hematopoietic stem cell transplantation of acute … · diagnosed in mar 2015 in the presentation...
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Hematopoietic Stem Cell Transplantation of Acute Lymphoblastic Leukemia
in Taiwan
Tran-Der Tan, Chair of Hematopoietic Stem Cell Transplantation Multidisciplinary Team, Koo Foundation Sun Yat-Sen Cancer Center, Taipei.
On Behalf of Taiwan Society of Blood and Marrow Transplantation (TSBMT)
Case 1
• 49-year old woman hair stylist, acute lymphoblastic leukemia diagnosed in Mar 2015 in the presentation of fever, malaise, easy fatigue, and abdomen fullness, and then anemia and hyperleukocytosis WBC 270000/ul found, underwent Imatinib and then Dasatinib plus dexamthasone with complete remission achieved, however, she declined to undergo more intensive chemotherapy or allo-transplant at outside hospital.
• 6 months later leukemia relapsed and then try nilotinib with temporary remission then relapsed, ie. triple TKIs failed then went to our hospital and CHR achieved after phase I GMALL induction chemotherapy then MMR achieved after phase II, s/p conditioning regimen TBI/Cy + ATG and stem cell infusion on 2016/01/29 and now post-transplant +3Y3M.
Case 2
• 44-year-old worker, Pre-B cell Acute lymphoblastic leukemia with normal cytogenetic and no specific gene mutation found, in the presentation of abdomen pain and hepatosplenomegaly in late Mar 2018 and then went to prior hospital then diagnosis made and anemia and thrombocytopenia found as well with WBC 53000/ul, Hgb 7.7gm/dl, and platelet 9000/ul; with packed cell and platelet transfusion, then 1st cycle of HyperCVADchemotherapy started with CR achieved, followed by subsequent Hyper-CVAD/MA for totally 6 cycles at our hospital then prepared for allogeneic hematopoietic stem cell transplant.
• Continued CHR but MRD(+) by FCM found in Sep 2018, just before the start of transplant, s/p one cycle of blinatumumab with CR with MRD negative achieved in Oct 2018.
• s/p Haploidentical allogeneic stem cell transplantation from his daughter on Nov 13, 2018 with TBI 12Gy/Flu + PTCY conditioning and now post-transplant +5 months.
Incidence of myeloid
malignancy in Taiwan,
2016
AML ALL CML, bcr-abl (+)
Incidence of ALL in Taiwan, 2016
Introduction
• This is a retrospective study with data base from registry of Taiwan Society of Blood and Marrow Transplantation (TSBMT).
• We want to know the real world outcome of patients of acute lymphoblastic leukemia whom underwent (allogeneic) hematopoietic stem cell transplantation after induction chemotherapy.
• Besides, after the introduction of targeted tyrosine kinase inhibitor and allogeneic hematopoietic stem cell transplantation the overall survival improved in historical comparison in Ph(+) ALL. We compared the outcome of Ph(+) versus Ph(-) patients.
• For relapsed patients, salvage chemotherapy could achieve few patients in remission and then 2nd transplant is an option for cure in limited patients and we will see the overall survival.
Incidence of cancer and mortality in Taiwan, 2016
Indcution therapy – pediatric inspired protocol
• GMALL protocol
• GRAALL protocol
• MDACC protocol, HyperCVAD/MA
• TPOG protocol
• *Tyrosine kinase inhibitor (imatinib or dasatinib) added if Ph(+).• **Rituximab added if CD20+.
Intensive consolidation therapy
• Allogeneic hematopoietic stem cell transplantation, with either myeloablative e.g. TBI/Cy, BUCY, FluBu4, or RIC conditioning regimen e.g. FluBu2, FluCy, or others as long as remission achieved for high risk patients.
• Autologous hematopoietic stem cell transplantation, with either TBI/Cy or BUCY conditioning regimen if complete remission achieved.
• Non-transplant regimen, to complete the various chemotherapy protocol.
Definition of high risk group
• > 30 yrs of age
• WBC count > 30K in B-ALL, > 100K in T-ALL
• Ph+ — t(9;22), BCR-ABL translocation
• Ph-like lesions
• Other chromosomal aberrations
– t(4;11), 11q23+, MLL rearrangement
– Hypodiploidy (≤ 44 chromosomes)
• CNS involvement
• MRD positive (> 10-4 or 0.01%) after induction
資料來源與分析目的
Patient Demographics
Survival Analysis
11
資料來源與分析目的
資料來源:中華民國骨髓移植學會收錄1995年6月至2017年9月間共526 位進行骨髓
移植之 Acute
lymphoblastic leukemia病人,追蹤至2018年11月(資料由譚醫師提供)。
目的:分析全台骨髓移植之Acute lymphoblastic leukemia病人:1.敘述統計:性別、年齡、追蹤狀況、移植類型、Donor of transplant、
死亡原因。2.存活分析:
(1) Overall Survival
(2) BCR/ABL(+):BCR/ABL(+) vs. Others
(3) Disease Status:CR1 vs. CR2/CR3 vs. induction failure vs. relapsed
(4) 第二次移植病人的存活:Do 2nd HSCT survival
12
資料驗證
1.病人追蹤狀態歸類:
存活(OPD F/U、Lost of F/U)
死亡(Dead)
2. 1位病人沒有癌症診斷日:
Dead Lost of F/U OPD F/U 總計
Alive (0) 0 7 274 281
Dead (1) 245 0 0 245
總計 245 7 274 526
no dxdt sex age lastfud Disease_status BCR_ABL2 HSCT_dt HSCT_dt2 fud_status2
5087 . M 38.21 2011/12/20 relapse Others 2010/12/20 . OPD F/U
13
資料驗證問題
1.第二次骨髓移植:
病人在HSCT sheet中註記沒有接受第二次移植,但HSCT2
sheet中有第二次移植日期,且移植日期在最後追蹤日之後,於是將四人歸類為無第二次移植。
no dxdt lastfud Do_2nd_HSCT HSCT_dt2 surv_ms_hsct2
1464 2010/2/23 2017/5/4 FALSE 2018/5/1 -11.9014
2089 2015/6/16 2016/12/20 FALSE 2017/12/19 -11.9671
2143 2015/11/20 2017/6/9 FALSE 2017/9/12 -3.1233
2152 2015/11/5 2017/7/3 TRUE 2017/7/11 -0.263
14
全台ALL病人接受骨髓移植人數(n=526)
3
10
19
39
53 54
71
43
68
6360
40
3
0
10
20
30
40
50
60
70
80
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Alive
Dead
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Total
1st HSCT 3 10 19 39 53 54 71 43 68 63 60 40 3 526
Alive . 6 6 11 28 25 42 26 35 35 35 30 2 281 (53%)
Dead 3 4 13 28 25 29 29 17 33 28 25 10 1 245 (47%)
Time from cancer diagnosis to 1st HSCT (years)
Mean / Median / Min-Max 1.3 / 0.6 / 0.1-17.1
Num
be
r o
f p
atie
nts
15
全台ALL病人接受第二次骨髓移植人數(n=50)
4 4
10
3 3
6
7 7
2
4
0
2
4
6
8
10
12
14
16
18
20
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018
Alive
Dead
2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 Total
2nd HSCT 0 0 0 4 4 10 3 3 6 7 7 2 4 50
Alive . . . . 1 2 1 1 1 1 2 1 1 11 (22%)
Dead . . . 4 3 8 2 2 5 6 5 1 3 39 (78%)
Time from 1st HSCT to 2nd HSCT (years)
Mean / Median / Min-Max 1.1 / 0.5 / 0.1-6.4
Num
be
r o
f p
atie
nts
16
Patient Demographics
17
Table1. Patient Demographics
Total Alive Dead
All Patients 526 281 (53%) 245 (47%)
Sex
F 238 (45%) 130 108
M 287 (55%) 150 137
Unknown 1 (0%) 1 .
Age
(Mean/Median/min-max) 31/31/0.7-69 32/32/3-69 31/31/0.7-66
Disease Status
CR1 295 (56%) 198 (70%) 97 (40%)
CR2 116 (22%) 50 (18%) 66 (27%)
CR3 19 (4%) 5 (2%) 14 (6%)
induction failure 29 (6%) 6 (2%) 23 (9%)
relapse 60 (11%) 18 (6%) 42 (17%)
Unknown 7 (1%) 4 (2%) 3 (1%)
BCR/ABL2
BCR/ABL(+) 93 (18%) 56 37
Others 433 (82%) 225 208
Follow up Status
OPD F/U 274 (52%) 274 .
Lost of F/U 7 (1%) 7 .
Dead 245 (47%) . 245
Cause of Death
01.Relapse/Progresive/Persistent disease . . 150 (61%)
24.Infection . . 49 (20%)
21.GVHD . . 22 (9%)
09.Unknown . . 5 (2%)
03.New malignancy . . 3 (1%)
26.VOD . . 3 (1%)
27.IP . . 2 (1%)
28.Hemorrhage . . 2 (1%)
22.Rejection/Poor graft function . . 1 (0%)
23.Cardiac toxicity . . 1 (0%)
25.Pulmonary toxicity . . 1 (0%)
99.Others . . 6 (2%) 18
Table2. HSCT sources and types
Total Alive Dead
All Patients 526 281 (53%) 245 (47%)
HSCT type
31 HLA-matched sibling 200 (38%) 118 (42%) 82 (33%)
22 HLA-mismatched unrelated donor 152 (29%) 69 (25%) 83 (34%)
21 HLA-matched unrelated donor 112 (21%) 69 (25%) 43 (18%)
32 HLA partial mismatched related donor 37 (7%) 13 (4%) 24 (10%)
33 Haplotype 18 (3%) 9 (3%) 9 (4%)
01 Autologus 5 (1%) 3 (1%) 2 (1%)
09 Others 1 (0%) . 1 (0%)
Unknown 1 (0%) . 1 (0%)
Donor of transplant
Bone marrow stem cell
TRUE 37 (7%) 18 19
FALSE 489 263 226
Peripheral blood stem cell
TRUE 502 (95%) 269 233
FALSE 24 12 12
Umbilical cord blood stem cell
TRUE 7 (1%) 1 6
FALSE 519 280 239
2nd HSCT
TURE 50 (10%) 11 39
FALSE 476 270 206
*526位病人其Donor of transplant中,有26位病人同時有BM和PBSC,有6位病人不屬於這三種分類
BM PBSC UCB Total Alive Dead
FALSE FALSE FALSE 6 3 3
TRUE 7 1 6
TRUE FALSE 476 259 217
TRUE FALSE FALSE 11 8 3
TRUE FALSE 26 10 16
19
Survival Analysis
20
全台ALL病人接受首次骨髓移植後存活率(n=526)
Years after 1st HSCT
Pro
ba
bili
ty o
f O
ve
rall
Su
rviv
al
40%44%
21
全台ALL病人接受首次骨髓移植後存活率(n=526)Disease Status
Years after 1st HSCT
Pro
ba
bili
ty o
f O
ve
rall
Su
rviv
al
53%55%
31%
41%
CR3, n=19
CR1, n=295
p-value= <0.001
Induction failure, n=29Relapse, n=60
Unknown, n=7
14%14%
15% CR2, n=11616%16%
22
全台ALL病人接受首次骨髓移植後存活率(n=526)Disease Status (合併CR2&CR3)
Years after 1st HSCT
Pro
ba
bili
ty o
f O
ve
rall
Su
rviv
al
53%55%
29%
38%
CR2&CR3, n=135
CR1, n=295
p-value= <0.001
Induction failure, n=29Relapse, n=60
Unknown, n=7
14%14%
15%
23
全台ALL病人接受首次骨髓移植後存活率(n=526)BCR/ABL(+) vs others
Years after 1st HSCT
Pro
ba
bili
ty o
f O
ve
rall
Su
rviv
al
49%49%
38%42%
BCR/ABL(+), n=93
Others, n=433
p-value= 0.11
24
ph(+) ALL vs. ph(-) B cell-ALL vs. T cell-ALL (n=526)
Ph(-) B-ALL, 231, 44%
T-ALL, 129, 25%
Ph(+) B-ALL, 127, 24%
Others, 39, 7%
Total Alive Dead
n % n % n %
All Patients 526 100% 281 53% 245 47%
Ph(+) B cell ALL 127 100% 80 63% 47 37%
Ph(-) B cell ALL 231 100% 107 46% 124 54%
T cell ALL 129 100% 70 54% 59 46%
Others 39 100% 24 62% 15 38%
25
ph(+) ALL vs. ph(-) B cell-ALL vs. T cell-ALL (n=526)
Total Ph(+) B-ALL Ph(-) B cell-All T-ALL Others
n % n % n % n % n %
All Patients 526 100% 127 100% 231 100% 129 100% 39 100%
CR1 295 56% 106 83% 104 45% 64 50% 21 54%
CR2 116 22% 13 10% 62 27% 29 22% 12 31%
CR3 19 4% 1 1% 15 6% 2 2% 1 3%
Unknown 7 1% 1 1% 4 2% 1 1% 1 3%
induction failure 29 6% 1 1% 17 7% 9 7% 2 5%
relapse 60 11% 5 4% 29 13% 24 19% 2 5%
26
ph(+) ALL vs. ph(-) B cell-ALL vs. T cell-ALL (n=526)
54%
38%
42%
55%
51%
33%
40%
55%
Ph(+) B-cell ALL,
n=127
Ph(-) B-cell ALL, n=231
T cell ALL, n=129
Others, n=39
p-value= 0.009
Pro
ba
bili
ty o
f O
ve
rall
Su
rviv
al
Years after 1st HSCT
27
全台ALL病人接受第二次骨髓移植後存活率(n=50)
Month after 2nd HSCT
Pro
ba
bili
ty o
f O
ve
rall
Su
rviv
al
32%
21%18%
28
Cause of Death
Relapse/progressive disease Infection GVHD
Unknown New malignancy VOD/SOS
Idiopathic pneumonitis Hemorrhage Rejection/graft failure
Cardiac toxicity Pulmonary toxicity Others
Table1. Patient Demographics
Total Alive Dead
All Patients 526 281 (53%) 245 (47%)
Sex
F 238 (45%) 130 108
M 287 (55%) 150 137
Unknown 1 (0%) 1 .
Age
(Mean/Median/min-max) 31/31/0.7-69 32/32/3-69 31/31/0.7-66
Disease Status
CR1 295 (56%) 198 (70%) 97 (40%)
CR2 116 (22%) 50 (18%) 66 (27%)
CR3 19 (4%) 5 (2%) 14 (6%)
induction failure 29 (6%) 6 (2%) 23 (9%)
relapse 60 (11%) 18 (6%) 42 (17%)
Unknown 7 (1%) 4 (2%) 3 (1%)
BCR/ABL2
BCR/ABL(+) 93 (18%) 56 37
Others 433 (82%) 225 208
Follow up Status
OPD F/U 274 (52%) 274 .
Lost of F/U 7 (1%) 7 .
Dead 245 (47%) . 245
Cause of Death
01.Relapse/Progresive/Persistent disease . . 150 (61%)
24.Infection . . 49 (20%)
21.GVHD . . 22 (9%)
09.Unknown . . 5 (2%)
03.New malignancy . . 3 (1%)
26.VOD . . 3 (1%)
27.IP . . 2 (1%)
28.Hemorrhage . . 2 (1%)
22.Rejection/Poor graft function . . 1 (0%)
23.Cardiac toxicity . . 1 (0%)
25.Pulmonary toxicity . . 1 (0%)
99.Others . . 6 (2%)
Take home message1. 294 ALL occurred in Taiwan in 2016, around
12~15% of all myloid malignancies (AML, ALL, MDS, MPN); bimodal distribution in male but not in female.
2. Allo-HSCT for high risk patients and Auto-HSCT for some patients after a variety of induction chemotherapy protocol.
3. Better outcome in CR1 > CR2 > induction failure and relapsed/refrctory.
4. Targeted therapy plus allo-HSCT can overcome the poor prognostic factor Ph(+) with statistically significant better overall survival.
5. For second transplant senario, durable survival is worse but is still worth to be considered.
• THANK YOU FOR YOUR LISTENING
Office of Epidemiology and Biostatistics
Koo Foundation Sun Yat-Sen Cancer Center
31
Acknowledgement
Thanks for all the members and transplant
centers and hospitals to take care of these
patients and provide data in TSBMT