Successful bridge therapy of gilteritinib to cord blood transplantation in relapsed acute myeloid leukemia after bone marrow transplantation.

The FMS-related tyrosine kinase 3 (FLT3) internal tandem duplication mutations (FLT3-ITD) positive acute myeloid leukemia (AML) is a disease with a dismal outcome. Gilteritinib is a second-generation FLT3 inhibitor with activity against ITD and high affinity toward the FLT3 receptor, thereby showing therapeutic potential for relapsed/refractory FLT3-mutated AML. Bone marrow transplantation (BMT) from a human leukocyte antigen (HLA) identical sibling donor was performed in a 38-year-old Japanese male with FLT3-ITD positive AML. Neutrophil engraftment (>0.5 × 109/L) was achieved on day 16, and bone marrow remission was revealed on day 32. The patient's AML relapsed hematologically four months after BMT and was resistant to salvage chemotherapy. Gilteritinib was administered and the patient achieved non-remission but 'stable disease' status according to the response criteria. During administration, liver damage was observed but controllable. The patient received cord blood transplantation (CBT) as the second hematopoietic stem cell transplantation (HSCT) three months after relapse and achieved second remission. There was no evidence of recurrence of AML four months after CBT. This case demonstrates that gilteritinib can control FLT3-ITD positive AML that relapsed early after initial HSCT and can bridge to second HSCT.

[Utility of core-needle biopsy as a primary diagnostic method for detecting aggressive B-cell lymphoma in the intensive care unit].

A 68-year-old male presented with appetite loss and abdominal distention. The whole-body computed tomography scan revealed an ileocecal mass with a large amount of ascites, which was consistent with malignant lymphoma. Due to the worsening of his general condition following admission, he was intubated and admitted to the intensive care unit (ICU). In the ICU, we performed a core-needle biopsy (CNB) on the left peritoneal mass, the findings of which showed a pathological diffuse infiltration of CD20+ middle-sized lymphoid cells. After chemotherapy was initiated, the patient showed complete response, suggesting that CNB can be performed immediately and safely even on a critically ill patient.

Development of Pre-Engraftment Syndrome, but Not Acute Graft-versus-Host Disease, Reduces Relapse Rate of Acute Myelogenous Leukemia after Single Cord Blood Transplantation.

The different effects of pre-engraftment syndrome (PES) and acute graft-versus-host disease (aGVHD) on outcomes after cord blood transplantation (CBT) are unclear. We retrospectively evaluated the impact of PES and aGVHD on relapse and survival after single-unit CBT in 138 adult patients with hematologic malignancies at our institution between 2004 and 2016. Multivariate analysis demonstrated that development of grade III-IV aGVHD, particularly with gut or liver involvement, significantly contributed to higher nonrelapse mortality (P < .001), but PES and grade II-IV aGVHD did not. In subgroup analyses of underlying disease type, the development of PES had a significant effect on decreased relapse (P = .032) and better disease-free survival (DFS) (P = .046) in patients with acute myelogenous leukemia (AML). These data suggest that PES is associated with a reduced relapse rate and better DFS in AML, indicating that the early immune reaction before neutrophil engraftment may provide a unique graft-versus-leukemia effect after single-unit CBT.

Platelet Transfusion Refractoriness in Single-Unit Cord Blood Transplantation for Adults: Risk Factors and Clinical Outcomes.

Platelet transfusion refractoriness (PTR) is frequently observed after allogeneic hematopoietic cell transplantation (HCT). However, the incidence of and risk factors for PTR, and impact of PTR on transplant outcomes after cord blood transplantation (CBT) have not been fully investigated. We retrospectively analyzed 185 adult patients who received single-unit CBT in our institute. The mean 16-hour corrected count increment (CCI) for the 5840 platelet transfusions was 3.68 × 109/L. Among them, 3196 transfusions (54.7%) were associated with a PTR with 16-hour-CCI <4.5 × 109/L. Results of multivariate analysis indicated that the following factors were significantly associated with decreased platelet transfusion responses: female sex with pregnancy history, male sex, the presence of HLA class I antibody, lower cord blood total nucleated cell dose, lower cord blood CD34+ cell dose, 3 locus HLA disparities, body temperature ≥38°C, C-reactive protein ≥10 mg/dL, cytomegalovirus reactivation, use of foscarnet, and use of liposomal amphotericin B. By contrast, graft-versus-host disease prophylaxis including methotrexate, ABO minor mismatch, use of ganciclovir, and use of linezolid were significantly associated with better platelet transfusion responses. PTR had a significant effect on poor neutrophil and platelet recovery, and overall mortality after CBT. These data suggest that early phase PTR may be predictive of engraftment and mortality after single-unit CBT for adults.

Efficacy and Safety of Low-Dose Liposomal Amphotericin B in Adult Patients Undergoing Unrelated Cord Blood Transplantation.

Liposomal amphotericin B (L-AMB) is widely used for empirical or preemptive therapy and treatment of invasive fungal infections after cord blood transplantation (CBT). We retrospectively examined the efficacy and safety of low-dose L-AMB in 48 adult patients who underwent CBT between 2006 and 2017 in our institute. Within the entire cohort, 42 patients (88%) received L-AMB as empirical or preemptive therapy. The median daily dose of L-AMB and the median cumulative dose of L-AMB were 1.20 mg/kg/day (range, 0.62 to 2.60 mg/kg/day) and 30.6 mg/kg (range, 0.7 to 241.5 mg/kg), respectively. The median duration of L-AMB administration was 21.5 days (range, 1 to 313 days). A documented breakthrough fungal infection occurred in 1 patient during L-AMB treatment, and 43 patients (90%) survived for at least 7 days after the end of L-AMB treatment. Grade 3 or higher hypokalemia and hepatotoxicity were frequently observed during L-AMB treatment. However, no patient developed an increase in serum creatinine levels of grade 3 or higher. In univariate analyses using a logistic regression model, a duration of L-AMB treatment of more than 21 days and a cumulative dose of L-AMB of more than 30 mg/kg were significantly associated with nephrotoxicity and grade 3 hypokalemia. These data suggest that low-dose L-AMB may be safe and effective in adult patients undergoing CBT.

Monocyte subsets and their phenotypes during treatment with BCR-ABL1 tyrosine kinase inhibitors for Philadelphia chromosome-positive leukemia.

BCR-ABL1 tyrosine kinase inhibitors (TKIs) are effective agents in the treatment of Philadelphia chromosome-positive leukemia. However, vascular events have developed in some patients receiving each TKI. The perturbation of circulating monocyte subsets and their expressions of chemokine and scavenger receptors are associated with the development of cardiovascular events. Here, we examined the subsets of circulating monocytes and their phenotypes in 51 patients treated with imatinib, nilotinib, and dasatinib, and 11 healthy subjects in our institute. Except for a negative association between the number of classical monocytes and imatinib treatment, the proportions and numbers of monocyte subsets were not significantly associated with TKI treatment. However, chemokine receptors, CCR2, CX3CR1 on classical monocytes, and scavenger receptor, CD204, on intermediate and non-classical monocytes were significantly associated with TKIs. These data demonstrated the relationships between alterations of chemokine and scavenger receptors on different monocyte subsets and the TKI treatments.

[Reduced-intensity umbilical cord blood transplantation for adult patients with fulminant aplastic anemia].

Allogeneic hematopoietic stem cell transplantation is recommended as a curative treatment option for fulminant aplastic anemia with no neutrophil despite the administration of granulocyte-colony stimulating factor. In the absence of an HLA-matched donor, unrelated cord blood transplantation (UCBT) is a treatment option that can be performed quickly. However, the optimal conditioning regimen of UCBT is yet to be established. We report two cases of fulminant aplastic anemia in adult patients who received UCBT. The first patient was a 52-year-old woman and the second was a 26-year-old man, both of whom received a conditioning regimen of total body irradiation (TBI; 2-4 Gy), fludarabine (Flu; 120 mg/kg), and cyclophosphamide (CY; 100 mg/kg) before UCBT. Short-term methotrexate and tacrolimus were used for prophylaxis of acute graft-versus-host disease (GVHD). Engraftments were achieved on days 26 and 19, and they exhibited complete donor chimerism by days 28 and 34. There was no evidence of acute GVHD, and therefore, the immunosuppressant drugs were discontinued. Reduced-intensity UCBT using a low-dose TBI/Flu/CY conditioning regimen could be an effective treatment option for fulminant aplastic anemia in the absence of a suitable donor.

Cryopreserved CD34+ Cell Dose, but Not Total Nucleated Cell Dose, Influences Hematopoietic Recovery and Extensive Chronic Graft-versus-Host Disease after Single-Unit Cord Blood Transplantation in Adult Patients.

Low cryopreserved total nucleated cell (TNC) dose in a cord blood (CB) unit has been shown to be associated with engraftment failure and mortality after single-unit cord blood transplantation (CBT) in adults. Although CB banks offer specific characteristics of cryopreserved cell dose, such as TNC, CD34+ cells, and colony-forming unit for granulocyte/macrophage (CFU-GM), the impact of each cell dose on engraftment and outcomes after single-unit CBT in adults remains unclear. We retrospectively analyzed the results of 306 CBTs for 261 adult patients in our institution between 1998 and 2016. The median age was 43 years (range, 16 to 68), the median actual body weight (ABW) was 56.2 kg (range, 36.2 to 104.0), the median ideal body weight (IBW) was 62.3 kg (range, 39.7 to 81.3), the median TNC dose was 2.46 × 107/ABW kg (range, 1.07 to 5.69), the median CD34+ cell dose was .91 × 105/ABW kg (range, .15 to 7.75), and the median CFU-GM dose was 24.46 × 103/ABW kg (range, .04 to 121.81). Among patients who achieved engraftment, the speed of neutrophil, platelet, and red blood cell engraftment significantly correlated with CD34+ cell dose, but not with TNC and CFU-GM dose, based on both ABW and IBW. In multivariate analysis, the incidence of extensive chronic graft-versus-host disease (GVHD) was significantly higher in patients receiving the highest CD34+ cell dose, based on both ABW and IBW. Nevertheless, no cell dose was associated with survival, transplantation-related mortality, and relapse. In conclusion, cryopreserved CD34+ cell dose was the best predictor for hematopoietic recovery and extensive chronic GVHD after CBT. The cryopreserved CD34+ cell dose should be used for unit selection criteria in single-unit CBT for adults.

Cytokine Profiles of Pre-Engraftment Syndrome after Single-Unit Cord Blood Transplantation for Adult Patients.

Clinical manifestation of high-grade fever and skin rash before neutrophil engraftment, termed pre-engraftment syndrome (PES) or pre-engraftment immune reaction, has been frequently observed after cord blood transplantation (CBT). The pathophysiology of PES is poorly understood, but cytokine storm during the early phase of CBT is thought to be 1 of the main cause of PES. However, the cytokine profiles of PES after CBT are unclear. Therefore, we examined the relationship between serum cytokine profiles and PES in 44 adult patients who received CBT in our institution between February 2013 and June 2016. Serum levels of 21 cytokines, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-17A, IL-17F, IL-18, IL-21, IL-22, IL-23, IL-33, monocyte chemoattractant protein-1, IFN-α, IFN-γ, and TNF-α, were measured by multiplex bead assays using a flow cytometer. The median time until the absolute neutrophil count was >.5 × 109/L was 21 days (range, 15 to 41 days). The cumulative incidence of PES was 79.6% (95% confidence interval, 63.3% to 88.5%) at 60 days after CBT. Serum levels of IL-5 (P = .009) and IL-6 (P = .01) at 2 weeks were significantly higher in patients who developed PES compared with those who did not develop PES. The conversion from naïve to effector or central memory phenotype of T cells was observed in PES. These data indicate that elevations of IL-5 and IL-6 around the time of clinical manifestation may be possible biomarkers for PES after CBT.

Contribution of post-transplantation therapy to sustained MRD negativity in multiple myeloma: a retrospective analysis.

Post-transplantation therapy is commonly performed in patients with myeloma and can prolong progression-free survival (PFS). However, whether post-transplantation therapy contributes to achieving and continuing MRD-negativity remains controversial. This retrospective analysis aimed to evaluate the clinical impact of post-transplantation therapy, including tandem autologous stem cell transplantation (ASCT), in myeloma patients. The subjects were 79 patients (median age: 62 years) who received induction therapy, including bortezomib and/or lenalidomide, of whom 58 underwent post-transplantation therapy. At the median follow-up time of 50 months, the 4-year PFS rate was significantly higher in patients who underwent post-transplantation therapy than those who did not (60.6% vs. 28.6%, P = 0.012). Multivariate analysis revealed post-transplantation therapy to be a significant prognostic factor for long PFS. Tandem ASCT followed by consolidation and/or maintenance therapies improved PFS and OS. The minimal residual disease (MRD)-negative rate was significantly higher in patients who underwent post-transplantation therapy than those who did not (50.9% vs. 16.7%, P = 0.006). Post-transplantation therapy contributed to sustained MRD-negativity, which predicted long PFS and overall survival. Patients frequently discontinued post-transplantation therapy due to adverse events within 4 months. In conclusion, post-transplantation therapy improved PFS and contributed to sustained MRD-negativity in myeloma patients.

Effect of Graft-versus-Host Disease on Post-Transplantation Outcomes following Single Cord Blood Transplantation Compared with Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for Adult Acute Myeloid Leukemia.

The possibility that HLA mismatches could reduce relapse after alternative HLA-mismatched allogeneic hematopoietic cell transplantation (HCT) is an attractive concept for treating acute myeloid leukemia (AML). However, it remains unclear whether the prognostic effect of graft-versus-host disease (GVHD) on survival differs between recipients of single-unit cord blood transplantation (CBT) and recipients of haploidentical HCT using post-transplantation cyclophosphamide (PTCy-haplo-HCT) for AML. The objective of this retrospective study was to compare the effect of acute GVHD and chronic GVHD on post-transplantation outcomes between recipients of CBT and recipients of PTCy-haplo-HCT. We retrospectively evaluated the effect of acute and chronic GVHD on post-transplantation outcomes following CBT and PTCy-haplo-HCT in adults with AML (n = 1981) between 2014 and 2020 using a Japanese registry database. In univariate analysis, the probability of overall survival was significantly greater in patients who developed grade I-II acute GVHD (P < .001, log-rank test) and limited chronic GVHD (P < .001, log-rank test) among CBT recipients, but these effects were not significant among PTCy-haplo-HCT recipients. In multivariate analysis, in which the development of GVHD was treated as a time-dependent covariate, the effect of grade I-II acute GVHD on reducing overall mortality differed significantly between CBT and PTCy-haplo-HCT (adjusted hazard ratio [HR] for CBT, .73, 95% confidence interval [CI], .60 to .87; adjusted HR for PTCy-haplo-HCT, 1.07; 95% CI, .70 to 1.64; P for interaction = .038). Our data demonstrate that grade I-II acute GVHD was associated with a significant improvement in overall mortality in adults with AML receiving CBT but not in recipients of PTCy-haplo-HCT.

Risk factors and survival impact of readmission after single-unit cord blood transplantation for adults.

Hospital readmissions have been used as a prognostic indicator for patients receiving allogeneic hematopoietic cell transplantation (HCT). However, the impact of readmission during early and mid-phase of cord blood transplantation (CBT) on long-term outcomes has not been fully investigated. We retrospectively analyzed 156 adult patients who received single-unit CBT in our institute. Among this cohort, thirteen patients (8%) were readmitted within 30 days after discharge, and 27 (17%) were readmitted within 90 days after discharge. The most common causes for readmission within 30 and 90 days of discharge were infection, chronic graft-versus-host disease, and relapse. Higher cryopreserved cord blood CD34+ cell count was only significantly associated with lower readmission within 90 days after discharge. The probabilities of overall survival were significantly lower in patients readmitted within 90 days after discharge compared with those who were not readmitted within 90 days after discharge in univariate and multivariate analysis. These data suggest that readmission within 90 days after discharge may have a significant impact on long-term mortality after single-unit CBT.

Circulating monocyte subsets in human chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is a major cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Monocytes/macrophages play a central role in inflammation, tissue repair, and fibrosis, which are the main clinical features of cGVHD. Here, we examined the expression levels of activation markers, chemokine receptors, and scavenger receptors for each circulating monocyte subset in 145 patients without disease recurrence at least 12 months after undergoing allogeneic HCT. There were no significant differences in the numbers and the proportions of each monocyte subset between patients without cGVHD and those with mild or moderate/severe cGVHD. Lower expression of CCR5 on classical monocytes, and higher expression of CD204 and lower expression of CX3CR1 on non-classical monocytes were associated with joint, and lung cGVHD, respectively. These data showed that alterations of activation markers and chemokine and scavenger receptors in each circulating monocyte subset were associated with the development of organ-specific cGVHD. Alterations of surface markers in each circulating monocyte subset may be candidate biomarkers for cGVHD.

Human T-cell Lymphotropic Virus Type-1 (HTLV-1)-associated Bronchioloalveolar Disorder Presenting with Mosaic Perfusion.

Human T-cell lymphotropic virus type-1 (HTLV-1)-associated bronchioloalveolar disorder (HABA) is a specific state with chronic and progressive respiratory symptoms caused by bronchiolar or alveolar disorder characterized by smoldering adult T-cell leukemia or the HTLV-I carrier state. We herein report a rare case of HABA with an initial presentation of mosaic perfusion in the lung. The diagnosis was made according to the results of a flow cytometry analysis of the bronchoalveolar lavage fluid and pathological findings. Clinicians must be careful to recognize that mosaic perfusion may be a radiological finding of HABA.