R-CHOP treatment for patients with advanced follicular lymphoma: Over 15-year follow-up of JCOG0203.

Anti-CD20 antibody in combination with chemotherapy extends overall survival (OS) in untreated advanced-stage follicular lymphoma (FL), yet the optimal associated therapy is unclear. Data on the cumulative incidence of secondary malignancies postrelapse after conventional immunochemotherapy are scarce. A long-term analysis of rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) as first-line treatment was conducted in a randomised clinical trial. A six-cycle R-CHOP regimen was administered every 2 or 3 weeks without rituximab maintenance. A prespecified evaluation was conducted 15 years after the completion of enrolment, following initial analysis results that showed no significant differences in outcomes at the 3-year mark. In-depth analyses were performed on the cohort of 248 patients with FL who were allocated to the two treatment arms. With a median follow-up period of 15.9 years, the 15-year OS was 76.2%. There were no protocol treatment-related deaths, nor were there any fatal infections attributable to subsequent lymphoma treatment. At 15 years, the cumulative incidence of non-haematological and haematological malignancies was 12.8% and 3.7% respectively. Histological transformation appeared after a median of 8 years. R-CHOP maintains safety and efficacy in patients with advanced FL over extended follow-up, making it a viable first-line option for patients with advanced-stage FL.

Analyzing the risk factors for disease progression within 2 years and histological transformation in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone as first-line treatment: A 15-year follow-up of patients with advanced follicular lymphoma in JCOG0203.

Follicular lymphoma (FL) is an indolent lymphoma that becomes aggressive due to histological transformation (HT), leading to reduced survival. Patients with FL have different clinical courses and various treatment options. Some patients exhibit shorter survival and experience disease progression within 24 months of diagnosis/treatment (POD24); the optimal treatment remains an unmet needs. Thus, identifying factors that predict shorter survival is essential to stratify treatment and prolong the survival of patients with FL. To analyze risk factors for POD24 and HT in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment, we performed this post-hoc analysis of patients with advanced indolent B-cell lymphoma in a randomized clinical trial wherein six cycles of R-CHOP were administered every 2-3 weeks. The primary analysis showed no differences in outcomes, which enabled the analysis of 248 patients with FL, assigned to two arms. All histopathological specimens from the 300 enrolled patients were reviewed by three expert hematopathologists. Multivariable analysis implicated Follicular Lymphoma International Prognostic Index (FLIPI) intermediate (odds ratio [OR] 2.531, 95% confidence interval [CI] 0.676-9.466) and high- (OR 2.236, 95% CI 0.160-31.226) risks, B symptoms (OR 2.091, 95% CI 0.747-5.851), and grade 3A (G3A) (OR 1.833, 95% CI 0.634-5.299) as risk factors for POD24. Furthermore, multivariable analysis through a median follow-up of 15.9 years implicated G3A (OR 2.628, 95% CI 0.806-8.575) and high-risk FLIPI (OR 4.401, 95% CI 0.186-104.377) as risk factors for HT. However, an analysis limited to the first 10 years revealed that the prognostic factors elucidated from the longer-term analysis had a greater impact on HT. G3A and high-risk FLIPI may independently predict POD24 and HT, thereby informing treatment stratification of patients with untreated advanced-stage FL in future trials, particularly to address the unmet needs of patients with POD24.

Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia.

Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.

Clinical outcomes of second-generation tyrosine kinase inhibitors versus imatinib in older patients with CML.

Age and comorbidities are important factors to be considered in the selection of tyrosine kinase inhibitors (TKIs) for first-line treatment in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, it is yet unclear whether TKI selection, particularly, imatinib versus second-generation TKIs (2GTKIs), impacts treatment outcomes in the clinical practice. To address this, we compared the clinical outcomes of prospectively registered 452 patients with CML-CP treated with imatinib and 2GTKIs, taking into consideration their age and/or comorbidities. A total of 136 patients (30.1%) were classified into an older cohort (≥65 years) and 316 (69.9%) into a younger cohort (18-64 years). The TKI selection did not vary based on age (70.6% received 2GTKIs in the younger cohort and 66.2% in the older cohort). The median follow-up period was 5.4 years. Treatment responses including the cumulative incidence of deep molecular response (BCR-ABL1 international scale ≤0.0032%) at any time were similar between the two age cohorts regardless of the type of TKI. The 5-year overall survival (OS) in the older cohort was lower than that in the younger cohort (95.9% vs 83.8%; p < 0.0001), whereas the 5-year OS in patients treated with 2GTKIs was not influenced by age factors and comorbidities. Therefore, our results suggest that the selection of 2GTKIs as first-line treatment is an effective option for both younger and older CML-CP patients with or without comorbidities. This trial was registered at UMIN-CTR as 00003581.

Subcutaneous epcoritamab monotherapy in Japanese adults with relapsed/refractory diffuse large B-cell lymphoma.

Epcoritamab is a subcutaneously administered CD3xCD20 bispecific Ab that showed deep, durable responses with a manageable safety profile in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the global multicenter pivotal phase II trial EPCORE NHL-1. Here, we present results from the similar EPCORE NHL-3 phase I/II trial evaluating epcoritamab monotherapy in Japanese patients with R/R CD20+ B-cell non-Hodgkin's lymphoma previously treated with two or more lines of therapy. Epcoritamab was dosed subcutaneously in 28-day cycles; once weekly during cycles 1-3, every 2 weeks during cycles 4-9, and every 4 weeks from cycle 10 until disease progression or unacceptable toxicity. Step-up dosing and cytokine release syndrome (CRS) prophylaxis were used during treatment cycle 1. As of January 31, 2022, 36 patients received treatment with 48 mg epcoritamab monotherapy. At a median follow-up of 8.4 months, overall response and complete response rates by independent review committee were 55.6% and 44.4%, respectively. The median duration of response, duration of complete response, and overall survival were not reached at the time of data cut-off. The most common treatment-emergent adverse events of any grade were CRS (83.3%), injection-site reactions (69.4%), infections (44.4%), neutropenia (38.9%), hypokalemia (27.8%), and decreased lymphocyte count (25.0%). Cytokine release syndrome occurrence was predictable; events were primarily low grade (grade 1-2), all resolved, and none led to treatment discontinuation. These encouraging results are consistent with previous findings and support the ongoing clinical evaluation of epcoritamab for the treatment of R/R DLBCL, including in earlier treatment lines.

Clinical utility of genomic profiling of AML using paraffin-embedded bone marrow clots: HM-SCREEN-Japan 01.

Next-generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)-SCREEN-Japan 01 is a multicenter study to detect actionable mutations using paraffin-embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R-AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High-quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1-RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R-AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP53 mutations had a poor prognosis. As for the detection of actionable mutations, 38% (n = 69) of patients had useful genetic mutation (FLT3-ITD/TKD, IDH1/2, and DNMT3AR822 ) for treatment selection. Comprehensive genomic profiling using paraffin-embedded BM clot specimens successfully identified leukemic-associated genes that can be used as therapeutic targets.

Long-term follow-up after R-High CHOP/CHASER/LEED with Auto-PBSCT in untreated mantle cell lymphoma-Final analysis of JCOG0406.

Progression-free survival after R-High CHOP/CHASER/LEED with auto-PBSCT in untreated mantle cell lymphoma in JCOG0406 study. A continuous pattern of relapse was observed.

Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia.

BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively. CONCLUSIONS: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).

Venetoclax plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy: an expanded access study in Japan.

BACKGROUND: In a Phase 3 international clinical trial (VIALE-C), venetoclax plus low-dose cytarabine improved the response rate and overall survival versus placebo plus low-dose cytarabine in patients with newly diagnosed acute myeloid leukemia who were ineligible for intensive chemotherapy. After the enrollment period of VIALE-C ended, we conducted an expanded access study to provide preapproval access to venetoclax in combination with low-dose cytarabine in Japan. METHODS: Previously, untreated patients with acute myeloid leukemia who were ineligible for intensive chemotherapy were enrolled according to the VIALE-C criteria. Patients received venetoclax (600 mg, Days 1-28, 4-day ramp-up in Cycle 1) in 28-day cycles and low-dose cytarabine (20 mg/m2, Days 1-10). All patients took tumor lysis syndrome prophylactic agents and hydration. Safety endpoints were assessed. RESULTS: Fourteen patients were enrolled in this study. The median age was 77.5 years (range = 61-84), with 78.6% over 75 years old. The most common grade ≥ 3 treatment-emergent adverse event was neutropenia (57.1%). Febrile neutropenia was the most frequent serious adverse event (21.4%). One patient developed treatment-related acute kidney injury, leading to discontinuation of treatment. Two patients died because of cardiac failure and disease progression that were judged not related to study treatment. No patients developed tumor lysis syndrome. CONCLUSIONS: The safety outcomes were similar to those in VIALE-C without new safety signals and were well managed with standard medical care. In clinical practice, more patients with severe background disease are expected, in comparison with in VIALE-C, suggesting that it is important to carefully manage and prevent adverse events.

Feasibility and preliminary effectiveness of a psychosocial support program for adolescent and young adult cancer patients in clinical practice: a retrospective observational study.

PURPOSE: Adolescent and young adult cancer patients (AYAs) often experience profound psychological distress, with various unmet supportive care needs that can be alleviated with appropriate screening and attention by healthcare workers. The Distress Thermometer and Problem List-Japanese version (DTPL-J) is our previously developed screening tool to facilitate individual support of AYAs. This study evaluated the feasibility and preliminary effectiveness of a psychosocial support program based on the DTPL-J for AYAs in clinical practice. METHODS: This multicenter, retrospective, observational study included 19 of 126 wards and 9 of 75 outpatient clinics at 8 institutions in Japan. Over 200 patients were expected to participate during the eligibility period. Patients participated in a support program at least once, and approximately once a month based on the DTPL-J results. The program was evaluated using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) implementation framework. RESULTS: The screening rate of the 361 participants was 90.3%, suggesting high feasibility. Distress Thermometer scores, the number of supportive care needs, and the rates of AYAs with high distress were significantly reduced 1 month after screening (p < 0.05), suggesting the preliminary effectiveness of the program. The program was continued at the 8 institutions as part of routine care after the study. CONCLUSION: Analysis using the RE-AIM suggested the sufficient feasibility and preliminary effectiveness of a psychosocial support program based on the DTPL-J for AYAs. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN CTR) UMIN000042857. Registered 25 December 2020-Retrospectively registered.

Prognostic value of the Kyoto Prognostic Index in higher-risk diffuse large B-cell lymphomas treated by upfront autologous stem cell transplantation in JCOG0908 trial.

BACKGROUND: There is currently no standard prognostic model optimized for the patients with diffuse large B-cell lymphoma (DLBCL) treated with upfront intensive immunochemotherapy including autologous stem cell transplantation (ASCT). The Kyoto Prognostic Index (KPI) has been proposed as a novel prognostic model for DLBCL, which can accurately identify especially high-risk patients. In this study, we investigated the prognostic value of the KPI in JCOG0908 trial in which higher-risk DLBCL patients defined by the conventional International Prognostic Index (IPI) were treated with upfront high dose therapy followed by ASCT. METHODS: Fifty-eight patients with DLBCL, not otherwise specified, enrolled in JCOG0908 and confirmed by the central pathological review were analyzed. The Kaplan-Meier method was used to estimate the probabilities of overall survival (OS) and progression-free survival (PFS). We compared the discrimination ability of the KPI with that of the IPI. RESULTS: According to KPI, 3-year OS and PFS rates were 86.7% and 76.7% in low-intermediate, 73.3% and 60.0% in high-intermediate, and 61.5% and 46.2% in high-risk group. According to IPI, 3-year OS and PFS rates were 75.0% and 50.0% in low-intermediate, 82.9% and 74.3% in high-intermediate, and 63.6% and 54.5% in high-risk group. The concordance-indices of KPI and IPI were 0.642 and 0.580 for OS and 0.606 and 0.606 for PFS. CONCLUSIONS: The KPI may be a suitable predictor of outcome than the IPI for patients with higher-risk DLBCL treated with upfront intensive immunochemotherapy including ASCT.

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy.

BACKGROUND: The phase 3 VIALE-A trial (NCT02993523) reported that venetoclax-azacitidine significantly prolonged overall survival compared with placebo-azacitidine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Herein, efficacy and safety of venetoclax-azacitidine are analyzed in the Japanese subgroup of VIALE-A patients. METHODS: Eligible Japanese patients were randomized 2:1 to venetoclax-azacitidine (N = 24) or placebo-azacitidine (N = 13). Primary endpoints for Japan were overall survival and complete response (CR) + CR with incomplete hematologic recovery (CRi). Venetoclax (target dose 400 mg) was given orally once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously on Days 1-7 of each 28-day cycle. RESULTS: Median follow-up was 16.3 months (range, 1.0-20.3). Median overall survival was not reached with venetoclax-azacitidine (hazard ratio 0.409 and 95% confidence interval: 0.151, 1.109); overall survival estimate was higher with venetoclax-azacitidine than placebo-azacitidine at 12 (67 and 46%) and 18 months (57 and 31%), respectively. CR and CRi rates were 67% with venetoclax-azacitidine and 15% with placebo-azacitidine. Most common any-grade adverse events were febrile neutropenia (79 and 39%), thrombocytopenia (54 and 77%), constipation (54 and 54%) and decreased appetite (54 and 38%) in the venetoclax-azacitidine and placebo-azacitidine arms, respectively. Only 1 patient in the venetoclax-azacitidine arm, and no patients in the placebo-azacitidine arm, had grade 4 febrile neutropenia that led to treatment discontinuation. CONCLUSIONS: This Japanese subgroup analysis of VIALE-A demonstrates comparable safety and efficacy outcomes compared with the global study and supports venetoclax-azacitidine as first-line standard-of-care for Japanese treatment-naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy.

Differences in the approaches of cancer specialists toward adolescent and young adult cancer care.

BACKGROUND: This study investigated the medical care of adolescent and young adult (AYA) cancer patients and compared approaches toward AYA cancer care by pediatric and adult cancer specialists. METHODS: An Internet survey was conducted among 1,305 specialists (192 pediatric and 1,109 adult) in 2016. RESULTS: The rate of awareness of the term "AYA" was lower for adult specialists than for pediatric specialists. The departments that are responsible for caring for AYA cancer patients change when they reach 20 years of age. For the treatment of AYA patients, both pediatric and adult specialists preferred a multidisciplinary team as a top priority issue. A special ward or hospital rooms for AYA was required mostly for AYA patients under 24, and the needs for special wards or rooms for AYA was higher in pediatric specialists than in adult specialists. However, for AYA patients over 25, about 60% of adult specialists and 35% of pediatric specialists believed that no special care was required. As for desirable follow-up protocols for pediatric cancer AYA survivors, half of the specialists considered that they should be conducted mainly by pediatric specialists in cooperation with adult specialists, and 30% to 40% of the specialists considered that transition to the corresponding adult medicine department would be preferable. CONCLUSIONS: There were obvious differences in medical care and support for AYA cancer patients according to their age, particularly under the age of 20 or 24, and according to whether the onset of disease occurred during the AYA period or whether it was secondary to pediatric cancers. For each aspect, appropriate programs would require close cooperation between pediatric and adult specialists.

Mutated KIT Tyrosine Kinase as a Novel Molecular Target in Acute Myeloid Leukemia.

KIT is a type-III receptor tyrosine kinase that contributes to cell signaling in various cells. Since KIT is activated by overexpression or mutation and plays an important role in the development of some cancers, such as gastrointestinal stromal tumors and mast cell disease, molecular therapies targeting KIT mutations are being developed. In acute myeloid leukemia (AML), genome profiling via next-generation sequencing has shown that several genes that are mutated in patients with AML impact patients' prognosis. Moreover, it was suggested that precision-medicine-based treatment using genomic data will improve treatment outcomes for AML patients. This paper presents (1) previous studies regarding the role of KIT mutations in AML, (2) the data in AML with KIT mutations from the HM-SCREEN-Japan-01 study, a genome profiling study for patients newly diagnosed with AML who are unsuitable for the standard first-line treatment (unfit) or have relapsed/refractory AML, and (3) new therapies targeting KIT mutations, such as tyrosine kinase inhibitors and heat shock protein 90 inhibitors. In this era when genome profiling via next-generation sequencing is becoming more common, KIT mutations are attractive novel molecular targets in AML.

Safety and antitumor activity of acalabrutinib for relapsed/refractory B-cell malignancies: A Japanese phase I study.

This multicenter, open-label, phase I study assessed the safety and antitumor activity of acalabrutinib in Japanese patients with relapsed/refractory (r/r) B-cell malignancies. Parts 1 (dose confirmation) and 2 (dose expansion) of this three-part study are reported. Treatment was a single dose of 100 mg acalabrutinib (day 1), followed by a washout period and then twice daily 100 mg acalabrutinib in part 1, or twice daily 100 mg acalabrutinib in part 2. Patients from parts 1 and 2 with r/r chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and r/r mantle cell lymphoma (MCL) were assessed as r/r CLL/SLL and r/r MCL cohorts, respectively. Twenty-five patients received treatment (part 1, n = 6). Median age was 71.0 years. Nine (one patient from part 1) and 13 (two patients from part 1) patients were included in the r/r CLL/SLL and r/r MCL cohorts, respectively. Treatment-related adverse events (AEs) occurred in 88% of patients (grade ≥3, 36%); the most common were headache (28%) and purpura (24%), both grade 1/2. No AEs resulted in treatment discontinuation or death. Median duration of treatment was 31, 20, and 7 months for part 1, r/r CLL/SLL cohort, and r/r MCL cohort, respectively. Overall response rate (ORR) was 89% and 62% for the r/r CLL/SLL and r/r MCL cohorts, respectively. The median progression-free survival (PFS) was not reached for the r/r CLL/SLL cohort and was 7 months for the r/r MCL cohort. Acalabrutinib (100 mg twice daily) was generally safe and well-tolerated in adult Japanese patients with B-cell malignancies.

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.

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.

Prognostic effect of comorbidities in patients with chronic myeloid leukemia treated with a tyrosine kinase inhibitor.

Comorbidities at diagnosis among patients with chronic myeloid leukemia in chronic phase (CML-CP) may affect their overall survival (OS) rate even in the tyrosine kinase inhibitor (TKI) era. However, the prognostic impact of comorbidities in patients with CML-CP treated with a second-generation TKI (2GTKI) has not been elucidated. We evaluated the effect of comorbidities on survival using the Charlson Comorbidity Index (CCI) in patients with CML-CP treated with imatinib or a 2GTKI (nilotinib and dasatinib). From April 2010 to March 2013, 506 patients with CML-CP were registered for the population-based cohort study, and 452 with a median age of 56 y were assessable. Treatment groups included 139 patients receiving imatinib, 169 receiving nilotinib, and 144 receiving dasatinib. Comorbidities were diagnosed in 99 patients. CCI scores were stratified as follows: 2, 353 patients; 3, 72 patients; and ≥4, 27 patients. Treatment response did not vary relative to CCI scores. However, across the entire cohort, the OS rate was significantly lower among patients with higher CCI scores than in those with a CCI score of 2 (94.4% in score 2, 89.0% in score 3, and 72.8% in score ≥4; P < .001). Multivariate analysis identified a CCI score of ≥4 as a strong adverse prognostic factor for OS rather than the disease-specific risk factor, older age, performance status, or selection of TKI (Wald test, P < .01). Our results demonstrated that comorbidities at diagnosis were the most important predictive factor for successful treatment, regardless of the TKI type used in CML-CP. This trial was registered at UMIN-CTR as 00003581.