Maki Oiwa-Monna

Single-Unit Cord Blood Transplantation after Granulocyte Colony-Stimulating Factor–Combined Myeloablative Conditioning for Myeloid Malignancies Not in Remission

High disease burden in myeloablative allogeneic hematopoietic stem cell transplantation is associated with adverse outcomes in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Quiescent leukemia stem cells could be induced to enter cell cycle by granulocyte colony-stimulating factor (G-CSF) administration and become more susceptible to chemotherapy. We report on the outcome of unrelated cord blood transplantation (CBT) using a conditioning regimen of 12 Gy total body irradiation, G-CSF-combined high-dose cytarabine, and cyclophosphamide in 61 adult patients with AML or advanced MDS not in remission. With a median follow-up of 97 months, the probability of overall survival and cumulative incidence of relapse at 7 years were 61.4% and 30.5%, respectively. In multivariate analysis, poor-risk cytogenetics and high lactate dehydrogenase values at CBT were independently associated with inferior survival. These data demonstrate that CBT after G-CSF-combined myeloablative conditioning is a promising curative option for patients with myeloid malignancies not in remission.

Effect of ABO Blood Group Incompatibility on the Outcome of Single-Unit Cord Blood Transplantation after Myeloablative Conditioning

ABO blood group incompatibility between donor and recipient has been associated with poor transplant outcomes in allogeneic hematopoietic stem cell transplantation. However, its effect on the outcome of cord blood transplantation (CBT) has yet to be clarified. We retrospectively analyzed 191 adult patients who received single-unit CBT after myeloablative conditioning for malignant disease in our institute. Major mismatch showed a significantly lower incidence of platelet engraftment compared with ABO match as a reference (hazard ratio, .57; P = .01). Nevertheless, there was no increase in graft-versus-host disease, transplant-related mortality, and overall mortality after ABO-incompatible CBT. These data suggested that donor-recipient ABO incompatibility does not have a significant impact on outcome after myeloablative CBT for hematological malignancies.

Single-unit cord blood transplant for acute lymphoblastic leukemia and lymphoma using an intensified conditioning regimen of total body irradiation, high-dose cytarabine and cyclophosphamide

Cord blood transplant (CBT) from an unrelated donor has recently been utilized as an alternative transplant method for patients with lymphoid neoplasms when patients are without related and unrelated adult donors [1–6]. However, a high incidence of graft failure remains one of the major disadvantages in CBT for adult patients. The purpose of a conditioning regimen prior to allogeneic hematopoietic stem cell transplant (allo-HSCT) for malignant disease is disease eradication and immunosuppression to achieve graft engraftment. With regard to stable engraftment, an optimal conditioning regimen prior to CBT for adult patients with lymphoid neoplasms is yet to be determined. In the present study, we analyzed the results of CBT after an intensified conditioning regimen of total body irradiation (TBI), highdose cytarabine (Ara-C) and cyclophosphamide (CY) in 32 adult patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) with long-term follow-up. This retrospective study included 32 consecutive adult patients who underwent unrelated allo-HSCT using single-unit cord blood (CB) for ALL or NHL at the Institute of Medical Science, The University of Tokyo between April 2004 and July 2013. Eleven patients had been included in our previous study [6], and extended the follow-up. The diagnosis of ALL and NHL was made according to the World Health Organization classification. CB units were obtained from the Japan Cord Blood Bank Network and selected as reported previously [7]. All patients received 12 Gy TBI in four divided fractions on days  8 and  7, Ara-C on days  5 and  4 (total dose 12 g/m2, 3 g/m2 every 12 h for 2 days) and CY (total dose 120 mg/kg) on days  3 and  2 as a conditioning regimen, and received cyclosporine A (3 mg/kg/day) with a short course of methotrexate (15 mg/m2 on day  1 and 10 mg/m2 on days  3 and  6) as a graft-versus-host disease (GVHD) prophylaxis. Although 28 patients received one or more courses of prophylactic intrathecal chemotherapy before the conditioning regimen, no patients received it after CBT. The institutional review board of the Institute of Medical Science, The University of Tokyo approved this study, which was conducted in accordance with the Declaration of Helsinki. The probability of overall survival (OS), which was defined as the time from the date of CBT to the date of death or last contact, was estimated according to the Kaplan–Meier method. The probabilities of relapse, which was defined by morphologic evidence of disease in peripheral blood, bone marrow or extramedullary sites, and transplant-related mortality (TRM), which was defined as death during remission, were estimated based on a cumulative incidence method to accommodate competing risks. Univariate analysis was performed with a Cox regression model for OS and the Fine and Gray regression model for relapse and TRM. The following variables were considered: patient age ( 40 vs.  40 years), disease type (ALL vs. NHL), disease status at CBT (standard risk vs. high risk), cord blood nucleated cell count ( 2.5 vs.  2.5  107/kg), cord blood CD34  cell count ( 1  105/kg vs.  1  105/kg), human leukocyte antigen (HLA) disparities based on HLA-A and -B antigen level and HLA-DRB1 allele level ( 2 vs.  3), sex compatibility (female donor to male recipient vs. other) and ABO compatibility (match vs. mismatch). Since the number of patients was small, we were unable to perform multivariate analysis to identify variables influencing outcomes. All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R 3.0.2 (R Foundation for Statistical Computing, Vienna, Austria) [8]. Analysis of data was performed in April 2014. The characteristics of patients, CB units and transplant procedures are shown in Table I. The median age was 39 years (range, 18–49 years), the median number of nucleated cells was 2.60  107/kg (range, 1.65–5.69  107/kg) and the median number of CD34  cells was 0.94  105/kg (range, 0.41–2.81  105/kg). Disease types were ALL in 27 patients, and NHL in five. Among patients with ALL, 11 patients had the Philadelphia chromosome abnormality. All patients achieved neutrophil and platelet recovery after CBT. The median time to more than 0.5  109/L absolute neutrophil L eu k L ym ph om a D ow nl oa de d fr om in fo rm ah ea lth ca re .c om b y JH U J oh n H op ki ns U ni ve rs ity o n 01 /0 1/ 15

Impact of sex incompatibility on the outcome of single-unit cord blood transplantation for adult patients with hematological malignancies.

Donor–recipient sex incompatibility has been associated with transplant outcomes in allogeneic hematopoietic SCT. Such outcomes might be because mHA encoded by Y chromosome genes could be immunological targets for allogeneic T cells and B cells to induce GVHD, GVL effect and graft failure. However, its effect on the outcome of cord blood transplantation (CBT) is yet to be clarified. We retrospectively analyzed 191 adult patients who received single-unit CBT after myeloablative conditioning for malignant disease in our institute. In multivariate analysis, male recipients with female donors had a higher incidence of extensive chronic GVHD (hazard ratio (HR) 2.97, P=0.02), and female recipients with male donors had a lower incidence of platelet engraftment (HR 0.56, P=0.02) compared with female recipients with female donors as the reference. Nevertheless, there was no increase in mortality following sex-incompatible CBT. These data suggested that donor–recipient sex compatibility does not have a significant impact on survival after myeloablative CBT for hematological malignancies.

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.

Comparison of graft-versus-host disease-free, relapse-free survival of transplantation using matched sibling donor, matched unrelated donor or unrelated cord blood after myeloablative conditioning for adult patients with hematological malignancies.

Abstract The novel composite endpoint of graft-versus-host disease/relapse-free survival (GRFS) was proposed to evaluate ideal healthy recovery without ongoing morbidity in patients undergoing allogeneic hematopoietic cell transplantation (HCT). We herein analyzed long-term GRFS based on the data of 256 patients with hematological malignancies who underwent allogeneic HCT after myeloablative conditioning. The probabilities of GRFS in the entire cohort were 60.1% at 1 year, and 48.6% at 5 years. Compared with unrelated cord blood, the probability of treatment failure as defined by GRFS at 5 years was similar with matched sibling donor (hazard ratio [HR]: 1.33; p = 0.28), but was significantly higher with matched unrelated donor (HR: 1.96; p = 0.01) in multivariate analysis. Unrelated cord blood achieved the highest proportion of patients who had not experienced any GRFS events at 5 years. These data suggest that long-term GRFS after HCT was similar in matched sibling donor recipients to unrelated cord blood recipients.

Early renal injury after myeloablative cord blood transplantation in adults

We report a retrospective analysis of acute renal failure (ARF) in a group of 54 adult patients with hematological malignancies treated with unrelated cord blood transplantation (CBT) after myeloablative conditioning. All patients received four fractionated 12 Gy total body irradiation and chemotherapy as myeloablative conditioning. ARF was defined as the doubling serum creatinine occurring within the first 100 days after CBT. A statistically significant decrement of renal function from baseline was observed in days between 11 and 20. ARF occurred in 27.8% of patients. Although no difference was seen in maximum cyclosporine trough levels, the maximum of vancomycin (VCM) trough levels were significantly higher in patients with ARF (p = 0.01). Our result suggests that it is important to monitor VCM dosing more strictly with pharmacokinetic assessment, especially in days 11 – 20, when the most frequently observed declining renal function.

Long-term outcomes of granulocyte colony-stimulating factor-combined conditioning in allogeneic hematopoietic stem cell transplantation from HLA-identical family donors for myeloid malignancies

Dormant leukemia cells, which might escape the cytotoxic effect of conditioning before hematopoietic stem cell transplantation (HSCT), could be induced to enter the cell cycle by granulocyte colony-stimulating factor (G-CSF) and become more susceptible to the cell-cycle-specific agent cytarabine arabinoside (Ara-C). Based on this effect, we have utilized G-CSF-combined high-dose Ara-C in myeloablative conditioning for allogeneic bone marrow or peripheral blood stem cell transplantation from HLA-identical family donors since 1988. We report on the long-term outcomes of allogeneic HSCT using a conditioning regimen of 12Gy total body irradiation and G-CSF-combined high-dose Ara-C in 89 adult patients with acute myeloid leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome. With a median follow-up of 135 months, the probability of overall survival and cumulative incidence of relapse at 5 years were 67.8% and 19.4%, respectively. In multivariate analysis, disease status at HSCT was associated with survival and relapse. These data demonstrate that G-CSF-combined myeloablative conditioning could be safely and effectively used for patients with myeloid malignancies.

Impact of hematogones on the long-term outcomes of single-unit cord blood transplantation for adult patients

Abstract Hematogones are normal B-lymphocyte precursors identified in the regenerative state of the bone marrow following allogeneic hematopoietic stem cell transplantation (HSCT). To evaluate the impact of hematogones on long-term outcomes after single-unit cord blood transplantation (CBT), we retrospectively analyzed 134 adult patients at our institute. At the median time of 41 days (range, 20 to 77 days) after CBT, the median proportion of morphological hematogones in bone marrow was found to be 2.4% (range, 0 to 13.0%). In the patients with standard-risk, the higher proportion of morphological hematogones was associated with lower transplant-related mortality (TRM) after CBT. The proportion of hematogones did not affect the subsequent absolute lymphocyte counts in the peripheral blood and serum immunoglobulin G levels six months later after CBT. These data shows that morphological hematogones in the routine bone marrow analysis might be a practical and easily evaluable method of predicting outcomes after CBT.

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.