Kaito Harada

CD25 expression on residual leukemic blasts at the time of allogeneic hematopoietic stem cell transplant predicts relapse in patients with acute myeloid leukemia without complete remission

Abstract Recent studies have shown that CD25 expression at the time of diagnosis of acute myeloid leukemia (AML) may be associated with an unfavorable outcome. We focus on patients with AML without complete remission (CR) and examine the clinical correlation between surface CD25 expression at the time of transplant and subsequent transplant outcomes. We observed a significant difference in overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) between CD25 positive (+) (n = 22) and negative (−) groups (n = 44) (2-year OS; CD25 (+) group: 5% vs. CD25 (−) group: 40%, p < 0.0001, 2-year DFS; 5% vs. 29%, p < 0.0001, 2-year CIR; 77% vs. 52%, p = 0.03). Multivariate analysis showed that CD25 expression was an independent adverse factor for OS (p = 0.002) and relapse (p = 0.001). Patients with AML with residual CD25 positive blasts at the time of transplant may require additional therapy before or after transplant to improve survival.

Effect of cytogenetic risk status on outcomes for patients with acute myeloid leukemia undergoing various types of allogeneic hematopoietic cell transplantation: an analysis of 7812 patients

Abstract This study aimed at determining how cytogenetic risk status affects outcomes for patients with acute myeloid leukemia (AML) after undergoing various types of allogeneic hematopoietic cell transplantation (HCT). Of 7812 patients eligible for analysis, cytogenetic risk was classified as favorable for 1088, intermediate for 5025, and poor for 1699. Overall, multivariate analysis showed significant intergroup differences in terms of relapse and survival, with the difference between poor- and intermediate-risk groups being greater than that between favorable- and intermediate-risk groups. Non-relapse mortality was identical for the three groups. Significant effects of cytogenetic risk status on survival were documented irrespective of donor type (related, unrelated, and umbilical cord blood), disease status at the time of transplantation (first or second complete remission, and more advanced disease status), and conditioning intensity (myeloablative and reduced-intensity). Our findings demonstrate robust and constant effects of cytogenetic risk status on survival after allogeneic HCT for patients with AML.

Allogeneic hematopoietic stem cell transplant overcomes poor prognosis of acute myeloid leukemia with myelodysplasia-related changes

Recent studies have shown that acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) exhibits a worse clinical outcome than AML not otherwise specified (AML-NOS). However, transplant outcomes of patients with AML-MRC have not been reported compared to patients with AML-NOS. We analyzed transplant outcomes among 147 patients with AML-MRC or AML-NOS who underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) in a single institution. There were no significant differences in the 2-year overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) between the two groups (2-year OS: 48% vs. 59%; 2-year CIR: 37% vs. 35%; 2-year NRM: 19% vs. 13%). Subgroup analysis adjusting for age and disease status demonstrated the same results between the two groups. Furthermore, multivariate analysis showed that AML-MRC was not an independent prognostic factor for poor prognosis in the setting of allo-HSCT (p = 0.7). These results suggest that allo-HSCT may overcome the poor prognosis of AML-MRC.

Mycophenolate mofetil is effective only for involved skin in the treatment for steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Dear Editor, Recently, mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), has been used for acute graft-versus-host disease (aGVHD) prophylaxis and as a treatment for steroid-refractory aGVHD (SR-aGVHD) [1–4]. In the setting of treatment for SR-aGVHD, only a few studies [2–4] have analyzed the individual response in three involved organs (only skin, only liver, and only gut) in a small number of patients treated with MMF. No study has reported the response in two or more involved organs. We evaluated whether MMF is effective for one, two, or three involved organs in patients who had received MMF for SR-aGVHD. From 2004 to 2014, we identified 42 patients who received oral MMF for the treatment of SR-aGVHD (grade I, n = 7; grade II–IV, n = 35) (Supplemental Table 1). Transplant procedures have been described in detail elsewhere [5]. All patients received aGVHD prophylaxis with cyclosporine (CsA) or tacrolimus (FK) as well as short-term methotrexate. aGVHD, SRaGVHD, and responses to MMF were diagnosed and graded according to previously established criteria [2, 6]. MMF was orally administered at a median dose of 1333 mg/day (range 500–3000) in addition to standard CsA or FK with more than 1 mg/kg steroid. Twice the initial amount of MMF was administered when aGVHD had not improved or worsened after the initiation of MMF treatment. The median duration of MMF administration was 97 days (range 11–674 days). Four weeks after the initiation of MMF, 24 patients achieved complete response (CR), 4 had partial response (PR), and 14 patients had no response (NR). The response including all organs was comparable in related or unrelated donor transplantation, and in bone marrow transplantation or peripheral blood stem cell transplantation (Supplemental Fig. 1a, d). All three recipients from human leukocyte antigen (HLA)-haploidentical donors received conditioning with antithymocyte globulin, and the response was NR (Supplemental Fig. 1b, c). However, the response was similar in HLA matched and one mismatched donor transplantation (Supplemental Fig. 1b). Regarding the involved organs, the response rate in patients who developed only skin GVHD was higher than in those with only liver, only gut, skin and liver, liver and gut, skin and gut, or all three organs (92.3 vs. 0, 0, 20, 0, 37.5, 0 %, respectively, p < 0.001, Fig. 1a). The response in skin was similar to that in liver among patients who developed skin and liver SR-aGVHD (CR and PR rate 20 vs. 20 %, Fig. 1b). Moreover, the response in skin was similar to that in gut among patients who developed skin and gut SRaGVHD (CR rate 50 vs. 37.5 %, Fig. 1c). This study demonstrated that patients with only skin SRaGVHD responded to MMF better than those with only liver, only gut, skin and liver, or skin and gut aGVHD. Furthermore, the response rate in skin was low, similar to that in liver or gut Electronic supplementary material The online version of this article (doi:10.1007/s00277-016-2854-0) contains supplementary material, which is available to authorized users.

Cytomegalovirus meningitis in a patient with relapsed acute myeloid leukemia

Cytomegalovirus meningitis/meningoencephalitis is a potentially fatal complication following hematopoietic stem cell transplantation that causes significant morbidity and mortality. In the pre-transplant setting, a few cases involving lymphoid malignancies have been reported. However, there have been no reports of patients with myeloid malignancies. A 36-year-old man with relapsed acute myeloid leukemia received high-dose cytarabine-containing salvage chemotherapies and then developed grade 4 lymphopenia for more than one month. Subsequently, the patient developed pyrexia, accompanying headache, nausea, and vomiting with no abnormal brain imaging. Despite receiving antimicrobial treatment, his febrile status and headache persisted. Given that the patient had symptoms consistent with viral meningitis with no evidence of etiology other than positive cytomegalovirus-DNA in his cerebrospinal fluid and cytomegalovirus pp65 antigenemia, cytomegalovirus meningitis was diagnosed. After commencing ganciclovir treatment, the patient’s headache and febrile status rapidly improved. Cytomegalovirus meningitis/meningoencephalitis is rare before hematopoietic stem cell transplantation, but may be useful in differential diagnoses in heavily treated acute myeloid leukemia patients with central nervous system symptoms.

Clinical impact of underweight status at diagnosis on elderly patients with acute myeloid leukemia: a retrospective study of JALSG GML200

Dear Editor, A recent study demonstrated that underweight status at diagnosis was an independent risk factor for survival and nonrelapse mortality (NRM) in adult patients with acute myeloid leukemia (AML) [1]. Similar results have been reported in pediatric AML patients [2]. However, the outcomes of underweight elderly AML patients have not been reported [3]. We therefore investigated the clinical outcomes of underweight patients among 241 newly diagnosed elderly AML patients who were registered in the GML200 study of the Japan Adult Leukemia Study Group. Patients were classified into three groups: underweight (body mass index [BMI] < 18.5 kg/ m), normal weight (18.5 ≤BMI < 25 kg/m), and overweight (BMI ≥ 25 kg/m). The detailed JALSG GML200 protocol has been reported elsewhere [4]. The median BMI was 22.4 kg/m (range, 16.0–36.9 kg/ m). Of the 241 patients, 15 were underweight, 176 were normal weight, and 50 were overweight. The patients’ characteristics by BMI classification at diagnosis are summarized in Supplementary Table 1. No significant differences were found among the three groups, except for performance status (PS). There was no significant difference in overall survival (OS) among the groups (1-year OS 45.7% in the underweight vs. 61.4% in the normal weight vs. 55.9% in the overweight group; p = 0.17; Fig. 1a). However, the 1-year relapse-free survival (RFS) rate was lower in the underweight group than that in the normal and overweight groups (20.0 vs. 47.0 vs. 35.3%; p = 0.025; Fig. 1b). After adjusting for the covariates, underweight was a significant risk factor for RFS (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.06–4.33; p =

Extramedullary Gastric Relapse at the Time of Bone Marrow Relapse of Acute Lymphoblastic Leukemia after Allogeneic Bone Marrow Transplantation

Extramedullary relapse (EMR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is relatively rare. The most commonly reported sites in acute lymphoblastic leukemia (ALL) patients after allo-HSCT are soft tissue and the central nervous system, and the gastrointestinal system is an uncommon site. We herein report a unique case with massive hematemesis resulting from gastrointestinal relapse of ALL after allo-HSCT. Upper gastrointestinal endoscopy showed bleeding from a 1.5-cm submucosal tumorous lesion with central ulceration on the anterior wall of the stomach. At the same time, computed tomography revealed extramedullary relapse at the breast and bilateral adrenal glands.

Outcomes after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia harboring t(7;11)(p15;p15)

Acute myeloid leukemia (AML) with chromosomal translocation between 7p15 and 11p15 [t(7;11)(p15;p15)], resulting in a fusion between the nucleoporin 98 and homeobox A9 genes (NUP98-HOXA9), is rare and has been reported sporadically in Asian countries. The NUP98-HOXA9 fusion gene can dysregulate hematopoietic precursor transcription, disrupt cell differentiation, enhance cell proliferation, and contribute to leukemogenesis. Although AML with t(7;11)(p15;p15) as the sole abnormality is classified as an intermediate-risk condition in recent cytogenetic stratifications, previous studies reported dismal outcomes, with a median survival of 8–13 months. Most patients in these studies underwent chemotherapy rather than allogeneic hematopoietic stem cell transplantation (HSCT). Moreover, the number of patients in each study was small. To date, no study has directly compared transplant outcomes between patients with AML harboring t(7;11)(p15;p15) and those with other AML variants. In this study, using nationwide registration data in Japan, we compared transplant outcomes of patients with AML harboring t(7;11)(p15;p15) with those of patients with intermediateor poor-risk AML variants. We also evaluated the risk factors for survival in patients with AML harboring t(7;11)(p15;p15) who underwent allogeneic HSCT. Clinical data were collected through the Transplant Registry Unified Management Program, which is the nationwide data registry of the Japan Society for Hematopoietic Cell Transplantation and the Japanese Data Center for Hematopoietic Cell Transplantation. The study endpoints were overall survival (OS), disease-free survival (DFS), relapse rate, and transplant-related mortality. Definitions of each endpoint, covariates considered in the univariate models for each analysis, and statistical methods are described in the Online Supplement. From 1986 through 2014, we identified 91 patients with AML harboring t(7;11)(p15;p15), 7,308 with intermediaterisk AML, and 2,406 with poor-risk AML with chromosomal changes other than t(7;11)(p15;p15). Among the survivors (n=4,278), the median follow-up period was 1,124 days. Patient and transplant characteristics are summarized in Online Supplementary Tables S1 and S2. At 3 years after allogeneic HSCT, OS and DFS probabilities were 40.1% and 37.8% in the t(7;11)(p15;p15) group; 48.0% and 44.8% in the intermediate-risk group; and 28.5% and 25.1% in the poor-risk group, respectively (Figure 1A,B). Patients in the poor-risk group exhibited significantly lower survival probabilities than those in the t(7;11)(p15;p15) group (OS, P=0.008; DFS, P=0.006),

Erythrocytosis after allogeneic hematopoietic stem cell transplantation

We read with great interest the recent report by Atilla et al.1 showing posttransplant erythrocytosis (PTE) following allogeneic hematopoietic stem cell transplantation (alloHSCT). Because the small number of cases has limited the impact of their conclusion, we would like to present the clinical features of our adult patients who developed erythrocytosis after alloHSCT. The study included 1540 patients who underwent alloHSCT in our institution between 1986 and 2014. Patients who had a history of pretransplant erythrocytosis, those who smoked after alloHSCT, or patients who relapsed after alloHSCT were not included in this analysis. Erythrocytosis was defined as a hemoglobin (Hb) level >18.5 g/dL in males and >16.5 g/dL in females, based on the WHO 2008 definition.2 Patients with a Hb level >17.0 g/dL in males or >15.0 g/dL in females and who had an increased Hb level of 2 g/dL or an elevated red cell mass (125%) compared to the individual’s baseline value were included. Seven patients were diagnosed with PTE (Table 1). The primary diseases were aplastic anemia (AA) (n = 4) and myelodysplastic syndrome refractory anemia (MDS (RA)) (n = 3). The median time from alloHSCT to the diagnosis of PTE was 776 days (range 2921561 days). Erythropoietin (EPO) levels were within the normal limit (median: 7.5 mU/mL, range 2.812.4 mU/mL), and the JAK2V617F mutation was not detected in any patients. No patients had leukocytosis, thrombocytosis, hyperviscosity symptoms, or splenomegaly. One patient developed Grade 0I acute graftversushost disease (GVHD), and Grade IIIV acute GVHD was observed in six patients. Four patients had chronic GVHD, and one patient was receiving calcineurin inhibitors (CIs) at the time of diagnosis of PTE. Six patients not taking CIs were diagnosed at a median of 370 days (range 165993 days) after the withdrawal of CIs. All causes for secondary polycythemia were ruled out by relevant investigations. Only one patient was managed with phlebotomies. Regarding the pathogenesis of PTE in renal recipients, excess EPO release from the native kidneys and nonEPO factors such as insulinlike growth factor1 may promote erythrocytosis.3 In the setting of