HAEMATOLOGY PRESENTATION TZE YENG YEOH MBChB II (2003)

HAEMATOLOGY PRESENTATION

TZE YENG YEOH

MBChB II (2003)

CASE 1 -1

Mary, 31 year old lady.

Presented to her GP with non-tender lumps in her neck. Otherwise, feeling well.

Also feeling very fatigued.

What are your differential diagnoses?

CASE 1 -2GP commenced her on oral antibiotics for 3 months.

Lumps persisted.

In the meantime, bloods were done.

Bloods were found to be “abnormal”.

Hence, she was referred to the haematologists at MMH.

CASE 1 -3Hb: 132RCC: 4.33PCV: 0.38MCV: 87MCH: 30.5Plt: 307WCC: 19.8 ()Neut: 6.7Monocytes: 0.4Lymphocytes: 6.9 ()Smear cells: 5.7 ()Interpret the blood result. What do you think she has? What would you do now?

CASE 1 -4

CASE 1 -51. Bone marrow aspirate and trephine

confirmed CLL.2. Other tests done include:3. Ig levels - Normal4. Serum electrophoresis – Oligoclonal

banding pattern in the gamma region.5. -2 microglobulin - 2.2 (1.3-2.2)6. Cytogenetics – Loss of 17p13.17. CT scan of neck, chest, abdo and

pelvis – Extensive lymphadenopathy in neck (with marked compression of airway), axilla, para-aortic region and around external iliac vessels and in the inguinal region. Also, left lung infiltration and splenomegaly.

CASE 1 -6Commenced on fludarabine PO with co-trimoxazole. Taken for 4 months with no significant change in cervical lymphadenopathy.Had another CT scan which confirmed this.Had one episode of spontaneous bruising on abdomen and upper limbs. Also has frequent bleeding from gums.Had a bout of pneumonia recently. Recovered well with no complications.

CASE 1 -7

Treatment changed to prednisone and chlorambucil PO.

Again, no significant change in cervical lymphadenopathy.

Came to Day Stay to commence on IV chemotherapy. Unfortunately, she developed a significant neutropenia.

CLL

Accounts for 25% of leukaemias seen in clinical practice.

Usually occurs in the elderly ( 60 years), with a male proponderance.

Etiology is unknown but a familial tendency has rarely been observed.

CLL – PATHOLOGYIt is known as a lymphoproliferative disorder.Accumulation of small, morphologically mature lymphocytes in bone marrow, lymph nodes, peripheral blood, spleen and liver.These are usually monoclonal B cells.Slow accumulation due to immunological non-reactivity and impaired apoptosis, rather than increased proliferation per se.

CLL – CLINICAL FEATURES

Lymphocytosis on routine FBC.

Symmetrical lymphadenopathy. Discrete and non-tender.

Systemic symptoms.

Symptoms of anaemia.

Splenomegaly and/or hepatomegaly.

Infections. (Which infections commonly?)

Symptoms of thrombocytopoenia.

CLL – LAB FINDINGS -1

FBC WCC due to lymphocytosis. Presence of smear cells. Normochromic, normocytic anaemia. platelets.

Cell markers (from blood film or marrow)

- To confirm monoclonal B cells. How?

CLL – LAB FINDINGS -2

Bone marrow Lymphocytic infiltration: 25-95% of all

the cells.

Biochemistry Ig. Paraprotein (rarely). Hyperuricaemia.

CLL – STAGING -1

2 systems: Rai and Binet.

CLL - RAIStage Features Median

survival (months)

0 Lymphocytosis 15x109/L 150 +

I Lymphocytosis + lymphadenopathy 105

II Lymphocytosis + enlarged spleen and/or liver adenopathy

71

III Lymphocytosis + anaemia adenopathy organomegaly

19

IV Lymphocytosis + thrombocytopenia adenopathy organomegaly

19

CLL - BINET

Stage Organ enlargement

Hb (g/L) Platelets (x109/L)

A 0, 1 or 2 areas

B 3, 4 or 5 areas ≥ 100 ≥ 100

C Not considered

100 100

CLL - MANAGEMENT

Treat only if symptomatic, complications develop or disease is rapidly progressive.Aim is to control disease and not to cure.Treatment options include:

1. Prednisone2. Alkylating agents e.g. chlorambucil or

cylcophosphamide (first line)3. Fludarabine (need to give co-trimoxazole

prophylactically) (second line)4. Combination chemotherapy5. Radiotherapy

CLL - COMPLICATIONS

Bone marrow failure (pancytopenia)

Autoimmune haemolytic anaemia.(How do you diagnose this?)

Decreased immunoglobulins – infections.

ITP.

Splenomegaly.

Leukostasis. (rarely)

CLL - PROGNOSISIndolent condition usually. Most patients have a favourable prognosis. Unlike CML, CLL does not transform into an acute leukaemia. However, immunoblastic transformation may occur as a terminal lymphoma (Richter’s syndrome).Many elderly patients with CLL die with CLL rather than from it.Death from CLL usually caused by infection due to bone marrow failure and immune deficiency.

CLL – PROGNOSTIC MARKERS

Age – Young, good prognosis.Sex – Female, good prognosis.Stage – Early, good prognosis.Disease progression – Slow, good prognosis.Response to treatment – Resistant, bad.-2 microglobulin – High, bad prognosis.Cell markers – CD 38, bad prognosisCytogenetics – specific chromosomal mutations predict disease progression and median survival.

CASE 2 -1

A 69-year old lady presents with a 3-month history of fatigue and breathlessness.

Physical examination revealed splenomegaly.

Blood results are as follows:

CASE 2 -2Hb 9.0 g/dlMCV 90 flPlatelets 500 x 109/l Total WBC 200 x 109/lWhite cell differential countBlasts 3% Promyelocytes 6% Myelocytes 12% Metamyelocytes 6% Neutrophils 55% Eosinophils 4% Basophils 4% Lymphocytes 5% Monocytes 5% What do you think?

CASE 2 -3

CML - INTRODUCTION

Is a myeloproliferative disorder.Comprises 20% of all the leukaemias.Seen most frequently in middle aged people, but can occur at any age.M:F = 1.4:1No predisposing factors in most cases.3 cardinal features:

1. Splenomegaly2. Leucocytosis – myeloid series: with blasts

through to neutrophils3. Bcr-abl gene/Ph chromosome

CML – PATHOLOGY -1

Acquired abnormality of haematopoietic stem cells. Myeloid proliferation with expansion of normal marrow, splenomegaly and peripheral blood leucocytosis.Abnormality is due to reciprocal translocation between chromosomes 9 and 22.This leads to formation of a fusion or hybrid gene (bcr-abl), known as the Ph chromosome. (basis of the diagnostic test for CML)

CML – PATHOLOGY -2

This new gene codes for an active tyrosine kinase which continuously switches on the haemopoietic stem cell.The Ph chromosome is present in most haemopoietic cell lineages, i.e. RBCs, megakaryocytes, basophils, monocytes and B cells.About 5% of people with CML will lack the Ph chromosome. However, at a DNA, RNA and protein level, the molecular pathology with formation of the bcr-abl gene is still present.

CML – PATHOLOGY -3

Ph chormosome can also be found in some ALL and AML.

CML – CLINICAL FEATURES

20% asymptomatic.

Splenomegaly.

Hypermetabolism symptoms e.g. weight loss, lassitude, anorexia or night sweats.

Features of anaemia.

Features of abnormal platelet function.

Gout or renal impairment – hyperuricaemia.

Infections – usually when neutropoenic.

CML – LAB FINDINGS -1

FBC Leucocytosis with left shift. basophils. Platelets , normal or . Giant platelets. Normochromic, normocytic anaemia.

Bone marrow biopsy Hypercellular, with granulopoietic

predominance. Ph’ chromosome.

NAP score- Low.

CML – LAB FINDINGS -2

Cytogenetics In bone marrow and/or peripheral blood

(FISH) – bcr-abl gene/Ph chromosome.

Biochemistry serum B12 and B12-binding capacity. serum uric acid.

CML - PHASES

Chronic

Accelerated

Blast crisis – Transforming to acute leukaemia, usually AML.

CML – MANAGEMENT -1

Chronic phase Hydroxyurea – shorter action.

Requires frequent monitoring and continuous therapy.

-interferon – Low platelets, depression.

Cytosine arabinoside. Glivec (imatinib) – specific inhibitor of

abnormal tyrosine kinase. Less useful in blast crisis.

CML – MANAGEMENT -2

Allogenic BMT – Potential cure. Only for those ≤ 55 years and with a HLA-matched donor.

Accelerated phase and blast crisis

Harder to treat as patient becomes refractory to therapy.

CML - PROGNOSIS

Chronic phase – 5-6 years, if treated. Usually shows an excellent response to chemotherapy.Accelerated phase – Few months.Blast crisis – Few months.Rough guides to outcome include age, spleen size, platelet count, blast cell percentage on presentation & degree of response to therapy.Death is usually due to terminal acute transformation or from intercurrent haemorrhage or infection.