Clinical bottom line
Relapsed or refractory hairy cell leukemia (HCL) remains a clinical challenge despite the efficacy of purine analogs in frontline therapy. Recent advances in targeted therapies, including recombinant immunotoxins, Bruton tyrosine kinase (BTK) inhibitors, and bispecific antibodies, offer promising chemotherapy-free options with distinct mechanisms of action. These agents demonstrate meaningful response rates and manageable safety profiles in heavily pretreated patients, potentially expanding therapeutic choices beyond conventional chemotherapy and splenectomy. However, optimal sequencing, long-term outcomes, and comparative effectiveness require further elucidation. Clinicians should consider these novel agents in relapsed/refractory HCL within the context of individual patient factors and emerging evidence.
What the evidence shows
Recombinant immunotoxins targeting CD22, such as moxetumomab pasudotox, have shown durable responses in relapsed/refractory HCL. Clinical experience reported by Kreitman et al. (2011, 2015) and summarized in nursing literature (2019) indicates that moxetumomab pasudotox induces complete remission in a substantial subset of patients with manageable toxicities, including capillary leak syndrome and hemolytic uremic syndrome. These agents offer a chemotherapy-free alternative with a unique mechanism distinct from purine analogs.
BTK inhibition with ibrutinib has been explored in the HCL variant subtype, which is typically less responsive to purine analogs. Bohn et al. (2016) reported that ibrutinib achieved partial responses and disease stabilization in relapsed/refractory HCL variant patients, suggesting a role for BTK inhibitors in this difficult-to-treat population.
More recently, bispecific antibodies such as mosunetuzumab, which engage CD3 on T cells and CD20 on leukemic cells, have demonstrated encouraging activity in relapsed/refractory HCL. Tadmor et al. (2024) described clinical responses in heavily pretreated patients, highlighting the potential of immunotherapy approaches that harness T-cell cytotoxicity without chemotherapy.
Comprehensive reviews by Brazel et al. (2025) and Paillassa et al. (2021, 2022) emphasize the evolving landscape of targeted therapies in HCL, underscoring the shift toward chemotherapy-free regimens and the importance of individualized treatment strategies based on disease variant and prior therapies.
Caveats and uncertainty
Most data derive from single-arm phase 1/2 studies or retrospective analyses with limited patient numbers, reflecting the rarity of HCL and its variants. Long-term follow-up data on durability of responses, late toxicities, and impact on overall survival remain sparse. The comparative efficacy of these novel agents versus each other or versus retreatment with purine analogs is not well established.
Additionally, the heterogeneity between classic HCL and HCL variant subtypes complicates generalization of results. Some targeted agents show differential activity depending on molecular and immunophenotypic features. The optimal sequencing or combination of these therapies has not been defined, and resistance mechanisms are incompletely understood.
Access and cost considerations may also limit widespread adoption of newer agents outside specialized centers. Finally, real-world tolerability and patient-reported outcomes require further study to guide clinical decision-making.
How this may change practice
The emergence of targeted therapies such as moxetumomab pasudotox, ibrutinib, and bispecific antibodies expands the therapeutic armamentarium for relapsed/refractory HCL beyond traditional chemotherapy and splenectomy. These options offer potential for durable remissions with less myelosuppression and improved quality of life.
Clinicians should incorporate molecular and immunophenotypic profiling to guide therapy selection, especially distinguishing classic HCL from variant forms. Targeted agents may be prioritized in patients with multiple relapses, contraindications to chemotherapy, or variant disease.
Ongoing clinical trials and real-world experience will clarify optimal sequencing and combination strategies. Multidisciplinary collaboration and referral to centers with expertise in HCL management and access to novel agents are advisable.
This evolving paradigm underscores the importance of personalized medicine approaches in rare hematologic malignancies and the need for continued research to optimize outcomes.