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RUXOLINIB FOR MYELOFIBROSIS
- 1. RUXOLINIB FOR MYELOFIBROSIS N Engl J Med 2012;366:799-807 N Engl J Med 2012;366:787-98. VS洪英中/R4洪逸平
- 2. 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
- 3. Cause of Bone Marrow Fibrosis
- 4. 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
- 6. Somatic mutations in classic MPD including primary myelofibrosis, PV and ET
- 7. Somatic mutations in classic MPD including primary myelofibrosis, PV and ET
- 8. The Dynamic International Prognostic Scoring System (DIPSS) • Weight loss 10% of baseline in the year • complex karyotype • Unexplained fever • 1 or 2 abnormalities that include • Excessive sweats persisting for 1 +8, 7/7q, i(17q), inv(3), 5/5q 12p, or month 11q23 rearrangement The Dynamic International Prognostic Scoring System (DIPSS) BLOOD, 31 MARCH 2011 VOLUME 117, NUMBER
- 9. Prognosis based on DIPSS Overall Survival Leukemia-free survival 185 78 16 35 J Clin Oncol 29:392-397
- 10. 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
- 11. Drug Respons Duration Effect Adverse Effect Special e Rate consideration Erythropoiesis- < 56% 1 year Drug-induced Symptomatic anemia, stimulation exacerbation not transfusion Factor (DPO) of dependent, serum EPO<125 splenomegaly Corticosteroid 20% 1 year (0.5mg/kg/d) Androgen(flu 20% 1 year hepatotoxicity oxymesteron and virilizing e 10mg tid) effects Danazole(600 20% 1 year mg/d) Thalidomide(5 20% 1 year Anemia, Peripheral May add with 0mg/d) thrombocytopeni neuropathy steroid a, and splenomegaly Lenalidomide( 20% 1 year Response in neutropenia or Favored in Del(5q) 10mg/d) Anemia and thrombocytop May add aspirin splenomegaly enia Hydroxyurea 35% 1 year Splenomegaly Myelosuppresion, Response lower in xeroderma, JAK2V617F(-) mucocutaneous ulcers
- 12. 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
- 13. 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
- 14. Allogeneic stem cell transplantation • The only treatment option in MF that is capable of inducing complete hematologic, cytogenetic, and molecular remissions. Study Case Regimen 3-y OS Recurrence Non-relapse Extensive Duprez rate mortality GVHD score rate Stewart 51 pts, CIC(conventio 44% 15% 41% 30% WA et al low:24%, nal-intensity) in UK intermedia te:33%, High:43% RIC(reduced 31% 46% 32% 35% intensity)
- 15. Allogeneic stem cell transplantation Study Case Treatment related 5-y OS 3-year DFS Duprez score mortality Ballen KK et al, 289 pts, 1 year:27% 37% 39% USA Low:32% 5 year:35% Intermediate: 36% High: 31% 1 year:43% 30% 17% 5 year:50% (unrelated donor) Francesca 100 pts 1 year:35% 31% 35% Patriarca et al, Low:10% 3 year:43% Italy Int.:58% High:32%
- 16. Myelofibrosis Treatment Algorithm BLOOD, 31 MARCH 2011 VOLUME 117, NUMBER 13
- 17. JAK inhibitors in Clinical Trial
- 19. Putative Mechanisms of Disease and Drug Action of JAK Inhibitors in Myelofibrosis
- 20. 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)
- 21. Compare the current 2 trial in NEJM COMFORT-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/o >18y/o Primary myelofibrosis Primary myelofibrosis Post-PV MF Post-PV MF Post-ET MF Post-ET MF IPSS ≧ 3 (int. 2 and high risk) IPSS ≧ 3 (int. 2 and high risk) ECOG ≦ 3 ECOG ≦ 3 Peripheral blast < 10% Peripheral blast < 10% plt > 100k plt > 100k palpable splenomegaly(≥5 cm palpable splenomegaly(≥5 cm below the left costal margin) below the left costal margin) Study design Double blind Randomly assigned, 2:1 ratio Randomly assigned, 1:1 ratio Ruxolitinib/ Best available therapy Ruxotinib/placebo The best available treatment group Crossover to Ruxotinib was may shift to Ruxotinib group if permitted if splenomegaly spleen volume > 25% worsening Drop out criteria Leukemic transformation or splenic irradiation Primary End reduction of 35% or more in spleen reduction of 35% or more in spleen
- 22. Result COMFORT-I(n=309) COMFORT-II (n=219) Spleen Size Ruxolitinib: 41.9% at week 24 32% at week 24, 28% at week 48 (reduction>35%) Placebo: 0.7% at week 24 0% at week 24, 0% at week 48 Biomarkers Ruxolitinib JAK2V617F allele Reduction in CRP, IL-6, TNF-alpha burden Increase in leptin, erythropoietin -10.9% at week 24 -21.5% at week 48 Reduction in CRP, TNF-alpha, IL-6 Increase in leptin, erythropoietin Placebo JAK2V617F allele burden 3.5% at week 24 6.3% at week 48 Overall Survival At median F/u 51 weeks At 12 months f/u 13 deaths in Ruxolitinib(8.4%) 6 deaths in Ruxoliinib (4%) 24 deaths in placebo(15.6%) 4 deaths in best.. Group (5%) Hazard ratio: 0.50, p=0.04 Hazard ratio: 0.7 (95% CI 0.20-2.49)
- 23. Spleen Size COMFORT-I COMFORT-II
- 24. COMFORT-I COMFORT-II
- 25. Overall Survival COMFORT-I COMFORT-II • 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!
- 26. Side Effect
- 27. 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
- 28. 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
- 29. Thanks for Your Attention!!