When we focus on the treatment of fit and younger patients with CLL [chronic lymphocytic leukemia] in the frontline setting, there is the ECOG 1912 study, which was particularly designed for young and fit patients with CLL. It excluded patients in the age group of 70 years and older. Here, we have an unusual population of patients who can withstand intense therapy, and for that reason, the standard arm in that trial was the most intense and most efficacious chemoimmunotherapy regimen that we have available: namely the FCR regimen, fludarabine, cyclophosphamide, and rituximab. This had been the standard for younger patients with CLL for a long time because it shows good efficacy, but there is also a considerable toxicity profile.

The remarkable thing about the ECOG 1912 trial is that the randomized comparison between [fludarabine, cyclophosphamide, rituximab] and ibrutinib plus rituximab, the IR regimen, showed with regard to the primary end point of progression-free survival [PFS], a significant superiority of ibrutinib-based therapy compared to [fludarabine, cyclophosphamide, rituximab]. Not only was the primary end point of PFS different, but remarkably, the trial also showed an overall survival difference with superiority of ibrutinib plus rituximab compared to [fludarabine, cyclophosphamide, rituximab]. This is surprising since overall survival differences in CLL trials are hard to find.

In addition to this superiority in efficacy, ibrutinib-based therapy was also better tolerated. In particular, hematologic toxicity, neutropenia, and infections were much more pronounced in the [fludarabine, cyclophosphamide, rituximab] treatment arm. Therefore, the ECOG 1912 study establishes ibrutinib plus rituximab as the preferred treatment option for the vast majority of young and fit patients with CLL in need of frontline treatment.

When searching for improved outcomes for our patients with CLL and leading to results that prolong their lives, the novel trial data using the nonchemotherapeutic agents, the targeted therapies focusing on BTK [Bruton tyrosine kinase], PI3K, and BCL2 are important. The novel agents such as ibrutinib, acalabrutinib, or venetoclax have shown in several randomized comparisons that they are superior with regard to efficacy as measured by progression-free survival, but they are also more well-tolerated compared to the classical chemoimmunotherapy standards that we had available in the past.

For our patients with CLL, these novel treatment options, either when used alone or in the experimental setting in novel combinations, provide tremendous benefits and prolong treatment-free intervals, progression-free survival, and in some instances even overall survival for our patients.

In the iLLUMINATE study, ibrutinib has been combined with obinutuzumab, a novel anti-CD20 antibody, and compared to chlorambucil plus obinutuzumab in the setting of elderly patients with comorbidities. The combination of ibrutinib plus obinutuzumab is proven to be superior in terms of progression-free survival compared to chlorambucil plus obinutuzumab, and this was regardless of any of the genetic features of the patient.

Unfortunately, in this study we are missing ibrutinib monotherapy, and the impression, though we cannot compare different studies, is that the benefit in terms of PFS is not much different. It is not much improved compared to ibrutinib alone. We know that ibrutinib in combination with rituximab is not improving PFS in patients compared with ibrutinib, and we know this from the Alliance study in which ibrutinib plus or minus rituximab was compared to bendamustine plus rituximab in the setting of the elderly, fit patient. There we did not see any difference; and also the iLLUMINATE study, the results are not as dramatic as from the previous study, so that is casting doubts on the need and benefit of adding a monoclonal antibody, including obinutuzumab, to ibrutinib.  

The advantage of the combination of ibrutinib with obinutuzumab is that the patient with obinutuzumab can achieve a complete remission much more frequently, and in particular, much more frequently, undetectable minimal residual disease, in the order of 20% of the patients, which is quite a remarkable number, thinking that with ibrutinib most, if not all, of the patients achieve only partial responses. 

I do not think that the addition of monoclonal antibodies, particularly obinutuzumab but also rituximab, can change the attitude of the physician in hematology when treating patients with chronic lymphocytic leukemia. Though the combination is available and accessible in some countries and to some of my colleagues, I hear that the use is particularly for young patients for whom the physician wants to achieve deeper responses to make the patient feel healthier with a much more controlled disease, in particular having a longer life expectancy. Besides that, I do not think at the moment that our evidence is that the addition of monoclonal antibodies to BTK inhibitors is changing the long-term perspective of our patients.

Videos

Experts Dr Stilgenbauer and Dr Ghia highlight and comment on the ECOG 1912 and iLLUMINATE trials.

A Look at the ECOG 1912 and iLLUMINATE Trials

 In the treatment-naïve setting, we have the ELEVATE-TN trial. This was a randomized trial comparing in the standard arm chlorambucil plus obinutuzumab vs 2 experimental arms, namely acalabrutinib monotherapy, and acalabrutinib combined with obinutuzumab. It was a 3-arm randomized trial, designed for patients who are elderly or who have comorbidities and are therefore not amenable to intensive chemoimmunotherapy treatments. It was a frontline trial in a 3-arm randomized design.

The outcome of the trial showed that both acalabrutinib arms were dramatically superior with regard to progression-free survival compared to the chlorambucil-based treatment. Although the trial was not powered to detect the difference, the addition of obinutuzumab to acalabrutinib led to a numerical improvement in progression-free survival, even. On the other hand, the addition of obinutuzumab also increased some of the [adverse] effects, particularly neutropenia, for instance, but there were also some infections in that trial. 

Overall, the outcome of that trial is that, compared to classical chemotherapy with chlorambucil-based treatment, acalabrutinib-based treatment leads to increased efficacy with regard to progression-free survival. It had good overall survival data as well, and it was proven to be a well-tolerated treatment. With regard to longer-term treatment tolerability, we have an update of the initial single-arm experience with acalabrutinib in treatment-naïve patients. There, we have outcome data now available with an almost 4-year follow-up time, and this not only showed that the efficacy is durable, but with regard to longer-term follow-up, the tolerability of treatment is good as well.

In the relapsed/refractory setting of CLL [chronic lymphocytic leukemia] treatment focusing on acalabrutinib, we have the ASCEND trial. This was an interesting trial because it compared salvage treatment of patients with relapsed/refractory CLL with acalabrutinib against an investigator’s choice arm in a randomized fashion. Investigator’s choice was of 2 different treatment options: namely either bendamustine plus rituximab, or idelalisib plus rituximab. For the vast majority of patients, about three-fourths of all patients, in that arm, the treatment chosen was idelalisib plus rituximab. For the first time, we have a head-to-head comparison of 2 novel nonchemotherapeutic treatment options. On the one hand was acalabrutinib and on the other hand was idelalisib plus rituximab.

The primary end point of the trial was progression-free survival, and there was statistically significant and clinically meaningful superiority of acalabrutinib compared to the investigator’s choice arm. This is important because as I said, this was the first head-to-head of 2 novel nonchemotherapeutic treatment approaches, and it proved that BTK [Bruton tyrosine kinase]-targeting with acalabrutinib was superior to PI3K-targeting with idelalisib with regard to efficacy, but also with regard to tolerability of treatment, which is obviously important for our patients in the relapsed/refractory setting.

For the key [adverse] effects of acalabrutinib, the most common is headache, which is generally time-limited. It almost always goes away within a month or two. In most patients, it goes away within a week or two. It is often responsive to caffeine, so it is important to counsel the patient ahead of time for that. We always see infections in our patients with CLL, so that is definitely an [adverse] effect. There is some diarrhea as well with acalabrutinib, less than with ibrutinib.

There is a lot of interest in cardiac [adverse] effects in the ELEVATE-TN study because we know with ibrutinib that we see significant rates of atrial fibrillation, up to 15% to 20%, at a several-year follow-up. Hypertension seems to occur in more than three-fourths of the patients over a several year follow-up. So far, there is no definite signal with the acalabrutinib arms in the ELEVATE-TN study in that regard. There is about a 4% rate of atrial fibrillation in each of the acalabrutinib arms, which is higher than the obinutuzumab-chlorambucil arm, but it is also representing 4 to 5 times as long duration of follow-up.

We are awaiting the head-to-head trial comparing acalabrutinib to ibrutinib, which will hopefully come out sometime in 2021 to clarify the relative cardiac risk. There are some data at ASH [the American Society of Hematology annual meeting] 2020 looking at a network meta-analysis as well as a single institution study from The Ohio State University, both of which showed substantially lower rates of atrial fibrillation or hypertension with acalabrutinib compared to ibrutinib.

The cardiac management with acalabrutinib is not as big an issue, but with all these BTK inhibitors, we have learned that we need to pay close attention to blood pressure in the clinic in our patients on these drugs and manage that aggressively, which was not something we used to do. With atrial fibrillation, you have to keep an eye out for it, but we generally monitor it clinically. If patients are not symptomatic, then you can do rate control and consider anticoagulation. I have gotten a lot more comfortable with anticoagulation in my patients on a BTK inhibitor if we use an oral anticoagulant, such as apixaban, which I typically use. I will sometimes use the lower dose, especially in an older patient even if they do not quite meet the usual criteria for the lower dose. I have had pretty good luck with that. It is also important to stop any antiplatelet agent if you need to add an anticoagulant in a patient already on a BTK inhibitor.

It is also very important with BTK inhibitors to hold them prior to any surgery. Generally, with acalabrutinib, I will do 3 to 5 days, and with ibrutinib, it is 3 to 7 days, based on whether it is a minor or major procedure. That is on either side of the procedure because most of the bleeding that we see with these drugs is periprocedural. Those are a lot of the key points for caring for patients on BTK inhibitors. 

Dr Stilgenbauer explains the ELEVATE-TN and ASCEND clinical trials; Dr Brown highlights the adverse effects seen with acalabrutinib.

A Look at the ELEVATE-TN and ASCEND Trials

Recently, we have a second-generation BTK [Bruton tyrosine kinase] inhibitor now approved and available in Europe. The second generation BTK inhibitors have been developed to decrease the adverse events that occur with the first-generation inhibitors, which is mainly ibrutinib. We know that continuous treatment with BTK inhibitors, ibrutinib in particular, is characterized by a number of so-called adverse events of clinical interest, including cardiovascular toxicity, atrial fibrillation, and hypertension. In the long term, they might also have arthralgia, myalgia, and an increased risk of bleeding. 

With more specific BTK inhibitors [BTKIs], we might decrease the number off-target effects and therefore adverse events as well. We now have a second-generation BTKI approved in Europe, acalabrutinib with or without obinutuzumab in the first-line setting or acalabrutinib monotherapy in the relapsed/refractory setting. The approval in the first-line setting is based on the elevated treatment-naïve patients and a combination of acalabrutinib alone or a combination with obinutuzumab being compared with relapsed/refractory disease in the older, comorbid patient, and it showed the benefit in terms of progression-free survival [PFS]. It is not clear, though: There are 2 arms in monotherapy vs the combination with obinutuzumab. It is not clear at this moment if there is any benefit of the addition of obinutuzumab to acalabrutinib because PFS is high in the range of 90% after 2 years of follow-up.

If you look at the previous experience with ibrutinib plus rituximab, for example, or obinutuzumab, it does not look like the addition of an antibody to BTK inhibitors changes the long-term benefit in terms of progression-free survival.

What is true is that the addition of obinutuzumab to acalabrutinib is increasing the number of complete responses, which is still always very few in the context of BTKI as monotherapy. Second of all, we can even achieve undetectable minimal residual disease [MRD] status with the addition of obinutuzumab. This might open the path in the future to stop treatment in patients based on the achievement of undetectable MRD. This is in the future, of course.

The presence and access to second-generation BTK inhibitors, of course, increases the range of alternatives for the treatment of patients with chronic lymphocytic leukemia [CLL]. If the benefit in terms of safety as shown in the ELEVATE-TN study are also confirmed in the real-world setting, then acalabrutinib could be a good option to rescue the patient who has to discontinue ibrutinib because of an adverse event or to start from scratch, particularly in patients with cardiovascular comorbidities or an increase in the risk of bleeding.

The next-generation BTK inhibitor, acalabrutinib, was approved for the treatment of frontline CLL with or without the addition of the anti-CD20 antibody obinutuzumab based on the ELEVATE-TN study. In this study, the primary end point was comparing acalabrutinib-obinutuzumab to obinutuzumab-chlorambucil. Both the single-agent acalabrutinib and the acalabrutinib and obinutuzumab were significantly better than the obinutuzumab-chlorambucil. They had 2-year progression-free survivals of 93% with the obinutuzumab vs 87% with single-agent acalabrutinib. That is a 6% difference with the addition of the obinutuzumab. The study was not powered to evaluate that difference, nor was it a planned comparison, unfortunately. 

It looks intriguing, and the shape of the curves looks interesting. We are going to want to see longer-term follow-up to understand that. It is an interesting observation. In my practice [at the Dana-Farber Cancer Institute], I tend to add obinutuzumab only for patients who are high-risk and have large-volume disease who I want a rapid response in.

Interestingly, in the study, the patients who benefited from the obinutuzumab were the lower-risk patients with IGHV mutations, which is a somewhat consistent finding that we have seen with targeted agents in patients with mutations: A single-agent drug does not have a PFS benefit over the chemoimmunotherapy, but adding an antibody getting a deeper remission does. This is probably consistent with the biology of mutated IGVH patients, and if we can get a deep remission, it is often sustained well over time.

Acalabrutinib is a second-generation BTK inhibitor. It was recently approved by the EMA [European Medicines Agency], and it was previously approved by the FDA for the treatment of patients with CLL in either the treatment-naïve or in the relapsed/refractory setting. Acalabrutinib is a second-generation BTK inhibitor. It is targeting BTK more specifically than ibrutinib did. At least theoretically, this may lead to better tolerability because off-target treatment effects are redacted with acalabrutinib compared with ibrutinib. 

Acalabrutinib is licensed as a single agent for the treatment of CLL or combined with CD20-antibody obinutuzumab. Both treatments provide good efficacy and good tolerability: at least in cross-trial comparisons, it looks like some of the ibrutinib adverse effects are reduced with acalabrutinib treatment. To prove this point, we obviously need head-to-head comparisons of ibrutinib-based therapy vs acalabrutinib-based therapies. Nevertheless, we already know that acalabrutinib was providing an important new treatment option for our patients with CLL.

Experts provide insight on the use of acalabrutinib in treating chronic lymphocytic leukemia.

Acalabrutinib in the Treatment of Chronic Lymphocytic Leukemia

The history of trials of BTK [Bruton tyrosine kinase] inhibitors in the frontline setting started with a 30-patient cohort that was added onto the phase 1B/2 study, which now has 8-year follow-up. The progression-free survival in those 30 patients is over 80%, which is quite remarkable, although those patients were also pretty low-risk.

The other message that I note from that study is that only half of them are still on ibrutinib. They fell off for various toxicities even though their disease has not progressed. That raises the possibility about how long patients can stay on ibrutinib: 5 years may be about the median, but they can still have a sustained remission even after discontinuation.

That was followed up reasonably well by the RESONATE-2 confirmatory frontline registration trial, which compared ibrutinib with single-agent chlorambucil. In 5-year follow-up, the progression-free survival for the ibrutinib arm is 70%. Again, 41% of patients have discontinued, but many are still in remission. It is perhaps similar in a way to what we saw in the earlier PCYC-1102 phase 1 study.

The Alliance trial has shorter follow-up, but this was the first randomized trial that compared a standard chemoimmunotherapy. This was in an older-patient population, over 65 years of age, and it compared ibrutinib with ibrutinib-rituximab with bendamustine-rituximab. It showed an improved progression-free survival for either of the ibrutinib arms compared with bendamustine-rituximab. At 2 years, that progression-free survival is about 88% in the ibrutinib arms. 

Interestingly, the benefit was almost entirely in the patients without IGHV mutation. There was not a significant difference in the patients with IGHV mutations. That has a 2- to 3-year follow-up. There was also no difference in overall survival in the entire study. Another point from that study is that there was no benefit to adding rituximab for ibrutinib. Most of us just use single-agent ibrutinib in the frontline setting.

Ibrutinib has revolutionized CLL [chronic lymphocytic leukemia] treatments. It has been a first-in-class drug targeting BTK, a critical survival molecule in the CLL cells. Targeting this biology led to good tolerability and high efficacy of the treatment. Nevertheless, compared with classical chemotherapy, we have to adjust our modalities to some new adverse effects that we have not known before. A specific feature of ibrutinib treatment, for instance, is early onset, usually relatively mild diarrhea that goes away with longer treatments. 

There are other adverse effects, cardiovascular disease in particular, such as arrhythmias and atrial fibrillation that require particular management. Over time, patients may suffer from arthralgia, and they may suffer from an increased rate of hypertension. All these adverse effects accumulate over time because ibrutinib is obviously a treatment of indefinite treatment duration; it is not a fixed duration of treatment. Management of the adverse effects of ibrutinib treatment is important because it is critical for treatment adherence and long-term treatment with ibrutinib. Staying on that treatment in the longer run is critical for a good outcomes for the patient.

Dr Brown provides a brief overview of data available that support the use of Bruton’s tyrosine kinase inhibitors in treating chronic lymphocytic leukemia; Dr Stilgenbauer comments on mitigating and managing adverse effects in the treatment of chronic lymphocytic leukemia.

Clinical Trials With BTK Inhibitors in Chronic Lymphocytic Leukemia

 Nowadays, we have a number of options, particularly novel therapies, that we can use in the treatment of patients with chronic lymphocytic leukemia [CLL], particularly in the first-line setting, where the landscape is becoming quite crowded. After all, we have to apply a number of criteria to get to the best decision in terms of therapy for each individual patient. What I usually do is to first consider the genetic features of the patient’s leukemia that I am going to treat, particularly the immunoglobin gene status and the 

Based on those who have operation of the 

genes and unmutated immunoglobin genes, I tend to avoid immunochemotherapy and prefer novel therapies, particularly for the few patients with TP53 aberrations who should not be treated with immunochemotherapy.

When I have decided this, I am then left with a small portion of patients with mutated immunoglobin genes devoid of any other poor prognosis or high-risk feature like 

gene. With those patients, I can theoretically propose immunochemotherapy only in young, fit patients for whom we know that FCR [fludarabine, cyclophosphamide, rituximab] is able to induce longer remission and response, which may last even more than 10 years. 

I always discuss openly with the patient in this setting. I have to say that, on the side of immunochemotherapy, there is the pro of being a fixed duration compared with the BTK [Bruton tyrosine kinase] inhibitors, like ibrutinib or more recently acalabrutinib, which are to be taken continuously. Nowadays, we also have the approval of the combination of ibrutinib plus rituximab, which can be administered for only 12 months, so it is another fixed duration. It is a bit longer than FCR for 6 cycles, but it is still a fixed-duration treatment.

We know from the initial data of the CLL for teams started by the German CLL study group that ibrutinib plus rituximab seems to be able to achieve a plateau in terms of response in the patient with mutations. The follow-up is still short: We have only 3½ years, so we have to wait for a longer follow-up, but this could definitely be a good option for a patient with mutated immunoglobin genes who could achieve a long-term remission without being exposed to immunochemotherapy. We will see with future follow-up.

On the other side, we have all the other patients with unmutated immunoglobin genes or 

aberrations, where we indeed prefer to give novel therapies. Here, we have to consider a number of things. The first thing is that, for the patients with 

aberrations, we know that the continuous treatment with acalabrutinib with BTK inhibitors is able to achieve responses in 61% of the patients even after 6 years of follow-up.

This has been recently published by in the 

: an update of the study in the first-line setting where a patient with 

aberrations had been treated with acalabrutinib continuous therapy. When we look at a fixed-duration treatment like venetoclax plus obinutuzumab, we see that, although the patient had a benefit compared with the comparator arm of chlorambucil plus obinutuzumab in the CLL14 study, they still progress much earlier than patients without 

aberration when treated with venetoclax plus obinutuzumab.

At the moment, the safest and most beneficial treatment for this particular patient with 

aberration remains a continuous BTK inhibitor, not because the BCF2 inhibitors are not effective. We also know that continuous therapy with BCF2 inhibitors and venetoclax is effective in this population, but the fixed duration is probably not the best option that we can propose to these patients in whom the clone needs to be kept under control in a continuous manner. 

We then move to the patient without mutations, and my consideration is this: I try to avoid immunochemotherapy as much as I can for all patient regardless of the age because there is no treatment that can achieve a plateau in terms of response. It is a durable response every time. At this point, we can think about a continuous treatment with BTK inhibitors or a fixed duration with venetoclax plus obinutuzumab. These patients definitely have a benefit from a fixed duration of venetoclax plus obinutuzumab when compared with chlorambucil plus obinutuzumab in a setting with older adults, but they progress a bit earlier than those with mutated immunoglobin genes. 

Since it is a fixed duration, we can envision that, when this patient relapses and then needs the next treatment, we might even treat them again with the same treatment based on venetoclax, somehow sparing another line of therapy. Unfortunately, this still has to be demonstrated, so we do not know if it is possible or if we can prolong the total progression-free survival of the patient by treating them with the same therapy. At this moment, I would say that, for patients without mutations, we know that we can have a long-term response with continuous treatment with BTK inhibitors with acalabrutinib. We know that we have 70% of our patients who are free of relapse after 5 years of treatment. At the moment, continuous treatment might be the best option to propose to the patient with high-risk features, definitely for patients with TP53 aberrations and potentially for patients with unmutated immunoglobin genes as well.

Dr Ghia provides an in-depth conversation on the use of Bruton tyrosine kinase inhibitors in treating chronic lymphocytic leukemia.

BTK Inhibitors in Treatment of Chronic Lymphocytic Leukemia

When it comes to the choice of a frontline treatment in CLL [chronic lymphocytic leukemia], several factors become of importance. On the 1 side, there are patient characteristics such age, comorbidities, and comedications. Here, there is also a role for decision-making together with the patient. For instance, with some of the new treatment options such as BTK [Bruton tyrosine kinase] inhibitors, I have long, indefinite treatment duration for our patients. Other new treatment options, such as BCL2 inhibitors, require dedicated tumor lysis syndrome monitoring and prophylaxis, sometimes in hospital stays when treatment is initiated.

Patient preference is of particular importance when it comes to questions such as, “Do I want finite treatment duration?” or “Do I want to add a gentle treatment that does not require extensive monitoring?” From a disease characteristic standpoint, we have high-risk disease features such as unmutated immunoglobulin mutation status or 

 mutation, which are the prime characteristics defining high-risk disease. Therefore, these are patient populations that would benefit very much from the novel treatment options.

The choice of frontline therapy for patients with CLL has gotten even more complicated than it was before. It is important to do certain key prognostic markers prior to trying to decide on therapy. These include a FISH [fluorescence in situ hybridization] test for 17p deletion, a somatic mutation profile for 

 mutation, which we treat similarly to 17p deletion, and 

 mutation status. Those are the key determinants that dictate therapeutic choices from the CLL biology standpoint.

Factors that also play into this are the fitness of the patient and their age. The younger and more fit they are, the more I tend to favor time-limited therapy where possible. As patients get older, I often find that they want an easier option that involves fewer visits to the clinic. In that case, it is sometimes the single-agent continuous BTK inhibitor. That is a patient-choice phenomenon. Key comorbidities that are more important than overall functional status with the targeted agents include cardiac problems, like low ejection fraction or history of arrhythmia, which would be more difficult to manage in a patient receiving ibrutinib, for example.

The next-generation covalent BTK inhibitors may improve on that. We have some new data emerging at ASH [American Society of Hematology Annual Meeting] 2020 that suggests a lower risk of cardiac complications with acalabrutinib, and we are awaiting a head-to-head trial of acalabrutinib vs ibrutinib. At the moment, cardiac issues remain something I worry about in patients in whom we would consider ibrutinib as well as anticoagulation. For venetoclax-based regimens, renal function is a critical parameter because the ability of the patients to clear the dying tumor cell helps us mange tumor lysis.

Generally, I sit down and have a discussion with the patient about time-limited therapy, which for young, fit patients could include FCR [fludarabine, cyclophosphamide, rituximab]. For older patients, it is venetoclax and obinutuzumab. FCR [fludarabine, cyclophosphamide, rituximab] is mostly for patients with 

 mutations. For unfit patients, time-limited treatment would be venetoclax and obinutuzumab vs the continuous BTK inhibitor therapy, and the pluses and minuses and what we know about the data.

With an approximately 3-year follow-up, the progression-free survival looks quite similar with continuous BTK inhibitor vs venetoclax and obinutuzumab, for example. We are still awaiting long-term follow-up and a head-to-head trial to help guide these sessions more effectively.

The experts comment on first-line treatment options in patients with chronic lymphocytic leukemia.

Frontline Treatment Options in Chronic Lymphocytic Leukemia

The work-up of a patient with newly diagnosed CLL [chronic lymphocytic leukemia] includes confirming the diagnosis with flow cytometry according to iwCLL [International Workshop on Chronic Lymphocytic Leukemia] guidelines and then assessing their disease status. Patients who have early stage disease and are asymptomatic remain patients who we should observe. None of the new drugs or new trial results suggests that we should change our approach of watching and waiting for patients without active disease. In fact, many patients can go many years without needing therapy.

The criteria for treatment also remain the same. Most commonly, they include cytopenias or large faulty lymphadenopathy that is symptomatic. There are a variety of other indications as well, which includes autoimmune cytopenias that are hard to control.

 In October 2020, the ESMO [European Society for Medical Oncology] guidance was updated, and this was expected because we had a lot of advancements and additions to the treatment in chronic lymphocytic leukemia. Indeed, the whole algorithms as shown in the ESMO Guidelines have completely changed. Now, the first criteria on which we are to base the certification of our patient is entirely genetic testing. On 1 side is the 

 mutations or division, so that is a FISH [fluorescence in situ hybridization] test for the deletions of the initial 17p and sequencing for the detection of 

 mutation. On the other side, there is also genetic certification based on immunoglobin and gene status. This is the first level. Based on this, we can choose who the patients are who can still benefit from immunochemotherapy. At the end, a minor portion of the patients are those with mutated immunoglobin genes. On the other side, the patient with unmutated immunoglobin genes, or 

 and deletion, should be treated with novel therapies.

At that point, for this patient, we should evaluate the fitness of the patient. The fitness is a different concept from what we were using in the era of immunochemotherapy. It is more about comorbidities, such as the age of the patient. The possibility to better tolerate 1 or another novel treatment is probably based mostly on the comorbidities and polypharmacy: other drugs that patients are taking.

In the ESMO Guidelines, there is a much higher number of drugs and alternatives for our patients since a number of novel drugs have been approved or are on the way to being approved. Besides continuous treatment with ibrutinib, we also have the second-generation BTK [Bruton tyrosine kinase] inhibitor acalabrutinib, and for the first time we have a fixed-duration treatment like venetoclax with obinutuzumab. It is approved in the first-line setting for 12 months of treatment or venetoclax plus rituximab, which is approved for 24 months in the relapsed/refractory setting. In the relapsed/refractory setting, these are all first-line treatments.

In the relapsed/refractory setting, the ESMO Guidelines have also been updated. Not much is new; the major criterion to decide therapy in the relapsed/refractory setting is still based on the length of response to the first-line treatment. We can see patients who carried the division 17p or PC3 mutations, and these patients should avoid being treated with immunochemotherapy. We then have patients who responded for less than 36 months, and these patients are considered refractory to the previous lines and not well responding; therefore, they should again avoid the use of immunochemotherapy.

A portion of patients have a long remission: a longer response of more than 36 months. These patients are probably the only subset of patients for whom we can propose a second-line treatment based on immunochemotherapy with a minimal exception. First, FCR [fludarabine, cyclophosphamide, rituximab] should not be repeated. It is now well defined in the ESMO Guidelines that FCR [fludarabine, cyclophosphamide, rituximab] is not advisable to be repeated because it is too toxic for bone marrow function. Therefore, if we consider a patient who has more than 36 months of response to the first-line chemotherapy, we remain with few options because this is not achievable with chlorambucil-based treatment; with bendamustine, that is quite rare. In the setting of a patient who achieves a longer remission with immunochemotherapy, the option of novel therapy remains to be considered strong.

The iwCLL guidelines are different because they refer how to diagnose CLL where it indeed strongly recommends that we have to perform an immunophenotype. Of course, we have known for many years if not decades that the diagnosis of CLL should be made only after looking at the immunophenotype to see the expression of the typical markers. It is not based only on the white blood cell count any more.

Second, we do not need to do a bone marrow biopsy for diagnosis because it is not adding anything to the diagnosis by definition. Leukemic cells from CLL are already present in the bone marrow. Third, we can follow that, and we do not need the radiologic assessment. In fact, we could use physical exam only. In addition, you can use a chest x-ray or abdominal ultrasound because this is enough to assess if lymph nodes are present.

It is for this simple reason that the iwCLL guidelines tell us how and when to treat the patient. It is not only when the disease is progressing. We also have a clear criterion that tells us when the moment to start initiating the treatment is. These are clear criteria, with the major 1 being either the presence of anemia or thrombocytopenia due to the invasion of the bone marrow by the leukemic cells. Second is having bulk lymph nodes, which in the chronic lymphocytic leukemia are those more than 10 cm in size. The third is being refractory to corticosteroids when having an autoimmune manifestation like hemolytic anemia or autoimmune thrombocytopenia.

In addition, we can also have other criteria—usually a companion anemia, thrombocytopenia, or bulk lymphadenopathy, symptoms like fatigue, weight loss, night fever, and night sweats. On the other side, there is also the increasing lymphocyte count, in particular the doubling of the lymphocyte count, which is again a criteria that should be considered only when the major criteria are present. In any case, in the presence of these symptoms or lymphocyte doubling, we always have to think about other reasons and causes, particularly when they are isolated.

The iwCLL guidelines also provide the criteria for how to treat the patient and the time of treatment needed. In this case, they underscore the relevance of the mutation metastasis or the immunoglobin genes as well as the status of the 

 gene, either the deletion or mutation, to decide and define the best therapy for our patient. The iwCLL is also indicating the strategy for the treatment, but we have to consider the iwCLL guidelines more as a general overview for how to manage patients with chronic lymphocytic leukemia.

Another important point is that the iwCLL guidelines underscore that, for the vast majority of patients—not all patients—a period of wait and watch is strongly recommended. It is rare that the patient needs the treatment and the therapy right at diagnosis. In addition, at the moment, there is no evidence that preemptive treatment can be more beneficial for patient compared with the wait-and-watch approach.

Dr Brown and Dr Ghia discuss the European Society for Medical Oncology [ESMO] and International Workshop on Chronic Lymphocytic Leukemia [iwCLL] recommended guidelines in assessing and treating chronic lymphocytic leukemia.

Guidelines for Chronic Lymphocytic Leukemia

Stephan Stilgenbauer, MD: The treatment options for chronic lymphocytic leukemia, or CLL, have dramatically changed in recent years. In the past, we had only chemoimmunotherapy, which is rather nonspecific and has several toxicities. In recent years, there has been the development of more targeted treatment options, which provide very high efficacy and good tolerability to patients. There are certain patient profiles that we must consider when selecting treatment. We must look at any comorbidities, comedications, and disease characteristics, such as genetic parameters of the leukemia cells. 

With new treatment options available, the fitness of the patients, defined by renal function or other comorbidities, becomes less and less relevant. These treatments can be delivered safely and can also be used in older patients who have comorbidities.

Risk stratification is mainly based on genetic disease characteristics, such as the mutational status of the immunoglobulin genes; the IGHV mutational status, with unmutated IGHV genes conferring a worse prognosis; and other things such as 17p deletions or TP53 mutations. We know that patients with these abnormalities do not benefit at all from chemotherapy. Rather, they are prime candidates for novel treatment options that target BTK [Bruton tyrosine kinase] or BCL2. These options are particularly well suited for patients with high-risk genetic disease features such as an unmutated IGHV status, 17p deletion, or TP53 mutations.

Paolo Ghia, MD, PhD: When I consider treatment for patients who have high-risk features, I first identify what those high-risk features are.

When we consider how to care for a patient, we have to look for any TP53 aberrations, and it can be either a deletion or the 17p chromosome or mutation in the TP53 gene. Those are definitely the types of patients who we want to avoid giving immunochemotherapy to, because we know that these patients are resistant to immunochemotherapy. These patients should be treated with novel therapies only, either BTK inhibitors or BCL2 inhibitors. 

On the other side, we may have a patient with unmutated immunoglobin genes, when we know that immunochemotherpy is not so effective. We know this patient doesn’t achieve longer remissions and continues to relapse after immunochemotherapy. For this type of patient, we prefer to use a novel therapy—a BTK or BCL2 inhibitor. The approach for this type of patient is less stringent, and it really depends on access to therapies. In Italy, for example, we don’t have access. The only therapy we can propose is immunochemotherapy. But for the unmutated patient, we tend to propose that the patient be enrolled in a clinical trial. 

We know that patients with mutated immunoglobin genes have much better outcomes, even when treated with immunochemotherapy. For these patients, we discuss the pros and cons of chemotherapy. If they are young and fit, they can be treated with FCR [fludarabine, cyclophosphamide, rituximab]. On the other side they can be treated with novel therapies. We know that patients with mutated immunoglobin genes who are treated with FCR [fludarabine, cyclophosphamide, rituximab] can achieve a long, stable remission—up to 10 years—without progression. This is true in 3 of 4 patients with mutated immunoglobin genes. We don’t expect 100% of patients to respond. We know that immunochemotherpy is a fixed duration treatment. They are given 6 cycles of therapy, and then the patient can enjoy a treatment holiday. However, we also know the long-term consequences of immunochemotherapy, like acute leukemia, MDS [myelodysplastic syndrome], or the long-standing risk for infections.

On the other side, we have novel therapies, in particular BTK inhibitors. Continuous treatment can be a disadvantage, in particular for young patients, but we also know we can achieve long-term remissions and responses. We see that 70% of patients are free of relapse after 5 years of follow-up.

Drs Stilgenbauer and Ghia provide insight on initial treatment considerations for patients with newly diagnosed chronic lymphocytic leukemia.

Paolo Ghia, MD, Phd, Universita Vita-Salute San Raffaele

Articles