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.

[Board-certified "hematologist" and "clinical laboratory physician": double jobbing-flow with the tide].

The Women Doctors Career Symposium entitled "Dreams: Female Hematologists' Talk" was held at the 84th Annual Meeting of the Japanese Society of Hematology. I would like to share my experience as a board-certified "hematologist" and "clinical laboratory physician." Certified clinical laboratory physician is one of the 19 fundamental areas in the Japanese Medical Specialty board, but the number is small, and it is also an area where hematologists can easily face challenges. It also allows you to balance career advancement and various life events. It is extremely difficult to forge one's own path, but it is relatively simple to take the advice of others and choose one's path. "We cannot direct the wind, but we can adjust the sails." This is one way to consider continuing a career.

[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.

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.

Differences in Diagnostic Properties Between Standard and Enrichment Culture Techniques Used in Periprosthetic Joint Infections.

BACKGROUND: Culture-negative infections can complicate the diagnosis and management of orthopedic infections, particularly periprosthetic joint infections (PJIs). This study aimed to identify differences in rate of detection of infection and organisms between cultured using standard and enriched methods. METHODS: This retrospective, cross-sectional study evaluated PJI samples obtained between January 2013 and December 2017 at Yokohama City University Hospital. Samples were assessed using standard and enrichment culture techniques. White blood cell counts, C-reactive protein levels, type of microorganism (coagulase-positive or coagulase-negative), and methicillin-resistant Staphylococcus were investigated. RESULTS: A total of 151 PJI samples were included in the analysis; of these, 68 (45.0%) were positive after standard culture while 83 (55.0%) were positive only after enrichment culture. The mean white blood cell counts and C-reactive protein levels were significantly lower in the enrichment culture group than in the standard culture group (P < .01). The rate of methicillin-resistant Staphylococcus and coagulase-negative Staphylococci was significantly higher in the enrichment culture group than in the standard culture group (P < .01). CONCLUSION: The enrichment culture method has a higher rate of detection of infection than standard culture techniques and should, therefore, be considered when diagnosing orthopedic infections, particularly PJI.

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.

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.

[Successful induction therapy for acute myeloid leukemia complicated with brain hemorrhage and hyperleukocytosis].

Adequate management of hyperleukocytosis in patients with acute myeloid leukemia (AML) is essential for the prevention of life-threatening complications related to leukostasis and tumor lysis syndrome, but the optimal therapeutic strategy remains unclear. We report a 15-year-old girl with newly diagnosed AML who had extreme hyperleukocytosis (leukocyte count at diagnosis, 733,000/µl) leading to a brain hemorrhage. She was initially treated with hydroxyurea, but presented with brain hemorrhage due to leukostasis and underwent leukapheresis emergently with intensive care and mechanical ventilation. Full-dose standard induction chemotherapy was initiated after achieving gradual cytoreduction (leukocyte count, 465,000/µl) within five days after the initiation of therapy with hydroxyurea and leukapheresis. These treatments were successful and she experienced no complications. The patient ultimately recovered fully and was discharged with complete remission of AML. Although the effects of hydroxyurea and leukapheresis in the setting of hyperleukocytosis are still controversial, these initial treatments may contribute to successful bridging therapy followed by subsequent induction chemotherapy, especially in AML cases with extreme hyperleukocytosis or life-threatening leukostasis.

Biweekly THP-COP therapy for newly diagnosed peripheral T-cell lymphoma patients.

Pirarubicin tetrahydropyranyl adriamycin (THP-ADR) is an analogue of doxorubicin. This agent exhibits activity against some doxorubicin-resistant cell lines. We performed a phase II study of biweekly THP-COP [50 mg/m(2) pirarubicin, 750 mg/m(2) cyclophosphamide, 1.4 mg/m(2) vincristine (2.0 mg maximum) on day 1, and 100 mg/body predonisolone on days 1-5] in patients with peripheral T-cell lymphoma (PTCL). Seventeen patients with newly diagnosed PTCL were enrolled. Histological diagnoses were of PTCL, not otherwise specified (n = 5), or angioimmunoblastic T-cell lymphoma (n = 12). All diagnostic specimens including those of the historical control group were centrally reviewed by hematological pathologists. All patients received six cycles of biweekly THP-COP. The patient group included 13 male and 4 female patients, with a median age of 62 years. The median follow-up time in surviving patients was 30 months. Overall response rate was 94% with 15 cases of complete remission (88%). The 3-year progression-free survival and overall survival rates were 57% and 75%, respectively. The most frequent adverse events associated with biweekly THP-COP were leukocytopenia (100%), neutropenia (100%), and lymphopenia (100%), followed by alopecia (92%) and anaemia (88%). All of these occurred only transiently, and the patients subsequently recovered. Biweekly THP-COP is a safe and promising therapy for patients with newly diagnosed PTCL. This study is registered in a public database (UMIN000010485).

[Analysis of prognostic factors in transplant-eligeble newly diagnosed myeloma patients treated with bortezomib plus dexamethasone as induction therapy].

We retrospectively analyzed, and herein discuss, the outcomes of and prognostic factors for 35 untreated multiple myeloma patients less than 65 years of age who received induction therapies with bortezomib (Bor) and dexamethasone (BD) for the purpose of up-front autologous peripheral blood stem cell transplantation (SCT). The overall response rate was 77% (27 cases, including 4 [11%] complete response and 13 [37%] very good partial response cases). The rate of SCT accomplishment was 51% (18 cases). The 3 year-progression free survival (PFS) rate for the SCT group was significantly higher than that of the non-SCT group (41% vs 0%, P=0.0037). This result reflects the significantly more severe adverse effects of induction therapy for the non-SCT than the SCT group. Among reasons for SCT drop-out, 29% of cases suffered severe peripheral neuropathy with features such as irreversible numbness and pain. The analysis of PFS revealed a cytogenetic factor, favorable chromosomal type at diagnosis, to predict a better outcome (P values on univariate and multivariate analyses were 0.0004 and 0.0405, respectively). Our observations suggest establishment of induction therapy, aimed at reducing adverse effects and overcoming unfavorable cytogenetic abnormalities, to be necessary for improving the outcomes of patients with multiple myeloma.

European Treatment and Outcome Study score does not predict imatinib treatment response and outcome in chronic myeloid leukemia patients.

The Sokal and Hasford scores were developed in the chemotherapy and interferon era and are widely used as prognostic indicators in patients with chronic myeloid leukemia (CML). Recently, a new European Treatment and Outcome Study (EUTOS) scoring system was developed. We performed a multicenter retrospective study to validate the effectiveness of each of the three scoring systems. The study cohort included 145 patients diagnosed with CML in chronic phase who were treated with imatinib. In the EUTOS low- and high-risk groups, the cumulative incidence of complete cytogenetic response (CCyR) at 18 months was 86.9% and 87.5% (P = 0.797) and the 5-year overall survival rate was 92.6% and 93.3% (P = 0.871), respectively. The cumulative incidence of CCyR at 12 months, 5-year event-free survival and 5-year progression-free survival were not predicted using the EUTOS scoring system. However, there were significant differences in both the Sokal score and Hasford score risk groups. In our retrospective validation study, the EUTOS score did not predict the prognosis of patients with CML in chronic phase treated with imatinib.

Peripheral blood absolute lymphocyte/monocyte ratio as a useful prognostic factor in diffuse large B-cell lymphoma in the rituximab era.

OBJECTIVES: The tumor microenvironment, including tumor-infiltrating lymphocytes and myeloid-derived cells, is an important factor in the pathogenesis and clinical behavior of malignant lymphoma. However, the prognostic significance of peripheral lymphocytes and monocytes in lymphoma remains unclear. METHODS: We evaluated the prognostic impact of the absolute lymphocyte count (ALC), absolute monocyte count (AMC), and lymphocyte/monocyte ratio (LMR) in 359 diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). RESULTS: The median follow-up time of the surviving patients was 58 months. Low ALC and an elevated AMC were both associated with poor survival rates. Receiver operating characteristic curve analysis showed that LMR was the best predictor of survival, with 4.0 as the cutoff point. Patients with LMR ≤4.0 were more likely to have an aggressive tumor, and this was associated with poor treatment responses. Patients with LMR ≤4.0 at diagnosis had significantly poorer overall survival (OS) and progression-free survival (PFS) than those with LMR >4.0. Multivariate analysis, which included prognostic factors of the International Prognostic Index, showed LMR ≤4.0 to be an independent predictor for the OS (hazard ratio [HR], 2.507; 95% confidence interval [CI], 1.255-5.007; P = 0.009) and PFS (HR, 2.063; 95% CI, 1.249-3.408; P = 0.005). CONCLUSIONS: The LMR at diagnosis, as a simple index which reflects host systemic immunity, predicts clinical outcomes in DLBCL patients treated with R-CHOP.

Impact of steroid medication before hospital admission on barotrauma in mechanically ventilated patients with acute respiratory distress syndrome in intensive care units.

PURPOSE: To investigate the association between steroid medication before hospital admission and barotrauma in mechanically ventilated patients with acute respiratory distress syndrome (ARDS). METHODS: An observational single-center retrospective study was conducted using patients admitted to the general intensive care unit (ICU) of a university hospital in Japan. We analyzed 149 mechanically ventilated patients with ARDS hospitalized between March 2008 and March 2011. ARDS was identified according to criteria from the Berlin Definition. Barotrauma was defined as pneumothorax, subcutaneous emphysema, or mediastinal emphysema occurring during mechanical ventilation in the ICU. The influence of steroid medication before hospital admission on barotrauma was studied using multiple logistic regression analysis. RESULTS: There were no differences in baseline patient characteristics except for congestive heart failure, peak pressure during mechanical ventilation, and steroid pulse therapy between the barotrauma and non-barotrauma groups. Logistic regression analysis showed that peak pressure ≥35 cmH2O was associated with barotrauma in patients with ARDS [odds ratio (OR), 17.34; P < 0.01], whereas steroid medication before hospital admission was not a significant factor for barotrauma (OR, 1.63; P = 0.51). CONCLUSIONS: Barotrauma in ARDS patients was associated with higher pressure during mechanical ventilation but not with steroid medication before hospital admission.

[T315I positive promyelocytic crisis of chronic myeloid leukemia].

Promyelocytic crisis (PMC) of chronic myelogenous leukemia (CML) is relatively rare. We report a patient who progressed to PMC with a T315I mutation during the initial treatment with dasatinib for CML. He obtained hematological remission after combination therapy with all-trans retinoic acid and chemotherapy for PMC, and PML-RARA was not detected by FISH analysis. Arsenic trioxide (ATO) and imatinib therapy induced a second complete cytogenetic response, and PML-RARA mRNA detected by real-time quantitative RT-PCR dropped below the detection limit. Finally, allogeneic stem cell transplantation was performed. This case suggests that combination therapy with imatinib and ATO achieves favorable outcomes for PMC.

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.

R-CHOP therapy alone in limited stage diffuse large B-cell lymphoma.

Long-term observation has identified a pattern of continuing relapse in limited stage diffuse large B-cell lymphoma (DLBCL) treated by three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved-field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R-CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5-year progression-free survival and 5-year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the 'standard' strategy of three cycles of R-CHOP followed by involved-field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R-CHOP alone.

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.

SIL index, comprising stage, soluble interleukin-2 receptor, and lactate dehydrogenase, is a useful prognostic predictor in diffuse large B-cell lymphoma.

Rituximab (R) plus doxorubicin, cyclophosphamide, vincristine, and prednisolone (CHOP) chemotherapy (R-CHOP) is widely accepted as standard care for diffuse large B-cell lymphoma (DLBCL) patients. The revised International Prognostic Index (R-IPI) was established in 2007 after the addition of rituximab to standard DLBCL treatment. To reassess the utility of R-IPI, we carried out a retrospective analysis of patients with DLBCL uniformly treated with standard R-CHOP. Progression-free survival (PFS) curves in "very good" and "good" risk groups as defined by the R-IPI showed no statistical difference. We added soluble interleukin-2 receptor (sIL-2R) level to the factors comprising the R-IPI. Five levels of sIL-2R were weighed with respect to their impact on PFS. sIL-2R of >2500 U/mL was determined as the most appropriate threshold. We developed a new prognostic SIL index, which includes three independent prognostic risk factors: clinical stage (S); sIL-2R level over 2500 U/mL (I); and elevated lactate dehydrogenase level (L). This index indicates standard risk (0 or 1 risk factors, 4-year PFS 83%, 4-year overall survival 91%) and high risk (2 or 3 risk factors, 4-year PFS 52%, 4-year overall survival 67%) outcomes. The SIL index is a simple and objective prognostic index for DLBCL patients to identify candidates for experimental therapy other than R-CHOP.

[Immune-mediated encephalomyelitis following varicella-zoster virus infection after allogeneic stem cell transplantation].

A 40-year-old Japanese man with acute myeloid leukemia received allogeneic bone marrow transplantation. On day 101, varicella-zoster virus (VZV) infection occurred, but was improved by administration of acyclovir and immunoglobulin. On day 119, he complained of numbness and double vision, and he was admitted due to exacerbation of the symptoms. The findings of cerebrospinal fluid and magnetic resonance image examination were consistent with the diagnosis of immune-mediated encephalomyelitis (IMEM). Intravenous immunoglobulin therapy was effective and his neurological findings dramatically improved without recurrence. IMEM is a rare non-infectious inflammatory demyelinating disease that can occur after transplantation. We herein describe a case report with a review of the associated literature.

[Retrospective analysis of treatment outcomes in 70 patients with t(8;21) acute myeloid leukemia].

We conducted a retrospective study to evaluate outcomes and prognostic factors of newly diagnosed patients with t(8;21) acute myeloid leukemia (AML). There were 70 patients (43 men and 27 women) with a median age of 48 years old (range, 17∼76 years old). Sixty-five patients achieved complete remission (CR) after induction chemotherapy. Fifty-seven patients received consolidation chemotherapy based on the policy of not performing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at the time of first CR. Twenty-seven of the 57 patients relapsed (relapse rate, 47%). The median time from the achievement of the first CR to relapse was 307 days (96∼1,256 days). A white blood cell count of more than 25,400/µl at diagnosis was associated with a higher relapse rate than a white blood cell count of less than or equal to 25,400/µl (75% vs. 43%, P=0.04). Nineteen of the 25 relapsed patients who received re-induction therapy experienced a second CR (second CR rate, 76%). Twenty-six patients (5 with first CR, 12 with second CR, and 9 without remission) received allo-HSCT. The five-year overall survival and disease-free survival rates were 61% and 45%, respectively. Patients with t(8;21) AML had a high CR rate, but about half of them relapsed. However, this report could not show prognostic factors for the identification of patients who should receive allo-HSCT at the time of their first CR.