VS洪英中 /R4洪逸平

RUXOLINIB FOR MYELOFIBROSIS

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• 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

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• 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 hypertensionsingle-fraction (100 cGy) whole-lung irradiation

• lower or upper extremity painSingle 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

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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!!