Overview of Myelofibrosis
연세대학교 의과대학 김 수 정
2008WHO classification of myeloid neoplasms
1. Acute myeloid leukemia
2. Myelodysplastic syndromes (MDS) 3. Myeloproliferative neoplasms (MPN)
3.1 Chronic myelogenous leukemia 3.2 Polycythemia vera
3.3 Essential thrombocythemia 3.4 Primary myelofibrosis
3.5 Chronic neutrophilic leukemia
3.6 Chronic eosinophilic leukemia, not otherwise categorized 3.7 Hypereosinophilic syndrome
3.8 Mast cell disease 3.9 MPNs, unclassifiable 4. MDS/MPN
4.1 Chronic myelomonocytic leukemia 4.2 Juvenile myelomonocytic leukemia 4.3 Atypical chronic myeloid leukemia 4.4 MDS/MPN, unclassifiable
5. Myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, FGFR1
5.1 Myeloid neoplasms associated with PDGFRA rearrangement 5.2 Myeloid neoplasms associated with PDGFRB rearrangement
5.3 Myeloid neoplasms associated with FGFR1 rearrangement (8p11 syndrome) Philadelphia negative classic MPN
Similarities Among Ph-Negative MPNs
• Predominant lineage undergoing proliferation
• Share similar clinical and laboratory findings
• Prevalent JAK2V617F mutation
• Hypersensitivity to many cytokines; TPO, EPO, GM-CSF, etc
• Overexpression of polycythemia rubra vera-1 (PRV-1) on granulocyt es
• Presence of endogenous erythroid colony formation
• Decreased expression of MPL receptor on platelets and mega
1. Smith CA, Fan G. The saga of JAK2 mutations and translocations in hematologic disorders: pathogenesis, diagnostic and therapeutic prospects, a nd revised World Health Organization diagnostic criteria for myeloproliferative neoplasms. Human Pathol. 2008;39:795-180.
2. Tefferi A, et al. Myeloproliferative neoplasms: contemporary diagnosis using histology and genetics. Nat Rev Clin Oncol. 2009;6:627-637.
Incidence of MPN
Disease Annual Incidence Prevalence CML 1-2/100,000 /yr
PV 0.2~2.8/100,000 /yr 22
ET 1-2.5/100,000 /yr 24
PMF 0.3-1.5/100,000 /yr 1.46
•Ma X, Vanasse G, Cartmel B, Wang Y, Selinger HA. Prevalence of polycythemia vera and essential thrombocythemia. Am J Hematol, 2008:83:359-62
•Mesa R, Silverstein M, Jacobson, Wollan P, Tefferi A. Population-based incidence and survival figures in essential
thrombocythemia and agnogenic myeloid metaplasia: an Olmsted county study, 1976-1995.Am J Hematol, 1999; 61:10-5
• Total of 65,243 patients with PV and 71,078 with ET in the United States in 2003, for a total of approximately 136,000 patients
5
Progression of MPN to other disease
1. Tefferi A. Am J Hematol. 2008;83:491-497.
2. Wolanskyj A. Mayo Clinic Proc. 2006;81:159-166.
3. Finazzi G. Blood. 2005;105(7):2664-2670.
4. Abdel-Wahab OI, Levine RL. Ann Rev Med. 2009;60:233-245.
5. Mesa RA, et al. Blood. 2005;105(3):973-977.
AML Polycythemia vera
Essential
thrombocythemia
Myelofibrosis
4% per 10 yr1 10% per 10 yr1
1.4% per 10 yr2 5%-21% per 10 yr3
2.9%-23%
per 10 yr1,4,5
Clinical Signs and Symptoms of PMF
• Anemia
• Splenomegaly or/and Hepatomegaly
• Megakaryocyte cluster formation
• Constitutional symptoms
• Fever
• Night sweats
• Weight loss
• Pruritus
• Fatigue
• Bone pain
• Spleen pain
Clinical Signs and Symptoms of PMF
• Anemia
Characteristics
• Median age at diagnosis is 67 years
• Median survival of approximately 5.7 years depends on risk factors – 2-year median survival in high-risk MF patients
• MF can result from progression of ET and PV – 10-year risk of post-ET MF is < 4%
– 10-year risk of post-PV MF is 10%
• 10-year risk of transformation to acute myeloid leukemia (AML) is 3.9%-23%
2008 WHO criteria of PMF
Megakaryocyte proliferation and atypia, typically accompanied by reticulin or collagen fibrosis
if significant reticulin fibrosis is not present, the megakaryocyte changes or must be associated with increased bone marrow cellularity distinguished by granulocytic proliferation and decreased erythropoiesis in some cases
Not meeting WHO criteria for PV, BCR-ABL1–positive CML, myelodysplastic syndrome, or other myeloid disorders
Increase in serum LDH level Palpable splenomegaly
Leukoerythroblastosis Anemia
Must meet 2/4
Minor Criteria
Must meet 3/3
Major Criteria
AND
Presence of JAK2 V617F mutation or other clonal marker such as MPL W515L/K (if no clonal markers present) the absence of bone marrow fibrosis secondary to infectioor
n, autoimmune disorder or other chronic inflammatory condition, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic myelopathies
Grading of fibrosis
• According to WHO-defined 4-point scoring system (0-3)1
Grade-0
Grade-2
Grade-1
Grade-3
Proposed IWG Diagnostic Criteria for Post-ET/PV MF
12
Required Criteria
Must meet 2
Additional Criteria
1. Previous diagnosis of ET meeting WHO criteria
and 2. Grade 2-3 bone marrow fibrosis (on 0-3 scale) or 3-4 (on 0-4 scale)
1. Previous diagnosis of PV meeting WHO criteria
and 2. Grade 2-3 bone marrow fibrosis (on 0-3 scale) or 3-4 (on 0-4 scale)
Anemia with a Hgb ≥ 2 g/dL decrea se from baseline
Leukoerythroblastic peripheral blo od picture
≥ 5-cm increase in palpable spleno megaly or appearance of new sple nomegaly
LDH increase
Development of more than 1 of 3 constitutional symptoms
Anemia or sustained loss of requir ement of cytoreductive treatment or phlebotomy
Leukoerythroblastic peripheral blo od picture
Development of more than 1 of 3 constitutional symptoms
≥ 5-cm increase in palpable spleno megaly or appearance of new sple nomegaly
Post-ET MF Post-PV MF
AND
Barosi G, et al. Leukemia. 2008;22:438-439.
Leukoerythroblastosis
• Presence of nucleated RBC, immature granulocyte,
dacryocyte (tear drop RBC) in perupheral blood
Janus kinase
• Just Another Kinase 1/2
• Janus kinase 1 & 2
V617F FERM domain
(Receptor interaction)
SH2-like domain
1. Wilks AF. Two putative protein-tyrosine kinases identified by application of the polymerase chain reaction. PNAS 1989;86(5):1603–7
FERM JH1
JH2
SH2
JAK kinase family
Kinase Interaction Expression
Janus Kinase
1 (JAK1) PTPN11, Glycoprotein 130, IL-10Ralpha, ELP2, STAT3, Grb2,
STAT5A, STAT5B, IL2RB, TNFRSF1A, IRS1, GNB2L1, STAM2 Ubiquitously on mammalian cells
Janus Kinase 2 (JAK2)
Growth hormone receptor, Protein arginine methyltransferase 5,STAT5A, STAT5B, IL-12RB2, PIK3R1, SH2B1, SHC1, TEC, SOCS3, PTPN11, PTPN6, IL-5Ra , Grb2, Epidermal growth factor receptor, PTK2, TNFRSF1A, Erythropoietin receptor, YES1, IRS1, DNAJA3, Signal transducing adaptor molecule, PPP2R4
Ubiquitously on mammalian cells
Janus Kinase
3 (JAK3) CD247, TIAF1, IL2RG Limited to
hematopoietic cells Tyrosine
Kinase 2
(TYK2) FYN, PTPN6, IFNAR1, Ku80, GNB2L1 Ubiquitously on
mammalian cells
Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 2010:24;1128–1138.
JAK-STAT pathway
Ref>
What would not be related to the survival of MF?
1. Age
2. Anemia
3. Patient’s symptom (fever, sweating, wt.
loss)
4. WBC count
5. All above
IPSS in MF
Cervantes F, et al. Blood. 2009;113(13):2895-2901.
Risk Factors at Presentation of PMF for death*
Risk Factor Frequency, % Hazard Ratio (95% CI)
Hgb < 10 g/dL 35.2 2.89 (2.46-3.61)
WBC count > 25 × 109/L 9.6 2.40 (1.83-3.14) Constitutional symptoms 26.4 1.97 (1.61-2.36)
Age > 65 years 44.6 1.95 (1.61-2.36)
Peripheral blood blasts > 1% 36.2 1.80 (1.50-2.17)
Risk Group No. of Factors Median Survival, Months (95% CI)
High ≥ 3 27 (23-31)
Intermediate II 2 48 (43-59)
Intermediate I 1 95 (79-114)
Low 0 135 (117-181)
Dynamic IPSS
Passamonti A et al. Blood. 2010 115: 1703-1708
DIPSS for survival in MF
Risk Factor 0 1 2
Hgb , g/dL ≥ 10 < 10
WBC count, × 109/L ≤ 25 > 25 Constitutional symptoms No Yes
Age , years ≤ 65 > 65
Peripheral blood blasts > 1% < 1 ≥ 1
Age adjusted DIPSS for survival in MF < 65 years
Risk Factor 0 1 2
Hgb , g/dL ≥ 10 < 10
WBC count, × 109/L ≤ 25 > 25
Constitutional symptoms No YES
Peripheral blood blasts > 1% < 1 ≥ 1
Dynamic IPSS plus
Gangat N et al. JCO. 2011 29: 392-398
Dynamic IPSS plus
Gangat N et al. JCO. 2011 29: 392-398
DIPSS Plus
Risk* No.
DIPSS Risk* Low
(n=74) Int-1
(n=249) Int-2
(n=370) High (n=100)
Low 66 66 0 0 0
Int-1 174 7 167 0 0
Int-2 360 1 78 267 14
High 193 0 4 103 86
Risk Factors of PMF for OS
Risk Factor Hazard Ratio (95% CI)
DIPSS int-1 1.9 (1.2 – 3.1)
DIPSS int-2 3.6 (2.1 – 6.0)
DIPSS High 7.3 (4.0 – 13.3)
Unfavorable karyitype 2.4 (1.7 – 3.4) Platelets < 100x109/L 1.6 (1.2 – 2.2) RBC transfusion dependent 1.4 (1/1 – 2.0)
**Unfavorable karyotype:
1) complex karyotype or 2) sole or two abnormalities that include 8, 7/7q-, i(17q), 5/5q-, 12p-, inv(3), or 11q23 rearrangement.
Score 1 Score 2 Score 3
DIPSS int-1 Karyotype Platelet Transfusion dependency
DIPSS int-2 DIPSS High
Low risk : 0 point Int-1 : 1 point Int-2 : 2-3 points High : ≥ 4 points
Tefferi A, et al. Am J Hematol. 2013
Points at treatment
Barbui T, et al. JCO. 2011
Risk adapted approach
Barbui T, et al. JCO. 2011
DIPSS plus category
High or Int-2 Low or Int-2
Age < 65 Age ≥ 65 Very High
Allo HSCT -conventional
-Reduced intensity
Symptom (-) Symptom (+)
Conventional Tx
Investigational Tx
Treatment of anemia
• Corticosteroid (0.5 to 1.0 mg/kg/d)
• Androgen therapy
– testosterone enanthate 400~600 mg weekly – oral fluoxymesterone 10 mg tid
– Danazol 400~600 mg/d
• Thalidomide low doses (50 mg/d) + PL 15~30 mg/d
• EPO
• Usually Tx start at Hb < 10g/dL
• Response rate 20~30%
Treatment of splenomegaly
• Hydroxyurea : response rate ~40%, duration limited
• oral melphalan
• oral busulphan
• INF- therapy
• Involved-field radiotherapy on spleen
– total dose of 0.1 to 0.5 Gy in five to 10 fractions – Transient effect 3~6 months only
• Splenectomy
– Increased risk of peri-operative mortality
– Increased risk of profound leukocytosis/thrombocytosis – Increased risk of thrombosis
Complication after splenectomy in PMF
Tefferi et al. Blood 2000;95:2226-33
Indication for Allo-HSCT
• Conventional-intensity alloSCT
– 1 yr TRM 30%, OS 50%
• Reduced-intensity alloSCT
– 5-year median survival 45%
• DIPSS plus high/int-2 risk
• RBC transfusion need
• unfavorable cytogenetic abnormalities
Recent advance in clinical trials
Trials with ruxolitinib
• COMFORT-1 : ruxolitinib vs placebo
• COMFORT-2 : ruxolitinib vs best available tx
COMFORT-II Study Design
• Randomized, open-label, multicenter phase 3 study1
• Patients were stratified based on baseline IPSS risk category2
Ruxolitinib 15 or 20 mg oral bid
n = 146
Best available therapy
(BAT) n = 73
Randomize Patients with
PMF, PPV-MF, or PET-MF with ≥ 2 IPSS risk factors2
N = 219 2:1
Ruxolitinib crossover and extension phase
1. Harrison C, et al. N Engl J Med. 2012;366(9):787-798.
2. Cervantes F, et al. Blood. 2009;113(13):2895-2901.
• Progression events that qualified for the crossover and extension phase:
– Splenectomy
– Progressive splenomegaly as defined by a 25% increase in spleen volume compared with the on-study nadir (including baseline)
35
-60 -50 -40 -30 -20 -10 0 10 20
0 12 24 36 48 60 72 84 96 108 120
Mean % Change From Baseline
Week
Ruxolitinib BAT (excluding crossover) BAT (including crossover)
Percent Change in Spleen Volume
36
136 125 111 98 78 64 53
Ruxolitinib, n = 146 42 31 10
60 44 39 34 24 16 6 2 0
73 0
n =
• BAT patients who crossed over to ruxolitinib had reductions in spleen volume after crossover
Excluding patients who crossed over to ruxolitinib BAT
n = 73 60 45 40 34 24 20 15 8 11 3
Including patients who crossed over to ruxolitinib BAT
Overall Survival
37 a P value for log-rank test is provided for descriptive purposes and was not adjusted for multiple comparisons.
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
0 24 48 72 96 120 144
Probability
Weeks 1.0
BAT
Ruxolitinib
146 73
138 127 117 109 30
61 51 49 45 12
n =
Lost to follow-up (cumul ative)
No. of Patients Events
Censored
146 20 (13.7%) 126 (86.3%)
73 16 (21.9%) 57 (78.1%) Ruxolitinib BAT
3.4% 9.6% 11.0% 14.4%
13.7% 24.7% 26.0% 27.4%
14.4%
27.4%
• Suggests a relative reduction in the risk of death with ruxolitinib compared with BAT
— HR = 0.51; 95% CI, 0.26-0.99 ‒ Log-rank test P = .041a
