1.
Primary graft failure, but not relapse, may be identified by early chimerism following double cord unit transplantation
Hough, R. E., Lopes, A., Patrick, P., Russell, N. H., Raj, K., Tholouli, E., Snowden, J. A., Collin, M., El-Mahidi, N., Lawrie, A., et al
Blood advances. 2021
Abstract
Umbilical cord blood transplantation (UCBT) has increased access to potentially curative therapy for patients with life-threatening disorders of the bone marrow and immune system. The introduction of reduced intensity conditioning (RIC) regimens and double cord unit infusions (DUCBT) has broadened the applicability of UCBT to more frail or larger recipients. The kinetics of chimerism following RIC DUCBT and their clinical utility are poorly understood. The RIC CBT trial reported here sought to prospectively evaluate the role of lineage specific chimerism following DUCBT in adult patients with haematological malignancies in the UK. Fifty-eight patients with a median age of 52 years were recruited, with an overall and progression free survival of 59% (95%CI 45% to 71%) and 52% (95%CI 39% to 64%) respectively at 2 years. Nonrelapse mortality was 4% (95% CI 1% to 13%) at day 100 and the relapse rate was 31% (95%CI 21% to 45%) at 1 year. Peripheral blood lineage specific chimerism was feasible from day 7 post-transplant onwards. Five patterns of chimerism were observed including i) complete single unit dominance (39 patients), ii) sustained donor-donor mixed chimerism (3 patients), iii) sustained donor-recipient mixed chimerism (5 patients), iv) dominance reversion (1 patient) and v) primary graft failure (4 patients). The RIC CBT trial enabled adult patients with high-risk hematological malignancies to safely access UCBT in the UK and provided novel insights into the kinetics of donor and recipient chimerism following RIC DUCBT which are clinically relevant. (Clinical Trials.gov identifier: NCT00959231; EudraCT identifier: 2004-003845-41).
2.
Cord blood maternal microchimerism following unrelated cord blood transplantation
Kanaan, S. B., Delaney, C., Milano, F., Scaradavou, A., Besien, K. V., Allen, J., Lambert, N. C., Cousin, E., Thur, L. A., Kahn, E., et al
Bone marrow transplantation. 2020
Abstract
Cord blood transplantation (CBT) is associated with low risk of leukemia relapse. Mechanisms underlying antileukemia benefit of CBT are not well understood, however a previous study strongly but indirectly implicated cells from the mother of the cord blood (CB) donor. A fetus acquires a small number of maternal cells referred to as maternal microchimerism (MMc) and MMc is sometimes detectable in CB. From a series of 95 patients who underwent double or single CBT at our center, we obtained or generated HLA-genotyping of CB mothers in 68. We employed a technique of highly sensitive HLA-specific quantitative-PCR assays targeting polymorphisms unique to the CB mother to assay CB-MMc in patients post-CBT. After additional exclusion criteria, CB-MMc was evaluated at multiple timepoints in 36 patients (529 specimens). CB-MMc was present in seven (19.4%) patients in bone marrow, peripheral blood, innate and adaptive immune cell subsets, and was detected up to 1-year post-CBT. Statistical trends to lower relapse, mortality, and treatment failure were observed for patients with vs. without CB-MMc post-CBT. Our study provides proof-of-concept that maternal cells of the CB graft can be tracked in recipients post-CBT, and underscore the importance of further investigating CB-MMc in sustained remission from leukemia following CBT.
3.
Adoptive immunotherapy with CB following chemotherapy for patients with refractory myeloid malignancy: chimerism and response
Chaekal, O. K., Scaradavou, A., Masson Frenet, E., Albano, M. S., Cushing, M., Desai, P., Dobrila, L., Gergis, U., Guarneri, D., Hsu, J. M., et al
Blood advances. 2020;4(20):5146-5156
-
-
Free full text
-
Abstract
We conducted a prospective evaluation of cord blood (CB)-derived adoptive cell therapy, after salvage chemotherapy, for patients with advanced myeloid malignancies and poor prognosis. Previously, we reported safety, feasibility, and preliminary efficacy of this approach. We present updated results in 31 patients who received intensive chemotherapy followed by CB infusion and identify predictors of response. To enhance the antileukemic effect, we selected CB units (CBU) with shared inherited paternal antigens and/or noninherited maternal antigens with the recipients. Twenty-eight patients with acute myeloid leukemia (AML), 2 with myelodysplastic syndrome, and 1 in chronic myeloid leukemia myeloid blast crisis were enrolled; 9 had relapsed after allogeneic transplant. Response was defined as <5% blasts in hypocellular bone marrow at 2 weeks after treatment. Thirteen patients (42%) responded; a rate higher than historical data with chemotherapy only. Twelve had CBU-derived chimerism detected; chimerism was a powerful predictor of response (P < .001). CBU lymphocyte content and a prior transplant were associated with chimerism (P < .01). Safety was acceptable: 3 patients developed mild cytokine release syndrome, 2 had grade 1 and 2 had grade 4 graft-versus-host disease. Seven responders and 6 nonresponders (after additional therapy) received subsequent transplant; 5 are alive (follow-up, 5-47 months). The most common cause of death for nonresponders was disease progression, whereas for responders it was infection. CB-derived adoptive cell therapy is feasible and efficacious for refractory AML. Banked CBU are readily available for treatment. Response depends on chimerism, highlighting the graft-versus-leukemia effect of CB cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02508324.