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Ruxolinib for Myelofibrosis

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

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Ruxolinib for Myelofibrosis

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  1. 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.

  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

  5. Pathogenesis of myelofibrosis

  6. Somatic mutations in classic MPD including primary myelofibrosis, PV andET

  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 • Unexplained fever • Excessive sweats persisting for 1 month • complex karyotype • 1 or 2 abnormalities that include +8, 7/7q, i(17q), inv(3), 5/5q 12p, or 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 35 16 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. 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

  12. 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

  13. Allogeneic stem cell transplantation • The only treatment option in MF that is capable of inducing complete hematologic, cytogenetic, and molecular remissions.

  14. Allogeneic stem cell transplantation

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

  16. JAK inhibitors in Clinical Trial

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

  18. 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)

  19. Compare the current 2 trial in NEJM

  20. Result

  21. Spleen Size COMFORT-I COMFORT-II

  22. COMFORT-II COMFORT-I

  23. 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!

  24. Side Effect

  25. 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

  26. 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

  27. Thanks for Your Attention!!

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