myeloid leukaemia Acute lymphoblastic leukaemia
(aggressiv (AML) (ALL)
e)
CHRONIC Chronic myeloid leukaemia Chronic lymphocytic leukaemia
(indolent) (CML) (CLL)
Myeloproliferative Non Hodgkin Lymphoma
neoplasms (MPNs) (high grade vs low grade)
Myelodysplastic syndrome Hodgkin Lymphoma
(MDS) Myeloma
