Abstract: Background . Staples closure technology has been widely used in total knee arthroplasty (TKA) and achieved good results. In recent years, a new type of material called skin closure tape (SCT) has been applied to TKA which also showed good treatment results. However, since it is still not clear yet which one is better, this paper collects literatures for statistical analysis so as to provide evidence for the use of SCT in TKA. Methods . The comparative study on effects between SCT and staples is reviewed after the primary release of TKA in PubMed, the Cochrane library, and the EMBASE database up to March 2019. The two researchers independently screened the literature and evaluated the quality of the literature using bias risk tools. Results . A total of four studies (3330 knees) have been included in our meta-analysis. For the main point, the results show that the SCT can reduce readmission rates compared to staples (RR 0.68, 95% CI 0.49–0.95, P = 0.03 ), with no significant difference in complications (RR 0.85, 95% CI 0.27–2.64, P = 0.77 ). Secondly, the results suggest that although there is no significant difference in removal time between the two groups, the SCT can reduce pains, save time and costs, and have a better cosmetic effect. Conclusions . Our study indicates SCT as a closure method with fewer complications and faster speed compared with staples. Nevertheless, the cost and pain need to be further confirmed because of the small sample size included in this study.

Abstract: INTRODUCTION HQP1351 (olverembatinib) is an orally active third-generation BCR-ABL TKI designed for treatment of the patients with CML, harboring T315I mutation, which confers resistance against all first- and second-generation TKIs. METHODS The TKI resistant CML patients harboring T315I mutations either in chronic-phase (CP), or in accelerated-phase (AP), were enrolled into two single-arm, multicenter, open-label pivotal studies: HQP1351-CC201 in and HQP1351-CC202, respectively. The HQP1351 was administered at 40 mg once every other day (QOD) for 28 consecutive days per cycle over 24 months. The primary objective was to evaluate efficacy by major cytogenetic response (MCyR) in patients with CML-CP and major hematologic response (MaHR) in CML-AP. Secondary objectives included safety, tolerability, and pharmacokinetics (PK). RESULTS Baseline characteristics Study CC201 (CML-CP) As of the study cut-off date of March 23, 2020, total 41 patients were enrolled, of whom 38 (92.7%) completed ≥ 6 cycles and 21 (51.2%) were male. Median (range) follow-up was 7.9 (3.1-11.1) months, median age was 47 (22-70) years old. Median (range) interval from CML diagnosis to first HQP1351 treatment was 5.31 (0.6-23.2) years, and 32 (78.1%) patients received ≥ 2 prior lines of TKI. Three patients withdrew from the study-due to progressive disease (PD), intolerance, or consent withdrawal. Study CC202 (CML-AP) As of the cut-off date of February 11, 2020, total 23 patients were enrolled, of whom 18 (78.3%) completed ≥ 6 cycles and 18 (78.3%) were male. Follow-up duration was 8.2 (1.4-9.6) months, median age was 41 (21-74) years old. Median interval from CML diagnosis to first dose of HQP1351 was 4.96 (0.4-10.2) years, and 18 (78.3%) patients received ≥ 2 prior TKIs. Five patients withdrew because of PD or intolerance before Cycle 6. Efficacy Study CC201 (CML-CP) Across a median follow-up of 7.9 months, the mean (95% CI) 3-month progression-free survival (PFS) was 100% (100-100%) and 6-month PFS 96.7% (78.6-99.5%) because of 1 PD. In 31 evaluable patients who did not have a complete hematologic response (CHR) at baseline, 30 (96.8%) achieved CHR. In 41 evaluable patients who did not have a complete CyR (CCyR) at baseline, 31 (75.6%) achieved MCyR, including 27 (65.9%) CCyR and 4 (9.8%) partial CyR (PCyR). Total 20 out of 41 (48.8%) evaluable patients achieved major molecular response (MMR; Figure 1). Study CC202 (CML-AP) Across a median follow-up of 8.2 months, the 3-month PFS was 100% (100-100%) and the 6- month PFS 95.5% (71.9-99.3%) because of 2 PDs. A total of 18 (78.3%) of 23 evaluable patients without MaHR at baseline achieved MaHR, including 14 (60.9%) with CHR. In the 23 evaluable patients without MCyR at baseline, 12 (52.2%) patients achieved MCyR, including 9 (39.1%) CCyR and 3 (13.1%) PCyR. A total of 6 out of 23 (26.1%) evaluable patients achieved MMR (Figure 1). HQP1351 was highly and durably efficacious in the CML patients with T315I mutation; the probability and depth of clinical response may increase with prolonged treatment period. Safety/tolerability Study CC201 Frequent treatment-related adverse events (TRAEs; all grades; G3-4) included thrombocytopenia (65.9%; 48.8%), followed by anemia (48.8%; 24.4%), leukopenia (46.3%; 12.2%), and neutropenia (36.6%; 19.5%). Common non-hematologic TRAEs of any grade included skin pigmentation (53.7%) as well as elevations in creatine kinase (48.8%), ALT (31.7%) and AST (26.8% which most were grade 1 - 2. No death occurred. Study CC202 Common TRAEs (all grades; G3-4; serious AE [SAE]) included thrombocytopenia (73.9%; 52.2%; 17.4%), anemia (65.2%; 39.1%; 13.0%), leukopenia (56.5%; 30.4%; 0%), and neutropenia (26.1%; 21.7%; 0%;). Common non-hematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (52.2%), hypertriglyceridemia (47.8%), hyperphosphatemia (43.5%), arthralgia (34.8%), and fatigue (26.1%), of which most were grade 1- 2. CONCLUSIONS HQP1351 has been shown highly efficacious in heavily TKI-pretreated patients with T315I-mutated CML-CP or CML-AP and was well tolerated. Registration: Clinicaltrials.gov identifier NCT03883087 (Study HQP1351-CC201) NCT03883100 (Study HQP1351-CC202). Disclosures Chen: Ascentage Pharma Group: Current Employment. Niu:Ascentage Pharma Group: Current Employment. Zeng:Ascentage Pharma Group: Current Employment. Men:Ascentage Pharma Group: Current Employment. Lu:Ascentage Pharma Group: Current Employment, Current equity holder in publicly-traded company. Wang:Ascentage Pharma Group: Current Employment. JI:Ascentage Pharma Group: Current Employment. Yue:Ascentage Pharma Group: Current Employment. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.

Abstract: BCR-ABL1 T315I mutations confer resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Olverembatinib is a new potent BCR-ABL1 TKI with preclinical activity against T315I-mutated CML. In phase 1/2 studies, we explored the safety and efficacy of olverembatinib in Chinese adults with TKI-resistant CML in the chronic phase (CML-CP) and accelerated phase (CML-AP). Methods In the phase 1 study, olverembatinib was orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg, and we evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics of olverembatinib. In the phase 2 studies, olverembatinib was administered at the RP2D of 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response by the end of Cycle 12 in CML-CP and CML-AP, respectively. Fine and Gray's hazard models were used to identify covariates associated with responses. Results A total of 165 patients ( 〉  80.0% of whom had received ≥ 2 TKIs) were enrolled in this study. Among 127 patients with CML-CP, the 3-year cumulative incidences of achieving MCyR, complete cytogenetic response (CCyR), major molecular response (MMR), MR 4.0 , and MR 4.5 were 79.0, 69.0, 56.0, 44.0 and 39.0%, respectively. The highest response rates were observed in patients with a single T315I mutation. Among 38 patients with CML-AP, the 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR 4.0 , and MR 4.5 were 47.4%, 47.4%, 44.7%, 39.3%, and 32.1%, respectively. In multivariate analyses, baseline BCR-ABL1 mutation status was significantly associated with cytogenetic and molecular responses. Common treatment-related adverse events included skin hyperpigmentation, hypertriglyceridemia, proteinuria, and severe thrombocytopenia. Conclusions Olverembatinib was well tolerated, with significant antileukemic activity in adults with TKI-resistant CML-CP and CML-AP, especially those with the T315I mutation. Trial registration : The phase 1 trial is registered at CTR20220566, and the two single-arm, open-label phase 2 studies are registered at ClinicalTrials.gov: NCT03883087 (CML-CP) and NCT03883100 (CML-AP).

Abstract: Background: Management of CML with TKIs is constrained by treatment resistance, which portends a poor prognosis particularly in pts failing 2 nd-generation TKIs. Cells with BCR-ABL1 T315I mutations are insensitive to 1 st- and 2 nd -generation TKIs, and compound BCR-ABL1 mutations complicate management with all TKIs (including 3 rd-generation ponatinib). Olverembatinib is a novel, potent, 3 rd-generation, orally active BCR-ABL1 TKI with promising activity against CML , largely irrespective of genotype and has a preliminary favorable safety profile. Methods: HQP1351-CC201 and HQP1351-CC202 are Chinese open, single-arm, multicenter phase 2 trials evaluating the safety and efficacy of olverembatinib in adults with TKI-resistant (BCR-ABL1 T351-mutated) CML-CP and CML-CP, respectively. Olverembatinib was administered at 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response (MaHR) by the end of Cycle 12 in CML-CP and CML-AP, respectively. Secondary study endpoints include : complete CyR (CCyR), complete hematologic response (CHR), major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety, including treatment-related adverse events (TRAEs) and serious AEs (SAEs). Results: Baseline characteristics Study CC201 （CML-CP ） On the study cutoff date of August 25,2020, 41 pts were enrolled, of whom 32 (78%) completed ≥ 12 cycles and 21 (51.2%) were male. The median (range) follow-up was 13 (3.1-16.3) months, age was 47 (22-70) years, and interval from CML diagnosis to first olverembatinib dose was 5.31 (0.6-23.2) years. In all, 32 (78.1%) pts had received ≥ 2 prior TKIs and 9 pts withdrew because of progressive disease (PD), intolerance, or consent withdrawal before Cycle 12. Study CC202 （CML-AP ） On the cut-off date of July 27, 2020, 23 pts were enrolled, of whom 14 (61%) had completed ≥ 12 cycles and 18 (78.3%) were male. The median (range) follow-up was 13.5 (1.4-15.2) months, age was 41 (21-74) years, and interval from CML diagnosis to first olverembatinib dose was 4.96 (0.4-10.2) years. In all, 18 (78.3%) pts had received ≥ 2 prior TKIs, and 11 pts withdrew because of PD or intolerance before Cycle 12. Efficacy Study CC201 （CML-CP ） After ≥ 12 treatment cycles in pts without responses at baseline, all 31 (100%) experienced CHR (10 other pts had CHR at baseline); 31/41 (75.6%) MCyR; 28/41 (68.3%) CCyR; and 23/41 (56.1%) MMR (Figure 1). The median time to CHR was 1 (95% CI = 1.0-1.9) month, the median time to MCyR was 2.8 (95% CI = 2.8-5.6) months, and the median time to MMR was 6.5 (95% CI = 2.8 to not reached [NR]) months. At 12 months, the PFS rate was 89.3% (95% CI = 73.9%-95.8%), and the OS was 100% (95% CI = 100%-100%). Study CC202 （CML-AP ） After ≥ 12 treatment cycles in pts without responses at baseline, 17/23 (73.9%) experienced MaHR (65.2% CHR and 8.7% no evidence of leukemia [NEL]); 12/23 (52.2%) MCyR; 11/23 (47.8%) CCyR; and 9/23 (39.1%) MMR (Figure 1). The median time to MaHR was 2.8 (95% CI = 1.0-4.7) months, the median time to MCyR was 5.6 (95% CI = 2.00-NR) months, and the median time to MMR was 13.1 (95% CI = 5.6-NR) months. At 12 months, the PFS rate was 74.1% (95% CI = 48.2%-88.4%), and the OS was 91.3% (95% CI = 69.5%-97.8%). Safety Study CC201 （CML-CP ） Frequent TRAEs (all grades; grade 3-4; SAEs) included thrombocytopenia (70.7%; 48.8%; 7.3%), followed by anemia (61%; 26.8%; 2.4%), leukopenia (43.9%; 17.1%; 0), and neutropenia (36.6%; 19.5%; 0). Common nonhematologic TRAEs (all grades; G3-4) included skin pigmentation (56.1%, 0%) and elevations in creatine kinase (51.2%, 14.6%), ALT (39%, 2.4%) and AST (34.1%, 0) (Table 1). No deaths occurred. Study CC202 （CML-AP ） Common TRAEs (all grades; G3-4; SAEs) included thrombocytopenia (73.9%; 56.5%; 17.4%), anemia (60.9%; 34.8%; 13.0%), leukopenia (56.5%; 30.4%; 0), and neutropenia (26.1%; 21.7%; 0). Common nonhematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (47.8%), hypertriglyceridemia (56.5%), hyperphosphatemia (47.8%), hyperuricemia (21.7%), and arthralgia (34.8%), of which most were grade 1-2 (Table 2). Conclusions: Olverembatinib was efficacious and well tolerated when administered as monotherapy in pts with TKI-resistant CP-CML and AP-CML and the BCR-ABL1 T315Imutation. Internal study identifiers: HQP1351-CC201-CC202. ClinicalTrials.gov identifiers: NCT03883087 and NCT03883100. Figure 1 Figure 1. Disclosures Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Niu: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.