財團法人台灣癌症臨床研究發展基金會
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
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)
•
•
complex karyotype
1 or 2 abnormalities that include +8,
7/7q, i(17q), inv(3), 5/5q 12p, or 11q23
rearrangement
•
•
•
Weight loss 10% of baseline in the year
Unexplained fever
Excessive sweats persisting for 1
month
The Dynamic International Prognostic Scoring System (DIPSS)
BLOOD, 31 MARCH 2011 VOLUME 117, NUMBER
Prognosis based on DIPSS
Overall Survival
16 35
78
Leukemia-free survival
185
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
Respons
e Rate
Duration
Erythropoiesisstimulation
Factor (DPO)
< 56%
1 year
Effect
Adverse Effect
Special
consideration
Drug-induced
exacerbation
of
splenomegaly
Symptomatic anemia,
not transfusion
dependent,
serum EPO<125
Corticosteroid 20%
(0.5mg/kg/d)
1 year
Androgen(flu
oxymesteron
e 10mg tid)
20%
1 year
Danazole(600
mg/d)
20%
1 year
Thalidomide(5 20%
0mg/d)
1 year
Anemia,
thrombocytopeni
a, and
splenomegaly
Peripheral
neuropathy
May add with
steroid
Lenalidomide( 20%
10mg/d)
1 year
Response in
Anemia and
splenomegaly
neutropenia or
thrombocytop
enia
Favored in Del(5q)
May add aspirin
Hydroxyurea
1 year
Splenomegaly
Myelosuppresion, Response lower in
xeroderma,
JAK2V617F(-)
mucocutaneous
ulcers
35%
hepatotoxicity
and virilizing
effects
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%,
intermedia
te:33%,
High:43%
CIC(conventio
nal-intensity)
44%
15%
41%
30%
RIC(reduced
intensity)
31%
46%
32%
35%
Allogeneic stem cell transplantation
Study
Case
Duprez score
Treatment related
mortality
5-y OS
3-year DFS
Ballen KK et al, 289 pts,
USA
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
100 pts
Patriarca et al, Low:10%
Italy
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 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
Primary myelofibrosis
Post-PV MF
Post-ET MF
IPSS ≧ 3 (int. 2 and high risk)
ECOG ≦ 3
Peripheral blast < 10%
plt > 100k
palpable splenomegaly(≥5 cm
below the left costal margin)
>18y/o
Primary myelofibrosis
Post-PV MF
Post-ET MF
IPSS ≧ 3 (int. 2 and high risk)
ECOG ≦ 3
Peripheral blast < 10%
plt > 100k
palpable splenomegaly(≥5 cm
below the left costal margin)
Study design
Double blind
Randomly assigned, 1:1 ratio
Ruxotinib/placebo
Crossover to Ruxotinib was
permitted if splenomegaly
worsening
Randomly assigned, 2:1 ratio
Ruxolitinib/ Best available therapy
The best available treatment group
may shift to Ruxotinib group if
spleen volume > 25%
Drop out criteria
Primary End
Leukemic transformation or splenic
irradiation
reduction of 35% or more in spleen
reduction of 35% or more in spleen
Result
COMFORT-I(n=309)
Spleen Size
Ruxolitinib: 41.9% at week 24
(reduction>35%) Placebo: 0.7% at week 24
Biomarkers
Ruxolitinib
JAK2V617F allele
burden
-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
13 deaths in Ruxolitinib(8.4%)
24 deaths in placebo(15.6%)
Hazard ratio: 0.50, p=0.04
COMFORT-II (n=219)
32% at week 24, 28% at week 48
0% at week 24, 0% at week 48
Reduction in CRP, IL-6, TNF-alpha
Increase in leptin, erythropoietin
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)
Spleen Size
COMFORT-I
COMFORT-II
COMFORT-I
COMFORT-II
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!
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!!