Evidence-based expert consensus on clinical management of safety of Bruton’s tyrosine kinase inhibitors(2024)

Bruton’s tyrosine kinase inhibitors(BTKis)have revolutionized the treatment of B-cell lymphomas.However,safety issues related to the use of BTKis may hinder treatment continuity and further affect clinical efficacy.A comprehensive and systematic expert consensus from a pharmacological perspective is lacking for safety issues associated with BTKi treatment.A multidisciplinary consensus working group was established,comprising 35 members from the fields of hematology,cardiovascular disease,cardio-oncology,clinical pharmacy,and evidencebased medicine.This evidence-based expert consensus was formulated using an evidence-based approach and the Delphi method.The Joanna Briggs Institute Critical Appraisal(JBI)tool and Grading of Recommendations Assessment,Development,and Evaluation(GRADE)approach were used to rate the quality of evidence and grade the strength of recommendations,respectively.This consensus provides practical recommendations for BTKis medication based on nine aspects within three domains,including the management of common adverse drug events such as bleeding,cardiovascular events,and hematological toxicity,as well as the management of drug-drug interactions and guidance for special populations.This multidisciplinary expert consensus could contribute to promoting a multi-dimensional,comprehensive and standardized management of BTKis.

免疫检查点抑制剂相关血液毒性处理的临床诊疗建议

免疫检查点抑制剂能够重新激活免疫系统,启动肿瘤杀伤,而T细胞过度激活导致各种免疫相关不良反应。血液系统不良反应报道少见,主要表现为单系或多系血细胞减少,包括自身免疫性溶血性贫血、免疫性血小板减少症、中性粒细胞减少症,严重时表现为再生障碍性贫血,甚至可能致命,如噬血细胞淋巴组织细胞增多症。我们将总结免疫检查点抑制剂相关血液不良反应的临床特点,并对诊断和治疗给予建议。

The combination of chidamide with the CHOEP regimen in previously untreated patients with peripheral T-cell lymphoma: a prospective, multicenter, single arm, phase 1b/2 study

Objective:To assess the efficacy and safety of the novel histone deacetylase inhibitor,chidamide,in combination with cyclophosphamide,doxorubicin,vincristine,etoposide,and prednisone(Chi-CHOEP)for untreated peripheral T-cell lymphoma(PTCL).Methods:A prospective,multicenter,single arm,phase 1 b/2 study was conducted.A total of 128 patients with untreated PTCL(18–70 years of age)were enrolled between March 2016 and November 2019,and treated with up to 6 cycles with the Chi-CHOEP regimen.In the phase 1 b study,3 dose levels of chidamide were evaluated and the primary endpoint was determination of the maximumtolerated dose and recommended phase 2 dose(RP2 D).The primary endpoint of the phase 2 study was 2-year progression-free survival(PFS).Results:Fifteen patients were enrolled in the phase 1 b study and the RP2 D for chidamide was determined to be 20 mg,twice a week.A total of 113 patients were treated at the RP2 D in the phase 2 study,and the overall response rate was 60.2%,with a complete response rate of 40.7%.At a median follow-up of 36 months,the median PFS was 10.7 months,with 1-,2-,and 3-year PFS rates of 49.9%,38.0%,and 32.8%,respectively.The Chi-CHOEP regimen was well-tolerated,with grade 3/4 neutropenia occurring in approximately two-thirds of the patients.No unexpected adverse events(AEs)were reported and the observed AEs were manageable.Conclusions:This large cohort phase 1 b/2 study showed that Chi-CHOEP was well-tolerated with modest efficacy in previously untreated PTCL patients.

An Open-Label Study of Pegylated Liposomal Doxorubicin,Vincristine, and Reduced-Dose Dexamethasone Combination Therapy in Newly Diagnosed Multiple Myeloma Patients in the Chinese Population

OBJECTIVE Though doxorubicin is highly activein the treatment of multiple myeloma, its toxicityprofile limits its therapeutic index. We performed thisstudy to evaluate the efficacy and safety of pegylatedliposomal doxorubicin (PLD, Caelyx^(?)), vincristine,and reduced-dose dexamethasone combinationtherapy in newly diagnosed multiple myeloma (MM)patients in a Chinese population.METHODS This was an open-label, single-armstudy in which newly diagnosed patients with MMreceived PLD 40 mg/m^2 intravenously on Day 1,vincristine 1.4 mg/m^2 intravenously (maximum 2 mg)on Day 1, and 40 mg of dexarnethasone (intravenouslyor orally) from Day 1 to Day 4. Treatment wasrepeated every 28 days for at least 4 cycles.RESULTS In the intent-to-treat (ITT) analysis, theoverall response rate was 68.29%, and the completeremission rate was 10.98%. The incidence of alladverse events was 46.34%. The most commonnon-hematologic toxicities were palmar-plantarerythrodysesthesia (13.4%) and stomatitis (6.1%).CONCLUSION PLD, vincristine, and a reduceddosedexamethasone combination (DVd) is aneffective and safe regimen in newly diagnosed MMpatients in a Chinese population.

Complete blood and urine paraprotein tests as response assessments in multiple myeloma patients treated with bortezomib,cyclophosphamide,and dexamethasone

Background: This study assessed the effect of standardized efficacy markers on prognosis in patients with newly diagnosed multiple myeloma(MM)during the induction phase of treatment with bortezomib,cyclophosphamide,and dexamethasone(BCD).Methods :We retrospectively analyzed clinical data in 197 newly diagnosed MM patients treated with BCD as front-line regimen at Peking Union Medical College Hospital from January 1,2013 to December 31,2018.Results: There were 107 patients with International Staging System(ISS)III and 51 with paraprotein of light chain.Of these,77 completed nine cycles of the BCD regimen.As the number of treatment cycles increased,the proportions of serum and urine immunofixation electrophoresis(IFE)tests elevated from 40.39%to 62.22%and 16.75%to 37.78%,respectively.More than 90%of intact immunoglobulin chain MM patients were evaluated for blood M protein per cycle,but that of urinary M protein was less than 60%.The detection rate of urinary M protein in light chain MM was more than 70%per cycle.Patients with a very good partial response(VGPR)had longer progression-free survival(PFS)than those with uncertain VGPR(32 vs.26 months,p=0.0336).Of the 141 patients who completed at least four cycles without undergoing autologous hematopoietic stem cell transplantation,those who were regularly assessed at every other cycle showed more favorable PFS than those who visited irregularly(27 vs.22 months,p=0.059).Conclusion: Urinary M protein detection rate is significantly lower than that in serum,leading to an overestimation of efficacy,premature reduction of treatment intensity,and shortened PFS.Precise response assessments are critical to treatment decisions and clinical diagnoses.

Efficacy and safety of JAK inhibitor INC424 in patients with primary and post-polycythemia vera or post-essential thrombocythemia myelofibrosis in the Chinese population

A phase II study （A2202） was performed to evaluate the efficacy and safety of JAK inhibitor ruxolitinib in 63 Chinese MF patients. Ruxolitinib was given twice a day （bid） at a starting dose of 15 mg （n = 25） or 20 mg （n = 38） based on a baseline platelet count. About 94.7% of the patients achieved a reduction in spleen size, 27.0% of which exhibited significant reduction （≥35%） at week 24. Significant improvement in debilitating constitutional symptoms, as assessed by MFSAF v2.0, was observed in patients treated with ruxolitinib. Ruxolitinib treatment was generally weli tolerated by Chinese patients. Although the treatment was associated with an increase in certain adverse events （AEs） that were established as identified risks （anemia and thrombocytopenia）, these AEs were considered manageable in this clinical setting. Ruxolitinib provided substantial reductions in splenomegaly and improvements in symptoms, and was well-tolerated by Chinese patients with MF.