Coutre Evaluates Treatment Options in Relapsed/Refractory CLL

Case-Based Peer Perspectives Spotlight Live, August 1 2020 CBPP Spotlight,

During a virtual Case Based Peer Perspectives event, Steven Coutre, MD, reviewed a case of a 53-year-old woman who first presented with elevated white blood cell count. The patient was later diagnosed with chronic lymphocytic leukemia.

During a virtual Case Based Peer Perspectives event, Steven Coutre, MD, professor of Medicine (Hematology), Standford University Medical Center, reviewed a case of a 53-year-old woman who first presented with elevated white blood cell count. The patient was later diagnosed with chronic lymphocytic leukemia (CLL).

Targeted Oncology™: What are your initial impressions of this case?

COUTRE: I think we’d all agree that this is a patient who requires observation at this point. Clinically, this patient is at Rai stage 0. That 1 × 1 cm [lymph node] doesn’t qualify as lymphadenopathy. It certainly doesn’t need a CT scan or a bone marrow, and we can choose whether to do mutation analysis or FISH, but those results are not going to change the management approach.

To establish a diagnosis, flow cytometry was carried out showing the typical immunophenotype. Additional testing was conducted, showing the patient has no cytogenetic abnormality by FISH. Unfortunately, the patient had a bone marrow done, and it showed evidence of CLL. She was observed and did fine for 5 years, and she’s still quite young. Her WBC count has more than doubled, she’s significantly anemic, her platelet count has gone down, and the lymphadenopathy is 4 cm × 3 cm on 1 of the nodes.

At age 60, she received FCR. She experienced a complete remission. Four years later, she has a relapse. Again, if you’re advising this person, you’ll get, on average, about 4.5 to 6 years of remission. Her WBC count is 80,000 now; hemoglobin, 9.5; platelets are 60,000; and, unfortunately, she’s got del(17p). And on sequencing, she has a TP53 mutation.

What are the treatment options for this patient?

The RESONATE trial [NCT01578707] evaluated patients who were previously treated for CLL and SLL [small lymphocytic leukemia] and who were randomized to receive ibrutinib [Imbruvica] at 420 mg once daily versus IV ofatumumab [Arzerra] at an initial dose of 300 mg, followed by 2000 mg for 11 doses over 24 weeks.¹

It’s no big surprise how well ibrutinib did compared with ofatumumab. The differences were highly significant. The most recent data involving 6-year follow-up published last year in Blood show that the median PFS [progression-free survival] is still not reached. These patients who entered this trial were not your average patients. The patient in our case would not have been eligible for the trial. Having a 4-year response to FCR would not [have met eligibility] for this trial. These were much worse relapsed patients, and yet here we are in 2020, and the median PFS has still not been reached with ibrutinib in this trial versus 8.11 months for the ofatumumab arm [HR, 0.133; 95% CI, 0.099-0.178].

When we look at IGHV-mutated versus unmutated disease, both agents work equally well with a median PFS not yet reached in either arm. The median PFS with ibrutinib in patients with del(17p) is about 3.5 years. Based on the patients we enrolled in this trial, we would have expected [the PFS] probably to be less than a year, so they did remarkably well.

A lot of the patients who were on this trial with 17p(del) and progressed went on our venetoclax [Venclexta] trial.

How were the overall survival (OS) and adverse effect (AE) profiles for this trial?

We’re not seeing a statistical diff erence in OS because the patients in the ofatumumab arm crossed over.

AEs, which were consistent with all the earlier ibrutinib trials, will occur at the very beginning. There were some cases of neutropenia. The hypertension and atrial fibrillation tend to show up within the first year.

What is the evidence for using acalabrutinib (Calquence) in the relapsed setting?

Acalabrutinib has been used in the relapse population in the phase 3 ASCEND trial [NCT02970318].² This was a trial evaluating acalabrutinib versus bendamustine/rituximab [BR]. Idelalisib [Zydelig] plus rituximab was approved at the time, so that was used as a control arm. Investigators allowed crossover, and results were presented at the European Hematology Association [Congress] last year.

The median PFS favored the acalabrutinib arm at 88% versus 68% for the control arm [HR, 0.31; 95% CI, 0.20%-0.49%; P < .0001]. The OS data are not yet mature, but this trial essentially got the drug approved for relapsed patients. Subgroup analyses also revealed a favorable outcome for acalabrutinib.

Regarding safety, acalabrutinib can cause headache, which can be managed and, fortunately, goes away, but it’s something you need to tell the patients about. Among AEs that occur in 15% of patients or more, there were no atrial fibrillation AEs reported in this trial.

Which other studies explored treatment in the relapsed setting?

The MURANO trial [NCT02005471] evaluated venetoclax and rituximab versus bendamustine and rituximab.³ This study included patients with del(17p). The primary end point was PFS. The 24-month PFS rate was 75%—quite respectable in this population, compared with chemoimmunotherapy.

The preplanned interim analysis showed that venetoclax worked equally well if del(17p) was present or absent. An earlier trial evaluating venetoclax alone in more than 100 patients with relapsed del(17p) demonstrated that the agent is highly active.

Regarding MRD [minimal residual disease], in patients who achieved undetectable levels, 87% had not progressed after 2 years’ follow-up, on average, off treatment. So again, you want to ask the question “If I treat a patient for 2 years, how long is the benefit going to last?” And that benefit clearly correlates with how deep that initial response is. Those who achieve undetectable MRD do better for a longer period of time.

But again, it begs the question of what we do with this information. Do we test everybody for MRD? Do we continue them on therapy if they’re still MRD positive? Does it matter? And I think those are important questions that remain unanswered, and some ongoing trials are attempting to answer them in a randomized way.

Patients in the venetoclax arm experienced more neutropenia than patients in the bendamustine arm. Venetoclax can result in neutropenia. Investigators reported 3.6% febrile neutropenia, despite 60% neutropenia and 5% pneumonia. There is low incidence of TLS [tumor lysis syndrome] when you use venetoclax appropriately. When you do implement the dose ramp-up, pay attention to the electrolytes.

What role do the PI3K inhibitors play in treatment?

There are 2 PI3K inhibitors available: duvelisib [Copiktra] and idelalisib [Zydelig]. Idelalisib is approved in combination with rituximab because of a randomized trial that we did comparing it with rituximab alone in relapsed/refractory patients. These are extremely effective drugs for CLL.

I was involved in all the early trials with idelalisib. The challenge is that it’s immunosuppressive. Many of the ongoing large, randomized trials that included the frontline setting were stopped because there was excess mortality in the idelalisib arms compared with chemoimmunotherapy, and it was due to infectious deaths.

[These agents] do suppress the immune system and can reactivate CMV [cytomegalovirus]. The other Achilles’ heel is microscopic colitis, diarrhea, intractable diarrhea, and the mouse knockout model shows that. So, that was my experience with the drug: As people stayed on it, eventually they would have to come off it and lose the benefit.

These [agents can be] relegated to the useful drugs [category]. They’re for that uncommon patient who cycled through venetoclax and the BTK [Bruton tyrosine kinase] inhibitors for whatever reason, and they can be very effective, but you have to realize that they’re really only temporizing. You’re probably not going to be able to keep a patient on it indefinitely. [These agents could serve as] a bridge to our T-cell protocol or, in some cases, transplant.

Would you recommend the use of MRD testing?

You hear so much about it. It’s meaningful, it’s validated, and it’s useful in some circumstances, but it is really not something that I would advocate using in routine clinical practice at this time. As attractive as it seems, you won’t get deep responses.

We still need to learn the meaning of it. Now, with a BTK inhibitor, it’s irrelevant. You don’t get the benefit from achieving MRD negativity. You get the benefit from staying on the drug. It’s a great tool to use in the context of a clinical trial in which we’re using a time-limited regimen, whether it is bendamustine/obinutuzumab [Gazyva] or ibrutinib/venetoclax or ibrutinib/venetoclax plus obinutuzumab. That’s where it’s going to give us useful information about how deep a response we can achieve and how long that response is maintained.

But if you understand the information it gives you, you may choose to use that to help manage a very specific patient. You’ve got that 50-year-old who needs treatment for CLL, who has del(17p) up front. You’ve already chosen to give them a combination regimen. You’re deciding if you really need to keep him on that regimen indefinitely. Are you comfortable, if they’re MRD negative, stopping it? [It’s useful in a] very specific circumstance like that.

So I would advise that if you haven’t managed many patients with CLL—and I mean, that’s understandable; CLL is not that common in a typical practice—then just ask your go-to person at one of the academic institutions who has more experience.

Like I said, it is useful. It does tend to correlate with duration of response. Then there are issues like: Is peripheral blood good enough? Do you have to do a bone marrow aspirate to get that information?

I think we’ll demonstrate the validity of using it just from peripheral blood, which is nice. And then flow cytometry for MRD is well established and it is available, and you get real-time data as compared with PCR [polymerase chain reaction].

But who knows, maybe we’ll eventually be using NGS like the clonoSEQ assay. You’ve probably used that for patients with ALL [acute lymphocytic leukemia]. That is sensitivity down to 1 in a million cells, and in trials, we’re exploring whether you can achieve even that depth of response.


1. Byrd JC, Hillmen P, O’Brien S, et al. Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood. 2019;133(19):2031-2042. doi:10.1182/ blood-2018-08-870238

2. Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 24th European Hematology Association Congress; June 13-16, 2019; Amsterdam, the Netherlands. Accessed July 27, 2020.

3. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax–rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. doi: 10.1056/NEJMoa1713976