Anaemias and other Pesky Haematology Questions

Anaemias and other Pesky Haematology Questions

3 main topics How do I work out an anaemia.. That oh too common paraprotein patient. Those mildly raised lymphocyte count

GP discussed patient with me over weekend 83 yr female. Hb 103g/L. Stable level for previous 2 years MCV= 100. Plats/neuts = N Asymptomatic though previous recent TIAs

FIRST QUESTION IS THERE DECREASED PRODUCTION with LOW numbers of RETICULOCYTES OR INCREASED DESTRUCTION with INCREASE in RETICULOCYTES (as long as the necessary building blocks are present)

Increased retics= increase RBC destruction 1. Acute bleed with sufficient iron stores Or 2. Haemolytic anaemia Relatively rare Most will be referred for further work up

DECREASED PRODUCTION=Decreased reticulocytes 1. Lack of nutrients 2. Inflammatory process 3. Hormonal causes including lack of erythropoietin -i.e. renal impairment. Hypothyroid= relatively rare cause 4. Malproduction of haemopoietic cells i.e. myelodysplasia 5. Infiltration of bone marrow by a)fibrosis or b) malignancy

Our patient = Low reticulocytes- decreased production 1. Lack of nutrients? B12/folate =N (also ferritin= N) 2. Inflammatory process? CRP =N 3. Hormonal causes including lack of erythropoietin -i.e. renal impairment? Creatinine - 116 µmol/l. May be contributing a bit towards the Anaemia. Thyroid function normal.

DECREASED PRODUCTION=Decreased reticulocytes continued 4. Malproduction of haemopoietic cells i.e. myelodysplasia Most important test= BLOOD FILM Variation in size and shape of the red cells Hypo granulation of neutrophils May have reduction in neutrophils and platelets Q12 1494

5. Infiltration of bone marrow by a)fibrosis or b) malignancy BLOOD FILM very helpful Fibrosis associated with TEARDROPS and LEUKOERYTHROBLASTIC picture Needs bone marrow examination

5. Infiltration of bone marrow by b) malignancy Stable over last 2 years therefore unlikely to be aggressive malignancy Blood film again gave the clue Rouleaux Occurs when there is increased immunoglobulins from infection or paraprotein

Serum Electrophoresis showed IgM paraprotein of 25g/L If you had one test in this lady what would you do to maximise her management? 1. Bone marrow as she probably has myeloma 2. Serum viscosity as the IgM may increasing her risk of TIAs 3. A Serum Free Light Chain level 4. Bence Jones Protein

Ig M paraprotein in an otherwise asymptomatic patient with stable bloods IgM paraproteins MGUS rarely become myeloma usually low grade NHL MUST ask about night sweats/wt. loss/infections at EACH visit and tell them to report these MUST look for LN/L/S/abdominal masses at EACH visit

Low Grade NHL No definite benefit of early treatment ( at any age) of a LG NHL If very high IgM, once off plasma viscosity. Viscosity > 4 significant

Keeping to the theme of patients with paraproteins..

65 year woman steps awkwardly off a small stool Very significant thoracic pain X-ray showed some old looking thoracic fractures -?skiing accidents Prescribed slow release oxycodone by orthopaedic reg Still taking oxycodone 4 weeks later and significant pain

1 month later still taking oxycodone Bloods show normal full blood count, standard biochemistry and Total Ig G of 12 g/l (7-14) with a paraprotein present Normal IgM/A Kappa free light chain=86 mg/l (3.3-19.4) Lambda free light chain = 63mg/L (5.7-26.3) with a kappa/lambda ratio of 0.3mg/L (0.2-1.6)

What would you do? Which is most correct? 1. Explain to her that the serum free light chain results indicate myeloma 2. Explain to her it was inappropriate for her to be on oxycodone and in view of the normal IgG, she doesn t need to be followed up for a couple of years. 3. Undertake a urinary Bence Jones Protein as they are more reliable that serum free light chains. 4. Refer her to exclude a plasmacytoma

Int. Myeloma Working Group BJH, 2003; 121:749-57 Monoclonal Gammopathy of undetermined significance strict definition. 3% over the age of 50 yrs., 5% over the age of 70 yrs. No evidence of other B-cell disorders or amyloidosis M-protein < 30g/l and <10% plasma cells on BM No myeloma-related symptoms/organ damage

Rate of progression of MGUS Progression at 10 yrs. 9% 20 yrs. 20% 25 yrs. 30% 1% progression per year, for patients who have not died of other causes R L Spearing

But can we predict which will progress i.e. which need closer monitoring? Just based on the lab results, what would this mans chance be of progressing at 20 years 1. 5% 2. 20 % 3. 40% 4. 60% 5. 80%

How do you predict which patients will progress? 3 important factors help predict: 1. Type of paraprotein- If IgA more likely to progress than IgG (remember if a IgM paraprotein progresses - usually associated with a low grade lymphoma, not myeloma) 2. If serum free light chain RATIO is abnormal, more likely to progress 3. If high level of paraprotein i.e. >15g/L. However many labs don t quantify the paraprotein

Risk-Stratification Model to Predict Progression of MGUS to Myeloma Risk Group Low Risk Monoclonal protein <15 g/l, IgG type, normal FLC ratio Low-Intermediate Risk Any one factor abnormal High-Intermediate Risk Any two factors abnormal High-Risk (5% of group) All three factors abnormal Absolute Risk of Progression at 20 years 5% 21% 37% 58% Rajkumar Blood, 2005;106: 812-817.

However this woman didn t have MGUS because she had bone pain Seen 7 months later, significant ongoing PAIN in thoracic region. Ig G now 18 g/l ( had been 12g/L, 7 months previously i.e. RATE of increase is important). Kappa serum free light chain=27 mg/l (3.3-19.4) Lambda free light chain = 10 mg/l (5.7-26.3) with a kappa/lambda ratio of 2.73 (0.2-1.6) MRI showed multiple lytic lesions in the spine and the bone marrow 18% plasma cells i.e. myeloma

Recent move to treat myeloma earlier Previously international guidelines= needed raised calcium /renal impairment/anaemia/bone pain (CRAB) before treating Now - low dose CTs performed on MGUS with high risk features Indication to treat = 2 lesions on MRI/CT scan; SFLC ration of >100 plasma cell >60% even without end organ damage

Lessons from this case Pain out of proportion to the injury Bence Jones protein is an obsolete test Ratio of the 2 light chains is what to look as both will go up in infection Rate of rise of the paraprotein or SFLC is important as well as total level

A sad case 51 yr. old woman 2006 - screening for a weight loss trial. Kappa paraprotein -low total IgG of 7g/L and an initially N SFLC ratio, though by the next year had become weakly positive - 3.39mg/L (0.2-1.6) Asymptomatic 5% risk of progressing to MM, lymphoma or other B Cell neoplasm at 20 years However, SFLC ratio and Ig level then stable for next 7 years and so FU extended to 6-12 monthly

SFCL Ratio Dec 2013 increased from 3.39 to 4.96 (0.2-1.6) Ig G unchanged Letter from locum is that increase significant? I am quite happy with her present IgG level and her SFLC ratio No absolute cut off for when a serum free light chain may be of significance but usually it is at least 100. Thank you for continuing to monitor her with 6 to 12 monthly serum free light chains, immunoglobulins, calcium, albumin, creatinine and full blood count and questions about weight loss, night sweats and bone pain. Examination should include looking for palpable liver spleen and lymph nodes.

What I didn t say was the RATE of rise = Important Oct 2014 SCLF =20.2 up from 4.9 ten months earlier (N=0.2-1.6) Jan 2015 developed pain visited new locum x9 times. Referred to musculoskeletal specialist in July who repeated the SFLC ratio now 16966. Bone marrow 90% plasma cells. Pain very difficult to control.

Myeloma update Newer drugs such as S/C weekly bortezomib/weekly 40mg dexamethasone plus cyclophosphamide followed by stem cell transplant for <70year olds = median survival of 7-9 years Bortezomib/dexa/cyclo without transplant reasonably tolerated up into 70s, some 80s. Dose of weekly dexa 20mg/wk. NB: Significant bone pain even with a low level paraprotein can be a plasmacytoma RATE of RISE of paraprotein/sflc important - Not absolute figure.

Chronic lymphocytosis GP referral- Written advice only Semi-urgent - 24-Jul-2015 15:26 chronic lymphocytosis.?monitor yearly or needs to be seen blood test shows lymphocytosis recommend marker studies no wt. loss no recurrent infections no night sweats. wt. 107 no lymphadenopathy neck axilla groin abdo snt. no hepatosplenomegaly. P lymphocyte marker studies.

Mild Lymphocytosis- When should one recheck it? Nothing hard and fast needs to be put into clinical context?viral symptoms/wt. loss/recurrent infections/night sweats/lymphadenopathy neck axilla groin/hepatosplenomegaly This man had only had 1 previous blood test - Lymphocytes had been 6 x10 9 /L in 2013.

Request a film on the FU film If no symptoms suggest do FU film at 6 weeks but instruct to return sooner if symptoms. Film may show large activated lymphocytes as per a viral infection May show smear cells occur in Chronic Lymphocytic Leukaemia but are non-specific The lab may see other significant abnormalities

What do you not want to miss? Common things are common most mild lymphocytosis=either viral or early CLL However diagnoses not to miss e.g. a Mantle Cell Lymphoma Therefore need surface markers (SM) -Can ask for surface markers please if lymphocytes still raised Costs around $400 so do it once only do NOT need repeating

Frequent result- Clonal B-Cell Lymphocytosis The phenotype is that of Chronic Lymphocytic Leukaemia. However, the clone of abnormal cells is less than 5x 10 9 /L, so unless there is a palpable spleen, or lymph nodes, it doesn t meet the full clinical criteria of Chronic Lymphocytic Leukaemia and would fall in to the category of Clonal B-Cell Lymphocytosis. Unless there are clinical features to indicate otherwise, only infrequent follow up is indicated. (Monoclonal B-Cell Lymphocytosis. Rawstron et al, NEJM 2008;359;6). See also Health Pathways

Clonal lymphocytosis of unknown significance (CLUS) Low level, subclinical "disease" <5 x1010 9 /l with classical Chronic Lymphocytic Leukaemia markers on immunophenotyping Present in 3.5% of normal adults - up to 8% of individuals over the age of 70 13% have 1st degree relatives with CLL Analogous to MGUS- unclear as to what % will progress: Appears to lead to mild disease

Again clinical history and examination all important MUST ask about night sweats/wt. loss/infections at EACH visit and tell them to report these MUST look for LN/L/S at EACH visit If no red flags, yearly or even 2 yearly follow up is appropriate No need to repeat SM when the increase in lymphocytes makes the diagnosis officially CLL

CLL In CLL, the height of the white count unimportant Indication to refer: Hb or platelet count dropping out of the normal range Development of splenomegaly Significant LNs

Summary of take home points Have a simple schema for anaemais Importance of reticulocyte count and blood film in sorting out anaemias If a patient has a even a low level of paraprotein with bone pain, think of plasmacytoma The RATE of change for immunoglobulins/sflc is important Bence Jones Protein = obsolete In a patient with a CLUS you don t need to repeat the surface markers when the count increases