原三信病院 血液内科 勉強会	

急性骨髄性白血病	  Acute	
  Myeloid	
  Leukemia	  （AML）	
  Version	  1.0	  2015年5月8日	
  原三信病院 血液内科	
  	  上村 智彦 作成	

急性骨髄性白血病	  Acute	
  myeloid	
  leukemia	
  (AML)	
白血球，赤血球，血小板などの血液細胞は，骨髄において造血幹細胞からそれぞれの前駆細胞を経て分化・増殖する．これらの血液前駆細胞が，「がん化」して異常に増殖することで起こる腫瘍性疾患
が急性白血病である．骨髄系細胞の場合は，急性骨髄性白血病（AML:	
  Acute	  Myeloid	
  Leukemia）と呼ばれる．AMLを発症すると，骨髄中で幼若な細胞（異常芽球）が大量に増殖し，正常な造血が抑制される．結果として，正常な白血球減少による易感染症状態や貧血，血小板減少による出血傾向来す．	
  骨髄における正常造血	
骨髄芽球	

前骨髄球	

骨髄球	

後骨髄球	
 桿状好中球	
 分葉好中球	

骨髄系	
  
前駆細胞	
単芽球	

造血幹細胞	

成熟単球	

自己複製	

巨核球	
前赤血芽球	

Bリンパ球	

リンパ系	
  
前駆細胞	

Pro-­‐B	

血小板	Pre-­‐B	

急性リンパ性白血病	

Tリンパ球	
Pro-­‐T	Pre-­‐T	

赤血球	
赤芽球	
Immature	  B	
 Mature	  B	
 Ac7vated	
  B	

形質細胞	
  

骨髄におけるAMLの発症	
骨髄芽球	

前骨髄球	

骨髄球	

後骨髄球	
 桿状好中球	
 分葉好中球	

骨髄系	
  
前駆細胞	
単芽球	

造血幹細胞	
自己複製	

成熟単球	

遺伝子異常	

巨核球	

遺伝子異常	

前赤血芽球	

AML幹細胞	

Bリンパ球	

リンパ系	
  
前駆細胞	

Pro-­‐B	

血小板	Pre-­‐B	

急性リンパ性白血病	

Tリンパ球	
Pro-­‐T	Pre-­‐T	

赤血球	
赤芽球	
Immature	  B	
 Mature	  B	
 Ac7vated	
  B	

形質細胞	
  

French-­‐American-­‐BriBsh（FAB）分類	
骨髄芽球	

前骨髄球	

骨髄球	

後骨髄球	
 桿状好中球	
 分葉好中球	AML	
  (M0,	
  M1,	
  M2)	
骨髄系	
  
前駆細胞	

AML	
  (M3)	
  急性前骨髄球性白血病（APL）	
  単芽球	

造血幹細胞	
自己複製	AML	
  (M6)	

急性白血病は	
  増殖能は保持するが	  分化能を喪失する	

成熟単球	

AML	
  (M4,	
  M5)	AML	
  (M7)	
巨核球	
前赤血芽球	

Bリンパ球	

リンパ系	
  
前駆細胞	

Pro-­‐B	

血小板	Pre-­‐B	

急性リンパ性白血病	

Tリンパ球	
Pro-­‐T	Pre-­‐T	

赤血球	
赤芽球	
Immature	  B	
 Mature	  B	
 Ac7vated	
  B	

形質細胞	
  

WHO分類（2008年）	
1.

特異的染色体相互転座を有するAML	
  
a.
b.
c.
d.
e.
f.

染色体転座t(8;21)(q22;q22)または融合遺伝子RUNX1-­‐RUNX1T1を有するAML	  染色体第16番逆位inv(16)(p13.1q22)または転座t(16;16)(p13.1;q22)または融合遺伝子CBFB-­‐MYH11を有するAML	  急性前骨髄球性白血病[染色体転座t(15;17)(q22;q12)または融合遺伝子PML-­‐RARAを有する]	
  	
  染色体転座t(9;11)(p22;q23)またはMLLT3-­‐MLLを有するAML	  染色体転座t(6;9)(p22;q34)またはDEK-­‐NUP214を有するAML	  
染色体第3番逆位 inv(3)(q21q26.2)または転座 t(3;3)(q21;q26.2)または融合遺伝子RPN1-­‐EVI1を有するAML	
  

g.
h.

染色体転座t(1;22)(p13;q13)またはRBM15-­‐MKL1を有する巨核芽球性AML	  暫定的病型:	
  遺伝子突然変異を伴うAML	  (NPM1遺伝子変異,	
  CEBPA遺伝子変異など)	
  2.

骨髄異形成関連の変化を伴うAML	
  
a.
b.
c.

3.
4.

治療に関連した骨髄性腫瘍	
  上記以外の急性骨髄性白血病	
  
a.
b.
c.
d.
e.
f.

g.
h.
i.

5.
6.

最小分化型AML:	
  	  未分化型AML:	
   	
  
	
  
分化型AML:	  	
  急性骨髄単球性白血病:	
  	
  FAB分類の”MO”に相当	
  	
  FAB分類の”M1”に相当	
  	
  FAB分類の”M2”に相当	
  	
  FAB分類の”M4”に相当	
  急性単芽球性および単球性白血病:
	  FAB分類の”M5”に相当	
  急性赤芽球性白血病	
  
A)
赤白血病
	
  
	
  FAB分類の”M6”に相当	
  B)
純赤芽球型	  急性巨核芽球性白血病:	
  	
  FAB分類の”M7”に相当	
  急性好塩基球性白血病	
  骨髄線維化を伴う急性汎骨髄症	
  

骨髄肉腫	
  
ダウン症候群関連骨髄増殖	
  
a.
b.

7.

多血球系に異形成を有するAML	  骨髄異形成症候群(MDS)から移行したAML	  
MDSに関連した染色体異常を有するAML	  一過性骨髄増殖異常症	
  ダウン症候群関連骨髄性白血病	
  芽球性形質細胞様樹状細胞腫瘍	
  薬物療法への治療反応性が良いもの。	
薬物療法への治療反応性が悪いもの。	

AMLの骨髄像	
正常骨髄（x400）	

AML（x600）	

AMLの疫学	
日本における骨髄性白血病の発症頻度は，毎年10万人あたり男性 3.5人，女性 2.1人で，成人の骨髄性白血病の70%がAMLといわれている．年齢別にみると，21～69歳では10万人あたり0.6～6人だが，70歳以上になると10～17人と発症頻度は増加する．	
Lim and Jamieson
25

発症年齢中央値	
  67歳	

25

Percentage

15
10
5

20
15
10

5–
10 9
–1
15 4
–1
20 9
–2
25 4
–2
30 9
–3
35 4
–3
40 9
–4
45 4
–4
50 9
–5
55 4
–5
60 9
–6
65 4
–6
70 9
–7
4
75
–7
80 9
–8
4
85
+

0

<1
1–
4

Age at diagnosis

5Lim	
  MY.	
  Clin	  Interv	
  Agin	  2014:	
  753-­‐62
	
0
3

0

Figure 1 Age-speciﬁc SEER incidence rates for acute myeloid leukemia, 2006–2010.
Abbreviation: SEER, Surveillance, Epidemiology and End Results.

7

米国における2013年のAML発症年齢分布	

Incidence rates

2030

AMLの症状	
正常な血液が造れない	• (正常)白血球減少	
   	
  =易感染症状態• 赤血球減少 	  	
  =貧血 	  	  • 血小板減少	
   	
  
	
  =	
  出血傾向	   	  	  …発熱，風邪が治らない etc		
  …めまい，だるさ，動悸，息切れ		
  …血が止まらない,出血しやすい	

血管外臓器への浸潤	
• 肝臓･脾臓 	  • 中枢神経 	  	
  → 肝腫大･肝機能異常，脾腫		
  → けいれん，頭痛，幻覚 etc	その他	
• 発熱(腫瘍熱)	
• 骨痛	
• 播種性血管内凝固症候群(DIC)	
  =	
  出血傾向と微小血栓による多臓器不全	AML診断のための検査	
1.	
  血液検査	●血液学的検査（末梢血中の異常芽球の形態）	
  ●生化学検査	  ●凝固系検査（播種性血管内凝固，DIC）	
  ●感染症検査（HCV，HBVなど）	
  2.	
  骨髄検査	●形態学的検査	  	
  （ギムザ染色，ミエロペルオキシダーゼ染色などの特殊染色）	
  ●染色体検査	  ●キメラ遺伝子スクリーニング検査	  ●FLT3-­‐ITD，c-­‐KIT遺伝子変異検査	
  3.	
  その他	●体幹部CT検査	
  	
  （肺炎などの感染評価，肝脾腫，リンパ節腫大の有無）	
  ●頭部CT	
  and/or	
  MRI（中枢神経浸潤が疑われる場合）	
  ●心エコー，腎機能検査など，臓器予備能，合併症評価の検査	

AML治療の考え方	
体内の白血病細胞をゼロにする	
  =	
  Total	  cell	
  kill	

化学療法	
  （抗がん剤治療）	

造血幹細
胞移植	

その他	
  
(放射線治療など)	

支持療法
感染症対策，出血対策，貧血対策，消化器症状対策 etc	

白血病に対する寛解導入療法の概念	
抗癌剤	

白血病細胞と好中球の減少と増加	

抗癌剤	
正常な白血球（好中球）	

再発	

白血病細胞	減少期	増加期	

白血病に対する抗癌剤治療の概念	
寛解導入療法	
強化療法	

強化療法	

強化療法	

強化療法	

再発	

白
血
病
細
胞
数

血液学的寛解	

分子遺伝学的寛解		経過	

原三信病院 血液内科 勉強会	

急性骨髄性白血病	  Acute	
  Myeloid	
  Leukemia	  （AML）	
  Version	  1.0	  予後分類	生存曲線について	
100	

生

3年生存率	
  60%	

存

A	

率 50	
（

％
）	

B	

3年生存率	
  30%	

C	
0	

0	

1	

2	

3	

期 間 （ 年 ）	4	

5	AMLの予後分類	
染色体異常による予後分類	
  
予後分類	

良好群	

中間群	

不良群	

SWOG/ECOG	
  
MRC	
  
{Slovak,	
  2000	  #6}	  {Grimwade,	
  2010	  #3}	  inv(16)	
  inv(16)	
  t(16;16)	
   Core-­‐binding	
  factor（CBF）	
  t(16;16)	
  t(8;21)	
  白血病	
t(8;21)	
  t(15;17)	
  正常核型、 -­‐Y	
  
+6	
  
良好群、不良群に+8	
  属さないもの	
del(12p)	
  abn(3q)	
  	
  t(3;5)を除く abn(3q)	
  	
  -­‐5/del(5q)	
  inv(3)	
  t(6;9)	
  	
  -­‐5/del(5q),	
  add(5q)	
  	
  -­‐7/del(7q)	
  -­‐7/del(7q),	
  add(7q)	
  t(9;22)	
  	
  t(6;11)	
  	
  abn(9q)	
  	
  t(10;11)	
  	
  abn(11q)	
  	
  t(11q23)	
  	
  abn(17p)	
  	
  t(9;22)	
  abn(20q)	
  	
  -­‐17/abn(17p)	
  	
  abn(21q)	
  複雑核型 (≧4	
  aberra7ons)	
  複雑核型 (≧3	
  aberra7ons)	
  Slovak.	
  Blood.	
  2000:4075-­‐83;	
  	  	
  Grimwade.	
  Blood	
  2010:354-­‐65	
  est on April 2, 2015. For personalAMLの予後分類	
use only.

染色体異常による全生存率	
  BLOOD, 15 DECEMBER 2000 z VOLUME 96, NUMBER 13
全生存率	

k statusble
4)

Unknown(n 5 26)

44
18-54

良好群	

35%
21.5

中間群	

83%
52%
9.0

不良群	

41
0%
4%

Figure 2. Estimated distributions of OS by cytogenetic risk status. OS was
Slovak.	
  lood.	
  2000:4075-­‐83	
  measured from date of entry into the study until death from any
cause.BTick
marks

30



Cox regression analyses with relapse-free and20
erall survival as end points, the genotype of
Other genotypes
10 P<0.001
utant NPM1 without FLT3-ITD and the mutant
0
BPA genotype again appeared to be associated
0
1
2
3
4
5
6
7
8
9
10
th a favorable outcome. The 4-year rate of over 
survival for patients with the mutant NPM1
* + (
notype without FLT3-ITD was 60% and for0
Other genotypes
212 90 60 38 27 149542
ose with AcutemutantMyeloid
CEBPA was
62%. These outMutant NPM1 without 136 102 83 64 50 34 24 13
8
3
1
Normal
Leukemia
FLT3-ITDme data are similar to those for patients with
Mutant CEBPA
62 40 32 26 17 11
6
4
4
3
0
re-binding-factor leukemias, which are categofavorable ed as diseases with cytogenetically
Rlapse	  fpatientsree	
  survival	
Overall	
  survival	
39-41
ks.
In contrast,
thesubgroups
of
100
100
th the FLT3-ITD genotype
or the triple-nega90
90
e genotype consisting of wild-type NPM1 and80
80
BPA without FLT3-ITD had similarly poor out70
70
mes, with 4-year rates
of relapse-free survival
Mutant CEBPA
Mutant NPM1 without FLT3-ITD
60
60
24% and 25%, respectively, and 4-year rates of
50 and 33%, respectively.
50
erall survival of 24%
Mutant NPM1
Mutant CEBPA
The influence of 40
FLT3-TKD mutations on the
without FLT3-ITD
40tcome is unsettled.
30 A negative influence was30
42 but in a recent
ported in a meta-analysis,
20
20
Other genotypes
udy by the Medical Research Council, TKD mu- Other genotypes
10 P<0.001
10 P<0.001
ions were associated with a favorable outcome00
the entire cohort as
0 well1 as2 in 3patients
4
5 with
6
7
8
9
10
0
1
2
3
4
5
6
7
8
9
10
ogenetically normal AML.43 In our study,
FLT3  
D mutations were not significantly associated* + (* + (
thOtherthegenotypes
outcome, possibly0
212 90because
60 38other27 genetic
14
9
5 Other
42genotypes
266 153 90 68 39 22 159740
MutantNPM1
without
136
102
83
64
50
34
24
13
8
3
1
MutantNPM1
without
150 123 101 75 56 38 25 14 10
42
arkers, NPM1 in particular, were considered in
FLT3-ITD
FLT3-ITD
Schlenk	
  RF.	  New	
  E6ngl	  5J	  M3ed	  02008	  e Mutant
multivariable
analysis.
of paCEBPA
62 40Notably,
32 26 54%17 11
6
4 Mutant
4
3 CEBPA067 54 39 30 19 13
8
nts with the mutant FLT3-TKD genotype were

AMLの予後分類	
正常核型AMLにおけるNPM1，CEBPAの影響	           Survival	
  esBmates,	
  according	
  to	
  genotype	AMLの予後分類	
FLT3-­‐ITD変異と予後の関連性	
  
全生存率	

累積再発率率	

Bornhäuser	
  M.Blood.	
  2007:	
  2264	

FLT3 gene (FLT3-TKD and FLT3-LMs, respectively) were foundat a much higher frequency in patients with a normal karyotype anda t(15;17) translocation. These data clearly show that activating
mutations of FLT3 and KIT are associated with certain cytogenetic
AML subtypes.

leukocyte counts were not. Thus, the negamutations was found to be independent of
The same analysis was conducted for p
cally intermediate karyotype (Figure 3B)
novo AML (Figure 3C). In contrast to t

AMLの予後分類	
CBF白血病*におけるNPM1，CEBPAの影響	  *CBF白血病（予後良好群）	
  	
  inv(16)またはt(8;21)	
  AML	

inv(16)	

t(8;21)	

KIT Mutations in inv(16) and t(8;21) AML

Table 5. Multivariable Analysis for CIR for Patients With t(8;21), According
to KIT Status
Endpoint

Model

CIR

mutKIT v
wtKIT †

HazardRatio!

95% CIP

5.2

1.7 to 15.7

.004

NOTE. Overall survival not listed because it was not significantly associatedwith the mutational status of KIT.
Abbreviations: CIR, cumulative incidence of relapse; mutKIT, patients with a
KIT mutation; wtKIT, patients without KIT mutations.
!
Statistically significant hazard ratio ! 1 indicates a higher risk of an event for
the first category listed for the dichotomous variable.
†Adjusted for percentage of peripheral blood blasts.

Figure 3. Overall and event-free survival of patients with
D816 mutations in subgroups with t(8;21) or with intermediate karyotype. OS and EFS for patients with mutated or nonmutated KIT-D816. (A) Only t(8;21) subgroup. (B) Patients withintermediate karyotype. (C) All AML. Figure shows Kaplan-Meieranalyses for the patient numbers indicated. to“Median”
indicates
determinethe exact type of KIT mutation in each case because
Fig 2. Predicted overall survival of patients with inv(16) according to the mutational
median survival time; survival curves were compared using
status of KIT (ie, wild-type KIT [wtKIT] v any type of KIT mutation [mutKIT]), adjusted
specific TK inhibitors are active against particular KIT mutations.
double-sided log rank test.

Paschka	
  P.	
  J	
  Clin	  Oncol	
  2006	

for sex. The 2- and 5-year survival estimates for the wtKIT group are 81% (95% CI,
70% to 94%) and 74% (95% CI, 62% to 90%) versus 44% (95% CI, 24% to 79%)

SchniPger	
  S.	
  Blood	
  2006	

In vitro experiments showed that cells carrying exon 17 mutations

AMLの予後分類	
予後因子となる遺伝子変異	
予後不良	
予後良好	
FLT3-ITD変異	CEBPA変異	
FLT3は、血液細胞の増殖と分化、造血幹細胞の自己複製に関与し、アポトーシスを制御する受容体型チロシンキナーゼで、13q12に座位する。骨髄内皮細胞より産生されるリガンドが結合すると活性化され、増殖が促進される。FLT3は正常造血幹細胞の生存に寄与し、
CEBPAは顆粒球造血に重要な役割を担っており38)、 CEBPA変異分化とともに発現レベルが低下するが26)、AML細胞では大部分に
はAML全体の9%、CN-AMLの13%に認められると報告されている34)。
発現している。FLT3遺伝子変異として、傍膜貫通領域が重複して繰
ドイツとオーストリアの多施設前向きコホート研究で、NPM1とともにり返されるFLT3-ITD変異とキナーゼ領域が変異または欠失する
CEBPA変異陽性が、良好な完全寛解率に有意に関連することが示
FLT3-KDMの2種類の遺伝子変異があり、これらの変異変異によりされた38)。またCEBPA変異陽性CN-AMLは、NPM1変異陽性かつ増殖シグナルが恒常的に活性化されることがAML発症の一因と考FLT3-ITD陰性CN-AMLとともに、それ以外のCN-AMLより全生存率えられる。CN-AMLの約30%にFLT3-ITD変異が、約10%にFLT3も有意に良好であった34)。CEBPA変異は、両対立遺伝子に変異を
27,28)KDM 変異が認められる。ドイツのAML 96 studyでは化学療法有するdouble CEBPA変異と単一対立遺伝子のみに変異を有するを施行されたAML予後中間群555例を、FLT3-ITD変異陽性 175例
single CEBPA変異があるが、多変量解析でdouble CEBPA変異陽（31.3%）とFLT3-ITD変異陰性 380例に分けて後方向視的に比較解性AMLのみが予後良好因子であるとされる38)。	
析した結果、FLT3-ITD変異陽性は再発率が有意に高く（21% vs.
46%; P=0.001）、全生存率が有意に劣っていた（94% vs. 49%;
P<0.001）29)。FLT3変異、特にFLT3-ITD変異は白血病細胞増加に関連するとされ、AMLにおける予後不良因子と考えられている30,31)。	
c-KIT変異	
NPM1変異	c-KIT変異は，AMLの2%に認められ，特にt(8;21)AMLやtrisomy 7を
NPM1は5q35に位置するAMLや悪性リンパ腫の責任遺伝子で、有するAMLでは比較的高頻度に認められる。t(8;21)AMLにおいて、NPM1変異はAML全体の25〜35%、CN-AMLの45〜60%に認められ
c-KIT変異は、生存期間（304日 vs. 1836日; P=0.006）と無イベントる4)。FLT3-ITD変異陽性AMLの約50%にNPM1変異が認められ、生存期（244日 vs. 744日; P=0.003）を有意に短縮すると報告されてFLT3-ITD変異と強い相関関係を示す33)。NPM1変異陽性AMLは、いる39)。またinv(16)AMLにおいても、無イベント生存率や無再発生
高い寛解導入率や化学療法高感受性を示し、FLT3-ITD変異陰性存率への関連性については否定的な報告もあるものの40)、c-KIT変であれば予後良好である34-37)。	
異陽性群は陰性群に比較して有意に再発率が高いとされる41) 。	

上村智彦,	
  宮本敏浩.	
  血液フロンティア	
  2015	  in	
  press	
  

31.

in	
  a	
  large	
  cohort	
  of	
  young	
  adult	
  pa7ents	
  with	  acute	  myeloid	
  leukemia.	
  Blood	
  2008;	
  111:	
  2776-­‐84.	
  Pratcorona	
  M,	
  Brunet	
  S,	
  Nomdedeu	
  J,	
  et	
  al.	  Favorable	
  outcome	  of	
  pa7ents	
  with	
  acute	  myeloid	
  leukemia	
  harboring	
  a	
  low-­‐allelic	
  burden	  FLT3-­‐ITD	
  muta7on	
  and	
  concomitant	
  NPM1	
  muta7on:	
  relevance	
  to	
  post-­‐remission	
  therapy.	
  Blood	  2013;	  121:	
  2734-­‐8.	
  Breccia	
  M,	
  Loglisci	
  G,	
  Loglisci	
  MG,	  et	
  al.	
  FLT3-­‐ITD	
  confers	
  poor	  prognosis	
  in	
  pa7ents	
  with	  acute	  promyelocy7c	
  leukemia	
  treated	
  with	  AIDA	  protocols:	
  long-­‐term	
  follow-­‐up	
  analysis.	
  Haematologica	
  2013;	
  98:	
  e161-­‐3.	
  Tong	
  WG,	  Sandhu	  VK,	
  Wood	  BL,	  et	
  al.	
  Correla7on	
  between	  peripheral	
  blood	
  and	
  bone	  marrow	  regarding	
  FLT3-­‐ITD	
  and	
  NPM1	
  muta7onal	
  status	
  in	
  pa7ents	
  with	
  acute	  myeloid	
  leukemia.	
  Haematologica	
  2015;	
  100:	
  e97-­‐8.	
  Schlenk	
  RF,	  Dohner	
  K,	
  Krauter	
  J,	
  et	
  al.	
  Muta7ons	
  and	
  treatment	
  outcome	  in	
  cytogene7cally	
  normal	
  acute	  myeloid	
  leukemia.	
  N	
  Engl	  J	
  Med	
  2008;	
  358:	  1909-­‐18.	
  Schlenk	
  RF,	  Dohner	
  K,	
  Kneba	
  M,	
  et	
  al.	  Gene	  muta7ons	
  and	  response	  to	
  treatment	
  with	  all-­‐trans	
  re7noic	
  acid	  in	
  elderly	
  pa7ents	
  with	  acute	  myeloid	  leukemia.	
  Results	
  from	  the	
  AMLSG	  Trial	
  AML	
  HD98B.	
  Haematologica	
  2009;	
  94:	
  54-­‐60.	
  Becker	
  H,	
  Marcucci	
  G,	
  Maharry	
  K,	
  et	
  al.	  Favorable	
  prognos7c	
  impact	
  of	
  NPM1	
  muta7ons	
  in	
  older	
  pa7ents	
  with	  cytogene7cally	
  normal	
  de	
  novo	  acute	  myeloid	
  leukemia	
  and	
  associated	
  gene-­‐	
  and	  microRNA-­‐expression	
  signatures:	  a	
  Cancer	
  and	
  Leukemia	
  Group	
  B	
  study.	
  J	
  Clin	  Oncol	
  2010;	
  28:	
  596-­‐604.	
  Buchner	
  T,	
  Berdel	
  WE,	
  Haferlach	
  C,	
  et	
  al.	
  Age-­‐related	
  risk	  proﬁle	
  and	
  chemotherapy	
  dose	  response	
  in	
  acute	  myeloid	
  leukemia:	
  a	
  study	
  by	
  the	
  German	  Acute	  Myeloid	
  Leukemia	
  Coopera7ve	
  Group.	
  J	
  Clin	  Oncol	
  2009;	
  27:	
  61-­‐9.	
  Taskesen	
  E,	
  Bullinger	
  L,	
  Corbacioglu	
  A,	
  et	
  al.	
  Prognos7c	
  impact,	
  concurrent	  gene7c	  muta7ons,	
  and	
  gene	  expression	
  features	
  of	
  AML	
  with	  CEBPA	  muta7ons	
  in	
  a	
  cohort	
  of	
  1182	
  cytogene7cally	
  normal	
  AML	
  pa7ents:	
  further	  evidence	
  for	
  CEBPA	
  double	
  mutant	
  AML	  as	  a	
  dis7nc7ve	
  disease	
  en7ty.	
  Blood	  2011;	  117:	
  2469-­‐75.	
  Schnirger	
  S,	
  Kohl	  TM,	
  Haferlach	
  T,	
  et	
  al.	
  KIT-­‐D816	
  muta7ons	
  in	
  AML1-­‐ETO-­‐
posi7ve	  AML	  are	
  associated	
  with	  impaired	
  event-­‐free	
  and	
  overall	  survival.	
  Blood	
  2006;	
  107:	
  1791-­‐9.	
  Boissel	  N,	
  Leroy	
  H,	
  Brethon	
  B,	
  et	
  al.	  Incidence	
  and	
  prognos7c	
  impact	
  of	
  c-­‐Kit,	
  FLT3,	
  and	
  Ras	
  gene	  muta7ons	
  in	
  core	  binding	
  factor	
  acute	  myeloid	
  leukemia	  (CBF-­‐AML).	
  Leukemia	
  2006;	
  20:	
  965-­‐70.	
  Paschka	
  P,	
  Marcucci	
  G,	
  Ruppert	
  AS,	  et	
  al.	  Adverse	
  prognos7c	
  signiﬁcance	
  of	
  
KIT	
  muta7ons	
  in	
  adult	
  acute	  myeloid	
  leukemia	
  with	  inv(16)	
  and	
  t(8;21):	  a	
  Cancer	  and	
  Leukemia	
  Group	
  B	
  Study.	
  J	
  Clin	  Oncol	
  2006;	
  24:	  3904-­‐11.	

AMLの予後分類	
予後因子となる遺伝子変異	
32.
33.

参考文献	
26.
27.

28.

29.
30.

31.

32.
33.
34.

Kikushige	
  Y,	
  Yoshimoto	  G,	
  Miyamoto	
  T,	
  et	
  al.	
  Human	  Flt3	
  is	
  expressed	
  at	
  the	
  hematopoie7c	
  stem	  cell	  and	  the	
  granulocyte/macrophage	
  progenitor	
  stages	
  to	
  maintain	
  cell	  survival.	
  J	
  Immunol	
  2008;	
  180:	
  7358-­‐67.	
Schnirger	
  S,	
  Schoch	
  C,	
  Dugas	
  M,	
  et	
  al.	
  Analysis	
  of	
  FLT3	
  length	
  muta7ons	
  in	
  
1003	
  pa7ents	
  with	  acute	  myeloid	
  leukemia:	
  correla7on	
  to	
  cytogene7cs,	
  FAB	
  subtype,	
  and	
  prognosis	
  in	
  the	
  AMLCG	
  study	
  and	
  usefulness	
  as	
  a	
  marker	
  for	  the	
  detec7on	
  of	
  minimal	
  residual	
  disease.	
  Blood	
  2002;	
  100:	
  59-­‐66.	
  Gale	
  RE,	
  Hills	
  R,	
  Koraridis	
  PD,	  et	
  al.	  No	  evidence	  that	  FLT3	
  status	
  should	
  be	
  considered	
  as	
  an	
  indicator	
  for	  transplanta7on	
  in	
  acute	  myeloid	
  leukemia	  (AML):	  an	
  analysis	
  of	
  1135	
  pa7ents,	
  excluding	
  acute	  promyelocy7c	
  leukemia,	
  from	
  the	  UK	  MRC	
  AML10	  and	  12	  trials.	
  Blood	
  2005;	
  106:	
  3658-­‐65.	
Bornhauser	
  M,	
  Illmer	
  T,	
  Schaich	
  M,	
  et	
  al.	
  Improved	
  outcome	  aser	  stem-­‐cell	
  transplanta7on	
  in	
  FLT3/ITD-­‐posi7ve	
  AML.	
  Blood	
  2007;	
  109:	
  2264-­‐5;	
  author	
  reply	
  2265.	
  Gale	
  RE,	  Green	
  C,	
  Allen	
  C,	
  et	
  al.	
  The	
  impact	
  of	
  FLT3	
  internal	
  tandem	
  duplica7on	
  mutant	
  level,	  number,	
  size,	  and	
  interac7on	
  with	  NPM1	
  muta7ons	
  
in	
  a	
  large	
  cohort	
  of	
  young	
  adult	
  pa7ents	
  with	  acute	  myeloid	
  leukemia.	
  Blood	
  2008;	
  111:	
  2776-­‐84.	
  Pratcorona	
  M,	
  Brunet	
  S,	
  Nomdedeu	
  J,	
  et	
  al.	  Favorable	
  outcome	  of	
  pa7ents	
  with	
  acute	  myeloid	
  leukemia	
  harboring	
  a	
  low-­‐allelic	
  burden	  FLT3-­‐ITD	
  muta7on	
  and	
  concomitant	
  NPM1	
  muta7on:	
  relevance	
  to	
  post-­‐remission	
  therapy.	
  Blood	  2013;	  121:	
  2734-­‐8.	
  Breccia	
  M,	
  Loglisci	
  G,	
  Loglisci	
  MG,	  et	
  al.	
  FLT3-­‐ITD	
  confers	
  poor	  prognosis	
  in	
  pa7ents	
  with	  acute	  promyelocy7c	
  leukemia	
  treated	
  with	  AIDA	  protocols:	
  long-­‐term	
  follow-­‐up	
  analysis.	
  Haematologica	
  2013;	
  98:	
  e161-­‐3.	
  Tong	
  WG,	  Sandhu	  VK,	
  Wood	  BL,	  et	
  al.	
  Correla7on	
  between	  peripheral	
  blood	
  and	
  bone	  marrow	  regarding	
  FLT3-­‐ITD	
  and	
  NPM1	
  muta7onal	
  status	
  in	
  pa7ents	
  with	
  acute	  myeloid	
  leukemia.	
  Haematologica	
  2015;	
  100:	
  e97-­‐8.	
  Schlenk	
  RF,	  Dohner	
  K,	
  Krauter	
  J,	
  et	
  al.	
  Muta7ons	
  and	
  treatment	
  outcome	  in	
  cytogene7cally	
  normal	
  acute	  myeloid	
  leukemia.	
  N	
  Engl	  J	
  Med	
  2008;	
  358:	  1909-­‐18.	

34.
35.

36.

37.

38.

39.
40.
41.

AMLの予後分類	
遺伝子変異による予後分類	
予後分分類	

予後良好群	

予後中間群	

予後不良群	

染色体	
CBF白血病	・t（8;21）	
・inv（16） or t (16;16）	
t(15;17)	
正常核型	
+8	
t（9;11）（p22;q23）	
その他の染色体異常	
-5/del(5q)	
-7/del(7q)	
t（9;11）以外の11q23	

遺伝子異常	
正常核型		
 NPM1遺伝子変異(+)および FLT3-ITD遺伝子変異(-)	
	
 両対立遺伝子のCEBPA遺伝子変異		
CBF白血病		 c-kit遺伝子変異(+)	
	
 	
	
 	
正常核型	
	
 FLT3-ITD遺伝子変異(+)	
	

inv(3), t(3;3)	

	t(6;9)	

	t(9;22)	

	

一染色体欠失染色体異常	

	

複雑核型 (≧3 abnormalities)	

	

FLT3-­‐ITDとc-­‐kitは	
  九州大学で解析?	

NCCN	
  guideline,	
  AML	  2015	
  version	
  1	
  原三信病院 血液内科 勉強会	

急性骨髄性白血病	  Acute	
  Myeloid	
  Leukemia	  （AML）	
  Version	  1.0	
  寛解導入療法	AMLに対する寛解導入療法	
  DNR/AraC	
  vs.	
  IDR/AraC	DNR（150程度）+Ara-­‐C	
 ＜
＜
DNR 	
  45mg/m2 	
  d.1-­‐3	
  Ara-­‐C	
  100mg/m2	
  	
  	
  d.1-­‐7	

IDR 	
  12mg/m2	
  d.1-­‐3	
  Ara-­‐C	
  100mg/m2	
  	
  	
  d.1-­‐7	
Albert	  EinsteinCCのIDRは13mg/m2,	
  d.1-­‐3	  
MSKCCのAra-­‐Cは200mg/m2,	
  d-­‐1-­‐5	  ＜＜

MSKCCのDNRは50mg/m2,	
  d/1-­‐3	  
MSKCCのAra-­‐Cは200mg/m2,	
  d-­‐1-­‐5	  
HOVONのAra-­‐Cは200mg/m2,	
  d.1-­‐7	
  

IDR+Ara-­‐C	

＝

ECOG	
  1900	  （若年）（NEJM	
  2009）	
HOVON-­‐AMLSG	  （高齢）（NEJM	
  2009）	

DNR（270）+Ara-­‐C	
DNR 	
  90mg/m2 	
  d.1-­‐3	
  Ara-­‐C	
  100mg/m2	
  	
  	
  d.1-­‐7	
HOVONのAra-­‐Cは200mg/m2,	
  d.1-­‐7	
  

DNR,	
  ダウノルビシン	
  IDR,	
  イダルビシン	  AraC,	
  シタラビン	

日本ではDNR	
  1	
  mg/kgまでが保険適応	
  DNR	
  50mg/m2	
  	
  d.1-­‐5	  

MSKCC： Memorial	
  Sloan-­‐Keaering	
  Cancer	
  Center（US）	
  Albert	  Einstein	  Cancer	
  Center （US）	
  
HOVON： Dutch-­‐Belgian	  CooperaBve	  Trial	
  Group	
  for	  Hemato-­‐Oncology	  AMLSG： German	
  AML	
  Study	  Group	  寛解導入療法	
  High-­‐dose	
  DNR	
Phase	
  III,	
  n	
  =	
  657,	
  age	
  17	
  –	
  60	
  yrs	
  
DNR	
  45	
  mg/sqm	
  x	
  3d	
  +	
  AraC	  100	
  mg/sqm	
  x	
  7d	
  	
  
	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  vs.	
  DNR	  90	  mg/sqm	
  x	
  3d	
  +	
  AraC	  100mg/sqm	
  x	
  7d	
  	
  
T h e n e w e ng l a n d j o u r na l o f m e dic i n e

寛解導入率(70.6%	
  vs.	
  57.3%;	
  p<0.001)，全Figure 2. Kaplan–Meier Estimates of Overa
生存率(median,	
  23.7	
  vs.	
  15.7ヶ月;	
  p=0.003)
Data from the intention-to-treat analysis ar
2群が，DNR	  of all patients (Panel A), those with
ともに有意にDNR	
  90	
  mg/msurvival
or an intermediate cytogenetic profile (Pan2those with an unfavorable cytogenetic profil
45mg/m 群に比べ，良好であった．	

          
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

High doseStandard dose

P=0.003
0

10

20

30

40

50

60

70

categorical variables, the hazard rati
in the high-dose group was 0.72 (95%0.89; P = 0.002). The median overall s
15.7 months in the standard-dose gromonths in the high-dose group (P = 0
log-rank test) (Fig. 2A).

        %(

'( #Standard dose (45 mg/m2/day)High dose (90 mg/m2/day)

330
327

199
168

131
159

           
1.0

#'
 

Effect of Age

The patient’s age at the time of induct
influenced the response rate. Of the 6
55% were under the age of 50 years.
dard-dosetheFernandez	
  H
F.	
  New	
  Egroup,ngl	
  J	
  Mpatientsed	
  2009under	
years had a complete-remission rate o
15.7 mo23.7 moFigure 2. Kaplan–Meier Estimates of Overall Survival.
Data from the intention-to-treat analysis are shown forsurvival of all patients (Panel A), those with a favorable
or an intermediate cytogenetic profile (Panel B), andthose with an unfavorable cytogenetic profile (Panel C).

          
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

寛解導入療法	  High-­‐dose	
  DNR	High dose

categorical variables, the hazard ratio for deathin the high-dose group was 0.72 (95% CI, 0.58 to
0.89; P = 0.002). The median overall survival was
15.7 months in the standard-dose group and 23.7
months in the high-dose group (P = 0.003 by the
log-rank test) (Fig. 2A).

Phase	
  III,	
  n	
  =	
  657,	
  age	
  17	
  –	
  60	
  yrs	
  
DNR	
  45	
  mg/sqm	
  x	
  3d	
  +	
  AraC	  100	
  mg/sqm	
  x	
  7d	
  	
  
	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  vs.	
  DNR	  90	  mg/sqm	
  x	
  3d	
  +	
  AraC	  100mg/sqm	
  x	
  7d	
  	
  
Effect of Age
Standard dose

P=0.003

0

10

20

30

40

50

60

70

 

       %(

'( ##'
 

Standard dose (45 mg/m2/day)High dose (90 mg/m2/day)

330
327

199
168

131
159

15.7 mo23.7 mo＜染色体異常分類＞	
                  
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

予後良好群	High doseStandard dose

P=0.004
0

10

20

30

40

50

70

60

 
'# "  '  &' 

 %(

'( ##'
 

Standard dose (45 mg/m2/day)

180
178

95
71

85
107

20.7 mo34.3 moHigh dose (90 mg/m2/day)              
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

予後不良群	High dose
P=0.450Standard dose

10

20

30

40

50

60

70

 ) &+
'# "  '  &' 

 %(

'( ##'
 

Standard dose (45 mg/m2/day)High dose (90 mg/m2/day)

59
63

46
45

13
18

10.2 mo10.4 mo

The patient’s age at the time of induction therapy
influenced the response rate. Of the 657 patients,
55% were under the age of 50 years. In the standard-dose group, patients under the age of 50
years had a complete-remission rate of 59.4% anda median survival of 19.0 months; in the highdose group, patients in this age group had a complete-remission rate of 74.3% and a median survival of 34.3 months (hazard ratio for death in
the high-dose group, 0.65; P = 0.004). Patients who
were 50 years of age or older had no significant
benefit from the high dose of daunorubicin; median survival was 12.2 months in the standard-dosegroup and 16.9 months in the high-dose group(hazard ratio, 0.83; P = 0.20). However, the interaction between treatment assignment and age category was not significant (P = 0.25).

DNR	
  90	
  mg/m2による改善効果
は，予後良好群，特にCBF白血病（2年非再発生存率	
  91%	
  vs.	
  55%;	  P=0.0033）および中間群の染色体異常では有意であったが、予後不良群では有意差は得られていない．	

Effect of Cytogenetic Profile

Patients were classified according to the risk associated with their cytogenetic profile, with 13.6%
of patients deemed to be at favorable risk, 41.1%
at intermediate risk, 26.6% at indeterminate risk,and 18.7% at unfavorable risk. Complete-remission rates for the favorable-risk, intermediate-risk,
and unfavorable-risk groups were 81.3%, 58.7%,
and 51.4%, respectively (P<0.001 for overall comparisons). Median survival was longest in the favorable-risk group but did not differ significantly
between the treatment groups (hazard ratio fordeath in the high-dose group, 0.61; P = 0.18). At
the time of the final analysis, median survival
had not been reached among patients in the favorable-risk group who were treated with highdose daunorubicin. The greatest difference between
the two treatment groups was seen in the inter-

Fernandez	
  HF.	  New	  Engl	  J	
  Med	
  2009	

0.30
10

20

30

40

 ) &+

Standard dose

0.1
0.0

P=0.002

Standard dose

0
50
70
10
20DNR	
30
4060
寛解導入療法	  High-­‐dose	
  Phase	
  III,	
  n	
  =	
  657,	
  age	
  17	
  –	
  60	
  y$
rs	
   )
()

 &+ )+ $   
*%$ *!  )*
! 
DNR	
  
4
5	
  
m
g/sqm	
  
x
	
  
3
d	
  
+
	
  
A
raC	
  
1
00	
  
m
g/sqm	
  
x
	
  
7
d	
  
	
  
45 mg/m2/day)
16
15
1
16.2 moStandard dose (45 mg/m2/day) 290	  	
  vs.	
  DNR	  1090	
  mg/sqm	
  +	
  AraC	
  x	
  7mg/md	  	
   2/day)mg/m2/day) 	
  	
  	
  	
  	
  	
  	
  	
  	
  15
5 x	
  3d	
  19.0
mo 100mg/sqm	  High dose (90296 ',
175
149

60

1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

115
147

FLT3-­‐ITD変異陽性群では、DNR増量の効果は認められなかった．	

Negative

Positive

P=0.009
0

10

20

30

40

50

60

 * ',

70

FLT3!! 

 ',

*, %% *
  

Negative
Positive

241
64

116
39

125
25

28.6 mo15.2 mon–Meier Estimates of Overall Survival, According to Mutation Status.
AUTHOR: Fernandez

Fernandez	
  HF.	  New	  Engl	  J	
  Med	
  2009	RETAKE1st70% *
*, %   

＜予後不良	
  FLT3-­‐ITD変異＞	
     

)

 



 * ',

50

15.1 mo25.0 mo原三信病院 血液内科 勉強会	

急性骨髄性白血病	  Acute	
  Myeloid	
  Leukemia	  （AML）	
  Version	  1.0	
  寛解後療法	
  （強化療法）	

Childrenʼs Leukaemia Working Parties. Blood. 1998 ; 92 （7） : 2322-33. （3iiiD）
6） 日本血液学会．日本リンパ網内系学会編．造血器腫瘍取扱い規約 第1版．2010年3月．（ガイドライン）
7） Kuriyama K, et al. Trial to extract prognostic factors prior to the start of induction
chemotherapy for adult AML. Berlin : Springer. 1998 ; pp901-5.
8） Dohner H, et al. Diagnosis and management of acute myeloid leukemia in adults :recommendations from an international expert panel, on behalf of the European LeukemiaNet.
Blood. 2010 ; 115 （3） : 453-74. （レビュー）

AMLに対する寛解後療法（地固め療法）	
  日本血液学会 ガイドライン	

アルゴリズム

日本血液学会 造血器腫瘍診療ガイドライン	
  2013年	
  Web版	
  hPp://www.jshem.or.jp/gui-­‐hemali/1_1.html#cq7	
  
より引用	

1．若年者AML
AMLと診断された場合は上記のアルゴリズムに従うことが推奨される。若年AMLに対する標準的寛解導入療AMLに対する寛解後療法（強化療法）	
  High-­‐dose	
  AraC	  de	
  novo	
  AML	  (n	  =	  1088),	
  DNR	
  45x3d	  (<	
  60y)	
  or	
  30mgx3d	
  (>60y)	
  +	
  AraC	  100mgx7	
  →	
  CR1	
  Phase	
  III,	
  n	
  =	
  596	  RCT,	  Consolida7on	
  therapy	
  x	
  4	
  cycles	
  
	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  	
  AraC	  100mg/sqm	
  x5d;	
  	
  AraC	  400mg/sqm	
  x4d;	
  	
  AraC	
  3g/sqmx2x3d	  (d1,3,5)	
  CALGB	
  8525	
無白血病生存率（LFS）	

Mayer	
  RJ.	  New	  Engl	  J	
  Med	  1994	

寛解後療法におけるHigh-­‐dose	
  AraCの意義	
de	
  novo	
  AML	  (<	
  60y)	
  (n	  =	
  474),	
  DNR	
  45x3d	
  +	
  AraC	  200mgx7	
  →	
  CR1	  (n	
  =	
  342)	
  
RCT	
  (n	
  =	
  309)	
  RCT,	
  High-­‐dose	
  AraC	
  3g	
  x2	
  x3d,	
  3	
  cycles	
  vs.	
  AraC	
  3g	
  x2	
  x3d,	
  Etop	
  +	
  CY,	  diaziquone	
  +	
  Mit	
  

多剤併用療法は、High-­‐dose	
  AraCと同等	

Overall	
  survival	

Disease	  free	  survival	

CALGBの報告以降，欧米ではHigh-­‐dose	
  AraC	  	
  (3g/sqm	
  x	
  2,	
  d1,	  3,	  5)	  ，3-­‐4回が標準的な寛解後療法	
Moore	
  JO.	
  Blood	
  2005	

Printed by Tomohiko Kamimura on 6/16/2014 6:12:03 AM. For personal use only. Not approved for distribution. Copyright © 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014
Acute Myeloid Leukemia

NCCN Guidelines Index
AML Table of Contents
Discussion

Printed by Tomohiko Kamimura on 6/16/2014 6:12:03 AM. For personal use only. Not approved for distribution. Copyright © 2014 National Comprehensive
mm,nn Cancer Network, Inc., All Rights Reserved.

AMLに対する寛解後療法	

CLASSIFICATIONTREATMENT INDUCTION

Clinical trial (preferred)

NCCN Guidelines Index
NCCN Guidelines
Version 2.2014
or
AML Table of Contents
Acute Myeloid Standard-dose
Leukemiacytarabine 100-200 mg/m continuous infusion x
Discussion
2

2

RISK STATUS(See AML-A)

AML kk,ll

Age <60 y
Better-risk cytogenetics
and/or molecularabnormalities

Age !60 y

Age <60

See Treatment
Induction (AML-11)

Intermediate-risk
cytogenetics and/or
molecular abnormalities2

7 days with idarubicin 12 mg/m or daunorubicin 90 mg/m x 3days oo,pp (category 1)
POST-REMISSION THERAPY
or
2
Clinical trial
Standard-dose
cytarabine 200 mg/m continuous infusion x 7
2or daunorubicin 60 mg/m x 3 days and cladribine 5days with
2
2HiDAC 3 g/m over 3 h qq
mg/m x 5 days (category 1) every 12 h on days 1, 3,
5 ! 3-4 cycles (category 1) ddd,eee
oror
2High-dosecytarabine(HiDAC) pp,rr 2
g/m every 12 hours x 61
to2
cyclesof
HiDAC-based
consolidation
2
tt with idarubicin 12 mg/m2
days ssor 3 g/mbyevery
12 h x 4
daysfff
followed
autologous
HSCT(category 2B)2or daunorubicin 60 mg/m x 3 days (1 cycle) (category 2B)

自家移植	

Clinical trial
orMatched sibling or alternative donor HSCTorHiDAC ggg 1-3 g/m2 over 3 h every 12 h on days 1, 3, 5
x 3-4 cycles
qq

See PostInduction
Therapy (AML-8)

See Surveillance(AML-14)
See PostInduction
Therapy (AML-9)

See Surveillance(AML-14)

kk Patients with blast counts >50,000/mcL are at higher risk for tumor lysis and organ

Holowiecki J, Grosicki S, Giebel S, et al. Cladribine, but not fludarabine, added todaunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid
dysfunction secondary to leukostasis. Measures to rapidly reduce the WBC countleukemia: a multicenter, randomized phase III study. J Clin Oncol 2012;30:2441-2448.
include apheresis or hydroxyurea. Prompt institution of definitive therapy is essential.
ll Poor performance status and comorbid medical condition, in addition to age, are factors
rr The use of high-dose cytarabine for induction outside the setting of a clinical trial is stillthat influence ability to tolerate standard induction therapy.
controversial. While the remission rates are the same for standard- and high-dose
mm See Supportive Care (AML-C 1 of 2).
cytarabine, two studies have shown more rapid marrow blast clearance after one cycle of
nn See Monitoring During Therapy
Treatment-relateddisease or(AML-E).
Clinical trial
high-dose therapy and a disease-free survival advantage for patients " age 50 who received
oo ECOG reported a significant increase in complete response rates and overall survival
the high-dose therapy (category 2B). Kern W and Estey EH. High-dose cytarabineorpoor-risk
cytogenetics and/or
2
2
Surveillanceusing daunorubicin 90 mg/m x 3 days versus 45 mg/m xvv,ccc
3 days in patients <60 years
arabinosidein the treatmentof acute
myeloidrandomized
trials.
hhhleukemia: review of threeSee
Matched siblingor alternative
donor
HSCT
molecularof age. Fernandez HF, Sun
Z, Yao X, etabnormalities
al. Anthracycline dose intensification in acute
Cancer 2006;107:116-124. There are no data using more than 60 mg of(AML-14)
daunorubicin or 12
myeloid leukemia. N Engl J Med 2009;361:1249-1259. If there is residual disease on
mg of idarubicin with high-dose cytarabine.
ss Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dosedays 12-14, the additional daunorubicin dose is 45 mg/m2 x 3 days.
pp For patients with impaired cardiac function, other regimens that combine a nonversus standard-dose cytosine arabinoside with daunorubicin in patients with previously
anthracycline (such as fludarabine or topotecan) with cytarabine have been published.
acute myeloid leukemia: a Southwest Oncology Group study. Blood 1996;88:2841vv Begin alternate donor search (unrelated donor or cord blood) if no appropriate
fffuntreated
While both options--multiple cycles of dose-intensive consolidation and one cycle of2851.
sibling donor is available and the patient is a candidate for an allogeneic HSCT. tt Bishop
dose-intensive
consolidation
followedbyrandomized
autologousstudy
HSCT--canproducegood inJF, Matthews
JP, Young GA,
et al. Aof high-dose
cytarabine
ccc FLT3-ITD mutations are also emerging as a poor-risk feature in the setting ofsurvival forpatients
with leukemia.
favorableBloodcytogenetics,
there are significant differences in
inductionin acute
myeloid
1996;87:1710-1717.

otherwise normal karyotype, and these patients should be considered for clinical
trials where available. There is controversy regarding allogeneic transplant for

toxicity. Patient age, comorbid conditions, and issues such as fertility and salvage
options should be considered when choosing consolidation.

Note: All recommendations are category 2A unless otherwise indicated.
ggg There is no evidence that HiDAC is superior to lower doses of cytarabine in
FLT3-ITD-only mutations in the absence of other poor prognostic features.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
ddd
intermediate-risk patient subgroup.
Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy
hhh Patients may require at least one cycle of high-dose cytarabine consolidation whilein adults with acute myeloid leukemia. N Engl J Med 1994;331:896-903.
eee Alternate
Version2.2014, 03/28/14© National
CancerInc. 2014, All rights
reserved.has
The NCCN
Guidelines
and this illustration
may notsearch
be reproduced
in anyform without tothe maintainexpress writtenremission.
permission of NCCN.
AML-7
dosingofComprehensive
cytarabine
for Network,
postremission
therapybeenreported
donor
is in
progress
Patients
may proceed directlyto®

(see Discussion). Lowenberg B, Pabst T, Vellenga E, et al. Cytarabine dose for®

transplant following achievement of remission if a donor (sibling or alternative) is血液がんに対する抗癌剤治療の概念	
血液がんに対する自家移植の概念	
化学療法	

自家末梢血幹細胞採取	
化学療法	

化学療法	

化学療法	

化学療法	

再発	

血
液

G-­‐CSF	

大量化学療法	

分子遺伝学的寛解	

細胞数	

＜自家移植＞	
  造血再構築	  略語	血液学的寛解	G-­‐CSF,	
  granulocyte-­‐colony-­‐s7mula7ng	
  factor	経過	血液がんに対する抗癌剤治療の概念	
血液がんに対する自家移植の概念	
あらかじめ自分の造血幹細胞を，末梢血から採取して（自家末梢血幹細胞），凍結保存する．	
抗がん剤の
大量投与	

血液がん病
細胞の強い
減少効果	

造血幹細
胞を解凍
して点滴	

•大量抗癌剤治療による悪性細胞への強い治療効果が得られる．
•大量抗癌剤による，様々な臓器に対する副作用が大きい．	

正常の血
液細胞も
破壊され
てしまう	
血液がん細胞	

正常の血
液細胞が
回復	
正常の血液細胞	化学療法	
  vs.	
  自家移植	  vs.	
  同種移植	  in	
  CR1	
CR1;	  第1寛解期	

AML全体	
Study Group
著者 発表年	

Study design（n）	

再発率（%）	

無病生存率（%）	

全生存率（%）	

化療	
 自家	
 同種	
 化療	
 自家	
 同種	
 化療	
 自家	
 同種	

EORTC/GIMEMA/AML8
Zittoun 1995	

化療 vs 自家 vs 同種（126 vs 128 vs 168)	

57	

41	

24	

30*	

48	

55	

54	

50	

53	

GOELAM
Harousseau 1997	

化療 vs 自家 vs 同種（71 vs 75 vs 73)	

55	

45	

37	

43	

48	

49	

54	

50	

53	

ECOG/SWOG/CALGB
Zittoun 1997	

化療 vs 自家 vs 同種（117 vs 116 vs 113)	

61	

48	

29	

34	

34	

43	

52	

43	

46	

MRC AML10
Burnett 1998	

化療 vs 自家（191 vs 190)	

58	

37	

	

40*	

53	

	

45	

57	

EORTC/GIMEMA/AML10
Suciu 2003	

自家 vs 同種
（441 vs 293)	

	

HOVON/SAKKCornelissen 2007	

	
52	

30	

化療 vs 自家 vs 同種
59
ドナー有無
ドナー無は化療と自（126 vs 128 vs 175)	
 家をまとめて解析	

32	

	

42*	

52	

ドナー無は化療と自家をまとめて解析	

48	

37*

	

58	

50	

ドナー無は化療と自家をまとめて解析	

54	

46* p<0.05	

⇒	
  染色体異常によるリスク別では？	

Disease-free s

Disease-free surviv

50

donor

50

grafts. TRM was also evaluated in early and late trial eras. No
improvementnoofdonor
TRM over time could be demonstrated in recipients who had received their allograft after the median date ofinclusion (date not shown) as compared with the early transplants.

donor

an autologous or allogeneic transplant
relapsing patients reached a second CR
of these either relapsed again (93 of 18
of 184; 25%). At the time of analysis
were still alive of whom 45 were in coprobability of survival after relapse at 3group and 15% in the no-donor group.
relatively more patients died in CR
compared with the no-donor group, thetreatment to OS was larger in the no-do

化学療法	
  vs.	
  自家移植	  vs.	
  同種移植	  in	
  CR1	
25

N
no donor 599

AML染色体異常によるリスク別	

bility on outcome

no donordonor

HOVON/SAKK	At risk:
ALLOGENEIC
VERSUSSCT INno donor 599
192 AUTOLOGOUS
121
67 AML
donor

326

140

91

1237
37

48

27

Disease-free survival

Good risk transplant (37%). Forty percent of thegrafts. TRM was also evaluated in A
early
and late trial eras. No an autologous or allogeneic
B 100
100
improvement of TRM over time could be demonstrated in recipi- relapsing patients reached a second CR (CR2, n ! 184), but mostgrafts. TRM was also evaluated in early and late trial eras. No an autologous or allogeneic transplant (37%). Forty percent of theents who had received their allograft after the median date of of these either relapsed again (93 of 184; 51%) or died in CR2 (46improvement of TRM over time could be demonstrated in recipi- relapsingpatients reached a second donor
CR (CR2, n ! 184), but most75 of the relapsed patients
75 theinclusion (date not shown) as compared withearly transplants. of 184; 25%). At the time of analysis 69
ents who had received their allograft after the median date of of these either relapsed again (93 ofno
184; 51%) or died in CR2 (46weredonor
still alive of whom 45 were in continued CR2. The actuarial
Salvagetreatment
after
relapseinclusion (date not shown) as comparedwiththe earlytransplants.
of 184; 25%). At the time of analysis 69 of the relapsed patientsprobability of survival after relapse at 3 years
was 16% in the donor
50
50 alive of whom 45 were in continued CR2. The actuarial
were still
Salvage treatment after relapse The smaller difference in OS between the donor and no-donor group and 15% in the no-donor group. Because in the donor groupprobability of survival after relapse at 3 years was 16% in the donor
1237
group compared with the difference in DFS can be explained by the relatively more patients died in CR1 and fewer relapsed as
The smaller difference in OS between the donor and no-donor group25and 15% in the no-donor group. Because in the donor group25
effect of salvage treatment. Most of the 457 relapsed patients compared with the no-donor group, the net
contribution of salvage
group compared with the difference in DFS can be explained by the relatively morepatients
died in CR1 and fewer relapsed as
N
F
NF
received salvage treatment (88%), either chemotherapy(51%)
ortreatmenttoOS
waslargerintheno-donorgroup.
no donor 333 199
no donor 73
28
donor
178
82
effect of salvage treatment. Most of the 457 relapsed patients compareddonor
with32the
11 no-donor group, the net contribution of salvage
Logrank P =.01
Logrank P =.43
00 to OS was larger in the no-donor group.
received salvage treatment (88%), either chemotherapy (51%) or treatment
0Low	
  risk	

Disease-free survival

75

donor
no donor
50

25

N
F
no donor 73
28
donor
32
11
Logrank P =.43

25

0

N
F
no donor 73
28
donor
32
11
Logrank P =.4300

At risk:
73
32

41
25

At risk:
73
32

27
19

Disease-free survivalC

41
25months 120

25

16
14

12
9

C

no d

no donor
donor

12
9

At risk:
333
178Standard
123 risk

78
47

78

Standard risk

Poor risk

100
75

no	
  donor	
  (auto-­‐SCT	
  28%)	
  
donor

75
50

no donor

donor

50

50
no donor
25

25
NF
no donor 333 199
donor
178
82
Logrank P =.0100
no donor
donor

16
14

100

C

no donor
75

27
19

27
19

100

0
no donor
donor

B

Good
risk
41

At risk:
73
32

donor

75

Intermediate	
  	
  
risk	

50

no donor
donor

B

Good risk

100no	
  donor	
  (auto-­‐SCT	
  63%)	
  Disease-free survival

no donor
donor

100

don

months 120

0AA

P=0.17	

192
140

Disease-freeDisease-freesurvival survival

donor	

0

At risk:
599
326

Disease-free survivalno	
  donor	group compared with the difference in months
DFS canbe explained by the120
effect of salvage treatment. Most of the 457 relapsed patients
121
67
37
months
120 treatment (88%),
receivedsalvageeither chemotherapy(51%) or
91
48
27

0

Disease-free survival

EORTC/GIMEMA	

CR1;	
  第1寛解期	

0

no donor 599 381
326 171
donor
Logrank P =.002

0

nor availability
tic groups were
ery bad risk (C),-year DFS rates
onor
availabilitynd theno donoretic
were
ear groups
cumulativeveryarebadgivenrisk (C),CRin
4-yearrates
s; O, DFS
observed
ALLOGENEIC
VERSUS AUTOLOGOUS SCT IN AML
and CR).
thenoPdonorfirst
wasyear cumulative
CR are given ins; O, observed
first CR). P was

E 102, NUMBER 4Salvage treatment after relapse

F381

326 171
donor
ALLOGENEIC VERSUS
AUTOLOGOUS
SCT IN AML
1237difference in OS between the donor and no-donor
Logrank P =.002
The smaller
F
N

12
9
123
78

F
199
82

F
no donor 193 154
donor
116
78
At risk:
no donor 333Logrank P =.006
donor0 178

months 120

16
14

At risk:
333
178

N
no donor 333
donor
178

25 Logrank P =.01
0
N
0

0
78
47

100

no donordonor

At risk:
193
116

40
18

P=0.014	donor
no donor

123
78
months 120

28 risk
Poor
37

23
9

78
47

months 120
40
18

23
9

months 120
16
25

11
16

2
9

Figure 2. Actuarial disease-freeof patients with acute myeloid leukemia in first complete remission according to risk
Poorsurvival
risk(A) Good risk (P ! .43), (B) intermediate risk (P ! .01), (C) poor risk (P ! .006).

100

75

High	
  risk	50

Disease-free survival

E 102, NUMBER 4

no donor

25

75

50
donor
25
donor

no donorNF
no donor 193 154
116
78
no donor donor
Logrank P =.006

25
NF
no donor 193 154
donor
116
78
Logrank P =.006000months 120

0
no donordonor

At risk:
193
116

Suciu	  S.	
  Blood	
  2003	
the estimated hazard ratios were 0.64, 0.68, and 0.92 in the 3 age
At risk:
193
116

28
37
months 120

16
25

11
16

2
9

Figure 2.noActuarial
disease-freewith acutein first complete remission according to risk category and donor availability.
donor
28 survival of patients16
11 myeloid leukemia
2
donor
37
25
16
9
(A) Good risk (P ! .43), (B) intermediate risk (P ! .01), (C) poor risk (P ! .006).
Figure 2. Actuarial disease-free survival of patients with acute myeloid leukemia in first complete remission according to risk category and donor availability.
(A) Good risk (P ! .43), (B) intermediate risk (P ! .01), (C) poor risk (P ! .006).

groups, respectively. An interaction between age (considered as anCornelissen	
  JJ.	
  Blood	
  2007	

寛解後療法における自家末梢血幹細胞移植	
AML	
  (n	
  =	
  81),	
  non-­‐M3,	
  retrospec7ve	
  analysis	  Induc7on	
  therapy,	
  IDR	  +	  AraC	  Consolida7on	
  therapy,	
  Mit	  +	
  idAraC	
  	  →	
  Etop	
  +	
  idAraC	
  →	
  PBSC	  collec7on	
  Myeloabla7ve	
  condi7oning	
  regimen	
  followed	
  by	
  auto-­‐PBSCT	
  Overall	
  survival	

福岡BMTグループの成績	

Months	
  from	  transplant	

Eto	
  T.	
  Int	  J	  Hematol	
  2013	

= 56) for the intermediateroup, and 33.3 % (95 % CI
.8–62.3, n = 9) for the poorsk group. The differencesmong these three groups wereot statistically significant (logank p = 0.0579)

寛解後療法における自家末梢血幹細胞移植	

AML	
  (n	
  =	
  81),	
  non-­‐M3,	
  retrospec7ve	
  analysis	  Induc7on	
  therapy,	
  IDR	  +	  AraC	  Consolida7on	
  therapy,	
  Mit	  +	
  idAraC	
  	  →	
  Etop	
  +	
  idAraC	
  →	
  PBSC	  collec7on	
  Myeloabla7ve	
  condi7oning	
  regimen	
  followed	
  by	
  auto-­‐PBSCT	
  Overall	
  survival	

福岡BMTグループの成績	

Months	
  from	  transplant	

sed for Allo-SCT, but the most effective conditioning

Eto	
  T.	
  Int	  J	  Hematol	
  2013	them into circulation from the bone marrow niche [23]. For

福岡BMTグループにおける移植前処置（自家移植）	
移植前処置:	  G-­‐CSF併用BEA大量化学療法		
G-­‐CSF-­‐combined	
  AraC	
 移植病日	G-­‐CSF	  シタラビン	-­‐12	  -­‐11	
  -­‐10	
   -­‐9	
   -­‐8	
   -­‐7	
   -­‐6	
   -­‐5	
   -­‐4	
   -­‐3	
   -­‐2	
   -­‐1	
   0	
  200μg/sqm,	
  

div.	
  

↓	
   ↓	
   ↓	
   ↓	
   ↓	
   ↓	
   ↓	
   	
 	
 	
 	
 	
 	

400μg/sqm,	
  

div.	
  

	

	

	
 ↓	
   ↓	
   	

	

	

	

100mg/sqm,	
   div.	
  

	

	
 ↓	
   ↓	
   ↓	
   ↓	
   ↓	
   ↓	
   ↓	
   	

	

	

	

	

	

	

	

	

	

	

	

	
 ↓	
   ↓	
   	

	

	

	

	

	

	

	

	

	

	
 ↓	
   ↓	
   	

	

	

3000mg/sqm,	
   div.	
  x	
  2	
  

	

	

	

	

ブスルファン	
 4mg/kg,	
  

po.	
  

	

	

	
 ↓	
   ↓	
   ↓	
   ↓	
   	

20mg/kg,	
  

div.	
  

	

	

	

エトポシド	

	

	

	

	

	

	

	

	
 ↓	
   ↓	
   	

	

	

	

Auto-­‐PBSCT	
  G-­‐CSF併用移植前処置の意義	
1.	
  	
   G-­‐CSF投与により，G-­‐CSF受容体を発現する静止期のAML幹細胞を刺激して細胞周期に導入し，細胞周期特異的な抗癌剤（シタラビン）に対する感受性を高める．	
  
	
  
2.	
  	
   G-­‐CSF投与により，成熟好中球が分泌した	  エステラーゼ，セリンプロテアーゼなどの	  蛋白分解酵素が接着分子を切断することで，	
  白血病幹細胞	
白血病幹細胞をnicheから解離させ，	
  未分化性や薬剤抵抗性が喪失，	
  成熟好中球	
抗癌剤感受性を高める．	
VLA4	

蛋白分解酵素の放出	
SDF1	

いかにしてAMLの抗癌剤感受性を高めるか	CXCR4	

VCAM1	

支持細胞	Randomization

therapy. To avoid interference of the second chemo- and a white
therapeutic agent with the cell-cycle–dependent millimeter
化学療法におけるG-­‐CSF併用効果	
fined by thnormalitie
Induction Cycle 1
Induction Cycle 2
togenetic cchromosom
Amsacrin, 120 mg/m2, days 4–6
2
ities of the
Idarubicin, 12 mg/m , days 6, 7, 8
2 every 12 hr,
Cytarabine,
1000
mg/m
Cytarabine, 200 mg/m2, days 1–7
t(6;9)(p23;days 1–6
arm of chrooccurred af
nonhemato
Amsacrin, 120 mg/m2, days 4–6
Idarubicin, 12 mg/m2, days 6, 7, 8
2
Cytarabine, 1000 mg/m every 12 hr,
occurred m
Cytarabine, 200 mg/m2, days 1–7
days 1–6
2
G-CSF, 150 µg/m , days 0–8
condition (G-CSF, 150 µg/m2, days 0–6
the unfavo
did not mee
Figure 1. Treatment Regimens.
risk were cPatients were randomly assigned to receive two cycles of induction chemotherapy alone or with the addition of granulocyte colony-stimulating factor(G-CSF) beginning one day before the start of chemotherapy (day 0) throughthe last day of chemotherapy.

study desPatients weceive G-CS

Löwenberg	
  B.	
  New	  Engl	  J	
  Med	
  2003	squaredose ofsquareapy. Itprimon the

化学療法におけるG-­‐CSF併用効果	

G-CSF

321

210

G-CSF (195 events)

No G-CSF (212 events)

24

36

48

60

130

94

56

Months159

No G-CSF
319
189
137
115
74
44
zation.
We used a dose of 1 g of cytarabine per square
BA
meter in cycle 2. The comparative effect of a dose of100
100
1 g per square meter and a dose of 3 g per square
meter has not been established in AML therapy. It
75
75
would
be of interest to know whether G-CSF priming would have a similarly positive effect on theprobabilityof relapse in regimens G-CSF
containinga50
G-CSF (148 events)
50(195 events)
dose of 3 g of cytarabine per square meter.
The fact that our results do not suggest a benefit
25
25
No G-CSF (177 events)
No G-CSF (212 events)of G-CSF priming in patients withfavorable-risk
AMLP=0.16
might relate to the small numbers of cases, or
P=0.020
it0 might indicate that the dose of 1 g of cytarabine
36
0
12
24
48
60
36
0
12
24
48
60
per square meter was optimal in terms of its ability
MonthsMonthsNo. at Risk
No. at Risk to kill neoplastic cells in this subgroup. After the
G-CSF
255
155
113
76
41
G-CSF
321induction
210 cycles with159 or without
130 G-CSF,
94 approx-56
102
two
No G-CSF
265
129
100
52
33
No G-CSF
319
189
137
115
74
44
87
imately one third of patients received a third cycle ofchemotherapy and another third went on to highFigure 2. Cumulative Rate of Overall Survival (Panel A) and Disease-freeB
dosechemotherapy
followedbystem-celltransSurvival (Panel B), According to the Assigned Treatment.
100
plantation. It is unlikely that the postinduction treatP values were calculated with use of the log-rank test. G-CSF denotes granulocyte colony-stimulating factor.
ment influenced the outcome of G-CSF treatment.
Löwenberg	
  B.	
  New	  Engl	  J	
  Med	
  2003	
75
The two groups were evenly matched in terms of as-

無病生存率	

Disease-free Survival (%)

Overall Survival (%)

全生存率	

rvival (%)

hethereasingsacrin,e used.
gimen
mg per
meter
ming.
shown
more
squaret in anstudy,
ber ofensiti-

Overall Survival (%)

ion of transplantation
duringa firstchemotherapeutic
remission as timeor the
combined
agents we used.
nitially dependent covariates
yieldedresults
similarto
those
In any case, the efficacy of a chemotherapy regimen
75
ion of of the unadjusted
analysis.
that included cytarabine at doses of 200 mg perncy of
The fact that
more meter
deathsas
occurred
inducsquarewell asduring1000 mg
per square meter
50
tion among patients
who receivedmay
was enhancedby the G-CSF
additionof exG-CSF priming.
o acti- plain the slightly
reducedratedoseof complete
remission
Studiesof theeffectrof
cytarabine have a
shown
AML	
  
(
n	
  
=
	
  
6
30),	
  
n
on-­‐M3,	
  etrospec7ve	
  nalysis	  ted in in this group.that
These
deathshadseveralcausesand
29,30
25
doses of 3 g per square meter
were morechemotherapy	
  
+
	
  
G
-­‐CSF	
  
v
s.	
  
c
hemotherapy	  	
  hours were RCT,	
  thus notduetoacommonproblem.
Howeveffective than doses of 200 or 400 mg per square
P=0.16s AML er, because
andreduction
incidence
ofdid
later
Aser	
  of2meter	
  cycle	  oinf	
  cthehemotherapy,	
  chemotherapy	  /	
  auto-­‐SCT	  /	
  allo-­‐SCT	
  in preventing
relapse but
notresult in an
0sistent deaths, the overall
deathrate
rateofamong
patients
in the in this study,
012increased
remission.
Similarly,
use of G-CSF grouponly
wasthelower
than ofthat
among thoseduration
remission,
not the number of
AMLに対する化学療法にG-­‐CSF併用の有無でランダム比較	
No. at Risk
levels treated with chemotherapy
alone.
remissions, changed as the result of G-CSF sensiti-

B Stan

A Standard-Risk AML

化学療法におけるG-­‐CSF併用効果	
Overall Survival (%)

100
75

AML	
  (n	
  =	
  630),	
  non-­‐M3,	
  retrospec7ve	
  analysis	
  RCT,	
  chemotherapy	
  +	
  G-­‐CSF	
  vs.	
  chemotherapy	
  	
  
50
nd
Aser	
  2 	
  cycle	  of	
  chemotherapy,	
  chemotherapy	
  /	
  auto-­‐SCT	
  /	
  allo-­‐SCT	  G-CSF (n=230; 128 events)

No G-CSF (n=234; 155 events)

25

AMLに対する化学療法にG-­‐CSF併用の有無でランダム比較	
P=0.02

予後中間群	The new england journal of medicine
0
36
0
12
24

予後不良群	
48
MonthsStandard-Risk AML
C BUnfavorable-Risk

A Standard-Risk AML

G-CSF(n=230; 128 events)
75

50

No G-CSF (n=234; 155 events)

25
P=0.02

P=0.0212

36

24

B Standard-Risk AML
75

50

50

25

No G-CSF (n=234; 155 events)

25
0

75

G-CSF (n=230; 128 events)

50

0

12

48

24

36

60
Months

48

100

100

25

Disease-free Survival (%)

100

Disease-free Survival (%)

Overall Survival (%)

A Standard-Risk AML

75Overall Survival (%)

Overall Survival (%)

100

0

G-CSF (n=201; 111 events)

50

G-CSF
(n=74;
61 events)
No G-CSF(n=202;136 events)

No G-CSF (n=202; 136 events)

25

No G-CSF (n=61; 49 events)
24

24Months
36

36

48

36 48

60

48 60

60

MonthsMonths

100

75

D Unfavorable-Risk
AMLof Overall Survival (Panels A and C) and Disease-fre
Figure3. Cumulative 75
Rates
100
Risk Acute Myeloid
Leukemia (AML) and Unfavorable-Risk AML.

50

50
P values were calculatedwith use of the log-rank test. G-CSF denote granulocyt

P=0.96

No G-CSF (n=61; 49 events)

Disease-free Survival (%)

G-CSF (n=74; 61 events)

25

urvival (%)

G-­‐CSFによるprimingはstandard	
  risk	  AMLには有用?	
Overall Survival (%)

vival (%)

75

G-CSF (n=201; 111 events)

D Unfavorable-Risk AML

100

100

75

P=0.006
P=0.96P=0.006
0
0
600
0
12
0 12
12 24
0

MonthsC Unfavorable-Risk AML

C Unfavorable-Risk AML

D UnfaThe new england journal of medicine

100

0

60

Löwenberg	
  B.	
  New	  Engl	  J	
  Med	
  2003	

75

No G-CSF (n=39; 30 events)

25

P=0.60G-CSF (n=41; 34 events)()5 mg/m2/day)
g/m2/day) &+

16
15

15
10

)+ $   
1
5

*%$

16.2 mo19.0 mo*!  )*! 

 ',

Standard dose (45 mg/m2/day)High dose (90 mg/m2/day)

290
296

175
149

FLT-­‐3-­‐ITD	
  (+)	
  AMLに対するHigh-­‐dose	
  DNR	

*11

     

)

 





1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0

High-­‐dose	
  DNRは，FLT-­‐3-­‐ITD(+)の	  予後不良を克服できない	

Negative

Positive

P=0.009
0

10

20

30

40

50

 * ',

60

70

FLT3!! 

 ',

*, %% *
  

Negative
Positive

241
64

116
39

125
25

28.6 mo15.2 mo–Meier Estimates of Overall Survival, According to Mutation Status.
RETAKE HF.	
  1st
AUTHOR: Fernandez
Fernandez	
  New	
  Engl	  J	
  Med	
  2009	ICM
for the overall survival of patients with the FLT3-ITD mutation (Panel A), those
2ndwithout the FLT3-ITD mut
REG F

FIGURE: 3 of 3

Diesease-freesurvival (%)
無病生存期間（%）	

FLT3遺伝子異常の有無による	  自家移植（auto-­‐PBSCT）の治療成績	
100

福岡BMTグループの成績	

90
80
70
60
50

P=0.9273	

40

FLT3 mutation(-) (n=24)	

30
20

FLT3/ITDs(+)(n=8)	

FLT3/ITDs(+) or FLT3 D835-Mt(+)

10(n=10)	
P=0.9614	

0
0

1

2

3

4

5

6

7

8

year
Auto-PBSCTからの年数	
Auto-­‐PBSCTはFLT3遺伝子異常を克服できる可能性	
Yoshimoto	
  et	
  al.	
  Bone	  Marrow	  Transplant	
  2005	
  FLT3-­‐ITD変異の有無による	
  
自家	
  or	
  同種移植の治療成績	

Bornhäuser	
  M.Blood.	
  2007:	
  2264	

Printed by Tomohiko Kamimura on 6/16/2014 6:12:03 AM. For personal use only. Not approved for distribution. Copyright © 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014
Acute Myeloid Leukemia

NCCN Guidelines Index
AML Table of Contents
Discussion

Printed by Tomohiko Kamimura on 6/16/2014 6:12:03 AM. For personal use only. Not approved for distribution. Copyright © 2014 National Comprehensive
mm,nn Cancer Network, Inc., All Rights Reserved.

AMLに対する寛解後療法	

CLASSIFICATIONTREATMENT INDUCTION

Clinical trial (preferred)

NCCN Guidelines Index
NCCN Guidelines
Version 2.2014
or
AML Table of Contents
Acute Myeloid Standard-dose
Leukemiacytarabine 100-200 mg/m continuous infusion x
Discussion
2

2

RISK STATUS(See AML-A)

AML kk,ll

Age <60 y
Better-risk cytogenetics
and/or molecularabnormalities

Age !60 y

Age <60

See Treatment
Induction (AML-11)

Intermediate-risk
cytogenetics and/or
molecular abnormalities2

7 days with idarubicin 12 mg/m or daunorubicin 90 mg/m x 3days oo,pp (category 1)
POST-REMISSION THERAPY
or
2
Clinical trial
Standard-dose
cytarabine 200 mg/m continuous infusion x 7
2or daunorubicin 60 mg/m x 3 days and cladribine 5days with
2
2HiDAC 3 g/m over 3 h qq
mg/m x 5 days (category 1) every 12 h on days 1, 3,
5 ! 3-4 cycles (category 1) ddd,eee
oror
2High-dosecytarabine(HiDAC) pp,rr 2
g/m every 12 hours x 61
to2
cyclesof
HiDAC-based
consolidation
2
tt with idarubicin 12 mg/m2
days ssor 3 g/mbyevery
12 h x 4
daysfff
followed
autologous
HSCT(category 2B)2or daunorubicin 60 mg/m x 3 days (1 cycle) (category 2B)

自家移植	

Clinical trial
orMatched sibling or alternative donor HSCTorHiDAC ggg 1-3 g/m2 over 3 h every 12 h on days 1, 3, 5
x 3-4 cycles
qq

See PostInduction
Therapy (AML-8)

See Surveillance(AML-14)
See PostInduction
Therapy (AML-9)

See Surveillance(AML-14)

kk Patients with blast counts >50,000/mcL are at higher risk for tumor lysis and organ

Holowiecki J, Grosicki S, Giebel S, et al. Cladribine, but not fludarabine, added todaunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid
dysfunction secondary to leukostasis. Measures to rapidly reduce the WBC countleukemia: a multicenter, randomized phase III study. J Clin Oncol 2012;30:2441-2448.
include apheresis or hydroxyurea. Prompt institution of definitive therapy is essential.
ll Poor performance status and comorbid medical condition, in addition to age, are factors
rr The use of high-dose cytarabine for induction outside the setting of a clinical trial is stillthat influence ability to tolerate standard induction therapy.
controversial. While the remission rates are the same for standard- and high-dose
mm See Supportive Care (AML-C 1 of 2).
cytarabine, two studies have shown more rapid marrow blast clearance after one cycle of
nn See Monitoring During Therapy
Treatment-relateddisease or(AML-E).
Clinical trial
high-dose therapy and a disease-free survival advantage for patients " age 50 who received
oo ECOG reported a significant increase in complete response rates and overall survival
the high-dose therapy (category 2B). Kern W and Estey EH. High-dose cytarabineorpoor-risk
cytogenetics and/or
2
2
Surveillanceusing daunorubicin 90 mg/m x 3 days versus 45 mg/m xvv,ccc
3 days in patients <60 years
arabinosidein the treatmentof acute
myeloidrandomized
trials.
hhhleukemia: review of threeSee
Matched siblingor alternative
donor
HSCT
molecularof age. Fernandez HF, Sun
Z, Yao X, etabnormalities
al. Anthracycline dose intensification in acute
Cancer 2006;107:116-124. There are no data using more than 60 mg of(AML-14)
daunorubicin or 12
myeloid leukemia. N Engl J Med 2009;361:1249-1259. If there is residual disease on
mg of idarubicin with high-dose cytarabine.
ss Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dosedays 12-14, the additional daunorubicin dose is 45 mg/m2 x 3 days.
pp For patients with impaired cardiac function, other regimens that combine a nonversus standard-dose cytosine arabinoside with daunorubicin in patients with previously
anthracycline (such as fludarabine or topotecan) with cytarabine have been published.
acute myeloid leukemia: a Southwest Oncology Group study. Blood 1996;88:2841vv Begin alternate donor search (unrelated donor or cord blood) if no appropriate
fffuntreated
While both options--multiple cycles of dose-intensive consolidation and one cycle of2851.
sibling donor is available and the patient is a candidate for an allogeneic HSCT. tt Bishop
dose-intensive
consolidation
followedbyrandomized
autologousstudy
HSCT--canproducegood inJF, Matthews
JP, Young GA,
et al. Aof high-dose
cytarabine
ccc FLT3-ITD mutations are also emerging as a poor-risk feature in the setting ofsurvival forpatients
with leukemia.
favorableBloodcytogenetics,
there are significant differences in
inductionin acute
myeloid
1996;87:1710-1717.

otherwise normal karyotype, and these patients should be considered for clinical
trials where available. There is controversy regarding allogeneic transplant for

toxicity. Patient age, comorbid conditions, and issues such as fertility and salvage
options should be considered when choosing consolidation.

Note: All recommendations are category 2A unless otherwise indicated.
ggg There is no evidence that HiDAC is superior to lower doses of cytarabine in
FLT3-ITD-only mutations in the absence of other poor prognostic features.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
ddd
intermediate-risk patient subgroup.
Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy
hhh Patients may require at least one cycle of high-dose cytarabine consolidation whilein adults with acute myeloid leukemia. N Engl J Med 1994;331:896-903.
eee Alternate
Version2.2014, 03/28/14© National
CancerInc. 2014, All rights
reserved.has
The NCCN
Guidelines
and this illustration
may notsearch
be reproduced
in anyform without tothe maintainexpress writtenremission.
permission of NCCN.
AML-7
dosingofComprehensive
cytarabine
for Network,
postremission
therapybeenreported
donor
is in
progress
Patients
may proceed directlyto®

(see Discussion). Lowenberg B, Pabst T, Vellenga E, et al. Cytarabine dose for®

transplant following achievement of remission if a donor (sibling or alternative) isAMLの予後分類	
遺伝子変異による予後分類	
予後分分類	

予後良好群	

予後中間群	

予後不良群	

染色体	
CBF白血病	・t（8;21）	
・inv（16） or t (16;16）	
t(15;17)	
正常核型	
+8	
t（9;11）（p22;q23）	
その他の染色体異常	
-5/del(5q)	
-7/del(7q)	
t（9;11）以外の11q23	

遺伝子異常	
正常核型		
 NPM1遺伝子変異(+)および FLT3-ITD遺伝子変異(-)	
	
 両対立遺伝子のCEBPA遺伝子変異		
CBF白血病		 c-kit遺伝子変異(+)	
	
 	
	
 	
正常核型	
	
 FLT3-ITD遺伝子変異(+)	
	

inv(3), t(3;3)	

	t(6;9)	

	t(9;22)	

	

一染色体欠失染色体異常	

	

複雑核型 (≧3 abnormalities)	

	

FLT3-­‐ITDとc-­‐kitは	
  九州大学で解析?	

NCCN	
  guideline,	
  AML	  2015	
  version	
  1	
  Printed by Tomohiko Kamimura on 6/16/2014 6:12:03 AM. For personal use only. Not approved for distribution. Copyright © 2014 National Comprehensive Cancer Network, Inc., All Rights Reserved.

NCCN Guidelines Version 2.2014
Acute Myeloid Leukemia

NCCN Guidelines Index
AML Table of Contents
Discussion

Printed by Tomohiko Kamimura on 6/16/2014 6:12:03 AM. For personal use only. Not approved for distribution. Copyright © 2014 National Comprehensive
mm,nn Cancer Network, Inc., All Rights Reserved.

AMLに対する寛解後療法	

CLASSIFICATIONTREATMENT INDUCTION

Clinical trial (preferred)

NCCN Guidelines Index
NCCN Guidelines
Version 2.2014
or
AML Table of Contents
Acute Myeloid Standard-dose
Leukemiacytarabine 100-200 mg/m continuous infusion x
Discussion
2

2

RISK STATUS(See AML-A)

AML kk,ll

Age <60 y
Better-risk cytogenetics
and/or molecularabnormalities

Age !60 y

Age <60

See Treatment
Induction (AML-11)

Intermediate-risk
cytogenetics and/or
molecular abnormalities2

7 days with idarubicin 12 mg/m or daunorubicin 90 mg/m x 3days oo,pp (category 1)
POST-REMISSION THERAPY
or
2
Clinical trial
Standard-dose
cytarabine 200 mg/m continuous infusion x 7
2or daunorubicin 60 mg/m x 3 days and cladribine 5days with
2
2HiDAC 3 g/m over 3 h qq
mg/m x 5 days (category 1) every 12 h on days 1, 3,
5 ! 3-4 cycles (category 1) ddd,eee
oror
2High-dosecytarabine(HiDAC) pp,rr 2
g/m every 12 hours x 61
to2
cyclesof
HiDAC-based
consolidation
2
tt with idarubicin 12 mg/m2
days ssor 3 g/mbyevery
12 h x 4
daysfff
followed
autologous
HSCT(category 2B)2or daunorubicin 60 mg/m x 3 days (1 cycle) (category 2B)

自家移植	

See PostInduction
Therapy (AML-8)

See Surveillance(AML-14)
See PostInduction
Therapy (AML-9)

同種移植	

Clinical trial
orMatched sibling or alternative donor HSCTorHiDAC ggg 1-3 g/m2 over 3 h every 12 h on days 1, 3, 5
x 3-4 cycles
qq

See Surveillance(AML-14)

kk Patients with blast counts >50,000/mcL are at higher risk for tumor lysis and organ

Holowiecki J, Grosicki S, Giebel S, et al. Cladribine, but not fludarabine, added todaunorubicin and cytarabine during induction prolongs survival of patients with acute myeloid
dysfunction secondary to leukostasis. Measures to rapidly reduce the WBC countleukemia: a multicenter, randomized phase III study. J Clin Oncol 2012;30:2441-2448.
include apheresis or hydroxyurea. Prompt institution of definitive therapy is essential.
ll Poor performance status and comorbid medical condition, in addition to age, are factors
rr The use of high-dose cytarabine for induction outside the setting of a clinical trial is stillthat influence ability to tolerate standard induction therapy.
controversial. While the remission rates are the same for standard- and high-dose
mm See Supportive Care (AML-C 1 of 2).
cytarabine, two studies have shown more rapid marrow blast clearance after one cycle of
nn See Monitoring During Therapy
Treatment-relateddisease or(AML-E).
Clinical trial
high-dose therapy and a disease-free survival advantage for patients " age 50 who received
oo ECOG reported a significant increase in complete response rates and overall survival
the high-dose therapy (category 2B). Kern W and Estey EH. High-dose cytarabineorpoor-risk
cytogenetics and/or
2
2
Surveillanceusing daunorubicin 90 mg/m x 3 days versus 45 mg/m xvv,ccc
3 days in patients <60 years
arabinosidein the treatmentof acute
myeloidrandomized
trials.
hhhleukemia: review of threeSee
Matched siblingor alternative
donor
HSCT
molecularof age. Fernandez HF, Sun
Z, Yao X, etabnormalities
al. Anthracycline dose intensification in acute
Cancer 2006;107:116-124. There are no data using more than 60 mg of(AML-14)
daunorubicin or 12
myeloid leukemia. N Engl J Med 2009;361:1249-1259. If there is residual disease on
mg of idarubicin with high-dose cytarabine.
ss Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dosedays 12-14, the additional daunorubicin dose is 45 mg/m2 x 3 days.
pp For patients with impaired cardiac function, other regimens that combine a nonversus standard-dose cytosine arabinoside with daunorubicin in patients with previously
anthracycline (such as fludarabine or topotecan) with cytarabine have been published.
acute myeloid leukemia: a Southwest Oncology Group study. Blood 1996;88:2841vv Begin alternate donor search (unrelated donor or cord blood) if no appropriate
fffuntreated
While both options--multiple cycles of dose-intensive consolidation and one cycle of2851.
sibling donor is available and the patient is a candidate for an allogeneic HSCT. tt Bishop
dose-intensive
consolidation
followedbyrandomized
autologousstudy
HSCT--canproducegood inJF, Matthews
JP, Young GA,
et al. Aof high-dose
cytarabine
ccc FLT3-ITD mutations are also emerging as a poor-risk feature in the setting ofsurvival forpatients
with leukemia.
favorableBloodcytogenetics,
there are significant differences in
inductionin acute
myeloid
1996;87:1710-1717.

同種移植	

otherwise normal karyotype, and these patients should be considered for clinical
trials where available. There is controversy regarding allogeneic transplant for

toxicity. Patient age, comorbid conditions, and issues such as fertility and salvage
options should be considered when choosing consolidation.

Note: All recommendations are category 2A unless otherwise indicated.
ggg There is no evidence that HiDAC is superior to lower doses of cytarabine in
FLT3-ITD-only mutations in the absence of other poor prognostic features.
Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
ddd
intermediate-risk patient subgroup.
Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy
hhh Patients may require at least one cycle of high-dose cytarabine consolidation whilein adults with acute myeloid leukemia. N Engl J Med 1994;331:896-903.
eee Alternate
Version2.2014, 03/28/14© National
CancerInc. 2014, All rights
reserved.has
The NCCN
Guidelines
and this illustration
may notsearch
be reproduced
in anyform without tothe maintainexpress writtenremission.
permission of NCCN.
AML-7
dosingofComprehensive
cytarabine
for Network,
postremission
therapybeenreported
donor
is in
progress
Patients
may proceed directlyto®

(see Discussion). Lowenberg B, Pabst T, Vellenga E, et al. Cytarabine dose for®

transplant following achievement of remission if a donor (sibling or alternative) is原三信病院 血液内科 勉強会	

急性骨髄性白血病	  Acute	
  Myeloid	
  Leukemia	  （AML）	
  Version	  1.0	
  同種造血	
  幹細胞移植	

造血器悪性腫瘍に対する治療	
治療の強度	
	
通常の抗癌剤治療＜自家移植＜同種移植	
１. 通常の抗癌剤治療	

再発	

合併症	

２. 超大量抗癌剤治療	
自家移植；骨髄, 末梢血（自分→自分）	
同種移植：骨髄, 末梢血, 臍帯血（他人→自分）	

超大量抗癌剤治療 + 免疫療法	
注：ミニ移植は「超大量化学療法」ではありません	免疫とは何か？	
同種造血幹細胞移植を理解するために	  非自己 = 自分ではなないもの	
人間の細胞	

•非自己を攻撃・排除	
攻撃	

攻撃	
ウイルスなど	•非自己を識別	•主にリンパ球が担当	
•リンパ球は造血幹細胞からできる	

免疫担当細胞＝リンパ球など	

•同種造血幹細胞移植後のリンパ球はドナー由来のものになる	

◆HLAやマイナー抗原などの蛋白質	血液がんに対する抗癌剤治療の概念	
血液がんに対する同種移植の概念	
同種造血幹細胞移植とは	
造血幹細胞を，他の人（ドナー）から提供を受け（骨髄，末梢血，臍帯血），点滴投与．	
抗がん剤
投与	

血液がん細
胞の減少	

ドナーの
移植片対宿主病
造血幹細
GVHD	
胞を点滴	
 「免疫反応」が患者の臓器を
攻撃	

•治癒の可
能性
正常の血
液細胞も
ドナー由来
減少	
 残っているから の血液細
胞が回復	
再発する	
血液がん細胞	

正常の血液細胞	「免疫反応」が血液がん細胞
を攻撃	

•免疫反応
による臓
器障害の
危険性	

同種移植後の免疫反応の功罪	
皮膚	

肝	
攻撃	

GVHD（graj-­‐versus-­‐host	
  disease）	
  ＝ドナー由来リンパ球が	
  患者の諸臓器を攻撃	

攻撃	

HLA	
GVL効果（graj-­‐versus-­‐leukemia）	
  

消化管	

＝ドナー由来リンパ球が	
  白血病細胞を攻撃	攻撃	
ドナー由来	
  
リンパ球	

マイナー
抗原	

攻撃	
移植後も患者体内に	  残存する白血病細胞	

Disease-free s

Disease-free surviv

50

donor

50

grafts. TRM was also evaluated in early and late trial eras. No
improvementnoofdonor
TRM over time could be demonstrated in recipients who had received their allograft after the median date ofinclusion (date not shown) as compared with the early transplants.

donor

an autologous or allogeneic transplant
relapsing patients reached a second CR
of these either relapsed again (93 of 18
of 184; 25%). At the time of analysis
were still alive of whom 45 were in coprobability of survival after relapse at 3group and 15% in the no-donor group.
relatively more patients died in CR
compared with the no-donor group, thetreatment to OS was larger in the no-do

化学療法	
  vs.	
  自家移植	  vs.	
  同種移植	  in	
  CR1	E 102, NUMBER 4

no donor25

25

N
no donor 599

Salvage treatment after relapse

F381

326 171
donor
ALLOGENEIC VERSUS
AUTOLOGOUS
SCT IN AML
1237difference in OS between the donor and no-donor
Logrank P =.002
The smallerF
N

AML染色体異常によるリスク別 （DFS）	
0

bility on outcome

group compared with the difference in months
DFS canbe explained by the120
effect of salvage treatment. Most of the 457 relapsed patients
121
67
37
months
120 treatment (88%),
receivedsalvageeither chemotherapy(51%) or
91
48
27

0

0

At risk:599
326

no donor
donor

192
140

EORTC/GIMEMA	 ALLOGENEIC VERSUS AUTOLOGOUS SCT IN AMLHOVON/SAKK	

1237
37

67
48

27

Disease-free survival

Disease-free survival

Good risk transplant (37%). Forty percent of thegrafts. TRM was also evaluated in A
early
and late trial eras. No an autologous or allogeneic
B 100
100
improvement of TRM over time could be demonstrated in recipi- relapsing patients reached a second CR (CR2, n ! 184), but mostgrafts. TRM was also evaluated in early and late trial eras. No an autologous or allogeneic transplant (37%). Forty percent of theents who had received their allograft after the median date of of these either relapsed again (93 of 184; 51%) or died in CR2 (46improvement of TRM over time could be demonstrated in recipi- relapsingpatients reached a second donor
CR (CR2, n ! 184), but most75 of the relapsed patients
75 theinclusion (date not shown) as compared withearly transplants. of 184; 25%). At the time of analysis 69
ents who had received their allograft after the median date of of these either relapsed again (93 ofno
184; 51%) or died in CR2 (46weredonor
still alive of whom 45 were in continued CR2. The actuarial
Salvagetreatment
after
relapseinclusion (date not shown) as comparedwiththe earlytransplants.
of 184; 25%). At the time of analysis 69 of the relapsed patientsprobability of survival after relapse at 3 years
was 16% in the donor
50
50 alive of whom 45 were in continued CR2. The actuarial
were still
Salvage treatment after relapse The smaller difference in OS between the donor and no-donor group and 15% in the no-donor group. Because in the donor groupprobability of survival after relapse at 3 years was 16% in the donor
1237
group compared with the difference in DFS can be explained by the relatively more patients died in CR1 and fewer relapsed as
The smaller difference in OS between the donor and no-donor group25and 15% in the no-donor group. Because in the donor group25
effect of salvage treatment. Most of the 457 relapsed patients compared with the no-donor group, the net
contribution of salvage
group compared with the difference in DFS can be explained by the relatively morepatients
died in CR1 and fewer relapsed as
N
F
NF
received salvage treatment (88%), either chemotherapy(51%)
ortreatmenttoOS
waslargerintheno-donorgroup.
no donor 333 199
no donor 73
28
donor
178
82
effect of salvage treatment. Most of the 457 relapsed patients compareddonor
with32the
11 no-donor group, the net contribution of salvage
Logrank P =.01
Logrank P =.43
00 to OS was larger in the no-donor group.
received salvage treatment (88%), either chemotherapy (51%) or treatment
0Low	
  risk	

Disease-free survival

75

donor
no donor
50

25

N
F
no donor 73
28
donor
32
11
Logrank P =.43

25

0

N
F
no donor 73
28
donor
32
11
Logrank P =.4300

At risk:
73
32

41
25

At risk:
73
32

27
19

Disease-free survivalC

41
25months 120

25

16
14

12
9

C

no d

no donor
donor

12
9

At risk:
333
178Standard
123 risk

78
47

78

Standard risk

Poor risk

100
75

no	
  donor	
  (auto-­‐SCT	
  28%)	
  
donor

75
50

no donor

donor

50

50
no donor
25

25
NF
no donor 333 199
donor
178
82
Logrank P =.0100
no donor
donor

16
14

100

C

no donor
75

27
19

27
19

100

0
no donor
donor

B

Good
risk
41

At risk:
73
32

donor

75

Intermediate	
  	
  
risk	

50

no donor
donor

B

Good risk

100no	
  donor	
  (auto-­‐SCT	
  63%)	
  Disease-free survival

no donor
donor

100

don

months 120

0AA

P=0.17	

121
91

Disease-free survival

donor	

192
140

N
no donor 333
donor
178

25 Logrank P =.010N0F
no donor 193 154
donor
116
78
At risk:
no donor 333Logrank P =.006
donor0 178

months 120

16
14

12
9

At risk:
333
178

123
78

F
199
82

0
78
47

100

no donordonor

At risk:
193
116

40
18

P=0.014	donor
no donor

123
78
months 120

28 risk
Poor
37

23
9

78
47

months 120
40
18

23
9

months 120
16
25

11
16

2
9

Figure 2. Actuarial disease-freeof patients with acute myeloid leukemia in first complete remission according to risk
Poorsurvival
risk(A) Good risk (P ! .43), (B) intermediate risk (P ! .01), (C) poor risk (P ! .006).

100

75

High	
  risk	50

Disease-free survivalno	
  donor	no donordonor

At risk:
599
326

Disease-freeDisease-freesurvival survival

nor availability
E 102, NUMBER 4
tic groups were
ery bad risk (C),-year DFS rates
onor
availabilitynd theno donoretic
were
ear groups
cumulativeveryarebadgivenrisk (C),CRin
4-yearrates
s; O, DFS
observed
ALLOGENEIC
VERSUS AUTOLOGOUS SCT IN AML
and CR).
thenoPdonorfirst
wasyear cumulative
CR are given ins; O, observed
first CR). P was0

no donor 599 381
326 171
donor
Logrank P =.002

OSはN.S.	
  (57%	
  vs.	
  48%;	
  p=0.23)	

75

50
donor
25
donor

no donorNF
no donor 193 154
116
78
no donor donor
Logrank P =.006

25
NF
no donor 193 154
donor
116
78
Logrank P =.006000months 120

0
no donordonor

At risk:
193
116

Suciu	  S.	
  Blood	
  2003	
the estimated hazard ratios were 0.64, 0.68, and 0.92 in the 3 age
At risk:
193
116

28
37
months 120

16
25

11
16

2
9

Figure 2.noActuarial
disease-freewith acutein first complete remission according to risk category and donor availability.
donor
28 survival of patients16
11 myeloid leukemia
2
donor
37
25
16
9
(A) Good risk (P ! .43), (B) intermediate risk (P ! .01), (C) poor risk (P ! .006).
Figure 2. Actuarial disease-free survival of patients with acute myeloid leukemia in first complete remission according to risk category and donor availability.
(A) Good risk (P ! .43), (B) intermediate risk (P ! .01), (C) poor risk (P ! .006).

groups, respectively. An interaction between age (considered as anCornelissen	
  JJ.	
  Blood	
  2007	

 

40

deve
afte
No donor
20
and
10 P=0.71
were
0
W
0
1
2
3
4
5
6
7
8
9
10
with
 
the
T h e n e w e ng l-
a n.d+j o u r na l o f m e dic i n e
to a
No donor
97 71 60 46 41 28 19 10
7
3
1
Donor
HLA
38 31 23 18
9
6
5
3
1
0
0
pati
respect
tooverallsurvival,bythefavorablere !.*  ,-.0 
Mutant	  NPM1	
  without	
  FLT-­‐3-­‐ITD	
Other	
  genotypes	 . ,.NPM1/.*-.FLT3#
—t
sults
of
receiptofatransplantfroman
HLA100100
tion
matched unrelated donor after relapse in the no90
90
anddonor group.
80
Excluding	  mutant	  any of the an a
80
The type of AML
did notthe	
  influence
Donor
CEBPA	  genotype	
70 end points we analyzed,
70
and amongpatients who firstwith
60 had the favorable genotype of mutant NPM1 with60
able
50 out FLT3-ITD or the favorable mutant CEBPA geno50
in whom AML the
40 type, the outcome for patients
40
Donor
diff
developedafteramyelodysplastic
syndromeor
30
30
after chemotherapy, radiation therapy, or both avai
No donor
20
20
No donorand the outcome of those withprimary AML tranbind
10 P=0.003
10 P=0.71
were similarly favorable.
00
We could assess any association of genotypes cyto
0
1
2
3
4
5
6
7
8
9
10
0
1
2
3
4
5
6
7
8
9
10
with the result of postremission therapy,38 since ber
 
 
the four trials we analyzed included assignment was- . +valu- . +toatreatment
group
accordingtowhether
an
No
donor
148
57 36 19 13
8
6
3
2
1
0
No donor
97 71 60 46 41 28 19 10
7
3
1
60
Donor
HLA-matched
was
33 24
19 donor
14RF.	  6N
3 available.
2
1Notably,
38 31 23 18
Schlenk	
  
ew	
  
Engl	
  
J2	
  Med	
  20008	
  only the
9
6
5
3
1
0 Donor0
patients with none of the favorable genotypes Gale
30



同種移植	
  (適合血縁)	
  vs.	
  非移植	
  染色体正常核型	
  AML	  in	
  CR1	

          





RFS	
  according	  to	
  availability	
  of	
  an	
  HLA-­‐MRD	AMLの予後分類（NCCN）からみた	
同種移植の適応	
予後分分類	

予後良好群	

予後中間群	

予後不良群	

染色体	
CBF白血病	・t（8;21）	
・inv（16） or t (16;16）	
t(15;17)	
正常核型	
+8	
t（9;11）（p22;q23）	
その他の染色体異常	
-5/del(5q)	
-7/del(7q)	
t（9;11）以外の11q23	

遺伝子異常	
正常核型		
 NPM1遺伝子変異(+)および FLT3-ITD遺伝子変異(-)	
	
 両対立遺伝子のCEBPA遺伝子変異		
CBF白血病	
基本的に同種移植適応		
 c-kit遺伝子変異(+)	
	
 	
	
 	
正常核型	
	
 FLT3-ITD遺伝子変異(+)	
	

inv(3), t(3;3)	

	t(6;9)	

	t(9;22)	

	

一染色体欠失染色体異常	

	

複雑核型 (≧3 abnormalities)	

	

FLT3-­‐ITDとc-­‐kitは	
  九州大学で解析?	

NCCN	
  guideline,	
  AML	  2015	
  version	
  1	
  治療抵抗性・難治性AML	

初発AML	
初回寛解導入療法でCR1達成	
  
	
   	
   	
   	
   	
   	
   	
  75〜80%	
  長期非再発生存率	
  
	
   	
   	
   	
   	
   	
   	
  30〜40%	

寛解導入不能	  15〜20%	

治療抵抗・難治	  50〜70%	再発	
  35〜50%	

BenneP	
  JM.	  Cancer	
  1997;	
  	
  Tallman	
  MS.	
  Blood	
  2005;	
  	
  Ohtake	
  Blood	
  2011	

ivBu-­‐based	
  MAC	
  vs.	
  TBI-­‐based	  	
  MAC	
3874

BREDESON et al

BLOOD, 5 DECEMBER 2013 x VOLUME 122, NUMBER 24

Center	  for	  Interna7onal	
  Blood	
  and	
  Marrow	  Transplant	
  Research	
  (CIBMTR)	

OS	

PFS	

TRM	

Relapse/progression	Bredeson	
  C.	
  Blood	
  2013	  Figure 1. Outcomes of allogeneic HCT with IV-BU or TBI conditioning regimens. (A) Survival by conditioning regimens. (B) Progression free survival by conditioning
regimens. (C) Cumulative incidence of TRM by conditioning regimens. (D) Cumulative incidence of disease relapse by conditioning regimens.

経口	
  or	
  静注	
  Bu/CY	
  vs.	
  TBI/CY	
Center	  for	  Interna7onal	
  Blood	
  and	
  Marrow	  Transplant	
  Research	
  (CIBMTR)	

AML	
  in	
  CR	
  (n	
  =	
  1230)	
経口BuCy vs Cy/TBI 静注BuCy vs Cy/TBI
RR (95% CI)
RR (95% CI)

	Oral BuCy vs IV
BuCy
RR (95% CI)

Overall P value

急性GVHD III-IV

0.72 (0.53-0.98)

0.72 (0.51-1.02)

1.00 (0.67-1.49)

0.048

慢性GVHD

1.01 (0.73-1.39)

1.13 (0.87-1.47)

0.89 (0.58-1.37)

0.65

非再発死亡率	0.72 (0.52-1.01)

0.58 (0.39-0.86)

1.24 (0.79-1.95)

0.011

再発 (1年以内)

0.81 (0.59-1.11)

1.06 (0.76-1.49)

0.76 (0.52-1.12)

0.31

再発 (1年以降)§

1.22 (0.78-1.90)

0.24 (0.084-0.66)

5.19 (1.85-14.57)

0.0074

無白血病生存率	

0.87 (0.72-1.06)

0.70 (0.55-0.88)

1.25 (0.96-1.62)

0.0096

全生存率	

0.78 (0.60-1.01)

0.68 (0.52-0.88)

1.15 (0.85-1.56)

0.0084

	  静注BuはTBIに比べ，全生存率，再発率，無白血病生存率，非再発死亡率を	
  有意に改善したが，経口Buではこうした改善は得られず．	
Copelan	
  E.	
  Blood	
  2013:3863-­‐70	
  静注Buを用いた至適前処置の開発	
TBI(12)/CY(120)	
  <	
  ivBu(12.8)/CY(120)	

前
処
置

	

強
度

Flu/Mel	  (±TBI	
  2Gy)	
Flu/ivBu(6.4)	
  (±TBI	
  2Gy)	
	
Flu/TBI(2)	
allo-­‐SCTの意義は	
  GVL効果にある	

主に生着安定	

TBI(2Gy)	
  Strob,	
  et	
  al.	
  Blood	
  1997	
  /	
  Int	  J	  Radiat	
  Oncol	
  Biol	  Phys	  1993	  	  	

included as a variable in this study.
For multivariate analyses, the main covariates were first entered together
into the model; with covariates found not to be significant at the .10 level
removed from the Cox model in a stepwise backward way. Type of conditioning regimen was held in the model at each step irrespective of its significancesince it was the main parameter of interest. Potential interactions between thecovariate type of conditioning regimen and the other remaining covariates

patients undergoing RIC had a significantly lowe
compared with those receiving SMC (32% v 44%
While patients older than 60 years had a higher
significantly different from the 50 to 60 age gro
36% v 39%; HR, 1.11; P # .39). When compare
Lim	
  Z.	
  siblingJ	
  Clin	
  donor,Oncol	
  an
2010	
  
HLA-matched
HLA-matched o

高齢者MDS/AML-­‐MDSに対するallo-­‐SCT	

Probability

Probability「allo-­‐SCTの意義はGVL効果にある」→	
  疑問	
50-­‐60歳	
61歳以上	骨 A
SMC 50-60 yrs
SMC > 60 yrs
B
1.0
1.0
Alive after relapse
Alive after relapse
髄
Dead after relapse
Dead after relapse
長期生存率	
Nonrelapse death
Nonrelapse death
0.8
破 0.8
0.6
壊 0.6
再発死亡	
的 0.4
0.4
非再発死亡	
前 0.2
0.2
（再発以外による死亡）	
処
00
高齢者に対して	
0
10
20
30
40
50
0
10
20
30
40
50
置
Time Since
Transplant (months)
Time Since Transplant (months)
非再発死亡（合併症死亡）を増加させず	
RIC 50-60 yrs
RIC > 60 yrs
C 1.0 Alive after relapse
D 1.0 Alive after relapse
移植前治療の抗白血病効果を	  減 0.8 Deadafter relapse
Dead after relapse
Nonrelapse death
Nonrelapse death
0.8
増強する前処置が模索されている	
Probability

Probability

	

	

量
前
処
置

0.6
0.4
0.2
0

0.6

再発死亡増加が打ち消している	

0.4
0.2

0

10

20

30

40

50

Time Since Transplant (months)

0

非再発死亡の減少の効果を-­‐-­‐-­‐-­‐-­‐	
  
0

10

20

30

40

50

Time Since Transplant (months)

Fig 2. Stacked
curves from a com
relapse and deatwith the study p
according to (A) adard myeloablativ(B) age ! 60 years
years, reduced inteand (D) age ! 60 y

静注Buを用いた至適前処置の開発	
TBI(12)/CY(120)	
  <	
  ivBu(12.8)/CY(120)	

前処
置

Flu/ivBu(12.8)	
  
	
  	
  	
  (±TBI	
  2Gy)	

Flu/Mel	  (±TBI	
  2Gy)	
Flu/ivBu(6.4)	
  (±TBI	
  2Gy)	
		

強度

Flu/TBI(2)	

抗腫瘍効果↑	allo-­‐SCTの意義は	
  GVL効果にある	

主に生着安定	

TBI(2Gy)	
  Strob,	
  et	
  al.	
  Blood	
  1997	
  /	
  Int	  J	  Radiat	
  Oncol	
  Biol	  Phys	  1993	  	  	静注Buを用いた至適前処置の開発	
TBI(12)/CY(120)	
  <	
  ivBu(12.8)/CY(120)	
Flu/ivBu(12.8)/G-­‐AraC	  	
  (±TBI	
  2Gy)	
抗腫瘍効果↑↑	

前処
置

Flu/ivBu(12.8)	
  
	
  	
  	
  (±TBI	
  2Gy)	

Flu/Mel	  (±TBI	
  2Gy)	
Flu/ivBu(6.4)	
  (±TBI	
  2Gy)	
		

強度

Flu/TBI(2)	

抗腫瘍効果↑	allo-­‐SCTの意義は	
  GVL効果にある	

主に生着安定	

TBI(2Gy)	
  Strob,	
  et	
  al.	
  Blood	
  1997	
  /	
  Int	  J	  Radiat	
  Oncol	
  Biol	  Phys	  1993	  	
  	JSCT-­‐Flu/Bu	
  13	
  Flu/ivBu(12.8mg/kg)	
  +	
  G-­‐CSF-­‐combined	
  AraC	  55〜70歳,	
  	
  	
  PS	
  0〜2,	
  	  	
  AML	  or	
  high	  risk	  MDS	  			G-­‐CSF-­‐combined	
  
AraC	
 	

-8	

-7	

-6	

-5	

-4	

-3	

-2	

-1	

0	

G-CSF 	

200μg/sqm	
div	

↓	

↓	

↓	

↓	

↓	

↓	

↓	

	

	

AraC	

100mg/sqm	
 cont. div	

	

↓	

↓	

↓	

↓	

	

	

	

	

	

2g/sqm	2hr div	

	

	

	

	

	

↓↓	
 ↓↓	

	

	

Fludarabine	
 30mg/sqm	

	

	

↓	

↓	

↓	

↓	

↓	

↓	

	

	

iv Busulfan	
 3.2mg/kg	

	

	

↓	

↓	

↓	

↓	

	

	

	

	

TBI 0 -4 Gy	
 	

	

←

移植	

	

	

	

この期間いずれの日に
	

	

	

	

	

→	
	

	

主要評価項目:	
  1年時点での無イベント生存割合 	

⇩	静注Buを用いた至適前処置の開発	
TBI(12)/CY(120)	
  <	
  ivBu(12.8)/CY(120)	
Flu/ivBu(12.8)/G-­‐AraC	  	
  (±TBI	
  2Gy)	

Flu/ivBu(12.8)/Mel	  	
  抗腫瘍効果↑↑	

前処
置

Flu/ivBu(12.8)	
  
	
  	
  	
  (±TBI	
  2Gy)	

Flu/Mel	  (±TBI	
  2Gy)	
Flu/ivBu(6.4)	
  (±TBI	
  2Gy)	
		

強度

Flu/TBI(2)	

抗腫瘍効果↑	allo-­‐SCTの意義は	
  GVL効果にある	

主に生着安定	

TBI(2Gy)	
  Strob,	
  et	
  al.	
  Blood	
  1997	
  /	
  Int	  J	  Radiat	
  Oncol	
  Biol	  Phys	  1993	  	
  	

Flu/MEL/Bu	
  for	  UCBT	

虎の門病院	TBI（全身放射線照射）を用いない臍帯血移植 前処置	

Flu 	
  
ivBu	
  
MEL	
  

	
  
	
  
	
  

	
  25-­‐30mg/sqm	
  	
  3.2mg 	
  /kg	  
	
  40mg 	  /sqm	-­‐7 	  -­‐6
⇩ 	
  ⇩
⇩ 	
  ⇩
	
  

	
  -­‐5
	
  ⇩
	
  ⇩
	
  

	
  -­‐4 	  -­‐3 	  -­‐2 	  -­‐1 	
  0	
  
	
  ⇩ 	
  ⇩ 	
  ⇩	
	
  ⇩	
  
	
  
	
  ⇩ 	
  ⇩ 	
  	
Tac	
  +	
  MMF	

⇒	
  生着率	
  90.2%	
Yamamoto	
  H.	
  ASH	  2013.	
  #P-­‐2024	
  Yamamoto	
  H.	
  Bone	  Marrow	  Transplant	
  2014:607-­‐9