A higher CD34 + cell dose correlates with better event-free survival after KIR-ligand mismatched cord blood transplantation for childhood acute myeloid leukemia.

Although killer Ig-like receptor ligands (KIR-L) mismatch has been associated with alloreactive natural killer cell activity and potent graft-versus-leukemia (GVL) effect among adults with acute myeloid leukemia (AML), its role among children with AML receiving cord blood transplantation (CBT) has not been determined. We conducted a retrospective study using a nationwide registry of the Japanese Society for Transplantation and Cellular Therapy. Patients who were diagnosed with de novo non-M3 AML and who underwent their first CBT in remission between 2000 and 2021 at under 16 years old were included. A total of 299 patients were included; 238 patients were in the KIR-L match group, and 61 patients were in the KIR-L mismatch group. The cumulative incidence rates of neutrophil recovery, platelet engraftment, and acute/chronic graft-versus-host disease did not differ significantly between the groups. The 5-year event-free survival (EFS) rate was 69.8% in the KIR-L match group and 74.0% in the KIR-L mismatch group (p = 0.490). Stratification by CD34 + cell dose into four groups revealed a significant correlation between CD34 + cell dose and EFS in the KIR-L mismatch group (p = 0.006) but not in the KIR-L match group (p = 0.325). According to our multivariate analysis, KIR-L mismatch with a high CD34 + cell dose (≥ median dose) was identified as an independent favorable prognostic factor for EFS (hazard ratio = 0.19, p = 0.029) and for the cumulative incidence of relapse (hazard ratio = 0.09, p = 0.021). Our results suggested that higher CD34 + cell doses are crucial for achieving a potent GVL effect in the context of KIR-L-mismatched CBT.

Reduced-intensity allogenic transplantation for children and adolescents with Philadelphia chromosome-positive acute lymphoblastic leukemia.

Survival rates of patients with Philadelphia chromosome-positive ALL (Ph+ALL) have improved considerably with the introduction of tyrosine kinase inhibitors (TKI); however, hematopoietic stem cell transplantation (HSCT) continues to play an important role. Reduced-intensity conditioning (RIC) regimens have been widely applied particularly for older patients, but their validity for children and adolescents with Ph+ALL has not been investigated. In this study, data from patients receiving HSCT for de novo Ph+ALL in first or second remission at ages younger than 25 years and with a history of pre-HSCT TKI therapy were retrospectively collected through the nationwide registry in Japan. In 265 patients who received myeloablative conditioning (MAC) and 33 patients receiving RIC, 5-year leukemia-free survival (LFS) rates were 67.3% and 79.8%, respectively (p = 0.142). Multivariate analysis of LFS, focusing on patients with good performance status, identified RIC as a significant prognostic factor for LFS (hazard ratio 0.32, p = 0.032), as well as older age, higher leukocyte count at diagnosis, and disease with additional chromosomal abnormalities. These trends were similar when we focused on patients who received prophylactic post-HSCT TKI treatment, as 5-year LFS was 81.0% for MAC and 84.4% for RIC (p = 0.748). In summary, HSCT with RIC regimen showed at least comparable LFS to HSCT with MAC regimen, and RIC was an independent favorable prognostic factor on multivariate analysis adjusting potential prognostic factors. While patient numbers were limited, our data suggest that RIC may be safely applied in this group, particularly combined with prophylactic post-HSCT TKI maintenance therapy.

Factors associated with employment status among mothers of survivors of childhood cancer: a cross-sectional study.

PURPOSE: To identify the factors associated with employment status among mothers of childhood cancer survivors (CCSs). METHODS: We conducted a questionnaire survey on mothers of survivors of childhood cancer to clarify practical factors such as care demands, psychological factors such as motivation to work, and support. After calculating descriptive statistics for all variables, binary logistic regression analysis was performed. RESULTS: Of 171 mothers, 129 (75.4%) were employed. The most common form of employment was non-regular (n = 83; 48.5%), including part-time, dispatched, and fixed-term workers. At the time of the survey, compared with nonworking mothers, working mothers tended to be more motivated to work and have lower scores for "Long-term Uncertainty" on the Parent Experience of Child Illness Scale. The results of the binary logistic regression analysis indicated that employment was related to higher motivation to work, the continuation of employment during treatment, more outpatient visits, and a higher amount of support. CONCLUSION: As employment of CCSs' mothers is associated with psychological factors such as motivation to work and long-term uncertainty, psychological support for CCSs' mothers might promote employment. In addition, because the continuation of employment during treatment affects the employment of mothers after the end of cancer treatment, a leave system that covers the treatment period for childhood cancer needs to be established.

Haematopoietic cell transplantation for children with acute megakaryoblastic leukaemia without Down syndrome.

Patients with acute megakaryoblastic leukaemia of Down syndrome (DS-AMKL) have an excellent survival rate; however, patients with non-DS-AMKL experience poor outcomes. Therefore, this study retrospectively analysed 203 children with non-DS-AMKL who underwent their first haematopoietic cell transplantation (HCT) from 1986 to 2015 using a nationwide Japanese HCT registry data to assess HCT outcomes for non-DS-AMKL. The 5-year overall survival (OS) and event-free survival (EFS) rates were 43% and 38% respectively. The 5-year OS rate was significantly higher for patients who underwent HCT in the first complete remission (CR1, 72%) than for those in the second CR (CR2, 23%) and non-CR (16%) (p < 0.001), and for those from a human leukocyte antigen (HLA)-matched (52%) than for those from an HLA-mismatched donor (27%) (p < 0.001). Multivariate analysis for OS revealed that HCT in CR2 and non-CR was a significant risk factor (hazard ratio, 5.86; 95% confidence interval, 3.56-9.53; p < 0.001). The 3-year EFS in patients who received HCT in CR1 using reduced-intensity conditioning (RIC, 35%) was significantly lower than in those using myeloablative conditioning (busulfan-based, 71%; total body irradiation-based, 58%) (p < 0.001). Risk stratification in patients with non-DS-AMKL should be established to determine HCT indication in CR1.

Annular choroidal detachment following intravitreal aflibercept injection in a patient with nivolumab treatment: a case report.

BACKGROUND: To present a novel case that developed annular choroidal detachment after intravitreal anti-vascular endothelial growth factor antibody injection in a patient after immune checkpoint inhibitor treatment. CASE PRESENTATION: A 58-year-old Japanese man presented visual impairment in the right eye. Ophthalmological examination revealed macular edema in the right eye, which suggested the possibility of age-related macular degeneration. Following the intravitreal aflibercept injection, the annular choroidal detachment was observed in the injected eye. As hypotony or thick sclera was not observed, choroidal detachment seemed to have appeared due to enhanced inflammation by intravitreal injection. The patient had a history of stage IV paranasal cavity cancer and was treated with nivolumab, an immune checkpoint inhibitor. The immune response might have been enhanced due to the use of nivolumab so that intravitreal injection triggered inflammation. Three weeks after sub-tenon injection of triamcinolone acetonide, macular edema and choroidal detachment improved. CONCLUSIONS: Intravitreal aflibercept injection caused annular choroidal detachment in our patient, presumably because the immune system was activated after nivolumab treatment. To the best of our knowledge, this is the first case report of annular choroidal detachment that developed after intravitreal injection in a patient with a history of nivolumab therapy. With the increasing use of immune checkpoint inhibitors in patients with various cancers, clinicians should be aware of these potentially associated immune-related adverse events.

Impact of human leukocyte antigen mismatch on outcomes after unrelated bone marrow transplantation in paediatric patients: A retrospective analysis by the JSTCT HLA working group.

The impact of human leukocyte antigen (HLA) mismatching at the HLA-A, -B, -C, and -DRB1 loci after unrelated bone marrow transplantation in paediatric patients with haematological malignancies has not been fully examined. Here, we analysed patients with haematological malignancies (all aged ≤15 years; n = 1330) who underwent a first unrelated bone marrow transplantation between 1993 and 2017 in Japan. The results show that although an HLA mismatch was significantly associated with a low relapse rate, it was also associated with higher non-relapse mortality. There was a significant association between HLA mismatch and low overall survival. Locus mismatch analysis revealed that, as in adults, an HLA-C mismatch had a significant negative impact on survival; however, in paediatric patients, an HLA-DRB1 mismatch did not have a negative impact, although these HLA mismatch effects are weakened in recent cases. Taken together, the results suggest that an HLA-matched donor should be the first candidate for paediatric patients; however, for patients without a matched sibling or matched unrelated donor, we can select an unrelated donor with a mismatch at HLA-DRB1 if available.

Impact of KIR-ligand mismatch on pediatric T-cell acute lymphoblastic leukemia in unrelated cord blood transplantation.

Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered to be indicated for children and adolescents with high-risk or relapsed T-cell acute lymphoblastic leukemia (T-ALL); however, the outcomes are unsatisfactory. Killer cell immunoglobulin-like receptors (KIRs) are the main receptors on natural killer (NK) cells that play an important role in the graft-versus-leukemia effect after allo-HSCT. In allo-HSCT, when the recipient lacks a donor KIR-ligand (KIR-ligand mismatch in the graft-versus-host [GVH] direction), donor NK cells will be activated against recipient cells. KIR-ligand mismatch in the GVH direction improves outcomes after unrelated cord blood transplantation (UCBT) with acute myeloid leukemia, but the effect in T-ALL is unclear. We evaluated the impact of KIR-ligand mismatch in the GVH direction on the transplantation outcomes of children and adolescents with T-ALL who received UCBT. We conducted a retrospective study using a nationwide registry of the Japanese Society for Transplantation and Cellular Therapy. Patients diagnosed with T-ALL, aged 0 to 19 years, and who underwent first UCBT between 1999 and 2017 were included. A total of 91 patients were included in this study. In all, 23 (25.3%) percent of patients had KIR-ligand mismatch in the GVH direction. The 5-year leukemia-free survival (LFS) and overall survival (OS) rates after UCBT were 65.8% and 69.6%, respectively. In a multivariate analysis, KIR-ligand mismatch in the GVH direction was associated with a significant reduction in the relapse rate (hazard ratio [HR], 0.19; P = .002), resulting in better LFS (HR, 0.18; P =.010) and OS (HR, 0.26; P = .048) without increasing non-relapse mortality (NRM; HR, 1.90; P = .264). The cumulative incidence of GVH disease (GVHD) did not differ between patients with and without KIR-ligand mismatch (grade II-IV acute GVHD, 39.1% versus 36.8%, P = .648, grade III-IV acute GVHD, 13.0% versus 11.8%, P =.857, and chronic GVHD, 26.1% versus 22.9%, P =.736, respectively). Furthermore, acute and chronic GVHD were not associated with good patient outcomes. Notably, no relapse was observed in patients who received KIR-ligand mismatched UCBT in complete remission. KIR-ligand mismatch in the GVH direction improved LFS and decreased relapse rates without increasing NRM in children and adolescents with T-ALL who received UCBT, which was not mediated by GVHD.

Prognostic Factors for Outcomes of Allogeneic HSCT for Children and Adolescents/Young Adults With CML in the TKI Era.

The breakthrough effects of tyrosine kinase inhibitors (TKIs) have lessened indications for allogeneic hematopoietic stem cell transplantation (HSCT) in chronic myeloid leukemia (CML). However, HSCT is still attractive for children and adolescents/young adults (AYAs) requiring lifelong TKI therapy. Nevertheless, little has been reported on the outcomes of large clinical studies of HSCT targeting these age groups. This study aimed to identify prognostic factors for the outcomes of HSCT, including reduced-intensity conditioning (RIC)-HSCT, for children and AYAs with CML in the TKI era. We performed a registry analysis for 200 patients with CML aged <30 years who underwent pretransplant TKI therapy from the observational nationwide database established by the Japanese Society for Transplantation and Cellular Therapy. The patients received bone marrow (BM), peripheral blood (PB), or cord blood (CB) from either related or unrelated donors. The indication for HSCT for individual patients was determined by the institution according to European LeukemiaNet recommendations and other guidelines. The 5-year overall survival (OS) rates for patients with chronic phase (CP) (n = 124), accelerated phase (AP) (n = 23), and blastic phase (BP) (n = 53) at diagnosis were 82.8%, 71.1%, and 73.3%, respectively, with no significant difference (P =.3293). The strongest predictor of engraftment was transplant source, with CB (hazard ratio [HR], 0.33) and PB (HR, 2.00) (compared with BM) being independent unfavorable and favorable predictors, respectively. Transplant source was also an independent predictor of chronic GVHD, with PB (HR, 1.81) and CB (HR, 0.39) (compared with BM) being unfavorable and favorable predictors, respectively. The strongest predictor of OS rate for patients with CP at diagnosis was disease phase at HSCT, with second or greater CP, AP, or BP (HR, 2.81) (compared with first CP [CP1]) being an unfavorable predictor. In addition, patients with CP at diagnosis who had major and complete molecular responses at HSCT had excellent outcomes, with 5-year OS rates of 100% and 94.4%, respectively. The 5-year OS rate was compared between RIC (n = 31) and myeloablative conditioning (MAC) (n = 58) in patients with CP1, both of which were 89.3%, with no significant difference (P = .9440). On univariate analysis for the RIC cohort with CP at diagnosis, the age at HSCT (HR, 1.27) (increase per year) and the time from diagnosis to HSCT (HR, 1.83) (increase per year) were significant predictors for OS. Our study demonstrates that RIC may be an appropriate alternative to MAC for children and AYAs with CP1. As for the transplant source, we recommend first selecting BM because of a higher engraftment rate compared to CB and a lower incidence of chronic GVHD compared to PB. Although HSCT in the status of a major molecular response is desirable, it is not advisable to continue TKI pointlessly long because age at HSCT and timing of HSCT are prognostic factors that determine survival. The decision to perform RIC-HSCT instead of continuing TKI should be carefully made, considering the possibility of transplant-related complications.

Registry data analysis of hematopoietic stem cell transplantation on systemic chronic active Epstein-Barr virus infection patients in Japan.

The effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on systemic chronic active Epstein-Barr virus infection (sCAEBV) are yet to be analyzed in a large number of patients. Using the Japanese registry database, Transplant Registry Unification Management Program, we investigated the outcomes of 102 sCAEBV patients who underwent allo-HSCT. The median age at HSCT was 21 years, and the three-year overall survival (3-year OS) rate was 72.5%. Of the 90 patients whose viral load after allo-HSCT was evaluated, 56 (62.2%) achieved a virological complete response, defined by the complete resolution of disease activity with a significant decrease in EBV-DNA in peripheral blood. The multivariate Cox proportional hazard model indicated that advanced age, in adolescents and young adults (AYA) (age, 15-39) and adults (age, ≥40 years) was a risk factor of poor OS. The hazard ratios (HRs) of the AYA and adult groups were 10.87 (95% confidence interval [CI]: 1.98-59.56, p = .006) and 15.93 (95% CI: 2.45-103.8, p = .004), respectively. Disease activity (HR 5.74), elevated soluble IL-2 receptor (sIL-2R) (≥ median, 691 U/mL) at HSCT (HR 6.93), and conditioning without radiotherapy (HR 3.53) were also independently associated with poor survival. Notably, 79% of radiotherapy doses were less than 6 Gy. Regardless of the presence of hemophagocytic lymphohistiocytosis, the group with a high sIL-2R level (≥2000 U/mL) showed a poorer prognosis. Although allo-HSCT is the only curative therapy for sCAEBV, treatment strategies need to be improved for high-risk patients, especially those with high levels of sIL-2R.

Prognostic factors of children and adolescents with T-cell acute lymphoblastic leukemia after allogeneic transplantation.

Acute lymphoblastic leukemia (ALL) is the most common cancer during childhood, and some high-risk patients with ALL require hematopoietic stem cell transplantation (HSCT). Mainly due to small patient numbers, studies focusing specifically on children and adolescents with T-cell ALL (T-ALL) are limited. Using a nationwide registry, we retrospectively analyzed data from patients under 20 years old who underwent their first HSCT for T-ALL between 2000 and 2018. As a result, total 484 patients were included, and their median follow-up period was 6.9 years after HSCT for survivors. While patients receiving HSCT at first complete remission (CR) showed relatively good 5-year leukemia free survival (5yLFS, 73.5%), once relapse occurred, their prognosis was much worse (44.4%) even if they attained second remission again (p < 0.001). Among patients receiving HSCT at CR1, grade II-IV acute graft versus host disease was associated with worse overall and LFS than grade 0-I (5yLFS 69.5% vs. 82.1%, p = 0.026) mainly due to high non-relapse mortality. Among those patients, patients receiving related bone marrow transplantation, unrelated bone marrow transplantation, or unrelated cord blood transplantation showed similar survival (5yLFS, 73.2%, 76.3%, and 77.0%, respectively). For patients undergoing cord blood transplantation at CR1, total-body irradiation-based myeloablative conditioning was associated with better 5yLFS than other conditioning regimens (85.4% vs. 62.2%, p = 0.044), as it reduced the risk of relapse. These results indicate that relapsed patients have much less chance of cure, and that identifying patients who require HSCT for cure and offering them HSCT with optimal settings during CR1 are crucial for children and adolescents with T-ALL.

HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning with very low-dose antithymocyte globulin for relapsed/refractory acute leukemia in pediatric patients: a single-institution retrospective analysis.

The prognosis of relapsed/refractory (R/R) pediatric acute leukemia is extremely poor. We retrospectively reviewed 20 consecutive pediatric patients with R/R acute leukemia who underwent a first HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning (haplo-RIC-PBSCT) with very low-dose antithymocyte globulin (ATG) between 2012 and 2019. Of these 20 patients, 7 patients had acute lymphoblastic leukemia, and 13 had acute myeloid leukemia. At the time of haplo-RIC-PBSCT, 15 patients had active disease. The median follow-up duration for survivors was 56 months (range 22-108 months). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, short-term methotrexate, methylprednisolone, and ATG 1.25 mg/kg on day-2. The 2-year cumulative incidence of transplant-related mortality and relapse were 5.0% [95% confidence interval (CI) 0.7-30.5%)] and 57.8% (95% CI 37.4-79.6%), respectively. Among the 20 patients, 16 (80.0%) developed grade III-IV acute GVHD, and 2 developed severe chronic GVHD. The 2-year event-free survival and overall survival rates were 40.0% (95% CI 19.3-60.0%) and 50.0% (95% CI 27.1-69.2%), respectively. Although the sample size is small, the survival outcomes of the present study are encouraging.

Hematopoietic Cell Transplantation for Inborn Errors of Immunity Other than Severe Combined Immunodeficiency in Japan: Retrospective Analysis for 1985-2016.

PURPOSE: Hematopoietic cell transplantation (HCT) is a curative therapy for most patients with inborn errors of immunity (IEI). We conducted a nationwide study on HCT for patients with IEI other than severe combined immunodeficiency (non-SCID) in Japan. METHODS: Data from the Japanese national database (Transplant Registry Unified Management Program, TRUMP) for 566 patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, were retrospectively analyzed. RESULTS: The 10-year overall survival (OS) and event-free survival (EFS) were 74% and 64%, respectively. The 10-year OS for HCT from unrelated bone marrow (URBM), accounting for 39% of HCTs, was comparable to that for HCT from matched sibling donor (MSD), 79% and 81%, respectively. HCT from unrelated cord blood (URCB), accounting for 28% of HCTs, was also common, with a 10-year OS of 69% but less robust engraftment. The intensity of conditioning was not associated with OS or neutrophil recovery; however, myeloablative conditioning was more frequently associated with infection-related death. Patients who received myeloablative irradiation showed poor OS. Multivariate analyses revealed that HCT in 1985-1995 (hazard ratio [HR], 2.0; P = 0.03), URCB (HR, 2.0; P = 0.01), and related donor other than MSD (ORD) (HR, 2.9; P < 0.001) were associated with poor OS, and URCB (HR, 3.6; P < 0.001) and ORD (HR, 2.7; P = 0.02) showed a higher incidence of retransplantation. CONCLUSIONS: We present the 1985-2016 status of HCT for non-SCID IEI in Japan with sufficient statistical power, highlighting the potential of URBM as an alternative donor and the feasibility of reduced intensity conditioning.

Radiation-sparing reduced-intensity unrelated umbilical cord blood transplantation for rare hematological disorders in children.

Graft failure is a major pitfall of unrelated umbilical cord blood transplantation (CBT) in children with rare hematological disorders other than acute leukemia, such as acquired and inherited bone marrow failure, myelodysplastic syndrome, juvenile myelomonocytic leukemia, and chronic myeloid leukemia. We developed a less-toxic conditioning regimen for CBT that achieves a higher rate of complete donor chimerism, and retrospectively compared it against two other conditioning regimens for CBT performed at our single institution. The engraftment rate with complete donor chimerism was 100% and 5-year event-free survival (5y-EFS) was 90.9% in patients using our latest regimen (n = 11) of reduced-intensity conditioning (RIC) containing fludarabine (Flu) 180 mg/m2, melphalan (MEL) 210 mg/m2, and low-dose rabbit anti-thymocyte globulin (LD-rATG) 2.5 mg/kg without irradiation (regimen C). Outcomes were better than in patients (n = 10) treated with previous regimens involving irradiation (5y-EFS 30.0%, p = 0.004): regimen A, consisting of myeloablative conditioning containing cyclophosphamide (CY) and total body irradiation (TBI) with 8-12 Gy, or regimen B, consisting of RIC with Flu, CY, horse ATG, and thoracoabdominal irradiation (TAI) with 6 Gy. In conclusion, Flu/MEL/LD-rATG (regimen C) without TBI/TAI may be preferable as RIC for unrelated CBT in children with rare hematological disorders.

Characterization of myeloid neoplasms following allogeneic hematopoietic cell transplantation.

We compared characteristics of myeloid neoplasms (MNs) following allogeneic hematopoietic cell transplantation (HCT) versus autologous HCT using a Japanese HCT registry database. Among 43 788 patients who underwent allogeneic (n = 18 874) or autologous HCT (n = 24 914) for non-myeloid malignancies or non-malignant diseases, 352 developed MNs. The cumulative incidence of MNs was lower after allogeneic HCT than after autologous HCT (0.3% vs. 1.8% at 10 years, respectively, p < .001). Compared with autologous HCT, MNs following allogeneic HCT developed in younger patients (median, 42 vs. 57 years old, respectively) and sooner after HCT (median, 16 vs. 33 months, respectively). Approximately half of MNs following allogeneic HCT were donor-derived and occurred later than recipient-derived MNs (median, 26 vs. 6 months, respectively, p = .003). In multivariate analysis, reduced-intensity conditioning and cord blood transplantation were associated with MN development after allogeneic HCT. Overall survival was similar in patients who developed MNs following allogeneic versus autologous HCT (18% vs. 22% at 5 years, respectively, p = .48). Patient age ≥ 55 years, the presence of previous HCT, AML subtype, and chromosome 5 or 7 abnormalities were adverse factors for overall survival after MN diagnosis. Further research is warranted to elucidate the mechanisms of MN development following allogeneic HCT.

Prediction of lateral lymph node metastasis using OSNA method for mesorectal lymph nodes in low rectal cancer: A prospective study by the Kanagawa Yokohama Colorectal Cancer Study Group (KYCC1801).

BACKGROUND AND OBJECTIVES: Contrary to the Japanese guidelines recommendations regarding lateral lymph node dissection (LatLND) for rectal cancer, its omission is common in clinical practice without reliable omission criteria. Negative pathological mesorectal lymph node metastasis (MesLNM) is reportedly highly correlated with negative pathological lateral lymph node metastasis (p-LatLNM); however, this cannot be used as a criterion because pathological features are revealed postoperatively. Herein, we prospectively evaluated the negative predictive value (NPV) of MesLNM diagnosed via the one-step nucleic acid amplification (OSNA) method for p-LatLNM. METHODS: This prospective study was conducted at a single academic study group in Japan. The key eligibility criterion was mid-to-low rectal cancer planned to be treated using mesorectal excision with LatLND. According to the study protocol, the OSNA method was considered useful if the point estimate of the NPV exceeded 95%. RESULTS: Preoperative case registration was conducted between 2018 and 2020; 34 patients were registered. Among these, 16 were negative for OSNA-MesLNM, and negative p-LatLNM was confirmed in all cases. The point estimate of the NPV was 100%, with the 95% confidence interval ranging from 79.4% to 100.0%. CONCLUSIONS: The OSNA method is useful in selecting patients in whom LatLND can be omitted in real-world clinical practice.

Comparison of safety and efficacy of fluorouracil + oxaliplatin + irinotecan (FOLFOXIRI) and modified FOLFOXIRI with bevacizumab for metastatic colorectal cancer: data from clinical practice.

PURPOSE: The efficacy of fluorouracil + oxaliplatin + irinotecan with bevacizumab (FOLFOXIRI + BV) has been verified for metastatic colorectal cancer (mCRC). In clinical practice, the original (O-FOLFOXIRI + BV) and modified dose settings (M-FOLFOXIRI + BV) are adopted for Asian patients. We aimed to compare the real-world efficacy and safety of these two regimens. METHODS: This retrospective cohort study reviewed clinical data of all consecutive mCRC patients treated with FOLFOXIRI + BV at a cancer centre in Japan. One hundred patients were divided into two groups: one that received O-FOLFOXIRI + BV (group O, n = 30) and another that received M-FOLFOXIRI + BV (group M, n = 70). Progression-free survival (PFS) was set as the primary endpoint, with overall survival (OS), overall response rate (ORR), and safety as secondary endpoints. RESULTS: PFS was superior in group M (median PFS; 8.7 vs. 11.5 months, P = 0.098). The use of O-FOLFOXIRI + BV emerged as an independent risk factor of poor PFS (hazard ratio = 2.155, P = 0.012). Both ORR (43.3 vs. 65.7%, P = 0.047) and OS (median OS; 17.9 vs. 27.0 months, P = 0.127) were more favourable in group M. Grade ≥ 3 adverse events were more frequently observed in group O (90 vs. 74.3%, P = 0.108), whereas dose intensity was higher in group M because a shorter duration was required for cytotoxic drug administration (2.9 vs. 2.6 weeks/course, P = 0.051) in the induction term. CONCLUSION: We found that M-FOLFOXIRI + BV had more favourable efficacy and safety than O-FOLFOXIRI + BV, which may be a better fit for Asian patients and can be potentially used as an alternative for upfront chemotherapy for mCRC.

Prognostic value of the revised International Prognostic Scoring System five-group cytogenetic abnormality classification for the outcome prediction of hematopoietic stem cell transplantation in pediatric myelodysplastic syndrome.

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.

Hematopoietic Cell Transplantation for Severe Combined Immunodeficiency Patients: a Japanese Retrospective Study.

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.

Off-the-shelf bone marrow-derived mesenchymal stem cell treatment for acute graft-versus-host disease: real-world evidence.

Temcell is a cryopreserved, human bone marrow-derived mesenchymal stem cell (MSC) product approved for the treatment of patients of all ages with acute graft-versus-host disease (GVHD). Initial experience with Temcell in a real-world setting from a cellular therapy registry in Japan is presented. A total of 381 consecutive patients were enrolled since its approval in 2016. The median cell number infused was 2.00 × 106/kg. The most common number of infusions was 8 in 100 patients. Of the 306 evaluable patients, the overall response rate (ORR) on day 28 after the start of MSC therapy was 56%. Of the 151 evaluable patients who received it as second-line therapy following first-line steroid therapy for classic acute GVHD, the ORR was 61%. Liver involvement of GVHD and ≥14 days from first-line steroid therapy to second-line MSC therapy was associated with a lower ORR. Day 28 ORR, patient age, GVHD grade, GVHD organ involvement, and a number of GVHD therapies before MSC therapy were associated with nonrelapse mortality. Overall survival at 6 months in 381 patients was 40%. This study suggests that Temcell is one of the treatment options for steroid-refractory acute GVHD until a new treatment with survival benefit is developed.