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
Spinal cord compression: symptoms
- 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
Cancers most commonly associated with spinal cord compression
Lung, Breast, Prostate, Renal, Lymphoma, Myeloma
27
Spinal cord compression management
- Imaging: Whole spine MRI
- Steroids: high dose dexamethasone
- Radiotherapy
- Pain relief
- Surgery
28
HLH
- 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
HLH acquired forms
- Malignancy: Lymphoma, Leukaemia, MDS
- Rheumatological conditions
- Infections: EBC, CMV, possibly Covid-19
- Recent treatments: chemo, transplant, immunosuppression
30
HLH symptoms
- Refractory fever
- Cytopenia: low haemoglobin, platelets and WCC
- Organomegaly
31
HLH investigations and treatment
- Been immunocompromised?
- Bloods: CRP, ferritin, Triglycerides, bone marrow
- Urgent treatment: Treat cause. Steroids, etoposide, ciclosporin, IvIG and the anti IFN gamma antibody (emapalumab)
32
When to suspect AML and APML
- Bruises
- Unusual tiredness
- Dizziness
- Infection
- Take a blood count
33
Neutrophils
- 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
Neutropenia categories
- 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
Causes of Neutropenia
- 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
Neutropenia investigations
- 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
Neutropenia management
- Neutrophil count <1 discuss with haematology
- Fever/signs of infection= emergency admission and treat for neutropenic sepsis
38
Neutropenic sepsis
- 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
Different chemotherapies and treatment options
- 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
Aims of chemo
- 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
Chemotherapy: Alkylating agents
- 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
Chemotherapy: Antimetabolites
- 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
Chemotherapy: Anti tumour antibiotics
- 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
Chemo: Mitotic inhibitors/Plant alkaloids
- 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
Chemo: steroids
- Mechanism of action not fully understood
- Oral: Prednisolone and Dexamethasone
- IV: Dexamethasone and Methylprednisolone
46
Generic side effects of chemo
- 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
Chemotherapy specific side effects
- 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
Long term side effects of Chemotherapy
- 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
Monoclonal antibodies (MoAb)
- 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
Side effects of MoAb and what are targeted therapies
- 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
