Oral HDAC inhibitor tucidinostat in patients with relapsed or refractory peripheral T-cell lymphoma: phase IIb results.

Tucidinostat (formerly known as chidamide) is an orally available, novel benzamide class of histone deacetylase (HDAC) inhibitor that selectively blocks class I and class IIb HDAC. This multicenter phase IIb study aimed to investigate the efficacy and safety of tucidinostat, 40 mg twice per week (BIW), in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL). The primary endpoint was overall response rate (ORR) assessed by an independent overall efficacy review committee. Between March 2017 and March 2019, 55 patients were treated, and 46 and 55 were evaluated for efficacy and safety, respectively. Twenty-one of 46 patients achieved objective responses with an ORR of 46% (95% confidence interval : 30.9-61.0), including five patients with complete response (CR). Responses were observed across various PTCL subtypes. In angioimmunoblastic T-cell lymphoma, there were two CR and five partial responses (PR) among eight patients, achieving an ORR of 88%. The disease control rate (CR + PR + stable disease) was 72% (33/46). The median progression-free survival, duration of response, and overall survival were 5.6 months, 11.5 months, 22.8 months, respectively. The most common adverse events (AE) (all grades) were thrombocytopenia, neutropenia, leukopenia, anemia, and diarrhea. The grade ≥3 AE emerging in ≥20% of patients included thrombocytopenia (51%), neutropenia (36%), lymphopenia (22%), and leukopenia (20%). Importantly, most of the AE were manageable by supportive care and dose modification. In conclusion, the favorable efficacy and safety profiles indicate that tucidinostat could be a new therapeutic option in patients with R/R PTCL (clinicaltrials gov. Identifier: NCT02953652).

Thermal Proteome Profiling Reveals Glutathione Peroxidase 4 as the Target of the Autophagy Inducer Conophylline.

Conophylline (CNP) is a vinca alkaloid extracted from the Tabernaemontana divaricata plant. It has been reported that CNP induces autophagy in a mammalian target of rapamycin-independent manner, and thereby inhibits protein aggregation. However, the mode of action of CNP in inducing autophagy remains unknown. In this study, we identified glutathione peroxidase 4 (GPX4) as a CNP-binding protein by using thermal proteome profiling. The technique exploits changes in the thermal stability of proteins resulting from ligand interaction, which is capable of identifying compound-binding proteins without chemical modification. GPX4, an antioxidant protein that uses reduced glutathione as a cofactor, directly catalyzes the reduction of hydrogen peroxide, organic hydroperoxides, and lipid peroxides. GPX4 suppresses lipid peroxide accumulation, and thus plays a key role in protecting cells from oxidative damage. We found that treatment with CNP caused accumulation of lipid reactive oxygen species (ROS) in cultured cells. Furthermore, similarly with CNP treatment, GPX4 deficiency caused accumulation of lipid ROS and induced autophagy. These findings indicate that GPX4 is a direct target of CNP involved in autophagy induction. SIGNIFICANCE STATEMENT: The present study identified glutathione peroxidase 4 (GPX4) as a binding protein of conophylline (CNP) by using thermal proteome profiling (TPP). This study showed that CNP treatment, similarly with the inhibition of GPX4, induced lipid reactive oxygen species accumulation and autophagy. The present findings suggest that GPX4 is the CNP target protein involved in autophagy induction. Furthermore, these results indicate that TPP is a useful technique for determining the mechanism of natural compounds.

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).

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 .

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

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.

Occurrence of Infusion-Related Reactions due to Obinutuzumab Therapy for Follicular Lymphoma.

BACKGROUND: Obinutuzumab is used to treat follicular lymphoma in Japan. Its characteristic adverse event is infusion- related reactions(IRRs). Although interruption of administration improves many IRRs, serious symptoms can occur; thus, timing the interruption to correspond with the onset of these symptoms is necessary. However, the specific symptoms and timing of IRRs caused by obinutuzumab remain unclear. Therefore, the purpose of this study was to clarify the specific symptoms and timing of the onset of IRRs with obinutuzumab treatment. METHODS: Thirty patients were administered obinutuzumab for one year from October 2018 to September 2019. The frequency of IRRs, expression time, severity, symptoms, and correspondence were investigated. RESULTS: IRRs occurred in 13 patients(43.3%), and all occurred after the first dosing. In 9 of 13 cases(69.2%), IRRs occurred within 90 min of the first dosage. Grade 3 symptoms were expressed in 1 of 13 cases (7.7%). The symptoms of IRRs were throat discomfort, breathing difficulty, skin rash, chills, and fever. CONCLUSIONS: Most IRRs due to obinutuzumab occurred within 90 min of the first dosage. They were mostly Grade 2 or lower, and the frequency of serious IRRs was low. Thus, careful observation of symptoms during treatment with obinutuzumab is necessary.

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).

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.

Chitin Heterodisaccharide, Released from Chitin by Chitinase and Chitin Oligosaccharide Deacetylase, Enhances the Chitin-Metabolizing Ability of Vibrio parahaemolyticus.

Vibrio parahaemolyticus RIMD2210633 secretes both chitinase and chitin oligosaccharide deacetylase and produces ß-N-acetyl-d-glucosaminyl-(1,4)-d-glucosamine (GlcNAc-GlcN) from chitin. Previously, we reported that GlcNAc-GlcN induces chitinase production by several strains of Vibrio harboring chitin oligosaccharide deacetylase genes (T. Hirano, K. Kadokura, T. Ikegami, Y. Shigeta, et al., Glycobiology 19:1046-1053, 2009). The metabolism of chitin by Vibrio was speculated on the basis of the findings of previous studies, and the role of chitin oligosaccharide produced from chitin has been well studied. However, the role of GlcNAc-GlcN in the Vibrio chitin degradation system, with the exception of the above-mentioned function as an inducer of chitinase production, remains unclear. N,N'-Diacetylchitobiose, a homodisaccharide produced from chitin, is known to induce the expression of genes encoding several proteins involved in chitin metabolism in Vibrio strains (K. L. Meibom, X. B. Li, A. Nielsen, C. Wu, et al., Proc Natl Acad Sci U S A 101:2524-2529, 2004). We therefore hypothesized that GlcNAc-GlcN also affects the expression of enzymes involved in chitin metabolism in the same manner. In this study, we examined the induction of protein expression by several sugars released from chitin using peptide mass fingerprinting and confirmed the expression of genes encoding enzymes involved in chitin metabolism using real-time quantitative PCR analysis. We then confirmed that GlcNAc-GlcN induces the expression of genes encoding many soluble enzymes involved in chitin degradation in Vibrio parahaemolyticus Here, we demonstrate that GlcNAc-GlcN enhances the chitin-metabolizing ability of V. parahaemolyticusIMPORTANCE We demonstrate that ß-N-acetyl-d-glucosaminyl-(1,4)-d-glucosamine (GlcNAc-GlcN) enhances the chitin-metabolizing ability of V. parahaemolyticus Members of the genus Vibrio are chitin-degrading bacteria, and some species of this genus are associated with diseases affecting fish and animals, including humans (F. L. Thompson, T. Iida, and J. Swings, Microbiol Mol Biol Rev 68:403-431, 2004; M. Y. Ina-Salwany, N. Al-Saari, A. Mohamad, F.-A. Mursidi, et al., J Aquat Anim Health 31:3-22, 2019). Studies on Vibrio are considered important, as they may facilitate the development of solutions related to health, food, and aquaculture problems attributed to this genus. This report enhances the current understanding of chitin degradation by Vibrio bacteria.

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

BCL2 expression in DLBCL: reappraisal of immunohistochemistry with new criteria for therapeutic biomarker evaluation.

Overexpression of the BCL2 is associated with a poor prognosis in diffuse large B-cell lymphoma (DLBCL). The assessment of MYC immunohistochemistry (IHC) is becoming optimized, whereas the criteria for BCL2 positivity are highly variable. Furthermore, data on the frequency and prognostic value of BCL2 positivity are conflicting. We aimed to evaluate BCL2 expression by IHC and assess the prognostic significance of the histopathologically scored BCL2 expression in 456 patients with DLBCL uniformly treated with standard immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, R-CHOP). We initially designed 4-grade BCL2 scoring criteria, from 0 to 3+, and found that ∼40% of DLBCL showed strong BCL2 expression (score 3+). The scores from the pathologist's visual estimation were confirmed to be reliable using a digital image analysis. A retrospective survival analysis revealed that BCL2 score 3+ was a significant prognostic factor independent of the international prognostic index (IPI), the IHC-determined cell of origin, and the MYC protein/rearrangement status in a training set (n = 218). The adverse prognostic impact of BCL2 score 3+ was confirmed in a validation set (n = 238). We also developed a prognostic model consisting of 3 groups with a combined BCL2 score and MYC protein/rearrangement status. Patients with BCL2 score 3+ showed a higher treatment failure rate; therefore, alternative therapeutic strategies should be considered for these patients. A highly selective BCL2 inhibitor, venetoclax, was recently introduced as breakthrough therapy. Our BCL2 scoring system could readily be used by pathologists to evaluate patients with DLBCL who might benefit from BCL2-targeted therapies.

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

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.

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

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

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.

Absolute peripheral monocyte count at diagnosis predicts central nervous system relapse in diffuse large B-cell lymphoma.

Recently, elevated peripheral blood monocyte counts at diagnosis have been shown to be an independent marker associated with poor prognosis in patients with both non-Hodgkin and Hodgkin lymphoma. In this study, we retrospectively analyzed the data from a total of 550 patients with diffuse large B-cell lymphoma and evaluated the relationship between central nervous system relapse and absolute monocyte counts at diagnosis. Twenty-six patients developed central nervous system relapse. The central nervous system relapse-free survival rate was significantly lower in patients with the absolute monocyte counts ≥ 0.51 × 10(9)/L (87.8% versus 96.4%; P<0.001). This association was independently significant after adjusting for other significant factors, including systemic relapse as a time-dependent covariate by multivariate analysis (hazard ratio 2.46; 95% confidence intervals 1.05-5.75; P=0.039). These results suggest that the absolute monocyte count at diagnosis is an independent significant risk factor for central nervous system relapse in patients with diffuse large B-cell lymphoma.

Multicenter cooperative case survey of hepatitis B virus reactivation by chemotherapeutic agents.

AIM: The purpose of this multicenter cooperative study was to elucidate the clinical features of hepatitis B virus (HBV) reactivation by chemotherapeutic agents and the patient outcomes after HBV reactivation by a retrospective review of accumulated patients' medical records. METHODS: Records of a total of 27 patients (hematological malignancy, 14 patients; solid tumor, 13 patients) from 11 institutions who were diagnosed between June 2005 and October 2010 as having HBV reactivation following chemotherapy were reviewed. RESULTS: Of the 27 patients with reactivation, 16 patients were hepatitis B surface antigen (HBsAg) positive and 11 were HBsAg negative prior to the commencement of chemotherapy. Of the 11 patients who were HBsAg negative prior to the chemotherapy, 10 had hematological malignancies and one had a solid tumor. Of the 14 patients with hematological malignancies with HBV reactivation enrolled in the study, the reactivation occurred more than 12 months after the completion of chemotherapy in five patients (36%); on the other hand, none of the patients (0%) with solid tumors developed HBV reactivation more than 12 months after the completion of chemotherapy. Of the 24 patients who had acute liver dysfunction at the diagnosis of HBV reactivation, nine (38%) had severe hepatitis and seven (29%) died of liver failure. CONCLUSION: Most of the patients with HBV reactivation who were HBsAg negative prior to the chemotherapy had underlying hematological malignancies. Furthermore, patients with hematological malignancies often developed late-onset HBV reactivation. The prognosis of patients who develop acute liver dysfunction as a complication of HBV reactivation is extremely dismal.

Phase I / II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma.

Brentuximab vedotin is an antibody-drug conjugate that selectively delivers the antimicrotubule agent monomethyl auristatin E into CD30-expressing cells. To assess its safety, pharmacokinetics, and efficacy in Japanese patients with refractory or relapsed CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma, we carried out a phase I/II study. Brentuximab vedotin was given i.v. on day 1 of each 21-day cycle up to 16 cycles. In the phase I part of a dose-escalation design, three patients per cohort were treated at doses of 1.2 and 1.8 mg/kg. In the phase II part, a dose of 1.8 mg/kg was given to 14 patients (nine with Hodgkin's lymphoma and five with systemic anaplastic large-cell lymphoma). The median number of treatment cycles was 16 (range, 4-16). In the phase I part, no dose-limiting toxicity event was observed. In the total population, common adverse events included lymphopenia (80%), neutropenia (65%), leukopenia (65%), and peripheral sensory neuropathy (60%). Grade 3/4 adverse events in more than two patients were lymphopenia (50%) and neutropenia (15%). The pharmacokinetic profile was similar to that observed in the previous studies in the USA. In the phase II part, six patients (67%) with Hodgkin's lymphoma achieved an objective response with 56% of complete response rate, and five patients (100%) with systemic anaplastic large-cell lymphoma achieved an objective response with 80% of complete response rate. These results show that brentuximab vedotin has an acceptable safety profile and promising antitumor activity in the Japanese population. This trial was registered in JAPIC Clinical Trials Information (JapicCTI-111650).

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.

Phase I study of obinutuzumab (GA101) in Japanese patients with relapsed or refractory B-cell non-Hodgkin lymphoma.

As CD20 has become an established target for treating B-cell malignancies, there is interest in developing anti-CD20 antibodies with different functional activity from rituximab that might translate into improved efficacy. Obinutuzumab (GA101) is a glycoengineered, humanized type II anti-CD20 monoclonal antibody that has demonstrated superior activity to type I antibodies in preclinical studies and is currently being investigated in phase III trials. In this phase I dose-escalating study in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma, the primary endpoint was to characterize the safety of GA101; secondary endpoints were efficacy, pharmacokinetics and pharmacodynamics. Patients received up to nine doses of GA101 with up to 52 weeks' follow up. Most adverse events were grade 1 or 2 infusion-related reactions, and 10 grade 3/4 adverse events occurred. No dose-limiting toxicities were observed and the maximum tolerated dose was not identified. Out of 12 patients, 7 responded (end-of-treatment response rate 58%), with 2 complete responses and 5 partial responses. Responses were observed from low to high doses, and no dose-efficacy relationship was observed. B-cell depletion occurred in all patients after the first infusion and was maintained for the duration of treatment. Serum levels of GA101 increased in a dose-dependent fashion, although there was inter-patient variability. This phase I study demonstrated that GA101 has an acceptable safety profile and offers encouraging activity to Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

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.