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Posttransplantation cyclophosphamide and tacrolimus for prevention of Graft-versus-host disease in allogeneic hematopoietic stem cell transplantation from HLA matched sibling or unrelated donor: a single center prospective phase II study (OCU16-1)

PTCy and tacrolimus for GVHD prevention after allo-HCT from HLA matched donor (OCU16-1)

39

Age(median, range):52(29-66) Disease:AML 19, ALL 5, MDS 6, ML 4, Other 5 Donor:HLA match related (MRD group) 17, HLA match unrelated (MUD group) 22 Stem cell source:BM19 (MRD 3, MUD 16), PBSCs 20 (MRD 14, MUD 6) Disease status, non-remission:MRD 6, MUD11 Conditioning:MAC 31 (MRD 12, MUD 19), RIC 8 (MRD 5, MUD 3)

This study was a single-center study conducted at Osaka City University Hospital. From October 2016 to May 2020, 39 patients were enrolled in this study, and enrollment was approximately on schedule. This study was conducted as a specified clinical trial from 3/20/2019 due to the enforcement of the Japanese Clinical Trials Act.

Before this study was approved as a specified clinical study, 3 cases of 4 serious adverse events had occurred and been reported urgently:1 case of viral hemorrhagic cystitis, nephropathy, and heart failure (death), 1 case of pneumonia, and 1 case of massive pleural effusion and idiopathic pneumonia syndrome (death), all of which were known adverse events. After the study was conducted as a specified clinical trial, there was 1 case (idiopathic pneumonia syndrome, death) of expedited reporting as "serious case of disease or the like" as defined in Japanese Clinical Trials Act.

The cumulative incidence of chronic GVHD at 1 year post-transplantation, the primary endpoint, was 13% overall (95% Cl 4.6-26%), and the cumulative incidence of moderate to severe chronic GVHD at 1 year were 12% in the MRD group and 9.1% in the MUD group. Neutrophil engraftment was achieved in all patients, with a median of 17 days in the MRD group and a median of 18 days in the MUD group. The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD at 100 days were 18% and 5.9% in the MRD group and 18% and 9.1% in the MUD group. The most common non-hematological treatment-related toxicity observed in the first 100 days was febrile neutropenia (72%). Two patients (5%) experienced grade >= 2 cardiotoxicity, and one (3%) experienced grade 4 pleural effusion. The 1-year overall survival rates after transplantation in the MRD and MUD groups were 88% and 64%. The 1-year cumulative incidences of relapse/progression in the MRD and MUD groups were 24% and 27%. The cumulative incidences of non-relapse mortality (NRM) at 100 days were 0.0% in both groups, whereas the cumulative incidences of NRM at 1 year were 0.0% in the MRD group and 14% in the MUD group. The 1-year GVHD-free, relapse free survival rates were 59% in the MRD group and 50% in the MUD group.

The result of this study suggests that GVHD prophylaxis with a less intensive double drug combination (PTCy and TAC) might be feasible after HLA-matched related or HLA-matched unrelated allo-HCT.

June. 30, 2022

Sept. 29, 2021

https://pubmed.ncbi.nlm.nih.gov/34586587/

No

Not applicable

https://jrct.mhlw.go.jp/latest-detail/jRCTs051180143

Nakamae Hirohisa

Osaka City University Hospital

1-5-7 Asahi-machi, Abeno-ku, Osaka, Japan

hirohisa@msic.med.osaka-cu.ac.jp

Nakamae Hirohisa

Osaka City University Graduate School of Medicine

1-4-3 Asahi-machi, Abeno-ku, Osaka, Japan

+81-6-6645-3881

crc-hematology@med.osaka-cu.ac.jp

Complete

Oct. 14, 2016

Interventional

single arm study

open(masking not used)

no treatment control/standard of care control

single assignment

treatment purpose

(1) Disease
(a) AML
(b) ALL
(c) Acute leukemias of ambiguous lineage
(d) MDS
1. IPSS int-2 or high, or IPSS-R intermediate, poor or very poor
2. Transfusion dependent MDS (more than 2 unit RBC or 10 unit platelet weekly transfusion)
(e) CML
1. CP beyond 1st CP
2. TKI failure in 1st CP
(f) malignant lymphoma
1. Indolent lymphoma after 1st relapse/progression
2. Aggressive lymphoma
*Chemo-refractory lymphoma after 1st relapse, or
*Lymphoma after 2nd relapse, or
*relapsed Lymphoma after auto-HCT
(g) Other, hematological malignancy that was judged as necessity of allo-HCT in our conference

(2) Age >=15 and < 70 years old
(3) ECOG PS 0 or 1
(4) Normal function of major organs
(5) donor: presence of available sibling or unrelated donor with HLA-A, B, C, and DRB1 allele 8/8 match in GVH direction
(Note: no limitation for conditioning regimen intensity)

1) Major organ dysfunction
a) Total bilirubin:>= 2.0mg/dl
b) Serum creatinine: >= 2.0mg/dl
c) Ejection fraction: < 50 %
d) Pulmonary function test: %VC <40%, FEV1.0% <50% or SaO2 <90% on room air
e) AST or ALT >= 3 x UNL
2) Uncontrolled active infection
3) Uncontrolled CNS invasion
4) Poorly controlled insulin-treated
diabetes mellitus
5) Poorly controlled hypertension
6) Patients with a severe complication including heart failure, liver failure, acute myocardial infarction within the last three months, liver cirrhosis and interstitial pneumonia
7) Pregnant, lactating or possible fertile women who may become pregnant
8) Patients with a severe mental who are likely to be unable to participate in the study

9) A history of hypersensitivity or allergy to any drugs in the conditioning regimen of this transplant
10) HIV antibody positivity
11) The administration of ATG is scheduled in conditioning regimen.
12) The physician in charge determines that there is no indication to perform this intervention.
(Note: HBs antigen positivity and HCV antibody positivity is not exclusion criterion.)

Both

Hematological malignancy

Cy is intravenously administered at 50mg/kg/day on days 3 and 4. Continuous intravenous infusion of Tac is started at 0.03mg/kg/day from day 5. Unless GVHD developed, Tac was tapered from day 60-100 and stopped until day 180.

1 year chronic GVHD cumulative incidence

1) Overall survival, relapse rate
2) Non-relapse mortality
3) GVHD and relapse-free survival: GRFS
4) Incidence of primary and secondary engraftment failure
5) Time to hematopoietic recovery, time to complete donor chimerism
6) Incidence and severity of acute and chronic GVHD
7) Regimen related toxicity
8) Incidence of bacterial, fungal and viral infections
9) Immune reconstruction

+81-6-6645-3456

Feb. 21, 2019

none