Y HOC VIET NAM THANG 2 • SO 2/2014
NGHIEN CU'U YEU TO DI TRUYEN TRONG PHAN NHOM TIEN LU'O'NG BENH NHAN L a XE MI CAP DONG TUY
T O M TAT
Bien doi di truyen la mot yeu to trong tien li/cJng 10 xe mi cap dong tiiy, Muc tieu: (1) Nghien cffu cac bien doi nhiem sac the, gen NPM1,FLT3-ITD va phan nhdm tien lUdng 6 nhan Id xe mi cap dong tiiy (2).
BUdc dau nghien cii'u dap ffng dieu tn tan cong d cac nhom tien lu'dng. Odi tu'dng va phu'dng phap nghien cffu: 100 benh nhan dUOc chan doan xac dinh Id xe mi cap dong tuy, dUcJc phan tich nhiem sac the, PCR xac djnh cac gen NPMl, FLT3-ITD, phan nhom ten lUdng va dieu tri tan cong bang phac do „3+7".
Ket qua: Co 27 kieu nhiem sac the, bp nhiem sac the binh thudng chiem ty (e cao nhat (55%). Ty le NPMl va FLT3-rTD la 33% va 27%. Ty le nhdm tien lu'dng tot la 32%, trung binh 53%, xau 14%., Ty le lui benh hoan toan cao nhat 6 nhdm tien lu'dng tdt (84,6%), thap nhat nhdm tien lupng xau (50%). Nhdm tien lupng tdt cd so ngay dieu tr;, thdi gian bach cau giam du'di IG/I, thdi gian phuc hoi bach cau hat trung tinh tren IG/I ngan nhat. Nhom tien lu'dng tot co ty le khong nhiem khuan cao nhat (46,2%), nhom tien li.i'dng xau cd ty le viem phoi va nhiem khuan huyet cao nhat (50% va 16,7%). Ket luan; Bien doi nhiem sac the va gen cd vai tro quan trgng trong tien lupng Id xe mi cap dong tuy.
Tu'khda: 10 xe mi cap ddng tuy, phan nhdm tien lu'dng
S U M M A R Y
STUDY PROGNOSTIC MARKERS OF GENETICS I N ACUTE MYELOGENOUS LEUKEMIA Cytogenetics and genes were markers in prognosis acute myelogenous leukemia. Subjects: (1) Study cytogenetics and NPMl, FLT3-ITD genes and classification of prognostic groups in acute myelogenous leukemia patients. (2) Firstly study response of induction therapy. Patiensts and method: 100 patients with acute myelogenous leukemia (AML) were studied. Cytogenebc analysis and PCR testing to detect NPMl, FLT3-IT0 was done before were taken the induction chemotherapy and the complete remission was estimated by classificabon of prognosis. Results: 27 cytogenetics karyotype was analysed. Rates of normal cytogenetics was highest (55%), Rate of NPMl anf FLT3-ITD positive was 33%
VuMinh PhWdng*, Kieu Thf Van Oanh**
and 27%. Rate of favorable, intermediate and unfavorblae groups was 32%, 53% nad 14%.
Complete remission was highest in favorable group (84,6%), lowest in unfavorable group (50%), The time of hospitalization, time of neutrophilia, time of neutropils recover was shorted in favorable group, Rate of un-infection was highest in favorable group (46,2%), rate of pneumonia and sepsis was highest in unfavorable group (50 and 16,7%), Conclusion:
Cytogenetics and genes had important role in prognosis acute myelogenous leukemia.
Keywords: acute myelogenous leukemia, prognostic markers
I. DAT V A N OE
Bien ddi di truyen cd vai trd quan trpng trong Id xe mi cap ddng tiiy ve chan doan, tien Iffdng va quyet dmh dieu t r i . Oac biet viec phan nhom tien Iffdng cd y nghia quyet dinh trong Iffa chpn phffdng phap ghep te bao gdc ddng loai cho benh nhan, nhffng benh nhan thudc nhdm nguy cd cao dffdc chi djnh ghep te bao gdc sdm ngay ddt lui benh dau tien. Nhieu nghien cffu di sau vao phan tfch cac bien ddi nhiem sac the, dac biet cac chuyen doan tai dien. Tuy nhien gan day phat hien cac bien doi gen khdng lien quan den chuyen doan nhiem sac the khien phan loai tien Iffdng Id xe mi cap tien them mdt bffdc mdi.
Cac bien doi gen dd la NPMl, FLT3-iTD, CEBPA, c-KIT. NCCN da bd sung cac bien dd'i gen nay cung vdi cac kieu nhiem sac the trong phan nhdm tien Iffdng [4], Tai Viet nam gan nhff rat it nghien cffu nao de cap den tien Iffdng Id xe mi cap ddng tiiy. Nam 2010, Vu Minh Phffdng va Pham Quang Vinh da nghien cffu ve nhdm nguy cd trong Id xe mi cap ddng tuy, tuy nhien chffa phan tich den cac bien ddi gen nay nen viec phan nhdm cdn han che. Vi vay chung tdi tien hanh nghien cffu nay vdi 2 muc tieu sau:
1. Nghiin c&u cac biin dd'i nhiem sac the, gen NPM1,FLT3-ITD va phan nhdm tien l&dng d nhan Idxi ml cip ddng tuy
2. B&dc dau nghiin c&u dap uhg dieu tri tin cdng d cac nhdm tien l&png
* Dai hgc Y Ha Npi
** Benh vien Bach Mai
Phan biin khoa hgc: PCS. TS Nguyen Thanh Ha
Y HOC VIET NAM THANG 2 - SO 2/2014 II. £)0I TUpWG VA PHl/CyNG P H A P NGHIEN CUlJ
2 . 1 . OOP tu'dng nghien cCTu: 100 benh nhan di/qlc chan doan xac dinh la 10 xe mi cap dong tuy theo tieu chuan cua WHO 2008 [5]
du'cfc dieu tri tai Khoa Huyet hoc - truyen mau B^nh vien Bach Mai t i f 9/2012 den 9/2013, tuoi tir 16, khong mac cac benh man tinh, suy tim, suy than, gia dinh va benh nhan cam ket dong y dieu tri hoa chat
2.2, Phu'dng phap nghien cu'u:
- Chan doan benh; Id xe mi cap dong tiiy the theo tieu chuan WHO 2008[5]
III, K E T QUA NGHIEN CU'U
3 . 1 , Dac d i e m n h o m b e n h nhan nghien cu'u:
- So lu'dng benh j i h a n : 100 benh nhan, ty le nam/niJ.' 49/51, tuoi trung binh: 39,24 i 3.2, Oac d l e m v e nhiem sac t h e va bien doi gen cua nhom b e n h nhan nghi
Bang 3,1. Dac diem ve nhiem sac the
- Phan tich bp nhiem sac the phat hien bat thu'dng va lam xet nghiem gen NPMl va FLT3- ITD
- Cac doi tuong nghien cii'u duOc chia lam 3 nhom tien luOng du'a vao dac diem cua di truyen theo tieu chuan ciia NCCN 2.2013[6]
- Tien hanh dieu tri hoa chat theo phac do 3+7 va danh gia dien bien dieu tri
- Oanh gia ket qua dieu tri bang huyet tiiy do (sau 4 tuan khi ket thuc dot dieu tri) theo tieu chuan ciia NCCN 2.2013[6]
STT 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Kieu nhiem sac the Binh thi/dnq (46XX hoac 45XY)
47 XY +8 47 XX +21 46 XY, XX /4n 46 XY del 9q22 +17+8+21
t(8;21) t{8;21), -Y
t{15;17) t(15;17)+7q t(15;17)+mar inv(16)(pl3,q22)
46 XY, t(9;22) t(3;3)(q25;q29) Nhieu ton thi/dnq (tren 3 bien doi)
t(9;21) 46XY del 15(pl2;pl3)
47 +mar -8,+6(q27),+2(q37)
47XX +22 del l l q l S del llq23 +8,-19 t(10;ll)(pl4,q21)
47XX, +10 46XX, 16q+
t(4,ll) Khong phan bao
S6lu'!(nq(N=100) 55
1 1 2 1 1 3 5 8
"/o
Nh^n xit: Nhom nghien ciru cd 28 kieu nhiem sac the, trong do ty le thffdng cao nhat
nhdm cd nhiem sac the binh
Y HOC VIET NAM THANG 2 - SO 2/2014
Bang 3.2. Dac diem ve
STT
1 2
phan bo cac bien doi gen NPMl va FLT3-rTD
Co bien doi gen
NPMl FLT3-ITD
Nhom nghien cu'u N^lOO n 33 27
% 33 27
Nhom CO NST binh thu'dng N=55 n 20 15
36,5 %
27,3 Nhan xet: Jy le cd NPMl cao hdn FLT3~ITD
Bang 3.3. Phan nhdm tien Iffdng nhdm benh nhan nghien cffu:
Nhom tien luong
Tot
Trung binh
Xau
Khong phan bao
Kieu bien doi t(15;17)
t(8;21) inv(16)
Nhiem sac the binh thu'dng vdi NPMl(+)/FLT3-ITD(-) Nhiem sac the binh thudng khong cd NPMl(+)/FLT3-rrD(-) hoac NPMl(-)/FLT3-rrD(+)
+8 ddn doc
Dang khong xac dinh khac Tir 3 bat thu'dng NST trd len Bat thu'dng llq23 khong co t(9;ll) t(3;3)
t(9,22)
Nhiem sac the binh thu'dng co NPMl(-)/FLT3-n"D{+)
So lUdng (N=lbo)
10 8 2 12 36 1 16 4 1 1 1 7 1
Tile
%
32
53
14
1 Nhan xet: Nhdm nguy cd trung binh cd b/ le cao nhat, nhdm nguy cd xau cd ty le thap nhat.
3.4. Ket qua di'eu trj nhom benh nhan nghien cu'u: sd benh nhan dieu tri: 61 Bang 3.5. Ket qua dieu tri theo phan nhdm tien Iffdng
Nhom tien lu'dng (N=61) • Tot (n=13) Trung binh (n=42)
Xau (n=6)
Lui benh hoan toan n
11 28 3
84,6% %
65,66%
5 0 %
Lui benh khong hoan toan n 0 7 2
0% %
16,67%
33,3%
Khong lui benh n 2 7 1
16,4% %
16,67%
16,7%
Nhan xet: Jy le lui benh hoan toan cao nhat d nhdm tien Iffdng tot, thap nhat d nhdm tien Iffdng xau
Nhom tien lu'dng (N=61) •
Tot Trung binh
Xau
So ngay dieu trj trung binh
25,2±6,5 28,2±5,2 28,8±6,2
Thdi gian BC giam
<1G/I 3,25±4,2
7,79±7,2 8,17±5,27
Th6i gian phuc hoi bach u u hat >1 G/l
8,8±7,13
16,05±7,4
15,7±5,57
Nhan xet: So ngay dieu tri, thdi gian giam BC <1G/I, thdi gian phuc hdi BC hat >1G/I ngan nhat d
nhdm tien Iffdng tdt
Y HQC VlgT NAM THANG 2 - SO 2/2014
Bang 3.7. J</\
Nhom tien luong {N=61) Tot(n=13) Trunq binh fn=42)
Xau (n=6)
; nhiem khuan sau dieu tri hda chat Nhiim khuan
huyet n 2 0
15,3 %
0 1 1 16,7
Viem phoi n 5 10 3
38,5 %
23,8 50
Nhi^m khuan khac n 3 % 23
13 1 31
Khong nhiem khuan n 6 19 1 i 16,7 1
46,2 %
45,2 16,7
Nhan xet: Ty le khdng nhiem khuan cao nhat d nhdm tien IffOng totIV. BAN LU^N
4 . 1 . f>ac diem di truy'en va phan nhom tien lu'dng d nhom b$nh nhan nghien cu'u
4.1.1. Dac diem di truyen:
a. Dac diem ve nhiem sac the:
Ket qua d bang 3.3 cho thay cd 27 kieu bien doi nhiem sac the gap d nhdm benh nhan nghien cffu, Nghien cffu cua Susanne Schnittger tren 1003 benh nhan Id xe ml cap ddng tuy thay b/ le benh nhan cd bp nhiem sac the binh thffdng la 42,7%. Nghien cffu cua Jonh C.Byrd tren 1213 benh nhan cd t / le la 4 8 % [ 1 ] . Nhff vay la ty le Id xe mi cap ddng tuy cd bd nhiem sac the binh thffdng trong nghien cffu cua chung tdi cd cao hdn cac nghien cffu khac. Sff khac biet nay cd the do chenh lech ve cd mau. Tien hanh xac dinh mpt so cac bien ddi gen can thiet trong nhdm nay mang nhieu y nghia trong danh gia tien Iffdng benh.
Nhdm cd bien dd'i nhiem sac the chiem 4 5 % bao gom 26 kieu bien ddi khac nhau. Cac chuyen doan cd y nghia tien Iffdng tdt nhff t{8;21), t(15;17} va inv(16) chiem lan Iffdt 8%, 10% va 2%, Nghien cffu cua Susanne Schnittger tren 1003 benh nhan thay ty le lan Iffdt la 6,9%, 6,8% va 4,7%. Tffdng tff, ty le nay ciJng kha thap d nghien cffu cua David Grimwade tren 1065 benh nhan la 2 % , 4 % va 1 % , d nghien cffu cua Chritian Thiede tren 979 benh nhan la 5,3%, 3,6% va 5% [3] [ 2 ] . Nghien cffu cua Jonh C.
Byrd co ty le t(8;21) va inv(16) la 6,7% va 7,9%
[1]. Nhin chung cac chuyen doan cd y nghia tien lu'dng tdt cd ty le kha thap. Trisomy 8 ddn ddc la bien ddi cd y nghia tien Iffdng trung binh, nghien cull cua Chung toi gap 1 trffdng hdp chiem 1 % . Ty le nay kha khac nhau d nhieu nghien cffu.
Nghien cffu cua David Grimwade cd b^ le la 10%, ngffdc lai khong g3p trffdng hdp nao trong nghien cffu ciia Chritian Thiede va Susanne Schnittger [3] [ 2 ] . Cac chuyen doan cd y nghia Men Iffdng xau nhff bat thffdng l l q 2 3 (khdng cd t ( 9 ; l l ) , t(3;3) va t(9;22) chung tdi deu gap 1
tru'dng hop chiem 1 % . Nhin chung cac bat thffdng nay d'eu la dang hiem gap va co ty le thap. Nghien cffu ciia David Grimwade va Susanne Schnittger thay bat thffdng l l q 2 3 chiem 1 % va 3,6% [ 3 ] . Chuyen doan t(3;3) d nghien cffu ciia Jonh C. Byrd va Chritian Thiede la 1 va 1 , 4 % [ 2 ] [ 1 ] . _
b. Dac diim vi phan bdgen NPMl va FL T3-TTD Bien ddi NPMl va FLT3-rrD la 2 bien ddi gen cd gia tri tien Iffdng chi'nh d nhdm cd bd nhiem sac the binh thffdng, trong dd NPMl cd tien Iffdng tdt, ngffoc lai FLT3-ITD cd tien IffOng xau, Theo ket qua d bang 3.4 va bang 3.5, ty le gen NPMl d nhdm benh nhan nghien cffu la 33%
thap hdn d nhdm cd bd nhiem sac the binh thffdng la 36,5%. Tatsuya Suzuki thay ty le gen nay d nhdm cd bp nhiem sac the binh thffdng la 47,4%, trai lai thap hdn d nhdm cd bien doi nhiem sac the: 12,5% d nhdm cd inv(16), 33,3%
d nhdm cd t(9;22). Ket qua d bang 3.4 va 3.5 cd ty Ie FLT3-ITD d nhdm nghien cffu la 27,3% va d nhdm cd bd nhiem sac the binh thffdng la 27%.
Ket qua nay kha tu'dng ddng vdi James M.Foran, ty le FLT3-ITD chiem khoang 25% Id xe mi cap ddng tiiy va 3 1 % 10 xe mi cap ddng tiiy cd bd nhiem sac the binh thffdng [4]..
4.2. Phan nhom tien tu'dng d nhom nghien cu'u
Theo ket qua d bang 3.6, nhdm cd tien Iffdng tdt chiem 32%, nhdm cd tien Iffdng trung binh chiem 53%, nhdm cd tien Iffong xau chiem 14%.
Nhin chung ty le nay kha khac nhau d nhieu nghien cffu, tuy nhien nhdm cd tien lu'dng trung binh van chiem ffu the, Nghien cffu ciia David Grimwade tren 1065 benh nhan cd cac ty le nay la 7,3%, 72,9% va 19,8% [ 3 ] . Cac ty le nay d nghien cffu cua Tatsuya Suzuki la 19,8%, 71,7%
va 8,4%. Cac nghien cffu ciia Susane Schnittger, ciia Jonh CByrd deu cd nhdm cd tien Iffdng trung binh chiem ty le cao nhat [ 1 ] .
Y HOC VIET NAM THANG 2 - SO 2/2014 4 . 3 . Ket qua di'eu trj hoa chat ta:i cong d
nhom nghien cu'u
Theo bang 3.7, ty le lui benh hoan toan cao nhat d nhdm tien Iffdng tdt (84,6%), thi'p nhat d nhdm cd tien Iffdng xau ( 5 0 % ) , ngffdc Ic i ty le lui benh khdng hoan toan cao nhat d nlidm tien Iu'dng xau (33,3%), thap nhat d nhdm ti in Iffdng tdt (0%). Nghien cffu ciia David Grimw.ide thay nhdm tien Iffdng tdt cd ty le lui benh cao ( 6 3 % d nhdm t(15;17), 8 7 % d nhdm t(8;21) va 7 5 % d nhdm cd inv(16)), ngffdc lai ty le nay rat thap d nhdm cd tien iffdng xau ( 2 6 % d nhdm cd tren 3 bat thffdng di truyen) [ 3 ] . Nghien cffu cua Sherif S. Farag cung cho ket qua tffdng tff [7]. Nhin chung cac benh nhan thudc nhdm tien Iffdng tot cd kha nana dat lui benh hoan toan cao hdn.
Theo ddi dien bien dieu trj qua bang 3.8 t\ ay so ngay dieu trj trung binh, thdi gian bach cau giam dffdi IG/I, thdi gian phuc hdi bach cau hat trung ti'nh tren IG/I ngan nhat d nhdm cd tien Iffdng tdt, cao hdn d nhdm cd tien Iffdng trung binh va tien Iffdng xau. Ket qua nay cho thay kha nang phuc hoi sau dieu tri hda chat tdt hdn d nhdm cd tien Iffdng tdt. Thdi gian giam bach cau cung nhff thdi gian phuc hoi bach cau hat trung tinh ngan giiip benh nhan tranh dffdc tinh trang nhiem trung benh vien cd the dan tdi cac ket qua xau.
Cac ket qua d bang 3.9 rat tffdng ddng vdi bang 3.8. Ty le khdng nhiem triing cao nhat d nhdm tien Iffdng tot, thap nhat d nhdm tien Iffdng xau.
Ngffdc lai ty le viem phoi cung nhff nhiem khuan huyet cao nhat d nhdm cd tien Iffdng xau.
V. KET LUAN
Nghien cffu tren 100 benh nhan Id xe mi cap ddng tiiy d khoa Huyet hoc truyen mau benh vien Bach mai thay:
5 . 1 . Oac diem di t r u y e n va phan nhom tien lu'dng:
Cd 27 kieu nhiem sac the, trong dd bd nhiem sac the binh thffdng chiem ty le cao nhat (55%).
Ty le NPMl va FLT3-ITD 3 3 % va 27%. Nhdm cd den Iffdng tdt chiem 3 2 % , trung binh chiem 53%, xau chiem 14%
5.2. Ket qua dieu trj hoa chat t a n cong theo phan nhom tien lu'dng:
- Nhdm tien Iffdng tdt cd ty le lui benh hoan toan cao nhat (84,6%), ty le lui benh khdng hoan toan
thap nhat ( 0 % ) , nhdm tien Iffdng xau co ty le lui benh hoan toan thap nhat ( 5 0 % ) , b/ le lui benh khdng hoan toan cao nhat (33,3%).
- Nhdm tien lu'dng t d t cd sd ngay dieu tri, thdi gian bach cau giam dffdi I G / I , thdi gian phuc hoi bach cau hat trung tinh tren I G / I ngan nhat.
- Nhdm tien Iffdng tdt cd ty le khdng nhiem khuan cao nhat (46,2%_), nhdm tien Iffdng xau co ty le viem phd'i va nhiem khuan huyet cao nhat ( 5 0 % va 16,7%)
TAI LIEU T H A M KHAO
1. Byrd JC, Mrozek K, Dodge RK et al.
Pretreatment cytogenetics abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adults patients with de novo acute myeloid leukemia:
results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100: 4325-4336.
2. Christian Thiede, Christine Steudel, Brigitte Mohr et al. Analysis of ELT3-ITD activating mutation in 979 ps tients with acute myelogenous leukemia: associtation with FAB subtype and identification of subgroups with poor prognosis:
Presented in part at the 42nd Annual Meeeting of American Society of Hematology, December 1-5, 2000, SanFrancisco, CA. Blood 2002 99:4326-4335 doi:10.1192/blood.V99.12.4326
3. Grimwade D, Walker H, Harrison G et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML); analysis of 1065 patients entered into the United Kingdom Medical Research Coundl AML 11 trial. Blood 2001; 98; 1312- 1320.
4. James M Foran. New prognostic marker in acute myelogenous leukemia: Perspective from the Clinic, Hematology Dec 4.2010 Vol 47-55 5. James W. Vardiman, Juergen Thiele, Daniel
A. Arber et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasm and acute leukemia: rationale and important changes. Blood, July 30, 2009 vol.114 no.5937-951
6. NCCN Guidelines. Acute Myelogenous Leukemia.
Version 2.2013
7. Sherif S.Farag, Kellie J. Archer, Krzysztof Mrozek et al. Pretreatment cytogenebcs add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia:
results from Cancer and Leukemia Group B 8461.
Blood July 1, 2006 vol. 108 no.l 63-73