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 ( AE s) were rash (35.3%) and vomiting (29.4%). Eight patients (47.1%) developed grade ≥3 AE s: 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 CD 79A/B or MYD 88 mutations, and 1 CLL patient with a TP 53 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.

E7777, a recombinant cytotoxic fusion protein comprising diphtheria toxin fragments A and B and human interleukin‐2, shares an amino acid sequence with denileukin diftitox but has improved purity and an increased percentage of active protein monomer species. A phase I study was carried out to evaluate the tolerability, safety, pharmacokinetics, and antitumor activity of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T‐cell lymphoma. E7777 (6, 12, and expanded 9 μg/kg/day) was given to 13 patients by i.v. infusion on five consecutive days per 21‐day cycle. Dose‐limiting toxicities, including increased alanine aminotransferase, hyponatremia (n = 2), hypokalemia, lymphopenia, fatigue, hypoalbuminemia, rash, and increased lipase (n = 1), were observed in all three patients in the 12 μg/kg/day cohort, whereas two of six patients in the 9 μg/kg/day cohort showed decreased appetite or fatigue. The maximum tolerated and recommended dose of E7777 was 9 μg/kg/day for five consecutive days per 21‐day cycle. The objective response rate was 38% (5/13) and did not appear to depend on tumor expression of CD25. E7777 was well tolerated, assuming careful management of adverse events during treatment, and preliminary but clinically meaningful antitumor activity was observed. Subsequent studies of E7777 for T‐cell lymphomas are warranted. This study was registered with www.ClinicalTrials.gov (NCT1401530).

The Japan Clinical Oncology Group conducted two multicenter phase II trials in 200 patients with advanced Hodgkin lymphoma (HL) in the 1990s. Among 181 patients whose histopathological specimens were available and reviewed by 6 hematopathologists, 167 (92.3%) were diagnosed with HL. Five-year overall survival (OS) among these 167 patients was 88.3%, including 89.2% among nodular sclerosis and 82.2% among mixed cellularity cases. International prognostic score was not closely associated with OS. Seven unfavorable prognostic factors for OS on univariate analysis were male, B symptoms, clinical stage of III or IV, elevated serum LDH, elevated alkaline phosphatase, elevated beta2-microglobulin, and pathological subtype (mixed cellularity and lymphocyte depletion). On multivariate analysis, male [HR 3.30 (95% CI 1.15-9.52, p = 0.027)] and elevated serum LDH [HR 2.41 (95% CI 1.07-5.43, p = 0.034)] were independent factors for OS. Based on these prognostic factors, the 5-year OS was 95.7% in the low-risk group (no adverse factor), 87.9% in the intermediate-risk group (1 adverse factor) and 73.3% in the high-risk group (2 adverse factors). This simple prognostic model for HL warrants further validation studies.

BACKGROUNDIrinotecan hydrochloride (CPT‐11) has a broad range of antitumor activity and has demonstrated little cross‐resistance with doxorubicin or vincristine. In the current study, the authors investigated the efficacy and adverse effects of irinotecan in the treatment of recurrent and refractory non‐Hodgkin lymphoma, for which current therapies appear to be unsatisfactory.METHODSIrinotecan was administered by intravenous infusion at a dose of 40 mg/m2/day for 3 days, and this regimen was repeated 2–3 times at weekly intervals, followed by 2 weeks off therapy. The subjects were 48 patients with recurrent or refractory non‐Hodgkin lymphoma. The histologic classification (Working Formulation) was low grade in 8 patients, intermediate grade in 36 patients, high grade in 1 patient, and other (angiocentric lymphoma, Ki‐1 lymphoma, and unidentified) in 3 patients.RESULTSForty‐five patients were determined to be evaluable. Therapy resulted in a complete disease remission in 2 patients and a partial remission in 15 patients. The response rate was 37.8%. The median duration of response was 64 days and the median time to disease progression was 77 days. The median survival time was 422 days. Major adverse reactions included myelosuppression and gastrointestinal toxicity. Leukopenia, anemia, and thrombocytopenia of Grade 3 or 4 (according to the National Cancer Institute Common Toxicity Criteria) was observed in 63.0%, 30.4%, and 6.5% of the patients, respectively, and Grade 3 or 4 diarrhea occurred in 30.4% of patients. Treatment was withdrawn because of diarrhea in three patients. Because of myelosuppression and diarrhea, approximately 67% of the patients required changes to the regimen, including dose reduction, prolongation of the interval between treatments, and reducing the number of days of consecutive treatment.CONCLUSIONSThe results of the current study suggest the activity of irinotecan as salvage therapy for patients with recurrent and refractory non‐Hodgkin lymphoma. However, the optimum dosing schedule remains to be determined. Cancer 2002;94:594–600. © 2002 American Cancer Society.DOI 10.1002/cncr.10266

Although cladribine has been reported to be an active purine analog against indolent B-cell non-Hodgkin lymphoma (B-NHL), there are few reports of combination use of cladribine and rituximab. This multicenter phase II study evaluated the efficacy and toxicity of cladribine with rituximab (R-2-CdA) therapy in relapsed or refractory indolent B-NHL. Twenty patients with the median age of 58.5 yrs (range, 42-72) were enrolled and received R-2-CdA therapy from April 2005 to July 2007. The median number of prior regimens was 2 (range, 1-3), and fifteen patients (75%) were previously treated with rituximab-containing regimens. Disease histology included follicular lymphoma in 16 patients, MALT lymphoma in two patients, nodal marginal B-cell lymphoma in one patient, and lymphoplasmacytic lymphoma in one patient. The overall response rate (ORR) was 90%, with a complete response rate (CRR) of 70%. Estimated median progression-free survival (PFS) time was 22.4 months (95%CI, 10.9-32.6 months) at a median follow-up time of 27 months (range, 12-43). Two-year PFS and 2-yr overall survival (OS) were 52.6% (95%CI, 31.0-73.2%) and 89.5% (95%CI, 66.1-97.3%), respectively. Grade 3 or grade 4 toxicities were neutropenia in 74% and thrombocytopenia in 11%. R-2-CdA therapy was demonstrated to have a high activity with durable PFS and acceptable toxicity in relapsed or refractory indolent B-NHL mostly pretreated with rituximab-containing therapy. Although a large-scale trial is needed for confirmation, R-2-CdA therapy could be a good salvage therapy option in relapsed or refractory indolent B-NHL.