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.

[Thoracic SMARCA4-deficient undifferentiated tumor resembling malignant lymphoma].

We present a case of thoracic SMARCA4-deficient undifferentiated tumor that needed to be differentiated from malignant lymphoma owing to multiple lymph node swelling and marrow involvement. A 52-year-old man developed multiple lymphadenopathies along with anorexia, general fatigue, fever, and sweating 2 months prior to admission. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scan revealed a mass lesion on the right upper lung, generalized lymph node swelling, and bone metastasis, indicating the presence of suspicious lung cancer; therefore, he was referred to our hospital. Malignant lymphoma was suspected at the time of admission because of elevated levels of lactate dehydrogenase (11,977 U/l) and soluble interleukin 2 receptor (2,152 U/ml) as well as marrow infiltration of large abnormal cells. On day 11, the patient died from rapid respiratory failure. Histological and immunohistochemical features of the pleural effusion cell block led to the diagnosis of thoracic SMARCA4-deficient undifferentiated tumor. Thoracic SMARCA4-deficient undifferentiated tumor was recently introduced in the 2021 World Health Organization classification of lung tumors, with most patients being young adults with a history of heavy smoking and poor prognosis. Because of the multiple lymph node swelling and marrow involvement, this undifferentiated tumor should be distinguished from malignant lymphoma.

Hematopoietic stem cells acquire survival advantage by loss of RUNX1 methylation identified in familial leukemia.

RUNX1 is among the most frequently mutated genes in human leukemia, and the loss or dominant-negative suppression of RUNX1 function is found in myelodysplastic syndrome and acute myeloid leukemia (AML). How posttranslational modifications (PTMs) of RUNX1 affect its in vivo function, however, and whether PTM dysregulation of RUNX1 can cause leukemia are largely unknown. We performed targeted deep sequencing on a family with 3 occurrences of AML and identified a novel RUNX1 mutation, R237K. The mutated R237 residue is a methylation site by protein arginine methyltransferase 1, and loss of methylation reportedly impairs the transcriptional activity of RUNX1 in vitro. To explore the biologic significance of RUNX1 methylation in vivo, we used RUNX1 R233K/R237K double-mutant mice, in which 2 arginine-to-lysine mutations precluded RUNX1 methylation. Genetic ablation of RUNX1 methylation led to loss of quiescence and expansion of hematopoietic stem cells (HSCs), and it changed the genomic and epigenomic signatures of phenotypic HSCs to a poised progenitor state. Furthermore, loss of RUNX1 R233/R237 methylation suppressed endoplasmic reticulum stress-induced unfolded protein response genes, including Atf4, Ddit3, and Gadd34; the radiation-induced p53 downstream genes Bbc3, Pmaip1, and Cdkn1a; and subsequent apoptosis in HSCs. Mechanistically, activating transcription factor 4 was identified as a direct transcriptional target of RUNX1. Collectively, defects in RUNX1 methylation in HSCs confer resistance to apoptosis and survival advantage under stress conditions, a hallmark of a preleukemic clone that may predispose affected individuals to leukemia. Our study will lead to a better understanding of how dysregulation of PTMs can contribute to leukemogenesis.

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy.

BACKGROUND: The phase 3 VIALE-A trial (NCT02993523) reported that venetoclax-azacitidine significantly prolonged overall survival compared with placebo-azacitidine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Herein, efficacy and safety of venetoclax-azacitidine are analyzed in the Japanese subgroup of VIALE-A patients. METHODS: Eligible Japanese patients were randomized 2:1 to venetoclax-azacitidine (N = 24) or placebo-azacitidine (N = 13). Primary endpoints for Japan were overall survival and complete response (CR) + CR with incomplete hematologic recovery (CRi). Venetoclax (target dose 400 mg) was given orally once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously on Days 1-7 of each 28-day cycle. RESULTS: Median follow-up was 16.3 months (range, 1.0-20.3). Median overall survival was not reached with venetoclax-azacitidine (hazard ratio 0.409 and 95% confidence interval: 0.151, 1.109); overall survival estimate was higher with venetoclax-azacitidine than placebo-azacitidine at 12 (67 and 46%) and 18 months (57 and 31%), respectively. CR and CRi rates were 67% with venetoclax-azacitidine and 15% with placebo-azacitidine. Most common any-grade adverse events were febrile neutropenia (79 and 39%), thrombocytopenia (54 and 77%), constipation (54 and 54%) and decreased appetite (54 and 38%) in the venetoclax-azacitidine and placebo-azacitidine arms, respectively. Only 1 patient in the venetoclax-azacitidine arm, and no patients in the placebo-azacitidine arm, had grade 4 febrile neutropenia that led to treatment discontinuation. CONCLUSIONS: This Japanese subgroup analysis of VIALE-A demonstrates comparable safety and efficacy outcomes compared with the global study and supports venetoclax-azacitidine as first-line standard-of-care for Japanese treatment-naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy.

Venetoclax plus low-dose cytarabine in Japanese patients with untreated acute myeloid leukaemia ineligible for intensive chemotherapy.

BACKGROUND: In a multinational phase 3 trial (VIALE-C), venetoclax plus low-dose cytarabine prolonged overall survival vs placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy, although it was not statistically significant. Herein, we assess the benefit of venetoclax plus low-dose cytarabine in the Japanese subgroup of VIALE-C patients (n = 27). METHODS: VIALE-C, a randomized (2:1), double-blind study (NCT03069352), enrolled untreated patients (≥18 years) with acute myeloid leukaemia. Patients received venetoclax (600 mg days 1-28, 4-day ramp-up in cycle 1) or placebo in 28-day cycles with low-dose cytarabine (20 mg/m2 days 1-10). The primary endpoint was median overall survival. RESULTS: In the Japanese subgroup, at a 6-month follow-up from the primary analysis, median overall survival for venetoclax (n = 18) and placebo (n = 9), plus low-dose cytarabine, was 4.7 and 8.1 months, respectively (hazard ratio, 0.928, 95% confidence intervals : 0.399, 2.156). The rate of complete remission plus complete remission with incomplete blood count recovery was higher with venetoclax plus low-dose cytarabine (44.4%) vs placebo plus low-dose cytarabine (11.1%). All patients experienced at least 1 adverse event. The most common grade ≥3 adverse events with venetoclax or placebo, plus low-dose cytarabine, were febrile neutropenia (50.0% vs 44.4%, respectively) and thrombocytopenia (27.8% vs 44.4%, respectively). Serious adverse events were reported in 50.0 and 33.3% of patients in the venetoclax and placebo, plus low-dose cytarabine arms, respectively; pneumonia was the most common (22.2% each). CONCLUSIONS: Limited survival benefit in the Japanese subgroup can be attributed to small patient numbers and to baseline imbalances observed between treatment arms, with more patients in the venetoclax plus low-dose cytarabine arm presenting poor prognostic factors. Venetoclax plus low-dose cytarabine was well tolerated in Japanese patients with acute myeloid leukaemia ineligible for intensive chemotherapy.

Allogeneic hematopoietic stem cell transplantation at the first remission for younger adults with FLT3-internal tandem duplication AML: The JALSG AML209-FLT3-SCT study.

In this phase II multicenter study (JALSG AML209-FLT3-SCT), we aimed to prospectively elucidate the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) for FLT3-internal tandem duplication (ITD)-positive AML. Newly diagnosed de novo AML patients with FLT3-ITD were enrolled at the achievement of CR1 and received allo-HSCT as soon as possible after the first consolidation therapy. Mutations of 57 genes in AML cells at diagnosis were also analyzed. Among 48 eligible patients with a median age of 38.5 (17-49) years, 36 (75%) received allo-HSCT at a median of 108 days after CR1. The median follow-up was 1726 days. The primary end-point, 3-year disease-free survival (DFS) based on an intent to treat analysis, was 43.8% (95% confidence interval [CI], 30%-57%), suggesting the efficacy of this treatment because the lower limit of the 95% CI exceeded the threshold response rate of 20%. The 3-year overall survival, post-transplant DFS, and non-relapse mortality rates were 54.2% (95% CI, 39%-67%), 58.3% (95% CI, 41%-72%), and 25.0% (95% CI, 12%-40%), respectively. The median ITD allelic ratio (AR) was 0.344 (0.006-4.099). Neither FLT3-ITD AR nor cooccurring genetic alterations was associated with a poor DFS. This prospective study indicated the efficacy and safety of allo-HSCT for FLT3-ITD AML patients in CR1. This study was registered at: www.umin.ac.jp/ctr/ as #UMIN000003433.

Clinical utility of target capture-based panel sequencing in hematological malignancies: A multicenter feasibility study.

Although next-generation sequencing-based panel testing is well practiced in the field of cancer medicine for the identification of target molecules in solid tumors, the clinical utility and clinical issues surrounding panel testing in hematological malignancies have yet to be fully evaluated. We conducted a multicenter prospective clinical sequencing study to verify the feasibility of a panel test for hematological tumors, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and diffuse large B-cell lymphoma. Out of 96 eligible patients, 79 patients (82%) showed potentially actionable findings, based on the clinical sequencing assays. We identified that genetic alterations with a strong clinical significance were found at a higher frequency in terms of diagnosis (n = 60; 63%) and prognosis (n = 61; 64%) than in terms of therapy (n = 8; 8%). Three patients who harbored a germline mutation in either DDX41 (n = 2) or BRCA2 (n = 1) were provided with genetic counseling. At 6 mo after sequencing, clinical actions based on the diagnostic (n = 5) or prognostic (n = 3) findings were reported, but no patients were enrolled in a clinical trial or received targeted therapies based on the sequencing results. These results suggest that panel testing for hematological malignancies would be feasible given the availability of useful diagnostic and prognostic information. This study is registered with the UMIN Clinical Trial Registry (UMIN000029879, multiple myeloma; UMIN000031343, adult acute myeloid leukemia; UMIN000033144, diffuse large B-cell lymphoma; and UMIN000034243, childhood leukemia).

Predictors of early death, serious hemorrhage, and differentiation syndrome in Japanese patients with acute promyelocytic leukemia.

Significant advancements have been achieved with regard to the outcomes of acute promyelocytic leukemia (APL) patients through the introduction of all-trans retinoic acid; however, early hemorrhagic death and differentiation syndrome remain the major causes of remission induction failure in patients with APL. To investigate early death, serious hemorrhage, and differentiation syndrome during remission induction therapy in terms of incidence, risk factors, influence on outcomes, and prophylactic effects of several new anticoagulants, the results of 344 patients enrolled in the Acute Promyelocytic Leukemia 204 study conducted by the Japan Adult Leukemia Study Group were analyzed. Early death was observed in 16 patients (4.7%), of whom 14 had serious hemorrhage and 2 had differentiation syndrome. Serious hemorrhage and differentiation syndrome of grade 2 or higher were observed in 21 and 54 patients, respectively. Patients who achieved complete remission had a 7-year disease-free survival of 84.8% if they did not experience serious hemorrhage and 40.0% if they experienced serious hemorrhage during remission induction therapy (P = 0.001). Risk factor analyses showed that higher white blood cell count was associated with early death, higher white blood cell count and lower platelet count with serious hemorrhage, and leukocytosis during induction therapy and higher body surface area with differentiation syndrome. In conclusion, these results indicate that patients with such high-risk features may benefit from more intensive supportive care. The hemorrhagic risk was not relieved by the introduction of new anticoagulants. Further studies are required to establish the predictive impact of body surface area on differentiation syndrome. This trial is registered with UMIN-CTR as C000000154 on September 13, 2005.

Bloodstream infection by multidrug-resistant Streptococcus oralis in a leukemic patient with febrile neutropenia after hematopoietic stem cell transplantation.

We reported the case of a patient with leukemia who developed febrile neutropenia after hematopoietic stem cell transplantation. Blood culture results revealed the presence of Streptococcus oralis, while antimicrobial susceptibility testing showed the resistance to penicillin and cephem. Furthermore, isolates were not susceptible to either meropenem or daptomycin but not to vancomycin. S oralis is known to belong to Streptococcus mitis group and be a causative agent of bacteremia in the neutropenic patients, but multidrug resistance of S oralis is rare. Our findings suggest that we might pay attention to the emergence of the microorganisms acquiring multidrug resistance in neutropenic patients.

[Therapy-related acute promyelocytic leukemia developing during chemotherapy for thymic carcinoma].

A 74-year-old man was admitted to hospital due to suspected acute leukemia. He had a history of thymic carcinoma, which had been treated with carboplatin in combination with either paclitaxel or amrubicin. However, the tumor remained unresponsive to these treatments. Administration of tegafur/gimeracil/oteracil (TS-1) was initiated, which resulted in tumor size reduction and a partial response. However, leukopenia persisted after the last TS-1 treatment, and four years after the initial treatment, increased blast cell counts were found in a blood film . Bone marrow analysis showed blasts with Auer rods, faggot cells, and dysplastic promyelocytes. Flow cytometry was positive for CD13, CD33, CD34, CD117, and myeloperoxidase, but negative for HLA-DR. PML-RARA fluorescence in situ hybridization was positive. Cytogenetic analysis revealed 47,XY,t (15;17) (q22;q21),+21. Thus, therapy-related acute promyelocytic leukemia (tAPL) was diagnosed. The patient achieved and maintained complete remission for more than 20 months by a de novo APL-treatment regimen including all-trans retinoic acid, arsenic trioxide and tamibarotene. Moreover, the thymic carcinoma has remained stable. Although secondary malignancies of thymic carcinoma have been previously reported, therapy-related leukemia, especially tAPL, is very rare.

TUBB1 dysfunction in inherited thrombocytopenia causes genome instability.

Inherited thrombocytopenia is a genetically heterogeneous disease characterized by varying degrees of thrombocytopenia and risk of haematological malignancy, and the genetic cause of many cases remains unknown. We performed whole-exome sequencing of a family with thrombocytopenia and myeloid malignancy and identified a novel TUBB1 variant, T149P. Screening of other thrombocytopenia pedigrees identified another TUBB1 variant, R251H. TUBB1 encodes the tubulin ß-1 chain, a major component of microtubules abundant in megakaryocytes. Variant TUBB1 disrupted the normal assembly of microtubules and impaired proplatelet formation in vitro. In addition, DNA damage response was severely attenuated by loss of TUBB1. We found that the nuclear accumulation of p53 (also termed TP53) and the expression of pro-apoptotic genes triggered by genotoxic stress were blocked in TUBB1-deficient cells and, accordingly, apoptosis after DNA damage was diminished by knockdown of TUBB1. Thus, we have demonstrated that microtubule dysfunction confers resistance to apoptosis, even in DNA damage-accumulated cells, which explains genome instability in the affected individuals. These studies will lead us to a better understanding of how microtubule dysfunction can contribute to the accumulation of DNA damage, genetic instability and leukaemogenesis.

Clinical significance of ASXL2 and ZBTB7A mutations and C-terminally truncated RUNX1-RUNX1T1 expression in AML patients with t(8;21) enrolled in the JALSG AML201 study.

We analyzed the clinical significance and genetic features of ASXL2 and ZBTB7A mutations, and the alternatively spliced isoform of the RUNX1-RUNX1T1 transcript, which is also called AML1-ETO9a (AE9a), in Japanese CBF-AML patients enrolled in the JALSG AML201 study. ASXL2 and ZBTB7A genes were sequenced using bone marrow samples of 41 AML patients with t(8;21) and 14 with inv(16). The relative expression levels of AE9a were quantified using the real-time PCR assay in 23 AML patients with t(8;21). We identified ASXL2 (34.1%) and ZBTB7A (9.8%) mutations in only AML patients with t(8;21). ASXL2-mutated patients had a significantly higher WBC count at diagnosis (P = 0.04) and a lower frequency of sex chromosome loss than wild-type patients (33 vs. 76%, respectively, P = 0.01). KIT mutations were the most frequently accompanied with both ASXL2 (36%) and ZBTB7A (75%) mutations. Neither ASXL2 nor ZBTB7A mutations had an impact on overall or event-free survival. Patients harboring cohesin complex gene mutations expressed significantly higher levels of AE9a than unmutated patients (P = 0.03). In conclusion, ASXL2 and ZBTB7A mutations were frequently identified in Japanese AML patients with t(8;21), but not in those with inv(16). Further analysis is required to clarify the detailed biological mechanism of AE9a regulation of the cohesin complex.

False-positive blood culture results in patients with hematologic malignancies.

Blood cultures are the most valuable tool when bacteremia is clinically suspected. Technical advances have led to the development of automated blood culture systems to detect bacterial infections. Usually positive signals in automated blood culture systems result from the proliferation of microorganisms. Cases are classified as false-positive when the automated blood culture system produces a positive signal but no microorganisms are detected on Gram-stained smears and no microorganism growth is observed in blood subcultures. False-positive blood culture results are very rare in patients with hematologic malignancies. Recently, we encountered four patients who had false-positive blood culture results. Two of the patients were diagnosed with acute leukemia, involving hyperleukocytosis and an excess of blasts. The other two patients were diagnosed with acute leukemia and diffuse large B cell lymphoma with leukocytopenia. Although hypercapnia or acidosis, apart from hyperleukocytosis, might also cause false-positive results, our cases clearly did not have these conditions. We should be aware of the possibility that false-positive blood culture results can occur in patients with leukocytopenia, as well as hyperleukocytosis. To understand the mechanisms responsible for the observed false-positive results, additional studies are needed after the accumulation of similar cases.

Features of vascular adverse events in Japanese patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a retrospective study of the CML Cooperative Study Group database.

This study investigated the incidence rate and features of vascular adverse events (VAEs) in Japanese patients with chronic myeloid leukemia (CML) who were treated with tyrosine kinase inhibitors (TKIs). The analysis included 369 CML patients in the chronic or accelerated phases, selected from the CML Cooperative Study Group database; 25 events in 23 (6.2%) of these patients were VAEs. At the time of VAE incidence, nine patients were on treatment with imatinib, 12 with nilotinib, three with dasatinib, and one with bosutinib. VAE incidence comprised 13 cases of ischemic heart disease (IHD), eight of cerebral infarction (CI), and four of peripheral arterial occlusive disease (PAOD). IHD incidence rate in the study population was higher than that in the age-matched general population, particularly in nilotinib-treated patients, while CI incidence rate was almost equivalent. Compared with the Suita score, the SCORE chart and the Framingham score risk assessment tools detected more patients with high or very high risk of VAEs. In conclusion, incidence of IHD requires closer monitoring in nilotinib-treated patients. More detailed investigations for determining the most useful tool to predict VAE incidence and long-term analysis of therapy-related VAE cases are needed for improving safety during TKI therapy.

[Acute promyelocytic leukemia: state-of-the-art management].

Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML) -retinoic acid receptor (RAR) α fusion protein generated by the chromosomal translocation t (15;17) which affects both nuclear receptor signaling and PML nuclear body (NB) assembly. The advent of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as molecular targeted therapies directed against PML-RARα has been a major breakthrough in APL treatment. ATRA and ATO target RARα and PML, respectively, and elicit PML-RARα degradation, leading to the reformation of normal NBs and cell differentiation. In several multicenter trials, more than 90% of newly diagnosed APL patients treated with ATRA and chemotherapy achieved complete remission, of whom 20%-30% subsequently relapsed; the overall survival was approximately 80% in these studies. However, several major clinical problems continue to account for treatment failure including early death due to hemorrhage, infection during consolidation, disease relapse, and secondary malignancies. These issues are associated mainly with anticancer agents used in combination with ATRA. Combination therapy using ATRA and ATO is the current standard therapy for untreated patients with APL in Western countries. The current problems in patients with APL treated with ATRA and ATO are APL differentiation syndrome and high risk of relapse in patients with an initial leukocyte count of more than 10×109/l.

Disease evolution and outcomes in familial AML with germline CEBPA mutations.

In-depth molecular investigation of familial leukemia has been limited by the rarity of recognized cases. This study examines the genetic events initiating leukemia and details the clinical progression of disease across multiple families harboring germ-line CEBPA mutations. Clinical data were collected from 10 CEBPA-mutated families, representing 24 members with acute myeloid leukemia (AML). Whole-exome (WES) and deep sequencing were performed to genetically profile tumors and define patterns of clonal evolution. Germline CEBPA mutations clustered within the N-terminal and were highly penetrant, with AML presenting at a median age of 24.5 years (range, 1.75-46 years). In all diagnostic tumors tested (n = 18), double CEBPA mutations (CEBPAdm) were detected, with acquired (somatic) mutations preferentially targeting the C-terminal. Somatic CEBPA mutations were unstable throughout the disease course, with different mutations identified at recurrence. Deep sequencing of diagnostic and relapse paired samples confirmed that relapse-associated CEBPA mutations were absent at diagnosis, suggesting recurrence was triggered by novel, independent clones. Integrated WES and deep sequencing subsequently revealed an entirely new complement of mutations at relapse, verifying the presentation of a de novo leukemic episode. The cumulative incidence of relapse in familial AML was 56% at 10 years (n = 11), and 3 patients experienced ≥3 disease episodes over a period of 17 to 20 years. Durable responses to secondary therapies were observed, with prolonged median survival after relapse (8 years) and long-term overall survival (10-year overall survival, 67%). Our data reveal that familial CEBPA-mutated AML exhibits a unique model of disease progression, associated with favorable long-term outcomes.

Diagnostic performance of procalcitonin, presepsin, and C-reactive protein in patients with hematological malignancies.

INTRODUCTION: Infections represent a major complication of hematological malignancies. C-reactive protein (CRP) and procalcitonin (PCT) have been used as diagnostic biomarkers of infections, but do not produce definitive findings. Recently, a new biomarker, presepsin, has been used as a diagnostic tool for detecting infections in the fields of emergency and neonatal medicine. However, the usefulness of presepsin for identifying infections in patients with hematological malignancies, including those who develop febrile neutropenia, remains unclear. METHODS: In this study, we retrospectively analyzed the utility of PCT, presepsin, and CRP as biomarkers of infections during 49 febrile episodes that occurred in 28 patients with hematological malignancies. RESULTS: The levels of PCT, but not those of CRP or presepsin, were significantly higher in the infection group than in the uninfected group (P<.03), indicating that PCT might be a more sensitive biomarker of infections. No differences in presepsin levels were detected between the patients with and without neutropenia, or between the infected and uninfected patients with neutropenia, indicating that presepsin might have less diagnostic value in patients with neutropenia. CONCLUSIONS: We conclude that PCT might provide additional information and could be used in combination with other biomarkers to detect infections in patients with hematological malignancies.

Myeloid neoplasms in the World Health Organization 2016 classification.

In the 2016 revision of the World Health Organization (WHO) classification, the categories of myeloid neoplasms have not been revised significantly from the 2008 fourth edition. However, recent discovery of molecular abnormalities provides a new perspective regarding the diagnostic and prognostic markers. In myeloproliferative neoplasms, the identification of CALR gene mutation, in addition to the JAK2 and MPL mutations, has impacted the diagnostic criteria. In myelodysplastic syndromes and acute myeloid leukemia, in addition to alterations in the transcription factors and signal transduction pathways, discovery of gene mutations in the epigenetic regulators that are involved in DNA methylation, histone modification, cohesin complex, and RNA splicing, by comprehensive genetic analyses, has improved our understanding of the pathobiology of these diseases. Moreover, recent large-scale sequencing studies have revealed the acquisition of clonal somatic mutations, in the myeloid neoplasm-associated genes of the hematopoietic cells. Such mutations were detected in people with normal blood cell counts, without any apparent disease. Presence of these mutations confers an increased risk for subsequent hematological neoplasms, indicating the concept of clonal hematopoiesis of indeterminate potential. This updated WHO classification incorporates the criteria of new clinical, prognostic, morphologic, immunophenotypic, and genetic findings in myeloid neoplasms.

Unrelated bone marrow transplantation or immediate umbilical cord blood transplantation for patients with acute myeloid leukemia in first complete remission.

BACKGROUND: While unrelated bone marrow transplantation (UBMT) has been widely used as alternative donor transplantation, the use of umbilical cord blood transplantation (UCBT) is increasing recently. METHODS: We conducted a decision analysis to address which transplantation procedure should be prioritized for younger patients with acute myeloid leukemia (AML) harboring high- or intermediate-risk cytogenetics in first complete remission (CR1), when they lack a matched related donor but have immediate access to a suitable umbilical cord blood unit. Main sources for our analysis comprised the data from three phase III trials for a chemotherapy cohort (n = 907) and the registry data for a transplantation cohort (n = 752). RESULTS: The baseline analysis showed that when the 8/8 match was considered for UBMT, the expected 5-year survival rate was higher for UBMT than for UCBT (58.1% vs. 51.8%). This ranking did not change even when the 7/8 match was considered for UBMT. Sensitivity analysis showed consistent superiority of UBMT over UCBT when the time elapsed between CR1 and UBMT was varied within a plausible range of 3-9 months. CONCLUSIONS: These results suggest that 8/8 or 7/8 UBMT is a better transplantation option than UCBT even after allowing time required for donor coordination.