Therapeutic delivery selectively to lymph nodes has the potential to address a variety of unmet clinical needs. However, owing to the unique structure of the lymphatics and the size-restrictive ...nature of the lymph node reticular network, delivering cargo to specific cells in the lymph node cortex and paracortex is difficult. Here, we describe a delivery system to overcome lymphatic and intra-lymph node transport barriers by combining nanoparticles that are rapidly conveyed to draining lymph nodes after administration in peripheral tissues with programmable degradable linkers. This platform enables the controlled release of intra-lymph-mobile small-molecular cargo, which can reach vastly more immune cells throughout the lymph node than either the particles or free compounds alone. The release rate can be programmed, allowing access to different lymph node structures and therefore specific lymphocyte subpopulations. We are thus able to alter the subtypes of drugged lymph node cells to improve immunotherapeutic effects.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Individual comorbidities have distinct contributions to nonrelapse mortality (NRM) following allogeneic hematopoietic cell transplantation (allo-HCT). We studied the impact of comorbidities ...individually and in combination in a single-center cohort of 573 adult patients who underwent CD34-selected allo-HCT following myeloablative conditioning. Pulmonary disease, moderate to severe hepatic comorbidity, cardiac disease of any type, and renal dysfunction were associated with increased NRM in multivariable Cox regression models. A Simplified Comorbidity Index (SCI) composed of the 4 comorbidities predictive of NRM, as well as age >60 years, stratified patients into 5 groups with a stepwise increase in NRM. NRM rates ranged from 11.4% to 49.9% by stratum, with adjusted hazard ratios of 1.84, 2.59, 3.57, and 5.38. The SCI was also applicable in an external cohort of 230 patients who underwent allo-HCT with unmanipulated grafts following intermediate-intensity conditioning. The area under the receiver operating characteristic curve (AUC) of the SCI for 1-year NRM was 70.3 and 72.0 over the development and external-validation cohorts, respectively; corresponding AUCs of the Hematopoietic Cell Transplantation–specific Comorbidity Index (HCT-CI) were 61.7 and 65.7. In summary, a small set of comorbidities, aggregated into the SCI, is highly predictive of NRM. The new index stratifies patients into distinct risk groups, was validated in an external cohort, and provides higher discrimination than does the HCT-CI.
•Cardiac, pulmonary, hepatic, and renal dysfunction were predictive of allo-HCT mortality and combined to form the SCI.•The new index stratified patients into distinct NRM risk groups and was valid in 2 cohorts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
CD34+ cell selection significantly improves GvHD-free survival in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, specific information regarding long-term prognosis and risk ...factors for late mortality after CD34+ cell-selected allo-HSCT is lacking. We conducted a single-center landmark analysis in 276 patients alive without relapse 1 year after CD34+ cell-selected allo-HSCT for AML (n=164), ALL (n=33) or myelodysplastic syndrome (n=79). At 5 years' follow-up after the 1-year landmark (range 0.03-13 years), estimated relapse-free survival (RFS) was 73% and overall survival (OS) 76%. The 5-year cumulative incidence of relapse and non-relapse mortality (NRM) were 11% and 16%, respectively. In multivariate analysis, Hematopoietic Cell Transplantation Comorbidity Index score⩾3 correlated with marginally worse RFS (hazard ratio (HR) 1.78, 95% confidence interval (CI) 0.97-3.28, P=0.06) and significantly worse OS (HR 2.53, 95% CI 1.26-5.08, P=0.004). Despite only 24% of patients with acute GvHD within 1 year, this also significantly correlated with worse RFS and OS, with increasing grades of acute GvHD associating with increasingly poorer survival on multivariate analysis (P<0.0001). Of 63 deaths after the landmark, GvHD accounted for 27% of deaths and was the most common cause of late mortality, followed by relapse and infection. Although prognosis is excellent for patients alive without relapse 1 year after CD34+ cell-selected allo-HSCT, risks of late relapse and NRM persist, particularly due to GvHD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cord blood transplantation (CBT) after high intensity or nonmyeloablative conditioning has limitations. We investigated cyclosporine-A/mycophenolate mofetil–based intermediate intensity ...(cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 10 mg/kg, total body irradiation 400 cGy) unmanipulated double-unit CBT (dCBT) with prioritization of unit quality and CD34+ cell dose in graft selection. Ninety adults (median age, 47 years range, 21-63; median hematopoietic cell transplantation comorbidity index, 2 range, 0-8; 61 68% acute leukemia) received double-unit grafts (median CD34+ cell dose, 1.3 × 105/kg per unit range, 0.2-8.3; median donor-recipient human leukocyte antigen (HLA) match, 5/8 range 3-7/8). The cumulative incidences of sustained CB engraftment, day 180 grade III-IV acute, and 3-year chronic graft-versus-host disease were 99%, 24%, and 7%, respectively. Three-year transplant-related mortality (TRM) and relapse incidences were 15% and 9%, respectively. Three-year overall survival (OS) is 82%, and progression-free survival (PFS) is 76%. Younger age and higher engrafting unit CD34+ cell dose both improved TRM and OS, although neither impacted PFS. Engrafting unit-recipient HLA match was not associated with any outcome with a 3-year PFS of 79% in 39 patients engrafting with 3-4/8 HLA-matched units. In 52 remission acute leukemia patients, there was no association between minimal residual disease (MRD) and 3-year PFS: MRD negative of 88% vs MRD positive of 77% (P = .375). Intermediate intensity dCBT is associated with high PFS. Use of highly HLA mismatched and unmanipulated grafts permits wide application of this therapy, and the low relapse rates support robust graft-versus-leukemia effects even in patients with MRD.
•Intermediate intensity double unit CBT is associated with high progression-free survival in adults, including those with MRD.•Use of highly HLA mismatched and unmanipulated grafts permits wide application of this therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background: While incorporation of HLA-allele matching has highlighted high degrees of CB unit-recipient HLA-disparity, the less stringent HLA-match requirements extends allograft access to many ...patients without matched adult donors. The extent to which HLA-mismatch can adversely affect CBT outcomes, & the maximum permitted degree of HLA-mismatch, however, are not established.
Methods: We analyzed TRM, relapse & PFS after intermediate intensity myeloablative cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI double unit CBT in adults transplanted for hematologic malignancies. Eligible patients (pts) were first allograft recipients ≤ 65 years transplanted for acute leukemia/ MDS/ MPD (≤ 10% blasts pre-CBT), B-cell or T-cell lymphomas between 1/2014 - 12/2017. TNC & CD34+ dose were typically given priority over HLA-match in unit selection.
Results: 102 pts 51 (50%) non-European, 59 (58%) CMV seropositive, median age 50 years (range 21-65), median weight 80 kg (range 36-137) were transplanted. Diagnoses included 71 acute leukemias, 17 CML/ MPD/ MDS, 14 B- or T-cell NHLs. All received double unit grafts comprised of 2 (1%) 6/6 units, 21 (10%) 5/6, 181 (89%) 4/6 HLA-match, median unit-recipient 8-allele HLA-match 5/8 (range 3-7), & median infused viable CD34+ dose 1.3 x 105/kg/unit (range 0.2-8.6). Forty-eight (47%) CB grafts were supplemented with haplo-identical CD34+ cells as a myeloid bridge. The cumulative incidence of sustained CB engraftment was 97% (95%CI 90-99) with 2 pts having graft failure. A dominant (engrafting) unit was identified in all pts but 1 who died on day +14. Day 180 incidences of grades II-IV & III-IV aGVHD were 89% (95%CI 81-94) & 23% (95%CI 15-31), respectively. 1-yr cGVHD was 4% (95%CI 1-9). Cumulative incidence of TRM was 9% (95%CI 4-15) at day 180 & 14% (95%CI 8-22) at 2 yrs. 11% (95%CI 6-19) of pts relapsed by 2 yrs. With a median survivor follow-up of 2 yrs 3 months (range 6 - 51), the 2-yr overall survival is 82% (95%CI 75-90) & PFS is 74% (95%CI 66-84). Causes of death were transplant-related in 16 pts 6 aGVHD, 4 infection (2 viral, 1 bacterial, 1 fungal), 4 organ failure, 1 graft failure, 1 unknown & due to relapse in 4 pts. By 2-yrs post-CBT, engrafting unit-recipient HLA-allele match had no association with TRM or PFS (Figure). Univariate analysis of the association between recipient variables age, age adjusted hematopoietic cell transplant-comorbidity index (aaHCT-CI), revised disease risk index (rDRI) & graft variables engrafting unit-recipient HLA-allele match & infused CD34+ cell dose & TRM, relapse & PFS are shown (Table). Age & aaHCT-CI were associated with 2-yr TRM with the 50 younger pts (< 50 years), & the 66 pts with aaHCT-CI 0-3, having especially low 2-yr TRM of 5% & 10%, respectively. Neither engrafting unit-recipient HLA-match nor CD34+ dose were associated with TRM. No pt or graft variable was associated with relapse. The only significant variable associated with 2-yr PFS was aaHCT-CI. The 66 pts with a lower aaHCT-CI score of 0-3 had a higher 2-year PFS 82% (95%CI 73-92) than the 36 high score 4-9 pts 60% (95%CI 46-79). rDRI, engrafting unit-recipient 8-allele HLA-match & CD34+ cell dose had no effect. Multivariate analysis of TRM was precluded by too few events. Multivariate analysis of PFS including aaHCT-CI, rDRI & engrafting unit-recipient HLA-match showed high aaHCT-CI was associated with worse PFS HR 2.82 (1.28-6.25) if score 4-9 vs 0-3, p = 0.01; neither rDRI HR 1.21 (0.54-2.69) if high-very high vs low-intermediate, p = 0.64 nor engrafting unit-recipient HLA-match HR 2.06 (0.89-4.74) if 5-7/8 vs 3-4/8 matched (p = 0.09 were significant.
Conclusions: Our finding that a high level of HLA-allele mismatch of the engrafting unit was not significantly associated with TRM or PFS in adult dCBT for hematologic malignancies has multiple implications. It supports the use of units with a relatively high degree of HLA-mismatch in the dCBT setting if needed in these pts. This facilitates extension of allograft access to the majority of pts including minorities. Moreover, the high PFS supports our centers unit selection strategy that gives unit quality & cell dose a priority in adults with malignancies to optimize engraftment. Finally, this data support CBT in many high-risk or urgent pts even if a well-matched CB graft cannot be identified. This is especially true in younger pts or those with a low 0-3 aaHCT-CI who had high 2-yr PFS.
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Perales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Novartis: Other: Personal fees; Abbvie: Other: Personal fees; Merck: Other: Personal fees; Takeda: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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