Selecting the best donor for PTCy-based HLA-haploidentical HSCT

JRCT ID: jRCTs051190011

Registered date:26/04/2019

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Hematological malignancy
• Date of first enrollment: 17/10/2019
• Target sample size: 80
• Study type: Interventional

Intervention(s)

1) Allogenic stem cell transplantation from HLA-haploidentical related donor
2) GVHD prophylaxis: Cyclophosphamide (50 mg/kg) is given on day 3, 4 after the graft infusion. Continuous intravenous tacrolimus (0.03mg/kg/day) and oral mycophenolate mofetil 3000mg/day are initiated from day 5 after transplantation.
3) Donor selection: Selecting the best donor who shows the highest score of HLA-haploidentical donors according to the following scoring.
Factor, Score
(1) Relation: child/sibling, 3/2
(2) CMV antibody: donor + or recipient -, 2.5
(3) HLA mismatch (GVH direction): 4 or 5 (A, B, C, DR and DQ allele), 1.5
(4) HLA-DR mismatch (GVH direction): mismatch, 1.5
(5) HLA-DP mismatch: Nonpermissive mismatch, 2
(6) KIR R-L mismatch: positive, 1.5
(7) KIR Haplotype: B/x with 2DS2, 2

Outcome(s)

• Primary Outcome: Comparison of progression free survival between the two groups divided by the donor scoring points

Secondary Outcome

1) Overall survival, event-free survival
2) Non-relapse mortality
3) Relapse/progression
4) Cumulative incidence of grade II to IV and III to IV acute GVHD
5) Cumulative incidence of chronic GVHD
6) GVHD-free relapse free survival (GRFS)
7) Immunosuppressant discontinuation rate
8) Neutrophil and platelet engraftment
9) Regimen related toxicity
10) Non-infections fever within 7 days after transplantation
11) Immune reconstitution
12) Subgroup analysis of the above endpoints stratified by donor relationship to patient, HLA incompatibility locus/number, direction, presence of KIR R-L mismatch, KIR haplotype, and presence of donor B/x with 2DS2
13) Subgroup analysis according to stem cell count
14) Subgroup analysis according to primary disease and disease risk index
15) Exploratory analysis of other factors for prediction of transplant prognosis

Key inclusion & exclusion criteria

• Age minimum: >= 16age old
• Age maximum: < 70age old
• Gender: Both

Include criteria

Among patients with hematological malignancy (indicated in the selection criteria) who are clinically adopted to allo-HSCT because they cannot expect to be cured or long-term survival by any other therapy, patients who do not have or not available HLA serological identical related donors and have HLA-haploidentical donors.
1) Age >= 16 and <70 years old
2) ECOG PS 0 or 1
3) Normal function of major organs
4) Informed consent has been acquired
5) Major Indication
(a) AML
1. Refractory to 1st induction therapy
2. Relapse after chemotherapy
3. Unfavorable chromosome abnormality including del(5q)/-5, -7/del(7q), abn 3q, 9q, 11q, 20q, 21q, 17q, t(6;9), t(9;22) or complex karyotype
4. Normal karyotype and FLT3-ITD mutation
5. Intermediate/poor group by JALSG score
6. AML with MRC
7. History of relapse after allo-HSCT
8. CR1 with standard risk or high risk
(b) ALL
1. Refractory to 1st induction therapy, MRD positive or unevaluable
2. Relapse after chemotherapy
3. Any of the following poor prognostic factors
i) t(9;22) or t(4;11)
ii) >= 35 years of age at diagnosis
iii) WBC count of more than 30,000/uL for B-ALL, or more than 100,000/uL for T-ALL at diagnosis
4. History of relapse after allo-HSCT
5.History of relapse after CAR-T therapy
(c) Acute leukemias of ambiguous lineage
1. Refractory to the first induction therapy
2. Relapse after chemotherapy
3. Unfavorable chromosome abnormality
4. History of relapse after allo-HSCT
(d) MDS
1. EB-1 or 2
2. IPSS intermediate-2 or high
3. Transfusion dependent
4. History of relapse after allo-HSCT
(e) CML
1. AP or BC: refractory to multiple TKIs
2. CP beyond 1st CP or AP
3. History of relapse after allo-HSCT
(f) ATLL, ML
1. ATLL
Acute or lymphoma type in the PR or better
2. ML
Malignant lymphoma which is classified in the WHO classification (revised 4th edition) which relapse after auto-HSCT or CAR-T therapy due to no sensitivity to chemotherapy or poorly controlled disease with conventional chemotherapy
(g) Other, among hematological malignancies, the disease which is approved as an indication of allo-HSCT in our conference

Exclude criteria

1) Major organ dysfunction
a) Total bilirubin: >= 2.0 mg/dl
b) Serum creatinine: >= 2.0 mg/dl
c) Left ventricular 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, coronary failure, acute myocardial infarction within the last three months, liver cirrhosis and uncontrolled interstitial pneumonia
7) Pregnant, lactating woman or woman of childbearing potential
8) Patients with a severe mental disorder 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) A history of administration of mogamulizumab
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.The positivity of donor-specific antigen (DSA) is not excluded but DSA with MFI >=5000 should be avoided as much as possible)

Related Information

• Primary Sponsor: Nakamae Hirohisa
• Secondary Sponsor: Hino Masayuki
• Secondary ID(s): Nil known