CML and myeloproliferative disorders Flashcards

Question

What is primary myelofibrosis (PMF)?

Answer 1

A clonal myeloproliferative disease with proliferation mainly of megakaryocytes and granulocytic cells, associated with reactive bone marrow fibrosis and extramedullary haematopoieisis

Answer 2

Incidence 0.5-1.5 /100000 Males=females 7th decade. Less common in younger patients Secondary to other haematological disease: progression from PV or ET

Answer 3

Incidental in 30% 1. Blood: Cytopenias (anaemia/ thrombocytopenia) Thrombocytosis 2. Organ: Massive Splenomegaly [Budd Chiari] Hepatomegaly 3. Metabolism: Hypermetabolic state (wt loss, fatigue, SOB, night sweats, hyperuricaemia)

Answer 4

Prefibrotic | Fibrotic

Answer 5

Blood changes mild but may also be confused with ET Hypercellular marrow

Answer 6

Splenomegaly and blood changes Dry tap Prominent collagen fibrosis Later Osteosclerosis

Answer 7

Severe anaemia <10g/dL Thrombocytopenia <100x109/l Massive splenomegaly Prognostic scoring system (DIPPS) Score 0 -- median survival 15years Score 4-6– median survival 1.3 years

Answer 8

Transfusions (for anaemia) Plt transfusions (but often ineffective) Splenectomy for symptomatic relief (but hazardous and worsens symptoms) Cytoreductive therapy: hydroxycarbamide for thrombocytosis, may lead to worsening of anaemia Ruxolotinib JAK2 inhibitor (high prognostic score) Bone marrow transplant in young patients may be curative (experimental)

Answer 9

M:F 1.4:1 | 40-60 years

Answer 10

* Weight loss, lethargy, night sweats * Splenomegaly * Features of anaemia * Bruising/bleeding * Gout

Answer 11

History Lethargy/ hypermetabolism/ thrombotic event : monocular blindness CVA Exam Massive splenomegaly +/- hepatomegaly

Answer 12

FBC Hb and platelets well preserved or raised Massive leucocytosis 50-200x109/L Blood film Neutrophils and some myelocytes (not blasts if chronic phase) Basophilia

Answer 13

Mature myeloid cells Bi phasic peak Neutrophils and myelocytes No excess (<5%) myeloblasts Platelet count raised/upper normal Basophils Leucocytosis between 50 – 500x109/l

Answer 14

-approximately 80% of patients with CML are diagnosed in the chronic-phase -can last from a few months to about 4-5 years -nearly 80% of patients with CML will progress from the chronic-phase to the accelerated-phase -5% or fewer of the cells in the blood and bone marrow are blast cells Median 5–6 years stabilisation

Answer 15

10-19% of the cells in the blood and bone marrow are blast cells Median duration6–12 months

Answer 16

≥20% of the cells in the blood and bone marrow are blast cells Median survival3–6 months

Answer 17

t(9;22) - BCR-ABL (210 kD protein made) Fusion oncoprotein with tyrosine kinase activity

Answer 18

FBC and measure leucocyte count Cytogenetics and detection of Philadelphia chromosome RT-PCR of BCR-ABL fusion transcript which can be quantified by RQ-PCR to determine response to therapy

Answer 19

Disease detectable: BCR-ABL / ABL (%) Disease undetectable: negative / [no. of ABL transcripts]

Answer 20

FBC Restored to normal FBC Cytogenetics Reduction in percentage of Ph metaphases RT-PCR Log reduction in BCR-ABL : ABL ratio

Answer 21

Haematological response Complete Haematological Response WBC<10x109/l ``` Cytogenetic response (on 20 metaphases) Partial 1-35% Philadelphia positive Complete 0% Ph positive ``` Molecular ( reduction in % BCR-ABL transcripts) BCR-ABL transcripts reduce 100% > 10% > 1% > 0.1% Major Molecular response (MMR) <0.1% (3 log reduction)

Answer 22

Oral active ABL kinase Inhibitor (TKIs) 1st Generation Imatinib (Glivec) 2nd generation Dasatanib, and Nilotinib

Answer 23

Pathogenesis is an activated Tyrosine Kinase cABL in CML

Answer 24

``` Poor response: > Failure to achieve CCyR > Loss of MMR > Acquiring abl point mutations leading to resistance > Evolution to blast crisis ``` Non compliance Side effects; fluid retention pleural effusions

Answer 25

Average 95% 5 year survival Annual mortality 2% Commence on oral TKI 1st generation- Monitor response FBC, Cytogenetics, RQ-PCR CCyR at 12mo 97% FFP at 6 years (Fail to achieve CCyr 80%)

Answer 26

Switch to 2nd Generation TKI | Consider allogeneic Stem cell transplant

Answer 27

T1: Mutations in Tyrosine Kinase genes cause excess proliferation (no effect on differentiation) • BCR-ABL1 CML • JAK2 MPD T2: Mutations in nuclear transcription factors may block differentiation. If present along with a proliferation mutation can cause acute leukaemia • PML-RARA in acute promyelocytic leukaemia Mutations in apoptosis genes may occur in lymphomas • BCL2 and Follicular lymphoma

Answer 28

Imatinib/ TyrK inhibitor

Answer 29

Leucoerythroblastic picture Tear drop poikilocytes Giant platelets Circulating megakaryocytes

Answer 30

> Increased reticulin or collagen fibrosis > Prominent megakaryocyte hyperplasia and clustering with abnormalities > New bone formation

Answer 31

Extramedullary haemopoiesis in spleen and liver