Background

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and comprises approximately 5-10% of all lymphomas. However, in Korea, MCL accounts for just 2% of B-cell lymphomas. In addition to the paucity of the disease, due to lack of feasibility of novel agents such as bendamustine, or ibrutinib for this disease, clinical outcomes of the novel agents have yet to be defined in Korea.

Background

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and comprises approximately 5-10% of all lymphomas. However, in Korea, MCL accounts for just 2% of B-cell lymphomas. In addition to the paucity of the disease, due to lack of feasibility of novel agents for this disease, clinical outcomes of the novel agents have yet to be defined in Korea.

Methods

We performed a retrospective study of MCL patients treated with ibrutinib in Korea. The primary endpoint of the analysis was progression free survival (PFS) out of ibrutinib treatment.

Results

Between 2013 to 2019, a total of 75 cases were eligible for analysis. Median age at diagnosis was 69 (range, 40 – 90) and 61 patients (81%) were male. Most patients had an advanced disease at diagnosis (II 10, III 10, IV 55). The received induction regimens were as follows, R-CHOP (N = 48); R-HyperCVAD/MA (N = 10); R-bendamustine (N = 5); VR-CAP (N = 3); others (N = 9) At time of ibrutinib treatment, median age was 71 (range, 41-92), and the median number of prior treatments was 1 (range, 1 – 6). Eleven patients (15%) had received salvage autologous stem cell transplantation. Complete and partial responses were achieved in 31 (41%) and 22 patients (29%), respectively. At a median follow-up duration of 30.5 months (95% CI 25.9 – 35.1), the estimated median PFS was 18.6 months (95% CI 11.0 – 26.2). Those who were classified as low- or intermediated-risk MIPI score at the time of ibrutinib start (24.4 vs. 9.9 months, p = 0.031) demonstrated superior PFS, and patients with tumor size < 5 cm (25.5 vs. 9.4 months, p = 0.092) demonstrated trends for prolonged PFS. Among elderly patients (≥ 65 yrs), those who had received ibrutinib as the first salvage treatment showed significantly prolonged PFS compared to those who had received ibrutinib as the later line of treatment (24.4 vs. 5.8 months, p = 0.015).

Conclusions

The response rate as well as the PFS data of the current study is similar to those of the Western reports. The current study provided additional evidence to support the use of ibrutinib in relapsed or refractory MCL, especially as the early salvage treatment. The compliance and safety data will be presented in the meeting.

Funding

Janssen, Korea.

Disclosure

All authors have declared no conflicts of interest.

Background

HLX01, the first China (CN)-manufactured rituximab (RTX) biosimilar, was approved by the National Medicinal Products Administration (NMPA) for the treatment of non-Hodgkin's lymphoma on 22-February-2019, and was concurrently developed as a novel drug for rheumatoid arthritis (RA) since the indication has not been approved in CN. Here, we describe the development of a population pharmacokinetic (PopPK) model derived from the PK data of HLX01 and rituximab in patients with RA, and external validation in patients with CD20⁺ diffuse large B-cell lymphoma (DLBCL).

Methods

A PopPK model of HLX01 and the European-sourced RTX (EU-RTX) from HLX01-RA01 study in 196 RA pts (serum sample number=4289) was developed using non-linear mixed-effect modelling (NONMEM^®) with the first-order estimation with interaction (FOCEI) method. PK and PK-pharmacodynamic (PK-PD) relationship were characterised with various covariates (i.e., demographics, pathophysiologic/disease conditions and medical history, etc) which were examined by using forward addition (p < 0.01) / backward elimination (p < 0.001). The model was then examined using Bayesian bootstrapping and visual predictive check (VPC) followed by 1000 simulations were tested using the observed covariates. The final model was validated using PK samples of HLX01 and CN-RTX from HLX01-NHL03 study in ∼110 patients with CD20⁺ DLBCL and bridged the Chinese data to other races by simulation of Caucasian RA data from publication.

Results

A two-compartment model with first-order elimination provided the best model fit. The estimated clearance (CL), central volume (V_c), peripheral compartment volume (V_p) and clearance-of-distribution from the central to the peripheral compartment (Q) were 27.32%, 16.56%, 21.61%, and 40.79%, respectively. The correlation between CL and V_c was 0.02239. The observed concentrations and simulations-based 95% confidence interval for the corresponding model successfully predicted all subjects in the dataset, demonstrating PK similarity of HLX01 and RTX in patients with RA and CD20⁺ DLBCL. No significant difference in area under the curve from zero to infinity (AUC_0-inf) was observed in two different sourced RTXs. This model was similar to the existing model in Caucasian population.Table: 266O

Estimated parameter of HLX01 and EU-rituximab from the final PopPK model

Conclusions

This PopPK model derived from RA patients adequately predicts HLX01 and CN-RTX in patients with CD20⁺ DLBCL. HLX01 and EU-/CN-RTXs had similar PK parameters and influential PK covariates. These results provided further evidence for PK similarity between HLX01 and RTXs in patients with RA or DLBCL regardless of ethnicity.

Clinical trial identification

HLX01-RA01 Phase 1/2 study (NCT03355872) in moderately-to-severely active rheumatoid arthritis; HLX01-NHL03 Phase 3 study (NCT02787239) in CD20⁺ diffuse large B-cell lymphoma.

Legal entity responsible for the study

Shanghai Henlius Biotech, Inc.

Funding

Shanghai Henlius Biotech, Inc.

Disclosure

Y. Shi: Advisory / Consultancy: Shanghai Henlius Biotech, Inc. X. Zhang: Full / Part-time employment: Shanghai Henlius Biotech,Inc. W. Jiang: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S. Liu: Full / Part-time employment: Shanghai Henlius Biotech,Inc. E. Liu: Full / Part-time employment: Shanghai Henlius Biotech,Inc. K. Chai: Full / Part-time employment: Shanghai Henlius Biotech,Inc. A. LUK: Full / Part-time employment: Shanghai Henlius Biotech,Inc. D. Yao: Full / Part-time employment: Shanghai Henlius Biotech,Inc. All other authors have declared no conflicts of interest.

Background

The phase 3 ICARIA study demonstrated that isatuximab (Isa) plus pomalidomide and dexamethasone (Pd) significantly improved progression free survival (PFS) compared with Pd in patients (pts) with relapsed/refractory multiple myeloma (RRMM) (HR = 0.596, 95%CI 0.44-0.81, P = 0.001). We evaluated the efficacy/safety of Isa-Pd in the East Asian pts (13 Japanese, 9 Korean and 14 Taiwanese pts) of ICARIA.

Methods

RRMM pts who had received ≥2 prior lines of therapies, including lenalidomide (len) and at least a proteasome inhibitor (PI), and were refractory to their last therapy were enrolled. Pts were randomized into either Isa-Pd arm who received Isa 10 mg/kg IV weekly for the first 4 weeks (wks) followed by biweekly or Pd arm, and all pts received Pom (4mg PO days 1-21) and dex (40mg [20mg if older than 75 yrs] PO or IV weekly) in 28 day cycle until disease progression or unacceptable toxicity.

Results

Data from 36 East Asian pts (21 Isa-Pd, 15 Pd) including Japanese pts (9 Isa-Pd, 4 Pd) were analyzed. Patient’s characteristics were similar in the East Asian subgroup and the entire population of ICARIA study (n = 307). Of these pts, median age: 65 (range, 41-85) yrs; median prior lines of therapy: 3 (range, 2-7); 91.7% and 69.4% were refractory to len and PI, respectively; and 13.9% had high-risk cytogenetics. After median follow-up of 11.6 months, median PFS was not reached yet in Isa-Pd arm and was 7.9 months in Pd arm (HR 0.517 [95% CI 0.19-1.39]). ORR (≥PR) was 71.4% in Isa-Pd arm 60% in Pd arm. The VGPR rate or better was 61.9% and 13.3% in Isa-Pd and Pd arm, respectively. Median time to first response was 32 days and 59 days for Isa-Pd and Pd arm, respectively. Grade ≥3 AEs were observed in 90.5% and 73.3% pts in Isa-Pd and Pd arm, respectively and which caused 9.5% pts in the Isa-Pd arm and 0 % in Pd arm to discontinue their treatment. Infusion associated reactions were reported in 57.1% pts receiving Isa-Pd but none of them were grade 3-4.

Conclusions

This subgroup analysis of ICARIA demonstrates that the efficacy and safety of Isa-Pd in East Asian population, including Japanese pts, are comparable with the entire population of ICARIA. Isa-Pd is a novel treatment option for East Asian pts with RRMM.

Clinical trial identification

Clinical trial information: NCT02990338.

Legal entity responsible for the study

Sanofi.

Funding

Sanofi.

Disclosure

K. Sunami: Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: GlaxoSmithKline; Speaker Bureau / Expert testimony: Janssen Pharmaceutical. M. Matsumoto: Speaker Bureau / Expert testimony: Celgene Co., LTD; Speaker Bureau / Expert testimony: Janssen Pharmaceutical Co., LTD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb K.K.; Speaker Bureau / Expert testimony: Ono Pharmaceutical Co., LTD. C. Shimazaki: Speaker Bureau / Expert testimony: Ono Pharmaceutical Co. Ltd.; Speaker Bureau / Expert testimony: Celgen Co. Ltd.; Speaker Bureau / Expert testimony: Fujimoto Pharmaceutical Co. Ltd. F. Campana: Full / Part-time employment: Sanofi. K. Tada: Full / Part-time employment: Sanofi. S. Iida: Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Daiichi-Sankyo; Speaker Bureau / Expert testimony: Chugai; Speaker Bureau / Expert testimony: Kyowa Hakko Kirin; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Gilead; Speaker Bureau / Expert testimony: AbbVie. K. Suzuki: Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Celgene; Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Fujimoto; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Sumitomo Dainippon ; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Sanofi. All other authors have declared no conflicts of interest.

Background

Incidence of imatinib-induced toxicity and its influence on clinical outcomes in Indian patients with CML is not well-studied. We investigated the influence of imatinib-induced toxicity on therapeutic outcomes in newly diagnosed patients with CML. We also studied the effect of drug levels on imatinib-induced hematological toxicity.

Methods

Two hundred and fifty newly diagnosed patients with chronic-phase CML, started on imatinib therapy, were enrolled and followed-up for 24 months. Toxicity due to imatinib were assessed and graded as per CTCAE. Cytogenetic and molecular responses were assessed by conventional bone-marrow cytogenetics and qRTPCR using international scale, respectively, based on which patients were categorized as imatinib responders and non-responders. Imatinib trough levels were measured using LC-MS/MS. Multivariate analysis was done to find the influence of various covariates on imatinib response.

Results

A total of 719 adverse reactions due to imatinib occurred among 250 enrolled patients. Hematological toxicity was the most common imatinib-induced toxicity and its incidence was significantly higher in non-responders than responders (65% vs. 35%; P < 0.001). Patients with thrombocytopenia [RR = 1.768; 95%CI (1.357, 2.302); P < 0.001] and neutropenia [RR = 1.654; 95%CI (1.322, 2.070); P < 0.001] were at high risk of imatinib failure. Patients without any hematological toxicity were at lower risk for failure of imatinib therapy [RR = 0.520; 95%CI (0.388, 0.698); P < 0.001]. Although patients with hematological toxicity had higher imatinib levels than those without (2039.1±1361.6 vs. 1833.8±1335.3 ng/mL), the difference was not statistically significant [mean difference 205.2; 95% CI (590.4, -180); P = 0.295]. Hematological toxicity requiring dose interruption or reduction emerged as an independent factor predicting cytogenetic and molecular response to imatinib in multivariate analysis.

Conclusions

Imatinib induced hematological toxicities significantly influence cytogenetic and molecular response in patients with CML. Active monitoring and prompt management of imatinib induced adverse events is indispensable to achieve optimal therapeutic outcomes.

Clinical trial identification

Not Applicable.

Editorial acknowledgement

Not Applicable.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.