iopofosine I-131 (CLR 131)

P2, N=120, Active, not recruiting, Cellectar Biosciences, Inc. | Trial completion date: Jun 2025 --> Dec 2026 | Recruiting --> Active, not recruiting

P1, N=12, Completed, University of Wisconsin, Madison | Active, not recruiting --> Completed | Trial completion date: Jul 2024 --> Feb 2024

P2, N=120, Recruiting, Cellectar Biosciences, Inc. | Active, not recruiting --> Recruiting

P2, N=120, Active, not recruiting, Cellectar Biosciences, Inc. | Recruiting --> Active, not recruiting

P1, N=50, Recruiting, Cellectar Biosciences, Inc. | Not yet recruiting --> Recruiting | Phase classification: P1b --> P1

P1b, N=50, Not yet recruiting, Cellectar Biosciences, Inc. | Initiation date: May 2023 --> Oct 2023

P1, N=12, Active, not recruiting, University of Wisconsin, Madison | Trial completion date: Sep 2023 --> Jul 2024

P1, N=30, Active, not recruiting, Cellectar Biosciences, Inc. | Recruiting --> Active, not recruiting

P1b, N=50, Not yet recruiting, Cellectar Biosciences, Inc. | Trial completion date: Dec 2026 --> Sep 2026 | Initiation date: Nov 2022 --> May 2023 | Trial primary completion date: Sep 2026 --> May 2026

P1b, N=50, Not yet recruiting, Cellectar Biosciences, Inc.

Therefore, and based on the above, BTK inhibitor monotherapy is preferred in patients with MYD88MUT/CXCR4WT disease, while the addition of rituximab to ibrutinib or zanubrutinib can be considered in patients with MYD88MUT/CXCR4MUT or MYD88MUT/ CXCR4WT disease. Rituximab-containing regimens such as bendamustine and rituximab, or bortezomib, dexamethasone and rituximab are safe and highly effective options in WM patients regardless of MYD88 or CXCR4 mutational status13,14. The BCL2 antagonist venetoclax is another option in the relapsed setting...Ongoing clinical trials are investigating triple, fi xed-duration BTK inhibitors-containing regimens as well as non-covalent BTK inhibitors and immunotherapeutic agents such as the phospholipiddrug conjugate CLR-131, the anti-CD19 antibody-drug conjugate loncastuximab, and chimeric antigen receptor T-cells. It would be of great interest to investigate the impact that the genomic profi le of patients WM might have on these novel agents. Also, additional research is needed to standardize MYD88 and CXCR4 mutational testing to further optimize the applicability of genomic profi le in the management of patients with WM.

The INNOVATE study randomized 150 patients with WM to either the combination of ibrutinib plus rituximab or placebo plus rituximab.2 The combination of ibrutinib plus rituximab was associated with a higher major response rate (72% versus 32%) and a higher 30-month PFS rate (82% versus 28%) than the combination of placebo plus rituximab, prompting the approval of the combination of ibrutinib plus rituximab for WM by the FDA in 2018...Three novel covalent BTK inhibitors are under active investigation for WM: zanubrutinib, acalabrutinib and tirabrutinib...The non-covalent BTK inhibitor pirtobrutinib was evaluated in a multicenter phase Iistudy in 26 patients with WM of whom 18 (12 had progressed and 6 were intolerant) were previously exposed to a covalent BTK inhibitor.6 The ORR to pirtobrutinib was 69%...A study evaluating the combination of ibrutinib and venetoclax in treatment-naïve patients with WM is ongoing...The CXCR4 inhibitor mavorixafor is being evaluated in combination with ibrutinib in WM patients who carry CXCR4 mutations. The PI3K inhibitor idelalisib show early efficacy in patients with WM but it seems to be associated with a high rate of liver toxicity.8 A multicenter study evaluating umbralisib in patients with WM has stopped accrual. The anti-CD38 monoclonal antibody daratumumab had a lower-than-expected efficacy rate in WM.9 Dasatanib is an HCK inhibitor being studied in patients with WM progressing on covalent BTK inhibitors. The phospholipid-drug conjugate CLR-131 was recently granted a Fast- Track Designation for WM patients having received two or more prior treatment regimens. In all, the treatment of patients with WM continues evolving. There are many reasons to be optimistic about the future of the treatment landscape of patients with WM.

P1, N=30, Recruiting, Cellectar Biosciences, Inc. | Trial completion date: Dec 2020 --> Dec 2024 | Trial primary completion date: Sep 2020 --> Sep 2022