Deep intronic founder mutations identified in the ERCC4/XPF gene are potential therapeutic targets for a high-frequency form of xeroderma pigmentosum.

Xeroderma pigmentosum (XP) is a genodermatosis defined by cutaneous photosensitivity with an increased risk of skin tumors because of DNA repair deficiency. The worldwide prevalence of XP is ~1 to 4 in million, with higher incidence in some countries and regions including Japan (1 in 22,000) and North Africa due to founder mutations and a high degree of consanguinity. Among XP, the complementation group F (XP-F), is a rare form (1% of worldwide XP); however, this is underdiagnosed, because the ERCC4/XPF gene is essential for fetal development and most of previously reported ERCC4/XPF pathogenic variants are hypomorphs causing relatively mild phenotypes. From the largest Japanese XP cohort study, we report 17 XP-F cases bearing two pathogenic variants, both identified in deep intronic regions of the ERCC4/XPF gene. The first variant, located in intron 1, is a Japanese founder mutation, which additionally accounts for ~10% of the entire Japanese XP cases (MAF = 0.00196), causing an aberrant pre-mRNA splicing due to a miss-binding of U1snRNA. The second mutation located in intron eight induces an alternative polyadenylation. Both mutations cause a reduction of the ERCC4/XPF gene expression, resulting in XP clinical manifestations. Most cases developed early-onset skin cancers, indicating that these variants need critical attention. We further demonstrate that antisense oligonucleotides designed for the mutations can restore the XPF protein expression and DNA repair capacity in the patients' cells. Collectively, these pathogenic variants can be potential therapeutic targets for XP.

Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes.

Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria lead to variability in interpretation and interobserver inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in HR-MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery and CR with partial hematologic recovery as provisional response criteria, the elimination of marrow CR, and specific recommendations for the standardization of time-to-event end points and the derivation and reporting of responses. The updated criteria should lead to a better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action.

Germ line DDX41 mutations define a unique subtype of myeloid neoplasms.

Germ line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained ∼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.

Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1­G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1­G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7­G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9­G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.

Clinical impact and characteristics of erythroid dysplasia in adult aplastic anaemia: Results from a multicentre registry.

Morphological dysplasia in haematopoietic cells, defined by a 10% threshold in each lineage, is one of the diagnostic criteria for myelodysplastic neoplasms. Dysplasia limited to the erythroid lineage has also been reported in some cases of aplastic anaemia (AA); however, its significance remains unclear. We herein examined the impact of erythroid dysplasia on immunosuppressive therapy responses and survival in AA patients. The present study included 100 eligible AA patients without ring sideroblasts. Among them, 32 had dysplasia in the erythroid lineage (AA with minimal dysplasia [mini-D]). No significant sex or age differences were observed between AA groups with and without erythroid dysplasia. In severe/very severe AA and non-severe AA patients, a response to anti-thymocyte globulin + ciclosporin within 12 months was observed in 80.0% and 60.0% of AA with mini-D and 42.9% and 90.0% of those without dysplasia, with no significant difference (p = 0.29 and p = 0.24 respectively). Overall survival and leukaemia-free survival did not significantly differ between the groups. Collectively, the present results indicate that the presence of erythroid dysplasia did not significantly affect clinical characteristics or outcomes in AA patients, suggesting that its presence in AA is acceptable. Therefore, erythroid dysplasia should not exclude an AA diagnosis.

Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN.

The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults are widely recognized among physicians and investigators. There have been major advances in our understanding of AML, including new knowledge about the molecular pathogenesis of AML, leading to an update of the disease classification, technological progress in genomic diagnostics and assessment of measurable residual disease, and the successful development of new therapeutic agents, such as FLT3, IDH1, IDH2, and BCL2 inhibitors. These advances have prompted this update that includes a revised ELN genetic risk classification, revised response criteria, and treatment recommendations.

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.

Whole-genome landscape of adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive neoplasm immunophenotypically resembling regulatory T cells, associated with human T-cell leukemia virus type-1. Here, we performed whole-genome sequencing (WGS) of 150 ATL cases to reveal the overarching landscape of genetic alterations in ATL. We discovered frequent (33%) loss-of-function alterations preferentially targeting the CIC long isoform, which were overlooked by previous exome-centric studies of various cancer types. Long but not short isoform-specific inactivation of Cic selectively increased CD4+CD25+Foxp3+ T cells in vivo. We also found recurrent (13%) 3'-truncations of REL, which induce transcriptional upregulation and generate gain-of-function proteins. More importantly, REL truncations are also common in diffuse large B-cell lymphoma, especially in germinal center B-cell-like subtype (12%). In the non-coding genome, we identified recurrent mutations in regulatory elements, particularly splice sites, of several driver genes. In addition, we characterized the different mutational processes operative in clustered hypermutation sites within and outside immunoglobulin/T-cell receptor genes and identified the mutational enrichment at the binding sites of host and viral transcription factors, suggesting their activities in ATL. By combining the analyses for coding and noncoding mutations, structural variations, and copy number alterations, we discovered 56 recurrently altered driver genes, including 11 novel ones. Finally, ATL cases were classified into 2 molecular groups with distinct clinical and genetic characteristics based on the driver alteration profile. Our findings not only help to improve diagnostic and therapeutic strategies in ATL, but also provide insights into T-cell biology and have implications for genome-wide cancer driver discovery.

Outcomes of transplant-eligible patients with myelodysplastic syndrome with excess blasts registered in an observational study: The JALSG-CS11-MDS-SCT.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the sole curative therapy for myelodysplastic syndrome (MDS). However, whether bridging therapy (BRT) including azacitidine (AZA) and combination chemotherapy (CCT) prior to allo-SCT should be performed is unclear. We analyzed BRT and the outcomes of patients with myelodysplastic syndrome with excess blasts (MDS-EB) who were ≤ 70 years old at the time of registration for a prospective observational study to clarify the optimal allo-SCT strategy for high-risk MDS. A total of 371 patients were included in this study. Among 188 patients (50.7%) who were considered for allo-SCT, 141 underwent allo-SCT. Among the patients who underwent allo-SCT, 64 received AZA, 29 received CCT, and 26 underwent allo-SCT without BRT as the initial treatment. Multivariate analysis identified BRT as an independent factor influencing overall survival (AZA vs. without BRT, hazard ratio [HR] 3.33, P = 0.005; CCT vs. without BRT, HR 3.82, P = 0.003). In multivariate analysis, BRT was independently associated with progression-free survival (AZA vs. without BRT: HR, 2.23; P = 0.041; CCT vs. without BRT: HR, 2.94; P = 0.010). Transplant-eligible patients with MDS-EB should undergo allo-SCT when clinically acceptable, and upfront allo-SCT without BRT may be superior to AZA or CCT.

Feasibility evaluation of a blood rotation system for efficient blood product utilization in remote island settings.

BACKGROUND AND OBJECTIVES: Geographical limitations in remote island medical facilities result in excessive wastage of blood products. To address this, we explored the feasibility of a novel blood rotation system, which enables the return and redelivery of blood products to/from the blood bank while ensuring the management of product quality, including temperature control. This study aimed to enhance the supply of blood products to these facilities. MATERIALS AND METHODS: The Japan Red Cross Nagasaki Blood Center, Nagasaki Goto Chuoh Hospital (NGCH) and Nagasaki University Hospital collaborated to coordinate the transport and supply of red blood cell (RBC) products. Type O, RhD-positive, irradiated RBC products were stored at a precise 4.0 ± 2.0°C in an active transport refrigerator (ATR). After transport from the Japan Red Cross Nagasaki Blood Center to NGCH, RBC products were held for 1 week in the ATR, and unused products were returned. Eligible returned products were reissued to the Nagasaki University Hospital. RESULTS: All the returned RBC products met the redelivery criteria. Among the 103 redelivered RBC preparations, 101 bags (98.1%) were successfully used. NGCH utilized 597 RBC products and discarded 80 samples. The ATR supplied 107 type O RBC bags without any wastage. The overall wastage rate was 10.2% during the study period compared with 24.2% in the same period in the previous year. CONCLUSION: This innovative supply and operation system ensures a consistent and secure RBC product supply to remote islands while maximizing blood product use.

Utility of allogeneic stem cell transplantation for adult Ph+ALL with complete molecular remission.

This study aimed to investigate the usefulness of allogeneic stem cell transplantation (allo-SCT) for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in the first complete remission (CR1) with complete molecular remission (CMR). We compared the outcomes between Ph+ALL patients who did or did not undergo allo-SCT in CR1. We included patients enrolled in the prospective clinical studies in the tyrosine kinase inhibitor era conducted by the Japan Adult Leukemia Study Group, who achieved CMR within 3 months. A total of 147 patients (allo-SCT: 101; non-SCT: 46) were eligible for this analysis. In the multivariate analyses, allo-SCT was significantly associated with both superior overall survival (OS) (adjusted hazard ratio (aHR): 0.54; 95% CI: 0.30-0.97; p = .04) and relapse-free survival (RFS) (aHR: 0.21; 95% CI: 0.12-0.38; p < .001). The 5-year adjusted OS and RFS were 73% and 70% in the allo-SCT cohort, whereas they were 50% and 20% in the non-SCT cohort. Despite the higher non-relapse mortality (aHR: 3.49; 95% CI: 1.17-10.4; p = .03), allo-SCT was significantly associated with a lower relapse rate (aHR: 0.10; 95% CI: 0.05-0.20; p < .001). In addition, allo-SCT was also associated with superior graft-versus-host disease-free, relapse-free survival (aHR: 0.43; 95% CI: 0.25-0.74; p = .002). Propensity score-matched analyses confirmed the results of the multivariate analyses. In patients who achieved CMR within 3 months, allo-SCT in CR1 had superior survival and lower relapse compared with the non-SCT cohort.

Functional inhibition of MEF2 by C/EBP is a possible mechanism of leukemia development by CEBP-IGH fusion gene.

CEBPA-IGH, a fusion gene of the immunoglobulin heavy-chain locus (IGH) and the CCAAT enhancer-binding protein α (C/EBPα) gene, is recurrently found in B-ALL cases and causes aberrant expression of C/EBPα, a master regulator of granulocyte differentiation, in B cells. Forced expression of C/EBPα in B cells was reported to cause loss of B-cell identity due to the inhibition of Pax5, a master regulator of B-cell differentiation; however, it is not known whether the same mechanism is applicable for B-ALL development by CEBPA-IGH. It is known that a full-length isoform of C/EBPα, p42, promotes myeloid differentiation, whereas its N-terminal truncated isoform, p30, inhibits myeloid differentiation through the inhibition of p42; however, the differential role between p42 and p30 in ALL development has not been clarified. In the present study, we examined the effect of the expression of p42 and p30 in B cells by performing RNA-seq of mRNA from LCL stably transfected with p42 or p30. Unexpectedly, suppression of PAX5 target genes was barely observed. Instead, both isoforms suppressed the target genes of MEF2 family members (MEF2s), other regulators of B-cell differentiation. Similarly, MEF2s target genes rather than PAX5 target genes were suppressed in CEBP-IGH-positive ALL (n = 8) compared with other B-ALL (n = 315). Furthermore, binding of both isoforms to MEF2s target genes and the reduction of surrounding histone acetylation were observed in ChIP-qPCR. Our data suggest that the inhibition of MEF2s by C/EBPα plays a role in the development of CEBPA-IGH-positive ALL and that both isoforms work co-operatively to achieve it.

Integrated genetic and clinical prognostic factors for aggressive adult T-cell leukemia/lymphoma.

The prognosis of aggressive adult T-cell leukemia/lymphoma (ATL) is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment. In order to identify favorable prognostic patients after intensive chemotherapy, and who therefore might not require upfront allo-HSCT, we aimed to improve risk stratification of aggressive ATL patients aged <70 years. The clinical risk factors and genetic mutations were incorporated into risk modeling for overall survival (OS). We generated the m7-ATLPI, a clinicogenetic risk model for OS, that included the ATL prognostic index (PI) (ATL-PI) risk category, and non-silent mutations in seven genes, namely TP53, IRF4, RHOA, PRKCB, CARD11, CCR7, and GATA3. In the training cohort of 99 patients, the m7-ATLPI identified a low-, intermediate-, and highrisk group with 2-year OS of 100%, 43%, and 19%, respectively (hazard ratio [HR] =5.46; P<0.0001). The m7-ATLPI achieved superior risk stratification compared to the current ATL-PI (C-index 0.92 vs. 0.85, respectively). In the validation cohort of 84 patients, the m7-ATLPI defined low-, intermediate-, and high-risk groups with a 2-year OS of 81%, 30%, and 0%, respectively (HR=2.33; P=0.0094), and the model again outperformed the ATL-PI (C-index 0.72 vs. 0.70, respectively). The simplified m7-ATLPI, which is easier to use in clinical practice, achieved superior risk stratification compared to the ATLPI, as did the original m7-ATLPI; the simplified version was calculated by summing the following: high-risk ATL-PI category (+10), low-risk ATL-PI category (-4), and non-silent mutations in TP53 (+4), IRF4 (+3), RHOA (+1), PRKCB (+1), CARD11 (+0.5), CCR7 (-2), and GATA3 (-3).

Allogeneic transplantation of bone marrow versus peripheral blood stem cells from HLA-identical relatives in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukemia: a propensity score analysis of a nationwide database.

Bone marrow (BM) and granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (PBSC) are used as grafts from HLA-identical-related donors for adults with myelodysplastic syndrome (MDS). To assess the impact of graft sources on post-transplant outcomes in MDS patients, we conducted a retrospective analysis of a nationwide database. A total of 247 and 280 patients underwent transplantation with BM and PBSC, respectively. The inverse probability of treatment weighting (IPTW) methods revealed that overall survival (OS) was comparable between BM and PBSC (P = .129), but PBSC transplantation was associated with worse graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) (hazard rate [HR], 1.24; 95% confidence intervals [CIs], 1.00-1.53; P = 0.049) and chronic GVHD-free and relapse-free survival (CRFS) (HR, 1.29; 95% CIs, 1.13-1.73; P = 0.002) than BM transplantation. In the propensity score matched cohort (BM, n = 216; PBSC, n = 216), no significant differences were observed in OS and relapse; 3-year OS rates were 64.7% and 60.0% (P = 0.107), while 3-year relapse rates were 27.1% and 23.5% (P = 0.255) in BM and PBSC, respectively. Three-year GRFS rates (36.6% vs. 29.2%; P = 0.006), CRFS rate (37.7% vs. 32.5%; P = 0.003), and non-relapse mortality rates (13.9% vs. 21.1%; P = 0.020) were better in BM than in PBSC. The present study showed that BM transplantation provides a comparable survival benefit with PBSC transplantation and did not identify an enhanced graft-versus-MDS effect to reduce the incidence of relapse in PBSC transplantation.

Hangeshashinto for prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation: a randomized phase II study.

PURPOSE: Oral mucositis (OM) is a side effect associated with cancer treatment. Hangeshashinto (HST), a Kampo medicine, was originally prescribed to treat diarrhea, gastritis, and stomatitis. Several reports have described the effects of HST for OM induced by chemotherapy in patients with gastric or colorectal cancer. In this study, the effects of HST for prevention of OM were investigated in patients undergoing hematopoietic stem cell transplantation (HSCT). METHODS: Thirty patients scheduled to receive allogeneic grafts were enrolled from July 2020 to December 2021. They were randomly assigned to two groups and instructed to wash their mouth using HST dissolved in saline solution or using only saline solution three times a day. The observation period was from the initiation date of the conditioning regimen to the date of engraftment, and the end point was the incidence of OM. RESULTS: Eighteen patients developed OM, the most severe of which was Grade (G)3. There was no significant difference in the incidence of OM between the HST group and the control group. However, a negative correlation tended to be observed between the duration using HST use and the duration of OM (G2-3: P = 0.027, G3: P = 0.047). CONCLUSIONS: The present study demonstrated that HST use did not clearly inhibit onset of OM but showed a tendency to inhibit OM exacerbation. However, further studies are necessary to fully understand the effects of HST on OM in patients undergoing HSCT. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials on 7 May 2020 (jRCTs071200012).

Lung Involvement in Adult T-Cell Lymphoma Diagnosed Using Bronchoscopic Cryobiopsy: A Case Report and Review of the Literature.

The diagnosis of pulmonary lymphoma using small tissue samples is difficult and often requires surgical procedures; thus, a less invasive sampling method is desirable. Moreover, pulmonary involvement in adult T-cell lymphoma (ATL) is often difficult to diagnose, especially in cases without characteristic flower cells. Here, we present the case of a 78-year-old man, in whom pathological examination of the transbronchial lung biopsy (TBLB) specimen did not reveal malignant findings; therefore, transbronchial lung cryobiopsy (TBLC) in combination with endobronchial ultrasonography (EBUS) was used to diagnose ATL based on the pathological findings. A literature review identified 18 cases of pulmonary lymphomas diagnosed using TBLC. Among the 19 cases, including our own, 16 cases were of B-cell lymphoma (84.2%), and the present case is the first case of ATL diagnosed using TBLC. Eighty percent of the cases underwent a biopsy (more than two samples) of the middle or lower lobe and were diagnosed without major complications. EBUS was used with TBLC in three cases to identify the location of the pulmonary lesions. In the present case, EBUS was also useful for avoiding vascular biopsy. Although large-scale prospective studies are required to establish precise guidelines for diagnosing pulmonary lymphomas using TBLC, our case report and review contributes to a deeper understanding of the diagnosis of rare diseases.

[Methotrexate-related lymphoproliferative disease showing different histological findings at recurrence].

A 55-year old female patient was treated with methotrexate (MTX) and infliximab (IFX) for rheumatoid arthritis (RA). She experienced unknown fever, generalized lymphadenopathy, and liver tumors. Histological examination of the inguinal lymph node and a liver tumor resulted in the pathological diagnosis of classic Hodgkin lymphoma, with many Reed-Sternberg cells with the positivity of Epstein-Barr virus (EBV). She was diagnosed with MTX-related lymphoproliferative disorders (MTX-LPDs). She received chemotherapy after the cessation of MTX and IFX and achieved complete remission. RA showed recurrence after a while, and she was treated with steroids or other drugs. Six years after the chemotherapy, she experienced low-grade fever and anorexia. Whole computed tomography images showed an appendix tumor and enlargement of the surrounding lymph nodes. Appendectomy with the radical lymph nodes dissection was performed. The pathological diagnosis was diffuse large B-cell lymphoma, resulting in the clinical diagnosis of the relapse of MTX-LPD. EBV was negative at this point. The pathological findings of MTX-LPD may change at relapse; thus, biopsy should be considered when the relapse of MTX-LPD is suggested.

Phase I study of alvocidib plus cytarabine/mitoxantrone or cytarabine/daunorubicin for acute myeloid leukemia in Japan.

Therapeutic improvements are needed for patients with acute myeloid leukemia (AML), particularly those who have relapsed or who have treatment-refractory (R/R) AML or newly diagnosed patients with poor prognostic factors. Alvocidib (DSP-2033), a potent cyclin-dependent kinase 9 inhibitor, has previously demonstrated promising clinical activity for the treatment of AML. In this multicenter, open-label, uncontrolled, 3 + 3 phase I study, we investigated the safety and tolerability of alvocidib administered in combination with either cytarabine and mitoxantrone (ACM) for R/R AML or cytarabine/daunorubicin (A + 7 + 3) for newly diagnosed AML. Alvocidib was administered to all patients as a 30-min intravenous (i.v.) bolus (30 mg/m2 /d), followed by a continuous i.v. infusion over 4 h on days 1-3 (60 mg/m2 /d). A total of 10 patients were enrolled: six received ACM (at two dose levels of cytarabine and mitoxantrone) and four received A + 7 + 3. Alvocidib was tolerated and no dose-limiting toxicities were observed. All patients experienced adverse events, of which diarrhea was the most frequent (100%); hematologic events were also common. Alvocidib concentration peaked at the end of dosing (4.5 h after start of administration), plasma accumulation after repeated dosing was minimal and urinary excretion was negligible. The rate of complete remission/complete remission with incomplete hematologic recovery was 66.7% with the ACM regimen in R/R AML, including four complete remission (median duration 13.6 months), and 75% (three complete remission) with the A + 7 + 3 regimen. Further development of alvocidib in hematologic malignancies is warranted. The trial is registered with Clinicaltrials.gov, NCT03563560.

TAS-116 (pimitespib), a heat shock protein 90 inhibitor, shows efficacy in preclinical models of adult T-cell leukemia.

Adult T-cell leukemia/lymphoma (ATL) is a highly chemoresistant malignancy of peripheral T lymphocytes caused by human T-cell leukemia virus type 1 infection, for which there is an urgent need for more effective therapeutic options. The molecular chaperone heat shock protein 90 (HSP90) plays a crucial role in nuclear factor-κB (NF-κB)-mediated antiapoptosis in ATL cells, and HSP90 inhibitors are new candidate therapeutics for ATL. Accordingly, we investigated the anti-ATL effects of a novel oral HSP90 inhibitor, TAS-116 (pimitespib), and the mechanisms involved in ex vivo and in vivo preclinical models. TAS-116 achieved IC50 values of less than 0.5 µmol/L in 10 ATL-related cell lines and less than 1 µmol/L in primary peripheral blood cells of nine ATL patients; no toxicity was observed toward CD4+ lymphocytes from healthy donors, indicating the safety of this agent. Given orally, TAS-116 also showed significant inhibitory effects against tumor cell growth in ATL cell-xenografted mice. Furthermore, gene expression profiling of TAS-116-treated Tax-positive or -negative cell lines and primary ATL cells using DNA microarray and multiple pathway analysis revealed the significant downregulation of the NF-κB pathway in Tax-positive cells and cell-cycle arrest in Tax-negative cells and primary ATL cells. TAS-116 suppressed the activator protein-1 and tumor necrosis factor pathways in all examined cells. These findings strongly indicate the efficacy of TAS-116, regardless of the stage of ATL progression, and its potential application as a novel clinical anti-ATL therapeutic agent.

Phase 1/2 study evaluating the safety and efficacy of DSP-7888 dosing emulsion in myelodysplastic syndromes.

DSP-7888 is an immunotherapeutic cancer vaccine derived from the Wilms' tumor gene 1 (WT1) protein. This phase 1/2 open-label study evaluated the safety and efficacy of DSP-7888 dosing emulsion in patients with myelodysplastic syndromes (MDS). DSP-7888 was administered intradermally (3.5 or 10.5 mg) every 2 weeks for 6 months and then every 2-4 weeks until lack of benefit. Twelve patients were treated in phase 1 (3.5 mg, n = 6; 10.5 mg, n = 6), with no dose-limiting toxicities reported. Thus, the 10.5 mg dose was selected as the recommended phase 2 dose, and 35 patients were treated in phase 2. Forty-seven patients received ≥1 dose of the study drug and comprised the safety analysis set. The most common adverse drug reaction (ADR) was injection site reactions (ISR; 91.5%). Grade 3 ISR were common (58.8%) in phase 1 but occurred less frequently in 2 (22.9%) following implementation of risk minimization strategies. Other common ADR were pyrexia (10.6%) and febrile neutropenia (8.5%). In the efficacy analysis set, comprising patients with higher-risk MDS after azacitidine failure in phases 1 and 2 (n = 42), the disease control rate was 19.0%, and the median overall survival (OS) was 8.6 (90% confidence interval [CI], 6.8-10.3) months. Median OS was 10.0 (90% CI, 7.6-11.4) months in patients with a WT1-specific immune response (IR; n = 33) versus 4.1 (90% CI, 2.3-8.1) months in those without a WT1-specific IR (n = 9; P = .0034). The acceptable safety and clinical activity findings observed support the continued development of DSP-7888 dosing emulsion.