The 2023 V1 CCCN CLL/SLL guidelines were updated with zebutinib becoming the only BTK inhibitor recommended by both the CSCO and NCCN guidelines as a double priority

In August 2022, the National Comprehensive Cancer Network (NCCN) published the V1 version

Innovation: 2023 V1

NCCN CLL/SLL Guidelines Update Points ^1,2

Compared with the 2022.

Update 1: Recommended classification for treatment of CLL/SLL without del(17p)/TP53 mutations: Qualifiers such as age and comorbidities are removed

Limitations such as age and comorbidities were removed, the treatment regimen was reorganized, and the patient was only organized by no del (17p)/TP53 mutation stratification factors

Update 2: The recommended status of BTK inhibitor zebutinib has been improved, the recommended status of limited treatment options has been improved, and the status of immunochemotherapy has declined

• In first-line treatment of CLL/SLL without del(17p)/TP53 mutations, the BTK inhibitor zebutinib was adjusted from Class 2A to Class 1 recommendation in the preferred recommended

  
  

• The recommended status of immunochemotherapy has further decreased, and the FCR (fludarabine, cyclophosphamide, rituximab) has been adjusted from other recommended regimens to "use in certain circumstances" (considered for CLL patients aged < 65 years of age with no significant comorbidities and with IGHV mutation); Immunochemotherapy regimens<b10> such as chlorambucil, rituximab (R), FR (fludarabine + rituximab) were removed from other recommendations.

  
  

• The recommendation of the BCL-2 inhibitor vinekla + optulizumab was adjusted from class 2A to class 1; And in other recommended options to add ibratinib + vinecra as a Class 2B recommendation

  
  

• In second- or third-line therapy with CLL/SLL without del(17p)/TP53 mutation, the addition of vinecra + optizumab as class 2A recommended for retreatment under specific conditions (previously used for first-line therapy, relapse after a period of remission); At the same time, the immunochemotherapy regimens

  
  

• In first-line therapy with del(17p)/TP53 mutations of CLL/SLL with increased ibratinib + vinectra as class 2B recommended; Second-line and follow-up therapy, due to limited clinical use and accessibility, removed olamumab

  
  

Update Three: Recommended Adjustments for Full-Line Treatment of First-Generation BTK Inhibitors

The first-generation BTK inhibitor ibratinib moved from the priority recommendation to other recommended regimens
throughout the treatment of CLL/SLL.

The new generation of BTK inhibitors zebutinib and acotinib remain preferred
.

Figure 1 2023.
v1 is updated with the 2022.
v3 version

Swipe left and right to see more

Tracing the source:

The new generation of BTK inhibitor zebutinib recommended status improved

Zebutinib is a new generation of structure-optimized BTKi independently developed in China, with more accurate target selectivity and lower off-target effect, thereby reducing the risk of adverse events such as atrial fibrillation, infection, rash, bleeding, etc.
Zebutinib has also shown good efficacy and reliable safety
in previous studies.

With this update of the NCCN guidelines, zebutinib for the treatment of CLL/SLL has been given a comprehensive priority recommendation, mainly based on the results of the
SEQUOIA study and the ALPINE study.

The SEQUOIA study, a randomized, multicenter, global phase III clinical study with 479 patients with first-treatment CLL/SLL without del (17p) in Cohort 1, was designed to evaluate the efficacy and safety of zebutinib versus the bedamustine plus rituximab (BR) regimen, the results of which were published in The Lancet Oncology
in August 2022.

The results showed that at 26.
2 months of median follow-up, neither group achieved the median progression-free survival (PFS) assessed by the Independent Review Committee (IRC), and at 24 months, the estimated PFS rates in the zebutinib group and the BR group were 85.
5% and 69.
5%, respectively.
Compared with BR, the PFS was significantly improved in the zebutinib group (HR = 0.
42, 95% CI: 0.
28-0.
63; bilateral P<0.
0001) (Figure 2)³
.

In terms of safety, the most common grade 3 adverse event ≥ was neutropenia, with a lower incidence in the zebutinib group than in the BR group (11% vs.
51%); The zebutinib group also had fewer serious adverse events (37% vs.
50%)
.

Figure 2 SEQUOIA study: PFS assessed by IRC

The ALPINE study was a global, randomized, phase III study of 625 relapsed refractory (R/R)CLL/SLL comparing efficacy and safety
of zebutinib and ibratinib head-to-head.

The results showed that zebutinib significantly improved the objective response rate (ORR) (78.
3% vs.
62.
5%, bilateral P-value = 0.
0006) (Figure 3).
The 12-month PFS rate was significantly increased in the zebutinib group (94.
9% vs 84.
0%, P=0.
0007) and the risk of disease progression was reduced by 60% (HR=0.
40 (95% CI: 0.
23-0.
69); P=0.
0007) (Figure 4) ⁴
.

In terms of safety, the incidence of atrial fibrillation or flutter events was lower in the zebutinib group (2.
5% vs.
10.
1%, P=0.
0014), and the incidence of adverse events such as major bleeding (2.
9% vs.
3.
9%), and discontinuation due to adverse events (7.
8% vs.
13.
0%) was also lower
.

Figure 3 ALPINE study: Investigator-assessed ORR

Figure 4 ALPINE study: PFS assessed by the investigators

Coming to the top: Zebutinib was recommended by both the CSCO and the NCCN guidelines

In fact, in the 2022 CSCO guidelines, zebutinib is recommended for treatment of CLL with a comprehensive Level I recommendation (Figure 5)⁵
.

This update of NCCN guidelines further makes zebutinib the only BTK inhibitor in CLL treatment to receive dual priority recommendation from CSCO and NCCN guidelines
.

Figure 5 2022 CSCO lymphoma diagnosis and treatment guidelines updated

Expert reviews

Professor Xu Wei

The First Affiliated Hospital of Nanjing Medical University

In recent years, with the continuous emergence of targeted drugs, research data and clinical experience, the efficacy of BTK inhibitors in CLL/SLL treatment has been gradually confirmed, and its therapeutic status has been continuously improved
.

Based on the fact that several phase III studies have confirmed the benefits of BTK inhibitors in the overall CLL population, regardless of age and comorbidities, this guideline update removes limitations such as age and comorbidities, and reorganizes
treatment options.

Secondly, it can be clearly seen in this update of NCCN guidelines that the status of immunochemotherapy has generally declined, and treatment options
such as chlorambucil, rituximab, and FR have been removed.

It is worth mentioning that in the treatment of first-line patients without del (17p)/TP53 mutation, the new generation of BTK inhibitor zebutinib independently developed in China has been upgraded from "Class 2A Recommendation" to "Class I Preferred Recommendation", and the first generation of BTK inhibitors has moved out of the priority recommendation, and this update may change the application pattern
of BTK inhibitors.

Expert profile

Professor Xu Wei

• Deputy Director, Chief Physician and Doctoral Supervisor of the Department of Hematology, the First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People's Hospital).
  

• Vice Chairman of the Hematology and Oncology Committee of the Chinese Anti-Cancer Association, and leader of the lymphoma group

• Chairman of the Hematological Lymphoma Committee of the China Junior Insurance Association

• Vice Chairman of the Lymphoma Committee of the Chinese Geriatric Health Care Association

• Vice Chairman of the Lymphoma Committee of the Chinese Medical Education Association

• Member of the Standing Committee of CSCO China Anti-Lymphoma Alliance

• Member of the Standing Committee of the Hematology Committee of the Chinese Association of Women Physicians

• Vice Chairman of the Hematology Society of Jiangsu Medical Association

• Vice President of Hematology Physician Branch of Jiangsu Medical Doctor Association

• Chairman of the Lymphoma Committee of Jiangsu Research Hospital Association

• Chairman of Jiangsu Anti-Lymphoma Alliance

• Vice Chairman of the Hematology Oncology Committee of Jiangsu Anti-Cancer Association

• Vice Chairman of Nanjing Hematology Society