2022 ASH Expert Interview | Professor Jorge Castillo: Exploration and prospect of targeted therapy for Waldenstrom macroglobulinemia

We wanted to develop a time-limited regimen with no chemotherapy and full oral administration, so we designed this investigator-initiated single-arm, multicenter, prospective phase II study with the following study design (Figure 1).

The primary endpoint was a very good partial response (VGPR) rate ≥45%.

Figure 1

Between July 2020 and January 2022, a total of 45 patients
were included in this study.
Baseline characteristics of patients are as follows (Table 1).

Table 1

Eighteen cases achieved VGPR (40%), 24 achieved partial response (PR) (53%), and three achieved mild response (MR) (7%), with an objective response rate (ORR) of 100% and a primary response rate of 93% (Figure 2).

Figure 2

At a median follow-up of 11 months, one patient progressed to aggressive lymphoma and two died of ventricular arrhythmias
.
The estimated progression-free survival (PFS) rate at 12 months was 92% and the overall survival (OS) rate was 95% (Figure 3).

Grade ≥ 3 adverse events included neutropenia (n=13; 29%), cardiac arrest/ventricular arrhythmias (n=3; 7%), oral mucositis (n=2; 4%), and tumor lysis syndrome (n=2; 4%) (Table 2).

Table 2

The results confirmed that the combination of the two drugs was very effective, however, the incidence of ventricular arrhythmias was higher than expected, which prompted the discontinuation of the study treatment, based on complications, which cannot be recommended for clinical use at this time, and I think future trials can also choose different drugs or low-toxicity drug combination therapy to develop treatment options
.

Yimaitong: What is the current development status of Waldenstrom macroglobulinemia targeted therapy? What is your vision for the future?

At present, the BTK inhibitors used clinically include ibrutinib, aclitinib, zebratinib, orelabrutinib and tirabrutinib, all of which are covalent BTK inhibitors that inhibit BTK kinase activity by irreversibly binding to C481 in the BTK protein kinase domain
.
Non-covalent BTK inhibitors do not bind to C481 and have higher targeting to BTK
.
Professor M.
Lia Palomba from Memorial Sloan Kettering Cancer Center presented a number of studies on non-covalent BTK inhibitors at this year's ASH conference, reporting on the activity and good tolerability of the non-covalent BTK inhibitor pirtobrutinib in patients with relapsed/refractory WM who have previously received multiple lines of therapy, with low
discontinuation rates due to drug-related toxicity.

I believe that future clinical trials should focus on the exploration of combination therapy, mainly targeted drugs such as BTK inhibitors, especially the exploration
of limited-stage treatment options.
Or immunotherapy, the treatment drugs are antibody-drug conjugates, bispecific T cell adapters, and chimeric antigen receptor T cell (CAR-T) therapy
.
It is expected that future clinical trials can lead to more effective, economical and less toxic treatment options
for WM patients.