Clinical outcomes of persistent colonization with multidrug-resistant Gram-negative rods in adult patients undergoing single cord blood transplantation.

Severe bacterial infections are a serious problem after cord blood transplantation (CBT). Colonization with multidrug-resistant Gram-negative rods (MRGNR) is associated with increased morbidity and mortality after allogeneic hematopoietic cell transplantation. However, its impact on outcomes after CBT is unclear. We aim to explore the impact of colonization with MRGNRs in adult patients undergoing CBT. We retrospectively analyzed 145 adult patients who received single-unit CBT in our institute. As a standard practice in our institute, all patients were screened for colonization with MRGNR by oral cavity swabs, urine, and stool specimens between the day of admission for CBT and the day of discharge or day 100 after CBT. There were 62 incidents of colonization with MRGNR in 52 patients, of which 25 involved Stenotrophomonas maltophilia, 19 multidrug-resistant Pseudomonas spp., and 18 extended-spectrum beta-lactamase-producing Enterobacteriaceae. On multivariate analysis, MRGNR persistence significantly affected increase in non-relapse mortality (NRM) (hazard ratio [HR], 8.96; 95% CI 1.85-43.46; P = 0.006) and the subsequent development of bloodstream infection due to MRGNR (HR 11.82; 95% CI 2.15-64.87; P = 0.004), but not MRGNR clearance, compared with non-colonized patients. These data suggest that persistent colonization with MRGNR is significantly associated with higher NRM in CBT for adults.

Efficacy and safety of micafungin in unrelated cord blood transplant recipients.

Micafungin (MCFG) is an echinocandin antifungal drug used for prophylaxis and treatment of fungal infections after allogeneic hematopoietic cell transplantation (HCT). However, its efficacy and safety in patients undergoing cord blood transplantation (CBT) has not been clarified. We retrospectively analyzed the efficacy and safety of MCFG in 92 adult patients undergoing CBT in our institute. Of the entire cohort, 83 patients (90%) received MCFG for empirical or preemptive therapy. Documented breakthrough fungal infection occurred in 2 patients during MCFG treatment. Among the 49 patients who received MCFG as empirical therapy for febrile neutropenia, 41 (84%) patients had resolution of fever during neutropenia. Elevation of serum levels of hepatobiliary parameters during MCFG treatment was commonly observed, but grade 3 or higher elevation was rare. We also compared the efficacy and safety of 2 different initial daily doses of MCFG (150 mg vs. 300 mg). There were no significant differences of efficacy and safety between the two groups. These data suggest that MCFG was effective and safe for adult patients undergoing CBT. The optimal daily dose of MCFG treatment is a matter of future investigation for adult patients undergoing CBT.

Early fluid overload predicts higher non-relapse and overall mortality in adults after single-unit cord blood transplantation.

Early fluid overload has been associated with poor transplant outcomes after allogeneic hematopoietic cell transplantation. However, its effects on the outcomes after cord blood transplantation (CBT) are unclear. We retrospectively analyzed the data of 227 adult patients who received single-unit CBT in our institute. The cumulative incidence of grade ≥2 fluid overload was 4% at day 30 after CBT with a median onset at 16 days (range, 9-30 days) after CBT. In the multivariate analysis, grade ≥2 fluid overload was significantly associated with higher non-relapse mortality (hazard ratio [HR], 5.73; P = 0.011) and overall mortality (HR, 3.81; P = 0.006). Among the entire cohort, 133 patients were treated with low-dose dopamine (0.5-2 µg/kg/min) with a median time of initiation of low-dose dopamine therapy at 10.5 days after CBT. Use of low-dose dopamine significantly increased daily urine output and decreased body weight. These data suggested that early fluid overload was significantly associated with non-relapse and overall mortality after single CBT. The early intervention of low-dose dopamine to prevent early fluid overload is a matter of future investigation for patients undergoing allogeneic hematopoietic cell transplantations (HCT), particularly for CBT.

Red blood cell transfusion burden by day 30 predicts mortality in adults after single-unit cord blood transplantation.

Increased red blood cell (RBC) transfusion requirements are associated with morbidity and mortality after allogeneic hematopoietic cell transplantation. However, its impact on the outcomes after cord blood transplantation (CBT) is unclear. We retrospectively analyzed the data of 278 adult patients who received single-unit CBT in our institute. The median number of RBC transfusions for each patient was 12 units (range, 4-66) by day 30 and 14 units (range, 4-70) by RBC engraftment. Sex, cord blood CD34+ cell dose, cytomegalovirus serostatus, total body irradiation dose in the conditioning regimen, ABO blood group incompatibility, and pre-CBT RBC transfusion requirements were significantly associated with the number of RBC transfusion units in the linear regression analysis. In the multivariate analysis, RBC transfusion ≥18 units by day 30 was significantly associated with higher overall mortality (hazard ratio, 1.86; P = 0.018). These data suggested that early RBC transfusion burden was significantly associated with overall mortality in adult patients undergoing single CBT. Early RBC transfusion burden might be a surrogate marker for poor outcomes after single CBT.

T memory stem cells after allogeneic haematopoietic cell transplantation: unique long-term kinetics and influence of chronic graft-versus-host disease.

T memory stem cells (TSCMs) are a subset of primitive T cells capable of both self-renewal and differentiation into all subsets of memory and effector T cells. Therefore, TSCMs may play a role in immune reconstitution and graft-versus-host disease (GVHD) in patients receiving allogeneic haematopoietic cell transplantation (HCT). We conducted a cross-sectional study to evaluate the proportions, absolute counts, phenotypes and functions of TSCMs in 152 adult patients without disease recurrence at least 12 months after undergoing HCT. CD4+ TSCMs were negatively correlated with number of months after transplantation in HCT patients that received cord blood transplantation, but not in patients that received bone marrow transplantation or peripheral blood stem cell transplantation. The proportions and absolute counts of CD4+ TSCMs and expression levels of inducible co-stimulator (ICOS) in CD8+ TSCMs were significantly higher in patients with mild and moderate/severe cGVHD compared to patients without cGVHD. These data suggested that, more than 12 months after allogeneic HCT, the kinetics of CD4+ TSCMs were dependent on the type of donor source, and further that CD4+ TSCMs and ICOS levels in CD8+ TSCMs were associated with cGVHD.

Fungemia due to Fusarium solani under low-dose liposomal amphotericin B in a patient after cord blood transplantation.

The introduction of the prophylactic use of antifungal drugs caused the increased occurrence of invasive fungal infections due to previously rare molds, such as fusariosis, after allogeneic hematopoietic stem cell transplantation. We herein report the case of a patient with diffuse large B-cell lymphoma who developed fungemia due to Fusarium solani during liposormal amphotericin B on day 25 after cord blood transplantation (CBT). Because Fusarium species might differ in virulence and drug susceptibility, the sequencing of the internal transcribed spacer region of the ribosomal RNA gene accurately identified Fusarium solani to be the cause of fungemia at the species level. This case highlights Fusarium solani as the cause of fungemia in a patient under liposormal amphotericin B treatment after CBT.

Development of Pre-Engraftment Syndrome, but Not Acute Graft-versus-Host Disease, Reduces Relapse Rate of Acute Myelogenous Leukemia after Single Cord Blood Transplantation.

The different effects of pre-engraftment syndrome (PES) and acute graft-versus-host disease (aGVHD) on outcomes after cord blood transplantation (CBT) are unclear. We retrospectively evaluated the impact of PES and aGVHD on relapse and survival after single-unit CBT in 138 adult patients with hematologic malignancies at our institution between 2004 and 2016. Multivariate analysis demonstrated that development of grade III-IV aGVHD, particularly with gut or liver involvement, significantly contributed to higher nonrelapse mortality (P < .001), but PES and grade II-IV aGVHD did not. In subgroup analyses of underlying disease type, the development of PES had a significant effect on decreased relapse (P = .032) and better disease-free survival (DFS) (P = .046) in patients with acute myelogenous leukemia (AML). These data suggest that PES is associated with a reduced relapse rate and better DFS in AML, indicating that the early immune reaction before neutrophil engraftment may provide a unique graft-versus-leukemia effect after single-unit CBT.

The Prognostic Impact of Pretransplantation Inflammatory and Nutritional Status in Adult Patients after Myeloablative Single Cord Blood Transplantation.

Markers of inflammatory and nutritional status, such as the Controlling Nutritional Status (CONUT) score, Prognostic Nutritional Index, Glasgow Prognostic Score, and C-reactive protein-albumin ratio (CAR) has been demonstrated to be associated with poor prognosis in patients with various cancers. Although the relatively low cell dose of a single cord blood unit restricts the indication for cord blood transplantation (CBT) to pediatric and relatively smaller and lighter adult patients, the impact of malnutrition on outcomes after CBT is unclear. We retrospectively analyzed 165 adult patients who underwent myeloablative single-unit CBT in our institute. In multivariate analysis, a higher CONUT score, which is indicative of poor inflammatory and nutritional status, was significantly associated with poor outcomes, including low neutrophil engraftment and development of extensive chronic graft-versus-host disease. A higher CAR, which is also suggestive of poor inflammatory and nutritional status, was significantly associated with poor neutrophil engraftment and higher overall mortality. Body mass index (BMI) was not associated with transplantation outcomes. These data suggest that poor pretransplantation inflammatory and nutritional status might be a more practical parameter than lower BMI, for predicting transplantation outcomes after single CBT for adults.

Reduced-Toxicity Myeloablative Conditioning Consisting of Fludarabine/Busulfan/Low-Dose Total Body Irradiation/Granulocyte Colony-Stimulating Factor-Combined Cytarabine in Single Cord Blood Transplantation for Elderly Patients with Nonremission Myeloid Malignancies.

The optimal intensity of a conditioning regimen might be dependent on not only age and comorbidities but also disease activity and the type of graft source. We evaluated the outcome of unrelated single cord blood transplantation (CBT) using a conditioning regimen of fludarabine 180 mg/m2, i.v. busulfan 9.6 mg/kg, 4 Gy total body irradiation, granulocyte colony-stimulating factor-combined high-dose cytarabine (12 g/m2) in 23 elderly patients (median, 64 years) with nonremission myeloid malignancies between 2013 and 2018 in our institution. All but 1 patient achieved neutrophil engraftment at a median of 23.5 days (range, 18 to 50). With a median follow-up of 28 months, the probabilities of overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse at 2 years were 62%, 52%, and 26%, respectively. The cumulative incidences of nonrelapse mortality at 100 days and 2 years were 9% and 22%, respectively. In the univariable analysis a higher proportion of blasts in bone marrow and in peripheral blood and a monosomal or complex karyotype were significantly associated with inferior OS and DFS. Poor cytogenetics were significantly associated with inferior DFS and increased relapse incidence. These data demonstrate that this reduced-toxicity myeloablative conditioning regimen was tolerable and effective in terms of engraftment, relapse, and survival in single CBT for elderly patients with nonremission myeloid malignancies.

Risk factors and survival impact of readmission after single-unit cord blood transplantation for adults.

Hospital readmissions have been used as a prognostic indicator for patients receiving allogeneic hematopoietic cell transplantation (HCT). However, the impact of readmission during early and mid-phase of cord blood transplantation (CBT) on long-term outcomes has not been fully investigated. We retrospectively analyzed 156 adult patients who received single-unit CBT in our institute. Among this cohort, thirteen patients (8%) were readmitted within 30 days after discharge, and 27 (17%) were readmitted within 90 days after discharge. The most common causes for readmission within 30 and 90 days of discharge were infection, chronic graft-versus-host disease, and relapse. Higher cryopreserved cord blood CD34+ cell count was only significantly associated with lower readmission within 90 days after discharge. The probabilities of overall survival were significantly lower in patients readmitted within 90 days after discharge compared with those who were not readmitted within 90 days after discharge in univariate and multivariate analysis. These data suggest that readmission within 90 days after discharge may have a significant impact on long-term mortality after single-unit CBT.

Efficacy and Safety of Low-Dose Liposomal Amphotericin B in Adult Patients Undergoing Unrelated Cord Blood Transplantation.

Liposomal amphotericin B (L-AMB) is widely used for empirical or preemptive therapy and treatment of invasive fungal infections after cord blood transplantation (CBT). We retrospectively examined the efficacy and safety of low-dose L-AMB in 48 adult patients who underwent CBT between 2006 and 2017 in our institute. Within the entire cohort, 42 patients (88%) received L-AMB as empirical or preemptive therapy. The median daily dose of L-AMB and the median cumulative dose of L-AMB were 1.20 mg/kg/day (range, 0.62 to 2.60 mg/kg/day) and 30.6 mg/kg (range, 0.7 to 241.5 mg/kg), respectively. The median duration of L-AMB administration was 21.5 days (range, 1 to 313 days). A documented breakthrough fungal infection occurred in 1 patient during L-AMB treatment, and 43 patients (90%) survived for at least 7 days after the end of L-AMB treatment. Grade 3 or higher hypokalemia and hepatotoxicity were frequently observed during L-AMB treatment. However, no patient developed an increase in serum creatinine levels of grade 3 or higher. In univariate analyses using a logistic regression model, a duration of L-AMB treatment of more than 21 days and a cumulative dose of L-AMB of more than 30 mg/kg were significantly associated with nephrotoxicity and grade 3 hypokalemia. These data suggest that low-dose L-AMB may be safe and effective in adult patients undergoing CBT.