An observational study of once-weekly carfilzomib in patients with multiple myeloma in Japan (Weekly-CAR study).

Background: The ARROW study demonstrated that once-weekly carfilzomib and dexamethasone (wKd) therapy significantly prolonged progression-free survival compared with twice-weekly carfilzomib and dexamethasone therapy in relapsed or refractory multiple myeloma patients. Aim: To describe the treatment patterns, effectiveness and safety of wKd therapy in real-world settings in Japan. Methods: We investigated data from the medical records of 126 Japanese patients with relapsed or refractory multiple myeloma. Results: The overall response rate was 66.3%. The median progression-free survival was 9.5 months. The incidence of treatment-emergent adverse events of any grade and grade ≥3 were 45.8 and 20.8%, respectively. Conclusion: There were no new or unexpected safety signals in this study. This study demonstrated the effectiveness and safety profiles of wKd therapy in Japan.

Carfilzomib became available for daily clinical practice as a drug for cancer of bone marrow (multiple myeloma) that comes back or does not respond to previous drug (relapsed or refractory). This drug was approved in the USA in 2012, and in Japan in 2016. In this study, we looked at how once-weekly carfilzomib works and how safe it is in real-life situations in Japan. We screened 126 patients with relapsed or refractory multiple myeloma in Japan. The median age of the patients was 70 years, with 25% being over 75 years. This study also included some patients who were not in the best overall health, had a history of many treatments or had heart complications. In 66.3% of patients, the cancer had disappeared or the extent of the cancer had reduced after treatment. Side effects and serious side effects occurred in 45.8 and 14.2% of patients, respectively. The most common side effects were low levels of blood platelets (9.2%), high blood pressure (5.8%), loose or watery stools (5.0%), fever (5.0%), and low levels of red blood cells (4.2%). Heart disorders occurred in five patients. But all patients recovered or improved with treatment such as blood pressure lowering drugs and diuretics. These results showed that once-weekly carfilzomib works well and is safe in real-world settings in Japan. This information can help us think about how to pick the right patients and handle heart disease risks when using carfilzomib treatment.

Live attenuated VZV vaccination induces antitumor immunity in ATLL patients.

Adult T cell leukemia/lymphoma (ATLL) is a CD4-positive peripheral T cell lymphoma caused by human T cell lymphotropic virus type 1 (HTLV-1). Although ATLL is quite difficult to be cured, up-regulation of cellular immunity such as HTLV-1 Tax-specific cytotoxic T lymphocytes (CTLs) has been proved to be important to obtain long-term survival. At present, no efficacious method to activate ATLL-specific cellular immunity is available. This study aimed to investigate whether live attenuated varicella-zoster virus (VZV) vaccination to ATLL can activate HTLV-1 Tax-specific cellular immune response. A total of 3 indolent- and 3 aggressive-type ATLL patients were enrolled. All aggressive-type patients had the VZV vaccination after completing anti-ATLL treatment including mogamulizumab, which is a monoclonal antibody for C-C chemokine receptor 4 antigen, plus combination chemotherapy, whereas all indolent-type patients had the VZV vaccination without any antitumor treatment. Cellular immune responses including Tax-specific CTLs were analyzed at several time points of pre- and post-VZV vaccination. After the VZV vaccination, a moderate increase in 1 of 3 indolent-type patients and obvious increase in all 3 aggressive-type patients in Tax-specific CTLs percentage were observed. The increase in the cell-mediated immunity against VZV was observed in all indolent- and aggressive-type patients after VZV vaccination. To conclude, VZV vaccination to aggressive-type ATLL patients after mogamulizumab plus chemotherapy led to the up-regulation of HTLV-1 Tax-specific CTLs without any adverse event. Suppression of regulatory T lymphocytes by mogamulizumab may have contributed to increase tumor immunity in aggressive-type ATLL patients. Japan Registry of Clinical Trials number, jRCTs051180107.

Oral histone deacetylase inhibitor tucidinostat (HBI-8000) in patients with relapsed or refractory adult T-cell leukemia/lymphoma: Phase IIb results.

This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI-8000) in patients with relapsed or refractory (R/R) adult T-cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty-three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end-point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression-free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.

Clinical significance of the immunoglobulin G heavy-chain repertoire in peripheral blood mononuclear cells of adult T-cell leukaemia-lymphoma patients receiving mogamulizumab.

'Monitoring of immune responses following mogamulizumab-containing treatment in patients with adult T-cell leukaemia-lymphoma (ATL)' (MIMOGA) is a multicentre prospective clinical study (UMIN000008696). In the MIMOGA study, we found that a lower percentage of CD2- CD19+ B cells in peripheral blood mononuclear cells (PBMC) was a significant unfavourable prognostic factor for overall survival (OS). Accordingly, we then analysed the immunoglobulin G (IgG) heavy-chain repertoire in PBMC by high-throughput sequencing. Of the 101 patients enrolled in the MIMOGA study, for 81 a sufficient amount of PBMC RNA was available for repertoire sequencing analysis. Peripheral IgG B cells in patients with ATL had a restricted repertoire relative to those in healthy individuals. There was a significant positive correlation between the Shannon-Weaver diversity index (SWDI) for the IgG repertoire and proportions of B cells in the PBMC of the patients. Multivariate analysis identified two variables significantly affecting OS: a higher serum soluble interleukin-2 receptor level, and a lower SWDI for the IgG repertoire [hazard ratio, 2·124; 95% confidence interval, 1·114-4·049; n = 44]. The present study documents the importance of humoral immune responses in patients receiving mogamulizumab-containing treatment. Further investigation of strategies to enhance humoral immune responses in patients with ATL is warranted.

No clear survival benefit of azacitidine for lower-risk myelodysplastic syndromes: A retrospective study of Nagasaki.

The efficacy of azacitidine (AZA) on survival of lower risk (LR) - myelodysplastic syndromes (MDS) is controversial. To address this issue, we retrospectively evaluated the long-term survival benefit of AZA for patients with LR-MDS defined by International Prognostic Scoring System (IPSS). Using data from 489 patients with LR-MDS in Nagasaki, hematologic responses according to International Working Group 2006 and overall survival (OS) were compared among patients that received best supportive care (BSC), immunosuppressive therapy (IST), erythropoiesis-stimulating agents (ESA), and AZA. Patients treated with AZA showed complete remission (CR) rate at 11.3%, marrow CR at 1.9%, and any hematologic improvement at 34.0%, with transfusion independence (TI) of red blood cells in 27.3% of patients. and platelet in 20% of patients, respectively. Median OS for patients received IST, ESA, BSC, and AZA (not reached, 91 months, 58 months, and 29 months, respectively) differed significantly (P < .001). Infection-related severe adverse events were observed in more than 20% of patients treated with AZA. Multivariate analysis showed age, sex, IPSS score at diagnosis, and transfusion dependence were significant for OS, but AZA treatment was not, which maintained even response to AZA, and IPSS risk status at AZA administration was added as factors. We could not find significant survival benefit of AZA treatment for LR-MDS patients.

Prognostic index for chronic- and smoldering-type adult T-cell leukemia-lymphoma.

Adult T-cell leukemia-lymphoma (ATL) has been divided into 4 clinical subtypes: acute, lymphoma, chronic, and smoldering. The aim of this study is to develop a novel prognostic index (PI) for chronic and smoldering ATL. We conducted a nationwide retrospective survey on ATL patients, and 248 fully eligible individuals were used in this analysis. In the univariate analysis, sex, performance status, log10 (soluble interleukin-2 receptor [sIL-2R]), neutrophils count, and lymphadenopathy showed values of P < .05 in training samples. A multivariate analysis was performed on these factors, and only log10 (sIL-2R) was identified as an independent prognostic factor in training samples. Using a regression coefficient of this variable, a prognostic model was formulated to identify different levels of risk: indolent ATL-PI (iATL-PI) = 1.51 × log10 (sIL-2R [U/mL]). The values calculated by iATL-PI were divided into 3 groups using a quartile point. In the validation sample, median survival times (MSTs) were 1.6 years, 5.5 years, and not reached for patients in the high-, intermediate-, and low-risk groups, respectively (P < .0001). To make the scoring system clinically practicable, we simplified iATL-PI according to trichotomizing sIL-2R at 1000 and 6000 U/mL, using a quartile point. Patients with more than 6000 U/mL sIL-2R were categorized into the high-risk group, less than and equal to 1000 U/mL into the low-risk group, and the others into the intermediate-risk group, and MSTs were 1.6 years, not reached, and 5.5 years, respectively (P < .0001). iATL-PI has potential as a novel tool for a risk-adapted therapeutic approach.

Chromosomal analysis of myelodysplastic syndromes among atomic bomb survivors in Nagasaki.

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 (<1·5 km from the hypocentre), chromosomal translocations and inversions were more frequent, and the frequency of structural alterations in chromosomes 3, 8, and 11 was significantly increased compared with unexposed cases. These results suggest that chromosomal alterations in MDS among survivors have different features compared with those in de novo or therapy-related MDS. Detailed molecular study is warranted.

Mogamulizumab for relapsed adult T-cell leukemia-lymphoma: Updated follow-up analysis of phase I and II studies.

The present study sought to elucidate the prognosis of adult T-cell leukemia-lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti-CCR4 monoclonal antibody. Progression-free survival (PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T-cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived >3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1-year PFS was 26%, whereas median OS was 14.4 months, and 3-year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1-year PFS was zero, with a median OS of 6.0 months, and 3-year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1-year PFS was 50%, with a median OS of 25.6 months, and 3-year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune-related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab.

Treatment and survival among 1594 patients with ATL.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes caused by human T-lymphotropic virus type I. Intensive combination chemotherapy and allogeneic hematopoietic stem cell transplantation have been introduced since the previous Japanese nationwide survey was performed in the late 1980s. In this study, we delineated the current features and management of ATL in Japan. The clinical data were collected retrospectively from the medical records of patients diagnosed with ATL between 2000 and 2009, and a total of 1665 patients' records were submitted to the central office from 84 institutions in Japan. Seventy-one patients were excluded; 895, 355, 187, and 157 patients with acute, lymphoma, chronic, and smoldering types, respectively, remained. The median survival times were 8.3, 10.6, 31.5, and 55.0 months, and 4-year overall survival (OS) rates were 11%, 16%, 36%, and 52%, respectively, for acute, lymphoma, chronic, and smoldering types. The number of patients with allogeneic hematopoietic stem cell transplantation was 227, and their median survival time and OS at 4 years after allogeneic hematopoietic stem cell transplantation was 5.9 months and 26%, respectively. This study revealed that the prognoses of the patients with acute and lymphoma types were still unsatisfactory, despite the recent progress in treatment modalities, but an improvement of 4-year OS was observed in comparison with the previous survey. Of note, one-quarter of patients who could undergo transplantation experienced long survival. It is also noted that the prognosis of the smoldering type was worse than expected.

Clinical features and prognosis of patients with myelodysplastic syndromes who were exposed to atomic bomb radiation in Nagasaki.

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 <1.5 km, 35 at 1.5-2.99 km, and 74 at ≥3.0 km. By the end of March 2014, 47 patients (34%) progressed to overt leukemia and 106 (75.7%) died. By comparing with patients exposed at ≥3.0 km, those exposed at <1.5 km had significantly higher frequencies of abnormal chromosome (P = 0.02), intermediate/poor IPSS, and intermediate/poor/very poor IPSS-R cytogenetic category (P = 0.0001, and P < 0.0001, respectively). As with de novo MDS, multivariate Cox regression analyses revealed that cytogenetic abnormalities, IPSS karyotype, and IPSS-R cytogenetics were significantly associated with poor survival, and cumulative incidence of leukemic transformation in MDS among atomic bomb survivors, but exposure distance was not associated with any poor outcomes. These suggest that exposure to the greater dose of atomic bomb radiation is associated with developing poor cytogenetic abnormalities in MDS, which might consequently lead to overt leukemia among atomic bomb survivors.

Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study.

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

HTLV-1 Tax-specific memory cytotoxic T lymphocytes in long-term survivors of aggressive-type adult T-cell leukemia/lymphoma.

PURPOSE: Adult T-cell leukemia/lymphoma (ATLL) is a relatively refractory peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type 1 (HTLV-1). The objective of this study was to investigate the characteristics of long-term survivors with ATLL. METHODS: We conducted an observational study of 75 aggressive-type ATLL patients. Flow cytometry was conducted to analyze HTLV-1 Tax-specific cytotoxic T-lymphocytes (CTLs) and T-cell receptor Vß gene repertoire. RESULTS: We first evaluated six long-term survivors among 37 patients who were newly diagnosed with ATLL and then treated with intensive chemotherapy without mogamulizumab, a monoclonal antibody for C-C chemokine receptor four antigen. Reversal of the CD4-to-CD8 ratio (CD4/CD8) in peripheral mononuclear cells was observed in all six patients. Three of these six patients showed reversed CD4/CD8 immediately after herpes virus infection. Four of these six patients who could be examined demonstrated long-term maintenance of HTLV-1 Tax-specific CTLs. We subsequently identified four long-term survivors among 38 patients who were newly diagnosed with ATLL and then treated with intensive chemotherapy plus mogamulizumab. All four patients showed reversed CD4/CD8, and three of the four patients contracted herpes virus infection during immunochemotherapy. Six of the total 10 patients were subjected to CTL analyses. Tax-specific CTLs were observed, and the CTLs that were almost entirely composed of memory CTLs in all patients were recorded. HTLV-1 provirus was also detected in all six patients. CONCLUSIONS: These data suggest that Tax-specific memory CTLs probably, together with anticancer agents, eradicate ATLL cells and exhibit long-term preventive effects from relapse ATLL. Thus, the strong activation of cellular immunity, such as herpes virus infection, seems to be necessary to induce such a potent number of Tax-specific CTLs.

Clonal Upregulation of Effector Cytotoxic T Lymphocytes in a Patient with Multiple Tyrosine Kinase Inhibitor-Refractory Chronic Myeloid Leukemia with Long-Term Survival.

We present the case of a patient with multiple tyrosine kinase inhibitor (TKI)-refractory chronic phase chronic myeloid leukemia (CP-CML) with a T315I mutation of abl1. Dasatinib, a second-generation TKI, was administered as the initial treatment but achieved neither a cytogenetic nor molecular response. A mutational analysis of abl1 revealed that the patient had a T315I mutation. The patient was then administered ponatinib, a third-generation TKI, which is thought to be effective against T315I; however, the complete blood counts became within normal limits, and neither a cytogenetic nor molecular response was achieved. However, the patient has maintained a healthy chronic phase (with no blast crises) for more than 5½ years since the diagnosis of CP-CML. T-cell receptor (TCR) repertoire analyses using peripheral blood revealed a remarkable clonal expansion of effector cytotoxic T lymphocytes (CTLs) that contained TCR V beta 13.6. We observed the clonal expansion of naïve CTLs with TCR V beta 13.6; however, no clonality was observed in the memory CTLs. The naïve and effector CTLs persisted at very high percentages since the seventh month after starting dasatinib. The CTLs could not have led to the molecular response; therefore, there might be plenty of CML stem cells remaining in the bone marrow. Therefore, although the CTLs might have prevented the disease from developing blast crises over more than 5 years, the CTLs might not have been able to become memory CTLs.

Efficacy and Cardiovascular Adverse Events of Long-term Treatment with Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia: A Report from the Nagasaki CML Study Group.

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.

Induction of Effector and Memory Cellular Immunity in a Patient with Long-Term Complete Molecular Response to Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

This case report is about a patient who suffered from Philadelphia chromosome (Ph1)-positive acute lymphoblastic leukemia. The blasts were positive for myeloid-lineage markers including CD13 and CD33, as well as B-cell-lineage markers. Minor bcr-abl1 mRNA was detected by real-time quantitative polymerase chain reaction. Chromosomal abnormality monosomy 7 was also observed, in addition to Ph1. Despite treatment difficulties that were anticipated based on these findings, the patient had long-time complete molecular response (CMR) for approximately 5 years using chemotherapy and two tyrosine kinase inhibitors, imatinib and dasatinib. Lymphocytes were elevated after the patient switched from imatinib to dasatinib, and a T-cell receptor (TCR) V beta gene repertoire analysis revealed oligoclonal expansion of effector and memory cytotoxic T lymphocytes (CTLs), including Wilms tumor 1-specific CTLs. More specifically, the two memory CTLs expressing TCR V beta 3 and V beta 7.1 gradually increased after dasatinib administration. The activation and maintenance of anti-leukemia immunity may have allowed the patient to obtain long-time CMR. These results highlight that obtaining memory CTLs for leukemia cells may lead to safe withdrawal from dasatinib in the patient.