Publications by authors named "Kiyohiko Hatake"

202 Publications

Factors for the optimal selection of granulocyte colony-stimulating factor preparations and predictors for R-CHOP dose reductions/delays among patients with non-Hodgkin B-cell lymphoma (STOP FN in NHL 2 subanalysis).

BMC Cancer 2021 Apr 6;21(1):358. Epub 2021 Apr 6.

Division of Hematology Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Background: A classification tree was used to analyze background factors for granulocyte colony-stimulating factor (G-CSF) preparation selection for febrile neutropenia (FN) prophylaxis in Japanese patients with non-Hodgkin B-cell lymphoma receiving the first R-CHOP cycle.

Methods: This was a subanalysis of the retrospective observational study STOP FN in NHL 2 (UMIN000029534). Patient characteristics, changes in neutrophil count, incidence and severity of neutropenia, and risk factors for dose reduction/delay of R-CHOP were assessed by G-CSF formulation.

Results: Among 234 patients in cycle 1, 25.6% received no G-CSF preparation, 52.1% received daily G-CSF, and 22.2% received pegfilgrastim. Pegfilgrastim use was most frequent among patients aged ≥ 80 years, while that of daily G-CSF was most frequent in patients with lymphocyte count (LC) < 1000 cells/μL. Changes in neutrophil count were more marked with pegfilgrastim compared with daily G-CSF and no G-CSF. Relevant factors for G-CSF preparation selection in the first R-CHOP cycle were age ≥ 80 years and LC < 1000 cells/μL; for chemotherapy dose reduction were FN onset in cycle 1 and female sex; and for dose delay was hemoglobin (< 12 g/dL). After cycle 2 and onward, pegfilgrastim use increased markedly (72.6%) compared with cycle 1 (22.2%), with significantly greater proportions continuing pegfilgrastim use and switching from daily G-CSF.

Conclusion: Relevant factors for G-CSF preparation selection were age ≥ 80 years and LC < 1000 cells/μL. The use of pegfilgrastim increased markedly after cycle 2. These results may be useful for selecting appropriate G-CSF preparations in the first R-CHOP cycle.

Trial Registration: UMIN000029534; registered on 13 October 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000033733 .
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http://dx.doi.org/10.1186/s12885-021-08068-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025521PMC
April 2021

A phase I, dose-escalation study of oral PIM447 in Japanese patients with relapsed and/or refractory multiple myeloma.

Int J Hematol 2021 Feb 27. Epub 2021 Feb 27.

Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

PIM447, a pan-proviral integration site for Moloney leukemia (PIM) kinase inhibitor, has shown preclinical activity in multiple myeloma (MM). This phase I, open-label, multicenter, dose-escalation study aimed to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) of PIM447 in Japanese patients with relapsed and/or refractory (R/R) MM. The study included 13 patients (250 mg once daily (QD), [n = 7]; 300 mg QD, [n = 6]). The sole dose-limiting toxicity observed was grade 3 QTc prolongation in one patient from the 300 mg group, and the MTD and RDE was not determined. The most common suspected PIM447-related adverse events (AEs) included thrombocytopenia (76.9%), anemia (53.8%), and leukopenia (53.8%). All patients experienced at least one grade 3 or 4 AE, most frequently thrombocytopenia or leukopenia (61.5% each). The overall response rate was 15.4%, disease control rate 69.2%, clinical benefit rate 23.1%, and two patients had a partial response (one in each dose group). Two patients treated with 250 mg QD had a progression-free survival > 6 months. PIM447 250 mg or 300 mg QD was tolerated in Japanese patients with R/R MM. Further studies are required to evaluate clinical outcomes of PIM447 in combination with other drugs for the treatment of MM.Trial registration: clinicaltrials.gov: (NCT02160951).
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http://dx.doi.org/10.1007/s12185-021-03096-9DOI Listing
February 2021

Safety profile of brentuximab vedotin in Japanese patients with relapsed/refractory Hodgkin lymphoma or systemic anaplastic large cell lymphoma: a post-marketing surveillance study.

Int J Hematol 2021 Mar 3;113(3):404-412. Epub 2021 Jan 3.

Department of Hematology and Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.

Brentuximab vedotin (BV) was initially approved in Japan for the treatment of relapsed/refractory (R/R) CD30-positive Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). As requested by the Japanese Ministry of Health, Labour and Welfare, we conducted a post-marketing surveillance (PMS) study to assess the safety of BV in Japanese patients with R/R HL or sALCL. PMS forms were collected from 284 patients (182 with HL, 101 with sALCL and one with another lymphoma) treated between April and September 2014. The median age was 62 (range 14-93) years and the median number of treatment cycles was 5.5 for HL and 4 for sALCL. Adverse drug reactions (ADRs) were reported in 74.3% of patients. The most commonly observed ADRs included peripheral sensory neuropathy (39.1%; grade ≥ 3, 6.3%), neutropenia (34.5%; grade ≥ 3, 22.2%) and lymphopenia (7.0%; grade ≥ 3, 5.3%). Ten patients had fatal ADRs including interstitial lung disease (n = 3). This study showed that BV has an acceptable safety profile in Japanese patients with R/R HL and R/R sALCL in the clinical practice setting. However, close monitoring rare, but potentially fatal, ADRs such as pulmonary toxicity may be warranted, especially in patients with prior or ongoing pulmonary disorders.
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http://dx.doi.org/10.1007/s12185-020-03039-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779085PMC
March 2021

New Concept of Onco-Hypertension and Future Perspectives.

Hypertension 2021 Jan 23;77(1):16-27. Epub 2020 Nov 23.

Department of Pharmacology, Faculty of Medicine, Kagawa University, Japan (S.K., A.N.).

Owing to aging populations, the prevalence of hypertension and associated cardiovascular events has been increasing worldwide. The morbidity and mortality due to cancer have also been increasing with aging populations. Several small-molecule inhibitors have been used in cancer therapy, which have a positive impact on the prognosis and survival of patients with cancer. Consequently, the number of cancer survivors with hypertension has been rapidly increasing. Anticancer therapy, including vascular endothelial growth factor inhibitors, increases blood pressure. However, both clinical and laboratory evidence are lacking regarding optimal blood pressure control in patients with hypertension with cancer. Here, we propose the concept of onco-hypertension, which is an evolving subspecialty focused on the complex pathophysiology of hypertension and cancer. In this review, we highlight blood pressure changes in cancer, hypertension induced by anticancer therapy, and optimal blood pressure management in patients with hypertension with cancer. In addition, we discuss needed studies to further establish this new onco-hypertension concept.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16044DOI Listing
January 2021

Phase I, multicenter, dose-escalation study of avadomide in adult Japanese patients with advanced malignancies.

Cancer Sci 2021 Jan 26;112(1):331-338. Epub 2020 Nov 26.

Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, Japan.

Non-Hodgkin lymphoma (NHL) treated with chemoimmunotherapy has limited efficacy in some patients, resulting in relapsed or refractory disease. Avadomide (CC-122) is a novel cereblon-binding agent that exhibits antilymphoma and immune-modulation activities with a biological profile distinct from similar agents, such as lenalidomide. This phase I multicenter study evaluated avadomide in Japanese patients with advanced solid tumors or NHL. Fourteen patients with NHL and one with a solid tumor (esophageal carcinoma), were enrolled in four dose-escalation cohorts using a 3 + 3 design. Primary endpoints included safety, dose-limiting toxicities (DLT), maximum-tolerated dose and/or recommended phase II dose (RP2D), and pharmacokinetics. Secondary endpoints included overall response rate (ORR) and duration of response. One patient with NHL experienced DLT, which included face edema, pharyngeal edema, and tumor flare (all grade 1) that led to a dose reduction. Eleven patients had grade ≥3 treatment-emergent adverse events, most frequently decreased neutrophil count (33%) and decreased lymphocyte count (20%). The ORR in patients with NHL (n = 13) was 54%, including four complete and three partial responses. The best response for the solid tumor patient was progressive disease. Avadomide dose intensity was consistent across cohorts, and the 3-mg dose given five consecutive days/week was established as the RP2D. This phase I study identified a tolerable dose of avadomide, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with previously treated NHL.
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http://dx.doi.org/10.1111/cas.14704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780008PMC
January 2021

Safety and pharmacokinetics of polatuzumab vedotin in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma: a phase 1 dose-escalation study.

Jpn J Clin Oncol 2021 Jan;51(1):70-77

Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.

Objective: A phase 1 dose-escalation study of polatuzumab vedotin (pola) was conducted to assess safety, pharmacokinetics and preliminary antitumor activity of pola in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Methods: Patients received pola (1.0 or 1.8 mg/kg) intravenously every 21 days until disease progression or intolerance. Intra-patient dose escalation was prohibited. Tolerability was determined by the standard 3 + 3 rule. Blood sampling was performed to characterize pharmacokinetics. Antitumor activity was evaluated through computed tomography and bone marrow sampling.

Results: Four patients received pola 1.0 mg/kg; three received 1.8 mg/kg. Patients had follicular lymphoma (n = 4) or diffuse large B-cell lymphoma (n = 3), median age of 62 years, received a median of 3 prior therapies; six were female. Pola was well tolerated in both cohorts, with no dose-limiting toxicities observed. The most common adverse event was peripheral sensory neuropathy (n = 4). Grade 3 adverse events were cholecystitis and neutrophil count decreased (one each; both 1.0 mg/kg), and syncope and cataract (one each; both 1.8 mg/kg). The plasma half-life of antibody-conjugate monomethyl auristatin E was 4.43-7.98 days, and systemic exposure of unconjugated monomethyl auristatin E was limited in both cohorts. Four patients achieved objective responses (three complete, one partial) without disease progression during the study.

Conclusions: This phase 1 dose-escalation study demonstrated that pola has an acceptable safety profile and offers encouraging antitumor activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma. Pola 1.8 mg/kg, the recommended phase 2 dose, was tolerable in Japanese patients.
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http://dx.doi.org/10.1093/jjco/hyaa169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7767980PMC
January 2021

The clonal evolution during long-term clinical course of multiple myeloma.

Int J Hematol 2021 Feb 30;113(2):279-284. Epub 2020 Aug 30.

Department of Hematology Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Somatic gene mutations related to acceleration disease and clonal evolution in multiple myeloma strongly influence severe clinical outcomes. In this study, we traced the transition of somatic mutations during the clinical course of myeloma patients over a long-term follow-up period (8.5 year average). Seven myeloma cases treated with immuno-chemotherapy at our institution were analyzed with clinical courses and the results of FISH and G-band analyses. Furthermore, the target sequences in regard to 121 genes, related to driver mutations or acceleration of disease in myeloma, were performed using bone marrow myeloma samples by next-generation sequencing, Ion Proton™ System. We detected a relationship between an increase in the dominant mutated gene (e.g., TP53, DIS3, FAM46C, KDM6B, and EGR1) and poor prognosis. In particular, clonal escalation of the TP53 mutation could not be overcome by any treatment. The selection of a combination treatment conducted in conjunction with the monitoring of gene mutations is appropriate for long-term survival. Our data demonstrate that long-term follow-up of somatic gene mutations during the clinical course of myeloma is helpful in the development of an effective treatment strategy.
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http://dx.doi.org/10.1007/s12185-020-02979-7DOI Listing
February 2021

Cost-effectiveness analysis of treatment regimens with obinutuzumab plus chemotherapy in Japan for untreated follicular lymphoma patients.

J Med Econ 2020 Oct 23;23(10):1130-1141. Epub 2020 Jul 23.

Department of Health Economics and Outcomes Research, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Aims: Obinutuzumab (GA101; G) is a new treatment for follicular lymphoma (FL) that is anticipated to have greater efficacy than the current treatment, rituximab (R). The aim of this study was to evaluate the cost-effectiveness of G plus chemotherapy (G + Chemo) against that of R plus chemotherapy (R + Chemo) for patients in Japan with previously untreated FL.

Materials And Methods: We localized a previously reported cost-effectiveness model using the Japanese cost data. For estimating costs adapted in the model, FL patients treated with R were identified from Japanese hospital-based claims database and classified into three treatment regimen groups according to chemotherapies used with R: CHOP, CVP, and bendamustine (B). Based on services per patient and cost items, parameters determining the cost amounts were derived using a multivariate generalized linear mixed model to estimate the direct medical costs for each treatment regimen group for G and R. For the utility, same values in the previous model were used. Lifetime cost and quality-adjusted life year (QALY) were estimated under the payer's perspective.

Results: The calculated incremental cost-effectiveness ratios (ICERs) in million JPY per QALY for G-CHOP vs. R-CHOP, G-CVP vs. R-CVP, and G-B vs. R-B were 5.4, 4.3, and 4.8, respectively. ICERs were lower than 7.5 million JPY per QALY, which is the cost-effectiveness threshold for cancer treatments, and showed that G + Chemo is a cost-effective treatment regimen for Japanese patients with previously untreated FL. Lifetime direct medical costs were lowest in the R-B group because hospitalization costs that accounted for most of the total cost were lowest in this group. The cost-effectiveness of G + Chemo is acceptable in Japan. Differences in the direct medical costs among treatment regimen groups were mostly due to hospitalization costs. This is probably because many Japanese hematologists choose inpatient treatments over outpatient treatments in CHOP-based induction therapy.
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http://dx.doi.org/10.1080/13696998.2020.1791890DOI Listing
October 2020

Phase I study of ibrutinib in Japanese patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma.

J Clin Exp Hematop 2019 ;59(4):179-186

This phase I study evaluated the safety and efficacy of single-agent ibrutinib in Japanese patients with treatment-naïve chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (aged 20-69 years and ineligible for chemotherapy using fludarabine or cyclophosphamide, or aged ≥70 years). Eight patients received oral ibrutinib 420 mg once daily until progressive disease or unacceptable toxicity. The primary endpoint was safety; secondary endpoints included the overall response rate (ORR). At the time of final analysis (August 22, 2018), eight patients (all with CLL; median age, 68.5 years) had received ibrutinib for a median of 32.2 months (range, 10.4-35.9); all patients had discontinued study treatment, with 50.0% of patients switching to marketing-approved ibrutinib as subsequent anticancer therapy. All patients had ≥1 adverse event (AE); the most common AEs included a decreased platelet count, upper respiratory tract infection, increased lymphocyte count, diarrhea, nasopharyngitis, peripheral edema and rash. Four patients (50.0%) had a total of eight grade ≥3 AEs, most commonly lung infection and decreased neutrophil count. Eight serious AEs were reported in four patients (50.0%); these included a case of muscle hemorrhage (grade 3), decreased neutrophil count (grade 4) that led to dose reduction and one case of fatal cardiac arrest. The ORR was 87.5% (7/8 patients [exact 95% confidence interval 47.3-99.7]). One patient had a complete response, six had a partial response and one had a partial response with lymphocytosis. Ibrutinib had an acceptable safety profile and high ORR in Japanese patients with treatment-naïve CLL.
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http://dx.doi.org/10.3960/jslrt.19023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954169PMC
June 2020

Elotuzumab plus lenalidomide and dexamethasone for newly diagnosed multiple myeloma: a randomized, open-label, phase 2 study in Japan.

Int J Hematol 2020 Jan 7;111(1):65-74. Epub 2019 Nov 7.

Department of Hematology, National Hospital Organization Disaster Medical Center, Tokyo, Japan.

Novel therapies are needed for patients with newly diagnosed multiple myeloma (NDMM). Elotuzumab plus lenalidomide and dexamethasone (ELd) is approved for the treatment of relapsed/refractory multiple myeloma (RRMM). This phase 2 study in Japan evaluated ELd vs lenalidomide and dexamethasone (Ld) in patients with NDMM who were ineligible for stem cell transplantation. Elotuzumab infusion was accelerated to 5 mL/min by dose 3, cycle 1, allowing most subsequent infusions to be completed within 1 h. The primary endpoint was overall response rate (ORR) in the ELd arm. Secondary endpoints were the difference in ORR between treatments, and progression-free survival (PFS). Patients were randomized to ELd (n = 40) or Ld (n = 42); median number of treatment cycles was 13 (ELd) and 12 (Ld). In the ELd arm, ORR was 88% [70% confidence interval (CI) 80-93]. The estimated difference in ORR between treatments was 13% (95% CI  - 4, 30) in favor of ELd. Progression-free survival data were immature. Safety was consistent with previous findings of ELd in Japanese patients with RRMM. No infusion reactions occurred at the maximum rate of 5 mL/min, which was used in 89% of elotuzumab infusions. ELd may be an effective, well-tolerated frontline treatment for patients with NDMM ineligible for stem cell transplantation.
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http://dx.doi.org/10.1007/s12185-019-02757-0DOI Listing
January 2020

Carfilzomib monotherapy in Japanese patients with relapsed or refractory multiple myeloma: A phase 1/2 study.

Cancer Sci 2019 Sep 10;110(9):2924-2932. Epub 2019 Aug 10.

Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.

This multicenter, open-label phase 1/2 study evaluated single-agent carfilzomib in 50 heavily pretreated Japanese patients with relapsed/refractory multiple myeloma (median of five prior treatments). In phase 1, patients were dosed at three levels: 15, 20, or 20/27 mg/m . Maximum tolerated dosage was not reached at the tolerability evaluation. Patients in phase 2 were treated with 20/27 mg/m carfilzomib. Median duration of exposure to carfilzomib in the 20/27 mg/m group at this final analysis was 4.7 months (range: 0.3-39.4). Overall response rate in the 20/27 mg/m group, primary endpoint of the study, was 22.5% (n = 9) (95% confidence interval, 12.3-37.5) with 2.5% (n = 1) stringent complete response. Median progression-free survival and overall survival in the 20/27 mg/m group were 5.1 months (95% CI, 2.8-13.6) and 22.9 months (95% CI, 14.1-not estimable), respectively. Frequently occurring grade ≥3 adverse events in the 20/27 mg/m group included lymphopenia (72.5%), neutropenia (40.0%), and leukopenia (32.5%). Giving long-term carfilzomib monotherapy led to long-term overall survival for heavily pretreated multiple myeloma patients with a favorable safety profile. Carfilzomib monotherapy can be a good option for heavily pretreated multiple myeloma patients.
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http://dx.doi.org/10.1111/cas.14139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726678PMC
September 2019

Prophylactic Antiemetics for Haematological Malignancies: Prospective Nationwide Survey Subset Analysis in Japan.

In Vivo 2019 Jul-Aug;33(4):1355-1362

Department of Hematology Oncology, The Cancer Institute Hospital of JFCR, Tokyo, Japan.

Background/aim: Although neurokinin-1 receptor antagonists are approved chemotherapy drugs in Japan, no nationwide surveys have been performed to validate chemotherapy-induced nausea and vomiting (CINV) guidelines in clinical practice. This study evaluated CINV in patients with haematological malignancies starting first-time chemotherapy.

Patients And Methods: A nationwide CINV survey on patients with haematological malignancies was conducted at 118 institutions. Patients undergoing moderately emetic chemotherapy (n=17) and highly emetic chemotherapy (HEC; n=180) were compared.

Results: Forty-one patients undergoing HEC received triple antiemetics. Female gender and young age were risk factors for early-phase nausea, while female gender remained a risk factor for late-phase nausea and vomiting. Among 125 patients receiving CHOP (doxorubicin, cyclophosphamide, vincristine, prednisone)-like regimens, complete response and complete control were increased in patients receiving triple antiemetics, compared to those with double antiemetics.

Conclusion: Guideline compliance was very low. Although not statistically significant, there was a trend for reduced CINV and improved disease control for triple versus double antiemetics, suggesting that triple antiemetics should be considered for HEC, especially in young female patients with non-Hodgkin lymphoma receiving CHOP-like regimens.
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http://dx.doi.org/10.21873/invivo.11611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689333PMC
December 2019

Incidence and risk factors for febrile neutropenia in Japanese patients with non-Hodgkin B cell lymphoma receiving R-CHOP: 2-year experience in a single center (STOP FN in NHL 2).

Support Care Cancer 2020 Feb 15;28(2):571-579. Epub 2019 May 15.

Division of Hematology Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Background: Myelosuppressive chemotherapy-induced febrile neutropenia (FN) is a life-threatening condition. Patients receiving granulocyte colony-stimulating factors (G-CSF) have shorter duration of neutropenia, faster recovery from fever, and shorter duration of antibiotics use. Most strategies for FN prevention using daily G-CSF and pegfilgrastim are based on overseas studies. Data on Japanese patients were lacking; thus, we previously determined the incidence of FN in non-Hodgkin B cell lymphoma (B-NHL) patients at our center. Here, we aimed to gain additional insights into pegfilgrastim use in this population.

Methods: This single-center, retrospective, observational study (STOP FN in NHL 2) enrolled patients with B-NHL who underwent a regimen comprising rituximab and CHOP therapy over a 2-year period (January 2015-June 2017). The incidence of FN in cycle 1 of chemotherapy, risk factors for FN development, and use of daily G-CSF and pegfilgrastim were evaluated.

Results: We evaluated 239 patients: 61 patients did not receive G-CSF and 178 received G-CSF. The incidence of FN was 10.5% (95% confidence interval [CI] 6.9-15.1%) in cycle 1 and 13.0% (95% CI 9.0-17.9%) in all cycles. The FN incidence was significantly lower (P = 0.0008) in patients receiving daily G-CSF and pegfilgrastim than patients not receiving G-CSF. Significant risk factors for FN were age ≥ 65 years, albumin < 3.5 g/dL, hemoglobin < 12 g/dL, and no prophylaxis with daily G-CSF/pegfilgrastim during cycle 1.

Conclusions: The incidence of FN in cycle 1 and in all cycles and the identified risk factors were similar with those we previously reported; thus, our results validate previous findings.

Trial Registration: UMIN000029534.
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http://dx.doi.org/10.1007/s00520-019-04802-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954143PMC
February 2020

Phase I study of tirabrutinib (ONO-4059/GS-4059) in patients with relapsed or refractory B-cell malignancies in Japan.

Cancer Sci 2019 May 28;110(5):1686-1694. Epub 2019 Mar 28.

Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.

We evaluated the safety, efficacy, pharmacokinetics, pharmacodynamics and predictive biomarkers of tirabrutinib, a second-generation, enhanced-selectivity Bruton's tyrosine kinase inhibitor in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-cell NHL) and chronic lymphocytic leukemia (CLL). This was an open-label, multicenter, phase I study. Seventeen patients (male N = 8) with a median age of 70 years were enrolled in 4 dose cohorts (160 mg once daily [N = 3], 320 mg once daily [N = 3], 480 mg once daily [N = 4] and 300 mg twice daily [N = 7]); 4 patients had continued tirabrutinib administration as of 4 January 2018. The maximum tolerated dose was not reached. Pneumonitis (N = 1) was the dose-limiting toxicity for 300 mg twice daily. Common adverse events (AEs) were rash (35.3%) and vomiting (29.4%). Eight patients (47.1%) developed grade ≥3 AEs: neutropenia (23.5%), anemia (11.8%) and leukopenia (11.8%) were frequent. The overall response rate (≥PR) was 76.5% (13/17 patients), including 4 DLBCL patients with no CD79A/B or MYD88 mutations, and 1 CLL patient with a TP53 mutation, providing promising data for future developments. Of 16 patients with measurable lesions during the screening period, 12 showed ≥50% reductions in tumor diameter. In many patients, the tumor size decreased soon after beginning treatment. The maximum serum concentration for tirabrutinib was 611, 1220, 1280 and 886 ng/mL on Day 1 and 484, 971 1940, and 961 ng/mL on Day 28 for Cohorts 1-4, respectively. Tirabrutinib pharmacokinetics were linear, with little accumulation following multiple doses. Tirabrutinib was well tolerated and showed promising efficacy for B-cell NHL/CLL.
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http://dx.doi.org/10.1111/cas.13983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500982PMC
May 2019

Safety, tolerability and pharmacokinetics of shorter duration of infusion of obinutuzumab in Japanese patients with B-cell non-Hodgkin lymphoma: final results of the phase II GATS study.

Jpn J Clin Oncol 2018 Aug;48(8):736-742

National Cancer Center Hospital, Tokyo, Japan.

Background: Shorter duration of infusion of monoclonal antibody treatments may reduce treatment burden and improve healthcare resource utilization.

Methods: This phase II study recruited Japanese patients with previously untreated CD20+ B-cell non-Hodgkin lymphoma. Patients received intravenous obinutuzumab 1000 mg by regular infusion on Days 1, 8 and 15 of Cycle 1, followed by 90-min shorter duration of infusion in up to seven subsequent cycles, provided they received ≥3 regular infusions without any grade ≥3 infusion-related reactions and had a lymphocyte count <5.0 × 109 cells/l. Standard cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy was given in Cycles 1-6. The primary endpoints were as follows: incidence of grade ≥3 infusion-related reactions in Cycle 2 in patients who started shorter duration of infusion in Cycle 2, serum obinutuzumab concentrations and pharmacokinetic parameters and the time course of cytokine release. Adverse events and serious adverse events were monitored.

Results: Of 35 patients treated, 28 completed eight cycles; 31 started shorter duration of infusion in Cycle 2 and two patients in subsequent cycles. Two patients discontinued before starting shorter duration of infusion. No grade ≥3 infusion-related reactions occurred in Cycle 2. Twenty-one infusion-related reactions (all grades 1-2) were reported in 17/35 (49%) patients overall, mostly in Cycle 1 (18/21 infusion-related reactions [86%]). Grade ≥3 AEs occurring in ≥10% of patients included neutropenia/neutrophil count decreased (66%) and leukopenia/white blood cell count decreased (23%). Steady-state pharmacokinetics of obinutuzumab were attained in Cycle 2 and were not affected by shorter duration of infusion. No relevant cytokine elevations were reported with shorter duration of infusion.

Conclusions: Regular infusion and shorter duration of infusion of obinutuzumab have comparable tolerability and pharmacokinetics in Japanese patients.
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http://dx.doi.org/10.1093/jjco/hyy087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057540PMC
August 2018

Efficacy and safety of obinutuzumab in patients with previously untreated follicular lymphoma: a subgroup analysis of patients enrolled in Japan in the randomized phase III GALLIUM trial.

Int J Hematol 2018 Nov 19;108(5):499-509. Epub 2018 Jul 19.

School of Medicine, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, Japan.

GALLIUM is a global phase III study that demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with obinutuzumab plus chemotherapy (G-chemo) versus rituximab plus chemotherapy (R-chemo) in previously untreated patients with follicular lymphoma (FL). In this single-country subgroup analysis, we explored patterns of efficacy and safety in patients enrolled in the GALLIUM study in Japan (Japanese subgroup). Patients were randomized to open-label induction treatment with G-chemo or R-chemo. Responders received maintenance monotherapy with their randomized antibody for up to 2 years. The primary endpoint was investigator-assessed PFS. Overall, 123 patients with FL were randomized in the Japanese subgroup (G-chemo, n = 65; R-chemo, n = 58). The majority of patients received cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (82.9 vs 33.1% in the global GALLIUM FL population). PFS at 3 years was 89.9% (G-chemo) vs. 74.7% (R-chemo); hazard ratio 0.42; 95% confidence interval 0.15, 1.15; P = 0.08. Higher rates of grade 3-5 adverse events (96.9 vs. 89.7%) and serious adverse events (35.4 vs. 22.4%) were observed with G-chemo vs R-chemo, respectively. Neutropenia was frequent in the Japanese subgroup (92.3% G-chemo; 79.3% R-chemo). Overall, the results in the Japanese subgroup were consistent with those in the global GALLIUM population.
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http://dx.doi.org/10.1007/s12185-018-2497-0DOI Listing
November 2018

Multicenter phase 1/2 study of forodesine in patients with relapsed peripheral T cell lymphoma.

Ann Hematol 2019 Jan 5;98(1):131-142. Epub 2018 Jul 5.

Department of Hematology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Peripheral T cell lymphomas are an aggressive group of non-Hodgkin lymphomas with poor outcomes for most subtypes and no accepted standard of care for relapsed patients. This study evaluated the efficacy and safety of forodesine, a novel purine nucleoside phosphorylase inhibitor, in patients with relapsed peripheral T cell lymphomas. Patients with histologically confirmed disease, progression after ≥ 1 prior treatment, and an objective response to last treatment received oral forodesine 300 mg twice-daily. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety. Forty-eight patients (median age, 69.5 years; median of 2 prior treatments) received forodesine. In phase 1 (n = 3 evaluable), no dose-limiting toxicity was observed during the first 28 days of forodesine treatment. In phase 2 (n = 41 evaluable), the ORR for the primary and final analyses was 22% (90% CI 12-35%) and 25% (90% CI 14-38%), respectively, including four complete responses (10%). Median PFS and OS were 1.9 and 15.6 months, respectively. The most common grade 3/4 adverse events were lymphopenia (96%), leukopenia (42%), and neutropenia (35%). Dose reduction and discontinuation due to adverse events were uncommon. Secondary B cell lymphoma developed in five patients, of whom four were positive for Epstein-Barr virus. In conclusion, forodesine has single-agent activity within the range of approved therapies in relapsed peripheral T cell lymphomas, with a manageable safety profile, and may represent a viable treatment option for this difficult-to-treat population.
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http://dx.doi.org/10.1007/s00277-018-3418-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334730PMC
January 2019

and alterations in diffuse large B-cell lymphoma: prognostic markers identified via exome analysis of cases with extreme prognosis.

Oncotarget 2018 Apr 13;9(28):19555-19568. Epub 2018 Apr 13.

Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, Koto, Tokyo, Japan.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype characterized by both biological and clinical heterogeneity. In refractory cases, complete response/complete response unconfirmed rates in salvage therapy remain low. We performed whole-exome sequencing of DLBCL in a discovery cohort comprising 26 good and nine poor prognosis cases. After candidate genes were identified, prognoses were examined in 85 individuals in the DLBCL validation cohort. In the discovery cohort, five patients in the poor prognosis group harbored both a mutation and 17p deletion. Sixteen mutations were identified in in nine patients in the good prognosis group, but none in the poor prognosis group. In the validation cohort, mutations and deletions were confirmed to be poor prognostic factors for overall survival (OS) (P = 0.016) and progression-free survival (PFS) (P = 0.023) only when both aberrations co-existed. mutations were validated as prognostic markers for excellent OS (P = 0.037) and PFS (P = 0.041). Significant differences in OS and PFS were observed when patients were stratified into three groups- mutation (best prognosis), the coexistence of both mutation and deletion (poorest prognosis), and others. In this study, the presence of both mutation and 17p/ deletion, but not the individual variants, was associated with poor prognosis in DLBCL patients after treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or similar regimens. We also identified mutation as a marker for patients with excellent prognosis in the R-CHOP era.
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http://dx.doi.org/10.18632/oncotarget.24656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929408PMC
April 2018

A Phase I/II Study for Dose-finding, and to Investigate the Safety, Pharmacokinetics and Preliminary Efficacy of NK012, an SN-38-Incorporating Macromolecular Polymeric Micelle, in Patients with Multiple Myeloma.

Intern Med 2018 Apr 8;57(7):939-946. Epub 2017 Dec 8.

Nippon Kayaku Co., Ltd., Japan.

Objective Multiple myeloma (MM) is the second most common hematological cancer. An attempt to treat MM using a topoisomerase I inhibitor was made based on our previous non-clinical studies suggesting the usefulness of an SN-38 derivative. Our aim was to conduct a phase I/II study of NK012, a micelle-forming SN-38 conjugate, in patients with relapsed/refractory multiple myeloma (RRMM). Methods NK012 was administered at doses of 12-24 mg/m and the safety, pharmacokinetics and preliminary efficacy were evaluated. Results Neutropenia was the most common grade 3 or 4 adverse drug reaction. Grade 4 neutropenia accounted for the majority of dose-limiting toxicities and only appeared at a dose of 24 mg/m. The maximum concentrations and the area under the concentration-time curves from time zero to infinity for both NK012 and its active metabolite SN-38 increased in a dose-dependent manner. The best overall response was stable disease, which was achieved in 12 out of 16 patients. Conclusion The recommended dose of NK012 monotherapy for RRMM patients was concluded to be 20 mg/m. However, this phase I/II study was terminated at the end of the phase I stage because no patients showed an objective response. Additional clinical studies of combination therapy with NK012 and other agents are warranted.
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http://dx.doi.org/10.2169/internalmedicine.9567-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919849PMC
April 2018

Delayed recovery of serum immunoglobulin G is a poor prognostic marker in patients with follicular lymphoma treated with rituximab maintenance.

Ann Hematol 2018 Feb 14;97(2):289-297. Epub 2017 Nov 14.

Department of Hematology Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ward, Tokyo, 135-8550, Japan.

Clinical trials involving various treatment schedules for rituximab maintenance have been conducted for patients with follicular lymphoma (FL) and have not confirmed their impact on serum immunoglobulin (sIg) levels until the completion of maintenance. However, the long-term use of rituximab is a concern because of circulating plasma cell-depletion risk, suggesting that the mechanism of change in sIg levels after RM has not been determined. Additionally, the relationship between host humoral immunity and the prognosis of patients with B cell malignancies has not been determined. We retrospectively investigated data from 213 patients with FL from a single institute who achieved at least a partial response with rituximab, cyclophosphamide, vincristine, and prednisolone with or without doxorubicin. Of these, 166 patients underwent RM with a median period of 1.6 years. A significantly delayed recovery of sIgG levels was observed in the maintenance group until 3 years after RM in comparison to the observation group. A multivariate analysis showed that a sIgG level of < 718 mg/dl 1 year after RM was an independent predictor for poor progression-free survival (PFS) (hazard ratio, 2.3; P = 0.04). Therefore, the sIgG levels scarcely recovered and were significantly delayed after RM, leading to shorter PFS in patients with FL.
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http://dx.doi.org/10.1007/s00277-017-3175-7DOI Listing
February 2018

Bearing 19q13 aberration predicts poor prognosis in non-germinal centre type of CD5 DLBCL.

Br J Haematol 2018 11 26;183(4):661-664. Epub 2017 Oct 26.

Department of Haematology Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

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http://dx.doi.org/10.1111/bjh.15001DOI Listing
November 2018

Combination therapy with monoclonal antibodies for treatment of newly diagnosed multiple myeloma.

Rinsho Ketsueki 2017 ;58(8):1006-1013

Division of Hematology Oncology, Cancer Institute Hospital of the Japanese Society for Cancer Research.

Monoclonal antibodies (mAbs) with new mechanisms of action are emerging as promising agents for patients with multiple myeloma (MM). Of these, anti-CD38 antibodies and anti-signaling lymphocytic activation molecule F7 (SLAMF7) antibody have demonstrated efficacy for relapsed and refractory myeloma (RRMM). Two CD38-targeting antibodies, daratumumab and isatuximab had significant activity as single agents, whereas the SLAMF7-targeting antibody, elotuzumab, did not. Patients with RRMM treated with 16 mg/kg daratumumab achieved at least PR of 36% and 29% in two distinct phase 2 studies. More favorable results of phase 3 study of 16 mg/kg daratumumab with lenalidomide and dexamethasone revealed that 92.9% of patients with RRMM achieved at least partial response (PR), with a 43.1% complete response (CR) rate. The median PFS was better in daratumumab arm (Not Reached) than control arm (18.4 months). When combined with lenalidomide plus dexamethasone, elotuzumab, at a dose of 10 mg/kg, improved the median PFS from 14.9 months to 19.4 months in a phase 3 study named ELOQUENT-2. In addition to IMiDs, bortezomib was a hopeful partner. Regarding toxicity, these mAbs are tolerable even in elderly patients. The most common adverse event is an infusion-related reaction. Based on several published reports, we suggest that mAbs combined with standard agents could be successfully adapted for the treatment of newly diagnosed patients with MM.
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http://dx.doi.org/10.11406/rinketsu.58.1006DOI Listing
December 2017

Bone metastases from breast cancer: associations between morphologic CT patterns and glycolytic activity on PET and bone scintigraphy as well as explorative search for influential factors.

Ann Nucl Med 2017 Dec 1;31(10):719-725. Epub 2017 Sep 1.

Department of Gastrointestinal Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.

Background: This study aimed to compare the detection of bone metastases from breast cancer on F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and bone scintigraphy (BS). An explorative search for factors influencing the sensitivity or uptake of BS and FDG-PET was also performed.

Methods: Eighty-eight patients with bone metastases from breast cancer were eligible for this study. Histological confirmation of bone metastases was obtained in 31 patients. The bone metastases were visually classified into four types based on their computed tomography (CT) appearance: osteoblastic, osteolytic, mixed, and negative. The sensitivity of BS and FDG-PET were obtained regarding CT type, adjuvant therapy, and the primary tumor characteristics. The FDG maximum standardized uptake value (SUV) was analyzed.

Results: The sensitivities of the three modalities (CT, BS, and FDG-PET) were 77, 89, and 94%, respectively. The sensitivity of FDG-PET for the osteoblastic type (69%) was significantly lower than that for the other types (P < 0.001), and the sensitivity of BS for the negative type (70%) was significantly lower than that for the others. Regarding tumor characteristics, the sensitivity of FDG-PET significantly differed between nuclear grade (NG)1 and NG2-3 (P = 0.032). The SUV of the osteoblastic type was significantly lower than that of the other types (P = 0.009). The SUV of NG1 was also significantly lower than that of NG2-3 (P = 0.011). No significant difference in FDG uptake (SUV) was detected between different histological types.

Conclusion: Although FDG-PET is superior to BS for the detection of bone metastases from breast cancer, this technique has limitations in depicting osteoblastic bone metastases and NG1.
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http://dx.doi.org/10.1007/s12149-017-1202-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691120PMC
December 2017

Pattern of Tumor Shrinkage during Neoadjuvant Chemotherapy Is Associated with Prognosis in Low-Grade Luminal Early Breast Cancer.

Radiology 2018 01 24;286(1):49-57. Epub 2017 Jul 24.

From the Department of Breast Medical Oncology, Breast Oncology Center (I.F., K.A., K.K., T.S., Y.I.), Department of Medical Oncology (S.T.), Department of Diagnostic Imaging (N.G., Y.K., K.O.), Department of Pathology (R.H., F.A.), Department of Breast Surgical Oncology, Breast Oncology Center (T.I.), Breast Oncology Center (S.O.), and Department of Hematology and Oncology (K.H.), the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan; and Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan (N.S.).

Purpose To evaluate the association between tumor shrinkage patterns shown with magnetic resonance (MR) imaging during neoadjuvant chemotherapy (NAC) and prognosis in patients with low-grade luminal breast cancer. Materials and Methods This retrospective study was approved by the institutional review board and informed consent was obtained from all subjects. The low-grade luminal breast cancer was defined as hormone receptor-positive and human epidermal growth factor receptor 2-negative with nuclear grades 1 or 2. The patterns of tumor shrinkage as revealed at MR imaging were categorized into two types: concentric shrinkage (CS) and non-CS. Among 854 patients who had received NAC in a single institution from January 2000 to December 2009, 183 patients with low-grade luminal breast cancer were retrospectively evaluated for the development set. Another data set from 292 patients who had received NAC in the same institution between January 2010 and December 2012 was used for the validation set. Among these 292 patients, 121 patients with low-grade luminal breast cancer were retrospectively evaluated. Results In the development set, the median observation period was 67.9 months. Recurrence was observed in 31 patients, and 16 deaths were related to breast cancer. There were statistically significant differences in both the disease-free survival (DFS) and overall survival (OS) rates between patterns of tumor shrinkage (P < .001 and P < .001, respectively). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .001) and OS (P = .009) rate. In the validation set, the median follow-up period was 56.9 months. Recurrence was observed in 20 patients (16.5%) and eight (6.6%) deaths were related to breast cancer. DFS rate was significantly longer in patients with the CS pattern (72.8 months; 95% confidence interval [CI]: 69.9, 75.6 months) than in those with the non-CS pattern (56.0 months; 95% CI: 49.1, 62.9 months; P ≤ .001). The CS pattern was associated with an excellent prognosis (median OS, 80.6 months; 95% CI: 79.3, 81.8 months vs 65.0 months; 95% CI: 60.1, 69.8 months; P = .004). Multivariate analysis demonstrated that the CS pattern had the only significant independent association with DFS (P = .007) and OS (P = .037) rates. Conclusion The CS pattern as revealed at MR imaging during NAC had the only significant independent association with prognosis in patients with low-grade luminal breast cancer. RSNA, 2017.
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http://dx.doi.org/10.1148/radiol.2017161548DOI Listing
January 2018

Epstein-Barr virus-negative extranodal "true" natural killer-cell lymphoma harbouring a KDM6A mutation.

Hematol Oncol 2018 Feb 10;36(1):328-335. Epub 2017 Jul 10.

Division of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL) is an extranodal aggressive T or NK-cell lymphoma that is characteristically associated with Epstein-Barr virus (EBV) infection and cytotoxic tissue-destructive features. Although ENKTL is described as a distinct entity according to the 2008 WHO classification, a considerable complexity is associated with the differential diagnosis of other T-cell lymphomas with respect to tumour cell origins, locations, and the presence of EBV infection, as well as molecular and cytogenetic abnormalities. Here, we report a rare case of EBV-negative ENKTL, where the absence of EBV in the true NK-lineage cells was confirmed by extensive phenotypic and genotypic analyses. Furthermore, using the next-generation sequencing approach, we identified mutations in the tumour suppressor genes KDM6A and TP53. The clinicopathological characteristics were almost similar to those of EBV-positive ENKTL, except for the absence of EBV and histologically apparent angioinvasiveness. This is the first reported ENKTL case with mutations in the KDM6A gene. KDM6A is one of the histone-modifying genes that are mutated in many human diseases including haematological cancers. Epigenetic regulation of gene expression has recently been demonstrated in ENKTL, and a similar pathway is thought to play an oncogenic role in EBV-negative ENKTL. Our report shows the extent of comprehensive examination required before making a definitive diagnosis for NK- and T-cell neoplasms and broadens the therapeutic options for potential targets.
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http://dx.doi.org/10.1002/hon.2459DOI Listing
February 2018

Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study.

Int J Hematol 2017 Nov 29;106(5):655-665. Epub 2017 Jun 29.

Celgene K.K., Tokyo, Japan.

This phase I/II multicenter study evaluated romidepsin treatment in Japanese patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Patients aged ≥20 years received romidepsin via a 4-h intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Phase I used a 3 + 3 design to identify any dose-limiting toxicity (DLT) for regimens of romidepsin 9 and 14 mg/m. The primary endpoints for phase I and II were DLT and overall response rate (ORR), respectively. Intent-to-treat patients were those who received ≥1 romidepsin dose (PTCL, n = 48; CTCL, n = 2). In phase I, none of the patients (n = 3, 9 mg/m; n = 6, 14 mg/m) exhibited DLT. In phase II, 40 patients with PTCL were treated with 14 mg/m romidepsin. The most common treatment-emergent grade ≥3 adverse events were lymphopenia (74%), neutropenia (54%), leukopenia (46%), and thrombocytopenia (38%). Patients in phase II showed a 43% ORR, including 25% complete responses. Median progression-free survival was 5.6 months and median duration of response was 11.1 months. This phase I/II study identified a well-tolerated dose of romidepsin, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with relapsed/refractory PTCL. ClinicalTrials.gov Identifier NCT01456039.
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http://dx.doi.org/10.1007/s12185-017-2286-1DOI Listing
November 2017

Efficacy of chemotherapy in extremely elderly patients with diffuse large B-cell lymphoma.

Rinsho Ketsueki 2017 ;58(5):427-432

Dept. of Hematology and Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research.

The safety and effective dose of chemotherapy in treating non-Hodgkin lymphoma in elderly patients is yet to be established. In this study, we assessed the prognosis of diffuse large B-cell lymphoma (DLBCL) in elderly patients (≥75 years) treated with an optimal dose of R-CHOP. No significant differences were observed in progression-free survival between elderly patients and patients aged <74 years with DLBCL. Furthermore, no differences were observed between full-dose R-CHOP and 80% dose R-CHOP groups. Median relative dose intensity was 0.80 in elderly patients with DLBCL. Thus, our data suggested that 80% dose R-CHOP is tolerable and effective in these patients.
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http://dx.doi.org/10.11406/rinketsu.58.427DOI Listing
November 2017

Incidence and risk factors of febrile neutropenia in patients with non-Hodgkin B-cell lymphoma receiving R-CHOP in a single center in Japan.

Support Care Cancer 2017 11 27;25(11):3313-3320. Epub 2017 May 27.

Division of Hematology Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Purpose: The incidence of and risk factors for febrile neutropenia (FN) in Japanese non-Hodgkin B-cell lymphoma (B-NHL) patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and predonisolone (R-CHOP) chemotherapy are unknown. We conducted this study to address this issue.

Methods: In this single-center, retrospective, observational study, 466 patients with B-NHL who completed an R-CHOP regimen within a 7-year period and who planned to undergo at least three cycles of this regimen were analyzed. The following FN-related factors were assessed: fever, infection, disease state, neutrophil count, and prophylactic interventions such as use of antibiotics and/or granulocyte colony-stimulating factor (G-CSF). We simulated the FN incidence and 95% confidence interval (CI) of patients without prophylaxis with G-CSF (cycle 1) using bootstrap sampling.

Results: The incidence of FN was 9.1% (42 of 462) in cycle 1 and 12.3% (57 of 462 patients) throughout all cycles, with 73.7% (42/57) developing FN during cycle 1. Risk factors for FN among patients with B-NHL treated with R-CHOP were albumin <35 g/L (p = 0.0047), relative dose intensity <85% (p = 0.0007), and lack of prophylaxis with G-CSF (p = 0.0006) in cycle 1. In the simulation analysis, the estimated FN incidence in cycle 1 was 16.2% (95% CI [10.9-22.2]).

Conclusions: At 9.1% in cycle 1 and 12.3% throughout all cycles, the incidence of FN was lower than previously reported, possibly reflecting the appropriate use of G-CSF in this clinical setting. For patients with risk factors, the prophylaxis with G-CSF may decrease the occurrence of FN.
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http://dx.doi.org/10.1007/s00520-017-3747-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610661PMC
November 2017