【ASH Express】Reproduce eye-catching data-a quick overview of the blockbuster study of the classic BTK inhibitor ibrutinib

The 2022 American Society of Hematology (ASH) Annual Meeting will be held in New Orleans from December 10 to 13 Eastern Time in the form of online + offline, the abstract will be announced at 22:00 Beijing time on November 3, in which the world's first listed BTK inhibitor ibrutinib submitted a number of heavy research results in this ASH annual meeting, the data is eye-catching, let's take a look at the representative 8 abstracts
.

Mantle cell lymphoma (MCL)

Summary No.
1.
TRIANGLE study: efficacy and safety of ibrutinib in combination with standard first-line therapy or alternative autologous hematopoietic stem cell transplantation (ASCT) in young patients with MCL

The TRIANGLE study, which ranked in the No.
1 abstract of this year due to its weight, is a randomized, open-label, international multi-center phase III clinical study that includes young patients with treatment-naïve MCL suitable for ASCT and is randomly assigned to 3 trial groups in a 1:1:1 ratio: R-CHOP/R-DHAP+ASCT (group A), ibrutinib + R-CHOP/R-DHAP+ASCT+ibrutinib for 2 years (group A+I) and ibrutinib+ R-CHOP/R-DHAP+ ibrutinib was maintained for 2 YEARS (GROUP I), WITH THE PRIMARY ENDPOINT BEING FAILURE-FREE SURVIVAL (FFS).

The results showed that after a median follow-up of 31 months, FFS was similar in group A and group I, with a 3-year FFS rate of 72% versus 86% (Group I; P = 0.
9979, HR was 1.
77); FFS in group A+I was better than group A, with a 3-year FFS rate of 88% (group A+I) vs 72% (group A; P=0.
0008, HR is 0.
52).

This study demonstrated that the addition of ibrutinib during induction therapy and maintenance therapy, with or without ASCT, showed considerable efficacy
.
Current standard high-dose regimens are not superior to newer regimens
containing ibrutinib and without ASCT.

Note: R-CHOP is rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisone; R-DCAP is rituximab plus dexamethasone, cytarabine, and cisplatin
.

Figure 1 Comparison of FFS in Group A, Group A+I and Group I

Abstract No.
1584: Efficacy comparing I+BR with R-CHOP and VR-CAP in first-line treatment with MCL: Efficacy comparison using inverse probability weighted (IPW) calibration

This study performed a corrected comparative analysis
of progression-free survival (PFS) and overall survival (OS) in the I+BR group in the SHINE study versus the R-CHOP and VR-CAP groups in the LYM-3002 study 。 The results showed that compared with the R-CHOP group, PFS and OS were statistically significantly improved in the I+BR group after correction for mean treatment effect (ATT), with median PFS of 80.
8 and 18.
4 months, respectively (HR 0.
24, p<0.
001).
The median OS was not reached (NR) and 64.
6 months (HR was 0.
62, p=0.
012),
respectively.
Compared with the VR-CAP group, the ATT-corrected PFS in the I+BR group had a statistically significant improvement, and the median PFS was 80.
8 months and 30.
7 months, respectively (HR was 0.
50, p=0.
001).
The median OS was NR and 64.
4 months (HR 0.
73, p=0.
093).

This result suggests that ibrutinib combination therapy is a highly effective treatment option compared with standard immunochemotherapy regimens in treatment-naïve
older patients with MCL.

Note: I is ibrutinib; BR is bendamustine in combination with rituximab; VR-CAP is bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone
.

Fig.
2 Comparison of efficacy in I+BR group, R-CHOP group and VR-CAP group

Chronic lymphocytic leukemia (CLL)

Abstract No.
92 CAPTIVATE study: 5-year follow-up of patients with cll with uMRD with ibrutinib plus venetex (Ibr+Ven) first-line therapy: fixed course (placebo) versus continuous ibrutinib

Ibr+Ven is an all-oral, once-daily chemotherapy-free regimen that provides deep, long-lasting clinical benefit
for patients with CLL.
In the CAPTIVATE study, patients with CLL who achieved uMRD with a fixed course of Ibr+Ven were randomly assigned to placebo (fixed course) or continuous ibrutinib in the first-line treatment, and the results showed that the 4-year OS rates were 98% and 100%, and the 4-year PFS rates were 88% and 95%,
respectively.
The placebo group achieved encouraging sustained uMRD with a 3-year disease-free survival (DFS) rate of 85%, providing a strong basis
for deep remission with a fixed course.
Combined with safety data, a good risk-benefit
of fixed-course Ibr+Ven was demonstrated.

Note: uMRD is an undetectable minimal residual disease
.

Table 1 Patient efficacy and adverse events

Abstract No.
93 GLOW study: kinetic results of residual lesions in patients with CLL with high-risk factors receiving a fixed course of Ibr+Vn versus chlorambucil combined with obinutuzumab (Clb+O).

The GLOW study showed that fixed-course Ibr+Ven achieved better sustained uMRD response than Clb+O regimens at 3 to 18 months after treatment (77.
6% vs 12.
2%)
.
Notably, uIGHV patients in the Ibr+Ven group had a higher proportion of uMRD (80 versus 76.
9 percent) and achieved earlier, while 77.
6 percent maintained their uMRD status from 3 months to 18 months
after treatment, regardless of IGHV status.
Even in patients with detectable MRDs 3 months after treatment≥^10-4, clinical progression was not likely to occur within 18 months after treatment in the Ibr+Ven group (6.
5% and 68.
1% of patients in the Ibr+Ven group and Clb+O group).

MRD kinetics and sustained remission confirm the efficacy of a fixed course of Ibr+Ven combination therapy in elderly patients with high-risk genomic features
.

Note: uIGHV is IGHV without mutation; mIGHV is an IGHV mutation
.

Figure 3 A.
Kinetic evaluation of MRD in peripheral blood based on IGHV status (Ibr+Ven group)

B.
Patient PFS based on IGHV status (Ibr+Ven group and Clb+O group)

Abstract No.
797: Real-world comparison of ibrutinib and acracitinib in patients with treatment-naïve CLL to next treatment (TTNT).

The study screened 710 patients with CLL who received ibrutinib and 373 who received acracitinib first-line therapy from US electronic medical records
.
Baseline results showed that patients treated with ibrutinib had more chronic lung disease (13.
6 versus 8.
8 percent, p=0.
024), peripheral vascular disease (7.
8 versus 4.
1 percent, p=0.
022), hypertension (41.
4 versus 32.
2%, p=0.
003), and combined antiplatelet drugs (7.
0 versus 3.
5 percent, p=0.
017).

。 After a mean follow-up of 17.
1 months in the ibrutinib group, 5.
9% of patients required the next line of treatment; After an average follow-up of 12.
5 months with aclitinib, 7.
5% of patients required the next line of treatment
.
After adjusting for baseline, patients treated with acracitinib were 89% more likely to require the next line or in combination with other therapies than those treated with ibrutinib (HR = 1.
89, 95% CI = 1.
12 to 3.
13, p=0.
016, Figure 4).

Data from this large US real-world study show that patients with first-line acracitinib are more likely to require initiation of the next treatment or combination/intensive therapy
compared with first-line patients with CLL who received ibrutinib.

Table 2 Baseline characteristics of patients in ibrutinib group and acracitinib group

Fig.
4 TTNT comparison of first-line patients receiving ibrutinib or acracitinib

Abstract No.
1809: First-line initiation of ibrutinib in patients with CLL improves OS, close to the age-matched general population ≥ 65 years

This study compared pooled OS with age-matched OS in 65-year-old patients with treatment-naïve CLL ≥ ibrutinib with age-matched OS, and compared the pooled features and OS outcomes
of ibrutinib versus CT/CIT in three phase III clinical trials.
The results showed that the estimated 8-year OS rate in patients aged ≥65 years after diagnosis of CLL treated with ibrutinib-containing regimen was 78%, compared with 77% in the age-matched general population, with no statistically significant difference between the two (HR 0.
97, p=0.
90).

At a median follow-up of 42 months, the estimated OS rates at 3 and 5 years were 93% and 88% for patients treated with ibrutinib-containing regimens, and 85% and 75% of patients treated with CT/CIT, respectively, with statistically significant differences (HR 0.
46, p<0.
0001).
<b12> This pooled analysis suggests that first-line initiation of ibrutinib therapy improves OS
compared with conventional CT/CIT, regardless of age or physical condition.
This is also the first time that patients who start ibrutinib first-line have similar survival estimates to the age-matched general population after 8 years of follow-up
.

Note: CT/CIT is chemotherapy/immunochemotherapy
.

Figure 5 The pooled OS of ≥65-year-old treatment-naïve CLL patients treated with ibrutinib was similar to that of the age-matched general population

Fig.
6 Compared with traditional CT/CIT, first-line ibrutinib therapy can improve OS

Abstract No.
4934: Comparison of early adherence and persistence of first-line ibrutinib or acracitinib in patients with CLL/SLL comorbid atrial fibrillation in the real world

The study included 542 patients with CLL/SLL who received ibrutinib first-line and 243 patients who received acracitinib first-line, comparing treatment adherence and continuity, defined as the percentage of treatment coverage days exceeding 80% during fixed periods of treatment at 2, 3, and 6 months, and continuous treatment defined as non-stop
treatment for more than 90 days 。 At months 2, 3, and 6 of follow-up, ibrutinib adherence in the overall population was 84.
7%, 81.
3%, and 76.
3%, compared with acracitinib 82.
8%, 77.
7%, and 76.
3%, and adherence and persistence were similar (OR 0.
9-1.
18, p>0.
05; OR 0.
79-1.
15, p>0.
05
), indicating that higher treatment adherence and persistence of acracitinib compared with ibrutinib were not observed in the real world 。 However, in patients with baseline concomitant atrial fibrillation, early compliance and persistence of ibrutinib were observed to be higher than that of acracitinib, but there were no statistically significant differences: ibrutinib compliance at months 2, 3, and 6 was 79.
4%, 76.
8%, and 72.
5%, respectively, compared with 76.
6%, 62.
5%, and 61.
9% of aclitinib (ORs adjusted for baseline were 1.
39, 3.
13, and 2.
13, p=0.
537, 0.
042, and 0.
309).

Fig.
7 Comparison of early medication adherence and persistence in patients treated with ibrutinib or acracitinib first-line monotherapy

Primary central nervous system lymphoma (PCNSL)

Abstract No.
2941: A prospective multicenter phase II clinical study of the MIT (methotrexate + ibrutinib + telmozolomide) regimen for the treatment of treatment-naïve PCNSL

The study is a prospective multi-center single-arm phase II clinical study led by Professor Huang Huiqiang and Professor Wang Xiaoxiao of Sun Yat-sen University Cancer Prevention and Control Center, aiming to evaluate the efficacy and safety of MIT in the treatment of treatment-naïve PCNSL, and the study comprehensively detects the gene mutation information of cerebrospinal fluid and tumor tissue and the dynamic changes
in the treatment process.
The MIT regimen consisted of six courses of high-dose methotrexate (MTX 3.
5 g/m2 every 3 weeks), ibrutinib (560 mg/day after MTX clearance), and temozolomide (150 mg/^m2, d1-d5 every 3 weeks).

After completing 6 cycles of induction therapy with the MIT regimen, ASCT can be used as consolidation therapy (for patients aged <65 years), ibrutinib (560 mg/day) maintenance therapy for 2 years or until disease progression or intolerance<b15>.
Efficacy is assessed by MRI or FDG-PET and cerebrospinal fluid testing
.
The primary endpoint was the overall response rate (ORR)
after completion of the 6-course MIT regimen.
From July 2021 to July 2022, a total of 31 patients with treatment-naïve PCNSL were enrolled, of which 28 had completed at least 2 courses of MIT regimen
.
The median age was 53 years, and 53.
6% (15/28) were male
.
At the time of data cut-off, 42.
9% (12/28) of patients completed 6 courses of treatment
.
32.
1% (9/28) completed 4 courses of treatment, and 25% (7/28) completed 2 courses of treatment
.
The ORR was 92.
9% (26/28) and the complete response (CR) rate was 67.
9% (19/28).

91.
7% of the 12 patients who completed 6 courses of treatment achieved CR.

Original link:

1.
https://ash.
confex.
com/ash/2022/webprogram/Paper163018.
html；

1584.
https://ash.
confex.
com/ash/2022/webprogram/Paper158259.
html；

92.
https://ash.
confex.
com/ash/2022/webprogram/Paper160338.
html；

93.
https://ash.
confex.
com/ash/2022/webprogram/Paper156070.
html；

797.
https://ash.
confex.
com/ash/2022/webprogram/Paper163387.
html；

1809.
https://ash.
confex.
com/ash/2022/webprogram/Paper163257.
html；

4934.
https://ash.
confex.
com/ash/2022/webprogram/Paper162797.
html；

2941.
https://ash.
confex.
com/ash/2022/webprogram/Paper169608.
html；

CRC: EM-115507

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