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