Collection and analysis of information on diseases and post-transplant courses of allogeneic hematopoietic stem cell transplant recipients have played important roles in improving therapeutic ...outcomes in hematopoietic stem cell transplantation. Efficient, high-quality data collection systems are essential. The introduction of the Second-Generation Transplant Registry Unified Management Program (TRUMP2) is intended to improve data quality and more efficient data management. The TRUMP2 system will also expand possible uses of data, as it is capable of building a more complex relational database. The construction of an accessible data utilization system for adequate data utilization by researchers would promote greater research activity. Study approval and management processes and authorship guidelines also need to be organized within this context. Quality control of processes for data manipulation and analysis will also affect study outcomes. Shared scripts have been introduced to define variables according to standard definitions for quality control and improving efficiency of registry studies using TRUMP data.
Genetic alterations, including mutations and copy-number alterations, are central to the pathogenesis of myelodysplastic syndromes and related diseases (myelodysplasia), but their roles in allogeneic ...stem cell transplantation have not fully been studied in a large cohort of patients. We enrolled 797 patients who had been diagnosed with myelodysplasia at initial presentation and received transplantation via the Japan Marrow Donor Program. Targeted-capture sequencing was performed to identify mutations in 69 genes, together with copy-number alterations, whose effects on transplantation outcomes were investigated. We identified 1776 mutations and 927 abnormal copy segments among 617 patients (77.4%). In multivariate modeling using Cox proportional-hazards regression, genetic factors explained 30% of the total hazards for overall survival; clinical characteristics accounted for 70% of risk. TP53 and RAS-pathway mutations, together with complex karyotype (CK) as detected by conventional cytogenetics and/or sequencing-based analysis, negatively affected posttransplant survival independently of clinical factors. Regardless of disease subtype, TP53-mutated patients with CK were characterized by unique genetic features and associated with an extremely poor survival with frequent early relapse, whereas outcomes were substantially better in TP53-mutated patients without CK. By contrast, the effects of RAS-pathway mutations depended on disease subtype and were confined to myelodysplastic/myeloproliferative neoplasms (MDS/MPNs). Our results suggest that TP53 and RAS-pathway mutations predicted a dismal prognosis, when associated with CK and MDS/MPNs, respectively. However, for patients with mutated TP53 or CK alone, long-term survival could be obtained with transplantation. Clinical sequencing provides vital information for accurate prognostication in transplantation.
•TP53 and RAS-pathway mutations predict very poor survival, when seen with CK and MDS/MPNs, respectively.•For patients with mutated TP53 or CK alone, long-term survival could be obtained with stem cell transplantation.
The Worldwide Network of Blood and Marrow Transplantation (WBMT) pursues the mission of promoting hematopoietic cell transplantation (HCT) for instance by evaluating activities through member ...societies, national registries and individual centers. In 2016, 82,718 first HCT were reported by 1,662 HCT teams in 86 of the 195 World Health Organization member states representing a global increase of 6.2% in autologous HCT and 7.0% in allogeneic HCT and bringing the total to 1,298,897 procedures. Assuming a frequency of 84,000/year, 1.5 million HCT were performed by 2019 since 1957. Slightly more autologous (53.5%) than allogeneic and more related (53.6%) than unrelated HCT were reported. A remarkable increase was noted in haploidentical related HCT for leukemias and lymphoproliferative diseases, but even more in non-malignant diseases. Transplant rates (TR; HCT/10 million population) varied according to region reaching 560.8 in North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in South East Asia/Western Pacific (SEA/WPR) and 27.8 in African/East Mediterranean (AFR/EMR). Interestingly, haploidentical TR amounted to 32% in SEA/WPR and 26% in Latin America, but only 14% in Europe and EMR and 4.9% in North America of all allogeneic HCT. HCT team density (teams/10 million population) was highest in Europe (7.7) followed by North America (6.0), SEA/WPR (1.9), Latin America (1.6) and AFR/EMR (0.4). HCT are increasing steadily worldwide with narrowing gaps between regions and greater increase in allogeneic compared to autologous activity. While related HCT is rising, largely due to increase in haploidentical HCT, unrelated HCT is plateauing and cord blood HCT is in decline.
Abstract
Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, ...diphosphatase NUDT15 was linked to thiopurine metabolism with
NUDT15
polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with
NUDT15
genotype (
P
= 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (
P
= 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and
NUDT15
variation contributes to inter-patient variability in their therapeutic effects.
Purpose
Hematopoietic cell transplantation (HCT) is a curative therapy for patients with severe combined immunodeficiency (SCID). Here, we conducted a nationwide study to assess the outcome of SCID ...patients after HCT in Japan.
Methods
A cohort of 181 SCID patients undergoing their first allogeneic HCT in 1974–2016 was studied by using the Japanese national database (Transplant Registry Unified Management Program, TRUMP).
Results
The 10-year overall survival (OS) of the patients who received HCT in 2006–2016 was 67%. Umbilical cord blood (UCB) transplantation was performed in 81 patients (45%). The outcomes of HCT from HLA-matched UCB (
n
= 21) and matched sibling donors (
n
= 22) were comparable, including 10-year OS (91% vs. 91%), neutrophil recovery (cumulative incidence at 30 days, 89% vs. 100%), and platelet recovery (cumulative incidence at 60 days, 89% vs. 100%). Multivariate analysis of the patients who received HCT in 2006–2016 demonstrated that the following factors were associated with poor OS: bacterial or fungal infection at HCT (hazard ratio (HR): 3.8,
P
= 0.006), cytomegalovirus infection prior to HCT (HR: 9.4,
P
= 0.03), ≥ 4 months of age at HCT (HR: 25.5,
P
= 0.009), and mismatched UCB (HR: 19.8,
P
= 0.01).
Conclusion
We showed the potential of HLA-matched UCB as a donor source with higher priority for SCID patients. We also demonstrated that early age at HCT without active infection is critical for a better prognosis, highlighting the importance of newborn screening for SCID.
The impact of acute and chronic graft-versus-host disease (GVHD) on clinical outcomes was retrospectively analyzed in 960 patients with non-malignant diseases (NMD) who underwent a first allogeneic ...hematopoietic stem cell transplantation (HSCT). Grade III–IV acute GVHD (but not grade I–II) was significantly associated with a lower rate of overall survival (OS), and higher non-relapse mortality (NRM) than that seen in patients without acute GVHD. Extensive (but not limited) GVHD was significantly associated with a lower OS rate and higher NRM than that seen in patients without chronic GVHD. Any grade of acute (but not chronic) GVHD was significantly associated with a lower incidence of relapse and a lower proportion of patients requiring a second HSCT or donor lymphocyte infusion for graft failure or mixed chimerism, but its impact on OS was almost negligible. Acute GVHD was significantly associated with lower OS rates in all disease groups, whereas chronic GVHD was significantly associated with lower OS rates in the primary immunodeficiency and histiocytosis groups. In conclusion, acute and chronic GVHD, even if mild, was associated with reduced OS in patients receiving HSCT for NMD and effective strategies should, therefore, be implemented to minimize GVHD.
Intravascular large B-cell lymphoma (IVLBCL) is a unique type of extranodal lymphoma characterized by selective growth of tumor cells in small vessels without lymphadenopathy. Greater understanding ...of the molecular pathogenesis of IVLBCL is hampered by the paucity of lymphoma cells in biopsy specimens, creating a limitation in obtaining sufficient tumor materials. To uncover the genetic landscape of IVLBCL, we performed whole-exome sequencing (WES) of 21 patients with IVLBCL using plasma-derived cell-free DNA (cfDNA) (n = 18), patient-derived xenograft tumors (n = 4), and tumor DNA from bone marrow (BM) mononuclear cells (n = 2). The concentration of cfDNA in IVLBCL was significantly higher than that in diffuse large B-cell lymphoma (DLBCL) (P < .0001) and healthy donors (P = .0053), allowing us to perform WES; most mutations detected in BM tumor DNA were successfully captured in cfDNA and xenograft. IVLBCL showed a high frequency of genetic lesions characteristic of activated B-cell–type DLBCL, with the former showing conspicuously higher frequencies (compared with nodal DLBCL) of mutations in MYD88 (57%), CD79B (67%), SETD1B (57%), and HLA-B (57%). We also found that 8 IVLBCL (38%) harbored rearrangements of programmed cell death 1 ligand 1 and 2 (PD-L1/PD-L2) involving the 3′ untranslated region; such rearrangements are implicated in immune evasion via PD-L1/PD-L2 overexpression. Our data demonstrate the utility of cfDNA and imply important roles for immune evasion in IVLBCL pathogenesis and PD-1/PD-L1/PD-L2 blockade in therapeutics for IVLBCL.
•Genetic alterations in immune checkpoint–related genes are frequent in IVLBCL.•Plasma cfDNA is an alternative tumor DNA source of IVLBCL to detect genetic alterations by comprehensive analyses.
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Graft failure (GF) remains a major complication of cord blood transplantation (CBT). Although the presence of pretransplant, donor-specific anti-HLA antibodies (DSA) was reported to be associated ...with an increased risk of GF after CBT, data are still limited. Thus, we conducted a retrospective analysis of recipients of single-unit CBT with pretransplant anti-HLA antibodies using the database of Japan Society for Hematopoietic Cell Transplantation (JSHCT). Data for recipients of single-unit CBT with pretransplant anti-HLA antibodies from 2010 to 2014 were obtained. In total, 343 patients who received CBT and who had detailed information about anti-HLA antibodies were included. The median age was 51 years (range, 0-71). Regarding DSA, 25 patients had a mean fluorescence intensity (MFI) ≥ 1000 (DSA-positive group) and 318 patients had a MFI <1000 (DSA-negative group). The cumulative incidence of neutrophil engraftment at 60 days after CBT was 75.7% (95% CI, 70.6-80.1) in the DSA-negative group and 56.0% (95% CI, 34.1-73.1) in the DSA-positive group (P = 0.03). In conclusion, pretransplant DSA with a MFI ≥ 1000 was associated with an increased risk of GF in single-unit CBT.
Cytogenetic abnormalities are a major risk factor for relapse after hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS). We aimed to evaluate the value of the five-group ...cytogenetic classification according to the revised International Prognostic Scoring System (R-IPSS) for predicting the outcome after HSCT in pediatric patients with MDS. We retrospectively analyzed the Japanese registration data of 242 pediatric patients with MDS. According to the R-IPSS classification, 112 (45.5%) patients had good, 55 (22.7%) had intermediate, 64 (26.4%) had poor, and 11 (4.6%) had very poor cytogenetics. The 5-year overall survival (5yOS) was 72%, 69%, 59%, and 30% in the good, intermediate, poor, and very poor cytogenetic subgroups (p = 0.026), respectively. The very good, good, and intermediate subgroups were grouped into a "standard" subgroup and reclassified into three subgroups (standard, poor, and very poor). Patients with very poor risk had worse 5yOS (hazard ratio 2.17, 95% confidence interval (CI) 1.02-4.61; p = 0.04) and a much higher 5yCIR (hazard ratio 2.52, 95% CI 1.05-6.04; p = 0.04) than those of patients in the standard group in the multivariate analysis, indicating that very poor risk cytogenetic characteristics independently predicted worse outcome after HSCT in pediatric patients with MDS.
Tyrosine kinase inhibitor (TKI) administration after allogeneic hematopoietic stem cell transplantation (HSCT) may carry a survival benefit in Philadelphia chromosome‐positive acute lymphoblastic ...leukemia (Ph+ ALL). Therefore, we investigated whether TKI prophylaxis for negative‐minimal residual disease (MRD) after HSCT would improve patient outcomes in this nationwide retrospective cohort study. We included patients with Ph+ ALL who underwent their first allogeneic HSCT between 2001 and 2016, received TKI before HSCT, and achieved negative‐MRD status within 180 days after HSCT. Of 850 patients for inclusion, 50 patients received TKI prophylaxis, mostly imatinib or dasatinib (median dose: 400 mg with imatinib and 40 mg with dasatinib). In a multivariate analysis, disease status at HSCT was the sole risk factor for relapse (hazard ratio, 3.58; P < .001 for positive‐MRD with complete remission CR and hazard ratio, 6.13; P < .001 for active disease). TKI prophylaxis was not associated with a decreased risk of relapse or superior overall survival in either the whole cohort or in the analysis limited to negative‐MRD or positive‐MRD with CR1 at HSCT. Meanwhile, TKI prophylaxis limited to dasatinib might be associated with a decreased risk of relapse (hazard ratio, 0.34; P = .140), unlike imatinib. Alternative strategies using new‐generation TKI for high‐risk patients are warranted to improve the outcomes after allogeneic HSCT.
Tyrosine kinase inhibitor prophylaxis was not associated with a decreased risk of relapse or superior overall survival despite MRD positivity at HSCT. Disease status at HSCT was a significant risk factor for relapse even in patients who achieved negative‐MRD early after HSCT.
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