2021 Efficacy and safety of ASCO Zebutinib vs. Rituximab-based immunochemotherapy in Waldenstrom's macroglobulinemia (WM): an indirect comparison of matching adjustments

The American Society of Clinical Oncology (ASCO) annual meeting is the world's top clinical oncology conference that integrates the scale of participation, academic level and authority
.

The ASCO annual meeting in 2021 will be held from June 4th to 8th.
Numerous international cutting-edge and high-profile clinical oncology research results and clinical data are grandly launched.
Zebutinib is the first Chinese independent research and development approved by both China and the United States.
New anti-cancer drugs, with outstanding performance in the treatment of diseases such as MCL, CLL, and WM
.

This article invites Professor Niu Ting from the Department of Hematology, West China Hospital of Sichuan University to explain the efficacy and safety of Zebutinib and Rituximab-based immunochemotherapy in Wahrenheit Macroglobulinemia (WM)
.

Research background Waldenstrom's macroglobulinemia (WM) is a rare indolent mature B-cell lymphoma.
Rituximab-based therapy or BTK inhibitors are common treatment options.
In February 2021, the US FDA based on 3 The phase clinical study ASPEN accepted zebutinib for patients with Waldenstrom's macroglobulinemia who had previously received a therapy, or as the first-line treatment for WM patients with immunochemotherapy
.

However, there is no randomized clinical study to directly compare the pros and cons of BTK inhibitors and immunochemotherapy
.

The purpose of this study is to compare Zebutinib with bendamustine-rituximab (BR) and dexamethasone-ritux through matching-adjusted indirect comparisons (MAIC).
Efficacy and safety of cilimab-cyclophosphamide (DRC) regimen
.

The research method systematically reviewed the comparison of two single-arm studies for indirect treatment
.

Using the MAIC method, the individual data of 102 WM patients (83 relapsed/refractory [R/R] and 19 naive [TN]) who received Zebutinib in the ASPEN trial (NCT03053440) were reweighted and weighted Later, patients who received Zebutinib could be matched with R/R patients (71 patients) who received BR and TN patients (72 patients) who received DRC
.

Variables adjusted with BR include age, previous treatment line, IgM concentration, WM score international prognostic scoring system and extramedullary disease (EMD); variables adjusted with DRC include age, platelet count, hemoglobin concentration and EMD
.

The Cox proportional hazards model and the modified Poisson model were used to compare the survival rate and the incidence of adverse events between different treatments
.

After the results are matched, the baselines of the studies are consistent
.

Compared with receiving DRC, Zebutinib treatment significantly prolonged PFS (pre-match hazard ratio [HR]: 0.
39 [95% confidence interval 0.
18-0.
82] and post-match HR: 0.
35 [95% confidence interval 0.
14-0.
86]), And there is a tendency to prolong OS (HR before matching: 0.
56 [0.
20-1.
53] and HR after matching: 0.
47 [0.
14-1.
62]), the incidence of neutropenia is slightly higher (relative risk before matching [RR] : 1.
63 [0.
71-3.
77] and RR after matching: 1.
47 [0.
58-3.
77])
.

Compared with receiving BR treatment, Zebutinib treatment significantly prolonged PFS (HR before matching: 0.
32 [0.
15-0.
69] and HR after matching: 0.
37 [0.
15-0.
91]) and OS (HR before matching: 0.
31 [0.
12, 0.
80 ] And post-match HR: 0.
29 [0.
10-0.
85]), and significantly reduce the incidence of neutropenia (pre-match RR: 0.
45 [0.
26-0.
78] and post-match RR: 0.
50 [0.
27-0.
91]), At the same time, the incidence of pneumonia is also lower (pre-match RR: 0.
18 [0.
02-1.
55] and post-match RR: 0.
26 [0.
03-2.
28])
.

Conclusion The matching adjustment analysis confirmed that compared with the DRC regimen, Zebutinib treatment significantly prolonged the PFS of patients, and compared with the BR regimen, it achieved significantly higher PFS and OS, and lower neutropenia.
Rate
.

Experts comment that Waldenstrom's macroglobulinemia (WM) is a rare type of indolent mature B-cell lymphoma with the clinical features of indolent lymphoma and multiple myeloma1
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Although there are many treatment options for WM, there is a lack of uniform standards.
Past treatments are mainly immunochemotherapy, which still cannot be cured, and many patients still need to undergo first-line, second-line or even more lines of treatment 2-3
.

The emergence of BTK inhibitors has created a new treatment pattern for WM, especially high-risk, high tumor burden, elderly patients who are not suitable for early relapse or drug resistance after chemotherapy and immunochemotherapy, but the VGPR is low, and the ORR in MYD88WT is only 50%.
4
.

The ASPEN study showed that the new generation of BTKi Zebutinib showed higher ORR (92%) in WM, especially CR/VGPR (43%); at the same time, it also showed a very good remission rate in MYD88WT patients (ORR 80.
8%, MRR 53.
8%, VGPR 23.
1%;) and tolerable treatment toxicity; bring more efficient and low-toxic treatment options to the treatment of WM5
.

However, there are currently no randomized controlled clinical studies that directly compare the pros and cons of BTK inhibitors and immunochemotherapy.
The indirect comparison method of matching adjustments is used to match individual patient data in the treatment trial to the summary baseline data reported by another treatment trial.
, By using a method similar to propensity score weighting to compare treatment results in a balanced trial population6
.

The MAIC method can be used to indirectly compare the efficacy and safety of Zebutinib and bendamustine-rituximab (BR) and dexamethasone-rituximab-cyclophosphamide (DRC) regimens.
Results Tip: Compared with DRC, Zebutinib significantly improved PFS (24-month PFS rate: 90% vs 79%), OS (24-month OS rate: 98% vs 87%), compared with BR, significantly improved PFS (24-month PFS rate: 81% vs 59%) and OS (24-month OS rate: 88% vs 77%)
.

Randomized trials are the gold standard for comparing drug effectiveness, but the incidence of Waldenstrom's macroglobulinemia is low.
Randomized clinical studies and comparison of different treatment options have limited data.
The MAIC method also has certain guiding significance for clinical practice
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Professor Niu Ting, Doctor of Medicine, Chief Physician, Professor, and Doctoral Supervisor, Director of the Department of Hematology, West China Hospital, Sichuan University, Member of the Standing Committee of the Chinese Medical Association Hematology Branch, Deputy Leader of the Lymphocytic Disease Group, Member of the Standing Committee of the Hematological Oncology Committee of the Chinese Anticancer Association Deputy Chairman of the Expert Committee of Hematology Public Welfare Projects of the Health Foundation Deputy Chairman of the Blood Committee of China Medical Education Association, Deputy Chairman of the Hemostasis and Thrombosis Branch, Deputy Editor-in-Chief of the International Journal of Blood Transfusion and Hematology, China Medical Association, National Medical Products Administration External expert of the Drug Evaluation Center, Chairman of the Hematology Oncology Committee of the Sichuan Cancer Society, Chairman of the Hematology Branch of the Sichuan Medical Association, Director of the Business Director of the Sichuan Hematology Medical Quality Control Center References: 1.
Siegfried Janz.
ISRN Hematol.
2013 ; 2013 815325.
2.
Kastritis G, et al.
Blood 2015:126:1392-1394 3.
Rummel MJ, et al.
Lancet 2013;381;1203-12104.
Kastritis E, et al.
Ann Oncol 2018; 29(Suppl 4) :iv41-iv50.
5.
2019 EHA abstract #PF4876.
James E.
S, Value Health.
Sep-Oct 2012;15(6):940-7 stamp "Read the original", we make progress together