An article to understand the individualized treatment strategy for Waldenstrom's macroglobulinemia

Waldenstrom's macroglobulinemia (WM) is a rare indolent lymphoma characterized by serum monoclonal IgM.
MYD88 mutation and CXCR4 mutation are common molecular changes that can affect the efficacy of WM therapy and progression-free survival Period (PFS)
.

About 50%-60% of WM patients have MYD88 mutations while CXCR4 has no mutations (MYD88MUT and CXCR4WT)
.

The oral small molecule targeted drug Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib is an ideal treatment option for patients with MYD88MUT and CXCR4WT.
The overall response rate (ORR) of ibrutinib monotherapy is 100%.
The 5-year PFS rate is 70%
.

However, the patient's own characteristics should be considered when choosing a treatment plan.
Patients with a history of cardiovascular disease or pre-existing arrhythmia should be alert to the occurrence of atrial fibrillation when using Ibritinib
.

In addition, patients and clinicians should also understand that BTKi monotherapy should continue until disease progression (PD) or intolerable adverse reactions occur.
Temporary or permanent discontinuation of BTKi may lead to withdrawal symptoms and rapid rebound of serum IgM levels
.

30%-40% of WM patients have MYD88MUT and CXCR4MUT
.

CXCR4MUT patients are more likely to have higher serum IgM levels, symptomatic hyperviscosity and acquired von Willebrand disease
.

In these patients, ibrutinib monotherapy is rarely the first choice.
In this case, chemoimmunotherapy or proteasome inhibitor-based treatment regimens are suitable
.

Data from a retrospective study of 63 WM patients (49 of which are known to have CXCR4 mutation status) showed that patients with CXCR4 mutations were compared with patients without CXCR4 mutations in PFS treated with bortezomib and rituximab There is no significant difference between OS and OS
.

In a prospective study involving 69 patients with WM, the patients received bendamustine combined with rituximab (BR) regimen, and the results showed that whether CXCR4 mutations are not related to the patient's disease remission rate or OS
.

In addition, similar results were reported in a pooled analysis of WM patients receiving bortezomib, carfilzomib, or ixazomib-containing regimens as first-line treatment
.

Among WM patients with or without CXCR4 mutations, no differences in remission rate, PFS, or OS were observed after the start of first-line treatment
.

The results of the INNOVATE study proved that ibrutinib combined with rituximab is a safe and effective treatment for WM patients.
The study reported a low incidence of IgM rebound (8%), and there were no patients requiring plasma exchange.
It shows that the combination therapy of ibrutinib and rituximab is a suitable treatment option for patients with CXCR4MUT
.

Therefore, this regimen can be used in this cohort, but at the same time, rituximab infusion-related reactions should be considered
.

5%-10% of WM patients are MYD88WT and CXCR4WT.
These patients have specific clinical features, such as shorter OS and increased risk of transforming to aggressive lymphoma
.

The results of a retrospective study show that BR can be used as a treatment option for such patients
.

However, another prospective study showed that 6 patients with MYD88WT who were treated with the BR regimen had a shorter PFS
.

A study using allele-specific polymerase chain reaction (AS-PCR) to detect the mutation status of MYD88 in bone marrow cells sorted by CD19 showed that the remission rate of MYD88WT patients treated with ibrutinib was lower
.

In the INNOVATE study, the ORR of MYD88WT and CXCR4WT patients receiving ibrutinib combined with rituximab was 81%, the primary response rate was 63%, and the very good partial response (VGPR) rate was 27%, 30 The monthly PFS rate is 80%
.

However, in this study, next-generation sequencing (NGS) was used to evaluate the MYD88 mutation status in bone marrow cells of 136 unselected patients, and 15% of the patients were MYD88WT and CXCR4WT
.

The sensitivity of NGS may be lower than that of AS-PCR, especially for patients with low disease burden
.

The results of a prospective study show that the new BTKi acatinib and zebutinib are effective for WM patients with MYD88WT
.

In the study using acatinib to treat WM, a total of 106 patients were enrolled, 47% of the patients were genotyped, and 28% of the patients were MYD88WT
.

The testing methods for MYD88 genotyping are determined by the participating centers.
The results showed that the ORR and major remission rates of these patients were 78% and 57%, respectively
.

Cohort 2 of the ASPEN study included 28 WM patients with MYD88WT.
The patients were treated with Zebutinib and NGS was used to assess MYD88 mutation status in unselected bone marrow tissue
.

The results of the study showed that the ORR, primary remission rate, and VGPR rate of Zebutinib treatment were 80%, 50%, and 27%, respectively, and the 18-month PFS rate was 68%
.

In general, genome analysis has become a potential basis for individualized treatment decisions for WM patients
.

Reference source: Jorge J.
Castillo.
2021 SOHO.
EXABS-136-NHL.
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