RUXOLINIB FOR MYELOFIBROSIS

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RUXOLINIB FOR MYELOFIBROSIS

  1. 1. RUXOLINIB FORMYELOFIBROSIS 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. 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. 3. Cause of Bone Marrow Fibrosis
  4. 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
  5. 5. Pathogenesis of myelofibrosis
  6. 6. Somatic mutations in classic MPD includingprimary myelofibrosis, PV and ET
  7. 7. Somatic mutations in classic MPD includingprimary myelofibrosis, PV and ET
  8. 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. 9. Prognosis based on DIPSSOverall Survival Leukemia-free survival 185 78 16 35 J Clin Oncol 29:392-397
  10. 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. 11. Drug Respons Duration Effect Adverse Effect Special e Rate considerationErythropoiesis- < 56% 1 year Drug-induced Symptomatic anemia,stimulation exacerbation not transfusionFactor (DPO) of dependent, serum EPO<125 splenomegalyCorticosteroid 20% 1 year(0.5mg/kg/d)Androgen(flu 20% 1 year hepatotoxicityoxymesteron and virilizinge 10mg tid) effectsDanazole(600 20% 1 yearmg/d)Thalidomide(5 20% 1 year Anemia, Peripheral May add with0mg/d) thrombocytopeni neuropathy steroid a, and splenomegalyLenalidomide( 20% 1 year Response in neutropenia or Favored in Del(5q)10mg/d) Anemia and thrombocytop May add aspirin splenomegaly eniaHydroxyurea 35% 1 year Splenomegaly Myelosuppresion, Response lower in xeroderma, JAK2V617F(-) mucocutaneous ulcers
  12. 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. 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. 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 rateStewart 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. 15. Allogeneic stem cell transplantationStudy Case Treatment related 5-y OS 3-year DFS Duprez score mortalityBallen 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. 16. Myelofibrosis Treatment Algorithm BLOOD, 31 MARCH 2011 VOLUME 117, NUMBER 13
  17. 17. JAK inhibitors in Clinical Trial
  18. 18. Putative Mechanisms of Disease and DrugAction of JAK Inhibitors in Myelofibrosis
  19. 19. 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)
  20. 20. 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 UKInclusion 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% worseningDrop out criteria Leukemic transformation or splenic irradiationPrimary End reduction of 35% or more in spleen reduction of 35% or more in spleen
  21. 21. 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 48Biomarkers 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 48Overall 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)
  22. 22. Spleen SizeCOMFORT-I COMFORT-II
  23. 23. COMFORT-I COMFORT-II
  24. 24. Overall SurvivalCOMFORT-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!
  25. 25. Side Effect
  26. 26. 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
  27. 27. 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
  28. 28. Thanks for Your Attention!!

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