•Liso-cel significantly improved EFS, CR rate, and PFS vs chemotherapy ± ASCT as a second-line treatment for LBCL.•Liso-cel was well tolerated as a second-line therapy, with low rates of any grade or ...severe cytokine release syndrome and neurological events.
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This global phase 3 study compared lisocabtagene maraleucel (liso-cel) with a standard of care (SOC) as second-line therapy for primary refractory or early relapsed (≤12 months) large B-cell lymphoma (LBCL). Adults eligible for autologous stem cell transplantation (ASCT; N = 184) were randomly assigned in a 1:1 ratio to liso-cel (100 × 106 chimeric antigen receptor–positive T cells) or SOC (3 cycles of platinum-based immunochemotherapy followed by high-dose chemotherapy and ASCT in responders). The primary end point was event-free survival (EFS). In this primary analysis with a 17.5-month median follow-up, median EFS was not reached (NR) for liso-cel vs 2.4 months for SOC. Complete response (CR) rate was 74% for liso-cel vs 43% for SOC (P < .0001) and median progression-free survival (PFS) was NR for liso-cel vs 6.2 months for SOC (hazard ratio HR = 0.400; P < .0001). Median overall survival (OS) was NR for liso-cel vs 29.9 months for SOC (HR = 0.724; P = .0987). When adjusted for crossover from SOC to liso-cel, 18-month OS rates were 73% for liso-cel and 54% for SOC (HR = 0.415). Grade 3 cytokine release syndrome and neurological events occurred in 1% and 4% of patients in the liso-cel arm, respectively (no grade 4 or 5 events). These data show significant improvements in EFS, CR rate, and PFS for liso-cel compared with SOC and support liso-cel as a preferred second-line treatment compared with SOC in patients with primary refractory or early relapsed LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03575351.
Abramson and colleagues report on the primary analysis of the TRANSFORM study, a randomized trial of lisocabtagene maraleucel (liso-cel) following a cycle of bridging therapy (if needed) vs standard-of-care salvage chemotherapy and autologous transplantation in second-line therapy of patients with primary refractory or early relapse large B-cell lymphoma. Liso-cel significantly improves event-free survival as well as complete response rate and progression-free survival but not overall survival after a median of 18 months follow-up. These data establish liso-cel as a standard of care for these patients with a previous poor prognosis.
Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory ...agent lenalidomide could increase the activity of rituximab.
A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.
A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63%
49%), neutropenia (58%
23%), and cutaneous reactions (32%
12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50%
13%) and leukopenia (7%
2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62;
< .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.
Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.
To explore a more effective treatment for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKL), we conducted a phase II study of the steroid ...(dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) regimen.
Patients with newly diagnosed stage IV, relapsed, or refractory disease and a performance status of 0 to 2 were eligible. Two cycles of SMILE chemotherapy were administered as the protocol treatment. The primary end point was the overall response rate (ORR) after the protocol treatment.
A total of 38 eligible patients were enrolled. The median age was 47 years (range, 16 to 67 years), and the male:female ratio was 21:17. The disease status was newly diagnosed stage IV in 20 patients, first relapse in 14 patients, and primary refractory in four patients. The eligibility was revised to include lymphocyte counts of 500/μL or more because the first two patients died from infections. No treatment-related deaths were observed after the revision. The ORR and complete response rate after two cycles of SMILE chemotherapy were 79% (90% CI, 65% to 89%) and 45%, respectively. In the 28 patients who completed the protocol treatment, 19 underwent hematopoietic stem-cell transplantation. The 1-year overall survival rate was 55% (95% CI, 38% to 69%). Grade 4 neutropenia was observed in 92% of the patients. The most common grade 3 or 4 nonhematologic complication was infection (61%).
SMILE chemotherapy is an effective treatment for newly diagnosed stage IV, relapsed or refractory ENKL. Myelosuppression and infection during the treatment should be carefully managed.
Tazemetostat is a selective, reversible, small‐molecule inhibitor of the histone methyltransferase enzyme, enhancer of zest homolog 2 (EZH2). In this multicenter, open‐label, phase II study, we ...assessed the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory (R/R) B‐cell non‐Hodgkin lymphoma harboring the EZH2 mutation. Tazemetostat (800 mg twice daily) was given orally (28‐day cycle) until disease progression or unacceptable toxicity. Among the 20 eligible patients, 17 were enrolled in cohort 1 (follicular lymphoma FL), and three were enrolled in cohort 2 (diffuse large B‐cell lymphoma). At data cut‐off, the objective response rate in cohort 1 was 76.5%, including six patients (35.3%) with complete response and seven patients (41.2%) with partial response (PR). All three patients in cohort 2 achieved PR. In cohort 1, median progression‐free survival (PFS) was not reached at the median follow‐up of 12.9 months. The estimated PFS rate at 12 and 15 months was 94.1% and 73.2%, respectively. The most common grade 3 treatment‐emergent adverse event (TEAE) was lymphopenia (n = 2). Grade 4 TEAEs included hypertriglyceridemia and pneumonia aspiration (n = 1 each), which were not related to tazemetostat. Treatment‐emergent adverse events leading to study drug discontinuation were reported in four of the 20 patients, indicating that the safety profile of tazemetostat was acceptable and manageable. Tazemetostat 800 mg twice daily showed encouraging efficacy in patients with R/R EZH2 mutation‐positive FL with a manageable safety profile in the overall population. Thus, tazemetostat could be a potential treatment for R/R EZH2 mutation‐positive FL.
Percentage change from baseline in sum of the product of the perpendicular diameters of target lesions based on independent reviewer assessment.
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.
We report the results of an open‐label, single‐arm study of polatuzumab vedotin 1.8 mg/kg, bendamustine 90 mg/m2, rituximab 375 mg/m2 in patients with transplant‐ineligible relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL). A complete response rate of 34.3% at the end of the treatment and consistent safety profile with previous studies with polatuzumab vedotin were observed.
Background
Tisagenlecleucel demonstrated a high rate of durable response in adult patients with relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) in the pivotal global phase 2 JULIET ...study. Here, we report the efficacy and safety of tisagenlecleucel in the Japanese subgroup.
Methods
JULIET (NCT02445248) is a single-arm, open-label, multicenter, phase 2 study involving adult patients with r/r DLBCL who either relapsed after or were ineligible for autologous stem cell transplant. Primary endpoint was best overall response rate (ORR; complete response CR + partial response PR) as judged by an independent review committee.
Results
In Japan, of 17 patients enrolled, 9 were infused with tisagenlecleucel and completed ≥ 3 months of follow-up. Best ORR was 77.8% (7/9; 95% confidence interval, 40.0–97.2), with 5 patients (55.6%) in CR and 2 (22.2%) in PR. Cytokine release syndrome (CRS) occurred in 6 patients (66.7%), with grade 3 CRS in 2 patients (Penn grading scale). Two patients received tocilizumab. Two deaths (22.2%) occurred more than 30 days after tisagenlecleucel infusion due to disease progression, neither of which were related to tisagenlecleucel.
Conclusion
Tisagenlecleucel showed a high best ORR with a manageable safety profile, thus offering a new treatment option in selected Japanese patients with r/r DLBCL.
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.
This phase I study assessed the safety and antitumor activity of acalabrutinib in Japanese patients with relapsed/refractory B‐cell malignancies. Twenty‐five patients received treatment, and adverse events occurred in 88% of patients; however, most were grade 1 or 2, and no adverse event resulted in treatment discontinuation. Acalabrutinib was generally safe and well‐tolerated in adult Japanese patients with B‐cell malignancies.
Treatment of Follicular Lymphoma Izutsu, Koji
Journal of Clinical and Experimental Hematopathology,
2014, Volume:
54, Issue:
1
Journal Article
Peer reviewed
Open access
Follicular lymphoma (FL) is the most common subtype of indolent lymphomas. Several lines of evidence suggest that the prognosis of patients with FL has improved since the introduction of rituximab, ...although cure cannot be achieved. Although the treatment paradigm for FL has changed over the past decade with the introduction of rituximab and other agents, there is still no standard therapy to fit all patients. Instead, treatment decisions are made taking into consideration disease status (stage, tumor burden, and presence of symptoms) and patient factors including patient preferences. Rituximab-containing chemotherapy such as R-CHOP, R-CVP, and bendamustine plus rituximab is usually recommended for symptomatic patients. However, optimal rituximab-containing chemotherapy has not been established. Rituximab maintenance is one of the post-induction options for patients responding to first-line chemoimmunotherapy. For patients without symptoms and low-tumor burden, both expectant management (watchful waiting) and rituximab monotherapy are reasonable options. A very limited proportion of patients with FL are diagnosed at stage I with rigorous staging using bone marrow biopsy and whole-body imaging with computed tomography (CT) and/or positron emission tomography/CT. Although local radiotherapy has been the standard approach for these patients, its role is being questioned. Patients with FL who achieve remission eventually relapse and require salvage therapy. The salvage regimen should be chosen taking into account previous treatment and its response duration. Moreover, the presence of histological transformation should be assessed. J Clin Exp Hematop 54(1): 31-37, 2014
Brentuximab vedotin (BV) was initially approved in Japan for the treatment of relapsed/refractory (R/R) CD30-positive Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL). As ...requested by the Japanese Ministry of Health, Labour and Welfare, we conducted a post-marketing surveillance (PMS) study to assess the safety of BV in Japanese patients with R/R HL or sALCL. PMS forms were collected from 284 patients (182 with HL, 101 with sALCL and one with another lymphoma) treated between April and September 2014. The median age was 62 (range 14–93) years and the median number of treatment cycles was 5.5 for HL and 4 for sALCL. Adverse drug reactions (ADRs) were reported in 74.3% of patients. The most commonly observed ADRs included peripheral sensory neuropathy (39.1%; grade ≥ 3, 6.3%), neutropenia (34.5%; grade ≥ 3, 22.2%) and lymphopenia (7.0%; grade ≥ 3, 5.3%). Ten patients had fatal ADRs including interstitial lung disease (
n
= 3). This study showed that BV has an acceptable safety profile in Japanese patients with R/R HL and R/R sALCL in the clinical practice setting. However, close monitoring rare, but potentially fatal, ADRs such as pulmonary toxicity may be warranted, especially in patients with prior or ongoing pulmonary disorders.
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