Associations between acute and chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is one of the major complications after allogeneic hematopoietic cell transplantation (allo-HCT). While various risk factors for chronic GVHD have been reported, limited data is available regarding the impact of acute GVHD on chronic GVHD. We examined the association between acute and chronic GVHD using a Japanese registry dataset. The landmark point was set at day 100 after allo-HCT and patients who died or relapsed before the landmark point were excluded. In total, 14618 and 6135 patients who underwent allo-HCT with bone marrow or peripheral blood (BM/PB) and umbilical cord blood (UCB) were analyzed. In the BM/PB cohort, the risk of chronic GVHD requiring systemic steroids increased with each increase within grade 0-II acute GVHD (Grade 0 vs. I: HR, 1.32, 95% CI, 1.19-1.46, P < 0.001; Grade I vs. II: HR, 1.41, 95% CI, 1.28-1.56, P < 0.001), but the risk was similar between grade II and III-IV acute GVHD (HR, 1.02; 95% CI, 0.91-1.15; P = 1.0). These findings were confirmed in the UCB cohort. We further observed that the risk of severe chronic GVHD increased with each increment in the grade of acute GVHD, even between Grades II and III-IV acute GVHD (Grade II vs. III-IV: HR, 1.70; 95% CI, 1.12-2.58; P = 0.025). In conclusion, the preceding profiles of acute GVHD should help to stratify the risk of chronic GVHD and its severity, which might be useful for the development of risk-adopted pre-emptive strategies for chronic GVHD.

Real-World Outcomes of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation in Japan: Retrospective Analysis of the Transplant Registry Unified Management Program Registry.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapeutic option for patients with hematologic malignancies. However, the development of graft-versus-host disease (GVHD) after allo-HSCT remains a challenge. Although systemic steroid therapy is the established first-line therapy for acute GVHD (aGVHD) and chronic GVHD (cGVHD), many patients are unresponsive or resistant to corticosteroid therapy, and the response is insufficient. This study aimed to evaluate the clinical characteristics of patients who developed aGVHD and cGVHD after allo-HSCT. This noninterventional, retrospective study used large national registry data from the Transplant Registry Unified Management Program. The study included 29,690 patients with a hematologic disease who underwent their first allo-HSCT between January 2010 and December 2019. The primary study endpoints were the cumulative incidence of aGVHD and cGVHD. The secondary endpoints were overall survival (OS) and nonrelapse mortality (NRM) of patients with aGVHD and cGVHD and OS and NRM of patients who received second-line therapy for aGVHD. Of 29,690 patients who underwent allo-HSCT, the graft source was related bone marrow (RBM) in 2807, related peripheral blood (RPB) in 6167, unrelated bone marrow in 10,556, unrelated peripheral blood (UPB) in 774, and unrelated cord blood in 9339. The cumulative incidence of grade II-IV aGVHD at 100 days was high after the related and unrelated mismatched transplantation. The response rates for first- and second-line therapy for aGVHD were low in the RBM/RPB-mismatched (59.6%/61.6%) and UPB-mismatched subgroups (45.5%), respectively. The 3-year NRM in patients with aGVHD was high in the RPB and UPB mismatched subgroups (37.9% and 31.2%, respectively). Developing a novel treatment for steroid-refractory aGVHD is necessary to improve transplantation outcomes, particularly for patients undergoing HLA-mismatched allo-HSCT.

Individual HLAs affect survival after allogeneic stem cell transplantation in adult T-cell leukaemia/lymphoma.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for adult T-cell leukaemia/lymphoma (ATL). Specific HLAs are associated with outcomes of immunotherapy and allo-HSCT. We hypothesised that individual HLAs would affect the clinical outcomes of ATL patients after allo-HSCT. Using data from a Japanese registry, we retrospectively analysed 829 patients with ATL who received transplants from HLA-identical sibling donors or HLA-A, -B, -C or -DRB1 allele-matched unrelated donors between 1996 and 2015. We evaluated the overall mortality risk of HLA-A, -B and -DR antigens with frequencies exceeding 3%. Outcomes were compared between transplants with or without specific HLA antigens. Of the 25 HLAs, two candidates were identified but showed no statistically significant differences by multiple comparison. HLA-B62 was associated with a lower risk of mortality (hazard ratio [HR], 0.68; 95% confidence interval [CI]: 0.51-0.90; p = 0.008), whereas HLA-B60 was associated with a higher risk of mortality (HR, 1.64; 95% CI: 1.19-2.27; p = 0.003). In addition, HLA-B62 was associated with a lower risk of transplant-related mortality (TRM) (HR, 0.52; 95% CI: 0.32-0.85, p = 0.009), whereas HLA-B60 was associated with a higher risk of grades III-IV acute graft-versus-host disease (HR, 2.63; 95% CI: 1.62-4.27; p < 0.001). Neither HLA influenced relapse. The higher risk of acute GVHD in HLA-B60-positive patients and the lower risk of TRM in HLA-B62-positive patients were consistent with previously obtained results from patients with other haematological malignancies. Consideration of HLA in ATL patients may help to predict risk and outcomes after allo-HSCT.

Trends in allogeneic hematopoietic cell transplantation survival using population-based descriptive epidemiology method: analysis of national transplant registry data.

Prognosis for patients undergoing hematopoietic cell transplantation (HCT) has been improving. Short-term survival information, such as crude survival rates that consider deaths immediately after the transplantation, may not be sufficiently useful for assessing long-term survival. Using the data of the Japanese HCT registry, the net survival rate of patients who survived for a given period was determined according to age, disease, and type of transplant. We included a total of 41,716 patients who received their first allogeneic hematopoietic cell transplantation between 1991 and 2015. For each disease, age group, graft source subcategory, net survival was calculated using the Pohar-Perme method, and 5-year conditional net survival (CS) was calculated. Ten-year net survivals of total patient cohort were 41.5% and 47.4% for males and females, respectively. Except for myelodysplastic syndrome, multiple myeloma, and adult T-cell leukemia/lymphoma, 5-year CS for 5-year transplant survivors exceeded 90%. CS was especially high for aplastic anemia, of which was over 100% for children and younger adults receiving cord blood, suggesting that these patients have similar longevity to an equivalent group from the general population. These findings provide useful information for long-term survival, and can serve as benchmark for comparisons among registries, including other cancers.

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.

Do oral conditions influence the incidence of bloodstream infection after hematopoietic stem cell transplantation? A retrospective study in Japan.

PURPOSE: This study aimed to evaluate the incidence of bloodstream infection (BSI) among patients undergoing hematopoietic stem cell transplantation (HSCT) for teeth indicated for extraction. METHODS: Patients who underwent HSCT at Toranomon Hospital (Tokyo, Japan) between January 2017 and December 2019 were retrospectively evaluated. The incidence of BSI among patients with teeth indicated for extraction who did not undergo extraction (oral high-risk group) and patients who did not have this risk (oral low-risk group) was compared. RESULTS: Among the 191 consecutive patients included in this study, 119 patients were classified as undergoing high-risk transplantation. BSI after HSCT was observed in 32 out of 60 (53.3%) patients and 56 out of 131 (42.7%) patients in the oral low-risk and oral high-risk groups, respectively (p = 0.173). Multivariable analyses revealed that the presence of > 3 teeth as intraoral sources of infection and age over 50 years were determinants of BSI originating from the oral cavity after engraftment (odds ratio [OR], 9.11; 95% confidential interval [CI] 2.27-36.61]; p = 0.002; OR, 3.22; CI [1.47-7.08], p = 0.004, respectively). CONCLUSION: In patients undergoing HSCT, the presence of less than three intraoral sources of infection did not affect the incidence of BSI after HSCT.

Significance of absolute neutrophil count before allogeneic hematopoietic stem cell transplantation in adult patients with aplastic anemia.

The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1-199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) ("ANC ≥ 200": 80.3% vs. "ANC 1-199": 71.7% vs. "ANC 0": 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation.

Prognostic impact of the conditioning intensity on outcomes after allogeneic transplantation for MDS with low blasts: a nationwide retrospective study by the adult MDS working group of the Japan Society for Transplantation and Cellular Therapy.

Poor prognostic factors, such as transfusion dependency and chromosomal risk, need to be considered in the indication of allogeneic hematopoietic cell transplantation (allo-HCT) for patients harboring myelodysplastic syndromes with less than 5% marrow blasts (MDS-Lo). We analyzed the post-transplant outcomes of 1229 MDS-Lo patients who received myeloablative (MAC)(n = 651), reduced-intensity (RIC)(n = 397), and non-myeloablative conditioning (NMAC) regimens (n = 181). The multivariate analysis revealed that the RIC group had better chronic graft-versus-host disease (GVHD)- and relapse-free survival (CRFS) (P = 0.021), and GVHD- and relapse-free survival (GRFS) than the MAC group (P = 0.001), while no significant differences were observed between the NMAC and MAC groups. In the subgroup analysis, the MAC group has better overall survival (P = 0.008) than the RIC group among patients with an HCT-comorbidity index (HCT-CI) score of 0, while the RIC group had better overall survival (P = 0.029) than the MAC group among those with an HCT-CI score ≥3. According to the type of conditioning regimen, total body irradiation 12 Gy-based MAC regimen showed better OS and CRFS than the other MAC regimen, and comparable outcomes to the RIC regimen. In conclusion, the RIC and NMAC regimens are promising options for MDS-Lo patients in addition to the MAC regimen.

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.

[Fulminant Clostridioides difficile infection during treatment with FLT3 inhibitor for acute myeloid leukemia].

An 80-year-old man with FLT3-TKD mutation-positive acute myeloid leukemia (AML) relapsed during consolidation therapy with venetoclax/azacitidine and was started on gilteritinib as salvage therapy. On the day after treatment initiation, febrile neutropenia was observed, but the fever resolved promptly after initiation of antimicrobial therapy. On the fifth day after completion of antimicrobial therapy, the patient experienced fever and watery diarrhea over 10 times a day, and a diagnosis of Clostridioides difficile infection (CDI) was made based on stool examination. The patient was treated with intravenous metronidazole, but renal dysfunction, hypotension, and hypoxemia developed, and a CT scan showed pleural and intraperitoneal effusion, significant intestinal wall thickening, and intestinal dilatation. Fidaxomicin was started under general monitoring in the intensive care unit and response was achieved. The patient was discharged from the intensive care unit on the 18th day after the onset of CDI. We report this case not only due to the rarity of fulminant CDI during AML treatment, but also because it is a valuable example of effective treatment of fulminant CDI with fidaxomicin.

Lymphocyte Crossmatch Testing or Donor HLA-DP and -DQ Allele Typing Effectiveness in Single Cord Blood Transplantation for Patients With Anti-HLA Antibodies Other Than Against HLA-A, -B, -C, and -DRB1.

Anti-human leukocyte antigen (HLA) antibodies other than those against HLA-A, -B, -C, and DRB1 are a risk factor for engraftment delay and failure, especially in cord blood transplantation (CBT). The primary objective of this study was to assess the impact of the presence of anti-HLA antibodies on CBT and to evaluate the utility of lymphocyte crossmatch testing or additional HLA-DP and -DQ typing of CB units in improving transplant outcomes. We retrospectively assessed the engraftment rates and transplant outcomes of 772 patients who underwent their first CBT at our hospital between 2012 and 2021. Donors were routinely typed for HLA-A, -B, -C, and-DRB1 alleles, and the anti-HLA antibodies of recipients were screened before donor selection in all cases. Among patients who had antibodies against other than HLA-A, -B, -C, and DRB1 (n = 58), lymphocyte crossmatch testing (n = 32) or additional HLA-DP/-DQ alleles typing of CB (n = 15) was performed to avoid the use of units with corresponding alleles. The median patient age was 57 years (16 to 77). Overall, 75.7% had a high-risk disease status at transplantation, 83.5% received myeloablative conditioning regimens, and >80% were heavily transfused. Two hundred twenty-nine of the 772 recipients (29.6%) were positive for anti-HLA antibodies. There were no statistical differences in the number of infused CD34-positive cells between the anti-HLA antibody-positive and the anti-HLA antibody-negative patients. Of the 229 patients with anti-HLA antibodies, 168 (73.3%) had antibodies against HLA-A, -B, -C, and-DRB1 (Group A), whereas 58 (25.3%) had antibodies against HLA-DP, HLA-DQ, or -DRB3/4/5 with or without antibodies against HLA-A, -B, -C, and -DRB1 (Group B). No patients in both Groups A and B exhibited donor-specific anti-HLA antibodies against HLA-A, -B, -C, and -DRB1. The neutrophil engraftment rate was lower in patients with anti-HLA antibodies than in those without antibodies (89.9% versus 94.1%), whereas nonrelapse mortality (NRM) before engraftment was higher in antibody-positive patients (9.6% versus 4.9%). In patients who received 2 or more HLA allele-mismatched CB in the host-versus-graft (HVG) direction (n = 685), the neutrophil engraftment rate was lower in the anti-HLA antibody-positive recipients than in the antibody-negative recipients with significant differences (88.8% versus 93.8%) (P = .049). Similarly, transplant outcomes were worse in the antibody-positive patients with respect to 2-year overall survival (OS) (43.1% versus 52.3%) and NRM (44.0% versus 30.7%) than in the antibody-negative patients. In contrast, the results of Group B were comparable to those of the antibody-negative patients, while those of Group A were statistically worse than the antibody-negative patients in terms of all engraftment rate (88.6%), OS (34.2%), and NRM (49.0%). The presence of anti-HLA antibodies negatively impacts engraftment, NRM, and OS in CBT. However, HLA-DP/-DQ allele typing of CB units or lymphocyte crossmatch testing could be a useful strategy to overcome poor engraftment rates and transplant outcomes, especially in patients with anti-HLA antibodies against HLA-DP, HLA-DQ, or -DRB3/4/5.

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.

Fatal outcome of BK virus encephalitis in an allogeneic stem cell transplantation recipient.

BK virus (BKV) encephalitis is a rare complication after hematopoietic stem cell transplantation (HSCT). A 43-year-old woman with recurrent follicular lymphoma after autologous HSCT received allogeneic bone marrow transplantation from a human leukocyte antigen-matched related donor. Neutrophil engraftment was achieved on post-transplant day 13. Memory loss and noncooperative attitude toward the medical staff were observed on day 16, and her mental status worsened progressively. Magnetic resonance imaging (MRI) showed nonspecific findings on day 19; however, cerebrospinal fluid (CSF) analysis including real-time polymerase chain reaction on day 20 revealed elevated levels of BKV 4.67 × 104 copy/mL. BKV encephalitis was diagnosed based on CSF findings, intravenous administration of immunoglobulin and cidofovir was started, and the immunosuppressive agent dose was reduced. Diffusion-weighted MRI on day 28 showed signal abnormalities in the bilateral periventricular white matter. Although the follow-up CSF analysis on day 35 was negative for BKV, her mental status and MRI findings did not improve, and she died on day 55 because of respiratory failure. This case emphasizes the importance of considering BKV encephalitis as a differential diagnosis of post-transplant encephalitis, considering the central nervous system-associated immune reconstitution inflammatory syndrome in patients with worsening central nervous system findings after eradication of BKV in the CSF.

Ponatinib-Related Vasospastic Angina.

Tyrosine kinase inhibitors (TKIs) are essential drugs for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Cardiovascular or arteriothrombotic adverse events have been reported in patients treated with TKIs. We report 3 cases of Ponatinib-related vasospastic angina, in which prophylactic administration of nitrates or calcium channel blockers was effective.

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.

Long-term lymphocyte subset number reconstitution is unique but comparable between umbilical cord blood and unrelated bone marrow transplantation.

The number of umbilical cord blood transplantation (U-CBT) procedures has been growing annually, but little research has been done on long-term immune recovery after U-CBT. Infection risk is high in U-CBT recipients, and this can be partially attributed to immature immunocompetent cells in umbilical cord blood. In this study, we analyzed lymphocyte subset (LST) number to determine the long-term recovery timeline. We included 36 U-CBT and 10 unrelated bone marrow transplantation (U-BMT) recipients who survived more than 2 years after transplantation, and followed them for up to 10 years post-transplant. Recovery kinetics in the early phase post-transplant was different for each LST. Recovery of CD19+ B cells was faster after U-CBT than after U-BMT in the first 5 years after transplantation. Although CD4+ T cells increased in the first several months after U-CBT, long-term cell count recovery was impaired in approximately 20% of patients. Thus, although the LST recovery pattern after U-CBT was unique, LST number recovery was statistically comparable between U-CBT and U-BMT past 5 years post-transplantation.

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.

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.

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.