Haematology Case based discussions Dr Nnenna Osuji Dr Stella Appiah-Cubi Dr Stella Kotsiopoulou 21/05/2014

Objectives Focus on primary/secondary care interface Discuss cases encountered and practical lessons Highlight diagnostic clues Encourage confidence around community care of chronic stable haematological malignancies Information gathering Sickle vaccinations USC referrals Marker analysis/immunophenotyping Serum free light chains

Quiz Name the current consultants. How do you contact haematology for advice? Blood film suggests CLL. How are you going to refer this patient? Indications for 2WR Haematology Referrals

MALIGNANT HAEMATOLOGY Monoclonal Protein MGUS Vs Multiple Myeloma Case Discussions CLL Case Discussion

Varies greatly with age. What is an M protein? It is a monoclonal immunoglobulin secreted by an abnormally expanded clone of plasma cells that can be detected by immunofixation of serum and/or urine. Varies greatly with age. 1 - 2% of people in their 6th decade 2-4% in their 7th decade 4-5% in their eighth decade 14% over the age of 90 Racial variation Twice as common in black people as white people

Incidence of M-proteins Varies greatly with age. 1 - 2% of people in their 6th decade 2-4% in their 7th decade 4-5% in their eighth decade 14% over the age of 90 Racial variation Twice as common in black people as white people

Monoclonal gammopathies occur in the following conditions Haematological malignancies Multiple myeloma Solitary plasmacytoma (skeletal or extra- medullary) Waldenstrom's macroglobulinaemia Low grade non-Hodgkin’s lymphoma Monoclonal gammopathy of undetermined significance ( MGUS) AL amyloidosis Connective tissue disorders RA, SLE, scleroderma, polymyositis and ankylosing spondylitis. Skin disorders Infections Hepatitis C virus (HCV)-related chronic liver disease HIV Helicobacter pylori

Predicting Progression There were only 2 statistically significant risk factors for progression The concentration of monoclonal protein The type of monoclonal protein IgA and IgM gammopathy more likely than IgG to progress IgM rarely becoming myeloma

Monitoring in the low risk group Low risk defined as IgG M-protein <15g/l IgA or IgM M-protein <10g/l No symptoms/signs of myeloma, lymphoproliferative disorders or AL amyloidosis This group forms the vast majority of M proteins detected in routine practice

Acronym: CRAB

New International Staging System: ISS Stage Criteria Median survival I Beta2 microglobulin<3.5 mg/L and Serum albumin >3.5 g/dl 62 mo. II Neither I or III 45 III Beta2 microglobulin >5.5 mg/L 29

Clinical presentation Symptoms of bone disease, persistent unexplained backache Impaired renal function Anaemia Hypercalcaemia Recurrent or persistent bacterial infection Hyperviscosity Spinal cord/nerve root compression Symptoms suggestive of amyloidosis (nephrotic syndrome, cardiac failure) High ESR (incidental finding)

Case 1. - Patient G.R. 13/07/2005 67-year old Afro-Caribbean Right hypochondrial pain Fatigue Recently treated for epistaxis

Patient G.R. FBC: Hb 6.6, WBC 5.0, plts 85 Urea 10.2, creatinine 128 Adj. Ca 4.38, albumin 28 ESR 138 mm/h

Patient G.R. Admit Anaemia due to 3 units of blood transfusion ? Malignancy ? Epistaxis 3 units of blood transfusion i.v. fluids + Pamidronate

Patient G.R IgA λ paraprotein 75 g/l (t.prot 127 g/l) β2 microglobulin 5.6mg/l BM – plasma cells 40% INR 1.32, APTTr 1.34, fibrinogen 1.67 g

Patient G.R Drowsy Transfer to ITU Bleeding from mouth HD Methylprednisolone Subsequent C-VAD, Z-Dex chemotherapy

EMERGENCY !!! Hyperviscosity Treatment – plasmapheresis, HD steroids, iv hydration

Case 2. Patient B.B. 05/08/2005 49-year old Afro-Caribbean Back pain - 9 mo. (6 mo. off work) Not able to mobilize from bed without help

Patient B.B. FBC – clotted Urea 6.5, creatinine 150 Adj. Ca 2.68, albumin 19 Total protein 174 g/L Paraprotein 141 g/L IgGκ

Patient B.B. Hb 3.4 (citrate blood) INR 1.5, APTTr 1.25, fibrinogen 1.41

Patient B.B. 3 sessions of plasmapheresis at RMH Blood transfusion after plasmapheresis Z-Dex chemotherapy Abnormal ECHO CThal Dex chemotherapy

Case 3. Patient J.M. 01/08/2005 48-year old Afro-Caribbean Sudden lower-back pain on sneezing 3 mo. prior to admission 5/7 history back pain and reduced power in left leg

Patient J.M. FBC: Hb 10.5, WBC 6.8, plts 278 Urea, creatinine, adj. Ca - N T. protein 99 paraprotein 45 g/L IgGκ

Patient J.M. 05/08/2005 Left leg – no movement Right leg – reduced power

EMERGENCY !!! Spinal cord compression Treatment – radiotherapy, Dexamethasone

Patient J.M. 1st August – Lumbar spine X ray 2nd August – MRI 2nd August – CT- guided biopsy 4th August - diagnosis ?MM, ?NHL 4/5th August – referral to haematology 5th August - referral for radiotherapy 6th August - radiotherapy

Patient J.M. 20 Gy – 5 doses 1 course Z-Dex, 3 courses C-VAD !! Able to take few steps with crutches Right leg – back to normal Left leg – much improvement

Case 4. Patient N.H. 12/08/2005 71-year old Caucasian 3/12 back pain Spine X-ray – lytic lesion lumbar

Patient N.H. FBC: Hb 15.6, N 5.7, plts 237 Us&Es, Ca, t. protein – normal Small IgG paraprotein BM – 3% plasma cells CT-guided biopsy – plasma cells

Patient N.H. PLASMACYTOMA Treatment 40 Gy in 20 fractions

Management of persistent pain SURGERY Contraindicated in the absence of structural instability Management of persistent pain Vertebroplasty – bone strengthening and pain relief but does not restore height (polymethacrylate) Kyphoplasty – vertebral height can be restored (small inflatable balloon)

Chronic Lymphocytic Leukaemia CLL

CLL Clonal B cell malignancy. Progressive accumulation of long lived mature lymphocytes Most common leukemia of Western world. Male to female ratio is 2:1. Median age at diagnosis is 65-70 years. Small proportion are familial Aetiology unknown

Clinical features Mostly disease of elderly with Often asymptomatic. Classic B symptoms recurrent infections Lymphadenopathy, hepatosplenomegaly. Marrow failure Autoimmune haemolytic anaemia/thrombocytopenia

Diagnosis Persistent lymphocytosis > 5 x 109/l. Morphology Mature looking lymphocytes -clumped chromatin Immunophenotyping BM not required for diagnosis.

Immunophenotyping Majority score 4/5 Score < 3 not CLL

Staging- classification systems

CLL Complications Infection Autoimmune – ITP/Haemolytic anaemia Bacterial – hypogammaglobulinaemi a Viral – T-cell dysfunction (H. Zoster) Autoimmune – ITP/Haemolytic anaemia Other malignancies Transformation Richter’s, Hodgkin’s Shingles High dose therapy 800mg 5 x per day for 10 days then prophylactic dose 400mg tds Neuropathic pain

CLL treatment Many watch and wait – stage A Chemotherapy Bone marrow failure=stage progression B symptoms – weight loss, sweats, fevers (unexplained) Symptoms from enlarged lymph nodes/spleen Transformation Not for high WBC alone Median survival 10 years What? Chemotherapy FCR- fludarabine, cyclophosphamide, rituximab Chlorambucil - elderly Steroids Alemtuzumab – anti CD52

“Watch and wait” policy When to refer back B symptoms Lymphadenopathy Hepatosplenomegaly Falling haemoglobin, platelets, rapidly rising lymphocyte count Recurrent infections Autoimmune complications How often? Every 3 months Then reduce frequency if stable

Mrs ID 2004 Aged 80, Routine FBC- lymphs 8. Normal Hb/neutrophils/plats Well , no B symptoms, lymphadenopathy or hepatosplenomegaly Diagnosis CLL ‘Watch and wait ’ policy Discharged 2011 – GP to monitor

BENIGN HAEMATOLOGY Anaemias B12 Deficiency Case Discussion Iron Deficiency Vs Thalassaemia Trait Elevated Ferritin

ANAEMIA Definition Categorized according to Red Cell indices MCV and MCH: Hypochromic and Microcytic (low indices) Normochromic and Normocytic (normal indices) Macrocytic (high MCV) Can you name one cause for each category?

MACROCYTIC ANAEMIA How do we investigate? 1st line tests: B12, Folate, TSH, reticulocyte count, LDH, LFTs, blood film: ? Any dysplastic features. ? History of alcohol consumption 2nd line tests: SPE, UPE, DAT/haemolysis screen 3rd Line: Bone Marrow investigations

A guide to the management of B12 deficiency in the primary care

Outline Sources of dietary vitamin B12 Vitamin B12 absorption Causes of B12 deficiency Indications for measuring B12 level Clinical presentation of B12 deficiency Investigations to help define the cause of B12 deficiency. A guide to management

Sources Foods of animal origin- meat, fish, eggs, milk, cheese but not in plants. Recommended daily requirement is 1- 2µg/day Total body stores of 2000-5000µg Mainly stored in the liver( up to 2yrs stores)

Absorption

Who is at Risk

Causes of B12 deficiency • Inadequate vitamin B12 in diet ▪ strict vegans • Vitamin B12 malabsorption ▪ Pernicious anaemia-loss of GP→IF↓( increased of CA stomach ~ 2-3%) ▪ Long term use of PPI or H2-antagonist ▪ Chronic alcoholism ▪ Coeliac disease ▪ Small bowel( esp. terminal ileal) surgery ▪ Generalised malabsorption e.g. Tropical sprue, IBD ▪ Blind loop syndrome +/- small bowel bacterial overgrowth ▪ Fish tapeworm •Drugs ▪ Biguanides e.g.. Metformin ▪ Oral contraceptive pill ▪ Slow K, Cholestyramine

Indications for measuring serum vitamin B12 level Haematological ▪ Isolated red cell macrocytosis ▪ Macrocytic anaemia ( esp. if MCV> 110fl) ▪ Pancytopenia ( esp. if MCV> 110fl) Neurological or psychiatric ▪ Peripheral neuropathy ▪ Cognitive change e.g. dementia ▪ Optic neuritis Gastrointestinal ▪ Investigation of possible malabsorption process Other (rare) ▪ Angular stomatitis, glossitis (sore beefy red tongue)

Clinical features Slow onset – symptoms of mild anaemia Pallor and mild Jaundice( ineffective erythropoesis) Glossitis & angular stomatitis Neurological changes( B12< 60ng/L)( SCDC) ▪ Glove and stocking parasthesia ▪ Early loss of vibration sense ▪ Progressive weakness and ataxia ▪ Dementia SCDC: Subacute Combined Degeneration of the Spinal Cord

Investigations FBC-Megaloblastic anaemia with hypersegmented neutrophils Serum B12 level- low Serum folate may be normal or high Anti-intrinsic factor ( anti-IF)- highly specific but +ve in 50-60% of PA. Parietal cell antibodies- +ve in 90%( PA) but less specific TSH & anti-thyroid Ab Test for coeliac disease Test for generalised malabsorption Endoscopy Schilling test- obsolete

Treatment-Symptomatic B12 deficiency without neurological involvement: ▪ 1mg Hydroxocobalamin 3 times a week for 2 weeks then every 3 months B12 deficiency with neurological involvement: ▪ 1mg Hydroxocobalamin every other day until no further improvement then every 2 months ▪ Folic acid 5mg daily for 4 weeks

Treatment-Asymptomatic Serum B12> 150ng/l- Confirm test Significant proportion of these patients will go on to become symptomatic. Treat with oral vitamin B12 supplements + monitor level every 2-3months If no response then consideration given to parenteral B12 replacement

Case 1- Patient LS 53y old legal secretary Previously fit & well A&E with RIF 3/12 general lethargy & inability to concentrate

Patient LS PMHx- Nil relevant SHx-Single, good diet with mixture of animal & diary products No alcohol or smoking

On examination Pale, mildly jaundiced, sore and smooth tongue. No pedal oedema, no hepatosplenomegally BP- 95/50, Pulse -110/min RIF tenderness with guarding? appendicitis

Investigations FBC- Hb- 6.8g/dl, WBC- 2.5 Plt- 58, MCV- 130fl, U&E- NAD, LFT-Normal except Bili=26( 21- …), LDH- 8498, TSH- Normal, Hepatitis, HIV –ve.

Blood film

What other investigations would you consider? Folate- 9 B12- 72 GP & IF ab- Positive Coeliac Screen Negative

What is the management Vitamin B12 replacement- 1mg X 3 for 2 weeks. Then 3 monthly Folic acid 5mg daily for 4 weeks

Case 2 - Patient MS 47yr man South East Asian origin Saw GP with tiredness, SOBO PMHz- II DM on metformin SHx- Banker, strict vegetarian, Alcoholo, smokingo O/E- Unremarkable

Investigations Hb- 10.6 WBC- 3.2 Plt- 223, MCV- 120, LFT-NAD, LDH-640, U&E-NAD, TSH- Normal Blood film- macrocytosis with occasional hypersegmented neutrophils seen Serum B12- 140, Folate- 12, Ferritin 45 GP & IF ab, Coeliac screen- Negative

What is the management? Oral supplementation Cyanocobalamin 50-100µg PO daily Recheck serum B12 in 2-3 months. Continue if replete If not, consider parenteral B12 injections.

Case 3- Patient DT 48y old Female Long H/O bloatedness Good diet. SHx- Research nurse, no smoking or alcohol

Patient DT O/E- Unremarkable Bloods- Hb-9.8 WBC- 7.8 Plt-350 MCV-86fl Blood film unremarkable U&E, LFT, TSH- NAD

Patient DT Ferritin- 6µ/dl, serum B12 – 160, Folate- 8 Tissue transglutaminase (tTG)

Patient DT Referred to gastroenterologist Given oral B12 and FeSO4 Recheck 3 monthly

MICROCYTIC HYPOCHROMIC ANAEMIA What tests would you consider in the following cases: (Fer Vs Fer+HbEP) 25 y.o. lady, Norwegian, fatigued, Hb:100 g/l, RBC: 3000, MCV: 74fl, MCH: 26pg 50 y.o. lady , Cypriot, routine check, Hb:100 g/l, RBC 5000, MCV 70fl, MCH 24 pg

Hb structure

Beta-Thalassaemia inheritance

Alpha-Thalassaemia inheritance

Regarding Ferritin Low Ferritin = Iron Deficiency Raised Ferritin = Too much iron??

Causes of raised ferritin Iron overload( Primary & Secondary) High Ferritin Without Iron Overload

Causes of Fe overload Primary ▪ Hereditary haemochromatosis Secondary ▪ Hereditary aceruloplasmin( Wilsons’ disease) Secondary ▪ Transfusion overload ▪ Ineffective erythropoiesis( thalassemia, sideroblastic anaemia) ▪ Excess dietary iron

Causes of high ferritin without Fe overload Liver disease Alcohol excess Chronic inflammatory conditions( RA, IBD, bacterial infection) Malignancy

Evaluation of Fe loading tendency FBC LFT Ferritin Transferrin saturation

Patient FT 59yr old female Severe RA On immunosuppressive drugs

Patient FT Hb- 99 WBC- 13.5 Plt-420 ESR- 43 CRP- 35, Ferritin 400µg/l U&E, LFT- NAD Blood film Normochromic normocytic anaemia Serum electrophoresis- polyclonal increase in immunoglobulin

Patient FT Cause of raised ferritin- acute phase response No specific therapy/investigations required for this Treat the RA

Patient GM 38yr old German ancestry Fit & well City Banker Alcohol- 10u/week Well man clinic

Patient GM Hb- 154 WBC- 8.7 Plt- 210 Ferritin- 200µg/l B12/Folate- within normal range U&E, LFT-NAD O/E- Nicely tanned but unremarkable otherwise Transferrin saturation ( serum Fe & TIBC)- 89%

What is the next specific test? Test for HFE mutation Homozygous for C282Y/C282Y Diagnosis: Hereditary Haemochromatosis

Hereditary haemochromatosis Elevated Fe with no obvious cause Family history TS > 55% for men & post menopausal women TS > 50% in premenopausal woman Test for HFE mutation Refer patient to gastro-enterologist in CUH Venesection will be done by haematologist

Other issues Sickle cell vaccination Community follow up for long term haematological conditions Any others?

Sickle cell vaccinations Pneumococcal Vaccine every 5 years Hib immunisation (once in lifetime) Tetravalent Meningococcal vaccine ACWY (once in lifetime) Hepatitis B vaccination Seasonal Flu Vaccination (annually) WHY????

Community Follow-up for long term haematological conditions Can you name 2 (previously presented in this talk)? Can you suggest others?

Any Questions??????

Thank you! Dr Stella Kotsiopoulou Haematology Specialty Doctor Croydon University Hospital