Multicenter single arm study to assess the safety and efficacy of allogeneic transplantation using cryopreserved bone marrow from deceased MMUD and PTCy, sirolimus and MMF for GVHD prophylaxis.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
pre-transplant conditioning treatment
pre-transplant conditioning treatment
pre-transplant conditioning treatment
Neutrophil engraftment
Run-in safety phase primary endpoint; Neutrophil engraftment is defined as neutrophil recovery by Day 35. Neutrophil recovery is defined as donor-derived absolute neutrophil count (ANC) ≥ 500/mm3 for three consecutive days with evidence of donor chimerism in bone marrow or peripheral blood. Full donor chimerism is \>95%, and mixed donor chimerism is defined as 5-95%.
Time frame: Day 35 Post HCT
Cumulative incidence and kinetics of neutrophil and platelet recovery
Main phase primary endpoint; Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) greater than or equal to 500/mm3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil recovery. The competing event is death without neutrophil recovery. For subjects who never drop ANC below 500/mm3, the date of neutrophil recovery will be Day 1 post-transplant. Platelet recovery is defined by two different metrics: the first day of a sustained platelet count greater than or equal to 20,000/mm3 or greater than or equal to 50,000/mm3 with no platelet transfusions in the preceding seven days. The first day of sustained platelet count above these thresholds will be designated the day of platelet engraftment. For subjects who never drop their platelet count below 20,000/mm3, the date of platelet recovery will be Day 1 post HCT.
Time frame: Day 35 Post HCT
Overall survival (OS)
Main phase primary endpoint; The primary endpoint for the study is OS at 1-year post-HCT. The event is death from any cause. The time to this event is the time from HCT to death, loss to follow-up, or end of study (whichever comes first). Subjects who are lost to follow-up prior to 1-year will be censored at the time of the last observation, and the OS probability will be estimated using the Kaplan-Meier method.
Time frame: 1-year Post HCT
Cumulative incidences of aGVHD and cGVHD
aGVHD is defined as any skin, gastrointestinal or liver abnormalities fulfilling the criteria of grades II-IV or grades III-IV. cGVHD is defined per National Institutes of Health (NIH) Consensus Criteria and includes organ involvement and severity, and overall global composite score (mild/moderate/severe).
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pre-transplant conditioning treatment
given with cyclophosphamide
post-transplant treatment for GVHD
post-transplant treatment for GVHD
post-transplant treatment for GVHD
post-transplant treatment for GVHD
Transplant with investigational bone marrow product
Time frame: 1-year Post HCT
Transplant-related mortality (TRM)
TRM is defined as death without evidence of disease progression or recurrence. TRM will be evaluated at Day 100, 180, and 1-year (Day 365).
Time frame: Day 100 and 1-year Post HCT
NK, B- and T-cell immune reconstitution
Quantitative assessments of peripheral blood CD3, CD4, CD8, CD19 positive lymphocytes will be done through flow cytometric analysis at Days 35, 100, 180, and 365 post-HCT. Qualitative assessments will be tabulated according to time from transplant.
Time frame: Days 35, 100, 180, and 1-year Post HCT
Progression free survival (PFS)
Progression free survival will be estimated at 1-year (Day 365) post-transplant. An event for this time to event outcome is defined as disease relapse or progression, or death by any cause.
Time frame: 1-year Post HCT
Event free survival (EFS)
EFS will be estimated at 12 months post-HCT. An event for this time to event outcome includes graft failure (PGF by Day 35 or secondary graft failure), relapse or progression of underlying disease, death, grade III-IV acute GVHD, or NIH-severe chronic GVHD.
Time frame: 1-year Post HCT
GVHD relapse free survival (GRFS)
GRFS will be estimated at 1-year (Day 365) post-transplant. An event for this time to event outcome is defined as relapse or progression of underling disease, graft failure, grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, or death by any cause.
Time frame: 1-year Post HCT
Cumulative incidence of cytokine release syndrome (CRS)
Overall incidence of CRS of any grade and grade 3 or 4 CRS post-transplant will be reported on all patients. CRS will be defined and graded using the American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading criteria.
Time frame: Day 14 Post HCT
Donor chimerism
Peripheral blood chimerism (% of donor chimerism) in whole blood (unsorted) will be described on Day 35, 56, 100, 180, and 1-year (Day 365). Donor cell engraftment will be assessed with donor/recipient chimerism studies at Day 100. Chimerism may be assessed in CD3 blood cell fraction. For the purpose of this protocol, mixed chimerism is defined as the presence of donor cells, as a proportion of total cells to be less than 95% but at least 5% in the bone marrow or peripheral blood. Full donor chimerism is defined as greater than or equal to 95% of donor cells. Mixed and full chimerism will be evidence of donor cell engraftment. Donor cells of less than 5% by Day 35 will be considered as graft rejection. The proportion of patients with each level of chimerism described above will be described as part of this outcome. For sorted blood cell fractions, CD3+ donor cell chimerism will be used to define the donor/recipient chimerism status.
Time frame: Days 35, 56, 100, 180, and 1-year Post HCT
Cumulative incidences of viral reactivations and infections
The incidence of Cytomegalovirus (CMV), Epstein-Barr virus (EBV), BK virus, Adenovirus (ADV), and Human herpesvirus (HHV-6) viral activations and infections at Days 100, 180 and 1-year (Day 365).
Time frame: Days 100, 180, and 1-year Post HCT
Cumulative incidence of primary disease relapse/progression
Testing for recurrent malignancy in the blood, bone marrow or other sites will be used to assess relapse and progression post-HCT. For the purpose of this study, relapse is defined by either morphological, cytogenetic/molecular or radiological evidence of disease consistent with pre-HCT features, in line with institutional standards. The event for this endpoint is the time interval from HCT to relapse/recurrence of disease or to last follow-up through 1-year (Day 365) post-HCT. Death in remission is considered a competing risk.
Time frame: 1-year Post HCT