epigenetic therapy for treatment of pediatric acute myeloid leukemia

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.