[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.

Safety and efficacy of high-dose cytarabine MEAM therapy and other treatments for auto-peripheral blood stem cell transplantation: A retrospective comparative study.

AIM: The MEAM regimen consisting of ranimustine (MCNU), etoposide (ETP), cytarabine (Ara-C), and melphalan (MEL) is widely used before auto-peripheral blood stem cell transplantation (auto-PBSCT) for malignant lymphoma in Japan. The MEAM regimen generally consists of 200-400 mg/m2 for 4 days, but we decided to increase the dosage of Ara-C from the standard to 2 g/m2 for 2 days with the aim of increasing drug transferability to the central nervous system. We evaluate the safety and therapeutic efficacy of high-dose Ara-C MEAM therapy. METHODS: The high-dose Ara-C MEAM protocol consisted of MCNU 300 mg/m2 on day -7, ETP 200 mg/m2 on days -6, -5, -4, -3 and Ara-C 2 g/m2 on day -4 -3, and MEL 140 mg/m2 on day -2. We retrospectively analyzed 37 cases of malignant lymphoma at our institution between May 2014 and July 2020. RESULTS: All patients got engraftment and there were no cases of treatment-related mortality. In all cases, the 3-year overall survival (OS) and progression-free survival (PFS) after transplantation were 80.6% and 65.7%, respectively. Twenty-one cases of diffuse large B-cell lymphoma recurrence, for which there is proven usefulness of auto-PBSCT, showed good results after transplantation, with the 3-year OS and PFS after transplantation being 100% and 74.3%, respectively. CONCLUSION: The safety and efficacy of high-dose Ara-C MEAM therapy were demonstrated, but the expected therapeutic effect on central nervous system lesions could not be fully evaluated owing to the small number of cases.

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.

Age and allogeneic hematopoietic cell transplantation outcomes in acute myeloid leukemia.

Although several studies have reported significant effects of patient age on outcomes of allogeneic hematopoietic cell transplantation (HCT), the prognostic relevance of age must be determined separately for myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC). We analyzed Japanese nationwide transplantation registry data of patients aged 20-79 years with acute myeloid leukemia who underwent allogeneic HCT using MAC (n = 7525) or RIC (n = 3154) between 2008 and 2019. Patient were divided into six groups by age, with each group representing a decade, and overall survival (OS), relapse, and non-relapse mortality (NRM) were compared between adjacent age groups. The adverse impact of age on OS increased each decade starting at age 40 among patients receiving MAC, but only differed significantly between patients in their 50s and 60s among those receiving RIC. In patients receiving both MAC and RIC, the detrimental effect of advanced age on OS was accompanied by an increased risk of NRM. These findings show that age affects NRM and OS significantly, but differs depending on conditioning intensity. RIC mitigates the adverse prognostic impact of older age and is thus considered a reasonable option for older patients.

[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.

[Haploidentical hematopoietic stem cell transplantation for graft failure in myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable complicated with Stenotrophomonas maltophilia bacteremia].

A 60-year-old woman with myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable underwent unrelated bone marrow transplantation from a human leukocyte antigen (HLA) 8/8 allele-matched male donor. Neutrophil engraftment was achieved on day 29. Fluorescence in situ hybridization of sex chromosomes demonstrated complete donor chimerism. The red blood cell and platelet transfusion dependence continued, and the neutrophil count decreased gradually. Despite prolonged administration of broad-spectrum antibiotics for febrile neutropenia, blood cultures on days 46 and 58 returned positive for Stenotrophomonas maltophilia (SM). Contrast-enhanced computed tomography revealed multiple nodules of septic emboli in the lungs and kidneys, suggesting a disseminated SM infection. Antibiotic therapy was conducted based on antimicrobial susceptibility testing. However, the blood cell count failed to normalize and a secondary graft failure was diagnosed. A HLA-haploidentical peripheral-blood stem-cell transplantation from the patient's son was performed on day 134 after the initial transplantation. Neutrophil engraftment was achieved on day 11. Red blood cells and platelets were also engrafted. After the resolution of the SM bacteremia, the patient was discharged on day 63. The prognosis of the SM bacteremia with neutropenia is poor. Antibiotic treatment based on antimicrobial susceptibility testing and a second transplant from an HLA-haploidentical donor likely contributed to the successful outcome in this patient.

Impact of lung function impairment after allogeneic hematopoietic stem cell transplantation.

Late-onset noninfectious pulmonary complications (LONIPC) are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). However, the clinical impact of lung function deterioration itself in long-term adult survivors of HSCT remains to be fully investigated. This retrospective, longitudinal study aimed to investigate pulmonary function following HSCT in terms of its change and the clinical significance of its decline. We examined 167 patients who survived for at least 2 years without relapse. The median follow-up period was 10.3 years. A linear mixed-effects model showed that the slope of pulmonary function tests values, including percent vital capacity (%VC), percent forced expiratory volume in one second (%FEV1), and FEV1/forced VC ratio (FEV1%), decreased over time. The cumulative incidence of newly obstructive and restrictive lung function impairment (LFI) at 10 years was 15.7% and 19.5%, respectively. Restrictive LFI was a significant, independent risk factor for overall survival (hazard ratio 7.11, P = 0.007) and non-relapse mortality (hazard ratio 12.19, P = 0.003). Our data demonstrated that lung function declined over time after HSCT and that the decline itself had a significant impact on survival regardless of LONIPC.

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.

Central Nervous System-related Graft-versus-host Disease after Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hemopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for refractory hematological malignancies. However, there are many treatment-related complications, including organ disorders, graft-versus-host disease (GVHD), and infectious diseases. Furthermore, there are many unclear points regarding central nervous system (CNS) complications, and the prognosis in patients with CNS complications is extremely poor. We herein report a 49-year-old woman who developed CNS-GVHD after a second transplantation for therapy-related myelodysplastic syndrome. CNS-GVHD in this case was refractory to all treatments, including steroids, and progressed. We also present a review of the literature about the symptoms, diagnosis, and treatment of CNS-GVHD.

Syngeneic hematopoietic stem cell transplantation for acute myeloid leukemia: a propensity score-matched analysis.

The present study evaluated outcomes and prognostic factors in adult patients with acute myeloid leukemia (AML) after syngeneic hematopoietic stem cell transplantation (HSCT). Among patients in first complete remission (CR1), outcomes of syngeneic HSCT (Syn) were compared with those of autologous HSCT (Auto), allogeneic HSCT from human leukocyte antigen (HLA)-matched sibling donor (MSD), or allogeneic HSCT from HLA-matched unrelated donor (MUD). Among 11,866 patients receiving first HSCT, 26 in the Syn group were analyzed. The 5-year overall survival (OS) rate, the cumulative incidence of relapse, and the cumulative incidence of non-relapse mortality (NRM) were 47.8%, 59.6%, and 4.6%, respectively. The OS was significantly better in patients in CR1 (n = 13) than in patients in non-CR1 (P = 0.012). Furthermore, 39 patients in CR1 each were assigned to the Auto, MSD, and MUD groups using propensity score matching. The 5-year OS in the Syn (68.4%) was not significantly different from those in the Auto (55.9%, P = 0.265), MSD (62.4%, P = 0.419), or MUD (63.7%, P = 0.409) groups. A higher relapse in the Syn than in the MSD and MUD groups was offset by lower NRM. In summary, syngeneic HSCT might be an alternative option for AML patients in CR1.

Altered effect of killer immunoglobulin-like receptor-ligand mismatch by graft versus host disease prophylaxis in cord blood transplantation.

The role of killer immunoglobulin-like receptor-ligand mismatch (KIR-ligand mismatch) between donors and recipients undergoing cord blood transplantation (CBT) is controversial. If each immunosuppressant differently affects natural killer (NK) cell function, the effect of KIR-ligand mismatch may be altered depending on the type of graft versus host disease (GVHD) prophylaxis. To verify this hypothesis, the difference in the effect of KIR-ligand mismatch was retrospectively assessed between patients who received CBT for acute leukemia, myelodysplastic syndrome, or chronic myeloid leukemia, as well as GVHD prophylaxis comprising tacrolimus plus methotrexate (MTX) or mycophenolate mofetil (MMF). In the MMF group (n = 1363), KIR-ligand mismatch augmented the incidence of non-relapse mortality (NRM; hazard ratio [HR], 1.40; P = 0.008), which worsened overall survival (OS; HR, 1.30, P = 0.0077). In the analysis of each KIR-ligand mismatch type, HLA-C2 mismatch had a favorable effect on relapse incidence (HR, 0.56; P = 0.0043) and OS (HR, 0.72; P = 0.037) only in the MTX group. In the MMF group, HLA-A3/A11 mismatch worsened NRM (HR, 1.93; P < 0.001) and OS (HR, 1.48; P = 0.014). These results imply that the effects of KIR-ligand mismatch differ with the type of GVHD prophylaxis and that assessing the KIR-ligand mismatch status is important for CBT.

Presence of Promyelocytes in Peripheral Blood as a Novel Predictor of Optimal Timing for Single-Step Peripheral Blood Stem Cell Collection.

BACKGROUND: Because peripheral blood stem cell (PBSC) collection places a burden on the patient and should ideally be completed in a single procedure, a convenient clinical predictive factor is needed. METHODS: This retrospective study included 72 patients who underwent autologous PBSC collection. A median volume of 3.9 × 106 CD34-positive cells/kg (range: 0.3-47.4 × 106 cells/kg) was collected on the first day. We defined failure as inability to collect 2.0 × 106 cells/kg on the first day. PBSC collection was classified as failed (n = 25, 34.7%) and successful (n = 47, 65.3%), and patient clinical characteristics were analyzed. RESULTS: The success group had significantly more cases in which a differential white blood cell count in peripheral blood on the day of PBSC collection detected promyelocytes (n = 34 [72.3%] vs. n = 11 [44.0%] in the failure group; P = 0.008). Sixty-two patients underwent autologous PBSC transplantation (median number of transplanted cells, 5.6 × 106/µL; range: 1.60-47.4 × 106 cells/µL). Among transplanted patients, the success and failure groups did not significantly differ in relation to the interval until neutrophil, platelet, or red blood cell engraftment. CONCLUSION: The presence of promyelocytes in peripheral blood may be a useful indicator of the optimal timing for single-step PBSC collection.

Outcomes of Patients with Early Hyperbilirubinemia after Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Because the cause of liver dysfunction after allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to identify in the early stages, treatment may be delayed. Therefore, early factors associated with unfavorable outcomes of liver dysfunction must be identified. The objective of this study was to identify unfavorable prognostic factors for liver dysfunction during the early period after transplantation. METHODS: We defined liver dysfunction as elevated liver or biliary enzyme levels (corresponding to Grade 2 in the Common Terminology Criteria for Adverse Events version 4.0) within 30 days of transplantation and retrospectively investigated data from 82 patients who had undergone allogeneic HSCT at our center. RESULTS: Elevated liver or biliary enzyme levels were observed in almost half of the patients studied (n=40, 48.7%). Elevated total bilirubin (T-Bil) level was the most frequently observed unfavorable prognostic factor and had the greatest effect on overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) (probability of unfavorable outcome in patients without and with elevated T-Bil level: OS, 58.9% vs. 15.4%, p < 0.001; PFS, 46.4% vs. 15.4%, p < 0.001; NRM, 10.7% vs. 53.8%, p < 0.001). Moreover, the probability of an unfavorable outcome increased in relation to the degree of T-Bil elevation and absence of improvement over time in T-Bil level. CONCLUSION: Elevated T-Bil level was an important marker of outcomes for liver dysfunction after allogeneic HSCT.

Risk Factors for Acute Kidney Injury and Chronic Kidney Disease following Allogeneic Hematopoietic Stem Cell Transplantation for Hematopoietic Malignancies.

BACKGROUND: Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered common complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). OBJECTIVES AND METHOD: In this study, 114 patients who had undergone allo-HSCT were retrospectively analyzed to investigate the risk factors for onset of posttransplant AKI and CKD as defined by the new Kidney Disease Improving Global Outcomes criteria. RESULTS: Seventy-four patients (64.9%) developed AKI and 25 (21.9%) developed CKD. The multivariate analysis showed that the risk factors for developing stage 1 or higher AKI were age ≥46 years at the time of transplant (p = 0.001) and use of ≥3 nephrotoxic drugs (p = 0.036). For CKD, the associated risk factors were disease status other than complete remission at the time of transplantation (p = 0.018) and onset of AKI after transplant (p = 0.035). The 5-year overall survival (OS) was significantly reduced by development of AKI (p < 0.001), but not CKD. Posttransplant AKI significantly increased the 5-year nonrelapse mortality (p < 0.001), whereas posttransplant CKD showed an increasing tendency, but the difference was not significant. CONCLUSIONS: Posttransplant AKI impacts OS, significantly increases the risk of CKD, and is significantly associated with disseminated intravascular coagulation and use of ˃3 nephrotoxic drugs.

Importance of prognostic stratification via gene mutation analysis in elderly patients with acute myelogenous leukemia.

INTRODUCTION: Acute myelogenous leukemia (AML) in elderly patients is associated with an increased incidence of complications and treatment-related toxicity because of the frequency of comorbid disease and age-related deterioration in organ function. Despite advances in AML treatment in recent years, elderly patients have experienced limited benefit, and their outcomes remain poor. This study aimed to perform a comprehensive gene mutation analysis in elderly AML patients and identify gene mutations that could serve as prognostic factors. METHODS: An analysis of gene mutations was performed for 281 AML patients, including 98 elderly patients aged 65 years or above. RESULTS: Compared to younger AML patients, elderly patients showed a higher frequency of the following gene mutations: TP53 (P = 0.026), PTPN11 (P = 0.006), RUNX1 (P = 0.024), TET2 (P = 0.002), and ASXL1 (P = 0.023). The complete remission rate was significantly lower in DNMT3A mutation-positive cases (4.26%, P = 0.011) and TP53 mutation-positive cases (2.13%, P = 0.031) than in negative cases. The overall survival rate was significantly poorer in cases with FLT3-ITD (P = 0.003), DNMT3A (P = 0.033), or TP53 mutation (P < 0.001). Conversely, cases with PTPN11 mutation (P = 0.014) had a significantly more favorable prognosis. In multivariate analysis, FLT3-ITD (P = 0.011) and TP53 mutation positivity (P = 0.002) were independent poor prognostic factors, as were a performance status of 3 or above (P < 0.001) and poor cytogenetic prognosis (P = 0.001). In contrast, PTPN11 mutation positivity (P = 0.023) was an independent favorable prognosis factor. CONCLUSION: Analysis of gene mutations in elderly AML patients is very important, not only for establishing prognosis, but also for introducing appropriate molecular-targeted treatments.