Acute Myeloid Leukemia In Japan Research Articles

A real-world, retrospective, observational study examining treatment patterns and clinical outcomes in patients with FLT3m + AML in Japan

Objective Acute myeloid leukemia (AML) is the most common form of leukemia among adults in Japan. This study aimed to understand the treatment patterns, health care resource utilization, and costs of FMS-like tyrosine kinase 3 mutation-positive (FLT3m+) AML patients in Japan. Methods A retrospective cohort study of Japanese FLT3m + AML patients was conducted using data extracted from a national hospital-based claims database provided by Medical Data Vision Co. Ltd. (MDV; Tokyo, Japan). Patients were identified from the MDV database between April 2008 and April 2021 inclusive. Results A total of 360 patients were included in this study. The study results suggest that cytarabine + anthracyclines was the most common first-line (1 L) treatment, accounting for 41.3% of the patients. FLT3 inhibitors (FLT3i) was the most common treatment across the study period (95.7%). The mean age of patients was 62.4 years, and most were 65 years or older. The median overall survival (OS) after initiating FLT3i treatment was 394 days. The median treatment duration of FLT3i was 88.5 days, while it was 66.0 days for patients treated with FLT3i within 60 days after hematopoietic stem cell transplantation (HSCT). The overall mean monthly total treatment cost was JPY 2,009,531.7/per patient per month (PPPM) (USD 17,967.9/PPPM). Conclusions The study found specific treatment patterns, trends and features in patients with FLT3m + AML. FLT3i was the most prescribed treatment across the study period and the overall median OS after initiating FLT3i treatment was over 1 year. The findings of this study could be helpful for clinicians to optimize treatment strategies for FLT3m + AML in Japan.

Interim results from a postmarketing surveillance study of patients with FLT3-mutated relapsed/refractory AML treated with the FLT3 inhibitor gilteritinib in Japan.

ObjectiveGilteritinib received approval for the treatment of FLT3-mutated relapsed or refractory acute myeloid leukemia in Japan in 2018. In accordance with regulatory requirements, we conducted a multicenter, observational surveillance of gilteritinib use in Japan.MethodsPatients were followed for 6 months from gilteritinib treatment initiation. The primary endpoint of the surveillance was incidence of adverse drug reactions related to each element of the safety specification defined in the Japanese Risk Management Plan. This interim analysis presents data collected from 3 December 2018 to 20 September 2020.ResultsAmong 204 patients with case report forms, 107 consented to data publication. Of these 107 patients, 59.8% (n = 64) were male and 58.9% (n = 63) were aged ≥65 years; most received a 120-mg/day initial (80.4%; 86/107) and maximum (74.8%; 80/107) daily dose. The discontinuation rate was 61.7% (66/107); the most common reasons for discontinuation were disease progression (18.7%), transplantation (16.8%) and adverse events (15.0%). The adverse drug reaction rate was 77.6%. The incidences of adverse drug reactions (grade ≥ 3) related to each element of the safety specification were myelosuppression, 44.9% (38.3%); liver function disorder, 24.3% (6.5%); infections, 24.3% (21.5%); prolonged QT interval, 10.3% (2.8%); hemorrhage, 9.3% (6.5%); renal dysfunction, 6.5% (0); hypersensitivity, 5.6% (1.9%); interstitial lung disease, 4.7% (3.7%); cardiac failure/pericarditis/pericardial effusion, 1.9% (0.9%); pancreatitis, 0.9% (0); posterior reversible encephalopathy syndrome, 0.9% (0.9%). The composite complete remission rate was 62.7%; the 6-month overall survival rate was 77.7%.ConclusionGilteritinib treatment for 6 months in Japan was associated with acceptable efficacy and no new safety concerns were observed.

Improved trends in survival and engraftment after single cord blood transplantation for adult acute myeloid leukemia

Unrelated cord blood transplantation (CBT) is an alternative curative option for adult patients with acute myeloid leukemia (AML) who need allogeneic hematopoietic cell transplantation (HCT) but lack an HLA-matched related or unrelated donor. However, large-scale data are lacking on CBT outcomes for unselected adult AML. To investigate the trends of survival and engraftment after CBT over the past 22 years, we retrospectively evaluated the data of patients with AML in Japan according to the time period of CBT (1998–2007 vs 2008–2013 vs 2014–2019). A total of 5504 patients who received single-unit CBT as first allogeneic HCT for AML were included. Overall survival (OS) at 2 years significantly improved over time. The improved OS among patients in ≥ complete remission (CR)3 and active disease at CBT was mainly due to a reduction of relapse-related mortality, whereas among patients in first or second CR at CBT, this was due mainly to a reduction of non-relapse mortality. The trends of neutrophil engraftment also improved over time. This experience demonstrated that the survival and engraftment rate after CBT for this group has improved over the past 22 years.

Real-world treatment patterns and clinical outcomes in patients with AML in Japan who were ineligible for first-line intensive chemotherapy

Acute myeloid leukemia (AML) predominantly affects elderly adults, and its prognosis worsens with age. Treatment options for patients in Japan ineligible for intensive chemotherapy include cytarabine/aclarubicin ± granulocyte colony-stimulating factor (CA ± G), azacitidine (AZA), low-dose cytarabine (LDAC), targeted therapy, and best supportive care (BSC). The country's aging population and the evolving treatment landscape are contributing to a need to understand treatment pathways and associated outcomes. This retrospective chart review evaluated outcomes in patients across Japan with primary/secondary AML who were ineligible for intensive chemotherapy and began first-line treatment or BSC between 01/01/2015 and 12/31/2018. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and healthcare resource utilization (HRU). Of 199 patients (58% > 75years), 121 received systemic therapy (38 CA ± G, 37 AZA, 7 LDAC, 39 other) and 78 received BSC. Median OS was 5.4, 9.2, 2.2, 3.8, and 2.2months for CA ± G, AZA, LDAC, other systemic therapy, and BSC, respectively; median PFS was 3.4, 7.7, 1.6, 2.3, and 2.1months, respectively. HRU rates were uniformly high, with > 80% patients hospitalized in each cohort. The poor clinical outcomes and high HRU among Japanese AML patients who are ineligible for intensive chemotherapy highlight an unmet need for novel therapies.

FLT3 inhibitors in the treatment of FLT3-mutated acute myeloid leukemia

Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene represent the most common genetic alteration in acute myeloid leukemia (AML), identified in approximately one third of patients newly diagnosed with AML. FLT3 internal tandem duplication mutations (FLT3-ITD) are associated with increased relapse and inferior overall survival. Multiple inhibitors of FLT3 signaling have been developed in the last few years with variable kinase-inhibitory properties, pharmacokinetics, and toxicity profiles. At present, two FLT3 inhibitors (gilteritinib and quizartinib) have been approved as monotherapies for relapsed/refractory FLT3-mutated AML in Japan, and many more drugs are currently being researched in clinical trials as monotherapies or in combination with conventional chemotherapy or hypomethylating agents and in various settings, including front line, relapsed/refractory disease, and maintenance therapy after consolidation chemotherapy or allogeneic stem cell transplantation. Despite significant advances, some issues need to be overcome, including the resistance to FLT3 inhibitors and controversies regarding the role of FLT3 inhibitors in maintenance therapies and the role of allogeneic stem cell transplantation in FLT3-mutated AML.

Pharmacological and clinical profile of gilteritinib (Xospata<sup>®</sup> tablets 40 mg), a therapeutic agent for relapsed or refractory <i>FLT3</i>-mutated acute myeloid leukemia

Gilteritinib fumarate (Xospata® tablets 40 mg) is a novel, highly selective, oral FMS-like tyrosine kinase 3 (FLT3) inhibitor used for the treatment of patients with relapsed or refractory FLT3-mutated acute myeloid leukemia (AML), and it was approved in Japan in September 2018. Preclinical studies demonstrated that gilteritinib inhibited FLT3 and showed antiproliferative activity against Ba/F3 cells expressing mutated FLT3. In addition, gilteritinib inhibited tumor growth, induced tumor regression, and prolonged survival in mice xenografted with MV4-11 cells endogenously expressing FLT3-internal tandem duplication. In clinical trials conducted in the United States, Europe, and Japan, plasma concentrations after administration of gilteritinib 20 to 450 mg/day were generally dose proportional, and gilteritinib was well tolerated. Multiple clinical trials, including a global Phase III study, in patients with relapsed or refractory FLT3-mutated AML treated with gilteritinib demonstrated higher response rates of complete remission or complete remission with partial hematologic recovery and longer overall survival compared with patients treated with salvage chemotherapy. Some clinical trials are ongoing in patients with FLT3-mutated AML at various treatment stages, such as induction therapy, maintenance therapy, and treatment after hematopoietic stem cell transplantation. In conclusion, in vitro, in vivo, and clinical data indicate that gilteritinib fumarate is an effective treatment option in adult patients with relapsed or refractory FLT3-mutated AML in Japan.

Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia conducted in Japan during the past quarter century.

Acute myeloid leukemia (AML) represents the most common indication for allogeneic hematopoietic cell transplantation (HCT). This study aimed to address the implementation status of allogeneic HCT for adults with AML in Japan and to provide a comprehensive overview of post-transplant outcomes. For this purpose, we analyzed data of 15,186 patients undergoing allogeneic HCT between 1992 and 2016 who were consecutively reported to the Japanese nationwide transplantation registry. The constant increase in the annual number of transplantations was clearly attributable to the growth of unrelated transplantation, and umbilical cord blood transplantation currently accounts for one-third of all allogeneic HCTs. The proportion of older patients has increased steadily since 2000, approximately, in parallel with the introduction of reduced-intensity conditioning. The probability of overall survival (OS) was estimated at 41% (95% confidence interval (CI), 40-42%) for the entire cohort, 56% (95% CI, 55-57%) for patients transplanted in complete remission (CR), and 22% (95% CI, 21-23%) for those transplanted in non-CR. Multivariate analysis identified age, sex, performance status, disease status, cytogenetic risk, donor type, graft source, sex mismatch between the donor and the recipient, and year of transplantation as factors significantly associated with OS. These findings represent the real-world data in Japan, showing the changes in transplantation practice and a detailed estimation of post-transplant outcomes.

Past, present, and future challenges to overcome in the treatment of pediatric acute myeloid leukemia in Japan

Past, present, and future challenges to overcome in the treatment of pediatric acute myeloid leukemia in Japan

Genetic analysis and targeted therapy for acute myeloid leukemia

Several chromosomal abnormalities and gene mutations involved in the onset and recurrence of acute myeloid leukemia (AML) were discovered with the recent progress of genome analysis technology. The founding not only have clinical application as prognostic factors and minimal residual disease markers but also contribute to the novel molecular-targeted drug development. Many new drugs such as first-generation FLT3 inhibitor, IDH1/2 inhibitor, and BCL2 inhibitor have been developed in Europe and the United States. In addition, second-generation FLT3 inhibitors, gilteritinib and quizartinib, were developed in Japan, and the treatment outcome of AML has been improved. However, a large disparity in the drug availability remains between Europe and the United States and Japan. As a result, treatment guidelines in Europe and the United States cannot be applied to the practical use in Japan. In this paper, molecular-targeted drug treatment by gene diagnosis will be considered for AML in Japan, and the future paradigm shift of gene diagnosis and treatment of AML will be outlined.

Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Myeloid Leukemia in Japan

Allogeneic Stem Cell Transplantation in Patients with Philadelphia Chromosome-Positive Acute Myeloid Leukemia in Japan

Autologous hematopoietic cell transplantation for acute myeloid leukemia in adults: 25years of experience in Japan.

Autologous hematopoietic cell transplantation (HCT) has not gained universal popularity in the treatment of acute myeloid leukemia (AML), and its status remains unclear. To determine the implementation status and outcomes of autologous HCT for adults with AML in Japan, we analyzed data from 1,174 patients (including 446 with acute promyelocytic leukemia [APL]) who underwent autologous HCT between 1992 and 2016 consecutively reported to the Japanese nationwide transplantation registry. The annual number of transplantations peaked at 82 cases in 1997, and has recently remained at around 40 cases. The percentage of APL has increased sharply since 2004, and currently exceeds 70%. While most non-APL patients underwent autologous HCT during first complete remission (CR), transplantation during second CR has become mainstream for APL patients since the early 2000s. The 5-year survival, relapse, and non-relapse mortality rates were 55.3%, 42.1%, and 8.6% for non-APL patients, and 87.6%, 12.9%, and 3.4% for APL patients, respectively. Patients transplanted in the later period showed better survival than those transplanted in the earlier period, both for non-APL (P < 0.001) and APL (P = 0.036). These results clearly show the various changes in transplantation practice and post-transplant outcomes in Japan over the past 25years.

First Successful Cord Blood Transplantation from the National Marrow Donor Program for Acute Myeloid Leukemia in Japan

First Successful Cord Blood Transplantation from the National Marrow Donor Program for Acute Myeloid Leukemia in Japan

Age is an independent adverse prognostic factor for overall survival in acute myeloid leukemia in Japan

Age is an independent adverse prognostic factor for overall survival in acute myeloid leukemia in Japan

Phase I Study of Clofarabine in Adult Patients with Acute Myeloid Leukemia in Japan

There are limited treatment options for relapsed/refractory acute myeloid leukemia patients or previously untreated elderly (≥60 years) patients with acute myeloid leukemia. In Phase II studies from the USA and Europe, single-agent clofarabine demonstrated activity and acceptable toxicity in elderly patients with previously untreated acute myeloid leukemia. This Phase I, multicenter study assessed the maximum-tolerated dose, safety, pharmacokinetics and efficacy of clofarabine in Japanese adults with acute myeloid leukemia. Intravenous clofarabine (20, 30 and 40 mg/m(2)/day) was administered for 5 days to Japanese adult patients with relapsed or refractory acute myeloid leukemia or elderly patients with newly diagnosed acute myeloid leukemia. Fourteen patients, median age of 67.5 (59-72) years, were enrolled in this study. Eleven out of 14 patients had relapsed/refractory acute myeloid leukemia. Three patients received clofarabine at 20 mg/m(2), six at 30 mg/m(2) and five at 40 mg/m(2). Frequently reported treatment-related adverse events included thrombocytopenia (100%), anemia (93%), neutropenia (86%), nausea (86%), alanine aminotransferase increase (71%), headache (71%) and febrile neutropenia (57%). Three patients experienced reversible dose-limiting toxicities; two had increased alanine aminotransferase with 30 and 40 mg/m(2) and one had Grade 3 elevation of serum amylase with 40 mg/m(2). The maximum-tolerated dose was 30 mg/m(2)/day. Cmax and exposure area under the curve0-24h increased with increasing dose and were proportional to dose through the tested dose range. Among the 14 assessable patients, four (29%) achieved complete remission and two (14%) complete remission without platelet recovery. The overall remission rate was 43%. These results demonstrate safety and preliminary, promising activity of clofarabine in Japanese patients with acute myeloid leukemia. Further investigation is warranted.

Heterogeneity in Infants with Acute Myeloid Leukemia: Retrospective Analysis of a Japanese Nationwide Survey

Abstract 1477 Introduction:When compared to older patients, infants with acute leukemia exhibit distinct cytogenetic features, such as higher prevalence of MLL gene rearrangement (MLL-R), and are known to have higher vulnerability to intensive cytotoxic therapy, such as hematopoietic stem cell transplantation. In contrast to acute lymphoblastic leukemia (ALL), there have been few reports on acute myeloid leukemia (AML) in infants. To develop more appropriate therapeutic strategies for infants with AML, it is necessary to elucidate the distinct clinical features of this subgroup. We therefore performed a retrospective analysis on infant AML in Japan. Patients: Infants with AML, aged less than 1 year at diagnosis, registered in any of the 6 Japanese AML clinical trials between 1991 and 2010 (TCCSG M91-13, TCCSG M96-14, AML99, CCLSG9805, CCLSG9805RE, and JPLSG AML-05) were included in this study. Patients with Down syndrome were excluded. Results: A total of 122 infant AML patients were included in the present analysis, which comprised approximately 10% of all pediatric AML patients. The most frequent FAB classification type was M5 (28.7%), followed by M7 (22.9%) and M4 (10.8%). About 30% of patients had 11q23 abnormalities/MLL -R, but there was no impact on prognosis. Several cases with normal karyotype were revealed to be MLL -R on FISH analysis or on MLL -fusion chimeric transcript analysis by RT-PCR. t(8;21), inv(16) and t(15;17) cases were very rare among the infant cohorts. Furthermore, 7.8% had t(1;22)(p13;q13), and 2.5% had t(7;12)(q36;p13). Genetic mutation results could be obtained in 11 cases in the AML99 study; only one case each was confirmed to have NRAS, KRAS or KIT gene mutation. No cases with FLT3-ITD were detected among the 11 cases in the AML99 or the 44 cases in the AML-05 study. Survival rate varied based on treatment received; 5-year OS rate was 58.3% to 71.4%, and 5-year EFS rate was 49.4% to 64.2%. Discussion: Survival rate in infant AML was identical to that in older pediatric AML. However, there was a possible underestimation of MLL -R patients based on sole chromosome analysis; the prevalence of MLL -R was less than 50% in infant AML patients, without any prognostic impact. Other well-known genetic alterations in pediatric AML also had no effect on outcome of infant AML. Infant AML is a heterogeneous subgroup of pediatric AML, and further studies, as well as novel biomarkers, will be necessary to fully understand its biology. Disclosures:No relevant conflicts of interest to declare.

Clinical significance of minimal residual disease in patients with t(8;21) acute myeloid leukemia in Japan

To examine the prognostic significance of minimal residual disease (MRD) in t(8;21) acute myeloid leukemia (AML), 96 bone marrow samples from 26 Japanese patients in complete remission (CR) were analyzed regarding the RUNX1/MTG8 transcript using real-time reverse transcriptase polymerase chain reaction assay. All patients were treated with intensive chemotherapy. The median copy number of the RUNX1/MTG8 transcript, measured after each treatment course decreased over time. However, an increase in the MRD level was documented in three patients after the second consolidation, and all of them subsequently relapsed. The relapse-free survival (RFS) did not differ between the patients whose MRD levels were below or above 1,000 copies/microg after the first consolidation, with respective 2-year rates of 62 and 86% (P = 0.21). With respect to the MRD level after induction therapy, our data also failed to show any favorable effect of a lower MRD on RFS. Although these findings need to be confirmed with a larger number of patients, our data indicate that the MRD level at a given time during the early course in CR does not predict the outcome in Japanese patients.

Clinical Characteristics and Outcomes in Patients with t(8;21) Acute Myeloid Leukemia in Japan.

Clinical characteristics of Japanese patients with t(8;21) acute myeloid leukemia (AML) have not been well described. From January 2000 to December 2005, a total of 147 Japanese adult de novo AML (FAB: M2) patients were newly diagnosed with t(8;21) AML (n=46) or without t(8;21) AML (n=101) in collaborating hospitals. Patients with t(8;21) (median age, 49.5 years; range, 18–86 years) were significantly younger than AML(M2) patients without t(8;21) (median age, 60 years; range 17–90 years) (p<0.001). Three-year overall survival rate in patients with t(8;21) was 70% (95% confidence interval (CI), 51–83%), significantly better than that in AML (M2) patients without t(8;21) (log-rank test, p=0.005) (Figure). Among patients <60-years-old, overall survival rates of patients with t(8;21) AML and patients with non-t(8;21) AML(M2) were 71% (95%CI, 47–86%) and 58% (95%CI, 41–72%), respectively (log-rank test, p=0.28). Of the 40 patients who achieved complete remission, 21 patients received high-dose cytarabine-containing consolidation therapy. Event-free survival rates at 3 years after diagnosis in patients with and without high-dose cytarabine were 60% (95%CI, 36–78%) and 57% (95%CI, 26–79%), respectively (log-rank, p=0.87). In multivariate analysis, age and white blood cell count at diagnosis represented significant predictors of overall survival. For the 147 AML(M2) patients, presence of t(8;21) was not a significant predictor of overall survival after adjusting for age (hazard ratio, 0.65; 95%CI, 0.34–1.24; p=0.19). Japanese patients with t(8;21) AML display more favorable survival rates than those in Western countries. Efficacy of high-dose cytarabine might differ between Japanese and Western patients. Clinicians must be aware of potential differences among different ethnicities. [Display omitted]

Clinical characteristics and outcomes in patients with t(8;21) acute myeloid leukemia in Japan

Clinical characteristics and outcomes in patients with t(8;21) acute myeloid leukemia in Japan