Iopofosine I-131 Shows Potential in R/R Waldenström Macroglobulinemia

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Iopofosine I-131 demonstrated sustained efficacy and a favorable tolerability profile in heavily pretreated patients with relapsed/refractory Waldenström macroglobulinemia, a population lacking standard-of-care options. These findings from the phase 2B CLOVER-WaM trial (NCT02952508) were presented at the 2024 ASH Annual Meeting.¹

Data from the trial demonstrated that the overall response rate (ORR) was 83.6% in the overall population (n = 55), which included a major response rate (MRR) of 58.2%. The complete response (CR)/very good partial response (VGPR) rate was 7.3%, and the clinical benefit rate (CBR) was 98.2%.

“The treatment options beyond the initial couple of lines of therapy [for patients with Waldenström macroglobulinemia] are relatively limited and heterogeneous,” lead study author Sikander Ailawadhi, MD, of Mayo Clinic in Jacksonville, Florida, said during an oral presentation of the data. “Iopofosine I 131 is a small molecule phospholipid drug conjugate [PDC] designed to provide targeted delivery of its payload, which in this case is iodine-131.”

CLOVER-WaM Trial Design and Baseline Patient Characteristics

Part A of the phase 2 trial—referred to as CLOVER-1—evaluated iopofosine I 131 in patients with select B-cell malignancies who have received prior lines of therapy.² The primary end point of Part A was CBR, measured within a time frame of 84 days.

The patient population included in the CLOVER-WaM phase 2B study had heavily pretreated for relapsed/refractory Waldenström macroglobulinemia.¹ Specifically, selected inclusion criteria included adult patients with histologically confirmedWaldenström macroglobulinemia who have previously received at least 2 lines of therapy and had measurable immunoglobin M (IgM) greater than upper limit of normal or at least 1 measurable nodal lesion.

The treatment of Iopofosine I 131 and the evaluation period was 1 year, in which patients received 4 doses at 15 mCi/m² per dose over 2 cycles within 71 days. Treatment for cycle 1 was administered on days 1 and 15 with 6 weeks between the initial infusion cycle and cycle 2. Ailawadhi and colleagues noted that the period between the initial infusion and cycle 2 could be delayed up to 20 weeks for COVID-19–related reasons or for patients experiencing grade 4 hematologic toxicities. Treatment for cycle 2 was administered on days 1 and 15 following the initial infusion period. Active evaluation period was for up to 28 weeks from initial infusion.

The study’s primary end point was MRR; secondary end points included ORR, treatment-free survival (TFS), duration of response (DOR), CBR, and safety. Long-term safety follow-up was 3 years.

Among the total patients in the study (n = 65), the median age was 70 years (range, 50-88), 73.8% were male, and 26.2% were female. International Prognostic Scoring System for Waldenström macroglobulinemia (IPSSWM) scores were low for 43.1% of patients, medium for 30.8%, and high for 26.2%. The median IgM was 2115 mdl (range, 252-7400), extramedullary disease was observed in 24.6% of patients, and median baseline hemoglobin was 11.7 g/dL (range, 11.1-14.1).

At baseline, bone marrow burden of no more than 50% was observed in 77.6% of patients, and it was above 50% in 28.6% of patients. Median prior lines of therapy were 4 (range, 2-15). Notably, prior treatment included BTK inhibitors (73.8%), rituximab (Rituxan; 92.3%), and chemotherapy (84.6%). Notably, 56.5% of patients were refractory to chemoimmunotherapy. Genotypes among patients included MYD88 wild-type (27.7%), MYD88 mutated (72.3%), CXCR4 wild-type (69.2%), CXCR4 mutated (12.3%), P53 wild-type (64.6%), and P53 mutated (15.4%).

Additional Efficacy and Safety Data

Patients with MYD88 wild-type disease (n = 16) achieved an MRR of 50.1%, with CR/VGPR occurring in 7.2% of patients, PR in 43.8%, and minor response (MR) in 31.3%; the ORR was 81.4%. Patients with MYD88 mutations (n = 39) had an MRR of 59.0%, with a CR/VGPR rate of 7.7%, a PR rate of 51%, and a MR of 25.6%; the ORR was 84.3%. In those with CXCR4 mutations (n = 5), the MRR and ORR were both 100%, with all patients achieving a PR. Patients with TP53 mutations (n = 5) had an MRR of 40.0% with a PR rate of 40.0% and a MR rate of 40.0%; the ORR was 80.0%.

Patients who were chemoimmunotherapy refractory (n = 26) had an MRR of 42.2%, with a CR/VGPR occurring in 7.6% of patients, PR in 34.6%, and MR in 30.8%; the ORR was 73.1%. Patients who received a prior BTK inhibitor (n = 39) had an MRR of 56.4%, a CR/VGPR rate of 7.7%, a PR rate of 48.7%, and a MR rate of 20.5%; the ORR was 76.9%.

At a median follow-up of 11.4 months, the median progression-free survival was 50.7 weeks (95% CI, 39-68.1) and the median overall survival was not reached. The median TFS was 62.3 weeks (95% CI, 39.3-infinite) and median DOR was 44.1 weeks (95% CI, 24.3-infinite). Ailawadhi and colleagues noted that the DOR was improved for patients who achieved a PR or better.

The safety analysis of the study determined that the most common any-grade treatment-emergent adverse effects (TEAEs) occurring in at least 10% of patients included hematologic and nonhematologic toxicities. The most common hematologic toxicities were thrombocytopenia (84.6%), neutropenia (83.1%), anemia (63.1%), decreased levels of white blood cells (33.8%), decreased levels of lymphocytes (13.8%), and febrile neutropenia (10.8%).

The most common nonhematologic toxicities included fatigue (33.8%), nausea (27.7%), diarrhea (20.0%), dyspnea (18.5%), headache (16.9%), dizziness (15.4%), epistaxis (13.8%), decreased appetite (13.8%), and constipation (12.3%).

Most common grade 3 or greater TEAEs in at least 10% of patients included thrombocytopenia (80.0%), neutropenia (69.2%), anemia (44.6%), decreased levels of white blood cells (27.7%), decreased levels of lymphocytes (13.8%), and febrile neutropenia (10.8%).

Among the 65 patients in the study, median nadir for platelets for cycles 1 and 2 were 34 x10⁹/L and 18 x10⁹/L, respectively. The respective median times to nadir for cycles 1 and 2 were 43 and 50 days, and median time to recovery for cycles 1 and 2 were 13 days and not evaluable, respectively, at data cut off.

Regarding absolute neutrophil count, median nadir for cycles 1 and 2 were 0.6 x10⁹/L and 0.8 x10⁹/L, respectively. Median time to nadir for cycles 1 and 2 were both 50 days. Median time to recovery for cycles 1 and 2 were 10 and 7 days, respectively.

Transfusion and granulocyte colony-stimulating factor (G-CSF) usage were received by all 65 patients in the study. Platelet utilization was given to 52% of patients, including 31% of patients during cycle 1 and 31% of patients during cycle 2. Platelet utilization was used during both cycles in 9% of patients. Median units administered was 8 (range, 1-46), with a median of 5 units administered during cycle 1 (range, 0-30) and a median of 3 units administered during cycle 2 (range, 0-25). G-CSF utilization was given in 65% of patients, specifically to 60% of patients during cycle 1 and 28% of patients during cycle 2.

There were 14 deaths that occurred during the study: 9 due to disease progression, 1 due to squamous cell carcinoma, 1 from neutropenic infection, 1 from nonneutropenic infection, and 2 unknown deaths. Of note, 1 patient experienced a secondary malignancy in the form of myelodysplastic syndrome.

“Iopofosine I 131 demonstrated clinically meaningful and durable efficacy in this difficult-to-treat population, where I should also point [out that] there is no standard-of-care treatment available for these patients,” Ailawadhi concluded.

References

1. Ailawadhi S, 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-WaM). Blood. 2024;144(supplement 1):861. doi:10.1182/blood-2024-200277

2. Study of iopofosine I 131 (CLR 131) in select B-cell malignancies (CLOVER-1) and pivotal expansion in Waldenstöm macroglobulinemia (CLOVER-WaM). ClinicalTrials.gov. Updated September 19, 2024. Accessed December 10, 2024. https://clinicaltrials.gov/study/NCT02952508