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Role of autotransplantation in the treatment ofacute promyelocytic leukemia patients in remission:
Fukuoka BMT Group Observations and a literature reviewේਃା∛㒮 ⴊᶧౝ⑼਄᧛ᥓᒾ દ⮮⢻ᷡ ઁ
Fukuoka Blood & Marrow Transplantation GoroupIntroduction⥄ኅ⒖ᬀ䈲㪘㪤㪣䈱ኡ⸃ᓟ≮ᴺ䈫䈚䈩ᐢ䈒↪䈇䉌䉏䈩䈇䉎䈏䋬㪘㪫㪩㪘૬↪ൻቇ≮ᴺ䈮䉋䉎ᴦ≹₸䈏ะ਄䈚䈢㪘㪧㪣䋬․䈮࿾࿕䉄
≮ᴺ䈏⚳ੌ䈚䈢ᤨὐ䈪ಽሶቇ⊛ኡ⸃䈱㪘㪧㪣䈪䈲䋬⥄ኅ⒖ᬀ䈲ᔅ䈝䈚䉅ᔅⷐ䈫䈘䉏䈭䈇䋮㪘㪧㪣ᴦ≮䈲⃻࿷䋬㪘㪫㪩㪘䈫䉝䊮䊃䊤䉰䉟䉪䊥䊮䉕ਛᔃ䈮⚵䉂┙䈩䉌䉏䋬䉲䉺䊤䊎䊮䋨㪚㪘䋩䈱ᗧ⟵䈏⇼໧ⷞ䈘䉏䉎䈭䈬䋬ᴦ≮ᒝᐲ䈏シᷫ䈘䉏䈩䈐䈢䋮䈚䈎䈚ᦨㄭ䈪䈲䊊䉟䊥䉴䉪⟲䈱ౣ⊒䉕ᛥ䈋䉎䈢䉄䋬㪚㪘ᄢ㊂≮ᴺ䈱ᗧ⟵䈏⷗⋥䈘䉏䋬㪜㪙㪤㪫䈱㪘㪧㪣䈮ኻ䈜䉎ㅧⴊᐙ⚦⢩⒖ᬀ䈱㫉㪼㫋㫉㫆㫊㫇㪼㪺㫋㫀㫍㪼㩷㪻㪸㫋㪸䈏ႎ๔䈘䉏䉎䈭䈬䋬㪘㪧㪣ᴦ≮䈻䈱⠨䈋ᣇ䈮䉅ᄌൻ䈏⷗䉌䉏䉎䋮㪝㪙㪤㪫㪞䈪䈲⃻࿷㪘㪧㪣䈱╙㪈ኡ⸃ᦼ䋨㪚㪩㪈䋩䈮䈍䈇䈩㫌㫇㪽㫉㫆㫅㫋䈮㪸㫌㫋㫆㪄㪧㪙㪪㪚㪫䉕ᣉⴕ䈚䈩䈇䈭䈇䈏䋬ㆊ෰䈮㪚㪩㪈䈪㪸㫌㫋㫆㪄㪧㪙㪪㪚㪫䉕ⴕ䈭䈦䈢㪉㪇଀䈫䋬╙㪉ኡ⸃ᦼ䋨㪚㪩㪉䋩䈪㪸㫌㫋㫆㪄㪧㪙㪪㪚㪫䉕ⴕ䈦䈢㪍଀䈮䈧䈇䈩䋬㐳ᦼ⊛䈭⚻ㆊ䉕ᬌ⸛䈚䋬䊥䉴䉪೎ጀ೎ൻᴦ≮䉇੝䊍㉄䋨㪘㪫㪦䋩䈏ዉ౉䈘䉏䈢⃻࿷䈱㪘㪧㪣ᴦ≮䈮䈍䈔䉎⥄ኅ⒖ᬀ䈱ᗧ⟵䈮䈧䈇䈩䋬ᢥ₂⊛⠨ኤ䉕ട䈋䈩ႎ๔䈜䉎䋮

Patients characteristics㪈㪐㪐㪉ᐕ㪋᦬ޯ㪉㪇㪇㪏ᐕ㪈㪈᦬䈮䋬㪝㪙㪤㪫㪞䈱㪍ᣉ⸳䈪ኡ⸃ᦼ䈮㛽㜑⎕უ⊛⒖ᬀ೨ᴦ≮䈱ᓟ䈮㪸㫌㫋㫆㪄㪧㪙㪪㪚㪫䉕ⴕ䈦䈢䋬㪘㪧㪣䈱㪉㪍଀䉕ኻ⽎䈫䈚䈢䋮ో଀䈏㪝㪘㪙ಽ㘃䈪㪘㪧㪣䈫⸻ᢿ䈘䉏䋬ᨴ⦡૕ᬌᩏ䈪 㫋㩿㪈㪌㪒㩷㪈㪎㪀㩿㫈㪉㪉㪒㩷㫈㪉㪈㪀䉕⹺䉄䉎䈎䋬㪩㪫㪄㪧㪚㪩ᬌᩏ䈪 㪧㪤㪣㪆㪩㪘㪩㱍䉨䊜䊤ㆮવሶ䈏ᬌ಴䈘䉏䈢䋮

Patients characteristics
Patients received auto-PBSCT in CR1 between April 1992 to November 2002
PatientNo.
1
2
34
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

Age/Sex34/F37/M
16/M
45/F
51/F
41/M
53/M
34/F
45/M
65/F
68/M
26/F
42/M
47/M
47/F
31/M
25/M
53/F
50/M
52/M

Initial WBC(x109/L)
2.5
21.9
1.0
0.6
17
10.2
0.85
0.8
20.6
0.5
0.8
2.6
13.2
2.0
1.8
5.5
1.2
8.9
1.4
4.76

Initial PLT(x109/L)
7.0
10
16
59
1210
1133
30
833
34
65
100
17
1.0
9.0
2467
24

Additional
chromosomal abnormality
6qcomplex-7
nonono+8
nononono
nono+8
no+8
nono
nono

Chemotherapy and collection of PBSC
Auto-PBSCT for CR1

Inductiontherapy

1stConsoli

2ndConsoli

Myeloablative
therapy

auto-PBSCTCR1G-CSF-combined BEA
Collection of
PBSC No.1

Collection of
PBSC No.2

Patients characteristics
Patients received auto-PBSCT in CR2 between August 1993 to November 2008
Patient

Age/Sex

No.
21
22
23
24
25
26

Initial WBC

Initial PLT(x109/L)(x109/L)

8.9
3.3
8.4
1.5
1.1
1.5

55
2.0
31
7.0
77
101

50/F
39/M
41/F
37/F
46/F
45/M

Additional
chromosomal
abnormality
nonononono-11q

Months from

Types ofDiagnosis to Relapse

Relapse2082354
2112

Hematological
Hematological
Molecular
Hematological
Molecular
Molecular

Chemotherapy and collection of PBSC
Re-induction therapy
Cytotoxic chemotherapy without ATO: 3 patients
ATO 0.15mg/m2 with or without IDA: 3 patients

Characteristics of 26 patientstransplanted in CR1 and CR2
CR1

CR2

(n = 20)(n = 6)45(16-68)

46(37-50)

12/8

2/4

>10x109/L

50㻡 10x109/L

15

6

Yes

61No

14

5

Months from diagnosis to auto-PBSCT

6 (5-13)25.5 (12-61)

Months from auto-PBSCT to present

133(37-193)

41 (2-187)

Infused CD34+ cells (x106cells/kg)

7.1(1.03-20.2)

6.1(0.5-11.2)

AgeSex (M / F)
WBC at Diagnosis

Additional chromosomal abnormality

G-CSF-combined BEA
Day
G-CSF 200㱘g/sqm,div.

-12 -11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 0㸣 㸣 㸣 㸣 㸣 㸣 㸣

400㱘g/sqm,div.

㸣 㸣

CA

100mg/sqm, div.

㸣 㸣 㸣 㸣 㸣 㸣 㸣

BU

4mg/kg,po.

Etop

20mg/kg,

div.

CA

3g/sqm,div. every 12hr㸣 㸣 㸣 㸣㸣 㸣㸣 㸣㸣 㸣

Auto-PBSCTResults
Auto-PBSCT in CR1(n = 20)Auto-PBSCT in CR2(n = 6)

Absolute granulocyte count > 0.5 x 109/L

15 (13–24) days

11 (9–12) days

Platelets > 20 x 109/L

11 (8–210) days

14 (11–15) days

Independence from platelet infusion

11 (6–191) days

11 (8–15) days

0%0%

133 (73–193) months

41 (2–187) months–

Negative: 6 patients

Negative:14 patients–

Days from auto-PBSCTTRMMedian follow-up time
MRD (PML/RAR㱍 mRNA)
Pretransplant BM
Graft (PBSC)

Discussion
AuthorN(Publication)
Mandelli et al187

Autotransplantation results in APL

AgeDisease Status

Source ofPretransplant BM

Graft(Median)at Transplant

autotransplantation

PCRPCR30

CR1: 129BM

Not available

Not available(1994)
Meloni et al

CR1
Outocome

18%(CR1)

48% 7-years LFS(CR1)

23%(CR2)

31% 7-years LFS(CR2)

Not available

0%Median survival

CR2: 58
1538

CR2: 15BM(1997)
Ferrant et al

TRM

Negative 8
Positive 728 months

36

Not available

CR1: 36BM

Not available

Not available

Not available

70% 3-years LFS

1047

CR1: 8BM 4

Negative 2

Not available

0%90% median survival

CR2: 1PB 6(1997)
Roman et al

83% at 3-years OS(1997)

41 monts

PR: 1Lo Coco et al840

CR2: 8BM

Negative 8

Not available

0%75% DFS at 9.5 months

1630

CR1: 13BM

Negative 12

Not available

0%

Median duration of(1997)
Ottaviani et al(1998)

PR: 1

Posirtive 3CR1: 55 months

CR2: 1CR3: 1
Thomas et al

22

Not available

CR2: 22(2000)
Ferrara et al

BM 5

Negative 9

Negative 2

PB 17

Positive 1

positive 4

9%79% at 3-years OS

638

CR2: 6BM or PB

Negative 6

Negative 60%83% at 36 months

5045

CR2: 50

BM 43

Negative 28

Negative 206%

79.4% LFS at 7 years

PB 7

Positive 2

Positive 2

Not available

Not available

10%(CR1)

70% 5-years LFS(CR1)

16%(CR2)

51% 5-years LFS(CR2)

Not available

0%83.3% 5-years EFS

CR1: Negative 150%

100% 11-years LFS(CR1)(2004)de Botton et al(2005)
Sanz et al344(2007)
Thirugnanam R et al1450(CR1)

CR1: 149

CR1: BM 92, PB 57

38(CR2)CR2: 195

CR2: BM 91, PB 104

33

CR2: 12PB(2009)
FBMTG(2010)

Negative 14CR3: 22645

CR1: 20
CR2: 6PB
CR2: Nevative 6

100% 3-years LFS(CR2)

Discussion
Design of the LPA99 and the APL2000 trials
PETEMA LPA 99

APL 2000
Ades, L. et al. Blood 2008;111:1078-1084

Discussion
AuthorN(Publication)
Mandelli et al

187

Autotransplantation results in APL

Age

Disease Status

Source ofPretransplant BM

Graft(Median)at Transplant

autotransplantation

PCR

PCR

30

CR1: 129BM

Not available

Not available(1994)
Meloni et al

CR1
Outocome

18%(CR1)

48% 7-years LFS(CR1)

23%(CR2)

31% 7-years LFS(CR2)

Not available0%Median survival

CR2: 58
1538

CR2: 15BM(1997)
Ferrant et al

TRM

Negative 8Positive 728 months

36

Not available

CR1: 36BMNot available

Not available

Not available

70% 3-years LFS

1047

CR1: 8BM 4

Negative 2

Not available

0%90% median survival

CR2: 1

PB 6(1997)
Roman et al

83% at 3-years OS(1997)

41 monts

PR: 1Lo Coco et al840

CR2: 8BM

Negative 8

Not available

0%75% DFS at 9.5 months

1630

CR1: 13BM

Negative 12

Not available

0%Median duration of(1997)
Ottaviani et al(1998)

PR: 1

Posirtive 3CR1: 55 months

CR2: 1CR3: 1
Thomas et al

22

Not available

CR2: 22(2000)
Ferrara et al

BM 5

Negative 9

Negative 2

PB 17

Positive 1

positive 4

9%79% at 3-years OS

638

CR2: 6BM or PB

Negative 6

Negative 60%

83% at 36 months

5045

CR2: 50

BM 43

Negative 28

Negative 20

6%79.4% LFS at 7 years

PB 7

Positive 2

Positive 2

Not available

Not available

10%(CR1)

70% 5-years LFS(CR1)

16%(CR2)

51% 5-years LFS(CR2)

Not available

0%83.3% 5-years EFS

CR1: Negative 150%

100% 11-years LFS(CR1)(2004)de Botton et al(2005)
Sanz et al344(2007)
Thirugnanam R et al1450(CR1)

CR1: 149

CR1: BM 92, PB 57

38(CR2)CR2: 195

CR2: BM 91, PB 104

33

CR2: 12PB(2009)
FBMTG(2010)

Negative 14

CR3: 22645

CR1: 20
CR2: 6PB
CR2: Nevative 6

100% 3-years LFS(CR2)

Discussion
AuthorN(Publication)
Mandelli et al

CR2
Autotransplantation results in APL

Age

Disease Status

Source of(Median)at Transplant

autotransplantation

PCR

PCR30

CR1: 129BM

Not available

Not available

187(1994)

Pretransplant BMGraft

TRM

Outocome

18%(CR1)

48% 7-years LFS(CR1)

23%(CR2)

31% 7-years LFS(CR2)

Not available

0%Median survival

CR2: 58

Meloni et al1538

CR2: 15BM(1997)

Negative 8
Positive 7Ferrant et al

28 months

36

Not available

CR1: 36BM

Not available

Not available

Not available

70% 3-years LFS

1047

CR1: 8BM 4

Negative 2

Not available

0%90% median survival

CR2: 1

PB 6(1997)

83% at 3-years OS

Roman et al(1997)

41 monts

PR: 1Lo Coco et al840

CR2: 8BM

Negative 8

Not available

0%75% DFS at 9.5 months

1630

CR1: 13BM

Negative 12

Not available

0%

Median duration of(1997)
Ottaviani et al(1998)

PR: 1

Posirtive 3CR1: 55 months

CR2: 1CR3: 1
Thomas et al

22

Not available

CR2: 22(2000)
Ferrara et al

BM 5

Negative 9

Negative 2

PB 17

Positive 1

positive 4

9%79% at 3-years OS

638

CR2: 6

BM or PB

Negative 6

Negative 60%83% at 36 months

50

45

CR2: 50

BM 43

Negative 28

Negative 206%

79.4% LFS at 7 years

PB 7

Positive 2

Positive 2

Not available

Not available

10%(CR1)

70% 5-years LFS(CR1)

16%(CR2)

51% 5-years LFS(CR2)

Not available

0%83.3% 5-years EFS

CR1: Negative 150%

100% 11-years LFS(CR1)(2004)de Botton et al(2005)
Sanz et al344(2007)
Thirugnanam R et al50(CR1)

CR1: 149

CR1: BM 92, PB 57

38(CR2)CR2: 195

CR2: BM 91, PB 104

33

CR2: 12PB14(2009)

Negative 14

CR3: 2

FBMTG

2645(2010)

CR1: 20PB

CR2: 6Discussion

CR2: Nevative 6

100% 3-years LFS(CR2)

Mmimal residual disease (MRD)

Induction: ATRA-based chemotherapy
Three consolidation course: 1st consoli䋺IDA 5mg d1-4
2nd consoli䋺Mit 10mg d1-5
3rd consoli䋺IDA 12mg d1

MRD-

Maintenance䋺ATRA(15d/3months䋩+ 6MP+ MTX

MRDInduction

MRD+34/69(49.3%) 35/69(50.7%)

MRD+

GIMEMA 60.3%
PETHEMA 51.3%

1st consoli

23/35

12/35

2nd consoli

10/12

2/12

3rd consoli

1/2

1/2

MRD+MRD-Lee. et al. Hematologica 2007;91:671-674

Conclusion
1. auto-PBSCT䉕CR1䈪ⴕ䈦䈢20଀䋬CR2䈪ⴕ䈦䈢6଀䈫䉅䈮䋬㊀◊䈭RRT䉇TRM䉕⹺䉄䈝䋬቟ో䈮ᣉⴕ䈪䈐䈢䋮
2. ೋ⸻ᤨWBC 10000/㱘lએ਄䈱∝଀䉕5଀䉕฽䉃䋬CR1䈪䈱
auto-PBSCTᣉⴕ䈚䈢20଀䈲䋬ⷰኤᦼ㑆ਛᄩ133䊱᦬䈪ో଀䈏ήౣ⊒↢ሽ䈚䈩䈇䈢䋮
3. CR2䈪auto-PBSCT䉕ⴕ䈦䈢6଀䈲䋬ಽሶቇ⊛ኡ⸃䈮㆐䈚䈢ᓟ䈱ౣ⊒䈪䈅䉍䋬auto-PBSCTᓟ䋬ⷰኤᦼ㑆41䊱᦬䈪ో଀䈏ήౣ⊒↢ሽ䈚䈩䈇䈢䋮
4. CR1䈪auto-PBSCT䈚䈢20଀ਛ䋬ᬌᩏ䈚䈢14଀ో଀䈏graft䋨PBSC䋩ਛ䈱MRD㒶ᕈ䈪䋬CR2䈪auto-PBSCT䈚䈢6଀ో଀䈏⒖ᬀ೨䈱㛽㜑MRD䈏㒶ᕈ䈣䈦䈢䋮