Micro Classroom No. 15 Professor Xu Shuangnian: Progress in the treatment of AL amyloidosis

Fig.
2 Hematologic response rates at median follow-up of 11.
4 months and 25.
8 months

Fig.
3 Cardiac and renal response rates at median follow-up of 6 and 18 months

Although the ANDROMEDA study has confirmed the good efficacy of daratumumab in the treatment of AL amyloidosis, the prognosis of AL amyloidosis patients with advanced cardiac involvement is extremely poor, and its benefit from daratumab treatment has also attracted much attention
.
The 2022 EHA Annual Meeting announced the latest progress in the treatment of newly diagnosed stage III AL amyloidosis in ^China16
initiated by Peking Union Medical College Hospital.
The study is a prospective, open-label, single-center phase II clinical trial that currently includes 38 patients with a median age of 59 years
.
The median number of organs involved was 2, 14 (36.
8%) patients with renal involvement and 9 (23.
7%) patients with liver involvement
.
The overall response rate (ORR) was as high as 89.
5%
in patients treated with bortezomib and dexamethasone plus daratumumab (DVd) at a median cycle of 3.
25 cycles.
With the prolongation of treatment time, the CR rate gradually increases (Figure 4).

Cardiac remission rates were 18.
5% at 3 months and 23.
5%
at 6 months.
After a median follow-up of 4.
5 months, median overall survival (OS) was not achieved
.
The 6-month OS rate for all patients was 76.
6% (Figure 5).

In terms of safety, the most common grade 3/4 adverse events were infection, etc.
, and no patients withdrew from the study
due to adverse events.
The DVd regimen has brought significant hematologic remission, organ remission and survival benefits to newly diagnosed stage III AL amyloidosis patients in China, and the safety profile is good
.

Fig.
4 CR rate of DVd regimen in Chinese patients with stage III AL amyloidosis

Fig.
5 OS rate of DVd regimen in Chinese patients with stage III AL amyloidosis

The latest authoritative guidelines at home and abroad also unanimously refer to the combination regimen of daratumumab as a class I recommended regimen for the treatment of AL amyloidosis (Figure 6).

The 2022 NCCN guidelines recommend D-VCd regimen as the only preferred regimen for transplant-suitable and transplant-unsuitable patients, and the Chinese Guidelines for the Diagnosis and Treatment of Systemic Light Chain Amyloidosis (Revised in 2021) also recommend D-VCd as the preferred regimen
for transplant-suitable and transplant-unsuitable patients.

Fig.
6 The latest authoritative guidelines at home and abroad recommend the treatment of AL amyloidosis

As an important representative of new immunotherapy drugs, daratumumab has the characteristics of high efficiency and low toxicity, which makes it feasible to combine with existing drugs, and the synergy between drugs may further improve the efficacy
.
In addition to CD38 monoclonal antibodies such as daratumumab, new drugs for the treatment of AL-type amyloidosis include the BCL-2 inhibitor venetoclax, antibody conjugates targeting BCMA, anti-amyloid fibril therapy such as CAEL-101, antiserum amyloid antibodies, and chimeric antigen receptor T cell (CAR-T) therapy
.

Among them, CAEL-101 is a chimeric immunoglobulin that binds specifically to misfolded light chain fibrils, thereby eliminating amyloid
deposited in tissues and organs.
An ongoing open-label Phase II ^study17 presented at the 2021 ASH Annual Meeting demonstrated good safety and tolerability of CAEL-101 in combination with VCd
.
Of the 20 cardiac evaluable patients, 18 (90%) were in remission (the amino-terminal natriuretic peptide precursor [NT-proBNP] decreased ≥30% from baseline) or remained steady (±30% change from baseline).

Of the nine patients with renal evaluation, 8 (89%) achieved renal remission (decreased proteinuria ≥ 30% after treatment) and 3 patients reduced proteinuria to <0.
5 g/24 hours (Figure 7).

Fig.
7 Percentage change from baseline in cardiac and kidney-related markers in patients treated with CAEL-101

In addition, data from a Phase II study of the antibody-conjugate drug Belantamab mafodotin monotherapy for relapsed/refractory AL amyloidosis were presented at the 2022 EHA Annual ^Meeting18
.
Results showed an ORR of 72.
7%, a median time to first hematological response of 8.
5 days, a median response to VGPR or better (≥VGPR) of 15.
0 days, and an organ (heart, kidney, or liver) response rate of 36.
4%
at 3 months.
≥1 serious adverse event
occurred in 36.
4% of patients.
Belantamab mafodotin monotherapy for relapsed/refractory AL amyloidosis induces rapid remission with a manageable
safety profile.

summary 

AL type amyloidosis is the most common type of systemic amyloidosis and can cause organ and tissue damage;

The goal of treatment of AL amyloidosis is to rapidly achieve deep hematologic remission as well as organ remission
.
At present, commonly used treatment options include autologous hematopoietic stem cell transplantation, alkylating agents, proteasome inhibitors, etc.
, and the high-quality hematological response rate of existing treatments is not high, and the associated toxicity is common, and the drug tolerance is very poor;

As the only approved AL amyloidosis indication drug, the combination of VCd regimen brings deeper and faster hematological relief to newly diagnosed AL amyloidosis patients, significantly improves the function of affected organs, and has a good safety profile.

CAEL-101 et al.
provide a new treatment option for AL amyloidosis patients, and look forward to more clinical trial data to explain its safety and efficacy
.