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Acute myeloid leukemia (AML) is a malignancy that requires immediate treatment. However, the factors that predict very early mortality are not well known. We retrospectively analyzed 70 patients who were newly diagnosed with AML at our institution between 2014 and 2020. Very early death within 30 days after the initial consultation with a hematologist occurred in eight patients, including seven men. They were older than 30-day survivors (70.5 vs. 47 years, P 0.01). In addition, four patients with a low score on the Glasgow Coma Scale (GCS) at diagnosis died within 30 days, and half of the early death group died due to cerebral hemorrhage. We next tried to predict early death using a ROC curve. Age, hemoglobin (Hb), estimated glomerular filtration rate (eGFR) and the international normalized ratio of prothrombin time (PT-INR) all had an area under the curve of greater than 0.8 for predicting very early death. A multivariate analysis revealed that older age (OR = 1.14, P = 0.033), Hb (OR = 0.48, P = 0.05), and low GCS (OR = 140.0, P = 0.0073) were significantly associated with very early death. Further studies will be needed to confirm which patients are at high risk for early death and to improve the treatment strategy for such patients.

Idiopathic pneumonia syndrome (IPS) is a fatal pulmonary complication after allogeneic hematopoietic stem cell transplantation (allo-HCT). However, it is often difficult to diagnose IPS, since a considerable number of IPS patients are critically ill, which makes it difficult for them to undergo bronchoscopy. In this study, we explored the risk factors of IPS based on two definitions. Definite IPS was diagnosed based on the results of bronchoscopy, whereas clinical IPS was diagnosed based on the clinical condition and bronchoscopy was not mandatory. Among 444 allo-HCT recipients at our center, 30 definite IPS and 54 clinical IPS were identified. In a multivariable analysis, a high ferritin level was associated with a higher incidence of definite IPS, whereas clinical IPS was frequently associated with older age, MAC, high ferritin level, low %DLCO and second allo-HCT due to graft failure. These risk factors may contribute to the accurate and early diagnosis of IPS.

The graft-versus-leukemia (GVL) effect is one of the curative mechanisms of allogeneic hematopoietic stem cell transplantation (allo-HCT). H-Y antigens, which are encoded by Y chromosome, are important targets of the GVL effect. Thus, deletion of the Y chromosome (del[Y]) might cause the GVL effect to deteriorate in a transplantation involving a female donor and male recipient, although the clinical significance of the del(Y) group remains to be elucidated. In this study, we evaluated adult male patients who underwent allo-HCT between 2010 and 2019 in Japan. There were 155 cases in the del(Y) group and 4149 cases without del(Y) who underwent female-to-male allo-HCT. Del(Y) was significantly associated with inferior overall survival (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.00-1.53; P = .049) and an increased risk of relapse (HR, 1.40; 95% CI, 1.08-1.80; P = .0098) in multivariate analyses. There was no significant difference in nonrelapse mortality between recipients with and without del(Y) (HR, 1.08; 95% CI, 0.769-1.51; P = .67). In contrast, del(Y) was not significantly associated with any clinical outcomes in the cohort of male-to-male allo-HCT. A higher incidence of relapse might have been caused by attenuation of the GVL effect resulting from a lack of H-Y antigens. Because a GVL effect resulting from sex mismatch may not be expected in men with del(Y) who undergo allo-HCT with a female donor, additional post–allo-HCT strategies might be required to prevent disease relapse.

Disease relapse is a major cause of treatment failure after allogeneic hematopoietic cell transplantation (HCT) and the mechanisms of relapse remain unclear. We encountered a 58-year-old man with chronic myelomonocytic leukemia (CMML) that relapsed after haploidentical HCT from his daughter. Peripheral blood samples collected at HCT and at relapse were analyzed, and CD14

TEMPI syndrome is a rare disease associated with plasma cell neoplasms. Although previous studies have reported that bortezomib is effective as a first-line treatment for TEMPI syndrome, some cases are refractory to this treatment. Pomalidomide, a kind of immunomodulatory drug, is widely used for the treatment of relapsed or refractory multiple myeloma and could be administered without dose modification in patients with renal dysfunction. We present a case of bortezomib-refractory TEMPI syndrome with renal insufficiency that was successfully treated with a combination of pomalidomide and low-dose dexamethasone with minimal adverse effects, followed by autologous hematopoietic stem cell transplantation (ASCT). To the best of our knowledge, this is the first case of TEMPI syndrome that was successfully treated with pomalidomide. Pomalidomide may be suitable for patients who do not respond to a proteasome inhibitor-based treatment. In addition, a subsequent ASCT could also be effective for achieving a further treatment response.

Total body irradiation (TBI) with ovarian shielding is expected to preserve fertility among hematopoietic stem cell transplant (HSCT) patients with myeloablative TBI-based regimens. However, the radiation dose to the ovaries that preserves ovarian function in TBI remains poorly understood. Furthermore, it is uncertain whether the dose to the shielded organs is associated with relapse risk. Here, we retrospectively evaluated the relationship between fertility and the dose to the ovaries, and between relapse risk and the dose to the pelvic bones. A total of 20 patients (median age, 23 years) with standard-risk hematologic diseases were included. Median follow-up duration was 31.9 months. The TBI prescribed dose was 12 Gy in six fractions for three days. Patients' ovaries were shielded with cylinder-type lead blocks. The dose-volume parameters (D98% and Dmean) in the ovaries and the pelvic bones were extracted from the dose-volume histogram (DVH). The mean ovary Dmean for all patients was 2.4 Gy, and 18 patients recovered menstruation (90%). The mean ovary Dmean for patients with menstrual recovery and without recovery were 2.4 Gy and 2.4 Gy, respectively, with no significant difference (P = 0.998). Hematological relapse was observed in five patients. The mean pelvis Dmean and pelvis D98% for relapse and non-relapse patients were 11.6 Gy and 11.7 Gy and 5.6 Gy and 5.3 Gy, respectively. Both parameters showed no significant difference (P = 0.827, 0.807). In conclusion, TBI with ovarian shielding reduced the radiation dose to the ovaries to 2.4 Gy, and preserved fertility without increasing the risk of relapse.

Isavuconazole is a convenient triazole antifungal agent with a broad antifungal spectrum. A randomized, open-label study (ClinicalTrials.gov, NCT03471988) was conducted to evaluate the efficacy and safety of isavuconazole in Japanese patients with deep-seated mycoses.In Cohort A, patients with aspergillosis (chronic pulmonary aspergillosis and invasive aspergillosis) were randomized in a 2:1 ratio to isavuconazole or voriconazole, and in Cohort B, patients with cryptococcosis and mucormycosis were assigned to isavuconazole for up to 84 days of treatment. The overall outcome was evaluated according to the clinical, radiological, and mycological responses at Days 42 and 84 and at the end of treatment (EOT).A total of 103 participants were enrolled and received the study drug. The overall response rate of patients with chronic pulmonary aspergillosis in the isavuconazole (52 patients) and voriconazole (27 patients) groups was 82.7% and 77.8% at EOT, respectively. The response rate in patients with cryptococcosis (10 patients, isavuconazole group only) was 90.0%. One of three participants with invasive aspergillosis and one of three participants with mucormycosis responded in the isavuconazole group. In the safety evaluation, the incidence of adverse events in participants with chronic pulmonary aspergillosis was similar in both groups. Adverse drug reactions were reported in 32 (61.5%) patients receiving isavuconazole and 23 (85.2%) patients receiving voriconazole.Isavuconazole showed efficacy and safety in Japanese patients with chronic pulmonary aspergillosis and cryptococcosis, for which the drug is not currently indicated.

This study aimed to evaluate the impact of standard-dose dipeptidyl peptidase-4 inhibitors (DPP-4i) on the incidence of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We retrospectively evaluated 207 diabetes mellitus patients undergoing allogeneic HCT between 2010 and 2019. The 100-day cumulative incidences (CI) of grade II–IV acute GVHD (aGVHD) in patients who took DPP-4i from day − 1 to 14, those who did not, and those who discontinued DPP-4i within 10 days after HCT because of difficulty taking the medicine were 33.9%, 32.8%, and 60.0% (P = 0.063), respectively. With regard to chronic GVHD (cGVHD), taking DPP-4i between days 21 and 60 was associated with a trend toward lower incidence of cGVHD (1-year CI: 25.4% vs. 35.6%, P = 0.094). In a multivariate analysis, the administration of DPP-4i between days 21 and 60 was significantly associated with lower incidence of cGVHD (hazard ratio 0.53, 95% confidence interval 0.30–0.96, P = 0.035). It was difficult to interpret the impact of standard-dose DPP-4i on the development of aGVHD since an inability to continue oral medication was significantly associated with higher incidence of aGVHD. On the other hand, taking DPP-4i over days 21–60 may suppress the development of cGVHD.

Chronic graft-versus-host disease (cGVHD) of the liver is often observed in allogeneic hematopoietic stem cell transplantation (allo-HSCT) during tapering or after stopping calcineurin inhibitors (CI). We conducted a retrospective analysis of 242 allo-HSCT recipients whose CI dose was reduced to less than 40 mg of cyclosporin A or 0.4 mg of tacrolimus to clarify the clinical characteristics of liver GVHD in patients on low-dose CI. Sixty patients (25%) developed clinically suspected liver cGVHD while on low-dose CI. Multivariate analysis showed that donor age ≥ 40 years [hazard ratio (HR) 2.20], myeloablative conditioning (HR 2.19), female donor to male recipient (HR 2.53) and recipient seropositivity for herpes simplex virus (HR 2.52) were significant risk factors for liver cGVHD during low-dose CI period. Peak aspartate aminotransferase and alanine aminotransferase levels were higher in patients with liver GVHD during low-dose CI period than in other periods. Twenty-seven patients were initially treated with resumption of CI or a CI dose increase and 21 responded. Among the 18 patients treated with corticosteroids, total bilirubin was a risk factor for failure of corticosteroid therapy. The results of this study clarified the clinical characteristics of liver GVHD in patients on low-dose CIs.

The efficacy and clinical significance of pre-conditioning intervention (PCI) before allogeneic hematopoietic cell transplantation (HCT) in patients with acute lymphoblastic leukemia (ALL) not in remission remain inconclusive. The purpose of this multicenter retrospective study was to clarify the clinical significance of PCI before HCT in patients with non-remission ALL. Patients with non-remission ALL who received HCT between 2005 and 2015 at 16 institutions were included. PCI was objectively defined and classified to three groups according to the intensity of PCI (no, intensive, or moderate). The study cohort consisted of 104 patients with a median age of 38 (range 17–68). A significant decrease of blast percentage in the peripheral blood (PB) was confirmed in both PCI groups, suggesting that PCIs were effective to stabilize the disease activity. The group with moderate PCI had higher nucleated cell count in the BM compared to the group with intensive PCI or the group without PCI. The overall survival (OS) rates of groups with intensive and no PCI showed comparable and significantly better compared to the group with moderate PCI (P = 0.009). Multivariate analysis demonstrated that the OS of moderate PCI group was significantly worse compared to that of intensive PCI group (HR = 2.43, 95% CI: 1.32–4.14, P = 0.004), while the OS of intensive PCI group was comparable to that of the group without PCI. These results suggest that the intensity of PCI rather than the response to PCI may contribute to improve the transplant outcome in patients with ALL not in remission.

Total body irradiation (TBI) with ovarian shielding is expected to preserve fertility among hematopoietic stem cell transplant (HSCT) patients with myeloablative TBI-based regimens. However, the radiation dose to the ovaries that preserves ovarian function in TBI remains poorly understood. Furthermore, it is uncertain whether the dose to the shielded organs is associated with relapse risk. Here, we retrospectively evaluated the relationship between fertility and the dose to the ovaries, and between relapse risk and the dose to the pelvic bones. A total of 20 patients (median age, 23 years) with standard-risk hematologic diseases were included. Median follow-up duration was 31.9 months. The TBI prescribed dose was 12 Gy in six fractions for three days. Patients’ ovaries were shielded with cylinder-type lead blocks. The dose–volume parameters (D98% and Dmean) in the ovaries and the pelvic bones were extracted from the dose–volume histogram (DVH). The mean ovary Dmean for all patients was 2.4 Gy, and 18 patients recovered menstruation (90%). The mean ovary Dmean for patients with menstrual recovery and without recovery were 2.4 Gy and 2.4 Gy, respectively, with no significant difference (P = 0.998). Hematological relapse was observed in five patients. The mean pelvis Dmean and pelvis D98% for relapse and non-relapse patients were 11.6 Gy and 11.7 Gy and 5.6 Gy and 5.3 Gy, respectively. Both parameters showed no significant difference (P = 0.827, 0.807). In conclusion, TBI with ovarian shielding reduced the radiation dose to the ovaries to 2.4 Gy, and preserved fertility without increasing the risk of relapse.

Purpose The Japanese Society of Medical Oncology published a guideline (GL) on febrile neutropenia (FN) in 2017. The study’s purpose is to reveal how widely GL penetrated among physicians and surgeons providing chemotherapy. Methods A questionnaire survey was conducted with SurveyMonkey™ for members of the Japanese Association of Supportive Care in Cancer and relevant academic organizations. Each question had four options (always do, do in more than half of patients, do in less than half, do not at all) and a free description form. Responses were analyzed with statistical text-analytics. Result A total of 800 responses were retrieved. Major respondents were experts with more than 10-year experience, physicians 54%, and surgeons 46%. Eighty-seven percent of respondents knew and used GL. Forty-eight percent assessed FN with Multinational Association of Supportive Care in Cancer (MASCC) score “always” or “more than half.” Eighty-one percent chose beta-lactam monotherapy as primary treatment in high-risk patients. Seventy-seven percent did oral antibacterial therapy in low-risk patients ambulatorily. Seventy-eight percent administered primary prophylactic G-CSF (ppG-CSF) in FN frequency ≥ 20% regimen. Fifty-nine percent did ppG-CSF for high-risk patients in FN frequency 10–20% regimen. Ninety-seven percent did not use ppG-CSF in FN frequency Conclusion GL is estimated to be widely utilized, but some recommendations were not followed, presumably due to a mismatch with actual clinical practices in Japan.

Background Despite a strong association between acute graft-versus-host disease (GVHD) and cytomegalovirus reactivation (CMVR), the joint effect of acute GVHD and CMVR on nonrelapse mortality (NRM) has not been well studied. Methods We evaluated the impact of CMVR on NRM stratified according to the development of acute GVHD using a landmark method. This study included 6078 patients who received their first allogeneic hematopoietic cell transplantation (HCT) with a preemptive strategy for CMVR between 2008 and 2017. Results The cumulative incidences of grade 2-4 acute GVHD (G24GVHD), CMVR by day 100, and CMV disease by day 365 were 37.3%, 52.1%, and 2.9%, respectively. Patients with G24GVHD were associated with the subsequent development of CMVR, and the presence of CMVR also increased the risk of G24GVHD. In a landmark analysis at day 65, the cumulative incidence of NRM at 1 year was 5.4%, 10.0%, 13.9%, and 19.7% in patients with G24GVHD–/CMVR–, G24GVHD–/CMVR+, G24GVHD+/CMVR–, and G24GVHD+/CMVR+, respectively. In a multivariate analysis, CMVR was respectively associated with an increased risk of NRM by day 365 in patients without G24GVHD (hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.24–2.05; P Conclusions These data regarding the close relationship between acute GVHD and CMVR should provide important implications for the treatment strategy after HCT.

Pancreatic atrophy after allogeneic hematopoietic cell transplantation (HCT) is one of the symptoms associated with chronic graft-versus-host disease (GVHD). Although pancreatic atrophy has been considered to cause exocrine insufficiency and weight loss, it is not yet clear what kinds of recipients can be expected to recover their body weight (BW) or pancreatic thickness. In addition, the effect of pancreatic atrophy on the prognosis has not been clarified.We retrospectively analyzed 170 recipients who received allogeneic bone marrow transplantation or peripheral blood stem cell transplantation, and evaluated them using the CT scan images obtained closest to 1, 2, 3, and 4 years after HCT.Fifty-five recipients (32.4%) demonstrated pancreatic atrophy, and 11 (20%) of them recovered their pancreatic thickness. While recipients without pancreatic atrophy gradually recovered their BW (P 0.001), those with atrophy did not (P = 0.12). Moderate and severe chronic GVHD tended to be slightly more common in the atrophy group (47.3% vs 38.3%), whereas the pancreatic thickness tended to recover in these recipients (30.8% vs 10.3%). HCT from a female donor to a male recipient showed superior pancreatic recovery compared to other donor and recipient sex combinations. Pancreatic atrophy treated as a significantly associated with inferior survival (HR 4.91, P 0.001) and an increased risk of non-relapse mortality (HR 8.75, P 0.001).These results suggest that it is important to monitor pancreatic thickness after HCT. Further prospective investigations are warranted to clarify the significance of pancreatic atrophy on clinical outcomes.

Objectives The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings. Methods From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy. Results The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2–79.4) and 79.6% (71.0–86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2–80.9%) and 78.0% (65.3–87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups. Conclusions The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT.

Autologous hematopoietic recovery after allogeneic hematopoietic cell transplantation (allo-HCT) is rare in patients who receive myeloablative conditioning (MAC). Autologous hematopoietic recovery suggests graft rejection, leading to concerns about subsequent disease relapse. We herein report a rare case of a patient with acute leukemia who experienced autologous hematopoietic recovery after cord blood transplantation (CBT) with total body irradiation-based MAC. Chromosomal abnormalities were repeatedly detected without any disease relapse for eight months. The accumulation of similar cases is required to accurately assess the incidence and clinical outcomes of autologous hematopoietic recovery after CBT with MAC.

Systemic chronic active Epstein-Barr virus infection (sCAEBV) was defined as a T- or NK-cell neoplasm in the 2017 World Health Organization (WHO) classification. To clarify the clinical features of sCAEBV under this classification and review the effects of chemotherapy, we performed a nationwide survey in Japan from 2016 through 2018 of patients with sCAEBV newly diagnosed from January 2003 through March 2016. One hundred cases were evaluated. The patients were aged 1 to 78 years (median, 21) and included 53 males and 47 females. Spontaneous regression was not observed in patients with active disease. In the childhood-onset group (age, 45 years) were female. The prognosis of the childhood-onset group was better than those of the adolescent/adult- and elderly-onset groups. The main chemotherapies used were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 cases and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) in 45 cases. The rate of complete response (CR), defined as complete resolution of disease activity, was 17% for cooling therapy and 13% for CHOP. Virological CR was not observed. The 3-year overall survival rates in patients treated with chemotherapy only (n = 20), chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT; n = 47), and allo-HSCT only (n = 12) were 0%, 65%, and 82%, respectively. Distinct characteristics were observed between childhood- and elderly-onset sCAEBV, and they appeared to be different disorders. Chemotherapy is currently insufficient to resolve disease activity and eradicate infected cells. The development of an effective treatment is urgently needed.

A multicenter retrospective study was performed to evaluate the prognostic factors in 104 patients with relapsed or refractory acute lymphoblastic leukemia (ALL), who underwent allogeneic hematopoietic cell transplantation (HCT) between 2005 and 2015. The median age was 38 (range, 17 to 68), and the median blast fraction in peripheral blood and bone marrow was 1% (range, 0 to 99%) and 52% (range, 0 to 100%), respectively. With a median follow-up of 47 months (range, 8.3 to 105 months), overall survival (OS), nonrelapse mortality, and relapse mortality at 1 year were 25%, 44%, and 31%, respectively. Multivariate analysis demonstrated independent predictors for poor OS, including nuclear cell count in the bone marrow ≥10 × 104/μL (hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.33 to 3.43; P = .002), elevated lactate dehydrogenase level (HR, 1.66; 95% CI, 1.05 to 2.62; P = .031), and no primary induction failure (HR, 2.05; 95% CI, 1.11 to 3.78; P = .022). A prognostic scoring index was designed based on these survival predictors. At 2 years, OS was 28%, 14%, and 0% for good (score 0 or 1; n = 47), intermediate (score 2; n = 40), and poor (score 3; n = 17), respectively (P

PURPOSE Empiric antifungal therapy (EAT) is recommended for persistent febrile neutropenia (FN), but in most patients, it is associated with overtreatment. The D-index, calculated as the area surrounded by the neutrophil curve and the horizontal line at a neutrophil count of 500/μL, reflects both the duration and depth of neutropenia and enables real-time monitoring of the risk of invasive fungal infection in individual patients at no cost. We investigated a novel approach for patients with persistent FN called D-index–guided early antifungal therapy (DET), in which antifungal treatment is postponed until a D-index reaches 5,500 or the detection of positive serum or imaging tests, and compared it with EAT in this multicenter open-label noninferiority randomized controlled trial. PATIENTS AND METHODS We randomly assigned 423 patients who underwent chemotherapy or hematopoietic stem-cell transplantation for hematologic malignancies to the EAT or DET group. The prophylactic use of antifungal agents other than polyenes, echinocandins, or voriconazole was allowed. Micafungin at 150 mg per day was administered as EAT or DET. RESULTS In an intent-to-treat analysis of 413 patients, the incidence of probable/proven invasive fungal infection was 2.5% in the EAT group and 0.5% in the DET group, which fulfilled the predetermined criterion of noninferiority of the DET group (−2.0%; 90% CI, −4.0% to 0.1%). The survival rate was 98.0% versus 98.6% at day 42 and 96.4% versus 96.2% at day 84. The use of micafungin was significantly reduced in the DET group (60.2% v 32.5%; P < .001). CONCLUSION A novel strategy, DET, decreased the use and cost of antifungal agents without increasing invasive fungal infections and can be a reasonable alternative to empiric or preemptive antifungal therapy.

Objective Although invasive fungal disease (IFD) is an important complication in allogeneic hematopoietic stem cell transplantation (HSCT), the clinical significance of surgery, including the role of surgical resection for persistent pulmonary fungal disease prior to allogeneic HSCT in the current era with a variety of available antifungal agents, is controversial. We investigated the role of surgical resection. Methods We retrospectively investigated six patients who underwent surgical resection of suspected pulmonary fungal disease prior to allogeneic HSCT between April 2007 and June 2016 at our medical center. Results We present six patients who underwent surgical resection of suspected pulmonary fungal disease prior to allogeneic HSCT. In our case series, three of four patients who were given a presurgical diagnosis of possible IFD were given a proven diagnosis after surgery, including two cases of invasive aspergillosis (IA) and one case of mucormycosis. All surgeries were performed by video-assisted thoracic surgery (VATS) for lobectomy without major complications. Recurrence of IFD was not observed after allogeneic HSCT in any of the six patients. Conclusion Our experience indicated that surgical resection of persistent localized pulmonary lesions of IFD before allogeneic HSCT was helpful for obtaining a definitive diagnosis and might be useful for reducing recurrence after HSCT.

Dasatinib, a potent tyrosine kinase inhibitor (TKI), is currently used as first-line treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, emergence of the T315I mutation has been found to be a main cause of failure after dasatinib-containing treatments. We assessed the prognostic value of small clones with the T315I mutation at specific time points using the novel technology digital polymerase chain reaction (PCR), which is more sensitive than direct sequencing. This study included 25 consecutive adult patients with Ph+ ALL who underwent allogeneic hematopoietic stem cell transplantation (HSCT) following dasatinib-based chemotherapy at our center. Among six patients who experienced hematologic relapse after HSCT, four harbored the T315I mutation at relapse. However, the detection of small subclones with T315I at either diagnosis or HSCT was not associated with an increased risk of relapse. In contrast, all patients with the T315I mutation at molecular relapse after HSCT (n = 4) eventually had a hematologic relapse, and only two of the 10 patients without the T315I mutation at molecular relapse after HSCT relapsed. In conclusion, the detection of small clones with the T315I mutation at molecular relapse after HSCT, but not before HSCT, could support an early clinical decision to change treatments.

Myeloablative conditioning regimens are associated with severe gonadal toxicity. To preserve ovarian function, we have been investigating ovarian shielding during total body irradiation (TBI) with a myeloablative dose. In this report, we update the clinical outcomes. Female patients with standard-risk hematologic diseases, aged 40 years or younger, who desired to have children, were included (n = 19). The conditioning regimen consisted of TBI at 12 Gy with ovarian shielding and cyclophosphamide (120 mg/kg) or cytarabine (24 g/m2). Ovarian shielding reduced the actual irradiation dose applied to the ovaries from 12 Gy to 2 to 3 Gy. The median age at hematopoietic stem cell transplantation (HSCT) was 24 years (range, 19 to 33 years). With a median follow-up period of 1449 days (range, 64 to 3694) after HSCT, 5-year overall survival and 1- and 5-year relapse rates were 67%, 17%, and 31%, respectively. Only 2 of 14 patients with acute myeloid or lymphoid leukemia in remission have relapsed thus far. The 6-month and 1-year cumulative rates of menstrual recovery were 42% and 78%, respectively. In all patients with menstrual recovery, menstruation recovered within 1 year. The serum anti-Mullerian hormone (AMH) level tended to gradually increase after menstrual recovery. Three patients with extensive chronic graft-versus-host disease experienced delayed recovery of menstruation and serum AMH. Five pregnancies in 3 patients resulted in normal delivery in 1, selective cesarean operation in 1, current pregnancy in 1, and natural abortion in 2. These results suggest that a myeloablative TBI regimen with ovarian shielding could preserve fertility after HSCT without an apparent increase in relapse in standard-risk patients. Because serum AMH recovered gradually over time, the AMH level during the early phase after HSCT may have little value as a marker of ovarian reserve.

High-dose cytarabine (HD-AraC) or anthracycline-containing chemotherapies are used as post-remission therapy for acute myeloid leukemia (AML) patients. However, it remains unclear which regimen would be better as post-remission therapy before allogeneic hematopoietic stem cell transplantation (allo-HSCT). Thus, we compared the incidence of cardiac events and event-free survival (EFS) after allo-HSCT at two Japanese hospitals between HD-AraC and anthracycline-containing post-remission therapy to clarify the safety of post-remission therapy. Of a total of 132 patients, 68 received HD-AraC (HD-AraC group) and 64 received anthracycline-containing chemotherapy (ANT group). HD-AraC was preferentially selected for core-binding factor AML patients (p = 0.008). The median cumulative anthracycline dose was 115.2 mg/m

In general, the recipient's ABO blood type changes to the donor's ABO blood type after ABO-incompatible allogeneic hematopoietic stem cell transplantation (HSCT). However, we experienced a 26-year-old male with acute myelogenous leukemia (AML) who underwent ABO-incompatible HSCT twice and persistently showed his original blood type even after demonstrating complete donor-type chimerism. Based on the results of various examinations, we considered that the antigen of the recipient's original blood type persistently synthesized in the recipient's non-hematopoietic organs was secreted and adsorbed on the surface of donor-derived RBCs. We should therefore perform detailed examinations to determine the precise blood type after ABO-incompatible HSCT.

Chromosome analysis is a powerful prognostic tool in myeloid malignancies. Recipients who experience relapse after allogeneic hematopoietic cell transplantation (allo-HCT) often show chromosomal changes between diagnosis and relapse. However, the clinical impact of chromosomal changes and the efficacy of post-relapse treatment according to chromosomal changes have not been fully investigated. We retrospectively analyzed 72 recipients who had experienced relapse after allo-HCT for acute myeloid leukemia or myelodysplastic syndrome. We categorized them into two groups: with or without clonal chromosomal changes at relapse after allo-HCT. Post-relapse survival was shorter in the clonal chromosomal change group (median 117 days vs 275 days, P = 0.019). Moreover, acquisition of chromosome 7 abnormality or complex changes tended to be associated with inferior survival in a univariate analysis (median 92 days vs median 173 days, P = 0.043), and this adverse impact was confirmed in a multivariate analysis (hazard ratio 2.07, P = 0.024). The patterns of chromosomal changes from diagnosis to relapse after allo-HCT were heterogenous, and further investigations are required to clarify the effect of individual chromosomal changes.

Purpose The Japanese Society of Medical Oncology (JSMO) published a guideline (GL) on febrile neutropenia (FN) in 2017. This study aims to identify promoting factors and disincentives for complying with GL recommendations according to attributes of doctors providing chemotherapy. Methods A questionnaire survey was conducted with SurveyMonkey™ for physician members of the Japanese Association of Supportive Care in Cancer and relevant academic organizations. Each question had four options (always do, do in more than half of patients, do in less than half, do not at all) and a free description form. Responses were analyzed according to the respondents’ attributes. Result Seven hundred eighty-eight out of retrieved 801 responses were available for analysis. Multivariable analysis demonstrated that the percentage of GL users was higher among women and Japanese Society of Clinical Oncology members. The overall compliance rate was higher among women, JSMO members, and board-certified medical oncologists. Internists emphasized the significance of collecting blood cultures at FN onset, and surgeons stressed the importance of G-CSF prophylaxis. Hematologists were less likely to adhere to recommendations on risk assessment of FN by the Multinational Association of Supportive Care in Cancer score and administration of gammaglobulin products. However, those are acceptable due to the characteristics of their practice. Eight recommendations had no difference in compliance rates between users and non-users, some of whose statements were ambiguous and discretionary. Conclusion Women were more likely to use and adhere to GL. The recommendations should be developed considering the characteristics of specialty and subspecialty and avoiding ambiguity and discretionary statements.

Summary Objectives By using data from the CEDMIC trial (n = 413), we conducted a post-hoc analysis of the diagnostic value of biomarker monitoring and chest computed tomography (CT) scans for the early detection of invasive fungal disease (IFD) in neutropenic hematological patients. Methods IFDs were defined in accordance with the EORTC/MSG definition with some modifications. Biomarkers such as Aspergillus galactomannan (GM) and (1→3)-β-D-glucan (βDG) were measured weekly. Results The positive predictive value (PPV) of GM and βDG in cases of high-risk treatment were 0.70 and 0.69, while those in low-risk treatment were 0.08 and 0, respectively. All of the positive biomarkers that were measured before the development of fever in low-risk treatment were false positives. The proportion of patients who had abnormal chest CT findings was 19% in persistent fever at 4–6 days, 57% at 7 days or later and 36% in recurrent fever. Sixty-nine percent of the patients who had abnormal findings at 7 days or later did not have abnormalities at 4–6 days. Conclusions Afebrile screening of biomarkers in low-risk treatment is not useful. Chest CT should be reevaluated in persistent fever lasting for 7 days or longer even in patients who did not have abnormalities within 6 days.

In general, the initial systemic treatment for chronic graft-versus-host disease (cGVHD) is 0.5 to 1 mg/kg of prednisolone (PSL). However, patients without high-risk features are sometimes treated with a calcineurin inhibitor (CI) or PSL at lower doses. Here we retrospectively evaluated patients with cGVHD who were treated with low-intensity immunosuppressive therapy (IST), defined as CI with or without PSL at.25 mg/kg. The primary outcome was failure-free survival (FFS), and we evaluated current FFS (cFFS) considering the state transition between low-intensity IST and high-intensity IST defined as the administration of.25 mg/kg of PSL or immunosuppressants other than CI or PSL. Fifty-four patients were evaluated, few of whom had a low performance status and intestinal or lung involvement. FFS at 24 months after treatment was 50.0% (95% confidence interval [CI], 36.0% to 62.3%). Risk factors for failure were use of IST before 6 months post-transplantation (hazard ratio [HR], 2.16; 95% CI, 1.05 to 2.16; P = .036) and transplantation from a female donor to a male recipient (HR, 2.65; 95% CI, 1.29 to 5.48; P = .008). At 6 months, 44.0% of patients had achieved a complete or partial response without a change in treatment. cFFS at 36 months was 67.0% (95% CI, 51.8 to 79.4%), which was greater than simple FFS (43.2%; 95% CI, 36.6% to 52.8%). There was no difference in simple FFS according to the National Institutes of Health global score. However, cFFS at 3 years varied according to the global score (mild, 91.7%; moderate, 64.0%; severe, 43.8%; P = .036). Low-intensity IST for cGVHD was effective in patients without high-risk features.

BACKGROUND We assessed the kinetics of cytomegalovirus (CMV) reactivation using the area under the curve (AUC), which simultaneously reflects both the viral load at each time point and the duration of CMV antigenemia (CMV-AG). METHODS We performed a single-institute retrospective analysis in patients who received allogeneic hematopoietic stem cell transplantation (HSCT) between 2007 and 2017 and survived more than 100 days after HSCT. The AUC of CMV-AG (CMV-AUC) was calculated by a trapezoidal method using the number of CMV-AG tested by the C10/C11 method after logarithmic transformation, and plotted weekly up to day 100. RESULTS CMV reactivation was observed in 195 cases and the median CMV-AUC for CMV-reactivated patients was 8.7 (range 0.5-30.7). Older age, corticosteroid administration, CMV-seropositive transplant recipients, HSCT from an unrelated donor, and underlying diseases were independent predictive factors for higher CMV-AUC. Higher CMV-AUC was associated with poor overall survival (OS) with borderline significance in a univariate analysis (p = .07), but was not significant in a multivariate analysis. Older age, high-risk disease status, and female gender were identified as significant factors associated with poor OS in this study. On the other hand, CMV-AUC (hazard ratio: no reactivation reference, low 0.98, high 2.49, p

Background: During chemotherapy for hematological malignancies, febrile neutropenia (FN) is a frequent and serious complication. The causative organisms of FN vary from era to era and depending on bacterial resistance in each country. Therefore, epidemiological data are required for each era and country from prospective large clinical trials. We previously reported a prospective clinical trial indicating the importance of the D-index, a measure of neutropenia severity (CEDMIC trial, J Clin Oncol. 2020 10; 38: 815). We hypothesized that analyzing these data would provide accurate contemporary epidemiological data for hematological malignancies. Furthermore, as encountered in practice, we suspected that gram-negative (GN) bloodstream infections (BSIs) are more common at high body temperatures (BTs) than at low BTs and examined the relationship between causative bacteria and BT. Patients and Methods: Between June 2013 and April 2017, we enrolled patients with hematological malignancies aged 16-79 years post-chemotherapy or -stem cell transplantation (SCT) with expected neutropenia durations >7 days. Neutrophil counts Results: In total, 423 patients were enrolled, and 413 (median age: 56 years) were included in the intention-to-treat analyses (Table 1). The treatments included induction chemotherapy (n=67), Allo-SCT (n=106), Auto-SCT (n=158), and others (n=82). Prophylactic Abx were administered in 281 (68.5%) patients (only quinolone, n=222; with β-lactam, n=59). Prophylaxis rates were significantly higher in the Allo-SCT (n=94, 88.7%, p38.5°C/ Conclusion: In FN patients with high-risk hematological malignancies in Japan, the frequency of GP BSIs is high. Prophylactic Abx use reduces the GN BSI risk but not the FN or BSI risk. Fever severity and BC positivity at FN onset are strongly associated. The BTs of patients with GN BSIs are high. Disclosures Kanda: Astellas Pharma: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Meiji Seika Kaisha: Honoraria; Merck Sharp & Dohme: Honoraria; Pfizer: Honoraria, Research Funding; Shionogi: Research Funding; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Eisai: Honoraria, Research Funding; Novartis: Honoraria; Kyowa Kirin: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Takeda Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Honoraria; Shire: Honoraria; Daiichi Sankyo: Honoraria; Ono Pharmaceutical: Honoraria; Nippon Shinyaku: Honoraria, Research Funding; Mochida Pharmaceutical: Honoraria; Otsuka: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Janssen: Honoraria; Mundipharma: Honoraria. Kimura:Takeda Pharmaceuticals: Honoraria; Astellas Pharma: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Merck Sharp & Dohme: Honoraria; Nippon Kayaku: Honoraria; Kyowa Hakko Kirin: Honoraria; Ono Pharmaceutical: Honoraria; Celgene: Honoraria; Asahi Kasei: Honoraria. Oyake:Astellas Pharma: Honoraria; Bayer: Research Funding; Chugai Pharma: Honoraria, Research Funding; Celgene: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria; Bristol-Myers Squibb Japan: Honoraria; Pfizer: Honoraria; Sionogi: Research Funding. Tamura:Asahi Kasei: Honoraria; Ono Pharmaceutical: Honoraria; Eisai: Honoraria; Kyowa Hakko Kirin: Honoraria.

CD34-positive monocytes (CD34+mono) have recently been identified in grafts mobilized by granulocyte-colony stimulating factor. We analyzed transplant outcomes of 73 patients whose donor’s peripheral blood cells were cryopreserved during mobilization. CD34+mono was detected more frequently in male donors (67% vs. 40%, P = 0.03), while the detection of CD34+mono in donors was not associated with the patient background. Although there was no significant difference in overall survival in the whole cohort, the detection of CD34+mono in donors were significantly associated with a decreased risk of non-relapse mortality (HR 0.23, P = 0.035). Fatal infectious events tended to be less frequent in donors with CD34+mono. Gene expression profile analyses of CD34+mono in humans revealed that the expressions of pro-inflammatory cytokines like IL6, CCL3, IL8, VEGFA, and IL1A were elevated in CD34+mono, and those cytokines were enriched in the immune response, especially against infectious pathogens in the gene ontology analyses. In addition, the expression of CD83 was specifically increased in CD34+mono. It might play a role of antigen presentation in the immune network, leading in a clinical benefit against infections. Further investigations will be required to confirm the biological functions and clinical roles of CD34+mono in transplantation.

Macrophages play a crucial role in the pathogenesis of chronic graft-versus-host disease (cGVHD). We hypothesized that galectin-3, Mac-2 binding protein (M2BP), or Wisteria floribunda agglutinin (WFA)(+)-M2BP, called M2BP glycan isomer (M2BPGi), might contribute to macrophage activation, and fibrosis would be associated with cGVHD and nonrelapse mortality (NRM) in hematopoietic stem cell transplant (HSCT) recipients. Patients who underwent their first allogeneic HSCT and survived for >180 days without relapse were included. The predictive potential of the 3 markers for NRM was assessed using the discovery cohort (n = 55) and validation cohort 1 (n = 55). When we used the threshold determined by a receiver operating characteristics curve analysis in the discovery cohort, only M2BPGi at day +180 was significantly associated with a higher NRM in the discovery cohort (15.0% vs 0.0% at 5 years, P = .001) and in validation cohort 1 (34.0% vs 8.4% at 5 years, P = .014). This result was confirmed in validation cohort 2 (n = 50). M2BPGi was not increased in healthy individuals or in patients who received autologous HSCT. In the entire cohort (N = 110), M2BPGi was significantly related to liver cGVHD but not to other organ involvement. In multivariate analyses, M2BPGi was an independent risk factor for NRM. In immunofluorescence staining of autopsy cases, WFA(+)-M2BP–positive macrophages were found only in the liver sections with cGVHD. In conclusion, M2BPGi could be a promising predictor of late NRM after HSCT and was associated with liver involvement.

Bloodstream infection (BSI) is a frequent complication observed in patients with febrile neutropenia (FN). BSI risk factors and incidence vary depending on chemotherapy types and prophylactic antimicrobial agents. We clarified these issues by post-hoc analysis of a prospective clinical trial cohort for severe FN in hematological malignancy.We performed an intention-to-treat analysis of 413 high-risk patients and 1272 blood culture sets.Overall, 356 patients (86.2%) developed FN, and 20.8% had BSI complications. Prophylactic antimicrobials did not prevent complications of FN and BSI, but the incidence of BSIs of Gram-negative (GN) bacteria was lower than in the non-prophylaxis group (23.8% vs. 56.7%). Multinational Association of Supportive Care in Cancer (MASCC) scores 20 were significantly correlated with the incidence of BSI, whereas MASCC scores 21 were not (41.7% vs. 17.2%). The only significant risk factors were hypotension and dehydration. axillary temperatures were higher in GN-caused BSIs than in Gram-positive-caused BSIs and in patients with negative blood culture results (38.7 °C vs. 38.2 °C vs. 38.0 °C). The higher the fever, the higher the incidence of BSI and GN bacteremia.MASCC score and axillary temperature are strong predictors of BSI. Non-administration of prophylactic antimicrobials and GN-caused BSI are correlated.UMIN00010411.

Recipient cytomegalovirus (CMV) seropositivity is known to be a risk factor for CMV reactivation after allogeneic hematopoietic stem cell transplantation (allo-HCT). We explored the association of CMV-IgG titer of recipients with CMV reactivation after allo-HCT and developed a model for predicting CMV reactivation for the purpose of identifying a high-risk group. In addition, we evaluated the impact of CMV-IgG titer on survival outcomes and acute graft-versus-host disease (GVHD). We retrospectively analyzed 309 patients who achieved neutrophil engraftment after allo-HCT and evaluated whether pretransplantation recipient CMV-IgG titer was associated with transplantation outcomes, including CMV reactivation. Using the best cutoff value determined by a receiver operating characteristic curve analysis, we divided the study cohort into 3 groups: high-titer, low-titer, and negative. CMV reactivation occurred most frequently in the high-titer group, followed by the low-titer and negative groups (81%, 37%, and 16%, respectively, at 180 days after allo-HCT; P.01). In a multivariate analysis, recipient CMV-IgG titer was significantly associated with subsequent CMV reactivation (hazard ratio [HR], 9.31 in the high-titer group [P.01] and 2.91 in the low-titer group [P = .023]). CMV diseases were observed exclusively in the high-titer group. Overall survival (OS) was lower in the high-titer group compared with the other 2 groups (2-year OS, 56%, 60%, and 80%, respectively; P = .075), whereas the cumulative incidences of grade II-IV acute GVHD, nonrelapse mortality (NRM), and relapse were not significantly different among the 3 groups. In multivariate analyses, CMV-IgG titer was not associated with increased risks of these outcomes, although CMV reactivation itself was identified as a risk factor for NRM (HR, 3.05; P = .002). Our data demonstrate that a higher titer of recipient CMV-IgG is predictive of CMV reactivation after allo-HCT. Further investigation is needed to determine how to apply these results to prophylactic or preemptive strategies against CMV, considering recipient CMV-IgG titer for effective risk stratification.

There is a matter of debate about the clinical impact of cytomegalovirus (CMV) reactivation on the development of late-onset invasive aspergillosis (IA), which occurs 40 days or later after allogeneic hematopoietic stem cell transplantation (HSCT). Using a Japanese transplant registry database, we analyzed the risk factors for the development of late-onset IA in 21,015 patients who underwent their first allogeneic HSCT between 2006 and 2017. CMV reactivation was defined as the initiation of preemptive anti-CMV antiviral therapy. Overall, there were 582 cases of late-onset IA, which occurred at a median of 95 days after HSCT. The 2-year cumulative incidence was 3.4% (95% confidence interval (CI), 3.0-3.9) in patients with CMV reactivation within 40 days after HSCT and 2.5% (95% CI, 2.3-2.8) in those without it (P 0.001). In a multivariate analysis, CMV reactivation as a time-dependent covariate was significantly associated with the development of late-onset IA (hazard ratio (HR) 1.40, P 0.001), as well as grade II-IV acute GVHD, age 50 and HCT-CI ≥ 3 in the entire cohort. If we focus on the subgroup without grade II-IV acute GVHD, which is generally an indication for systemic corticosteroid therapy (n = 12,622), CMV reactivation was still a significant factor for the development of late-onset IA (HR 1.37, P = 0.045) as well as age 50 years, HCT-CI ≥ 3, and cord blood transplantation. In conclusion, CMV reactivation was associated with an increased risk of late-onset IA after allogeneic HSCT independently of acute GVHD. Close monitoring for late-onset IA is necessary for patients who develop CMV reactivation even without grade II-IV acute GVHD.

Although graft failure (GF) is a fatal complication after allogeneic stem cell transplantation (SCT), no mortality risk assessments after salvage SCT have been reported. We developed a comprehensive prognostic scoring system consisting of patient and comorbidity factors with 470 patients as a training cohort out of 940; these patients underwent salvage SCT for GF. The multivariate analysis demonstrated that older age, poorer performance status, a continuation of antimicrobial treatment, and severe organ dysfunction were independently associated with worse overall survival (OS) and non-relapse mortality (NRM). Based on each factor’s hazard ratio, weighted scores of 1–3 were assigned to these factors. Using the summed scores (0–8), a prognostic scoring system successfully stratified outcomes after salvage SCT in the cohort. For patients in the low (0–2, n = 122), intermediate (3–4, n = 209), and high score (5–8, n = 110) groups, the 1-year OS was 62.8%, 40.8%, and 14.2%, respectively (P