The Complete FRCPath Course Myeloproliferative disorders Dr Joanne Ewing September 2014 Take-home messages • Diagnosis (WHO 2008 vs BCSH) • Diagnostic issues • Implications of CAL-R mutation • Prognosis • Current management strategy for ET and PV • Implications of OHU resistance/intolerance Diagnosis JAK2 and CAL-reticulin BJH 2010 Erythrocytosis - causes Primary Secondary Congenital Congenital Oxygen-sensing pathway defects High O2 affinity Hb EPO receptor abnormalities Acquired Central Hypoxia eg. lung disease, smokers right-left shunt, sleep apnoea Acquired Polycythaemia Rubra Vera (via constitutively activated JAK2 signalling) Local hypoxia Renal artery stenosis Pathologic EPO production Tumours Exogenous EPO-driven Post renal transplant Both major criteria + 1 minor or A1 plus 2 minor BCSH Criteria for PV Major A1 High haematocrit (>52 men, >0.48 women) or RCM >25% above predicted A2 Presence of JAK2 mutation Both must be present JAK2 negative PRV Both major criteria + 1 minor or A1 plus 2 minor A1 A2 No JAK2 A3 No secondary cause Plus either A4 Palpable spleen A5 Acquired genetic abnormality (NOT BCR) Or two of... Plts>450, neuts>10 (>12.5 smoker), radiological splenomegaly, low EPO • • • • • Complications of the myeloproliferative neoplasms Thrombosis Progression to myelofibrosis AML Constitutional symptoms Side effects of medication – hydroxycarbamide Blood count during treatment of ET and risk of thrombosis/haemorrhage– lessons from PT1 Cyto-PV study PEGASYS study Ruxolitinib Response study and MAJIC trial Hydroxyurea resistant/intolerant patients • 166 ET patients followed 1986 -2009 assessed for response/ resistance to HU using ELN criteria (Barosi 2009) • 33 or 20% fulfilled the ELN criteria Patients with anaemia had worse prognosis 7/15 post ET MF Hernández-Boluda et al 2010 3077 Skin Toxicity of Hydroxyurea In Ph- Myeloproliferative Neoplasms: Incidence and Clinical Features Primary Response at Week 32 Primary Endpoint Individual Components of Primary Endpoint P < .0001 OR, 28.64 (95% CI, 4.50-1206) • 77% of patients randomized to ruxolitinib met at least 1 component of the primary endpoint SV, spleen volume. 70 Duration of Primary Response • Only 1 patient lost primary response 37.1 weeks after start of that response 100 80 Probability Ruxolitinib Censoring times 60 40 20 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 Time from initial response (weeks) At risk 23 23 23 22 22 21 18 15 14 14 14 10 10 10 6 Events 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 • 6 1 4 1 1 1 1 0 1 1 0 1 The probability of maintaining primary response for 1 year was 94% 71 Complete Hematologic Remission at Week 32 P = .0028b OR, 3.35 (95% CI, 1.43-8.35) n = 26 n = 10 • 88.5% of patients who achieved CHR had a durable response at Week 48 CHR is defined as Hct control, PLT count ≤ 400 × 109/L, and WBC count ≤ 10 × 109/L. b P-value, odds ratio and 95% CI were calculated using stratified exact Cochran-Mantel-Haenszel test by adjusting for the WBC/PLT status (abnormal vs normal) at baseline. WBC/PLT status was defined as abnormal if WBC count was > 15 × 109/L, and/or PLT count > 600 × 109/L. 72 Improvement in Symptoms (Week 32) Percentage of Patients with a ≥ 50% Improvement in MPN-SAF Symptom Score at Week 32a n= 74 81 MPN-SAF Total Symptom Score 74 71 80 Cytokine Symptom Cluster Tiredness Itching Muscle ache Night sweats Sweating while awake 80 63 71 Hyperviscosity Symptom Cluster Splenomegaly Symptom Cluster Headache Dizziness Skin redness Vision problems Ringing in ears Concentration problems Numbness/tingling in hands/feet Fullness/early satiety Abdominal discomfort a In patients with scores at both baseline and week 32. MPN-SAF, Myeloproliferative Neoplasm Symptom Assessment Form. 73
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