Medical Roundtable: The Changing Pharmacologic Treatment Landscape in Chronic Lymphocytic Leukemia

Moderated by: Jennifer R. Brown, MD, PhD¹

Discussants: Jeffrey A. Jones, MD, MPH²; Jacqueline C. Barrientos, MD³

From the Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA1; Ohio State University, Columbus, OH²; Hofstra North Shore-LIJ School of Medicine, Lake Success, NY

Address for correspondence: Jennifer R. Brown, MD, PhD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215

E-mail: [email protected]

Biographical Sketch

From Dana-Farber Cancer Institute and Harvard Medical School:

Jennifer R. Brown, MD, PhD is the Director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and an Associate Professor of Medicine at Harvard Medical School in Boston, Massachusetts. Dr. Brown completed a BS and MS simultaneously in molecular biophysics and biochemistry (MB&B) at Yale, graduating summa cum laude with distinction in MB&B. She proceeded to Harvard Medical School where she received her MD and PhD in molecular genetics in 1998 and was awarded the James Tolbert Shipley Prize for research accomplishment in the graduating class. She then served as an intern and resident in Internal Medicine at Massachusetts General Hospital followed by fellowship in Hematology and Medical Oncology at the Dana-Farber Cancer Institute. Dr. Brown joined the faculty of DFCI and Harvard Medical School in 2004, where she has an active clinical-translational research program in CLL.

Her particular interests include the development of novel targeted therapeutics for CLL, as well as the genomics of CLL. She has been instrumental in the clinical development of both idelalisib and ibrutinib, leading to their regulatory approvals in CLL.

In the area of genomics she has been instrumental in the description of the somatic mutation profile of CLL, and is now particularly interested in the implementation of genomic technology in the clinic, including for prognosis and targeted therapy. She also has a longstanding research interest and focus on the inherited predisposition to CLL.

To date she has published over 130 papers in the scientific literature, predominantly in CLL. She is an active member of the CLL Research Consortium and serves on the Alliance Leukemia and Leukemia Correlative Science Committees as well as the NIH Cancer Biomarkers Study Section. In 2014 she was the recipient of two awards from Dana-Farber Cancer Institute, the Clinical Innovation Award, as well as the George Canellos Award for Excellence in Clinical Investigation and Patient Care. She enjoys a worldwide reputation as a CLL expert and is in much demand as an international speaker.

From Hofstra North Shore-LIJ School of Medicine:

Jacqueline C. Barrientos, MD, is Attending Physician at the Chronic Lymphocytic Leukemia (CLL) Research & Treatment Program of the Division of Hematology and Medical Oncology, Department of Medicine, in the North Shore – LIJ Cancer Institute in Lake Success, New York. She is also Assistant Professor of Medicine at the Hofstra North Shore-LIJ School of Medicine. Dr. Barrientos works in close collaboration with her mentors, Dr. Kanti R. Rai and Dr. Nicholas Chiorazzi of the Feinstein Institute for Medical Research. 

Dr. Barrientos received her medical degree at the Ponce School of Medicine in Puerto Rico, where she was elected vice-president of Alpha Omega Alpha Honor Medical Society. During her medical studies, she was the recipient of two Research Fellowship Awards from the Howard Hughes Medical Institute. She completed her internship and residency in internal medicine at Yale-New Haven Hospital of the Yale School of Medicine, and her fellowship in Hematology/Oncology at New York Presbyterian Hospital of Weill Cornell Medical College in New York City, where she also served as Chief Fellow. She is board certified in internal medicine, hematology and oncology.

Dr. Barrientos’ research focus is on chronic lymphocytic leukemia and lymphoma. She has extensive experience with the new promising agents targeting the B-cell receptor signaling pathway in B-cell malignancies, serving as Principal Investigator on several phase I-III clinical trials.

Dr. Barrientos actively participates in multi-institutional clinical trials with the Chronic Lymphocytic Leukemia Research Consortium (CRC) and the Alliance for Clinical Trials in Oncology. She is a cadre member of the Leukemia Committee of the Alliance for Clinical Trials in Oncology and in this capacity is co-chair of a study comparing chemoimmunotherapy against a combination of targeted agents. She is a member of the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH).

She has been an invited speaker for ASCO University “CLL Tumor Board”, ASH “State of the Art Symposium”, and “Highlights of ASH in Latin America”.  Dr. Barrientos is the recipient of a 2015 American Society of Hematology-Harold Amos Medical Faculty Development Program (ASH-AMFDP) Fellowship award.

DR. BROWN: I am Jennifer Brown, Director of the Chronic Lymphocytic Leukemia (CLL) Center at Dana-Farber Cancer Institute, and Associate Professor of Medicine at Harvard Medical School. Today, I will be speaking with two of my esteemed CLL colleagues, Drs. Jeffrey Jones and Jacqueline Barrientos, about the new drug approvals in CLL. 

DR. BARRIENTOS: I’m Jacqueline Barrientos, Assistant Professor of Hematology/Oncology at the Hofstra North Shore-LIJ School of Medicine, and Attending Hematologist at the CLL Research and Treatment Program in Long Island, NY. Our center participates in clinical trials and we perform correlative basic research. I’m very happy to participate in this expert roundtable discussion.

DR. JONES: I’m Dr. Jeffrey Jones, Associate Professor of Internal Medicine and Section Chief for CLL in the Division of Hematology at The Ohio State University.

DR. BROWN: Thank you Jeff and Jacquie for joining me today. I think we’re all aware what an exciting time this is in CLL with the approvals last year of the targeted inhibitors ibrutinib and idelalisib as well as the new antibody approval obinutuzumab as well as the additional indication for ofatumumab. Let’s start our discussion with ibrutinib and idelalisib. Jeff, please introduce the approvals that these inhibitors received and get us started.

DR. JONES: February 2014 marked a really important time in CLL medicine with the approval of the first oral kinase inhibitor, ibrutinib, for the treatment of CLL after one prior therapy.^1,2 This ushered in an entirely new era of molecularly-targeted therapy for CLL. Later that year, ibrutinib received approval for deletion 17p CLL, the highest risk genetic subtype of CLL, whether previously untreated or relapsed disease. The drug has rapidly entered the clinic, although I think most of us are still trying to determine how best to incorporate them into our practice.

DR. BROWN: Jacquie, please comment on how you’re using ibrutinib now in your practice.

DR. BARRIENTOS: In CLL patients with the presence of a mutation of TP53 or deletion 17p, we use ibrutinib. We essentially do not use chemotherapy on this particular set of patients. If, for any reason, they are not able to tolerate the drug, then we consider idelalisib, which is not approved separately for this 17p deletion indication. Idelalisib is approved for use in combination with rituximab for the treatment of relapsed or refractory CLL patients. Idelalisib has shown clinical activity in several clinical trials in patients with deletion 17p.

At this moment, we mainly are using ibrutinib or idelalisib for our relapsed or refractory CLL patients.  Clinical trials are underway in the frontline setting and we hope to see the results of the frontline use of ibrutinib in elderly patients soon. As of right now, we don’t use ibrutinib as a frontline therapy unless there is a reason, and usually it’s that they carry the 17p deletion or they are participating in a clinical trial.

DR. JONES: Outside of clinical trials our practice has really been to follow the label indications for ibrutinib. For previously untreated patients, our use has been limited to patients with deletion 17p or TP53 mutated disease, as Jacquie said, since that is the group for which the drug has been approved in the frontline.

DR. BROWN: I would agree. That’s been my practice as well. We should perhaps review the data from the registration trial that led to the ibrutinib approval for relapsed refractory CLL. The initial approval was from the stage IB2 study and was an accelerated approval.¹ The confirmatory registration trial, RESONATE, randomized relapsed refractory CLL patients to ibrutinib versus the anti-CD20 antibody ofatumumab.2 Ibrutinib was found to be significantly better in improving both progression free and overall survival, although there was crossover later. As a result, this has moved into our relapse refractory use very rapidly. Although we still use chemoimmunotherapy for upfront therapy for patients without 17p deletion, for those in relapse we have moved entirely to targeted inhibitors. Would you both agree?

DR. JONES: For sure. I think it is very hard in 2015 to think of the patient for whom chemo-immunotherapy is the better choice than ibrutinib for relapsed disease.I think it is very hard in 2015 to think of the patient for whom chemoimmunotherapy is the better choice than ibrutinib for relapsed disease. The benefit is most marked for the group with higher-risk disease as characterized by genetic risk features, not just deletion 17p, but patients with complex abnormal karyotype or deletions of chromosome 11q. All of these patients particularly benefit from treatment with ibrutinib in the second line vs chemoimmunotherapy, as do patients who had either a suboptimal response to frontline chemoimmunotherapy or a brief duration of first remission. All of us are sometimes asked, “Well, who is the patient with relapsed CLL for whom ibrutinib is the best choice?” Right now, in most clinical situations, my response is, “For which patient is ibrutinib not the best choice in first relapse?”

DR. BROWN: That’s actually a good question. Jacquie, how would you answer that? Are there patients for whom you would not choose ibrutinib in first relapse?

DR. BARRIENTOS: I feel a hesitant to use ibrutinib in some patients with a particular comorbidity or medical history. For example, patients with a previous intracranial bleed or a recent history of bleeding, I would prefer to avoid using ibrutinib because there have been rare cases of spontaneous intracranial bleed or severe bleeding after trauma. The other type of patient where I would be cautious is a patient with uncontrolled atrial fibrillation because there are data that in the minority of patients (up to 10% of patients), atrial fibrillation has been an issue. We have some patients that are so frail that they couldn’t tolerate another episode of uncontrolled atrial fibrillation and as such they would not be ideal candidates for the drug. For that type of patient, I would probably abstain from using ibrutinib and consider the use of another therapy. Finally, I would be careful in patients on antiplatelet and anticoagulation therapy because ibrutinib affects platelet functions increasing the risk of bleeding. The bleeding events seen with ibrutinib are mostly grade 1 or grade 2. If the patients have had a serious bleed or serious gastrointestinal bleed or a recent surgery, then I would preferably use another agent.

DR. BROWN:Yes, so that gets to the toxicities of ibrutinib. The more medically significant ones do include perhaps a 5% to 10% risk of atrial fibrillation as well as bleeding risks, which as Jacquie points out are low and usually low grade, but there are occasional higher-risk bleeds. I personally still try to avoid combining anticoagulation with ibrutinib, as we don’t fully understand the mechanism or the risk factors for the more serious bleeds. Jeff, please comment.

DR. JONES: I think the data from the randomized study are actually the most helpful since, as you say, mild bleeding events (grade 1 or 2) were indeed more common amongst the group of patients who were treated with ibrutinib.² Major bleeding events—which are typically defined as intracranial hemorrhage, bleeding requiring transfusion, or inpatient management—were actually similar between the two arms of the trial. An important caveat in interpreting these data is to know that patients in this trial were excluded if they were anticoagulated with warfarin, if they had an antecedent history of intracranial hemorrhage or recent bleeding, or recent surgery. In line with those exclusions, we will often consider other options. If there is any specific concern for bleeding, such as a patient who has experienced bleeding complications during routine anticoagulation, which is also a patient for whom ibrutinib may not be the best choice. In these clinical situations, it is important to involve the patient in discussing the balance of risks and benefits.

DR. BROWN: Yes. Jacquie, please comment on some of the side effects the patients on ibrutinib have, and how you manage those.

DR. BARRIENTOS: I usually mention to my patients that over the first 2 or 3 months about half of them will have a possible change in their bowel movements. Usually they report some diarrhea or loose stools. Usually these episodes are mild, nothing that requires hospitalization. In any case, if it becomes severe, I definitely make sure that it’s not an infection. We all know that our patients with CLL are prone to infections. The other thing I tell the patients is that in some cases patients may develop a rash on the skin. Many times it may look like a rash, but it’s actually ecchymosis—an effect from the drug on the platelets. Essentially, they are grade 1 and don’t require intervention. I just tell them that eventually they will go away. It can be scary for the patients if they are not expecting these. We have had patients with large areas of hematomas in the arms or in the legs. That is unexpected with a drug that they are taking by mouth. They usually expect that with other drugs like warfarin, but not with ibrutinib, so it is important to mention before they start the drug.

Last but not least, I mention the fact that they may get arthralgias—joint pain—in different areas of their bodies. I would say that I see that in about 20% to 30% of patients. Usually it’s very mild, but on occasion I’ve had patients with arthritis so severe that we’ve had to hold the drug and give them some steroids to help them improve their ability to maneuver their hands or move their joints. I’m sure you have seen some of those same side effects.

DR. BROWN: Yes, definitely. In general, it’s pretty well tolerated but it’s best to warn the patients, then there are no surprises. Let’s turn our attention for a moment back to the highest risk genetic subgroup, the 17p deleted patients—which Jeff had mentioned get particularly strong benefit from ibrutinib. This is certainly true, although it’s also the case that it appears, depending on the data set you look at, that they may relapse earlier than other patients on ibrutinib. In the original phase IB2, the median progression survival for the 17p deleted patients was 28 months. More recent data from Ohio State and MD Anderson suggest that complex karyotype may be a risk factor.3,4 Given these data, how are you two handling the question of allogeneic stem cell transplantation for these patients in this new era?

DR. BARRIENTOS: At our center, if the patient is young and they have access and are fit to tolerate a reduced-intensity allogeneic transplant, we recommend that they be evaluated for a transplant. Unfortunately, if they lose the response to the best drug available for their particular genetic mutation, then we have limited options of salvage therapy. It’s risky to think that they will not relapse at some point, and then what do we do at the time of relapse? We can use other targeted agents that are available, like idelalisib, with the knowledge that they may not always respond to the salvage therapy. Promising clinical activity has been reported for patients with 17p deletion treated with venetoclax in clinical trials. Venetoclax is a new targeted agent in development stages but the drug is only available in clinical trials.Promising clinical activity has been reported for patients with 17p deletion treated with venetoclax in clinical trials. Venetoclax is a new targeted agent in development stages but the drug is only available in clinical trials. One problem is that in order to participate in a clinical trial the patient needs to be able to get to the center to get the drug. Additionally, the patient needs to satisfy certain eligibility criteria for study entry. For these patients that stop responding to ibrutinib, the options of care are very limited at this time. This is the reason why I send all my young patients with a 17p deletion for a transplant evaluation.

At the end of the day it is tough to convince the patients to go for a transplant when they’re feeling in excellent shape. It’s still difficult to make a case to go for a procedure that may have its complications on its own. It is well known that there are some increased mortality risks and infection risks that can arise as a result of a transplant. They may not want to do it because they are feeling so great with their routine. I still sit down and have a long frank talk with the patients, especially if they have complex karyotype and 17p deletion. I am concerned that at some point they’re going to stop responding to ibrutinib.

DR. BROWN: That’s generally my practice as well. What about you, Jeff?

DR. JONES: Until there is greater clarity regarding which of the newer agents can salvage patients progressing after ibrutinib, I think it is still important for younger, transplant eligible patients with deletion 17p disease to undergo evaluation for allograft. It remains potentially curative therapy, and I think the availability of ibrutinib has not really changed the importance of that evaluation.

DR. BROWN: Yes, I would agree. I think that was a good discussion on ibrutinib. Why don’t we turn our attention now to idelalisib, the phosphoinositide 3-kinase (PI3K) inhibitor. How are you using idelalisib in your practices? Is this after ibrutinib in general?

DR. JONES: Published data regarding the sequencing of the new agents are relatively limited since all of the registration trials for idelalisib excluded patients who had received prior therapy with an inhibitor of B-cell receptor signaling, including Bruton’s tyrosine kinase inhibitors like ibrutinib.^5,6 A small number of patients enrolled on the phase IB2 trial of ibrutinib, as well as the subsequent randomized trial, had received prior therapy with idelalisib and responded similarly to patients who had not received prior idelalisib.^1,2 In our practice, the use of idelalisib has pretty much been limited to patients who have either received prior ibrutinib or patients who are not eligible to receive ibrutinib because of some important contraindication, such as an inherited bleeding defect, perceived increased bleeding, or history of difficult to control atrial fibrillation, since that event also seems to be more likely among patients treated with ibrutinib.

DR. BROWN: How about you, Jacquie?

DR. BARRIENTOS: The same type of patient with the addition of patients with kidney disease. The rationale for this is based on the phase III trial for idelalisib and rituximab, the enrollment allowed participation of patients with decreased renal function, that was one of the entry criteria for eligibility to participate in the trial.6 In most of the ibrutinib trials the creatinine clearance needed to be adequate, whereas this was allowed to be lower on the idelalisib trials. For those patients with severe renal impairment, I tend to prefer idelalisib rather than ibrutinib—only because I feel more comfortable and have more experience treating patients with impaired kidney function with idelalisib.

DR. BROWN: I have seen some episodic elevations in creatinine in patients on ibrutinib, but they’re fairly sporadic and it’s a little hard to assess the direct drug relationship. It is true that the patients in the idelalisib studies had a high level of comorbidity deliberately on the initial registration trial and generally did reasonably well with idelalisib. The toxicity profile of idelalisib is pretty characteristic, and is potentially harder to manage than that of ibrutinib. I think it also dictates some of how it’s being used in later line therapy. Does one of you wish to comment on the pattern of the key toxicities?

DR. BARRIENTOS: One key toxicity that is very particular to this drug that may happen overnight and is very striking is transaminitis. It usually happens more with non-Hodgkin lymphoma patients compared to relapsed CLL patients, but transaminitis can still be very severe. Patients can develop transaminitis even after more than a cycle on therapy even if they were tolerating the drug well without other issues. It’s very important to educate physicians and healthcare providers about the need to monitor the liver function tests, at least every 2 weeks for the first 2 months. Transaminitis events can be very prompt, very rapid, and usually asymptomatic. My patients that developed transaminitis never complained and had we not been cautious about it, we may have missed it.

DR. BROWN: Yes, I even check weekly. The recent safety analysis said the overall incidence of grade 3 to 4 transaminitis is about 15% in relapse patients.7 That’s pretty significant.

DR. JONES: I think it’s important to know that the transaminitis, if monitored carefully and managed with drug interruption and/or dose reduction upon reintroduction, need not lead to discontinuation. Discontinuations for transaminitis are actually the minority of patients who experience the side effect.

DR. BROWN: Absolutely. Do you want to comment on some of the other side effects that may more often lead to discontinuation?

DR. JONES: We should mention that there are some preclinical animal data suggesting that the molecular target of idelalisib, the PI3K delta isoform, is an important signaling molecule in regulatory T cells important for self-tolerance. While it has efficacy in treating B-cell disorders, inhibiting PI3K-delta may also be impairing T regulatory cell function. That may be what leads to the more characteristic later side effects of idelalisib, including pneumonitis and colitis. Pneumonitis is relatively rare, but because it can masquerade as other respiratory ailments in an older patient population with comorbid medical illnesses like chronic obstructive pulmonary disease and preexisting immune dysfunction because of CLL or prior therapy, inflammatory pneumonitis can be misdiagnosed. This rare but potentially life-threatening complication of idelalisib treatment requires prompt recognition, discontinuation of the drug, and appears to be most effectively managed with corticosteroids.

The other commonly occurring late toxicity, colitis, is often one that also eludes prompt recognition since many times patients are seen by primary care practitioners between oncology visits, and these doctors may not yet be aware that colitis can occur as a late side effect of idelalisib. Sometimes the colitis is misdiagnosed as gastroenteritis or Clostridium difficile colitis and eludes initial management. Like the pneumonitis, this problem, which may occur in more than a quarter of patients, is really best managed by prompt recognition and, in many cases, interruption of the drug. In some cases, patients have been managed with interruption of the drug and perhaps rechallenge at a lower dose, but in many other cases, colitis has been a treatment-limiting side effect and is a leading cause of drug discontinuation for toxicity.

DR. BROWN: Yes, I would agree. It can occur even at much later times in people who have tolerated the drug for even a couple of years, which is surprising compared to typical drug-related diarrhea.

DR. JONES: Right. With many other drugs, a patient starts taking the drug and expects the treatment-related side effects to become manifest very early. The diarrhea and rash associated with ibrutinib, for instance, are really timed very close to drug initiation, similar to antibiotics and other medications that we commonly prescribe. When side effects occur late in the course of treatment, I think it is just not on anyone’s radar to suspect that they could be related to a drug that they have been receiving for some time. That is an important message to communicate to patients, as well as to doctors who are just beginning to prescribe these new drugs for the first time.

DR. BROWN: Exactly. Why don’t we turn our attention now to the approval of obinutuzumab, and review the registration trial data there and then how you’re using that in practice. Jacquie?

DR. BARRIENTOS: Obinutuzumab is a third generation monoclonal antibody targeting the CD20 receptor on B cells. It was approved in November of 2013 by the US Food and Drug Administration for use in combination with chlorambucil to treat patients with previously untreated CLL.8 The trial enrolled patients with comorbidities as measured by the Cumulative Index Rating Scale, the scale helps define fitness. The patients that participated in the registration trial were patients that due to their comorbidities would not tolerate well a chemoimmunotherapy regimen like fludarabine, cyclophosphamide, and rituximab (FCR), and possibly the combination of bendamustine and rituximab. In patients older than age 65 with multiple comorbidities, chlorambucil monotherapy is widely used worldwide due to concerns of complications from the use of other chemoimmunotherapy regimens like the ones mentioned above. In the United States, we usually see that physicians prefer to use rituximab as a single agent in frail patients with multiple comorbidities.

The combination of obinutuzumab with chlorambucil compared to chlorambucil as a single agent showed that the patients treated with the combination therapy had a higher rate of response, a higher rate of progression free survival, and an improved overall survival. The main issue with obinutuzumab is the fact that the infusion reactions are much greater than what we traditionally see with rituximab. Severe and life-threatening infusion reactions have been reported. The reactions can also be more abrupt, although they typically occur very early in infusion, so they are more predictable. If the patient develops an infusion reaction or can’t tolerate the drug, the infusion needs to be interrupted. If the patient does not experience any further infusion reaction symptoms, the infusion may be restarted at a lower rate. I believe grade 3 to grade 4 events were higher than 10% in the registration trial, with infusion reactions of any grade seen in 50%–70%, so it can be common—usually within the first day. By the third infusion, the rate of reaction decreases significantly. Most of the time after that third infusion, most patients won’t have any more issues with tolerability.

Who are the patients that develop these infusion reactions? It has been noted that the level of interleukin 6 is elevated in patients that develop an infusion reaction. That’s the reason why all patients should be premedicated with potent steroids (methylprednisolone or dexamethasone, not hydrocortisone). In addition, patients need to be premedicated with acetaminophen and an antihistamine. In the future hopefully we will be able to use other agents like tocilizumab to lessen the risk of infusion reactions, this is currently being tested in clinical trials as its use is theoretical at this point based on the observation of the elevated interleukin 6 levels.

There are other important side effects with this combination regimen that were noted in the registration trial. There was a higher rate of neutropenia in the patients receiving obinutuzumab and chlorambucil, although this did not correlate with a higher rate of grade 3 or grade 4 infections. The rate of grade 3 or 4 infections was the same all across the board in patients that received chlorambucil, chlorambucil in combination with rituximab, or chlorambucil in combination with obinutuzumab.

DR. BROWN: Are you using much obinutuzumab chlorambucil in your practice?

DR. BARRIENTOS: In select patients, yes. For untreated patients with comorbidities that are not participating in a clinical trial, we discuss with them data from the frontline bendamustine and rituximab combination and obinutuzumab and chlorambucil combination. For the most part, most patients prefer obinutuzumab with chlorambucil because the obinutuzumab chlorambucil combination might be better tolerated and possibly less myelosuppressive than the bendamustine rituximab combination. Unfortunately, most of my patients have already been treated by the time we see them. We have a minority of patients that come recently diagnosed, we just don’t see that many untreated patients.

DR. BROWN: How about you, Jeff? Are you using it?

DR. JONES: Yes, it is a consideration for frontline therapy in patients who don’t have deletion 17p. As we discussed before, most of us have already adopted ibrutinib as our first choice in that 17p deleted population outside of clinical trial. For the remainder of patients, I think the first question remains whether their age and health are permissive to safely give FCR, since that regimen has been associated with the best survival outcomes, even some really long survival, in a group of patients with IgVH mutated, favorable cytogenetic risk disease.

For patients who are not eligible or willing to receive FCR, I think the choice between bendumustine and rituximab (BR) and chlorambucil and obinutuzumab is a relatively challenging one. Part of the reason is that while the overall response rates and complete response rates are lower with obinutuzumab and chlorambucil, the toxicity is also a bit lower. That makes it an appealing choice, particularly when we have the availability of drugs like ibrutinib and idelalisib in the second line. For older patients with comorbid medical illnesses in particular, it may be that the duration of first remission after chemotherapy may not matter as much when we have more effective second line options.

DR. BROWN: Yes, I think that’s definitely true. I just want to highlight two points. Your point about the long-term efficacy of FCR, particularly in the IgVH mutated patients—it is important to note that we now have data from both MD Anderson and the German CLL Study Group. The MD Anderson data with 10 year follow up, 60% of that genetic subgroup are progression free after FCR suggesting that a subset of them may in fact be cured. We don’t want to forget that with the excitement of the new inhibitors. I would second your point also about the potential toxicities of BR which can be as myelosuppressive as FCR even though it is not in every case. Again, it’s very important to assess the comorbidities of the patient not just for FCR but also for BR, particularly when FCR has this chance of very long-term remission which is not seen with BR.

DR. JONES: Yes, and there’s also a risk for opportunistic infections with both regimens. Like fludarabine-treated patients, there are patients treated with bendumustine who experience pneumocystis pneumonia or viral reactivation from immune suppression beyond just the neutropenia.

DR. BROWN: Yes, absolutely. Let’s talk briefly about where we see CLL therapy going in the next few years given these exciting new drugs. I’ll just leave that open and see what you have to say. Jacquie?

DR. BARRIENTOS: Some of the possible developments that we may see over the next couple of years are the use of these targeted agents or small molecules as initial therapy either as monotherapy or in combination regimens. We are expecting to see the data of the clinical trial of frontline ibrutinib against chlorambucil in patients that are older than age 65. Idelalisib has other ongoing clinical trials in the frontline setting as monotherapy and in combination therapy. Data have been presented of idelalisib in combination with rituximab as frontline therapy. It was interesting to note that some of these side effects that we saw in the relapsed or refractory setting occurred more often in patients in the frontline setting, although efficacy was very high. These promising data may eventually lead to a change in the way that we treat patients in the frontline, not only as monotherapy. There are several clinical trials that incorporate chemoimmunotherapy with these new targeted agents to see if maybe we will obtain deeper remissions or longer duration of response.

DR. JONES: What preliminary data exist in small phase 1 or phase 2 studies suggest that the new agents may be even more effective in previously untreated disease, with higher overall response rates, higher complete response rates, and more durable remissions than observed among patients with relapsed and refractory disease.9,10 These results underscore that the individual agents are among the most effective drugs that have been developed for CLL in terms of their single-agent activity. If you include the oral BCL-2 inhibitor in development, venetoclax, these drugs have really had remarkable single-agent efficacy. If these newer agents are like older cytotoxic chemotherapy agents, like fludarabine, they may become superstars when used in combination. While we will soon see these drugs move into the frontline setting as single agents, I think the real potential for magic is when they get combined. There we may see the kinds of deep remissions that we only achieve now with chemoimmunotherapy, remissions that will allow similar long-term treatment-free survival without cytotoxic chemotherapy. I’d like nothing more than to see a 60% 10 year survival after a nonchemotherapy-containing combination that emerges when we use these new drugs in ways that maximize their benefit in combination.

DR. BROWN: I would certainly agree. I think that although we have remarkable single-agent activity of these drugs, we know that in the context of single-agent activity, resistance is likely to develop over time. For a subset of patients that may not matter. If they’re older and have comorbidities, they may get enough durability of response from their first single agent that it doesn’t matter, particularly the patients with lower risk CLL. For our younger patients, I think the combinations will have the opportunity to minimize the development of resistance and also allow shorter courses of therapy so that patients can be off treatment still with deep remissions. That is what most excites me about the future of these agents.

Let’s just talk about the future of watch and wait. We now have great drugs and great therapies. Are you considering treatment earlier in any of your patients at this point, Jacquie?

DR. BARRIENTOS: I have been very hesitant to start our patients on any drug before they develop symptoms from the disease. I still wait to initiate therapy according to the International Workshop on CLL (IWCLL) guidelines.¹¹ The reason is that anytime that we start a new agent, the patients may develop some mutation that is driven by these new agents. At this point, there are no data for us to start therapy before symptoms develop. The German CLL study group is currently doing a high risk study in patients that are asymptomatic but have a high risk profile like 17p deletion to see if maybe a drug like ibrutinib could have a benefit. I think that will be very interesting once the data come out. There are certain patients with whom you are always wondering, “Am I doing more harm by withholding therapy at this moment?” So far, early intervention with chemotherapy before symptoms has not shown any additional benefit. We still do the watch and wait for the time being, but this may change in the future for certain patients with certain high-risk characteristics.

DR. BROWN: Yes, I share your concerns about the possibility of evolution of the disease in the context of any treatment. Even though we hope that there will be less clonal evolution with these targeted inhibitors, there is some increasing evidence that some adverse clones like TP53 mutated or 17p deleted clones are preexisting in many cases. Then, under the influence of treatment, these mutations become more evident, ie a higher percentage of the disease. Personally, I would like to see overall survival data before we start treating patients earlier.

DR. JONES: I would absolutely agree. I think if you want to undertake the systematic treatment of patients before they actually progress clinically, those are the kind of data that you want. You want to know whether you are impacting the natural history of the disease. I’ll take a slightly contrarian point of view in talking about elderly patients in particular. Some of our colleagues who treat low-grade lymphoma—where watch and wait is often employed in the initial asymptomatic setting—have argued that there is a strong rationale to treat earlier rather than later because you may find that toxicity becomes more prohibitive if you wait until the patients become ill. There’s a somewhat perverse logic underlying our current approach to therapy—we don’t treat to maintain health, we treat when patients become sick. I think there is room for a slightly different approach still operating within current consensus guidelines. There is a group of elderly patients with comorbid medical illnesses that as it seems their disease is starting to progress, I am inclined to consider—at least discuss—the feasibility of treatment then as a way of limiting both the morbidity from the disease, as well as the morbidity of treatment. When the only available treatments were chemotherapy drugs like fludarabine, which has not clearly resulted in survival benefits for elderly patients, that was as feasible as when the treatment is perhaps obinutuzumab and chlorambucil, or maybe in the near future drugs like ibrutinib and idelalisib. Therefore I think we may all want to start rethinking our approach, cautiously. Ultimately, this is a research question.

DR. BROWN: That’s interesting. I certainly agree that in the setting of chemotherapy or chemoimmunotherapy patients with a higher disease burden have a lot harder time getting started on therapy. If in fact the targeted inhibitors move to upfront therapy, it’s not so clear to me that those drugs have more initial toxicity in patients with a greater disease burden—at least for ibrutinib. Do you disagree?

DR. JONES: No, I think that’s true. You will even hear an argument sometimes that a single-agent rituximab for follicular lymphoma or obinutuzumab and chlorambucil would be better tolerated, and you have more room for management of toxicity when you give them to patients who are healthier at baseline. Part of that is with less extensive disease, but you’re right. I agree that there is no indication right now that the novel, targeted agents are more toxic in older patients. However, I will say that our own retrospective analysis from Ohio State suggested that age was one of the factors associated with early discontinuation among our patients.⁴

DR. BROWN: Right, but to me, the fact that age is a predictor of less tolerability of therapy suggests that maybe we should save the therapy until the patient really needs it. The toxicities of ibrutinib are not as clearly disease-burden related necessarily.

DR. JONES: Yeah, I think that our disagreement really suggests that it’s a question to study.

As the treatment becomes more manageable and potentially more effective, you start to question whether our goal is to treat patients as they become ill, or to prevent them from ever becoming ill in the first place.DR. BROWN: Oh, absolutely.

DR. JONES: These are important questions that we will necessarily revisit. As the treatment becomes more manageable and potentially more effective, you start to question whether our goal is to treat patients as they become ill, or to prevent them from ever becoming ill in the first place.

DR. BROWN: Right, absolutely. I would say that I feel that we don’t always let the patients become symptomatically ill even in following IWCLL criteria. For example, their counts may be relatively poor, requiring treatment, but the patients are not yet suffering from that.

DR. JONES: Right.

DR. BROWN: I think this was a great discussion. It’s obviously an extremely exciting time in CLL research as we learn how to use our targeted inhibitors, our new antibodies, and hopefully soon we’ll have another targeted inhibitor with ABT199 the BCL-2 inhibitor. Jacquie or Jeff, do you have any points you would like to add before we wrap up?

DR. BARRIENTOS: No. I think we covered most of the important concepts.

DR. JONES: I will just say that with analogy to a cousin disease, chronic myeloid leukemia, after imatinib and the subsequent oral kinase inhibitors were introduced in that disease people thought that the final chapter of the story had been. I think we’re going to find the same thing in CLL medicine. These phenomenally effective agents, safer than the ones we have had available to employ before, are going to open up a whole new range of investigations that we will continue innovating over the next decade.

DR. BROWN: To summarize, in 2014 we saw four new drug approvals for CLL, including two new antibodies for upfront therapy, obinutuzumab and ofatumumab, and two new targeted inhibitors for relapsed therapy, ibrutinib and idelalisib. These innovations are starting to revolutionize the treatment of CLL for the benefit of our patients. However, many questions remain about how best to use each of these drugs, about toxicity, and about resistance. The next 5 years in CLL research will be a very exciting time as we start to answer these questions. Hopefully, ultimately, we will cure more and more of our patients, maybe eventually all of them.

References

1. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42.

2. Byrd JC, Brown JR, O’Brien S, et al. for the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–223.

3. Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125(13):2062–2067.

4. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1(1):80–87.

5. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390–3397.

6. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed in chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997–1007.

7. Coutre S, Leonard J, Flowers C, et al. Idelalisib monotherapy results in durable responses in patients with relapsed or refractory Waldenstrom’s macroglobulinemia (WM). Poster presented at: 20th Congress of European Hematology Association; June 11–14, 2015; Vienna, Austria. Abstract P690.

8. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–1110.

9. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48–58.

10. O’Brien S, Lamanna N, Kipps TJ, et al. Update of a phase 2 study of idelalisib in combination with rituximab in treatment-naïve patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Program and abstracts of the 56th ASH Annual Meeting and Exposition; December 6–9, 2014; San Francisco, CA. Abstract 1994.

11. Hallek M, Cheson BD, Catovsky D, et al. for the International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446–5456.
 

Moderated by: Jennifer R. Brown, MD, PhD¹

Discussants: Jeffrey A. Jones, MD, MPH²; Jacqueline C. Barrientos, MD³

From the Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA1; Ohio State University, Columbus, OH²; Hofstra North Shore-LIJ School of Medicine, Lake Success, NY

Address for correspondence: Jennifer R. Brown, MD, PhD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215

E-mail: [email protected]

Biographical Sketch

From Dana-Farber Cancer Institute and Harvard Medical School:

Jennifer R. Brown, MD, PhD is the Director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and an Associate Professor of Medicine at Harvard Medical School in Boston, Massachusetts. Dr. Brown completed a BS and MS simultaneously in molecular biophysics and biochemistry (MB&B) at Yale, graduating summa cum laude with distinction in MB&B. She proceeded to Harvard Medical School where she received her MD and PhD in molecular genetics in 1998 and was awarded the James Tolbert Shipley Prize for research accomplishment in the graduating class. She then served as an intern and resident in Internal Medicine at Massachusetts General Hospital followed by fellowship in Hematology and Medical Oncology at the Dana-Farber Cancer Institute. Dr. Brown joined the faculty of DFCI and Harvard Medical School in 2004, where she has an active clinical-translational research program in CLL.

Her particular interests include the development of novel targeted therapeutics for CLL, as well as the genomics of CLL. She has been instrumental in the clinical development of both idelalisib and ibrutinib, leading to their regulatory approvals in CLL.

In the area of genomics she has been instrumental in the description of the somatic mutation profile of CLL, and is now particularly interested in the implementation of genomic technology in the clinic, including for prognosis and targeted therapy. She also has a longstanding research interest and focus on the inherited predisposition to CLL.

To date she has published over 130 papers in the scientific literature, predominantly in CLL. She is an active member of the CLL Research Consortium and serves on the Alliance Leukemia and Leukemia Correlative Science Committees as well as the NIH Cancer Biomarkers Study Section. In 2014 she was the recipient of two awards from Dana-Farber Cancer Institute, the Clinical Innovation Award, as well as the George Canellos Award for Excellence in Clinical Investigation and Patient Care. She enjoys a worldwide reputation as a CLL expert and is in much demand as an international speaker.

From Hofstra North Shore-LIJ School of Medicine:

Jacqueline C. Barrientos, MD, is Attending Physician at the Chronic Lymphocytic Leukemia (CLL) Research & Treatment Program of the Division of Hematology and Medical Oncology, Department of Medicine, in the North Shore – LIJ Cancer Institute in Lake Success, New York. She is also Assistant Professor of Medicine at the Hofstra North Shore-LIJ School of Medicine. Dr. Barrientos works in close collaboration with her mentors, Dr. Kanti R. Rai and Dr. Nicholas Chiorazzi of the Feinstein Institute for Medical Research. 

Dr. Barrientos received her medical degree at the Ponce School of Medicine in Puerto Rico, where she was elected vice-president of Alpha Omega Alpha Honor Medical Society. During her medical studies, she was the recipient of two Research Fellowship Awards from the Howard Hughes Medical Institute. She completed her internship and residency in internal medicine at Yale-New Haven Hospital of the Yale School of Medicine, and her fellowship in Hematology/Oncology at New York Presbyterian Hospital of Weill Cornell Medical College in New York City, where she also served as Chief Fellow. She is board certified in internal medicine, hematology and oncology.

Dr. Barrientos’ research focus is on chronic lymphocytic leukemia and lymphoma. She has extensive experience with the new promising agents targeting the B-cell receptor signaling pathway in B-cell malignancies, serving as Principal Investigator on several phase I-III clinical trials.

Dr. Barrientos actively participates in multi-institutional clinical trials with the Chronic Lymphocytic Leukemia Research Consortium (CRC) and the Alliance for Clinical Trials in Oncology. She is a cadre member of the Leukemia Committee of the Alliance for Clinical Trials in Oncology and in this capacity is co-chair of a study comparing chemoimmunotherapy against a combination of targeted agents. She is a member of the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH).

She has been an invited speaker for ASCO University “CLL Tumor Board”, ASH “State of the Art Symposium”, and “Highlights of ASH in Latin America”.  Dr. Barrientos is the recipient of a 2015 American Society of Hematology-Harold Amos Medical Faculty Development Program (ASH-AMFDP) Fellowship award.

DR. BROWN: I am Jennifer Brown, Director of the Chronic Lymphocytic Leukemia (CLL) Center at Dana-Farber Cancer Institute, and Associate Professor of Medicine at Harvard Medical School. Today, I will be speaking with two of my esteemed CLL colleagues, Drs. Jeffrey Jones and Jacqueline Barrientos, about the new drug approvals in CLL. 

DR. BARRIENTOS: I’m Jacqueline Barrientos, Assistant Professor of Hematology/Oncology at the Hofstra North Shore-LIJ School of Medicine, and Attending Hematologist at the CLL Research and Treatment Program in Long Island, NY. Our center participates in clinical trials and we perform correlative basic research. I’m very happy to participate in this expert roundtable discussion.

DR. JONES: I’m Dr. Jeffrey Jones, Associate Professor of Internal Medicine and Section Chief for CLL in the Division of Hematology at The Ohio State University.

DR. BROWN: Thank you Jeff and Jacquie for joining me today. I think we’re all aware what an exciting time this is in CLL with the approvals last year of the targeted inhibitors ibrutinib and idelalisib as well as the new antibody approval obinutuzumab as well as the additional indication for ofatumumab. Let’s start our discussion with ibrutinib and idelalisib. Jeff, please introduce the approvals that these inhibitors received and get us started.

DR. JONES: February 2014 marked a really important time in CLL medicine with the approval of the first oral kinase inhibitor, ibrutinib, for the treatment of CLL after one prior therapy.^1,2 This ushered in an entirely new era of molecularly-targeted therapy for CLL. Later that year, ibrutinib received approval for deletion 17p CLL, the highest risk genetic subtype of CLL, whether previously untreated or relapsed disease. The drug has rapidly entered the clinic, although I think most of us are still trying to determine how best to incorporate them into our practice.

DR. BROWN: Jacquie, please comment on how you’re using ibrutinib now in your practice.

DR. BARRIENTOS: In CLL patients with the presence of a mutation of TP53 or deletion 17p, we use ibrutinib. We essentially do not use chemotherapy on this particular set of patients. If, for any reason, they are not able to tolerate the drug, then we consider idelalisib, which is not approved separately for this 17p deletion indication. Idelalisib is approved for use in combination with rituximab for the treatment of relapsed or refractory CLL patients. Idelalisib has shown clinical activity in several clinical trials in patients with deletion 17p.

At this moment, we mainly are using ibrutinib or idelalisib for our relapsed or refractory CLL patients.  Clinical trials are underway in the frontline setting and we hope to see the results of the frontline use of ibrutinib in elderly patients soon. As of right now, we don’t use ibrutinib as a frontline therapy unless there is a reason, and usually it’s that they carry the 17p deletion or they are participating in a clinical trial.

DR. JONES: Outside of clinical trials our practice has really been to follow the label indications for ibrutinib. For previously untreated patients, our use has been limited to patients with deletion 17p or TP53 mutated disease, as Jacquie said, since that is the group for which the drug has been approved in the frontline.

DR. BROWN: I would agree. That’s been my practice as well. We should perhaps review the data from the registration trial that led to the ibrutinib approval for relapsed refractory CLL. The initial approval was from the stage IB2 study and was an accelerated approval.¹ The confirmatory registration trial, RESONATE, randomized relapsed refractory CLL patients to ibrutinib versus the anti-CD20 antibody ofatumumab.2 Ibrutinib was found to be significantly better in improving both progression free and overall survival, although there was crossover later. As a result, this has moved into our relapse refractory use very rapidly. Although we still use chemoimmunotherapy for upfront therapy for patients without 17p deletion, for those in relapse we have moved entirely to targeted inhibitors. Would you both agree?

DR. JONES: For sure. I think it is very hard in 2015 to think of the patient for whom chemo-immunotherapy is the better choice than ibrutinib for relapsed disease.I think it is very hard in 2015 to think of the patient for whom chemoimmunotherapy is the better choice than ibrutinib for relapsed disease. The benefit is most marked for the group with higher-risk disease as characterized by genetic risk features, not just deletion 17p, but patients with complex abnormal karyotype or deletions of chromosome 11q. All of these patients particularly benefit from treatment with ibrutinib in the second line vs chemoimmunotherapy, as do patients who had either a suboptimal response to frontline chemoimmunotherapy or a brief duration of first remission. All of us are sometimes asked, “Well, who is the patient with relapsed CLL for whom ibrutinib is the best choice?” Right now, in most clinical situations, my response is, “For which patient is ibrutinib not the best choice in first relapse?”

DR. BROWN: That’s actually a good question. Jacquie, how would you answer that? Are there patients for whom you would not choose ibrutinib in first relapse?

DR. BARRIENTOS: I feel a hesitant to use ibrutinib in some patients with a particular comorbidity or medical history. For example, patients with a previous intracranial bleed or a recent history of bleeding, I would prefer to avoid using ibrutinib because there have been rare cases of spontaneous intracranial bleed or severe bleeding after trauma. The other type of patient where I would be cautious is a patient with uncontrolled atrial fibrillation because there are data that in the minority of patients (up to 10% of patients), atrial fibrillation has been an issue. We have some patients that are so frail that they couldn’t tolerate another episode of uncontrolled atrial fibrillation and as such they would not be ideal candidates for the drug. For that type of patient, I would probably abstain from using ibrutinib and consider the use of another therapy. Finally, I would be careful in patients on antiplatelet and anticoagulation therapy because ibrutinib affects platelet functions increasing the risk of bleeding. The bleeding events seen with ibrutinib are mostly grade 1 or grade 2. If the patients have had a serious bleed or serious gastrointestinal bleed or a recent surgery, then I would preferably use another agent.

DR. BROWN:Yes, so that gets to the toxicities of ibrutinib. The more medically significant ones do include perhaps a 5% to 10% risk of atrial fibrillation as well as bleeding risks, which as Jacquie points out are low and usually low grade, but there are occasional higher-risk bleeds. I personally still try to avoid combining anticoagulation with ibrutinib, as we don’t fully understand the mechanism or the risk factors for the more serious bleeds. Jeff, please comment.

DR. JONES: I think the data from the randomized study are actually the most helpful since, as you say, mild bleeding events (grade 1 or 2) were indeed more common amongst the group of patients who were treated with ibrutinib.² Major bleeding events—which are typically defined as intracranial hemorrhage, bleeding requiring transfusion, or inpatient management—were actually similar between the two arms of the trial. An important caveat in interpreting these data is to know that patients in this trial were excluded if they were anticoagulated with warfarin, if they had an antecedent history of intracranial hemorrhage or recent bleeding, or recent surgery. In line with those exclusions, we will often consider other options. If there is any specific concern for bleeding, such as a patient who has experienced bleeding complications during routine anticoagulation, which is also a patient for whom ibrutinib may not be the best choice. In these clinical situations, it is important to involve the patient in discussing the balance of risks and benefits.

DR. BROWN: Yes. Jacquie, please comment on some of the side effects the patients on ibrutinib have, and how you manage those.

DR. BARRIENTOS: I usually mention to my patients that over the first 2 or 3 months about half of them will have a possible change in their bowel movements. Usually they report some diarrhea or loose stools. Usually these episodes are mild, nothing that requires hospitalization. In any case, if it becomes severe, I definitely make sure that it’s not an infection. We all know that our patients with CLL are prone to infections. The other thing I tell the patients is that in some cases patients may develop a rash on the skin. Many times it may look like a rash, but it’s actually ecchymosis—an effect from the drug on the platelets. Essentially, they are grade 1 and don’t require intervention. I just tell them that eventually they will go away. It can be scary for the patients if they are not expecting these. We have had patients with large areas of hematomas in the arms or in the legs. That is unexpected with a drug that they are taking by mouth. They usually expect that with other drugs like warfarin, but not with ibrutinib, so it is important to mention before they start the drug.

Last but not least, I mention the fact that they may get arthralgias—joint pain—in different areas of their bodies. I would say that I see that in about 20% to 30% of patients. Usually it’s very mild, but on occasion I’ve had patients with arthritis so severe that we’ve had to hold the drug and give them some steroids to help them improve their ability to maneuver their hands or move their joints. I’m sure you have seen some of those same side effects.

DR. BROWN: Yes, definitely. In general, it’s pretty well tolerated but it’s best to warn the patients, then there are no surprises. Let’s turn our attention for a moment back to the highest risk genetic subgroup, the 17p deleted patients—which Jeff had mentioned get particularly strong benefit from ibrutinib. This is certainly true, although it’s also the case that it appears, depending on the data set you look at, that they may relapse earlier than other patients on ibrutinib. In the original phase IB2, the median progression survival for the 17p deleted patients was 28 months. More recent data from Ohio State and MD Anderson suggest that complex karyotype may be a risk factor.3,4 Given these data, how are you two handling the question of allogeneic stem cell transplantation for these patients in this new era?

DR. BARRIENTOS: At our center, if the patient is young and they have access and are fit to tolerate a reduced-intensity allogeneic transplant, we recommend that they be evaluated for a transplant. Unfortunately, if they lose the response to the best drug available for their particular genetic mutation, then we have limited options of salvage therapy. It’s risky to think that they will not relapse at some point, and then what do we do at the time of relapse? We can use other targeted agents that are available, like idelalisib, with the knowledge that they may not always respond to the salvage therapy. Promising clinical activity has been reported for patients with 17p deletion treated with venetoclax in clinical trials. Venetoclax is a new targeted agent in development stages but the drug is only available in clinical trials.Promising clinical activity has been reported for patients with 17p deletion treated with venetoclax in clinical trials. Venetoclax is a new targeted agent in development stages but the drug is only available in clinical trials. One problem is that in order to participate in a clinical trial the patient needs to be able to get to the center to get the drug. Additionally, the patient needs to satisfy certain eligibility criteria for study entry. For these patients that stop responding to ibrutinib, the options of care are very limited at this time. This is the reason why I send all my young patients with a 17p deletion for a transplant evaluation.

At the end of the day it is tough to convince the patients to go for a transplant when they’re feeling in excellent shape. It’s still difficult to make a case to go for a procedure that may have its complications on its own. It is well known that there are some increased mortality risks and infection risks that can arise as a result of a transplant. They may not want to do it because they are feeling so great with their routine. I still sit down and have a long frank talk with the patients, especially if they have complex karyotype and 17p deletion. I am concerned that at some point they’re going to stop responding to ibrutinib.

DR. BROWN: That’s generally my practice as well. What about you, Jeff?

DR. JONES: Until there is greater clarity regarding which of the newer agents can salvage patients progressing after ibrutinib, I think it is still important for younger, transplant eligible patients with deletion 17p disease to undergo evaluation for allograft. It remains potentially curative therapy, and I think the availability of ibrutinib has not really changed the importance of that evaluation.

DR. BROWN: Yes, I would agree. I think that was a good discussion on ibrutinib. Why don’t we turn our attention now to idelalisib, the phosphoinositide 3-kinase (PI3K) inhibitor. How are you using idelalisib in your practices? Is this after ibrutinib in general?

DR. JONES: Published data regarding the sequencing of the new agents are relatively limited since all of the registration trials for idelalisib excluded patients who had received prior therapy with an inhibitor of B-cell receptor signaling, including Bruton’s tyrosine kinase inhibitors like ibrutinib.^5,6 A small number of patients enrolled on the phase IB2 trial of ibrutinib, as well as the subsequent randomized trial, had received prior therapy with idelalisib and responded similarly to patients who had not received prior idelalisib.^1,2 In our practice, the use of idelalisib has pretty much been limited to patients who have either received prior ibrutinib or patients who are not eligible to receive ibrutinib because of some important contraindication, such as an inherited bleeding defect, perceived increased bleeding, or history of difficult to control atrial fibrillation, since that event also seems to be more likely among patients treated with ibrutinib.

DR. BROWN: How about you, Jacquie?

DR. BARRIENTOS: The same type of patient with the addition of patients with kidney disease. The rationale for this is based on the phase III trial for idelalisib and rituximab, the enrollment allowed participation of patients with decreased renal function, that was one of the entry criteria for eligibility to participate in the trial.6 In most of the ibrutinib trials the creatinine clearance needed to be adequate, whereas this was allowed to be lower on the idelalisib trials. For those patients with severe renal impairment, I tend to prefer idelalisib rather than ibrutinib—only because I feel more comfortable and have more experience treating patients with impaired kidney function with idelalisib.

DR. BROWN: I have seen some episodic elevations in creatinine in patients on ibrutinib, but they’re fairly sporadic and it’s a little hard to assess the direct drug relationship. It is true that the patients in the idelalisib studies had a high level of comorbidity deliberately on the initial registration trial and generally did reasonably well with idelalisib. The toxicity profile of idelalisib is pretty characteristic, and is potentially harder to manage than that of ibrutinib. I think it also dictates some of how it’s being used in later line therapy. Does one of you wish to comment on the pattern of the key toxicities?

DR. BARRIENTOS: One key toxicity that is very particular to this drug that may happen overnight and is very striking is transaminitis. It usually happens more with non-Hodgkin lymphoma patients compared to relapsed CLL patients, but transaminitis can still be very severe. Patients can develop transaminitis even after more than a cycle on therapy even if they were tolerating the drug well without other issues. It’s very important to educate physicians and healthcare providers about the need to monitor the liver function tests, at least every 2 weeks for the first 2 months. Transaminitis events can be very prompt, very rapid, and usually asymptomatic. My patients that developed transaminitis never complained and had we not been cautious about it, we may have missed it.

DR. BROWN: Yes, I even check weekly. The recent safety analysis said the overall incidence of grade 3 to 4 transaminitis is about 15% in relapse patients.7 That’s pretty significant.

DR. JONES: I think it’s important to know that the transaminitis, if monitored carefully and managed with drug interruption and/or dose reduction upon reintroduction, need not lead to discontinuation. Discontinuations for transaminitis are actually the minority of patients who experience the side effect.

DR. BROWN: Absolutely. Do you want to comment on some of the other side effects that may more often lead to discontinuation?

DR. JONES: We should mention that there are some preclinical animal data suggesting that the molecular target of idelalisib, the PI3K delta isoform, is an important signaling molecule in regulatory T cells important for self-tolerance. While it has efficacy in treating B-cell disorders, inhibiting PI3K-delta may also be impairing T regulatory cell function. That may be what leads to the more characteristic later side effects of idelalisib, including pneumonitis and colitis. Pneumonitis is relatively rare, but because it can masquerade as other respiratory ailments in an older patient population with comorbid medical illnesses like chronic obstructive pulmonary disease and preexisting immune dysfunction because of CLL or prior therapy, inflammatory pneumonitis can be misdiagnosed. This rare but potentially life-threatening complication of idelalisib treatment requires prompt recognition, discontinuation of the drug, and appears to be most effectively managed with corticosteroids.

The other commonly occurring late toxicity, colitis, is often one that also eludes prompt recognition since many times patients are seen by primary care practitioners between oncology visits, and these doctors may not yet be aware that colitis can occur as a late side effect of idelalisib. Sometimes the colitis is misdiagnosed as gastroenteritis or Clostridium difficile colitis and eludes initial management. Like the pneumonitis, this problem, which may occur in more than a quarter of patients, is really best managed by prompt recognition and, in many cases, interruption of the drug. In some cases, patients have been managed with interruption of the drug and perhaps rechallenge at a lower dose, but in many other cases, colitis has been a treatment-limiting side effect and is a leading cause of drug discontinuation for toxicity.

DR. BROWN: Yes, I would agree. It can occur even at much later times in people who have tolerated the drug for even a couple of years, which is surprising compared to typical drug-related diarrhea.

DR. JONES: Right. With many other drugs, a patient starts taking the drug and expects the treatment-related side effects to become manifest very early. The diarrhea and rash associated with ibrutinib, for instance, are really timed very close to drug initiation, similar to antibiotics and other medications that we commonly prescribe. When side effects occur late in the course of treatment, I think it is just not on anyone’s radar to suspect that they could be related to a drug that they have been receiving for some time. That is an important message to communicate to patients, as well as to doctors who are just beginning to prescribe these new drugs for the first time.

DR. BROWN: Exactly. Why don’t we turn our attention now to the approval of obinutuzumab, and review the registration trial data there and then how you’re using that in practice. Jacquie?

DR. BARRIENTOS: Obinutuzumab is a third generation monoclonal antibody targeting the CD20 receptor on B cells. It was approved in November of 2013 by the US Food and Drug Administration for use in combination with chlorambucil to treat patients with previously untreated CLL.8 The trial enrolled patients with comorbidities as measured by the Cumulative Index Rating Scale, the scale helps define fitness. The patients that participated in the registration trial were patients that due to their comorbidities would not tolerate well a chemoimmunotherapy regimen like fludarabine, cyclophosphamide, and rituximab (FCR), and possibly the combination of bendamustine and rituximab. In patients older than age 65 with multiple comorbidities, chlorambucil monotherapy is widely used worldwide due to concerns of complications from the use of other chemoimmunotherapy regimens like the ones mentioned above. In the United States, we usually see that physicians prefer to use rituximab as a single agent in frail patients with multiple comorbidities.

The combination of obinutuzumab with chlorambucil compared to chlorambucil as a single agent showed that the patients treated with the combination therapy had a higher rate of response, a higher rate of progression free survival, and an improved overall survival. The main issue with obinutuzumab is the fact that the infusion reactions are much greater than what we traditionally see with rituximab. Severe and life-threatening infusion reactions have been reported. The reactions can also be more abrupt, although they typically occur very early in infusion, so they are more predictable. If the patient develops an infusion reaction or can’t tolerate the drug, the infusion needs to be interrupted. If the patient does not experience any further infusion reaction symptoms, the infusion may be restarted at a lower rate. I believe grade 3 to grade 4 events were higher than 10% in the registration trial, with infusion reactions of any grade seen in 50%–70%, so it can be common—usually within the first day. By the third infusion, the rate of reaction decreases significantly. Most of the time after that third infusion, most patients won’t have any more issues with tolerability.

Who are the patients that develop these infusion reactions? It has been noted that the level of interleukin 6 is elevated in patients that develop an infusion reaction. That’s the reason why all patients should be premedicated with potent steroids (methylprednisolone or dexamethasone, not hydrocortisone). In addition, patients need to be premedicated with acetaminophen and an antihistamine. In the future hopefully we will be able to use other agents like tocilizumab to lessen the risk of infusion reactions, this is currently being tested in clinical trials as its use is theoretical at this point based on the observation of the elevated interleukin 6 levels.

There are other important side effects with this combination regimen that were noted in the registration trial. There was a higher rate of neutropenia in the patients receiving obinutuzumab and chlorambucil, although this did not correlate with a higher rate of grade 3 or grade 4 infections. The rate of grade 3 or 4 infections was the same all across the board in patients that received chlorambucil, chlorambucil in combination with rituximab, or chlorambucil in combination with obinutuzumab.

DR. BROWN: Are you using much obinutuzumab chlorambucil in your practice?

DR. BARRIENTOS: In select patients, yes. For untreated patients with comorbidities that are not participating in a clinical trial, we discuss with them data from the frontline bendamustine and rituximab combination and obinutuzumab and chlorambucil combination. For the most part, most patients prefer obinutuzumab with chlorambucil because the obinutuzumab chlorambucil combination might be better tolerated and possibly less myelosuppressive than the bendamustine rituximab combination. Unfortunately, most of my patients have already been treated by the time we see them. We have a minority of patients that come recently diagnosed, we just don’t see that many untreated patients.

DR. BROWN: How about you, Jeff? Are you using it?

DR. JONES: Yes, it is a consideration for frontline therapy in patients who don’t have deletion 17p. As we discussed before, most of us have already adopted ibrutinib as our first choice in that 17p deleted population outside of clinical trial. For the remainder of patients, I think the first question remains whether their age and health are permissive to safely give FCR, since that regimen has been associated with the best survival outcomes, even some really long survival, in a group of patients with IgVH mutated, favorable cytogenetic risk disease.

For patients who are not eligible or willing to receive FCR, I think the choice between bendumustine and rituximab (BR) and chlorambucil and obinutuzumab is a relatively challenging one. Part of the reason is that while the overall response rates and complete response rates are lower with obinutuzumab and chlorambucil, the toxicity is also a bit lower. That makes it an appealing choice, particularly when we have the availability of drugs like ibrutinib and idelalisib in the second line. For older patients with comorbid medical illnesses in particular, it may be that the duration of first remission after chemotherapy may not matter as much when we have more effective second line options.

DR. BROWN: Yes, I think that’s definitely true. I just want to highlight two points. Your point about the long-term efficacy of FCR, particularly in the IgVH mutated patients—it is important to note that we now have data from both MD Anderson and the German CLL Study Group. The MD Anderson data with 10 year follow up, 60% of that genetic subgroup are progression free after FCR suggesting that a subset of them may in fact be cured. We don’t want to forget that with the excitement of the new inhibitors. I would second your point also about the potential toxicities of BR which can be as myelosuppressive as FCR even though it is not in every case. Again, it’s very important to assess the comorbidities of the patient not just for FCR but also for BR, particularly when FCR has this chance of very long-term remission which is not seen with BR.

DR. JONES: Yes, and there’s also a risk for opportunistic infections with both regimens. Like fludarabine-treated patients, there are patients treated with bendumustine who experience pneumocystis pneumonia or viral reactivation from immune suppression beyond just the neutropenia.

DR. BROWN: Yes, absolutely. Let’s talk briefly about where we see CLL therapy going in the next few years given these exciting new drugs. I’ll just leave that open and see what you have to say. Jacquie?

DR. BARRIENTOS: Some of the possible developments that we may see over the next couple of years are the use of these targeted agents or small molecules as initial therapy either as monotherapy or in combination regimens. We are expecting to see the data of the clinical trial of frontline ibrutinib against chlorambucil in patients that are older than age 65. Idelalisib has other ongoing clinical trials in the frontline setting as monotherapy and in combination therapy. Data have been presented of idelalisib in combination with rituximab as frontline therapy. It was interesting to note that some of these side effects that we saw in the relapsed or refractory setting occurred more often in patients in the frontline setting, although efficacy was very high. These promising data may eventually lead to a change in the way that we treat patients in the frontline, not only as monotherapy. There are several clinical trials that incorporate chemoimmunotherapy with these new targeted agents to see if maybe we will obtain deeper remissions or longer duration of response.

DR. JONES: What preliminary data exist in small phase 1 or phase 2 studies suggest that the new agents may be even more effective in previously untreated disease, with higher overall response rates, higher complete response rates, and more durable remissions than observed among patients with relapsed and refractory disease.9,10 These results underscore that the individual agents are among the most effective drugs that have been developed for CLL in terms of their single-agent activity. If you include the oral BCL-2 inhibitor in development, venetoclax, these drugs have really had remarkable single-agent efficacy. If these newer agents are like older cytotoxic chemotherapy agents, like fludarabine, they may become superstars when used in combination. While we will soon see these drugs move into the frontline setting as single agents, I think the real potential for magic is when they get combined. There we may see the kinds of deep remissions that we only achieve now with chemoimmunotherapy, remissions that will allow similar long-term treatment-free survival without cytotoxic chemotherapy. I’d like nothing more than to see a 60% 10 year survival after a nonchemotherapy-containing combination that emerges when we use these new drugs in ways that maximize their benefit in combination.

DR. BROWN: I would certainly agree. I think that although we have remarkable single-agent activity of these drugs, we know that in the context of single-agent activity, resistance is likely to develop over time. For a subset of patients that may not matter. If they’re older and have comorbidities, they may get enough durability of response from their first single agent that it doesn’t matter, particularly the patients with lower risk CLL. For our younger patients, I think the combinations will have the opportunity to minimize the development of resistance and also allow shorter courses of therapy so that patients can be off treatment still with deep remissions. That is what most excites me about the future of these agents.

Let’s just talk about the future of watch and wait. We now have great drugs and great therapies. Are you considering treatment earlier in any of your patients at this point, Jacquie?

DR. BARRIENTOS: I have been very hesitant to start our patients on any drug before they develop symptoms from the disease. I still wait to initiate therapy according to the International Workshop on CLL (IWCLL) guidelines.¹¹ The reason is that anytime that we start a new agent, the patients may develop some mutation that is driven by these new agents. At this point, there are no data for us to start therapy before symptoms develop. The German CLL study group is currently doing a high risk study in patients that are asymptomatic but have a high risk profile like 17p deletion to see if maybe a drug like ibrutinib could have a benefit. I think that will be very interesting once the data come out. There are certain patients with whom you are always wondering, “Am I doing more harm by withholding therapy at this moment?” So far, early intervention with chemotherapy before symptoms has not shown any additional benefit. We still do the watch and wait for the time being, but this may change in the future for certain patients with certain high-risk characteristics.

DR. BROWN: Yes, I share your concerns about the possibility of evolution of the disease in the context of any treatment. Even though we hope that there will be less clonal evolution with these targeted inhibitors, there is some increasing evidence that some adverse clones like TP53 mutated or 17p deleted clones are preexisting in many cases. Then, under the influence of treatment, these mutations become more evident, ie a higher percentage of the disease. Personally, I would like to see overall survival data before we start treating patients earlier.

DR. JONES: I would absolutely agree. I think if you want to undertake the systematic treatment of patients before they actually progress clinically, those are the kind of data that you want. You want to know whether you are impacting the natural history of the disease. I’ll take a slightly contrarian point of view in talking about elderly patients in particular. Some of our colleagues who treat low-grade lymphoma—where watch and wait is often employed in the initial asymptomatic setting—have argued that there is a strong rationale to treat earlier rather than later because you may find that toxicity becomes more prohibitive if you wait until the patients become ill. There’s a somewhat perverse logic underlying our current approach to therapy—we don’t treat to maintain health, we treat when patients become sick. I think there is room for a slightly different approach still operating within current consensus guidelines. There is a group of elderly patients with comorbid medical illnesses that as it seems their disease is starting to progress, I am inclined to consider—at least discuss—the feasibility of treatment then as a way of limiting both the morbidity from the disease, as well as the morbidity of treatment. When the only available treatments were chemotherapy drugs like fludarabine, which has not clearly resulted in survival benefits for elderly patients, that was as feasible as when the treatment is perhaps obinutuzumab and chlorambucil, or maybe in the near future drugs like ibrutinib and idelalisib. Therefore I think we may all want to start rethinking our approach, cautiously. Ultimately, this is a research question.

DR. BROWN: That’s interesting. I certainly agree that in the setting of chemotherapy or chemoimmunotherapy patients with a higher disease burden have a lot harder time getting started on therapy. If in fact the targeted inhibitors move to upfront therapy, it’s not so clear to me that those drugs have more initial toxicity in patients with a greater disease burden—at least for ibrutinib. Do you disagree?

DR. JONES: No, I think that’s true. You will even hear an argument sometimes that a single-agent rituximab for follicular lymphoma or obinutuzumab and chlorambucil would be better tolerated, and you have more room for management of toxicity when you give them to patients who are healthier at baseline. Part of that is with less extensive disease, but you’re right. I agree that there is no indication right now that the novel, targeted agents are more toxic in older patients. However, I will say that our own retrospective analysis from Ohio State suggested that age was one of the factors associated with early discontinuation among our patients.⁴

DR. BROWN: Right, but to me, the fact that age is a predictor of less tolerability of therapy suggests that maybe we should save the therapy until the patient really needs it. The toxicities of ibrutinib are not as clearly disease-burden related necessarily.

DR. JONES: Yeah, I think that our disagreement really suggests that it’s a question to study.

As the treatment becomes more manageable and potentially more effective, you start to question whether our goal is to treat patients as they become ill, or to prevent them from ever becoming ill in the first place.DR. BROWN: Oh, absolutely.

DR. JONES: These are important questions that we will necessarily revisit. As the treatment becomes more manageable and potentially more effective, you start to question whether our goal is to treat patients as they become ill, or to prevent them from ever becoming ill in the first place.

DR. BROWN: Right, absolutely. I would say that I feel that we don’t always let the patients become symptomatically ill even in following IWCLL criteria. For example, their counts may be relatively poor, requiring treatment, but the patients are not yet suffering from that.

DR. JONES: Right.

DR. BROWN: I think this was a great discussion. It’s obviously an extremely exciting time in CLL research as we learn how to use our targeted inhibitors, our new antibodies, and hopefully soon we’ll have another targeted inhibitor with ABT199 the BCL-2 inhibitor. Jacquie or Jeff, do you have any points you would like to add before we wrap up?

DR. BARRIENTOS: No. I think we covered most of the important concepts.

DR. JONES: I will just say that with analogy to a cousin disease, chronic myeloid leukemia, after imatinib and the subsequent oral kinase inhibitors were introduced in that disease people thought that the final chapter of the story had been. I think we’re going to find the same thing in CLL medicine. These phenomenally effective agents, safer than the ones we have had available to employ before, are going to open up a whole new range of investigations that we will continue innovating over the next decade.

DR. BROWN: To summarize, in 2014 we saw four new drug approvals for CLL, including two new antibodies for upfront therapy, obinutuzumab and ofatumumab, and two new targeted inhibitors for relapsed therapy, ibrutinib and idelalisib. These innovations are starting to revolutionize the treatment of CLL for the benefit of our patients. However, many questions remain about how best to use each of these drugs, about toxicity, and about resistance. The next 5 years in CLL research will be a very exciting time as we start to answer these questions. Hopefully, ultimately, we will cure more and more of our patients, maybe eventually all of them.

References

1. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42.

2. Byrd JC, Brown JR, O’Brien S, et al. for the RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213–223.

3. Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125(13):2062–2067.

4. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1(1):80–87.

5. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390–3397.

6. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed in chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997–1007.

7. Coutre S, Leonard J, Flowers C, et al. Idelalisib monotherapy results in durable responses in patients with relapsed or refractory Waldenstrom’s macroglobulinemia (WM). Poster presented at: 20th Congress of European Hematology Association; June 11–14, 2015; Vienna, Austria. Abstract P690.

8. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101–1110.

9. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48–58.

10. O’Brien S, Lamanna N, Kipps TJ, et al. Update of a phase 2 study of idelalisib in combination with rituximab in treatment-naïve patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Program and abstracts of the 56th ASH Annual Meeting and Exposition; December 6–9, 2014; San Francisco, CA. Abstract 1994.

11. Hallek M, Cheson BD, Catovsky D, et al. for the International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446–5456.
 

Moderated by: Jennifer R. Brown, MD, PhD¹

Discussants: Jeffrey A. Jones, MD, MPH²; Jacqueline C. Barrientos, MD³

From the Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA1; Ohio State University, Columbus, OH²; Hofstra North Shore-LIJ School of Medicine, Lake Success, NY

Address for correspondence: Jennifer R. Brown, MD, PhD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215

E-mail: [email protected]

Biographical Sketch

From Dana-Farber Cancer Institute and Harvard Medical School:

Jennifer R. Brown, MD, PhD is the Director of the CLL Center of the Division of Hematologic Malignancies at Dana-Farber Cancer Institute and an Associate Professor of Medicine at Harvard Medical School in Boston, Massachusetts. Dr. Brown completed a BS and MS simultaneously in molecular biophysics and biochemistry (MB&B) at Yale, graduating summa cum laude with distinction in MB&B. She proceeded to Harvard Medical School where she received her MD and PhD in molecular genetics in 1998 and was awarded the James Tolbert Shipley Prize for research accomplishment in the graduating class. She then served as an intern and resident in Internal Medicine at Massachusetts General Hospital followed by fellowship in Hematology and Medical Oncology at the Dana-Farber Cancer Institute. Dr. Brown joined the faculty of DFCI and Harvard Medical School in 2004, where she has an active clinical-translational research program in CLL.

Her particular interests include the development of novel targeted therapeutics for CLL, as well as the genomics of CLL. She has been instrumental in the clinical development of both idelalisib and ibrutinib, leading to their regulatory approvals in CLL.

In the area of genomics she has been instrumental in the description of the somatic mutation profile of CLL, and is now particularly interested in the implementation of genomic technology in the clinic, including for prognosis and targeted therapy. She also has a longstanding research interest and focus on the inherited predisposition to CLL.

To date she has published over 130 papers in the scientific literature, predominantly in CLL. She is an active member of the CLL Research Consortium and serves on the Alliance Leukemia and Leukemia Correlative Science Committees as well as the NIH Cancer Biomarkers Study Section. In 2014 she was the recipient of two awards from Dana-Farber Cancer Institute, the Clinical Innovation Award, as well as the George Canellos Award for Excellence in Clinical Investigation and Patient Care. She enjoys a worldwide reputation as a CLL expert and is in much demand as an international speaker.

From Hofstra North Shore-LIJ School of Medicine:

Jacqueline C. Barrientos, MD, is Attending Physician at the Chronic Lymphocytic Leukemia (CLL) Research & Treatment Program of the Division of Hematology and Medical Oncology, Department of Medicine, in the North Shore – LIJ Cancer Institute in Lake Success, New York. She is also Assistant Professor of Medicine at the Hofstra North Shore-LIJ School of Medicine. Dr. Barrientos works in close collaboration with her mentors, Dr. Kanti R. Rai and Dr. Nicholas Chiorazzi of the Feinstein Institute for Medical Research. 

Dr. Barrientos received her medical degree at the Ponce School of Medicine in Puerto Rico, where she was elected vice-president of Alpha Omega Alpha Honor Medical Society. During her medical studies, she was the recipient of two Research Fellowship Awards from the Howard Hughes Medical Institute. She completed her internship and residency in internal medicine at Yale-New Haven Hospital of the Yale School of Medicine, and her fellowship in Hematology/Oncology at New York Presbyterian Hospital of Weill Cornell Medical College in New York City, where she also served as Chief Fellow. She is board certified in internal medicine, hematology and oncology.

Dr. Barrientos’ research focus is on chronic lymphocytic leukemia and lymphoma. She has extensive experience with the new promising agents targeting the B-cell receptor signaling pathway in B-cell malignancies, serving as Principal Investigator on several phase I-III clinical trials.

Dr. Barrientos actively participates in multi-institutional clinical trials with the Chronic Lymphocytic Leukemia Research Consortium (CRC) and the Alliance for Clinical Trials in Oncology. She is a cadre member of the Leukemia Committee of the Alliance for Clinical Trials in Oncology and in this capacity is co-chair of a study comparing chemoimmunotherapy against a combination of targeted agents. She is a member of the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH).

She has been an invited speaker for ASCO University “CLL Tumor Board”, ASH “State of the Art Symposium”, and “Highlights of ASH in Latin America”.  Dr. Barrientos is the recipient of a 2015 American Society of Hematology-Harold Amos Medical Faculty Development Program (ASH-AMFDP) Fellowship award.

DR. BROWN: I am Jennifer Brown, Director of the Chronic Lymphocytic Leukemia (CLL) Center at Dana-Farber Cancer Institute, and Associate Professor of Medicine at Harvard Medical School. Today, I will be speaking with two of my esteemed CLL colleagues, Drs. Jeffrey Jones and Jacqueline Barrientos, about the new drug approvals in CLL. 

DR. BARRIENTOS: I’m Jacqueline Barrientos, Assistant Professor of Hematology/Oncology at the Hofstra North Shore-LIJ School of Medicine, and Attending Hematologist at the CLL Research and Treatment Program in Long Island, NY. Our center participates in clinical trials and we perform correlative basic research. I’m very happy to participate in this expert roundtable discussion.

DR. JONES: I’m Dr. Jeffrey Jones, Associate Professor of Internal Medicine and Section Chief for CLL in the Division of Hematology at The Ohio State University.

DR. BROWN: Thank you Jeff and Jacquie for joining me today. I think we’re all aware what an exciting time this is in CLL with the approvals last year of the targeted inhibitors ibrutinib and idelalisib as well as the new antibody approval obinutuzumab as well as the additional indication for ofatumumab. Let’s start our discussion with ibrutinib and idelalisib. Jeff, please introduce the approvals that these inhibitors received and get us started.

DR. JONES: February 2014 marked a really important time in CLL medicine with the approval of the first oral kinase inhibitor, ibrutinib, for the treatment of CLL after one prior therapy.^1,2 This ushered in an entirely new era of molecularly-targeted therapy for CLL. Later that year, ibrutinib received approval for deletion 17p CLL, the highest risk genetic subtype of CLL, whether previously untreated or relapsed disease. The drug has rapidly entered the clinic, although I think most of us are still trying to determine how best to incorporate them into our practice.

DR. BROWN: Jacquie, please comment on how you’re using ibrutinib now in your practice.

DR. BARRIENTOS: In CLL patients with the presence of a mutation of TP53 or deletion 17p, we use ibrutinib. We essentially do not use chemotherapy on this particular set of patients. If, for any reason, they are not able to tolerate the drug, then we consider idelalisib, which is not approved separately for this 17p deletion indication. Idelalisib is approved for use in combination with rituximab for the treatment of relapsed or refractory CLL patients. Idelalisib has shown clinical activity in several clinical trials in patients with deletion 17p.

At this moment, we mainly are using ibrutinib or idelalisib for our relapsed or refractory CLL patients.  Clinical trials are underway in the frontline setting and we hope to see the results of the frontline use of ibrutinib in elderly patients soon. As of right now, we don’t use ibrutinib as a frontline therapy unless there is a reason, and usually it’s that they carry the 17p deletion or they are participating in a clinical trial.

DR. JONES: Outside of clinical trials our practice has really been to follow the label indications for ibrutinib. For previously untreated patients, our use has been limited to patients with deletion 17p or TP53 mutated disease, as Jacquie said, since that is the group for which the drug has been approved in the frontline.

DR. BROWN: I would agree. That’s been my practice as well. We should perhaps review the data from the registration trial that led to the ibrutinib approval for relapsed refractory CLL. The initial approval was from the stage IB2 study and was an accelerated approval.¹ The confirmatory registration trial, RESONATE, randomized relapsed refractory CLL patients to ibrutinib versus the anti-CD20 antibody ofatumumab.2 Ibrutinib was found to be significantly better in improving both progression free and overall survival, although there was crossover later. As a result, this has moved into our relapse refractory use very rapidly. Although we still use chemoimmunotherapy for upfront therapy for patients without 17p deletion, for those in relapse we have moved entirely to targeted inhibitors. Would you both agree?

DR. JONES: For sure. I think it is very hard in 2015 to think of the patient for whom chemo-immunotherapy is the better choice than ibrutinib for relapsed disease.I think it is very hard in 2015 to think of the patient for whom chemoimmunotherapy is the better choice than ibrutinib for relapsed disease. The benefit is most marked for the group with higher-risk disease as characterized by genetic risk features, not just deletion 17p, but patients with complex abnormal karyotype or deletions of chromosome 11q. All of these patients particularly benefit from treatment with ibrutinib in the second line vs chemoimmunotherapy, as do patients who had either a suboptimal response to frontline chemoimmunotherapy or a brief duration of first remission. All of us are sometimes asked, “Well, who is the patient with relapsed CLL for whom ibrutinib is the best choice?” Right now, in most clinical situations, my response is, “For which patient is ibrutinib not the best choice in first relapse?”

DR. BROWN: That’s actually a good question. Jacquie, how would you answer that? Are there patients for whom you would not choose ibrutinib in first relapse?

DR. BARRIENTOS: I feel a hesitant to use ibrutinib in some patients with a particular comorbidity or medical history. For example, patients with a previous intracranial bleed or a recent history of bleeding, I would prefer to avoid using ibrutinib because there have been rare cases of spontaneous intracranial bleed or severe bleeding after trauma. The other type of patient where I would be cautious is a patient with uncontrolled atrial fibrillation because there are data that in the minority of patients (up to 10% of patients), atrial fibrillation has been an issue. We have some patients that are so frail that they couldn’t tolerate another episode of uncontrolled atrial fibrillation and as such they would not be ideal candidates for the drug. For that type of patient, I would probably abstain from using ibrutinib and consider the use of another therapy. Finally, I would be careful in patients on antiplatelet and anticoagulation therapy because ibrutinib affects platelet functions increasing the risk of bleeding. The bleeding events seen with ibrutinib are mostly grade 1 or grade 2. If the patients have had a serious bleed or serious gastrointestinal bleed or a recent surgery, then I would preferably use another agent.

DR. BROWN:Yes, so that gets to the toxicities of ibrutinib. The more medically significant ones do include perhaps a 5% to 10% risk of atrial fibrillation as well as bleeding risks, which as Jacquie points out are low and usually low grade, but there are occasional higher-risk bleeds. I personally still try to avoid combining anticoagulation with ibrutinib, as we don’t fully understand the mechanism or the risk factors for the more serious bleeds. Jeff, please comment.

DR. JONES: I think the data from the randomized study are actually the most helpful since, as you say, mild bleeding events (grade 1 or 2) were indeed more common amongst the group of patients who were treated with ibrutinib.² Major bleeding events—which are typically defined as intracranial hemorrhage, bleeding requiring transfusion, or inpatient management—were actually similar between the two arms of the trial. An important caveat in interpreting these data is to know that patients in this trial were excluded if they were anticoagulated with warfarin, if they had an antecedent history of intracranial hemorrhage or recent bleeding, or recent surgery. In line with those exclusions, we will often consider other options. If there is any specific concern for bleeding, such as a patient who has experienced bleeding complications during routine anticoagulation, which is also a patient for whom ibrutinib may not be the best choice. In these clinical situations, it is important to involve the patient in discussing the balance of risks and benefits.

DR. BROWN: Yes. Jacquie, please comment on some of the side effects the patients on ibrutinib have, and how you manage those.

DR. BARRIENTOS: I usually mention to my patients that over the first 2 or 3 months about half of them will have a possible change in their bowel movements. Usually they report some diarrhea or loose stools. Usually these episodes are mild, nothing that requires hospitalization. In any case, if it becomes severe, I definitely make sure that it’s not an infection. We all know that our patients with CLL are prone to infections. The other thing I tell the patients is that in some cases patients may develop a rash on the skin. Many times it may look like a rash, but it’s actually ecchymosis—an effect from the drug on the platelets. Essentially, they are grade 1 and don’t require intervention. I just tell them that eventually they will go away. It can be scary for the patients if they are not expecting these. We have had patients with large areas of hematomas in the arms or in the legs. That is unexpected with a drug that they are taking by mouth. They usually expect that with other drugs like warfarin, but not with ibrutinib, so it is important to mention before they start the drug.

Last but not least, I mention the fact that they may get arthralgias—joint pain—in different areas of their bodies. I would say that I see that in about 20% to 30% of patients. Usually it’s very mild, but on occasion I’ve had patients with arthritis so severe that we’ve had to hold the drug and give them some steroids to help them improve their ability to maneuver their hands or move their joints. I’m sure you have seen some of those same side effects.

DR. BROWN: Yes, definitely. In general, it’s pretty well tolerated but it’s best to warn the patients, then there are no surprises. Let’s turn our attention for a moment back to the highest risk genetic subgroup, the 17p deleted patients—which Jeff had mentioned get particularly strong benefit from ibrutinib. This is certainly true, although it’s also the case that it appears, depending on the data set you look at, that they may relapse earlier than other patients on ibrutinib. In the original phase IB2, the median progression survival for the 17p deleted patients was 28 months. More recent data from Ohio State and MD Anderson suggest that complex karyotype may be a risk factor.3,4 Given these data, how are you two handling the question of allogeneic stem cell transplantation for these patients in this new era?

DR. BARRIENTOS: At our center, if the patient is young and they have access and are fit to tolerate a reduced-intensity allogeneic transplant, we recommend that they be evaluated for a transplant. Unfortunately, if they lose the response to the best drug available for their particular genetic mutation, then we have limited options of salvage therapy. It’s risky to think that they will not relapse at some point, and then what do we do at the time of relapse? We can use other targeted agents that are available, like idelalisib, with the knowledge that they may not always respond to the salvage therapy. Promising clinical activity has been reported for patients with 17p deletion treated with venetoclax in clinical trials. Venetoclax is a new targeted agent in development stages but the drug is only available in clinical trials.Promising clinical activity has been reported for patients with 17p deletion treated with venetoclax in clinical trials. Venetoclax is a new targeted agent in development stages but the drug is only available in clinical trials. One problem is that in order to participate in a clinical trial the patient needs to be able to get to the center to get the drug. Additionally, the patient needs to satisfy certain eligibility criteria for study entry. For these patients that stop responding to ibrutinib, the options of care are very limited at this time. This is the reason why I send all my young patients with a 17p deletion for a transplant evaluation.

At the end of the day it is tough to convince the patients to go for a transplant when they’re feeling in excellent shape. It’s still difficult to make a case to go for a procedure that may have its complications on its own. It is well known that there are some increased mortality risks and infection risks that can arise as a result of a transplant. They may not want to do it because they are feeling so great with their routine. I still sit down and have a long frank talk with the patients, especially if they have complex karyotype and 17p deletion. I am concerned that at some point they’re going to stop responding to ibrutinib.

DR. BROWN: That’s generally my practice as well. What about you, Jeff?

DR. JONES: Until there is greater clarity regarding which of the newer agents can salvage patients progressing after ibrutinib, I think it is still important for younger, transplant eligible patients with deletion 17p disease to undergo evaluation for allograft. It remains potentially curative therapy, and I think the availability of ibrutinib has not really changed the importance of that evaluation.

DR. BROWN: Yes, I would agree. I think that was a good discussion on ibrutinib. Why don’t we turn our attention now to idelalisib, the phosphoinositide 3-kinase (PI3K) inhibitor. How are you using idelalisib in your practices? Is this after ibrutinib in general?

DR. JONES: Published data regarding the sequencing of the new agents are relatively limited since all of the registration trials for idelalisib excluded patients who had received prior therapy with an inhibitor of B-cell receptor signaling, including Bruton’s tyrosine kinase inhibitors like ibrutinib.^5,6 A small number of patients enrolled on the phase IB2 trial of ibrutinib, as well as the subsequent randomized trial, had received prior therapy with idelalisib and responded similarly to patients who had not received prior idelalisib.^1,2 In our practice, the use of idelalisib has pretty much been limited to patients who have either received prior ibrutinib or patients who are not eligible to receive ibrutinib because of some important contraindication, such as an inherited bleeding defect, perceived increased bleeding, or history of difficult to control atrial fibrillation, since that event also seems to be more likely among patients treated with ibrutinib.

DR. BROWN: How about you, Jacquie?

DR. BARRIENTOS: The same type of patient with the addition of patients with kidney disease. The rationale for this is based on the phase III trial for idelalisib and rituximab, the enrollment allowed participation of patients with decreased renal function, that was one of the entry criteria for eligibility to participate in the trial.6 In most of the ibrutinib trials the creatinine clearance needed to be adequate, whereas this was allowed to be lower on the idelalisib trials. For those patients with severe renal impairment, I tend to prefer idelalisib rather than ibrutinib—only because I feel more comfortable and have more experience treating patients with impaired kidney function with idelalisib.

DR. BROWN: I have seen some episodic elevations in creatinine in patients on ibrutinib, but they’re fairly sporadic and it’s a little hard to assess the direct drug relationship. It is true that the patients in the idelalisib studies had a high level of comorbidity deliberately on the initial registration trial and generally did reasonably well with idelalisib. The toxicity profile of idelalisib is pretty characteristic, and is potentially harder to manage than that of ibrutinib. I think it also dictates some of how it’s being used in later line therapy. Does one of you wish to comment on the pattern of the key toxicities?

DR. BARRIENTOS: One key toxicity that is very particular to this drug that may happen overnight and is very striking is transaminitis. It usually happens more with non-Hodgkin lymphoma patients compared to relapsed CLL patients, but transaminitis can still be very severe. Patients can develop transaminitis even after more than a cycle on therapy even if they were tolerating the drug well without other issues. It’s very important to educate physicians and healthcare providers about the need to monitor the liver function tests, at least every 2 weeks for the first 2 months. Transaminitis events can be very prompt, very rapid, and usually asymptomatic. My patients that developed transaminitis never complained and had we not been cautious about it, we may have missed it.

DR. BROWN: Yes, I even check weekly. The recent safety analysis said the overall incidence of grade 3 to 4 transaminitis is about 15% in relapse patients.7 That’s pretty significant.

DR. JONES: I think it’s important to know that the transaminitis, if monitored carefully and managed with drug interruption and/or dose reduction upon reintroduction, need not lead to discontinuation. Discontinuations for transaminitis are actually the minority of patients who experience the side effect.

DR. BROWN: Absolutely. Do you want to comment on some of the other side effects that may more often lead to discontinuation?

DR. JONES: We should mention that there are some preclinical animal data suggesting that the molecular target of idelalisib, the PI3K delta isoform, is an important signaling molecule in regulatory T cells important for self-tolerance. While it has efficacy in treating B-cell disorders, inhibiting PI3K-delta may also be impairing T regulatory cell function. That may be what leads to the more characteristic later side effects of idelalisib, including pneumonitis and colitis. Pneumonitis is relatively rare, but because it can masquerade as other respiratory ailments in an older patient population with comorbid medical illnesses like chronic obstructive pulmonary disease and preexisting immune dysfunction because of CLL or prior therapy, inflammatory pneumonitis can be misdiagnosed. This rare but potentially life-threatening complication of idelalisib treatment requires prompt recognition, discontinuation of the drug, and appears to be most effectively managed with corticosteroids.

The other commonly occurring late toxicity, colitis, is often one that also eludes prompt recognition since many times patients are seen by primary care practitioners between oncology visits, and these doctors may not yet be aware that colitis can occur as a late side effect of idelalisib. Sometimes the colitis is misdiagnosed as gastroenteritis or Clostridium difficile colitis and eludes initial management. Like the pneumonitis, this problem, which may occur in more than a quarter of patients, is really best managed by prompt recognition and, in many cases, interruption of the drug. In some cases, patients have been managed with interruption of the drug and perhaps rechallenge at a lower dose, but in many other cases, colitis has been a treatment-limiting side effect and is a leading cause of drug discontinuation for toxicity.

DR. BROWN: Yes, I would agree. It can occur even at much later times in people who have tolerated the drug for even a couple of years, which is surprising compared to typical drug-related diarrhea.

DR. JONES: Right. With many other drugs, a patient starts taking the drug and expects the treatment-related side effects to become manifest very early. The diarrhea and rash associated with ibrutinib, for instance, are really timed very close to drug initiation, similar to antibiotics and other medications that we commonly prescribe. When side effects occur late in the course of treatment, I think it is just not on anyone’s radar to suspect that they could be related to a drug that they have been receiving for some time. That is an important message to communicate to patients, as well as to doctors who are just beginning to prescribe these new drugs for the first time.

DR. BROWN: Exactly. Why don’t we turn our attention now to the approval of obinutuzumab, and review the registration trial data there and then how you’re using that in practice. Jacquie?

DR. BARRIENTOS: Obinutuzumab is a third generation monoclonal antibody targeting the CD20 receptor on B cells. It was approved in November of 2013 by the US Food and Drug Administration for use in combination with chlorambucil to treat patients with previously untreated CLL.8 The trial enrolled patients with comorbidities as measured by the Cumulative Index Rating Scale, the scale helps define fitness. The patients that participated in the registration trial were patients that due to their comorbidities would not tolerate well a chemoimmunotherapy regimen like fludarabine, cyclophosphamide, and rituximab (FCR), and possibly the combination of bendamustine and rituximab. In patients older than age 65 with multiple comorbidities, chlorambucil monotherapy is widely used worldwide due to concerns of complications from the use of other chemoimmunotherapy regimens like the ones mentioned above. In the United States, we usually see that physicians prefer to use rituximab as a single agent in frail patients with multiple comorbidities.

The combination of obinutuzumab with chlorambucil compared to chlorambucil as a single agent showed that the patients treated with the combination therapy had a higher rate of response, a higher rate of progression free survival, and an improved overall survival. The main issue with obinutuzumab is the fact that the infusion reactions are much greater than what we traditionally see with rituximab. Severe and life-threatening infusion reactions have been reported. The reactions can also be more abrupt, although they typically occur very early in infusion, so they are more predictable. If the patient develops an infusion reaction or can’t tolerate the drug, the infusion needs to be interrupted. If the patient does not experience any further infusion reaction symptoms, the infusion may be restarted at a lower rate. I believe grade 3 to grade 4 events were higher than 10% in the registration trial, with infusion reactions of any grade seen in 50%–70%, so it can be common—usually within the first day. By the third infusion, the rate of reaction decreases significantly. Most of the time after that third infusion, most patients won’t have any more issues with tolerability.

Who are the patients that develop these infusion reactions? It has been noted that the level of interleukin 6 is elevated in patients that develop an infusion reaction. That’s the reason why all patients should be premedicated with potent steroids (methylprednisolone or dexamethasone, not hydrocortisone). In addition, patients need to be premedicated with acetaminophen and an antihistamine. In the future hopefully we will be able to use other agents like tocilizumab to lessen the risk of infusion reactions, this is currently being tested in clinical trials as its use is theoretical at this point based on the observation of the elevated interleukin 6 levels.

There are other important side effects with this combination regimen that were noted in the registration trial. There was a higher rate of neutropenia in the patients receiving obinutuzumab and chlorambucil, although this did not correlate with a higher rate of grade 3 or grade 4 infections. The rate of grade 3 or 4 infections was the same all across the board in patients that received chlorambucil, chlorambucil in combination with rituximab, or chlorambucil in combination with obinutuzumab.

DR. BROWN: Are you using much obinutuzumab chlorambucil in your practice?

DR. BARRIENTOS: In select patients, yes. For untreated patients with comorbidities that are not participating in a clinical trial, we discuss with them data from the frontline bendamustine and rituximab combination and obinutuzumab and chlorambucil combination. For the most part, most patients prefer obinutuzumab with chlorambucil because the obinutuzumab chlorambucil combination might be better tolerated and possibly less myelosuppressive than the bendamustine rituximab combination. Unfortunately, most of my patients have already been treated by the time we see them. We have a minority of patients that come recently diagnosed, we just don’t see that many untreated patients.

DR. BROWN: How about you, Jeff? Are you using it?

DR. JONES: Yes, it is a consideration for frontline therapy in patients who don’t have deletion 17p. As we discussed before, most of us have already adopted ibrutinib as our first choice in that 17p deleted population outside of clinical trial. For the remainder of patients, I think the first question remains whether their age and health are permissive to safely give FCR, since that regimen has been associated with the best survival outcomes, even some really long survival, in a group of patients with IgVH mutated, favorable cytogenetic risk disease.

For patients who are not eligible or willing to receive FCR, I think the choice between bendumustine and rituximab (BR) and chlorambucil and obinutuzumab is a relatively challenging one. Part of the reason is that while the overall response rates and complete response rates are lower with obinutuzumab and chlorambucil, the toxicity is also a bit lower. That makes it an appealing choice, particularly when we have the availability of drugs like ibrutinib and idelalisib in the second line. For older patients with comorbid medical illnesses in particular, it may be that the duration of first remission after chemotherapy may not matter as much when we have more effective second line options.

DR. BROWN: Yes, I think that’s definitely true. I just want to highlight two points. Your point about the long-term efficacy of FCR, particularly in the IgVH mutated patients—it is important to note that we now have data from both MD Anderson and the German CLL Study Group. The MD Anderson data with 10 year follow up, 60% of that genetic subgroup are progression free after FCR suggesting that a subset of them may in fact be cured. We don’t want to forget that with the excitement of the new inhibitors. I would second your point also about the potential toxicities of BR which can be as myelosuppressive as FCR even though it is not in every case. Again, it’s very important to assess the comorbidities of the patient not just for FCR but also for BR, particularly when FCR has this chance of very long-term remission which is not seen with BR.

DR. JONES: Yes, and there’s also a risk for opportunistic infections with both regimens. Like fludarabine-treated patients, there are patients treated with bendumustine who experience pneumocystis pneumonia or viral reactivation from immune suppression beyond just the neutropenia.

DR. BROWN: Yes, absolutely. Let’s talk briefly about where we see CLL therapy going in the next few years given these exciting new drugs. I’ll just leave that open and see what you have to say. Jacquie?

DR. BARRIENTOS: Some of the possible developments that we may see over the next couple of years are the use of these targeted agents or small molecules as initial therapy either as monotherapy or in combination regimens. We are expecting to see the data of the clinical trial of frontline ibrutinib against chlorambucil in patients that are older than age 65. Idelalisib has other ongoing clinical trials in the frontline setting as monotherapy and in combination therapy. Data have been presented of idelalisib in combination with rituximab as frontline therapy. It was interesting to note that some of these side effects that we saw in the relapsed or refractory setting occurred more often in patients in the frontline setting, although efficacy was very high. These promising data may eventually lead to a change in the way that we treat patients in the frontline, not only as monotherapy. There are several clinical trials that incorporate chemoimmunotherapy with these new targeted agents to see if maybe we will obtain deeper remissions or longer duration of response.

DR. JONES: What preliminary data exist in small phase 1 or phase 2 studies suggest that the new agents may be even more effective in previously untreated disease, with higher overall response rates, higher complete response rates, and more durable remissions than observed among patients with relapsed and refractory disease.9,10 These results underscore that the individual agents are among the most effective drugs that have been developed for CLL in terms of their single-agent activity. If you include the oral BCL-2 inhibitor in development, venetoclax, these drugs have really had remarkable single-agent efficacy. If these newer agents are like older cytotoxic chemotherapy agents, like fludarabine, they may become superstars when used in combination. While we will soon see these drugs move into the frontline setting as single agents, I think the real potential for magic is when they get combined. There we may see the kinds of deep remissions that we only achieve now with chemoimmunotherapy, remissions that will allow similar long-term treatment-free survival without cytotoxic chemotherapy. I’d like nothing more than to see a 60% 10 year survival after a nonchemotherapy-containing combination that emerges when we use these new drugs in ways that maximize their benefit in combination.

DR. BROWN: I would certainly agree. I think that although we have remarkable single-agent activity of these drugs, we know that in the context of single-agent activity, resistance is likely to develop over time. For a subset of patients that may not matter. If they’re older and have comorbidities, they may get enough durability of response from their first single agent that it doesn’t matter, particularly the patients with lower risk CLL. For our younger patients, I think the combinations will have the opportunity to minimize the development of resistance and also allow shorter courses of therapy so that patients can be off treatment still with deep remissions. That is what most excites me about the future of these agents.

Let’s just talk about the future of watch and wait. We now have great drugs and great therapies. Are you considering treatment earlier in any of your patients at this point, Jacquie?

DR. BARRIENTOS: I have been very hesitant to start our patients on any drug before they develop symptoms from the disease. I still wait to initiate therapy according to the International Workshop on CLL (IWCLL) guidelines.¹¹ The reason is that anytime that we start a new agent, the patients may develop some mutation that is driven by these new agents. At this point, there are no data for us to start therapy before symptoms develop. The German CLL study group is currently doing a high risk study in patients that are asymptomatic but have a high risk profile like 17p deletion to see if maybe a drug like ibrutinib could have a benefit. I think that will be very interesting once the data come out. There are certain patients with whom you are always wondering, “Am I doing more harm by withholding therapy at this moment?” So far, early intervention with chemotherapy before symptoms has not shown any additional benefit. We still do the watch and wait for the time being, but this may change in the future for certain patients with certain high-risk characteristics.

DR. BROWN: Yes, I share your concerns about the possibility of evolution of the disease in the context of any treatment. Even though we hope that there will be less clonal evolution with these targeted inhibitors, there is some increasing evidence that some adverse clones like TP53 mutated or 17p deleted clones are preexisting in many cases. Then, under the influence of treatment, these mutations become more evident, ie a higher percentage of the disease. Personally, I would like to see overall survival data before we start treating patients earlier.

DR. JONES: I would absolutely agree. I think if you want to undertake the systematic treatment of patients before they actually progress clinically, those are the kind of data that you want. You want to know whether you are impacting the natural history of the disease. I’ll take a slightly contrarian point of view in talking about elderly patients in particular. Some of our colleagues who treat low-grade lymphoma—where watch and wait is often employed in the initial asymptomatic setting—have argued that there is a strong rationale to treat earlier rather than later because you may find that toxicity becomes more prohibitive if you wait until the patients become ill. There’s a somewhat perverse logic underlying our current approach to therapy—we don’t treat to maintain health, we treat when patients become sick. I think there is room for a slightly different approach still operating within current consensus guidelines. There is a group of elderly patients with comorbid medical illnesses that as it seems their disease is starting to progress, I am inclined to consider—at least discuss—the feasibility of treatment then as a way of limiting both the morbidity from the disease, as well as the morbidity of treatment. When the only available treatments were chemotherapy drugs like fludarabine, which has not clearly resulted in survival benefits for elderly patients, that was as feasible as when the treatment is perhaps obinutuzumab and chlorambucil, or maybe in the near future drugs like ibrutinib and idelalisib. Therefore I think we may all want to start rethinking our approach, cautiously. Ultimately, this is a research question.

DR. BROWN: That’s interesting. I certainly agree that in the setting of chemotherapy or chemoimmunotherapy patients with a higher disease burden have a lot harder time getting started on therapy. If in fact the targeted inhibitors move to upfront therapy, it’s not so clear to me that those drugs have more initial toxicity in patients with a greater disease burden—at least for ibrutinib. Do you disagree?

DR. JONES: No, I think that’s true. You will even hear an argument sometimes that a single-agent rituximab for follicular lymphoma or obinutuzumab and chlorambucil would be better tolerated, and you have more room for management of toxicity when you give them to patients who are healthier at baseline. Part of that is with less extensive disease, but you’re right. I agree that there is no indication right now that the novel, targeted agents are more toxic in older patients. However, I will say that our own retrospective analysis from Ohio State suggested that age was one of the factors associated with early discontinuation among our patients.⁴

DR. BROWN: Right, but to me, the fact that age is a predictor of less tolerability of therapy suggests that maybe we should save the therapy until the patient really needs it. The toxicities of ibrutinib are not as clearly disease-burden related necessarily.

DR. JONES: Yeah, I think that our disagreement really suggests that it’s a question to study.

As the treatment becomes more manageable and potentially more effective, you start to question whether our goal is to treat patients as they become ill, or to prevent them from ever becoming ill in the first place.DR. BROWN: Oh, absolutely.

DR. JONES: These are important questions that we will necessarily revisit. As the treatment becomes more manageable and potentially more effective, you start to question whether our goal is to treat patients as they become ill, or to prevent them from ever becoming ill in the first place.

DR. BROWN: Right, absolutely. I would say that I feel that we don’t always let the patients become symptomatically ill even in following IWCLL criteria. For example, their counts may be relatively poor, requiring treatment, but the patients are not yet suffering from that.

DR. JONES: Right.

DR. BROWN: I think this was a great discussion. It’s obviously an extremely exciting time in CLL research as we learn how to use our targeted inhibitors, our new antibodies, and hopefully soon we’ll have another targeted inhibitor with ABT199 the BCL-2 inhibitor. Jacquie or Jeff, do you have any points you would like to add before we wrap up?

DR. BARRIENTOS: No. I think we covered most of the important concepts.

DR. JONES: I will just say that with analogy to a cousin disease, chronic myeloid leukemia, after imatinib and the subsequent oral kinase inhibitors were introduced in that disease people thought that the final chapter of the story had been. I think we’re going to find the same thing in CLL medicine. These phenomenally effective agents, safer than the ones we have had available to employ before, are going to open up a whole new range of investigations that we will continue innovating over the next decade.

DR. BROWN: To summarize, in 2014 we saw four new drug approvals for CLL, including two new antibodies for upfront therapy, obinutuzumab and ofatumumab, and two new targeted inhibitors for relapsed therapy, ibrutinib and idelalisib. These innovations are starting to revolutionize the treatment of CLL for the benefit of our patients. However, many questions remain about how best to use each of these drugs, about toxicity, and about resistance. The next 5 years in CLL research will be a very exciting time as we start to answer these questions. Hopefully, ultimately, we will cure more and more of our patients, maybe eventually all of them.

References

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