•OS and NRM were similar between patients aged ≥ 60 and <60 after CD34+ selected allo-HCT.•Infectious, hematologic, and oral/gastrointestinal toxicities were common.•Most common toxicities were ...independent risk factors for death and NRM.
Ex vivo CD34+ selection before allogeneic hematopoietic stem cell transplantation (allo-HCT) reduces graft-versus-host disease without increasing relapse but usually requires myeloablative conditioning. We aimed to identify toxicity patterns in older patients and the association with overall survival (OS) and nonrelapse mortality (NRM). We conducted a retrospective analysis of 200 patients who underwent CD34+ selection allo-HCT using the ClinicMACS® system between 2006 and 2012. All grade 3 to 5 toxicities by CTCAE v4.0 were collected. Eighty patients aged ≥ 60 years with a median age of 64 (range, 60 to 73) were compared with 120 patients aged < 60 years. Median follow-up in survivors was 48.2 months. OS and NRM were similar between ages ≥ 60 and <60, with 1-year OS 70% versus 78% (P = .07) and 1-year NRM 23% versus 13% (P = .38), respectively. In patients aged ≥ 60 the most common toxicities by day 100 were metabolic, with a cumulative incidence of 88% (95% CI, 78% to 93%), infectious 84% (95% CI, 73% to 90%), hematologic 80% (95% CI, 69% to 87%), oral/gastrointestinal (GI) 48% (95% CI, 36% to 58%), cardiovascular (CV) 35% (95% CI, 25% to 46%), and hepatic 25% (95% CI, 16% to 35%). Patients aged ≥ 60 had a higher risk of neurologic (HR, 2.63 95% CI, 1.45 to 4.78; P = .001) and CV (HR, 1.65 95% CI, 1.04 to 2.63; P = .03) toxicities but a lower risk of oral/GI (HR, .58 95% CI, .41 to .83; P = .003) compared with those aged < 60. CV, hepatic, neurologic, pulmonary, and renal toxicities remained independent risk factors for the risk of death and NRM in separate multivariate models adjusting for age and hematopoietic cell transplantation–specific comorbidity index. Overall, the toxicity of a more intense regimen is potentially balanced by the absence of toxicity related to methotrexate and calcineurin inhibitors in older patients. Prospective study of toxicities after allo-HCT in older patients is essential.
Background: The optimal timing for SARS-CoV-2 vaccines within the first year after allogeneic hematopoietic cell transplant (HCT) is poorly understood. Methods: We conducted a prospective, ...multicentre, observational study of allogeneic HCT recipients who initiated SARS-CoV-2 vaccinations within 12 months of HCT. Participants were enrolled at 22 academic cancer centers across the United States. Participants of any age who were planning to receive a first post-HCT SARS-CoV-2 vaccine within 12 months of HCT were eligible. We obtained blood prior to and after each vaccine dose for up to four vaccine doses, with an end-of-study sample seven to nine months after enrollment. We tested for SARS-CoV-2 spike protein (anti-S) IgG; nucleocapsid protein (anti-N) IgG; neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains; and SARS-CoV-2-specific T-cell receptors (TCRs). The primary outcome was a comparison of anti-S IgG titers at the post-V2 time point in participants initiating vaccinations <4 months versus 4–12 months after HCT using a propensity-adjusted analysis. We also evaluated factors associated with high-level anti-S IgG titers (≥2403 U/mL) in logistic regression models. Findings: Between April 22, 2021 and November 17, 2021, 175 allogeneic HCT recipients were enrolled in the study, of whom all but one received mRNA SARS-CoV-2 vaccines. SARS-CoV-2 anti-S IgG titers, neutralizing antibody titers, and TCR breadth and depth did not significantly differ at all tested time points following the second vaccination among those initiating vaccinations <4 months versus 4–12 months after HCT. Anti-S IgG ≥2403 U/mL correlated with neutralizing antibody levels similar to those observed in a prior study of non-immunocompromised individuals, and 57% of participants achieved anti-S IgG ≥2403 U/mL at the end-of-study time point. In models adjusted for SARS-CoV-2 infection pre-enrollment, SARS-CoV-2 vaccination pre-HCT, CD19+ B-cell count, CD4+ T-cell count, and age (as applicable to the model), vaccine initiation timing was not associated with high-level anti-S IgG titers at the post-V2, post-V3, or end-of-study time points. Notably, prior graft-versus-host-disease (GVHD) or use of immunosuppressive medications were not associated with high-level anti-S IgG titers. Grade ≥3 vaccine-associated adverse events were infrequent. Interpretation: These data support starting mRNA SARS-CoV-2 vaccination three months after HCT, irrespective of concurrent GVHD or use of immunosuppressive medications. This is one of the largest prospective analyses of vaccination for any pathogen within the first year after allogeneic HCT and supports current guidelines for SARS-CoV-2 vaccination starting three months post-HCT. Additionally, there are few studies of mRNA vaccine formulations for other pathogens in HCT recipients, and these data provide encouraging proof-of-concept for the utility of early vaccination targeting additional pathogens with mRNA vaccine platforms. Funding: National Marrow Donor Program, Leukemia and Lymphoma Society, Multiple Myeloma Research Foundation, Novartis, LabCorp, American Society for Transplantation and Cellular Therapy, Adaptive Biotechnologies, and the National Institutes of Health.
Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control graft-versus-host disease (GvHD) in haploidentical (Haplo) transplantations. In this retrospective registry study, ...we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated 2 cohorts: patients with grade 2 to 4 acute GvHD (aGvHD) including 264 and 1163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation ± antithymocyte globulin (ATG), grade 3-4 aGvHD (28% versus 39%, P = .001), stage 3-4 lower gastrointestinal (GI) tract aGvHD (14% versus 21%, P = .01), and chronic GI GvHD (21% versus 31%, P = .006) were less common after Haplo/PTCy transplantation. In patients with grade 2-4 aGvHD, cGvHD rate after Haplo/PTCY was also lower (hazard ratio HR = .4, P < .001) in comparison with MUD/conventional transplantation without ATG in the nonmyeloablative conditioning setting. Irrespective of the use of ATG, non-relapse mortality rate was lower (HR = .6, P = .01) after Haplo/PTCy transplantation, except for transplants that were from a female donor into a male recipient. In patients with cGvHD, irrespective of ATG use, Haplo/PTCy transplantation had lower non-relapse mortality rates (HR = .6, P = .04). Mortality rate was higher (HR = 1.6, P = .03) during, but not after (HR = .9, P = .6) the first 6 months after cGvHD diagnosis. Our results suggest that PTCy-based GvHD prophylaxis mitigates the development of GI GvHD and may translate into lower GvHD-related non-relapse mortality rate.
Abstract
Background
High rates of discontinuation of voriconazole (VCZ) antifungal prophylaxis (AFP) due to toxicities have been reported from single centers in allogeneic hematopoietic (allo-HCT) ...recipients. We sought to describe (i) adherence to AFP guidelines and (ii) reasons for premature VCZ discontinuation (D/C).
Methods
Retrospective review of 215 adult allo-HCT recipients from September 1, 2014–December 31, 2015 at our center. Per standards of care (SOC), patients received micafungin from Day 2 post-allo-HCT, then switched to VCZ by D7 unless contraindicated, and remained on AFP until cessation of immunosuppression or D100 for high-risk patients. AFP modification, D/C and treatment emergent adverse events (TEAE) regardless of causality were captured through D100. Standard definitions were used for invasive fungal infections (IFI).
Results
Of 215 patients, 42 had contraindications to VCZ at baseline. Of 173 patients included in the analysis, 65 (37.6%) received ex vivo T-cell depleted (TCD) peripheral blood (PB), 15% cord and 47.4% conventional PB or marrow allografts. All TCD recipients received myeloablative conditioning (MA) and all cord recipients received reduced intensity conditioning (RIC). For conventional transplant, 65.9 and 26.8% of the patients received RIC and MA, respectively. One hundred and sixty-eight (97%) patients had normal liver function tests (LFT) at VCZ initiation. One hundred and twenty-nine (74.6%) patients started VCZ by D7 and 95% started by D15. Median duration of VCZ AFP was 68D (IQR 22–91). Abnormal LFTs was the most frequently encountered TEAE (42/58, 72%), followed by neurologic/visual TEAE (11/58, 19%) leading to VCZ D/C. Median time to VCZ D/C due to neurologic/visual TEAE (4D, IQR 4–9) was significantly shorter than abnormal LFTs (25D, IQR 16–42) (P < 0.05). Eight (5%) breakthrough proven/probable IFIs were observed by D180, without significant difference based on transplant types or AFP duration. Duration and reasons for VCZ D/C were shown in Table 1 by HCT type.
Conclusion
75% of the patients started VCZ per SOC and 95% by D15. Most TEAE leading to VCZ D/C were abnormal LFTs in all HCT types, and most commonly in cord HCT. 3) Neurologic/visual TEAE were similar across types. Rates of IFI were 3–4% in CONV and TCD and 12% in UCB.
Disclosures
Y. T. Huang, Merck & Co.: Grant Investigator, Research grant. M. A. Perales, Merck: Consultant, Grant Investigator and Investigator, Consulting fee and Research grant. Astella: Consultant, Grant Investigator and Investigator, Consulting fee and Research grant. G. Papanicolaou, Astellas Pharma: Consultant and Grant Investigator, Consulting fee, Research grant and Research support. Merck &Co: DSC member and Investigator, Consulting fee, Research grant and Research support
Abstract
Background
CMV viremia is associated with adverse transplant outcomes despite preemptive therapy (PET). Establishing benchmarks for the burden of CMV is important for optimal implementation ...of novel strategies for CMV prevention. The objectives of this study are to (1) quantify CMV antiviral use and (2) study impact of CMV viremia on hospital length of stay (LOS) in HCT treated in a single center.
Methods
Retrospective analysis of adult CD34+ selected (TCD) or unmodified (CONV) peripheral blood HCT patients at MSK from June 2010 through December 2014 for leukemia, myelodysplastic syndrome, and lymphoma managed by CMV monitoring and PET per standards of care. Days of antiviral treatment (tx)/100 patients-days was adjusted to total patients-days by day + 180. The cumulative incidences of viremia at day +180 were estimated by the Kaplan–Meier method. Standardized incidence ratios (SIR) were used for (LOS), number of readmissions (after admission for HCT), and readmission LOS by day +180. Estimated utility value (EUV) was calculated as standardized rate (SR) multiplied 100 patients.
Results
Of 88 CONV HCT (52% CMVR+), 22 (26.3%) patients had CMV viremia with median onset 41 (interquartile range IQR 35–49) days post-HCT. The median (IQR) duration of CMV tx was 44 (28–57) days; a total 697 antiviral tx days were given. CMV viremia was associated with increased LOS (SIR: 1.15; 95% CI: 1.08–1.22; P < 0.001) and readmissions (SIR: 1.54; 95% CI: 1.08–2.12; P < 0.01). Of 230 TCD HCT (61% CMV R+) 96 (41.9%) patients had CMV viremia with median onset 28 (25–33) days post HCT. The median duration of CMV tx was 48 (33–95) days for a total 5,849 antiviral tx days. CMV viremia was associated with longer LOS (SIR: 1.27; 95% CI: 1.23–1.31; P < 0.001), readmission LOS (SIR: 1.59; 95% CI: 1.51–1.68; P < 0.001), and readmissions (SIR: 1.73; 95% CI: 1.45–2.06; P < 0.001). Table 1 shows SR and EUT for CMV antivirals.
Conclusion
(1) CMV viremia was associated with longer LOS and readmissions by d+180 in CONV and TCD HCT. (2) Estimated burden of CMV antivirals was higher in TCD; (3) Our data support that CONV and TCD HCT may benefit from more effective strategies for CMV management. (4) Further studies are needed to identify subgroups of patients that may benefit most from targeted prophylaxis.
Disclosures
Y. T. Huang, Merck & Co.: Grant Investigator, Research grant. G. Papanicolaou, Astellas Pharma: Consultant and Grant Investigator, Consulting fee, Research grant and Research support. Merck &Co: DSC member and Investigator, Consulting fee, Research grant and Research support
1.Haplo-HCT have similar survival as MUD-HCT in myelofibrosis.2.Strategies to prevent graft failure in haplo-HCT need to be investigated.
We aim to evaluate impact of donor types on outcomes of ...hematopoietic cell transplantation (HCT) in myelofibrosis, using CIBMTR registry data for HCTs done between 2013 and 2019. In all 1597 undergoing HCT for myelofibrosis, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study eligible, 1032 patients who received peripheral blood grafts for chronic phase myelofibrosis, 38% recipients of haploidentical-HCT were of non-White/Caucasian ethnicity. Matched sibling donor (MSD)-HCTs were independently associated with superior overall survival (OS) in the first 3 months reference MSD, haploidentical HR 5.80 (95% CI 2.52-13.35), matched unrelated HR 4.50 (95% CI 2.24-9.03), and mismatched unrelated HR 5.13 (95% CI 1.44-18.31), P<0.001. This difference in OS aligns with lower graft failure with MSD haploidentical HR 6.11 (95%CI 2.98-12.54), matched unrelated HR 2.33 (95%CI 1.20-4.51), mismatched unrelated HR 1.82 (95%CI 0.58-5.72). There was no significant difference in OS among haploidentical, matched unrelated, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months post-HCT, relapse, disease-free survival or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. While MSDs remain a superior donor option due to improved engraftment, there is no significant difference in HCT outcomes from haploidentical and matched unrelated donors. These results establish haploidentical-HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.
Clostridium difficile infection (CDI) is characterized by a high delayed and unrelated mortality. Predicting delayed mortality in CDI patients could allow the implementation of interventions that ...could reduce these events. A prospective multicentric study was carried out to investigate prognostic factors associated with mortality. It was based on a cohort (July 2015 to February 2016) of 295 patients presenting with CDI. Logistic regression was used and the model was calibrated using the Hosmer-Lemeshow test.
The mortality rate at 75 days in our series was 18%. Age (>65 years), comorbidity (defined by heart failure, diabetes mellitus with any organ lesion, renal failure, active neoplasia or immunosuppression) and fecal incontinence at clinical presentation were associated with delayed (75-day) mortality. When present, each of the aforementioned variables added one point to the score. Mortalities with 0, 1, 2 and 3 points were 0%, 9.4%, 18.5% and 38.2%, respectively. The area under the ROC curve was 0.743, and the Hosmer-Lemeshow goodness-of-fit test p value was 0.875. Therefore, the prediction of high delayed mortality in CDI patients by our scoring system could promote measures for increasing survival in suitable cases.
•CDI patients present a high, non-infection related, delayed mortality.•Age, comorbidity and fecal incontinence at diagnosis are related to patient outcome.•A scoring system based on these variables may predict mortality.•Preventive measures could eventually be implemented to improve patient prognoses.
Abstract The inclusion of antithymocyte globulin (ATG) in cord blood transplantation is controversial. We evaluated outcomes according to ATG inclusion in 297 children and adolescents with acute ...lymphoblastic leukemia (ALL) who received myeloablative total body irradiation–based conditioning and either single-unit (74%) or double-unit (26%) grafts. Ninety-two patients (31%) received ATG and 205 (69%) did not. ATG recipients were more likely to be cytomegalovirus seronegative. The incidences of day 100 grades II to IV acute graft-versus-host disease (GVHD; 30% versus 54%, P = .0002) and chronic GVHD (22% versus 43%, P = .0008) were lower with ATG compared with non-ATG regimens. However, day 100 grades III to IV acute GVHD was comparable (11% versus 17%, P = .15). The 3-year incidences of transplant-related mortality (16% versus 17%, P = .98), relapse (17% versus 27%, P = .12), and leukemia-free survival (66% versus 55%, P = .23) in ATG and non-ATG recipients were similar. There were no differences in viral reactivation between treatment groups (60% versus 58%, P = .83). Therefore, the data suggest that incorporation of ATG with myeloablative conditioning regimens may be useful in reducing the risk of acute and chronic GVHD without any deleterious effect on transplant-related mortality, relapse, or leukemia-free survival in children and adolescents with ALL.
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