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Haematology: Malignant Conditions Dr Jack Taylor-Stuart MBBS BSc (Hons) MRCP ST4 Haematology Registrar Royal Marsden Hospital ©Nature About Me • Graduated 2017 • Haematology BSc – 1 class honours • FY1/2 SW London • IMT1/2 NW London • Haematology training SW London • Have done MRCP, sitting FRCPath part 1 March :) • I like haematology T opics • Acute Leukaemias • Chronic Myeloid Leukaemia and Myeloproliferative disorders • Chronic Lymphocytic Leukaemia • Lymphomas • Myeloma • Myelodysplastic syndromes & Bone Marrow Failure • Bone Marrow Transplantation Aims of this lecture (a) • Help you all pass the pathology exam! – Recognise the presentations of acute and chronic leukaemias – Interpret blood test results in a patient with suspected haematological malignancy – Understand the clinical and biochemical abnormalities in myeloma – Learn how to differentiate between hodgkins and non-hodgkin’s lymphomas Aims of this lecture (b) • Help you all get an excellent score in the haematology section! – Recognise serious abnormalities on blood films – Learn some common cytogenetic abnormalities – Identify targeted treatments which may be appropriate in haematological malignancies Aims of this lecture (c) • Give you an idea of the clinical management of these conditions – I will include some details which are probably beyond the scope of year 5 pathology, for interest only – Hopefully I can convince you all that Haematology is an interesting specialty! Leukaemia - pathophysiology • “White blood” • Caused by mutations in white blood cells or their precursors • Mutations cause proliferation through a variety of mechanisms • Can be rapidly progressive or indolent – (Acute vs Chronic)Blood cancers- pathophysiology Acute leukaemias AML/CML ALL MPNs (PV / ET / MF) CLL + lymphomas Myeloma Leukaemias – clinical presentation • Acute leukaemias – Rapid proliferation of cells, replacing normal bone marrow – Results in bone marrow failure – neutropenianifestations – anaemia, thrombocytopenia, – Splenomegaly less common than chronic leukaemias – Bone pain. Occassional mild lymphadenopathy. – Fevers from disease – Rarer manifestations: gum infiltrates, skin infiltrates, testicular infiltrates Leukaemias – clinical presentation • Anaemia: shortness of breath, chest pain on exertion, fatigue • Thrombocytopenia: easy bruising, petechial rashes, spontaneous bleeding e.g. epistaxis • Neutropenia: frequent or severe infections including opportunistic infections Leukaemias – clinical presentation • Chronic Leukaemias: – Slower proliferation of malignant cells – Less burden of disease in bone marrow – Clonal cells can pool in lymph nodes or in the spleen – Clinical manifestations – lymphadenopathy, splenomegaly Leukaemias – leukostasis • Leukostasis: – Haematological emergency – High white cell count causes blood to be viscous and end-organ damage – Retinopathy, pulmonary infiltrates, bleeding, thrombosis – White cell count needed depends on size of cell (AML ~50, ALL ~100, CML ~300, CLL unusual) – Treatment: leukaphoresis or chemo / steroids Acute vs Chronic Acute Chronic Anaemia Yes – almost always May be absent at diagnosis but will develop if progresses Thrombocytopenia Neutropenia Lymphadenopathy Less common but can be Yes – particularly in CLL present in ALL Not always present Splenomegaly May be slightly enlarged Frequently present. CML can cause “massive splenomegaly” Asymptomatic Unusual Common in CLL Prognosis untreated Weeks – months Years Types of Leukaemia Leukaemia Acute Chronic AML ALL CML CLL APL B-cell CMML T-cell T-cell B-cell Types of Leukaemia Leukaemia Acute Chronic AML ALL CML CLL APL B-cell CMML T-cell T-cell B-cell For year 5 pathology it is sufficient to be aware that there are 4 groups of leukaemias However, as with most things, there are subdivisions below APL: Acute promyelocytic leukaemiaCMML: Chronic myelo-monocytic leukaemia THERE ARE LOADS MORE but you don't need to know them Acute Lymphoblastic Leukaemia • Things to look for in the history: – Child – typically 2-5 yrs old • Hepatosplenomegaly • Bone pain / limp • Fevers • CNS symptoms (up to 10% have CNS disease) • Testicular swelling (rare but specific) – Adults – similar to AML, lymphadenopathy Acute Lymphoblastic Leukaemia • Blood tests: – Usually present with thrombocytopenia and anaemia – High white cell count (but not always) – Some analysers will indicate presence of blasts but sometimes these will be flagged as lymphocytes. – Circulating blasts are not normal ALL – blood film • Blood film High nucleus – cytoplasm ratio Larger than RBCs (normal lymphocytes are same size) but not as big as AML blasts usually. It is not possible to tell ALL from AML on blood film most of the time! The "hand-mirror" / table tennis bat shaped cells are typical of ALL but until you have further tests you cannot know for sure. ALL – diagnosis • Diagnosis usually relies on Bone Marrow & Flow Cytometry • Typical features: • TdT + CD34+ • CD19 / CD10 /CD22 = B cells (more common) • CD 2 / CD 3 / CD 4/8 = T cells Note: beyond scope of yr 5 path ALL – Genetics (paeds) ETV6-RUNX1 fusion gene & hyperdiploidy (extra chromosomes) are most common abnormalities Both have a favourable prognosis MLL gene mutations (now renamed KMT2A) have bad prognosis but are rare. Blood journal, 2012 Note: beyond scope of yr 5 path ALL – Genetics (adults) Note: BCR-ABL1 t(9;22) associated with 20-30% of ALL in adults This is the genetic mutation which also causes CML (covered later) ALL – treatment • Adults and children – similar aims Transplant Induction Consolidation Maintenance Remission +/- novel targeted therapies (and CAR T-cell therapy!) AML – clinical features • Things to look for in the history: – Incidence increases with age – Might have had pre-existing myelodysplastic syndrome (MDS) – Symptoms of cytopenias AML – blood tests Hb 90 Anaemia – due to bone marrow suppression (130-170) Leukocytosis – high numbers of circulating white cells WCC 20 (4-11) Platelets 70 Thrombocytopenia – due to bone marrow suppression (150-400) Neuts 0.5 Neutropenia – lack of mature white cells due to excess of blasts (1.5-6) Blasts 18 High number of circulating blasts (not always flagged by analysers) INR 1.0 Normal INR – normal for AML (0.8-1.2) 2.5 Abnormal INR – possible DIC due to acute promyelocytic leukaemiaAML – blood film A single Auer rod is enough to diagnose AML* But sometimes there are lots… *or MDS AML - diagnosis • If no Auer rods present, flow cytometry needed to diagnose • Typical expression pattern: MPO CD34 CD13 / CD33 / CD117 / HLADR Note: beyond scope of yr 5 path AML – treatment T(15;17) Acute Promyelocytic Leukaemia – Presents with DIC. Good prognosis after induction – All-Trans Retinoic Acid (ATRA) • Forces cells to differentiate, stops proliferation Others: • Similar to ALL with intensive chemo • Some targeted treatments for FLT3 mutations, IDH mutations, CD33 • Poor prognosis particularly in elderly who won’t tolerate stem cell transplant Question time: Which of these is most concerning for an acute leukaemia? 1. Neutrophil count of 12 2. 10cm splenomegaly 3. Microcytic anaemia 4. Blast cells present on blood film examination 5. Cervical lymphadenopathyMyeloproliferative Neoplasms (MPNs) • Increased production of myeloid lineage• What can cause a high platelet count? Myeloproliferative Neoplasms (MPNs) • Increased production of myeloid lineage 1. Essential Thrombocythaemia Platelet Count >450 consistently with no other cause Increased risk of thrombotic events arterial + venous Small risk of transformation to myelofibrosis or AML JAK2 mutation in 55% CALR mutations & MPL mutations in most of remaining patients Treatment: Aspirin to reduce stroke risk Hydroxycarbamide to lower count (or other agents e.g. IFN) Thrombocytosis • Causes of a high platelet count: – Acute infection – Chronic inflammation – Malignancy (5-10%) – Essential thrombocythaemia – Polycythaemia rubra vera https://bjgp.org/content/67/659/e405 If there is no evidence of infection or inflammation, thrombocytosis should be investigated Myeloproliferative Neoplasms (MPNs) • Increased production of myeloid lineage 2. Polycythaemia Vera Haematocrit >0.52 / 0.48 (M / F) Often thrombocytosis as well High risk of thrombotic events e.g. MI, Stroke, Budd-Chiari Risk of transformation to MF / AML JAK2 mutation in 95% Treatment: Aspirin to reduce stroke risk Venesection (taking blood to lower haematocrit) Hydroxycarbamide to lower count Polycythaemia • Causes: – Primary: • Polycythaemia rubra vera – Secondary: • Altitude • Chronic hypoxia: e.g. severe COPD, cyanotic heart disease, obstructive sleep apnoea • Erythropoietin-secreting renal cancers Investigations • High platelets – History to exclude other cause – Bloods including CRP/ESR – If persistent, send mutation panel JAK2/CALR/MPL – If negative panel and high suspicion, bone marrow bx • High haematocrit – History to exclude other cause – Bloods including EPO level – If persistent, sent mutation panel for JAK2 – If negative panel: • Consider scanning kidneys • Consider respiratory referral Myeloproliferative Neoplasms (MPNs) • Increased production of myeloid lineage 3. Myelofibrosis Clonal proliferation of stem cells in the bone marrow This results in cytokine release and fibrosis of the bone marrow As a result, there is reduced production of all cell lineages Risk of transformation to AML Features: JAK2 mutation present in 50%, CALR mutations also common Pancytopenia Splenomegaly (can be massive splenomegaly) “dry tap ” on bone marrow aspiration “tear drop poikilocytes ” on blood film Treatment: Stem cell transplant likely only cure Ruloxitinib - JAK inhibitor Myeloproliferative Neoplasms (MPNs) • Increased production of myeloid lineage 4. Chronic Myeloid Leukaemia (CML) Classed as a MPN CML • History and examination: – Typical onset age 35-55 in EMQs – LUQ pain - Splenomegaly – Mostly asymptomatic if diagnosed in chronic phase – May have lethargy, fatigue, fever, night sweats – May present with symptoms of acute leukaemia if in accelerated / blast phase (~10%) CML – Blood tests In chronic phase – unlikely significantly anaemic (but can be) Hb 110 WCC 30 Leukocytosis In chronic phase – unlikely thrombocytopenia. 50% have elevated platelet count Platelets 450 Neuts 22 Neutrophilia Basophils 1 Might be elevated basophil count (note: very few other causes of this!) Monocytes 1 Monocyte count should be low (high monocyte count would indicate CMML) May be precursor cells flagged on blood differential. E.g. promyelocytes, myelocytes Leukocytosis • Causes of a high white cell count depend on the cell type: – Acute bacterial infection • Usually a high neutrophil : lymphocyte ratio – Acute viral infection • Usually a low neutrophil : lymphocyte ratio • note: covid 19 causes lymphopenia – Fungal / parasitic infection • Usually a high eosinophil count – Monocytosis • Unusual but seen in: TB, endocarditis, inflammatory conditions Leukocytosis In severe acute infections, there may be some precursor cells (myelocytes, metamyelocytes) Elevated basophil and eosinophil counts are concerning for malignancyCML – blood film Features: • “Left shift” • Precursor cells present • Leukocytosis • Eosinophilia • Basophilia • Hypolobated megakaryocytes in bone marrow CML - diagnosis • Nearly all CML is associated with the Philadelphia chromosome • BCR-ABL1 fusion gene results from translocation of • t(9;22) and formation of the • Philadelphia chromosome • In exams they may use one of these three descriptions. • Detected by FISH or RQ-PCR to quantify. CML - diagnosis • Phases of disease: – Chronic (85-90%) – Accelerated • Increasing number of blasts in BM • Lack of response to therapy • Additional abnormalities in addition to BCR-ABL1 • Recently removed from classification! – Blast phase • >20% blasts in bone marrow • Behaves like an acute leukaemia CML - Treatment • Tyrosine Kinase Inhibitors – 1 Generation: Imatinib – 2 Generation: Dasatinib, Nilotinib, Bosutinib – 3 Generation: Ponatinib – Ascimimab – works in slightly different way, for patients who don't respond to above • >90% 10 yr survival • Small percentage of patients will fail treatment and need transplants Lymphoproliferative disorders • This includes CLL and lymphomas CLL – signs and symptoms • Things to look out for: – Usually asymptomatic – Picked up on routine blood tests – Age >50 – incidence increases with age – Twice as common in Men:Women – Can present with lymphadenopathy/splenomegaly – Can present with ITP (immune-mediated thrombocytopenic purpura) / Haemolytic anaemias CLL – blood tests Hb 130 Normally – no anaemia at presentation Anaemia at presentation = more aggressive disease or 90 haemolytic anaemia present WCC 100 High white cell count, often >100 x10 Platelets 200 Normally – no thrombocytopenia at presentation Neutrophils 3 Normally – no neutropenia Lymphocytes 95 WCC is made up of mature lymphocytesCLL – blood film • Smear cells / Smudge cells • Lymphocytosis CLL - diagnosis • Aided by flow cytometry: – Identifying a “clonal” population of cells – Will express same cell markers e.g. Kappa/Lambda light chains • Affects B-cells • Same pathology as Small Lymphocytic Lymphoma but different distribution of disease (blood/marrow vs lymph nodes) CLL - treatment • Staging - Binet: – A – no cytopenia, <3 areas of lymphoid involvement – B – no cytopenia, 3+ areas of lymphoid involvement – C – cytopenias • A – watch and wait • B – consider treatment • C – treat Richters syndrome: transformation of CLL to aggressive disease (ALL / high grade lymphoma) CLL - treatment • IGHV and TP53 mutation status determine response to treatment. • IGHV mutated cases do well with Rituximab and chemo • TP53 mutated do not - we tend to use BTK inhibitors • Options: – FCR, BR, RCVP)uximab/obinutuzumab) + chemo (e.g. – BTK inhibitors (e.g. ibrutinib, acalabrutinib) – BCL2 inhibitor (venetoclax) Note: beyond scope of yr 5 path Question time Which of these blood differentials is most in keeping with CML? 1 2 3 4 5 Hb (125-155) 100 130 71 180 115 Platelets 600 350 52 890 120 (150-400) White cells 45 110 2.1 7 15 (4-11) Neutrophils 20 3 0.7 4 14 (1.5-6) Lymphocytes 1 106 0.9 1.5 0.7 (1-4) Basophils 3 0.2 0.1 0.2 0.1 (0.1-1) Eosinophils 4 0.8 0.3 0.5 0.1 (0.1-1) What is the most likely diagnosis for 2? 2 Hb (125-155) 130 Platelets 350 (150-400) White cells 110 (4-11) Neutrophils 3 (1.5-6) Lymphocytes 106 (1-4) Basophils 0.2 (0.1-1) Eosinophils 0.8 (0.1-1) Differential diagnosis for 3? 3 Hb (125-155) 71 Platelets 52 (150-400) White cells 2.1 (4-11) Neutrophils 0.7 (1.5-6) Lymphocytes 0.9 (1-4) Basophils 0.1 (0.1-1) Eosinophils 0.3 (0.1-1) Pancytopenia Causes of pancytopenia are numerous! A good history is essential • B12/Folate deficiency • Medication induced (many! Co-trimoxazole, linezolid) • Malignancy: – Acute leukaemia – Bone marrow infiltration from other cancers e.g. prostate • Aplastic anaemias – e.g. related to sepsis – Autoimmune – Virus-induced (parvovirus B19) • Myelodysplastic syndromes • Myelofibrosis ALL AML CLL CML Low Low Normal -> low Normal ->low Haemoglobin WCC High High Very high High -> very high Low if early Low if early Platelet Count Low Low Normal High / Normal Neutrophils Low Low Normal High Lymphocytes Very High Basophils High Eosinophils High / Normal CMML – high Monocytes CML – normal Myelocytes etc Present Blast cells Present Present Film Auer rods Smear cells Left Shift Marrow >20% blasts <20% blasts Myelodysplastic Syndromes • Dysplastic changes (abnormal cells) • 1 or more myeloid cell lines (erythroid, megakaryocyte, granulocyte) • Usually asymptomatic, but risk of progression to AML • Present with incidental cytopenia Anaemia in MDS • Anaemia with normal ferritin (iron), B12, Folate and erythropoitin levels raises suspicion of MDS • Usually this is macrocytic anaemia Anaemia will be covered in the other haematology lecture! MDS – blood film Blood journal (2013) http://www.bloodjournal.org/content/122/25/4021?sso-checked=true MDS – Classification (WHO HAEM 5) • Changed only this year • Not important for you to know • Prognostic factors: – Number and extent of cytopenias – BM blast percentage – Cytogenetic changes – Specific mutations e.g. TP53 mutation (which has very poor prognosis) MDS – Prognosis • ~30% would progress to AML • Risk is assessed using IPSS-R/IPSS-M score MDS - Treatment ESA – Erythropoietin HMA – hypomethylating agent IST – immunosuppressive therapy Note: far beyond scope of yr 5 path Blood cancer journal (2018) https://www.nature.com/articles/s41408-018-0085-4/figures/1 Lymphomas Hodgkins Non-Hodgkins Age Young Increases with age Lymph nodes Mediastinum (anywhere) Anywhere Painful on drinking alcohol Course Aggressive Variable Prognosis Mostly curable Variable Lymphomas There are ~60 types of lymphoma Broadly classified into: • Hodgkins vs Non-Hodgkins Lymphoma • B-cell vs T-cell • Very high vs High vs Low grade Non- Hodgkins Hodgkin’s B-cell T-cell 4 subtypes Burkitt’s DLBCL Mantle cell Follicular ATLL Lymphomas - Staging Ann-Arbor staging Note: - Bone marrow / spleen involvement = stage IV “B Symptoms” • Fever >38 degrees • Drenching sweats at night • Unintentional weight loss >10% body weight in 6 months Lymphomas Hodgkin’s Lymphoma: Summary for Yr 5 pathology: • Affects many young people (but also a peak in older adults)mphoma • Presentation with lymphadenopathy or “B”-symptoms • Frequently mediastinal lymphadenopathy • Reed-Sternburg cells are diagnostic (only 1 needed) Hodgkins Hodgkin’s B-cell T-cell 4 subtypes Burkitt’s DLBCL Mantle cell Follicular ATLL Lymphomas Hodgkin’s Lymphoma: Summary for Yr 5 pathology: Lymphoma • Affects many young people • Presentation with lymphadenopathy or “B”-symptoms • Frequently mediastinal lymphadenopathy • Reed-Sternburg cells are diagnostic (only 1 needed) Hodgkin’s Hodgkins Extra information: • Nodular sclerosing is the most common type • Can be associated with EBV infection T-cell 4 subtypes • Treatment is with ABVD chemotherapy usually + radiotherapy • Most patients have a good chance of cure • StBurkitt’sranspDLBCL for raMantle cello faFolliculart ATLL Lymphomas Lymphoma Non- Hodgkins Hodgkin’s Non-Hodgkin’s Lymphoma: B-cell T-cell 4 subtypes Summary for Yr 5 pathology: • Many sub-types – mostly B-cell origin, can be T-cell. • Present with B-symptoms or lymphadenopathy • InBurkitt’sncreasDLBCLth age Mantle cell Follicular ATLL Lymphomas Non-Hodgkin’s Lymphoma: Indolent Summary for Yr 5 pathology: • Most common “indolent” lymphoma is Follicular Lymphoma Lymphoma • Small lymphocytic lymphoma is similar to CLL but with dise se in nodes • Present with lymphadenopathy – usually few very large nodes • Risk of transformation to high grade lymphoma Non- Extra information: Hodgkin’s Hodgkins Follicular Lymphoma: - Large numbers of centroblasts on lymph node biopsy - t(14;18) causes fusion of BCL2 gene T-cell 4 subtypes - Treatment is watchful waiting unless high burden of disease. Burkitt’s DLBCL Mantle cell Follicular ATLLImage from pathpedia Lymphomas Non-Hodgkin’s Lymphoma: High grade Summary for Yr 5 pathology: • Most common “high grade” lymphoma is Diffuse Large B-Cell Lymphoma Lymphoma • Present with lymphadenopathy & frequently B-symptoms • May have Bone Marrow involvement • Risk of Tumour Lysis Syndrome with treatment Non- Extra information: Hodgkin’s Hodgkins Mantle Cell Lymphoma: - t(11;14) causes overexpression of Cyclin D1 - Treatment is with chemotherapy T-cell 4 subtypes - May have “leukaemic phase” Burkitt’s DLBCL Mantle cell Follicular ATLL Lymphomas Cleft in “mantle cell” Lymphomas Non-Hodgkin’s Lymphoma: High grade Summary for Yr 5 pathology: • Most common “high grade” lymphoma is Diffuse Large B-Cell Lymphoma Lymphoma • Present with lymphadenopathy & frequently B-symptoms • May have Bone Marrow involvement • Risk of Tumour Lysis Syndrome with treatment Non- Extra information: Hodgkin’s Hodgkins Diffuse Large B-Cell Lymphoma (DLBCL) - Treatment is with Rituximab-CHOP chemotherapy - Can be associated with EBVcell T-cell 4 subtypes Burkitt’s DLBCL Mantle cell Follicular ATLL Lymphomas Non-Hodgkin’s Lymphoma: Very High grade Summary for Yr 5 pathology: • Some lymphomas are very fast growing Lymphoma • Commonest example is Burkitt’s Lymphoma • High risk of Tumour Lysis Syndrome with treatment Extra information: Non- Burkitt’s Lymphoma Hodgkin’s Hodgkins - “Starry sky” appearance on histology - Mostly associated with t(8;14) - Associated with EBV + HIV-cell T-cell 4 subtypes - Large fast growing lymph nodes in neck / elsewhere Burkitt’s DLBCL Mantle cell Follicular ATLL Lymphomas Non-Hodgkin’s Lymphoma: T-Cell Summary for Yr 5 pathology: • T-cell lymphomas are less common Lymphoma • ATLL is one example • Cutaneous T-cell lymphomas are rare and present with weird rashes Extra information: Non- Adult T-cell Leukaemia / Lymphoma Hodgkin’s Hodgkins - More common in far east - Associated with HTLV-1 - “flower cells” on blood filmll T-cell 4 subtypes Burkitt’s DLBCL Mantle cell Follicular ATLLRank these in order of Ann-Arbor staging (top stage 1 -> bottom stage 4) 1. Cervical lymphadenopathy and bone marrow infiltration 2. Mediastinal and axillary lymphadenopathy 3. Inguinal and Cervical lymphadenopathy 4. A single enlarged lymph node in the axillaA patient with newly diagnosed burkitt lymphoma has these blood results 6 hours after chemotherapy: Creatinine 200 (baseline 90) Urea 14.4 (baseline 6) Potassium 7.1 (3.5-5.5) Sodium 140 (135-145) Calcium 1.81 (2.2-2.6) Phosphate 2.6 (1-1.6) Uric acid 800 (<400) What is the diagnosis? What is the treatment? Multiple Myeloma • “Plasma cell dyscrasia” • Clonal population of plasma cells which proliferate and produce monoclonal immunoglobulin light chains – In blood, found as paraprotein – In urine, found as Bence Jones Protein Left - shows the spike in the "gamma" region Right - shows the protein is a monoclonal IgG Kappa Myeloma - progression MGUS Smouldering Myeloma Multiple Myeloma Myeloma - progression Myeloma: Clonal bone marrow plasma cells >10% in the marrow or plasmacytoma And end organ damage Smouldering 1 or more:US • Calcium: Hypercalcaemia >2.75 Myeloma • Renal: Creatinine clearance <40ml/min / Creatinine >177 • Anaemia Hb <100g/l • Bone lesions – lytic lesions • SLIM (>Sixty percent plasma cells in BM, Light chain ratio >100, MRI lesions) Multiple Myeloma Myeloma - progression MGUS Smouldering Myeloma Smouldering / Asymptomatic Myeloma: Serum monoclonal protein (IgG / IgA) >30g/l or Bence Jones Protein And/or Clonal bone marrow plasma cells 10%-60% in the marrow Multiple No end organ damaMyeloma Most will progress to myeloma untreated Myeloma - progression Smouldering MGUS Myeloma MGUS: Monoclonal Gammopathy of Unknown Significance Serum monoclonal protein <30g/l Plasma cells <10% on Bone Marrow No end organ damage Multiple No evidence of other disorder Myeloma 1-2% per year progress to myeloma VERY common in the elderly - if low risk, for yearly blood test Myeloma - diagnosis MGUS SM MM Paraprotein <30 >30 ANY (usually >30) Plasma cells in BM <10% 10-60% >10% CRAB - - + Lesions on MRI - - + Free light chain ratio <100 <100 >100 Progression rate 1-2% per year 10% per year n/a Note: there is also a rare condition called Waldenstrom’s macroglobulinaemia which is similar to myeloma with the following differences: - The paraprotein is always IgM (you can also get IgM Myeloma) - They present with lymphadenopathy and similar to follicular lymphoma - There is an abnormality in the lymphoplasmatoid cells as well as plasma cells - They are at risk of hyperviscosity syndrome Waldenstrom’s is unlikely to be tested in your exam Myeloma – diagnosis Plasma cells. Rouleaux formation Myeloma - management • MGUS: annual blood test • Smouldering myeloma – no proven benefit in treating until progression to myeloma • Myeloma – treat in most cases Myeloma - treatment • Changing every year! • Principles: – Younger patients: chemotherapy then autologous stem cell transplant – Older patients: chemotherapy then maintenance therapy Myeloma - treatment • Commonly used drugs in initial treatment: – Proteasome inhibitors: Velcade (bortezomib) – Imids: Thalidomide / lenaloidomide – Dexamethasone – Anti-CD38: Daratumumab • Subsequent treatments: – Other imids (pomalidomide) – Other PIs: Carfilzomib, ixazomib – Melphalan – BiTEs, CAR-T therapy Note: beyond scope of yr 5 pathWhat investigations are needed for this patient? Dear doctor, I have referred this fit and well 60-year-old man with an IgG lambda paraprotein of 25g/l discovered on a routine blood test. Haematopoietic Stem Cell Transplant • Autologous or Allogeneic • Principles: – Stem cells harvested from bone marrow / blood – Recipient receives chemotherapy to destroy their marrow – Stem cells infused into recipient • Approximately 10% die in the first year Question 1 55 year old man with no past medical history presents with fatigue to his GP. Blood results show: WCC 7 Hb 90 MCV 95 Na 140 K 4.0 Creatinine 90 Calcium 2.5 Serum electrophoresis shows an IgG kappa paraprotein of 37 g/l Full body MRI shows no lytic lesions. Bone marrow aspirate shows a clonal population of plasma cells, 15% of marrow cells. What is the most likely diagnosis? a) Acute leukaemia b) Multiple Myeloma c) Smouldering Myeloma d) MGUS e) Waldenstrom’s Macroglobulinaemia Question 2 55 year old man presents to his GP after a 2 week history of fatigue and easy bruising. Blood results show: WCC 27 Hb 90 Plt 30 Na 140 K 4.0 Creatinine 90 Calcium 2.5 Blood film shows presence of blasts, with 27% blasts in marrow Flow cytometry shows a clonal population of cells expressing CD34, CD19 and TdT. Cytogenetic analysis shows the presence of t(9;22) What is the most likely diagnosis? a) Acute Myeloid Leukaemia b) Acute Lymphoblastic Leukaemia c) Mixed Phenotype Acute Leukaemia d) Adult T-cell leukamia-lymphoma e) Burkitt’s lymphoma Question 3 55 year old man presents to his GP after a 2 week history of fatigue and easy bruising. Blood results show: WCC 27 Hb 90 Plt 30 Na 140 K 4.0 Creatinine 90 Calcium 2.5 Blood film shows presence of blasts (see below) with 27% blasts in marrow Flow cytometry shows a clonal population of cells expressing CD34, MPO.Question 3 Question 4 25 year old man presents to his GP after a 4 week history of intermittent fevers and drenching night sweats. Blood results show: WCC 7 Hb 120 Plt 300 Na 140 K 4.0 Creatinine 90 Calcium 2.5 Examination reveals cervical lymphadenopathy, which is biopsied. On biopsy there are multinucleated cells: What is the most likely diagnosis? a) Mantle Cell Lymphoma b) Disseminated tuberculosis c) Chronic Lymphocytic Leukaemia d) Hodgkin’s Lymphoma e) Burkitt’s Lymphoma Question 5 A 50 year old woman presents to her GP with left sided abdominal pain. Examination reveals palpable splenomegaly. Blood tests: WCC 30 Hb 110 Platelets 500 Neuts 20 Mono 0.7 (<1) A blood film shows left shifted granulocytes. Urgent FISH shows presence of the BCR-ABL1 fusion gene What is the most likely diagnosis? a) Chronic Myeloid Leukaemia b) Chronic Myelomonocytic Leukaemia c) Myelodysplastic syndrome d) Essential Thrombocythaemia e) Myelofibrosis Question 6 A 60 year old lady presents to her GP with tiredness. Examination reveals a mass in the left side of the abdomen. Blood tests show: WCC 3.0 Hb 70 Platelets 50 Neuts 1.5 medications.te counts are normal. She is not on any Blood film is shown on the right. What is the most likely diagnosis? a) Myelodysplastic syndrome b) Acute Myeloid Leukaemia c) Acute Lymphocytic Leukaemia d) Chronic Myeloid Leukaemia e) Myelofibrosis Question 7 A 50 year old man suffers with recurrent infections and is found to be neutropenic and anaemic on a blood test. Hb 70g/l WCC 2.1 neutrophils 0.3 Platelets 170 B12 and Folate are normal He is not on any medications and undergoes a bone marrow aspiration. This shows hyposegmented neutrophils, binucleated erythroid precursors and erythroid nuclear bridging. What is the most likely diagnosis: A) Iron deficiency B) Acute myeloid leukaemia C) Multiple myeloma D) Myelodysplastic syndrome E) Myelofibrosis EMQ buzz words ALL Testicular swelling, 3-5 yrs old AML Auer rods CML Philadelphia chromosome / t(9;22) / BCR-ABL1; Left shift CLL Smear cells / smudge cells PCV JAK2 +, high haematocrit, flushed appearance, strokes / budd chiari ET High platelets, strokes, may have JAK2 mutation Myelofibrosis Dry tap, teardrop cells (dacrocytes), massive splenomegaly Hodgkins Painful LNs with alcohol, Reed-sternberg cells, EBV + Follicular T(14;18); centroblasts Mantle T(11;14), mantle cells Burkitt’s t(8;14), starry sky appearance, EBV + , HIV + Myeloma CRAB + bence jones protein / IgG/A >30 MGUS No CRAB, paraprotein <30 Reversing anticoagulants • Warfarin: INR No bleed Minor bleed Major bleed <5 Reduce dose Reduce dose Hold warfarin 5-8 Hold warfarin Hold warfarin Vitamin K Vitamin K Prothrombin complex concentrate (PCC) >8 Hold warfarin Or 5mg Vitamin K Fresh frozen plasma (FFP) Reversing anticoagulants • Heparin/LMWH: Protamine • Rivaroxaban, apixaban: Prothrombin complex concentrate (PCC) • Dabigatran: Antibody (Idarucizumab - expensive) or PCC • Aspirin / clopidogrel: platelet transfusion Adult vs Child Neonate Child Adult WCC 10-26 5-17 4-11 Neuts 3-15 1.5-8.5 1.7-7.5 Lymph 2-7.3 1.5-10.5 1.5-4.5 Hb (g/l) 149-237 115-135 115-165 (F) 130-180 (M) HCT 0.47-0.75 0.35-0.45 0.36-0.5 MCV fL 100-135 75-87 82-98 Platelets 150-450 NB: NO NEED to learn all the values. But be aware of the trends Blood transfusions Red Cells Platelets FFP Dose ~1 per 10g/l Hb rise ~1 per 25 count rise 10-15ml/kg Ordering Crossmatched ABO/D identical ABO identical Storage Fridge Agitated, room temp Frozen (need thawing) Infusion 2-3 hours ideally 30 mins ideally Over 30-60 mins Red blood cells • Complications (immediate): • Fever: – Acute haemolytic transfusion reaction – Transfusion-related acute lung injury (TRALI) – Sepsis (commoner from platelets) – Febrile non-haemolytic transfusion reaction • No fever: – Anaphylaxis – Transfusion-associated circulatory overload – UrticariaAskhaematologist.combiochemistryformedicsHalfdanarsan, Blood journal 2007American Society of HematologyLibrary.med.utah.eduCleveland clinicWikimediaWikimediaPathology studentGabeents.com