Jeff Sharman, MD

 Idelalisib is a PI3 kinase inhibitor. Therefore, it is differentiated from the BTK inhibitors or the BCL2 inhibitors. Idelalisib inhibits PI3 kinase, which is one of the proximal signaling molecules in the B-cell receptor signaling pathway. In that particular study, idelalisib clearly outperformed rituximab. It was a combination ofidelalisib and rituximab versus rituximab alone.

The combination clearly outperformed rituximab monotherapy, so in this particular patient, having them started on rituximab monotherapy might be one place where I would differ from prior management. Had that patient been in my practice at the time, I probably would have gone straight to the combination of idelalisib and rituximab.

The progression-free survival was about a year and a half. Overall survival in this very difficult treatment population was, of course, longer than that. Recall that these patients all had multiple prior cytotoxic regimens, so whether or not they’re representative of current patients who are relapsed refractory is less clear.

My own personal experience with this combination is that it can serve a useful purpose in selected, carefully monitored patients. It’s important when starting a patient on a PI3 inhibitor to monitor liver function tests quite closely. The label provides very specific recommendations for the timing to do that because liver function test abnormalities occur primarily within the first 3 months. Once they occur, it’s important to interrupt idelalisib and allow the patient to recover. Once they’ve recovered, it’s very rare for those liver function tests to become abnormal again, so it appears to be a one-and-done phenomenon.

However, diarrhea is another consideration, and grade 3 diarrhea in this trial was reported around 16%. It’s important to know that even grade 2 diarrhea can be quite symptomatic for patients. The appropriate intervention is actually to suspend therapy, and it’s important to do so early if the patient has diarrhea. You need to train a patient to stop idelalisib if they experience diarrhea, even if they haven’t been in to be seen, because if there’s a delay and they continue their idelalisib until they’re waiting to be seen, that can become quite serious. We also monitor for atypical infections, such as cytomegaly virus or PCP. In many cases, if we can, we try to utilize PCP prophylaxis.

Finally, we’re asked to describe the ongoing challenges in treating relapsed/refractory CLL, and discuss future directions and unmet needs in relapsed refractory CLL.

We are definitely seeing more patients who are experiencing progression after novel agents, so perhaps progression after BTK or BCL2. What good options remain for those patients? I think that recognizing idelalisib-rituximab as a useful combination can be quite helpful amongst these patients, potentially even utilizing that prior to rituximab-venetoclax in some situations where medical comorbidities may make venetoclax more challenging.

I think it will be interesting to see if the noncovalent inhibitors can move forward and restore efficacy of targeting BTK, even amongst patients with prior BTK inhibitor resistance. We’ll be excited to see how cellular therapies evolve in this space, including chimeric antigen receptor T-cell therapy, which is going to be great for those patients young and robust enough to get it. But, again, this older population may be excluded from such strategies.

Case: A 79-Year-Old Man With Relapsed Chronic Lymphocytic Leukemia

A 79-year-old man presented to a new medical oncologist for the first time complaining of vague intermitted abdominal pain, and progressive fatigue

After a period of watchful waiting he began treatment with ibrutinib 420 mg PO qDay; symptoms improved and achieved stable disease, resolution of lymphadenopathy

After 5 years of disease control on ibrutinib he complained of increasing fatigue and decreased appetite, on physical exam there was return of palpable lymphadenopathy; spleen was palpable ~4 cm below costal margin

Currently after 6 months on rituximab monotherapy he presents to the clinic

PE: palpable bilateral cervical and right-sided inguinal lymphadenopathy



Labs: WBC 55,000, lymphocyte 82%, ANC 3100/mm3, Hb 9.4 g/dL, plt 90 x 109/L, LDH 220 U/L, Beta-2-microglobulin 3.9 mg/L; creatinine clearance 31 mL/min

FC CD 5+, CD19+, CD20+ monoclonal B-cell population

Treatment of idelalisib 150 mg PO BID was added to rituximab

Videos

Understanding the Trial With Idelalisib and Rituximab

 After first-line treatment, what is the trigger to start second-line therapy in CLL? Again, the same indications that we talked about for first-line therapy are true in second-line therapy: rapid progression of lymphocyte count, symptomatic bulky lymph nodes, emergence of bone marrow dysfunction. Those are true in both the front-line and relapsed refractory setting.

When you’re considering treatment for patients with therapy in the relapsed setting, that’s going to be strongly influenced by what they received in the first-line setting. For a patient such as this with the deletion of 17p, you don’t have a whole lot of options. They would include venetoclax in combination with rituximab, similar to the MURANO study, or idelalisib and rituximab. Because this patient has significant chronic kidney disease, the risk of tumor lysis is quite high.

Furthermore, we know that if there’s a sweet spot for PI3 kinase inhibitors, it tends to be in that older population with significant medical comorbidities. I think this is a great patient for whom to consider idelalisib-rituximab. It wouldn’t be wrong to pick rituximab with venetoclax; however, it would need to be very carefully monitored for risk of tumor lysis, likely even admitting that patient to the hospital for the first several dose levels. With some 79-year-old patients, that’s a difficult proposition to make, so I think in this particular case starting idelalisib-rituximab would be very reasonable.

We’re asked to comment on the patient’s status at the current time. Does his risk status matter? The answer is yes. We’re probably going to get about a year and a half median progression-free survival for idelalisib-rituximab. The question will be what to do next.

In a 79-year-old, perhaps other medical comorbidities may limit survival beyond that, but this is a patient where if the next therapy is going to be venetoclax-based treatment, I don’t want that patient to develop bulky adenopathy before transitioning to that therapy because the risk of tumor lysis may be too great.

Regarding next treatment options, there are clinical trials in this space looking at BTK inhibitors that may work even after a prior BTK inhibitor has stopped working. LOXO305 is one potential option, and ARQ 531 is another BTK inhibitor that could work in this space. If the patient is able to travel for a clinical trial, that might be an option.

Second-Line Treatment in Chronic Lymphocytic Leukemia

 MRD testing at this point is prognostic; it tells you how likely a patient is to maintain their response. But to date, there’s nothing that tells us how to change therapy based on MRD status. There are studies coming that will potentially have MRD-adapted treatment decisions. Findings from those studies have not reported. MRD testing, therefore, really just helps us to understand the likelihood of length of a response.

With patients treated with BTK strategies, MRD isn’t so much a consideration. That’s primary amongst patients treated with venetoclax. We’re asked how accurately it predicts the risk of relapse and how widely is it being used. Well, again, following obinutuzumab-venetoclax, you can check MRD status. From the MURANO Study, which is a population of relapsed-refractory patients treated with obinutuzumab-venetoclax, you can stratify based upon MRD high, low, and negative. If you’re negative, chances are you’re going to maintain your response considerably longer than those patients who are low or high. Those patients are going to have relatively short durations of response.

Disease Testing in Chronic Lymphocytic Leukemia

 I think all patients who are going to be treated with CLL, it’s imperative for us to know their mutation status, their IgHV mutation status, as well as their FISH upfront. In this particular case, it may be that it was done, and we don’t have records. Or, possibly, it wasn’t done. We know that there is an inadequate degree of testing with FISH for patients with CLL who need therapy, so it depends on whether or not that was done.

I do think that ibrutinib is an appropriate first-line treatment option for patients with CLL. This has been a field that has been changing very quickly, and we’re seeing a number of new treatment options in this setting, including acalabrutinib, with or without obinutuzumab. Also, obinutuzumab-venetoclax can be utilized in the front-line setting. I certainly would not fault ibrutinib monotherapy, particularly since this likely predated the approval of acalabrutinib- or venetoclax-based therapies.

When you’re thinking about comorbidities that determine upfront treatment, there are several that are important; more and more, it used to be that treatment was decided based upon IgHV status, FISH status, and patient fitness. More and more, we can say that all these novel agents are particularly effective in the front-line setting, so it becomes more about the patient’s unique features. So, patients with cardiac risk factors, hypertension, maybe a history of atrial fibrillation who has left atrial enlargement on EKG, these are patients for whom ibrutinib, over the long-term, may exacerbate those symptoms. We don’t have head-to-head data, but at least it appears from preliminary data that acalabrutinib may not have those same toxicities in the front-line setting. Although, again, head-to-head studies are pending on this.

In a patient with cardiac risk factors, I may choose obinutuzumab-venetoclax. However, as this case importantly highlights, this patient had some significant chronic kidney disease, and that certainly exacerbates the risk of tumor lysis syndrome with venetoclax. In fact, a glomerular filtration rate of less than 80 increases the risk of tumor lysis syndrome when patients are treated with venetoclax.

For a patient with a very significant renal insufficiency, such as this patient with a GFR of just 30, that’s an important consideration. I’ll think about the medications that they’re on. Patients who are on proton pump inhibitors, that’s going to reduce their absorption of acalabrutinib but not impact the absorption of ibrutinib.

Conversely, if patients are on medications with CYP3A4 interactions, that may influence their exposure to BTK, or increase their exposure to venetoclax, you have to be very careful about drug interactions. Those are some of the things I think about when addressing a patient’s fitness or comorbidities when picking a therapy.

In terms of triggers to initiate therapy, those haven’t changed. Just because a patient has a 17p does not influence when we choose to pursue therapy. In fact, I’ve had many patients in my own practice who can have 17p and maintain asymptomatic disease for a length of time. Indications for therapy remain, like a rapid rise in the white blood cell count. By rapid, we generally mean lymphocyte doubling in less than 6 months. Symptomatic bulky lymphadenopathy can be an indication for therapy, as is an emergence of bone marrow dysfunction, such as anemia or thrombocytopenia. These are the reasons to initiate therapy, and it is inaccurate to begin therapy just because the patient has a diagnosis or a high-risk marker.

With the BTK agents, we do continue that until disease progression, and at this point, there’s no science that would support treatment discontinuation. However, for patients started on obinutuzumab venetoclax, that is an approach that is fixed duration with 6 months of obinutuzumab and 12 months of venetoclax.

Jeff Sharman, MD | Authors

Articles

Understanding the Trial With Idelalisib and Rituximab

Second-Line Treatment in Chronic Lymphocytic Leukemia

Disease Testing in Chronic Lymphocytic Leukemia

First-Line Treatment in Chronic Lymphocytic Leukemia