Phase II study of novel orally PI3Kα/δ inhibitor TQ-B3525 in relapsed and/or refractory follicular lymphoma.

This registration study assessed clinical outcomes of TQ-B3525, the dual phosphatidylinositol-3-kinase (PI3K) α/δ inhibitor, in relapsed and/or refractory follicular lymphoma (R/R FL). This phase II study (ClinicalTrials.gov NCT04324879. Registered March 27, 2020) comprised run-in stage and stage 2. R/R FL patients after ≥2 lines therapies received oral 20 mg TQ-B3525 once daily in a 28-day cycle until intolerable toxicity or disease progression. Primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR). Based on results (ORR, 88.0%; duration of response [DOR], 11.8 months; progression-free survival [PFS], 12.0 months) in 25 patients at run-in stage, second stage study was initiated and included 82 patients for efficacy/safety analysis. Patients received prior-line (median, 3) therapies, with 56.1% refractory to previous last therapies; 73.2% experienced POD24 at baseline. At stage 2, ORR was 86.6% (71/82; 95% CI, 77.3-93.1%), with 28 (34.2%) complete responses. Disease control rate was 95.1% due to 7 (8.5%) stable diseases. Median time to response was 1.8 months. Among 71 responders, median DOR was not reached; 18-month DOR rate was 51.6%. with median follow-up of 13.3 months, median PFS was 18.5 (95% CI, 10.2-not estimable) months. Median overall survival (OS) was not reached by cutoff date; 24-month OS rate was estimated as 86.1%. Response rates and survival data were consistent across all subgroups. Grade 3 or higher treatment-related adverse events were observed in 63 (76.8%) cases, with neutropenia (22.0%), hyperglycemia (19.5%), and diarrhea (13.4%) being common. TQ-B3525 showed favorable efficacy and safety for R/R FL patients after ≥2 lines prior therapies.

Efficacy and safety of generic pomalidomide plus low-dose dexamethasone in relapsed or refractory multiple myeloma: a multicenter, open-label, single-arm trial.

This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1-21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39-76) years, a median prior line of therapy of 4 (range, 1-16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44-50.01). The disease control rate was 67.1% (95% CI, 56.02-76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68-7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.

Autologous hematopoietic stem cell transplantation improves survival outcomes in peripheral T-cell lymphomas: a multicenter retrospective real-world study.

The aim of this study is to evaluate the survival benefit of consolidative autologous hematopoietic stem cell transplantation (ASCT) in patients with peripheral T-cell lymphomas (PTCL). In this retrospective study, the ASCT group underwent consolidative ASCT after first-line therapy at 14 transplantation centers in China between January 2001 and December 2019. Data were collected over the same time frame for the non-ASCT group from the database of lymphoma patient records at Peking University Cancer Hospital & Institute. A total of 120 and 317 patients were enrolled in the ASCT and non-ASCT groups, respectively, and their median ages were 43 years and 51 years, respectively. In the ASCT group, 101 patients had achieved complete remission (CR) and 19 patients had achieved partial remission at the time of ASCT. The median follow-up time was 40.2 months and 68 months, and the 3-year overall survival (OS) rate was 80.6% and 48.9% (p < 0.001) for the ASCT and non-ASCT groups, respectively. The beneficial effect of ASCT for OS remained even after propensity score-matched (PSM) analysis (81.6% vs 68.3%, p = 0.001). Among the 203 patients who were aged ≤ 65 years and achieved CR, ASCT conferred a significant survival benefit (3-year progression-free survival [PFS]: 67.4% vs 47.0%, p = 0.004; 3-year OS: 84.0% vs 74.1%, p = 0.010), and this was also maintained after PSM analysis (3-year PFS: 66.6% vs 48.4%, p = 0.042; 3-year OS: 84.8% vs 70.5%, p = 0.011). Consolidative ASCT improved the survival outcome of PTCL patients, even those who achieved CR after first-line therapy.

[Multicenter Prospective Study of Different Induction Regimens of Azacytidine in Treatment of Elderly Patients with Acute Myeloid Leukemia].

OBJECTIVE: To observe the efficacy and safety of different induction regimens of same total dosage of azacitidine (Aza), including standard dose (standard dose group) and low-dose long-term (adjusted dose group), in the treatment of elderly acute myeloid leukemia (AML). METHODS: A total of 103 elderly patients with AML (non-acute promyelocytic leukemia) from January 2020 to June 2021 were enrolled. Aza was administered at the standard dose of 75 mg/(m2·d) for 7 days in the standard dose group (50 cases), while at 100 mg/d for 7-12 days in the adjusted dose group (53 cases). The administration days in adjusted dose group was calculated based on the total standard dose of the patient's single course of treatment. The efficacy and safety between standard dose group and adjusted dose group were compared. Subgroup analysis were performed in the two groups for Aza alone, Aza combined with BCL-2 inhibitor, and Aza combined with low-dose chemotherapy for efficacy and safety. RESULTS: There were no significant differences in overall response rate (ORR), incidence of adverse reaction, and 1-year overall survival (OS) rate between standard dose group and adjusted dose group (P >0.05). The ORR of combination was higher than that of Aza alone (P < 0.05), while there was no significant difference in ORR between Aza combined with BCL-2 inhibitor and Aza combined with low-dose chemotherapy (P >0.05). The combination of BCL-2 inhibitor did not increase the incidence of adverse reactions compared wtih Aza alone. There was a higher risk of myelosuppression and pulmonary infection with a combination of low-dose chemotherapy than with a combination of BCL-2 inhibitor and Aza alone (P <0.05). No significant difference was observed in 1-year OS between Aza alone, Aza combined with BCL-2 inhibitor, and Aza combined with low-dose chemotherapy (P >0.05). CONCLUSIONS: Both two induction regimens can be used in elderly AML patients who cannot tolerate intensive chemotherapy with similar overall effectiveness and safety. Aza combined with low-dose chemotherapy may result in increased ORR and an increased incidence of serious adverse reactions, and may not result in longer survival compared with Aza alone. Aza combined with BCL-2 inhibitor not only has similar effect in complete remission, objective response rate, and OS compared with Aza combined with low-dose chemotherapy, but also has higher safety.

High-dose dexamethasone plus recombinant human thrombopoietin vs high-dose dexamethasone alone as frontline treatment for newly diagnosed adult primary immune thrombocytopenia: A prospective, multicenter, randomized trial.

We conducted a prospective, multicenter, randomized, controlled clinical trial to compare the efficacy and safety of high-dose dexamethasone (HD-DXM) plus recombinant human thrombopoietin (rhTPO), vs HD-DXM alone in newly diagnosed adult immune thrombocytopenia (ITP) patients. Enrolled patients were randomly assigned to receive DXM plus rhTPO or DXM monotherapy. Another 4-day course of DXM was repeated if response was not achieved by day 10 in both arms. One hundred patients in the HD-DXM plus rhTPO arm and 96 patients in the HD-DXM monotherapy arm were included in the full analysis set. So, HD-DXM plus rhTPO resulted in a higher incidence of initial response (89.0% vs 66.7%, P < .001) and complete response (CR, 75.0% vs 42.7%, P < .001) compared with HD-DXM monotherapy. Response rate at 6 months was also higher in the HD-DXM plus rhTPO arm than that in the HD-DXM monotherapy arm (51.0% vs 36.5%, P = .02; sustained CR: 46.0% vs 32.3%, P = .043). Throughout the follow-up period, the overall duration of response was greater in the HD-DXM plus rhTPO arm compared to the HD-DXM monotherapy arm (P = .04), as estimated by the Kaplan-Meier analysis. The study drugs were generally well tolerated. In conclusion, the combination of HD-DXM with rhTPO significantly improved the initial response and yielded favorable SR in newly diagnosed ITP patients, thus could be further validated as a frontline treatment for ITP. This study is registered as clinicaltrials.gov identifier: NCT01734044.

Comparison of acalabrutinib plus obinutuzumab, ibrutinib plus obinutuzumab and venetoclax plus obinutuzumab for untreated CLL: a network meta-analysis.

The optimal chemotherapy-free regimens for treatment-naive CLL still remains undefined. We searched relevant published reports. Three trials with 1017 subjects were identified. In the network meta-analysis, acalabrutinib plus obinutuzumab (Aca + Obi) improved PFS than ibrutinib plus obinutuzumab (Ibu + Obi) (HR:0.43, p = .02) and venetoclax plus obinutuzumab (Ven + Obi) (HR:0.30, p < .001) as IRC assessment. Sensitivity analysis of investigator assessment also showed improved PFS with Aca + Obi than Ibu + Obi (HR:0.46, p = .04) and Ven + Obi (HR:0.34, p = .002). Among these first-line treatments (Aca + Obi, Ibu + Obi, Ven + Obi and chlorambucil plus obinutuzumab (Chl + Obi)), Aca + Obi regimen had the highest probability of 99.1% (IRC assessment) or 98.0% (investigator assessment) to reach the longest PFS. The survival advantage with Aca + Obi was not statistically significant, compared to Ibu + Obi (HR:0.51, p = .21) and Ven + Obi (HR:0.38, p = .07). No significant difference was found in AEs analysis. Our data indicated that Aca + Obi seemed to prolong the PFS than Ibu + Obi and Ven + Obi. Considering our limits, prospective clinical trials directly comparing these regimens are warranted.

[Clinical Comparation of Two Kinds of Chemotherapy Regimens in the Treatment of Patients with MDS-RAEB/AML-MRC].

OBJECTIVE: To investigate the influence of conventional CAG regimen and decitabine + decreased dose CAG (D+dCAG) regimen on the clinical efficacy and safety of patients with MDS-RAEB/AML-MRC. METHODS: The clinical data of 67 patients with MDS-RAEB/AML-MRC hospitalized in our hospital from March 2012 to July 2017 were analyzed retrospectively. According to chemotherapecctic regimens, 76 patients were divided into 2 groups: 37 patients treated with conventional CAG regimen were enrolled in control group, 30 patients treated with decitabine + decreased dose CAG regimen were enrolled in D+dCAG group. The complete remission (CR) rate, overall remission rate (ORR), OS and PFS time and incidence of adverse reactions in 2 groups were compared. RESULTS: The CR in D+dCAG group was significantly higher than that in control group (P＜0.05). ORR was not significanly different between 2 groups (P＞0.05). There was no significant difference in the cumulative OS rate between 2 groups (P＞0.05). There was no significant difference in the cumulative OS rate and PFS rate in nonimplantation between 2 groups (P＞0.05). The incidence of adverse reactions of hematological system, pulmonary infection, skin and soft tissue infection, agranulocytosic fever and mycotic infection was not significanly different between 2 groups (P＞0.05). The duration of granulocyte deficiency and platelet count less than 20×109/L were not significanly different between 2 groups (P＞0.05). CONCLUSION: Compared with conventional CAG regimen, decitabine + decreased dose CAG regimen in the treatment of patients with MDS-RAEB/AML-MRC can efficiently improve the remission effects and showed the well overall safety, but can not increase the survival rate.

Daratumumab added to standard of care in patients with newly diagnosed multiple myeloma: A network meta-analysis.

PURPOSE: To investigate the activity and safety of daratumumab added to standard of care and evaluate the relative efficacy of DRd vs DVMP and other regimens on survival endpoints for untreated myeloma, we undertook this meta-analysis. METHODS: We searched published reports that described the activity and safety of daratumumab added to standard of care for untreated myeloma. RESULTS: Six daratumumab trials were identified, covering 5106 subjects. Daratumumab containing combinations for untreated myeloma attained an impressive complete response or better (≥CR) rate of 24%, very good partial response or better (≥VGPR) rate of 67%, overall response rate (ORR) of 92%. Daratumumab added to standard of care significantly improved progression free survival (PFS): the HR for PFS was 0.52 [0.44, 0.61], P < .001. The HR for overall survival (OS) was 0.73 [0.52, 1.04], P = .09. In the network meta-analysis for patients ineligible for autologous stem-cell transplantation (ASCT), DRd regimen produced significant PFS advantage vs other first-line treatments (VMP HR:0.39 P < .001, Rd HR:0.55 P < .001, MPT HR:0.38 P < .001, and MP HR:0.22 P < .001); DVMP regimen also produced significant PFS advantage vs VMP (HR:0.50 P < .001), MPT (HR:0.49 P < .001), and MP (HR:0.28 P < .001). Among these first-line regimens (DRd, DVMP, VMP, Rd, MPT, and MP), DRd regimen had the highest probability to be the best intervention, with 83.4% and 91.0% probability to reach the longest PFS and OS, respectively. Toxicity consisted primarily of myelosuppression. And, the vital non-hematologic adverse events (AEs) were peripheral sensory neuropathy (41% of all grades) and upper respiratory tract infection (39% of all grades). CONCLUSIONS: Daratumumab added to standard of care could produce clinical benefits in newly diagnosed patients with multiple myeloma. DRd and DVMP could be good combination options for those patients ineligible for ASCT.

A meta-analysis of autologous transplantation for newly diagnosed multiple myeloma in the era of novel agents.

To evaluate the role of high-dose melphalan plus autologous stem-cell transplantation (ASCT) as consolidation therapy for patients with newly diagnosed multiple myeloma (NDMM) in the era of novel agents, we undertook this meta-analysis. Medline, Embase, the Cochrane controlled trials register, the SCI, ASH, EHA, and ASCO were searched for clinical trials including high-dose chemotherapy plus ASCT for patients with NDMM. Finally, we identified four RCTs of ASCT versus novel agents based consolidations, and 10 single-arm prospective trials of ASCT alone. Pooled analysis indicated that response quality improved further after ASCT in the era of novel agents (≥CR rates of 13% pre-ASCT versus 29% post-ASCT, p = .003). When compared to novel agents containing consolidation regimens, high-dose chemotherapy plus ASCT significantly improved progression-free survival (PFS) (HR =0.56, p < .001). No significant difference in overall survival (OS) was found between them (HR =0.66, p = .22). Of note, subgroup analysis indicated that ASCT could significantly improve OS (HR =0.49, p = .0004) when compared to alkylating agent-based regimens plus lenalidomide consolidation. In summary, response quality and PFS improved further over ASCT in the era of novel agents. ASCT could improve survival than alkylating agent-based regimens plus lenalidomide consolidations for patients with NDMM.

[Ratio of Primary Bone Marrow Cells after Induction Chemothrapy for Two Weeks in the Patients with Ph- ALL and Its Influence on Complete Remission and Overall Progrosis].

OBJECTIVE: To investigate the influence of bone marrow blasts ratio after induction chemotherapy for 2 weeks in patients with Ph- ALL, and it's influence on complete remission (CR) and overall prognosis. METHODS: A total of 172 patients with Ph- ALL in our hospital from March 2012 to February 2016 were selected. The bone marrow blast ratio was analyzed by the receiver-operating characteristic curve (ROC) in patients after induction chemotherapy for 2 weeks, at same time its influence on CR and overall prognosis of Ph- ALL patients was evaluated. RESULTS: The cutoff value of CR was 0.075, its area under ROC was 0.763; the comparison of area under ROC with Az=0.5 showed statistically significant difference, therefore 172 patients with Ph- ALL were grouped according to bone marrow blast ratio after induction chemotherapy for 2 weeks: 104 cases (60.5%) with bone marrow blast ratio <0.075, 68 cases (39.5%) with bone marrow blast ratio ≥0.075. The Ph- ALL patinets with bone marrow blast ratio <0.075 who achieved CR and finally achieved CR after induction chemotherapy for 4 weeks acconnted for 89 (85.6%) and 99(95.2%) respectively, which were significantly higher than those in Ph- ALL patients with bone marrow blast ratio≥0.075, [29(42.6%) and 52 (76.5%)](P<0.05). In addition, the influencing factor clinically reducing the OS and DFS rate of patients and enhancing the ralapse rate of patients were mainly chemotherapy, the failure of induction chemotherapy (patients did not achieve CR after induction therapy for 4 weeks), the bone marrow blast ratio≥0.075 after induction treatment for 2 weeks, and CNSL at diagnosis and so on, while the enhaced WBC count at diagnosis was poor factor affecting the DFS rate of patients. CONCLUSION: After induction chemotherapy for 2 weeks, the elevated bone marrow blast ratio in Ph- ALL patients will be infavourable to CR, and the overall prognosis is poor.

Carfilzomib/pomalidomide single-agent or in combination with other agents for the management of relapsed/refractory multiple myeloma: a meta-analysis of 37 trials.

PURPOSE: The use of carfilzomib/pomalidomide single-agent or in combination with other agents in patients with refractory/relapsed multiple myeloma (RRMM) was not clearly clarified in clinical practice. We sought to compile the available clinical reports to better understand the efficacy and safety of carfilzomib (CFZ) and pomalidomide (POM). RESULTS: Based on our research criteria, we identified 37 prospective studies that evaluated 1160 patients. Analysis of subgroup differences between carfilzomib single-agent and CFZ/DEX dual combination showed significantly(P < 0.001, I2 = 96.3%), suggesting the overall response rate (ORR) of 66% attained from CFZ/DEX dual combination seemed to be higher than that of 28% from carfilzomib single-agent. And, the same trend favoring CFZ/DEX dual combination was found in ≥VGPR and CBR analysis. The ORR of 31% attained from POM/DEX dual combination was superior to that of 19% from pomalidomide single-agent(P < 0.001, I2 = 94.4%). And, the same trend favoring POM/DEX dual combination was found in ≥VGPR and CBR analysis. However, the ORR of 83% attained from POM/BOR/DEX triplet combination was superior to that of 31% from POM/DEX dual combination(P < 0.001, I2 = 99.1%). And, the same trend favoring POM/BOR/DEX triplet combination was found in ≥VGPR analysis. METHODS: We searched published reports including carfilzomib and (or) pomalidomide therapy for RRMM who had received bortezomib and (or) lenalidomide. CONCLUSION: Pomalidomide/Carfilzomib plus dexamethasone seemed to attain a superior response rate compared with pomalidomide/carfilzomib single-agent. Furthermore, the combination of pomalidomide, bortezomib and dexamethasone resulted in a much higher response rate compared with pomalidomide plus dexamethasone regimen. These results needed more validation in future trials.

[Prospective multicentre study of chemotherapeutic regimen containing pirarubicin on the treatment of relapsed or refractory acute myeloid leukemia in adults].

OBJECTIVE: To compare the efficacy and toxicity of the chemotherapeutic regimen containing pirarubicin and mitoxantrone on the treatment of relapsed or refractory acute myeloid leukemia (AML) in adults. METHODS: In this open prospective multicentre study, we randomly assigned patients with relapsed or refractory AML to receive TAE regimen (pirarubicin+cytarabine+etoposide) versus MAE regimen (mitoxantrone + cytarabine + etoposide). The efficacy and toxicity were compared between the two groups. RESULTS: 56 patients entered this clinical trial. The complete remission (CR) rate on TAE arm was 79.0% versus 55.6% on MAE arm with the overall response (OR) rates of 86.8% versus 88.9%, respectively. The CR was higher on TAE arm (P=0.035) but with no significant difference between the two groups regarding the overall response (OR) rate. The regimens were well tolerated in both groups. Hematologic and non-hematologic toxicity were similar except relatively lower the mean dosage of G-CSF, red blood cells and platelets transfusion on TAE arm. No significant differences were seen between the two groups regarding the overall survival and relapse free survival rates. CONCLUSION: TAE regimen might be an effective salvage therapy in patients with relapsed or refractory AML.

[The influence of CD44 on the adhesive, migratory and infiltrative abilities of leukemia cells].

OBJECTIVE: To investigate the expression of CD44 in leukemia cell lines and its role in adhesion, migration and infiltration of leukemia cells. METHODS: The expression levels of CD44 in four leukemia cell lines SHI-1, THP-1, NB4 and K562 were assayed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot when they were in logarithmic phase. And these cell lines were divided into control group (treated with same species and isotype IgG) and experimental group (treated with anti-CD44 mono-clonal antibody). The assays of cell-cell adhesion to endothelial cells line ECV304, migration through the artificial matrix membrane and infiltration through the Matrigel were performed. RESULTS: The relative expression ratios of CD44 to GAPDH in SHI-1, THP-1, NB4 cells were 0.0731 ± 0.0072, 0.0827 ± 0.0151 and 0.1473 ± 0.0365, respectively, which were significantly higher than that in K562 cells (0.0002 ± 0.0000, P < 0.01). Cell-cell adhesion assay showed that the adhesion rates of SHI-1, THP-1 and NB4 cells in the experimental group decreased to 72.78%, 64.09% and 57.42%, respectively, and were lower than those of the control groups, while that of K562 cells in the experimental group was 106.16%. Migration assay showed that the transmembrane rates of SHI-1,THP-1 and NB4 cells were 55%, 29% and 25% in the control group, respectively, and decreased to 32%, 18% and 12% in the experimental group, respectively, while those of K562 cells in both control group and experimental group remained 2%. The infiltration rates of SHI-1, THP-1 and NB4 cells decreased from 24%, 15% and 13% in the control group to 12%, 8% and 4% in the experimental group, respectively, while K562 cells in both groups could not pass through the Matrigel. CONCLUSION: CD44 antigen might play an important role in the adhesion, migration and infiltration of leukemia cells and be involved in the extra-medullary infiltration of leukemia cells.

Novel agents-based regimens as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: a meta-analysis of randomized controlled trials.

To investigate the effect of novel agents like bortezomib, lenalidomide and thalidomide as part of induction treatment prior to autologous stem-cell transplantation (ASCT) for previously untreated patients with multiple myeloma, we performed a meta-analysis of randomized controlled trials (RCTs). Medline, Embase, the Cochrane controlled trials register and the Science Citation Index were searched for RCTs of novel agents as part of induction therapy before ASCT. Three RCTs of bortezomib, two RCTs of thalidomide and no RCT of lenalidomide were identified, covering a total of 2,316 subjects. Due to different mechanisms of action, we performed a subgroup analysis by type of agent (thalidomide or bortezomib). The weighted risk ratios of a complete response (CR) were 4.25 [95% CI: 2.44-7.41] (p < 0.001) for bortezomib and 1.66 [95% CI: 1.15-2.38] (p = 0.007) for thalidomide, respectively. The summary hazard ratios for progression-free survival (PFS) were 0.73 [95% CI: 0.59-0.89] (p = 0.002) for bortezomib and 0.68 [95% CI: 0.59-0.79] (p < 0.001) for thalidomide, respectively. The corresponding ratios for overall survival (OS) were 0.87 [95% CI: 0.64-1.18] (p = 0.37) and 0.88 [95% CI: 0.73-1.05] (p = 0.14), respectively. Additionally, there was a statistically significant heterogeneity between subgroups (thalidomide and bortezomib) for CR (p = 0.005) but nonsignificant for PFS (p = 0.64) and OS (p = 0.97). In conclusion, our analysis showed novel agents as induction treatment prior to ASCT improved CR and PFS but not OS.