Successful treatment of two cases with Philadelphia-chromosome positive acute lymphoblastic leukemia who relapsed after allogeneic stem cell transplantation and the treatments with novel immunotherapies and ponatinib.

The outcomes of relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant to new drugs such as tyrosine kinase inhibitors, inotuzumab ozogamicin (InO) and blinatumomab are dismal. We treated two cases of Ph+ALL resistant to these drugs that achieved long-term survival after treatment with chimeric antigen receptor (CAR)-T cell therapy or a second allogeneic hematopoietic stem cell transplantation (HCT) with a sequential conditioning regimen. Case 1: A 15-year-old boy was diagnosed with Ph+ALL. Despite the second HCT after the treatment of ponatinib and blinatumomab, hematological relapse occurred. InO was ineffective and he was transferred to a CAR-T center. After the CAR-T cell therapy, negative measurable residual disease (MRD) was achieved and maintained for 38 months without maintenance therapy. Case 2: A 21-year-old man was diagnosed with Ph+ALL. Hematological relapse occurred after the first HCT. Despite of the treatment with InO, ponatinib, and blinatumomab, hematological remission was not achieved. The second HCT was performed using a sequential conditioning regimen with clofarabine. Negative MRD was subsequently achieved and maintained for 42 months without maintenance therapy. These strategies are suggestive and helpful to treat Ph+ALL resistant to multiple immunotherapies.

Association between human herpesvirus-6 encephalitis and antiviral prophylaxis after allogeneic hematopoietic stem cell transplantation in the letermovir era.

The impact of letermovir (LTV)-an anti-cytomegalovirus (CMV) drug-on human herpesvirus-6 (HHV-6) encephalitis is unclear. We hypothesized that LTV prophylaxis may increase the incidence of HHV-6 encephalitis by reducing anti-CMV therapies after allogeneic hematopoietic stem cell transplantation (HSCT). To evaluate the association between HHV-6 encephalitis and antiviral prophylaxis, 7985 adult patients from a nationwide registry who underwent their first HSCT between January 2019 and December 2021 were analyzed. The incidence of HHV-6 encephalitis on day 100 after HSCT was 3.6%; 11.5% for the broad-spectrum antiviral group (foscarnet, ganciclovir, or valganciclovir); 2.8% for the LTV group, and 3.8% for the other antiviral group (p < 0.001). These differences persisted when cord blood transplantation (CBT) was analyzed separately (14.1%, 5.9%, and 7.4%, p < 0.001). In the multivariate analysis, CBT (hazard ratio [HR]: 2.90), broad-spectrum antiviral prophylaxis (HR: 1.91), and grade II-IV acute graft-versus-host disease requiring systemic corticosteroids (HR: 2.42) were independent risk factors for encephalitis (all p < 0.001). The findings of this large modern database study indicate that broad-spectrum antiviral prophylaxis, rather than LTV prophylaxis, is paradoxically associated with HHV-6 encephalitis in the LTV era. This paradoxical finding needs to be further explored in future studies.

WT1-guided pre-emptive therapy after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia.

Measurable residual disease (MRD)-guided pre-emptive therapies are now widely used to prevent post-transplant hematological relapse in patients with acute myeloid leukemia (AML). This single-center retrospective study aimed to clarify the significance of pre-emptive treatment based on Wilms' tumor gene-1 mRNA (WT1) monitoring for MRD in patients with AML who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with AML who received chemotherapy for hematological relapse or WT1 increase after allo-HSCT were eligible for inclusion. From January 2017 to June 2022, 30 patients with a median age of 57 (16-70) years were included and stratified into two groups: 10 with WT1 increase and 20 with hematological relapse. The median times from HCT to WT1 increase or hematological relapse were 309 days (range: 48-985) or 242 days (range: 67-1116), respectively. Less intensive chemotherapy using azacitidine or cytarabine was selected for all patients with WT1 increase and 12 (60%) with hematological relapse. The 1-year overall survival and event-free survival rates for WT1 increase and hematological relapse were 70% vs. 44% (P = 0.024) and 70% vs. 29% (P = 0.029), respectively. These real-world data suggest that WT1-guided pre-emptive therapy may be superior to therapy after hematological relapse in patients with AML who have undergone allo-HSCT.

Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical sibling donors for hematological malignancies in 6064 adults from 2003 to 2020: different impacts on survival according to time period.

BACKGROUND: Mobilized peripheral blood stem cells (PBSC) have been widely used instead of bone marrow (BM) as the graft source for allogeneic hematopoietic cell transplantation (HCT). Although early studies demonstrated no significant differences in survival between PBSC transplantation (PBSCT) and BM transplantation (BMT) from human leukocyte antigen (HLA)-identical sibling donors to adults with hematological malignancies, recent results have been unclear. OBJECTIVE: The objective of this retrospective study was to compare overall survival (OS), relapse, non-relapse mortality (NRM), hematopoietic recovery and graft-versus-host disease (GVHD) between PBSCT and BMT according to the time period of HCT (2003-2008, 2009-2014, or 2015-2020). STUDY DESIGN: We retrospectively compared the outcomes after PBSCT versus BMT in 6064 adults with hematological malignancies using a Japanese registry database between 2003 and 2020. RESULTS: The adjusted probability of OS was significantly higher in BMT recipients compared to PBSCT recipients during the early period of 2003-2008 (adjusted hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.70-0.91; P < 0.001) and the middle period of 2009-2014 (adjusted HR, 0.80; 95% CI, 0.70-0.91; P < 0.001). However, during the late period of 2015-2020, the adjusted probability of OS was comparable between BMT and PBSCT recipients (adjusted HR, 0.94; 95% CI, 0.79-1.13; P = 0.564), which were mainly due to the reduction of NRM. There was no significant difference in the relapse rate between the groups, irrespective of the time period. Compared to BMT, PBSCT led to faster neutrophil and platelet recovery and the cumulative incidences of grades II-IV and grades III-IV acute and overall and extensive chronic GVHD were significantly higher in PBSCT recipients, irrespective of the time period. CONCLUSIONS: PBSCT and BMT had similar survival outcomes and relapse rates in adult patients with hematological malignancies during the late time period of 2015-2020 despite the hematopoietic recovery and acute and chronic GVHD being higher in PBSCT recipients in all time periods.

Investigation of biomarkers to predict outcomes in allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Various biomarkers have been developed and evaluated to predict the prognosis and complications of allogeneic hematopoietic cell transplantation (HCT). Most previous studies conducted on different biomarkers evaluated single effects such as those associated with inflammation, immunology, iron metabolism, and nutrition, and only a few studies have comprehensively analyzed markers. OBJECTIVE: The study aimed to survey comprehensive multiple markers prior to HCT and extract those that significantly predict the outcomes. STUDY DESIGN: A prospective multicenter observational study was performed. (UMIN000013506) Patients undergoing HCT for hematologic diseases were consecutively enrolled. Besides the usual clinical biomarkers, serum samples for extra-clinical biomarkers were collected and cryopreserved before starting the conditioning regimen. A total of 32 candidate biomarkers were selected, 23 from hematology, biochemistry, immunology, nutrition, and iron metabolism, and 9 from composite markers. Based on the area under the curve (AUC) values for survival, promising biomarkers was extracted. Internal validation for these markers was applied based on bootstrap methods. Setting the cut-off values for them, log-rank test was applied and outcomes including overall survival (OS), relapse, and non-relapse mortality (NRM) were evaluated using multivariate analyses. Furthermore, detailed analysis including transplant-related complications and external validation were conducted focusing on C-reactive protein (CRP) to platelet (Plt) ratio. RESULTS: A total of 152 patients with hematologic malignancies were enrolled from April 2014 to March 2017. CRP, soluble interleukin-2 receptor (IL2R), CRP to albumin (Alb) ratio, CRP to Plt ratio, Plt to IL2R ratio, and IL2R to Alb ratio were identified as promising markers. Internal validation successfully confirmed their reliability of AUC and multivariate analysis demonstrated the statistical significance between the higher and the lower markers. Above all, a higher CRP to Plt ratio was significantly associated with a lower OS (hazard ratio [HR] 2.77; 95% confidence interval [CI] 1.30-5.91; P = 0.008) and higher non-relapse mortality rates (HR 2.79; 95%CI 1.14-6.80; P = 0.024) at 180 days. Furthermore, univariate analysis showed that a higher CRP to Plt ratio was significantly associated with a higher incidence of sinusoidal obstructive syndrome (P < 0.001) and bloodstream infection (P = 0.027). An external validation test confirmed the significance of the CRP to Plt ratio for these outcomes. CONCLUSION: The multicenter prospective observational study successfully identified significant biomarkers in patients with hematologic malignancies who received HCT. In particular, CRP to Plt ratio was identified as a novel and useful biomarker for predicting transplant outcomes. Further investigations are needed to validate the novel markers, analysis of the pathophysiology, and application to treatment settings other than HCT.

Acute mixed-lineage leukemia treated with desensitization therapy prior to HLA-haploidentical transplantation with high donor-specific antibodies.

A 43-year-old woman was referred to our department for hematopoietic stem cell transplantation for acute myeloid leukemia, as she failed to achieve remission following induction therapy. Umbilical cord blood transplantation was initially planned; however, multiple anti-human leukocyte antigen (HLA) antibodies with a mean fluorescence intensity of over 10,000 were detected, and optimal umbilical cord blood could not be obtained. The plan was then switched to peripheral blood stem cell transplantation (PBSCT) from the patient's son, who had a 5/8 HLA haploidentical match. However, the patient had donor-specific antibodies against the donor's HLA-B 0702 and HLA-C 0702. To address this issue, after rituximab therapy, the patient was given platelet transfusions from B0702- and C0702-positive donors on day - 1 and day 0, and immunoglobulin on day 0, followed by PBSCT. Donor-specific antibodies decreased by over 90%, and engraftment was confirmed on day 13. Since then, the patient has remained relapse-free and healthy. This case suggests that appropriate management of donor-specific antibodies can enable safe transplantation, even in donors who test positive for these antibodies.

RhD mismatch does not affect haematopoietic recovery, graft-versus-host disease and survival in allogeneic haematopoietic cell transplantation: A Japanese registry-based study.

BACKGROUND AND OBJECTIVES: ABO blood group mismatch between the donor and the recipient can affect the success of the transplant as well as problems with the red blood cells during allogeneic haematopoietic cell transplantation (HCT). However, the impact of the Rhesus (Rh) D mismatch on transplant outcomes in allogeneic HCT has been poorly elucidated. MATERIALS AND METHODS: We retrospectively evaluated the impact of the RhD mismatch on post-transplant outcomes in 64,923 patients who underwent allogeneic HCT between 2000 and 2021 using a Japanese registry database. RESULTS: Out of the whole group, 64,293, 322, 270 and 38 HCTs were done when the recipient or donor was RhD-mismatched with (+/+), (-/+), (+/-) or (-/-) combinations. The difference in RhD between recipient/donor (-/+), (+/-) and (-/-) did not affect haematopoietic recovery, acute and chronic graft-versus-host disease (GVHD), overall survival (OS), non-relapse mortality (NRM) or relapse when RhD (+/+) was used as the reference group in multivariate analysis. CONCLUSION: Our registry-based study demonstrated that RhD mismatch between recipient and donor did not significantly impact haematopoietic recovery, GVHD, OS, NRM or relapse after allogeneic HCT. These data suggest that RhD mismatches may not need to be avoided for recipient and donor combinations in allogeneic HCT.

Updated comparable efficacy of cord blood transplantation for chronic myelomonocytic leukaemia: a nationwide study.

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy with a poor prognosis. Allogeneic haematopoietic stem cell transplantation remains the only curative approach. Without human leucocyte antigen-matched related sibling donors, the optimal alternative donor has yet to be established. Although unrelated bone marrow transplantation (UBMT) has been extensively studied, cord blood transplantation (CBT) for CMML remains largely unexplored. This nationwide retrospective study compared the outcomes of UBMT and single-unit umbilical CBT in patients with CMML. This study included 118 patients who underwent their first allo-HSCT during 2013-2021. Of these, 50 received BMT (UBMT group), while 68 underwent CBT (CBT group). The primary endpoint was the 3-year overall survival (OS). There were comparable 3-year OS rates between the UBMT (51.0%, 95% confidence interval [CI]: 34.1-65.5%) and CBT (46.2%, 95% CI: 33.2-58.1%; P = 0.60) groups. In the inverse probability of treatment weighting analysis, CBT did not show significantly improved outcomes compared with UBMT regarding the 3-year OS rate (hazard ratio 0.97 [95% CI: 0.57-1.66], P = 0.91). Thus, CBT may serve as an alternative to UBMT for patients with CMML. Further research is necessary to optimise transplantation strategies and enhance outcomes in patients with CMML undergoing CBT.

Comparative Analysis of Allogeneic Bone Marrow Transplantation Outcomes Between Japanese and Non-Japanese Populations.

BACKGROUND: As the Japanese population may have less genetic diversity than other ethnic groups, treatment outcomes may be affected when allogeneic hematopoietic cell transplantation is performed in other races. However, evidence explaining the effect of racial differences is limited. METHODS: We used the Japanese National Database to examine the outcomes of first allogeneic bone marrow transplantations (BMTs) performed between Japanese and non-Japanese patients from 1996 to 2021. We performed propensity score matching using sex, age group, underlying disease group, HLA mismatch, conditioning regimen intensity, and BMT implementation age to select Japanese-to-Japanese BMT patients as the controls. RESULTS: The numbers of non-Japanese-to-Japanese and Japanese-to-non-Japanese BMT cases included in the analysis were 48 and 75, respectively, and the following outcomes were compared: overall survival, non-relapse mortality, acute graft-vs-host disease (GVHD) ≥ grade II, chronic GVHD, and engraftment of neutrophils and platelets. Most parameters did not differ when comparing BMTs according to ethnicity; only platelet engraftment was delayed in Japanese-to-non-Japanese BMT but not in non-Japanese-to-Japanese BMT. CONCLUSIONS: The results of this study suggested that BMT performed in Japanese and non-Japanese patients has little effect on treatment outcomes. The results of this study may be useful for donor selection in Japan, where internationalization has progressed in recent years.

Machine Learning Prediction Model for Neutrophil Recovery after Unrelated Cord Blood Transplantation.

Delayed neutrophil recovery is an important limitation to the administration of cord blood transplantation (CBT) and leaves the recipient vulnerable to life-threatening infection and increases the risk of other complications. A predictive model for neutrophil recovery after single-unit CBT was developed by using a machine learning method, which can handle large and complex datasets, allowing for the analysis of massive amounts of information to uncover patterns and make accurate predictions. Japanese registry data, the largest real-world dataset of CBT, was selected as the data source. Ninety-eight variables with observed values for >80% of the subjects known at the time of CBT were selected. Model building was performed with a competing risk regression model with lasso penalty. Prediction accuracy of the models was evaluated by calculating the area under the receiver operating characteristic curve (AUC) using a test dataset. The primary outcome was neutrophil recovery at day (D) 28, with recovery at D14 and D42 analyzed as secondary outcomes. The final cord blood engraftment prediction (CBEP) models included 2991 single-unit CBT recipients with acute leukemia. The median AUC of a D28-CBEP lasso regression model run 100 times was .74, and those for D14 and D42 were .88 and .68, respectively. The predictivity of the D28-CBEP model was higher than that of 4 different legacy models constructed separately. A highly predictive model for neutrophil recovery by 28 days after CBT was constructed using machine learning techniques; however, identification of significant risk factors was insufficient for outcome prediction for an individual patient, which is necessary for improving therapeutic outcomes. Notably, the prediction accuracy for post-transplantation D14, D28, and D42 decreased, and the model became more complex with more associated factors with increased time after transplantation.

Utility of allogeneic stem cell transplantation for adult Ph+ALL with complete molecular remission.

This study aimed to investigate the usefulness of allogeneic stem cell transplantation (allo-SCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in the first complete remission (CR1) with complete molecular remission (CMR). We compared the outcomes between Ph+ALL patients who did or did not undergo allo-SCT in CR1. We included patients enrolled in the prospective clinical studies in the tyrosine kinase inhibitor era conducted by the Japan Adult Leukemia Study Group, who achieved CMR within 3 months. A total of 147 patients (allo-SCT: 101; non-SCT: 46) were eligible for this analysis. In the multivariate analyses, allo-SCT was significantly associated with both superior overall survival (OS) (adjusted hazard ratio (aHR): 0.54; 95% CI: 0.30-0.97; p = .04) and relapse-free survival (RFS) (aHR: 0.21; 95% CI: 0.12-0.38; p < .001). The 5-year adjusted OS and RFS were 73% and 70% in the allo-SCT cohort, whereas they were 50% and 20% in the non-SCT cohort. Despite the higher non-relapse mortality (aHR: 3.49; 95% CI: 1.17-10.4; p = .03), allo-SCT was significantly associated with a lower relapse rate (aHR: 0.10; 95% CI: 0.05-0.20; p < .001). In addition, allo-SCT was also associated with superior graft-versus-host disease-free, relapse-free survival (aHR: 0.43; 95% CI: 0.25-0.74; p = .002). Propensity score-matched analyses confirmed the results of the multivariate analyses. In patients who achieved CMR within 3 months, allo-SCT in CR1 had superior survival and lower relapse compared with the non-SCT cohort.

Comparison of Melphalan Dose in Patients with Myelodysplastic Syndrome Undergoing Allogeneic Transplantation with Reduced-Intensity Conditioning.

The present study compared lower-dose melphalan (80 mg/m2, FM80) and higher-dose melphalan (140 mg/m2, FM140) when administering reduced-intensity conditioning with fludarabine in adult patients with myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We retrospectively analyzed nationwide registry data (2006 to 2019) and compared transplant outcomes between the 2 groups. Ninety-two patients (median age, 61 [interquartile range, 56 to 65] years) were assigned to the FM80 and FM140 groups by propensity score matching. The 3-year overall survival (OS) rate in the FM140 group (63.9%; 95% confidence interval [CI], 52.9% to 73.0%) was significantly higher than that in the FM80 group (54.2%; 95% CI, 37.1% to 52.1%) (P = .038). The FM140 group had a nonsignificantly (P = .095) lower 3-year cumulative incidence of relapse (15.5%; 95% CI, 8.9% to 23.8% versus 26.0%; 95% CI, 17.3% to 35.5%). The 3-year cumulative incidences of nonrelapse mortality were 22.3% (95% CI, 14.1% to 31.8%) and 23.7% (95% CI, 15.4% to 33.2%) in the FM80 and FM140 groups, respectively (P = .49). The beneficial effect of FM140 was more evident in patients with a poor cytogenetic risk. Our findings suggest the superiority of FM140 in patients with MDS undergoing allo-HSCT, especially in high-risk patients.

Impact of Different Fludarabine Doses in the Fludarabine-Based Conditioning Regimen for Unrelated Bone Marrow Transplantation.

The purine analog fludarabine (Flu) plays a central role in reduced-intensity conditioning and myeloablative reduced-toxicity conditioning regimens because of limited nonhematologic toxicities. Few reports assess the impact of different dose of Flu on the clinical outcomes and the Flu doses vary across reports. To compare the effect of Flu dose, the clinical outcomes of patients who received Flu and busulfan (FB; n = 1647) or melphalan (Flu with melphalan (FM); n = 1162) conditioning for unrelated bone marrow transplantation were retrospectively analyzed using Japanese nationwide registry data. In the FB group, high-dose Flu (180 mg/m2; HFB) and low-dose Flu (150/125 mg/m2; LFB) were given to 1334 and 313 patients, respectively. The 3-year overall survival (OS) rates were significantly higher in the HFB group than in the LFB group (49.5% versus 39.2%, P < .001). In the HFB and LFB groups, the cumulative incidences were 30.4% and 36.6% (P = .058) for 3-year relapse and 25.1% and 28.1% (P = .24) for 3-year nonrelapse mortality (NRM), respectively. In the multivariate analysis for OS and relapse, Flu dose was identified as an independent prognostic factor (hazard ratio: 0.83, P = .03; hazard ratio: 0.80, P = .043). In the FM group, high-dose Flu (180 mg/m2; HFM) and low-dose Flu (150/125 mg/m2; LFM) were given to 118 and 1044 patients, respectively. The OS, relapse, and NRM after 3 years did not differ significantly between the HFM and LFM groups (48.3% versus 48.8%, P = .92; 23.7% versus 27.2%, P = .55; 31.9% versus 30.8%, P = .67). These findings suggest that high-dose Flu was associated with favorable outcomes in the FB group but not in the FM group.

First complete remission favours haploidentical haematopoietic stem cell transplantation with post-transplant cyclophosphamide over cord blood transplantation in acute lymphoblastic leukaemia.

To assess the benefits of HLA-haploidentical haematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) relative to those of umbilical cord blood (UCB) transplantation in acute lymphoblastic leukaemia (ALL), we analysed 1999 patients (PTCy-haplo, 330; UCB, 1669), using the nationwide Japanese registry. PTCy-haplo was associated with a significantly higher relapse rate, but lower non-relapse mortality, which results in overall survival and disease-free survival, comparable to those of UCB. Among patients in CR1, PTCy-haplo showed a significantly higher survival than UCB regardless of the CD34+ cell dose. Our findings provide valuable insights into the donor selection algorithm in allogeneic HSCT for adult patients with ALL.

Association of individual comorbidities with outcomes in allogeneic hematopoietic cell transplantation from unrelated adult donors versus unrelated cord blood: A study on behalf of the Donor/Source and Transplant Complications Working Groups of the Japanese Society for Transplantation and Cellular Therapy.

We retrospectively evaluated the effect of 17 individual comorbidities, defined by the hematopoietic cell transplantation (HCT)-specific comorbidity index, on non-relapse mortality (NRM) and overall survival (OS) in 9531 patients aged between 16 and 70 years who underwent their first allogeneic HCT from 8/8 and 7/8 allele-matched unrelated donors (8/8 and 7/8 MUDs) or single-unit unrelated cord blood (UCB) between 2011 and 2020 using data from a Japanese registry database. In the multivariate analysis, infection (adjusted hazard ratio [HR], 1.62, 95% confidence interval [CI], 1.33-1.99 for 8/8 and 7/8 MUDs; adjusted HR, 1.33, 95%CI, 1.12-1.58 for UCB) and moderate/severe hepatic comorbidity (adjusted HR, 1.57, 95%CI, 1.04-2.38 for 8/8 and 7/8 MUDs; adjusted HR, 1.53, 95%CI, 1.09-2.15 for UCB) had a significant impact on NRM in both donor groups. Cardiac comorbidity (adjusted HR, 1.40, 95%CI, 1.08-1.80), mild hepatic comorbidity (adjusted HR, 1.22, 95%CI, 1.01-1.48), rheumatologic comorbidity (adjusted HR, 1.67, 95%CI, 1.11-2.51), renal comorbidity (adjusted HR, 2.44, 95%CI, 1.46-4.09), and severe pulmonary comorbidity (adjusted HR, 1.40, 95%CI, 1.11-1.77) were significantly associated with an increased risk of NRM but only in UCB recipients. Renal comorbidity had the strongest impact on poor OS in both donor groups (adjusted HR, 1.73, 95%CI, 1.10-2.72 for 8/8 and 7/8 MUDs; adjusted HR, 2.24, 95%CI, 1.54-3.24 for UCB). Therefore, unrelated donor selection should be taken into consideration along with the presence of specific comorbidities, such as cardiac, rheumatologic, renal, mild hepatic, and severe pulmonary comorbidities.

Comparison of fludarabine-based conditioning regimens in adult cord blood transplantation for myeloid malignancy: A retrospective, registry-based study.

Fludarabine/busulfan and fludarabine/melphalan are viable options as conditioning regimens. However, the optimal fludarabine-based conditioning in cord blood transplantation (CBT) remains unclear. Therefore, this retrospective, registry-based study aimed to analyze the impact of five fludarabine-containing conditioning regimens on 1395 adult patients (median age, 61 years) with acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia who underwent their first CBT. Treatment outcomes of fludarabine combined with melphalan (100-140 mg/m2 ) and low-dose total body irradiation (TBI; FM140T); melphalan (80-99 mg/m2 ) and TBI (FM80T); busulfan (12.8 mg/kg) and melphalan (FB4M); busulfan (12.8 mg/kg) and TBI (FB4T); and busulfan (6.4 mg/kg) and TBI (FB2T) were compared. The 3-year survival rate was 67%, 53%, 44%, 36%, and 39%, respectively (p < .0001). The FM140T survival rate was the most favorable after adjusting for confounders, and the hazard ratios (vs. FM140T) for overall mortality were as follows: FM80T, 1.6 (95% confidence interval [CI], 1.2-2.2); FB4M, 2.1 (95% CI, 1.6-2.8); FB4T, 2.7 (95% CI, 2.0-3.7); and FB2T, 2.2 (95% CI, 1.6-3.1). The better survival observed with FM140T, regardless of the disease, disease risk, age, or transplant year, was attributed to the lower relapse rate and lower non-relapse mortality (NRM) associated with fewer infectious deaths. Conversely, FB4T was associated with a higher relapse rate and higher NRM. The findings indicate that the outcomes of CBT in myeloid malignancies were highly dependent on both the alkylating agent and its dose in combination with fludarabine. Therefore, compared with fludarabine/busulfan-based conditioning, FM140T may be the preferred regimen.

Development of an umbilical cord blood transplantation-specific nonrelapse mortality risk assessment score.

ABSTRACT: Higher rate of nonrelapse mortality (NRM) remains yet to be resolved in umbilical cord blood transplantation (UCBT). Considering that UCBT has some unique features compared with allogeneic hematopoietic cell transplantation from other graft sources, a UCBT-specific NRM risk assessment system is required. Thus, in this study, we sought to develop a UCBT-specific NRM Risk Assessment (CoBRA) score. Using a nationwide registry database, we retrospectively analyzed 4437 recipients who had received their first single-unit UCBT. Using the backward elimination method, we constructed the CoBRA score in a training cohort (n = 2687), which consisted of recipients age ≥55 years (score 2), hematopoietic cell transplantation-specific comorbidity index ≥3 (score 2), male recipient, graft-versus-host disease prophylaxis other than tacrolimus in combination with methotrexate, performance status (PS) 2 to 4, HLA allele mismatch ≥ 2, refined Disease Risk Index high risk, myeloablative conditioning, and CD34+ cell doses < 0.82 × 105/kg (score 1 in each). The recipients were categorized into 3 groups: low (0-4 points), intermediate (5-7 points), and high (8-11 points) groups according to the CoBRA score. In the validation cohort (n = 1750), the cumulative incidence of NRM at 2 years was 14.9%, 25.5%, and 47.1% (P < .001), and 2-year overall survival (OS) was 74.2%, 52.7%, and 26.3% (P < .001) in the low, intermediate, and high groups, respectively. In summary, the CoBRA score could predict the NRM risk as well as OS after UCBT. Further external validation will be needed to confirm the significance of the CoBRA score.

Pretransplantation Inflammatory and Nutritional Status in Elderly Allogeneic Hematopoietic Stem Cell Transplantation: Prognostic Value of C-Reactive Protein-to-Albumin Ratio.

There are no clear criteria for selecting elderly patients with hematologic malignancies eligible for allogeneic hematopoietic stem cell transplantation (HSCT). This study aimed to evaluate inflammatory and nutritional status biomarkers as prognostic indicators of allogeneic HSCT in elderly patients. We compared the prognostic effects of 4 representative pretransplantation biomarkers: C-reactive protein-to-albumin ratio (CAR), Glasgow Prognostic Score (GPS), prognostic nutritional index (PNI), and albumin-to-globulin ratio (AGR). A total of 143 patients age ≥60 years who underwent their first allogeneic HSCT for a hematologic malignancy were enrolled between 2010 and 2020 in our single-center cohort. The median patient age was 65 years (range, 60 to 72 years). Pretransplantation high CAR, high GPS, and low PNI scores were associated with poor overall survival (OS), but the AGR was not associated with OS. Among the 4 biomarkers, CAR stratified OS most significantly (P < .001). Multivariate analyses identified only high CAR as an independent prognostic factor associated with OS (hazard ratio [HR], 1.98; P = .031) and showed that a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score ≥3 also was associated with OS (HR, 2.04; P = .012). High CAR was correlated with poor performance status, male sex, and high Disease Risk Index, but not with high HCT-CI score. When the patients were stratified into 3 groups according to a composite risk assessment using CAR and HCT-CI, the 3-year OS decreased significantly with increasing scores (82.8%, 50.3%, and 27.0%, respectively; P < .0001). In conclusion, CAR is the most useful prognostic indicator among the inflammatory and nutritional status biomarkers for allogeneic HSCT in elderly patients. Inflammatory and nutritional status in the elderly may be important prognostic factors for allogeneic HSCT independent of HCT-CI score.

Outcomes of Cessation of Nucleos(t)ide Analog Administration on Hepatitis B Virus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation: A Nationwide Retrospective Study.

Monitoring of hepatitis B virus (HBV)-DNA and HBV-DNA-guided preemptive therapy using nucleos(t)ide analogs (NAs) are recommended to prevent the development of hepatitis due to HBV reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in recipients with resolved HBV infection. However, little is known about the appropriate duration of NA treatment and the effect of NA cessation on the recurrence of HBV reactivation. This study aimed to clarify the consequences of NA cessation in allo-HSCT recipients with resolved HBV infection who experienced HBV reactivation following transplantation. We retrospectively reviewed the clinical records of recipients with resolved HBV infection (hepatitis B surface antigen [HBsAg]-negative, anti-HBc-positive) before allo-HSCT who had been diagnosed with HBV reactivation (HBsAg-positive and/or HBV-DNA detectable) after allo-HSCT between January 2010 and December 2020. A total of 72 patients from 16 institutions were registered (median age, 60 years; age range, 27 to 73 years; 42 males and 30 females). The day of initial HBV reactivation ranged from day 10 to day 3034 after allo-HSCT (median, 513 days). Anti-HBs were lost in >80% of the patients at the time of HBV reactivation. All 72 patients received preemptive NAs, and no fatal HBV reactivation-related hepatitis was observed. HBV-DNA without hepatitis was continuously detected in 5 patients during the follow-up period. Administration of NAs was discontinued in 24 of 72 patients (33%) by physician decision. Second HBV reactivation occurred in 11 of the 24 patients (46%) in whom administration of NAs was discontinued. The duration of NA treatment did not differ significantly between patients with or without second HBV reactivation. The frequency of further HBV reactivation tended to be lower in patients with an anti-HBs titer of >10 mIU/mL at the time of NA cessation. Multiple reactivations of HBV after NA cessation was common in patients with HBV reactivation who underwent allo-HSCT despite the long duration of NAs. Careful monitoring of HBV-DNA is important even after the discontinuation of NAs in the case with HBV reactivation after allo-HSCT, because multiple reactivations could occur. Active immunization by HB vaccine might be effective for suppressing further HBV reactivation after cessation of NAs.

Single-unit unrelated cord blood transplantation versus HLA-matched sibling transplantation in adults with advanced myelodysplastic syndrome: A registry-based study from the adult MDS working group of the Japanese society for transplantation and cellular therapy.

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potential curative therapeutic modality for advanced myelodysplastic syndrome (MDS). Within HCT, the advancement of cord blood transplantation (CBT) procedures has resulted in a drastic expansion of CBT as a donor source for MDS. However, data comparing matched sibling donors (MSDs) HCT with CBT for advanced MDS, which was defined as refractory anemia with an excess of blasts (RAEB)-1 and RAEB-2 according to the World Health Organization classification at the time of HCT, have not been explored. We retrospectively compared survival and other posttransplant outcomes in 999 adult patients with advanced MDS after receiving allogeneic HCT in Japan between 2011 and 2020, using either MSD (n = 331) or single-unit unrelated cord blood (UCB) (n = 668). In the multivariate analysis, there were no significant differences in overall survival (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.90-1.34; P = 0.347), disease-free survival (HR, 1.01; 95% CI, 0.84-1.23; P = 0.845), relapse (HR, 0.88; 95% CI, 0.68-1.15; P = 0.370), or non-relapse mortality (HR, 1.15; 95% CI, 0.87-1.50; P = 0.310) between MSD recipients and UCB recipients. UCB was significantly associated with lower neutrophil (HR, 0.28; 95% CI, 0.24-0.33; P < 0.001) and lower platelet (HR, 0.29; 95% CI, 0.23-0.36; P < 0.001) recovery compared to MSD. UCB was significantly associated with a lower incidence of chronic graft-versus-host disease (GVHD) (HR, 0.57; 95% CI, 0.44-0.75; P < 0.001) and extensive chronic GVHD (HR, 0.46; 95% CI, 0.32-0.67; P < 0.001) compared to MSD. Similar results were observed after adjusting for differences between MSD and UCB recipients by propensity score matching analysis. Our study demonstrated that single CBT and MSD HCT had similar survival outcomes for adult patients with advanced MDS despite the lower hematopoietic recovery in CBT recipients and higher chronic GVHD in MSD recipients.