Here, we report on a phase IIa study to determine the intubation rate, survival, viral clearance, and development of endogenous Abs in patients with COVID-19 pneumonia treated with convalescent ...plasma (CCP) containing high levels of neutralizing anti-SARS-CoV-2 Abs. Radiographic and laboratory evaluation confirmed all 51 treated patients had COVID-19 pneumonia. Fresh or frozen CCP from donors with high titers of neutralizing Abs was administered. The nonmechanically ventilated patients (n = 36) had an intubation rate of 13.9% and a 30-day survival rate of 88.9%, and the overall survival rate for a comparative group based on network data was 72.5% (1625/2241). Patients had negative nasopharyngeal swab rates of 43.8% and 73.0% on days 10 and 30, respectively. Patients mechanically ventilated had a day-30 mortality rate of 46.7%; the mortality rate for a comparative group based on network data was 71.0% (369/520). All evaluable patients were found to have neutralizing Abs on day 3 (n = 47), and all but 1 patient had Abs on days 30 and 60. The only adverse event was a mild rash. In this study on patients with COVID-19 disease, we show therapeutic use of CCP was safe and conferred transfer of Abs, while preserving endogenous immune response.
The use of ASCT is highly established as consolidation or salvage for multiple myeloma (MM) and post salvage therapy in non-Hodgkin Lymphomas (NHL), particularly diffuse large B-cell lymphoma (DLBCL) ...with chemosensitive disease, as well as upfront consolidation in PTCL given poor outcomes after standard therapy (Philip et al., NEJM 1995, Kewalramani et al., Br J Haematol 2006, Gisselbrecht et al., J Clin Oncol 2010, Kumar et al., Leukemia 2012). Although a significant number of pts experience long-term disease-free survival following ASCT, those with high-risk disease (i.e.high-risk cytogenetics in MM, primary refractory DLBCL) are likely to present early relapses, particularly in the first 18 months post-ASCT, illustrating the need for better disease control strategies following ASCT. The rapidly rising impact of checkpoint inhibitors in oncology provides an opportunity for its usage as post-ASCT consolidation, especially given the favorable immunologic milieu found in the immediate post-ASCT setting (i.e. decreased T-regs, increased effector T-cells) and minimal expected tumor burden at that time. Here, we report preliminary safety and efficacy data of a Phase I trial evaluating I and N as post-ASCT consolidation.
Pts with the following malignancies were eligible, if they presented at least stable disease after most recent line of therapy: DLBCL: primary refractory or relapsed, PTCL: de novo stage III/IV or relapsed, MM: transplant-naïve with high-risk cytogenetics or relapse within 3 years of upfront ASCT.
Pts were enrolled prior to ASCT, starting in July 2016. Total accrual goal is 42 patients. All pts with DLBCL/PTCL received BEAM (carmustine 300 mg/m2 day -6, etoposide 200 mg/m2 and cytarabine 200 mg/m2 days -5 to -2, melphalan 140 mg/m2 day -1) as conditioning regimen for ASCT, all pts with MM received melphalan 200 mg/m2 on day -1.
For pts who achieved appropriate hematologic recovery (ANC >800/mm3 and platelets > 20,000/mm3), I/N were started between days 14 and 28 post ASCT. The infusion schedule was:
• I: 1 mg/kg; 6 doses Weeks 1, 4, 7, 10, 16, 22
• N: 3 mg/kg; 12 doses Weeks 1, 4, 7, 10, 12, 14, 16, 18, 20, 22, 24, 26
At this time, 25 patients have been enrolled and received at least one dose of I/N. Additional pts are in screening and results will be updated.
Median follow-up from time of first I/N infusion is 24 weeks (range 2-49). Adverse events (AEs) were documented starting week 1, day 1 of I/N infusion. AEs deemed at least possibly related to I and/or N were termed immune-related (irAEs) with 80% of pts developing irAEs of any grade (table 1). Treatment-related AEs of any grade that led to discontinuation of I/N occurred in 6 pts (24% total: colitis 12%, pneumonitis 4%, adrenal crisis 4% and hepatotoxicity 4%). One death attributable to I/N occurred (due to recurrent pneumonitis complicated by parainfluenza). Therapy with systemic steroids for management of irAEs was required for 19 pts (76%). 70% of irAEs improved within one week and 65% resolved within 2 weeks of initiation of steroids. Median time on treatment with I/N for development of irAEs was 9 weeks (range 2-25). For pts who discontinued treatment due to toxicity, the median time on I/N was 5 weeks (range 3-14). Incidence of irAEs was similar across disease groups.
With a median follow-up of 24 weeks, OS is 92% and PFS is 88% for the entire cohort. 100% of the pts with relapsed MM after first ASCT (50% of whom had less than CR to 1st ASCT) are now in stringent complete remission (sCR). 100% of pts with primary refractory DLBCL are in CR (table 2).
The toxicity profile of consolidation with I/N following ASCT was within expectations. Although there has been a significant number of irAEs (80%) given the mechanism of action of these drugs, this rate is not higher than what has been previously reported with I/N combination in other disease settings (Larkin et al., NEJM 2015, Postow et al., NEJM 2015) and all patients except 1 had resolution of irAEs with the use of systemic steroids . With a median follow-up of 6 months, 84% of pts across disease groups are in complete remission. Interestingly, 5 of 6 patients who had early discontinuation due to AEs, presented sustained remission. Correlative studies evaluating blood immunophenotype are being reported in a separate abstract.
Display omitted
Skarbnik:Novartis: Speakers Bureau; Genentech: Speakers Bureau; Gilead: Speakers Bureau; Abbvie: Other: Ad board, Speakers Bureau; Seattle Genetics: Speakers Bureau. Goy:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics / J&J: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Siegel:Merck: Consultancy; Celgene, Takeda, Amgen Inc, Novartis and BMS: Consultancy, Speakers Bureau. Biran:Takeda: Speakers Bureau; Celgene, Amgen: Consultancy, Speakers Bureau. Richter:Janssen: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Feldman:Kite Pharma: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau; Bristol-Myers Squibb: Consultancy; AbbVie: Speakers Bureau. Leslie:seattle genetics: Speakers Bureau; KITE pharma: Speakers Bureau; celgene: Speakers Bureau. McKiernan:Novartis: Speakers Bureau. McNeill:pharmacyclics: Speakers Bureau; celgene: Speakers Bureau; seattle genetics: Speakers Bureau. Pecora:Caladrius Biosciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
Introduction: Autologous stem cell transplantation (ASCT) is a treatment option for hematologic malignancies. Current techniques may include placement of an apheresis central venous catheter (aCVC), ...for the purpose of autologous leukapheresis (LA) (Kalantari et al, Journal Clinical Apheresis, 2012). CVCs are associated with a risk of bloodstream infections (BSI) and venous thromboembolism (Johansson et al, BMT, 1999). The aim of this analysis was to evaluate the effect of instituting formal LA venous assessment (intervention) prior to mobilization on the rate of CVC placement in patients (pts) undergoing ASCT.
Method: 254 pts divided into 2 cohorts (pre and post intervention) were retrospectively reviewed. Cohort 1 included 135 consecutive pts treated in 2012, pre-intervention. Cohort 2 included 119 consecutive pts treated in 2015-2016, post intervention. Pts in cohort 2 had a formal venous assessment performed by a LA-specialized nurse prior to mobilization. Central venous catheterization was performed if veins were deemed unsuitable for cannulation. Pts identified as having insufficient peripheral venous access (PVA) had placement of an antibiotic-coated short-term aCVC, which was either kept for the duration of ASCT or removed prior to ASCT followed by insertion of a dual-lumen PICC for ASCT. Pts who collected via PVA for LA then had planned PICC placement for the duration of ASCT. Blood cultures (BC) were obtained in pts who developed fever (temperature >100.5°F). Screening BC were not performed. Positive blood cultures were not classified as central line-associated bloodstream infections (CLABSI) unless specific criterion was met.
Results: Patient characteristics between the 2 groups were comparable in terms of age, diagnosis and gender. 52% in cohort 1 were male; 55% in cohort 2 were male (p= 0.082); 60% in cohort 1 and 70% in cohort 2 had a diagnosis of multiple myeloma (p= 0.997). Pts with an aCVC for LA were greater in cohort 1 (93% vs. 59%, p<0.0001); the proportion of PVA was significantly greater in cohort 2 (38% vs 7%, p<0.0001). 12% of male pts in cohort 1 and 53% of male pts in cohort 2 were successfully collected using PVA (p<0.001). Only 1% of patients in the entire sample required conversion from PVA to aCVC due to poor venous access. The number of PICC lines for ASCT increased from 14% to 77% across the intervention period (p<0.001), and the number of aCVC for ASCT decreased from 79% to 13% (p<0.001).
Median number of CD34+ cells collected was 12.44 x 106/kg for the full sample. There were no significant differences between the 2 cohorts in terms of number of CD34+ cells. 82% of pts who had LA using PVA post intervention had planned PICC line insertion for ASCT. The incidence of positive blood cultures during the transplant period increased from 19% in the 2012 cohort, to 36.4% in the 2015-2016 cohort (p<0.0001).
Conclusion: There are no statistical differences between pts undergoing LA using PVA and aCVC in terms of number of days of apheresis and number of CD34+ cells collected. Peripheral venous access is a less invasive procedure, and is the preferred method in eligible pts. The statistically significant increase in positive blood cultures during the transplant phase may be explained by the use of non-antibiotic coated PICC lines during ASCT in cohort 2. Use of antibiotic coated PICC lines is currently being evaluated at our center. Our study demonstrates that 38% of all pts and 53% of male pts can undergo apheresis using PVA. The process of formal venous assessment by a LA-specialized nurse is recommended and can effectively predict who can complete LA using peripheral access.
Skarbnik:Genentech: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau. Goy:Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Writing support, Speakers Bureau; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vesole:Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau; Janssen: Speakers Bureau; Novartis: Speakers Bureau.
Haploidentical (HAPLO) and unrelated donors (URD) are established cell sources for patients (pts) who lack HLA-matched siblings. Limited data are available comparing transplant (TP) outcomes using ...cells from HAPLO vs URD donors. We performed a retrospective analysis of sequential pts (n=54) undergoing HAPLO transplants with post-transplant cyclophosphamide (Cy). A control group of HLA 7/8 or 8/8 matched URD recipients (n=59) matched by diagnosis, transplant date, and cell source (PBSC or marrow) was identified (Table). Most HAPLO pts received cycles of pre-TP fludarabine (Flu) for lymphodepletion to achieve CD4 <0.2x109/l. HAPLO pts received Flu 30 mg/m2 qd x 5 with Cy 14.5 mg/kg qd x 2, followed by TBI, 200-400 cGy in 1 or 2 fractions (physician discretion). PB (n= 30) or BM (n= 24) was infused from 1st or 2nddegree related HAPLO donors. Post-transplant immunosuppression was Cy 50-60 mg/kg on days +3 and +4, followed by tacrolimus (tacro) and mycophenolate (MMF) starting on day +5. Pts received filgrastim daily starting at day +5. URD recipients were conditioned with a variety of standard myeloablative (n=23) or reduced intensity (n=36) regimens, and received PB (n= 40) or BM (n= 19), with daily filgrastim starting on day +9. GvHD prophylaxis was tacro and short-course methotrexate (n= 53) or tacro/MMF (n=6). CD3+ and CD15+ cell chimerisms were assessed at 4 week intervals commencing at day +28. Bone marrow staging and CD34+ cell chimerism were assessed at day +84. GvHD was staged per standard guidelines. Analysis of categorical variables was performed using the Fisher’s exact test. Non-parametric analysis of median values was used for continuous variables. Survival was assessed using the log-rank test. Informed consent for analysis of transplant outcome data was obtained before transplantation for all patients and donors.
Engraftment kinetics in the HAPLO cohort was slightly slower compared to the URD cohort, ANC >0.5x109/l at a median of 16 days (range: 13-45) vs 13 days (range: 9-25, p<0.001); PLT >20x109/l median 24 days (range: 13-109) vs 15 days (range: 8-216, p= 0.02). ANC and PLT recoveries were faster for URD PB compared to BM recipients. However, engraftment kinetics did not differ for HAPLO PB or BM recipients, (ANC median days 16.5 vs. 16, p=0.38; PLT median 24 vs 26 days p=0.80). HAPLO donor CD3 engraftment was robust, with 44 of 48 (92%) HAPLO compared to 37 of 52 (71%) URD recipients achieving >95% CD3+ chimerism at day +28 (p=0.01). Engraftment failure defined by failure to achieve ANC recovery and day +28 donor CD3 chimerism >5% was reported in 4 (7.4%) HAPLO and 2 (3%) URD recipients (p=0.42).
The cumulative incidence of grade II-IV aGVHD by day 100 was similar for both groups (61% vs 47%, p=0.19). The cumulative incidences of cGVHD in the HAPLO vs URD cohorts were comparable (39% vs 36%, p=0.84) and the incidence of moderate or severe cGVHD was 15% and 22%, respectively (p=0.34). At time of analysis, relapse occurred for 37% HAPLO pts (n=20) compared to 33% (n=20) in the URD group (p=0.84). 23 pts died (43%) in the HAPLO group: 12 from relapse, 5 from infection, 6 from other causes. In the URD group, 23 (39%) died: 13 from relapse, 3 from infection, 7 from other causes. The one-yr survival probabilities were 56% HAPLO and 66% URD, with median OS probabilities 18 mo and 22 mo (p=0.85). OS was lower for recipients of 7/8 vs 8/8 matched URD grafts, but the difference was not significant (not shown).
These results show similar outcomes after HAPLO and URD transplant for engraftment, GvHD, relapse and OS. Almost all HAPLO pts achieved full donor CD3+ chimerism by day +28. In conclusion, HAPLO transplant with post transplant Cy is an option for pts lacking HLA matched siblings; prospective studies are needed to validate these findings.
Display omitted
;
Display omitted
No relevant conflicts of interest to declare.
A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) ...(2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test–stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.
The optimal neoadjuvant treatment for resectable carcinoma of the thoracic esophagus (TE) or gastroesophageal junction (GEJ) remains a matter of debate. We performed an individual participant data ...(IPD) network meta-analysis (NMA) of randomized controlled trials (RCTs) to study the effect of chemotherapy or chemoradiotherapy, with a focus on tumor location and histology subgroups.
All, published or unpublished, RCTs closed to accrual before December 31, 2015 and having compared at least two of the following strategies were eligible: upfront surgery (S), chemotherapy followed by surgery (CS), and chemoradiotherapy followed by surgery (CRS). All analyses were conducted on IPD obtained from investigators. The primary end point was overall survival (OS). The IPD-NMA was analyzed by a one-step mixed-effect Cox model adjusted for age, sex, tumor location, and histology. The NMA was registered in PROSPERO (CRD42018107158).
IPD were obtained for 26 of 35 RCTs (4,985 of 5,807 patients) corresponding to 12 comparisons for CS-S, 12 for CRS-S, and four for CRS-CS. CS and CRS led to increased OS when compared with S with hazard ratio (HR) = 0.86 (0.75 to 0.99),
= .03 and HR = 0.77 (0.68 to 0.87),
< .001 respectively. The NMA comparison of CRS versus CS for OS gave a HR of 0.90 (0.74 to 1.09),
= .27 (consistency
= .26, heterogeneity
= .0038). For CS versus S, a larger effect on OS was observed for GEJ versus TE tumors (
= .036). For the CRS versus S and CRS versus CS, a larger effect on OS was observed for women (
= .003, .012, respectively).
Neoadjuvant chemotherapy and chemoradiotherapy were consistently better than S alone across histology, but with some variation in the magnitude of treatment effect by sex for CRS and tumor location for CS. A strong OS difference between CS and CRS was not identified.
PDF
