Ayumu Ito

Diabetes mellitus is associated with high early-mortality and poor prognosis in patients with autoimmune hemolytic anemia

Abstract The incidence of autoimmune hemolytic anemia (AIHA) is highest among the elderly, and thus it is frequently associated with co-morbidities such as diabetes mellitus (DM). However, there have been few reports on the impact of these co-morbidities on survival in patients with AIHA. Therefore, we retrospectively reviewed the records of 53 consecutive AIHA patients and assessed the impact of DM on survival. Eighteen of the 53 patients had DM. The estimated 4-year overall survival (4y-OS) for all patients was 84·9%. Infection was the most frequent cause of death, and fatal infections were exclusively observed in patients with DM. The deaths in DM patients occurred frequently within 1 year, to give significantly poor survival (4y-OS; 69·3% versus 93·6%, P=0·0064). The presence of DM was identified as the only significant risk factor for survival. A large prospective investigation is warranted to assess the impact of co-morbidities on survival in patients with AIHA.

Pancreatic atrophy is associated with gastrointestinal chronic GVHD following allogeneic PBSC transplantation

Pancreatic atrophy is associated with gastrointestinal chronic GVHD following allogeneic PBSC transplantation

Double-Expressor Lymphoma Is Associated with Poor Outcomes after Allogeneic Hematopoietic Cell Transplantation

Double-expressor lymphoma (DEL) is a diffuse large B cell lymphoma that exhibits co-expression of MYC and BCL2 proteins by immunohistochemistry. Patients with double-expressor lymphoma have a poor prognosis after standard chemoimmunotherapy or after high-dose chemotherapy with autologous transplantation, but the prognostic impact of DEL after allogeneic hematopoietic cell transplantation has not been well characterized. We retrospectively analyzed 60 consecutive patients with de novo diffuse large B cell lymphoma or transformed follicular lymphoma who underwent allogeneic transplantation at our center and had available immunohistochemistry data. Thirty-seven patients (62%) had DEL. The 2-year progression-free and overall survival rates were lower in patients with DEL than in those without DEL (20% versus 78%; overall P <.001 and 46% versus 77%; overall P = .016, respectively). The cumulative incidence of disease progression at 2 years was higher in patients with DEL (60% versus 13%; overall P = .005). The cumulative incidence of nonrelapse mortality did not differ statistically in the 2 groups. Even in patients with DEL and chemosensitive disease at transplantation, the 2-year progression-free survival rate was only 27% due to early disease progression. Multivariate analysis showed associations between DEL and increased risks of progression-free survival events (hazard ratio [HR], 4.58; 95% confidence interval [CI], 2.07-10.2; P <.001), overall mortality (HR, 2.29; 95% CI, 1.03-5.09; P = .042) and disease progression (HR, 3.60; 95% CI, 1.38-9.44; P = .009). Patients with DEL had poor outcomes after allogeneic transplantation. Innovative strategies are needed to improve outcomes in this population.

Prognostic importance of pretransplant disease status for posttransplant outcomes in patients with adult T cell leukemia/lymphoma

Adult T cell leukemia/lymphoma (ATL) is an aggressive T cell lymphoma with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be a curative treatment for ATL, a significant proportion of allo-HSCT recipients suffer from relapse/progression of ATL. Here we aimed to clarify the risk factors for and outcomes after posttransplant relapse/progression. We retrospectively reviewed 76 patients with ATL who received allo-HSCT at our institute. At the time of allo-HSCT, disease status was complete response in 17 patients, partial response in 29, stable disease (SD) in 18, and progressive disease (PD) in 12. In multivariate analysis, SD/PD at allo-HSCT, lymphoma subtype, reduced-intensity conditioning regimen, and time from diagnosis to allo-HSCT were associated with risk of relapse/progression. After allo-HSCT, 26 patients had relapse/progression at a median of 66 days (range, 13–2064 days). The 2-year overall survival rate after relapse/progression was only 19%. Compared with acute-type, lymphoma-type experienced local recurrence more frequently (1/15 acute vs. 7/11 lymphoma, P < 0.01) and had a significantly longer OS after relapse/progression (median; 112 days in acute vs. 554 days in lymphoma, P < 0.01). Since the prognosis of patients with ATL who experienced relapse/progression after allo-HSCT was poor, strategies to reduce the risk of these outcomes are warranted.

A higher number of infused CD34(+) cells has a positive impact on the clinical outcome after related PBSC transplantation.

A higher number of infused CD34 + cells has a positive impact on the clinical outcome after related PBSC transplantation

Beneficial impact of low-dose rabbit anti-thymocyte globulin in unrelated hematopoietic stem cell transplantation: focusing on difference between stem cell sources

Recently, Lee SJ et al. [1] showed that unrelated bone marrow transplantation (uBMT) was favored because patients who underwent BMT had less long-term complications such as chronic graft-versus-host disease (GVHD) than those who underwent unrelated peripheral blood stem cell transplantation (uPBSCT). In order to prevent longterm complications, it is crucial to establish a strategy to effectively prevent severe chronic GVHD after PBSCT without compromising overall survival (OS). Although anti-T lymphocyte globulin (ATG) might be an option to prevent chronic GVHD, there is still controversy regarding the benefit of ATG [2, 3]. The use of high ATG doses can lead to profound depletion of donor-derived T cells, which can increase the risk of viral infection and attenuate graft-vs.-leukemia effects. Since T-cell profiles vary significantly among stem cell sources, the optimal ATG dose might also differ. We previously reported that use of low-dose ATG-Thymoglobulin (ATG-T; median dose, 1.5 mg/kg) was associated with a lower incidence of severe/refractory chronic GVHD and superior GVHD-free, relapse-free survival (GRFS) in unrelated hematopoietic stem cell transplantation (HSCT), and 98% of patients received uBMT in this study [4]. To evaluate the impact of low-dose ATG-T on clinical outcomes in unrelated HSCT including both uBMT and uPBSCT, we performed a single-center, retrospective analysis of 232 patients with hematological disorders who received unrelated HSCT at the National Cancer Center Hospital from 2012 to 2016 (uBMT, n= 199; uPBSCT, n= 33). This study was approved by the Institutional Review Board of the National Cancer Center, Tokyo, Japan. In this cohort, all patients in the ATG-T group received rabbit ATG (Thymoglobulin; Genzyme-Sanofi, Lyon, France). Acute and chronic GVHD and GRFS were defined according to previously published criteria [5–7]. Chronic lung dysfunction was diagnosed with computed tomography and a respiratory function test according to Bacigalupo’s report [8]. The probability of OS and GRFS were calculated using the Kaplan–Meier method, and groups were compared using the log-rank test. The cumulative incidences of NRM, relapse, acute GVHD, chronic GVHD, and viral infection were calculated by Gray’s method. In the competing risk models for GVHD and viral infection, relapse and death before these events were defined as competing risks. In the competing risk models for NRM, relapse was defined as competing risk. The variables that were evaluated in these analysis were as follows: patient age at transplant (age ≥ 40 vs. age< 40), patient gender (male vs. female), ECOG performance status (0–1 vs. 2–4), disease status (CR vs. non-CR), disease risk index (DRI) (low vs. intermediate vs. high vs. very high) [9], hematopoietic cell transplantation-comorbidity index (HCT-CI) score (0 vs. 1–2 vs. ≥3) [10], intensity of the conditioning regimen (myeloablative conditioning [MAC] vs. reduced-intensity conditioning [RIC]), ATG as GVHD prophylaxis (yes vs. no), HLA disparity assessed by allele typing of HLA-A, B, C, and DRB1 in the GVH-direction (none vs. 1 allele vs. * Shigeo Fuji fujishige1231@gmail.com

The putative anti-leukemic effects of anti-thymocyte globulins in patients with CD7-positive acute myeloid leukemia

Polyclonal anti-thymocyte globulins (ATGs) are widely used in allogeneic stem cell transplantation (allo-SCT) for GvHD prophylaxis. ATGs exerted anti-tumor effects in in vitro experiments, but in vivo studies are lacking. We experienced a case of relapsed AML with cells positive for CD7 who underwent haploidentical SCT and unexpectedly achieved a significant reduction of AML cells in the peripheral blood after receiving ATGs before the administration of other drugs in the conditioning regimen. This patient achieved long-term survival after haploidentical SCT. To assess the impact of ATGs on clinical outcomes in patients with AML, we performed a retrospective analysis of allo-SCT for relapsed/refractory AML and divided 132 patients into four groups according to the expression of CD7 in AML cells and use of ATGs as part of the conditioning regimen, as follows: CD7-positive ATG group (n = 15), CD7-positive no-ATG group (n = 32), CD7-negative ATG group (n = 19), and CD7-negative no-ATG group (n = 66). The overall survival rates in the CD7-positive ATG group were significantly higher than those in the CD7-positive no-ATG group, whereas these rates did not differ statistically between the CD7-negative ATG and CD7-negative no-ATG groups. Our results indicate a possible anti-leukemic effect of ATGs against CD7-positive AML in humans.

Severe immune-related complications early after allogeneic hematopoietic cell transplantation for nivolumab-pretreated lymphoma

Immune checkpoint blockade has been increasingly used for treatment of advanced malignant lymphomas [1]. Two anti-programmed cell death 1 (PD-1) monoclonal antibodies, nivolumab and pembrolizumab, have been shown to be safe and effective for relapsed and refractory classic Hodgkin lymphoma and several types of non-Hodgkin lymphoma in large clinical trials [2–6]. While these novel drugs are promising as salvage treatments for relapsed/refractory lymphomas, data are limited on the safety and efficacy of PD-1 blockade before and after allogeneic hematopoietic cell transplantation (allo-HCT) [7–12]. Although PD-1 blockade could theoretically enhance the graft-versus-lymphoma effect, there is a significant concern that immune modulation with PD-1 blockers can exacerbate alloimmune toxicity. We previously reported that pre-transplant mogamulizumab therapy increased graft-versus-host disease (GVHD)-related mortality in adult T-cell leukemia/lymphoma patients [13], which might be attributed to depletion of CCR-4-expressing regulatory T cells and a subsequent decrease in posttransplant immune tolerance. In the largest retrospective study thus far, 39 patients with advanced lymphoma who had received PD-1 blockade prior to allo-HCT had a high incidence of severe GVHD, and febrile syndrome occurred in the peri-engraftment period [9]. In that report, patients who had bone marrow transplantation had a lower risk of grade III–IV acute GVHD than those who had peripheral blood stem cell transplantation (0% vs 32%). In another report that included nine cases of peripheral blood stem cell transplantation after nivolumab, all patients experienced acute GVHD, five with grade III and one with grade IV [10]. Based on these existing data, the recommendation on transplant strategies in this setting was recently published [7]. To reduce the risk of immune-related complications or GVHD, bone marrow source, reduced-intensity conditioning, post-transplant cyclophosphamide-based GVHD prophylaxis, and at least 6-week interval from the last administration to transplant are recommended in the PD-1blocker-pretreated patients. No published data are available on cord blood transplantation. Here, we report three patients who received allo-HCT following salvage therapy with nivolumab (Table 1). Two of them underwent bone marrow transplantation and the other underwent cord blood transplantation. All patients developed severe engraftment syndrome (ES) complicated with rapidly progressing non-cardiogenic pulmonary edema and hypoxia. Their symptoms were ameliorated after the administration of high-dose corticosteroids. However, they developed acute GVHD and multiple viral infections during the course of the steroid taper, leading to prolonged hospitalization. Case 1: A 40-year-old woman with lymphocyte-depletedtype Hodgkin lymphoma had disease recurrence with systemic nodal lesions at 7 months after autologous HCT. She had already received three regimens of chemotherapy, including brentuximab vedotin, and was salvaged with nivolumab at 3 mg/kg every 2 weeks. She showed a partial response at the end of nine cycles of nivolumab. She had no immune-related adverse events associated with nivolumab. She underwent bone marrow transplantation from a human leukocyte antigen (HLA) 6/8 allele-matched unrelated donor at 43 days after the last administration of nivolumab. GVHD prophylaxis included anti-thymocyte globulin (2 mg/kg), tacrolimus, and methotrexate. At day 14 after transplantation * Ayumu Ito ayuito@ncc.go.jp

Characterization of Late Acute and Chronic Graft-Versus-Host Disease according to the 2014 National Institutes of Health Consensus Criteria in Japanese Patients

To characterize the incidences and outcomes of late acute (LA) and chronic graft-versus-host disease (GVHD) in East Asians according to the 2014 National Institutes of Health criteria, we retrospectively analyzed 506 consecutive Japanese patients who had a first allogeneic hematopoietic cell transplantation (HCT) at our center between 2006 and 2013. According to manifestations at onset 91 patients (60%) had LA GVHD and 60 (40%) had chronic GVHD. The cumulative incidences of LA and chronic GVHD were 20% and 17%, respectively, at 48 months after HCT. The involved sites at the onset of LA GVHD included the skin (71%), gut (13%), and liver (8%). The cumulative incidences of relapse, nonrelapse mortality (NRM), transition to chronic GVHD, and discontinued systemic treatment were 11%, 6%, 22%, and 46%, respectively, at 48 months after onset of LA GVHD. Cox models showed that prior acute GVHD was associated with NRM, and HCT from a female donor to a male patient, myeloablative conditioning, and low Karnofsky performance status were associated with a longer duration of systemic treatment after LA GVHD. The most frequently involved sites at the onset of chronic GVHD included the mouth (83%), liver (75%), skin (69%), and eyes (62%). Cox models showed that use of antithymocyte globulin in conditioning regimens was associated with a higher risk of discontinued systemic treatment after the onset of chronic GVHD. The cumulative incidences of relapse, NRM, and discontinued systemic treatment were 16%, 11%, and 41%, respectively, at 48 months after the onset of chronic GVHD. Our results suggested several potential differences between Japanese patients and those of other ethnicities. A direct comparison is needed to formally investigate ethnic differences.