Polatuzumab vedotin in previously untreated DLBCL: an Asia subpopulation analysis from the phase 3 POLARIX trial.

In the phase 3 POLARIX study in previously untreated diffuse large B-cell lymphoma, polatuzumab vedotin combined with rituximab plus cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) significantly improved progression-free survival (PFS) compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with similar safety. Patients were randomized 1:1 to 6 cycles of Pola-R-CHP or R-CHOP plus 2 cycles of rituximab alone. For registration of POLARIX in China, consistency of PFS in an Asia subpopulation (defined as ≥50% of the risk reduction in PFS expected in the global population) was evaluated. Overall, 281 patients were analyzed: 160 patients from Asia in the intention-to-treat (ITT) population of the global study and 121 from an ITT China extension cohort. Of these, 141 were randomized to Pola-R-CHP and 140 to R-CHOP. At data cutoff (28 June 2021; median follow-up 24.2 months), PFS met the consistency definition with the global population, and was superior with Pola-R-CHP vs R-CHOP (hazard ratio, 0.64; 95% confidence interval [CI], 0.40-1.03). Two-year PFS was 74.2% (95% CI, 65.7-82.7) and 66.5% (95% CI, 57.3-75.6) with Pola-R-CHP and R-CHOP, respectively. Safety was comparable between Pola-R-CHP and R-CHOP, including rates of grade 3 to 4 adverse events (AEs; 72.9% vs 66.2%, respectively), serious AEs (32.9% vs 32.4%), grade 5 AEs (1.4% vs 0.7%), AEs leading to study treatment discontinuation (5.0% vs 7.2%), and any-grade peripheral neuropathy (44.3% vs 50.4%). These findings demonstrate consistent efficacy and safety of Pola-R-CHP vs R-CHOP in the Asia and global populations in POLARIX. This trial was registered at https://clinicaltrials.gov/ct2/home as # NCT03274492.

Phase 2 study of ibrutinib plus venetoclax in Japanese patients with relapsed/refractory mantle cell lymphoma.

BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.

Two-year outcomes of tirabrutinib monotherapy in Waldenström's macroglobulinemia.

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.

Long-term outcomes and central nervous system relapse in extranodal natural killer/T-cell lymphoma.

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

Bendamustine plus rituximab in Japanese patients with relapsed or refractory diffuse large B-cell lymphoma.

This single-arm phase 3 study was conducted to confirm the results of our phase 2 study of bendamustine (B)-rituximab (R) in patients with relapsed/refractory diffuse large B cell lymphoma (rrDLBCL). The primary endpoint was overall response rate (ORR). Autologous stem cell transplantation-ineligible rrDLBCL patients with ≤ 2 prior chemotherapy regimens received R 375 mg/m2 IV on day 1 and B 120 mg/m2/day IV on days 2 and 3 every 21 days up to 6 cycles. Thirty-eight patients with a median age of 74 years (range, 43-86) received BR. The ORR and complete response rates were 76.3% and 47.4%, respectively. With a median follow-up of 19.5 months including long-term follow-up, median progression-free survival was 11.9 months. Median OS was 29.2 months. Discontinuation of treatment due to Gr3-5 TEAE was observed among 13 of 38 patients (34.2%). One patient with cytomegalovirus enterocolitis died during follow-up. This BR regimen was confirmed to be effective and tolerable in studied patients. ClinicalTrials.gov Identifier: NCT03372837 registered on 14 December 2017, NCT04354402 registered on 21 April, 2020.

A phase 2, open-label, multicenter study of ixazomib plus lenalidomide and dexamethasone in adult Japanese patients with relapsed and/or refractory multiple myeloma.

BACKGROUND: TOURMALINE-MM1 was a global study that demonstrated a significant improvement in progression-free survival with ixazomib plus lenalidomide and dexamethasone compared with placebo plus lenalidomide and dexamethasone, in patients with relapsed and/or refractory multiple myeloma. The current study was conducted to evaluate further the efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients. METHODS: This phase 2, open-label, single-arm, multicenter study enrolled patients aged ≥ 20 years with relapsed and/or refractory multiple myeloma at 16 sites in Japan. Patients refractory to lenalidomide or proteasome inhibitor-based therapy at any line were excluded. The primary endpoint was the rate of very good partial response or better in the response-evaluable analysis set. Secondary endpoints were progression-free survival, overall response rate, duration of response, time to progression, overall survival and safety. RESULTS: In total, 34 patients were enrolled. The rate of very good partial response or better was 50.0% (95% confidence interval 31.9-68.1) and the overall response rate was 84.4% (95% confidence interval 67.2-94.7). Median progression-free survival was 22.0 months (95% confidence interval 17.3-not evaluable) and median overall survival was not estimable. The safety profile of ixazomib plus lenalidomide and dexamethasone in this study was similar to that in the TOURMALINE-MM1 study. CONCLUSIONS: The efficacy and safety of ixazomib plus lenalidomide and dexamethasone in Japanese patients with relapsed and/or refractory multiple myeloma are comparable with reported TOURMALINE-MM1 study results. CLINICALTRIALS. GOV IDENTIFIER: NCT02917941; date of registration September 28, 2016.

Phase I, multicenter, dose-escalation study of avadomide in adult Japanese patients with advanced malignancies.

Non-Hodgkin lymphoma (NHL) treated with chemoimmunotherapy has limited efficacy in some patients, resulting in relapsed or refractory disease. Avadomide (CC-122) is a novel cereblon-binding agent that exhibits antilymphoma and immune-modulation activities with a biological profile distinct from similar agents, such as lenalidomide. This phase I multicenter study evaluated avadomide in Japanese patients with advanced solid tumors or NHL. Fourteen patients with NHL and one with a solid tumor (esophageal carcinoma), were enrolled in four dose-escalation cohorts using a 3 + 3 design. Primary endpoints included safety, dose-limiting toxicities (DLT), maximum-tolerated dose and/or recommended phase II dose (RP2D), and pharmacokinetics. Secondary endpoints included overall response rate (ORR) and duration of response. One patient with NHL experienced DLT, which included face edema, pharyngeal edema, and tumor flare (all grade 1) that led to a dose reduction. Eleven patients had grade ≥3 treatment-emergent adverse events, most frequently decreased neutrophil count (33%) and decreased lymphocyte count (20%). The ORR in patients with NHL (n = 13) was 54%, including four complete and three partial responses. The best response for the solid tumor patient was progressive disease. Avadomide dose intensity was consistent across cohorts, and the 3-mg dose given five consecutive days/week was established as the RP2D. This phase I study identified a tolerable dose of avadomide, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with previously treated NHL.

Phase II study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma.

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.

A phase 2 study of polatuzumab vedotin + bendamustine + rituximab in relapsed/refractory diffuse large B-cell lymphoma.

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m2 , rituximab 375 mg/m2 (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography-computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.

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.

A multicenter, open-label, phase II study of tirabrutinib (ONO/GS-4059) in patients with Waldenström's macroglobulinemia.

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).

Final results of a phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma.

BACKGROUND: Many patients with classical Hodgkin lymphoma show increased programmed death-1 ligand expression in Reed-Sternberg cells. We report the final results of a phase II study of nivolumab, an anti-programmed death-1 monoclonal antibody, in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. METHODS: Japanese patients with previously treated classical Hodgkin lymphoma (aged ≥ 20 years) were administered nivolumab (3 mg/kg on Day 1 of 14-day cycles) until progressive disease, an unacceptable adverse event, or another clinically relevant reason. Treatment could continue beyond progressive disease at the investigator's discretion in selected patients. RESULTS: Seventeen patients (median age: 63.0 years) were enrolled. The median follow-up was 38.8 months. One patient with non-Hodgkin lymphoma was excluded from efficacy analyses. The centrally assessed overall response rate in 16 classical Hodgkin lymphoma patients was 87.5% (95% confidence interval = 61.7-98.4%) and the disease control rate was 93.8% (95% confidence interval = 69.8-99.8%). The median (95% confidence interval) duration of response and progression-free survival were 8.5 (2.4-12.6) and 11.7 (1.8-42.3) months, respectively. The 3-year overall survival rate was 80.4% (95% confidence interval = 50.6-93.2%). Nivolumab was continued beyond progressive disease in seven patients; six were alive at the data cut-off. Adverse drug reactions occurred in all 17 patients with grades 3-4 adverse drug reactions in eight patients and no grade 5 adverse drug reactions. Pulmonary toxicities occurred in five patients; four of these occurred ≥17 months after starting nivolumab. CONCLUSION: Nivolumab is effective and tolerable in Japanese relapsed or refractory classical Hodgkin lymphoma patients. Continued monitoring may be necessary to detect late-onset pulmonary toxicities. CLINICAL TRIAL REGISTRATION: JapicCTI-142755 (Japan Pharmaceutical Information Center).

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.

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.

Multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma.

Overexpression of programmed death-1 (PD-1) ligands contributes to an immunosuppressive microenvironment. Nivolumab is a PD-1-blocking antibody that inhibits the PD-1 pathway and showed good efficacy in several types of malignancy. This phase II study examined the efficacy and safety of nivolumab in 17 Japanese patients with refractory/relapsed classical Hodgkin lymphoma previously treated with brentuximab vedotin. Sixteen patients were included in efficacy analyses and 17 in safety analyses. The primary endpoint was the centrally assessed objective response rate (ORR). The study was commenced in March 2015. We report data obtained at a cutoff of 16 March 2016, at which time 11 patients were still receiving nivolumab. The median (range) duration of treatment and follow-up were 7.0 (1.4-10.6) months and 9.8 (6.0-11.1) months, respectively. All 17 patients had previously received brentuximab vedotin. The ORR was 81.3% (95% confidence interval [CI]: 54.4-96.0%; 13/16 patients), with complete remission and partial remission in 4 and 9 patients, respectively. The overall survival (OS) and progression-free survival (PFS) rates at 6 months were 100 and 60.0% (95% CI: 31.8-79.7%), respectively; the median OS and PFS were not reached. The most common adverse events (AE) were pyrexia (41.2%), pruritus (35.3%), rash (35.3%) and hypothyroidism (29.4%). Four patients (23.5%) experienced grade 3 or 4 AE, but most AE were of grade 1 or 2. In conclusion, nivolumab is a potentially effective and tolerable treatment option for Japanese patients with relapsed/refractory classical Hodgkin lymphoma previously treated with brentuximab vedotin.

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.

Combination therapy with monoclonal antibodies for treatment of newly diagnosed multiple myeloma.

Monoclonal antibodies (mAbs) with new mechanisms of action are emerging as promising agents for patients with multiple myeloma (MM). Of these, anti-CD38 antibodies and anti-signaling lymphocytic activation molecule F7 (SLAMF7) antibody have demonstrated efficacy for relapsed and refractory myeloma (RRMM). Two CD38-targeting antibodies, daratumumab and isatuximab had significant activity as single agents, whereas the SLAMF7-targeting antibody, elotuzumab, did not. Patients with RRMM treated with 16 mg/kg daratumumab achieved at least PR of 36% and 29% in two distinct phase 2 studies. More favorable results of phase 3 study of 16 mg/kg daratumumab with lenalidomide and dexamethasone revealed that 92.9% of patients with RRMM achieved at least partial response (PR), with a 43.1% complete response (CR) rate. The median PFS was better in daratumumab arm (Not Reached) than control arm (18.4 months). When combined with lenalidomide plus dexamethasone, elotuzumab, at a dose of 10 mg/kg, improved the median PFS from 14.9 months to 19.4 months in a phase 3 study named ELOQUENT-2. In addition to IMiDs, bortezomib was a hopeful partner. Regarding toxicity, these mAbs are tolerable even in elderly patients. The most common adverse event is an infusion-related reaction. Based on several published reports, we suggest that mAbs combined with standard agents could be successfully adapted for the treatment of newly diagnosed patients with MM.