Peer Questions, Expert Answers in CLL

Peer Questions, Expert Answers published on January 26, 2017

Managing Adverse Events & Comorbidities

Question: At your institution, when do you consider using G-CSF or filgrastim in your patients with neutropenia who are taking venetoclax?

Answer by Heidi Finnes, PharmD, BCOP: In my clinical practice, I don’t have much experience using G-CSF in my patients receiving venetoclax, as of yet. However, I have a few patients in clinical trials who are receiving venetoclax and required it. In patients who are at a high risk of infection or have Grade 3 or 4 neutropenic fever, it is appropriate to interrupt venetoclax therapy and initiate G-CSF; once the neutropenia has resolved to less than Grade 1, venetoclax can be resumed.

Answer by Jeffrey Jones, MD: At my institution, particularly when patients are early in therapy, we consider primary prophylaxis when the neutrophil count starts falling significantly below 1,000 so that we can keep the patients on venetoclax. Part of the rationale is to try and keep patients moving through dose escalation, to keep them on venetoclax until they have a response. In patients who are mature on therapy, meaning they have been on drug for several months, neutropenia starts to diminish as their disease comes under better control. As the neutropenia becomes less severe, it does not require pharmacologic intervention with G-CSF or other blood cell growth factors.

Question: Do you give prophylactic sulfamethoxazole/trimethoprim (Bactrim®), and acyclovir in all of your patients receiving idelalisib? When do you not give it?

Answer by Heidi Finnes, PharmD, BCOP: This is something that has changed based on the most recent prescribing information. We do give prophylaxis for PJP as well as for HSV in all of our patients now on idelalisib. We did not previously. In patients who would not be appropriate to receive prophylactic sulfamethoxazole/trimethoprim (Bactrim) prophylaxis, one must look at how the drug is metabolized and what metabolism pathways it inhibits. Alternative prophylaxis that I use in some patients who perhaps are on antidiabetic agents that are metabolized via CYP2C8 and CYP2C9, which are pathways that both idelalisib and prophylactic sulfamethoxazole/trimethoprim (Bactrim) inhibit, include pentamidine inhalation or atovaquone 1500 mg once daily. It really takes review of the types of medications that those patients are on and then deciding which product would be best for prophylaxis.

Question: Do you need to dose-reduce venetoclax in patients with renal impairment?

Answer by Heidi Finnes, PharmD, BCOP: Data is available from a pharmacokinetic study of patients with normal (creatinine clearance (CrCl) ≥90 mL/min), mild (CrCl 60-90 mL/min) and moderate (30-60 mL/min) renal impairment. Venetoclax exposures were similar in patients with mild and moderate renal impairment, compared to those with normal renal function. Pharmacokinetic studies have not occurred to date in patients with severe renal impairment (CrCl <30 mL/min). However, 99.9% of venetoclax is eliminated via the feces and only 0.1% of the dose is excreted in the urine; there is likely no need to adjust venetoclax in renal dysfunction. Patients with renal dysfunction and tumor lysis syndrome should be monitored carefully and dosage adjustments made to venetoclax based on toxicity; please consult the prescribing information for venetoclax.

Question: How long do you hold antiplatelet or antithrombotic drugs before and after procedures for patients taking ibrutinib?

Answer by Heidi Finnes, PharmD, BCOP: This can be a gray area depending on the patient’s platelet counts and the combination of antiplatelet and antithrombotic medications they are receiving. In addition, the type of procedure and associated bleeding risk must be taken into consideration. Antiplatelet drugs are irreversible inhibitors of platelet function and will maintain their effect for the lifespan of the platelet, which is seven to ten days; this is the length of time I usually recommend for discontinuing therapy. If my patients are taking ibrutinib and an antiplatelet agent like aspirin, I sometimes stop one medication (ie, the aspirin) before the ibrutinib, in attempts to minimize the effects. For patients who are taking concomitant warfarin, I recommend discontinuing therapy five to seven days before surgeries with high bleeding risk; in some patients, it may be safest to switch from warfarin to a low-molecular-weight heparin (LMWH) bridge, then hold the LMWH right before therapy. As always, it is important to assess each patient as an individual case, as variations in blood counts, bleeding history, and the type of procedure will influence the optimal length of time to hold antiplatelet and antithrombotic therapy.

Question: How long do you wait to immunize patients who have received venetoclax?

Answer by Heidi Finnes, PharmD, BCOP: I think the first thing to state is there really is not any data that is available on the safety and efficacy of immunizations during or following venetoclax therapy. It is important to remember not to administer live attenuated vaccines at any time to a patient with CLL receiving venetoclax therapy. Vaccines are less effective on patients who are receiving CLL therapies. The optimal time is usually the first cycle. We generally will wait a week or so after the patient receives that therapy to be sure they are tolerating it and administer non-live viruses at that period of time.

Question: I am thinking of initiating idelalisib in my elderly patient who is being treated for chronic constipation. Should I discontinue treatment for their constipation?

Answer by Beth Faiman, PhD, CNP: The short answer to that is no, I would not just yet, because know that diarrhea may have a delayed onset. For severe diarrhea, you need to use budesonide and other agents to manage it. Loperamide (Imodium®) can help as well. But you have to think about why they are constipated, and rule out those causes. For example: Do they have chronic pain and are taking opioids? Are they taking calcium channel blockers for cardiovascular disease? Let the patient know that diarrhea is a risk, and make sure that they are aware of the medications they are using to treat the constipation, so that if they do develop diarrhea, they do not keep taking their polyethylene glycol 3350 (MiraLAX®) or other drugs concurrently. Then, let them know to notify you if diarrhea does occur. I would not stop the treatment for constipation, but give a little bit of time to ensure the constipation does not become an issue.

Question: Should idelalisib be avoided in patients with Crohn’s disease or inflammatory bowel disease?

Answer by Beth Faiman, PhD, CNP: The goal should be symptom management in order to maintain therapy with idelalisib, if it will be the most beneficial agent for their disease. Although idelalisib may worsen symptoms associated with Crohn’s disease and inflammatory bowel disease (IBD), implementing symptom management with budesonide, loperamide, or whatever agent works the fastest, is critical. It is important to remember that idelalisib-related diarrhea may be late onset, so it is important to closely monitor patients for signs and symptoms, even if it doesn’t occur upfront. Overall, I want to emphasize that disease control is of the utmost importance, and bowel control is secondary.

Question: What anticoagulant do you prefer in a patient receiving concomitant ibrutinib?

Answer by Heidi Finnes, PharmD, BCOP: I would say my opinion has changed based on new published literature and experience with novel oral anticoagulants and ibrutinib. When clinical trials initially came out, warfarin was prohibited with concomitant ibrutinib because of the risk of bleeding. At my institution, we switched most patients to a low-molecular-weight heparin (LMWH) product. As time passed, we have had some experience with patients receiving warfarin and concomitant ibrutinib, as well as LMWH, which of course are easier to stop and reverse more rapidly. More recently, direct thrombin or direct factor Xa inhibitors such as the apixaban or rivaroxaban have also been used with success in patients receiving ibrutinib. The key is to monitor each patient carefully for bleeding risk.

Answer by Jeffrey Jones, MD: I agree, as we have found that the novel oral anticoagulants, apixaban or rivaroxaban in particular, are associated with lower risk of bleeding. There are risks and benefits with all of these drugs, but due to the exclusion of concomitant warfarin in most studies, we generally avoid using it due to limited experience. We typically pick the same agents that Heidi has been talking about, and then first and foremost, always question whether there really is a strong indication for anticoagulation.

Question: What blood chemistry changes should I be concerned about for my patients receiving venetoclax?

Answer by Beth Faiman, PhD, CNP: We know venetoclax can cause tumor lysis syndrome (TLS) which is an oncologic emergency. With frequent monitoring, again looking at the tumor burden, determining hospitalization or not, making sure that you are implementing the dosing ramp-up phase appropriately, in accordance with the prescribing information. In my practice, we look at the markers of TLS, including hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia. Even if the changes are mild, it is important to take fluctuations in levels under serious consideration; this is especially true if you have someone that is high risk. Ensure that the patients remain adequately hydrated, and continue to monitor for those TLS-associated laboratory changes.

Question: What do you tell your patients to self-monitor for when they are sent home on venetoclax?

Answer by Beth Faiman, PhD, CNP: I think it is important to advise the patients to continue adequate hydration. They are still in the dosing ramp-up phase in many cases. Patients should be instructed to promptly report signs and symptoms associated with tumor lysis syndrome, such as fevers, chills, nausea, and confusion. In terms of volume, it is recommended to drink about six to eight glasses or 56 ounces in total of fluids. We know they are at risk for neutropenia, so paying attention to signs and symptoms of infection and neutropenic fever are also important. In addition, patients should be counseled on important drug-to-drug interactions. I think we sometimes forget to remind patients not to eat certain types of oranges like the Seville oranges, grapefruits, and star fruits, as they can interfere with venetoclax. Finally, instructing patients on how they going to take their medication. Making sure that the patient keeps it in the original packaging, especially during the first 4 weeks of treatment; they should not transfer the tablets to a container. Patients should also understand the different aspects of their dosing schedule, including the current dose of venetoclax, the time of day they will be taking their medication each day, and swallowing the tablet whole with water and a meal; they should not chew, crush, or break their tablets.

Question: What risk factors for bowel perforation do I need to assess for when my patients are treated with idelalisib?

Answer by Beth Faiman, PhD, CNP: Bowel perforations occur when a hole forms all the way through the stomach, large bowel, or small intestine. A bowel perforation can occur at any time when being treated with idelalisib. Risk factors include diverticulitis and bulky disease. It is important to assess for the appropriate signs and symptoms, which may include severe stomach pain with or without vomiting or fever and lower left quadrant pain. For any of my patients experiencing acute onset abdominal pain, I like to order a CT scan of the abdomen, especially if they have been experiencing diarrhea for an extended time, as this could be an oncologic emergency.

Question: What should I do if the antidiarrheals like loperamide are not managing idelalisib-related diarrhea?

Answer by Beth Faiman, PhD, CNP: We know that the onset of diarrhea typically occurs about 2 months at any grade, but the more severe diarrhea occurs a little bit later. Whenever anybody has diarrhea, regardless of the agent, I like to obtain a diet history and blood-diarrhea history, ensuring that I assess for the number of stools compared to baseline. The diet intake should ensure that patients are not taking any magnesium-containing supplements because that can produce diarrhea, in addition to consumption of alcohol and greasy, fried foods. The next step would be using this information to classify the severity of the diarrhea. It is important to exclude any infectious causes during your work-up. Once the infectious causes are ruled out, then you can initiate loperamide or other agents. Now, budesonide is an oral topical steroid that can be administered. Budesonide was given to 23 patients in a clinical study, and the diarrhea or colitis tended to resolve. Prednisone is something that people have been given, too. I have used cholestyramine, and anecdotally, that has been helpful as well.

Question: When would I give rasburicase to my patients receiving venetoclax?

Answer by Heidi Finnes, PharmD, BCOP: The decision to give rasburicase requires weighing the risks versus the benefits. In each hospital, there is often a tumor burden risk assessment, which is used to determine whether the patient should receive fluids and allopurinol versus rasburicase. In patients with a high tumor burden, as defined in the prescribing information for venetoclax, as: any lymph node (LN) ≥10 cm, or absolute lymphocyte count (LNC) ≥25x109/L plus any LN ≥5 cm. In those patients, it is recommended to hydrate orally with 1.5-2 L and intravenously with 150-200 mL/hr, as tolerated, and administer allopurinol. Rasburicase is recommended for patients who also have an elevated baseline uric acid level, and I recommend its use in those patients who are at a higher risk for tumor lysis syndrome and can be monitored appropriately. Remember to consult your own health institutions’ protocols, as well as the prescribing information for venetoclax.

Question: Which of the three agents, ibrutinib, idelalisib, or venetoclax, create the greatest risk of cytopenia?

Answer by Beth Faiman, PhD, CNP: Each of these three therapies carry a risk of neutropenia or thrombocytopenia. Ibrutinib does carry a risk for hemorrhage, as well as Grade 3/4 neutropenia in about 20-30% of patients. Idelalisib also carries a risk of neutropenia, which occurs in about 30% of patients receiving this therapy. However, it is my opinion that venetoclax carries the greatest risk for Grade 3/4 neutropenia, which occurs in about 40% of patients. In my practice, I monitor complete blood counts (CBCs) for patients receiving idelalisib, about every 2 weeks for the first 6 months, but more often if there is Grade 3/4 myelosuppression. I believe patients on venetoclax will need more frequent CBC monitoring, and receive the appropriate dose interruption or modification dependent on the severity of neutropenia.

Treatment Selection & Pharmacotherapy Considerations

Question: Are there any baseline laboratory values that would prevent you from using venetoclax?

Answer by Heidi Finnes, PharmD, BCOP: One of the most vital monitoring parameters for patients receiving venetoclax is assessing the risk for tumor lysis syndrome. The patient should be hospitalized and undergo renal assessment via monitoring of serum creatinine, as well as liver function tests as venetoclax is hepatically metabolized. At this point in time, there aren’t any baseline values that I would strongly recommend avoiding venetoclax completely, as long as appropriate monitoring parameters are in place and dose modifications are implemented according to the prescribing information for venetoclax.

Question: How often do you monitor FISH studies on patients who have deletion 13q, very high white blood cell counts, and otherwise do not have criteria for treatment?

Answer by Jeffrey Jones, MD: Typically, we do not do surveillance fluorescence in situ hybridization (FISH) testing, meaning we do not do it at routine intervals. The best time to obtain that information is when you are trying to make a treatment decision because that is when you are interested in acting on it. So, for instance, if a patient had a 13q deletion at diagnosis, it really only matters for predicting the course of the disease and helping you plan. The next point where you really want to know their genetic information is before selecting therapy. As the program content really stresses, the most important feature is identification of deletion 17p since those are patients that should not receive chemotherapy by most experts’ opinions, including mine.

Question: In a patient who is refractory to ibrutinib, what therapy would you recommend next?

Answer by Jeffrey Jones, MD: Refractory to ibrutinib is important first to define because patients could be refractory in two situations. One is if they are intolerant to ibrutinib. The other is if they have developed disease that has progressed during therapy with ibrutinib. For patients who are intolerant to ibrutinib, there are second-generation agents with greater specificity for BTK that might be employed as part of clinical trials. Among available agents, idelalisib, venetoclax, or even in some cases, immunotherapy with drugs like obinutuzumab or in selected cases, chemoimmunotherapy might still be appropriate. For patients who have progressed during ibrutinib therapy, it is important to distinguish between patients who are progressing as a result of resistant CLL harboring mutations that confer resistance to ibrutinib, or who are progressing because their disease has undergone Richter transformation into large-cell lymphoma. In that latter case, patients are typically treated either as part of clinical trials or using standard lymphoma chemotherapy regimens like R-CHOP, R-EPOCH, R-Hyper-CVAD, and transplant. For patients who are refractory to ibrutinib, there are retrospective data suggesting that idelalisib and venetoclax can both be appropriate in that instance. The only drug that has been prospectively assessed is venetoclax. In a study that was presented in follow-up this year at the 2017 American Society of Hematology Annual Meeting, patients progressing on ibrutinib therapy achieved about 70% response rate to single-agent venetoclax, and 80% of those patients were still in remission about a year later. These results are a significant improvement on historical results in a very challenging patient population.

Question: In patients who relapsed, a first, second, and third time, what sequence of drugs do you most commonly see?

Answer by Jeffrey Jones, MD: This has really changed dramatically just within the last several years and is expected to change even more significantly in the next several years with the front-line approval of ibrutinib early in 2016. I think today most patients still receive some chemoimmunotherapy combination that is typically rituximab in combination with fludarabine regimen, maybe more frequently in the US, rituximab and bendamustine or chlorambucil and obinutuzumab. Most patients as they relapsed have had prior exposure to chemotherapy. While there are some patients who are receiving a second line of chemoimmunotherapy, increasingly patients are being treated with kinase inhibitors; this usually entails treatment with ibrutinib more frequently than idelalisib. For patients who have deletion 17p-positive CLL at the time of relapse, they often receive ibrutinib first, but some are also being treated with venetoclax before ibrutinib. Following an ibrutinib or idelalisib treatment failure, probably the most commonly used drug is either the alternate kinase inhibitor or, increasingly, venetoclax, in deletion 17p patients. We are going to see in the coming years that patients will have received ibrutinib upfront. Then the question will become, ‘Is there still a role for chemoimmunotherapy in the second or third relapse?’ That is very speculative since most of the results today suggest that chemoimmunotherapy does not work very well in that context.

Question: Is there a cutoff for tumor burden above which you would avoid using venetoclax due to the risk of tumor lysis syndrome?

Answer by Jeffrey Jones, MD: Well, the brief answer is no. There is no specific threshold beyond which venetoclax is prohibitively unsafe. But it is important to assess tumor burden prior to initiating therapy in all patients with CLL who receive venetoclax because the specific interventions employed to prevent tumor lysis depend upon tumor bulk. This is very well outlined in the US prescribing information. In general, in patients who have lymph nodes in excess of 10 cm or in patients who have lymph nodes greater than 5 cm and a white count greater than 25 and/or impaired creatinine clearance, those patients should probably be hospitalized for close monitoring and aggressive interventions such as rasburicase, IV hydration and such, during the time that they are initiated on therapy, both at the 20 mg and 50 mg dose levels. If the patient makes it through without any significant electrolyte excursions, the remainder of the dose escalation can generally be employed safely on an outpatient basis. But again, no specific threshold but very important to assess the patient’s risk to employ the right strategies to prevent a problem.

Question: The NCCN panel disagreed on obinutuzumab and chlorambucil. Where do you use it in practice? In other words, what is the most appropriate front-line therapy for an elderly or less-well CLL patient requiring first-line therapy?

Answer by Jeffrey Jones, MD: Part of the disagreement is in looking at the longer-term benefit of patients treated with ibrutinib as compared to chemoimmunotherapy. There are many CLL experts who think that the best first-line therapy is ibrutinib based on duration of remission and generally favorable toxicity profile. I would agree that for most elderly patients, that probably represents the first best choice for front-line. On the other hand, there are some patients for whom ibrutinib is contraindicated for reasons we have already suggested or because of drug-drug interactions, making other options more favorable. Then there are still some patients who are not able or willing to undertake long-term therapy with an oral agent, which really requires an ability to adhere to medication administration for many months, and in many cases, years. In those cases, patients are better treated with a shorter duration of therapy, which is often chemoimmunotherapy-based. In those patients, I think the risk/benefit for older, frail patients really favors chlorambucil and obinutuzumab. If patients run into cytopenia problems because of the combination, many patients can still be well treated just by continuing the obinutuzumab without the chlorambucil. Understanding the duration of response, progression-free survival may be shorter than ibrutinib, but it may be better in a particular patient’s case to receive a shorter duration of therapy for all of the reasons I just described. That is where some of the disagreement lies. What is really great is that we have the opportunity to disagree about efficacious therapies and we have options to present patients. Without options, we would not have the opportunity to disagree. So, it is testament to the advances in this disease.

Question: What are the biggest issues with reimbursement or prior authorization that I should be prepared for with the new agents?

Answer by Beth Faiman, PhD, CNP: I am pleased to report that we have an influx of these new oral therapies, which are helping patients live longer than ever, but contributes significantly to financial toxicity. The fact of the matter remains that many of our patients with CLL are found to be of older age and likely to be on Medicare. In my practice, I like to first establish that the patients have insurance. Second, I partner with several specialty pharmacies in my area to establish a good relationship. I have a mechanism where if I need to write a new prescription for these drugs, I send it to the pharmacist with the insurance information. They will screen them, and if there is a high copayment for that medication, oftentimes that pharmacy group will do a lot of the legwork to find reimbursement assistance. There are many different assistant opportunities from the pharmaceutical manufacturers, professional societies, such as the Leukemia and Lymphoma Society, and other patient-support organizations.

Question: Which of the three drugs is least expensive and which is most?

Answer by Beth Faiman, PhD, CNP: I feel like we should not look at a drug from a cost perspective. We need to balance the risks and the benefits in trying to personalize the therapy to their comorbid conditions. What worked before, what did not work, and taking all those into your equation is extremely important. In the majority of cases we will find copayment assistance for the majority of our patients, whether they have commercial or government insurance. By working with social workers and pharmacies, we can come to an agreement with the copayment, so that patients can have access to the best treatment for their disease.

Question: What are the key clinical trials to look out for investigating ibrutinib, idelalisib, or venetoclax?

Answer by Jeffrey Jones, MD: With respect to ibrutinib, the next wave of trials is investigating the combination of ibrutinib with other medications to see if patients can achieve better responses, and then whether patients can discontinue therapy, since ibrutinib is now prescribed as an indefinite therapy. These trials include investigations of the ibrutinib and venetoclax combination. There has been some preliminary data presented at the 2017 American Society of Hematology (ASH) annual meeting, and additional European trials will have data available shortly. These include a large study from the German CLL Study Group, CLL14, which includes an arm of patients treated with venetoclax, ibrutinib, and obinutuzumab. There is also a study from the large British CLL clinical trials group investigating the combination of ibrutinib and venetoclax without obinutuzumab. Venetoclax has also been assessed in a very important trial, the MURANO study (NCT02005471), that will likely lead to broader approval in combination with rituximab. In this trial, patients are being randomized to bendamustine and rituximab, a very standard therapy for relapsed CLL, with a combination of venetoclax and rituximab; the results are anticipated to be promising, given that response rates of venetoclax and rituximab have reached 50% complete response.

Question: What do you think about treating CLL with curcumin?

Answer by Heidi Finnes, PharmD, BCOP: I am seeing a lot of patients that want to contribute to their therapy by using over-the-counter herbal supplements. This can sometimes cause problems with their medications. I recommend that you have a pharmacist review the medications that the patient is on. Curcumin can inhibit CYP3A4, and so, it can be problematic, especially with the ibrutinib and venetoclax.

Question: What is the use of venetoclax in the first-line treatment of deletion 17p-positive CLL?

Answer by Jeffrey Jones, MD: The short answer: that is not recommended. The drug is approved specifically for the treatment of deletion 17p positive disease after one prior therapy. There are some early stage clinical trial data suggesting that the drug is efficacious in that setting. There are other larger trials ongoing, but for now, the abundance of data is in the relapse setting. Fortunately, there are still other options, such as ibrutinib, that are specifically approved for the first-line treatment of deletion 17p-positive disease.

Question: What therapies are recommended for aggressive versus slow relapse?

Answer by Jeffrey Jones, MD: In terms of aggressive relapse, I imagine that means highly proliferative or rapidly progressing disease. The first question to answer is whether or not that patient is progressing as CLL or if it is Richter transformation. If the progression is Richter transformation, which has to be demonstrated by biopsy, then that patient follows a treatment paradigm for large cell lymphoma or Hodgkin disease, and transplant becomes important in appropriate patients. If a patient is progressing rapidly with CLL, then the clinical context matters. For patients who are progressing rapidly after ibrutinib, which now represents an emerging and important subgroup, there is data that should be soon published showing that venetoclax is active in that context, as well as some retrospective data suggesting that those patients can be treated effectively in about 50% of cases with idelalisib and rituximab. If the patient has not been receiving prior therapy with one of the novel agents and is previously exposed to only chemotherapy or antibody therapy, then kinase inhibitors are probably the cornerstone of therapy in that group. Either ibrutinib or idelalisib, with the choice made in large part based on the toxicity profile, drug-drug interactions, and the need to give rituximab in the case of idelalisib.

Question: What therapies do you recommend for patients taking a strong CYP3A inducer, given the recommendation to avoid concomitant ibrutinib, idelalisib, and venetoclax?

Answer by Heidi Finnes, PharmD, BCOP: All three of these drugs are fairly sensitive to CYP3A inducers. It is actually not recommended to take any of these medications; otherwise, you may have to increase the dose. At my institution, I have had a lot of experience with the ibrutinib. In some patients that require strong CYP3A inducers, like rifampin, we have started at the 420 mg dose of the ibrutinib and escalated to 560 mg in patients who were not demonstrating the appropriate response. Depending on the cytogenetic profile of the patient, it may be more appropriate to initiate therapy with other agents, such as rituximab or obinutuzumab.

Question: What would you consider an aggressive relapse in a patient with CLL?

Answer by Jeffrey Jones, MD: The first issue always has been patients who relapsed early after chemoimmunotherapy, either with FCR or bendamustine and rituximab. Patients who relapsed before the expected median duration of remission or progression-free survival often demonstrated an aggressive disease course, and those were patients that responded poorly to second-line therapy and beyond. Increasingly, we understand that it is because those patients have acquired additional genetic abnormalities in their CLL, particularly acquisition of deletion 17p, that make them more resistant to therapy. The initial treatment tends to target the more benign cells, thereby selecting for more resistant cells, allowing them to dominate, and thereby resulting in a more aggressive disease course. Another aggressive relapse would be patients who have sudden changes in their symptoms. Such patients develop night sweats, which they did not have before, rapid progression of lymphadenopathy, and in some cases, elevation of lactate dehydrogenase on laboratory evaluation signifying Richter transformation to higher-grade lymphoma. This occurs most commonly as large cell lymphoma, but in a minority of cases Hodgkin disease is found. It is very important that if the pattern of disease course is changing abruptly that you consider a repeat biopsy to ensure that you are still dealing with CLL rather than Richter transformation. Finally, in the era of targeted therapies, we know that some patients with very resistant, heavily pretreated CLL will experience a very rapid disease course as their disease becomes resistance to ibrutinib. Now, that is a minority of patients, and that does not mean that ibrutinib is causing this. What it does mean, though, is that in the patient who is progressing on ibrutinib, it is very important to quickly begin planning the next line of therapy because the window to intervene may be relatively limited.

Question: When would you use idelalisib without rituximab?

Answer by Jeffrey Jones, MD: Well, first, it seems the question comes from someone who knows that idelalisib is approved to be given in combination with rituximab. It has certainly been studied as a single agent, that is without rituximab, and does appear to have similar clinical activity. The benefit of rituximab seems primarily in hastening the achievement of an objective response primarily through faster clearance of peripheral blood lymphocytosis. Whether that is truly a meaningful clinical outcome for patients is unclear. In patients who have no problem taking rituximab in the past, no infusion reactions of any significance, for the patients who have no concerns about transit to and from the infusion center, we typically would go ahead and give rituximab. However, if the patient had an intolerance or some history of significant infusion reactions to rituximab or other anti-CD20 monoclonal antibody therapy, I think you could comfortably give idelalisib as a single agent, although you might have to justify that decision to the payer since many times when we have done that the payer will reject the claim without further explanation.

Question: When would you use venetoclax, before ibrutinib or idelalisib?

Answer by Jeffrey Jones, MD: To date most of the data describing venetoclax in sequence with ibrutinib or idelalisib has been venetoclax after ibrutinib or idelalisib. That is where the data exists. But there really is not any reason that you could not give venetoclax to a patient with deletion 17p CLL relapsed after one prior therapy before ibrutinib or idelalisib, particularly if you thought that the toxicity profile of venetoclax was preferable to the other two agents. As we have talked about in the presentation, there are comorbid medical illnesses and drug-drug interactions that may make one or more of these therapies better or worse for your particular patient. Toxicity and comorbid medical illnesses influence part of the decision. The existence of data showing the activity of venetoclax after ibrutinib or idelalisib is also helpful in informing drug sequencing strategies. Finally, there are differences between these drugs with regards to duration of response and progression-free survival. That data is still relatively immature for venetoclax and for patients with deletion 17p. Ibrutinib still has the most robust progression-free survival data. That is often why it is chosen first, although there are still patients for whom venetoclax might be the first best option.

Testing Strategies & Navigating Cytogenetics

Question: Because CLL patients are generally older, are there any specific geriatric assessment tools that you use?

Answer by Beth Faiman, PhD, CNP: This is an excellent question because many of us use the eyeball test where you look at the individual to determine if they “look sick,” or if they are bedridden. We use the Eastern Cooperative Oncology Group testing, etc., but many of us do not have the time in the clinic or the resources to set and administer comprehensive examination. I know the CLL 9 trial of the German CLL study group published a paper last year about geriatric assessment. There was also a simplified score that was presented at the 2017 American Society of Hematology (ASH) annual meeting this year by an Italian group. There are still no gold standards in terms of the geriatric assessment. In my practice, the independent activity daily living scale from Katz is something that we integrate. I am embarrassed to say that I do not do a comprehensive evaluation for everybody, but I ensure that my team asks the patients, caregivers, and the support system for their feedback as well.

Question: Do you adhere strictly to a cut-off value for 17p deleted metaphases?

Answer by Beth Faiman, PhD, CNP: We know 17p is probably new in clinical practice and confers a particularly poor prognosis. The patients with de novo 17p deletion have a longer survival, whereas those who have acquired the mutation through clonal evolution have a shorter survival. In terms of the cut-off, there have been a couple of different studies that have suggested a cut-off percentage; I think about 3% was initially established. At the end of the day, we have drugs that can overcome to some extent some of the poor prognosis. I guess it just depends if the patients are newly diagnosed, or relapsed and evaluating prior therapies, age, biological fitness, and performance status. But to answer the question, no, I do not strictly adhere to it when selecting a therapy. I rather look at the bigger picture because 17p is such a negative prognosticator. I try to guide my treatment toward people that may benefit from drugs that can overcome this poor prognosticator.

Question: In your patients with relapsed refractory disease, do you always order FISH before starting a new line of therapy? Are there any instances where you would not?

Answer by Beth Faiman, PhD, CNP: The majority of patients who relapse will have repeat fluorescence in situ hybridization (FISH) testing, as clonal evolution may have occurred during primary therapy, resulting in a higher percentage of clones with specific cytogenetic abnormalities, such as del(17p). FISH testing is generally quite expensive, so that may be a barrier to repeat testing in some institutions, and is something to consider on a case-by-case scenario.

Question: Why would deletion 17p not be demonstrated on initial FISH testing?

Answer by Beth Faiman, PhD, CNP: CLL is a clonal disorder in which the clones may change over time. At first, you may not detect the del(17p) abnormality on the initial marrow, as there aren’t enough CLL cells that harbor the mutation and it is too early in the transition. However, there are some studies that have demonstrated that about 25% of patients will have clonal evolution five years after diagnosis. Although it isn’t guaranteed that patients will have the del(17p) mutation at diagnosis, the risk for developing the mutation increases with duration of disease and duration of therapy. Despite the costs associated with fluorescence in situ hybridization (FISH), repeat testing for del(17p) in a patient who did not demonstrate the mutation at diagnosis is important for identifying new clones that may be present and subsequently, selecting therapy; insurance will often approve the repeat testing for this reason.
Last modified: January 26, 2017