Table 1 Myeloablative conditioning regimens in allogeneic hematopoietic stem cell transplantation for hematological malignancies, especially for acute lymphoblastic leukemia

ETP 60 mg/kg × 1 + TBI 1.2 Gy × 11

13

16 (6–36)

MRD

BM

CR2, IF, or relapse

54 % (≧100 d)

15 %

31 %

23 %

ND

It was not clear whether ETP 60 mg/kg was better than ETP 30 mg/kg according to a phase I/II (dose-finding) study using 25 to 70 mg/kg of ETP.

Blume KG, et al. Blood 1987;69:1015.

ETP 50 to 70 mg/kg × 1 + TBI 2 Gy × 6

17

19 (4–38)

MRD

BM

Non-CR1, IF, or relapse except 1

65 % (≧182 d)

6 %

35 %

85 %

50 %

Anti-leukemic effect was observed in a phase I/II study with ETP + BI, but the rejection rate was high. Thus, the immunosuppressive effect was worse than CY + TBI. A dose of more than 60 mg/kg of ETP was too toxic.

Schmitz N, et al. Blood 1988;72: 1567.

ETP 36 mg/kg or 52 mg/kg × 1 + CY 67 mg/kg or 103 mg/kg × 1 + TBI 2 Gy × 6

7

15 (6–35)

MRD

BM

Relapse

0 % (≧899 d)

ND

ND

ND

ETP (36 mg/kg) + CY (67 mg/kg) + TBI was well tolerated for allogeneic HSCT (phase I study).

Petersen FB, et al. Bone Marrow Transplant. 1992; 10:83.

ETP 60 mg/kg × 1 + TBI 1.2 Gy × 11

25/122

2–48

MRD

BM

CR2: 8

3-Y DFS: 63 %

8 %

4 %

ND

ND

ETP + TBI appeared to be better for a good-risk group than for a poor-risk one according to a randomized controlled study. Hepatic toxicity and severe mucositis were marked with ETP of 60 mg/kg. The age range for the patients with ALL was shown, but the mean was unclear.

Blume KG, et al. Blood 1993;81: 2187.

CR3, Non-CR: 17

12 %

40 %

12 %

ND

ND

BU 1 mg/kg × 16 + CY 60 mg/kg × 2

23/122

5–48

CR2: 6

4 %

17 %

4 %

ND

ND

CR3, Non-CR: 17

17 %

34 %

22 %

ND

ND

ETP 60 mg/kg × 1 + TBI 1.2 Gy × 11

34

27 (1–45)

MRD

BM

CR1

3-Y DFS: 64 %

12 %

ND

18 % (gr.≧II)

38 %

A relatively good outcome was observed in a phase II study, but relapse and TRM rates were high. Thirty of the 34 patients were high-risk.

Snyder DS, et al. Blood 1993;82: 2920.

High-risk

<20 y 3-Y DFS : 100 %

0 %

≧20 y 3-Y DFS: 54 %

17 %

ETP 30–60 mg/kg × 1 + CY 60–200 mg/kg × 2 + TBI 1.2Gy × 11 (1.5 Gy × 8)

20/44

18 (1–54)

MRD

BM

ND

Early death: standard-risk 2/18 high-risk 2/26

ND

ND

ND

ND

Fourty-four patients with hematological malignancies were analyzed in a retrospective study. Among them, 20 patients were ALL. Sixty to 65 mg/kg of ETP resulted in a fatal toxicity, but 30 to 50 mg/kg did not. Fifty mg/kg of ETP was considered to be the maximally tolerated dose.

Spitzer TR, et al. Int. J. Radiat. Oncol. Biol. Phys. 1994;29:39

ETP 25–60 mg/kg × 2

10/32

18 (3–49)

MRD

BM

ND

Early death: standard-risk 1/12 high-risk 5/20

ND

BU 1 mg/kg × 12–16

Standard

20 (1–39)

MRD

BM

CR2: 20

7-Y OS: 52 %

34 %

25 %

48 % (gr.≧II)

41 %

A retrospective study suggested that high-dose conditioning regimens did not improve the outcome of patients transplanted for high-risk leukemia.

Mengarelli A, et al. Haematologica 2002;87:52.

TBI 2 Gy × 6 + CY 120 mg/kg × 2

7/38

CR3: 9

1st Rel.: 5

Adv.: 4

BU 16 mg/kg × 4 + CY 120 mg/kg × 2

24/38

BU 16 mg/kg × 4 + CY 120 mg/kg × 4

7/38

Alternative

23 (3–44)

MRD

BM: 60

CR2: 47

7-Y OS: 25 %

58 %

32 %

47 % (gr.≧II)

44 %

ETP 60 mg/kg × 1 + TBI 2 Gy × 6 TBI 2 Gy × 6 + CY 120 mg/kg × 2

43/66

PB: 6

CR3: 9

1st Rel.: 6

Adv.: 13

BU 16 mg/kg × 4 + CY 120 mg/kg × 2 +IDA 42 mg/m² × 2

BU-CY + VP 20 mg/kg × 1

BU-CY + Ara-C 2 g/m² × 4

ETP 40 mg/kg × 1 + CY 60 mg/kg × 2 + TBI 2 Gy × 6

39

34 (15–52)

MRD: 35

BM

CR1

6-Y OS: 41 %

10 %

15 %

ND

ND

Autologous HSCT by ETP + CY + TBI regimen showed 41 % of 6-Y OS in a prospective study, whereas allogeneic BMT with the same regimen showed a 6-Y OS of 75 %. This result suggested a possibility of GVL effect. ETP was administered in 4 consecutive infusions of 10 mg/kg lasting 2 hours each.

Hunault M, et al. Blood 2004;104:3028.

MUD: 4

(<50 years old: 75 %)

ETP 15 mg/kg × 2 + CY 60 mg/kg × 2 + TBI 2 Gy × 6

37

26 (15–58)

MRD: 13

BM: 3

CR1: 28

3-Y OS: 89 %

8 %

5 %

78 % (gr.≧II: 41 %)

55 % (ext.: 36 %)

Excellent outcome was observed in addition to low relapse and TRM rates in a retrospective study.

Shigematsu A, et al. Biol. Blood Marrow Transplant. 2008;14:568.

MUD: 18

PB: 4

CR2: 7

MMRD: 2

CB: 1

Non-CR: 2

MMUD: 4

ETP 15 mg/kg × 2 + CY 60 mg/kg × 2 + TBI 2 Gy × 6 or 3 Gy × 4

35

28 (15–58)

MRD:16

BM: 29

CR1: 28

5-Y OS:82 %

14 %

3 %

71 % (gr.≧II: 37 %)

46 % (ext.: 30 %)

A retrospective analysis in Japan showed ETP + CY + TBI was associated with lower relapse and NRM rates, resulting in better survival than that with CY + TBI.

Shigematsu A, et al. Int. J. Hematol. 2011;94:463.

MUD: 11

PB: 6

CR2:7

MMUD: 6

Unknown: 2

CY 60 mg/kg × 2 + TBI 2 Gy × 6 or 3 Gy × 4

494

34 (15–59)

MRD: 235

BM: 405

CR1: 414

5-Y OS: 55 %

29 %

16 %

62 % (gr.≧II: 37 %)

45 % (ext.: 27 %)

MUD: 180

PB: 89

CR2: 80

MMRD: 1

MMUD: 70

Unknown: 2

ETP 15 mg/kg × 2 + CY 60 mg/kg × 2 + TBI 2 Gy × 6

50

34 (17–49)

MRD: 26

BM: 40

CR1: 47

1-Y OS: 80 %

10 %

14 %

66 % (gr.≧II: 58 %; gr.≧III: 12 %)

56 % (ext.: 38 %)

A prospective multi-center phase II study in Japan confirmed the excellent outcome of ETP + CY + TBI for adult ALL patients.

Shimemastu A, et al. Transplant. Direct. 2015;1:1

MUD: 24

PB: 10

CR2: 3

2-Y OS: 67 %

1-Y EFS: 76 %

2-Y EFS: 65 %