1. Current Treatment Landscape in MF
Francesco Passamonti
University Hospital Fondazione Macchi, Varese, Italy

2. Treatment Landscape in MF
Hydroxyurea
Anti-anemia agents
Splenectomy
Splenic irradiation
Bone marrow transplantation

3. Hydroxyurea in MF When do we use HU?
Presence of constitutional symptoms (55%), symptomatic splenomegaly (45%), thrombocytosis (40%), leukocytosis (28%), pruritus (10%), and bone pain (8%)
ELN recommendations: the drug of choice for symptomatic splenomegaly is hydroxyurea, which is also used for controlling symptomatic thrombocytosis and/or leukocytosis
Martinez Trillos et al. Ann Hematol Dec; 89 (12):
Barbui T. et al. J Clin Oncol Feb 20;29(6):761-70

4. Efficacy of HU in MF (n=40 naïve pts)
Response on bone pain (100%), constitutional symptoms (82%), pruritus (50%), splenomegaly (40%), and anemia (12.5%)
Clinical improvement (IWG-MRT): 40%
Median duration of response: 13.2 months
Worsening of anemia or appearance of pancytopenia: 45%
Martinez Trillos et al. Ann Hematol Dec; 89 (12):

5. Is HU able to prevent thrombosis in MF?
Rate of major thrombotic events in 707 PMF mainly treated with HU: 2.2 x 100 pt/yr
Main risk factors: age over 60 yrs, presence of the JAK2 (V617F), WBC >15 x 109/L (borderline)
Rate of severe thrombosis in 68 post-PV MF: 4.2 x 100 pt/yr
Barbui et al, Blood Jan 28; 115 (4):
Passamonti et al, Blood Apr 1; 111 (7):

6. Leukemia in MF AML occurs in 10-20% of MF
Risk factors: DIPSS categories, advanced age, high leukocyte count, adverse cytogenetic profile [complex, sole or two including +8, -7/7q-, i(17q), inv (3), -5/5q-, 12p-, 11q23 rearrangements], RBC transfusion- dependency, low platelet count, low JAK2 (V617F) allele burden, IDH mutations, EZH2 mutations
Passamonti et al, Blood 2010; Caramazza et al, Leukemia 2011; Tefferi et al, Leukemia 2008;
Gangat et al, JCO 2011, Elena et al, Haematologica 2010; Tefferi et al, Leukemia 2011;
Guglielmelli et al, Blood 2011

7. A Caveat on HU-leukemogenicity FPSG Prospective Trial in PV
283 PV patients treated with HU alone (#94 for 12 yrs) and PB alone (#130 for 9.5 yrs)
Estimate in a competing risk setting
AML: less in HU
OS: longer in HU
No increase of AML switching chemo
Of AML/MDS (probability)
Cumulative Incidence
Overall Survival (probability)
Kiladjian et al, J. Clin. Oncol. 2011

8. Retrospective Studies on AML in HU-treated PV Patients
No differences among treatments
in terms of AML
High WBC count predicts AML
Chemo
AML cases
No chemo
3/123 (2.4%)
HU alone
7/153 (4%)
Other than HU
15/129 (11.6%)
≥ 2 chemos
9/54 (16.7%)
Gangat et al, British J. Hematol 138, 354–358, 2007
1638 PV patients (ECLAP)
Incidence of 0.29 x 100 p/y for
HU and 1.8 x 100 p/y for others
Advanced age predicts AML
Chemo
HR for AML
No chemo 1
HU alone
0.86 ( )
Other than HU
5.46 ( )
Finazzi et al, Blood 106 (7), ; 2005

9. Population–based Data from Sweden
11,039 MPN: 162 post-MPN AML, 242 matched controls
25% of post-MPN AML patients were never exposed to cytotoxic drugs
HU at any dose is not associated with an increased risk of AML
Increasing cumulative dose of alkylators is associated with AML
≥ 2 drugs more AML
Fraction Without AML
Bjorkholm et al, J. Clin. Oncol. 29 (17), ; 2011

10. Anemia in MF How big a problem?
Median Hgb at presentation g/dL
35-54% have Hgb <10 g/dL
Anemia is a predictor for inferior survival
IPSS
DIPSS
DIPSS-Plus

11. Treatment of Anemia in MF
Corticosteroids
Danazol ≈ 30-40% response, transient
Erythropoietin
Thalidomide + PDN ≈ 20% response
Lenalidomide ≈ 20-23% response
Fontana et al, Hematology 2011; Shimoda et al, Int J Hematol May; 85(4):338-43; Cervantes et al, Br J Haematol Jun;129(6):771-5; Hasselbach et al, Am J Hematol Jun;70(2):92-9; Damaj et al, Eur J Haematol Apr;68(4):233-5; Cervantes et al, Haematologica Jun;85(6):595-9; Tsiara et al Acta Haematol. 2007;117(3):156-61; Cervantes et al Br J Haematol Jul;134(2):184-6; Mesa et al, Blood Nov 25;116(22):4436-8; Tefferi et al, Blood Aug 15;108(4): ; Mesa et al, Blood Apr 1;101(7): ; Marchetti et al, J Clin Oncol Feb 1;22(3):

12. Phase I-II with Pomalidomide (84 pts)
Anemia improvement
- Poma 2 mg 38%
- Poma 2 mg + Pred 23%
- Poma 0.5 mg + Pred 40%
- Pred 25%
Durable response, better without leukocytosis
Toxicity PMN PLT Thrombosis
- Poma 2 9% 14% 9%
- Poma 2 + Pred 16% 16% 5%
- Poma Pred 5% 9% 0%
- Pred 5% 5% 0%
Tefferi et al. J Clin Oncol Sep 20;27(27):

13. Phase II Trial with Pomalidomide 58 pts; dose: 0.5 mg/day
JAK2V617F
Positive
Negative
16 patients
Anemia response = 0%
42 patients
Anemia response = 24%
Spleen <10 cm
Spleen
>10 cm
Additional observations:
Well tolerated with Gr 3 anemia (5%) and
thrombocytopenia (2%)
Early basophilia predicted anemia response
58% PLT response in patients with < 100k PLT
No spleen responses
Response
38%
Response
11%
Begna et al. Leukemia Feb;25(2):301-4.

14. Phase III Trial with Pomalidomide currently recruiting
A Phase-3, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Compare Efficacy and Safety of Pomalidomide in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Red Blood Cell Transfusion Dependence R
Pomalidomide 0.5 mg
Placebo
Transfusion dependent
MF patients
Primary end-point: proportion of subjects achieving
RBC-transfusion-independence at 6 months

15. Splenectomy Perioperative mortality: 5-10%
Postsplenectomy complications: 50%
Complications: surgical site bleeding, thrombosis, subphrenic abcess, accelerated hepatomegaly, extreme thrombocytosis, and leukocytosis with excess blasts
Tefferi et al, Blood Apr 1;95(7): ;
Barosi er at, Blood May 15;91(10):

16. Splenectomy: Still a Role in MF?
Symptomatic portal hypertension
Drug-refractory marked splenomegaly
RBC transfusion-dependent anemia
Caveat if severe thrombocytopenia (marker of AML), unaffected by splenectomy
Barbui T. et al. J Clin Oncol Feb 20;29(6):761-70

17. Radiotherapy Symptomatic relief from splenomegaly
Transient response, 3 to 6 months
Mortality: 10% for complications of cytopenia
Useful for nonhepatosplenic extramedullary hematopoiesis

18. Graft versus MF Effect of Bone Marrow Transplant
A patient with PMF received HSCT obtaining CR. Few months later PMF relapsed. Donor lymphocytes were infused resulting in normalization of CBC count and BM fibrosis.
BM pre HSCT
BM post DLI
Cervantes et al, BMT 2000

19. Ablative Allogeneic Stem Cell Transplantation in MF TBI-Cy or busulphan-Cy
# patients 55
Median age
42 years
a-GVHD
60%
NRM
27% CR
40%
5-years Survival
14% (age > 45 y)
62% (age <45 y)
Guardiola et al, Blood May 1;93(9):2831-8;
Guardiola et al, N Engl J Med Aug 31;343(9):650.

20. RIC Allogeneic Stem Cell Transplantation in MF
# patients
103
Median age
55 years ( )
Regimen
BU-Fludarabine
a-GVHD
27%
NRM
16% CR
74%
5-year survival
67%
Kroger et al, Blood Dec 17;114(26):

21. RIC Allogeneic Stem Cell Transplantation in MF
5y DFS: 51%
Adverse factors: MMUD; high Lille
5y OS: 67%
Adverse factors: MMUD; age > 55 yrs
Survival (no MMUD)
5y DFS: 59%
5y OS: 74%
Survival, by age
< 55 years: 82%
> 55 years: 48%
Kroger et al, Blood Dec 17;114(26):

22. JAK2 in the ASCT Setting 139 genotyped patients with MF
Inferior outcome of JAK2wt patients due to an increased TRM and relapse rate (trend)
Persistence of JAK2mut at 6 months post-ASCT is associated with higher risk of relapse
Negative
Positive
Alchalby et al. Blood 2010;116:

23. Transplant Score to Predict Survival (46 patients, thiotepa–based RIC transplant)
Independent risk factors:
RBC transfusion >20 U
Spleen size > 22 cm from CM
Alternative donors
HR patients have an higher TRM (6 fold) and relapsed related death (7.6 fold)
Low risk (n=24)
Bacigalupo et al, Bone Marrow Transplant Mar;45(3):

24. BMT in Lower Risk Categories: an Option for the Cure?
Age > 57 years
JAK2 wt
Constitutional symptoms
Alchalby et al, EBMT Meeting 2011

25. Pressing Issues in PMF Splenomegaly Constitutional symptoms Anemia
Eradication of JAK2mut clone
AML/Overall survival

26. Current Risk Stratification in PMF
Low risk
No factor (IPSS/DIPSS)
IPSS-DIPSS
Intermediate-1 risk score 1 (IPSS)
score 1-2 (DIPSS)
Age > 60 years
Hb < 10 g/dL
WBC > 25 x109/L
Blasts ≥ 1%
Constitutional
symptoms
Intermediate-2 risk score 2 (IPSS)
score 3-4 (DIPSS)
High risk score ≥ 3 (IPSS)
score ≥ 5 (DIPSS)
Passamonti et al, Blood 2010; 115:
Cervantes et al, Blood 2009; 113:

27. The IPSS at Diagnosis of MF
1.0
0.8
0.6
0.4
0.2
0.0 2 4 6 8 10 12 14 16 18 20 22
Probability
Years 24
95 % CI
Low
Intermediate 1
Intermediate 2
High
135 months
22%
95 months
29%
48 months
28%
27 months
21%
Risk group
Low
Int
Int
High ≥3
Cervantes et al, Blood 2009; 113:

28. The DIPSS during Follow-up of MF
Risk Factors
Score value 1 2
Age > 65 yrs x
WBC >25 x109/L
Hb < 10 g/dL
PB blasts ≥ 1%
Const. symptoms
Risk
Score
Low
Intermediate-1
1 to 2
Intermediate-2
3 to 4
High
5 to 6
Passamonti et al, Blood 2010; 115:

29. Conclusions
All current therapies except bone marrow transplant do not affect any event in MF
Bone marrow transplant is currently considered for patients at higher risks