Rare severe constrictive pericarditis complication in Erdheim-Chester disease: A case report and literature review.

Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis with diverse clinical features. It is characterized by systemic histiocyte infiltration of the bone, skin, central nervous system, lung, kidney, and cardiovascular system. Pericardial involvement is frequently revealed through either pericardial effusion or pericardial thickening in patients with ECD. Although most patients remain asymptomatic, progressive pericarditis, effusion, or cardiac tamponade may occur. Herein, we report a rare and unusual presentation of ECD in a 51-year-old man who experienced severe constrictive pericarditis. The patient presented with uncontrolled fluid retention and heart failure. After the diagnosis of ECD, interferon alpha treatment was administered. The patient recovered dramatically with decreased pleural and pericardial effusion, as well as improvements in the echocardiographic signs of constrictive pericarditis. Despite several therapeutic options described in the literature for managing ECD-related pericardial disease, a standard treatment has not been established. This report highlights the importance of early treatment based on accurate diagnosis of an unusual ECD complication.

Clinical and genetic features of Japanese cases of MDS associated with VEXAS syndrome.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a new disease entity with autoinflammatory disorders (AID) driven by somatic variants in UBA1 that frequently co-exists with myelodysplastic syndromes (MDS). Clinicopathological and molecular features of Japanese cases with VEXAS-associated MDS remain elusive. We previously reported high prevalence of UBA1 variants in Japanese patients with relapsing polychondritis, in which 5 cases co-occurred with MDS. Here, we report clinicopathological and variant profiles of these 5 cases and 2 additional cases of MDS associated with VEXAS syndrome. Clinical characteristics of these cases included high prevalence of macrocytic anemia with marked cytoplasmic vacuoles in myeloid/erythroid precursors and low bone marrow (BM) blast percentages. All cases were classified as low or very low risk by the revised international prognostic scoring system (IPSS-R). Notably, 4 out of 7 cases showed significant improvement of anemia by treatment with prednisolone (PSL) or cyclosporin A (CsA), suggesting that an underlying inflammatory milieu induced by VEXAS syndrome may aggravate macrocytic anemia in VEXAS-associated MDS. Targeted deep sequencing of blood samples suggested that MDS associated with VEXAS syndrome tends to involve a smaller number of genes and lower risk genetic lesions than classical MDS.

[Treatment strategy for acute lymphoblastic leukemia in adolescent and young adults].

Acute lymphoblastic leukemia (ALL) in adolescents and young adults (AYA) is a relatively new concept that refers to patients aged 15-39 years with unique pathophysiology and requiring specific clinical care. Many clinical studies have revealed that treatment with the pediatric protocol has better disease-free and overall survival than the adult protocol for AYA-ALL. AYA-ALL survival was significantly improved from 30% with the adult regimen to 60-70% with the pediatric regimen. Two types of strategies are available to adapt pediatric regimens to AYA-ALL, a pediatric-inspired and a fully pediatric regimen. Determining the recommended strategy from these two strategies is difficult at this time. New knowledge of AYA-ALL-specific genetic characteristics provides new strategies for targetable ALL, especially Ph-like ALL. New immunotherapy has been approved for refractory and recurrent ALL; however, treatment results of AYA-ALL were improved by introducing the first line of immunotherapy in BCP-ALL, which may have a poor prognosis such as residual MRD. Pediatric and adult hematologists must work together to improve the prognosis of AYA-ALL.

Clinical risk factors for patients with myelodysplastic syndromes undergoing allogeneic hematopoietic stem cell transplantation.

Objectives: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only curative treatment for myelodysplastic syndromes (MDS), although predicting post-transplant outcomes remains inconclusive. This study evaluated patients who underwent allo-HCT for MDS to identify prognostic factors and develop a clinical risk model.Methods: We evaluated 55 patients between June 2000 and March 2015 to identify prognostic factors and develop a model for three-year overall survival (OS) and event-free survival (EFS). Cox regression analysis was performed on four factors: age ≥55 years; Hematopoietic Cell Transplant-Comorbidity Index >2; intermediate or worse cytogenetic status based on revised International Prognostic Scoring System; and unrelated donor status associated with poor OS in the univariate analysis. A clinical risk model was constructed using the sum of the regression coefficients and evaluated using receiver operating characteristic analysis and five-fold cross-validation.Results: Patient median age was 51 (range: 30-67) years. Median follow-up was 45.8 (range: 1.27-193) months; the three-year OS and EFS rates were 61.8% and 56.4%, respectively. The areas under the curves (AUCs) for OS and EFS were 0.738 and 0.778, respectively, and the average AUC for 50 times five-fold cross-validation were 0.711 and 0.723 for three-year OS and EFS, respectively.Conclusion: A four-clinical-risk-factor model that could effectively predict post-transplantation outcomes and help decision-making in MDS treatment was developed.

Two novel high-risk adult B-cell acute lymphoblastic leukemia subtypes with high expression of CDX2 and IDH1/2 mutations.

The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear, and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA) (15 to 39 years old, n = 193) and adults (40 to 64 years old, n = 161) with Philadelphia chromosome-negative (Ph-) B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with 2 novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2 and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1 R132C or IDH2 R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified 2 novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL.

Passenger lymphocyte syndrome after ABO-incompatible allogeneic hematopoietic stem cell transplantation; dynamics of ABO allo-antibody and blood type conversion.

Passenger lymphocyte syndrome (PLS) is a specific subtype of graft versus host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) characterized by an immune-mediated hemolysis caused by donor-derived B cells. However, precise nature of PLS has not been well characterized due to its rarity. We herein report two cases of PLS following ABO-incompatible HSCT whose clinical course and dynamics of anti-ABO allo-antibody and blood type conversion were closely examined. Both cases demonstrated acute hemolysis upon engraftment, and the presence of high titer allo-antibody against recipients' red blood cells (RBCs) helped us to reach the diagnosis of PLS. Hemolysis in both cases showed spontaneous improvement with prednisolone and supportive therapy including transfusion and fluid support. In one case with blood type O, the patient recursively developed PLS in the second and the third HSCT from ABO-mismatch donors, leading to a hypothesis that original blood type O may serve as a background for acute elevation of serum anti-ABO antibody and therefore a risk for developing PLS in multiple ABO-incompatible HSCTs. When hemolysis is noted following ABO-incompatible HSCTs, PLS should be considered and measurement of anti-ABO antibodies is warranted.

Clinical characteristics and risk factors for culture-negative periprosthetic joint infections.

BACKGROUND: Culture-negative periprosthetic joint infections (PJIs) can complicate diagnosis and management of PJI. This study aimed to identify risk factors for culture-negative PJI and differences in clinical characteristics between culture-positive and culture-negative PJI group. METHODS: This retrospective, cross-sectional study evaluated PJI cases obtained between January 2013 and October 2019 at our institution. These PJI cases were divided into culture-positive and culture-negative groups and then compared. The demographics, laboratory findings, and details of patient's clinical characteristics were investigated. Univariate and multivariate logistic regression analysis were performed to investigate risk factors for culture-negative PJI. RESULTS: A total of 109 PJI cases were included in the analysis: 82 (75%) culture-positive and 27 (25%) culture-negative. The mean serum white blood cell (WBC) count, C-reactive protein level, and erythrocyte sedimentation rate in the culture-negative group were significantly lower than those in the culture-positive group (p < 0.05). There were no significant differences between the two groups regarding history of prior antibacterial administration or treatment success rates. Multivariate analysis identified a low serum WBC count as a risk factor for culture-negative PJI (odds ratio = 0.78; 95% confidence interval [CI] = 0.63-0.97; p = 0.027). CONCLUSIONS: A low serum WBC count is a risk factor for culture-negative PJI, but prior antimicrobial therapy is not. The results suggest that PJI cases with lower levels of systemic inflammation are likely to be culture-negative; therefore, the possibility of a culture-negative result should be considered in suspected cases of PJI with low inflammatory markers, regardless of prior antibiotic exposure.

Combination of clofarabine, etoposide, and cyclophosphamide in adult relapsed/refractory acute lymphoblastic leukemia: a phase 1/2 dose-escalation study by the Japan Adult Leukemia Study Group.

This phase 1/2 study aimed to identify the maximum tolerated dose, the recommended phase 2 dose (RP2D), and efficacy of the clofarabine, etoposide, and cyclophosphamide combination regimen in adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients aged ≥ 15 years with relapsed/refractory ALL were enrolled. Escalating doses of clofarabine (20-30 mg/m2/day × 5 days), etoposide (50-100 mg/m2/day × 5 days), and cyclophosphamide (200-440 mg/m2/day × 5 days) were administered. Dose-limiting toxicity was defined as Grade 3 or more non-hematological toxicities and others. A total of 18 patients (B-ALL; n = 13, T-ALL; n = 5) were recruited in phase 1; however, the protocol was amended to close study without proceeding to phase 2. Three patients were enrolled in cohort 1, three in cohort 2, six in cohort 3, and six in cohort 4. The RP2D of clofarabine, etoposide, and cyclophosphamide was 30, 100, and 440 mg/m2 daily, respectively. Complete remission (CR) was achieved in four patients (22%) and CR without platelet recovery in four patients (22%), with an overall response rate of 44%. The RP2D of the combination therapy was successfully determined in this study.

Establishment of a High-risk MDS/AML Cell Line YCU-AML1 and its Xenograft Model Harboring t(3;3) and Monosomy 7.

Acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) with both inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7 defines an extremely aggressive myeloid cancer whose molecular pathogenesis and optimal therapeutic strategy still remain unclear. We established a new MDS/AML cell line, YCU-AML1, and its patient-derived xenograft (PDX) model from a high-risk MDS patient who later transformed into AML harboring both t(3;3)(q21;q26.2) and monosomy 7. YCU-AML1 cells propagated in co-culture system with stromal cells in granulocyte macrophage colony-stimulating factor (GM-CSF)-dependent manner. CD34+ bone marrow cells derived from our PDX model showed high EVI1 and low GATA2 expression. Moreover, mutational profile of our MDS/AML model was consistent with recently published mutational spectrum of myeloid malignancies with inv(3)/t(3;3). These data suggest that YCU-AML1 cells and its MDS/AML model strongly mimics a high-risk human myeloid cancer with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7 in terms of both clinical phenotype and molecular basis. We believe our model can be used as a feasible tool to further explore molecular pathogenesis and novel treatment strategy of high-risk MDS/AML with t(3;3)(q21;q26.2) and monosomy 7.

Computed tomography-defined sarcopenia: prognostic predictor of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation: a multicenter retrospective study.

We analyzed clinical cutoffs for defining computed tomography (CT) methods for sarcopenia and examined the prognostic value of CT for allogeneic hematopoietic stem cell transplantation (allo-HCST) outcomes of patients with myeloid malignancy. One hundred twenty-five adult patients with acute myeloid leukemia and myelodysplastic syndrome who underwent first allo-HSCT between 2000 and 2017 were included. Sarcopenia was assessed using CT-based skeletal muscle index (SMI) and mean muscle attenuation at L3. A statistical difference in SMI was confirmed between sarcopenia (n = 52) and nonsarcopenia (n = 73) patients. There were no significant correlations of muscularity with age, performance status, or other characteristics of HSCT. After 2 years, overall survival (OS) was 43.5% and 70.1%, disease-free survival was 52.9% and 68.6%, nonrelapse mortality (NRM) was 20.8% and 8.4%, incidence of acute GVHD (≥ grade 2) was 38.8% and 39.1%, that of chronic GVHD was 53.2% and 37.3%, and median duration of hospitalization was 88 days and 74 days (P = 0.026), respectively, in the sarcopenia and nonsarcopenia groups. Multivariate analysis showed that presence of sarcopenia is a novel adverse factor for high NRM and poor OS. Pretransplant CT-defined sarcopenia is correlated with decreased OS, increased NRM, and prolonged hospitalization.

Allogeneic hematopoietic stem cell transplantation for aplastic anemia with pre-transplant conditioning using fludarabine, reduced-dose cyclophosphamide, and low-dose thymoglobulin: A KSGCT prospective study.

The optimal pre-transplant conditioning for aplastic anemia (AA) remains unclear. We performed a prospective study on allogeneic transplantation from a related or unrelated donor for adult patients with AA. We assessed whether reduced-dose cyclophosphamide (CY) could decrease toxicity while maintaining engraftment, and low-dose thymoglobulin could safely prevent graft-vs-host disease (GVHD). The pre-transplant conditioning regimen consisted of fludarabine 120 mg/m2 , CY 100 mg/kg, and thymoglobulin 2.5 mg/kg with or without 2 Gy of total body irradiation. Twenty-seven patients with a median age of 36 years were analyzed. Sixteen patients received graft from related donors. The stem cell source was bone marrow in 26 patients. All of the patients but one, who died early, achieved neutrophil engraftment at a median of 19 days. Mixed chimerism was observed in six and five patients at days 30 and 90, respectively. Only one patient experienced secondary engraftment failure with complete donor-type chimerism. None of the patients developed severe acute GVHD. The cumulative incidence of chronic GVHD was 37.7% at 1 year. The overall survival rate was 96.3% at 1 year and 3 years. A high EB virus-DNA load was detected in one patient at days 60. No one developed EBV-lymphoproliferative disorder within a year. The results suggest that the conditioning regimen in this study was safe and effective. However, relatively high incidence of chronic GVHD needs further improvement.

Impact of treatment-related weight changes from diagnosis to hematopoietic stem-cell transplantation on clinical outcome of acute myeloid leukemia.

We hypothesized that treatment-related weight loss is associated with worse outcomes following HSCT. Overall, 184 patients with AML who underwent induction therapy were classified according to d-BMI (BMI at transplant minus BMI at diagnosis) (kg/m2) as < -2, - 2 to + 2, and > + 2. At 1 year, OS was 67.9% (95% CI, 60.7-74.2), DFS was 64.1% (95% CI, 56.7-70.6), and GRFS was 40.2% (95% CI, 33.1-47.2). For d-BMI groups < - 2, - 2 to + 2, and > + 2, GRFS at 1 year was 16.1% (95% CI, 5.1-31.4), 45.4% (95% CI, 36.4-53.7), and 41.7% (95% CI, 22.2-60.1), respectively (P = 0.0067). Multivariate analysis showed that both worse OS (HR, 1.78; 95% CI, 1.02-3.14; P = 0.007) and GRFS (HR, 2.34; 95% CI, 1.26-4.35; P = 0.007) were associated with reduced BMI (d-BMI < - 2). Treatment-related weight reduction in AML was associated with poor outcome after HSCT.

Septicemia from Lactobacillus rhamnosus GG, from a Probiotic Enriched Yogurt, in a Patient with Autologous Stem Cell Transplantation.

Probiotic-rich foods are consumed without much restriction. We report here, a case of septic shock caused by yogurt derived Lactobacillus species in a 54-year-old male patient with acute promyelocytic leukemia, in second complete remission, and who was an autologous stem cell transplantation recipient. He received high dose chemotherapy and autologous peripheral blood stem cell transplantation. He ingested commercially available probiotic-enriched yogurt because of severe diarrhea. One week later, he developed septic shock, and the pathogen was determined by strain-specific PCR analysis as Lactobacillus rhamnosus GG (ATCC 53103), which was found to be identical with the strain in the yogurt he consumed. Thus, because even low virulent Lactobacilli in the probiotic products can be pathogenic in the compromised hosts, ingestion of such products should be considered with caution in neutropenic patients with severe diarrhea, such as stem cell transplantation recipients.

A multi-center prospective study randomizing the use of fat emulsion in intensive glucose control after allogeneic hematopoietic stem cell transplantation using a myeloablative conditioning regimen.

BACKGROUND & AIMS: Although parenteral nutrition (PN) is often used after allogeneic hematopoietic stem cell transplantation (allo-HSCT), there is controversy regarding PN management, for instance in the use of fat emulsion and glucose control (GC). To clarify these issues, we conducted a multi-center prospective study with intensive GC, randomizing the use of fat emulsion after allo-HSCT using a myeloablative conditioning regimen. METHODS: The primary endpoint was the cumulative incidence of documented infectious disease, namely bacterial and fungal infection, at day 100 after allo-HSCT. Between August 2007 and March 2012, we enrolled 81 patients at 5 centers. Excluding 5 ineligible patients, 76 patients received the protocol treatment. The target fasting glucose level was 80-110 mg/dL. RESULTS: The median follow-up of surviving patients was 1796 days. The cumulative incidences of documented infectious disease at day 100 were 16% (95% confidence interval [CI] 6-29%) in the no-fat group and 19% (95% CI 8-32%) in the fat group, indicating no significant difference. The mean glucose level at 28 days after allo-HSCT was 107 mg/dL in the no-fat group and 111 mg/dL in the fat group. Grade 3 hyperglycemia (>250 mg/dL) and grade 3 hypoglycemia (<40 mg/dL) occurred in 4 patients each (5.3%). Overall survival and non-relapse mortality rates at 4 years were 75% and 11% in the no-fat group and 69% and 8% in the fat group, respectively. CONCLUSIONS: Irrespective of the use of fat emulsion, the long-term clinical outcomes of the enrolled patients were favorable under intensive GC. To further clarify the benefits of GC after allo-HSCT, a prospective study randomizing the level of GC is warranted.

Targeting complete response with upfront bortezomib consolidation versus observation after the achievement of complete response following autologous transplantation for multiple myeloma (TUBA study).

Complete response (CR) after treatment for multiple myeloma is associated with superior progression-free survival (PFS). Multiple myeloma patients were prospectively recruited for induction treatment with bortezomib and dexamethasone (BD) followed by autologous hematopoietic cell transplantation (auto-HCT) between 2010 and 2012. If patients did not achieve CR after auto-HCT, BD consolidation therapy was added to target CR. After the BD induction phase (n = 46), greater than or equal to CR was achieved in 4 patients (8%). After auto-HCT (n = 34), greater than or equal to CR was achieved in 9 patients (20%) and very good partial response (VGPR) was achieved in 11 (24%). Of the 24 patients who received auto-HCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses. Finally, the maximum response with or without BD consolidation was greater than or equal to CR in 19 (41%), VGPR in 7 (15%), and PR in 6 (13%). Through BD consolidation, CR was achieved in 8 of 11 patients with post-HCT VGPR and in 2 of 12 patients with post-HCT PR. In total, 4 year PFS and overall survival were 43 and 80%, respectively. After adjusting for clinical factors, there was no difference in PFS between CR patients after auto-HCT and BD consolidation, while patients with less than or equal to VGPR after consolidation had a significantly lower PFS. Patients with post-HCT CR showed good PFS, and targeting CR through BD consolidation could improve the CR rate. It would be worthwhile to prospectively compare the efficacy of consolidation only for patients who failed to achieve CR to a universal consolidation strategy.

Body mass index is a prognostic factor in adult patients with acute myeloid leukemia.

Body mass index (BMI), which represents the proportion of weight to height, is a controversial prognostic factor for acute myeloid leukemia (AML). We evaluated prognostic value of BMI in Japanese AML. The study included 369 adult patients with newly diagnosed AML who were administered either daunorubicin or idarubicin with cytarabine as induction chemotherapy. The patients were categorized into two groups according to their BMI: the NW group (BMI < 25.0 kg/m2; normal and underweight) and OW group (BMI ≥ 25.0 kg/m2; overweight and obese). We analyzed treatment efficacy and toxicity of induction chemotherapy, and survival outcomes in each group. Patients in the OW group showed a better complete remission rate than the NW group (86.1 versus 76.5%, P = 0.045), no early death (0.0 versus 4.1%, P = 0.042), and better overall survival (OS) at 3 years (62.2 versus 50.1%, P = 0.012). Multivariate analysis showed BMI is an independent prognostic factor for OS (hazard ratio 0.62, 95% confidence interval 0.42-0.92, P = 0.017). These results indicate the prognostic value of BMI in adult AML patients.

Hyper-recovery of platelets after induction therapy is a predictor of relapse-free survival in acute myeloid leukemia.

We verified the association between standard clinical and laboratory variables and the risk of relapse in acute myeloid leukemia (AML), which led us to retrospectively examine the effect of regeneration of hematopoiesis in patients with newly diagnosed AML. We used data from 230 patients who obtained remission after cytarabine-based induction chemotherapy. Platelet counts ≥500 × 109/L and hemoglobin levels ≥9 g/dL on day 28 after treatment initiation were significantly associated with relapse-free survival (RFS) rate, conferring respective multivariate risk ratios of 0.38 (95% CI: 0.18-0.79) and 0.60 (95% CI: 0.40-0.89) for the occurrence of relapse or death. No disease relapse occurred in core binding factor leukemia patients whose platelet counts recovered ≥500 × 109/L at 28 days after therapy initiation. We conclude that regeneration of hematopoiesis, especially platelet hyper-recovery, after induction chemotherapy is a significant predictor of RFS in patients with AML.

Diagnostics for multiple myeloma.

Multiple myeloma (MM) has been diagnosed based on the International Myeloma Working Group (IMWG) diagnostic criteria since 2003. In 2014, the IMWG updated these diagnostic criteria to add three specific biomarkers, i.e., 1) Clonal bone marrow plasma cell percentage ≥60%; 2) Involved: uninvolved serum free light chain ratio ≥100; 3) >1 focal lesion on MRI studies, based on CRAB features (hypercalcemia, renal failure, anemia, and bone lesions). An early diagnosis of MM can be made, allowing timely anti-MM treatment, in patients with the ultra-high-risk smoldering form of this disease. This review focuses on the new IMWG diagnostic criteria for MM and evaluation of patients newly diagnosed with MM.