Polycytemia Vera, Essential Thrombocythemia and Myelofibrosis: prognosis and treatment BHS Training course 2013-2015 Timothy Devos
POLYCYTEMIA VERA
PV: clinical manifestations thrombosis (art > ven) facial plethora, pruritus (aquagenic) (40%), constitutional Σpt abdominal discomfort (splenomegaly) microvascular disturbances: headaches, erythromelalgia hyperviscosity: dizziness, visual disturbances, headaches Landolfi et al. Leukemia 2008
PV: complications thrombosis can be life-threatening risk factors (known): advanced age ( > 60 yr) history of thrombosis smoking and other cardiovascular risk factors risk factors (more recent): leukocytosis (Landolfi et al. Blood 2007) n = 1638 (ECLAP); followed for 2.7 yr; 205 thromboses in 169 patients multivariate analysis: WBC > 15000/µl significantly associated with vascular risk mainly a risk of myocardial infarction lack of correlation between platelet number and thrombosis!
PV: complications leukemic transformation (incidence 5-15% over 10 yr) development of PPV myelofibrosis (PPV-MF)
PV: complications risk factors (still under debate ): V617F JAK2 allele burden (Passamonti et al. Leukemia 2010) n = 338; prospective study allele burden > 50% significantly related to the risk of developing myelofibrosis (p=0.029) the risk of developing thrombosis or AML NOT significantly related to allele burden!
PV: risk stratification Low risk - age below 60 years - no history of trombosis - absence of cardiovascular risk factors (DM, smoking, cholesterol, AHT ao.) High risk - age 60 years or older - history of thrombosis
PV: management Low risk - flebotomy - low dose ASA (75-100 mg/d if no contra indication) - manage CV risk factors aggressively High risk - flebotomy - low dose ASA (75-100 mg if no C-I) - cytoreductive therapy (HU of IFNα) - manage CV risk factors aggressively target Hct < 0.45
PV: cytoreductive medication HYDROXUREA (HU): antimetabolite, DNA synthesis through inhibition of ribonucleoside reductase starting dose 15-20 mg/kg/d target hct < 45 % (additional flebotomy if necessary) female patients on HU: avoid pregancies.
PV: cytoreductive medication HYDROXUREA (HU): side effects leukopenia en macrocytic anemia drug fever mucocutaneous ulcerations cutaneous leg ulcers hyperpigmentation skin and nails
PV: cytoreductive medication INTERFERON α (IFNα) Silver et al. 1993 dose: 3 x 3 10 6 U / week; PEG-IFN: 0.5 µg à 1.0/kg/week overall response: 50% reduction hct < 0,45 77% reduction spleen volume 75% reduction itching contra-indications thyroid or psychological disturbances side effects +++ 1/3 of the patients interrupts treatment indications IFNα selected patient groups young patients (< 40 yr) pregnancy untreatable pruritus hydroxurea intolerance
- other therapies - busulfan (> 65 yr) (chlorambucil) ( 32 P radiophosporus) (pipobroman)
PV and JAK inhibitors Vannucchi et al. EHA 2014.
Vannucchi et al. EHA 2014.
ESSENTIAL THROMBOCYTHEMIA
ET: clinical symptoms - mostly asymptomatic - 10 15 %: thrombosis (art > ven) - microcirculatory disturbances: headache, dizziness, distal paresthesias, acrocyanosis, erythromelalgia - bleedings (cave: BP > 1500000/µl) - itching (15 40 %)
ET: risk factors for thrombosis known: age > 60 years history of thrombosis cardiovascular risk factors (important in high risk ET-patients: manage them aggressively!) presence of thrombophilic conditions (but: no reason to screen the patients!) novel markers / risk factors: leukocytosis MPL W515 mutation (rare in ET) no conclusive data JAK2 V617F higher thrombosis risk if JAK2 V617F + CALR lower thrombosis risk if CALR +
Passamonti et al. Best Practice and Research Clinical Hematology 2014.
ET: risk stratification Low risk Intermediate risk - younger < 60 yr - no history of thrombosis - BP < 1500000/µl - no clear cut definition (not low, not high) - operational definition : low risk patients with one or more of the following risk factors: CV disease, diabetes, smoking, hypertension, familial thrombophilia, ea. High risk - older > 60 yr - history of thrombo-embolic event(s) - BP > 1500000/µl
ET: management Low risk low dose ASA (if no contraindication) Intermediate risk low dose ASA treat C-V risk factors aggressively in some patients: BP reduction (decision on individual base) High risk low dose ASA reduce BP to < 400000/µl treat C-V risk factors
IPSET thrombosis score Risk group numer risk factors (points) Thrombosis free survival (TFS) Low (41%) 0-1 87% (after 15 yr) Intermediate (47%) 2 first 10 yr as low risk; next 5 yr as high risk High (12%) 3-6 50% (after 7 yr) Risk factors: age > 60 yr: 1 point (< 60 yr: 0 points) CV risk factors: YES 1 point (no 0 points) history thrombo-embolic events : YES 2 points (no: 0 points) JAK2 V617F mutation: present 2 points (absent: 0 points) Barbui et al. Blood 2012
ET: cytoreductive medication HYDROXUREA IFN α reserved for young females or contra-indication for anagrelide ANAGRELIDE (Xagrid ) - inhibits cyclic AMP phosphodiesterase III - selective inhibitory effect on the megakaryocytic cell line - effective reduction of BP overall response (76-94%) Harrison et al. NEJM 2005
ET: cytoreductive medication ANAGRELIDE : side effects headache (13-35 %) palpitations / tachycardia (9-21 %) increasing cardiac insufficiency ANAGRELIDE : indications HU resistance HU intolerance HU contra-indication Birgegård G. Ann Hematol 2008
ET and pregnancy 50 70 % ET patients succesfull pregnancy pregnancy loss during first trimester 25 40 % estimation of risk: treatment: high risk: history of major thrombosis or bleeding, history of serious pregnancy complications, BP > 1500000/µl, hereditary thrombophilia factors Low risk - low dose ASA (50-100 mg/d) - LMWH 4000 U/d after delivery until 6 weeks postpartum High risk - LMWH during the entire pregnancy (exception: (previous) bleeding complications!) - IFN-α if BP > 1500000/µl, previous bleeding complications
MYELOFIBROSIS
Prognostic score (IPSS PMF) Risk group number of risk factors median survival (years) Low 0 11,3 Intermediate 1 1 7,9 Intermediate 2 2 4 High 3 2,3 Risk factors: age > 65 yr Hb < 10 g/dl WBC > 25000/µl peripheral blasts 1 % consitutional Σpt (weight loss > 10 %, night sweats, unexplained fever) Cervantes et al. Blood 2009
- prognostic scoring - Dynamic IPSS (DIPSS) (Passamonti, Blood 2010) same 5 prognostic variables as IPSS, but anemia = 2 points for use at any time during the disease course (not only at diagnosis) DIPSS-plus (Gangat JCO 2011) 3 additional (D)IPSS independent risk factors o red cell transfusion need o BP < 100000/µl o unfavorable karyotype: complex karyotype, trisomy 8, monosomy 7, 12p-, 11q23 rearrangement, inv(3), -5/5q
- myelofibrosis: treatment - natural evolution of PMF: slowly, over several years if blast phase acceleration phase: very bad prognosis AML < PMF median survival 2.6 months (Mesa et al, Cancer 2006) risk-adapted therapy in myelofibrosis!
Myelofibrosis: risk adjusted treatment 1) Curative treatment: allogeneic stem cell transplantation - intermediate-2 - high risk - blast-phase MF eligibility for Tx also based on: - age - co-morbidities - patient s preference blast-phase MF or fit patients < 45 yrs considered for MAC 45-65 yr RIC (older patients sibling donor needed) T. Devos et al. Belg J Hematol 2013; 4: 127
allogeneic stem cell transplantation (2) prognosis ~ transplantation risk transplant related mortality (TRM) at 1 yr: 16 43 % overall survival (OS) at 5 yr: 35-50% disease free survival (DFS) at 5 yr: 33 % if sibling donor, 27 % if MUD Ballen K, Blood Cancer Journal 2012
Myelofibrosis: risk adjusted treatment 2) conventional therapies: supportive (not curative, no survival benefit) - hydroxurea non-lasting effect on splenomegaly and constitutional symptoms - transfusions - ESA: if low endogenous EPO levels (symptomatic anemia) - androgens or danazol: response rate 30% - lenalidomide: - first choice for (few) MF patients with isolated 5q - can be combined with prednisone - RR: anemia 22%, thrombocytopenia 50%, splenomegaly 33% - side effect: myelosuppression - thalidomide: - with or without tapering doses of prednisone - side effect: PNP - splenic irradiation non-lasting effect on splenomegaly and constitutional symptoms T. Devos et al. Belg J Hematol 2013; 4: 127
Splenectomy indications: drug refractory splenomegaly (> 10 cm below left costal margin) severe discomfort pain (+77%) symptomatic portal hypertension (+ 40%) complications: perioperative mortality 6% morbidity rate 27% short term: bleeding, thrombosis, infections long term: thrombocytosis (HU!), leukocytosis, hepatomegaly (20%) Mesa et al, Cancer 2006 Mesa et al, Blood 2009
JAK inhibitors
COMFORT-II Study Design Randomized, open-label, multicenter phase III trial Patients were stratified based on baseline IPSS risk category Patients with PMF, PPV-MF, or PET-MF with 2 IPSS risk factors 1 N = 219 Randomize 2:1 INC424 (ruxolitinib) 15 or 20 mg oral BID n = 146 Best available therapy (BAT) n = 73 Ruxolitinib Crossover and Extension Phase Progression events that qualified for the crossover and extension phase: Splenectomy Progressive splenomegaly as defined by a 25% increase in spleen volume compared with the on-study nadir (including baseline) NEJM 2012 + courtesy Harrison C.
COMFORT-II Primary endpoint: Proportion of patients achieving 35% reduction in spleen volume from baseline (BL) at week 48 as measured by MRI (assessed at weeks 12, 24, 36, and 48) NEJM 2012
% With 35% spleen volume reduction Comfort II - primary endpoint 40 35 30 Ruxolitinib P <.001 25 20 15 28% BAT 10 5 0 % 0 Ruxolitinib Week 48 BAT Median time to response, 12.29 weeks NEJM 2012 + courtesy Harrison C.
Better Q of L and reduction of symptoms Worsening Improvement 9.5 Ruxolitinib (n = 69) BAT (n = 28) 6 4.8 3 0.4-1.9-6.3-8.2-12.3-12.8 15 10 5 0-5 -10-15 Mean change from baseline Appetite loss Insomnia Dyspnea Pain Fatigue Meaningful improvements were observed by week 8 and continued through week 48 NEJM 2012 + courtesy Harrison C.
Anemia and Thrombocytopenia Worst Lab Value on Study Grade 1 n (%) Grade 2 n (%) Grade 3 n (%) Grade 4 n (%) Hemoglobin Ruxolitinib (n = 146) 24 (16) 55 (38) 50 (34) 12 (8) BAT (n = 70) 16 (23) 28 (40) 15 (21) 7 (10) Platelet count Ruxolitinib (n = 146) 46 (32) 41 (28) 9 (6) 3 (2) BAT (n = 69) 11 (16) 4 (6) 3 (4) 2 (3) The majority of patients (63% ruxolitinib; 67% BAT) had grade 1/2 anemia at baseline In both arms, all patients who entered the study had grade 0-1 thrombocytopenia at baseline manageable with RUX dose reductions or brief interruptions only 1 patient discontinued RUX < thrombopenia, none < anemia
How can we improve JAK-TKI results? combination trials with different targets: overcome the problem of resistance reduce adverse events of JAK-TKI reduce the clone/s PI3K/mTOR inhibitors HDAC inhibitors Smo inhibitors (LDE225)
Myelofibrosis treatment algorithm Odenike O Hematology 2013;2013:545-552
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