Hairy cell leukemia (HCL) is a rare, slow-growing cancer of the blood characterized by an overproduction of abnormal B lymphocytes in the bone marrow and spleen. These cells, which possess fine projections giving them a distinct “hairy” appearance under a microscope, accumulate and interfere with the production of healthy blood cells. While HCL is considered a highly treatable cancer, a significant number of patients eventually experience a relapse. This reality has driven the development of innovative treatments focusing on targeted molecular mechanisms and novel biological agents.
The Established Baseline Treatment
The historical standard of care for HCL established a high bar for new therapies due to its remarkable effectiveness. This baseline treatment centers on the use of purine analogs, specifically cladribine and pentostatin, which function as powerful chemotherapy agents. These drugs achieve high rates of complete remission, often exceeding 80% with initial treatment.
Patients who achieve a complete response can expect a median disease-free survival of up to 16 years. While highly effective, these purine analogs can lead to significant and prolonged immunosuppression. Approximately half of patients will eventually experience a relapse, and retreatment often leads to a lower rate of complete response, driving the need for less toxic options for relapsed or refractory disease.
Targeted Molecular Therapy
A major advancement in understanding HCL came with the discovery that nearly all classic HCL cases harbor a specific genetic alteration: the BRAF V600E mutation. This mutation causes the BRAF protein, a component of a cell signaling pathway, to become constantly active, which drives the leukemia cells’ growth and survival. Targeted therapies are designed to specifically inhibit this hyperactive protein, distinguishing them from chemotherapy.
Vemurafenib and dabrafenib are BRAF inhibitors that directly block the function of the mutated BRAF protein. By shutting down this specific signaling pathway, these oral medications effectively stop the proliferation and survival of the HCL cells. These inhibitors have shown high response rates in patients with relapsed or refractory HCL, offering a chemotherapy-free strategy, which is beneficial for patients with existing infections.
Other small-molecule inhibitors are also being investigated, including Bruton’s tyrosine kinase (BTK) inhibitors like ibrutinib. BTK is involved in the signaling pathway of the B-cell receptor, and inhibiting it can block the growth signals in the cancerous B-cells. Furthermore, combining BRAF inhibitors with MEK inhibitors, such as trametinib, targets multiple points within the same hyperactive signaling cascade for a potentially more durable response. This combination strategy aims to prevent resistance mechanisms that might emerge when using a single targeted agent.
Novel Biological Agents
Another distinct class of new treatments involves novel biological agents that harness the body’s immune system or deliver a targeted payload to the cancer cells. This category includes immunotoxins and monoclonal antibodies. Monoclonal antibodies like rituximab, which targets the CD20 protein on the surface of B-cells, have been used in combination with purine analogs to improve response durability, especially in relapsed disease.
A sophisticated approach is the use of immunotoxins, such as moxetumomab pasudotox. This agent is a recombinant protein engineered to combine an antibody fragment with a potent bacterial toxin, creating a highly specific targeted delivery system. The antibody fragment is designed to bind specifically to the CD22 protein, which is highly expressed on the surface of HCL cells.
Once bound to the CD22 protein, the immunotoxin is internalized by the hairy cell. The toxin component is then released inside the cell, where it acts by inhibiting protein synthesis, leading directly to the death of the cancer cell. Moxetumomab pasudotox has shown the ability to achieve high rates of complete remission, often without detectable minimal residual disease, which is a factor for long-term remission. This non-chemotherapy mechanism is valuable for patients who have exhausted other treatment options.
Practical Considerations: Access and Clinical Trials
The introduction of these targeted and biological treatments is shifting the landscape of HCL care toward more personalized medicine. Moxetumomab pasudotox received regulatory approval in 2018 for adult patients with relapsed or refractory HCL who have previously received at least two systemic therapies, including a purine nucleoside analog. This status means the drug is available for a specific subset of patients whose disease has returned or not responded to standard treatment.
In contrast, while BRAF inhibitors like vemurafenib have demonstrated clear efficacy, they are often used off-label or within clinical trial settings for HCL, as they may not have full regulatory approval specifically for this indication. Patients and their physicians must consider the different side effect profiles. Targeted therapies carry risks like skin toxicity or fatigue, which differ from the blood count suppression and infection risk associated with purine analogs.
Clinical trials remain an important avenue for patients to gain access to the newest therapeutic strategies, including combinations of existing drugs or entirely new agents. For instance, trials are actively comparing standard cladribine plus rituximab with a newer combination of a BRAF inhibitor and a monoclonal antibody in the frontline setting. Participating in these trials contributes to the ongoing evolution of treatment protocols for HCL.