Leukemic transformation of MPN:
Therapy‐related or unrelated?
Jean‐Jacques KILADJIAN, MD, PhD
Clinical Investigations Center
Saint‐Louis Hospital ‐ Paris Diderot University
Leukemic transformation: a long term issue
Passamonti, Haematologica, 2003
1
Registry data
2
Registry data
292
AML/MDS
11 039
MPN
‐ 14 (5%)
14 (5%)
unclear Dg or prior Chemo/Radio
278
‐ 51 (17%)
AML/MDS
lack of information
227
‐ 65 (22%)
AML/MDS
no matched control
162
AML/MDS
cases (55%)
Registry data
Median follow‐up?
Median follow
up?
3
Registry data
Median follow‐up?
Median follow
up?
4
Therapy‐related MDS/AML
Sterkers et al, Blood. 1998;91(2):616‐22.
Therapy‐related MDS/AML
Berk et al, Semin Hematol. 1986;23:132‐143 5
Therapy‐related MDS/AML
Finazzi et al, Blood. 2005, 105(7):2664‐70
Therapy‐related MDS/AML
• ECLAP median F‐U: 2.8 years
Finazzi et al, Blood. 2005, 105(7):2664‐70
6
Therapy‐related MDS/AML
• ECLAP median F‐U: 2.8 years
Finazzi et al, Blood. 2005, 105(7):2664‐70
• 2 drugs approved for the treatment of PV:
g pp
• HU and pipobroman
• Their leukemogenic potential when used as single agent is debated
• Long term prospective studies to assess their impact on outcome of PV
7
• Phase 2 study of pipobroman
• 164 PV patients analyzed for very long‐term outcomes, median follow‐up 12 years
• 32 leukemic events
• Actuarial risk:
• 14% at 10 years
• 19% at 15 years
LEUKEMIC EVENTS
MDS/AL ‐ risk factors
Added / switched drug
P = 0.65
Age at diagnosis
P = 0.96
Hematocrit  60%
P = 0.54
Platelet count  400.109/l
P = 0.35
Splenomegaly
P = 0.64
WBC  10.109/l
P = 0.032
8
p= 0.032
LEUKEMIC EVENTS
Cytogenetics
Available in 10 cases :
in 10 cases :
del(7q), del(20q)
‐7
 complex, ‐7, +8, ‐17, t(4;10)
 +8
 del(5q),+8, dic(17)t(16;17)
 ‐9
9, ‐13
13, +3mar +3mar
 add(6q), +14
 complex, del(17p), t(1;22)
 complex
 normal


> 3 anomalies
n=3
-7, del(7q)
n=3
17p deletion
n=3
+8
n=3
del(5q)
n=1
del(20q)
n=1
t(1;22)
n=1
9
Long‐term evolution
• Causes of death:
• ECLAP study
• median F‐U: 2.8 yrs
Causes of Deaths (n= 164)
Cardio‐vascular
45%
Cancer
19%
Hematological transformation
13%
Marchioli et al, J Clin Oncol, 2005; 23(10):2224-32.
Median follow-up: 11.4 years
Causes of deaths
All patients
n = 89
Leukemic events
26 (29%)
Vascular events
19 (21%)
Solid tumors
13 (15%)
Unrelated
16 (18%)
Unknown
15 (17%)
10
Median follow-up: 11.4 years
< 60 years
 60 years
All patients
n = 35
n = 54
n = 89
18 (51%)
8 (15%)
26 (29%)
Vascular events
2 (6%)
17 (31%)
19 (21%)
Solid tumors
5 (14%)
8 (15%)
13 (15%)
Unrelated
8 (23%)
8 (15%)
16 (18%)
Unknown
2 (6%)
13 (24%)
15 (17%)
Causes of deaths
Leukemic events
 Analyses in 1997
 Median FU: 9 years
 13 leukemic events
•
9 AL •
4 MDS
 Incidence: 10% at 13 years
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Median FU: 16 3 years
Median FU: 16.3 years
 Analyses in 1997
 Median FU: 9 years
 13 leukemic events
•
9 AL •
4 MDS
 Incidence: 10% at 13 years
• Median overall survival: 17 years (95% CI: 15.4 ‐ 19.4)
• SMR: 1.84 (95% CI: 1.5 ‐ 2.2)
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• Median overall survival: 17 years (95% CI: 15.4 ‐ 19.4)
• HU: 20.3 years
• Pipobroman: 15.4 years
• Median overall survival: 17 years (95% CI: 15.4 ‐ 19.4)
• Causes of deaths (n=95): 
MDS/AML: 54%

Vascular event: 19%

Solid tumor: 12%
ECLAP ‐ Causes of Deaths
Cardio‐vascular
45%
Cancer
19%
Hematological transformation
13%
13
• Evolution to AML/MDS
10 years 15 years 20 years
Total cohort
9.8%
24%
34%
HU (ITT)
6.6%
16.5%
24%
Pipo (ITT)
13%
34%
52%
• Evolution to AML/MDS
10 years 15 years 20 years
Total cohort
9.8%
24%
34%
HU (ITT)
6.6%
16.5%
24%
Pipo (ITT)
13%
34%
52%
HU (PP)
7.5%
14%
22%
Pipo
p (PP)
( )
12%
37%
56%
14
• Evolution to AML/MDS
10 years 15 years 20 years
Total cohort
9.8%
24%
34%
HU (ITT)
6.6%
16.5%
24%
Pipo (ITT)
13%
34%
52%
HU (PP)
7.5%
14%
22%
Pipo
p ((PP))
12%
37%
56%
HU (alone, n=94)
7.3%
11%
17%
Pipo (alone, n=130)
14.6%
34%
49.4%
Multicenter observational study in ET

108 newly diagnosed consecutive ET patients

S
Started in 1979
d i 1979

HU only as first line therapy

Median follow‐up: 22.3 years

Cumulative incidence of AL/MDS:
•
12% at 10 years
12% at 10 years
•
15% at 15 years
•
20% at 20 years
Kiladjian, ASH, 2008
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Multicenter observational study in ET
1.0
Leukemic evolution: predictive factors WBC
0.8
<7275
>11150
0.2
0.4
0.6
Leukocytosis: p=0.018
0.0

0
5
10
15
20
Years
Summary ‐ Hematological transformation with “conventional” drugs At 15 years
HU
Pipobroman
PV
16%
19% (Phase 2)
30% (Phase 3)
ET
15%
Is hydroxyurea leukemogenic?
16
Hydroxyurea in sickle cell disease
 HU approved in the USA for the treatment of adults with SCD
 Included RCTs, observational studies, case reports
Hydroxyurea in sickle cell disease
Darbari et al.,
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Hydroxyurea in sickle cell disease
 SCD is not a neoplastic disease Predisposition
 Case‐control study in ET and PV
 64 AML cases vs 358 without progression
 Median FU: 8.6 years
 5 SNPs in 4 DNA repair genes (XPD, XPG, XPC, XRCC1)
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Predisposition

Predisposition

19
Conclusions
• Evolution to leukemia could be the first cause of deaths in the long‐term in properly managed MPN patients
• Evolution to leukemia is part of the natural history of MPN, but this risk can clearly be enhanced by medicines like alkylating agents
• Pipobroman is clearly leukemogenic
is clearly leukemogenic and should not be used as and should not be used as
first line therapy
Conclusions
• Hydroxyurea has never been shown to increase the risk of leukemic evolution
• The higher than previously reported incidence of evolution to leukemia in HU‐treated PV patients we found in the randomized trial could be due to natural disease evolution not altered by HU therapy
• However, clearly non‐leukemogenic drugs should be favored to treat patients <60 years
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Acknowledgements B. Cassinat
B. Cassinat
C. Chomienne
F. Delhommeau
W. Vainchenker
S. Chevret
S. Chevret
J.D. Rain
L. Knoops
L. Aljassem
S. Bellucci
N. Cambier
Y. Chait
J.L. Dutel
K. Ghomari
N. Parquet
M. Roussel
P. Rousselot
P Turlure
P. Turlure
J.M. Zini
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