Novel therapies such as ibrutinib can be associated with a prolonged lymphocytosis that does not indicate a suboptimal response to therapy. The pattern of response is rapid shrinkage of lymph nodes; however, the white blood cell count may remain elevated for some time, and, sometimes, you will also see a relatively slow resolution of cytopenias. In these scenarios, when patients do not have much palpable peripheral adenopathy and are mainly being treated for low hematocrit levels, low platelet counts, and high white blood cell counts, it used to be relatively common that we would receive questions about whether the patient was responding. In this context, when patients’ white blood cell counts remain elevated after starting treatment, you should essentially assume that they are, in fact, responding, as long as they are feeling better. And, usually, they do not become more transfusion dependent if they are responding. If an individual’s hemoglobin level was 8 g/dL at the start of therapy, it is probably not going to go down to 6 g/dL consistently if the patient is responding—it might initially, but it should hopefully stabilize somewhat and then slowly improve over the next 4 to 6 months, in the worst-case scenario. However, you certainly cannot decide that the patient is not responding to therapy for at least 6 to 8 months of observation, in cases when the white blood cell count remains elevated and the resolution of cytopenias is relatively slow.

For patients who stop therapy, it is important to know whether the discontinuation was due to disease progression or to an adverse event. Patients who discontinue treatment because of an adverse event are likely not resistant to the drug class. In other words, stopping a drug for an adverse event does not convey the same poor prognosis that actual progression while taking ibrutinib or idelalisib does. So, it is important to understand the reasons for discontinuation, and reasons other than disease progression may be underestimated in the community. Compliance to treatment is also an important issue that should be explored, especially for those who are not responding or are progressing. Some patients will stop treatment or may decide to take fewer pills, although that is less of a problem now that we have fixed-dosage formulations.