Adoptive immunotherapy has shown efficacy in patients with relapsed/refractory acute myelogenous leukemia (AML). We conducted a prospective evaluation of cord blood (CB)-based adoptive cell therapy following salvage chemotherapy in patients with AML or myelodysplastic syndrome (MDS) and describe the safety and early outcomes of this approach. To enhance the antileukemic effect, we selected CB units (CBUs) with a shared inherited paternal antigen (IPA) and/or noninherited maternal antigen (NIMA) match with the recipients. Furthermore, the CBUs had total nucleated cell (TNC) dose <2.5 £ 10 7 /kg and were at least 4/6 HLA-matched with the patients; a higher allele-level match was preferred. Heavily pretreated adult patients with AML/MDS were enrolled. CBU searches were performed for 50 patients. CBUs with shared IPA targets were identified for all, and CBUs with NIMA matches were found for 80%. Twenty-one patients underwent treatment (AML, primary induction failure, n = 8; refractory relapse, n = 10, including 7 recipients of previous allogeneic HSCT; blast crisis chronic myelogenous leukemia, n = 1; MDS, n = 2). Most received combination chemotherapy; those not fit for intensive treatment received a hypomethylating agent. Response was defined as <10% residual blasts in hypocellular bone marrow at approximately 2 weeks after treatment. Ten of the 19 evaluable patients responded, including 5 of the 7 recipients of previous transplant. Response was seen in 4 of 4 patients with full CBU-derived chimerism, 2 of 2 of those with partial, low-level chimerism and 4 of 12 of the recipients with no detectable CBU chimerism. The most common adverse events were infections (bacterial, n = 5; viral, n = 2; fungal, n = 5). Grade IV acute graft-versus-host disease (GVHD) developed in 2 patients with full CBU chimerism; 2 other patients had grade 1 skin GVHD. A total of 11 patients died, 7 from disease recurrence and 4 from infections (1 early death; the other 3 in remission at the time of death). Overall, 12 patients proceeded to allogeneic HSCT; of those, 7 had responded to treatment, 3 had not (and had received additional therapy), and 2 had persistent minimal residual disease. In conclusion, the use of CB as adoptive immunotherapy in combination with salvage chemotherapy for patients with refractory AML/MDS is feasible, can induce disease control, can serve as a bridge to allogeneic HSCT, and has an acceptable incidence of adverse events. Alloreactivity was enhanced through the selection of CBUs targeting a shared IPA and/or NIMA match with the patients. CBUs with lower cell doses, already available in the CB bank and unlikely to be adequate grafts for adult transplants, can be used for cell therapy within a short time frame.
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.
Background: CBU selection for transplant is based on HLA match and potency/quality determinations associated with the speed of hematopoietic engraftment. Total Nucleated Cell (TNC) count, viable (v) CD45+ and CD34+ cells and Colony Forming Units (CFU) have been used as surrogate markers of hematopoietic stem cells. However, besides TNC measurements, most of the assays still have poor standardization among laboratories. The NCBP has manufactured over 60,000 clinical CBU (as of 07/2018). Of those, 32,413 CBU had pre-cryopreservation samples tested prospectively (period: 03/2008-04/2018) using validated assays for TNC (Sysmex XE-2100), vCD45+ and vCD34+ cells (single platform flow cytometry using ISHAGE strategy and 7-AAD for viability) and HRDI-CFU assay (High Resolution Digital Imaging CFU strategy, Albano et al, Blood 2011;118:485). Among those, 754 CBU have been shipped to US Transplant Centers (TC) for single or double unit transplants. Prior to release for clinical use, CBU had also quality/potency tests conducted prospectively in post-thaw samples from attached segments, using the same assays. Aims and study design: 1) to evaluate the quality/potency of 754 NCBP CBU provided for transplantation (period: 03/24/2008-12/31/2017) by pre-cryopreservation characteristics, post-thaw segment evaluations and their correlations, and 2) to assess their impact on engraftment in two patient subsets after myeloablation: cohort 1, N=99 patients (pts), who received single CBU transplants, and cohort 2, N=139 pts with double unit grafts, who engrafted with the NCBP CBU. All laboratory evaluations were performed by NCBP. Clinical data were provided by CIBMTR; only pts with information on time to engraftment (ANC>500) and established donor chimerism were analyzed. Results: The 754 CBU selected by TC had quality/potency parameters showing a strong correlation between cell numbers and function pre-cryopreservation and post-thaw (Table 1; Pearson correlation). Segment post-thaw median recoveries were 73% (SD: 21.8%) for vCD45+ cells; 69% (SD: 20.7%) for vCD34+ cells and 60% (SD: 22.9%) for CFU, with a strong correlation between pre-cryopreservation and post-thaw values (Pair T Test: 0.74; 0.87 and 0.79, respectively; all P<0.001) and excellent segment post-thaw CD34+ viability (median: 95.8%; SD: 3.5%). There were no differences between CBU released as FDA-licensed products (N=208) or those under IND (N=546). Median time from CBU collection to transplant was 2.1 years (range: 0.1-9.6). Median time to engraftment was 19 days (range: 14-205) for the pts that received myeloablative regimens (N=238 total). Cohort 1 included primarily children with average age 9 years, average weight 24 kg (range 3-116), who received median pre-cryopreservation TNC 8.6x10^7/kg and vCD34+ 3.4x10^5/kg. Median time to ANC>500 was 16 days (range: 7-45). Cohort 2 had 85% adult pts with average age 33 years, average weight 69 kg (range: 11-129) and median time to ANC>500 19 days (range: 6-68). Engrafting CBU median pre-cryopreservation TNC was 2.6x10^7/kg and vCD34+ 1.4x10^5/kg. CBU pre-cryopreservation and segment quality/potency markers showed very good correlation also (Table 1). In cohort 1 all pre-cryopreservation cell doses and segment vCD34+ and CFU correlated with neutrophil engraftment (Table 2). Pts with earlier engraftment (≤16 vs >17 days) received CBU with significantly higher doses of TNC, vCD34+, vCD45+ and CFU (pre-cryopreservation and post-thaw tests). In the recipients of double CB transplants, the engrafting CBU TNC and vCD45+ cell doses did not correlate with neutrophil engraftment, but the vCD34+ and CFU did (Table 2). Similarly, pts with earlier engraftment (≤19 vs >20 days) received CBU with higher doses of vCD34+ and CFU, but not TNC or CD45+. Conclusions: Prospective testing of HPC, CB products manufactured by a single CB Bank over a 10-year period and provided for transplant show consistent, highly significant correlation among pre-cryopreservation graft characteristics and segment measurements. Pre-cryopreservation values were predictive of time to ANC>500 in myeloablated recipients; in those cases, segment evaluation did not improve the correlations. Notably, vCD34+ and CFU correlations are consistently maintained after cryopreservation and thaw ensuring a HPC, CB product with reliable performance for transplantation, cell therapies or use with expansion technologies. Disclosures No relevant conflicts of interest to declare.
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