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

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

27

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).

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.

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.

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.

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.

Mar. 01, 2022

Jan. 15, 2021

https://www.jstage.jst.go.jp/article/hct/10/1/10_20-015/_article/-char/ja/

No

IPD sharing is not planned.

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

Kanda Yoshinobu

Jichi Medical University, Saitama Medical Center

1-847, Amanuma-cho, Omiya-ku, Saitama-shi, Saitama, Japan

ycanda-tky@umin.ac.jp

Kako Shinichi

Jichi Medical University, Saitama Medical Center

1-847, Amanuma-cho, Omiya-ku, Saitama-shi, Saitama, Japan

+81-48-647-2111

shinichikako@asahi-net.email.ne.jp

Complete

July. 14, 2015

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

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 according 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.

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.

Both

Patients with high-risk advanced hematological disease

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)

High-risk advanced hematological disease

Allogeneic hematopoietic stem cell transplantation

D006402

D033581

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

Relapse rate, non-relapse mortality, and overall survival at 1 year

+81-285-58-8933

Feb. 25, 2019

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