[FLT3-ITD mutation-positive acute myeloid leukemia undergoing clonal transition with PTPN11 mutation at relapse].

A 28-year-old man was diagnosed with acute myelomonocytic leukemia. He achieved complete remission (CR) after two cycles of induction therapy. However, after consolidation therapy, bone marrow aspiration performed to prepare for allogeneic hematopoietic stem cell transplantation revealed disease relapse. Companion diagnostics confirmed the presence of the FLT3-ITD mutation. The patient received gilteritinib monotherapy and achieved CR. Subsequently, he underwent unrelated allogeneic bone marrow transplantation. One year after transplantation, the patient relapsed, and gilteritinib was resumed. However, the leukemia progressed, and panel sequencing using a next-generation sequencer showed that the FLT3-ITD mutation disappeared. A mutation in PTPN11, which regulates the RAS/MAPK signaling pathway, was also detected. Gilteritinib was discontinued, and the patient achieved CR with salvage chemotherapy. He underwent related haploidentical peripheral blood stem cell transplantation but died of relapse. This was a case in which genetic analysis revealed clonal transition and acquisition of resistance to treatment.

[Ruptured mycotic cerebral aneurysm in an adult T-cell leukemia/lymphoma patient undergoing allogeneic stem cell transplantation].

A 63-year-old man with adult T-cell leukemia-lymphoma underwent allogeneic bone marrow transplantation from an HLA-matched unrelated donor. On day 17 after transplantation, chest computed tomography (CT) showed nodules in the lower lobes of both lungs, and invasive pulmonary aspergillosis (IPA) was suspected. Treatment with liposomal amphotericin B was started, and improvement of infectious lesions was confirmed with CT on day 28. The antifungal agent was changed to voriconazole on day 52 because of progressive renal dysfunction. Disorders of consciousness and paralysis of the left upper and lower extremities developed on day 61. Brain CT showed subcortical hemorrhage in the right parietal and occipital lobes, and the patient died on day 62. An autopsy revealed filamentous fungi, suspected to be Aspergillus, in the pulmonary nodules and a ruptured cerebral aneurysm. Although IPA occurs in 10% of transplant recipients, vigilant monitoring for mycotic cerebral aneurysms is required to prevent hematogenous dissemination of Aspergillus, which is associated with a high mortality rate.

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.

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.

[Kidney transplantation for end-stage renal disease after third allogeneic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia].

An 18-year-old man underwent allogenic bone marrow transplantation (BMT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). Ph+ALL relapsed 3 months after the first BMT, and the patient underwent a second BMT. However, Ph+ALL relapsed 4 months after the second BMT, and he received a haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) from his father. Molecular complete remission was confirmed 29 days after haplo-PBSCT. However, the patient needed dialysis for end-stage renal disease due to thrombotic microangiopathy 3 years and 2 months after haplo-PBSCT. He received a kidney transplantation from his father 7 years and 10 months after haplo-PBSCT, and got off dialysis after the kidney transplantation. Immunosuppressive therapy with methylprednisolone, tacrolimus, and mycophenolate mofetil was started for kidney transplantation, but the dose of immunosuppressive agents was reduced successfully without rejection soon after kidney transplantation. The patient has maintained long-term remission since the haplo-PBSCT, and his kidney function was restored by the kidney transplantation from his father.

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.

Elevation of Urinary Liver-Type Fatty Acid-Binding Protein Is a Harbinger of Poor Patient Prognosis after Allogeneic Stem Cell Transplantation.

Several recent studies have demonstrated that urinary levels of liver-type fatty acid-binding protein (L-FABP) can be used to stratify the prognosis of cardiac disease, cardiac intensive care unit admission, cirrhosis, and coronavirus disease 2019. Our initial prospective study revealed that urinary L-FABP (uL-FABP) was associated with a high probability of acute kidney injury after stem cell transplantation (SCT); however, the relevance of elevated uL-FABP to the prognosis of patients undergoing SCT remains to be determined. We aimed to investigate whether uL-FABP levels can be used to stratify patient prognosis after SCT. To achieve this aim, we conducted a new long-term follow-up study using data from patients enrolled in our preceding prospective cohort study. Patients were classified into high and low uL-FABP groups based on levels measured at baseline (ie, before initiating the conditioning regimen), using an uL-FABP cutoff of 8.4 µg/gCr, which was determined based on data from healthy adults. uL-FABP levels were also measured on days 0, 7, and 14 after SCT. Cox proportional hazard regression was used to examine the effects of each factor on survival outcomes, and Fine-Gray regression was used in the presence of competing risks. Multivariate analysis incorporating confounders was then performed for factors with P < .1 in univariate analysis. In total, 20 of 84 patients (23.8%), 57 of 84 patients (67.9%), 34 of 49 patients (69.4%), and 34 of 46 patients (73.9%) were classified into the high uL-FABP group at baseline and on days 0, 7, and 14, respectively. The 5-year overall survival (OS) rate was 23.9% in the high uL-FABP group and 68.9% in the low uL-FABP group. The multivariate analysis identified a high uL-FABP level at baseline as a significant prognostic factor for poor OS (hazard ratio [HR], 3.54; P = .002). The 5-year cumulative incidence rate for nonrelapse mortality (NRM) was 50.0% in the high uL-FABP group and 19.9% in the low uL-FABP group. In the multivariate analysis, high uL-FABP at baseline was a significant prognostic factor for NRM (HR, 3.37; P = .01). uL-FABP levels did not significantly stratify the cumulative incidence of relapse (HR, 2.13; P = .11). uL-FABP levels on days 0, 7, and 14 were not significant predictors of survival. High uL-FABP level before initiation of conditioning significantly influences OS and NRM following SCT, whereas a high uL-FABP level at any point after the conditioning regimen does not. Our results show that measuring uL-FABP level at baseline may be a simple way to predict survival in patients undergoing SCT.

Combination of Donor Lymphocyte Infusion and Blinatumomab for B-Cell Lymphoblastic Lymphoma Relapse after Allogeneic Stem-Cell Transplantation.

A woman in her forties with relapsed B-cell lymphoblastic lymphoma was treated with blinatumomab, but the drug proved ineffective. Salvage therapy with clofarabine induced a complete remission, and she received an allogeneic stem-cell transplantation (allo-SCT) from an HLA-matched sibling donor. However, her disease relapsed only 4 months after the allo-SCT. Three courses of combination therapy with donor lymphocyte infusion (DLI) and blinatumomab were administered, and the tumor progression was well controlled for 6 months, leading to a second allo-SCT from an HLA-haploidentical donor. The remission was persistent for approximately 1 year, but the disease relapsed in her central nervous system, and she eventually died. Our case demonstrated the efficacy and safety of concomitant use of DLI and blinatumomab. This combination presumably enhanced a graft-versus-lymphoma effect of allogeneic T-cells without provoking graft-versus-host disease.

Clinical outcomes in transplant-eligible patients with relapsed or refractory diffuse large B-cell lymphoma after second-line salvage chemotherapy: A retrospective study.

OBJECTIVE: The prognosis of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Although patients who fail first-line salvage chemotherapy are candidates for second-line salvage chemotherapy, the optimal treatment strategy for these patients has not yet been established. METHODS: The present, single-center, retrospective study included transplant-eligible patients with R/R DLBCL who received second-line salvage chemotherapy with curative intent. RESULTS: Seventy-six patients with R/R DLBCL received second-line salvage chemotherapy. Eighteen (23.7%) patients were responders to the first-line salvage chemotherapy. The overall response rate was 39.5%, and overall survival (OS) was significantly longer in patients who responded to second-line salvage chemotherapy than those who did not. Forty-one patients who proceeded to potentially curative treatment (autologous hematopoietic stem cell transplantation [ASCT], chimeric antigen receptor [CAR] T-cell therapy, or allogeneic hematopoietic stem cell transplantation) had a better prognosis than those who did not. Among the 46 patients who failed to respond to the second-line salvage regimen, only 18 (39.1%) could proceed to the curative treatments. However, among the 30 patients who responded to the second-line salvage regimen, 23 (76.7%) received one of the potentially curative treatments. Among 34 patients who received CAR T-cell therapy, OS was significantly longer in those who responded to salvage chemotherapy immediately prior to CAR T-cell therapy than in those who did not respond. In contrast, the number of prior lines of chemotherapy was not identified as a statistically significant prognostic factor of survival. No significant difference was detected in OS between patients receiving ASCT and those receiving CAR T-cell therapy after the response to second-line salvage chemotherapy. DISCUSSION: In this study, we demonstrated that chemosensitivity remained a crucial factor in predicting survival outcomes following CAR T-cell therapy irrespective of the administration timing, and that both ASCT and CAR T-cell therapy were acceptable after the response to second-line salvage chemotherapy.

Selection of Cord Blood Unit by CD34+ Cell and GM-CFU Numbers and Allele-Level HLA Matching in Single Cord Blood Transplantation.

In Japan, only single-unit cord blood transplantations (CBTs) are typically performed, and their number has increased over the last 23 years, with ongoing improvement in results. In most cases, CBTs with multiple HLA mismatches are used, owing to a low HLA barrier, and lower engraftment rate is a problem that must be overcome. Here, as part of an effort to improve guidelines for the selection and processing of CB units for transplantation, we sought to assess the present status of CBT in Japan and to elucidate factors contributing to the favorable outcomes, focusing in particular on selection by cell components of CB unit and HLA allele matching. We conducted a nationwide study analyzing 13,443 patients who underwent first CBT between in Japan between December 1997 and December 2019 using multivariate regression analysis. Both patient- and transplantation-related variables, such as age and Hematopoietic Cell Transplantation Comorbidity Index, as well as selected CB unit characteristics, were included in the analysis. The interaction analysis elucidated that CB unit selection favoring higher counts of CD34+ cells and granulocyte macrophage colony-forming units (GM-CFU)/kg, but not of total nucleated cells, contributed to improved engraftment after transplantation. Moreover, a higher CD34+ cell dose was associated with improved overall survival (OS). Distinctive HLA allele matching was observed. A 0 or 1 HLA allele mismatch between patient and donor had favorable engraftment and carried significantly lower risks of acute GVHD and chronic GVHD but had a significantly higher leukemia relapse rate, compared with a 3-HLA allele mismatch. HLA-DRB1 mismatches were associated with reduced risk of leukemia relapse. Notably, the number of HLA allele mismatches had no incremental effect on engraftment, acute and chronic GVHD, or relapse incidence. As a result, 5-year overall survival did not differ significantly among patients receiving CB units with 0 to 7 HLA allele mismatches. The main points of CB unit selection are as follows. First, selection according to a higher number of CD34+ cells/kg and then of CFU-GM/kg is recommended to obtain favorable engraftment. A unit with .5 × 105 CD34+ cells/kg is minimally acceptable. For units with a CD34+ cell dose of .5 to 1.0 × 105 cells/kg, applying the parameter of ≥20 to 50 × 103 GM-CFU/kg (66.5% of transplanted CB units in this cohort) is associated with a neutrophil engraftment rate of approximately 90%. A unit with ≥1.0 × 105 CD34+ cells/kg can achieve a ≥90% mean neutrophil engraftment rate. Subsequently, HLA allele matching of HLA-A, -B, -C, and -DRB1 at the 2-field level should be searched for units with 0 or 1 HLA allele mismatch in the host-versus-graft direction for favorable engraftment. Units with 2 to 6 HLA allele mismatches are acceptable in patients age ≥15 years and units with 2 to 4 HLA allele mismatches are acceptable in patients age ≤14 years. Units with HLA-DRB1 and/or -B allele mismatch(es) might not be preferable owing to an increased GVHD risk. Our analysis demonstrates that single-unit CBT with the selection of adequate CD34+/kg and GM-CFU/kg and HLA allele matching showed favorable outcomes in both pediatric and adult patients.

[Polatuzumab vedotin, bendamustine, and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma, including the outcome as a bridging treatment to CAR-T cell therapy or allogeneic hematopoietic stem cell transplant].

Pola-BR (polatuzumab vedotin, bendamustine, and rituximab) therapy received approval for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in Japan in March 2021. There have been few reports on the efficacy and safety of Pola-BR therapy in Japanese clinical practice. A retrospective analysis was performed on twenty-nine patients with R/R DLBCL who received Pola-BR therapy at our institution (intent to cellular immunotherapy cohort: 20 patients, stand-alone treatment cohort: nine patients). The overall response rate was 69.0% (complete response 27.6%). The median progression-free survival was 5.1 months, with a 9.5-month median overall survival. In the intent to cellular immunotherapy cohort, 11 of 19 patients received chimeric antigen receptor T-cell (CAR-T) infusions, and one patient received allogeneic stem cell transplantation. Four patients received Pola-BR therapy, including bendamustine before leukapheresis, and all produced CAR-T products successfully. 3 of the 28 patients experienced grade3 or higher adverse events, and two required treatment discontinuation. Our single institution, a real-world cohort of R/R DLBCL patients showed high efficacy outcomes and a tolerable toxicity profile for Pola-BR therapy, which is comparable to previous studies. More cases are needed to determine its impact on CAR-T therapy and stem cell transplantation.

Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical relatives in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukemia: a propensity score analysis of a nationwide database.

Bone marrow (BM) and granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSC) are used as grafts from HLA-identical-related donors for adults with myelodysplastic syndrome (MDS). To assess the impact of graft sources on post-transplant outcomes in MDS patients, we conducted a retrospective analysis of a nationwide database. A total of 247 and 280 patients underwent transplantation with BM and PBSC, respectively. The inverse probability of treatment weighting (IPTW) methods revealed that overall survival (OS) was comparable between BM and PBSC (P = .129), but PBSC transplantation was associated with worse graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) (hazard rate [HR], 1.24; 95% confidence intervals [CIs], 1.00-1.53; P = 0.049) and chronic GVHD-free and relapse-free survival (CRFS) (HR, 1.29; 95% CIs, 1.13-1.73; P = 0.002) than BM transplantation. In the propensity score matched cohort (BM, n = 216; PBSC, n = 216), no significant differences were observed in OS and relapse; 3-year OS rates were 64.7% and 60.0% (P = 0.107), while 3-year relapse rates were 27.1% and 23.5% (P = 0.255) in BM and PBSC, respectively. Three-year GRFS rates (36.6% vs. 29.2%; P = 0.006), CRFS rate (37.7% vs. 32.5%; P = 0.003), and non-relapse mortality rates (13.9% vs. 21.1%; P = 0.020) were better in BM than in PBSC. The present study showed that BM transplantation provides a comparable survival benefit with PBSC transplantation and did not identify an enhanced graft-versus-MDS effect to reduce the incidence of relapse in PBSC transplantation.

Prognostic factors for the development of lower respiratory tract infection after influenza virus infection in allogeneic hematopoietic stem cell transplantation recipients: A Kanto Study Group for Cell Therapy multicenter analysis.

OBJECTIVES: Influenza virus infection (IVI) occasionally causes lower respiratory tract infection (LRTI) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Although the progression to LRTI entails a high mortality, the role of early antiviral therapy for its prevention has not been fully elucidated. METHODS: This was a multicenter retrospective study using an additional questionnaire. Allo-HSCT recipients who developed IVI between 2012 and 2020 were included. RESULTS: A total of 278 cases of IVI after allo-HSCT were identified from 15 institutions. The median patient age was 49 years, and the median time from allo-HSCT to IVI was 918 days. Neuraminidase inhibitors were administered within 48 hours of symptom onset (early neuraminidase inhibitor [NAI]) in 199 (76.9%) patients. Subsequently, 36 (12.3%) patients developed LRTI. On the multivariate analysis, age ≥50 years (hazard ratio [HR], 2.16; 95% confidence interval [CI], 1.02-4.58) and moderate to severe chronic graft-versus-host disease (HR, 2.28; 95% CI, 1.14-4.58) were significantly associated with progression to LRTI, whereas early NAI suppressed the progression (HR, 0.17; 95% CI, 0.06-0.46). The IVI-related mortality rate was 2.2%. CONCLUSION: To reduce the risk of LRTI development after IVI, early NAI therapy should be considered in allo-HSCT recipients, especially with older patients and those with chronic graft-versus-host disease.

Clinical impact and early prediction of carbapenem-resistant Pseudomonas aeruginosa bacteraemia in allogeneic hematopoietic stem cell transplantation recipients.

OBJECTIVE: Although antipseudomonal agents are administered in high-risk patients, no reports have focused on the risk of carbapenem-resistant (CR) Pseudomonas aeruginosa bacteraemia in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. METHODS: We retrospectively studied a cohort of adult allo-HSCT recipients with P. aeruginosa bacteraemia, focusing on a comparison between carbapenem-sensitive (CS) and CR P. aeruginosa after initiating conditioning chemotherapy at our institute between January 2005 and December 2020. The incidence, all-cause 30-d mortality of P. aeruginosa bacteraemia, and risk factors for carbapenem resistance among patients with P. aeruginosa bacteraemia in allo-HSCT recipients were evaluated. RESULTS: Forty-eight patients with P. aeruginosa bacteraemia were included, with an incidence of 3.84/100 recipients (CS = 1.92 vs. CR = 1.92). The all-cause 30-d mortality was significantly higher in CR P. aeruginosa bacteraemia (CS = 4.2% vs. CR = 39.1%; P = 0.003). The factor significantly associated with CR P. aeruginosa bacteraemia was carbapenem use for at least 3 d within 30 d before the onset of bacteraemia (odds ratio = 8.92; 95% confidence interval: 1.35-58.90). Inappropriate antimicrobial selection was significantly more frequent in CR P. aeruginosa bacteraemia (CS = 0% vs. CR = 29.2%; P ˂ 0.009). CONCLUSION: Empirical combination therapy with reference to antimicrobial susceptibility profiles in each institution should be considered when CR P. aeruginosa bacteraemia is suspected in allo-HSCT recipients based on the risk of carbapenem exposure.

Impact of gene alterations on clinical outcome in young adults with myelodysplastic syndromes.

Young adults with myelodysplastic syndrome (MDS) are rare, and the clinical significance of driver mutations has not yet been analysed. We analysed the gene mutations and copy number alterations (CNAs) in younger MDS patients using next-generation sequencing, targeting 68 genes that were recurrently mutated in myeloid malignancies, to investigate the correlation between their genetic alterations and clinical outcomes. We enrolled 55 patients retrospectively (aged < 50 years). At least one mutation was detected in 56% of the patients. The most frequently mutated genes were ASXL1 and RUNX1, 13% each. We defined higher-risk patients as those with ≥ 2 mutations, except for SF3B1 mutation, and/or CNA. The 3-year overall survival (OS) in patients with a higher-risk was lower than that in those with a lower-risk (50.8% vs. 71.8%, P = 0.024). Among the 44 transplant recipients, patients with higher-risk had a significantly lower OS and tended to have a higher cumulative incidence of relapse (CIR) than those with a lower-risk (3-year OS: 38.0% vs. 64.4%, P = 0.039; 3-year CIR: 44.0% vs. 24.1%, P = 0.076). Our results showed that genetic aberrations can predict clinical outcomes in younger MDS patients, despite the low rate of genetic mutations.

Attenuated humoral response against SARS-CoV-2 mRNA vaccination in allogeneic stem cell transplantation recipients.

Antibody persistence several months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination in allogeneic stem cell transplantation recipients remains largely unknown. We sequentially evaluated the humoral response to two doses of mRNA vaccines in 128 adult recipients and identified the risk factors involved in a poor response. The median interval between stem cell transplantation and vaccination was 2.7 years. The SARS-CoV-2 S1 Ab became positive after the second vaccination dose in 87.6% of the recipients, and the median titer was 1235.4 arbitrary units (AU)/ml. In patients on corticosteroid treatment, the corticosteroid dose inversely correlated with Ab titer. Multivariate analysis identified risk factors for poor peak response such as an interval from stem cell transplantation ≤1 year, history of clinically significant CMV infection, and use of >5 mg/day prednisolone at vaccination. Six months after vaccination, the median titer decreased to 185.15 AU/ml, and use of >5 mg/day prednisolone at vaccination was significantly associated with a poor response. These results indicate that early vaccination after stem cell transplantation (<12 months) and CMV infection are risk factors for poor peak response, while steroid use is important for a peak as well as a persistent response. In conclusion, although humoral response is observed in many stem cell transplantation recipients after two doses of vaccination, Ab titers diminish with time, and factors associated with persistence and a peak immunity should be considered separately.

Phase I trial of myeloablative conditioning with 3-day total marrow and lymphoid irradiation for leukemia.

This prospective phase I trial aimed to determine the recommended dose of 3-day total marrow and lymphoid irradiation (TMLI) for a myeloablative conditioning regimen by increasing the dose per fraction. The primary end-point of this single-institution dose escalation study was the recommended TMLI dose based on the frequency of dose-limiting toxicity (DLT) ≤100 days posthematopoietic stem cell transplantation (HSCT); a 3 + 3 design was used to evaluate the safety of TMLI. Three dose levels of TMLI (14/16/18 Gy in six fractions over 3 days) were set. The treatment protocol began at 14 Gy. Dose-limiting toxicities were defined as grade 3 or 4 nonhematological toxicities. Nine patients, with a median age of 42 years (range, 35-48), eight with acute lymphoblastic leukemia and one with chronic myeloblastic leukemia, received TMLI followed by unrelated bone marrow transplant. The median follow-up period after HSCT was 575 days (range, 253-1037). Three patients were enrolled for each dose level. No patient showed DLT within 100 days of HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. All patients achieved neutrophil engraftment at a median of 19 days (range, 14-25). One-year overall and disease-free survival rates were 83.3% and 57.1%, respectively. Three patients experienced relapse, and no nonrelapse mortality was documented during the observation period. One patient died due to disease relapse 306 days post-HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. The efficacy evaluation of this regimen is currently being planned in a phase II study.

Case report: Immune pressure on hematopoietic stem cells can drastically expand glycosylphosphatidylinositol-deficient clones in paroxysmal nocturnal hemoglobinuria.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disease characterized by intravascular hemolysis, thrombosis, and bone marrow (BM) failure. Although PNH is caused by excessive proliferation of hematopoietic stem cell (HSC) clones with loss of function mutations in phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIGA) genes, what drives PNH clones to expand remains elusive. Case description: We present a case of a 26-year-old female who presented with hemolytic anemia, thrombocytopenia, and leukopenia. Flow cytometry analysis of peripheral blood showed that 71.9% and 15.3% of the granulocytes and erythrocytes were glycosylphosphatidylinositol-anchored protein deficient (GPI[-]) cells. The patient was diagnosed with PNH with non-severe aplastic anemia. Deep-targeted sequencing covering 390 different genes of sorted GPI(-) granulocytes revealed three different PIGA mutations (p.I69fs, variant allele frequency (VAF) 24.2%; p.T192P, VAF 5.8%; p.V300fs, VAF 5.1%) and no other mutations. She received six cycles of eculizumab and oral cyclosporine. Although the patient's serum lactate dehydrogenase level decreased, she remained dependent on red blood cell transfusion. Six months after diagnosis, she received a syngeneic bone marrow transplant (BMT) from a genetically identical healthy twin, following an immune ablative conditioning regimen consisting of cyclophosphamide 200 mg/kg and rabbit anti-thymocyte globulin 10 mg/kg. After four years, the patient's blood count remained normal without any signs of hemolysis. However, the peripheral blood still contained 0.2% GPI (-) granulocytes, and the three PIGA mutations that had been detected before BMT persisted at similar proportions to those before transplantation (p.I69fs, VAF 36.1%; p.T192P, VAF 3.7%; p.V300fs, VAF 8.6%) in the small PNH clones that persisted after transplantation. Conclusions: The PNH clones that had increased excessively before BMT decreased, but persisted at low percentages for more than four years after the immunoablative conditioning regimen followed by syngeneic BMT. These findings indicate that as opposed to conventional theory, immune pressure on HSCs, which caused BM failure before BMT, was sufficient for PIGA-mutated HSCs to clonally expand to develop PNH.

[Tisagenlecleucel for relapsed/refractory diffuse large B-cell lymphoma: real-world data from single institute experience].

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the approach to patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). This study retrospectively analyzed patients treated with commercially available tisagenlecleucel at our hospital and evaluated its safety and effectiveness. Of the 21 patients evaluated, any grade and grade ≥3 cytokine release syndrome (CRS) occurred in 85.7% and 9.5% of the patients, respectively. A total of 66.7% received tocilizumab and 28.6% received glucocorticoids for the treatment of CRS. The complete response (CR) rate at 3 months was 61.9% (95% confidence interval [CI] 38.4-81.9). After a median follow-up of 6.3 months following CAR-T infusion, the progression-free survival (PFS) and overall survival rates at 6 months were 53.1% (95%CI 28.3-72.7) and 69.2% (95%CI 43.7-84.9), respectively. Severe cytopenia and hypogammaglobulinemia occurred frequently following CAR-T infusion. Eight patients (38.1%) had comorbidities that would have made them ineligible for leukapheresis in the JULIET trial. However, the presence of comorbidities at the time of leukapheresis had no significant effect on the rates of CR, PFS, and adverse events. Tisagenlecleucel for r/r DLBCL in the real-world setting showed high efficacy and manageable safety profile comparable with the pivotal trial.

Outcomes of allogeneic haematopoietic stem cell transplantation with intensity-modulated total body irradiation by helical tomotherapy: a 2-year prospective follow-up study.

BACKGROUND AND OBJECTIVES: Intensity-modulated radiation therapy (IMRT) helps achieve good radiation dose conformity and precise dose evaluation. We conducted a single-centre prospective study to assess the safety and feasibility of total body irradiation with IMRT (IMRT-TBI) using helical tomotherapy in allogeneic haematopoietic stem cell transplantation (allo-HSCT). PATIENTS AND METHODS: Thirty-nine adult patients with haematological malignancy (acute lymphoblastic leukaemia [n = 21], chronic myeloid leukaemia [n = 6], mixed phenotype acute leukaemia [n = 5], acute myeloid leukaemia [n = 4], and malignant lymphoma [n = 3]) who received 12 Gy IMRT-TBI were enrolled with a median follow-up of 934.5 (range, 617-1254) d. At the time of transplantation, 33 patients (85%) achieved complete remission. The conditioning regimen used IMRT-TBI (12 Gy in 6 fractions twice daily, for 3 d) and cyclophosphamide (60 mg/kg/d, for 2 d), seven patients were combined with cytarabine, and five with etoposide. We set dose constraints for the lungs, kidneys and lens as the organs at risk. RESULTS: The mean doses for the lungs and kidneys were 7.50 and 9.11 Gy, respectively. The mean maximum dose for the lens (right/left) was 5.75/5.87 Gy. The 2-year overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 69, 64, 18 and 18%, respectively. Thirty-six patients developed early adverse events (AEs) (including four patients with Grade 3/4 toxicities), most of which were reversible oral mucositis and may partially have been related to IMRT-TBI. However, the incidence of toxicity was comparable to conventional TBI-based conditioning transplantation. None of the patients developed primary graft failure, or Grade III-IV acute graft-versus-host disease (GVHD). In late complications, chronic kidney disease was observed in six patients, a lower incidence compared to conventional TBI-based conditioning transplantation. No radiation pneumonitis or cataracts were observed in any of the patients. CONCLUSIONS: IMRT-TBI is safe and feasible for haematological malignancies with acceptable clinical outcomes.KEY MESSAGESIMRT-TBI-helical tomotherapy aids in accurate dose calculation and conformity.It could be used without any considerable increase in the rate of TBI-related AEs.Allo-HSCT with IMRT-TBI may be an alternative to conventional TBI for clinical use.