Danielle M. Brander, MD

 I’d like to note that in this discussion we’ve been weaving a lot of the conversation around some of the toxicities to look for when treating patients with a novel agent. Some of these are agent-specific. Others, like risk for infection, are really shared among all treatments. Therefore, learning about these toxicities and how to manage them is really important and can be found across several guidelines.

I also want to point out that in this case the patient had disease progression, or resistance to ibrutinib. However, as we’re learning across several retrospective studies and clinical trials, resistance to ibrutinib, especially in the frontline setting, is relatively uncommon. Rather, the more common reason for patients to discontinue ibrutinib, including in 2 large randomized frontline studies, was intolerance. In other words, development of toxicities where the patient could no longer continue on the therapy.

Managing patients who develop intolerance or an adverse effect to therapy that can no longer be managed safely for the patient to continue on that treatment is still an important area of unmet need for patients with CLL [chronic lymphocytic leukemia]. It is very important that we follow the clinical trials that specifically look for agents, for therapies, for these patients who develop intolerance. It also is a good reminder that more treatment options for patients, including both next-generation inhibitors for certain targets as well as different targets entirely, or clinical trials that combine with a fixed-duration drug, remain important for our patients.

Other unmet needs that deserve attention in clinical trials are especially important for patients, such as this one in our case, who develop resistance to ibrutinib. We know other targeted therapies can achieve response in these settings, but often these responses, especially if patients don’t achieve a complete response or have MRD [minimal residual disease] negativity, may not be long-lived and they progress to their next line of therapy.

Other options such as cellular therapy, CAR T-cell treatments, and, as I mentioned, combination therapies will remain important to try to address these challenges and allow patients with CLL to achieve the best response with the best quality of life for as long as possible.

And this, I think, remains and will continue to be what drives us all to continue clinical trials and consider clinical trials for all patients with relapsed or refractory CLL.

Case: A 73-Year-Old Man With Relapsed Chronic Lymphocytic Leukemia

A 73-year-old man presented to his PCP for an annual checkup; he complained of mild intermittent fatigue and occasional night sweats

PE: palpable axillary and right-sided cervical lymphadenopathy



Labs: WBC 48,000, lymphocyte 72%, ANC 3700/mm3, Hb 9.4 g/dL, plt 100 x 109/L, LDH 240 U/L, Beta-2-microglobulin 4.1 mg/L

FC CD 5+, CD23+, CD20+ monoclonal B-cell population

FISH: normal for all CLL probe set tested, no evidence t11;14

He was started on ibrutinib 420 mg PO qDay; symptoms improved and achieved stable disease resolution of lymphadenopathy

After about 3 years he complained of increasing fatigue and decreased appetite, on PE return of palpable lymphadenopathy spleen was palpable ~4 cm below costal margin; creatinine clearance 56 mL/min

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Addressing Treatment Challenges in CLL

 Another one of the options that we mentioned for patients with relapsed or refractory CLL [chronic lymphocytic leukemia] that is currently approved is the combination of idelalisib with or without rituximab. In a clinical trial led by Dr Sharman and colleagues, patients with relapsed or refractory CLL were randomized to either rituximab monotherapy, which was considered a standard of care at the time of the trial, versus rituximab with idelalisib. Idelalisib belongs to a family of compounds called PI3-kinase inhibitors. They’re often subclassified by the isoform that they target. For example, idelalisib is a delta isoform-specific inhibitor. This is important, as this isoform is particularly what is thought to be driving progression for patients with CLL and lymphoid malignancies.

For patients who are started on idelalisib and rituximab, as was done in the clinical trial, they are followed closely for both response and to monitor for toxicities, including LFT abnormalities or diarrhea that can occur early—within the first couple of weeks.

On the clinical trial as well as per the labeled prescribing information, one can learn how to follow patients, but also, importantly, how to treat patients should they develop any toxicities. This usually involves holding the drug. In the case of diarrhea, depending on the severity and concern for colitis and dehydration, you might also employ testing for other co-infections. If negative, it is recommended to use antimotility agents until the toxicities resolve to a lower grade. In the clinical trial, patients were also followed closely for other late onset of toxicities.

In the conclusion of the study and the follow-up of these patients randomized to either rituximab and placebo versus rituximab and idelalisib, there was a significant improvement in both progression-free survival and overall survival for the idelalisib/rituximab patients. This adds to the list of options for patients, outside of clinical trials.

PI3K/Anti-CD20 Therapy for Relapsed/Refractory CLL

 In this case, the patient received ibrutinib and was treated as one would be per the standard of care, which is continuously until the time of progression. However, after approximately 3 years on therapy, he was demonstrating evidence of progression by both his symptoms as well as palpable disease in the lymph nodes and in the spleen, and then he was confirmed to have progressive disease.

Because he was confirmed to have progressive disease, in this case, in the second-line setting, he would meet the indication for transitioning fairly quickly to the next line of therapy because the disease was progressive.

In other situations, like if a patient had received chemoimmunotherapy on the frontline setting, for example, they obviously would not have been receiving this continuously and may have been off treatment for a period of time until you saw the return of the CLL [chronic lymphocytic leukemia]. Or, in some cases, now with their approval of fixed duration therapy with venetoclax and obinutuzumab in the frontline setting, those patients are treated for 1 year then stop treatment.

In both of those latter cases, when patients have cessation of therapy they are monitored until the time of disease relapse. A patient may not need to start the second line of therapy right away. During the patient’s routine follow-up, you might notice that their white blood cell count and lymphocyte count are starting to increase, but they have no symptoms. Or, they might have slow return in their lymph nodes, but, again, they are not large or symptomatic.

In the second-line setting, if patients are not progressing on continuous therapy, you should monitor again and consider the iwCLL [International Workshop on Chronic Lymphocytic Leukemia] indications for a treatment option, as was discussed before, because patients might not need treatment right away upon initial relapse.

At the time of relapse, though, they should receive full work-up, including consideration to resend some of the prognostic markers, namely FISH [fluorescence in situ hybridization] testing, chromosome testing, and TP53 mutational analysis. Again, the results of those tests would not necessarily change whether they need to start treatment right away at relapse. However, patients who might not have had the highest-risk markers, such as deletion 

 mutations, at the time of their first treatment may be found to have this at the time of relapse. That could inform several conversations with the patient, including consideration of clinical trials if found to have this higher-risk disease.

In this case, though, I want to go back to the fact that ibrutinib or other BTK [Bruton tyrosine kinase] inhibitors, or many B-cell receptor downstream targeted therapies are administered continuously until the time of progression. In this case, the patient does need treatment transitioned fairly quickly. And I should also point out that because they’re on active treatment, at the time of progression on ibrutinib one should not stop the medication abruptly until you’ve had time to review options with the patient and plan accordingly for the next line of therapy. Even though they’re progressing on treatment, it may still have some effect on some of the CLL cells. Stopping the drug quickly could result in a flare of the disease or an even more rapid progression.

In terms of options in the relapsed/refractory setting, or specifically for this patient with resistance to ibrutinib, multiple trials in the relapsed/refractory setting have shown an overall survival benefit to targeted agents. There is no evidence for transitioning this patient back to chemoimmunotherapy.

Among the other targeted agent options in the relapsed/refractory setting would be venetoclax, a BCL-2 inhibitor, either as monotherapy or in combination with rituximab; idelalisib with or without rituximab, which is a PI3-kinase delta isoform inhibitor. And if this was for third-line treatment, also duvelisib, which is a dual gamma-delta inhibitor.

If this patient was being transitioned to either of the targeted agents I mentioned, either the venetoclax-based regimen or idelalisib, I would have treatment planning for that patient, and again, not stop the ibrutinib until I was ready to start the next line of therapy.

Just like in the frontline setting, patient-specific factors are important in treatment planning—namely, the patient’s comorbidities. For example, this patient with a chronic kidney disease had reduced creatinine clearance. This is important because if venetoclax therapy is chosen, patients are at risk for tumor lysis, and this is part of the dose ramp-up and monitoring. Tumor lysis risk and the need for hospitalization during the initial dosing depends on the disease but also patient-specific factors such as renal dysfunction.

In terms of choosing a PI3-kinase inhibitor as the next line of therapy, the toxicities that one must be mindful of that can develop with treatment of these agents can include both early and late onset of symptoms such as colitis, which can lead to diarrhea and dehydration as it can be very profound. Patients can also have other immune-like conditions such as increases in their LFTs or pneumonitis. Many have looked at baseline clinical factors that might predict the development of these agents, but it is not entirely clear, for example, whether patients with a baseline dysfunction, such as lung disease, are necessarily at higher risk. All patients should be considered at risk for the development of these toxicities.

In any case, if this patient is transitioned, for example, to next-line therapy, we sometimes draw from some clinical trials that have specifically studied agents after ibrutinib progression. These studies are fairly limited and patient numbered to date, and that’s largely due to the timing of the development of these agents. Also, many patients on the initial relapsed/refractory clinical trials had been treated in earlier settings only with chemoimmunotherapy.

There is 1 series using venetoclax in patients following ibrutinib therapy. This explored approximately 90 patients. The patients were treated with venetoclax after ibrutinib, either if they stopped ibrutinib due to resistance or if they stopped it due to intolerance. Here, the response rates were approximately 60% for the entire population. Again, however, one must be considerate of tumor lysis. And in this case, with a patient with reduced renal function, if they were receiving venetoclax I would counsel the patient on the high tumor lysis risk and consider hospitalization for tumor lysis monitoring.

Treatment Options for Relapsed CLL

 When patients are initiated on ibrutinib in the frontline or relapsed setting, patients are started at the full dose of the drug, and monitoring is usually by in-visit, in-clinic visits that include a physical exam as well as routine blood work. The purpose of this monitoring is to ensure that the patient is responding to treatment and tolerating the therapy. Though many patients with bulky lymph nodes or other disease may be started on allopurinol or other medications to mitigate any cell turnover and rise in uric acid, tumor lysis monitoring is not otherwise standardly employed, or certainly not frequently for patients receiving ibrutinib.

In terms of response, patients can have response often within the week in terms of improvement in symptoms or their lymph nodes. Their subsequent follow-up appointments, again, will consist of an exam as well as testing to make sure that they are responding and tolerating their medication. If patients are doing well, these visits are spaced out to every several weeks. And moving forward, visits are adjusted if the patient develops any adverse effects or toxicities.

Monitoring patients’ responses outside of the clinical trial, as mentioned, should include the physical exam as well as bloodwork. CT scans and imaging are not necessarily required unless there’s bulky disease that needs to be monitored that way and there’s lack of evidence of response in other regions.

Development of resistance for ibrutinib, especially in the frontline setting, is not common and would be incredibly rare, especially in the first year on the drug. Therefore, if a patient has evidence of any kind of progressive disease early on during therapy, one should look for other causes such as transformation of the CLL [chronic lymphocytic leukemia].

In terms of response, this is looking for reduction in whatever symptoms or disease is the reason for patients to start on therapy. Complete responses to ibrutinib often take time, usually in the period of years. One study suggested that after 5 years of frontline follow-up, complete response rates increased to almost 30%. But these responses took time.

Minimal residual disease, or MRD-negativity, has historically been an important milestone to predict length of remission for patients receiving chemoimmunotherapy, and more studies are also showing the importance of MRD in predicting longitudinal responses and PFS [progression-free survival] with venetoclax. However, because MRD achievement is an uncommon event for patients receiving ibrutinib monotherapy and doesn’t necessarily mean that patients can’t have very long responses on the drug, MRD testing is not employed outside of clinical trials for ibrutinib, certainly not as monotherapy.

In terms of patients and their risk of relapse, as mentioned for ibrutinib monotherapy, as used in this case, one would not use MRD monitoring in clinical practice. In clinical trials, when the drug is used in combination with other targeted agents, or anti-CD20 antibodies, one might use MRD testing. But again, this is done within the context of clinical trials.

MRD Assessment and Treatment Selection in CLL

 In this case, the patient was started on ibrutinib monotherapy and had an excellent response, as measured by the symptoms he had prior to starting treatment—the fatigue as well as the lymphadenopathy. Patients started on ibrutinib can often see rapid reduction in their bulky disease, both the lymphadenopathy or splenomegaly. Most patients will have a rise in their lymphocyte counts when they first start treatment. This does not represent disease progression but instead movement of the atypical CLL [chronic lymphocytic leukemia] lymphocytes from the lymph nodes to the blood. But, as in this case, that improves over time, and then you often will see improvements in the blood counts.

So patients can have rapid improvement. Most patients started on ibrutinib or other BTK [Bruton tyrosine kinase] inhibitors as monotherapy will not achieve what is called a complete response [CR], mostly because they have residual CLL in the bone marrow, if the bone marrow were to be tested.

However, in the case of ibrutinib and other BTK inhibitors, achievement of CR initially, even in a lower percentage of patients, does not necessarily translate to the fact that the patient could not have long progression-free survival on the drug. It would not be standard in clinical practice, for example, to have to perform serial bone marrow to look for complete response, but the data that we derive from clinical trials can help us determine what to expect for these patients.

In this case, the patient was found to have mild symptoms and started on therapy fairly quickly after the time of diagnosis. However, even with all of these novel agents, by iwCLL [International Workshop on Chronic Lymphocytic Leukemia] criteria, patients start treatment only if they meet indications for therapy. These indications are mainly based on disease-related symptoms that cannot be managed and affect quality of life significantly, big or bulky lymphadenopathy or splenomegaly that is symptomatic to the patient or is causing organ dysfunction, or disease that is impacting their other blood counts due to marrow involvement. In this case, after work-up the patient had both anemia and borderline thrombocytopenia that would have met indications for treatment. But again, regardless of the novel agents, regardless of patient risk factors, even patients with highest-risk disease do not start treatment upon diagnosis unless they meet indications for therapy.

In this case, the patient was started on ibrutinib in the frontline setting as a result of randomized clinical trials. The standard of care for treatment with ibrutinib, acalabrutinib, or certain other targeted therapies is that they are continued daily until the patient shows evidence of clinical progression or is not tolerating the drug. There are other targeted agents, like venetoclax, that have been studied in a time-limited course in the frontline setting, including venetoclax for a total of 12 months.

BTK Monotherapy as Frontline Treatment of CLL

 In the past several years, we have seen an increase in the number of available therapies for patients as frontline treatment. Therefore, beyond chemotherapy there was a recent approval for the BTK [Bruton tyrosine kinase] inhibitors, originally ibrutinib, now acalabrutinib. And last year, also in the frontline setting, we saw the approval of the BCL-2 inhibitor, venetoclax. With these multiple treatment options, there’s not necessarily a head-to-head comparison of the novel agents.

However, there are important frontline randomized studies that have compared chemoimmunotherapy versus the targeted therapies in the frontline setting. Based on randomized clinical trials, data have shown superior results with a targeted agent versus chemoimmunotherapy. Therefore, for this patient I would consider using one of the targeted agents.

There are not contraindications to using ibrutinib, acalabrutinib, or venetoclax in patients in the frontline setting. They do have different mechanisms of actions and known toxicities. Therefore, there are several different comorbidities you might consider when selecting therapy for a patient in the frontline setting.

It should be noted that unlike in the past where patients with certain comorbidities, renal function, or by age were excluded from chemoimmunotherapy, all of the targeted agents have also shown success in older patients or those with comorbidities. In fact, many of the trials studied these populations specifically.

Ibrutinib is known to increase risk for atrial fibrillation. It can also increase one’s risk for bleeding. The risk for bleeding is shared among other BTK inhibitors, including acalabrutinib. Therefore, if you have a patient already on anticoagulation, other antiplatelets, or with extensive cardiac comorbidities, this is something you should discuss with the patient and, potentially, their cardiologist. They may lean you away from using agents if you have other options available.

On the other side, patients using venetoclax are at risk of tumor lysis syndrome. So if they’re at high risk due to bulky disease and they may have problems with tumor lysis due to renal function or other comorbidities, this, again, is a specific consideration that should be made when talking about these agents with patients.

Danielle M. Brander, MD | Authors

Articles

Addressing Treatment Challenges in CLL

PI3K/Anti-CD20 Therapy for Relapsed/Refractory CLL

Treatment Options for Relapsed CLL

MRD Assessment and Treatment Selection in CLL

BTK Monotherapy as Frontline Treatment of CLL

Frontline Targeted Therapy for CLL