Khan Implements a Treatment Plan for a Patient With CLL

Cyrus M. Khan, MD

Cyrus M. Khan, MD, a hematologist/oncologist, at Allegheny Health Network in Pittsburgh, PA, discussed the case of a 61-year-old patient with bone marrow biopsy confirmed chronic lymphocytic leukemia (CLL).

Targeted Oncology™: Is molecular testing for CD38 and Zap-70 still used in a prognostic panel?

KHAN: Not any more. It used to be there, but now it’s supplanted by all the newer testing that we have, such as IgH3 status, and then del(17p), del(11q). Sometimes del(13q) even gives you a better prognosis. So those are more commonly done now.

Do you usually do a routine bone marrow biopsy for patients?

Not always. At diagnosis, it’s rare that you get a flow cytometry that’s [uncertain], and I have only had 2 or 3 patients over the last year where the flow cytometry said it was CLL, but I was concerned because it was unusual, and then when we did the eventual bone marrow [biopsy] and further testing, it turned out to be the leukemic variety of mantle cell lymphoma. You can be confused sometimes—so I do not always [do a bone marrow biopsy].

What do you think of the answers in the polling question about optimal therapy for this patient?

I see 33% [of participants] chose ibrutinib [Imbruvica], about 25% chose ibrutinib plus monoclonal antibody, 16% chose acalabrutinib [Calquence], 25% chose venetoclax [Venclexta] plus monoclonal antibody, and none chose chemoimmunotherapy.

[Ibrutinib is] a great choice. It’s the first BTK [Bruton tyrosine kinase] inhibitor that came on the market, and it works well. We have realized [this] over many years [and] a lot of long-term data. And so a lot of people are familiar with it.

One of the benefits of using [venetoclax plus an anti-CD20 monoclonal antibody] approach would be finite duration of therapy. Any BTK inhibitors we use, you have to continue the treatment until progression or toxicity. With venetoclax plus an anti-CD20 antibody, at least it’s time defined and you can stop therapy at a certain point.

How do the National Comprehensive Cancer Network (NCCN) guidelines suggest treating these patients?

The NCCN tells us for patients who are unable to tolerate chemotherapy, are above 65 years, or have significant comorbidities, the preferred agents are all the novel therapies.1 It’s ibrutinib, acalabrutinib plus/minus obinutuzumab [Gazyva], and venetoclax plus obinutuzumab.

There are other frontline therapies, depending on what category of evidence we have. For patients who are younger, less than 65 years, the preferred agents are novel therapies.

We have almost 6 to 7 years’ worth of data with the BTK inhibitors. We have BCL2 inhibitors, and a lot of head-to-head comparisons have been done.

What are the data supporting acalabrutinib in this setting?

The acalabrutinib data come from the phase 3 ELEVATE treatment-naïve [TN] study [NCT02475681].2 This was in 535 patients; they had to be either above 65 years or below 65 years with comorbid conditions. They were randomized into 1:1:1 to acalabrutinib plus obinutuzumab [or acalabrutinib monotherapy or obinutuzumab/chlorambucil].

Crossover was allowed from obinutuzumab plus chlorambucil to acalabrutinib monotherapy if the patient had progression. Off the bat, we know that the overall survival [OS] might eventually not be that different because crossover is allowed.

Which regimens did the best in the ELEVATE TN trial?

As far as the progression-free survival [PFS] is concerned, obinutuzumab plus chlorambucil showed a median PFS of almost 2 years. When we look at acalabrutinib monotherapy, median PFS has not been reached at 28.3 months. The same goes for acalabrutinib plus obinutuzumab.

Almost all the patients [by subgroup] did better with the acalabrutinib approach, whether it’s monotherapy or with obinutuzumab. It doesn’t matter [about] the age or if there’s palliative disease; most of the patients do better. Whether it’s the mutational status del(11q), del(17p) or not, everyone favored an acalabrutinib approach.

I think a deep response is needed if you’re going to do a finite therapy. But with BTK inhibitor use, we’ve noticed that even if you don’t get a complete response or a deep response, the longer you use these BTK inhibitors, the deeper the responses get. But if you are somebody who takes into account the response rates, acalabrutinib and obinutuzumab had the greatest response rate at 94% and complete response of 13%. Acalabrutinib monotherapy had about 85% response rate and chlorambucil/obinutuzumab had about 79% response rate.

OS was similar [for all 3 cohorts]. CLL is a disease that’s indolent, unless it’s high risk, so you need follow-up for many years if you’re going to realize any OS difference. Also, when patients progress, they can be retreated with good options. This is a crossover design, so we’re not going to see a lot of differences in the future.

As far as safety is concerned, about 12 patients had pneumonia on acalabrutinib plus obinutuzumab, and 5 patients on acalabrutinib monotherapy. There was some anemia, but overall low numbers. Febrile neutropenia was observed in 3 patients versus 2 patients, respectively. So these were low numbers and well tolerated. I’m sure this reflects the practice of those who have used the drug.

When you look at toxicities that are specific to BTK inhibitors, only 1 patient had atrial fibrilation [AF] of grade 3. Six patients had it of any grade. There was hypertension also developing over time; 5 patients had grade 3 hypertension. Major bleeding was seen in only 3 patients—1.7% in acalabrutinib plus obinutuzumab, and similarly low numbers with acalabrutinib monotherapy. Infections are part and parcel of CLL, unfortunately, because it’s an immune dysregulation with CLL, especially in the relapsed setting. That was seen in 20.8% at grade 3 with acalabrutinib plus obinutuzumab.

What other regimens are relevant for this patient?

Ibrutinib has been around for many years. The phase 3 RESONATE-2 trial [NCT01722487] looked at frontline ibrutinib for CLL.3 There were 269 patients either above 65 years or who had some comorbidities. Patients with del(17p) were excluded. They were randomized to ibrutinib 420 mg daily until progression or toxicity versus chlorambucil, which we’ve had for many years. That was the comparator many years ago. This was a crossover design, so 55 patients did cross over.

At 18-month follow-up, there was a big difference in the PFS between ibrutinib and chlorambucil [not reached vs 18.9 months; HR, 0.16; P <.001]. But we also have 5-year data. The median PFS still has not been reached, and chlorambucil [had a median PFS of 15 months; HR, 0.146].

The subgroup analysis showed del(11q), [which] is a bad prognostic marker. But if you use ibrutinib with del(11q) compared with ibrutinib without del(11q), it’s similar. When you use a chemotherapy approach [such as] chlorambucil, patients don’t do as well, and the patients with del(11q) do even worse.

When you look at IGHV status, patients with unmutated or mutated IGHV had similar [responses]. If you use chlorambucil, the patients with unmutated IGHV do worse than the ones with mutated IGHV.

Please describe the more recent data for this setting.

There are newer data, with the ECOG E1912 trial [NCT02048813].4 This was a groundbreaking trial because the idea was to see whether ibrutinib was better than FCR [fludarabine, cyclophosphamide, and rituximab], which has been the gold standard for many years. E1912 had new patients, previously untreated CLL, young patients [who were] able to tolerate FCR, because not everybody can do that. There were no patients with del(17p). Arm A was ibrutinib plus rituximab. Generally, rituximab was continued for 6 cycles, and then ibrutinib was continued until progression or toxicity. FCR was the standard 6 cycles, and for rituximab, the dosing was different.

The PFS at 48 months [showed] ibrutinib plus rituximab looked better. This was statistically significant [HR, 0.39; 95% CI, 0.26- 0.57; P <.0001]. OS was similar, so we’ll have to see how this pans out. But for now, it’s statistically significant; ibrutinib had 4 deaths, and chemotherapy had 10 deaths [HR, 0.17; 95% CI, 0.05-0.54; P <.001].

What are the data for treating patients with venetoclax?

The newest treatment on the block is the CLL14 trial [NCT02242942], which looked at obinutuzumab plus venetoclax versus chlorambucil and obinutuzumab in patients with previously untreated CLL.5 This was in the front line; they had to be patients unfit for chemoimmunotherapy. Obinutuzumab was 6 cycles, and venetoclax was [given for] 1 year. With chlorambucil and obinutuzumab, obinutuzumab was for 6 cycles and chlorambucil for 12 cycles. This was a randomized phase 3 clinical trial.

With a median follow-up of 28 months, venetoclax plus obinutuzumab—even though it was stopped at 12 months—still showed PFS superiority over chlorambucil and obinutuzumab, at 88% versus 64%, respectively. Even at 40 months, for venetoclax plus obinutuzumab, the median PFS had not been reached; this is statistically significant [HR, 0.31; 95% CI, 0.22-0.44; P <.0001].

As far as mutational status is concerned, if a patient’s disease is mutated, they do well [with venetoclax]. If [their disease is] unmutated, they do equally well, but there was a slight drop-off later on. The difference is even wider if you’re using chlorambucil and obinutuzumab.

The more interesting part is del(17p). The patients without TP53 mutations do well with venetoclax. There was a drop [after a while], so we have an idea that patients with del(17p) do poorly no matter what you do.

Looking at minimal residual disease [MRD], there’s low MRD negative, medium, and then there’s high MRD negative. We have many things showing that if your patient does achieve MRD-negative status with chemotherapy or these time-defined treatments, that does show that the PFS is longer. Even with this all-novel approach without chemotherapy, undetectable MRD was seen in the peripheral blood in 76% of the patients with venetoclax plus obinutuzumab. So two-thirds had MRD-negative status. If it was checked in the bone marrow, almost half the patients had undetectable MRD. Not as many patients had it with chlorambucil and obinutuzumab. This was checked 3 months after completion of treatment. It was the monoclonal antibody treatment that this was checked in. At 9 months, MRD was checked, and then at the end of treatment, as well.

These are important data. Even if you stop treatment at 12 months, [patients with undetectable MRD were] doing well. But later on, with venetoclax plus obinutuzumab and undetectable MRD, [patients] continue to do well. On chlorambucil and obinutuzumab, even if patients are undetectable, they drop off quickly.

In patients receiving venetoclax/obinutuzumab, if they’re MRD positive before they stop, the drop-off [in efficacy] starts happening. Unfortunately, if you can’t get a quick response, it doesn’t matter whether you stop or not; the drop-off continues.

_Reference:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/ small lymphocytic lymphoma; version 4.2020. Accessed August 25, 2020. http:// bit.ly/34vUU7s}

_{2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2}

_{3. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798. doi:10.1038/s41375-019-0602-x}

_{4. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443. doi:10.1056/ NEJMoa1817073}

_{5. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225‐2236. doi:10.1056/ NEJMoa1815281}