ADVERTISEMENT
How I Treat: A Patient With Chronic Lymphocytic Leukemia With Deletion of 13q
Susan O’Brien, MD, University of California Irvine Medical Center, California, discusses frontline therapy she recommends for a patient with chronic lymphocytic leukemia (CLL) with a deletion of 13q, following 4 years of observation for disease progression.
Transcript:
Hi, I'm Dr. Susan O 'Brien, and I'm a professor of medicine at the University of California, Irvine Medical Center, the ChaoFamily Comprehensive Cancer Center. Today we're [going to] talk about the frontline treatment of a patient with [chronic lymphocytic leukemia] (CLL.)
In this case, we have a 66-year-old man who is referred to an oncologist after his [complete blood count] CBC, that was done as part of pre-op[erative] work for a knee replacement, showed he had lymphocytosis. The patient was completely asymptomatic. His past medical history was positive for kidney stones and well-controlled hypertension. He had not had any labs done in many years. His physical exam showed some shoddy cervical and axillary nodes, no palpable hepatosplenomegaly. His white [blood] count was about 32,000, mostly lymphocytes. [His] hemoglobin [was] 12.6, [and] platelets 120,000. Flow cytometry was done on the peripheral blood and was consistent with CLL, CD38 negative. At that time, he had a fluorescence in situ hybridization [FISH] panel that showed a 13q deletion, and his immunoglobulin heavy-chain variable region gene [IGHV] status was IGHV mutated. So, favorable characteristics.
Because he was asymptomatic and didn't have much disease, he was followed on a regular basis. About 2 years later, he now had some mild fatigue, [and] occasional night sweats. His nodes were a bit bigger, still no palpable hepatosplenomegaly. His white [blood] count was about 56,000. [His] hemoglobin was 11.8, so a little bit more anemic, but not terribly anemic. [His] platelets were 113. At that time, the plan was also [to] continue observation. He's followed periodically, and now he's about 4 years from diagnosis.
He has increasing fatigue and night sweats almost every night. He has 2-to-3-centimeter cervical nodes, 4-centimeter axillary nodes, and a 3-centimeter palpable spleen. His lymphocyte count is up to 74,000. He has a hemoglobin of 10.9 and platelets of 101. At this point, he has symptomatology with fatigue and night sweats, and he's fairly anemic. In fact, now his hemoglobin is below 11. At this point, we decide to start therapy. We repeat the FISH [panel] because we know that there can be clonal evolution over time, and now this is 4 years from the original diagnosis. The FISH [panel] shows a 13q deletion, so that hasn't changed. We also do a p53 mutation status and that shows [wild] types, so no p53 mutation. We don't have to repeat the immunoglobulin status, we know he's mutated and that never changes.
The question now would be what are the therapeutic options for this patient? We have 4 therapeutic options. We have the [Bruton's tyrosine kinase] (BTK) inhibitors, namely ibrutinib, acalabrutinib plus or minus obinutuzumab, or zanubrutinib, and then we also have venetoclax and obinutuzumab.
Let's look briefly at all of these. In 2022, we had the [8 years] long-term follow-up of the RESONATE-2 trial, that was the trial that led to the frontline approval of Ibrutinib, and that was in a randomized trial versus chlorambucil. [The] trial data showed that at 7 years, 59% of the patients were still in remission, so there still was an immediate progression-free survival, and really excellent data if the patient can tolerate the drug, and most [patients] can, because we know with the BTK inhibitors, it's continuous therapy, [so] the patient can stay in remission for a long time.
Something else that's important to point out is that unlike with chemo-immunotherapy, there is no difference in outcomes between those who are IGHV-mutated or unmutated, whereas with chemo-immunotherapy-based treatment, we know that the unmutated patients have a much shorter progression-free survival. At [the American Society of Hematology] (ASH) [meeting] last year, so only a couple months ago, we got [a] 6-year follow-up of the ELEVATE-TN study. That was a 3-arm randomized trial that led to the approval of acalabrutinib. That trial design was acalabrutinib plus obinutuzumab. In that case, the antibody was front-loaded and only given for 6 cycles, and then the acalabrutinib was given indefinitely, or a single agent acalabrutinib. or chlorambucil plus obinutuzumab.
Not surprisingly, both [acalabrutinib] arms produced a significantly longer progression-free survival. What was very interesting, though, is that [in] this 6-year follow-up, the median [progression-free survival] had not been reached, but it was 62 months with acalabrutinib and 78 months with acalabrutinib plus obinutuzumab, which to me was really interesting because remember, the antibody is only given for the first 6 months, and yet it seemed to be having this very significant impact with long-term follow-up. Since both arms were better than chlorambucil, both arms were approved by the FDA, so the physician can choose.
I [also] mentioned zanubrutinib; that drug was approved based on the SEQUOIA trial. That was a randomized trial in patients without deletion 17P who [were] randomized to zanubrutinib, again continuously, or bendamustine and rituximab. At the [International Conference on Malignant Lymphoma] (ICML) meeting last summer, we got an update with a median follow-up of about 3.5 years. What that showed is that [among] patients, at 3.5 years, 82% were still in remission. The bottom line is all these drugs are excellent. We do have differences in the toxicity profile. Both zanubrutinib and acalabrutinib are less likely to cause atrial fibrillation. And acalabrutinib is significantly less likely to cause hypertension, which of course might be very relevant in our case.
And then finally, the treatment that I would choose, is venetoclax and obinutuzumab. That received frontline approval based on the CLL14 trial, which was a randomized trial of venetoclax-obinutuzumab versus chlorambucil-obinutuzumab. The antibody, again, was front-loaded for 6 cycles. And then in either arm, the treatment was continued for a total of 1 year. What we see is that, unlike the BTK inhibitor regimens, the venetoclax-obinutuzumab is a finite therapy.
So, patients come off [the] drug and are done with treatment after 1 year. We recently got long-term follow-up [data] from that trial, [which] was presented at the European Hematology meeting last summer. The median progression-free survival for the whole group is 76 months, [which is] excellent. But here, unlike with the BTK inhibitors, there is a significant difference based on the IGHV mutation status. In unmutated patients, the median [progression-free survival] came in at about 64 months, [which is] quite good. Because remember, that's off therapy for several years, but the ones who are doing exceptionally well are the [patients with mutated disease].
We're at that 6-year follow-up, [and] about 80 % of them are still in remission. So, [this is] 5 years off therapy and still in remission if they're in that subset, which is where our patient is. The other thing to point out is that unlike the BTK inhibitors, there are no issues with cardiovascular side effects with this drug, so we don't have to worry about any worsening of the hypertension if we use this regimen.
That's why I would choose this regimen for this patient. It's a very well-tolerated regimen. There is the risk for tumor lysis [syndrome], [so] we do have to do tumor lysis monitoring as very clearly described in the package insert. The good news is once you get past the risk for tumor lysis, the drug is incredibly well-tolerated. Also, people only have to stay on it for 1 year which helps with compliance, and certainly helps from a financial point of view, since we know sometimes our patients have fairly large copays. In this example, venetoclax-obinutuzumab would be my [treatment] choice.
