Cord blood transplantation (CBT) is curative for many patients with hematologic malignancies but is associated with delayed immune recovery and an increased risk of viral infections compared to human ...leukocyte antigen (HLA) matched bone marrow or peripheral blood progenitor cell transplantation. In this study we evaluated the significance of lymphocyte recovery in 125 consecutive patients with hematologic malignancies who underwent double-unit CBT (DUCBT) with an anti-thymocyte globulin-containing regimen at our institution. A subset of 65 patients were prospectively evaluated for recovery of T, natural killer (NK) and B cells and in 46 patients we also examined viral-specific T cell recovery against Adenovirus, Epstein-Barr virus, cytomegalovirus, BK virus, respiratory syncytial virus and Influenza antigen.
Our results indicate that in recipients of DUCBT, the day 30 absolute lymphocyte count is highly predictive of non-relapse mortality (NRM) and overall survival (OS). Immune recovery post-DUCBT was characterized by prolonged CD8+ and CD4+ T lymphopenia associated with preferential expansion of B and NK cells. We also observed profound delays in quantitative and functional recovery of viral-specific CD4+ and CD8+ T-cell responses for the first year post-CBT. Taken together, our data support efforts aimed at optimizing viral-specific T cell recovery to improve outcomes post-CBT.
Reduced-intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unable to withstand myeloablative ...conditioning. We prospectively analyzed the outcomes of 123 patients (median age, 57 years; range, 23-70 years) with hematologic malignancies treated with a uniform RIC regimen of cyclophosphamide, fludarabine, and total-body irradiation (200 cGy) with or without antithymocyte globulin followed by related donor allogeneic HCT at the University of Minnesota between 2002 and 2008. The cohort included 45 patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), 27 with aggressive non-Hodgkin lymphoma (NHL), 8 with indolent NHL, 10 with Hodgkin lymphoma (HL), 10 with myeloma, and 23 with acute lymphocytic leukemia, chronic myelogenous leukemia, other leukemias, or myeloproliferative disorders. The probability of 4-year overall survival was 73% for patients with indolent NHL, 58% for those with aggressive NHL, 67% for those with HL, 30% for those with AML/MDS, and only 10% for those with myeloma. Corresponding outcomes for relapse in these patients were 0%, 32%, 50%, 33%, and 38%, and those for progression-free survival were 73%, 45%, 27%, 27%, and 10%. The incidence of treatment-related mortality was 14% at day +100 and 22% at 1 year. The incidence of grade II-IV acute graft-versus-host disease was 38% at day +100, and that of chronic graft-versus-host disease was 50% at 2 years. Multivariate analysis revealed superior overall survival and progression-free survival in patients with both indolent and aggressive NHL compared with those with AML/MDS, HL, or myeloma. Worse 1-year treatment-related mortality was observed in patients with a Hematopoietic Cell Transplantation Comorbidity Index score ≥3 and in cytomegalovirus-seropositive recipients. These results suggest that (1) RIC conditioning was well tolerated by an older, heavily pretreated population; (2) patients with indolent and aggressive NHL respond well to RIC conditioning, highlighting the importance of the graft-versus-lymphoma effect; and (3) additional peri-transplantation manipulations are needed to improve outcomes for patients with AML/MDS or myeloma receiving RIC conditioning before HCT.
GVHD-prophylaxis with post-transplant cyclophosphamide (CY) following ablative HLA-matched bone marrow (BM) transplantation has been reported to have comparable rates of acute GVHD with an apparent ...reduction in chronic GVHD and infections. We conducted a phase II trial of post-CY following reduced-intensity conditioning (RIC) using intravenous busulfan (AUC of 4,000 micromolar-minutes), Fludarabine (40mg/m
2
) for 4 days and CY 50mg/kg on days +3 and +4 following BM or peripheral blood (PB) transplants from matched related (MRD) or unrelated donors (MUD). MUD- recipients received anti-thymocyte globulin (ATG); however, a later amendment removed ATG. 49 patients were treated (AML/MDS: 82%). Median age was 62 years (range, 39–72). Fifteen patients received a MRD (9 PB/6 BM); 34 had a MUD (2 PB/32 BM). The cumulative incidence of grade II–IV, III–IV acute and chronic GVHD was 58%, 22% and 18%. A matched-cohort analysis compared outcomes to tacrolimus/methotrexate GVHD prophylaxis and indicated higher rates of acute GVHD grade II–IV (46% versus 19%, HR=2.8, p=0.02) and treatment-related mortality (HR 3.3, p=0.035) and worse overall survival (HR=1.9, p=0.04) with post-Cy. The incidence of chronic GVHD and CMV reactivation did not differ. This study suggests that post-transplant CY should not be used as sole GVHD-prophylaxis following a RIC transplant from HLA matched donors.
Allogeneic stem-cell transplantation for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) has been performed primarily with an HLA matched donor. Outcomes of ...haploidentical transplantation have recently improved, and a comparison between these donor sources in a uniform cohort of patients has not been performed. We evaluated outcomes of 227 patients with AML/MDS treated with melphalan-based conditioning. Donors were matched related (MRD) (N=87, 38%), matched unrelated (MUD) (N=108, 48%), or haploidentical (N=32, 14%). No significant differences were found between haploidentical and MUD transplant outcomes; however, there was a trend for improved outcomes in the MRD group with a 3-year progression-free survival for patients in remission of 57%, 45% and 41% for MRD, MUD and haploidentical, respectively (P=0.417). Recovery of T-cell subsets was similar for all groups. These results suggest that haploidentical donors can safely extend transplantation for AML/MDS patients without an HLA matched donor. Prospective studies comparing haploidentical and MUD transplants are warranted.
Reduced intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unable to withstand myeloablative ...conditioning. We prospectively analyzed the outcomes of 123 patients, median age of 57 (range 23-70), with hematologic malignancies treated with a uniform RIC regimen of cyclophosphamide, fludarabine, and total body irradiation (200 cGy) with or without anti-thymocyte globulin (ATG) followed by related donor allogeneic HCT at the University of Minnesota from 2002-2008. Forty-five patients had acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), 27 patients had aggressive non-Hodgkin lymphoma (NHL), 8 indolent NHL, 10 Hodgkin Lymphoma (HL), 10 myeloma and the remaining 23 had acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), other leukemias, or myeloproliferative disorders. Probability of four year overall survival (OS) was 73% for patients with indolent NHL, 58% for aggressive NHL, 67% for HL, 30% for AML/MDS, and only 10% for those with myeloma. Corresponding outcomes for relapse were 0%, 32%, 50%, 33%, and 38% and for progression free survival (PFS) were 73%, 45%, 27%, 27%, and 10%, respectively. The incidence of treatment related mortality (TRM) was 14% at day +100 and 22% at 1 year. The incidence of grade II-IV acute graft-versus-host disease (aGVHD) at day +100 was 38% and chronic GVHD at 2 years was 50%. Multivariate analysis revealed superior OS and PFS in patients with both indolent and aggressive NHL compared with AML/MDS, HL, or myeloma. Worse 1 year TRM was observed with hematopoietic cell transplant comorbidity index (HCT-CI) score ≥ 3 and CMV seropositive recipients. These results suggest that: 1) RIC conditioning was well tolerated by an older, heavily pre-treated population; 2) indolent and aggressive NHLs respond well to RIC conditioning highlighting the importance of the graft versus lymphoma (GVL) effect; and 3) additional peri-transplant manipulations are needed to improve outcomes for patients with AML/MDS or myeloma undergoing RIC conditioning.
Tailoring hydrogel properties by modifications of the crosslinker structure is a good method for the design of hydrogels with a wide range of properties. In this study, two novel carboxylic ...acid‐functionalized dimethacrylate crosslinkers (1a and 2a) are synthesized by the reaction of poly(ethylene glycol) or 2‐hydroxyethyl disulfide with tert‐butyl α‐bromomethacrylate followed by cleavage of tert‐butyl groups using trifluoroacetic acid. Their copolymerization reactivity with 2‐hydroxyethyl methacrylate (HEMA) investigated by photopolymerization studies performed on photo‐differential scanning calorimetry shows higher reactivity of 2a compared to 1a. These crosslinkers are then used at different ratios for fabrication of pH‐ and redox‐responsive poly(2‐hydroxyethyl methacrylate)‐based hydrogels. The swelling behavior of the hydrogels is found to be dependent on the structure of the crosslinker, degree of crosslinking, pH, and CaCl2 concentration. The redox‐responsive behavior is demonstrated by degradation of the hydrogel upon exposure to 1,4‐dithiothreitol. The dye Rhodamine 6G and the drug resorcinol are used as models to demonstrate the pH and redox dependent release of loaded compounds from the hydrogels. The electrostatic interactions between the carboxylate groups and the positively charged R6G are found to govern the release profile in DTT and counteract the diffusion of dye molecules and significant amount of release (79% in 120 hr) occurs only at highly acidic conditions. The degradation mediated release in DTT is observed better in case of resorcinol (around 88% in 5 hr). Overall, these hydrogels can be regarded as good candidates for several applications, such as matrices for controlled release, tissue repair, and regeneration.
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