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Haematology > Haem Malignancies 1 > Flashcards

Haem Malignancies 1 Flashcards

1
Q

Diagnosis of MGUS, Smoldering MM and MM

A

MGUS

  • M protein < 3g/dL
  • Clonal plasma cells in BM < 10%
  • No myeloma defining events

Smoldering

  • M protein >3g/dL (serum) or >500mg/24 hours (urine)
  • Clonal plasma cells in BM 10-60%
  • No myeloma defining events
MM 
- Clonal BM plasma cells > 10% or >1 biopsy proven plasmacytoma AND 1 or more MM defining events 
- > 1 CRAB feature
Hypercalcaemia 
Renal failure 
Anaemia
Bone lesions
- Biomarkers of malignancy 
Clonal plasma cells in BM > 60%
Serum FLC ratio > 100 (or < 0.01)
>1 MRI focal lesion >5mm in size on MRI
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2
Q

Clinical features of MM

A
  • Fatigue
  • Bone pain with negative bone scan
  • Low BMD with paraprotein
  • Normo/macrocytic anaemia with high total protein
  • Acute renal failure with anaemia
  • Back pain with anaemia
  • Hyperviscosity
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3
Q

Features of hyperviscosity

A
  • Confusion
  • Headache
  • Visual changes
  • Mucosal haemorrhage
  • High output CCF
  • Fundoscopy: flame haemorrhages

Occurs due to high levels of immunoglobulin - Worry if IgM >50 (as IgM is a pentamer), IgA >70, IgG >100

Will require plasmapheresis !

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4
Q

When can free light chains be elevated?

A
  • Serum free light chains can be abnormal in benign conditions (polyclonal hypergammaglobulinaemia) and renal failure
  • Abnormal RATIO only in monoclonal plasma cell disorders

Can be high in:

  • Non secretory MM
  • Oligosecretory disease
  • Light chain MM
  • AL amyloidosis - 98% cases positive
  • Solitary plasmacytomas and smouldering MM = high levels and risk of changing to MM
  • MGUS - risk stratification
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5
Q

What mutations are poor prognostic markers in MM?

A

t (4;14) - this has now been less bad due to bortezimb
t (14;16)
Del (17p)

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6
Q

Staging for MM

A

Stage 1:

  • Serum albumin > 35g/L
  • B2 microglobulin < 3.5mg/L
  • None of the following high risk cytogenetics: del (17p), t(4;14), t(14;16) or gain 1q
  • Median survival 62m

Stage 2: B2 microglobulin > 3.5 but < 5.5
Albumin < 35
Median survival 46m

Stage 3:
- Serum B2 microglobulin > 5.5
- High risk cytogenetics or elevated serum LDH
Median survival 29m

Serum B2 microglobulin and albumin determine the stage and are prognostic factors

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7
Q

MM Causes of renal impairment

A
  • Myeloma cast nephropathy: excess monoclonal free light chains precipitate in distal tubules and cause tubulointerstitial damage
  • Hypercalcemia (most common with cast nephropathy)
  • Light chain deposition disease
  • Amyloidosis (AL)
  • Acquired fanconi
  • Hyperuricaemia
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8
Q

Treatment of MM

A

Autologous stem cell transplant

  • <70yo
  • Good ECOG/medical comorbidities
  • Usually involves induction therapy with bortezomib (4 months) and then autologous stem cell transplant with melphalan

Transplant ineligible
- Lenalidomide + dex (oral) or
Not good in renal failure, oral therapy
- Bortezomib (SC weekly) + cyclophosphamide + dex
Safe in renal failure
Chemoimmunotherapy
- Steroids: Dex, pred
- Chemotherapy (alkylating agents): melphalan, cyclophosphamide
- Proteasome inhibitor: bortezomib (first line), carfilzomib (normally for relapsed disease)
- Immunomodulator: thalidomide, lenalidomide, pomalidomide
- Monoclonal antibody:
Daratumumab CD38 (which is highly expressed in plasma cells)
Isatuximab: CD38
SALMF7 (Elotuzumab)

Supportive Therapy
- RT for lytic lesions in the spine, long bones
- Bisphosphonate therapy
Pamidronate reduces the risk of skeletal related complications in symptomatic myeloma
Zoledronic acid protects against skeletal related events, even in patients without evidence of bone disease on skeletal survey

Require pamidronate or zoledronic acid once ever 3-4 weeks for a minimum of 2 years

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9
Q

Investigation findings of MM

A
  • FBC: normocytic anaemia, cytopenia
  • Blood film: rouleaux, circulating plasma cells
  • Hypercalcemia
  • High creatinine
  • High total protein
  • Low albumin
  • Can have high LDH ‘

Ix:

  • FBC + Film
  • Biochemistry
  • Serum EPG, immunofixation
  • Serum light chains
  • 24 hour EPG and immunofixation
  • BM aspirate/biopsy
  • Cytogenetics (karyotype + FISH)
  • B2 microglobulin + LDH

Immunofixation

  • Confirm and type M component
  • Can detect small M proteins when routine EPG normal
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10
Q

SE of bortezomib and thalidomide

A

Neuropathy

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11
Q

SE of lenalidomide and pomalidomide and thalidomide

A

Cytopenia

Increased risk of VTE

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12
Q

SE of carfilzomib

A

Cardiac issues

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13
Q

Complications of autologous stem cell transplant

A

Early:
- Sepsis normally bacterial
Neutropenia for 7 days and then recover between day 10-14
- Mucostitis
- Rare: idiopathic pulmonary syndrome, engraftment syndrome, sinusoidal obstructive syndrome

Late:
- Infection: viral, PJP
Require prophylaxis for 6/12 months, revaccinate at 6+ months
- Secondary cancers: MDS/AML, skin, solid cancers
- Psychological

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14
Q

Infections during autograft transplant

A

Pre-engraftment

  • HSV
  • Candida

Post-engraftment

  • CMV
  • Varceilla
  • PJP

Present in pre and post-engraftment

  • Respiratory virus
  • Gram + and gram - organisms
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15
Q

Features of plasmacytoma

A

All 4 criteria must be met

  • Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
  • Normal bone marrow with no evidence of clonal plasma cells or <5% clonal plasma cells
  • Normal skeletal surve and MRI/CT of spine/pelvis (except for the primary solitary lesion)
  • Absence of end organ damage (CRAB)
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16
Q

Waldenstrom

A
  • IgM is associated with Waldenstrom
  • MYD88 gene
  • Can lead to paraproteinemic neuropathies, axonal > demyelinating
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17
Q

What is the M protein

A

M protein = monoclonal antibody detectable in blood or urine
PCDs produce an M protein consisting of a heavy
chain (IgG, IgA, lgD, or lgM) complexed with a kappa/lambda light chain or of kappa/lambda free light chains (FLCs) without a heavy chain component.

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18
Q

Bone features in MM

A

Osteolytic bone lesions

PTH independent hypercalcemia

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19
Q

Plasma cell dyscrasia associated with peripheral neuropathy

A
  1. AL amyloidosis: sensorimotor axonal polyneuropathy - associated with MGUS, MM
    - PAINFUL length dependent peripheral neuropathy
    - Autonomic: orthostatic hypotension
  2. POEMs syndrome: involves IgG, IgA, lambda
    - Sensorimotor inflammatory demyelinating polyneuropathy (similar to CIDP), hepatomegaly, endocrinopathies (hypogonadism, adrenal insufficiency), hyperpigmentation, hypertrichosis - associated with MGUS, MM, plasmacytoma
  3. Anti-MAG neuropathy: sensory demyelinating polyneuropathy - associated with IgM MGUS, Waldenstrom
  4. Cryoglobulinaemic vasculitis: sensory/senorimotor polyneuropathy, mononeuropathy multiplex - associated with mGUS, MM, hodgkin lymphoma (eg: WM)
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20
Q

What is the most sensitive test for detecting monoclonal FLC gammopathies?

A

The serum free light chain (FLC) assay can detect monoclonal FLCs before they are detectable by urine protein electrophoresis and is the most sensitive test for detecting monoclonal FLC gammopathies.

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21
Q

What is POEMS syndrome

A
  • POEMS syndrome is an extremely rare paraneoplastic syndrome. Paraneoplastic syndromes are caused by an abnormal immune response to a cancerous tumor (neoplasm) where the body accidently attacks normal cells in the nervous system.
  • POEMS is an acronym that stands for the disorder’s five major signs and symptoms, which include Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin abnormalities.

Additional Features

  • Sclerotic bone lesions
  • Castleman’s disease :
  • Elevated levels of VEGF
  • Common symptoms include progressive weakness of the nerves in the arms and legs (sensorimotor polyneuropathy), an abnormally enlarged liver and/or spleen (hepatosplenomegaly), enlarged lymph nodes (lymphadenitis), darkening of the skin (hyperpigmentation), thickening of the skin and excessive hair growth (hypertrichosis).

Castleman Disease: UCD is characterized by a single enlarged lymph node or multiple enlarged lymph nodes in a single region of the body, such as the chest, abdomen, or neck. In most cases of UCD, individuals exhibit no symptoms (asymptomatic).

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22
Q

For MGUS, in which situations is it more likely to change to MM or waldenstrom

A
  • Patients with non-IgM and light chain
    MGUS are more likely to develop multiple myeloma
  • Patients with IgM MGUS are more likely to develop
    Waldenstrom macroglobulinemia or other B-cell non-Hodgkin
    lymphoma.
  • MGUS may infrequently transform to immunoglobulin
    light-chain (AL) amyloidosis.
  • The presence of an IgA
    or IgM gammopathy, an M protein level of 1.5 g/dL or more,
    and an abnormal serum FLC ratio are predictive of progression
    to multiple myeloma or other PCD in non-light-chain MGUS
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23
Q

What complication is associated with MGUS

A

Patients with MGUS are at increased
risk of osteoporosis and associated skeletal complications, most notably vertebral body compression fractures (hazard ratio 2.37) and should be considered for bone mineral density testing

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24
Q

What are the following amyloidosis associated with?

  • AL amyloidosis
  • AA amyloidosis
  • Hereditary amyloidosis
A

AL Amyloidosis

  • Plasma cell dyscrasias: MGUS, MM,
  • Waldenstrom is rare
  • Monoclonal free kappa/lambda light chains

AA Amyloidosis

  • RA
  • IBD
  • Familial mediterranean fever
  • Chronic infection
  • Serum amyloid A protein

Hereditary Amyloidosis

  • Inherited
  • Mutated transthyretin, fibrinogen a chain
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25
Q

Features of AL amyloidosis

A
  • Associated with MM, MGUS and rarely waldenstrom
  • Associated with tissue deposition of monoclonal kappa/lambda chains
  • Clinical symptoms vary depending on where the chains deposit
  • MGUS + extracellular tissue deposition of fibrils composed of fragments of monoclonal light chains
  • Organ inovelement:
    Kidney: nephrotic syndrome, renal failure
    Cardiac: diastolic dysfunction, raised NT-pro BNP
    GIT: diarrhoea, bleeding risk
    Skin: amyloid plaques

Diagnosis

  • Diagnosis is via abdominal fat pad aspirate and bone marrow biopsy or biopsy of affected organ
  • Apple green birefringence under polarised light with congo red staining

Treatment

  • Autologous stem cell transplant for selected patients
  • Chemoimmunotherapy: bortezomib based regimens
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26
Q

What predicts prognosis in AL amyloidisis?

A
  • The prognosis of systemic AL amyloidosis is driven by the extent of cardiac involvement and levels of affected serum FLCs.
  • A prognostic model incorporates an elevated serum troponin T level or NT-proBNP level and a significant difference
    in the involved to uninvolved serum FLC level; patients with
    0, 1, 2, or 3 risk factors have a median overall survival of 94.1,
    40.3, 14.0, or 5.8 months, respectively.
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27
Q

Treatment of AL amyloid

A

Treatment with autologous hematopoietic stem cell transplantation in select patients with AL amyloidosis
has demonstrated high hematologic response rates,
improved organ function, and durable progression-free
and overall survival.

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28
Q

Features of waldenstrom macroglobulinaemia

A
  • Waldenstrom macroglobulinemia is an indolent B-cell non- Hodgkin lymphoma characterized by production of an lgM kappa or lambda M protein
  • Lymphoplasmacytic lymphoma in the bone marrow and IgM monoclonal gammopathy

Systemic symptoms:
- Fatigue
- Anaemia
- B symptoms: fever, weight loss, night sweats
- Neuropathy, axonal > demyelinating
- Hyperviscosity: headache. blurred vision, hearing loss. tinnitus, dizziness, altered mental status, and
nasal and oropharyngeal bleeding. Funduscopic evaluation may reveal hyperviscosity-related findings including dilated retinal veins, papilledema. and flame hemorrhages
- A bleeding diathesis is present in one quarter or patients at diagnosis attributable
to hyperviscosity, qualitative platelet dysfunction, or less commonly, dysfibrinogenemia

Symptoms related to IgM

  • Can act as an autoantibody: peripheral neuropathy
  • May precipitate out in the serum in cold temperatures - cryoglobulinemia
  • Pentamer - increases serum viscosity - hyperviscosity syndrome
  • Can deposit as amorphous extracellular material in GIT - malabsorption
Infiltration of haematopoietic tissue by neoplastic B cells 
- Cytopenias
- Hepatosplenomegaly 
Physical Examination: 
- Symptomatic lymphadenopathy
- Hepatosplenomegaly

Lab: cytopenia (anaemia, thrombocytopenia)

Diagnosis

  • IgM paraprotein
  • > 10% of the bone marrow is infiltrate of small lymphocytes
  • MYD88 L265P gen mutation in >90 of patients

Tx

  • Plasma exchange if hyperviscosity syndrome
  • Chemoimmunotherapy - rituximab + ibrutinib
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29
Q

Features of hyperviscosity syndrome

A

Hyperviscosity:
- headache. blurred vision, hearing loss. tinnitus, dizziness, altered mental status, and
nasal and oropharyngeal bleeding. = Funduscopic evaluation may reveal hyperviscosity-related findings including dilated retinal veins, papilledema. and flame hemorrhages
- A bleeding diathesis can be present - spontaneous gum bleeding, epistaxis, rectal bleeding, menorrhagia, persistent bleeding after minor procedures

Investigations

  • FBC + film: rouleaux formation is often present with increased serum viscosity
  • WCC > 100,000/μL in leukostasis causing HVS, but it may be lower in the blast crises of the leukemias

Treatment: plasmapharesis

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30
Q

Environmental exposures causing haematological maligancies

A
  1. Chemotherapy causing therapy related AML/MDS
    - Alkylating agents (5-10 years): cyclophosphamide, melphalan, busulfan
    - Topoisomerase II inhibitors (1-5 years): etoposide, mitoxantrone
  2. Radiotherapy
    - Secondary AML/CML/MDS
    - 5-10 years after
  3. Pesticides/hair dyes can cause follicular lymphoma
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31
Q

What are some oncogenic viruses?

A

(A) EBV or human herpes 4 (HHV4)
- Immunocompetent: infects B lymphocytes and persists in naive memory B cells
- Immunocompromised: strong association with B CELL LYMPHOMA
Burkitt lymphoma, classical hodgkin lymphoma, DLBCL, PCNSL, plamablastic lymphoma
Post transplant lymphoproliferative disorder
- Establishes latent infection

(B) Human T cell Leukemia VIRUS (HTLV-1)

  • Retrovirus
  • Adult T cell leukemia/lymphoma
  • Endemic in Japan, Caribbean, central Africa

(C) Human Herpes Virus 8 (HHV8)

  • Kaposi sarcoma associated herpes virus
  • Primary effusion lymphoma
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32
Q

What is the diagnostic test for lymphoma?

A

LN biopsy - surgical excision or core needle biopsy

Fine needle aspirate - no utility in diagnosis of lymphoma

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33
Q

What is CVID associated with?

A

Increased risk of lymphoma

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34
Q

What is Sjogrens associated with?

A

Increased risk of marginal zone lymphoma

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35
Q

What is CD45 a marker of?

A

CD45 is used as a marker of all hematopoietic cells (blood cells), except for mature erythrocytes (red blood cells) and platelets

Used to gate blast population

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36
Q

What’s the karyotype of Turners and Klinefelters?

A

Turners: 45X
Klinefelter: 47 XXY

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37
Q

When PET is used, which lymphomas uptake 18-flurodeoxyglucose (FDG)?

A

Classical Hodgkin
Diffuse large B cell
Follicular
Mantle cell (not FDG avid)

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38
Q

Risks of premature ovarian insufficiency or testicular dysfunction

A

Risks

  • Increasing age
  • Pelvic radiotherapy increase risk of uterine rupture
  • Alkylating agents, eg: cisplatin, cyclophosphamide, melphalan, oxaliplatin
  • Platinum based treatments: cisplatin, carboplatin and oxaliplatin
  • Anthracyclines (doxorubicin) and anti-metabolites: lower risk
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39
Q

When should you suspect MDS?

A

In patients with pancytopenia or macrocytic anaemia where B12 and folate deficiency has been excluded
Diagnosis and prognosis require bone marrow biopsy
and aspiration with cytogenetic studies

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40
Q

What is MDS and causes?

A

Myelodysplastic syndromes (MDS) are a group of haematological cancers in which malfunctioning pluripotent stem cells lead to hypercellularity and dysplasia of the bone marrow. This, in turn, leads to cytopenia of one or more cell lines (thrombocytopenia, erythrocytopenia, leukocytopenia).

Primary (90% of cases): tend to occur in ELDERLY patients >60yo

Secondary (10% cases): caused by exogenous bone marrow damage

  • Treatment related MDS eg: alkylating agents, topoisomerase II inhibitors
  • Benzene or other organic solvents
  • Radiation damage
  • Paroxysmal nocturnal hemoglobinuria

Associated with

  • Bone marrow failure
  • Peripheral cytopenias
  • Propensity for progression to AML
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41
Q

Clinical features of MDS

A
  • Asymptomatic in 20% of cases
  • Depending on the affected cell line
    Erythrocytopenia: symptoms of anaemia
    Leukocytopenia: increased susceptibility of bacterial infections, febrile neutropenia
    Thrombocytopenia: petechial bleeding
  • Typical presentation: macrocytic anaemia+/- neutropenia/thrombocytopenia
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42
Q

Investigations for MDS

A
  • FBC + blood film
    usually pancytopenia or macrocytic/normocytic anaemia, dysplasia
  • Can have nucleated RBC, howell jolly bodies

Bone marrow biopsy:

  • hypercellular
  • dysplastic bone marrow with blasts 1-3 lineages
  • ringed sideroblasts
  • conventional cytogenetics ( del5q, monosomy 7)
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43
Q

Management of MDS

A

LOW risk patients
- Supportive with blood transfusions
RBC for Hb < 80
Platelets for <10 or <20 if febrile
Growth factors: EPO + GCSF
- Due to multiple blood transfusions (after 20 units RBC), need to use iron chelating agents like DEFERASIROX to eliminate iron buildup
- Disease modifying agents: Luspatercept or sotatercept (activin type IIB receptor fusion protein that regulates late stage erythropoiesis) reduces red cell transfusion requirements
Fusion protein that blocks transforming growth factor beta (TFGB) inhibitors of erythropoiesis essentially allow erythropoesis to occur!

HIGH risk patients

  • Azacitidine therapy (hypomethylating agent)
  • Allogenic BM transplant considered in younger person which is CURATIVE <60yo or 60-70 and fit
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44
Q

In MDS, what treatment is used for 5q - syndrome

A

Lenalidomide

5q minus syndrome
Clinical syndrome characterised by hypoplastic anaemia, a normal or elevated platelet count, atypical marrow megakaryocytes with relatively indolent clinical course.

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45
Q

Complication of MDS

A

30% can progress to form AML

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46
Q

CML

A

Characterised by slow onset of constitutional symptoms, leukocytosis, marked splenomegaly

  • CML is caused by the Philadelphia chromosome t (9:22) leading to the production of BCR-ABL fusion protein which leads to activation of tyrosine kinases and unchecked proliferation and survival
  • Can enter transitional accelerated phase or progress to blast crisis which is a secondary form of acute leukemia –> 80% AML or 20% ALL.
  • Affects GRANULOCYTES, CML cells divide too quickly.

Clinical Features (CAB)

  • Chronic phase
  • Accelerated phase 20-30% blasts
  • Blast Phase >30% blasts - often caused by trisomy 8, doubling of Philadelphia chromosome
  • Additional chromosomal changes and mutations of tumor suppressor genes and oncogenes (p53, Rb1, or Ras), which emerge during the course of the disease, are responsible for the progression from chronic to accelerated phase and, ultimately, the transition to acute leukemia.

Features

  • Elevated WCC (EXTREME LEUKOCYTOSIS) and basophilia
  • Neutrophilia, eosinophilia, Basophilia, thrombocytosis, anaemia
  • Hepatosplenomegaly
  • Non-specific: fatigue, fever, weight loss, night sweats
  • Blood film: Neutrophilia with LEFT SHIFT –> towards blasts
  • Lymphadenopathy not common in CML
  • Unlike AML, CML is not characterised by recurrent infections during early stages as the granulocytes are still fully functional
  • Hyperuricemia

Tx: tyrosine kinase inhibitors

  • Imatinib (1st gen): low risk CP- CML
  • Dasatinib, Nilotinib (2nd gen): AP-CML
  • Ponatinib (3rd gen): especially effective in patients with additional mutations

Aim of treatment is to ensure complete haematological response (normalisation of blood counts) and not transition to acute leukemia.

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47
Q

What is the Philadelphia chromosome?

A

BCR-ABL positive
t (9:22)
Found in CML (chronic myeloid leukemia)

t (9:22) leads to the formation of a BCR-ABL fusion protein which activates dysregulated tyrosine kinases leading to unchecked proliferation and survival

Leads to a tyrosine kinase signalling protein that is “always on”, causing the cell to divide uncontrollably by interrupting the stability of the genome and impairing various signaling pathways governing the cell cycle.

Tx: tyrosine kinase inhibitors

  • Imatinib (1st gen)
  • Dasatinib, Nilotinib (2nd gen)
  • Ponatinib (3rd gen)
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48
Q

What is the blast crisis of CML?

A

The blast crisis is the terminal stage of CML.

Symptoms resemble those of acute leukemia.

  • Rapid progression of bone marrow failure → pancytopenia, bone pain
  • Severe malaise

Subtypes :

  • Myeloid blast crisis → AML(⅔ of cases)
  • Lymphoid blast crisis → ALL (⅓ of cases)

Tx is similar to acute leukemia
Aggressive chemotherapy + TKI
Allogenic stem cell transplant if patient is eligible

49
Q

Treatment for CML

A

Tx: tyrosine kinase inhibitors

  • Imatinib (1st gen): low risk CP- CML
  • Dasatinib, Nilotinib (2nd gen): AP-CML
  • Ponatinib (3rd gen): especially effective in patients with additional mutations

Aim of treatment is to ensure complete haematological response (normalisation of blood counts) and not transition to acute leukemia.

Check BCR-ABL levels to assess response to TKI

Adjunctive treatment

  • Hydroxyurea or IFN-a can be used to reduce leukocyte counts and control symptoms associated with leukocytosis or thrombocytosis
  • Chemotherapy
  • Allogenic HSCT
Prognosis of CML 
- Overall survival at 8 years = 89%
- Reasons for treatment failure
Development of mutations leading to drug resistance, eg; T315I
Poor compliance
50
Q

MOA and Side effects of

  • Imatinib (1st gen)
  • Dasatinib (2nd gen)
  • Nilotinib (2nd gen)
  • Ponatinib (newest)
A

MOA

  • Selective inhibition of tyrosine kinase (e.g., by blocking its ATP binding site): inhibits tyrosine phosphorylation of downstream signaling proteins (no phosphate transfer from ATP to tyrosine residues)
  • Disruption of the BCR-ABL1 pathway: inhibits proliferation and induces apoptosis in BCR-ABL1-positive cells

SE: All TKIs can lead to:

  • QT prolongation
  • Not safe in pregnancy
  • Common effects: marrow suppression, elevated LFTs, rash

Imatinib

  • Fluid retention, facial oedema
  • Muscle cramps
  • GI effects; diarrhoea, nausea
  • Generally well tolerated in the elderly

Dasatinib

  • Pericardial and pleural effusions
  • Can cause pulmonary artery HTN
  • moderate increase risk of vascular disease
  • Faster and deeper molecular response compared to imatinib

Nilotinib
- Pancreatitis
- Significant increased risk of Vascular disease
- LFT abnormalities
- BD administration
Faster and deeper molecular response compared to imatinib

Ponatinib

  • New TKI to overcome resistance
  • Can cause severe VTE/vascular events
  • Rash, pancreatitis
  • Effective if resistant or intolerant to 2nd gen
  • Effective with T315I (development of this mutation causes drug resistance)
51
Q

Chronic myelomonocytic leukemia features (myelodysplastic/myeloprolferative neoplasm)

A

Chronic myelomonocytic leukemia (myelodysplastic/myeloprolferative neoplasm) - crossover syndrome

MDS Features
- Dysplasia of myeloid lineages

MPN Features

  • Leukocytosis, monocytosis >1 x 10^9 for longer than 3 months (excluded reactive)
  • Splenomegaly
  • Circulating immature myeloid cells
  • ABSENCE of MPN driver mutations (JAK2, BCR-ABL1)
  • Somatic mutations commonly encountered (TET2, SRSF2, ASXL1)

Tx

  • Supportive
  • Cytoreductive agents if proliferative - hydroxyurea
  • Hypomethylating agents: azacytidine
52
Q

Summary of myeloproliferative neoplasms

A
  1. PV: Increased haemoglobin and haematocrit [JAK2]
  2. Essential thrombocythaemia: thrombocytosis [CALR, MPL]
  3. Primary myelofibrosis (overt fibrotic stage)[CALR, MPL]
    - Leucoerythroblastic blood film
    - Tear drop RBC
    - Only JAK2 inhibitors work here
  4. Primary myelofibrosis (prefibrotic stage)
    - Thrombocytosis
    - May also have mild anaemia, high LDH, splenomegaly

Abnormalities in JAK2, CALR, MPL are usually somatic and not germline mutations

  • Somatic mutations – occur in a single body cell and cannot be inherited (only tissues derived from mutated cell are affected)
  • Germline mutations – occur in gametes and can be passed onto offspring (every cell in the entire organism will be affected)
53
Q

What are the driver mutation in myeloproliferative neoplasms?

A

JAK2, CALR, MPL

  • Mutations in JAK2, CALR, and MPL drive excessive myeloproliferationvia constitutively active signalling downstream of JAK2.
  • JAK2 associates with the cytoplasmic portion of a variety of receptors, such as those for erythropoietin (EPOR), thrombopoietin (MPL), and granulocyte/macrophage colony-stimulating factor (G-CSFR).
  • JAK2 is also activated in response to additional cytokines (e.g., growth hormone and IL-5)
  • Mutant JAK2, is constitutively active and leads to variable levels of erythroid, megakaryocytic, and, to a lesser degree, granulocytic proliferation and differentiation.
  • Mutations in CALR and MPL result in aberrant activation of signalling downstream of the MPL receptor. Both mutations in CALR and MPL result in activation of JAK2-

JAK2 and MPL mutations are associated with higher rates of THROMBOSIS

54
Q

CALR Mutations

A

Somatic mutations of CALR exon 9

  • Almost exclusively in myeloid neoplasms with thrombocytosis
  • Essential thrombocythemia and primary myelofibrosis
  • Mutant calreticulin activates JAK-STAT pathway via thrombopoietin receptor

CALR type 1 (deletion) mutation

  • MYELOFIBROSIS phenotype
  • Significantly higher risk of MF transformation
  • Male sex predominates

CALR type 2 (insertion) mutation

  • ET phenotype
  • Younger patients
  • Low risk of thrombosis
  • Very high platelet counts
  • Indolent clinical course
55
Q

Features of polycythemia vera

A
  • Disorder of the myeloid/erythroid stem call that causes ERYTHROPOIETIN INDEPENDENT proliferation of ERYTHROCYTES - PERSISTENT ELEVATION OF HB/HCT
  • JAK2 mutation
  • Hb >16.5g/dL in men, >16g/dL in women
  • Erythrocytosis frequently combined with thrombocytosis +/- leukocytosis
  • Bone marrow hypercellularity with trilineage growth
  • Suppressed endogenous erythropoietin production

Clinical Features;

  • Pruritus after a warm shower
  • Erythromelalgia: rare condition that primarily affects the feet and, less commonly, the hands (extremities). It is characterized by intense, burning pain of affected extremities, severe redness (erythema), and increased skin temperature that may be episodic or almost continuous in nature
  • TIA
  • DVT/PE
  • Splenomegaly
  • Plethora: flushed face with purple hue, cyanotic lips
  • Increased risk of VENOUS + ARTERIAL thrombosis
  • Hyperviscosity syndrome: triad of mucosal bleeding, neurological symptoms, visual changes
  • Unusual clots especially PORTAL OR SPLANCHNIC clots are classic for MPNs in general and PV specifically
  • Diagnosis of hepatic vein thrombosis (budd chiari syndrome) or portal vein thrombosis should prompt consideration of PV.
56
Q

Causes of erythrocytosis

A

Erythropoietin independent
- Polycythemia vera

Erythropoietin dependent (secondary causes) - RAISED HB/HCT WITH EPO LEVEL NORMAL/HIGH

  • JAK2 mutations negative
  • High altitude, COPD, smoking, sleep apnoea, drugs (EPO, testosterone)
  • Hypoxemia secondary to COPD, sleep apnoea, congenital heart disease, elevated altitude, renal artery stenosis - thrombosis, TIA
  • Ectopic or excessive erythropoietin: RCC, hepatocellular cancer, uterine fibroids
57
Q

Investigations for PV

A
  • Erythroctosis (Elevated Hb, men >16.5, females >16)
  • Thrombocytosis
  • Leukocytosis
  • Elevated uric acid, LDH
  • Elevated leukocyte alkaline phosphatase
  • Low EPO
58
Q

Diagnostic criteria for PV

A

All 3 major criteria or 2 major + 1 minor

MAJOR
1. Increased RBC
Elevated Hb (men > 165, females > 160) or
Elevated haematocrit (men > 49%, females > 48%)

  1. Bone marrow biopsy showing hypercellularity with trilineage growth (erythopoiesis, granulopoeisis, megakaryopoeisis), pleomorphic mature megakaryocytes
  2. JAK2 mutation exon 12

MINOR
- Low EPO levels

59
Q

Treatment for polycythemia vera

A
  • Main consequence is arterial thrombosis
  • Phlebotomy to haemocrit <45% and aspirin 100mg in ALL patients
  • Addition of hydroxyurea if high risk (history of thrombosis)

Risk Stratification
- Low Risk: age < 60, no hx PV associated arterial/venous thrombosis
Microvascular symptoms, CV risk factors (especially HTN), leukocytosis: BD aspirin

  • High risk: age > 60, hx of prior PV associated arterial/venous thrombosis
    Add cytoreductive therapy: hyroxyurea, IFN-a
    Arterial thrombosis: BD aspirin
    Venous thrombosis: therapeutic anticoagulation
    Long term AC recommended for splanchnic venin thrombosis, cerebral vein thrombosis, unprovoked proximal DVT/PE
  • Low dose ASPIRIN for all
  • HCT target < 0.45 (haemocrit)
  • Venesection
  • Addition of cytoreductive therapy (hyroxyurea or interferon) in high risk patients
  • Can consider JAK2 inhibitor: ruxolitinib jak 1/2 (but not on PBS for PV)
60
Q

Complications of polycythemia vera

A
  • PV remain stable with therapy (70%), enter a spent/burned out phase (20%) or evolve into secondary AML 910%)
  • In spent phase, secondary fibrosis occur in bone marrow and extramedullary hematopoiesis leads to progressive splenic and hepatic enlargement

(A) Thrombotic complications
More common than bleeding complications
- Hyperviscosity: headache, blurred vision, plethora
- Venous thrombosis: DVT, pulmonary emboli, splanchnic vessels, renal vein/mesenteric vein/portal vein/splenic vein thrombosis
- Arterial thrombosis: stroke, peripheral arterial emboli, MI
- Thrombosis in small blood vessels: cyanosis, erythromelalgia, ulceration or gangrene in fingers/toes

(B) Haemorrhagic complications

  • Petechiae
  • Epistaxis
  • Bleeding gums
  • Severe bleeding episodes are rare

(C) Gout
- High number of cell turnover - increased uric acid

Late Stages

  • AML,MDS
  • Myelofibrosis
61
Q

Risk factors of thrombosis in PV

A

RF for thrombosis in PV patients

  • Thrombosis history
  • Advanced age > 60
Other disease and patient related factors 
- Leukocyte count > 15
- Hypertension 
RF for arterial thrombosis 
Even in low risk patients 
ACEi treatment of choice
62
Q

When do you consider BD aspirin for patients with PV

A
  • Arterial thrombosis hx
  • Microvascular symptoms not controlled with daily therapy
  • High risk pts with cardiovasculr RF (HTN) and leukocytosis
63
Q

Indications for cytoreduction in PV

A

High risk patients

  • Age >60yo or
  • Previous thrombotic event

Additional indications

  • Poor tolerance of phlebotomy
  • Platelets >1500
  • Wcc > 15
  • Uncontrolled myeloproliferation, eg: increasing splenomegaly
  • Uncontrolled PV related systemic symptoms

1st Line:

  • Hydroxyurea (hyroxycarbamide)
  • IFN-a

2nd Line
- Buslfan: intermittent therapy in elderly
- Ruxolitinib: not PBS funded for PV (JAK2 inhibitor)
Ruxolitinib used in patients with splenomegaly who have failed hydroxyurea

64
Q

Features of essential thrombocythemia

A
  • Suspected when platelet count >450 x 10^9/L is detected on 2 occasions at least 1 month apart in the absence of secondary causes
  • Iron deficiency anaemia is the most common cause of secondary thrombocytosis followed by reactive states due infection/inflammation.
  • JAK2 in 60-65%, CALR exon 9 in 20-25%, MPL exon 10 in 4-5%
  • ~10% do not carry any somatic mutations
Clinical Features
- Most are asymptomatic 
- Increased risk of venous and arterial thrombosis 
Digital ischaemia 
Erythromelalgia
TIA
Visual disturbances 
VTE
Bleeding due to dysfunctional platelets 
- Acute gouty arthritis 
- Triple negative have low incidence of vascular events

Diagnosis

  • Is a diagnosis of exclusion, need to exclude all other causes of thrombocytosis
  • Thrombocytosis > 600 x 10^9
  • Elevated LDH, uric acid
  • Bone marrow aspirate: hyperplasia of megakaryocytes.

Tx
- Many patients with ET can be observed.
- Low risk is defined as meeting all the following criteria
1. Age < 60yo
2. Nil previous thrombosis
3. JAK mutation
These patients can be observed without platelet lowering therapy

High risk patients
Thrombosis history OR age >60 with JAK mutation
- Aspirin 
- Hydroxyurea 
- Interferon alfa safe in pregnancy

Prognosis

  • Less likely to progress to AML or secondary fibrosis
  • Least likely to present with symptomatic splenomegaly or constitutional symptoms

Complications
- Acquired von willebrand disease

65
Q

Diagnostic criteria for ET

A

All 4 major criteria or first 3 major and the minor criterion

MAJOR

  1. Platelets >450 x 10^9/L
  2. BMB showing proliferation mainly of megakaryocyte lineage (enlarged, mature, hyperlobulated megakaryocytes)
  3. Not meeting WHO criteria for CML, PV, PMF or MDS
  4. Presence of JAK2, MPL or CALR mutation

MINOR
1. Presence of clonal marker or absence of evidence for reactive thrombocytosis

66
Q

Indication for aspirin and/or cytoreductive therapy in ET

A

Indications for Aspirin

  • Age > 60
  • Cardiovascular risk factors
  • JAK mutation

Contraindications to Aspirin

  • Extreme thrombocytosis
  • Acquired von willebrand
  • Low risk CALR- positive ET

Indications for cytoreduction
- High risk patients:
Prior thrombosis OR
Age > 60yo with JAK mutations

  • Additional indications
    Platelets >1500 x 10^9
    Uncontrolled myeloproliferation
    Uncontrolled ET related systemic symptoms
67
Q

Treatment algorithm depending on risk for ET

A 
(A) Very Low Risk 
- Age < 60
- No history of thrombosis 
- JAK2/MPL unmutated 
No cardiovascular RF: observation alone 
Cardiovascular RF: aspirin (avoid aspirin in the presence of extreme thrombocytosis and acquired vWS)
(B) Low Risk 
- Age < 60
- No history of thrombosis 
- JAK2/MPL mutated 
Aspirin daily or BD
(C) Intermediate Risk 
- Age > 60 
- No hx of thrombosis
- JAK/MPL unmutated 
Hydroxyurea + aspirin

(D) High Risk
- Hx of thrombosis OR
- Age >60 with JAK/MPL mutation
Arterial thrombosis hx: hydroxyurea + BD aspirin
Venous thrombosis: hydroxyrurea + AC
If JAK/MPL mutated OR cardiovascular RF = add aspirin

1st line cytoreductive agent: hydroxyurea
2nd line cytoreductive agent: anagrelide - interferes with terminal differentiation of megakaryocytes
Interferon in the young/pregnant

68
Q

Primary myelofibrosis

A
  • Clonal myeloid disorder characterised by abnormal, proliferating megakaryocytes that produce excess fibroblast growth factor
  • Causes marrow fibrosis and leads to extramedullary hematopoiesis
  • Blood film: leucoerythroblastic peripheral blood smear with left shifted granulopoiesis and nucleated and TEAR DROP-shaped erythrocytes
  • Bone marrow aspiration leads to “dry tap”
  • Markers of increased cell turnover, eg: elevated LDH, uric acid
  • JAK2 in 60-65%
  • CALR exon 9 25-30%
  • MPL exon 10 4-5%
  • About 5-10% patient do not carry any of above mutations. , MPL, CALR mutations

Clinical Features

  • Prefibrotic Phase: anaemia, leukocytosis, elevated LDH, splenomegaly
  • Cytokine mediated symptoms: fever, chills, night sweats, malaise
  • Early satiety, weight loss
  • Abdominal discomfort from MARKED SPLENOMEGALY
  • Gout

Treatment:

  • Supportive
  • In young patients allogenic: HSCT
  • Disease modifying JAK2 inhibitor: Ruxolitinib approved for high risk myelofibrosis, help with reduction in spleen size. Improves symptoms and survival.
  • Treatment is mostly palliative

Prognosis: risk of leukemic transformation
PV and ET can both progress to myelofibrosis

69
Q

Primary myelofibrosis diagnosis

A

Diagnosis: 3 major criteria and >1 minor

Major Criteria

  1. Megakaryocyte proliferation and atypia, with reticulin and /or collagen fibrosis grades 2 or 3
  2. Not meeting criteria for CML, PV, ET, MDS
  3. Presence of JAK2, CALR or MPL mutation

Minor Criteria

  1. Anaemia not due to comorbid condition
  2. WCC >11 (leukocytosis >11)
  3. Palpable splenomegaly
  4. Increased LDH
  5. Leukoerythroblastic film
70
Q

Features of pre-MF with ET

A
  • Higher risk of bleeding
  • Higher rates of transformation into overt-MF or AML
  • Shorter median overall survival
  • No difference in thrombosis rate
71
Q

Management for prefibrotic myelofibrosis (pre-MF)

A
  • Vascular risk +/- marked leukocytosis/thrombocytosis: aspirin + cytoreductive therapy
  • Disease symptoms impacting QOD: JAKi (Ruxolitinib)
  • Symptomatic splenomegaly: cytoreductive therapy or JAKi
  • High risk disease or progressive refractor splenomegaly +/- high molecular risk factors: consider allogenic SCT
72
Q

Treatment for primary myelofibrosis

A

Observation alone unless:

  • Significant symptoms
  • Anaemia
  • Splenomegaly (palpable spleen >10cm)
  • Leukocytosis (WCC >25)
  • Marked thrombocytosis >1000
  • If very high risk (10 year survival <5%) and transplant eligible : allogenic SCT
  • If transplant ineligible: Ruxolitinib (JAK 2 inhibitor)
  • Anaemia: androgens, danazol, thalidomide, prednisone
  • Splenomegaly: hydroxyurea, ruxolitinib, splenectomy
  • Constitutional symptoms: ruxolitinib, hydroxyurea
  • Localised bone pain: RT
73
Q

MOA and SE of ruxolitinib

A

MOA: JAK2 inhibitor

Effects

  • Improves splenomegaly
  • Promotes weight gain, improves pruritus (resolution of constitutional symptoms)
  • May reduce thrombosis risk
  • Reduce transfusion requirements

SE:

  • Anaemia especially in first 3 months
  • Thrombocytopenia
  • Infection
74
Q

Features of acute leukemia

A

Divided into:

  • Acute Lymphocytic Leukemia (ALL): most common childhood malignancy
  • Acute Myeloid Leukemia (AML): primarily affects adults
  • Characterised by the proliferation of immature, nonfunctional WBCs (blasts) in the bone marrow which impairs normal hematopoiesis.
  • Leads to pancytopenia which manifests as anaemia, thrombocytopenia and increased risk of infections.
75
Q

Features of AML

A
  • Can have high WCC leading to leukostasis and DIC

Diagnosis
- FBC and blood film
Pancytopenia
Elevated WCC with blasts in peripheral blood
- Raised LDH with pancytopenia is a red flag
- Bone marrow aspirate and trephine:
>20% myeloblasts
Blasts with AUER RODS
-Immunohistochemstry: MPO positive, TDT negative
- Flow Cytometry: CD33, CD34, CD117, HLA-DR

Karyotype:

  • AML: t(8:21), inv (16), t(16:16)
  • APML: t(15:17) in acute promyelocytic leukemia (APML)
  • FLT3-ITD associated with poor prognosis
76
Q

Where are bone marrow biopsy taken from?

A
  • Iliac crest: aspirate + trephine

- Sternum: aspirate only

77
Q

Risk factors for AML

A
  • Advanced age (median diagnosis 69yo)
  • History of myelodysplastic syndrome or myeloproliferative syndrome
  • Prior chemo or radio
  • 1st degree relative with AML

Known predisposing genetic disorders

  • Down syndrome
  • Trisomy 8
  • Ataxia-telangectasia
  • Neurofibromatosis 1
  • Fanconia anaemia
  • Diamond Blackfan anaemia
  • Shwachman diamond syndrome
78
Q

What are favourable and poor genetics for AML?

A

FAVOURABLE

  • t(8:21), inv (16), t (16:16)
  • mutated NPM1 without FLT3-ITD or with low FLT3-ITD

INTERMEDIATE
- Mutated NPM1 and FLT3-ITD high

ADVERSE

  • t(6,9), t(3,3)
  • Wild type NPM1 and FLT3-ITD high
NPM1 = good 
FLT3 = bad
79
Q

Prognostic factors for AML

A

Patient Related Factors

  • Age > 60yo
  • ECOG
  • Comorbidities

Disease Related Factors : Genetic abnormalities

  • FLT3-ITD mutations confer an adverse prognosis
  • FLT3-ITD co-occurrence with NPM1 mutation partially improves response and survival
  • FLT3-TKD/NPM1 double mutation is associated superior relapse free survival compared to NPM1 only mutated AML

Good Prognosis

  • AML with eosinophilia t (8:21)
  • Acute myelomonocytic leukemia (AMML) associated with inv 16

Inferior Prognsis

  • Acute megakaryoblastic luekemia: often transformed from prior MPN
  • Acute erythroid leukemia
80
Q

Treatment for AML

A

CURATIVE INTENT

(1) Intensive
- 7+3 regimen: 7 days of cytarabine and 3 days of an anthracycline (eg: doxorubicin)
- Allogenic haematopoietic stem cell transplant

(2) Non Intensive
- Consider for patients >70yo
- Low dose cytarabine or
- Azacitidine if <30% blasts or
- Azacitidine + Venetoclax
Venetoclax = BCL2 inhibitor causing cells to undergo apoptosis
SE: increases rate of neutropenia and infection
Note: BCL2 overexpression allow cancer cells to evade apoptosis by sequestering pro-apoptotic proteins

TARGETED THERAPIES

  • Midostaurin (FLT3 inhibitor)
  • Gilteritinib: FLT3 inhibitor
  • Enasidenib: IDH2 inhibitor
  • Ivasidenib IDH 1 inhibitor
81
Q

Complications of AML

A
  • DIC - catastrophic internal/intracranial haemorrhage
  • Hyperleukocytosis (WBC >100): pulmonary infiltration, hypoxaemia
  • Febrile neutropenia
82
Q

Subtypes of AML

A

Monoblast AML

  • buildup of monoblasts
  • Often no myeloperoxidase
  • Infiltrates gums

Megakaryoblast AM

  • Often no myeloperoxidase
  • Associated with down syndrome
83
Q

Features of APML (acute promyelocytic leukemia)

A
  • Characterised by t(15:17)
  • Associated with DIC
    Due dysfunctional retinoic acid receptor –> buildup of promyelocytes –> LOTS of auer rods –> increase coagulation risk –> DIC
  • Requires rapid diagnosis with PML-RARA PCR or FISH

Treatment

  • Platelet transfusion + fibrinogen replacement
  • ATRA (all trans retinoic acid) + arsenic +/- chemotherapy
  • Complete response rate 91%
  • Risk of death during induction 5%, mainly due to haemorrage
  • Prompt initiation of ATRA reverses DIC

ATRA = vitamin A derivative and promotes differentiation of promyelocytes to cell death

84
Q

Complication of using ATRA (all trans retinoic acid) + arsenic

A

ATRA (all trans retinoic acid) + arsenic
- Can cause DIFFERENTIATION syndrome

Cell differentiation induced by ATRA leads to rising WCC and cytokine release

Characterised by:

  • Fever
  • Oedema and weight gain due to leaky capillaries
  • Hypoxemia with Pulmonary infiltrates
  • Pleuropericardial effusion
  • Renal and hepatic dysfunction

Requires DEX 10mg BD and consider delaying chemo

85
Q

What is down syndrome associated with?

A

Increased risk of acute leukemia

  • <5yo: megakaryoblastic AML
  • > 5yo: Acute lymphoblastic leukemia
86
Q

What is prognosis in AML predicted by?

A
  • Age
  • ECOG
  • Genetic abnormalities
87
Q

Pathophysiology of DIC and APML

A
  • Tissue factor and cancer procoagulant are both increased in promyelocytes and serum of patients with APML
  • Initiates massive thrombin generation which crosslinks to a fibrin clot and activates fibrinolytic cascade
  • Plasminogen is cleaved to generate plasmin which degrades fibrin
  • Excessive fibrinolysis leads to hypofibrinogenaemia and bleeding
  • DIC in APML primarily manifests as bleeding (not microvascular clotting)
  • Aggressive management
    Replacement of fibrinogen with cryoprecipitate if fibrinogen <2
88
Q

Types of Renal disease in MM

A

Tubular

  • Light chain cast nephropathy (myeloma kidney) : 30-50%
  • Interstitial nephritis/fibrosis : 20-30%
  • Acute Tubular Necrosis : 10%

Glomerular
- Amyloidosis : 10%
- Monoclonal immunoglobulin deposition disease (light chain deposition disease) : 5%
- Rare: Cryoglobulinemia/MCGN, C3 GN, DDD, Fibrillary GN and immunotactoid
glomerulopathy

Others: Hypercalcemia, use of NSAIDs for bone pain and IV contrast

Do not forget Fanconi Syndrome though…………

89
Q

Pathogenesis of cast nephropathy in MM

A
  • Free light chains(FLC) have 2-6 hours ½ life due to glomerular filtration unlike Immunoglobulins which have few weeks ½ life
  • Filtered FLC reabsorbed in PCT……leads to PCT epithelial cell damage….leading to Fanconi Syndrome (Type 2 RTA)
  • Injury to PTC allows FLC to escape to distal nephron…bind to Tamm- Horsfall protein (THP) in the ascending limb…lead to tubular casts - cast nephropathy seen in 30-50% of cases on renal biopsy
  • REMEMBER: FLCs levels will go up in AKI due to any cause but usually only upto 20-30 times and both Lambda and Kappa elevated (ratio <3:1)… in myeloma only one of the FLCs elevated (ratio >3:1)
  • More likely in those with higher serum FLC
  • Casts precipitated by- dehydration, acidification, hypercalciuria, radiocontrast
    agents, frusemide and NSAIDs

Biopsy findings: Distal tubular casts that are

  • strongly eosinophilic
  • consist of light chain and TH protein
  • often fractured after fixation
  • IF shows only one type of light chain
  • Glomeruli typically spared unless there is associated amyloidosis or light
    chain deposition disease
90
Q

Treatment of AKI in myeloma

A
  • Rapid reduction of FLC-immediate commencement of high dose
    dexamethasone (40 mg OD) and Bortezomib based therapy
  • Correct reversible factors contributing to AKI- IV fluids and bisphosphonate for hypercalcemia , treat sepsis, cease NSAIDs
  • Try to avoid frusemide as risk of precipitating cast formation
  • Plasma exchange ineffective as FLCs have large volume of distribution
  • Dialysis should be initiated for the usual indications (fluid overload, hyperkalemia etc.) and not for the removal of FLCs
91
Q

Where are myeloma casts formed?

A

They develop in the distal convoluted tubule or the collecting duct.

Urinary casts are cylindrical structures that are formed from coagulated protein (Tamm-Horsfall protein) secreted by tubular cells.

92
Q

How do you cover aspergillus

A

Posaconazole

93
Q

Features of acute lymphoblastic leukemia

A

(1) FBC + blood film
- Pancytopenia
- Blasts in peripheral blood

(2) Bone marrow aspirate and trephine
- >20% leukocytes
- NO auer rods

Immunophenotyping of the Blasts

  • Lymphoid antigens
  • B Lineage: CD19, CD79a
  • T Lineage: CD7, CD2, CD5, CD1a, CD3
94
Q

Poor risk markers for B-ALL

A

BCR-ABL - t (9;22)

95
Q

Treatment for adult ALL

A

(1) Induction Chemo
- BCR-ABL inhibitor if Ph+ ALL, eg: imatinib, dasatinib

(2) Maintenance chemo for up to 2 years
(3) Allogenic BMT

Assess for MRD - minimal residual disease

(4) Targeted Therapies
- Rituximab CD20
- Inotuzumab CD22
- T cell Mediated
(a) CAR-T Cells
(b) Bispecific T cell engaging (BiTE) antibodies
Blinotumomab (CD19/CD3)

96
Q

What is BiTE therapy and CAR-T cells

A

Bispecific T-cell engager (BiTE) and chimeric antigen receptor (CAR) use single chain variable fragments to direct cytotoxic T lymphocytes (CTL) to specific surface antigens on cancer cells to facilitate a polyclonal T-cell response to tumor antigens.
Essentially - T cells are engineered to FIND AND KILL CANCER CELLS

BiTE Therapy: generated from 2 antibodies with specificity for a T-cell activation molecule and a tumour-associated antigen
Eg: Blinatumomab is a CD19/CD3 bispecific T cell engager that directs T cells to CD19+ cells

CAR T cells: compromises of an extracellular domain, which is an short chain variable fragment targeting tumour-associated antigen

97
Q

Diagnosis of chronic lymphocytic leukaemia (CLL)

A

Disease of the ELDERLY
Common Symptoms: lymphadenopathy, fatigue, weight loss

(1) FBE and Blood Film
- Isolated lymphocytosis, >5 x 10^9/L B lymphocytes (95% are B phenotype)
- Cytopenias
- Blood Film: SMUDGE CELLS

(2) Immunophenotyping Peripheral Blood
- CD5+, CD19+, CD23+ clonal B cells

Associated with CLL

98
Q

Clinical staging of CLL

A

Rai and Binet Classification

Low Risk
- Stage 0: lymphocytosis only

Intermediate Risk

  • Stage 1: lymphocytosis
  • Stage 2: lymphadenopathy at any site, hepatosplenomegaly

High Risk

  • Stage 3: disease related anaemia <10g/dL
  • Stage 4: disease related thrombocytopenia

These cytopenias are non-immune and due to bone marrow replacement.

99
Q

Prognostic factors

A

Good Prognosis
- 13q deletion

Poor Prognosis

  • 11q, 17p deletion
  • CD38+
100
Q

Predictive markers for CLL

A

Only validated predictive markers in CLL are 17p deletion and TP53 variants

  • CLL without del (17p)/TP53 mutations
  • CLL with del (17p)/TP53 mutation - less likely to respond to chemo, resistance to traditional chemo

Favourable: del 13q

101
Q

Difference between acute and chronic leukemia

A

Acute Leukaemia: cells DON’T MATURE

Chronic Leukaemia: cells MATURE PARTIALLY

  • CML cells divide too quickly –> BUILDUP + HEPATOSPLENOMAGALY
  • CLL cells don’t die as they should –> BUILDUP + LYMPHADENOPATHY
102
Q

3 phase B cell differentiation

A

(1) Somatic rearrangement of Ag receptor genes
VDJ for the heavy chains, V and J for the light chains

(2) Somatic Hypermutation
(3) Class switch recombination

103
Q

Poor prognostic markers for CLL

A
  • Elevated B2 microglobulin
  • Elevated LDH
  • Unmutated IgH (heavy chains)
    CLL cells which have not entered the germinal centres and haven’t undergone the “hypermutation” of the IgVH has a much poorer prognosis than those who have undergone the activation process
104
Q

Clinical course of CLL

A
  • Rising lymphocytosis
  • Increasing lymphadenopathy and splenomegaly
  • Progressive BM failure
  • Progressive immuneparesis & B cell immunosuppression
  • Secretion of a paraprotein

Autoimmune complications (>10%)
• Autoimmune haemolytic anaemia
• Immune thrombocytopenia purpura

•Secondary skin cancers. (non melanomatous.

105
Q

When to treat CLL

A

Do not treat unless symptomatic!

  • Worsening anaemia or thrombocytopenia (<100)
  • Massive, or progressive or symptomatic splenomegaly
  • Massive or progressive or symptomatic lymphadenopathy
  • Progressive lymphocytosis (>50% ↑ < 2 months or lymphocyte doubling time < 6 months), or LDT < 6 months (with caveats)
  • AIHA or ITP unresponsive to steroids
  • Symptomatic extranodal involvement
  • Constitutional symptoms
106
Q

Treatment for CLL

A

<60yo: FCR

  • Rituximab + Fludarabine + Cyclophosphamide
  • UNLESS 17p deletion or TP53 mutation - IBRUTINIB (bruton tyrosine kinase inhibitor) OR
  • VENETOCLAX: inhibits BCL-2, an anti-apoptotic protein

For FRAIL ELDERLY
- OBINTUZUMAB (Type II anti CD20) + CHLORAMBUCIL

ENZYME INHIBITORS

  • IBRUTINIB: BRUTON TKI
  • VENETOCLAX: INHIBITS BCL-2
  • IDELASLISIB: PI3 KINASE INHIBITOR - increased PJP, infections
107
Q

Ibrutinib
MOA
SE

A

MOA: Bruton kinase inhibitor
BTK plays an important role in B CELL MATURATION
Blocking it causes - induce APOPTOSIS, BLOCKS MIGRATION/ADHERENCE

SE:

  • Redistribution lymphocytosis
  • Bruising ++ (WH 7 days prior to and after major procedures)
  • Diarrhoea
  • Fatigue
  • AF
108
Q

Venetoclax

MOA

A

BH3 mimetic/BCL2 inhibitor
Venetoclax mimics the action of the BH3 proteins and restores ability to undergo apoptotic death

Works very quick so graduated oral dosing is required to avoid TLS

109
Q 
Budd Chiari syndrome is most associated with which myeloproliferative disorder
A. Chronic myeloid leukaemia
B. Chronic myelo-monocytic  leukaemia
C. Essential thrombocythemia
D. Idiopathic myelofibrosis
E. Polycythemia Rubra Vera
A

E. Polycythemia Rubra Vera

110
Q

Which of the following factors are associated with a good prognosis in acute lymphoblastic leukaemia (ALL)?

A. Male sex
B. Rapid fall in white count following commencement of treatment
C. Rapid rise in white count following commencement of treatment
D. Expression of T-lineage markers

A

B. Rapid fall in white count following commencement of treatment

111
Q

Causes of splenomegaly

A

CML
Myelofibrosis
Malaria

112
Q 
Which of the following types of lymphoma is most characteristic of Ritcher's transformation in patients with CLL?
A. Classic Hodgkins Lymphoma 
B. Diffuse large B cell lymphoma 
C. Follicular lymphoma 
D. Small lymphocytic lymphoma
A

B. Diffuse large B cell lymphoma

Richter syndrome is a rare condition in which chronic lymphocytic leukemia (CLL) changes into a fast-growing type of lymphoma. Symptoms of Richter syndrome can include fever, loss of weight and muscle mass, abdominal pain, and enlargement of the lymph nodes , liver, and spleen.

Currently, the treatment of Richter’s transformation with diffuse large B-cell lymphoma consists of combination chemotherapy plus rituximab.

113
Q

How does CART therapy work?

A

(1) T cells are collected from patient
(2) DNA introduced into them, to produce chimeric antigen receptors (CARs) on the surface of the cells
(3) Patients are given chemotherapy
(4) CART cells are put back into patient’s bloodstream

114
Q

Side effects of CAR-T cell

A

(A) CYTOKINE RELEASE SYNDROME (CRS): As CAR T cells multiply, they can release large amounts of chemicals called cytokines into the blood, which can ramp up the immune system. Serious side effects from this release can include:

  • High fever and chills
  • Trouble breathing
  • Severe nausea, vomiting, and/or diarrhea
  • Feeling dizzy or lightheaded
  • Headaches
  • Fast heartbeat
  • Feeling very tired
  • Muscle and/or joint pain

(B) Immune effector cell associated neurotoxicity syndrome

  • Occur 3-10 days post
  • Encephalopathy with confusion
  • Visual + auditory hallucinations
  • Seizures
  • Cerebral oedema with coma
  • Death secondary to malignant cerebral oedema
  • STEROIDS
115
Q

What are the most commonly affected sites in GVHD?

A

Organs most often affected include the skin, gastrointestinal (GI) tract and the liver.

116
Q

What are the most common immunoglobulin found in MM?

A

The most common type of heavy chain produced in myeloma is IgG, followed by IgA and then IgD. IgM myelomas are rare, but when IgM is elevated in the blood, the patient more likely has a related disorder, known as Waldenstrom’s Macroglobulinemia.

(GAD)

117
Q

What is the long term target of therapy for CML on imatinib?

A

BCR- ABL < 0.1%

118
Q

Severe thrombocytopenia is a side effect of quinine. The mechanism of thrombocytopenia is?

A

Quinine dependent platelet antibodies
Quinine is reported to be one of the most frequent causes of drug-induced thrombocytopenia. It is thought to be able to bind to platelet membranes and then stimulate IgG antibodies.

119
Q

For cytokine release syndrome, what characteristics are assessed to determine its severity?

A
  • Fever
  • Hypotension
  • Hypoxia

Haematology (7 decks)

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