Top 15 Questions About Ibrutinib

1. Can I take this at any time of the day? Studies with ibrutinib have been done giving it together with food and on an empty stomach. The absorption of the drug is slightly higher with food but is also good on an empty stomach. Identifying a single time during the day to take it is probably the most important thing to do. This will assure you take it at a set time every 24 hours which assures the best chance of it working.
2. Should I start at a lower dose and titrate up? With some drugs used in CLL like lenalidomide, this is the best way to safely start the drug. This is not the case with ibrutinib because starting at a dose that is lower than the recommended (420 mg, 3 tablets) could be sub-therapeutic and predispose the CLL cells to becoming resistant to this over time. Everyone with CLL should start the drug at 420 mg (3 tablets) given once daily. If side effects are observed, it is acceptable to decrease the dose by one tablet for a period of time. However, in most patients this is not necessary.
3. My white blood cell count is high. Does this increase my risk for complications with ibrutinib? Ibrutinib, and other drugs (idelalisib) which target B-cell receptor signaling, typically causes the white blood cell count to increase early in therapy. Typically this occurs over the first 1-2 months, reaches a plateau, and then diminishes slowly over time. In general, the rise in the white blood count is greatest in patients who start with relatively low counts, whereas those with high counts (100-200 or >) generally have modest rises. Patient side effects from the white blood cell count rising early during treatment are quite rare, whereas for mantle cell lymphoma it does sometimes occur. With appropriate monitoring (weekly during the first month), there is little concern of harm based upon current data.
4. Since starting ibrutinib, I have noticed that the bruising on my arms and legs have increased. Does this mean I am at a big risk for having major bleeding complications? Several studies comparing ibrutinib to other therapies have shown that there is a risk of minor bleeding complications such as bruising. In virtually all cases, this effect is not one that leads to debilitating or life-threatening bleeding. The bruising is often cosmetic and can occur in sensitive spots of the body, such as the face where no trauma has occurred. These spots are generally concealable by makeup and go away with time. The exception is, if surgery is required or other blood thinners are used, then continuing to take ibrutinib can increase the risk of serious bleeds. For blood thinners, the most dangerous one is Coumadin and most clinical trials performed with ibrutinib excluded patients taking this.
5. I am having a surgical procedure. How long should I hold my ibrutinib and what should be expected when this is stopped? In general, we ask patients to hold their ibrutinib for 3 days before and after minor procedures (tooth extractions, bunion surgery, etc.) and 7 days before and after for major surgeries (gall bladder removal, knee surgery). Also, we do not start ibrutinib until all bleeding complications have resolved post-surgery. In some patients whose therapy is stopped even for brief periods of time, the lymph nodes can transiently increase. If the patient was responding before, it almost always happens that re-starting the drug will result in these nodes shrinking again. In general, this does not signify that patients are resistant to the drug. This flare effect generally does not occur when people have been on ibrutinib for a long time. For this reason, I generally recommend putting off elective surgery until 9-12 months after starting ibrutinib when possible.
6. I just started ibrutinib and have noted much more fatigue, heart burn, diarrhea, and arthralgias. Can I expect this to get better with time? The irritating side effects that sometime occur with ibrutinib including fatigue, heart burn, diarrhea, and arthritic symptoms typically are noted more at the beginning of therapy. Interestingly, for most patients, these tend to resolve quickly with time and are often non-existent within 2-3 month. In general, older patients tend to have more side effects such as this with ibrutinib, as well as bruising. Why older patients are more likely to have side effects and actually discontinue ibrutinib is uncertain and warrants study. However, this is not isolated to ibrutinib because virtually all other therapy used in the therapy of CLL has a similar profile.
7. I started ibrutinib 12 months ago and my lymph nodes and symptoms improved rapidly but my lymphocyte count remains elevated. Because my lymphocyte count remains elevated my doctor wants to treat me with something else.  Does this make sense? Unlike chemotherapy treatment where the failure to resolve lymphocytosis in the blood signifies a sub-optimal response, this is not true with ibrutinib. Studies have looked at the impact of continued lymphocytosis in the blood after treatment with ibrutinib and have not showed any difference in outcome as compared to those who have complete resolution. Therefore, outside of a clinical trial it is not recommended to add therapies to ibrutinib simply to make the blood count come down. Such additions have the potential to increase side effects and have no defined benefits.
8. I am on long-term warfarin therapy due to having several blood clots in my leg. Is it okay for me to start ibrutinib? The early studies with ibrutinib identified a potential safety signal where bleeding into the space around the brain (subdural hematomas) where noted when ibrutinib was given to patients who also were on warfarin. As a consequence of this, all ibrutinib trials excluded patients who required the use of warfarin. Thus, most experienced physicians who care for CLL patients on ibrutinib avoid using this together with warfarin. For patients requiring chronic anticoagulation, it is probably better to use another class of B-cell receptor signaling agents such as idelalisib which is not associated with a bleeding risk.
9. Since starting ibrutinib I have noticed more loose stools, heart burn, and also a rash on my face and chest. Is this something that I will have to live with for life?  In general, the early side effects commonly seen with ibrutinib include fatigue, loose stools, heart burn, and rash.  The loose stools associated with ibrutinib can often be treated with Imodium (loperamide) or Lomotil (diphenoxylate/atropine).  We also use Questran powder (cholestyramine) several times a day which also alleviates this side effect in most patients.  Lowering the dose or holding ibrutinib is not something that should be done unless the symptoms of diarrhea cannot be controlled. In general, diarrhea, rash, and also heart burn side effects diminish over the first 1-2 months of therapy.
10. I have had a good response to ibrutinib over the past 6 months and now it has been suggested to stop treatment. Is this something I should do? Ibrutinib is a very effective CLL drug and provides evidence of rapid patient benefit with respect to symptoms improving, lymph nodes decreasing, and blood counts improving. For some a very good partial or clinical complete response can emerge clinically by 3-6 months. However, all the trials performed with ibrutinib to date have kept patients on therapy indefinitely irrespective of how good the response was. This treatment strategy is one that is commonly employed with targeted therapy in both solid tumor cancers and chronic myeloid leukemia. When ibrutinib is stopped, it is not uncommon for disease symptoms and lymph nodes to enlarge again at a relatively short time period, particularly if patients have not been on therapy for a long time or have had many other therapies before ibrutinib. So the resounding answer to stopping ibrutinib even if the early response is good is NO. The follow-up to this question is: Why would this be considered by my oncologist? For most other chemo-immunotherapies used in CLL, we treat for a fixed period of time similar to this because these drugs cannot be given continuously due to short and long-term side effects. The paradigm for treating CLL is different with ibrutinib and the new targeted drugs and some providers are not sufficiently familiar with this.
11. Does treatment with ibrutinib increase my chance of developing Richter’s transformation? Richter’s transformation is a form of progression observed in CLL patients where the disease changes to a more aggressive large cell lymphoma. In rare cases, Hodgkin’s disease can also be a form of Richter’s transformation. The common type of Richter’s transformation (Large cell lymphoma) is treated with aggressive combination chemotherapy + rituximab and is often resistant to therapy. Even when response to therapy is noted, relapse often occurs and death almost always ensues shortly after. For patients with large cell Richter’s transformation, the only long-term survival strategy is therefore including a allogeneic stem cell transplant as consolidation. Two exceptions to the unfavorable outcome of Richter’s exist. The first is when Richter’s with large cell lymphoma originates separate from the CLL. This can be tested for in the laboratory with very sophisticated tests, but is important to assess because a cure for this type is possible. The second exception is when Richter’s transformation manifests as Hodgkin’s disease. This can be treated like regular Hodgkin’s disease and often effectively eradicated. Early in the development of ibrutinib, there was concern that Richter’s transformation might be increased with this treatment. This observation came, in part because the patient population being treated with ibrutinib were already at high risk for Richter’s transformation and there was no comparator arm in any of these trials. The randomized clinical trials comparing ibrutinib to other therapies in CLL have uniformly demonstrated no increased risk of developing Richter’s transformation. Thus, fear of developing Richter’s syndrome should never be a reason to avoid using ibrutinib for the treatment of CLL.
12. Does Ibrutinib work in everyone with CLL and if it stops working, what should I expect? Most patients with CLL respond to ibrutinib. It is very unusual for a patient to be resistant to this treatment at the beginning, unless for some reason they cannot tolerate taking ibrutinib at the prescribed dose and schedule. So assuming almost everyone responds to therapy, what is the pattern of relapse? In our own center’s experience we have seen both early relapse (within 18 months) and later relapse (after 18 months) with ibrutinib. For early relapse, it is more common to see Richter’s transformation emerge as the most common type of progression on ibrutinib. Typically, this presents in the setting of most sites of disease showing tumor reduction whereas enlargement in 1-2 nodal areas is seen. This is often accompanied by a rising LDH or an increase in disease symptoms. CLL relapse almost never occurs before 12 months, but can occur within the 12-18 month time period in a small number of patients. This more frequently occurs beyond 18 months and manifests with slow enlargement of lymph nodes or increase in blood lymphocyte count. Both the lymphocyte count and lymph nodes can fluctuate up and down in CLL patients, so it is important to see this pattern on at least two successive exams and blood tests. For patients relapsing with CLL, there are two common mutations observed involving genes where ibrutinib binds to (BTK) or an immediate down-stream target (PLCG2). A blood test can be used to monitor for mutations in this gene.
13. Are there therapies available after ibrutinib stops working? There are several effective drugs in clinical trials at this time that can work for ibrutinib-resistant disease. However, transitioning off ibrutinib to these treatments can be very tricky and it is best to have this done working with a medical center that has considerable experience managing this. Ibrutinib resistance is not very common and most general oncologists have little experience with it. Most important in the management of these patients is not stopping ibrutinib until the new therapy is started. If ibrutinib is stopped in someone who is showing early signs of progression, often these symptoms amplify and can quickly become life-threatening. The early studies noting very short survival after ibrutinib therapy are likely reflective of this not being recognized and also there not being other treatments available for ibrutinib-resistant disease. Several short-term options do exist to treat ibrutinib-resistant disease, but this generally should be done in the setting of a clinical trial. For young patients who develop resistance to ibrutinib, it is important to consider other long-term options such as non-ablative allogeneic stem cell transplant. This modality has the potential to produce long-term remission in CLL.
14. I have been on ibrutinib for more than 2 years. Are there long-term side effects I should expect? In general, the side effects observed with ibrutinib generally decrease with time. The long-term follow-up study with ibrutinib noted this with exception of hypertension (high blood pressure) which did go up minimally with time. Patients receiving ibrutinib for extended periods of time in my experience often complain of joint aches, muscle cramps (particularly at night), and intermittent joint swelling. This is generally managed with vitamin D supplements, mineral (calcium or magnesium) supplements, and non-steroidal anti-inflammatory drugs like Motrin or Advil (ibuprofen). In rare cases, we have to give a short course of low-dose steroids for this. Cracking fingernails is also something frequently reported with ibrutinib and our advice is to maintain short nails with frequent clipping and to consider biotin supplements. For most patients, these are manageable with supportive issues.
15. I am nervous about staying on a medication for my entire lifetime. Is there a chance that this might not be necessary? Clinical trials are now addressing whether combining ibrutinib either with chemotherapy or with highly effective targeted therapies will produce minimal residual disease negative complete remissions (no detectable CLL in body) where treatment could be stopped. This is very exciting research that is just beginning. It is clear that the treatment of CLL is rapidly changing and promising opportunities exist for the future with respect to this disease.

Dr. Byrd is the D Warren Brown Chair of Leukemia Research and Director, Division of Hematology at The Ohio State Comprehensive Cancer Center in Columbus, OH. He is a member of the Medical Advisory Board for the CLL Society.

Originally published in The CLL Tribune Q3 2015.