Search

Objective The standard treatment for chronic myeloid leukemia (CML) is the continuous use of tyrosine kinase inhibitors (TKIs), which results in a favorable prognosis for the majority of patients. Recent studies have identified cardiovascular diseases (CVDs) as late adverse events (AEs) related to TKIs. In this study, we evaluated the long-term efficacy and AEs of TKIs, focusing on CVDs. Methods We performed a retrospective survey of CML patients (diagnosed from 2001 to 2016) treated with TKIs in Nagasaki Prefecture. Clinical data were obtained from their medical records. We analyzed the survival, estimated cumulative incidence of CVDs, and risk factors for CVD among CML patients treated with TKIs. Results The overall survival rate of 264 CML patients treated with TKIs (median age 58 years old) was 89.6% [95% confidence interval (CI), 84.9-92.9%], and 80.5% (95% CI, 73.4-85.9%) at 5 and 10 years after the CML diagnosis, respectively. CVD events occurred in 26 patients (9.8%, median age 67.5 years old) with a median 65.5 months of TKI treatment. The cumulative incidences at 2 and 5 years was 2.4% (95% CI, 1.0-4.8%) and 5.2% (95% CI, 2.8-8.6%), respectively. Hypertension and a high SCORE chart risk at the diagnosis of CML were associated with CVD events during TKI treatment. Conclusion TKI treatment contributed to the long-term survival of CML patients in Nagasaki Prefecture in a “real-world” setting, but the incidence of CVDs seemed to be increased in these patients. A proper approach to managing risk factors for CVD is warranted to reduce CVD events during TKI treatment.

We present the case of a 78-year-old male patient who was diagnosed with anaplastic lymphoma kinase (ALK)-negative, CC chemokine receptor 4 (CCR4)-negative, and CD30-positive anaplastic large cell lymphoma (ALCL). The patient had a past medical history of adult T-cell leukemia/lymphoma and colon cancers that had developed simultaneously approximately 2 years prior to the development of ALCL that were treated with immunochemotherapy and resection, respectively. Initial treatment for ALCL included brentuximab vedotin, an anti-CD30 monoclonal antibody-monomethyl auristatin E conjugate; however, we were unable to achieve a sufficient treatment effect. Romidepsin, an oral histone deacetylase inhibitor, was introduced as salvage chemotherapy; complete remission was attained. Interestingly, a reversal of the CD4/CD8 ratio and a reduction in human T-lymphotropic virus type 1 (HTLV-1) virus load was observed after 2 cycles of immunochemotherapy; the patient experienced upregulation of HTLV-1 Tax-specific cytotoxic T lymphocytes after a herpes zoster infection and the completion of immunotherapy. The immunologic status was maintained from the time of diagnosis through the completion of romidepsin therapy. Our findings indicate that romidepsin can be used safely and effectively to treat ALCL without impairing cellular immunity to HTLV-1.

The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in patients who cannot tolerate platinum-based regimens has not been clarified. We aimed to develop a new treatment regimen for patients with R/M SCCHN who are ineligible for platinum-based therapy, by evaluating the effects and safety of tegafur/gimeracil/oteracil (S-1) and cetuximab. Platinum-ineligibility was defined as: elderly (aged ≥ 75 years), poor PS, comorbidity, platinum resistance and refusal to undergo platinum-based therapy. Patients received S-1 (80 mg/m2/day for 14 days followed by a seven-day break) and cetuximab (initial dose, 400 mg/m2, followed by 250 mg/m2 weekly) until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Between September 2014 and September 2018, we enrolled 23 patients. Among the 21 patients who were evaluable, 20 were male [median age, 69 years (range 49–82)]. The ORR was 9 (43%) of 21 patients [95% confidence interval (CI) 22–66]. One and eight patients achieved complete response (CR) and partial response (PR), respectively. The median overall survival (OS) was 13.7 months (95% CI 9.0–18.3) and progression-free survival (PFS) was 5.7 months (95% CI 3.1–8.2). Grade 3/4 adverse events included acneiform rash and skin reactions (33%), hypomagnesemia (19%), hand-foot syndrome (14%), fatigue (14%), mucositis (10%), and anorexia (10%). Combination treatment with S-1 and cetuximab was effective and tolerated well by patients with platinum-ineligible R/M SCCHN. Registered clinical trial number: UMIN000015123

Background/aim Adult T-cell leukemia/lymphoma (ATLL) is a relatively refractory CD4-positive peripheral T-cell lymphoma. VCAP-AMP-VECP (mLSG15) is one of the standard chemotherapeutic regimens for patients with aggressive ATLL. Mogamulizumab (moga), a monoclonal antibody for C-C chemokine receptor 4 antigen expressed on the cell surface, has recently been poised for use as monotherapy and in combination with chemotherapy. However, to date, a significant survival benefit has not been obtained with the combination of moga + mLSG15 therapy. Patients and methods We retrospectively analyzed 77 patients diagnosed with aggressive ATLL. Of them, 22 were treated with moga + a chemotherapy regimen comprised of etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisolone (EPOCH), 16 with moga + mLSG15, and 39 with chemotherapy alone. Results A risk reduction of approximately 30% was obtained with moga + EPOCH compared with moga + mLSG15. Conclusion The addition of moga to chemotherapy did not result in a survival benefit compared with chemotherapy alone. However, a statistically significant overall survival benefit was observed in patients with moga-induced skin disorders.

Cytomegalovirus (CMV) is an opportunistic pathogen, and careful monitoring of CMV is important for immunocompromised patients. Antigenemia-based CMV monitoring is a standard test used for managing CMV infection in transplant recipients;however, in Japan, there are no reports of CMV monitoring using the standardized test. The utility of a standardized CMV nucleic acid test (NAT) was evaluated during antigenemia-based CMV monitoring after hematopoietic stem cell transplantation (HSCT) or liver transplantation. Blood collection for CMV monitoring was performed under the physician's instructions depending on the condition of the patient, and CMV NAT and antigenemia was evaluated. For HSCT recipients, blood collection only for NAT was additionally performed during the pre-engraftment phase. The results of the NAT were blinded to those evaluating the results. A total of 34 patients were enrolled (11 HSCT recipients and 23 liver transplant recipients). NAT detected the first CMV episode no later than antigenemia in 2 (18.2%) HSCT recipients and 3 (13.0%) liver transplant recipients, earlier than antigenemia in 3 (27.3%) HSCT recipients and 7 (30.4%) liver transplant recipients, and later than antigenemia in 1 (9.1%) HSCT recipient and 1 (4.3%) liver transplant recipient. In 5 HSCT recipients, NAT was positive during the pre-engraftment phase. Among the 468 blood samples which were evaluated by both NAT and antigenemia, 124 (26.7%) were positive in NAT and 51 (10.9%) were positive in antigenemia. The standardized CMV NAT is useful for accurately diagnosing CMV infection and determining appropriate therapeutic interventions for HSCT recipients and liver transplant recipients., The Tohoku journal of experimental medicine, 247(3), pp.179-187; 2019

We present the case of a 63-year-old male with pure white cell aplasia (PWCA), a rare complication of thymoma, who was successfully treated with cyclosporine A (CyA) and thymectomy. The patient presented with high fever and agranulocytosis. Complete blood count revealed a white blood cell count of 0.9 × 109/L (3% neutrophils), a hemoglobin level of 15.8 g/dL, and a platelet count of 308 × 109/L. Bone marrow (BM) aspiration revealed a hypocellular marrow lacking granulocytes. Computed tomography showed a large anterior mediastinal mass, and the patient was diagnosed with PWCA associated with thymoma. Thirteen days after the initiation of CyA treatment, myeloid cells appeared in the BM, and the neutrophil count in peripheral blood started to increase on day 18. Thymectomy was performed 3 months later. Although CyA treatment was discontinued after thymectomy, complete remission has been maintained for over 4 years. In vitro colony-forming unit granulocyte–macrophage (CFU-GM) assay using the patient’s serum showed severe suppression of CFU-GM colonies in the presence of the patient’s serum, suggesting the presence of CFU-GM inhibitor in the patient’s serum. The efficacy of the immunosuppressive therapy and the CFU-GM assay suggests the potential involvement of an immunological mechanism in patients with thymoma-associated PWCA.

We performed a retrospective analysis of DLBCL with breast involvement to compare the prognosis of primary breast lymphoma (PBL) to secondary breast lymphoma (SBL; especially in limited stage cases). We retrospectively reviewed records of 25 diffuse large B-cell lymphoma (DLBCL) patients with breast involvement who received chemotherapy between January 2000 and August 2012. We compared clinical features and prognosis among patients with PBL (n = 11), limited stage SBL (LSBL; n = 6), and advanced stage SBL (ASBL, n = 8). The PBL group had significantly lesser patients with breast tumours (BTs) > 5 cm than the SBL group (P = 0.02). After a median follow-up of 71.3 months, we observed significantly better 5-year overall survival (OS) in the PBL group (90.0%) than in the LSBL (33.3%, P = 0.01) group, but not for progression-free survival (PFS). Patients with BT > 5 cm had worse OS (P = 0.01) and PFS (P = 0.04) than those with BT ≤ 5 cm. PBL had a better prognosis than SBL among limited stage DLBCL.

Treatment options for patients with adult T cell leukemia/lymphoma (ATLL) who have relapsed disease after allogeneic hematopoietic stem cell transplantation (allo-HSCT) are limited. To clarify which patients with ATLL are likely to benefit from these treatment options and to define patient populations for novel treatments, we performed a nationwide retrospective analysis of 252 Japanese patients who had relapsed ATLL after allo-HSCT. Some long-term survivors remained after tapering and withdrawal of immunosuppressive agents. Thirty-six patients who received donor lymphocyte infusion had a better overall survival (OS) in comparison to those who did not [hazard ratio (HR), 0.63; 95% confidence interval (CI), 0.43-0.93; P = .02], suggesting the efficacy of a graft-versus-ATLL (GvATLL) effect even after relapse. Multivariate analysis demonstrated that skin lesions at initial relapse of ATLL were independently associated with higher OS (HR, 0.41; 95% CI, 0.22-0.74; P = .003), indicating that the skin is a susceptible target organ of GvATLL. This study suggested that enhancement of a GvATLL effect is a potential therapeutic option for relapsed disease after allo-HSCT. Further investigations of incorporation of immune-based approaches with new molecular target drugs into the therapeutic options of patients with ATLL before and after transplantation are warranted.

We herein report a rare case of oral mucormycosis following allogeneic hematopoietic stem cell transplantation. Oral mucormycosis due to Rhizopus microsporus manifested as localized left buccal mucositis with a 1-cm black focus before neutrophil recovery. Combination therapy with liposomal amphotericin B was initiated and surgical debridement was performed; however, the patient died due to progressive generalized mucormycosis. Considerable attention needs to be paid to the diagnosis and management of oral mucormycosis in post-transplant patients, thereby suggesting the importance of fully understanding the risk factors.

Aim Primary malignant lymphomas arising from the female genital tract are very rare, with an incidence rate of 0.5%. Because of its rarity, its clinical characteristics, prognosis and optimal treatment are still unclear. Here, we retrospectively evaluated female patients with uterine lymphoma. Methods Between January 2000 and October 2016, 4362 patients were newly diagnosed with malignant lymphoma by the participating institutions of YACHT. Among these 4362 patients, we retrospectively evaluated 14 adult patients with primary uterine lymphoma. Results The median follow up time was 41 months. The median age at diagnosis was 68 years. Of 14 patients, 10 (72%) were diagnosed with diffuse large B-cell lymphoma. Seven patients presented with vaginal bleeding and three with abdominal pain. Eleven patients (79%) had advanced stages at diagnosis. Three patients (21%) had ovarian involvement and 2 (14%) had vaginal involvement. Induction chemotherapy regimens were R-CHOP in seven patients (50%), CHOP in three (21%) and other regimens in four (29%). Among 14 patients, 12 patients (86%) achieved a complete response and 2 (14%) experienced disease progression. Three patients (21%) showed relapse. Five patients (36%) died because of malignant lymphoma. The 3-year overall survival rate was 57.9%. Soluble interleukin-2 receptor levels > 5000 U/mL, anemia, a bulky mass and the presence of > 1 extranodal sites, B symptom at diagnosis were associated with a poor prognosis. Conclusion Female genital lymphoma is very rare, and further study of more cases is warranted.

POEMS syndrome is a rare plasma cell dyscrasia presenting with polyneuropathy, λ-type M protein, vascular endothelial growth factor elevation, and systemic manifestations. The standard treatment has not been established, but autologous stem cell transplantation (ASCT) has exhibited effectiveness in this syndrome. However, the efficacy and long-term outcomes of ASCT have not been systematically studied. To clarify the efficacy and long-term outcomes of ASCT-treated patients in Japan, we performed a multicenter retrospective study assessing the clinical course of patients registered to the Japan Society for Hematopoietic Cell Transplantation Transplant Registry Unified Management Program (TRUMP) database. Between January 2000 and December 2011, 95 patients (58 men) were registered to the TRUMP database with a median age of 53 years (range, 28 to 72). The conditioning regimen was melphalan in 93 of 94 patients (99%), and 69 patients (74.2%) received a melphalan dose ≥ 200 mg/m2. The median CD34 cell dose was 2.47 × 106/kg (range, .31 to 20). After ASCT, patient performance status was dramatically improved (Eastern Cooperative Oncology Group performance status 0 to 1: 20.0% versus 71.6%, P

A 62-year-old male was diagnosed with blastic plasmacytoid dendritic cell neoplasm (BPDCN) with a MYC rearrangement. Four months after the first unrelated bone marrow transplantation (BMT), he developed the relapsed BPDCN. After the achievement of partial remission following re-induction therapy, he underwent a second BMT from another unrelated donor, and experienced complete remission with grade II acute graft-versus-host disease and moderate chronic graft-versus-host disease. He remains alive in complete remission more than 71 months after the second BMT. These results suggested that donor change at the second transplantation may represent a considerable therapeutic option for patients with relapsed BPDCN., Leukemia Research Reports, 11, pp.31-33; 2019

Background: Although introduction of pediatric-type Berlin-Frankfurt-Munster (BFM) chemotherapy has markedly improved the prognosis of adolescent and young adult (AYA) patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-negative ALL), their higher toxicity has become an emerging issue with an increased post-remission mortality in AYA patients than pediatric patients. Allogeneic stem cell transplantation (allo-SCT) with myeloablative conditioning (MAC) regimens containing total body irradiation (TBI) is recognized as an important treatment option for patients with higher risk diseases. However, safety and efficacy of allo-SCT with TBI-MAC have not been fully investigated among AYA patients who received pediatric-type chemotherapy. Patients and methods: AYA was defined as 16 to 39 years old. Of the 143 AYA patients with Ph-negative ALL who underwent the first allo-SCT in the first remission between 2007 and 2016 at the 20 institutions, 106 patients who were treated with one BFM chemotherapy regimen before transplant and were conditioned with MAC regimens containing more than or equal to 8 Gy of TBI dose. The reasons for the transplant were surveyed with a multi-answer questionnaire. Overall survival (OS) was defined as the interval from the date of transplant to the date of death. Fisher's exact test was used to compare binary variables. The cumulative incidence (CI) of non-relapse mortality (NRM) and relapse were evaluated with Gray's test, considering relapse and NRM as a competing risk, respectively. OS was estimated with the Kaplan-Meier method and compared using the log-rank test. Factors associated with at least borderline significance (p < 0.20) in univariate analyses were subjected to multivariate analysis. The Fine-Gray and Cox proportional hazard model were used for multivariate analysis of risk factors and prognostic factors, respectively. Values of p < 0.05 were considered to indicate statistical significance. Results: Of the 106 patients included in this study, 61 were male, and 45 were female. The median age at transplant was 29 years (range, 16-39 years). Donor types were related, unrelated, and cord blood in 47 (44%), 47 (44%), and 12 (12%) patients, respectively. The difficulty of continuing chemotherapy due to side effects as the reason for transplant was included in 13 patients (12%). As chemotherapy before transplant, pediatric-type and adult-type regimens were used in 56 (53%) and 50 patients (47%), respectively. There was no significant difference in baseline characteristics and transplant procedures between the pediatric-type group and the adult-type group, except for proportion of patients over 30 years (14% vs. 64%, respectively; p < 0.01), those with more than or equal to 2 of hematopoietic cell transplant comorbidity index (13% vs. 36%, respectively; p < 0.01), and transplant between 2007 and 2011 (36% vs. 64%, respectively; p < 0.01). The CI of NRM, the OS rates, and the CI of relapse were not significantly different between two groups (NRM: 4% vs. 12% at three years after transplant, respectively; p = 0.26), (OS: 86% vs. 70%, respectively; p = 0.14), and (relapse: 16% vs. 24%, respectively; p = 0.32), respectively. Multivariate analysis for NRM revealed that more than or equal to 1 of performance status at transplant (hazard ratio [HR] = 4.8; p < 0.01) and transplant due to side effects of chemotherapy (HR = 3.5; p = 0.04) were identified as independent risk factors, but not pediatric-type chemotherapy (HR = 0.48; p = 0.23). The proportions of transplant due to side effects of chemotherapy were similar between two groups (13% vs. 12%, respectively; p = 1). No independent prognostic factor for OS was found, while transplant between 2007 and 2011 (HR = 2.5; p = 0.04) was extracted as an independent risk factor of relapse. Regarding transplant complications, significant differences were not shown in CI of grade II to IV acute graft-versus-host disease (GVHD), chronic GVHD, bacteremia, cytomegalovirus reactivation, hemorrhagic cystitis, and avascular necrosis between two groups. No characteristic cause of NRM was found in the pediatric-type group. Conclusion: These findings suggested that conventional allo-SCT with TBI-MAC can be performed without increasing NRM in AYA patients with Ph-negative ALL even after pediatric-type chemotherapy. Disclosures Kimura: MSD: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Kyowa Kirin: Honoraria; Chugai Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical: Honoraria; Eisai: Honoraria; Nippon Kayaku: Honoraria; Takeda Pharmaceutical: Honoraria; SymBio Pharmaceutical: Honoraria. Usuki: MSD: Speakers Bureau; Alexion: Speakers Bureau; Pfizer: Research Funding; Kyowa Kirin: Research Funding, Speakers Bureau; Eisai: Speakers Bureau; Nippon shinyaku: Research Funding, Speakers Bureau; Astellas-Amgen-Biopharma: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Takeda: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Research Funding; Ono: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Symbio: Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Astellas: Research Funding, Speakers Bureau; Mundipharma: Research Funding; Yakult: Speakers Bureau; PharmaEssentia: Speakers Bureau. Sakaida: Bristol Myers Squibb: Research Funding; Chugai: Research Funding; Ono: Research Funding; Kyowa Kirin: Research Funding. Fujisawa: Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Handa: Abbvie: Honoraria; MSD: Research Funding; Shionogi: Research Funding; Sanofi: Honoraria, Research Funding; Ono: Honoraria; BMS: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding. Hatta: Bristol-Myers Squibb: Honoraria; Novartis KK: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical.: Honoraria. Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding; Sanofi: Research Funding; MSD: Honoraria.

The myelodysplastic syndromes (MDS) are clonal haematopoietic disorders that develop de novo and also secondary to chemotherapy and/or radiation therapy. We previously demonstrated that the risk of MDS is increased among atomic bomb survivors with significant correlation to radiation dose; however, the clinical characteristics of these survivors have not been well analysed. In this study, we investigated chromosomal abnormalities of MDS among survivors. The frequency of abnormal karyotypes was significantly higher, with more very poor risk karyotypes, according to the revised International Prognostic Scoring System, among those exposed close to the hypocentre compared with unexposed cases. However, abnormal karyotype frequency did not reflect the prognosis of exposed cases with respect to distance from the hypocentre. In addition, there was no difference in prognosis between exposed and unexposed cases. Among proximally exposed cases (

Steroid-refractory acute graft-versus-host disease (SR-aGVHD) is a serious complication that negatively affects the prognosis and quality of life of patients who receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). Antithymocyte globulin (ATG) is one of the second-line treatments for SR-aGVHD. We retrospectively evaluated Karnofsky Performance Status (KPS) recovery and clinical response in 11 patients who received the response-guided low-dose ATG treatment for SR-aGVHD after allo-HSCT using alternative donors. The median dose of ATG per cycle was 1.0 mg/kg (range, 1.0–1.25 mg/kg) and the median number of cycles of ATG was 2 (range, 1–4). The overall response rate was 63.6%, and the estimated overall survival rate at 1 year was 63.6%. Two out of seven patients who survived 1 year after the response-guided ATG treatment had KPS of 80 or higher. The remaining 5 patients had KPS of lower than 80 due to moderate chronic GVHD (cGVHD) and/or ≥grade 3 infectious complications. Based on the poor prognosis of patients with SR-aGVHD, the response-guided ATG treatment represents one therapeutic option. The present results also suggest that chronic GVHD and infectious complications after the response-guided ATG treatment were associated with decreased KPS recovery and impaired social function.

Body mass index (BMI), which represents the proportion of weight to height, is a controversial prognostic factor for acute myeloid leukemia (AML). We evaluated prognostic value of BMI in Japanese AML. The study included 369 adult patients with newly diagnosed AML who were administered either daunorubicin or idarubicin with cytarabine as induction chemotherapy. The patients were categorized into two groups according to their BMI: the NW group (BMI

Dismal outcome of allogeneic hematopoietic stem cell transplantation for relapsed adult T-cell leukemia/lymphoma, a Japanese nation-wide study

Mogamulizumab (Mog) and lenalidomide (Len) are new therapeutic candidates for relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present study, we retrospectively analyzed 12 patients who received Mog or Len monotherapy for relapsed ATL after allo-HSCT. Eight and three patients received Mog and Len, respectively. The remaining patient received Mog for the first relapse and Len for the third relapse. A complete response was achieved by three and two patients who received Mog and Len, respectively, two and one of whom remained alive with a complete response for more than 20 months. In terms of adverse events, the emergence or progression of graft-versus-host disease was observed in three out of four patients treated with Len and in none of the patients treated with Mog. The development or progression of cytomegalovirus reactivation was detected in four out of eight patients treated with Mog and in none of those treated with Len. The present results suggest that Mog and Len would be promising treatment options for relapsed ATL after allo-HSCT and need to be selected based on adverse event profiles.

Although cytogenetic abnormalities at diagnosis are recognized as an important prognostic factor in patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL), the prognostic impact has not been evaluated in allogeneic stem cell transplant (allo-SCT) recipients. Thus, we assessed 373 Ph-negative ALL patients who underwent allo-SCT. The high-risk (HR) group included those with t(4;11), t(8;14), low hypodiploidy, and complex karyotype, and the standard risk (SR) group included all other karyotypes. Among the 204 patients who underwent a transplant during the first remission (167 in the SR group and 37 in the HR group), the overall survival (OS) rates were similar between these groups (64.1% vs. 80.0% at 5 years, respectively; p = 0.12). Conversely, among the 106 patients who underwent a transplant while not in remission (84 in the SR group and 22 in the HR group), patients in the SR group showed a significantly superior OS rate compared to the HR group (15.4% vs. 4.5% at 5 years, respectively; p = 0.022). These results suggested that treatment outcomes of Ph-negative ALL patients with HR cytogenetic abnormalities may improve following allo-SCT, especially in the first remission. Innovative transplant approaches are warranted in patients who are not in remission.

We hypothesized that treatment-related weight loss is associated with worse outcomes following HSCT. Overall, 184 patients with AML who underwent induction therapy were classified according to d-BMI (BMI at transplant minus BMI at diagnosis) (kg/m2) as + 2. At 1 year, OS was 67.9% (95% CI, 60.7–74.2), DFS was 64.1% (95% CI, 56.7–70.6), and GRFS was 40.2% (95% CI, 33.1–47.2). For d-BMI groups + 2, GRFS at 1 year was 16.1% (95% CI, 5.1–31.4), 45.4% (95% CI, 36.4–53.7), and 41.7% (95% CI, 22.2–60.1), respectively (P = 0.0067). Multivariate analysis showed that both worse OS (HR, 1.78; 95% CI, 1.02–3.14; P = 0.007) and GRFS (HR, 2.34; 95% CI, 1.26–4.35; P = 0.007) were associated with reduced BMI (d-BMI

There is evidence that radiation exposure is a causative factor of myelodysplastic syndromes (MDS). However, little is known about whether radiation exposure is also a prognostic factor of MDS. We investigated the impact of radiation exposure on the prognosis of MDS in Nagasaki atomic bomb survivors using the International Prognostic Scoring System (IPSS) and the revised version (IPSS-R). Subjects were 140 patients with primary MDS diagnosed between 1985 and 2011 and evaluable for IPSS, IPSS-R, and exposure distance. Of those, 31 were exposed at, Cancer Science, 107(10), pp.1484-1491; 2016

Acute erythroid leukemia (FAB-M6) and acute megakaryoblastic leukemia (FAB-M7) exhibit closely related properties in cells regarding morphology and the gene expression profile. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered the mainstay of the treatment for both subtypes of leukemia due to their refractoriness to chemotherapy and high rates of relapse, it remains unclear whether allo-HSCT is curative in such cases due to their scarcity. We retrospectively examined the impact of allo-HSCT in 382 patients with M6 and 108 patients with M7 using nationwide HSCT data and found the overall survival (OS) and relapse rates of the M6 patients to be significantly better than those of the M7 patients after adjusting for confounding factors and statistically comparable with those of the patients with M0/M1/M2/M4/M5 disease. Consequently, the factors of age, gender, performance status, karyotype, disease status at HSCT and development of graft-vs.-host disease predicted the OS for the M6 patients, while the performance status and disease status at HSCT were predictive of the OS for the M7 patients. These findings substantiate the importance of distinguishing between M6 and M7 in the HSCT setting and suggest that unknown mechanisms influence the HSCT outcomes of these closely related subtypes of leukemia. © 2016 Elsevier Ltd., Embargo Period 12 months

Summary Background Patients with adult T-cell leukaemia-lymphoma have few treatment options after relapse and poor survival outcomes with current therapies. We aimed to determine the maximum tolerated dose of lenalidomide, an oral immunomodulator, in Japanese patients with relapsed adult T-cell leukaemia-lymphoma and other peripheral T-cell lymphomas. Methods In this phase 1 study, we enrolled patients aged 20 years or older with Eastern Cooperative Oncology Group performance status 0–2, documented diagnosis of aggressive adult T-cell leukaemia-lymphoma or other peripheral T-cell lymphoma subtypes, and at least one previous antilymphoma therapy. Patients were sequentially assigned to lenalidomide 25 mg/day, days 1–21 of a 28-day cycle (cohort 1), 25 mg/day continuously (cohort 2), and 35 mg/day continuously (cohort 3) in a 3 + 3 design. The primary study endpoint was to identify the maximum tolerated dose of lenalidomide. Analyses were performed per protocol for efficacy and in the intent-to-treat patient population for safety. This completed trial is registered with ClinicalTrials.gov, number NCT01169298. Findings We enrolled 14 patients from six centres in Japan. Of 13 assessable patients (nine with adult T-cell leukaemia-lymphoma, four with other peripheral T-cell lymphomas) receiving lenalidomide, dose-limiting toxic effects were reported in three patients during cycle 1 (one grade 4 thrombocytopenia [cohort 2], one grade 3 QT prolongation on electrocardiogram [cohort 3], and one grade 3 fatigue and grade 4 thrombocytopenia [cohort 3]). The maximum tolerated dose was identified as lenalidomide 25 mg/day given continuously. The most common grade 3 or worse adverse events were neutropenia (eight [62%] patients), lymphopenia (seven [54%] patients), and thrombocytopenia (four [31%] patients); myelosuppression was similar in each cohort. Serious adverse events occurred in eight (62%) patients; thrombocytopenia, which occurred in three (23%) patients, was the only serious adverse event reported in more than one patient. Interpretation We were able to determine the dose and schedule for lenalidomide treatment in previously treated patients with aggressive, adult T-cell leukaemia-lymphoma. This dose will be used in a subsequent phase 2 study. Funding Celgene Corporation.

In the original publication of the article, the authors would like to alter the color of characters in the Supplemental Table 1 and 2.

e20055 Background: Bendamustine plus rituximab therapy (BR) is one of the mainstays of therapy for follicular lymphoma (FL) patients (pts). Adverse events such as lymphopenia, neutropenia, and skin lesions sometimes prevent the completion of six cycles of BR. Till date, the bendamustine dose, treatment cycle of BR, and prognostic markers of FL response to BR have not been analyzed sufficiently. Methods: We retrospectively evaluated 56 FL pts treated with BR from January 2011toJanuary 2019 at our hospital; 19 pts and 37 pts received BR as first-line therapy and salvage therapy, respectively. Results: There was no statistical difference in the response rate, OS, and PFS between the first-line group and the salvage group. The table summarizes the survival analyses. Comparing the OS and PFS according to FL grades 1, 2, and 3 in all pts, there were significant differences in both OS (P = 0.0028) and PFS (P = 0.0058). Patients were divided into two groups based on a cutoff sIL-2R value of 682 U/mL; survival benefits were observed in the sIL-2R-low group in OS (P = 0.0226) and PFS (P = 0.0265). Similarly, on dividing the pts into two groups based on a cutoff LDH value of 225 U/L, survival benefits were observed in the LDH-low group in OS (P = 0.0375) and PFS (P = 0.0453). The LDH value was significantly high in pts with progression of disease within 24 months (POD24) compared to pts without POD24 (P = 0.0134). However, there was no statistical relationship between sIL-2R and POD24.The rate of treatment cycles ≧4 was 69%, and the mean number of treatment cycles was 4.3. Survival benefits were observed in pts who were treated for more than 3 cycles in OS (P = 0.0094) and PFS (P = 0.0103). The mean bendamustine dose was 78.5 mg/m2. Conclusions: Approximately 30% pts could not receive more than 3 cycles of BR, probably because of adverse events and preexisting bone marrow suppression with previous chemotherapy, suggesting that 90 mg/m2of bendamustine in BR may be excessive, especially in pts requiring salvage therapy. Our data suggest that 75−80 mg/m2of bendamustine may be appropriate. Our survival data also suggest that new treatment strategies may be needed for FL pts with high levels of sIL-2 ( >682 U/mL) and LDH ( >225 U/L) and grade 3 disease. [Table: see text]

Background Azacitidine (AZA) is one of the hypomethylating agents (HMAs) proven to significantly prolong overall survival (OS) for patients with higher-risk myelodysplastic syndromes (h-MDS) via a prospective phase 3 trial. However, the optimal treatment schedule of AZA for h-MDS has not yet been prospectively determined. As a 7-day treatment schedule includes weekends, a 5-day administration has also been applied with h-MDS, though solid evidence has not been established. Based on this background, we planned to compare AZA treatment on 7-day and 5-day schedules. Patients Patients diagnosed with de novo or treatment-related MDS (FAB-defined RAEB and RAEB-t), aged 16 years or older were eligible for this study, if they showed adequate performance status (ECOG PS 0-2) and no history of HMA treatment or chemotherapy. Candidates for allogeneic stem-cell transplantation were excluded. Study design This was a multicenter, randomized, open-label, phase 3 trial to compare the efficacy of AZA treatment for 7-days (AZA-7) to 5-days (AZA-5). The primary endpoint was 2-year OS rate (2y OS). AZA was given subcutaneously at 75 mg/m² every 28 days. To test the non-inferiority of AZA-5 to AZA-7, 2y OS of AZA-7 was estimated at 30%, and the delta was defined as 11%, for which 410 patients were needed to complete the trial. However, because of the poor recruitment, this study closed prematurely, and the protocol-planned interim analysis (when 200 patients were registered) was performed. This protocol was approved by the IRB at each trial center. All patients provided written informed consent, and the trial was conducted in accordance with the Declaration of Helsinki. The efficacy of AZA was evaluated using IWG2006 criteria, and treatment was continued until study completion, or relapse, unacceptable toxicity, or disease progression was observed. Efficacy was analyzed by intention-to-treat. Secondary endpoints were the hematological response rate, 2-year leukemia-free survival (2y LFS) rate, the cytogenetic response, and occurrence of adverse events. Results Between January 2013 and Jun 2018, 201 patients were randomly assigned to AZA-7 (n=99) or AZA-5 group (n=102). The median age of all patients at the enrollment was 73.5 years old (range, 48 to 91). Between the two groups, there was no significant difference in the baseline characteristics, such as sex, type of MDS (de novo or treatment-related), percent of BM blasts, FAB and WHO classification, and IPSS and IPSS-R risk. After excluding 5 and 6 patients from AZA-7 and AZA-5, respectively (poor data entry, change in diagnosis), at the time of last follow-up, 59 and 67 patients died in AZA-7 and AZA-5, respectively. The Kaplan-Meier estimates of the 2y OS and 2y LFS were 35.1% (95% CI, 23.8 to 46.7) and 27.3% (95% CI, 17.3 to 38.3) for AZA-7, and 22.4% (95% CI, 13.1 to 33.3) and 20.5% (95% CI, 11.6 to 31.2) for AZA-5, respectively. There was no significant difference in the frequency of erythroid, platelet or neutrophil improvement, or hematological response (complete or partial response, or any hematological improvement) between the two groups. The most common non-hematological adverse event of grade 3 to 4 (in ≥20% of the patients in either group) was febrile neutropenia (33.7% for AZA-7, and 30.5% for AZA-5). Conclusion and Discussion Because of the premature termination of this trial, statistical analysis for the primary endpoint (2y OS of 35.1% for AZA-7, and 22.4% for AZA-5) could not provide any solid evidence. However, considering the difference of more than 10% in 2y OS, and no major differences in the safety profiles, we favor AZA-7 to AZA-5 for MDS patients with RAEB and RAEB-t. Figure Disclosures Kiguchi: Tejin Co., Ltd.: Research Funding; Taiho Pharmaceutical Co., Ltd.: Research Funding; SymBio Pharmaceutical Co., Ltd.: Research Funding; Celgene Co., Ltd.: Research Funding; Janssen Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharmaceutical Co., Ltd.: Research Funding; MSD CO., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Bristol-Myeres Squibb Co., Ltd.: Research Funding; Sanofi K.K., Ltd.: Research Funding; Celltrion, Inc.: Research Funding. Usuki:Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Astellas Pharma Inc: Research Funding, Speakers Bureau. Suzuki:kyowa Hakko Kirin: Consultancy, Honoraria; MSD k.k.: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; takeda: Research Funding; Incyte and Pfizer: Research Funding; astellas: Research Funding; Celgene: Honoraria; Chugai: Honoraria, Research Funding; daiichi sankyo: Research Funding; eisai: Research Funding. Tomita:Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Taiho Pharma: Research Funding. Handa:Ono: Research Funding. Maeda:Janssen Pharmaceutical K.K..: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria. Iyama:Otsuka Pharmaceutical Co., Ltd.: Honoraria; Otsuka Pharmaceutical Factory: Honoraria; Astellas Pharma: Honoraria; Daiichi Sankyo: Honoraria; Allexion Pharma: Honoraria; CSL Behring: Honoraria. Yamauchi:Astellas, AbbVie: Consultancy; Pfizer, Chugai, Teijin, Solasia: Research Funding. Kiyoi:Daiichi Sankyo Co., Ltd: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Japan Inc.: Honoraria; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Perseus Proteomics Inc.: Research Funding; FUJIFILM Corporation: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding. Miyazaki:Chugai: Research Funding; Otsuka: Honoraria; Novartis: Honoraria; Nippon-Shinyaku: Honoraria; Dainippon-Sumitomo: Honoraria; Kyowa-Kirin: Honoraria.

Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a rare and quite refractory peripheral T-cell lymphoma. The human T-lymphotropic virus type 1 (HTLV-1) retrovirus causes ATLL. Tax protein produced by HTLV-1 has oncogenic activities, and its peptides can be recognized as tumor antigens by the host immune system. Therefore, some immunological approaches to treat ATLL are effective. Mogamulizumab (Moga), an anti-CCR4 monoclonal antibody, and lenalidomide, an immunomodulator, have been recently approved for newly diagnosed and/or relapsed/refractory aggressive ATLL in Japan. However, to date, satisfactory treatment results have not been obtained with these drugs. Before approval of Moga and lenalidomide, VCAP-AMP-VECP (mLSG15) therapy was one of the standard combination chemotherapies for aggressive ATLL. A randomized phase II study comparing Moga plus mLSG15 and mLSG15 alone showed a higher %CR in Moga plus mLSG15 arm but no significant difference in overall survival (OS) between the two arms. In this study, we compared the outcomes of Moga plus EPOCH with those of Moga plus mLSG15. Methods: Aggressive ATLL patients, who were ineligible for hematopoietic stem cell transplantation (HSCT) and were newly diagnosed after June 2000 in our hospital, were retrospectively analyzed. Results: Table 1 summarizes the patient characteristics. Twenty-two patients were treated with Moga plus EPOCH, and 16 were treated with Moga plus mLSG15. There was no significant difference in gender and disease subtype between the groups. Moga-induced skin disorders, such as rash and erythema, were observed in 14 (64%) patients treated with Moga plus EPOCH group and 9 (56%) patients treated within Moga plus mLSG15; the difference was not significant. Figure 1 shows OS of both groups. There was no significant difference (P=0.3092), but a 30% risk reduction was observed in the Moga plus EPOCH group (hazard ratio [HR]: 0.6859, 95% confidence interval [CI]: 0.3165−1.430), though patients treated with Moga plus EPOCH were significantly older than those treated with Moga plus mLSG15 (Table 1). Figure 2 shows OS of patients with and without Moga-induced skin disorders in both groups. The OS of patients with skin disorders was significantly greater than that of those without skin disorders (P Conclusion: Improved OS was observed more frequently in the Moga plus EPOCH group than in the Moga plus mLSG15 group. However, to date, Moga plus chemotherapy has not shown a significant impact on OS for newly diagnosed aggressive ATLL patients in non-HSCT settings, except for patients with Moga-induced skin disorders. Elevation of the Tax-specific CTL percentage was observed in some patients with Moga-induced skin disorders. We previously reported in the 2014 ASH annual meeting that several aggressive ATLL patients, who obtained long-time survival using chemotherapy alone, had maintained Tax-specific CTLs for long periods. Therefore, it might be necessary to induce, up-regulate, and maintain ATLL-specific CTLs to obtain long-time survival. Moga is useful, but insufficient, for inducing such CTLs by suppressing regulatory T-cells. No effective method is available to activate an ATLL-specific cellular immune response. Further studies are urgently needed to establish effective methods for attaining ATLL-specific CTLs. Disclosures No relevant conflicts of interest to declare.

Background The standard of care for first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) is combination treatment with platinum, 5-FU and cetuximab (PFE). However, this regimen requires hospitalization to ensure proper hydration and continuous infusion of 5-FU, and causes severe nausea and anorexia. We evaluated the efficacy and safety of paclitaxel, carboplatin and cetuximab (PCE) as first-line treatment in patients with R/M SCCHN. Patients and methods Eligibility criteria included recurrent and/or metastatic, histologically proven SCC of the oropharynx, oral cavity, hypopharynx or larynx; PS 0-1; adequate organ function; no suitable local therapy for R/M SCCHN; and no prior systemic chemotherapy for R/M SCCHN. Chemotherapy consisted of paclitaxel 100 mg/m2 on days 1, 8; carboplatin area under the blood concentration-time curve 2.5 on days 1, 8, repeated every 3 weeks for up to 6 cycles; and cetuximab at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly until disease progression or unacceptable toxicities. Primary end point was overall response rate. Secondary end points were safety, treatment completion rate, progression-free survival, overall survival, and clinical benefit rate. Planned sample size was 45 patients. Results Forty-seven subjects were accrued from July 2013 to October 2014. Of 45 evaluable, 40 were male; median age was 63 years; Eastern Cooperative Oncology Group Performance Status was 0/1 in 23/22 cases; site was the hypopharynx/oropharynx/oral cavity/larynx in 17/11/10/7 cases; and 36/9 cases were smokers/nonsmokers, respectively. Overall response rate, the primary end point, was 40%. Median overall survival was 14.7 months and progression-free survival was 5.2 months. Grade 3/4 adverse events included neutropenia (68%), skin reaction (15%), fatigue (9%) and febrile neutropenia (9%). A potentially treatment-related death occurred in one patient with intestinal pneumonia. Conclusions The PCE regimen shows promising activity with acceptable toxicity in the outpatient clinic. Further studies are needed to compare PCE with PFE in this population. Registered clinical trial number UMIN000010507.

Adult T-cell leukemia–lymphoma (ATL) is an intractable hematopoietic malignancy with a very poor prognosis. Although improved responses have been achieved through intensive chemotherapy in newly diagnosed patients with aggressive ATL, most patients suffer from relapse or disease recurrence, and an effective salvage therapy, especially for candidates for allogeneic hematopoietic stem cell transplantation (allo-HSCT), is yet to be established. The efficacy of the EPOCH regimen has been reported for several lymphoid malignancies; however, its efficacy for ATL has not been sufficiently evaluated. Here, we report results of a study of the EPOCH regimen as a salvage therapy for ATL. We retrospectively analyzed patients with relapsed or refractory ATL treated in our institution, with EPOCH as a first salvage therapy. Fourteen patients with a median age of 58 years were analyzed, among whom eight achieved a response, including a complete response in one patient and partial responses in seven. Seven patients underwent allo-HSCT after EPOCH therapy; however, the median overall survival (OS) could not be determined, whereas OS at 2 years after allo-HSCT was estimated to be 85.7%. These results suggest that EPOCH is an option for salvage therapy in patients with ATL, including candidates for allo-HSCT.

Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/μL for NK cells and 347/μL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP.

A multicenter retrospective study was performed to determine the significance of adding cytarabine (CA) or thiotepa (TT) in the context of total body irradiation (TBI) and cyclophosphamide (CY). A total of 322 patients who underwent allogeneic hematopoietic cell transplantation (HCT) were distributed to the following three groups: TBI/CY (n = 75), TBI/CY/CA (n = 77), and TBI/CY/TT (n = 170). In the TBI/CY/TT group, 164 of patients (96 %) received HCT during the previous year (2000-2005). Multivariate analysis revealed that the TBI/CY/TT group demonstrated a trend of poorer survival rate than the TBI/CY group, [hazard ratio (HR) = 1.49, 95 % confidence interval (CI) 0.99-2.24, P = 0.055] with a higher non-relapse mortality (NRM) (HR = 2.34, 95 % CI 1.35-4.06, P = 0.002) rates, while TBI/CY/CA group demonstrated similar outcomes. Even in the subgroup analyses of disease type or disease risk, the outcomes with intensified conditioning regimens were not superior to those with TBI/CY. In conclusion, although the significant bias has to be carefully considered, the clinical benefit of adding CA or TT to the TBI/CY regimen was not demonstrated.

The aim of this study was to evaluate the feasibility of induction docetaxel, cisplatin, and 5-fluorouracil chemotherapy followed by concurrent weekly cisplatin chemoradiotherapy for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Between 2010 and 2013, 30 patients with Stage IV HNSCC were treated in Hokkaido University Hospital with three cycles of induction chemotherapy (docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2), day 1; and 5-fluorouracil 750 mg/m(2)/day 120 h continuous infusion, every 3 weeks) followed by concurrent weekly cisplatin (40 mg/m(2), on weeks 1, 2, 3, 5, 6 and 7) chemoradiotherapy. Three courses of induction chemotherapy were performed in 25 patients (83 %) with grade 3-4 toxicities during induction chemotherapy observed in 22 patients (73 %). The major toxicities were hematologic, with 22 cases (73 %) showing grade 3-4 neutropenia. Radiotherapy was completed (70 Gy) in 29 patients (97 %), while a total of 19 patients (63 %) completed five (13 patients) or six (6 patients) courses of chemotherapy. During concurrent chemoradiotherapy, no grade 4 hematological toxicities were observed. Grade 4 dermatitis was observed in one patient, and grade 3 mucositis was observed in 12 patients. There were no treatment-related deaths during the induction chemotherapy or concurrent chemoradiotherapy. The 1- and 2-year progression-free survival rates and the 1- and 2-year overall survival rates were 86 %, 72 %, and 89 %, 81 %, respectively. Sequential therapy composed of induction chemotherapy followed by concurrent weekly cisplatin chemoradiotherapy is feasible, showing encouraging results in patients with locally advanced HNSCC. Concurrent weekly cisplatin chemoradiotherapy following induction chemotherapy appears to be a suitable alternative to three-weekly high-dose cisplatin therapy.

This prospective study aimed to investigate the influence of pretransplant serum ferritin levels on the outcomes of allogeneic hematopoietic SCT (HSCT). In total, 190 patients with acute leukemia or myelodysplastic syndrome were consecutively enrolled. The patients were divided into two groups: low-ferritin group (

Objective Myelodysplastic syndromes (MDS) are a group of hematological neoplasms associated with ineffective hematopoiesis and that transform to acute leukemia. Distinguishing MDS from other cytopenias is sometimes difficult even for trained hematologists. WT1, the gene mutated in Wilms’ tumor, was found expressed in acute myeloid leukemia and MDS. The amount of WT1 in peripheral blood and bone marrow (BM) is low in low-risk MDS subtypes, and is high in high-risk MDS subtypes. However, the role of WT1 in the differential diagnosis between MDS and other diseases showing cytopenia has not been fully addressed. The present study evaluated whether WT1 expression level can assist in the differential diagnosis of MDS from other cytopenias. Methods The amount of WT1 message was evaluated among 56 MDS patients and 47 patients with cytopenia for various other reasons (cytopenia VR) at the Nagasaki University Hospital. Results The level of WT1 was significantly related to the percentage of blasts in BM among MDS cases, and the type of French-American-British classification of MDS; refractory anemia (RA) cases showed significantly lower WT1 level than patients with RA with excess blasts. WT1 level was significantly related to the prognostic risk categories of MDS by the International Prognostic Scoring System (IPSS) and the revised IPSS. Although the blast percentage in the BM of RA and cytopenia VR were both less than 5%, there was a significant difference in the level of WT1 between MDS and cytopenia VR. Conclusion WT1 might be a good marker to differentiate low blast percentage MDS and cytopenia VR., Internal Medicine, 54(5), pp.445-451; 2015

Donor cell-derived leukemia is a rare, but severe complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dozens of cases of donor cell-derived acute myeloid leukemia and my...

Adult T-cell leukemia-lymphoma is a distinct type of peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I. Although allogeneic stem cell transplantation after chemotherapy is a recommended treatment option for patients with aggressive adult T-cell leukemia-lymphoma, there is no consensus about indications for allogeneic stem cell transplantation because there is no established risk stratification system for transplant eligible patients. We conducted a nationwide survey of patients with aggressive adult T-cell leukemia-lymphoma in order to construct a new, large database that includes 1,792 patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who were diagnosed between 2000 and 2013 and received intensive first-line chemotherapy. We randomly divided patients into two groups (training and validation sets). Acute type, poor performance status, high soluble interleukin-2 receptor levels (> 5,000 U/mL), high adjusted calcium levels (≥ 12 mg/dL), and high C-reactive protein levels (≥ 2.5 mg/dL) were independent adverse prognostic factors used in the training set. We used these five variables to divide patients into three risk groups. In the validation set, median overall survival for the low-, intermediate-, and high-risk groups was 626 days, 322 days, and 197 days, respectively. In the intermediate- and high-risk groups, transplanted recipients had significantly better overall survival than non-transplanted patients. We developed a promising new risk stratification system to identify patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who may benefit from upfront allogeneic stem cell transplantation. Prospective studies are warranted to confirm the benefit of this treatment strategy.

The International Harmonization Project on Lymphoma recommends 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) for the routine assessment of treatment efficacy in patients with FDG-avid lymphomas such as Hodgkin’s and diffuse large B cell lymphomas. The utility of FDG-PET in predicting outcomes in patients with peripheral T cell lymphomas (PTCL) has not been fully elucidated. We retrospectively determined the predictive value of FDG-PET after first-line treatment (post-PET) for outcome in PTCL. Of the 36 patients enrolled, 16 were histologically diagnosed with PTCL not otherwise specified and 20 were diagnosed with angioimmunoblastic T cell lymphoma. All patients received curative-intent anthracycline-containing chemotherapy regimens. Post-PET images were visually evaluated by local nuclear medicine physicians. The median observation period for the surviving patients was 44 months. Positive and negative post-PET results were obtained in 31 % (11/36) and 69 % (25/36) of patients, respectively. The 3-year progression-free survival rates in the positive and negative post-PET result groups were 18 % and 62 %, respectively (P < 0.001). Nine of the 11 patients in the positive post-PET result group experienced progressive disease (PD) (positive predictive value, 82 %), whereas 16 of the 25 patients in the negative post-PET result group did not experience PD (negative predictive value, 64 %). The 3-year overall survival rates in the positive and negative post-PET result groups were 44 % and 84 %, respectively (P = 0.03). Our findings indicate that post-PET is predictive of outcome in patients with PTCL.

This study evaluated the efficacy of central nervous system (CNS) prophylaxis using intrathecal methotrexate (IT-MTX) in patients with diffuse large B-cell lymphoma (DLBCL). We retrospectively studied 322 patients who achieved first complete remission (CR) after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. The CNS prophylaxis consisted of four doses of IT-MTX (15 mg) with hydrocortisone (25 mg) administered after CR was achieved. Forty patients (12%) received CNS prophylaxis (group A) and 282 patients (88%) did not (group B). Three patients in group A (8%) and eight in group B (3%) experienced isolated CNS relapse during the first CR, although this difference was not statistically significant (p = 0.14). Ten of 11 CNS relapses occurred in the brain parenchyma with (n = 3) or without (n = 7) leptomeningeal involvement, and the remaining patient had exclusive leptomeningeal involvement. In patients with DLBCL attaining CR after R-CHOP, IT-MTX administration was insufficient to prevent CNS relapse.

To clarify the significance of post-transplant serum ferritin (SF), we retrospectively assessed pre- and post-transplant SF. Among 256 patients undergoing allogeneic stem cell transplant (SCT) for hematologic malignancies between 2000 and 2011, those who had relapsed within 1 year were excluded, and 110 patients surviving for more than 1 year were included in the analysis. The cut-off value of SF was 1000 ng/mL, and four pre- and post-SF groups were defined: low-low (n = 62), low-high (n = 12), high-low (n = 13) and high-high (n = 23). Outcomes at 5 years for each group were as follows: overall survival (OS) 88.2, 38.1, 92.3 and 76.7%, respectively, p = 0.004, and non-relapse mortality (NRM) 11.3, 53.6, 7.7 and 18.9%, respectively, p = 0.037. Patients receiving larger transfusion volumes or developing chronic graft-versus-host disease (GVHD) demonstrated higher 1-year SF values. In multivariate analysis for OS and NRM, low-high SF remained a significant predictor of OS (hazard ratio [HR] = 3.49, 95% confidence interval [CI]: 1.10-11.0, p = 0.032) and NRM (HR = 2.95, 95%CI: 1.04-8.36, p = 0.041). These results suggest that the elevation of SF at 1 year after SCT, which may reflect transfusion and the development of chronic GVHD, may have an aggravating influence on outcomes after SCT. This study provides a clue to clarifying the clinical significance of SF in a transplant setting.

Background Although rituximab added to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) is the standard chemotherapy for untreated DLBCL, its therapeutic effect is limited in younger patients with high-intermediate risk or high-risk disease according to the age-adjusted international prognostic index. In fact, the efficacy and safety of HDT plus rituximab followed by ASCT for such patients remain unclear. Patients and Methods We retrospectively investigated the safety and effectiveness of HDT/ASCT in patients with untreated DLBCL. Twenty-two patients, aged 60 years and younger, with untreated DLBCL (classified as high-intermediate [n = 14 (64%)] or high [n = 8 (32%)] risk) underwent upfront HDT/ASCT between January 2004 and December 2008, achieving either a complete response (CR; n = 15 (68%)) or a partial response (PR; n = 7 (32%)). Results The 5-year overall survival rate was 81.0% and the progression-free survival rate was 73.0%, with no significant difference between risk groups based on the international prognostic index. The most common nonhematologic toxicity was febrile neutropenia [n = 9 (41%)]. The cause of all 3 fatalities was exacerbation of the underlying disease, and no treatment-related mortality was observed. No variables with a significant influence on overall survival were identified, but a correlation of the treatment response before transplanation with progression-free survival was suggested (CR vs. PR: 92% vs. 30%, P = .002). Conclusion These results suggest that adding rituximab to upfront HDT/ASCT is feasible and can improve the outcome in untreated patients with poor-prognosis DLBCL. In the future, upfront HDT/ASCT should be more extensively evaluated in clinical trials.

It has been reported that cord blood transplantation (CBT) for patients with aggressive adult T-cell leukemia/ lymphoma (ATL) results in poorer outcomes than transplantation using other stem cell sources. To identify a subset of ATL in which CBT is feasible, we retrospectively analyzed 27 patients treated with CBT at three institutions in Nagasaki Prefecture, Japan. The estimated overall survival (OS) rate at 3 years was 27.4 %. Of 16 patients who received CBT during remission (complete, CR, or partial, PR), the OS rate at 3 years was 50 %, while during refractory periods (non-CR or non-PR), the OS rate was 9.1 %. Reduced intensity conditioning (RIC) was given to 18 patients, and myeloablative conditioning (MAC) was used in nine, with 3-year OS of 50.0 and 0 %, respectively. Of the 19 deaths, nine were due to progressive disease, eight (five MAC and three RIC) to infection, and two to multiple organ failure. These results suggest that CBT provides similar results with those in other transplantation procedures for selected ATL patients, such as those in CR or PR. Further studies are needed to evaluate the use of CBT in aggressive ATL., International Journal of Hematology, 97(4), pp.485-490; 2013

Abstract 1630 Background: In almost all cases, follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are CD20 positive. Since the introduction of rituximab (R), the outcome of the patients with FL or DLBCL has improved perceptively. Since 2001 and 2003, the Yokohama City University Hematology Group in Japan has uniformly treated FL and DLBCL patients, respectively, with 6 cycles of standard (21 days) R-CHOP therapy with curative intent, except in the case of stage 1 FL. Here, we report our experience. Patients and Methods: Five hundred and twenty-six untreated consecutive patients (158, FL; 368, DLBCL) between 2001 and 2009 were the subjects of this study. All the patients were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP in our 7 hospitals. Patients who had partial remission (PR) after the 4 initial cycles were administered a total of 8 R-CHOP cycles. Patients who did not achieve PR after the 4 initial R-CHOP cycles or those with disease progression at any given time received salvage therapy, and that time point was designated as the point at which the disease had started progressing. Patients who required more than 20% dose reduction were excluded from the study. Those with special forms of DLBCL, such as intravascular lymphoma, primary mediastinal large B-cell lymphoma, and T-cell-rich B-cell lymphoma, were also excluded. Additional local irradiation was performed in patients with PR or complete remission (CR) if deemed necessary by the attending physician. No patients received maintenance therapy with R. DLBCL patients who achieved CR but were initially at risk of central nervous system (CNS) involvement received methotrexate (15 mg) and hydrocortisone (25 mg) 4 times intrrathecally for CNS prophylaxis. Central pathological reviews were not performed; only the individual institutional diagnoses were used. Results: In the cases of FL, the pathological grading was grade 1 for 65 patients, grade 2 for 61 patients, grade 3a for 20 patients, and grade 3b for 12 patients. There were 81 men and 77 women, and the median age at diagnosis was 57 years (range, 25–76). In accordance with the International Prognostic Index (IPI), 60 patients were at low risk (L); 60, at low-intermediate risk (LI); 26, at high-intermediate risk (HI); and 12, at high risk (H). According to the Follicular Lymphoma IPI, 43 patients were classified as L; 49, as being at intermediate risk; and 59, as H. For 7 patients, the risk was undetermined. Ten patients received additional local irradiation in PR/CR at the end of the R-CHOP therapy. None received CNS prophylaxis. Twelve deaths were observed among the FL patients, 10 of which were due to the lymphoma. In the DLBCL group, there were 209 men and 159 women, and the median age at diagnosis was 64 years (range, 18–80). According to the IPI, 158 patients were classified as L; 93, as LI; 57, as HI; and 60, as H. Thirty-seven patients received additional local irradiation in PR/CR at the end of the R-CHOP therapy. CNS prophylaxis was performed in 42 patients who had an initial CNS risk and achieved CR. In the observaton period, there were 58 deaths among the DLBCL patients, 50 of which were due to the lymphoma. The median observation period for the living patients with FL and DLBCL was 45 months and 43 months, respectively. For the FL group, the CR, 5-year progression-free survival (PFS), and 5-year overall survival (OS) rates were 86%, 50%, and 92%, respectively. Between patients with grade 1–2 FL, and grade 3 FL, the PFS (P = 0.16) and OS (P = 0.17) were not significantly different. This was found to also be true when the PFS (P = 0.19) and OS (P = 0.32) of grade 1–3a and grade 3b FL patients were compared. For the DLBCL group, the CR, 5year PFS, and 5-year OS rates were 89%, 72%, and 80%, respectively. The PFS rate was significantly higher in the DLBCL group compared to the FL group (Fig 1(A), P = 0.001), but the OS was significantly greater in the FL group (Fig 1(B), P = 0.006). Conclusion: Standard R-CHOP therapy is effective for patients with FL and DLBCL, with the 5-year OS rate exceeding 80% for both. However, in the FL group, the PFS did not show a plateau, suggesting the incurability of this lymphoma with R-CHOP therapy. The good OS indicated the effectiveness of salvage therapy for FL patients. Since the OS and PFS in patients with grade 3 FL were similar to those in patients with grade 1–2 FL, all grades of FL should probably be categorized simply as “FL” with regard to R-CHOP therapy. Disclosures: No relevant conflicts of interest to declare.

The prognosis for disease relapse after first hematopoietic cell transplantation (HCT1) is poor. Here, we present a retrospective multicenter study to evaluate the clinical outcome and the prognostic factors for second hematopoietic cell transplantation (HCT2). The cohort in this study comprised 60 patients diagnosed with acute leukemia, who underwent HCT2 due to hematological relapse after HCT1. The overall survival (OS) at two years, non-relapse mortality (NRM), and relapse mortality (RM) were 30.3%, 40.9%, and 28.8%, respectively. Multivariate analysis for OS identified the use of a donor other than matched-related (MR) donor (hazard ratios [HR] = 4.10, 95% confidence intervals [CI]: 1.72-9.74, p = .001) and high disease status (HR = 2.90, 95% CI: 1.28-6.56, p = .011) as the adverse risk factors for HCT2. On analyzing the combination of factors during HCT1 and HCT2, MR donor, reduced intensity conditioning regimen, and standard status were found to be significant as favorable prognostic factors for OS. Therefore, evaluating these prognostic factors would be helpful in taking decisions regarding post-relapse management.

We previously developed a prognostic index, SIL, which includes advanced stage (S), soluble interleukin-2 receptor level (I), and elevated lactate dehydrogenase level (L) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, hydroxydaunomycin, oncovin, and prednisone (R-CHOP). This time we evaluated the index in a larger cohort and its utility in the risk stratification. The above three factors were independent risk of progression-free survival (PFS). Five-year PFS rates in the standard-risk (SIL index: 0 or 1, n = 367) and high-risk groups (SIL index: 2 or 3, n = 205) were 79% and 53%, respectively (p 0.0001). When the patients were divided by age (≤60 years and60 years), the SIL index was a good prognostic indicator for PFS in both groups as well as divided by the number of extranodal involvement site (0-1 and1). The SIL index is a simple and objective prognostic indicator in DLBCL.

We verified the association between standard clinical and laboratory variables and the risk of relapse in acute myeloid leukemia (AML), which led us to retrospectively examine the effect of regeneration of hematopoiesis in patients with newly diagnosed AML. We used data from 230 patients who obtained remission after cytarabine-based induction chemotherapy. Platelet counts ≥500 × 109/L and hemoglobin levels ≥9 g/dL on day 28 after treatment initiation were significantly associated with relapse-free survival (RFS) rate, conferring respective multivariate risk ratios of 0.38 (95% CI: 0.18–0.79) and 0.60 (95% CI: 0.40–0.89) for the occurrence of relapse or death. No disease relapse occurred in core binding factor leukemia patients whose platelet counts recovered ≥500 × 109/L at 28 days after therapy initiation. We conclude that regeneration of hematopoiesis, especially platelet hyper-recovery, after induction chemotherapy is a significant predictor of RFS in patients with AML.

A 53-year-old man was diagnosed with adult T-cell leukemia-lymphoma (ATL) acute type transformed from chronic type. A bone marrow analysis showed diffuse infiltration of abnormal lymphocytes and diffuse fibrotic change. He received unrelated cord blood transplantation (CBT) following reduced-intensity conditioning with complete remission of ATL after two courses of chemotherapy and achieved neutrophil and platelet engraftment. At 99 days after CBT, a bone marrow biopsy showed apparent resolution of myelofibrosis. These results suggest the therapeutic potential of CBT for patients with chemosensitive ATL with myelofibrosis., Internal Medicine, 55(2), pp.197-201; 2016

Rituximab (R) plus doxorubicin, cyclophosphamide, vincristine, and prednisolone (CHOP) chemotherapy (R‐CHOP) is widely accepted as standard care for diffuse large B‐cell lymphoma (DLBCL) patients. The revised International Prognostic Index (R‐IPI) was established in 2007 after the addition of rituximab to standard DLBCL treatment. To reassess the utility of R‐IPI, we carried out a retrospective analysis of patients with DLBCL uniformly treated with standard R‐CHOP. Progression‐free survival (PFS) curves in “very good” and “good” risk groups as defined by the R‐IPI showed no statistical difference. We added soluble interleukin‐2 receptor (sIL‐2R) level to the factors comprising the R‐IPI. Five levels of sIL‐2R were weighed with respect to their impact on PFS. sIL‐2R of >2500 U/mL was determined as the most appropriate threshold. We developed a new prognostic SIL index, which includes three independent prognostic risk factors: clinical stage (S); sIL‐2R level over 2500 U/mL (I); and elevated lactate dehydrogenase level (L). This index indicates standard risk (0 or 1 risk factors, 4‐year PFS 83%, 4‐year overall survival 91%) and high risk (2 or 3 risk factors, 4‐year PFS 52%, 4‐year overall survival 67%) outcomes. The SIL index is a simple and objective prognostic index for DLBCL patients to identify candidates for experimental therapy other than R‐CHOP. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02331.x, 2012)

BCX1777 (forodesine), a novel purine nucleoside phosphorylase inhibitor, induces apoptosis, mainly in T cells. To evaluate the safety, tolerability, and pharmacokinetics of BCX1777, we conducted a phase I study in patients with relapsed or refractory peripheral T/natural killer‐cell malignancies. Eligible patients had relapsed or refractory peripheral T/natural killer‐cell malignancies without any major organ dysfunction. BCX1777 was administered orally once daily (dose escalation: 100, 200, and 300 mg) until disease progression requiring new therapy or unacceptable adverse events occurred. A total of 13 patients were enrolled and treated in three dose cohorts (100 mg/day, five patients; 200 mg/day, three patients; 300 mg/day, five patients). Although none of the patients developed dose‐limiting toxicities, further dose escalation was not performed based on data from overseas. Therefore, the maximum tolerated dose was not determined. Adverse events of grade 3 or greater (≥2 patients) included lymphopenia (62%), anemia (15%), leukopenia (8%), and pyrexia (8%). Plasma pharmacokinetics parameter of BCX1777 (area under the plasma concentration‐time curve) at day 1 in each cohort was 1948 ± 884, 4608 ± 1030, and 4596 ± 939 ng•h/mL, respectively. Disease control was achieved in approximately half of patients. One patient with anaplastic large cell lymphoma, which was negative for anaplastic lymphoma kinase, achieved a complete response, and two patients with cutaneous T‐cell lymphoma achieved partial responses. BCX1777 was well tolerated at doses up to 300 mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer‐cell malignancies, warranting further investigation. (Cancer Sci 2012; 103: 1290–1295)