UMIN-CTR Clinical Trial

Public title

HLA-mismatched allogeneic hematopoietic stem cell transplantation for high-risk advanced hematological disease with the adjustments of immunosuppressants and low-dose alemtuzumab.

Acronym

HLA-mismatched HSCT for high-risk hematological disease with adjusted immunosuppressabts and low-dose alemtuzumab

Scientific Title

HLA-mismatched allogeneic hematopoietic stem cell transplantation for high-risk advanced hematological disease with the adjustments of immunosuppressants and low-dose alemtuzumab.

Scientific Title:Acronym

HLA-mismatched HSCT for high-risk hematological disease with adjusted immunosuppressabts and low-dose alemtuzumab

Region

Japan

Condition

High-risk advanced hematological disease(leukemia and malignant lymphoma in non-remission, MDS with more than 20% of blast, and relapsed disease after allogeneic transplantation)

Classification by specialty

Hematology and clinical oncology

Classification by malignancy

Malignancy

Genomic information

NO

Narrative objectives1

To evaluate the safety and efficacy of HLA-mismatched allogeneic HSCT for High-risk advanced hematological malignancy with adjusted immunosuppressants and low-dose alemtuzumab

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Trial characteristics_2

Developmental phase

Primary outcomes

Survival rate at 60 days after transplantation with the engraftment of donor cells and without grade III-IV GVHD

Key secondary outcomes

Study type

Interventional

Basic design

Single arm

Randomization

Non-randomized

Randomization unit

Blinding

Open -no one is blinded

Control

Uncontrolled

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

1

Purpose of intervention

Treatment

Type of intervention

Medicine

Interventions/Control_1

Conditioning regimen: Patients who are intolerable to conventional conditioning regimen due to either higher age (55>=), previous ASCT, organ dysfunction, or active infection will receive regimen 2-1 or 2-2.(Mainly, regimen 2-1 will be selected in patients with lymphoid malignancy and regimen 2-2 will be selected in patients with myeloid malignancy.) In patients who were not eligible for TBI-containing regimen, regimen 2-3 may be selected. The other patients will receive regimen 1.

Regimen 1
Cyclophosphamide
60mg/kg/day iv. for 2 days
TBI
2Gy twice daily for 3 days
Alemtuzumab
0.25mg/kg/day iv. day-4,-3
(Maximum dose: 15mg/body/day for 2 days)
*Cytarabine 2g/m2 twice/day iv. for 2-3 days
or etoposide 15ng/kg/day iv. for 2 days may be added.
*Cyclophosphamide may be replaced with fludarabine 30mg/m2/day iv. for 4 days

Regime 2-1
Fludarabine
25mg/m2/day iv. for 5 days
Melphalan
40mg/m2/day iv. for 2 days
Alemtuzumab
0.25mg/kg/day iv. day-4,-3
(Maximum dose: 15mg/body/day for 2 days)

Regimen 2-2
Fludarabine
30mg/m2/day iv. for 6 days
Busulfan
3.2mg/kg/day iv. for 2-4 days
TBI
2Gy once or twice daily for 1 day
Alemtuzumab
0.25mg/kg/day iv. day-4,-3
(Maximum dose: 15mg/body/day for 2 days)

Regimen 2-3
Fludarabine
30mg/m2/day iv. for 6 days
Busulfan
3.2mg/kg/day iv. for 4 days
Melphalan
80-140mg/m2/day iv. for 1 days
Alemtuzumab
0.25mg/kg/day iv. day-4,-3
(Maximum dose: 15mg/body/day for 2 days)

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

16

years-old

<=

Age-upper limit

70

years-old

>=

Gender

Male and Female

Key inclusion criteria

1.Patients who do not have an available HLA-matched or one locus-mismatched related donor.
2.Patients who have a two- or three-locus-mismatched haploidentical related donor in good condition.(This donor should precede an HLA-matched or one locus-mismatched related donor accoridng to the disease status.)
3.Patients who do not have an HLA-matched or one allele-mismatched unrelated donor, or patients whose disease status preclude time-consuming donor coordination.
4.Patients with high-risk advanced hematological disease. Leukemia and malignant lymphoma in non-remission, MDS with more than 20% of blast, and relapsed disease after allogeneic transplantation are included in high-risk group.
5.Patients who are 16 to 70 years old
6.Patients in performance status of 0 or 1.
7.Patients whose major organ functions are preserved.

Key exclusion criteria

1.Patients with poorly controlled active infection.
2.Patients with coexistence of malignancy.
3.Patients who are pregnant or nursing.
4.Patients with serious mental disorder.
5.Patients with HIV antibody positive.
6.Patients who are allergic to drugs used in conditioning regimen or GVHD prophylaxis.

Target sample size

28

Name of lead principal investigator

1st name	Yoshinobu
Middle name
Last name	Kanda

Organization

Saitama Medical Center, Jichi Medical University

Division name

Division of Hematology

Zip code

330-8503

Address

1-847 Amanuma, Omiya-ku, Saitama-city, Saitama 330-8503, Japan

TEL

0486472111

Email

shinichikako@asahi-net.email.ne.jp

Name of contact person

1st name	Shinichi
Middle name
Last name	Kako

Organization

Saitama Medical Center, Jichi Medical University

Division name

Division of Hematology

Zip code

330-8503

Address

1-847 Amanuma, Omiya-ku, Saitama-city, Saitama 330-8503, Japan

TEL

0486472111

Homepage URL

Email

shinichikako@asahi-net.email.ne.jp

Institute

Division of Hematology, Saitama Medical Center, Jichi Medical University

Institute

Department

Personal name

Organization

Grant-in-Aid from the Ministry of Health, Labor and Welfare of Japan

Organization

Division

Category of Funding Organization

Japanese Governmental office

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

Jichi Medical University Central Clinical Research Ethics Committee

Address

3311-1, Yakushiji, Shimotsuke-shi, Tochigi, Tochigi

Tel

+81-285-58-8933

Email

jmu-crb2020@jichi.ac.jp

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

自治医科大学附属さいたま医療センター（埼玉県）
自治医科大学附属病院（栃木県）

Date of disclosure of the study information

2015

Year

07

Month

13

Day

URL releasing protocol

https://jrct.niph.go.jp/latest-detail/jRCTs031180237

Publication of results

Partially published

URL related to results and publications

https://jrct.niph.go.jp/latest-detail/jRCTs031180237

Number of participants that the trial has enrolled

27

Results

The rate of the achievement of primary outcome measure was more than 80%, but the RR at 1 year was high. Most patients had uncontrollable, non-remission disease, and in addition, many patients had a history of previous allogeneic transplantation. These affected outcomes a lot, but we need to decrease a relapse rate by inducing new methods, such as the further reduction of immunosuppressants after transplantation and donor lymphocyte infusion (DLI) at the early phase after transplantation.

Results date posted

2022

Year

07

Month

19

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

Baseline Characteristics

The median age of patients who were enrolled in this study was 46 years (range 17-68 years). Twenty-one patients were male. The underlying diseases were acute myelogenous leukemia (AML) in 16, acute lymphoblastic leukemia (ALL) in 3, mixed phenotype acute leukemia in 1, myelodysplastic syndrome (MDS) in 1, malignant lymphoma in 4, and adult T-cell leukemia/lymphoma (ATLL) in 1. Twelve patients had a history of previous allogeneic transplantation. Ten donors were siblings, 5 were parents, and 12 were sons or daughters. Their median age was 38 years (range 19-62 years).

Participant flow

In the protocol, 43 patients were planned to be enrolled between June 2015 and December 2023. But the enrollment was delayed, and the 28th patient who was enrolled in February 2020 was the last patient. In December 2020,the use of alemtuzumab, the main drug of this study, in the pre-transplant conditioning regimen, became coverd by Japanese health insurance, and it was expected that the further enrollment became difficult. Therefore, we decided to stop this study. All 28 patients but one, who was dequalified after the enrollment, underwent transplantation, and 15 and 13 underwent transplantation at Jichi Medical University Hospital and Jichi Medical University Saitama Medical Center, respectively. The median follow-up period for survivors was 408 days. Treatment based on the protocol stopped in 23 patients due to their death. Among them, 15 died after relapse, and 8 died with non-relapse cause.

Adverse events

An adverse event which was subject to reporting according to the protocol was observed in 5 patients. Four patients died within 60 days after transplantation due to heart failure in 2, infection in 1, and thrombotic microangiopathy (TMA) in 1. One patient developed grade III acute GVHD. In addition, veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) was reported as an adverse event who has a risk for death based on a clinical trial act. These were all known complications.

Outcome measures

The primary outcome measure was the rate of achievement of the following three criteria: neutrophil engraftment of donor cells, patient alive at day 60, and the absence of Grade III-IV acute GVHD.Twenty-two of 27 patients who actually underwent transplantation (81.5%) achieved this primary outcome measure. Secondary outcome measures were overall survival (OS), relapse rate (RR), and non-relapse mortality (NRM) at 1 year. Each rate was 11.1%, 63.0%, adn 25.9%, respectively.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2015

Year

06

Month

30

Day

Date of IRB

2015

Year

06

Month

30

Day

Anticipated trial start date

2015

Year

07

Month

14

Day

Last follow-up date

2020

Year

02

Month

10

Day

Date of closure to data entry

2020

Year

12

Month

08

Day

Date trial data considered complete

2020

Year

12

Month

08

Day

Date analysis concluded

2020

Year

12

Month

08

Day

Other related information

Registered date

2015

Year

07

Month

13

Day

Last modified on

2023

Year

07

Month

20

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000021179