Turkish Journal of Hematology Volume: 37 Issue: 1 / 2020

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Li SJ, et al: The Efficacy and Safety of Bortezomib in MCL Turk J Hematol 2020;37:13-19Figure 1. Pooled analyses of progression-free survival and overall survival.CI: Confidence interval.Serious Adverse EventsThree studies reported SAEs, including grade III/IV peripheralneuropathy, grade III/IV neutropenia, and grade III/IV infection[11,13,14]. The pooled OR for grade III/IV peripheral neuropathy,grade III/IV neutropenia, and grade III/IV infection was 2.44 (95%CI=1.02-5.83; p=0.04), 2.73 (95% CI=1.80-4.13; p<0.00001),and 1.83 (95% CI=1.15-2.92; p=0.01) respectively. SAEs wereincreased significantly in combination therapy compared withchemotherapy alone.Heterogeneity and Sensitivity AnalysisThe heterogeneity of ORR was significantly different amongthe 4 pooled trials (χ 2 =12.72; df=2; I 2 =84%; p=0.002). Theheterogeneity of grade III/IV peripheral neuropathy (χ 2 =0.74;df=2; I 2 =0%; p=0.69), grade III/IV neutropenia (χ 2 =0.66; df=2;I 2 =0%; p=0.72), and grade III/IV infection (χ 2 =1.11; df=2; I 2 =0%;p=0.57) exhibited a non-significant difference among the fourpooled trials.DiscussionMCL is an incurable aggressive B-cell lymphoma with poorprognosis. The better treatment choice for MCL patients ishigh-dose chemotherapy containing cytarabine, followedby ASCT [16,17]. For patients who are either ineligible or notconsidered for intensive chemotherapy and ASCT, the standardR-CHOP regimen followed by rituximab maintenance is mostcommonly used [18], which could improve response durationcompared with currently available therapies [19], but relapseis inevitable. A number of novel agents have been approvedin the treatment of MCL, including bortezomib, lenalidomide,and ibrutinib. Among them, ibrutinib, a first-generation BTKinhibitor, obtained the most significant effects with over 60%ORR and almost 20% CR in R/R MCL [7]. On the contrary,lenalidomide obtained the minimum ORR and CR in R/R MCL[8]. Although ibrutinib has changed the landscape of therapyfor MCL, it needs continuous administration until diseaseprogression or unacceptable drug-related toxicity. That willbe expensive and it is not widely available for patients indeveloping countries, especially in China. In addition, most ofthe patients receiving ibrutinib experienced common adverseevents, including diarrhea (54%), fatigue (50%), bleeding(50%), nausea (33%), cytopenias (20%), atrial fibrillation (11%),dyspnea (32%), and pneumonitis (8%) [7,20], inevitably leadingto the discontinuation of therapy. More recently, acalabrutinib,a second-generation BTK inhibitor, has demonstrated promisingefficacy with 81% ORR and 40% CR for R/R MCL in a phaseII study along with lower rate of toxicities [21]. However, itstill needs continuous administration until disease progressionor unacceptable drug-related toxicity, which would beunacceptable for most patients.16
Turk J Hematol 2020;37:13-19Li SJ, et al: The Efficacy and Safety of Bortezomib in MCLBortezomib, the first proteasome inhibitor, regulates multiplecell signaling pathways related to the progress of MCL. It canreversibly depress the 26S proteasome for inhibition of nuclearfactor-κB and TP53, and it can induce cell cycle arrest andapoptosis [22]. Bortezomib was approved by the FDA for thetreatment of MCL patients in relapse after it was confirmed tohave 31% OS and median response duration of 9.3 months insingle-agent activity for R/R MCL [9]. Afterwards, bortezomibobtained significant prolongation of PFS and OS in newlydiagnosed MCL patients when combined with standardchemotherapy in a phase 3 clinical trial [13]. Based on thesestudies, bortezomib was approved in the USA and Europe for thetreatment of MCL patients in both relapsed and upfront settings[23,24]. Furthermore, bortezomib is low-cost and easy to obtain.However, in a randomized phase II study, there was a nonsignificantimprovement in PFS (16.5 months vs. 8.1 months;p=0.12) when assessing the efficacy of bortezomib-CHOP(cyclophosphamide, doxorubicin, vincristine, and prednisone)versus CHOP in relapsed MCL patients [11]. We thus collectedbortezomib-based clinical trials to explain the efficacy andsafety of bortezomib-based regimens.In this meta-analysis, four studies were included [11,13,14,15].There were no significant differences in baseline characteristicsbetween the treatment group and control group in eachclinical trial. Among them, three studies proved the benefits ofbortezomib regimens in MCL patients. The Furtado et al. [11]and Wu et al. [14] studies showed the efficacy and toxicity ofa CHOP-bortezomib regimen compared with the CHOP regimenin MCL patients at first relapse. In Furtado et al. [11], a markedimprovement in the quality of responses was achieved whenbortezomib was added to CHOP chemotherapy, with 82.6%vs. 47.8% of patients obtaining an objective response (CHOPbortezomibvs. CHOP, respectively). The OS in the CHOPbortezomibarm was 35.6 months compared with 11.8 monthsin the CHOP arm, but there was no difference in PFS betweenthe CHOP-bortezomib arm (16.5 months) and CHOP arm(8.1 months), although 30.4% of patients progressed duringtreatment in the CHOP arm compared to 8.7% in the CHOPbortezomibarm [11]. Moreover, there were slightly more patientsexperiencing additional toxicities attributed to the inclusion ofbortezomib. Wu et al. [14] also proved the benefits of a CHOPbortezomibregimen for ORR and OS without increasing adverseevents. The ORR of CHOP-bortezomib was higher than that ofthe CHOP arm (84.2% vs. 42.1%), and the median OS of theCHOP-bortezomib arm was 56.0 months, which was longerthan the 29.0 months of the CHOP arm. Robak et al. [13]compared the efficacy and toxicity between newly diagnosedMCL patients who received R-CHOP and VR-CAP (bortezomib,rituximab, cyclophosphamide, doxorubicin, and prednisone).The results showed that the VR-CAP group had a significantimprovement in PFS but no significant improvement in OS andORR. Because the median OS was not reached in the VR-CAParm at the time of the study, there was only a non-significantimprovement in OS with an improved 4-year OS rate comparedwith the R-CHOP arm (64% vs. 54%). Compared with theR-CHOP group, the patients receiving VR-CAP treatment alsohad more adverse events, which were mainly neutropenia andthrombocytopenia. In addition, William et al. [15] compared theOS and PFS between a BEAM (carmustine, etoposide, cytarabine,and melphalan)-bortezomib regimen and a BEAM regimen inMCL patients who were evaluated as CR1. The results showedthat patients receiving the BEAM-bortezomib regimen hadnon-significant improvement in OS and PFS compared withthe BEAM regimen. In that study, the patients enrolled werein the first CR after receiving upfront therapy with a rituximaband hyper-CVAD regimen, and they received ASCT after aBEAM-bortezomib/BEAM regimen treatment. Although therewere no significant improvements in OS and PFS, the authorsconsidered the benefit of bortezomib to have not been revealedin the presence of ASCT; in other words, bortezomib could offerbenefits for MCL patients who are ineligible for ASCT. After all,ASCT benefits only about 60% of MCL patients.The reported ORR, OS, PFS, and SAE values were pooled fromthe above four trials. The meta-analysis showed that patientswho received bortezomib-based therapy had longer PFS and OScompared with those receiving chemotherapy alone, but therewas no significant difference in ORR. The reasons might be asfollows: first, the pooled data on ORR were extracted from threestudies (Furtado et al. [11], Robak et al. [13], and Wu et al. [14]),among which Robak et al. [13] enrolled the most patients andheld the highest weight; however, Robak et al. [13] showed thatthe bortezomib-based group had no significant improvementin ORR, which might have influenced the heterogeneity ofORR. Thus, more research should be conducted to reevaluatethe pooled ORR. Second, Robak et al. [13] showed that theVR-CAP arm had a non-significant improvement in OS withan improved 4-year OS rate compared with the R-CHOP arm(64% vs. 54%); meanwhile, 132 patients (54%) in the R-CHOParm and 82 patients (34%) in the VR-CAP group receivedsubsequent anti-lymphoma therapy, and the type of subsequenttherapy was generally similar in the two groups. However, theother three studies did not mention subsequent anti-lymphomatherapy after disease progression, and subsequent antilymphomatherapy might influence OS. Despite the advantages,our results suggest that a bortezomib-based regimen mightcause significant increases in SAEs (i.e. grade III/IV peripheralneuropathy, infection, and neutropenia).In addition, the post hoc sub-analysis of Robak et al. [13]assessed the efficacy and safety of VR-CAP and R-CHOP in 80MCL patients aged <60 years who did not receive stem celltransplantation despite medical eligibility [25]: the medianPFS and the median OS in the two groups were 42.6 vs. 20.617
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