Ruxolitinib is an oral JAK1 and JAK2 inhibitor that has shown efficacy in reducing splenomegaly and improving symptoms in patients with myelofibrosis based on two phase 3 clinical trials. In COMFORT-I, ruxolitinib resulted in >35% spleen reduction in 42% of patients at week 24 versus 1% on placebo and improved survival. In COMFORT-II, 32% had >35% spleen reduction at week 24 with ruxolitinib versus 0% with best available treatment. While ruxolitinib improved spleen size and symptoms, it did not provide a clear survival benefit in COMFORT-II likely due to
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
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
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
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%
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)
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
