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E7777 is a recombinant cytotoxic fusion protein composed of the diphtheria toxin fragments A and B and human interleukin‐2. It shares an amino acid sequence with denileukin diftitox, but has improved purity and an increased percentage of active monomer. We undertook a multicenter, single‐arm phase II study of E7777 in patients with relapsed or refractory peripheral T‐cell lymphoma (PTCL) and cutaneous T‐cell lymphoma (CTCL) to evaluate its efficacy, safety, pharmacokinetics, and immunogenicity. A total of 37 patients were enrolled, of which 17 and 19 patients had PTCL and CTCL, respectively, and one patient with another type of lymphoma (extranodal natural killer/T‐cell lymphoma, nasal type), diagnosed by the Central Pathological Diagnosis Committee. Among the 36 patients with PTCL and CTCL, objective response rate based on the independent review was 36% (41% and 31%, respectively). The median progression‐free survival was 3.1 months (2.1 months in PTCL and 4.2 months in CTCL). The common adverse events (AEs) observed were increased aspartate aminotransferase (AST) / alanine aminotransferase (ALT), hypoalbuminemia, lymphopenia, and pyrexia. Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common AEs were manageable, but increase in ALT / AST, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment., Among 36 patients with refractory peripheral T‐cell lymphoma (PTCL) and cutaneous T‐cell lymphoma (CTCL), objective response rate based on the independent review was 36% (41% in PTCL and 31% in CTCL). Our results indicated that a 9 µg/kg/d dose of E7777 shows efficacy and a manageable safety profile in Japanese patients with relapsed or refractory PTCL and CTCL, with clinical activity observed across the range of CD25 expression. The common adverse events were manageable, but increase in alanine aminotransferase / aspartate aminotransferase, hypoalbuminemia, and capillary leak syndrome should be carefully managed during the treatment.

We conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)‐positive patients with diffuse large B‐cell lymphoma (DLBCL) and 278 HBsAg‐negative patients with DLBCL, as a control cohort, who received rituximab‐containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation‐related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg‐positive patients were divided into three groups based on anti–HBV prophylactic therapy: no nucleos(t)ide analogue (non–NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4‐year cumulative incidence (CI) of hepatitis in HBsAg‐positive and HBsAg‐negative patients was 21.1% and 14.6% (P = .081), respectively. The 4‐year CI of HBV reactivation‐related hepatitis was higher in HBsAg‐positive patients than in HBsAg‐negative patients (8.0% vs 0.4%; P, Prophylactic use of entecavir reduced HBV‐related hepatitis and mortality in HBsAg‐positive DLBCL treated with R‐chemotherapy. The 4‐year overall survival rate in HBsAg‐positive DLBCL patients receiving prophylactic entecavir was similar to that in HBsAg‐negative DLBCL.

For patients who have chronic myeloid leukemia (CML), one of the primary treatment options is administration of nilotinib 300 mg twice daily (BID). In previous studies which compared outcomes associated with nilotinib or imatinib treatment, nilotinib achieved a higher rate of deep molecular response (MR). We conducted a phase II, open‐label, multicenter study to investigate an intrapatient nilotinib dose‐escalation strategy for patients with newly diagnosed chronic‐phase (CP) CML based on early MR4.5 achievement. The primary study endpoint was achievement of MR4.5 by 24 months following the initiation of nilotinib 300 mg BID. Fifty‐three patients were enrolled, 51 received nilotinib, and 37 completed the treatment. An increase in the nilotinib dose (to 400 mg BID) was allowed when patients satisfied our criteria for no optimal response at any time point. The median (range) dose intensity was 600 (207‐736) mg/day. Of 46 evaluable patients, 18 achieved an optimal response and 28 did not. Of the latter, nine patients underwent dose escalation to 400 mg BID, and none achieved MR4.5. The remaining 19 patients could not undergo dose escalation, 12 (63%) because of adverse events (AEs), and 7 (37%) for non‐AE related reasons. Four of these patients achieved MR4.5. The MR4.5 rate by 24 months was 45.7%. The progression‐free, overall and event‐free survival were each 97.6%. No new safety concerns were observed. Our findings support the use of continuous nilotinib at a dose of 300 mg BID for newly diagnosed patients with CML‐CP., The N‐Road study aimed to determine the optimal treatment strategy for nilotinib use in patients with newly diagnosed CML‐CP based on early achievement of deep molecular response. Most patients received nilotinib at a dose of 300 mg BID and were able to achieve an early deep molecular response. Together with the finding that none of the patients whose dose was escalated to 400 mg BID achieved MR4.5, we consider that continuous nilotinib at a dose of 300 mg BID may be the optimal treatment strategy for newly diagnosed patients with CML‐CP.

Dasatinib is one of the key treatment options for chronic myeloid leukemia (CML) patients. Increase in lymphocyte counts has been known to be predictive of a good treatment response under dasatinib treatment as a second line therapy. However, clinical significance of lymphocyte dynamics in the upfront setting has yet to be clarified. To investigate the significance of lymphocyte dynamics in newly diagnosed chronic phase (CP)-CML, patient data of D-First study (ClinicalTrials.gov NCT01464411) were analyzed. Fifty-two CML-CP patients enrolled to this study were treated with dasatinib (100 mg day(-1) ) and all were followed-up for 18 months. The incidence of lymphocyosis was observed in 14 (27%), but it was not associated with deep molecular response achievement. However, natural killer (NK) cell or cytotoxic T lymphocyte (CTL) counts at 1 month were significantly higher in patients with deep molecular response (DMR) by 18 months compared to those without DMR. When the patients were divided into two groups according to those calculated thresholds by receiver operating characteristic curve (407/μL for NK cells and 347/μL for CTLs), the cumulative DMR rates by 18 months were significantly better in higher value group compared to lower value group. In contrast, regulatory T cell counts were significantly lower at 12 and 15 months in patients achieved DMR. These results suggest the presence of dual effects of dasatinib on immune system through the cytotoxic lymphocytes activation and Treg deregulation in different periods in newly diagnosed CML-CP.

CHOP combined with rituximab (R-CHOP) is regarded as one of the most effective treatments for indolent B-cell non-Hodgkin lymphoma (B-NHL), however, its optimal combination schedule remains unknown. We performed a randomized phase II study to explore a more promising schedule in untreated, advanced indolent B-NHL. Patients were randomized to receive either six courses of CHOP concurrently with rituximab (Arm C), or six courses of CHOP followed by six courses of weekly rituximab (Arm S). A total of 69 patients received the concurrent (n=34) or sequential (n=35) regimen. Overall response rate (ORR) in Arm C was 94% (95% confidence interval [CI], 79 to 99), including a 66% complete response (CR) compared with 97% (95% CI, 85-100), including a 68% CR in Arm S. Patients in Arm C experienced more grade 4 neutropenia (85%versus 70%) and experienced more grade 3 or greater non-hematological toxicities (21%versus 12%). Both arms were tolerated well. With a median follow-up of 28.2 months, the median progression-free survival (PFS) time was 34.2 months in Arm C, and was not reached in Arm S. R-CHOP is highly effective in untreated indolent B-NHL, either concurrent or in a sequential combination. Both combination schedules deserve further investigation.

We conducted a phase I study to evaluate the safety and efficacy of radioimmunotherapy with yttrium-90-ibritumomab tiuxetan (Y2B8) in Japanese patients with relapsed or refractory indolent B-cell lymphoma. Indium-111-labeled ibritumomab tiuxetan (In2B8; 3.5 or 5 mCi [129.5 or 185 MBq]) was administered on day 1, followed by serial gamma-camera imaging to investigate the distribution of In2B8 in the whole body of patients and to judge the feasibility of Y2B8 administration. Y2B8 with a dose of 0.3 mCi/kg (11.1 MBq/kg) or 0.4 mCi/kg (14.8 MBq/kg) was administered on day 8. Grade 4 neutropenia and grade 3 thrombocytopenia were observed in three of nine of the patients evaluated for safety. Critical toxicities (prolonged thrombocytopenia or severe non-hematological toxicities) were observed in two of six patients in the 0.4 mCi/kg (14.8 MBq/kg) dose group but were not seen in any of the three patients in the 0.3 mCi/kg (11.1 MBq/kg) dose group. The non-hematological toxicities of the nine patients were of grade 2 or less, except in two patients who had been heavily treated previously. They experienced critical toxicities such as infection, diarrhea, hyponatremia and prolonged thrombocytopenia, as well as other frequent grade 2 non-hematological toxicities. Although the pharmacokinetic profiles were similar to those in the US study, one of the two patients was clarified retrospectively as showing abnormal biodistribution of In2B8 in the bone marrow, as judged by an independent third party panel of radiologists. Five of the 10 participants achieved complete responses or unconfirmed complete responses and two partial responses. In conclusion, the recommended dose of Y2B8 for the subsequent phase II study for Japanese patients is 0.4 mCi/kg (14.8 MBq/kg). This dose of radioimmunotherapy was feasible when patients with altered biodistribution of In2B8 were excluded, and it was highly effective. (Cancer Sci 2005; 96: 903-910).

PSC-833 reverses multidrug resistance by P-glycoprotein at concentrationsor = 1000 ng / ml. A phase I study of PSC-833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC-833 was intravenously infused as a 2-h loading dose (LD) and a subsequent 24-h continuous dose (CD). Doxorubicin was infused over 5 min, 1 h after the LD. The starting dose was 1 mg / kg for both LD and CD with 30 mg / m(2) doxorubicin; these dosages were increased to 2 and 10 mg / kg and 50 mg / m(2), respectively. Thirty-one patients were treated. Nausea / vomiting was controllable with granisetron and dexamethasone. Neutropenia and ataxia were dose limiting. Steady-state concentrations of PSC-8331000 ng / ml were achieved at a 2 mg / kg LD and a 10 mg / kg CD. Ex-vivo bioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC(50) of P-glycoprotein expressing 8226 / Dox(6) in patients' serum was decreased from 5.9 to 1.3 microg / ml (P0.0001) by PSC-833 administration. Doxorubicin clearance was 24.3 +/- 13.7 (mean +/- SD) liter / h/m(2), which was lower than the 49.0 +/- 16.9 liter / h/m(2) without PSC-833 (P0.0001). The relationship between doxorubicin exposure and neutropenia did not differ between patients treated and not treated with PSC-833. The recommended phase II dose of PSC-833 was 2 and 10 mg / kg for LD and CD, respectively, which achieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay. The dose of doxorubicin should be reduced to 40 mg / m(2), not because of the pharmacodynamic interaction between PSC-833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.

The objective of this study was to develop a limited sampling model (LSM) to estimate the area under the curve (AUC) of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and that of 7-ethyl-10-hydroxycamptothecin (SN-38) as predictive pharmacokinetic variables for leukopenia and episodes of diarrhea induced by CPT-11 administration. The model was developed with a training set consisting of pharmacokinetic studies in 36 patients who received a 90-min i.v. infusion of CPT-11 at a dose of 100 mg/m2. A multiple regression analysis of CPT-11 or SN-38 concentrations observed at each time point in the training set was used to predict the AUC of CPT-11 or SN-38. The final sampling models using only two time points were: AUCCPT-11=3.7891★C2.5+14.0479*C13.5+1.5463 AUCSN-38=0.5319★C2.5+19.1468*C13.5+72.7349 where C2.5 and C13.5 are the plasma concentration of CPT-11 (μg/ml) or SN-38 (ng/ml) at 2.5 and 13.5 h after the initiation of CPT-11 infusion, respectively. The models were validated prospectively on a separate test data set of 12 patients receiving the same dose of CPT-11 investigated in a previous study. Validation of the final LSM on the test data set gave values of root mean square error (RMSE) of 12.72% and 5.97% for the AUC of CPT-11 and that of SN-38, respectively. The model can be used to monitor the AUCs of both CPT-11 and SN-38 for the early prediction of toxicities and to establish a pharmacokinetically based dose modification strategy for safe administration of CPT-11.

The pharmacokinetics of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), were examined to establish the pharmacokinetic variability of the active lactones of CPT-11 and SN-38 in comparison with that of the total (lactone and carboxylates) plasma CPT-11 and SN-38. Twelve patients with malignancies were entered in the study. All received 100 mg/m2 of CPT-11 by intravenous drip infusion over 90 min. Blood was sampled at 10 time points in heparin-containing syringes. Analysis by high-performance liquid chromatography showed that the ratio of CPT-11 lactone to total CPT-11 concentration was highest (66%) just after the end of infusion and gradually decreased to 30% at 24 h. Almost 70% of SN-38 lactone was detected after the end of infusion and this decreased to 50% within 24 h. The standard errors of percent lactone of CPT-11 of SN-38 to total drug concentration at each sampling point were less than 12%. The area under the concentration-time curve (AUC) of total CPT-11 and that of total SN-38 were significantly correlated with the AUCs of the lactone CPT-11 and those of lactone SN-38, respectively. We conclude that, for practical purposes, monitoring of total CPT-11 and SN-38 has essentially the same clinical significance as monitoring of lactone CPT-11 and SN-38.

Inactivation of the retinoblastoma susceptibility (Rb) gene has been observed in various cancers. Nevertheless, in several cancer cases, including non-Hodgkin's lymphoma, previous investigations showed that the Rb gene product (pRb) was abundantly expressed with varying degree. Here we report the THS-SP1.1 cell line isolated from non-Hodgkin's lymphoma. The THS-SP1.1 cells abundantly expressed pRb and showed resistance against radiation-induced apoptosis. Culture with the antisense phosphorothioate oligonucleotide complementary to the Rb gene augmented the apoptosis of THS-SP1.1 cells after radiation, whereas the control oligonucleotides did not. These data showed that pRb abundantly expressed in the lymphoma cells inhibited radiation-induced apoptosis.