Iopofosine I 131 Shows Durable Responses in Heavily Pretreated Waldenström Macroglobulinemia

Key Clinical Summary:

• Design/Population: The phase 2 CLOVER-WaM trial (NCT02952508) was a multicenter, open-label study evaluating iopofosine I 131 among 65 patients with previously treated symptomatic Waldenström macroglobulinemia (median 4 prior lines; 71% prior BTK inhibitor exposure, 56% BTK inhibitor-refractory; 29% MYD88-wild type). The modified ITT population (n = 55) received ≥ 60 mCi total dose.
• Key Outcomes: The major response rate was 56.4% (95% CI, 42.3 to 69.7), exceeding the prespecified threshold, with an overall response rate of 80% (81% in MYD88–wild type; 72% post-BTKi). The clinical benefit rate was 98%. At 8.8 months median follow-up, median DOR and treatment-free survival were not reached, and 72% of responders remained progression-free at 18 months. Grade ≥ 3 cytopenias were common (thrombocytopenia 80%, neutropenia 69%), with 1 treatment-related death.
• Clinical Relevance: Iopofosine I 131 demonstrated durable, high response rates across biologic subgroups, including BTKi-refractory and MYD88-wild type WM, supporting its development as a novel option in a heavily pretreated population with limited standard therapies, despite notable but manageable hematologic toxicity.

Iopofosine I 131 demonstrated high response rates and durable disease control among patients with previously treated Waldenström macroglobulinemia (WM), including those refractory to Bruton’s tyrosine kinase (BTK) inhibitors, according to results from the phase 2 CLOVER-WaM study (NCT02952508).

For patients with WM, treatment options remain limited. Researchers conducted a multicenter, open-label trial to determine the safety and efficacy of iopofosine I 13, a lipid raft-targeting phospholipid ether covalently bound to ¹³¹I, among patients who previously received treatment for WM. 

Patients received 2 cycles of iopofosine I 131 at 15 mCi/m² on days 1 and 15 of each 57-day cycle, with dose reduction permitted in select cases. The primary end point was major response rate (MMR), defined as a partial response or better, secondary end points included overall response rate (ORR), treatment-free survival (TFS), duration of response (DOR), and clinical benefit rate (CBR). 

Overall, 65 patients with symptomatic WM who had received at least 2 prior lines of therapy were enrolled. The modified intent-to-treat (mITT) population included 55 patients who received at least 60 mCi total dose and were evaluable for efficacy. Among all patients, the median age was 7- years (range, 50 to 88). The median number of prior therapies was 4 (range, 2 to 15), 71% had prior BTK inhibitor exposure and 56% were BTK inhibitor-refractory. About 29% of patients had MYD88-wild type disease and 9% had CXCR4 mutations.

The MRR was 56.4% (95% confidence interval [CI], 42.3 to 69.7), exceeding the prespecified threshold of 20%. The ORR was 80%, including 81% among patients with MYD88-wild type disease and 72% among patients who previously received BTK inhibitor therapy. The CBR was 98%. At a median follow-up of 8.8 months, the median DOR and TFS were not reached and an estimated 72% of responders remained progression-free at 18 months.

Among all patients, any-grade adverse events were reported among 87% of patients, of which grade ≥ 3 treatment-emergent adverse events included thrombocytopenia (80%), neutropenia (69.2%), anemia (44.6%), lymphopenia (13.8%), infections (12.3%), and febrile neutropenia (10.8%). One treatment-related death due to bacterial sepsis was reported.

The researchers concluded, “Iopofosine I 131 demonstrated durable efficacy in previously treated WM patients, with no current standard of care therapy.”

They added, “The treatment was well-tolerated with a manageable toxicity profile across broad biologic and clinical subgroups, irrespective of risk stratification. Based on the results of this trial, iopofosine I 131 shows promise as a novel treatment for WM patients.”

Source:

Sikander Ailawadhi, Gavriatopoulou M, Peterson J, et al. Iopofosine I 131 in previously treated patients with Waldenström Macroglobulinemia (WM): efficacy and safety results from the international, multicenter, open-label phase 2 study (CLOVER-WaMTM). Blood. Published online November 5, 2024. doi:10.1182/blood-2024-200277