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year 4 CDM 2 > Case 15: Myeloproliferative neoplasma > Flashcards

Case 15: Myeloproliferative neoplasma Flashcards

1
Q

Diagnosing ET and PV

A

FBC, Genetic testing, Bone marrow biopsy

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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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15
Q

The 6 Haematological emergencies

A
  • Neutropenic sepsis
  • Hypercalcaemia
  • Tumour lysis syndrome
  • Spinal cord compression
  • (HLH)
  • Could it be Leukaemia?
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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
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17
Q

Neutropenic sepsis assessment

A
  • Clinical especially: BP, clammy?, urine output, source?
  • Bloods: Blood culture
  • CXR often
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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)
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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
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20
Q

Hypercalcaemic causes

A
  • PTH-related peptide released by tumours
  • Lytic bone lesions
  • 1,25 hydroxy Vit D increased production by tumours
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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

year 4 CDM 2 (39 decks)

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