In those patients who fail to respond to either front-line drug (Cladribine or Pentostatin), it is important to establish that the correct diagnosis was made. This normally requires flow cytometry of the blood, and preferably the bone marrow. There are specific markers that are characteristically found on the leukemic cells from patients with classic hairy cell leukemia. In those patients who demonstrate resistant disease, it is worthwhile to confirm the accuracy of the underlying diagnosis. The markers on the leukemic cell may provide a clue that the non-responding patient has a variant of hairy cell leukemia. These patients can undergo analysis of the BRAF expression to further delineate whether or not the patient has either the classic form of the disease or a variant. Confirmation of the accuracy of the underlying diagnosis enables decisions to be made regarding further choices of therapy.

Before undergoing retreatment due to “assumed failure to respond”, one should also make sure that response is not actually occurring. For example, in many cases, patients have low blood counts for many months after treatment, due to the toxicity of either cladribine or pentostatin, and given time, will achieve a remission. To avoid being retreated too early or unnecessarily, it may be helpful to consult a HCL expert. Furthermore, patients may eventually develop “resistant” disease after having had multiple relapses with progressively shorter remission durations over time. Therefore, it is important to understand the context of the presumed resistant disease (i.e., either incorrect diagnosis, delayed recovery from treatment-induced toxicity, or eventual evolution of resistant clones of leukemic cells following extensive prior treatments). Consequently, evaluation of the patient by a hematologist with experience in the management of hairy cell leukemia may enable the reason for lack of response to be delineated.

Patients with the atypical variant of this disease do not respond as well to these standard agents. Alternatively, they may have a short-lived partial response. If the patient is non-responsive to medical therapy, splenectomy may be required. Some elderly patients who are poor surgical risks have been treated with splenic irradiation. Patients may also have progression of the variant form of the disease with involvement of other tissues (e.g., enlargement of lymph nodes or the liver). Patients with the rare variant of this disease may also be referred to those centers with expertise in dealing with this atypical unresponsive disease.

Some patients with the variant form of hairy cell leukemia have responded to the combination of Cladribine and Rituximab. Alternatively, the patient could be referred to a center of excellence for participation in a clinical trial. The variant form of hairy cell leukemia is now recognized as a separate clinical entity from the classic disease, and is recognized as being less responsive to therapy with standard treatment. There are opportunities for designing new trials in the treatment of this rare variant form of disease.