Susumu Tanoue

Cryopreserved CD34+ Cell Dose, but Not Total Nucleated Cell Dose, Influences Hematopoietic Recovery and Extensive Chronic Graft-versus-Host Disease after Single-Unit Cord Blood Transplantation in Adult Patients

Low cryopreserved total nucleated cell (TNC) dose in a cord blood (CB) unit has been shown to be associated with engraftment failure and mortality after single-unit cord blood transplantation (CBT) in adults. Although CB banks offer specific characteristics of cryopreserved cell dose, such as TNC, CD34+ cells, and colony-forming unit for granulocyte/macrophage (CFU-GM), the impact of each cell dose on engraftment and outcomes after single-unit CBT in adults remains unclear. We retrospectively analyzed the results of 306 CBTs for 261 adult patients in our institution between 1998 and 2016. The median age was 43 years (range, 16 to 68), the median actual body weight (ABW) was 56.2 kg (range, 36.2 to 104.0), the median ideal body weight (IBW) was 62.3 kg (range, 39.7 to 81.3), the median TNC dose was 2.46 × 107/ABW kg (range, 1.07 to 5.69), the median CD34+ cell dose was .91 × 105/ABW kg (range, .15 to 7.75), and the median CFU-GM dose was 24.46 × 103/ABW kg (range, .04 to 121.81). Among patients who achieved engraftment, the speed of neutrophil, platelet, and red blood cell engraftment significantly correlated with CD34+ cell dose, but not with TNC and CFU-GM dose, based on both ABW and IBW. In multivariate analysis, the incidence of extensive chronic graft-versus-host disease (GVHD) was significantly higher in patients receiving the highest CD34+ cell dose, based on both ABW and IBW. Nevertheless, no cell dose was associated with survival, transplantation-related mortality, and relapse. In conclusion, cryopreserved CD34+ cell dose was the best predictor for hematopoietic recovery and extensive chronic GVHD after CBT. The cryopreserved CD34+ cell dose should be used for unit selection criteria in single-unit CBT for adults.

Cytokine Profiles of Pre-Engraftment Syndrome after Single-Unit Cord Blood Transplantation for Adult Patients

Clinical manifestation of high-grade fever and skin rash before neutrophil engraftment, termed pre-engraftment syndrome (PES) or pre-engraftment immune reaction, has been frequently observed after cord blood transplantation (CBT). The pathophysiology of PES is poorly understood, but cytokine storm during the early phase of CBT is thought to be 1 of the main cause of PES. However, the cytokine profiles of PES after CBT are unclear. Therefore, we examined the relationship between serum cytokine profiles and PES in 44 adult patients who received CBT in our institution between February 2013 and June 2016. Serum levels of 21 cytokines, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-17F, IL-18, IL-21, IL-22, IL-23, IL-33, monocyte chemoattractant protein-1, IFN-α, IFN-γ, and TNF-α, were measured by multiplex bead assays using a flow cytometer. The median time until the absolute neutrophil count was >.5 × 109/L was 21 days (range, 15 to 41 days). The cumulative incidence of PES was 79.6% (95% confidence interval, 63.3% to 88.5%) at 60 days after CBT. Serum levels of IL-5 (P = .009) and IL-6 (P = .01) at 2 weeks were significantly higher in patients who developed PES compared with those who did not develop PES. The conversion from naïve to effector or central memory phenotype of T cells was observed in PES. These data indicate that elevations of IL-5 and IL-6 around the time of clinical manifestation may be possible biomarkers for PES after CBT.

Alloimmune hemolysis due to major RhE incompatibility after unrelated cord blood transplantation

Masamichi Isobe, Takaaki Konuma, Yuka Abe-Wada, Kyoko Hirata, Kazuo Ogami, Seiko Kato, Maki Oiwa-Monna, Susumu Tanoue, Tokiko Nagamura-Inoue, Satoshi Takahashi and Arinobu Tojo Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Cell Processing and Transfusion, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

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.

Monocyte subsets and their phenotypes during treatment with BCR-ABL1 tyrosine kinase inhibitors for Philadelphia chromosome-positive leukemia

BCR‐ABL1 tyrosine kinase inhibitors (TKIs) are effective agents in the treatment of Philadelphia chromosome‐positive leukemia. However, vascular events have developed in some patients receiving each TKI. The perturbation of circulating monocyte subsets and their expressions of chemokine and scavenger receptors are associated with the development of cardiovascular events. Here, we examined the subsets of circulating monocytes and their phenotypes in 51 patients treated with imatinib, nilotinib, and dasatinib, and 11 healthy subjects in our institute. Except for a negative association between the number of classical monocytes and imatinib treatment, the proportions and numbers of monocyte subsets were not significantly associated with TKI treatment. However, chemokine receptors, CCR2, CX3CR1 on classical monocytes, and scavenger receptor, CD204, on intermediate and non‐classical monocytes were significantly associated with TKIs. These data demonstrated the relationships between alterations of chemokine and scavenger receptors on different monocyte subsets and the TKI treatments.

Does marital status affect the outcomes after allogeneic hematopoietic cell transplantation

Marital status has been reported to be associated with survival in patients with several types of cancer, including acute myeloid leukemia, and those receiving solid organ transplantation [1–5]. However, there have been no reports detailing the impact of marital status on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this study, we retrospectively analyzed whether marital status at the time of HCT affected the outcomes of allogeneic HCT in 309 adult patients with hematological diseases at our institute. To clarify the impact of marital status on transplant outcomes, we analyzed data from the first allogeneic HCT for 309 patients aged older than 20 years at our institute between January 2000 to January 2017. During the study period, monogamy is the rule of marriage in Japan. The probability of overall survival (OS) was estimated according to the Kaplan–Meier method, and the groups were compared using the log-rank test. The risks of relapse, transplant-related mortality (TRM), acute graft-versus-host disease (aGVHD), and chronic graft-versus-host disease (cGVHD) were estimated based on a cumulative incidence method to accommodate competing risks, and the groups were compared using Gray’s test. A multivariate analysis was performed with a Cox proportional hazard model for overall mortality or a Fine and Gray proportional hazards model for others using these factors: marital status (yes vs. no), age (<45 vs. ≥45 years), sex (male vs. female), recipient cytomegalovirus serostatus (positive vs. negative), disease status at HCT (standard risk vs. high risk), donor source [bone marrow transplantation/peripheral blood stem cell transplantation from an HLA matched-related donor (MRBMT/PBSCT) vs. bone marrow transplantation/peripheral blood stem cell transplantation from an HLA mismatched-related donor (MMRBMT/PBSCT) vs. BMT from an unrelated donor (UBMT) vs. cord blood transplantation from an unrelated donor (UCBT)], conditioning regimen [myeloablative conditioning (MAC) vs. reducedintensity conditioning (RIC)], ABO compatibility between donor and recipient (match vs. mismatch), and year of HCT (2000–2006 vs. 2007–2017). The disease status at HCT was classified as standard or high risk based on the risk scoring scheme of the American Society for Blood and Marrow Transplantation Request for Information 2006 risk scoring schema, as previously described [6]. Acute leukemia in the first or second complete remission, myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), chronic myelomonocytic leukemia (CMML) without excessive numbers of blasts, chronic myelogenous leukemia (CML) in the first chronic phase, Hodgkin’s or non-Hodgkin’s lymphoma in complete or partial chemotherapysensitive remission, and severe aplastic anemia were classified as standard risk; all other situations were classified as high risk. The MAC regimen was defined according to the criteria of the Center for International Blood and Marrow Transplant Research (CIBMTR), and others were classified as RIC [7]. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [8], a graphical user interface for R 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria). P values of <0.05 were considered to be significant. This retrospective study was approved by the institutional review board of the Institute of Medical Science, the University of Tokyo. These authors contributed equally: Tomoko Sato, Takaaki Konuma.

Circulating monocyte subsets in human chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) is a major cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Monocytes/macrophages play a central role in inflammation, tissue repair, and fibrosis, which are the main clinical features of cGVHD. Here, we examined the expression levels of activation markers, chemokine receptors, and scavenger receptors for each circulating monocyte subset in 145 patients without disease recurrence at least 12 months after undergoing allogeneic HCT. There were no significant differences in the numbers and the proportions of each monocyte subset between patients without cGVHD and those with mild or moderate/severe cGVHD. Lower expression of CCR5 on classical monocytes, and higher expression of CD204 and lower expression of CX3CR1 on non-classical monocytes were associated with joint, and lung cGVHD, respectively. These data showed that alterations of activation markers and chemokine and scavenger receptors in each circulating monocyte subset were associated with the development of organ-specific cGVHD. Alterations of surface markers in each circulating monocyte subset may be candidate biomarkers for cGVHD.

Platelet Transfusion Refractoriness in Single-Unit Cord Blood Transplantation for Adults: Risk Factors and Clinical Outcomes

Platelet transfusion refractoriness (PTR) is frequently observed after allogeneic hematopoietic cell transplantation (HCT). However, the incidence of and risk factors for PTR, and impact of PTR on transplant outcomes after cord blood transplantation (CBT) have not been fully investigated. We retrospectively analyzed 185 adult patients who received single-unit CBT in our institute. The mean 16-hour corrected count increment (CCI) for the 5840 platelet transfusions was 3.68 × 109/L. Among them, 3196 transfusions (54.7%) were associated with a PTR with 16-hour-CCI <4.5 × 109/L. Results of multivariate analysis indicated that the following factors were significantly associated with decreased platelet transfusion responses: female sex with pregnancy history, male sex, the presence of HLA class I antibody, lower cord blood total nucleated cell dose, lower cord blood CD34+ cell dose, 3 locus HLA disparities, body temperature ≥38°C, C-reactive protein ≥10 mg/dL, cytomegalovirus reactivation, use of foscarnet, and use of liposomal amphotericin B. By contrast, graft-versus-host disease prophylaxis including methotrexate, ABO minor mismatch, use of ganciclovir, and use of linezolid were significantly associated with better platelet transfusion responses. PTR had a significant effect on poor neutrophil and platelet recovery, and overall mortality after CBT. These data suggest that early phase PTR may be predictive of engraftment and mortality after single-unit CBT for adults.

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. ABSTRACT 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.

Long-term persistent donor–recipient mixed chimerism without disease recurrence after myeloablative single-unit cord blood transplantation in adult acute myeloid leukemia following myelodysplastic syndrome

Susumu Tanoue, Takaaki Konuma, Satoshi Takahashi, Eri Watanabe, Natsuko Sato, Nobukazu Watanabe, Masamichi Isobe, Seiko Kato, Jun Ooi and Arinobu Tojo Department of Hematology/Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Department of IMSUT Clinical Flow Cytometry Laboratory, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Oncology, Hematology and Infectious Diseases, Department of Internal Medicine, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; Department of Hematology/Oncology, Teikyo University School of Medicine, Tokyo, Japan