Epigenetic Therapy for Treatment of Pediatric Acute Myeloid Leukemia. - презентация

1 Epigenetic Therapy for Treatment of Pediatric Acute Myeloid Leukemia

2 Oncology Hospitals Moscow Balashiha Krasnodar Rostov-on-Don Ekaterinburg Sankt-Petersburg Archangelsk Voronezh Protocol AML-2002: from 07/2002 to 09/2006 Protocol AML-2007: from 10/2006 to 02/2012 Results on 10/31/2013

3 AML-2002, N=51 (42,1%) AML-2007, N=70 (57,9%) Diagnosis Marrow, blood and cerebrospinal fluid is examined 1. Cytomorphology, 2. Flow cytometry, 3. Tested for chromosomal abnormalitis by cytogenetics

4 Patient Characteristics AML-2002 N=51 (42,1%) AML-2007 N=70 (57,9%) Р value N%N% Gender0,32 male2651,04260,0 female2549,02840,0 AgeAverage age 8,9±0,8 years Average age 7,1±0,7 years 0,23 ˂ 1 years 47,81420,0 1,1 – 3 years 713,71318,6 3,1- 7 years 1121,61115,7 7,1-14 years 2243,12231,4 >14 years 713,71014,3

5 Cytogenetic Characteristics (р=0,2) KaryotypeAML AML Total N%N%N% 46XX/46XY820,5817,8 1619,0 t(8;21)820,536,71113,1 t(8;21) + et. all37,748,978,3 inv16/t(16;16)410,3715,61113,1 t(6;9)t(6;9)12,211,2 t(9;11)25,124,444,8 More 337,736,767,1 t(6;11)12,611,2 Other717,91635,6 2327,4 47XX/47XY (+21)37,733,6 del 11(q23)12,211,2 Total39 out of the 5147 out of the 7084

6 Risk Groups Standard risk Intermediate riskHigh risk AML with t(8;21), inv(16) or t(16;16). FAB-М1, М2 or FAB-М4 with normal cytogenetic or loss of sex chromosome; AML with 11q23 exclude t(10;11), AML with (+8), chromosome arm 3 abnormality 3 or AML with erythroid markers FAB М0, М5, М6, М7. FAB М1, М2, М4 with t(6;9), t(10;11), t(9;22), del(7q-), del(5q-), -7, -5, t(3;5); t(3;3), ring chromosome, complex findings (3 clonal chromosomal abnormalities). Bone marrow > 15% blasts after induction therapy

7 Frequency Risk Groups Patients Enrolled on AML-2002 and AML-2007 RISK GROUPSAML-2002AML-2007TotalP value N%N%N% Standard1325,51318,62621,50,02 Intermediate2549,02231,44738,80,02 High1325,53550,04839,70,02 Unfavourable3874,55781,49578,50,36

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11 Response to Induction Therapy Response on the 15 day: Good Response (М-1) – bone marrow < 5% blasts, peripheral blood 0% blasts Partial Response (М-2) – bone marrow % blasts, peripheral blood 0% blasts Non Response (М-3) – bone marrow > 25% blasts Response after induction therapy: Complete remission - Bone marrow: < 5% blasts - Peripheral blood: Neutrophils > 1,0 ×10 9 /L, Platelets > 100×10 9 /L, Hgb> 10 g/dL - Non extra medullar tumor No remission - Bone marrow: > 6-25% blasts - Refractory AML - Bone marrow: >25% blasts

12 Response in 15 Day AML-2002 AML ОтветN% М-13976,5 М-2611,8 М-359,8 Mortality12,0 ОтветN% М-15578,6 М-2710,0 М-3710,0 Mortality 11,4 Р=0,14

13 Frequency Response in 15 day in Terms of Risk Groups RISK GROUPSМ-1М-2М-3 P value AML AML AML AML AML AML Standard12 92,3% % 1 7,7% ---0,3 Intermediate16 64,0% 18 81,8% 5 20,0% 2 9,1% 4 16,0% 1 4,5% 0,2 High11 84,6% 24 68,6% -5 14,3% 1 17,1% 6 14,6% 0,1 Unfavourable27 71,1% 42 73,7% 5 13,2% 7 12,3% 5 9,8% 7 10,0% 0,98

14 Response After Induction Therapy р=0,1 AML-2002 AML-2007 ResponseN% Complete remission3568,6 No remission1325,4 Mortality 35,9 ResponseN% Complete remission6592,8 No remission44,3 Mortality 12,9

15 Statute After Induction Therapy RISK GROUPS Complete remissionNo remissionP value AML-2002AML-2007AML-2002AML-2007 Standard13 100% % --- Intermediate21 84,0% 20 90,9% 4 16,0% 1 9,1% 0,48 High9 69,2% 32 91,4% 4 30,8% 3 8,6% 0,05 Unfavourable30 78,9% 52 91,2% 8 21,1% 5 8,8% 0,1

16 Disease-Free Survival

17 Event-Free Survival

18 Overall Survival

19 Disease-Free Survival (Standard risk)

20 Overall Survival (Standard risk)

21 Disease-Free Survival (Intermediate risk)

22 Overall Survival (Intermediate risk)

23 Disease-Free Survival (High risk)

24 Overall Survival (High risk)

25 Disease-Free Survival (Unfavourable risk)

26 Overall Survival (Unfavourable risk)

27 Five-year DFS Five-year OS AgeAML-2002AML-2007 р ˂ 1 years25,0±21,7 (n=4)82,5±11,3 (n=14)0,005 1,1 – 3 years21,4±18,8 (n=7)48,4±15,0 (n=13)0,18 3,1 – 7 years36,4±14,5 (n=11)52,5±18,6 (n=11)0,33 7,1 – 14 years41,6±11,0(n=22)58,8±11,3 (n=22)0,23 more 14 years85,7±13,2 (n=7)25,0±15,3 (n=10)0,02 AgeAML-2002AML-2007 р ˂ 1 years25,0±21,7 (n=4)84,6±10,0 (n=14)0,01 1,1 – 3 years28,6±17,1 (n=7)52,7±14,1 (n=13)0,24 3,1 – 7 years43,6±15,5 (n=11)60,0±15,5 (n=11)0,41 7,1 – 14 years39,4±10,7(n=22)53,8±10,8 (n=22)0,32 more 14 years100 (n=7)25,0±15,3 (n=10)0,007

28 2 patients of Standard risk group (after Induction therapy more 5% blasts in bone marrow) 10 patients of Intermediate risk group (25 patients needed) 2 patients of High risk group (13 patients needed)

29 Disease-Free Survival (AML-2002 Protocol)

30 Overall Survival (AML-2002 Protocol)

31 Toxicity All-trans-retinoic acid (ATRA) Side effects – headache in 12 children (17,1%) – «ATRA syndrome» was present in remission induction period in only one patient Valproic acid Side effects – Myelosuppression no different average duration of neutropenia 21,3±3,7 days after AML ,1±4,2 days after AML-2007

32 Conclusions 1. The number of remissions in patients, who were treated after AML-2007 protocol was higher. The number of complete remissions has risen accurately as a result of induction therapy in children with a high risk of AML, that received treatment after AML-2007 including epigenetic therapy. 2. Thanks to putting on epigenetic drugs improved values of DFS, EFS and OS were reached in children with AML. 3. DFS has been increased accurately in the combination of epigenetic and chemotherapy in patients with high or unfavorable risk of AML. 4. The survival values grew up more and accurately in children under one year old. 5. Epigenetic drugs did not increase toxicity while being added to the chemotherapy.