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This single‐arm confirmatory study (JCOG1305) aimed to evaluate the utility of interim positron emission tomography (iPET)‐guided therapy for newly diagnosed advanced‐stage classic Hodgkin lymphoma (cHL). Patients aged 16–60 years with cHL received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and then underwent an iPET scan (PET2), which was centrally reviewed using a five‐point Deauville scale. PET2‐negative patients continued an additional four cycles of ABVD, whereas PET2‐positive patients switched to six cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP). The co‐primary endpoints were 2‐year progression‐free survival (PFS) among all eligible and PET2‐positive patients. Ninety‐three patients were enrolled between January 2016 and December 2019. One patient was ineligible because of a diagnostic error. The median age of the 92 eligible patients was 35 (interquartile range, 28–48) years. Forty (43%) patients had stage III disease, and 43 (47%) had stage IV disease. The remaining nine (10%) patients had stage IIB disease with risk factors. Nineteen PET2‐positive (21%) patients received eBEACOPP, 18 completed six cycles of eBEACOPP, 73 PET2‐negative (79%) patients continued ABVD, and 70 completed an additional four cycles of ABVD. With a median follow‐up period of 41.1 months, the 2‐year PFS of 92 eligible patients and 19 PET2‐positive patients were 84.8% (80% confidence interval [CI], 79.2–88.9) and 84.2% (80% CI, 69.7–92.1), respectively. Both primary endpoints were met at the prespecified threshold. This study demonstrates that iPET‐guided therapy is a useful treatment option for younger patients with newly diagnosed advanced‐stage cHL. Registration number: jRCTs031180218. [ABSTRACT FROM AUTHOR]

The phase II study of tirabrutinib monotherapy at a daily dose of 480 mg under fasting conditions for treatment‐naïve and relapsed/refractory Waldenström's macroglobulinemia (ONO‐4059‐05 study) demonstrated a promising efficacy and tolerable safety profile. We conducted an unplanned analysis with a median follow‐up of 24.8 months to update the efficacy and safety results and to report patient‐reported quality of life. Of 27 enrolled patients, 22 patients continued receiving the study drug. The major response assessed by an independent review committee was observed in 25 patients (93%), including one and five patients who newly achieved complete response and very good partial response, respectively, after the primary analysis. The progression‐free and overall survival rates at 24 months were 92.6% and 100%, respectively. Serum IgM levels in all patients except one declined and were maintained at low levels, although transient increases occurred after temporal interruption of the study drug. The disease‐related symptoms including recurrent fever and hyperviscosity mostly disappeared. Health‐related quality of life, assessed by cancer‐specific questionnaires, was mostly maintained. Grade 3–4 neutropenia, lymphopenia, and leukopenia were newly recognized in three, two, and one patient, respectively. Grade 3 treatment‐related hypertriglyceridemia was also recognized. Nine patients experienced grade 1–2 bleeding events (33%), one patient experienced grade 2 treatment‐related atrial fibrillation, and one patient experienced grade 1 treatment‐related hypertension. Treatment‐related skin adverse events were observed in 14 patients (52%). Taken together, tirabrutinib has durable efficacy with an acceptable safety profile for treatment‐naïve and refractory/relapsed Waldenström's macroglobulinemia. [ABSTRACT FROM AUTHOR]

Watchful waiting (WW) is one of the standard approaches for newly diagnosed follicular lymphoma (FL) patients with low‐tumor burden. However, the impact of WW in FL patients at the first progression, remains unclear. We reviewed 206 FL patients who experienced the first progression after responding to the initial treatment at our institution between 1998 and 2017. Patients were classified into either the WW cohort (132 patients) or the immediate treatment cohort (74 patients). Overall, the median follow‐up from the first progression was 79.8 months (range, 2.1–227.0 months). In the WW cohort, the estimated median time to next treatment (TNT) was 19.7 months (95% confidence interval [CI], 13.4–30.2), and 76.5% (95% CI, 68.0–84.1) of the patients subsequently underwent the second‐line treatment at 5 years. There was a significant difference in the median time to treatment failure in the WW cohort (72.8 months; 95% CI, 64.6–94.0) compared to the immediate treatment cohort (23.3 months; 95% CI, 13.4–38.8) (HR, 2.13; 95% CI, 1.48–3.06), whereas overall survival and the cumulative incidence of histological transformation were not significantly different between two cohorts. In a multivariate analysis, rituximab refractory status, progression of disease within 24 months from the induction of first‐line therapy, and a high Follicular Lymphoma International Prognostic Index score at diagnosis were significantly associated with shorter TNT. Interestingly, 15 patients (11%) of the WW cohort experienced spontaneous tumor regression during WW, and their TNT (median, 82.1 months, 95% CI, 11.7‐NA) was longer than that of the remaining patients in the WW cohort (median, 16.5 months, 95% CI, 13.0–25.4), with a significant difference (p = 0.01). The results of the present study suggested that WW could be a safe and reasonable option even at the first progression for the selected FL patients, without a negative impact on clinical outcomes. [ABSTRACT FROM AUTHOR]

The diagnosis of histological transformation of follicular lymphoma can be challenging and ambiguous. We investigated the distribution of the Ki‐67 labeling index of histological transformation of follicular lymphoma and determined its cutoff value to predict poor outcomes. The diagnostic criteria for histological transformation were a diffuse pattern of proliferation and a proportion of large lymphoma cells ≥20%. Of the 1121 patients with follicular lymphoma, 171 (15%) showed histological transformation to diffuse large B‐cell lymphoma. Of these, 76 patients, whose biopsies were obtained from the sites with the highest maximum standardized uptake values, according to the positron emission tomography findings, were included. The Ki‐67 index ranged from 16.8% to 98.4% (median, 60.6%). In patients with histological transformation, the most significant differences were found in progression‐free survival (p = 0.087, 58% vs. 87% at 2 years) and overall survival (p = 0.024, 53% vs. 85% at 5 years) when a 70% cutoff was used. Additionally, overall survival was significantly shorter in patients with histological transformation with maximum standardized uptake values of ≥20 (p < 0.0001) and absence of a follicular lymphoma component (p = 0.004). A Ki‐67 index of ≥70% was a significant adverse factor for overall survival in patients with histological transformation of follicular lymphoma and may predict poor outcomes. [ABSTRACT FROM AUTHOR]

Background: Approximately 15% of patients with diffuse large B‐cell lymphoma (DLBCL) experience refractory or early relapsed disease after initial rituximab‐containing chemoimmunotherapy is regarded as a primary refractory disease. Although the standard treatment for relapsed DLBCL is high‐dose chemotherapy and autologous stem cell transplantation (HDC‐ASCT), the efficacy of this approach for primary refractory DLBCL is not well understood. We aimed to investigate the clinicopathological characteristics and outcomes of patients with primary refractory DLBCL. Methods: Sixty‐nine consecutive patients with primary refractory DLBCL who were treated at our institution were categorized as partial responders (partial response to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone [R‐CHOP] or relapse within 6 months of R‐CHOP) (n = 41) or primary progressors (no response to R‐CHOP) (n = 28). Survival curves were constructed using the Kaplan–Meier method and compared using the log‐rank test. Results: At initial diagnosis, 70% of patients had Ann Arbor stage III/IV disease, 56% had non‐germinal center B‐cell‐like type DLBCL, and 42% had double‐expressor lymphoma (MYC and BCL2 expression). The 3‐year overall survival rate was significantly poorer in the primary progressors group than in the partial responders' group (15% vs. 48%, p < 0.001). Four of 17 patients treated with HDC‐ASCT were primary progressors; only one patient survived without relapse. Although double‐expressor lymphoma status did not significantly impact overall survival among all patients (p = 0.794), it was identified as an independent poor prognostic factor in HDC‐ASCT‐treated patients (p = 0.002). Conclusions: We identified a subgroup of patients with primary refractory DLBCL who may not benefit from current treatment strategies. Further treatment development is needed to improve the outcomes of these patients. [ABSTRACT FROM AUTHOR]

Objectives: In this study, we aimed to determine the clinicopathological factors influencing the treatment‐free period in patients with follicular lymphoma (FL) using a watch‐and‐wait (WW) strategy. Methods: We retrospectively assessed histopathological parameters of 82 patients with FL. Results: The median time from diagnosis to WW discontinuation was 62 months (range, 3‐138), and median follow‐up was 86 months (range, 3‐183). Intermediate or high‐risk Follicular Lymphoma International Prognostic Index score (P =.012), non‐duodenal‐type (P =.011), higher numbers of interfollicular CD4+ (P =.038) and intrafollicular FOXP3+ cells (P =.024) in the tumor microenvironment, and Ki‐67 index ≥10% (P =.031) were significant adverse factors for WW discontinuation in univariate analyses. Conclusion: Patients with adverse factors for WW discontinuation should be carefully observed during follow‐up. [ABSTRACT FROM AUTHOR]

Background: Tazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B‐cell non‐Hodgkin‐type lymphoma (B‐NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity. Methods: Tazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28‐day/cycle manner. Tazemetostat dose‐limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations. Results: As of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B‐cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59‐85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment‐related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment‐related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment. Conclusions: Tazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B‐NHL. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to evaluate the outcomes of local radiotherapy (LRT) in patients with histologic transformation (HT) following rituximab‐containing chemotherapy. Methods: We retrospectively analysed 92 patients with biopsy‐confirmed HT undergoing rituximab‐containing chemotherapy at our institution between 2003 and 2015. Results: Of the 36 patients with limited‐stage disease at diagnosis of HT, 29 (78%) received LRT. The estimated 5‐year progression‐free survival (PFS) rate was significantly better in patients who underwent LRT than in those who did not (93% and 42%, respectively; P < 0.05). Multivariate analyses employing age, sex, performance status, LRT and treatment response demonstrated that LRT was an independent prognostic factor for PFS (hazard ratio [HR]: 11.8; 95% confidence interval [CI]: 1.28‐108.1; P < 0.05). Of the 32 patients who underwent LRT for HT lesion treatment, 31 (97%) did not show disease progression within radiation fields; among them, 27 patients (84%) survived without disease progression during the follow‐up period. One patient developed hypothyroidism due to LRT; the others had no acute or late‐onset complications of LRT. Conclusions: Our data support the recommendation of LRT for HT lesion treatment following rituximab‐containing chemotherapy in select patients with localised HT, as a rational treatment approach with potentially limited toxicity. [ABSTRACT FROM AUTHOR]

Although histologic analysis is the gold standard for diagnosing follicular lymphoma (FL) transformation, many patients are diagnosed with transformation by clinical factors as biopsy specimens often cannot be obtained. Despite the frequency of clinical diagnosis, no clinical assessment tool has yet been established for FL transformation in the rituximab era. We derived and validated a transformation scoring system (TSS) based on retrospective analyses of 126 patients with biopsy‐proven FL and histologic transformation (HT) at two hospitals of the National Cancer Center of Japan. In the derivation set (76 patients), the detailed analyses of the clinical characteristics at disease progression showed that lactate dehydrogenase (LDH) elevation, focal lymph nodal (LN) enlargement, hemoglobin <12 g/dl, and poor performance status (PS) (2‐4) were associated with HT. The weights of these variables were decided based on the regression coefficients. Next, we constructed a TSS encompassing the above four factors: LDH, (> upper limit of normal [ULN], ≤ULN ×2) (1 point), (≥ULN ×2) (2 points); focal LN enlargement, (≥3 cm, <7 cm) (1 point), (≥7 cm) (2 points); hemoglobin <12 g/dl (1 point); poor PS (2 points). We identified a high positive predictive value (PPV) (96.4%) and negative predictive value (NPV) (85.4%) for diagnosing HT when a cutoff score of 2 was selected for our TSS. In an external validation set (50 patients), the probability of HT was high with scores ≥2 (PPV, 93.3%; NPV, 82.9%). We developed a TSS that offers a simple, yet, valuable tool, for diagnosing HT, especially in patients who cannot undergo biopsy. [ABSTRACT FROM AUTHOR]

Tirabrutinib is a second‐generation Bruton's tyrosine kinase inhibitor with greater selectivity than ibrutinib. Here, we conducted a multicenter, phase II study of tirabrutinib in patients with treatment‐naïve (Cohort A) or with relapsed/refractory (Cohort B) Waldenström's macroglobulinemia (WM). Patients were treated with tirabrutinib 480 mg once daily. The primary endpoint was major response rate (MRR; ≥ partial response). Secondary endpoints included overall response rate (ORR; ≥ minor response), time to major response (TTMR), progression‐free survival (PFS), overall survival (OS), and safety. In total, 27 patients (18 in Cohort A; 9 in Cohort B) were enrolled. The median age was 71 y, and the median serum immunoglobulin M level was 3600 mg/dL. Among the patients, 96.2% had the MYD88L265P mutation. MRR and ORR were 88.9% and 96.3%, respectively (Cohort A: MRR, 88.9%; ORR, 94.4%; Cohort B: MRR, 88.9%; ORR, 100%). Median TTMR was 1.87 mo. PFS and OS were not reached with a median follow‐up of 6.5 and 8.3 mo for Cohorts A and B, respectively. The most common adverse events (AEs) were rash (44.4%), neutropenia (25.9%), and leukopenia (22.2%), with most AEs classified as grade 1 or 2. Grade ≥ 3 AEs included neutropenia (11.1%), lymphopenia (11.1%), and leukopenia (7.4%). No grade 5 AEs were noted. All bleeding events were grade 1; none were associated with drug‐related atrial fibrillation or hypertension. Although the follow‐up duration was relatively short, the study met the primary endpoint. Therefore, tirabrutinib monotherapy is considered to be highly effective for both untreated and relapsed/refractory WM with a manageable safety profile. (JapicCTI‐173646). [ABSTRACT FROM AUTHOR]

Aims: The Lugano classification is a novel staging system for lymphomas established in 2014. In this staging system, 18F‐fluorodeoxyglucose‐positron emission tomography/computed tomography (FDG‐PET/CT) was formally incorporated into standard staging for FDG‐avid lymphomas, including Hodgkin lymphoma (HL). We retrospectively analyzed patients with HL who were newly diagnosed and treated at our institution to evaluate the utility of the Lugano classification compared to the Ann Arbor classification in Japanese patients with this type of lymphoma. Methods: Patients newly diagnosed with HL between 2005 and 2011 were identified through our departmental database. Data from neck‐chest‐abdomen‐pelvis CT scans, BM examinations, and FDG‐PET/CT that were routinely performed for staging at our clinical practice were retrieved and analyzed. Results: Fifty‐four patients with a median age of 35.5 years (range: 15‐78 years) were investigated in this retrospective study. The Lugano stage matched the Ann Arbor stage in 46 patients (85%). Six patients (11%) were upstaged while two (4%) were downstaged per the Lugano classification. Four patients (7%) were converted from early stage to advanced stage, but none was converted in the reverse. Among 11 patients (20%) with PET‐positive bone/bone marrow lesions, only one (2%) exhibited biopsy‐proven bone marrow involvement of HL cells. Conclusion: Our data revealed a high concordance rate between the Lugano and Ann Arbor staging system in Japanese patients with HL. Because of its low diagnostic value, routine bone marrow examination might be unnecessary for staging when FDG‐PET/CT is used as a substitute. [ABSTRACT FROM AUTHOR]

This is the first case report of alectinib as a bridge to allo‐SCT in a patient with ALK‐positive ALCL refractory to both conventional chemotherapies and BV. This report offers a ray of hope for a condition with poor prognosis. [ABSTRACT FROM AUTHOR]

Epstein‐Barr virus (EBV) infection is associated with pathogenesis of various cancers, including extranodal natural killer/T‐cell lymphoma, nasal type (ENKL). ENKL tumor cells are positive for EBV‐encoded RNA1 (EBER1), which is the most useful marker to identify ENKL tumor cells in histopathology. Currently, EBER1 in situ hybridization (ISH) is recommended to evaluate bone marrow (BM) involvement of ENKL. However, the actual burden of EBER1‐positive cells in normal BM specimens remains unclear. In the present study, we performed EBER1 ISH on 111 BM specimens, which were obtained during an initial staging procedure in patients with EBV‐negative cancers and were also negative for BM involvement. One or more EBER1‐positive cells per whole specimen were observed in 38 specimens (34%). The number of EBER1‐positive cells was distributed as follows: single positive cell, n = 17; two positive cells, n = 13; three positive cells, n = 3; and four positive cells, n = 5. These findings suggest that four or fewer EBER1‐positive cells can be observed in BM specimens of patients with non‐EBV‐related cancers. The clinical implications of a small number of EBER1‐positive cells in BM specimens of patients with ENKL should be evaluated in further studies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: We aimed at investigating the relationship between classical Hodgkin lymphoma (cHL), primary mediastinal large B‐cell lymphoma (PMBL), and gray zone lymphoma (GZL) with intermediate characteristics between cHL and PMBL, from the perspective of the aberration in programed cell death 1 and the programed death ligands (PDLs) network. Methods: We explored the expression levels of PDLs and chromosomal anomalies in 67 cases: 34 cases with cHL, 20 with PMBL, and 13 with GZL, using immunohistochemical analyses and Fluorescence In Situ Hybridization (FISH). Results: Twenty‐one cHL (62%), 3 PMBL (15%), and 6 GZL (46%) cases showed staining to PD‐L1 antibodies in more than 70% of tumor cells. Two cHL (6%), 10 PMBL (50%), and 3 GZL (23%) cases were not stained by PD‐L1 antibodies. Patients over 40 years old manifest more frequent expression of PD‐L1 in cHL. Proportion of tumors stained by PD‐L2 antibody was increased in PMBL. FISH analyses with a PD‐L1/PD‐L2 probe detected 5 amplification, 1 gain, and 7 polysomy cases in cHL, 1 amplification and 1 polysomy case in GZL, and amplification in 1 PMBL case. Conclusion: We identified increased staining of PD‐L1 in cHL and that of PD‐L2 in PMBL. GZL had a pattern similar to that of cHL. [ABSTRACT FROM AUTHOR]

The hedgehog signaling pathway regulates multiple morphogenetic processes during embryogenesis. Aberrant activation of the hedgehog pathway signal transduction in adult tissues is associated with the pathogenesis of hematologic malignancies and solid tumors. We report findings from an open-label, multicenter phase I trial of the selective, small-molecule hedgehog signaling inhibitor glasdegib ( PF-04449913) in Japanese patients with select advanced hematologic malignancies. Glasdegib was administered as once-daily oral doses (25, 50 and 100 mg) in 28-day cycles after a lead-in dose on Day −5. The primary objectives were to determine first-cycle dose-limiting toxicities, safety, vital signs and laboratory test abnormalities. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics and preliminary evidence of clinical activity of glasdegib. No dose-limiting toxicities were noted in the 13 patients in the present study. All patients experienced at least one treatment-emergent, all-causality adverse event. The most frequent treatment-related adverse events (observed in ≥3 patients) were dysgeusia ( n = 9), muscle spasms ( n = 5), alopecia, decreased appetite ( n = 4 each), and increased blood creatinine phosphokinase, constipation and diarrhea ( n = 3 each). Two deaths occurred during the study and were deemed not to be treatment-related due to disease progression. Glasdegib demonstrated dose-proportional pharmacokinetics, marked downregulation of the glioma-associated transcriptional regulator GLI1 expression in normal skin, and evidence of preliminary clinical activity, although data are limited. Glasdegib was safe and well tolerated across the dose levels tested. It is confirmed that the 100-mg dose is safe and tolerable in Japanese patients, and this dose level will be examined in the future clinical trial. [ABSTRACT FROM AUTHOR]

This study analysed incidence, patient outcome, immunophenotype and prognostic factors of histological transformation ( HT) from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue ( MALT lymphoma) to diffuse large B-cell lymphoma ( DLBCL) in 467 patients (median age, 61 years). The primary sites of MALT lymphoma were the stomach (43%), ocular adnexa (25%), lung (8%), systemic (8%) and other tissues (16%). HT occurred in 8% of MALT lymphomas. Risk of HT by 15 years was 5%: 4% in limited-stage diseases ( n = 385) and 16% in advanced-stage diseases ( n = 56) ( P = 0·02). The median time to HT was 48 months (range, 4-139). Five-year progression-free survival ( PFS) and overall survival ( OS) rates after HT were 80% and 94%, respectively. Immunohistochemical results of DLBCL were as follows: germinal centre B-cell ( GCB)/non- GCB, 37%/63%; CD10, 9%; BCL6, 59%; MUM1, 38%; MYC, 42%; BCL2, 35%; Ki67 ≥ 90%, 23%; and CD5, 3%. The majority (75%, 9/12) of GCB-type DLBCLs exhibited CD10−, BCL6+ and MUM1− immunophenotypes; the remainder had CD10+ immunophenotypes. Multivariate analysis revealed that only advanced stage at HT was a significant adverse factor for PFS ( P = 0·037). Thus, overall risk of HT was low and prognosis after HT was favourable; however, in advanced-stage cases, risk of HT was relatively high and prognosis was unfavourable. [ABSTRACT FROM AUTHOR]

We carried out a multicenter dose-escalation phase I study of oral OPB-51602, a signal transducer and activator of transcription 3 phosphorylation inhibitor, in patients with relapsed or refractory hematological malignancies to evaluate the safety, maximum tolerated dose ( MTD), pharmacokinetics, and preliminary antitumor activity. Twenty patients were treated with OPB-51602 at doses of 1, 2, 3, 4, and 6 mg in the '3 + 3' dose escalation design. The most common treatment-related adverse events included nausea (55%), peripheral sensory neuropathy (45%), and diarrhea (40%). The most frequently observed grade 3 or 4 drug-related adverse events were neutropenia (20%), leukopenia (15%), lymphopenia (10%), and thrombocytopenia (10%). The MTD was 6 mg, with dose-limiting toxicities of grade 3 lactic acidosis and increased blood lactic acid levels observed in one of three patients and grade 1-2 peripheral neuropathy in three of three patients. The recommended dose was determined to be 4 mg. OPB-51602 was rapidly absorbed, and exposure tended to increase in a dose-dependent manner. Accumulation of OPB-51602 was seen with 4 weeks of multiple treatments. No clear therapeutic response was observed. Durable stable disease was observed in two patients with acute myeloid leukemia and one with myeloma. In conclusion, the MTD of OPB-51602 was 6 mg. OPB-51602 was safe and well tolerated in a dose range of 1-4 mg. However, long-term administration at higher doses was difficult with the daily dosing schedule, and no response was seen. Therefore, further clinical development of OPB-51602 for hematological malignancies with a daily dosing schedule was terminated. [ABSTRACT FROM AUTHOR]

The article discusses research on incidental detection of malignant lymphoma in a cancer surveillance programme in Japan. Topics discussed include use of usefulness of [18F] fluoro-deoxyglucose (FDG) positron emission tomography/computerized tomography (PET/CT) in monitoring cancer, demonstration of superiority of PET/CT over conventional scintigraphy for diagnosing malignant lymphoma (ML), and diagnosis of mucosa-associated lymphoid tissue (MALT) lymphoma of the gastrointestinal tract.

To investigate the clinicopathological and prognostic significance of a nodular pattern and immunophenotypes in primary mediastinal large B-cell lymphoma ( PMBL), histopathological features, including a nodular pattern and immunophenotypes, were analyzed in 58 Japanese PMBL patients. The patients were 23 men and 35 women with a median age of 31 years. The 4-year progression free survival ( PFS) rate was 78%, and the 4-year overall survival ( OS) rate was 89%. Among the histopathological and immunohistochemical features, Bcl6+ ( P = 0.013), MUM1+ ( P = 0.091), and pale cytoplasm ( P = 0.064) were favorable prognostic indicators of PFS, and Bcl6+ ( P = 0.051) and MUM1+ ( P = 0.07) were favorable prognostic indicators of OS. Patients with Bcl2 negativity ( n = 11) had 4-year PFS and OS rates of 100%. Histologically, a nodular pattern, resembling nodular sclerosis classical Hodgkin lymphoma ( CHL), was observed in 22 patients (38%). However, this was not a significant prognostic indicator. In conclusion, Bcl6+, MUM1+, Bcl2-, and pale cytoplasm are candidate favorable prognostic indicators for PMBL and should be further examined in larger studies. We suggest that PMBL with a nodular pattern may belong to the same histological spectrum as nodular sclerosis CHL. [ABSTRACT FROM AUTHOR]

This study aimed to clarify the clinicopathological prognostic parameters of de novo diffuse large B-cell lymphoma ( DLBCL) in the rituximab era. We examined the correlation of 22 clinicopathological parameters with progression-free survival ( PFS), overall survival ( OS), and primary refractory disease in 285 DLBCL patients treated with rituximab-containing chemotherapy. Complete response rate was 87%, overall response rate was 91%, 5-year PFS rate was 72%, and 5-year OS rate was 91%. By log-rank test, higher International Prognostic Index ( IPI) ( P < 0.0001), Bcl-2 positivity ( P = 0.0013), Bcl-6 negativity ( P = 0.0112), and no irradiation ( P = 0.0371) were significantly correlated with shorter PFS; higher IPI ( P = 0.0107), starry sky pattern ( P = 0.0466), and no irradiation ( P = 0.0264) correlated with shorter OS. In multivariate analyses, higher IPI ( P = 0.0006), Bcl-2 positivity ( P = 0.0015), and Bcl-6 negativity ( P = 0.04) were significantly correlated with shorter PFS; higher IPI ( P = 0.0045) correlated with shorter OS. Bcl-2 ( P = 0.0029), Bcl-6 ( P = 0.002), and IPI ( P < 0.0001) were significantly correlated with primary refractory disease. In conclusion, Bcl-2 positivity, Bcl-6 negativity, and higher IPI were indicators of shorter PFS and OS plus primary refractory disease in patients with DLBCL in the rituximab era. [ABSTRACT FROM AUTHOR]

Objectives: Primary breast lymphoma (PBL) is rare, and its clinical behavior and standard initial treatment are not yet established. Methods: We retrospectively analyzed the clinicopathological features and treatment outcomes of 14 patients with primary breast diffuse large B-cell lymphoma. Results: There were nine patients with stage IE and five with stage IIE disease. The median largest tumor diameter was 4.5 cm, and five patients had bulky disease >5 cm. The complete response rate was 94%. However, the 5-year progression-free survival rate was 52% with a median follow-up of 5.2 years. Patients with bulky disease had an unfavorable prognosis. All five patients with bulky disease progressed or relapsed. Of the four patients that recurred in the central nervous system (CNS), three had bulky disease although some received rituximab. There were no CNS recurrences in the three patients who received CNS prophylaxis. All eight patients who responded to radiotherapy (RT) did not have recurrences in the ipsilateral breast, although one patient with bulky disease relapsed in the adjacent regional lymph nodes within the RT field despite immunochemotherapy. Conclusions: Patients with bulky disease had a poorer prognosis and recurred frequently in the CNS. CNS prophylaxis might yield better outcomes, but a larger, prospective trial is needed to elucidate the optimal initial treatment of PBL in the rituximab era. [ABSTRACT FROM AUTHOR]