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財團法人台灣癌症臨床研究發展基金會. Ruxolinib for Myelofibrosis. VS 洪英中 /R4 洪逸平. N Engl J Med 2012;366:799-807. N Engl J Med 2012;366:787-98. Myelofibrosis. Epidemiology Mainly in middle aged and elder patients, the median age at presentation is 67 y/o Clinical Manifestation Constitutional symptoms - PowerPoint PPT Presentation
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VS洪英中 /R4洪逸平
RUXOLINIB FOR MYELOFIBROSIS
N Engl J Med 2012;366:799-807N Engl J Med 2012;366:787-98.
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
Somatic mutations in classic MPD including primary myelofibrosis, PV and ET
The Dynamic International Prognostic Scoring System (DIPSS)
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 DIPSSOverall Survival Leukemia-free survival
185783516
J Clin Oncol 29:392-397
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
Drug Response Rate
Duration
Effect Adverse Effect
Special consideration
Erythropoiesis-stimulation Factor (DPO)
< 56% 1 year Drug-induced exacerbation of splenomegaly
Symptomatic anemia, not transfusion dependent, serum EPO<125
Corticosteroid(0.5mg/kg/d)
20% 1 year
Androgen(fluoxymesterone 10mg tid)
20% 1 year hepatotoxicity and virilizing effects
Danazole(600mg/d)
20% 1 year
Thalidomide(50mg/d)
20% 1 year Anemia, thrombocytopenia, and splenomegaly
Peripheral neuropathy
May add with steroid
Lenalidomide(10mg/d)
20% 1 year Response in Anemia and splenomegaly
neutropenia or thrombocytopenia
Favored in Del(5q)May add aspirin
Hydroxyurea
35% 1 year Splenomegaly 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 (100-500 cGy in 5-10 fractions).• pulmonary hypertension
single-fraction (100 cGy) whole-lung irradiation• lower or upper extremity pain
Single fraction of 100-400 cGy
Allogeneic stem cell transplantation• The only treatment option in MF that is capable of inducing complete hematologic, cytogenetic, and molecular remissions.Study Case
Duprez score
Regimen 3-y OS
Recurrence rate
Non-relapse mortality rate
Extensive GVHD
Stewart WA et al in UK
51 pts,low:24%, intermediate:33%, High:43%
CIC(conventional-intensity)
44% 15% 41% 30%
RIC(reduced intensity)
31% 46% 32% 35%
Allogeneic stem cell transplantation
Study CaseDuprez score
Treatment related mortality
5-y OS 3-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 ptsLow: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 NEJMCOMFORT-I (n=309) COMFORT-II (n=219)
Initiater Srdan Verstovsek et al in the US
Claire Harrison et al in the UK
Inclusion criteria
>18y/oPrimary myelofibrosisPost-PV MFPost-ET MFIPSS ≧ 3 (int. 2 and high risk)ECOG ≦ 3Peripheral blast < 10%plt > 100kpalpable splenomegaly(≥5 cm below the left costal margin)
>18y/oPrimary myelofibrosisPost-PV MFPost-ET MFIPSS ≧ 3 (int. 2 and high risk)ECOG ≦ 3Peripheral blast < 10%plt > 100kpalpable splenomegaly(≥5 cm below the left costal margin)
Study design Double blindRandomly assigned, 1:1 ratioRuxotinib/placeboCrossover to Ruxotinib was permitted if splenomegaly worsening
Randomly assigned, 2:1 ratioRuxolitinib/ Best available therapyThe best available treatment group may shift to Ruxotinib group if spleen volume > 25%
Drop out criteria
Leukemic transformation or splenic irradiation
Primary End Point
reduction of 35% or more in spleen volume
reduction of 35% or more in spleen volume
ResultCOMFORT-I(n=309) COMFORT-II (n=219)
Spleen Size (reduction>35%)
Ruxolitinib: 41.9% at week 24
32% at week 24, 28% at week 48
Placebo: 0.7% at week 24 0% at week 24, 0% at week 48
Biomarkers Ruxolitinib
JAK2V617F allele burden-10.9% at week 24 -21.5% at week 48Reduction in CRP, TNF-alpha, IL-6Increase in leptin, erythropoietin
Reduction in CRP, IL-6, TNF-alphaIncrease in leptin, erythropoietin
Placebo JAK2V617F allele burden3.5% at week 24 6.3% at week 48
Overall Survival
At median F/u 51 weeks13 deaths in Ruxolitinib(8.4%)24 deaths in placebo(15.6%)Hazard ratio: 0.50, p=0.04
At 12 months f/u6 deaths in Ruxoliinib (4%)4 deaths in best.. Group (5%)Hazard ratio: 0.7 (95% CI 0.20-2.49)
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 0.20-2.49)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
Thanks for Your Attention!!