Cord blood transplantation (CBT) is an alternative donor transplantation method and has the advantages of rapid availability and the possibility of inducing a more potent graft-versus-leukemia ...effect, leading to a lower relapse rate for patients with non-remission relapse and refractory acute myeloid leukemia (R/R AML). This study aimed to investigate the impact of CBT, compared to human leukocyte antigen-matched related donor transplantation (MRDT). This study included 2451 adult patients with non-remission R/R AML who received CBT (1738 patients) or MRDT (713 patients) between January 2009 and December 2018. Five-year progression-free survival (PFS) and the prognostic impact of CBT were evaluated using a propensity score (PS) matching analysis. After PS matching, the patient characteristics were well balanced between the groups. The five-year PFS was 25.2% (95% confidence interval CI: 21.2-29.5%) in the CBT group and 18.1% (95% CI: 14.5-22.0%) in the MRDT group (P = 0.009). The adjusted hazard ratio (HR) was 0.83 (95% CI: 0.69-1.00, P = 0.045); this was due to a more pronounced decrease in the relapse rate (HR: 0.78, 95% CI: 0.69-0.89, P < 0.001) than an increase in the NRM (1.42, 1.15-1.76, P = 0.001). In this population, CBT was associated with a better 5-year PFS than MRDT after allogeneic HSCT.
To investigate optimal unit selection for umbilical cord blood transplantation (UCBT), we conducted a registry-based study of 1355 adults with acute myeloid leukemia in first or second complete ...remission who underwent single-unit UCBT. To be eligible for analysis, UCB units had to contain a total nucleated cell (TNC) dose of 2.0 × 10
/kg or higher and present at least a 4/6-match for HLA-A, -B, and -DR antigens in line with clinical practice in Japan, both of which are less stringent criteria than those used in Western countries. Neither TNC dose nor the degree of HLA matching affected survival (P = 0.138 and P = 0.696, respectively). As for HLA-A, -B antigens and -DRB1 allele, better HLA matching was associated with lower non-relapse mortality (P = 0.011) but higher relapse (P = 0.046), resulting in no improvement in survival (P = 0.680). Taking the allele level for each HLA-A, -B, and -DRB1 into consideration was less useful for predicting non-relapse mortality (P = 0.198). These findings suggest that the less stringent criteria for UCB unit selection are acceptable for Japanese patient population and perhaps even more beneficial in terms of providing a better chance to find a suitable UCB unit.
WT4869 is a synthetic peptide vaccine derived from the Wilms’ tumor gene 1 (WT1) protein. This phase 1/2 open‐label study evaluated the safety and efficacy of WT4869, and biomarkers for response, in ...patients with myelodysplastic syndrome. WT4869 (5–1200 μg/dose) was administered intradermally every 2 weeks, according to a 3 + 3 dose‐escalation method in higher‐risk (International Prognostic Scoring System score ≥1.5) or lower‐risk (score <1.5) red blood cell transfusion‐dependent patients with myelodysplastic syndrome. Twenty‐six patients were enrolled and treated (median age, 75 years; range, 32 to 89). The most common adverse event was injection site reaction (61.5%). Main grade 3 or 4 adverse events were neutropenia (30.8%), febrile neutropenia, pneumonia, elevated blood creatine phosphokinase levels and hypoalbuminemia (all 7.7%). Dose‐limiting toxicities occurred in 1 patient in the 50 μg/dose cohort (pyrexia, muscle hemorrhage and hypoalbuminemia) and 1 patient in the 400 μg/dose cohort (pneumonitis); however, the maximum tolerated dose could not be determined from this trial. The overall response rate was 18.2%, the disease control rate was 59.1% and median overall survival was 64.71 weeks (95% confidence interval: 50.29, 142.86) as assessed by the Kaplan–Meier method. Subgroup analysis of azacitidine‐refractory patients with higher‐risk myelodysplastic syndrome (11 patients) showed median overall survival of 55.71 weeks (approximately 13 months). WT1‐specific cytotoxic T lymphocyte induction was observed in 11 of 25 evaluable patients. WT4869 was well tolerated in patients with myelodysplastic syndrome and preliminary data suggest that WT4869 is efficacious. This trial was registered at www.clinicaltrials.jp as JapicCTI‐101374.
This was a phase 1/2 open‐label study in 26 MDS patients, which demonstrated that WT4869 is both well tolerated and effective. The most common adverse event was injection site reaction (61.5%) and the main grade 3 or 4 adverse events were neutropenia (30.8%), febrile neutropenia, pneumonia, elevated blood creatinine phosphokinase levels, and hypoalbuminemia (all 7.7%). The overall response rate was 18.2%, with a disease control rate of 59.1%, and the median overall survival was 64.71 weeks while a subgroup analysis showed that 11 azacitidine‐refractory patients with higher‐risk MDS had a median overall survival of 55.71 weeks.
Unrelated cord blood transplantation (CBT) is an alternative curative option for adult patients with acute myeloid leukemia (AML) who need allogeneic hematopoietic cell transplantation (HCT) but lack ...an HLA-matched related or unrelated donor. However, large-scale data are lacking on CBT outcomes for unselected adult AML. To investigate the trends of survival and engraftment after CBT over the past 22 years, we retrospectively evaluated the data of patients with AML in Japan according to the time period of CBT (1998-2007 vs 2008-2013 vs 2014-2019). A total of 5504 patients who received single-unit CBT as first allogeneic HCT for AML were included. Overall survival (OS) at 2 years significantly improved over time. The improved OS among patients in ≥ complete remission (CR)3 and active disease at CBT was mainly due to a reduction of relapse-related mortality, whereas among patients in first or second CR at CBT, this was due mainly to a reduction of non-relapse mortality. The trends of neutrophil engraftment also improved over time. This experience demonstrated that the survival and engraftment rate after CBT for this group has improved over the past 22 years.
Reduced-intensity conditioning (RIC) has been facilitating allogeneic hematopoietic cell transplantation (allo-HCT) for patients originally considered ineligible for HCT with myeloablative ...conditioning. Fludarabine (Flu) with reduced doses of busulfan (Bu) (Flu + Bu) and Flu with reduced doses of melphalan (Mel) (Flu + Mel) are widely used RIC regimens for acute myeloid leukemia (AML). A nationwide retrospective study comparing clinical outcomes of adult patients with AML receiving first allo-HCT after RIC between 2001 and 2010 was performed. Cumulative incidences of relapse were not significantly different among the Flu + ivBu-based (FBiv), Flu + poBu-based (FBpo), and Flu + Mel-based (FM) groups (p = 0.29). Non-relapse mortality (NRM) was significantly lower in patients receiving FBiv compared with FBpo (p = 0.003) and FM (p < 0.001). On multivariate analysis, there was no significant difference in overall survival, but FM was associated with a significantly lower risk of relapse (hazard ratio (HR) = 0.65, 95% confidence interval (CI): 0.50-0.85, p = 0.002), higher NRM (HR = 1.60, 95% CI: 1.10-2.33, p = 0.013) and better leukemia-free survival (HR = 0.77, 95% CI: 0.63-0.95, p = 0.015) compared with FBiv. These results suggest that Flu + Mel has a more intense disease control potential and Flu + ivBu is less toxic than the other. Both RIC regimens provide similar survival outcomes and are effective and useful regimens for patients with AML who received allo-HCT.
Allogeneic hematopoietic stem cell transplantation is the sole curative therapy for myelodysplastic syndrome (MDS). However, there is concern regarding graft failure and relapse in patients who ...undergo cord blood transplantation (CBT). We conducted a retrospective study of the CBT outcomes in MDS patients using the Japanese Data Center for Hematopoietic Cell Transplantation database. Seven hundred fifty-two de novo MDS patients of ≥18 years of age (median, 58 years) undergoing their first CBT between 2001 and 2015 were examined. Two-thirds of the patients were male, and were RAEB. The cumulative incidences of neutrophil and platelet engraftment at day 100 were 77 and 59%, respectively. The 3-year overall survival (OS) was 41% and the median survival of the patients was 1.25 years. A multivariate analysis of pre-transplant variables showed that the age, gender, cytogenetic subgroups, number of RBC transfusions, HCT-CI and year of CBT significantly influenced the outcome. The cumulative incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) was 32 and 21%, respectively. A survival benefit was observed in patients who developed cGVHD, but not aGVHD. Our results suggest that CBT is an acceptable alternative graft and that a graft-versus-MDS effect can be expected, especially in patients who develop cGVHD.
Bortezomib is a novel proteasome inhibitor with significant antimyeloma activity. Its frequent adverse effects are manageable, including gastrointestinal symptoms, peripheral neuropathy, and ...thrombocytopenia. Severe lung toxicity has not previously been reported. Between June 2004 and September 2005, 13 Japanese patients with multiple myeloma were treated with bortezomib in Toranomon Hospital, Juntendo University School of Medicine, and Jichi Medical School. Four of them developed severe pulmonary complications, and 2 died of respiratory failure without progression of underlying disease. To our knowledge, this is the first report on life-threatening pulmonary adverse effects after bortezomib therapy. Previous clinical studies on bortezomib, mostly in the United States and Europe, have shown low incidences of pulmonary adverse effects. Our study suggests that bortezomib can cause serious lung injury, and that its incidence might vary among different ethnicities. Clinicians need to be alert to the possibility.
Summary
Umbilical cord blood transplantation (CBT) is widely accepted, but one critical issue for adult patients is a low engraftment rate, of which one cause is haemophagocytic syndrome (HPS). We ...aimed to identify the contribution of HPS to engraftment failure after CBT, following preparative regimens containing fludarabine phosphate, in 119 patients (median age, 55 years; range; 17–69 years) with haematological diseases. Graft‐versus‐host disease prophylaxis comprised continuous infusion of a calcineurin inhibitor with or without mycophenolate mofetil. Of the 119 patients, 20 developed HPS within a median of 15 d (cumulative incidence; 16·8%) and 17 of them did so before engraftment. Donor‐dominant chimaerism was confirmed in 16 of 18 evaluable patients with HPS. Despite aggressive interventions including corticosteroid, ciclosporin, high‐dose immunoglobulin and/or etoposide, engraftment failed in 14 of 18 patients. Of these 14 patients, four received second rescue transplantation and all resulted in successful engraftment. Overall survival rates significantly differed between patients with and without HPS (15·0% vs. 35·4%; P < 0·01). Univariate and multivariate analysis identified having fewer infused CD34+ cells as a significant risk factor for the development of HPS (P = 0·01 and 0·006, respectively). We concluded that engraftment failure closely correlated with HPS in our cohort, which negatively impacted overall survival after CBT.
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