Search

Fludarabine with intravenous busulfan (6.4 mg/kg; FB2) and fludarabine with intermediate-dose melphalan (140 mg/m2; FM140) are the most widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation. FM140 generally has a lower relapse rate and higher non-relapse mortality (NRM), resulting in overall survival (OS) comparable to that seen with FB2. To evaluate the effect of reducing the melphalan dose, we retrospectively compared transplant outcomes in 156 patients who received FB2 (n = 103) or FM80 (n = 53) at our center (median age: 63 years; range 27–72 years). All patients received 4-Gy total body irradiation. Three-year OS, the cumulative incidence of relapse, and NRM were comparable between groups (FB2 vs. FM80, 58% vs. 47%, p = 0.24; 30% vs. 36%, p = 0.57; 17% vs. 21%, p = 0.44, respectively). There was no significant difference in the cumulative incidence of graft-versus-host disease (GVHD) at day 100, chronic GVHD at 3 years, or the 3-year GVHD-free/relapse-free survival rate. In the high-risk disease group, patients receiving FM80 tended to have lower 3-year OS (FB2 vs. FM80, 48% vs. 17%, p = 0.06). In summary, transplant outcomes following FB2 or FM80 were comparable except in patients with high-risk disease.

Dihydroorotate dehydrogenase (DHODH) catalyzes a rate-limiting step in de novo pyrimidine nucleotide synthesis. DHODH inhibition has recently been recognized as a potential new approach for treating acute myeloid leukemia (AML) by inducing differentiation. We investigated the efficacy of PTC299, a novel DHODH inhibitor, for myelodysplastic syndrome (MDS). PTC299 inhibited the proliferation of MDS cell lines, and this was rescued by exogenous uridine, which bypasses de novo pyrimidine synthesis. In contrast to AML cells, PTC299 was inefficient at inhibiting growth and inducing the differentiation of MDS cells, but synergized with hypomethylating agents, such as decitabine, to inhibit the growth of MDS cells. This synergistic effect was confirmed in primary MDS samples. As a single agent, PTC299 prolonged the survival of mice in xenograft models using MDS cell lines, and was more potent in combination with decitabine. Mechanistically, a treatment with PTC299 induced intra-S-phase arrest followed by apoptotic cell death. Of interest, PTC299 enhanced the incorporation of decitabine, an analog of cytidine, into DNA by inhibiting pyrimidine production, thereby enhancing the cytotoxic effects of decitabine. RNA-seq data revealed the marked downregulation of MYC target gene sets with PTC299 exposure. Transfection of MDS cell lines with MYC largely attenuated the growth inhibitory effects of PTC299, suggesting MYC as one of the major targets of PTC299. Our results indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells and acts in a synergistic manner with decitabine. This combination therapy may be a new therapeutic option for the treatment of MDS.

Even in the era of high-intensity chemotherapy, disease recurrence remains a major cause of treatment failure in adult patients with Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (Ph-negative B-ALL). For patients who achieved second complete remission (CR2) with salvage chemotherapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be the best curative treatment. However, limited data are available on the outcomes of allo-HSCT for adult Ph-negative B-ALL in CR2 in the high-intensity chemotherapy era. We evaluated the transplantation outcomes of adult patients with Ph-negative B-ALL in CR2 compared with those in CR1. We also clarified the prognostic factors among adult allo-HSCT recipients with Ph-negative B-ALL in CR2. We conducted a nationwide retrospective study using the data form Japanese transplant registry database. Patients aged ≥16 years and underwent their first allo-HSCT between 2003 and 2017 were included. The 3-year overall survival (OS) rate of the patients in CR2 (n = 382) was significantly lower than that in first complete remission (n = 1375) (51.8% versus 68.1%; P.001), accompanied by a higher relapse rate (34.2% versus 17.6% at 3 years; P.001). In a multivariate analysis among CR2 patients, time from diagnosis to allo-HSCT (≤2 years) was a significant factor for OS (hazard ratio [HR] 1.87; P.001) and relapse (HR = 1.88; P.001), whereas age at allo-HSCT (≥30 years) was a significant factor for OS (HR = 2.10, P.001) and nonrelapse mortality (HR = 2.68; P.001). By assigning a score of 1 to each factor, the 3-year OS rate of CR2 patients significantly stratified: 70.7% in patients with score 0, 56.4% with score 1, and 28.4% with score 2 (P.001). The survival outcomes of allo-HSCT in adult Ph-negative B-ALL patients in CR2 were inferior to those in CR1 in the high-intensity chemotherapy era, mainly because of the higher relapse rate. Among the CR2 patients, the short time between diagnosis and allo-HSCT was a significant risk factor for disease recurrence and overall mortality. Better disease control with novel treatment strategies may be needed for early relapse. In addition, the nonrelapse mortality rate in patients over 30 years of age was particularly high among CR2 patients, suggesting the need for improved supportive care for these patients. Further studies are warranted on the outcomes of allo-HSCT after achieving CR2 with novel drugs, such as inotuzumab ozogamicin and blinatumomab.

Cytomegalovirus (CMV) infection is a major complication in allogeneic stem cell transplantation. The utility of CMV prophylaxis with letermovir has been reported; however, the specific applications remain unclear. In this study, we retrospectively analyzed large-scale registry data (N = 10 480) to clarify the risk factors for nonrelapse mortality (NRM) in connection with CMV reactivation. First, we identified risk factors for CMV reactivation using multivariate analysis and developed a scoring model. Although the model effectively stratified reactivation risk into 3 groups (43.7% vs 60.9% vs 71.5%; P < .001), the 3-year NRM was significantly higher in patients with CMV reactivation, even in the low (20.9% vs 13.0%, P < .001), intermediate (21.4% vs 15.6%; P < .001), and high (29.3% vs 18.0%; P < .001) reactivation risk groups. Next, survival analysis considering competing risks, time-dependent covariates, and interaction terms for exploring the heterogeneous impact of CMV reactivation on NRM in the training cohort revealed that chronic myeloid leukemia (CML) (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.05-2.96; P = .033), good performance status (PS) (HR, 1.42; 95% CI, 1.04-1.94; P = .028), HLA-matched donor (HR, 1.34; 95% CI, 1.06-1.70; P = .013), and standard-risk disease (HR, 1.28; 95% CI, 1.04-1.58; P = .022) were associated with increased NRM. In the test cohort, CMV reactivation was significantly associated with increased 3-year NRM among patients with 2 to 4 factors (22.1% vs 13.1%; P < .001) but was comparable among patients with 0 or 1 factor (23.2% vs 20.4%; P = .62). We propose that CMV prophylaxis should be determined based on reactivation risk, as well as these other factors.

Platelet-derived growth factor receptor (PDGFRβ) gene is located on chromosome 5q31-33; its rearrangement leads to constitutive tyrosine kinase activity [1]. Hematological malignancies associated w...

There are few reports on allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult B-cell acute lymphoblastic leukemia (B-ALL) harboring t(1;19)(q23;p13.3). We used nationwide registry data of Japan for 2003–2016 to evaluate transplant outcomes and clarified prognostic factors among adult allo-HSCT recipients with B-ALL harboring t(1;19)(q23;p13.3) (n = 125). Compared with cytogenetically normal (CN) B-ALL patients (n = 1057), their 3-year overall survival (OS) rates were comparable (55.4% for t(1;19) and 54.4% for CN; P = 0.76). Considering only patients in first complete hematological remission (CR1), the 3-year OS rates remained comparable (70.5% for t(1;19) and 67.8% for CN; P = 0.86). For t(1;19) patients in CR1, minimal residual disease (MRD) at transplantation was associated with relatively worse outcomes. The 3-year OS rates were 43.6% for patients with MRD and 77.4% for those without it (P = 0.016). The 3-year relapse rates were 54.5% for patients with MRD and 12.8% for those without it (P

Allogeneic hematopoietic stem cell transplantation (HSCT) could be the only curative therapy for patients with relapsed/refractory acute leukemia (RRAL). Many reports have described unmanipulated haploidentical HSCT (HID-HSCT) using high-dose antithymocyte globulin (ATG). However, the transplant outcomes of HID-HSCT using very low-dose ATG (thymoglobulin, 2–2.5 mg/kg) and methylprednisolone (mPSL, 1 mg/kg) for patients with RRAL have not been reported. We compared the outcomes of 46 patients with RRAL who underwent HID-HSCT using very low-dose ATG (thymoglobulin) and mPSL with the outcomes of 72 patients who underwent non-HID-HSCT. Patient characteristics differed regarding conditioning intensity (myeloablative; 19.6% in HID-HSCT vs. 61.1% in non-HID-HSCT, P

We compared the transplant outcomes of adult patients with B-cell acute lymphoblastic leukemia characterized by high hyperdiploidy (HeH; 51–65 chromosomes) (n = 29) and those with a normal karyotyp...

Vacuolar myelopathy (VM) is known to be a neurological complication in patients with acquired immunodeficiency syndrome (AIDS). In autopsy-based studies, VM was reported in approximately 20-50% of patients with AIDS. It manifests in various says, mainly presenting as a painless spastic paraparesis with a sensory ataxia. We present a rare case of VM after bone marrow transplantation (BMT) in a patient without AIDS. A 50-year-old man developed weakness in the lower legs, leg muscle atrophy, and difficulty in walking 86 days after BMT. The patient died from septic shock on day 309. The autopsy revealed intralamellar vacuolation in the spinal white matter, which was compatible with VM.

Total body irradiation using intensity-modulated radiation therapy total body irradiation (IMRT-TBI) by helical tomotherapy in allogeneic hematopoietic stem cell transplantation (allo-HSCT) allows for precise evaluation and adjustment of radiation dosage. We conducted a single-center pilot study to evaluate the safety of IMRT-TBI for allo-HSCT recipients. Patients with hematological malignancies in remission who were scheduled for allo-HSCT with TBI-based myeloablative conditioning were eligible. The primary endpoint was the incidence of adverse events (AEs). Secondary endpoints were engraftment rate, overall survival, relapse rate, non-relapse mortality, and the incidence of acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively). Between July 2018 and November 2018, ten patients were recruited with a median observation duration of 571 days after allo-HSCT (range, 496–614). D80% for planning target volume (PTV) in all patients was 12.01 Gy. Average D80% values for lungs, kidneys and lenses (right/left) were 7.50, 9.03 and 4.41/4.03 Gy, respectively. Any early AEs (within 100 days of allo-HSCT) were reported in all patients. Eight patients experienced oral mucositis and gastrointestinal symptoms. One patient experienced Bearman criteria grade 3 regimen-related toxicity (kidney and liver). All cases achieved neutrophil engraftment. There was no grade III–IV aGVHD or late AE. One patient died of sinusoidal obstruction syndrome 67 days after allo-HSCT. The remaining nine patients were alive and disease-free at final follow-up. Thus, IMRT-TBI was well tolerated in terms of early AEs in adult patients who underwent allo-HSCT; this warrants further study with longer observation times to monitor late AEs and efficacy.

Although Stenotrophomonas maltophilia causes substantial morbidity and mortality in immunocompromised patients, it has not been described as a causal pathogen of neutropenic enterocolitis (NEC). We describe the first case of histologically-confirmed NEC caused by S. maltophilia accompanied by bacteremia and pneumonia after salvage chemotherapy for acute myeloid leukemia relapse following a second hematopoietic stem cell transplantation. S. maltophilia should be included as a pathogenic organism of NEC in severely immunocompromised patients to prevent a delayed diagnosis, which carries a high risk of inappropriate antimicrobial selection and fatal outcome.

The World Health Organization (WHO) has categorized acute undifferentiated leukemia (AUL) as a rare subtype of acute leukemias of ambiguous lineage (ALAL). The prognosis of AUL is considered poor a...

There have been many reports regarding tyrosine kinase inhibitor (TKI) administration to prevent relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, there are no commonly accepted standards for the choice of TKIs. We retrospectively analyzed the clinical features of Ph+ALL patients who received TKIs after allo-HSCT at our institution. The prophylactic administration of TKIs (pro) occurred in eight patients, and six patients received preemptive TKI administration (pre). The median follow-up period after allo-HSCT was 1,427 (range, 161-2,428) days in the pro group and 773.5 (range, 156-2,243) days in the pre group. Only one patient with non-hematological complete remission before allo-HSCT relapsed among the patients in the pro group. In the pre group, four patients treated with only TKIs achieved negativity of minimal residual disease. The 2-year overall survival rate after allo-HSCT was 85.7% in the pro group and 100% in the pre group. We used lower doses of TKIs compared with previous reports and this analysis shows that the dose is safe and effective as the treatment.

Although the indications for allogeneic hematopoietic stem cell transplantation (allo-HSCT) as a treatment for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) and Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (B-ALL) are similar, few studies have compared its outcomes for T-ALL/LBL and Ph-negative B-ALL. The clinical data of 28 patients with T-ALL, 16 with T-LBL, and 99 with Ph-negative B-ALL who underwent the first allo-HSCT from 2000 to 2019 were retrospectively analyzed. Complete remission (CR) rates at allo-HSCT were 79 %, 63 %, and 75 % for T-ALL, T-LBL, and B-ALL, respectively; the 3-year overall survival (OS) rates were 55.7 %, 56.2 %, and 58.6 %, respectively (p = 0.92). Univariate analysis revealed that disease subtypes were not significantly associated with OS (B-ALL vs. T-ALL: hazard ratio [HR]=0.89, p = 0.70; T-LBL vs. T-ALL: HR=0.87, p = 0.75), and CR at allo-HSCT was the only prognostic factor for OS (HR=0.25, p < 0.001). Multivariate analysis demonstrated that CR at allo-HSCT was the only predictor of OS (HR=0.24, p < 0.001). In all three disease subtypes, patients in CR at allo-HSCT tended to have a lower cumulative incidence of relapse than did those in non-CR (T-ALL: 13.6 % vs. 50.0 %, p = 0.10; T-LBL: 20.0 % vs. 50.0 %, p = 0.21; B-ALL: 10.0 % vs. 56.0 %, p < 0.01). Thus, the outcomes of allo-HSCT for T-ALL/LBL were comparable to those of Ph-negative B-ALL. Irrespective of the disease subtypes, achieving CR before allo-HSCT was associated with a favorable OS. Further advances in chemotherapy before allo-HSCT and defining the optimal timing of allo-HSCT would improve the prognosis of patients with T-ALL/LBL.

Recent reports suggested that central nervous system (CNS) involvement (CNS+) in patients with acute myeloid leukemia (AML) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not an independent predictor of survival after allo-HSCT. However, these studies did not analyze minimal residual disease in the CNS at the time of allo-HSCT. We evaluated the effect of residual CNS+ on the transplant outcomes of 214 AML patients in a single institution. Twenty-one (10%) patients were diagnosed with CNS+ prior to allo-HSCT. Of these, 13 patients had CNS disease at the time of allo-HSCT. The patients in CNS+ AML remission at the time of allo-HSCT had better overall survival (OS) than the patients who were not in remission (2-year OS: 55% vs. 7.7%, p = 0.0001). In multivariate analyses, CNS+ at the time of allo-HSCT (hazard ratio (HR), 1.9; 95% confidence interval (CI), 1.05-3.59; p = 0.04), age over 50 years at the time of allo-HSCT, and non-complete remission disease status in bone marrow at the time of allo-HSCT were independent adverse factors for OS. However, a prior history of CNS+ before allo-HSCT did not independently affect OS (HR, 1.27; 95% CI 0.53-2.07; p = 0.6). Early diagnosis and eradication of CNS+ at the time of allo-HSCT may be necessary to improve the outcome for patients with CNS+ AML.

Extramedullary relapse (EMR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is relatively rare. The most commonly reported sites in acute lymphoblastic leukemia (ALL) patients after allo-HSCT are soft tissue and the central nervous system, and the gastrointestinal system is an uncommon site. We herein report a unique case with massive hematemesis resulting from gastrointestinal relapse of ALL after allo-HSCT. Upper gastrointestinal endoscopy showed bleeding from a 1.5-cm submucosal tumorous lesion with central ulceration on the anterior wall of the stomach. At the same time, computed tomography revealed extramedullary relapse at the breast and bilateral adrenal glands.

Polycomb repressive complexes (PRCs) are epigenetic regulators that mediate repressive histone modifications. PRCs play a pivotal role in the maintenance of hematopoietic stem cells through repression of target genes involved in cell proliferation and differentiation. Next-generation sequencing technologies have revealed that various hematologic malignancies harbor mutations in PRC2 genes, such as EZH2, EED, and SUZ12, and PRC1.1 genes, such as BCOR and BCORL1. Except for the activating EZH2 mutations detected in lymphoma, most of these mutations compromise PRC function and are frequently associated with resistance to chemotherapeutic agents and poor prognosis. Recent studies have shown that mutations in PRC genes are druggable targets. Several PRC2 inhibitors, including EZH2-specific inhibitors and EZH1 and EZH2 dual inhibitors have shown therapeutic efficacy for tumors with and without activating EZH2 mutations. Moreover, EZH2 loss-of-function mutations appear to be attractive therapeutic targets for implementing the concept of synthetic lethality. Further understanding of the epigenetic dysregulation associated with PRCs in hematological malignancies should improve treatment outcomes.

Background Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder characterized by ineffective and clonal hematopoiesis accompanied by morphological dysplasia and variable cytopenia. Although DNA methyltransferase inhibitors have been used as chemotherapeutic agents for high-risk MDS, the disease become uncontrolled in many cases. Dihydroorotate dehydrogenase (DHODH) catalyzes a rate-limiting step in de novo pyrimidine nucleotide synthesis. DHODH inhibition has recently been recognized as a potential new approach for treating acute myeloid leukemia (AML) by inducing differentiation. We herein investigated the efficacy of PTC299, a novel DHODH inhibitor, for MDS. Methods Anti-MDS efficacy of PTC299 was studied using human MDS cell lines and primary MDS cells in vitro. In addition, we assessed the efficacy of PTC299 in xenograft mouse models of MDS by AkaBLI system, which is composed of AkaLumine-HCl and Akaluc. AkaBLI system has improved performance by a factor of 100 to 1,000 over the conventional bioluminescence imaging system composed of D-luciferin and firefly luciferase. Mechanistic studies were conducted via LC-MS/MS, cell cycle analysis, RNA-seq and RT-qPCR. Results In contrast to AML cells, PTC299 was inefficient at inhibiting growth and inducing the differentiation of MDS cells, but synergized with hypomethylating agents to inhibit the growth of MDS cells. As a single agent, PTC299 prolonged the survival of mice in xenograft models using MDS cell lines, and was more potent in combination with decitabine. Of interest, PTC299 enhanced the incorporation of decitabine, an analog of cytidine, into DNA by inhibiting pyrimidine production, thereby enhancing the cytotoxic effects of decitabine. Conclusions Our results indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells and acts in a synergistic manner with decitabine.

Autologous stem-cell transplantation is an effective procedure for the treatment of multiple myeloma, and involves the collection of hematopoietic stem cells (HSCs). However, in some patients, HSCs in the bone marrow fail to mobilize. Pomalidomide upregulates CXCR4 in hematopoietic stem cells, in a manner similar to that of lenalidomide, and is, thus, likely to have a negative impact on hematopoietic stem-cell mobilization in multiple myeloma patients. Here, we report the two cases in which hematopoietic stem cells were mobilized using plerixafor plus granulocyte-colony stimulating factor after exposure to lenalidomide and pomalidomide. Use of plerixafor with a sufficient washout period may lead to successful mobilization following pomalidomide use, although further study of this potential use is needed.

A 24-year-old man with acute lymphoblasticleukemia underwent allogeneicperipheral blood stem cell transplantation (allo-PBSCT)from a human leukocyte antigen-matched sibling after myeloablative conditioning, with a regimen including total body irradiation(TBI)(12 Gy/6 fractions), 6 years ago. The patient developed extensive chronic graft-versus-host disease(cGVHD)of the skin, mouth, liver, and gut four months after allo-PBSCT. Treatment with cyclosporine and prednisolone was necessary to control the cGVHD. Six years after allo-PBSCT, the patient experienced odynophagia and was diagnosed with cervical esophageal squamous cell carcinoma(cT1bN1M0, cStage II B). Because we considered laryngeal preservation, risk of anastomotic leakage, and infection related to the operation, the patient was planned to receive chemoradio- therapy with 5-fluorouracil and cisplatin. Regarding irradiation, the patient received radiotherapy(50.4 Gy/28 fractions)for a primary tumor and lymph node without an elective nodal area. The patient achieved complete response and remained disease- free without any treatment-related complications for 3 years.

Key Points Bacterial diversity was restored after FMT with oral frozen capsules, with improvement of diarrhea. Oral FMT for steroid-refractory acute gGVHD is feasible and could be effective.

Dealing with the recent series of allogeneic hematopoietic stem cell transplantation (allo-SCT) performed this decade, we reassessed the clinical impact of pretransplant surgical procedures (SP) for pulmonary lesions of invasive fungal disease (IFD) on subsequent transplant outcome. We focused on the clinical outcomes of seven patients with pulmonary IFD who underwent segmentectomy (n = 4), lobectomy (n = 2) or abscess incision with drainage only (n = 1), and compared results to those of 21 patients carrying pulmonary IFD who never underwent invasive SP before allo-SCT. The rate of exacerbation of pulmonary lesions by 180 days after allo-SCT did not differ significantly between groups (32.2% vs 42.9%, P = 0.69). Moreover, no significant differences in non-relapse mortality (46.4% vs 42.3%, P = 0.93) or overall survival (53.6% vs 30.9%, P = 0.45) at 1 year were evident between groups. These results indicate that pretransplant SP for pulmonary lesions might have no survival benefit under the current antifungal prophylaxis or treatment modality.

A 35-year-old man who previously underwent splenectomy for hereditary spherocytosis at age 29 visited our hospital complaining of fatigue that had started 7 days ago and right upper abdominal pain. Laboratory data showed increased white blood cell and eosinophil count accompanied by severe transaminitis and clotting abnormalities. Computed tomography scan showed multiple embolisms in the portal vein, superior mesenteric vein, right pulmonary artery, and inferior vena cava. Severe liver damage presumably caused by portal vein thrombosis was also observed. Anticoagulant therapies consisting of continuous arterial infusion of urokinase from the superior mesenteric artery and an intravenous infusion of recombinant human thrombomodulin and heparin dissolved the systemic thrombosis. Concurrently administered prednisone decreased the eosinophil count. With regard to eosinophilia, we were unable to find any connective tissue diseases, antibodies to parasites, or genetic anomalies including PDGFRA, PDGFRB, and FGFR1. Hence we diagnosed the patient with idiopathic hypereosinophilic syndrome (HES). Although thromboembolisms in patients with HES have been reported, the literature on portal vein thrombosis associated with HES is scarce. In the present case, the previous splenectomy may have contributed to the portal vein thrombosis.

We report three cases of fusariosis that occurred during the treatment of acute leukemia, during the past 5 years at our institution. Case 1: A 70-year-old male with relapsed and refractory acute lymphoblastic leukemia (ALL) developed fever and multiple nodular lesions in both the lungs. Blood culture that was subsequently obtained revealed Fusarium species. Treatment with liposomal-amphotericin B (L-AMB) was ineffective, and the condition of the patient deteriorated rapidly leading to death. Case 2: A 28-year-old male with T-ALL developed echthyma gangrenosum (EG) ulcers on the scrotum during conditioning for transplantation. Antifungal therapy with L-AMB was ineffective, and later, itraconazole and micafungin (MCFG) were introduced. However, the engraftment was not achieved, and the patient died on day 27. Microbiological examination of EG samples collected on day 13 revealed infection by Fusarium species post mortem. Case 3: A 50-year-old male with blast crisis of chronic myeloid leukemia developed EG primarily on the trunk during chemotherapy. The patient died without any response to L-AMB and MCFG. A culture obtained from EG on day 19 yielded Fusarium species, post mortem. The prognosis of fusariosis is extremely poor. However, skin lesions such as EG may assist in the early diagnosis of the disseminated disease.

No standard therapy for peripheral T-cell lymphomas (PTCLs) has been established, and treatment outcomes are poor. Upfront stem cell transplantation has been investigated in several studies, some of which have reported promising outcomes. However, some patients maintain long-term remission after chemotherapy alone. It is thus important to predict sensitivity to first-line chemotherapy to optimize treatment strategies. In the present study, we retrospectively analyzed time to treatment failure (TTF) of first-line chemotherapy in 59 patients with PTCLs. On multivariate analysis for TTF, elevated lactate dehydrogenase level, hypoalbuminemia, and high neutrophil-to-lymphocyte ratio were significant prognostic factors. Using these three factors, we also developed a new model that effectively distinguished patient outcomes. The TTF rate at 1 year from diagnosis was 71.4% in patients with score 0 (0 factor), 31.8% with score 1 (1 factor) and 4.5% with score 2 (2–3 factors) (P

We describe herein the clinical outcomes of 16 patients with chronic myeloid leukemia in the chronic phase who stopped the administration of tyrosine kinase inhibitors (TKI) after maintaining undetectable levels of major BCR-ABL1, based on real-time quantitative polymerase chain reaction, for prolonged periods (undetectable MR for a median of 2,100 days (822-4,068). The reasons for discontinuing TKI were enrollments in a clinical trial testing discontinuation of these agents (n=9), adverse effects (n=2) or financial problems (n=5). After TKI discontinuation, patients were followed for a median of 551 days (154-2,446). A total of 8 patients (50%) experienced molecular relapse after a median of 119 days (28-171). Among them, 6 patients who lost major molecular response (MMR) were treated with imatinib (n=2) or dasatinib (n=4), while 2 patients who lost undetectable MR after discontinuing TKI (1 each had taken bostinib and imatinib) but maintained MMR were carefully monitored without re-administration of TKI. Of 6 patients who re-started TKI, 4 (67%) achieved undetectable MR but the other 2 achieved only MMR. The results of this small, retrospective study may support the current understanding of treatment discontinuation, possibly leading to a sustained deep molecular response in some patients.

A 60-year-old man with myelodysplastic syndrome underwent allogeneic transplantation of female umbilical cord blood in 2010 and sustained a complete remission. He experienced severe pain in his left hip joint and was admitted to the orthopedic surgery division of our institution in February 2015. After admission, he was suspected to have hemophagocytic syndrome (HPS) and was thus transferred to the hematology division. Bone marrow aspiration revealed hyper-cellular marrow filled with abnormal collapsed cells, consistent with bone marrow necrosis (BMN). As there was no evidence of infection, collagen disease, or occult cancer, he was diagnosed with HPS of unknown origin and treated with dexamethasone, cyclosporine A, and etoposide according to the HLH-2004 protocol. Although his general condition and laboratory findings showed amelioration, morphologically abnormal cells appeared in peripheral blood two weeks after treatment. Bone marrow aspiration showed BMN with increased abnormal cells, positive for CD117 and MPO. Sex chromosome FISH analysis revealed donor chimerism and cytogenetic analysis showed 46XX, +1, der (1;7) (q10;q10). He was diagnosed with donor cell leukemia (DCL) and received salvage chemotherapy. However, he died because of severe pneumonia and sepsis without neutrophil recovery at day 68. We herein report this rare case of DCL with BMN.

From January 2012 to September 2015, 49 patients received biosimilar filgrastim (BF) after allogeneic bone marrow transplantation (BMT, n = 31) or peripheral stem cell transplantation (PBSCT, n = 18) in our institution. To evaluate the clinical impact of BF on transplant outcomes of these patients, we compared hematological recovery, overall survival (OS), disease-free survival (DFS), transplantation-related mortality (TRM), cumulative incidence of relapse (CIR), and acute and chronic graft-versus-host disease (GVHD) with those of control patients who received originator filgrastim (OF) after BMT (n = 31) or PBSCT (n = 18). All cases were randomly selected from a clinical database in our institution. In both the BMT and PBSCT settings, neutrophil recovery (17 vs. 19 days in BMT; 13 vs. 15 days in PBSCT) and platelet recovery (27 vs. 31 days in BMT; 17 vs. 28 days in PBSCT) were essentially the same between BF and OF. They were also comparable in terms of OS, DFS, TRM, CIR, and the incidence of acute GVHD and chronic GVHD. On multivariate analysis, the use of BF in both BMT and PBSCT was not a significant factor for adverse transplant outcomes. Although BF significantly reduced filgrastim costs in both BMT and PBSCT, total hospitalization costs were not significantly different between BF and OF.

A 58-year-old female was diagnosed with Philadelphia chromosome positive chronic myeloid leukemia (CML) in blast crisis (BC) in 2004. The patient received imatinib, which quickly induced molecular remission, and subsequently underwent bone marrow transplantation (BMT) from an unrelated human leukocyte antigen (HLA)-identical donor. The post-transplant clinical course was essentially uneventful. In 2014, ten years after the BMT, the patient was admitted to our hospital complaining of lymphadenopathy, and blasts were observed in peripheral blood. The patient was diagnosed as having a CML relapse in myeloid BC, with leukemic infiltration in lymph nodes, and was treated with dasatinib. Subsequently, pleural effusion developed and nilotinib was administered, which induced normal blood counts without blasts and partial cytogenetic remission, one month after administration. Six months after the relapse, this patient underwent a second BMT from an HLA-matched unrelated donor. Recent studies have demonstrated the cumulative incidence of CML relapse more than five years after allogeneic hematopoietic stem cell transplantation (allo-HSCT) to be higher than in acute myeloid leukemia. Although rare, the possibility of late relapse should be considered in patients diagnosed with CML after allo-HSCT.

A 53-year-old woman was admitted with right upper-extremity pain and multiple subcutaneous masses. Bone marrow aspirate showed hypercellular marrow with increased myeloid components at all stages of maturation. Cytogenetic analysis of the bone marrow revealed 100% Philadelphia chromosome positivity along with BCR/ABL gene rearrangement, as demonstrated by polymerase chain reaction (PCR). A diagnosis of chronic phase of chronic myeloid leukemia (CML) was therefore made. Biopsy of one of the subcutaneous masses showed proliferation of granulocytes in various stages of differentiation. There were also erythroid cells and megakaryocytes, without p53 and CD34-positive blasts. These results suggested that the subcutaneous masses had developed from extramedullary hematopoiesis, not blastomas. The patient was administered dasatinib (DA) 140 mg, combined with radiation therapy for pain and peripheral neuropathy from the right axial extramedullary tumor. The patient showed complete hematological remission and the subcutaneous masses had disappeared 1 month after starting administration of DA. Because the patient did not achieve a cytogenetic response, the tyrosine kinase inhibitor nilotinib was administered. She will undergo allogeneic stem cell transplantation in the near future. Extramedullary hematopoiesis in the early stages of CML is uncommon. Our case emphasizes the need to elucidate the pathogenesis of extramedullary hematopoiesis in the early stages of CML.

Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for acute myeloid leukemia (AML), but non-relapse mortality (NRM) remains obstacles to this treatments. Therefore, precise comorbidity evaluation before transplantation is crucial for better outcomes. One of the most frequently used tools for assessing the risk profile of transplant recipients is the hematopoietic cell transplantation comorbidity index (HCT-CI), which only incorporates information of the antibiotics use on day 0 as an infection-related factor, however, some important components, such as the number and severity of infectious episodes, are not included. Methods From December 2001 to December 2005, 1,057 newly diagnosed adult AML patients were registered to JALSG AML201 (Blood 2011; 117: 2358-65, 2366-72). Of them, the 121 evaluable patients who underwent allo-HSCT in the first hematological complete remission were analyzed. We have checked the above mentioned components, in addition to the interval from the last chemotherapy to transplantation, in these 121 patients and analyzed whether these factors might affect the subsequent transplant outcome. Results The median age was 37 years (range, 15-61). Regarding cytogenetic risk, 7 (6%), 92 (76%), and 15 (12%) patients were categorized as favorable, intermediate and high risk, respectively. The median follow-up period after transplantation was 939 days (range 19-2204). At 2 years after allo-HSCT, overall survival, leukemia free survival, cumulative incidence of relapse (CIR), and NRM for all patients were 73.2%, 65.4%, 19.4%, and 15.8%, respectively. A total of 106 (88%) patients developed at least one infectious episode as 102 (84%) patients faced to febrile neutropenia (FN), 45 (37%) patients experienced severe infection (≥ grade 3), and 27 (22%) patients eventually developed sepsis. Regarding the episode of FN, 52 (43%) patients experienced more than 2 times during chemotherapy. The median cycles of chemotherapy before transplantation was 4 (range, 1-6) and the median interval from the first day of last chemotherapy to transplantation was 77 days. The ROC curve indicated mild correlations between NRM and the interval with an area under the curve of 52% and the cutoff value at 113 days. The number of infectious episodes or severity of infection did not carry a significant impact on NRM at 2 years as 19.2% in FN with ≥3 episodes vs. 13.2% in FN with 0-2 episodes; p=0.18, 18.0% in patients with severe infection vs. 14.5% in patients without severe infection; p=0.49. However, in view of bone marrow transplant (BMT) recipients (n=76), multiple FN episodes was significantly associated with higher NRM (23.5% vs. 7.2% at 2 years, p=0.029) (Fig 1A). While, the relative shorter interval ( Conclusion Combining the number of infectious episodes and interval of chemotherapy to transplantation may predict a transplant outcome in AML patients. Providing an adequate interval from the last chemotherapy to transplantation may reduce NRM especially in BMT recipients who developed multiple FN episodes during induction or consolidation chemotherapy. Figure 1. Figure 1. Disclosures Kiyoi: Astellas Pharma Inc.: Research Funding; Novartis Pharma K.K.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sanofi K.K.: Research Funding; Celgene Corporation: Research Funding; FUJIFILM Corporation: Research Funding; Phizer Japan Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Bristol-Myers Squibb: Honoraria. Naoe:Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Pfizer Japan Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding.

We herein describe the case of a 77-year-old woman with acquired factor X deficiency that was likely caused by atypical amyloidosis. The patient developed severe gastrointestinal bleeding as a result of a significant decrease of factor X activity. Neither proteinuria nor diarrhea was observed as an initial manifestation. Although a bone marrow examination revealed direct fast scarlet-positive extracellular deposits, they did not exhibit red-to-green dichroism under polarized light. Immunofluorescence microscopy showed that the fibrillar proteins were positive for CD138 but negative for β2-microglobulin or amyloid A antibodies. These atypical pathological features of immunoglobulin light chain-amyloidosis in this patient might be related to its unique clinical presentation.

We present the case of a 53-year-old woman with breast cancer who developed vertebral body metastases at the 7-10th thoracic vertebrae (Th7-10) and started radiotherapy in April 2011. Radiotherapy was administered in 15 fractions of 2.5 Gy each to the vertebral bodies. Total dose to the tumor was 37.5 Gy. She gradually developed severe paresthesia and numbness of the lower extremities, and sensory deficit below the Th7 level was revealed in July 2013. Laboratory tests, which included cerebrospinal fluid analysis, were unremarkable. Magnetic resonance imaging (MRI) of the spinal cord demonstrated an intramedullary enhanced lesion extending at the Th7-8 level on gadolinium-enhanced images (Fig. 1a). T2-weighted images showed an oval hyperintense signal area and edema (Fig. 1b). Suspected diagnoses according to MRI were intramedullary spinal cord metastasis (ISCM) or delayed radiation myelopathy (DRM). Subsequent F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG PET/CT) (injected dose, 267.7 MBq; serum glucose level, 103 mg/dl; time between injection and acquisition: 60 min [early], 120 min [delayed]) showed focal uptake at the Th7 to Th8 level of the spinal cord (maximum standardized uptake value [SUVmax]: 2.76, early; 3.60, delayed) on early (Fig. 1c) and delayed (Fig. 1d) slices. The avid lesion had fusiform morphology. Delayed FFDG PET-CT showed a 30.4 % increment of SUVmax (retention index was 30.4 %) that suggested malignancy; therefore we suspected ISCM. She received steroid pulse therapy for discrimination from DRM, but it was not effective and neurological findings were getting worse. Follow-up MRI showed expansion of the intramedullary lesion and new appearance of the vertebral body metastasis at Th3 on gadolinium-enhanced images in April 2014 (Fig. 1e). On the basis of her clinical and radiological findings, ISCM was diagnosed. The results of such studies showed that most of the SUV values in malignant lesions were increased in the delayed scan and for most benign lesions these delayed values decreased [1]. In F-FDG PET/CT images, ISCM showed pathological FDG uptake, but, on the other hand, DRM showed no pathological FDG uptake [2, 3]. In conclusion, F-FDG PET/CT has an important role to play in the diagnosis of ISCM and the differentiation from DRM. * Yoshiharu Miura ymiura@cick.jp

Background: Stenotrophomonas maltophilia (S. maltophilia) bacteremia in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is associated with significant morbidity and mortality rate. Although several predisposing risk factors for S. maltophilia bacteremia following allo-HSCT have been identified, there is no agreement or consistency among clinical factors on whether to predict treatment outcome or not. Methods: From January 2005 to December 2014, data on demographic and clinical characteristics, treatment and outcome were collected for all S. maltophilia bacteremia cases observed at an 800-bed tertiary care hospital with a 32-bed transplantation ward. They were analyzed with respect to incidence and 90-day mortality. The risk factors associated with 90-day mortality of allo-HSCT recipients with S. maltophilia bacteremia were also analyzed by Log-rank test according to age, sex, neutropenia, platelet, C-reactive protein (CRP), albumin, creatinine, engraftment, graft-versus-host disease, primary disease risk, severe sepsis or septic shock, complicated infection, and conditioning intensity. Significant variables in the univariate analysis were included in the multivariate Cox proportional-hazards regression model. Results: A total of 65 patients (47 patients in allo-HSCT recipients and 18 patients in non allo-HSCT recipients) with S. maltophilia bacteremia were identified, with the incidence of 1.17 cases per 100 admissions and 0.35 cases per 1000 patient-days. The incidence was significantly high in allo-HSCT recipients compared to non allo-HSCT recipients (6.53 vs 0.36 per 100 admission, p In multivariate analysis, the independent risk factors associated with 90-day mortality of allo-HSCT recipients were a high CRP level (>=10.0 mg/dl) (adjusted hazard ratio [aHR], 4.43; 95% confidence interval [CI], 1.55-12.63; p Conclusion: The incidence of S. maltophilia bacteremia was increasing during the last 5 years and 90-day mortality was high in allo-HSCT setting compared to non allo-HSCT setting. Higher CRP value or lower albumin level as a result of more complicated infection may predict poor prognosis of patients with S. maltophilia bacteremia. Disclosures No relevant conflicts of interest to declare.

This paper introduces a novel way to enable users to create temporal smart surroundings easily at open-air events. The final goal of this research was to support social activities in public spaces, such as festivals, camps, and outdoor-ceremonies with ubiquitous computing technologies. We designed and developed universal modular units called "I/O-CRATEs", which are box-shaped units embedded with microcomputers, sensors, actuators, and batteries. We demonstrated the possibilities of our units with a one-night special event. Through this practical experience, we found "I/O-CRATEs" could easily be used to create smart and enjoyable surroundings in many places