KIT is a type-III receptor tyrosine kinase that contributes to cell signaling in various cells. Since KIT is activated by overexpression or mutation and plays an important role in the development of ...some cancers, such as gastrointestinal stromal tumors and mast cell disease, molecular therapies targeting
mutations are being developed. In acute myeloid leukemia (AML), genome profiling via next-generation sequencing has shown that several genes that are mutated in patients with AML impact patients' prognosis. Moreover, it was suggested that precision-medicine-based treatment using genomic data will improve treatment outcomes for AML patients. This paper presents (1) previous studies regarding the role of
mutations in AML, (2) the data in AML with
mutations from the HM-SCREEN-Japan-01 study, a genome profiling study for patients newly diagnosed with AML who are unsuitable for the standard first-line treatment (unfit) or have relapsed/refractory AML, and (3) new therapies targeting
mutations, such as tyrosine kinase inhibitors and heat shock protein 90 inhibitors. In this era when genome profiling via next-generation sequencing is becoming more common,
mutations are attractive novel molecular targets in AML.
FMS-like tyrosine kinase 3 (
FLT3
) internal tandem duplication (ITD) mutations in patients with acute myeloid leukemia (AML) are associated with early relapse and poor survival. This multicenter, ...single-arm, two-stage phase 2 study (NCT02984995) was conducted to evaluate the efficacy and safety of quizartinib hydrochloride (initial dose 20/30 mg/day), an oral, highly potent, selective
FLT3
inhibitor in Japanese patients (median age 65 years) with
FLT3
-ITD positive relapsed/refractory (R/R) AML. The composite complete remission (CRc) rate (primary endpoint) was 53.8% (90% confidence interval 36.2–70.8%) for evaluable patients in the efficacy analysis set. The median duration of CRc and overall survival was 16.1 weeks and 34.1 weeks, respectively. The most frequent treatment-emergent adverse events (TEAEs) were febrile neutropenia (43.2%), platelet count decreased (37.8%), and QT prolonged (35.1%). Two (5.4%) patients experienced TEAEs associated with treatment discontinuation. All serious TEAEs (45.9%), except febrile neutropenia (16.2%), were reported in ≤ 2 patients. The incidence of QTcF 451–480 ms and 481–500 ms was 37.8% and 2.7%, respectively. No QTcF > 500 ms, events of torsade de pointes or arrhythmia with clinical symptoms were reported. Quizartinib monotherapy was well tolerated and resulted in clinically meaningful reductions in blast count in Japanese patients with
FLT3
-ITD R/R AML.
Objective In Japan, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG), and cyclosporine A (CsA) is the standard of care in patients with aplastic anemia (AA) who are not indicated ...for stem-cell transplantation, although some patients may experience relapse. This study assessed the efficacy and safety of eltrombopag in combination with rabbit-ATG/CsA in IST-naïve patients with non-severe or severe AA in Japan. Methods In this non-randomized, open-label, single-arm, phase II study, rabbit-ATG/CsA and eltrombopag were initiated on Days 1 and 15 (±3 days), respectively, and continued for ≥26 weeks; rabbit-ATG was given for 5 days (Days 1 to 5). The primary endpoint was the overall response rate (ORR) at Week 26. Patients Patients with AA who were IST-naïve and ≤70 years old or between 71 and 75 years old based on the recommendation of the investigator were enrolled in Japan. Results Of the 11 enrolled patients, 10 started treatment with eltrombopag. The ORRs at Weeks 26 and 52 were 70.0% and 60.0%, respectively. The ORR at Week 26 was 100% (all 3 patients) in patients with non-severe AA and 57.1% (4/7) in patients with severe AA. Among transfusion-dependent patients, 66.7% (4/6) and 62.5% (5/8) became red blood cell- and platelet-transfusion independent, respectively. The most common adverse events were nausea and headache. No deaths or hematologic malignancies were reported. A cytogenetic abnormality was reported in one patient. Conclusion This study confirmed the clinical benefit of eltrombopag plus rabbit-ATG/CsA in IST-naïve patients with non-severe or severe AA in Japan.
Venetoclax plus azacitidine is indicated in the USA for the treatment of newly diagnosed acute myeloid leukaemia in older patients (≥75 years) or those ineligible for induction chemotherapy due to ...co-morbidities.
In this phase 1/2 study (NCT02265731), Japanese patients (≥60 years) with untreated (ineligible for induction chemotherapy) or relapsed/refractory acute myeloid leukaemia received oral venetoclax 400 mg/day (3-day ramp up in cycle 1) plus subcutaneous or intravenous azacitidine 75 mg/m2 on days 1-7 per 28-day cycle until disease progression or unacceptable toxicity.
As of 10 December 2019, six patients were enrolled (median age: 75 years; untreated: n = 5; relapsed/refractory: n = 1); median treatment duration: 10.3 months (range, 0.7-29.4). Most common grade ≥ 3 adverse events were lymphopaenia and febrile neutropaenia (n = 4 each). Four patients reported serious adverse events; only an event of grade 3 fungal pneumonia was considered possibly related to both study drugs, requiring dose interruption of venetoclax and delay of azacitidine. Five (83%) patients had responses (complete remission: n = 3). Median time to first response of complete remission/complete remission with incomplete count recovery was 1.0 month (range, 0.8-5.5); median overall survival: 15.7 months (95% confidence interval: 6.2, not reached).
Venetoclax plus azacitidine was well tolerated and showed high response rates in Japanese patients with acute myeloid leukaemia.
Expanded therapeutic options are warranted for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) ...mutations. The present phase 1, multicenter, open-label, dose-escalation and dose-expansion study was conducted to assess the safety, pharmacokinetics, and efficacy of multiple-dose monotherapy of the FLT3 inhibitor, quizartinib, in Japanese patients with R/R AML. Patients received oral quizartinib, once daily, under fasting conditions in 28-day cycles. Sixteen patients (median age, 68.0 years; male, 56.3%; FLT3-ITD positive, 43.8%) received quizartinib (9, 3, and 4 patients at 20, 30, and 60 mg/day, respectively; median treatment duration, 95.0 days; median relative dose intensity, 100.0%). No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were electrocardiogram QT prolonged (43.8%, grade 1 or 2) followed by nausea and pyrexia (37.5% each). No quizartinib-related deaths were reported. A dose-dependent increase of quizartinib and its active metabolite AC886 levels was observed at the steady state. The composite complete remission rate was 37.5%. Quizartinib was well tolerated in Japanese R/R AML patients at doses up to 60 mg/day; quizartinib 60 mg/day was considered as the recommended dose for the Japanese patient population in a subsequent study.
Trial registration
ClinicalTrials.gov identifier NCT02675478.
In this article, we report the case of a 78-year-old woman who consulted our hospital for a right breast mass detected on mammography during her cancer screening. Biopsy specimens showed atypical ...lymphocytic infiltration with a follicle-like growth pattern, suggesting a follicular lymphoma (FL). Immunohistochemically, the atypical lymphoid cells were diffusely and strongly positive for CD20, BCL2, and BCL6, but negative for CD10. IGH-BCL2 translocation was confirmed by fluorescence in situ hybridization analysis, leading to the diagnosis of primary breast FL. The most important differential diagnosis of this case was marginal zone lymphoma (MZL), which usually shows a CD10−/BCL2+ immunophenotype and is one of the common histological types in primary breast lymphomas. FLs with an atypical immunophenotype exist in a certain percentage of patients. Therefore, FL is considered to be a heterogeneous entity. It is important to distinguish FL from MZL in primary breast lymphomas because FLs may have a worse prognosis than MZLs.
Abstract
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-azacitidine was well tolerated in the Japanese subgroup of VIALE-A (N = 37) and showed improved efficacy versus placebo-azacitidine in patients with acute myeloid leukemia ineligible for intensive chemotherapy, supporting use as first-line standard-of-care.
A multicenter retrospective study was performed to explore a prognostic scoring index in order to identify a population who are least likely to benefit from allogeneic hematopoietic cell ...transplantation (HCT) in patients with relapsed or refractory acute myeloid leukemia (AML). The cohort included 519 patients with AML, who received HCT between 2005 and 2015 at a status of relapse or primary induction failure. Multivariate analysis demonstrated five independent predictors for OS, including C-reactive protein ≥ 1 mg/dL, peripheral blood blast fraction ≥ 20%, poor-risk karyotype, performance status ≥ 2, and bone marrow unrelated donor as a stem cell source. A prognostic scoring index was explored based on these predictors, and successfully separated the cohort into four groups. At 2 years, OS was 47%, 24%, 8%, and 0% for Good (Score 0, 1: n = 118), Intermediate-1 (Score 2: n = 75), Intermediate-2 (Score 3: n = 39), and Poor (Score 4: n = 24), respectively (P < 0.001). The predicting value of the index was confirmed in a validation cohort. Although a further validation study is warranted, the scoring index may be useful to predict survival and to identify the population with the lowest survival prior to HCT in patients with relapsed or refractory AML.
Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and frequent progression to leukemia. It has long remained ...unresolved how MDS cells, which are less proliferative, inhibit normal hematopoiesis and eventually dominate the bone marrow space. Despite several studies implicating mesenchymal stromal or stem cells (MSCs), a principal component of the HSC niche, in the inhibition of normal hematopoiesis, the molecular mechanisms underlying this process remain unclear. Here, we demonstrate that both human and mouse MDS cells perturb bone metabolism by suppressing the osteolineage differentiation of MSCs, which impairs the ability of MSCs to support normal HSCs. Enforced MSC differentiation rescues the suppressed normal hematopoiesis in both in vivo and in vitro MDS models. Intriguingly, the suppression effect is reversible and mediated by extracellular vesicles (EVs) derived from MDS cells. These findings shed light on the novel MDS EV-MSC axis in ineffective hematopoiesis.
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