Can veneclax be used for the treatment of patients with relapsed/refractory Waldenström macroglobulinemia?

Introduction Waldenström macroglobulinemia (WM) is characterized by the malignant accumulation of IgM-secreting plasma cells in the bone marrow (BM) and other organs
.

Treatment options for WM include alkylating agents, anti-CD20 monoclonal antibodies, proteasome inhibitors, and Bruton's tyrosine kinase (BTK) inhibitors
.

The study found that two genes, MYD88 and CXCR4, have highly reproducible somatic mutations in WM patients, and these mutations can affect the disease performance, prognosis and response to BTK inhibitor therapy
.

There is currently no cure for WM and new treatments are needed
.

The BCL2 gene expression product is an important regulator of the intrinsic pathway of apoptosis in normal and malignant cells
.

Abnormal plasma cells of WM patients overexpress the BCL2 gene, especially those with MYD88 mutations
.

However, CXCR4 mutation had no significant effect on BCL2 gene expression
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Veneclax is an oral BCL2 inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML)
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In vitro experiments found that veneclax induced apoptosis in MYD88-mutated WM cells, which were genetically engineered to be CXCR4 wild-type or mutant, to sensitize them to chemotherapeutics, including BTK inhibitors
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In a prospective phase I clinical trial, all WM patients (n=4) achieved a major response with veneclax
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Based on this, some researchers conducted a prospective, multicenter phase II clinical trial to evaluate the safety and efficacy of veneclax in previously treated patients with relapsed/refractory WM
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Research Methods The study was a multicenter, prospective Phase II clinical trial (NCT02677324), recruited from June 2016 to February 2018 from Dana-Farber Cancer Institute, Weill Cornell Medical Center, Hope Patients at City National Medical Center and Stanford University Medical Center
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Data cutoff date is December 31, 2020
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Inclusion criteria: previously treated adult patients with WM; Eastern Cooperative Oncology Group performance status score ≤2; good bone marrow function (neutrophil count ≥1.
0K/uL, platelet count ≥50K/uL, and hemoglobin ≥8g/dL) ; Creatinine clearance rate ≥ 50mL/min; good liver function; meet the treatment criteria
.

Exclusion criteria: disease involving the central nervous system (CNS); active HIV; infection with hepatitis B or C; during treatment for other cancers; pregnancy or breastfeeding
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The first 6 patients included received oral veneclax at 200 mg once daily for 1 week, followed by 400 mg daily for 1 week, and then 800 mg daily for 2 years
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Beginning in patient 7, veneclax was administered orally at 400 mg once daily for 1 week, followed by 800 mg daily for 2 years
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For the first 3 days of veneclax use, all patients received allopurinol 300 mg once daily along with 2 L of quoted water daily to prevent tumor lysis
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Allopurinol treatment continued for 4 weeks
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If oral rehydration is ineffective, administer 2 L of normal saline intravenously before the first dose of veneclax
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The primary endpoint of the study is the overall response rate (ORR), which includes the rate of minor response, partial response (PR), very good partial response (VGPR) and complete response (CR); the secondary endpoint is the primary Response rate, time to response, duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT) and safety
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Study Results Patient Baseline Characteristics Ultimately, the study included 32 patients who received veneclax
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The median time from prior therapy to first use of veneclax was 9 months (range: 1-115 months)
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Seven patients were treated at first relapse, four were previously on bortezomib, dexamethasone, and rituximab, one was bendamustine and ofatumumab, and one was It was a BTK inhibitor, and one case was ofatumumab
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Among 11 patients with refractory WM, 4 were resistant to proteasome inhibitor-based regimens, 3 were resistant to BTK inhibitors, 2 were resistant to anti-CD20 mAbs, and 1 was resistant to bendamustine and rituximab resistance, 1 case was resistant to phosphatidylinositol 3-kinase inhibitor
.

Sixteen patients (50%) had received prior BTK inhibitor therapy
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All patients (n=32) had MYD88L265P mutations; 17 had CXCR4 mutations, including 12 nonsense mutations and 5 frameshift mutations
.

Compared with patients without CXCR4 mutations, patients with CXCR4 mutations were less likely to have enlarged lymph nodes (≥1.
5 cm) (12% vs 53%; P=0.
01) and had lower median serum β2-microglobulin levels (2.
6 vs 4.
9 mg/dL; P=0.
002)
.

The specific baseline characteristics are shown in Table 1
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Table 1 Effectiveness analysis ORR was 84% ​​(95%CI, 66-95), of which the VGPR rate was 19% (n=6); the PR rate was 61% (n=19); the minimal response rate was 3% (n=6).
=1)
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The primary response rate was 81% (95% CI, 63-93)
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No patient achieved CR
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The ORR was lower in patients with refractory and relapsed WM, 60% and 95%, respectively (P=0.
03); the ORR in patients who had received ≥3 lines and <3 lines of therapy was 63% and 95%, respectively (P=0.
03).
0.
04)
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Previous BTK inhibitor exposure and CXCR4 mutation status were not associated with ORR
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The primary response rate was significantly lower in patients with refractory WM than in patients with relapsed WM (50% vs 95%; P=0.
007)
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No other clinical and genomic factors were associated with major response rates
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No baseline characteristics were associated with VGPR
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The specific efficacy analysis results are shown in Figure 1
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Figure 1 At a median follow-up of 33 months (range: 24-38 months), 19 patients developed progression
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The median PFS was 30 months (95% CI, 27-38)
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The 12- and 24-month PFS rates were 83% (95% CI, 64-93) and 80% (95% CI, 60-90), respectively
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Refractory WM and ≥3 previous lines of therapy were associated with shorter PFS
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Twelve patients started new therapy after veneclax without reaching median TTNT
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The 30-month follow-up treatment-free rate was 76% (57%-88%)
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The 30-month follow-up treatment-free rate in the refractory group was lower than that in the relapsed group, 60% (95%CI, 25-83) and 85% (95%CI, 60-95), respectively (P=0.
006)
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At data cutoff, all 32 patients were alive, with a 30-month overall survival (OS) rate of 100% (95% CI, 89-100)
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Safety Analysis Seven (22%) patients had reduced veneclax doses due to neutropenia (n=2), pancytopenia (n=1), unattributable fatigue (n=1) 1), diarrhea (n=1), multiple grade 2 events (n=1), and poor adherence (n=1)
.

Dose reduction was not associated with ORR, major response rate, VGPR rate and PFS (p>0.
05)
.

Veneclax was discontinued early due to pancytopenia in 1 patient
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Thirty-one patients (94%) experienced grade ≥ 2 adverse events
.

Seven (22%) patients experienced grade 4 adverse events, including neutropenia (n=6) and febrile neutropenia (n=1)
.

One patient with generalized lymphadenopathy (3.
7cm), splenomegaly (27cm), and leukocytosis (59K/uL) developed laboratory tumor lysis syndrome (TLS) who was hospitalized and received intravenous Fluid therapy and a dose of rasburicase
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Adverse events are detailed in Table 2
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Conclusions of the study in Table 2 are that veneclax is safe and highly effective in patients with WM who have previously received other treatments including BTK inhibitors
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CXCR4 mutation status does not affect treatment response
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Of course, the study needs further support from phase III clinical trial data
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Reference: Jorge J.
Castillo, John N.
Allan, Tanya Siddiqi, et al.
Venetoclax in Previously Treated Waldenström Macroglobulinemia.
J Clin Oncol.
2022 Jan 1;40(1):63-71.
doi: 10.
1200/JCO.
21.
01194 .
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