Aiko Igarashi

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.

Clinical impact of hematogones on outcomes of allogeneic hematopoietic stem cell transplantation

Increased levels of normal B cell precursors, termed hematogones (HGs), are observed in regenerating bone marrow after chemotherapy or hematopoietic stem cell transplantation (HSCT). Recent reports suggest that emergence of HGs is associated with better outcomes following allogeneic HSCT (allo-HSCT). We reviewed the emergence of HGs and the clinical features of 192 patients after allo-BMT. Patients undergoing allo-BMT from related donors were more likely to develop HGs at day 30 compared to unrelated donors. Furthermore, patients undergoing allo-BMT from HLA-mismatched donors were less likely to develop HGs at day 30. The emergence of HGs at day 30 was an independent prognostic factor among patients who underwent BMT. We found no difference in the relapse rate between HG-positive (+) and HG-negative (−) patients undergoing BMT. HG (−) patients had high non-relapse mortality, grade II to IV acute graft-versus-host-disease (GVHD), fungal infection, and lower IgG levels compared to HG (+) patients. The emergence of HGs at day 30 among patients undergoing BMT may be a very useful indicator of subsequent survival outcomes or acute GVHD in common clinical practice.

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.

Clinical impact of CD25 expression on outcomes of allogeneic hematopoietic stem cell transplant for cytogenetically intermediate-risk acute myeloid leukemia

Approximately 50% of adult patients with acute myeloid leukemia (AML) do not show clonal chromosome aberrations at diagnosis, and although this group shows an intermediate prognosis, a minority of patients eventually become long-term survivors. [1]. Th is emphasizes the need for new molecular markers that can be used to predict disease aggressiveness and to determine the leukemic response to treatment, including allogeneic hematopoietic stem cell transplant (allo-HSCT) [2]. Recent data have shown that molecular analysis of the presence of mutated FMS-like tyrosine kinase-3 (FLT3), nucleophosmin 1 (NPM1), CCAAT/ enhancer-binding protein alpha (CEBPA), mixed lineage leukemia (MLL) or neuroblastoma RAS viral oncogene homolog (N-Ras) may be useful for this purpose [3]. However, molecular analyses may be costly and not always available, as not all the mutations are detected by sequencing. As an alternative approach, we may be able to focus on distinct clinical features that depend on specifi c genetic aberrations. For example, patients with a FLT3-internal tandem duplication (ITD) mutation tend to have higher white blood cell count and blast count [4], and moreover a high percentage of these patients may have high CD25 (the α -chain of the interleukin-2 [IL-2] receptor) antigen expression as observed with fl ow cytometry [5 – 7]. Recent studies have shown that CD25 is highly expressed in chemotherapy-resistant, cell cycle-quiescent leukemic stem cells, and high CD25 expression may be associated with an unfavorable outcome after conventional chemotherapy, including autologous and allogeneic transplant [5 – 7]. Th us, evaluation of CD25 expression may be an alternative, cost-eff ective non-molecular tool for cytogenetically intermediate (CI)-AML. Here we report the clinical impact of surface expression of the CD25 antigen on transplant outcomes in a total of 40 patients with CI-AML who underwent allo-HSCT in a single institution. In this study, intermediate-risk AML included patients with a normal or indeterminate karyotype. Bone marrow and peripheral blood samples from 40 patients with CI-AML were available for analysis of CD25 expression at the initial diagnosis. Th ese patients eventually underwent allo-HSCT in our institution between January 2001 and January 2013. We list the chemotherapies, conditioning regimens and outcomes (Supplementary Table I to be found online at http://informahealthcare.com/doi/ abs/10.3109/10428194.2014.974044). Patients with French – American – British (FAB) classifi cation M3 were excluded. Flow cytometry analyses were performed in-house using standard immunofl uorescence methods with monoclonal antibodies directed against CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11b, CD13, CD14, CD19, CD20, CD25, CD33, CD34, CD38, CD41, CD56 and human leukocyte antigen (HLA)-DR antigens, and were considered to be positive if at least 20% of leukemic blasts expressed the antigen [5]. Th e cut-off level of CD25 depends on the report, for example 10% [6,7] and 20% [5]. Generally the cut-off level of 20% has been known as the standard, and we consider this as the best cut-off level to exclude false-positive results. Transplant procedures have been described in detail elsewhere [8]. Myeloablative conditioning mainly included busulfan (3.2 mg/kg for 4 days) and cyclophosphamide (60 mg/kg for 2 days). Th e main preparative regimen for the reduced-intensity procedure consisted of fl udarabine (30 mg/m 2 for 6 days), melphalan (40 mg/m 2

Central nervous system infection following allogeneic hematopoietic stem cell transplantation.

OBJECTIVE/BACKGROUND Here, we described the clinical characteristics and outcomes of central nervous system (CNS) infections occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a single institution over the previous 6 years. METHODS Charts of 353 consecutive allogeneic transplant recipients were retrospectively reviewed for CNS infection. RESULTS A total of 17 cases of CNS infection were identified at a median of 38 days (range, 10-1028 days) after allo-HSCT. Causative pathogens were human herpesvirus-6 (n=6), enterococcus (n=2), staphylococcus (n=2), streptococcus (n=2), varicella zoster virus (n=1), cytomegalovirus (n=1), John Cunningham virus (n=1), adenovirus (n=1), and Toxoplasma gondii (n=1). The cumulative incidence of CNS infection was 4.1% at 1 year and 5.5% at 5 years. CONCLUSION Multivariate analysis revealed that high-risk disease status was a risk factor for developing CNS infection (p=.02), and that overall survival at 3 years after allo-HSCT was 33% in patients with CNS infection and 53% in those without CNS infection (p=.04).

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.

Occurrence of Donor Cell-derived Lymphoid Blast Crisis 24 Years Following Related Bone Marrow Transplantation for Chronic Myeloid Leukemia.

We herein report a unique case of donor cell leukemia (DCL), as donor cell-derived lymphoid blast crisis of chronic myeloid leukemia (CML) was observed 24 years after related bone marrow transplantation for CML in the chronic phase. Short tandem repeat testing of the leukemic blast sample revealed full donor chimerism, strongly indicative of DCL. The original donor is healthy with a normal complete blood cell count for the past 24 years. This rare case may provide a precious opportunity to consider not only the underlying mechanism of DCL, but also the pathogenesis of CML.

Outcome of patients with acute undifferentiated leukemia after allogeneic hematopoietic stem cell transplantation

The World Health Organization (WHO) has categorized acute undifferentiated leukemia (AUL) as a rare subtype of acute leukemias of ambiguous lineage (ALAL). The prognosis of AUL is considered poor and it expresses no known lineage-specific marker [1,2]. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) can potentially cure various hematological malignancies, little is known about the transplant modality and outcomes of patients with AUL. Most published reports to date have analyzed the clinical characteristics and prognosis of AUL together with those of mixed-phenotypic acute leukemia (MPAL) although they have quite different clinical characteristics [3–5]. Therefore, these studies might not be particularly informative for patients with AUL. Here, we analyzed the clinical outcomes of 10 patients with AUL after allo-HSCT at our institution. We retrospectively reviewed 911 patients with acute leukemia who were admitted to our institution between April 2005 and March 2017. Consensus diagnostic criteria for AUL have not yet been established. Therefore, we defined AUL based on the WHO classification [2] as leukemic cells that were not positive for any lineage-specific markers (myeloid lineage: myeloperoxidase [cytochemistry, immunohistochemistry, or flow cytometry]; B cell lineage: CD19, CD79a, or cytoplasmic CD22; T cell lineage: cytoplasmic CD3 or surface CD3). Our institutional committee on research ethics approved the study (approval number: 1973), which proceeded according to the Declaration of Helsinki. Transplant procedures have been described in detail elsewhere [6]. Generally, myeloablative conditioning mainly included a total body irradiation (TBI) regimen (12Gy) in combination with cyclophosphamide (CY) at 120mg/kg, or a non-TBI regimen that included intravenous busulfan at 12.8mg/kg, and CY at 120mg/kg. The preparative regimen for the reduced-intensity procedure consisted of fludarabine (30mg/m for 6 d), melphalan (40mg/m for 2 d), and TBI (4 Gy). The patients were given intravenous infusion of donor hematopoietic stem cells on day 0. All patients received acute graft-versus-host disease (GVHD) prophylaxis with cyclosporine or tacrolimus and short-term methotrexate. Tacrolimus was used in cases involving either unrelated or human leukocyte antigen (HLA) mismatched transplantation. Engraftment in alloHSCT is defined as the first of three consecutive days with an absolute neutrophil count of 0.5 10/l or greater. The probability of overall survival (OS) was estimated using Kaplan–Meier product limit method. We calculated OS from the date of allo-HSCT to the last assessment for survivors. The cumulative incidence of non-relapse mortality (NRM), relapse and acute GVHD were evaluated using Gray’s method. For each estimation of the cumulative incidence of an event, death without event was defined as a competing risk. All statistical analyses were performed with EZR, a graphical user interface for R software (The R Foundation for Statistical Computing, version 2.13.0; www.r-project.org). Among the 911 patients with acute leukemia, AUL was classified in only 12 (1.3%). Among those, one patient refused to undergo allo-HSCT and another died early. Table 1 shows the characteristics of 10 patients with AUL who underwent allo-HSCT. The median age at the time of transplantation was 45 (range: 22–63) years. Seven (70.0%) and three (30.0%) patients were male and female, respectively. Marrow fibrosis was found in two (20.0%) patients, but extramedullary disease was not present in any patient. Cytochemical findings were negative for myeloperoxidase in all patients. Immunophenotyping revealed the common expression of CD34 (90.0%), HLADR (80.0%), and CD13 (60.0%), but the lineage-specific markers were absent in all patients. Cytogenetic studies of nine patients revealed chromosomal abnormalities in five (55.6%) of them. In five patients (cases 2, 4, 5, 9, and 10) with available data, polymerase chain reaction (PCR)

Diagnostic open brain biopsy following initial negative results of cerebrospinal fluid assessment for Toxoplasma

Cerebral toxoplasmosis is a rare but fatal complication after allogeneic hematopoietic stem cell transplantation (HSCT), and reaching an accurate antemortem diagnosis with pathological proof is difficult.1,2 We describe herein the clinical course of a patient with cerebral toxoplasmosis following allogeneic HSCT. The diagnosis was successfully made by aggressive open brain biopsy following initial negative results from cerebrospinal fluid (CSF) assessment for Toxoplasma. This article is protected by copyright. All rights reserved.

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.