Case 15: Myeloproliferative neoplasma Flashcards
1
Q
Diagnosing ET and PV
A
FBC, Genetic testing, Bone marrow biopsy
2
Q
Polycycthaemia
A
- Relative (pseudo) polycythaemia – i.e. reduction in plasma volume (e.g. dehydration, alcohol, diuretics)
- True (absolute) polycythaemia – i.e. red cell mass increased. Tend to have secondary cause
- Raised Haemoglobin and Haematocrit
- Investigate if HCT >0.52 in men and 0.48 in women
3
Q
Causes of true Polcythaemia
A
- Respiratory disease e.g. hypoxic respiratory failure, OSA, smoking
- Cyanotic congenital cardiac disease
- Abnormal epo production (renal or hepatocellular carcinoma) or high altitude
- Endocrine – testosterone, anabolic steroids, doping
4
Q
Primary Polycythaemia (Polycythaemia Vera)
A
- JAK2 V617F mutation results in activation of JAK/STAT signalling pathway resulting in erythropoiesis not reliant on EPO (high PLT and WCC)
- Primary bone marrow malignancy
- Majority have JAK2 mutation
- Results in: Arterial and venous thrombosis (Hyper viscosity), Headache, Migraine, Blurred vision, Hypertension, Pruritus (after shower/bath), Plethora (red face), Splenomegaly, Haemorrhage, Fatigue
- Mostly >50 years
5
Q
Primary polycythaemia investigations
A
- FBC/blood film: raised haematocrit, neutrophils, basophils, platelets
- JAK2 mutation
- Ferritin, LFT, U&E, ESR (low), LAP (raised)
- If negative JAK2: oxygen stats, abdo US, serum erythropoietin, bone marrow aspiration
6
Q
Polycythaemia Management
A
- Aspirin for all
- Review other cardiovascular risk factors e.g. hypercholesterolemia, hypertension etc.
- Venesect to HCT <0.45 (avoid iron supplements)
- If high risk ( >65 years, previous thrombotic event, other cardiovascular risk factors)- Cytoreduction other than venesect
- Cytoreduction: Hydroxycarbamide (reduces thrombotic events), other options are interferon, phosphorus 32 and busulfan
- Good prognosis though risk of MF or acute Leukaemia
7
Q
Myelofibrosis (MF)
A
- Clonal stem cell disease – Hyperplasia of abnormal megakaryocytes (platelets) causing progressive marrow fibrosis
- Around 85% have mutation in JAK2, CALR, MPL
- More aggressive than ET and PV: less good outcome with increased risk of acute leukaemia
- Weight loss, sweats, itch, fatigue and massive splenomegaly
- Patients usually anaemic with varying platelets or white cell depending on stage of disease
- Leucoerythroblastic blood film with tear drop cells
8
Q
Myelofibrosis (MF) laboratory findings
A
- Diagnosed by: FBC, blood film, genetic testing, bone marrow biopsy
- anaemia
- high WBC and platelet count early in the disease
- ‘tear-drop’ poikilocyteson blood film
- unobtainable bone marrow biopsy - ‘dry tap’ therefore trephine biopsy needed
- high urate and LDH (reflect increased cell turnover)
9
Q
Myelofibrosis management
A
- Supportive care for anaemia, splenomegaly and portal Hypertension
- Epo injections or transfusion for anaemia
- Ruxolitinib (JAK2 inhibitor) – improves spleen size and quality of life. Use if systemic symptoms or large spleen
- Hydroxycarbamide for high platelets/WCC
- Allogeneic haematopoietic stem cell transplant if fit enough and high risk
10
Q
MDS: Myelodysplastic syndrome
A
- Abnormal stem cell in the bone marrow (can affect a single lineage or all)
- Eventually results in the production of blast cells (acute myeloid leukaemia)
- Risk factors: smoking, chemical exposure (benzene), chemotherapy, elderly
- Causes low blood count: anaemia, leukopenia, neutropenia, thrombocytopenia
11
Q
Causes of Neutrophilia
A
- Infection/inflammation (autoimmune disease, IBD, pneumonia etc)
- Malignancy – including aberrant cytokine release from neoplasm
- Steroids
- Smoking (causes mixed Leucocytosis)
- Hyposplenism
- Rebound post chemo or GCSF
12
Q
Neutrophilia investigations
A
- Raised Neutrophils
- First line: ESR, CRP. Blood film if persistent with no cause
- If acute cause repeat FBC when over
- Investigate further if: persistent, no secondary cause, Splenomegaly
- Possible rare haematological causes: MPN (PV, PMF, CML, CNL)
- Contact haematology if persistent with no secondary cause and if basophilia, splenomegaly or abnormal blood film
13
Q
Chronic Myeloid Leukaemia
A
- Results in (very) high WCC and often high PLT and Basophils (if you see >Basophils consider CML)
- Often asymptomatic – may have splenomegaly, vague symptoms or systemic symptoms e.g. weight loss, bone pains, fatigue
- Due to translocation between chromosomes 9 and 22 resulting in Philadelphia chromosome and the BCRABL1 fusion gene
14
Q
Summary of Myeloproliferative neoplasms
A
- Polycythaemia: high RBC
- Essential Thrombocytopaenia: high platelets
- Chronic Myeloid Leukaemia: high WCC (esp Basophils)
- Myelofibrosis: blood pictures variable but film changes and splenomegaly
15
Q
The 6 Haematological emergencies
A
- Neutropenic sepsis
- Hypercalcaemia
- Tumour lysis syndrome
- Spinal cord compression
- (HLH)
- Could it be Leukaemia?
16
Q
Neutropenic sepsis
A
- 20% mortality rate- treat quickly
- Critical to give antibiotic within 60 minutes
- Fever to act on: one measurement >38.5, two measurement an hour apart >38
- Neutropenia is <0.5 neutrophils
17
Q
Neutropenic sepsis assessment
A
- Clinical especially: BP, clammy?, urine output, source?
- Bloods: Blood culture
- CXR often
18
Q
Neutropenic sepsis management
A
- Call for help: Don’t wait for blood results.
- Antibiotics – within 60 mins. If in doubt, treat
- Usually a local policy
- ITU - early warning
- fluids
- granulocyte CSF (stimulates bone marrow to produce neutrophils)
19
Q
Hypercalcaemic ranges
A
- Normal range 2.2 to 2.6mmol/l
- Mild hypercalcaemia 2.6-3.0; moderate 3.0-3.4; severe >3.4
- Can be incidental or associated with bone pain, muscle weakness, polyuria, kidney stones, constipation, depression, confusion
20
Q
Hypercalcaemic causes
A
- PTH-related peptide released by tumours
- Lytic bone lesions
- 1,25 hydroxy Vit D increased production by tumours
21
Q
Hypercalcaemia treatment
A
- Fluids: Isotonic saline
- Furosemide only if fluid overloaded
- Bisphosphonates: Pamidronate or Zoledronate
- Calaitonin: only used in life threatening hypercalcaemia
- Steroids
22
Q
Tumour lysis syndrome pathophysiology
A
- Occurs when cancer treatment begins. As cancer cells break down release: DNA, Phosphate, K+ and cytokines. Can cause renal failure.
- Hyperuricemia: due to catabolism of purines
- Hyperphosphatemia: Phosphate concentration 4x higher in malignant cells
- Uric acid precipitates in calcium phosphate readily: Uric acid is poorly soluble in kidneys
- Crystals deposit in renal tubules → ARF
23
Q
Tumour lysis: clinical presentation
A
- Electrolyte derangement: Hyperuricaemia, Hyperphosphataemia, Hyperkalaemia, secondary hypocalcaemia
- Acute renal failure
- Symptoms: N+V, diarrhoea, anorexia, lethargy, cardiac dysrhythmia, syncope, tetany, death
- Tumours more at risk: bulky lymphoid tumour, Non Hodgkins lymphoma
24
Q
Tumour lysis syndrome management
A
- Check Tumor Lysis Labs/G6PD
- Aggressive hydration
- Start Allopurinol before treatment
- Consider rasburicase beforehand if high risk
- Consult renal early
25
Q
Spinal cord compression: symptoms
A
- Worsening and severe backpain that doesn’t go away with pain killers, prevents sleep, made worse by straining, lying down or moving
- Pain which is like a sharp band around the body or which spreads down arms or legs
- Sudden weakness in your arms or legs or new difficulty in walking
- Loss of feeling in arms or legs or problems with bladder or bowel control
26
Q
Cancers most commonly associated with spinal cord compression
A
Lung, Breast, Prostate, Renal, Lymphoma, Myeloma
27
Q
Spinal cord compression management
A
- Imaging: Whole spine MRI
- Steroids: high dose dexamethasone
- Radiotherapy
- Pain relief
- Surgery
28
Q
HLH
A
- HLH: Hemophagocytic Lymphoma Histiocytosis
- Severe Hyperinflammation: uncontrolled activation of the immune system. Increased cytokines, activated lymphocytes and Macrophages
- Hereditary: 5 genetic subtypes, T and NK cells
29
Q
HLH acquired forms
A
- Malignancy: Lymphoma, Leukaemia, MDS
- Rheumatological conditions
- Infections: EBC, CMV, possibly Covid-19
- Recent treatments: chemo, transplant, immunosuppression
30
Q
HLH symptoms
A
- Refractory fever
- Cytopenia: low haemoglobin, platelets and WCC
- Organomegaly
31
Q
HLH investigations and treatment
A
- Been immunocompromised?
- Bloods: CRP, ferritin, Triglycerides, bone marrow
- Urgent treatment: Treat cause. Steroids, etoposide, ciclosporin, IvIG and the anti IFN gamma antibody (emapalumab)
32
Q
When to suspect AML and APML
A
- Bruises
- Unusual tiredness
- Dizziness
- Infection
- Take a blood count
33
Q
Neutrophils
A
- Produced by bone marrow from granulocyte monocyte progenitors
- Most abundant white cell
- Key component of the innate immune system: Do phagocytosis. release cytokines modulating the immune response of other cells, lymphocytes and antigen presenting cells
34
Q
Neutropenia categories
A
- Normal is 2-7
- Neutropoenia= <1.5 × 109/L
- Mild neutropenia is 1-1.5 × 109/L
- moderate neutropenia is 0.5-0.99 × 109/L
- severe neutropenia <0.49 × 109/L
- Increase risk of potentially life threatening infection in moderate or severe neutropenia
35
Q
Causes of Neutropenia
A
- Common: Medications (chemotherapy/immunosuppressants), viral infection/sepsis, autoimmune disease, B12 or folate deficiency
- Less common: Ethnic variation (particularly Black African), Hypersplenism, Thyroid dysfunction, Anorexia
- Haematological: Bone marrow failure disorders (myelodysplasia, aplastic anaemia), bone marrow infiltration (acute leukaemia), congenital syndrome (cyclical neutropenia- reduction in neutrophil count every 3 weeks)
36
Q
Neutropenia investigations
A
- History - recurrent infections, mouth ulcers, family history
- Examine – signs of liver disease/autoimmune disease/lymphadenopathy/splenomegaly
- Bloods: FBC, LFT, HIV, Hep B and C, Blood film, TSH, B12 and folate, Ferritin, autoimmune screen
37
Q
Neutropenia management
A
- Neutrophil count <1 discuss with haematology
- Fever/signs of infection= emergency admission and treat for neutropenic sepsis
38
Q
Neutropenic sepsis
A
- Medical emergency
- Fever (38) or non-specific symptoms
- Gram-negative sepsis – patients can deteriorate rapidly
- Requires urgent broad spectrum antibiotics – 1 hour ‘door to needle’ time
- Fluid resuscitation
- GCSF (Granulocyte colony stimulating factor)
39
Q
Different chemotherapies and treatment options
A
- Chemotherapies may be given on their own, ‘single agent’. Or with..
- Or with other chemotherapies. For example, DA regimen for AML
- Or with Monoclonal antibodies: On their own or with chemotherapies. For example, R-CHOP regimen for lymphoma
- With Targeted treatments. For example: ibrutinib, imatinib, venetoclax
- With Steroids
40
Q
Aims of chemo
A
- Target different stages of the cell cycle to prevent normal replication of cancer cells
- As a curative treatment: Put the cancer into a complete remission (no symptoms or detection on scans) AND it doesn’t come back (relapse)
- Disease control: Can’t cure the cancer; reduce its burden for as long as possible
- Palliative treatment: Use to help with symptoms
- Chemo targets different stages of the cell cycle preventing replication (cancer cells divide more). Normal cells are also affected causing side effects
41
Q
Chemotherapy: Alkylating agents
A
- Alkylating agents cause cross links within DNA by adding alkyl groups to guanine bases
- Examples: Cyclophosphamide, Bendamustine, Chlorambucil, Melphalan, Iosfamide
- Cause DNA damage. Are cytotoxic through the whole cell cycle
42
Q
Chemotherapy: Antimetabolites
A
- Interfere with DNA and RNA synthesis by acting as a substitute for normal bases (C, A, T, G). Are cytotoxic during the S (synthesis) phase of the cell cycle. Examples;
- Purine analogues: Fludarabine,6-mp (6-mercaptopurine)
- Pyramidine analogues: Cytarabine, Gemcitabine, Azacitadine
- Antifolate: Methotrexate
43
Q
Chemotherapy: Anti tumour antibiotics
A
- Derived from Streptomyces
- Anthracyclines and others
- Anthracyclines: intercalates between base pairs in DNA preventing replication. Inhibits topoisomerase II (relaxes coiled DNA to allow for Transcription and Replication), creates oxygen free radicals
- Examples: Daunorubicin, Doxorubicine, Epirubicin, Idarubicin, Bleomycin
- Cytotoxic during the S phase of the cell cycle
44
Q
Chemo: Mitotic inhibitors/Plant alkaloids
A
- Vinca alkaloids inhibit microtubule polymerisation and are mitotic inhibitors (prevent tubulin production- which makes microtubules which forms the mitotic spindle)
- Examples: Vincristine, Vinblastine
- Interfere with the mitosis phase of the cell cycle
45
Q
Chemo: steroids
A
- Mechanism of action not fully understood
- Oral: Prednisolone and Dexamethasone
- IV: Dexamethasone and Methylprednisolone
46
Q
Generic side effects of chemo
A
- Myelosuppression: Pan-Cytopenia’s (anaemia, neutropoenia, thrombocytopaenia). May need antibiotics and blood and platelet transfusion
- Gut toxicity: Sore mouth (ulcers), change in taste. Diarrhoea. Neutropaenic colitis/ typhyllitis (causes infections)
- Nausea and vomiting- given antiemetics
- Hair loss
- Effect on fertility
- Liver toxicity
- Teratogenicity
- Fatigue Tend to have symptoms up to 2 weeks after chemo
47
Q
Chemotherapy specific side effects
A
- Anthracyclines (anti-tumour antibiotics): Cardiac toxicity- can cause arrhythmias or issues with the ejection fraction. Get a baseline echo then monitor. Life time dose: cant exceed a certain dose over your lifetime
- Vinca alkaloids: Peripheral neuropathy, Constipation
- Bleomycin (anti-tumour antibiotics): Interstitial lung damage/ fibrosis. Void if older, smoking or previous chest history
- Ifosfamide: encephalopathy but reversible when chemo stops, given as an inpatient.
48
Q
Long term side effects of Chemotherapy
A
- Cardiotoxicity (Anthracyclin), interstitial lung damage (Bleomycin)
- Fertility problems
- Bone problems (steroids)
- Secondary malignancies: Include haematological cancers e.g. MDS, AML- poorer prognosis than primary MDS/ AML or Skin cancers
49
Q
Monoclonal antibodies (MoAb)
A
- Work by targeting cancer cell protein and inducing antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity. Some of the targeted proteins will also be found on normal cells.
- Rituximab: bonds to cell surface CD20 protein, CD20 expressed by B cells
- Obinutuzumab: 2nd generation anti CD20 monoclonal antibody
- Daratumumab: anti CD38 monoclonal antibody. Used in myeloma
50
Q
Side effects of MoAb and what are targeted therapies
A
- Infusion related reactions (IRR’s): fever, hypotension, rash, anaphylaxis. Tend to get these during the infusion
- Increased susceptibility to infections
- More specific to cancer cells so cause less side effects
Targeted therapies: More specific to cancer cells and cause less wide ranging side effects
