epigenetic therapy for treatment of pediatric acute myeloid leukemia
DESCRIPTION
Epigenetic Therapy for Treatment of Pediatric Acute Myeloid Leukemia. 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 - PowerPoint PPT PresentationTRANSCRIPT
Epigenetic Therapy for Treatment of Pediatric Acute Myeloid
Leukemia
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
• 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
Patient Characteristics AML-2002
N=51 (42,1%) AML-2007N=70 (57,9%)
Р value
N % N %
Gender 0,32
male 26 51,0 42 60,0
female 25 49,0 28 40,0
Age Average age 8,9±0,8 years
Average age7,1±0,7 years
0,23
˂ 1 years 4 7,8 14 20,0
1,1 – 3 years 7 13,7 13 18,6
3,1- 7 years 11 21,6 11 15,7
7,1-14 years 22 43,1 22 31,4
>14 years 7 13,7 10 14,3
Cytogenetic Characteristics (р=0,2)
Karyotype AML - 2002 AML - 2007 Total
N % N % N %
46XX/46XY 8 20,5 8 17,8 16 19,0t(8;21) 8 20,5 3 6,7 11 13,1
t(8;21) + et. all 3 7,7 4 8,9 7 8,3
inv16/t(16;16) 4 10,3 7 15,6 11 13,1
t(6;9) 1 2,2 1 1,2
t(9;11) 2 5,1 2 4,4 4 4,8
More 3 3 7,7 3 6,7 6 7,1
t(6;11) 1 2,6 1 1,2
Other 7 17,9 16 35,6 23 27,447XX/47XY (+21) 3 7,7 3 3,6
del 11(q23) 1 2,2 1 1,2
Total 39 out of the 51 47 out of the 70 84
Risk Groups
Standard risk
Intermediate risk High 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
Frequency Risk Groups Patients Enrolled on AML-2002 and AML-2007
RISK GROUPS AML-2002 AML-2007 Total P value
N % N % N %Standard 13 25,5 13 18,6 26 21,5 0,02Intermediate 25 49,0 22 31,4 47 38,8 0,02High 13 25,5 35 50,0 48 39,7 0,02Unfavourable 38 74,5 57 81,4 95 78,5 0,36
Response to Induction TherapyResponse on the 15 day:• Good Response (М-1) – bone marrow < 5% blasts, peripheral blood
0% blasts• Partial Response (М-2) – bone marrow 6 - 25% 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 ×109/L, Platelets > 100×109/L,
Hgb> 10 g/dL- Non extra medullar tumor• No remission - Bone marrow: > 6-25% blasts - Refractory AML - Bone marrow: >25% blasts
Response in 15 Day
AML-2002
М-1
М-2М-3
Mortality
AML -2007
М-1
М-2М-3 Mortality
Ответ N %
М-1 39 76,5
М-2 6 11,8
М-3 5 9,8
Mortality 1 2,0
Ответ N %М-1 55 78,6М-2 7 10,0М-3 7 10,0Mortality 1 1,4
Р=0,14
Frequency Response in 15 day in Terms of Risk Groups
RISK GROUPS М-1 М-2 М-3 P value
AML-2002
AML-2007
AML-2002
AML-2007
AML-2002
AML-2007
Standard 1292,3%
13100%
17,7%
- - - 0,3
Intermediate 16 64,0%
1881,8%
520,0%
29,1%
416,0%
14,5%
0,2
High 1184,6%
2468,6%
- 514,3%
117,1%
614,6%
0,1
Unfavourable 2771,1%
4273,7%
513,2%
712,3%
59,8%
710,0%
0,98
Response After Induction Therapy р=0,1
AML-2002
Com-plete re-
mis-sion
No re-mission Mortality
AML-2007
Complete remission
No remission Mortality
Response N %
Complete remission 35 68,6
No remission 13 25,4Mortality 3 5,9
Response N %
Complete remission 65 92,8
No remission 4 4,3Mortality 1 2,9
Statute After Induction Therapy
RISK GROUPS
Complete remission No remission P valueAML-2002 AML-2007 AML-2002 AML-2007
Standard 13100%
13100%
- - -
Intermediate 2184,0%
2090,9%
416,0%
19,1%
0,48
High 969,2%
3291,4%
430,8%
38,6%
0,05
Unfavourable 3078,9%
5291,2%
821,1%
58,8%
0,1
Disease-Free Survival
Event-Free Survival
Overall Survival
Disease-Free Survival (Standard risk)
Overall Survival (Standard risk)
Disease-Free Survival (Intermediate risk)
Overall Survival (Intermediate risk)
Disease-Free Survival (High risk)
Overall Survival (High risk)
Disease-Free Survival (Unfavourable risk)
Overall Survival (Unfavourable risk)
• Five-year DFS
• Five-year OS
Age AML-2002 AML-2007 р
˂ 1 years 25,0±21,7 (n=4) 82,5±11,3 (n=14) 0,005
1,1 – 3 years 21,4±18,8 (n=7) 48,4±15,0 (n=13) 0,18
3,1 – 7 years 36,4±14,5 (n=11) 52,5±18,6 (n=11) 0,33
7,1 – 14 years 41,6±11,0(n=22) 58,8±11,3 (n=22) 0,23
more 14 years 85,7±13,2 (n=7) 25,0±15,3 (n=10) 0,02
Age AML-2002 AML-2007 р
˂ 1 years 25,0±21,7 (n=4) 84,6±10,0 (n=14) 0,01
1,1 – 3 years 28,6±17,1 (n=7) 52,7±14,1 (n=13) 0,24
3,1 – 7 years 43,6±15,5 (n=11) 60,0±15,5 (n=11) 0,41
7,1 – 14 years 39,4±10,7(n=22) 53,8±10,8 (n=22) 0,32
more 14 years 100 (n=7) 25,0±15,3 (n=10) 0,007
HIGH-DOSE OF CHEMOTHERAPY &AUTOLOGOUS SCT
AML-2002
• 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)
Disease-Free Survival (AML-2002 Protocol)
Overall Survival (AML-2002 Protocol)
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-2002 22,1±4,2 days after AML-2007
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.