Haem Flashcards
DLBCL
30-40% of NHL (most common form on NHL among adults)
Middle-aged and elderly patients with lymphadenopathy
Rf: H Pylori and Coxiella Brunetti are known to cause DLBCL.
High grade lymphoma - large lymphoid cells, prominent nucleoli , high mitotic figures, produce
sheets of large lymphoid cells.
Arise from germinal centre post germinal centre at extra nodal sites ( GC - CD10 BCL 6. ) can also be secondary to richter transformation of CLL/SLL/MZL.
Lymph node is effaced so follicles and germinal centres cannot be identified
Good prognosis – germinal centre phenotype
Poor prognosis – p53-positive and high proliferation fraction, age >60, high LDH, any extra nodal states
Mx: R- CHOP (for aggressive NHL) (Rituximab, Cyclophosphamide, Adriamycin, Vincristine, Prednisolone) curative in 50% and autologous SCT salvage 25% of patients
T cell lymphoma
Middle-aged and elderly patients with lymphadenopathy
NOTE: these are aggressive
Histology: Very heterogeneous you see Large T lymphocytes (CD3, CD5) and associated reactive cell population (especially eosinophils)
Types:
1. Adult T cell leukaemia/lymphoma – HTLV1 (Japan, Caribbean) (hyerlobated nuclei -> flower cells) associated with hypercalcaemia due to lymphoma stimulating osteoclasts and zidovudine interferon alpha (AZT-IFN) therapy has good sucess.
2.Enteropathy-associated T cell lymphoma EATL– due to Coeliac disease
Mature T cells
Very aggressive clinical course
Present with pain obstruction, GI bleeding, malabsorption
Respond poorly to chemo and generally fatal
- Cutaneous T cell lymphoma (manifests as mycosis fungoides)
- Anaplastic large cell lymphoma
Children and young adults with lymphadenopathy
Large epithelioid lymphocytes, variably sized nuclei (some elongated, kidney, oval etc)
T cell or null phenotype (anaplastic)
CD30 typicall, but can be absent.
2;5 translocation and Alk-1 protein expression – BETTER prognosis
Burkitt’s
Rapidly growing tumour of NHL, Germinal Cell tumour. “most aggressive tumour that affects humans” There are three forms: 1. Endemic form Jaw mass in young adults EBV implicated in all cases 2. Sporadic Common in the west Presents with abdominal mass EBV in 10% cases Rf: Solid organ transplant 3. Immunodeficient aka HIV-related EBV in ⅓ cases
Ix: Arises from germinal centre cells,
Starry sky appearance (the vacuoles create a starry sky appearance. These are vacuoles of macrophages which engulf the debris of dead apoptotic material. The sky is the background of tumour cells- they are tightly packed, dark chromatin nuclei, high mitotic figures. The stars are macrophages.
FISH: c-Myc translocation (8;14, 2;8 or 8;22) or myc
CD: Cells look blastic on film but surface Ig +ve and Tdt-ve (markers of maturity)
Mx: Chemotherapy (rituximab (anti CD20 - found on B cells) & leukaemia protocol) or SCT
Mantle cell lymphoma
(Mantle is the crescent shape around the GC inside the follicle)
PC: Typically affects middle-aged males, it often present with disseminated disease
Start in the mantel zones of lymph nodes, but can also appear in extranodal sites e.g. GI tract
Ix: Pre-GC cell with aberrant CD5 and cyclin D1 expression*. 11;14 translocation results in the cyclin d1 overexpression.
Prog: poor, median survival = 3-5 years
*(Cyclin D1 drives from M stage in cell division to G1) Cyclin D1 also phosphorylates Rb, which removes Rb from e2f. When e2f is liberated, it goes to act as TF-> increase transcription. The phosphorylated Rb which drives cell cycle
MZL
Arise from post-germinal centre memory B cells. They are mature cells that are non-circulating and reside in the marginal zone of the spleen (Splenic MZL) but also in other places such as peyer’s patch (MALT), tonsils (MALT) and lymph nodes (Nodal MZL). Relatively indolent (slow growing).
PC: Manifest mainly in extranodal sites (e.g. gut, spleen), epigastric pain, ulcer, bleeding
Classified as stage I e (e- extra nodal, 1 - single sight of involvement)
Aetiology: Thought to arise due to chronic antigenic stimulation
Ix: Histology- lymphomatous cells infiltrate and destroy normal epithelium of that location e.g. glandular epithelium of the gastrum.
Mx: Low-grade disease can be treated by non-chemotherapeutic methods (e.g. H. pylori eradication) may cure 75% of pts. 25% might need cure.
MZL Aetiology
Chronic H Pylori increases the incidence of gastric MALT 6 fold and only 5-10% of gastric MALT lymphoma lack it. The addition of t(11;18) mutation results in an aggressive lymphoma characterised by the formation of BIRC3-MALT1 fusion gene and causes BCL10 dysregulation. Gastric lymphomas with this translocation are refractory to H Pylori eradication.
Mechanism:
1. Gastric mucosa antigens cause Polyclonal B cells to proliferate in Chronic gastritis
2. Further genetic events (e.g. hypermethylation of CDKN2B) lead to the emergence of antigen dependent lymphoma
3. Further genetic events e.g. t(1;14) or t(14;18) lead to emergency of antigen independent lymphoma
4. Further genetic events e.g. mutation of TP53 lead to high grade transformation.
Other causes of MALT are
Borrelia burdorferi in causing primary cutaneous MALT,
hep C and Sjögren syndrome causing salivary gland MALT.
Campylobacter jejuni is a bacterium, that is known to cause intestinal malt lymphoma IPSID, (immunoproliferative small intestinal disease).
Mycobacterium tuberculosis (Pyothroax-associated lymphoma)
Chlamydophila psittaci (ocular adnexal MALT lymphoma)
SLL
PC: middle-aged or elderly patients, Lymphadenopathy (SLL) or high blood lymphocyte count (CLL)
Histology:Sheets of Small, uniformed lymphocytes. They replace the entire lymph node so that you can no longer identify follicles or T cell areas
Arise form naïve B cells or post-germinal centre memory B cells
Ix: Cells are CD5 (should never be seen in b cell) and CD23 positive
Cx: Richter transformation (>DLBCL)
Follicular Lymphoma
⅓ of NHL
PC: Lymphadenopathy in middle-aged or elderly patients. Indolent disease, incurable, 12-15 years
Aetiology: FISH will show 14;18 translocation involving Bcl2 gene (normal follicles shouldn’t have bcl2) (results in an over expression of antiapoptotic protein BCL2 under influence Ig promoter)
Ix:
Cells have a germinal centre cell origin (positive staining for CD10 and Bcl6)
Histology: Follicular pattern – the follicles are neoplastic and spread from the node into
adjacent tissues
Cx: Usually indolent but can transform into a high-grade lymphoma
Mx: will require 2-3 different chemotherapy schedules. Monitor patients, only treat if clinically indicated e.g. painful LN, nodal compression, recurrent infections. E.g. year 5 give one chemo regiment, wait for relapse etc. Duration of each remission is shorter. Treatment is with R-COP or bendamustine. Not curative.
WHO Grading system and interpretation of it
LOW=
Follicular lymphoma
Small lymphocytic lymphoma (CLL)
Marginal (MALT)
High=
Very Aggressive: Burkitt, T or B cell lymphoblastic leukaemia/lymphoma (treated like acute leukaemia)
Aggressive: Diffuse large B cell lymphoma, Mantle Cell (R-CHOP)
The more aggressive lymphomas have median survival of weeks compared to 10+ without chemo.
However, the aggressive ones tend to be curable in the long term should the pt survive the chemo regimen, compared to the low grade which are generally not curable.
Classical Hodgkings Lymphoma (PC + Background)
PC: Young and middle-aged patients with only a single group of lymph nodes involved. Painless LNs, may cause obstructive symptoms and signs e.g. stridor, jaundice. Constitutional symptoms: fever, drenching night sweats, unexplained weight loss 10% in 6 months (the b symptoms) and pruritus may be present. Rarely alcohol induced pain.
Background: Associated with EBV. Spread continguously. Arise from germinal centre or post-germinal centre cells. Bimodal: One peak 20-30 other peak is 50-60 yo.
Types:
1. Nodular sclerosis (peak in 20-29, M>F, presenting with cervical & mediastinal lymphadenopathy) (most common and best prognosis)
2. Mixed cellularity population of Reed-Sternberg cells - good prognosis
3. Lymphocyte rich (rare) - good prognosis
4. Lymphocyte depleted (rare) - POOR prognosis
cHL Ix
Histology: Lymphoma cells are few in number and are scattered around Eosinophils, large prominent nucleoli, often binucleate (RS cells)
CD15, CD30, BUT negative for CD20
FDG-PET/CT scan for staging ad consider biopsy if metastasised
cHL Mx
Combination therapy (chemo + Radio); Ab against cd30 (brentuximab)
ABVD: Adriamycin, Bleomycin, Vincristine, Dacarbazine chemotherapy is needed by all pts (4-wkly intervals for 2-6 cycles.) and fertility is preserved! Woo!
Interim PET/CT after 2 cycles and end of treatment will be needed and this will guide the need for radiotherapy.*
Relapse treatment
10-20% relapse after remission and ⅓ of these will respond to ‘salvage chemotherapy’ (high dose chemotherapy and autologous PB SCT)
If they relapse after the salvage chemotherapy, you can try brentuximab vedotin (cd30 is expressed on RS cells. Cd30 is conjugated to cytotoxic agent which is internalised upon binding)
Nivolumab - PD1 checkpoint inhibitor
cHL Complications and prognosis
Cx:
Radiation can cause collateral damage to surrounding tissues such as pulmonary fibrosis and cardiomyopathy, secondary breast cancer
NOTE: intensifying chemotherapy will lead to an increased cure rate but it will also lead to an increase in secondary cancers
Prognosis: Chance of cure for stage I and II >80% and Stage IV>40%. Of those who aren’t cured, 10% die in first 10 years due to HL. After 10 years, they are more likely to die from secondary condition related e.g. cardio or secondary malignancy.
Why do we use PET/CT to guide the use of radiotherapy?
HL responds well to radiotherapy but it doesn’t prevent haematogenous spread. Therefore chemotherapy is first line for every HL patient. We only radiotherapy the affected area. It is very good at killing HL in the field, it doesn’t kill any HL outside the field and results in a lot of bystander damage. There is a higher risk of secondary malignancy as breast carcinoma, lung/skin cancer and leukaemia/MDS. Combination therapy - really increases the risk of secondary malignancy
The other type of HL?
Nodular/lymphocyte predominant Hodgkin lymphoma.
5% of HL.
Disorder of the elderly (multiple recurrences)
Isolated lymphadenopathy
NO association with EBV
Histo: B cell rich nodules, Scattered around L&H cells, Reactive population in the background consisting of small lymphocytes, NO eosinophils and macrophages
CD: CD20+. Negative = CD15, CD30 (unlike classical Hodgkin lymphoma)
Cx: Indolent but can transform to high grade b cell lymphoma
CLL prognostic factors
Binet:
A: < 3 lymphoid areas + good BM
B: >3 Lymphoid areas + good BM
C: Hb <100 and platelets <100
Rai
IgH gene status (by sequencing the variable region of Ig)- is it unmutated? (i.e. hasn’t undergone somatic hypermutation and therefore is pre GC or vise versa) Unmutated has much worse prognosis (8 vs 25 year median survival)
P53 deletion or 17p deletion is very bad prognosis
CLL complications
- Increased risk of infection, recurrent sinopulmonary infection with normal organisms
- BM failure -> ANT
- peripheral lymphocytes circulate to node and spleen causing lymphocytosis and splenomegaly
- Unstable poulation of lymphocytes are suscptible to further mutations -> further mutations can add to the utagenic burden of the clone -> transform to high grade lymphoma (DLBCL subtype - called Richter’s transformation, 1% per year and treat as high grade lymphoma)
- Disease of immune cells -> AIHA
- Incurable (indolent)
CLL
TREAT ONLY IF NEEDED
C: Vaccination, anti-infective prophylaxis and treatment
(aciclovir for zoster, Septrin for PCP, IVIG for hypogammaglobulinaemia, Immunisation for pneumococcus and seasoal flu, void live vaccine (herpes zoster main vaccination is live))
M: Treat if
- Progressive lymphocytosis (doubles in less than 6 months)
- Marrow failure (ANT)
- Massive lymphadenopathy or splenomegaly
- B symptoms
Most intense: combo (Ritux and fludrabine cyclophosphaid)
Medium : Obinutuzumab (anti cd20) + chlorambucil
Less: supportive care only e.g. abx
High risk cases or relapse patient won’t benefit from more chemo so give them Ibrutinib (bruton TKI) or venetoclax (anti BCL2 oral agent, TLS risk)
Lymphoma investigations
Histopathological diagnosis - Biopsy is gold standard. There are three types of biopsy FNA, Core NA or excision bipsy. FNA (individual small cells that are smeared out on slide) - useless for lymphoma, better for infectious causes. Excision biopsy (take out whole LN, analyse architecture etc.) CT/PET- analyse the extent of the disease as you cannot palpate more proximal LN e.g. mediastinal. BM biopsy and LP can also be checked for the presence of malignant cells. (Important to check for CNS involvement as most chemotherapy drugs don’t pass BBB and won’t treat CNS involvement) Blood test, LDH/B2 microglobulin - give marker of severity and cell turnover; albumin and kidney function tests to see how fit and well the patient is for aggressive chemo; chronic infection screen (HIV & Hep B serology) as these reduce T cell function and can predispose to lymphoma
Physiogloical haematological changes in pregnancy
- Mild anaemia
net dilution due to increased plasma volume
red cell mass rises too just not as much as the plasma
This occurs by 2nd trimester - High MCV
Physiological macrocytosis
Be aware of B12 and folate deficiency) - High neutrophils
4. Low platelets 10% decline after 28 weeks Increased turnover Increased clearance Younger platelets are larger and therefore there is an increase in platelet size
HL staging
Staging (Ann-Arbor)
Stage 1 – one LN region (LN region can include spleen)
Stage 2 – two or more LN regions on the same side of the diaphragm
Stage 3 – two or more LN regions on opposite sides of the diaphragm
Stage 4 – extranodal sites (liver, BM)
Iron and folate requirements in pregnancy
WHO recommends 60 mg iron & 400 µg folic acid
RCOG recommends 400 µg folic acid (before conception to 12 weeks GA) NO routine iron supplementation but may be given on an individual basis to those at high risk
The different causes of thrombocytopenia in pregnancy and how we can differentiate between them.
GIT, ITP, Pre-eclampsia and other causes of TP.
GIT
- Platelet count rises d2-d5 in pregnancy
- Tends to occur later in pregnancy
- Doesn’t affect the baby
- 81% of pts with counts <150 are due to GT but 44% of pts with counts <100 are due to GT
- Mechanism is poorly defined but thought to be due to dilution and increase consumption
Pre-eclampsia:
- 50% of pre-eclampsia pts can get thrombocytopenia e.g. due to DIC
- These patients can have a normal PT and APTT at the start of the DIC due to raised clotting factors.
- Remits following delivery
ITP:
- EARLY onset
- 5% of thrombocytopenia pts
- CAN affect baby:
Unpredictable affect (not related to severity) but rare (only 5% have plt <20)
- During birth take care and minimise head trauma. Don’t use ventouse or FBS.
- After birth, make sure you check cord blood and if low then check baby blood count daily as NADIT AT D5
- Mx: Only treat <20: IVIg (blocks splenic macrophage receptors from engulfing plts in the spleen), steroids
Microangiopathic Syndromes:
Characterised by Schistocytes
All other causes: DIC, hypersplenism, leukaemia, BM failure etc.
Causes of microangiopathic syndromes that would give rise to thrombocytopenia in pregnancy
Pre-eclampsia, HELLP, TTP (needs PEX, not helped by delivery), HUS, APS, SLE, AFLP (acute fatty liver)
Changes to clotting factors in pregnancy
Factor 8 and vWF – increase 3-5 fold
Fibrinogen – increase 2 fold
Factor 7 – increase 0.5 fold
Protein S – falls by 0.5
PAI-1 – increase 5 fold (fibrinolysis inhibitors produced by EC)
PAI-2 – produced by the placenta
All of these changes lead to a procoagulant state (hypercoagulable and hypofibrinolytic) due to the need of rapid control of bleeding from the placental site at time of delivery 700ml/min.
What is the clinical impication of thrombocytopenia in pregnancy
There is a risk a risk of spinal haematoma with an epidural anaesthesia, (70 is required for epidural but for delivery 50 is okay). Spinal haematoma can cause paraplegia etc.
- During birth take care and minimise head trauma. Don’t use ventouse or FBS.
VTE in pregnancy
When is the risk highest and how do we investigate and manage it
10 fold higher risk than gen pop. Blood is hypercoaguable, reduced venouse return and vessel wall changes (all three of virchows triad)
Highest risk is 40-46 weeks. But the second highest period is the first trimester.
Rf: Obesity, FHx of VTE, air travel, OHS, hyperemesis/dehydration, Preeclampsia, older age (>35), Csection has higher risk, as does instrumental. After 4 pregnancies, risk rises.
Ix: Doppler ultrasound scan & VQ scan (D-dimer is often elevated in pregnancy anyway)
Mx: Ideally identify those at risk! Prophylactic (heparin + TED stockings, Mobilise early, Ensure good hydration) LMWH (as is used in non-pregnant people) (barely any side effects, more inconvenience, slightly osteopenia risk very small.) After first trimester, monitor anti-Xa. Stop LMWH during labour/planned delivery time and don’t do epidural until free of LMWH normal for 24 hours or 12 hours if prophylactic dose. Warfarin crosses the placenta and has teratogenic effects (between weeks 6-12), only consider in those with mechanical heart valves after 1st trimester.
Complication of thrombophilia in pregnancy
IUGR Rec misscrriage Late fetal loss etc PLacental abruption NOTE: there is a hypothesis that thrombosis tendency in pregnancy is associated with impaired placental circulation
APS
Recurrent miscarriage, DVT/PE, Thrombocytopaenia
Ix: Lupus anticoagulant and/or Anticardiolipin antibodies + recurrent miscarriages
Poor prognostic factors: 3 or more miscarriages <10 weeks, 1 or more morphologically normal foetal losses after 10 weeks or 1 or more preterm births < 34 weeks owing to placental disease
Mx: Aspirin and heparin
NB: there are a lot of FVL polymorphisms that do not result in any clinical manifestations.
Complications of SCD in pregnancy
Consequences: More frequent vaso-occlusive crises Foetal growth restriction Miscarriage Preterm labour Pre-eclampsia Venous thrombosis Manage: Red cell transfusion Prophylactic transfusion Becareful of Alloimmunisation and make sure you test for all antibodies as they have a higher rate.
NAIT
Neonatal alloimmune thrombocytopenia, (NAIT) is caused by maternal antibodies raised against alloantigens carried on fetal platelets. Although many cases are mild, NAIT is a significant cause of morbidity and mortality in newborns and is the most common cause of intracranial haemorrhage in full-term infants.
MM clinical presentation
Osteolytic bone lesion due to stimulatory soluble factors produced by the MM cells. As a result these activate osteoclasts, which then in turn produce cytokines which further activate MM cells. Manifests as BACK PAIN (gets worse rapidly). Severe, paralysis - cord compression.
Anaemia - myeloma cells replace cells of the bone marrow and also causes a ACD(?), fatigue, SOB
Hypogammaglobulinaemia - infections e.g. pneumonia
Rarer nowadays: kidney failure (paraproteins clogging up kidneys, hypercalcaemia damaging kidneys or infection causing dehydration)
Stroke
Cause of MM: Unknown but suspected by chronic inflammation can be a risk factor eg. rheum arthritis and viral HHVI/HIV.
MGUS vs Smouldering
MGUS - premalignant condition (5% of those above 70)- as we age, we increase clonal haematopoiesis. <30g/L serum monoclonal protein and plasma cells take up less than 10% of bone marrow. 1-2% annual progression risk.
Smouldering Myeloma >30g/L serum monoclonal protein, >10% BM plasma cells, annual risk of progression to MM 10%.
MM background and epidemiology
Quite common, 1% of all cancers, 2nd most common haematopoietic malignancy (after B cell lymphomas)
Myeloma is debilitating and incurable with median survival of 4-7 years. 6-10 if fit for intensive treatment. Even if caught early- still incurable.
More common in black people than white people.
Median age of diagnosis 65-70Y,
Plasma cell ultrastructure
Endoplasmic reticulum and golgi body. This is where immunoglobulins are assembled, folded and modified before secretion. NOTE: plasma cells are the most secretory cells in the body (10,000
immunoglobulin per second)
Pathogenesis of MM
Translocations at 14q32 (50%) or deletion of chromosome 13 bring proto-oncogenes under the control of B cell promoters for immunoglobulin expression. As this is a plasma cell, the promoter genes are switched on and oncogene proteins are upregulated. This drives the clonal expansion of a particular plasma cell.
Along the way, these cells pick up additional mutations e.g. K-ras, N-ras (these are quite generic cancer mutations)
Also, infection/inflammation can be involved in the aetiology
MM investigations
- BM aspirate needed for diagnosis - myeloma cells seen in the aspirate with large golgi (which makes cytoplasm bigger and creates a paler halo around nucleus)
- Immunophenotype: CD38, CD138 and CD58/56, cytoplasmic Ig (only plasma cells have cytoplasmic Ig, B cells only have surface Ig) (monotypic cytoplasmic Ig), LC restricted. Negative for CD19/20- this means we can’t treat using rituximab (anticd20) but can use daratummacb (anti cd38)
- EM of B cells which show enlarged ER and golgi app (Takes 7 days to reach full enlargement)
- Monoclonal gammopathy (electrophoresis all the B cells will show a range of antibodies resulting in a smear, but in - MM there will be a concentration of a specific type of antibody causing a peak). The most common type of heavy chain produced in myeloma is IgG, followed by IgA and then IgD.
MM treatment strategies
- Classical cytostatic drugs
- DNA alkylating agents
Melphalan (prevents dna replication by adding alkylating agent) autologous hsct in under 65:
- 6 months of induction therapy with steroids, PI, imid- this reduces myeloma load by 90%
- Remove pt’s stem cells from their blood (as a safety net rescue)
- One high dose melphalan to kill myeloma which wipes out haematopoiesis
- Reinfuse stem cells (which takes ~10d to synthesise BM cells again)
- Steroids (dexa, prendnis) - this works in all leuk/lymph
- IMIDs (thalidomide)
Modulates immune system to fight myeloma cells better
They lead to the enhanced degradation of TF that are required for b cell development - MoAbs (Daratumumab- CD38)
- Proteasome inhibitors
Old proteins that aren’t needed anymore are ubiquinated (tagged) which signals that they can be destroyed by the proteasome (molecular shredder) which produce amino acids that can be recycled.
It is really important that these proteins are destroyed because dead proteins can accumulate, precipitate and block cellular function. Furthermore, myeloma cells really rely on this pathway because they need their dead proteins to be recycled in order to get amino acids to make new proteins.
Causes of the different types of polycythaemia
Pseudo
Low plasma volume
Alcoholics, Obesity, Diuretics
True (increased red cell mass and unchanged plsama volume):
- Primary/Malignant - Polycythaemia Vera
- Secondary (non-malignant), responding to too much EPO. Raised EPO can be appropriate (high altitude, hypoxic lung disease, cyanotic heart disease, high affinity haemoglobin) or inappropriate (doping, renal disease/tumour, uterine myoma, other tumours .e.g liver, cerebellar)
Investigations in polycythaemia
plasma volume, Hct (cells/volume), Hb (g/l), Dilutional studies: 51-Cr labelled RBC to measure red cell mass or 131-I labeled albumin to measure plasma volume.
What are the myeloproliferative disorders?
The myeloproliferative disorders are a unique group of hematopoietic stem cell disorders that share in common mutations which continuously activate JAK2 (Janus kinase 2), an enzyme that normally stimulates the production of they myeloid lineage (RBC, WBC, plt, not lymphocytes). JAK2 is normally only activated when additional blood cell production is needed. Because the blood cells in the myeloproliferative disrders are usually normal in appearance, these disorders mimic clinically benign or reactive blood conditions in which blood production is increased because of stimuli such as hypoxia, inflammation or infection as well as certain blood malignancies such as chronic myelogenous leukemia and myelodysplasia.
- > PCV (most common)
- > Essential Thrombocytosis (most indolent)
- > Primary Myelofibrosis (most aggressive but rarest)
How MPN present and how do we investigate?
PC: Splenomegaly
Ix: FBC ± BM biopsy, EPO level, mutation testing
PCV
PC: Incidental, due to viscosity (e.g. lightheaded ness, visual disturbances, stroke) or due to inceased histamine release (aquagenic pruritus or peptic ulceration)
Ix: JAK2 V617F testing (present in 99% cases)
Mx: aim to reduce HCT (target <45%) and aim to reduce risk of thrombosis:
venesection is 1st line unless elderly/poor veins in which case there is gentle, oral chemotherapy (hydroxycarbamide)
Aspirin, keep plts <400
ET
Chronic MPN involving mainly the megakaryocytic lineage
MAO bimodal at 30 (F=M) and 55 (F>M)
PC: thrombosis (Arterial or venous, DVT, TIA, PE etc) in some, plts are not functional + PC: bleeding (mucous membrane and cutanoues)
Ix: plts >600
Mx: aspirin, hydroxycarbamide, anagrelide (specific inhibitor of plt but has s/e of palpitations and flushing
Prog: Good but risk of palpitations
Primary myelofibrosis
Clonal MPN with associated BM fibrosis causes extramedullary haematopoiesis
PCV & ET can > to PMF
Presents 70+
PC: incidental, cytopenia or thrombocytosis, splenomegaly can be MASSIVE (Budd Chiari syndrome), hepatomegaly, hypermetabolic state (weight loss, fatigue, night sweats, hyperuricaemia). Extramedullary haematopoiesis in liver spleen.
Ix: Leukoerythroblastic blood film, dacrocytes (fibrosis), giant plts /circulating megas, BM aspirate will be ‘dry tap’ and trephine will show increased reticulin / collagen fibrosis, mega hyperplasia
Mx: Supportive (RBC/plt transfusion), Cytoreducive (hydroxycarbamide for thrombocytosis but may worsen anaemi), Ruxolotinib (JAK2i), SCT, splenectomy for sx relief
Prognosis is poor, 3-5 year survival. Poor sx ANT, massive splenomegaly
CML PC and Ix
CAB. Chronic phase <10%, A- 10-19% B 20 =
CML Mx
Imatinib - ABL TK inhibitors (blocks ATP pocket in protein binding site and so downstream TK are not phosphorylated and is active towards highly proliferating cells)
(ibrutinib is not specific to malignant cells as all b cells express BK)
If fail to get response switch to 2nd gen (Dasatinib) or 3rd gen (Bosutinib).
If fail again, alloSCT.
CML Prognosis
Prognosis: Imatinib allows better predictors of prognosis. After 18 months, if complete cytogenetic response is not achieved (i.e. number of translocations is less than 5%), this is an accurate predictor of slightly worse prognosis i.e. at 6 years is 85% survival as opposed to 98%+ for those who did achieve cytogenetic response
Types of remission after imatinib CML
Haematological response - <10 x 10^9 WBC
Cytogenetic response 0% Ph positive of 20 cells in meteaphases (1-35% +ve is partial resp.)
Molecular response - Look at 10,000 cells and see how many generate BCR-ABL transcripts from RQ-PCR. <0.1% of those 10,000 cells geerate BCR-ABL = MMR major molecular response
Why aren’t TKI a panacea?
Not every pt will respond
Non-compliance
Side effects (fluid retention, pleural effusion)
MMR loss (can get point mutation leading to blast crisis)
Features of MDS syndromes
Recurrent genetic abnormalities;
Increased risk of transforming to acute myeloid malignancies;
Dysplasia in one or more lineages;
Ineffective haematopoiesis Increased apoptosis > cells die inside the BM space, before they enter the blood stream resulting in cytopenias (in contrast to cytopenias, the underlying bone marrow is hyperactive hypercellular);
Cytopenias
Presentation and blood film signs of MDS
PC: General marrow failure
Epi: Tends to be of the elderly
Ix: Dysplastic cells: Pelger Huet anomaly (hypolobated neutrophils e.g. bilobed), RBC nuclear bridging, micromegakaryocytes, increased proportion of blasts, abnormal granulations (e.g. 2-3 instead of loads), if you stain for iron it would show accumulation of iron in mitochondria (ringed sideroblast - blue), auer rods
MDS subtypes
- R Unilineage cytopenia (<15% ringed sideros in BM)
- R. Cytopenia with multilineage dysplasia (RCMD) in BM
- R Anaemia RS (RARS) (>15% ringed siders in BM)
The above have no blasts in periphery - R Anaemiea with EB1, <5% no auers
- R Anaemia with EB2, >5-19%, auers
- MDS associated with del5q (hypolobated megas in the BM)
- Unclassified MDS
MDS prognosis
IPSS-R is a scoring system to help with prognosis and it takes into account blood count findings, karyotype findings and % BM blasts.
⅓ die from infection, ⅓ die from bleeding and ⅓ acute leukaemia
MDS Mx
AlloSCT - donor (donor that isn’t them)
Intensive chemotherapy
Neither of the above is suitable for elderly people.
Supportive care: Blood product support, antimicrobial therapy, growth factors (EPO, G-CSF)
Immunosuppressive therapy: Hypomethylating agents (azacytidine) and lenalidomide (IMIDS)
Oral Chemotherapy with hydroxyurea/carbamide
Primary Bone Marrow Failure Syndromes
Fanconi Anaemia (cf Fanconi Syndrome = renal) (AR)
- Pancytopenia
- Presents at 5-10yrs
- Skeletal abnormalities (radii, thumbs), renal malformations, microopthalmia, short stature,
skin pigmentation
- MDS (~30%), AML risk (10% progress)
Dyskeratosis Congenita (XL) Chromosome instability (telomere shortening) Skin pigmentation, nail dystrophy, oral leukoplakia (triad) + BM failure
Schwachman-Diamond Syndrome (AR) Primarily neutrophilia +/- others Skeletal abnormalities, endocrine and pancreatic dysfunction, hepatic impairment, short stature AML risk
Diamond-Blackfan Syndrome
Pure red-cell aplasia; normal WCC and platelets
Presents at 1yr/neonatal
Dysmorphology
Kostmann’s (AR)
Severe, congenital neutropenia disorder characterized by a lack of mature neutrophils associated with frequent, recurrent bacterial infections (e.g. otitis media, pneumonia, sinusitis, urinary tract infections, abscesses )
Secondary BM failure causes
Haematological: Marrow infiltration Non-haematological - Radiation - Drugs - Cytotoxic drugs (dose dependent) - Abx (sulphonamide, chloramphenicol) - Thiazides - Carbimazole - Chemical (benzene) - Autoimmune - Infection (parovirus, viral hepatitis)
