VS 洪英中 /R4 洪逸平 RUXOLINIB FOR MYELOFIBROSIS N Engl J Med 2012;366: N Engl J Med 2012;366: 財團法人台灣癌症臨床研究發展基金會

Myelofibrosis Epidemiology Mainly in middle aged and elder patients, the median age at presentation is 67 y/o Clinical Manifestation Constitutional symptoms Weight loss 10% of baseline in the year Unexplained fever Excessive sweats persisting for 1 month Splenomegaly Hepatomegaly Extramedullary hematopoiesis Thrombotic events Bone and joint involvement

Cause of Bone Marrow Fibrosis

Primary Myelofibrosis Major Criteria Atypical megakaryocytic hyperplasia, often accompanied by reticulin and/or collagen fibrosis or in the absence of fibrosis, megakaryocytic atypia and marrow hypercellularity with myeloid hyperplasia and erythroid hypoplasia Exclusion of WHO criteria for PV, CML, MDS, or other MPDs JAK2V617F mutation or other clonal marker or if no clonal marker, exclusion of marrow fibrosis secondary to inflammatory or other neoplastic disorders Minor Criteria Leukoerythroblastosis Elevated serum lactate dehydrogenase level Anemia Palpable splenomegaly

Pathogenesis of myelofibrosis

Somatic mutations in classic MPD including primary myelofibrosis, PV and ET

The Dynamic International Prognostic Scoring System (DIPSS) Weight loss 10% of baseline in the year Unexplained fever Excessive sweats persisting for 1 month BLOOD, 31 MARCH 2011 VOLUME 117, NUMBER complex karyotype 1 or 2 abnormalities that include +8, 7/7q, i(17q), inv(3), 5/5q 12p, or 11q23 rearrangement

Prognosis based on DIPSS Overall SurvivalLeukemia-free survival J Clin Oncol 29:

Treatment Option Low- or intermediate 1–risk disease Asymptomatic: Watch and Wait Symptomatic: Conventional drug therapy is indicated Intermediate 2– or high-risk disease Conventional drug therapy Splenectomy Radiotherapy Allo-SCT Experimental drug therapy

DrugRespons e Rate DurationEffectAdverse EffectSpecial consideration Erythropoiesis- stimulation Factor (DPO) < 56%1 yearDrug-induced exacerbation of splenomegaly Symptomatic anemia, not transfusion dependent, serum EPO<125 Corticosteroid (0.5mg/kg/d) 20%1 year Androgen(flu oxymesteron e 10mg tid) 20%1 yearhepatotoxicity and virilizing effects Danazole(600 mg/d) 20%1 year Thalidomide(5 0mg/d) 20%1 yearAnemia, thrombocytopeni a, and splenomegaly Peripheral neuropathy May add with steroid Lenalidomide( 10mg/d) 20%1 yearResponse in Anemia and splenomegaly neutropenia or thrombocytop enia Favored in Del(5q) May add aspirin Hydroxyurea35%1 yearSplenomegaly Myelosuppresion, xeroderma, mucocutaneous ulcers Response lower in JAK2V617F(-)

Splenectomy Indication: drug-refractory symptomatic splenomegaly severe discomfort or pain, frequent red blood cell transfusions, severe thrombocytopenia, symptomatic portal hypertension, profound cachexia Response rate: >50% Duration: 1 year Perioperative mortality rate: 5-10%, Morbidity rate: 25% Leukemia transformation: Indeterminate

Radiotherapy Indication: non–hepatosplenic EMH, vertebral column (spinal cord compression), lymph nodes (lymphadenopathy), pleura (pleural effusion), peritoneum (ascites), skin(cutaneous nodules)  low-dose radiotherapy ( cGy in 5-10 fractions). pulmonary hypertension  single-fraction (100 cGy) whole-lung irradiation lower or upper extremity pain  Single fraction of cGy

Allogeneic stem cell transplantation The only treatment option in MF that is capable of inducing complete hematologic, cytogenetic, and molecular remissions. StudyCase Duprez score Regimen3-y OSRecurrence rate Non-relapse mortality rate Extensive GVHD Stewart WA et al in UK 51 pts, low:24%, intermedia te:33%, High:43% CIC(conventio nal-intensity) 44%15%41%30% RIC(reduced intensity) 31%46%32%35%

Allogeneic stem cell transplantation StudyCase Duprez score Treatment related mortality 5-y OS3-year DFS Ballen KK et al, USA 289 pts, Low:32% Intermediate: 36% High: 31% 1 year:27% 5 year:35% 37%39% 1 year:43% 5 year:50% (unrelated donor) 30%17% Francesca Patriarca et al, Italy 100 pts Low:10% Int.:58% High:32% 1 year:35% 3 year:43% 31%35%

Myelofibrosis Treatment Algorithm BLOOD, 31 MARCH 2011 VOLUME 117, NUMBER 13

JAK inhibitors in Clinical Trial

Putative Mechanisms of Disease and Drug Action of JAK Inhibitors in Myelofibrosis

Ruxolitinib (INCB018424) Potent inhibitor of JAK1 and JAK2 Had durable reduction in splenomegaly and improve myelofibrosis related symptom Related Trial: the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment I(COMFORT-I) the Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment II (COMFORT-II)

Compare the current 2 trial in NEJM COMFORT-I (n=309)COMFORT-II (n=219) InitiaterSrdan Verstovsek et al in the USClaire Harrison et al in the UK Inclusion criteria>18y/o Primary myelofibrosis Post-PV MF Post-ET MF IPSS ≧ 3 (int. 2 and high risk) ECOG ≦ 3 Peripheral blast < 10% plt > 100k palpable splenomegaly(≥5 cm below the left costal margin) >18y/o Primary myelofibrosis Post-PV MF Post-ET MF IPSS ≧ 3 (int. 2 and high risk) ECOG ≦ 3 Peripheral blast < 10% plt > 100k palpable splenomegaly(≥5 cm below the left costal margin) Study designDouble blind Randomly assigned, 1:1 ratio Ruxotinib/placebo Crossover to Ruxotinib was permitted if splenomegaly worsening Randomly assigned, 2:1 ratio Ruxolitinib/ Best available therapy The best available treatment group may shift to Ruxotinib group if spleen volume > 25% Drop out criteriaLeukemic transformation or splenic irradiation Primary End Point reduction of 35% or more in spleen volume

Result COMFORT-I(n=309)COMFORT-II (n=219) Spleen Size (reduction>35%) Ruxolitinib: 41.9% at week 2432% at week 24, 28% at week 48 Placebo: 0.7% at week 240% at week 24, 0% at week 48 Biomarkers Ruxolitinib JAK2V617F allele burden -10.9% at week % at week 48 Reduction in CRP, TNF-alpha, IL-6 Increase in leptin, erythropoietin Reduction in CRP, IL-6, TNF-alpha Increase in leptin, erythropoietin Placebo JAK2V617F allele burden 3.5% at week % at week 48 Overall SurvivalAt median F/u 51 weeks 13 deaths in Ruxolitinib(8.4%) 24 deaths in placebo(15.6%) Hazard ratio: 0.50, p=0.04 At 12 months f/u 6 deaths in Ruxoliinib (4%) 4 deaths in best.. Group (5%) Hazard ratio: 0.7 (95% CI )

Spleen Size COMFORT-I COMFORT-II

COMFORT-I COMFORT-II

Overall Survival At 12 months f/u 6 deaths in Ruxoliinib (4%) 4 deaths in best.. Group (5%) Hazard ratio: 0.7 (95% CI ) No survival benefit! COMFORT-I COMFORT-II

Side Effect

Discussion Ruxolitinib resulted in a rapid reduction of splenomegaly, which was observed at week 8 and continued through week 48 Ruxolitinib also resulted in change of cytokine levels Ruxolitinib was associated with increased frequencies of anemia and thrombocytopenia Response rate was higher in JAK2 V617F positive group (33%:14%) The minimal benefit to survival in COMFORT-II may be due to 25% patient in the best available treatment group crossover to Ruxolitinib group and 12% withdrawn consent. However, OS benefit is noted in COMFORT-I

Take Home Message Myelofibrosis is a disease of bone marrow fibrosis, manifested as splenomegaly, fatigue, extramedullary hematopoiesis, and thrombotic events Treatment includes: Conventional drugs, Splenectomy Radiotherapy Allo-SCT New drugs Ruxolitinib is a JAK1 and JAK2 inhibitor Ruxolitinib is effective on reduction of spleen size, improve the symptoms and quality of life, however OS indeterminate

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