Leukemic transformation of MPN: Therapy related or unrelated?

Transcription

1 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,

2 Registry data 2

3 Registry data (5%) unclear Dg or prior Chemo/Radio AML/MDS MPN (17%) AML/MDS lack of information (22%) AML/MDS no matched control 162 AML/MDS cases (55%) Registry data Median follow up? 3

4 Registry data Median follow up? 4

5 Therapy related MDS/AML Sterkers et al, Blood. 1998;91(2): Therapy related MDS/AML Berk et al, Semin Hematol. 1986;23:

6 Therapy related MDS/AML Finazzi et al, Blood. 2005, 105(7): Therapy related MDS/AML ECLAP median F U: 2.8 years Finazzi et al, Blood. 2005, 105(7):

7 Therapy related MDS/AML ECLAP median F U: 2.8 years Finazzi et al, Blood. 2005, 105(7): drugs approved for the treatment of PV: 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

8 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 /l P = 0.35 Splenomegaly P = 0.64 WBC /l P =

9 p= LEUKEMIC EVENTS Cytogenetics Available 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, 13, +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

10 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): 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

11 Median follow-up: 11.4 years Causes of deaths < 60 years n = years n = 54 All patients n = 89 Leukemic events 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%) Analyses in 1997 Median FU: 9 years 13 leukemic events 9 AL 4 MDS Incidence: 10% at 13 years 11

12 Analyses in 1997 Median FU: 16.3 years Median FU: 9 years 13 leukemic events 9 AL 4 MDS Incidence: 10% at 13 years Median overall survival: 17 years (95% CI: ) SMR: 1.84 (95% CI: ) 12

13 Median overall survival: 17 years (95% CI: ) HU: 20.3 years Pipobroman: 15.4 years Median overall survival: 17 years (95% CI: ) 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

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% 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 (PP) 12% 37% 56% 14

15 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 (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 Started din 1979 HU only as first line therapy Median follow up: 22.3 years Cumulative incidence of AL/MDS: 12% at 10years 15% at 15 years 20% at 20 years Kiladjian, ASH,

16 Multicenter observational study in ET Leukemic evolution: predictive factors WBC 1.0 <7275 > Leukocytosis: p= 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

17 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., 17

18 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) 18

19 Predisposition Predisposition 19

20 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 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 20

21 Acknowledgements B. Cassinat S. Chevret C. Chomienne F. Delhommeau W. Vainchenker 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 J.M. Zini 21