Details of a Researcher - Sakurai, Masatoshi

Papers - Sakurai, Masatoshi

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Chemically defined cytokine-free expansion of human haematopoietic stem cells

Sakurai M., Ishitsuka K., Ito R., Wilkinson A.C., Kimura T., Mizutani E., Nishikii H., Sudo K., Becker H.J., Takemoto H., Sano T., Kataoka K., Takahashi S., Nakamura Y., Kent D.G., Iwama A., Chiba S., Okamoto S., Nakauchi H., Yamazaki S.

Nature (Nature) 615 ( 7950 ) 127 - 133 2023.03

ISSN 00280836

Haematopoietic stem cells (HSCs) are a rare cell type that reconstitute the entire blood and immune systems after transplantation and can be used as a curative cell therapy for a variety of haematological diseases1,2. However, the low number of HSCs in the body makes both biological analyses and clinical application difficult, and the limited extent to which human HSCs can be expanded ex vivo remains a substantial barrier to the wider and safer therapeutic use of HSC transplantation3. Although various reagents have been tested in attempts to stimulate the expansion of human HSCs, cytokines have long been thought to be essential for supporting HSCs ex vivo4. Here we report the establishment of a culture system that allows the long-term ex vivo expansion of human HSCs, achieved through the complete replacement of exogenous cytokines and albumin with chemical agonists and a caprolactam-based polymer. A phosphoinositide 3-kinase activator, in combination with a thrombopoietin-receptor agonist and the pyrimidoindole derivative UM171, were sufficient to stimulate the expansion of umbilical cord blood HSCs that are capable of serial engraftment in xenotransplantation assays. Ex vivo HSC expansion was further supported by split-clone transplantation assays and single-cell RNA-sequencing analysis. Our chemically defined expansion culture system will help to advance clinical HSC therapies.

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Clinical characteristics of steroid-responsive but dependent chronic graft-versus-host disease: a multicenter retrospective analysis

Oyama T., Matsuda K., Honda A., Maki H., Masamoto Y., Murakami D., Toya T., Sakurai M., Kataoka K., Doki N., Kurokawa M.

International Journal of Hematology (International Journal of Hematology) 117 ( 2 ) 260 - 268 2023.02

ISSN 09255710

Chronic graft-versus-host disease (cGVHD) is a long-term complication of allogeneic hematopoietic stem cell transplantation. The clinical importance of long-term corticosteroid dependency in steroid-responsive cGVHD is undetermined. We retrospectively reviewed the data of 120 consecutive patients who received systemic steroid therapy for cGVHD between January 2007 and December 2018 at three institutions. Among patients with steroid-responsive cGVHD, those who successfully tapered off corticosteroids within 1 year were defined as the early withdrawal group (EW-cGVHD) and others were defined as the dependent group (Dp-cGVHD). Twenty-six patients were classified as EW-cGVHD and 55 as Dp-cGVHD. The proportion of men was significantly higher and performance status was significantly better in EW-cGVHD. The 5-year overall survival and cGVHD recurrence-free survival rates were significantly higher in EW-cGVHD than Dp-cGVHD (96% vs. 68%, p = 0.017 and 84% vs. 41%, p = 0.002, respectively). While the relapse-free survival rate did not differ significantly (84% vs. 65%, p = 0.15), the proportion of patients requiring readmission, mainly due to cGVHD recurrence or infection, was significantly increased in Dp-cGVHD (38% vs. 84%, p < 0.001). In summary, steroid dependency in cGVHD for more than 1 year was significantly associated with poor transplant outcomes.

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Concurrent de novo Thymoma-associated Paraneoplastic Type 1 Autoimmune Hepatitis and Pure Red Cell Aplasia after Thymectomy: A Case Report and Literature Review

Sakata R., Chu P.S., Kawaida M., Emoto K., Sakurai M., Nishida R., Asakura K., Morikawa R., Taniki N., Kataoka K., Kanai T., Nakamoto N.

Internal Medicine (Internal Medicine) 62 ( 2 ) 243 - 249 2023

ISSN 09182918

The precise manipulation of immune tolerance is the holy grail of immunotherapies for both autoimmunity and cancer immunity. Thymomas are well known to be associated with autoimmune diseases. The exact mechanism by which autoreactivity is induced after thymectomy remains to be elucidated. We herein present the case of a 50-year-old lady with concurrent de novo type 1 autoimmune hepatitis (AIH) and pure red cell aplasia (PRCA), 1 month after undergoing a successful total thymectomy for combined squamous cell carcinoma and thymoma (Masaoka stage II). Corticosteroids yielded short-term effects for both AIH and PRCA. Literature on thymoma-associated AIH, an extremely rare immune-related comorbidity, was also reviewed.

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Improved survival after single-unit cord blood transplantation using fludarabine and melphalan-based reduced-intensity conditioning for malignant lymphoma: impact of melphalan dose and graft-versus-host disease prophylaxis with mycophenolate mofetil

Sakatoku K., Kim S.W., Okamura H., Kanaya M., Kato K., Yamasaki S., Uchida N., Kobayashi H., Fukuda T., Takayama N., Ishikawa J., Nakazawa H., Sakurai M., Ikeda T., Kondo T., Yoshioka S., Miyamoto T., Kimura T., Ichinohe T., Atsuta Y., Kondo E.

Annals of Hematology (Annals of Hematology) 101 ( 12 ) 2743 - 2757 2022.12

ISSN 09395555

We evaluated 413 adult patients with lymphoma who underwent unrelated cord blood transplantation (UCBT) with fludarabine and melphalan (FM)-based reduced-intensity conditioning between 2002 and 2017 to investigate longitudinal changes in outcomes and the optimal melphalan dose and graft-versus-host disease (GVHD) prophylaxis regimen. Outcomes were compared between FM80/100 (melphalan dose: 80 or 100 mg/m2) and FM140 (melphalan dose: 140 mg/m2), as well as between calcineurin inhibitor (CNI) plus methotrexate (MTX), CNI plus mycophenolate mofetil (MMF), and CNI alone. The 3-year overall survival (OS) and non-relapse mortality (NRM) rates improved over time (OS: 27% in 2000s vs. 42% in 2010s, p < 0.001; NRM: 43% in 2000s vs. 26% in 2010s, p < 0.001). Multivariable analysis showed that in the 2000s, melphalan dose and GVHD prophylaxis regimen did not affect any outcomes. In the 2010s, FM80/100 (vs. FM140) related to better OS (hazard ratio [HR] 0.62, p = 0.01) and NRM (HR 0.52, p = 0.016). MTX + CNI and CNI alone (vs. CNI + MMF) related to worse OS (CNI + MTX, HR 2.01, p < 0.001; CNI alone, HR 2.65, p < 0.001) and relapse/progression (CNI + MTX, HR 2.40, p < 0.001; CNI alone, HR 2.13, p = 0.023). In recent years, the use of FM80/100 and CNI + MMF significantly reduced the risk of NRM and relapse/progression, respectively, and resulted in better OS after UCBT for lymphoma.

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Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation

Mizuno K., Sakurai M., Kato J., Yamaguchi K., Abe R., Koda Y., Kataoka K., Mori T.

Transplant Infectious Disease (Transplant Infectious Disease) 24 ( 6 ) 2022.12

ISSN 13982273

Background: Letermovir has been approved as a novel cytomegalovirus (CMV) prophylactic agent after allogeneic hematopoietic stem cell transplantation (HSCT). However, there are still insufficient data to properly evaluate the real-world role of letermovir, and the risk factors for CMV reactivation under letermovir prophylaxis have not been clarified. Methods: We performed a single-institution retrospective analysis of patients under prophylaxis with or without letermovir who underwent allogeneic HSCT between March 2012 and December 2019. In August 2018, letermovir was added to the clinical practice at our institution for the prophylaxis of CMV reactivation in allogeneic HSCT recipients. Patients who underwent HSCT without prophylactic letermovir from March 2012 until September 2018 served as a historical control. Results: The cumulative incidence of clinically significant CMV infection (CS-CMVi) was significantly lower in the letermovir group than in the historical control group not receiving letermovir (30.2% vs. 71.6%, p <.05, at 100 days). In addition, the cumulative incidence of non-relapse mortality (NRM) at day 500 was significantly lower in the letermovir group (4.7% vs. 19.8%, p <.05). We then performed a risk factor analysis for developing CS-CMVi in the letermovir group. The only significant factor identified by this multivariable analysis was transplantation from a CMV seronegative donor to a seropositive recipient (Hazard ratio = 2.76, 95% confidence interval 1.14–6.68, p <.05). Conclusion: Our study showed that letermovir prophylaxis significantly reduced the incidence of CS-CMVi and NRM in a real-world setting and that the CMV serostatus of the donor remained as a risk factor for CS-CMVi even under letermovir prophylaxis.

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Simultaneous quantification of dasatinib, nilotinib, bosutinib, and ponatinib using high-performance liquid chromatography–Photodiode array detection

Yokoyama Y., Nozawa E., Morita M., Ishikawa E., Mori T., Sakurai M., Kikuchi T., Matsuki E., Yamazaki R., Kataoka K., Jibiki A., Kawazoe H., Suzuki S., Nakamura T.

Journal of Clinical Laboratory Analysis (Journal of Clinical Laboratory Analysis) 36 ( 8 ) 2022.08

ISSN 08878013

Background: Dasatinib, nilotinib, and bosutinib, second-generation tyrosine kinase inhibitors (TKIs), and ponatinib, a third-generation TKI, are approved pharmaceuticals used in the treatment of chronic myeloid leukemia (CML). Although liquid chromatography-tandem mass spectrometry assays for simultaneous quantification of the four TKIs in human serum have been reported in the literature, a high-performance liquid chromatography (HPLC) assay that simultaneously quantifies these compounds has not yet been developed. This study aims to establish and validate an efficient HPLC analytical method using a photodiode array (PDA) detector for the simultaneous quantification of the four TKIs. Methods: Calibration standards were prepared by serial dilution of serum samples containing the four TKIs, followed by solid-phase extraction. The four TKIs were eluted in order within 10 min using a binary HPLC gradient system. Results: The calibration ranges were 2–500 ng/ml for dasatinib, 100–5000 ng/ml for nilotinib, and 10–500 ng/ml for bosutinib and ponatinib. Intra-day and inter-day precision and accuracy values were found to be in accordance with the U.S. Food and Drug Administration guidelines. The recovery rates were 92.9%–96.0%, 80.7%–86.1%, 91.6%–99.0%, and 86.4%–92.6% for dasatinib, nilotinib, bosutinib, and ponatinib, respectively. Conclusion: To the best of our knowledge, this is the first report of an HPLC-PDA analytical method that allows efficient simultaneous quantification of the four TKIs in the serum of patients with CML. We believe that the method developed herein can improve the efficiency of therapeutic drug monitoring in patients with CML in clinical practice.

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Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors

Hirai I., Funakoshi T., Kamijuku H., Fukuda K., Mori M., Sakurai M., Koda Y., Kato J., Mori T., Watanabe N., Noji S., Yaguchi T., Iwata T., Ohta S., Fujita T., Tanosaki R., Handa M., Okamoto S., Amagai M., Kawakami Y.

Cancer Science (Cancer Science) 112 ( 8 ) 3163 - 3172 2021.08

ISSN 13479032

To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune-checkpoint inhibitor therapy, an open-label, single-arm, pilot study was conducted. We investigated the immunological and genetic factors of the pretreatment tumor and expanded TILs that may be associated with the clinical response. The treatment protocol comprised preparation of TIL culture, lympho-depleting non-myeloablative preconditioning with cyclophosphamide and fludarabine, TIL infusion, and intravenous administration of low-dose IL-2. Three patients of clinical subtypes mucosal, superficial spreading, and acral melanoma underwent TIL-ACT. Most severe adverse events, including fever and leukopenia, were manageable with the supportive regimen specified in the protocol, suggesting that the TIL-ACT regimen is suitable for Japanese patients with melanoma. One patient showed a short-term partial response, one relatively long-stable disease, and one experienced disease progression. Whole-exome and transcriptional sequencing of isolated tumor cells and immunohistochemical analyses before TIL-ACT revealed various immunostimulatory factors, including a high tumor mutation burden and immune cell-recruiting chemokines, as well as various immunosuppressive factors including TGF-β, VEGF, Wnt/β-catenin, and MAPK signaling and epithelial-to-mesenchymal transition, which might influence the efficacy of TIL-ACT. Our results imply mechanisms for the antitumor effect of and resistance to TIL-ACT. Further studies of immune-resistant mechanisms of TIL-ACT are warranted. This study is registered with the UMIN Clinical Trial Registry (UMIN 000011431).

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Cytomegalovirus retinitis after allogeneic hematopoietic stem cell transplantation under cytomegalovirus antigenemia-guided active screening

Mori T., Kikuchi T., Koh M., Koda Y., Yamazaki R., Sakurai M., Tomita Y., Ozawa Y., Kohashi S., Abe R., Saburi M., Kato J.

Bone Marrow Transplantation (Bone Marrow Transplantation) 56 ( 6 ) 1266 - 1271 2021.06

ISSN 02683369

Although cytomegalovirus (CMV) remains a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), the incidence of CMV retinitis is considered to be lower than the incidence of CMV infection in other organs following allogeneic HSCT. In this study, the incidence and characteristics of CMV retinitis were retrospectively evaluated in recipients of allogeneic HSCT. Ophthalmological screening was performed at the development of ocular symptoms or positive CMV infection using peripheral blood evaluated by pp65 antigenemia or polymerase chain reaction. Of the 514 patients, 13 patients developed CMV retinitis. The median onset of CMV retinitis was day 34 (range, 21–118) post transplant, and the cumulative incidence was 2.5% (95% CI, 1.6–4.2) at 6 months after transplantation. Five patients presented ocular symptoms at the onset. In the remaining eight asymptomatic patients, the diagnosis of CMV retinitis was made by the screening guided by positive CMV infection. All evaluable patients responded to antiviral treatment but three showed incomplete improvement with ocular sequela. Our results suggest that the incidence of CMV retinitis after allogeneic HSCT is not negligible and active ophthalmological screening based not only on symptoms but also positive CMV infection monitoring contributes to the early diagnosis of CMV retinitis.

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Phase 1 study of plerixafor in combination with total body irradiation-based myeloablative conditioning for allogeneic hematopoietic stem cell transplantation

Mori T., Kikuchi T., Yamazaki R., Koda Y., Saburi M., Sakurai M., Shigematsu N., Okamoto S., Kato J.

International Journal of Hematology (International Journal of Hematology) 113 ( 6 ) 877 - 883 2021.06

ISSN 09255710

Plerixafor, a CXCR4 inhibitor, has the potential to mobilize leukemic cells, which may contribute to their chemosensitization. This phase 1 study evaluated the safety of myeloablative conditioning combined with plerixafor for allogeneic hematopoietic stem cell transplantation (HSCT). Patients with high-risk leukemia undergoing allogeneic HSCT after total body irradiation (TBI, 12 Gy)-based myeloablative conditioning were eligible; 9 patients were enrolled. The study was performed using a 3 + 3 design with an escalating total dose of plerixafor. Plerixafor was given subcutaneously 8 h before TBI and chemotherapeutic agents. Plerixafor was successfully escalated to the maximum dose (0.72 mg/kg) without dose-limiting toxicities. Underlying diseases were acute myelogenous and lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. As adverse events, plerixafor administration was associated with transient Grades 2–3 diarrhea (n = 7) and abdominal pain (n = 4). In 6 patients, leukemic cell mobilization into the peripheral blood by plerixafor was confirmed by a morphological or molecular method. All patients achieved neutrophil engraftment and 5 were alive in remission at a follow-up after 30–40 months. Plerixafor-combined myeloablative conditioning for allogeneic HSCT was well tolerated. Leukemic-cell mobilization into peripheral blood was observed in half of the patients. Further study is required to evaluate the efficacy and safety of this concept.

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Toxoplasmosis after allogeneic hematopoietic stem cell transplantation: Impact of serostatus-based management

Amikura T., Kikuchi T., Kato J., Koda Y., Sakurai M., Yamazaki R., Mikita K., Saburi M., Nakazato T., Mori T.

Transplant Infectious Disease (Transplant Infectious Disease) 23 ( 3 ) 2021.06

ISSN 13982273

Toxoplasmosis caused by Toxoplasma gondii (T. gondii) is a serious infectious complication after allogeneic hematopoietic stem cell transplantation (HSCT). The incidence of toxoplasmosis varies widely because of the variabilities of seroprevalence among patient populations. The incidence and the optimal management of toxoplasmosis after allogeneic HSCT in a patient population with a low seroprevalence have not been fully evaluated. We conducted a single-center retrospective study evaluating toxoplasmosis in Japanese patients who underwent allogeneic HSCT. Of the 728 evaluable patients, only 5 developed toxoplasmosis with a median onset of day 60 post-transplant (range, day 55-393). The cumulative incidence was 0.7% (95% CI: 0.3%-1.5%) at day 500 post-transplant. Four of the five patients succumbed due to toxoplasmosis. The more recently treated 220 patients (not the earlier 508 patients) were screened for the T. gondii serostatus, and prophylactic treatment with trimethoprim/sulfamethoxazole was applied. All five patients with toxoplasmosis were in the unscreened group, and there was no case of toxoplasmosis after the introduction of the screening and prophylactic treatment. Our results suggest that toxoplasmosis after allogeneic HST is rare but can develop as a life-threatening complication even in the populations with low seroprevalence, and that prophylactic treatment for seropositive patients could effectively prevent toxoplasmosis.

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Impact of Specific Antibody Level on Human Herpesvirus 6 Reactivation after Allogeneic Stem Cell Transplantation: H. Nakayama et al

Nakayama H., Yamazaki R., Kato J., Koda Y., Sakurai M., Mori T.

Transplantation and Cellular Therapy (Transplantation and Cellular Therapy) 27 ( 2 ) 174.e1 - 174.e5 2021.02

ISSN 26666367

The majority of adults are seropositive for human herpesvirus 6 (HHV-6). HHV-6 reactivation can occur after allogeneic hematopoietic stem cell transplantation (HSCT) and lead to life-threatening central nervous system disorders. In this prospective study, we evaluated the relationship between HHV-6 reactivation and anti-HHV-6 IgG antibody levels in recipients of allogeneic HSCT. The HHV-6 viral load in the plasma was quantitatively measured weekly after allogeneic HSCT by real-time polymerase chain reaction. The level of anti-HHV-6 IgG antibody was measured by enzyme‐linked immunosorbent assay before and serially after transplantation. In 28 of the 56 evaluated patients (50%), HHV-6 reactivation was detected after transplantation. In a multivariate analysis, cord blood as the stem cell source was the only significant factor associated with HHV-6 reactivation (odds ratio, 8.6; 95% confidence interval, 2.3 to 32.6; P < .01). When evaluated in the recipients of cord blood transplantation (CBT), the anti-HHV-6 antibody level before transplantation was significantly lower in the patients with HHV-6 reactivation compared with those without (sample positivity index: median, 2.04 [range, 0.95 to 5.98] versus 4.15 [range, 3.93 to 5.65]; P < .05). The anti-HHV-6 antibody level was significantly decreased at 3 months post-transplantation compared with before transplantation (P < .01). Such differences were not observed in other stem cell sources. Our results demonstrate that the low anti-HHV-6 antibody level before transplantation was associated with the reactivation of HHV-6 after CBT, and that the anti-HHV-6 antibody level was significantly decreased specifically after CBT. These results suggest that HHV-6-specific humoral immunity plays a role in HHV-6 reactivation after CBT.

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Detection of residual disease in chronic myeloid leukemia utilizing genomic next generation sequencing reveals persistence of differentiated Ph<sup>+</sup> B cells but not bone marrow stem/progenitors

Karigane D., Kasahara H., Shiroshita K., Fujita S., Kobayashi H., Tamaki S., Yamazaki R., Yahagi K., Yatabe Y., Kondoh N., Arai T., Katagiri H., Shimizu N., Sakurai M., Kikuchi T., Kato J., Shimizu T., Hayakawa T., Yaguchi T., Matsushita M., Nakajima H., Kawakami Y., Murata M., Mori T., Sasaki T., Okamoto S., Takubo K.

Leukemia and Lymphoma (Leukemia and Lymphoma) 62 ( 3 ) 679 - 687 2021

ISSN 10428194

Persistence of leukemic stem cells (LSCs) results in the recurrence of chronic myeloid leukemia (CML) after the administration of tyrosine kinase inhibitors (TKIs). Thus, the detection of minimal residual disease (MRD) with LSC potential can improve prognosis. Here, we analyzed 115 CML patients and found that CD25 was preferentially expressed on the phenotypic stem and progenitor cells (SPCs), and TKI therapy decreased the number of CD25-positive cells in the SPC fraction. To detect MRD harboring BCR-ABL1 fusion DNA, we developed a highly-sensitive method using patient-specific primers and next-generation sequencing. By using this method, we identified that in patients who achieved molecular remission, almost all residual CD25-positive SPCs were BCR-ABL1-negative. Moreover, in some patients BCR-ABL1 was detectable in peripheral B cells but not in SPCs. We conclude that CD25 marks LSCs at diagnosis but does not mark MRD following TKI treatment and that analysis of peripheral B cells can allow sensitive detection of MRD.

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Efficacy of ondansetron against emesis induced by a multiple-day cisplatin-based chemotherapy regimen for malignant lymphoma

Kamiya T., Sakurai M., Kikuchi T., Okayama M., Mizuno K., Tanigawa T., Koda Y., Kato J., Mori T.

Hematology (United Kingdom) (Hematology (United Kingdom)) 26 ( 1 ) 945 - 949 2021

ISSN 10245332

Objectives: This study aimed to evaluate the antiemetic efficacy of a 5-hydroxytryptamine-3 receptor antagonist (5-HT3RA), ondansetron, in patients with malignant lymphoma receiving multi-day cisplatin-based combination chemotherapy. Methods: We conducted a single-institution retrospective analysis of patients receiving the first course of an ESHAP (etoposide, cisplatin, methylprednisolone, cytarabine) regimen including 4-day continuous infusion of cisplatin (25 mg/m2/day). All patients received ondansetron 4 mg intravenously during 5-day administration of ESHAP. The primary endpoint was complete response (CR) for emesis, which was defined as absence of both emesis and rescue medications. Total control (TC) was defined as an absence of emetic episodes, including nausea and emesis, and complete protection (CP) was defined as an absence of emesis with addition of rescue antiemetics. Nausea and vomiting were assessed and graded daily by medical staff. Results: Eighty-two patients were analyzed. Nausea and vomiting were generally well controlled, with the CR rates of emesis being 79% in the overall phase, 82% in the early phase (days 1–6), and 89% in the delayed phase (days 7–10). TC and CP were achieved in 51 patients (62%) and 77 patients (94%) in the overall phase. Discussion: Most of the chemotherapy regimens for lymphoid malignancies include high-dose corticosteroid which may be also effective as antiemetics. Although NK1 receptor antagonist (NK1RA) is generally recommended for cisplatin-containing chemotherapy, it can interact with variety drugs. Conclusion: Although NK1RA is generally recommended for cisplatin-containing regimen, our results suggest that ondansetron effectively controlled emesis in patients receiving ESHAP therapy which includes high-dose corticosteroid.

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Outcome of stem cell transplantation for Waldenström’s macroglobulinemia: analysis of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) Lymphoma Working Group

Sakurai M., Mori T., Uchiyama H., Ago H., Iwato K., Eto T., Iwasaki H., Kawata T., Takamatsu H., Yamasaki S., Takanashi M., Ichinohe T., Atsuta Y., Suzuki R.

Annals of Hematology (Annals of Hematology) 99 ( 7 ) 1635 - 1642 2020.07

ISSN 09395555

The role of stem cell transplantation (SCT) for patients with Waldenström’s macroglobulinemia (WM) remains undetermined. Therefore, we retrospectively evaluated the outcome of autologous and allogeneic SCT for patients with WM using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-six patients receiving autologous and 31 receiving allogeneic SCT were analyzed. The allogeneic SCT group included more patients with advanced disease status at transplant and received more lines of chemotherapy. The cumulative incidences of non-relapse mortality (NRM) at 1 year were 30.0% (95% CI, 14.7–46.9%) in the allogeneic SCT and 0% in the autologous SCT group. The estimated 3-year overall (OS) and progression-free (PFS) survival rates were 84.5% (95% CI, 66.0–93.4%) and 70.8% (95% CI, 53.0–82.9%) in the autologous SCT group, and 52.2% (95% CI, 32.5–68.6%) and 45.0% (95% CI, 26.3–62.0%) in the allogeneic SCT group. No patients died after the first 2 years following allogeneic SCT. In univariate analyses, disease status at SCT was significantly associated with PFS in autologous SCT, and with OS and PFS in allogeneic SCT. These results suggest that both autologous and allogeneic SCT have each potential role in WM. Allogeneic SCT is more curative for WM, but is associated with high NRM.

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Treatment outcomes of chronic-phase chronic myeloid leukemia with resistance and/or intolerance to a 1st-line tyrosine kinase inhibitor in Japan: the results of the New TARGET study 2nd-line

Sakurai M., Okamoto S., Matsumura I., Murakami S., Takizawa M., Waki M., Hirano D., Watanabe-Nakaseko R., Kobayashi N., Iino M., Mitsui H., Ishikawa Y., Takahashi N., Kawaguchi T., Suzuki R., Yamamoto K., Kizaki M., Ohnishi K., Naoe T., Akashi K.

International Journal of Hematology (International Journal of Hematology) 111 ( 6 ) 812 - 825 2020.06

ISSN 09255710

We herein report the results of the New TARGET study 2nd-line, which collected data on patients with chronic-phase (CP) chronic myeloid leukemia (CML) who received a 2nd-line tyrosine kinase inhibitor (TKI) because of resistance and/or to a 1st-line TKI. A total of 98 patients were enrolled intolerance between April 2010 and March 2013, and 82 patients were analyzed. The median age was 54 years (range 22–88 years). Seventy-six patients (93%) received imatinib as the 1st-line TKI. Forty-five (55%) and 37 (45%) patients began nilotinib and dasatinib treatments at entry, respectively. First-line TKI treatment achieved complete hematological response in 79 patients (96%) and complete cytogenetic response (CCyR) in 49 patients (60%), respectively. Nine patients (11%) had BCR-ABL1 kinase domain point mutations at enrollment. The estimated 3-year progression-free-survival rate after enrollment was 98.7% (95% CI 91.1–99.8%). Overall, the probabilities of achieving CCyR and a major molecular response were 89.3% (95% CI 81.4–94.8%) and 87.2% (95% CI 78.1–93.8%), respectively. There were no new safety issues. This study demonstrated that CML-CP patients in Japan who are resistant and/or intolerant to a 1st-line TKI can achieve an extremely good outcome by 2nd-line TKI treatment.

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Clinical characteristics of human herpesvirus-6 myelitis after allogeneic hematopoietic stem cell transplantation and its favorable outcome by early intervention

Shiroshita K., Mori T., Kato J., Sakurai M., Koda Y., Abe R., Murakami K., Sumiya C., Fujita S., Yamaguchi K., Yamazaki R., Nakayama H., Suzuki S., Nakahara J., Okamoto S.

Bone Marrow Transplantation (Bone Marrow Transplantation) 55 ( 5 ) 939 - 945 2020.05

ISSN 02683369

After allogeneic hematopoietic stem cell transplantation (HSCT), human herpesvirus-6 (HHV-6) can cause serious central nervous system (CNS) disorder and typically presents as encephalitis. Another manifestation of HHV-6 is myelitis, which has not been fully evaluated. In this study, we retrospectively analyzed 19 patients who developed HHV-6 myelitis after allogeneic HSCT. Median onset was 20 days after transplantation (range, 13–31), with a cumulative incidence of 4.1% at day 40 after transplantation. Median age at transplant was 50 years (range, 17–61). Median copy number of HHV-6 DNA was 3000 copies/ml in cerebrospinal fluid (CSF; range, 200–100,000). The most common symptoms were pruritus, pain of the extremities/back, and numbness. Three patients subsequently developed encephalitis in the clinical course of myelitis; their HHV-6 copy numbers in CSF had been higher than 10,000 copies/ml at the onset of myelitis. Antiviral agents were initiated shortly after onset in all patients, resulting in recovery. These results suggest that myelitis would be an important subtype of HHV-6-associated CNS disorders after allogeneic HSCT, whose prognosis could be favorable by an early intervention. Transplant physicians should recognize early posttransplant neurological symptoms such as pruritus, pain, or numbness as possible signs of HHV-6 myelitis, which could also progress to encephalitis.

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Seasonal changes in indoor airborne fungal concentration in a hematology ward

Mori T., Kikuchi T., Kato J., Koda Y., Sakurai M., Kikumi O., Inose R., Murata M., Hasegawa N., Nakayama H., Yamazaki R., Okamoto S.

Journal of Infection and Chemotherapy (Journal of Infection and Chemotherapy) 26 ( 4 ) 363 - 366 2020.04

ISSN 1341321X

Invasive fungal disease (IFD) is an important infectious complication of hematological disorders, especially in hematopoietic stem cell transplantation recipients. Evidences suggest seasonal and/or geographical variations in the airborne fungal counts and a relationship between those counts and the incidence of IFD. We evaluated the concentrations of indoor airborne fungi quantitated over the course of one year in a hematology ward in Japan. In January, April, July, and October, fixed volumes of air samples were obtained by an air sampler in a hematology ward not equipped with a high-efficiency particulate air filter and incubated in fugal cultures. Samples were also obtained from a protective environment in the same ward and were evaluated. The number of fungal colonies per 50 L of sampled air was highest in October (median 2.25 (range, 0.2–7.0)), which was significantly higher than those in the other three months (0.1 (range, 0–1.0) in January; 0 (0-0) in April; 0.55 (0–2.5) in July; P < 0.01)). Commonly identified pathogens included Penicillium and Cladosrporium species, but Aspergillus species was detected only in July and October samples. These results suggest a seasonal variation in indoor airborne fungal concentrations in Japan, which could affect the epidemiology of IFD.

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Achievement of Durable and Complete Remission of Graft-versus-host Disease After Liver Transplantation With Ruxolitinib: A Case Report

Endo Y., Oshima G., Hibi T., Shinoda M., Sakurai M., Koda Y., Izawa Y., Obara H., Kitago M., Yagi H., Abe Y., Matsubara K., Yamada Y., Fukushima A., Yokose T., Mori T., Kuroda T., Kitagawa Y.

Transplantation (Transplantation) 103 ( 11 ) e375 - e377 2019.11

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Comparative study on baseline clinical characteristics of Asian versus non-Asian patients with paroxysmal nocturnal hemoglobinuria

Sakurai M., Jang J.H., Chou W.C., Kim J.S., Wilson A., Nishimura J.i., Chiou T.J., Kanakura Y., Lee J.W., Okamoto S.

International Journal of Hematology (International Journal of Hematology) 110 ( 4 ) 411 - 418 2019.10

ISSN 09255710

A difference in clinical manifestations of paroxysmal nocturnal hemoglobinuria (PNH) among different races has been suggested. The aim of this study was to clarify whether the clinical characteristics of patients with PNH in the International PNH Registry differ by ethnic background. Patients, who were eculizumab naïve at baseline and had ≥ 1% PNH clone size, were eligible for this analysis. Totally, 1793 patients were enrolled and divided into two cohorts, Asian (N = 246) and non-Asian (N = 1547). The Asian cohort was further divided into Asians in Asia cohort (N = 202) and Asians in non-Asia cohort (N = 44), based on geographical region. The Asian cohort had significantly higher PNH clone size in granulocytes, higher lactate dehydrogenase levels, and lower hemoglobin levels. However, the frequencies of symptoms including abdominal pain, backache, easy bleeding, fatigue and headache at baseline were significantly lower in the Asian cohort. The proportion of patients with a history of thromboembolism (TE) was significantly lower in the Asian than in the non-Asian cohort (3.6% vs. 8.9%, P < 0.01); however, there was no difference between Asians in Asia and Asians in non-Asia (3.3% vs. 4.9%, P = 0.61). These findings suggested that genetic factors may play a stronger role in developing TE than lifestyle factors in PNH patients.

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Human Herpesvirus 6 Reactivation Evaluated by Digital Polymerase Chain Reaction and Its Association with Dynamics of CD134-Positive T Cells after Allogeneic Hematopoietic Stem Cell Transplantation

Nakayama H., Yamazaki R., Kato J., Koda Y., Sakurai M., Abe R., Watanuki S., Sumiya C., Shiroshita K., Fujita S., Yamaguchi K., Okamoto S., Mori T.

Journal of Infectious Diseases (Journal of Infectious Diseases) 220 ( 6 ) 1001 - 1007 2019.08

ISSN 00221899

Background: Human herpesvirus 6 (HHV-6) causes life-threatening central nervous system disorders after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent studies implicated CD134 as a specific receptor of HHV-6B and demonstrated that its expression levels in CD4-positive T cells after allo-HSCT could be related to the reactivation of HHV-6. We prospectively evaluated the relationship between HHV-6 reactivation and CD134+ T cells in the recipients of allo-HSCT. Methods: HHV-6 viral load in plasma was quantitatively measured weekly after allo-HSCT by digital polymerase chain reaction in 34 patients. The ratio of CD134 in CD4+ T cells (CD134/CD4 ratio) was serially measured by flow cytometry before and after transplantation. Results: HHV-6 reactivation was detected in 23 patients (68%). The CD134/CD4 ratio before conditioning was significantly higher in patients with HHV-6 reactivation than in those without (median, 3.8% vs 1.5%, P <. 01). In multivariate analysis, a higher CD134/CD4 ratio before conditioning was significantly associated with the incidence of HHV-6 reactivation (odds ratio, 10.5 [95% confidence interval, 1.3-85.1], P =. 03). Conclusions: A higher CD134/CD4 ratio before conditioning was associated with a higher risk of HHV-6 reactivation, suggesting that the rate may be a promising marker for predicting HHV-6 reactivation after allo-HSCT.

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