Safety and pharmacokinetics of milademetan, a MDM2 inhibitor, in Japanese patients with solid tumors: A phase I study.

Milademetan (DS-3032, RAIN-32) is an orally available mouse double minute 2 (MDM2) antagonist with potential antineoplastic activity owing to increase in p53 activity through interruption of the MDM2-p53 interaction. This phase I, dose-escalating study assessed the safety, tolerability, efficacy, and pharmacokinetics of milademetan in 18 Japanese patients with solid tumors who relapsed after or were refractory to standard therapy. Patients aged ≥ 20 years received oral milademetan once daily (60 mg, n = 3; 90 mg, n = 11; or 120 mg, n = 4) on days 1 to 21 in a 28-day cycle. Dose-limiting toxicities, safety, tolerability, maximum tolerated dose, pharmacokinetics, and recommended dose for phase II were determined. The most frequent treatment-emergent adverse events included nausea (72.2%), decreased appetite (61.1%), platelet count decreased (61.1%), white blood cell count decreased (50.0%), fatigue (50.0%), and anemia (50.0%). Dose-limiting toxicities (three events of platelet count decreased and one nausea) were observed in the 120-mg cohort. The plasma concentrations of milademetan increased in a dose-dependent manner. Stable disease was observed in seven out of 16 patients (43.8%). Milademetan was well tolerated and showed modest antitumor activity in Japanese patients with solid tumors. The recommended dose for phase II was considered to be 90 mg in the once-daily 21/28-day schedule. Future studies would be needed to further evaluate the potential safety, tolerability, and clinical activity of milademetan in patients with solid tumors and lymphomas. The trial was registered with Clinicaltrials.jp: JapicCTI-142693.

Significant role of magnetic resonance imaging for the diagnosis and evaluation of cardiac amyloidosis in primary light chain amyloidosis.

A 47-year-old male with macroglossia presented with dyspnea on effort and chest pain at rest. Cardiac MRI revealed diffuse global subendocardial late gadolinium enhancement below the left ventricular endocardium and a dark blood pool of intracardiac contrast medium. Tongue biopsy revealed amyloid deposition, which was limited in the myocardium. He was diagnosed with primary light chain amyloidosis. His condition was stage I according to the Mayo Clinic staging system. He underwent autologous peripheral blood stem cell transplantation. On Day 10, he developed chest pain and died suddenly on Day 11. Postmortem examination revealed amyloid deposition throughout the heart.

A Case of Primary Myelofibrosis in Which Ruxolitinib Therapy Ameliorated the Fibrosis, but Resulted in Fatty Marrow.

A 63-year-old woman was referred to our department in 2015 because of anemia and thrombocytosis. MPL W515/K was positive, JAK-2V617F and CALR exon 9 were negative. Bone marrow(BM)biopsy led to a diagnosis of primary myelofibrosis (PMF)in the prefibrotic/early stage(Grade 1). BMbiopsy performed in 2016 showed overt fibrotic stage(Grade 2). She was classified according to the Dynamic International Prognostic Scoring System(DIPSS)as intermediate(Int)-Ⅱrisk. Ruxolitinib 10 mg daily was initiated. Ruxolitinib was suspended for hepatic dysfunction after the dose was increased to 15 mg. Subsequently, ruxolitinib was resumed at 10 mg. BM biopsy performed in 2017 showed progression of myelofibrosis(MF)to Grade 3. BM biopsy performed in 2018 showed improved to Grade 0-1, however, BM was fatty. Currently in 2019, she continues to be on ruxolitinib. Results of immunohistochemical staining of BM biopsy specimens for cytokines and CD34 suggested the role of cytokines in the pathogenesis of the PMF. It was speculated that ruxolitinib blocked the production of cytokines to ameliorate the MF and restore the hematopoietic function of the BM. Although the pathogenesis of the fatty marrow remained unclear, the possibility of involvement of ruxolitinib cannot be denied.

Methotrexate-associated Hodgkin Lymphoma in a Patient with Rheumatoid Arthritis Successfully Treated with Brentuximab Vedotin in Combination with Doxorubicin, Vinblastine, and Dacarbazine (BV+AVD).

A 53-year-old woman had been diagnosed with rheumatoid arthritis (RA) in X-6. She was started on methotrexate (MTX) in X-1. She developed a cough, and chest computed tomography showed abnormalities. In X, MTX was discontinued, but the cough persisted. A lung biopsy revealed a diagnosis of nodular sclerosis classic Hodgkin lymphoma (CHL-NS). She was considered to have "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" (OIIA-LPD), MTX-associated Hodgkin lymphoma (MTX-HL). She received six courses of brentuximab vedotin (BV) in addition to AVD (BV+AVD). A complete metabolic response was obtained, and the RA went into remission. This is the fourth reported case of BV+AVD for MTX-HL.

Retrospective Analysis of 20 Patients with DLBCL Who Received MCVAC Followed by Autologous Peripheral Blood Stem Cell Transplantation.

Autologous peripheral blood stem cell transplantation(auto-PBSCT)combined with high-dose chemotherapy has been considered as the standard therapy for relapsed or induction therapy-refractory aggressive lymphomas sensitive to chemotherapy. While various regimens have been applied as the conditioning,none has yet been established as the standard. We have begun to employ high-dose ranimustine,cytarabine,etoposide and cyclophosphamide(MCVAC)regimen. The present study was undertaken to review the efficacy and safety of MCVAC. Regimen: We carried out a retrospective analysis of 20 patients diagnosed as diffuse large B-cell lymphoma. The median follow-up duration of 20 patients was 13.05 months(range, 0.57-49.5 months). The 4-year OS and PFS were 57.8% and 30.2%,respectively. Relapse was the most frequent cause of treatment failure(n=7). The major toxicities were anorexia/nausea(95%),diarrhea (75%),hypokalemia (70%). One patient died of hepatic veno-occlusive disease(VOD). The serious adverse events included hypokalemia,arrhythmia,cerebral hemorrhage,and heart failure(1 case[5%]each). There was 1 case of a late-onset adverse event: therapy-related myelo- dysplastic syndrome/acute myeloblastic leukemia(MDS/AML). MCVAC regimen was concluded as effective and well-toler- ated. However,we should carefully monitored for the possible development of VOD and MDS/AML. Further follow-up is needed to evaluate the long-term efficacy and safety.

Efficacy and safety of quizartinib in Japanese patients with FLT3-ITD positive relapsed or refractory acute myeloid leukemia in an open-label, phase 2 study.

FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations in patients with acute myeloid leukemia (AML) are associated with early relapse and poor survival. This multicenter, single-arm, two-stage phase 2 study (NCT02984995) was conducted to evaluate the efficacy and safety of quizartinib hydrochloride (initial dose 20/30 mg/day), an oral, highly potent, selective FLT3 inhibitor in Japanese patients (median age 65 years) with FLT3-ITD positive relapsed/refractory (R/R) AML. The composite complete remission (CRc) rate (primary endpoint) was 53.8% (90% confidence interval 36.2-70.8%) for evaluable patients in the efficacy analysis set. The median duration of CRc and overall survival was 16.1 weeks and 34.1 weeks, respectively. The most frequent treatment-emergent adverse events (TEAEs) were febrile neutropenia (43.2%), platelet count decreased (37.8%), and QT prolonged (35.1%). Two (5.4%) patients experienced TEAEs associated with treatment discontinuation. All serious TEAEs (45.9%), except febrile neutropenia (16.2%), were reported in ≤ 2 patients. The incidence of QTcF 451-480 ms and 481-500 ms was 37.8% and 2.7%, respectively. No QTcF > 500 ms, events of torsade de pointes or arrhythmia with clinical symptoms were reported. Quizartinib monotherapy was well tolerated and resulted in clinically meaningful reductions in blast count in Japanese patients with FLT3-ITD R/R AML.

Safety and pharmacokinetics of quizartinib in Japanese patients with relapsed or refractory acute myeloid leukemia in a phase 1 study.

Expanded therapeutic options are warranted for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) who have FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations. The present phase 1, multicenter, open-label, dose-escalation and dose-expansion study was conducted to assess the safety, pharmacokinetics, and efficacy of multiple-dose monotherapy of the FLT3 inhibitor, quizartinib, in Japanese patients with R/R AML. Patients received oral quizartinib, once daily, under fasting conditions in 28-day cycles. Sixteen patients (median age, 68.0 years; male, 56.3%; FLT3-ITD positive, 43.8%) received quizartinib (9, 3, and 4 patients at 20, 30, and 60 mg/day, respectively; median treatment duration, 95.0 days; median relative dose intensity, 100.0%). No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were electrocardiogram QT prolonged (43.8%, grade 1 or 2) followed by nausea and pyrexia (37.5% each). No quizartinib-related deaths were reported. A dose-dependent increase of quizartinib and its active metabolite AC886 levels was observed at the steady state. The composite complete remission rate was 37.5%. Quizartinib was well tolerated in Japanese R/R AML patients at doses up to 60 mg/day; quizartinib 60 mg/day was considered as the recommended dose for the Japanese patient population in a subsequent study.Trial registration ClinicalTrials.gov identifier NCT02675478.

Clinical Evaluation of the Efficacy and Safety of Anagrelide Used with or without Hydroxycarbamide in Japanese Patients with Essential Thrombocythemia-A Retrospective Single-Center Study of 35 Cases.

OBJECTIVE: The clinical features(CF), laboratory data, disease transformation pattern and drug metabolism in essential thrombocythemia(ET)differ between Japan and Western countries. The CF of ET in clinical practice(CP)are more diverse than in prospective clinical studies. We should conduct retrospective analyses in CP. The present study was aimed at evaluating the efficacy, safety and tolerability of anagrelide(ANA)monotherapy and combined ANA plus hydroxycarbamide(HC)in Japanese ET. PATIENTS AND METHODS: We have a total of 35 cases. Sixteen patients received ANA monotherapy, 10 received ANA plus HC, and 9 received ANA plus other drugs. RESULTS: Comparison among three groups revealed the absence of differences in response rate(platelet count C60×10 / / 4/mL, platelet count C40×104/mL)(43.8%, 6.3% vs. 50.0%, 10.0% vs. 44.4%, 11.1%), treatment continuation rate(81.3% vs. 40.0% vs. 55.6%), median daily dose of ANA(1.00 mg in all three groups)or median treatment period(days)(259 vs. 198.5 vs. 161.0), the treatment continuation rate tended to be lower in the combined ANA plus HC. The incidence of all adverse events(AEs)was higher in the ANA monotherapy(45.7%)than ANA plus HC(28.6%)or ANA plus other drugs(25.7%), the AEs were mild in all groups. CONCLUSION: The tolerability of ANA monotherapy, ANA plus HC, and ANA plus other drugs were good.

A Case of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with Aspergillus Brain Abscess and Invasive Pulmonary Aspergillosis Successfully Treated with Voriconazole Followed by Cord Blood Transplantation.

A 59-year-old female was diagnosed as pulmonary aspergillosis(IPA)while remission induction therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia. Liposomal amphotericin B improved the fungal serodiagnostic markers, however,the IPA worsened. She also developed an Aspergillus brain abscess,which, while being undetectable on CT,was detected as multiple nodular lesions by MRI. A definitive diagnosis was made by polymerase chain reaction(PCR)of brain biopsy specimens. Voriconazole(VRCZ)was effective,and cord blood transplantation was performed. She has received VRCZ for a long time. There are no relapse of either the IPA or the Aspergillus brain abscess.

Rapid progression of anemia related to tumor-lysis syndrome associated with bortezomib treatment in myeloma patients.

OBJECTIVE: Tumor-lysis syndrome is a rare complication in patients with multiple myeloma. However, bortezomib treatment for myeloma is often associated with tumor-lysis syndrome. METHODS: We developed an index called the rapid anemia progression index, which represents the duration and progression of anemia, to evaluate risk factors for tumor-lysis syndrome. We retrospectively reviewed 35 relapsed or refractory myeloma patients treated with bortezomib-containing treatment in our institution. We analyzed various parameters, including albumin, lactase dehydrogenase, ß2-microglobulin and creatinine, similar to the rapid anemia progression index, and evaluated the risk factors for tumor-lysis syndrome associated with bortezomib by the Cairo-Bishop definition. RESULTS: Clinical tumor-lysis syndrome occurred in six patients (17.1%). Tumor-lysis syndrome occurred during the first course of bortezomib-containing treatment among all the patients. The result of the area under the receiver operating characteristic curve for the rapid anemia progression index was 0.759 (P = 0.049). The rapid anemia progression index was more accurate than the index of lactate dehydrogenase, ß2-microglobulin, albumin and creatinine according to the receiver operating characteristic curve. For a cut-off point of -1.12 for the rapid anemia progression index, the sensitivity and specificity were 66.7 and 82.8%, respectively. CONCLUSIONS: The rapid anemia progression index is related to clinical tumor-lysis syndrome associated with bortezomib treatment for multiple myeloma patients with a cut-off point of -1.12 g/dl/month.

Infusion Rate Escalation Study of Rituximab in Patients with CD20+ B-Cell Lymphomas: A Single Institution Analysis in Japan.

Background. To determine the maximum tolerable infusion rate of rituximab, and investigate the safety and feasibility of rapid infusion of rituximab for patients with CD20 positive B-cell lymphomas (CD20+NHL). Patients and Methods. 18 patients with CD20+NHL were registered. This study had six cohorts of administration rate of rituximab. The median age was 56 years (range, 38-79), and five of 18 patients were male. Two patients (11%) with diffuse large B-cell lymphoma were receiving R-CHOP therapy, two (11%) with indolent lymphoma were receiving R-CVP therapy, and 14 (78%) with indolent lymphoma were receiving rituximab as maintenance therapy. Results. A total of 88 cycles of rituximab was administered. Rapid infusion of rituximab was well tolerated, with only one grade 3 leukocytepenia and one grade 4 neutropenia. Four patients (22%) developed grade 1 infusion-related toxicities at the first administration of rituximab. No patient with severe drug-related events was observed. Conclusions. We determined that the maximum tolerable infusion rate of rituximab is 300 mL/h (under 700 mg/h), and confirmed that administration of over 60 minutes is safe and feasible. We recommend rapid administration of rituximab for practice setting in patients with CD20+NHL being treated with rituximab or rituximab-containing chemotherapy. (Clinical trial no. JFCR2009-1027).

Prognostic value of high thymidine kinase activity in patients with previously untreated diffuse large B-cell lymphoma treated by rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone.

The purpose of this study was to investigate prognostic factors for overall survival (OS) among patients with previously untreated diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). We evaluated four biological parameters, including thymidine kinase (TK) activity. This study included 183 patients. The median level of TK was 14.0 IU/L, which we chose as the cut-off. After a median follow-up time of 50.0 months, the OS rate at 4 years in the high and low TK arm were 46.7% and 66.7%, respectively (p = 0.001). By multivariate analysis, OS was significantly inferior in the high TK arm (hazard ratio 2.705; p = 0.045). The complete response (CR) rate in the high TK arm was significantly worse than in the low TK arm. OS was significantly better in patients who had achieved CR than in those with partial response or less. In conclusion, high TK activity was a strong predictor for short OS and poor response among patients with previously untreated DLBCL treated with R-CHOP.

Non-gastric advanced mucosa-associated lymphoid tissue (MALT) lymphoma has worse prognosis than gastric MALT lymphoma even when treated with rituximab-containing chemotherapy.

The aim of this study was to assess the clinical characteristics, treatment results, and analyze the prognostic factors among patients with extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). We retrospectively reviewed 98 patients with MALT lymphoma consecutively diagnosed at the Cancer Institute Hospital. Eighty-one patients (82%) had localized disease and 17 patients (17%) had advanced disease. The primary site was gastric in 52, and extra-gastric in 46. With a median follow-up of 40 months, the estimated 3-year overall survival (OS) and progression free survival (PFS) of the entire group were 100% and 89%, respectively. Three-year PFS was significantly better in patients with gastric lymphoma than in those with non-gastric lymphoma (95% vs. 82%, p = 0.043). Patients with localized disease had significantly better 3-year PFS than those with advanced disease (94% vs. 73%, p = 0.026). Upon multivariate analysis, non-gastric lymphoma retained prognostic significance for PFS.

Prognostic value of C-reactive protein, lactase dehydrogenase and anemia in recurrent or refractory aggressive lymphoma.

OBJECTIVE: Prognostic predictors for newly diagnosed malignant lymphoma are well known. However, they have not been compared for patients with recurrent or refractory malignant lymphoma. METHODS: We retrospectively analyzed biological prognostic predictors for patients with recurrent or refractory aggressive lymphoma, such as serum levels of C-reactive protein, lactate dehydrogenase, hemoglobin, ß2-microglobulin and soluble interleukin-2 receptor before salvage therapy. The primary endpoint was overall survival after salvage treatment. First, univariate and multivariate analyses were performed for each of the parameters, using the log-rank test and Cox regression analysis, respectively. Secondly, we classified the patients into three risk groups on the basis of significant poor predictors. RESULTS: Sixty-three patients, including 41 patients with diffuse large B-cell lymphoma, were included in this study. Overall survival was significantly worse in patients with elevated C-reactive protein level (hazard ratio 3.757; P = 0.017), elevated lactate dehydrogenase level (hazard ratio 3.948; P = 0.010) and anemia (hazard ratio 3.925; P = 0.016) by multivariate analysis. We classified patients into two groups based on these three biological parameters. The median overall survival of the high- and low-risk patients was 5.8 and 60.1 months, respectively (log-rank test; P < 0.001). The overall response rate was significantly higher among the low-risk patients than among the high-risk patients (71.4 versus 28.6%, P = 0.005). Those results were similar among all aggressive lymphoma and diffuse large B-cell lymphoma. CONCLUSIONS: Elevated C-reactive protein level, elevated lactate dehydrogenase level and anemia before salvage treatment predicted poorer outcomes among patients with recurrent or refractory aggressive lymphoma.

R-CHOP with dose-attenuated radiation therapy could induce good prognosis in gastric diffuse large B cell lymphoma.

BACKGROUND: The treatment strategy for gastric diffuse large cell lymphoma (DLBCL) has not been standardized in such as to the cycles of chemotherapy, dose of radiation, or necessity for the surgery. Although the results of CHOP or R-CHOP treatments have demonstrated the good prognosis, the treatments have been controversial in many cases. METHODS: We retrospectively analyzed 40 gastric DLBCL patients receiving chemotherapy with or without radiation in our institute. Those in stages II-IV were treated with six cycles of R-CHOP without radiation; for those in stage I, we administered three cycles of R-CHOP with radiation. RESULTS: The three-year overall survival (OS) and progression-free survival (PFS) rates were 95.2 and 91.8%, respectively. Those in stage I obtained 100% of OS. The radiation dose prescribed was 30.6 Gy for CR cases and 39.6 to 40 Gy for PR after chemotherapy. Although survival rates tended to correlate with staging groups or age-adjusted IPI classifications, multivariate statistical analysis did not show clear differences. All 14 patients with initial bleeding were successfully managed without surgery during treatment. CONCLUSION: R-CHOP therapy was very effective for gastric DLBCL. It may be not necessary to use more than 30.6 Gy of radiotherapy in the highly chemo-sensitive cases. Less toxic treatments should be made available to gastric DLBCL patients.

Feasibility and efficacy of combined cisplatin and irinotecan chemotherapy for poorly differentiated neuroendocrine carcinomas.

OBJECTIVE: No standard treatment has been established for poorly differentiated neuroendocrine carcinoma; the usual recommended treatment is based on the strategy for small cell lung carcinoma. The aim of this study was to evaluate the response of poorly differentiated neuroendocrine carcinoma to the combination of irinotecan and cisplatin in one institution. METHODS: We retrospectively reviewed 50 poorly differentiated neuroendocrine carcinoma patients treated from September 2005 to April 2011 in our institution. Patients were divided into two stages: limited disease or extensive disease. Forty-four patients received the combination chemotherapy of irinotecan and cisplatin, consisting of 4-week cycles of 60 mg/m(2) irinotecan on days 1, 8, 15 and 60 mg/m(2) cisplatin on day 1. RESULTS AND CONCLUSION: Median age was 60 years. Median follow-up time was 11.4 months. Overall survival did not reach the median, and 1-year overall survival was 67%. The response rate was 50% (64% at first line), and progression-free survival was 4.8 months (7.3 months at first line). Grade 3-4 hematologic adverse events were seen in 29 patients (66%) and Grade 3-4 non-hematologic adverse events were seen in 20 patients (45%), but no patients died of adverse events. Multivariate analysis showed a statistically significant relationship with neuron-specific enolase elevation and poor overall survival (P= 0.016, hazard ratio 6.261, 95% confidence interval). The combination chemotherapy of irinotecan and cisplatin is moderately effective and feasible, and it should be considered as a treatment option for poorly differentiated neuroendocrine carcinoma.

A phase I study of oral panobinostat (LBH589) in Japanese patients with advanced solid tumors.

OBJECTIVE: The objective was to determine the maximum tolerated dose and the dose-limiting toxicity of panobinostat (LBH589) when administered as a single agent to adult patients with advanced solid tumors or cutaneous T-cell lymphoma whose disease had progressed despite standard therapy or for whom no standard therapy existed. METHODS: Panobinostat was administered orally once daily on Monday, Wednesday, and Friday of each week. A total of 13 patients were treated with one of three initial doses: 10 mg (n = 3), 15 mg (n = 4), or 20 mg (n = 6). RESULTS: No dose-limiting toxicity was observed in 12 evaluable patients. The most frequently reported adverse events, regardless of whether they were related to the study drug, were diarrhea and nausea in 10 patients (76.9%). Thrombocytopenia was reported in 12 of 13 patients (92.3%). Five of 11 patients (45.4%) had stable disease. CONCLUSION: Panobinostat administered orally once daily on Monday, Wednesday, and Friday of each week was well tolerated at doses up to 20 mg in Japanese patients. Dose escalation did not proceed after exploration of the 20 mg dose due to emerging global clinical data at that time.

High thymidine kinase activity is a strong predictive factor for poor prognosis in peripheral T-cell lymphoma treated with cyclophosphamide, adriamycin, vincristine and prednisone.

The prognosis of patients with peripheral T-cell lymphoma (PTCL) treated with cyclophosphamide, adriamycin, vincristine and prednisone (CHOP) is poor, but their laboratory prognostic parameters had not previously been evaluated. We retrospectively reviewed 55 patients with newly diagnosed PTCL treated with CHOP from August 1999 to May 2009 at our institution. We analyzed six laboratory parameters, including thymidine kinase (TK) activity, to evaluate overall survival, which was the primary end-point. In multivariate analysis, the overall survival was significantly worse in patients with high TK activity (hazard ratio 34.8, 95% confidence interval [CI] 1.03-1176.23). The overall response rate among patients with high TK activity was 21.4%, significantly poorer compared with other parameters (p = 0.001). High TK activity predicts poor overall survival among patients with newly diagnosed PTCL treated with CHOP. Response to CHOP treatment is significantly decreased in patients with PTCL with high TK activity.

[Efficacy of CHOP+/-Rituximab-like therapy plus radiation therapy for patients with diffuse large B-cell lymphoma stage I].

Clinically, R-CHOP-like therapy plus radiation therapy is commonly performed for patients with limited stage diffuse large B-cell lymphoma. However, the efficacy and the safety of the management have not been evaluated properly. In particular, we have few definitive reports about patients with stage I DLBCL. This time we evaluated the effect of CHOP+/-R-like therapy plus radiation therapy, by analyzing 28 patients with stage I DLBCL, retrospectively. 15 patients were treated with the RCHOP-like therapy, and 13 received CHOP-like therapy combined with radiation therapy. A complete response was observed in all of the patients. With a median follow-up time of 14 months, 1-year progression-free survival (PFS) was 100%, and the 1-year overall survival (OS) was 100% for the patients receiving the R-CHOP-like therapy. With a median follow-up time of 68 months, 5-year PFS was 84. 6%, and 5-year OS was 100% for patients receiving the CHOP-like therapy. Since the followup time was not enough and the patient numbers were too few, the benefit of the addition of Rituximab to the CHOP therapy could not be clarified. We need to assess the safety and the efficacy of the combined modality therapy for patients with limited-stage DLBCL by a larger prospective study.