Initiating Therapy for CLL

Jan A. Burger, MD, PhD: Patients who develop active disease need treatment. That is something that has been accepted for decades, and I don’t see that changing in the near future. So, patients present to our clinic, and if they have symptoms such as B symptoms—night sweats, weight loss, all large lymph nodes, organomegaly-like big spleen, big liver—those would be indications to treat. Other treatment indications would be worsening of blood counts, and that goes into the staging system. We use the Rai or Binet staging system, which basically talks about decline in hemoglobin and platelet levels, which then prompt us to consider frontline treatment. Other indications could be autoimmune complications, and another indication could be rapid lymphocyte doubling time. If patients have lymphocyte doubling time of less than 6 months, that would be another indication that the disease is quite active and needs treatment. One last possibility, progressive fatigue, sometimes is also a considered treatment indication, as are recurrent infections if they are severe and they are felt to be disease leukemia-related.

Thinking about what frontline treatment to use for somebody who needs treatment: it is probably good to go a little bit back in time and think how we traditionally have approached frontline treatment. It was largely based on either young fit patients versus older patients. Younger, fit patients were considered to be candidates for chemoimmunotherapy, and most patients were recommended to undergo chemoimmunotherapy. And elderly patients traditionally have been offered either dose-attenuated or less myelosuppressive chemotherapy, or antibodies. But that has changed with the novel agents, and now we have more options. We pursue more individualized therapy, meaning that we take into consideration risk factors, age, and also preference of patients because we have these additional choices. So, what we do is if we have a younger patient who has low-risk disease, who has, for example, mutated IgVH genes, then we know these patients have a good possibility of long-term benefit from chemoimmunotherapy, like with the FCR (fludarabine, cyclophosphamide, and rituximab) regimen.

From the original study, the FCR study with 300 patients, we have follow-up of over 10 years. We know that approximately 60% of low-risk patients are still in remission after 10 years, and that’s still something we discuss and offer patients if they have these low-risk disease features. But if they are younger and have more high-risk disease, especially 17p deletion, then we recommend targeted therapy with the novel agents because we know chemoimmunotherapy in these patients may work—but their remissions are generally short. And for elderly patients, antibodies, like obinutuzumab, are approved and are a good option. But now we also have frontline approval for ibrutinib, which is also a good option, especially for patients who have higher-risk disease and who want an oral drug rather than an intravenous drug.

The two groups, fit versus unfit patients, come from the chemoimmunotherapy history where we’re not considering frail patients to be good candidates for chemoimmunotherapy. Does that still play a role with the novel agents? Not so much. Frail patients would be good candidates for new agents. Also, for antibodies, chemoimmunotherapy is not a consideration for them. So, it still plays a role. For younger, fit patients, we still have the possibility of chemoimmunotherapy. But just in general, it’s less used because we know the higher-risk patients probably should not be offered chemoimmunotherapy.

Case 1:A Fit Elderly Patient with Newly-Diagnosed Chronic Lymphocytic Leukemia.