2021 EHA first reports Zebutinib + Lenalidomide + R-CHOP in the treatment of DLBCL

The 26th European Hematology Association (EHA) Annual Meeting will be held on June 9-17, 2021.
As an annual academic feast in the field of blood, the content of this meeting is still brilliant
.

In the era of contending new drugs, Zebutinib, as the first Chinese-American dual-approved anti-cancer drug, is not only used in mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and Waldenstrom's macroglobulinemia ( Data in disease fields such as WM) are eye-catching, and they are also beginning to show their edge in the field of diffuse large B-cell lymphoma (DLBCL)
.

Please see the latest exploration of the use of Zebutinib combined with R2-CHOP in the treatment of DLBCL from Pukou Chronic Lymphoma Center of Jiangsu Provincial People's Hospital
.

Research background • R-CHOP is the standard first-line treatment for DLBCL
.

Although more than half of the patients are cured under R-CHOP, the prognosis of relapsed/refractory patients is still very poor, and the median survival (OS) upon progression after first-line treatment is less than 1 year
.

• Zebutinib is a new-generation BTK inhibitor that can block BCR signaling and reduce NF-κB activity
.

Lenalidomide is an oral immunomodulator that can down-regulate IRF4 and MYD88 signals
.

Preliminary results show that the two drugs have a better effect on certain types of DLBCL
.

Research method 1 The enrolled population included DLBCL patients aged 18 to 75, mainly for newly-treated high-risk DLBCL, including but not limited to double-strike, double-expressing DLBCL
.

2 Treatment methods 1) Zebutinib d0 starts at 160 mg bid; 2) Lenalidomide 25 mg d1-7; 3) Rituximab (375 mg/m2, d0), cyclophosphamide (750 mg/m2) , D1), doxorubicin (50 mg/m2, d1), vincristine (1.
4 mg/m2, d1) and prednisone (50 mg Bid, d1-5)
.

All patients are recommended to receive 6 cycles of ZR2-CHOP treatment (R-CHOP/R2-CHOP is allowed in the first 1-2 cycles of poor physical condition), and patients >70 years old receive ZR2-miniCHOP treatment2
.

3 Study endpoints 1) Primary endpoint: Interim CT/PET-CT assessed complete response rate (CRR), PET-CT assessed CRR after 6 cycles; 2) Secondary endpoints: total response rate (ORR), dynamic changes in ctDNA (Before treatment, 3 cycles and after 6 cycles) and adverse events (AE)
.

Study Results 1 Baseline • 2020.
7-2021.
2, 10 patients with DLBCL diagnosed at Pukou Chronic Lymphocyte Center of Jiangsu Provincial People’s Hospital were included, of which 9 were newly treated patients and 1 was relapsed/refractory patient (bendamustine plus Disease progression after 4 cycles of rituximab treatment)
.

• The median age is 55 years, and the ECOG-PS of all patients is ≤2
.

• 1 case of double-strike DLBCL, 7 cases of dual-expression DLBCL; 8 cases of non-GCB DLBCL, 2 cases of GCB type; 7 patients were assessed as NCCN-IPI high-medium-risk and high-risk groups
.

• As of March 1, 2021, with a median follow-up of 5 months, all patients have completed at least 3 cycles of treatment and can undergo mid-term evaluation
.

2 Efficacy • ORR was 100.
0%, of which 9 patients achieved complete remission (CR) and 1 patient achieved partial remission (PR)
.

• Dynamic detection of ctDNA in 5 patients
.

The median number of somatic mutations at baseline was 5, and ctDNA was undetectable in all 5 patients after 3 cycles
.

4 patients have received 6 cycles of treatment, all reached CR, and ctDNA could not be detected
.

3 Safety• The most common hematological toxicity events: decreased lymphocyte count, decreased neutrophil count, thrombocytopenia and anemia, the incidence of grade 3-4 is 70.
0%, 30.
0%, 20.
0% and 20.
0%, respectively
.

• The most common non-hematological toxicity events: nausea and fatigue
.

One patient stopped zebutinib and lenalidomide for more than 7 days due to drug eruption
.

Research conclusions • ZR2-CHOP can be used in high-risk DLBCL patients with acceptable physical conditions to obtain higher CRR and a higher proportion of negative rates of early ctDNA testing; it is safe and has good overall tolerance
.

• ZR2-CHOP may be one of the promising options for the treatment of high-risk DLBCL
.

Experts comment that DLBCL is the most common type of lymphoma with a high degree of heterogeneity, including non-germinal center-derived ABC/Non-GCB DLBCL, double-hit/triple-hit, double expression, IPI≥3, etc.
, which are common with poor prognosis Patient subtype, poor treatment with standard R-CHOP regimen
.

Therefore, for the first-line poor prognosis DLBCL patients, many studies have actively explored in combination with new drugs on the basis of R-CHOP
.

Among them, there have been many exploratory data of nalidomide combined with R-CHOP (R2-CHOP).
Although the representative study Robust3 did not reach the primary endpoint, it suggested that patients with ABC-DLBCL with IPI≥3 and stage III/IV were more comfortable In the drug + R-CHOP group, the risk of disease progression and death in the R2-CHOP group were reduced by 19% and 26%, respectively; in addition, the EA14124 study reported at the same time showed that R2-CHOP has significantly better efficacy than R-CHOP, that is, disease progression or death The risk is reduced by 33%, p=0.
03
.

On the other hand, BTK inhibitors have similar explorations
.

Although the PHOENIX5 study did not achieve the primary endpoint of the benefit of event-free survival (EFS), in patients <60 years old, Ibritinib combined with R-CHOP treatment of non-GCB DLBCL EFS, progression-free survival (PFS) and Compared with R-CHOP, OS has been improved
.

The SMART study also saw no difference in the time to tumor progression (TTP) between patients with dual expression and non-dual expression of IR2+chemo treatment6
.

Considering that Zebutinib has been structurally optimized on the basis of a first-generation BTK inhibitor, the 160 mg BID dose in the peripheral blood can completely inhibit BTK.
In the lymph nodes, this dose can make the BTK occupancy rate of 94% of patients exceed 90%.
The administration method combined with Zebutinib BID may have a better killing effect on tumor cells of aggressive lymphoma than QD
.

At the same time, Zebutinib has lower off-target effects and better safety7
.

Therefore, in this study, the combination of Zebutinib+lenalidomide+R-CHOP was used to treat medium- to high-risk DLBCL.
Up to now, the latest statistics show that a total of 13 patients with DLBCL were enrolled in the Pukou Chronic Lymphocyte Center, with a median follow-up of 7 months.
, The ORR of 12 patients in the interim evaluation reached 100%, and the CRR was 83.
3%.
Among them, the ORR of 8 patients with dual expression was 100% and the CRR was 87.
5%; compared with Robust (ORR 91%, CRR 65%) and the PHOENIX study ( ORR 89.
3%, CRR 67.
3%), the remission rate has a trend of further improvement
.

Therefore, our center intends to further carry out prospective, multi-center clinical trials, in order to better confirm the good disease control and survival benefits of ZR2-CHOP for patients with medium and high risk DLBCL in the future
.

Professor Li Jianyong, Pukou Chronic Lymphoma Center, Jiangsu Provincial People's Hospital, Director of the Department of Hematology, Doctoral Supervisor, and Postdoctoral Cooperative Supervisor of the First Affiliated Hospital of Nanjing Medical University, Class A Distinguished Professor of Nanjing Medical University, Member of the Standing Committee of the Chinese Medical Association Hematology Branch, and leader of the Lymphocytic Disease Group The 4th Chairman of the Hematology Oncology Committee of the Chinese Anti-Cancer Association, the 5th Honorary Chairman, and the Leader of the Lymphoma Group Leader of the Chinese Chronic Lymphocytic Leukemia Working Group CSCO Vice Chairman of the Chinese Lymphoma Alliance Chinese Medical Association Oncology Branch Lymph Oncology Group Deputy Leader, Jiangsu Geriatrics Association Hematology Branch Chairman, Jiangsu Provincial Medical Association Hematology Branch, Jiangsu Provincial Medical Association Hematology Branch, Former Chairman, Nanjing Medical Association Hematology Branch, Nanjing Medical Association, Hematology Branch, Chinese Medical Doctor Association Integration References for the Deputy Chairman of the Hematology Professional Committee 1.
Zhu H, et al.
2021EHA, EP548.
2.
Lancet Oncol.
2011 May;12(5):460-8.
3.
J Clin Oncol.
2021 Feb 23;JCO2001366.
4 .
2019 ICML oral #6.
5.
JClin Oncol 2019; 37(15):1285-1295.
6.
2019ICML Abstract 042.
7.
Blood.
2019;134(11):851-859.
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