Leukaemia

Question 1

Remind yourself of haemopoiesis process

Answer 1

Question 2

What is leukaemia?

State 4 types of leukaemia you should be aware of (note: there are other more rarer forms)

Answer 2

Leukaemia is a haematological cancer characterised by distorted proliferation and development of leukocytes (white cells) and their precursors in the blood and bone marrow

Four types you should know:

• Acute myeloid leukaemia
• Acute lymphoblastic leukaemia
• Chronic myeloid leukaemia
• Chronic lymphocytic leukaemia

Question 3

Broadly speaking, what is the difference between leukaemia and lymphoma?

Answer 3

There is lots of cross-over hence the distinction is some what artificial. However, in general cancers affecting mainly the bone marrow with or without release of circulating neoplastic cells into the blood are called leukaemia’s. Whereas those predominantly nodal or organ-based are lymphomas.

Question 4

What is the difference between acute and chronic leukaemia?

Answer 4

Acute or chronic is based on the degree of cell differentiation (NOT duration of disease):

• Acute: accumulation of young, immature blast cells (immature cells found in bone marrow; not fully developed and therefore don’t carry out particular function. Up to 5% normal)
• Chronic: accumulation of mature, differentiated cells

Question 5

For each of the leukaemia’s you need to know:

• Acute myeloid leukaemia
• Acute lymphoblastic leukaemia
• Chronic myeloid leukaemia
• Chronic lymphocytic anaemia

… discuss the ages at which they commonly present

*HINT: use mnemonic ALL CeLLmates have CoMmon AMbitions

Answer 5

• Acute lymphoblastic leukaemia: <5yrs and >45yrs
• Chronic lymphocytic leukaemia: >55/60yrs (median age diagnosis is 65-70yrs)
• Chronic myeloid leukaemia: >65yrs (median 70yrs)
• Acute myeloid leukaemia: >75yrs

Question 6

Explain how leukaemia can lead to pancytopenia

Answer 6

Genetic mutation in precursor cell in bone marrow leads to excessive production of a single type of abnormal leucocyte (white blood cell). Excessive production of this single type of cell can lead to suppression of other cell lines causing pancytopenia

Question 7

State some risk factors for leukaemia (think about which leukaemia each is a risk factor for)

Answer 7

• Age (depends on age- see other FC)
• Down’ syndrome (ALL)
• Philadelphia chromosome (CML, ALL)
• Myeloproliferative disorders e.g. polycythaemia ruby vera or myelofibrosis (AML)
• Previous radiation exposure
• Chemotherapy

Question 8

State signs & symptoms of leukaemia

Answer 8

Presentation can be non-specific:

• Fatigue
• Fever
• Failure to thrive
• Pallor (anaemia)
• Abnormal bruising
• Petechiae
• Abnormal bleeding
• Frequent infections
• Unintentional weight loss
• Night sweats
• Pruritis
• Anaemia symptoms (SOB, palpitations, cold hands/feet)
• Lumps/lymphadenopathy
• Splenomegaly
• Hepatomegaly

Question 9

Which leukaemia is CNS involvement most common in and why?

What would be signs & symptoms?

What do we do to prevent CNS recurrence?

Answer 9

• CNS involvement most common in ALL but can also occur in AML.
• More common ALL, compared to AML, as lymphocytes pass more readily through BBB
• Signs & symptoms: headache, neck stiffness, cranial nerve palsies
• Hence, prophylactic intrathecal chemotherapy often given in ALL to reduce rate of CNS recurrence

*NOTE: by CNS recurrence don’t mean they had it in CNS and then it came back. Mean the leukaemia has come back and place it’s back in is the CNS (<10% have CNS involvement at diagnosis, but without prophylaxis 50-70% will develop CNS recurrence 1yr post-remission)

Question 10

What investigations would you do if you suspect leukaemia?

Answer 10

• FBC with differential (URGENT within 48hrs): leucocytosis, anaemia, thrombocytopenia, neutropenia (despite leucocytosis)
• Blood film: look for abnormal cells (e.g. blast cells)
• U&Es: baseline
• LFTs: baseline
• LDH:
• Coagulation/clotting screen:
• Bone marrow biopsy: main investigation for diagnosing leukaemia
• Immunophenotyping: look for specific antigens on cells
• Cytogenetic analysis: look for genetic mutations

Others: CXR (show infection or mediastinal lyphadenopathy), lymph node biopsy (assess lymph node involvement or investigate for lymphoma), lumbar puncture (if CNS involvement), CT, MRI and PET scans (for staging & assessing lymphoma & other tumours)

Question 11

What is a bone marrow biopsy?

There are two types of bone marrow biopsy; describe each

Answer 11

Bone marrow biopsy involves taking a sample of bone marrow for analysis under LA. Usually taken from iliac crest. Types:

• Bone marrow aspiration: take liquid sample from bone marrow, which is full of cells, using needle
• Bone marrow trephine: take a solid core sample of bone marrow i.e. sample of solid bone with bone marrow inside (allows better assessment of cells & structure)

Samples from aspiration can be examined straight away but trephine sample requires few days of preparation.

Question 12

For acute lymphoblastic leukaemia, discuss:

• Proliferation of which cells
• Which syndrome it is associated with
• What genetic mutation associated with
• What signs & symptoms you may see in ALL (other than those already discussed)
• Investigation findings (FBC, blood film, BM biopsy, immunophenotyping, LP)

Answer 12

• Malignant change in one of lymphocyte precursor cells/lymphoid blast cells- usually develops from precursor of B lymphocytes ~80% (but can be T lymphocyte precursor)
• Downs syndrome
• Philadelphia chromosome (reciprocal translocation between chromosome 9 and 22); results in oncogenic gene fusion (BCR-ABL) with tyrosine kinase activity resulting in proliferation, differentiation & inhibition of apoptosis
• As with all leukaemias can get generalised symptoms & BM failure symptoms but can also get infiltrative symptoms & signs (following are less common): thymic mass (leading to SVCO), testicular enlargement, gingival hypertrophy
• Investigation findinds:
  
  • FBC: WBC can be low, normal (bone marrow not yet supressed) or high (dependent on how differentiated lymphoblast’s are as they may or may not be counted as a white cell), +/-thrombocytopenia, +/- anaemia. Usually see neutropenia
  • Blood film: blast cells (might not see if still confined to bone marrow)
  • BM biopsy: >20% blast cells is diagnostic
  • Immunophenotyping: presence of lymphoid antigens and absence of myeloid antigens. Also helps determine if B or T cell as can’t distinguish based on morphology
  • LP: all with ALL with have LP to assess for CNS involvement

Question 13

For chronic lymphocytic leukaemia, discuss:

• Proliferation of which cells
• Whether it is symptomatic
• What type of haemolytic anaemia it can cause
• What it can transform into
• Investigation findings (FBC, blood film, immunophenotyping, Coombs)
• Classification
  *

Answer 13

• Proliferation of single type of well differentiated lymphocyte- usually B lymphocytes “monoclonal proliferation of B lymphocytes”
• Often asymptomatic (incidental finding on FBC) but can present with infections, anaemia, bleeding, weight loss, lymphadenopathy etc…
• Warm autoimmune haemolytic anaemia
• Can transform into high-grade non-Hodgkin’s lymphoma- most commonly large B cell lymphoma (Richter’s transformation). Pts become unwell suddenly.
• Investigation findings:
  
  • FBC: lymphocytosis
  • Blood film: smear or smudge cells (due to aged or fragile lymphocytes rupturing and leaving smudge on film)
  • Immunophenotyping: clonal B lymphocytes expressing CD5 and CD23 antigens
  • Coombs test: should be done in all anaemic patients to before therapy to identify autoimmune-related haemolytic anaemia
• Binet classification (most commonly used in Europe) or Rai classification (USA). Classification used to guide treatment (stage C is anaemia and/or thrombocytopenia)

Question 14

For acute myeloid leukaemia, discuss:

• Proliferation of which cells
• Two conditions which can transform into AML
• Investigation findings (FBC, blood film, coagulation studies, bone marrow biopsy)
• WHO classification
• What is a common complication of APML (acute promyelocytic leukaemia)- a subtype of AML?

Answer 14

• Proliferation of myeloid blast cells
• Myeloproliferative disorders such as polycythaemia ruby vera or myelofibrosis can transform into AML
• Investigation findings:
  
  • FBC: WCC low, normal or raised; thrombocytopenia, anaemia
  • Blood film: myeloblast cells which have rods in cytoplasm “Auer rods”
  • Coagulation studies: raised PT and APTT, low platelets, increased D-dimer and decreased fibrinogen in DIC in APML
  • Bone marrow biopsy: >/=20% myeloblasts is diagnostic
• WHO classification classifies based on potential aetiology (6 groups, some of which are):
  
  • AML with recurrent genetic abnormalities (includes APML which is t(15:17)
  • AML with myelodysplastic-related changes (those with pre-existing myelodysplastic disease)
  • Therapy related AML
  • AML not otherwise specified
• Common complication of APML is DIC (85%) because promyelocytes produce tissue factor

Question 15

Explain why patients newly diagnosed/not yet treated AML can have raised LDH, hyperkalaemia & hyperuricaemia

Answer 15

• High turnover of cancerous cells
• High rate cell lysis
• Release intracellular contents

Question 16

For chronic myeloid leukaemia, discuss:

• Whether organomegaly is common
• Three phases
• Associated mutation
• Investigation findings (FBC, blood film, bone marrow)

Answer 16

• Often associated with massive spleen
• Phases:
  
  • Chronic phase: last ~5yrs, often asymptomatic, diagnosed accidentally. Most cases (80-90%) diagnosed in this phase. <10% blasts
  • Accelerated phase: lasts months. Abnormal blast cells take up high proportion of cells in bone marrow and pt becomes more symptomatic (develops anaemia, thrombocytopenia, immunocompromised). 11-19% blasts
  • Blast phase: >20% myeloblasts in bone marrow, blood or both. Transformation to blast phase is called blast crisis. Severe symptoms & pancytopenia; often fatal.
• Philadelphia chromosome (reciprocal translocation between chromosome 9 and 22); results in oncogenic gene fusion (BCR-ABL) with tyrosine kinase activity resulting in proliferation, differentiation & inhibition of apoptosis
• Investigation findings:
  
  • FBC: leucocytosis (differential shows increased numbers from myeloid cell lineage), thrombocytosis or thrombocytopenia, anaemia is common
  • Bone marrow: increased proliferation of myeloid cells (neutrophils, eosinophils, basophils) & myeloid progenitor cells. May also see megakaryocytes
  • Blood film: myeloid cells (neutrophils, eosinophils, basophils) & myeloid progenitor cells
  • Cytogenetics: Philadelphia chromosome

Question 17

Which is the most common leukaemia in adults?

Which is most common leukaemia in children?

Answer 17

• Adults: chronic lymphocytic leukaemia (AML is most common acute leukaemia in adults)
• Children: acute lymphoblastic leukaemia

Question 18

Management of leukaemia involves treating the leukaemia but also offering supportive management for symptoms & complications; discuss the supportive management of leukaemias

Answer 18

• Transfusions: RBCs, platelets
• Prophylactic abx, antivirals, antifungals
• Vaccines
• Treatment of complications (e.g. neutropenic sepsis, TLS)

Question 19

Discuss the management of leukaemia’s (not including supportive therapy)

Answer 19

MDT management often involving chemotherapy & steroids. Other treatments include immunotherapy, radiotherapy, bone marrow transplant and surgery.

• Acute lymphoblastic leukaemia: multi-drug chemotherapy (induction, consolidation & maintenance including intrathecal chemotherapy) and steroids (see separate FC for more detail of chemotherapy regime). May consider bone marrow or stem cell transplant
• Acute myeloid leukaemia: chemotherapy (induction, consolidation & maintenance), consider stem cell or bone marrow transplant
• Chronic myeloid leukaemia: tyrosine kinase inhibitors (e.g. imantinib) are first line. In later phases may consider chemotherapy and stem cell transplant
• Chronic lymphocytic leukaemia: because CLL has long indolent course and most pts present with no symptoms treatment is only considered when pt is symptomatic or signs of bone marrow failure. Options include chemotherapy or targeted treatments & immune treatments (e.g. ibrutinib a BCR inhibitor, venetoclax a BCL-2 inhibitor, obinutuzumab a monoclonal antibody targeting CD20)

Question 20

What are indications for treatment in CLL?

Answer 20

• Anaemia or thrombocytopenia (Binet C; Rai III-IV)
• Symptomatic disease (painful lymphadenopathy, fever, chills, and weight loss)
• Rapidly progressive disease (doubling time of lymphocytes <6 months) and rapidly enlarging lymph nodes or organs (liver/spleen- can do splenectomy or localised radiotherapy)
• Autoimmune haemolytic anaemia or immune thrombocytopenic purpura refractory to immunosuppressive therapy.

Question 21

Briefly outline chemotherapy phases used in ALL & AML

Answer 21

• Pre-induction steroids (to try and destroy as much of leukaemia as can)
• Induction chemotherapy
• Consolidation & intensification (we know that even if leukaemia in remission after first cycle pt has to continue treatment or it will come back. Options include chemo, bone marrow or stem cell transplant, total body irradiation)
• Maintenance chemotherapy (usually a tablet and maybe some injections every few months- ~2yrs)

*Image is specific to ALL

Question 22

Briefly discuss the prognosis of each of the 4 main types of leukaemia

Answer 22

Acute lymphoblastic leukaemia: in children cure rates are ~85-90% however in adults prognosis is heavily age dependent (ranging from >50% if less than 54yrs to <20% if over 65yrs)

Acute myeloid leukaemia: prognosis better if younger (about ⅓ cured). If older (>60yrs) then 90% chance of relapse within 3yrs of treatment

Chronic lymphocytic leukaemia: 25-50% will see remission with first line treatment but majority of pts relapse needing further treatment in a few years

Chronic myeloid leukaemia: prognosis worsens as you go from chornic to accelerated to blast phase. However, now considered potentially curable with TKIs

Chronic lymphocytic leukaemia:

Question 23

What values are classed as pancytopenia?

Answer 23

• Hb: Women <120g/L (115g/L in UHL), men <130g/L
• WBC: <0.5 x 10⁹/L
• Platelets: <20 x 10⁹/L

Question 24

In what time frame, must you investigation pancytopenia?

Answer 24

• Investigation mandatory within 24-48hrs
• Differentials:
  
  • B12 or folate deficiency (can actually cause pancytopenia)
  • BM infiltration
  • Myelodysplasia
  • Splenomegaly or hepatomegaly (causing sequestration)
  • CLL
  • Non-hodgkin lymphoma
  • Chemotherapy
  • Radiotherapy