Hoffman Decides on BTK Inhibitor Therapy in a Patient With Relapsed CLL and Del(17p)

Marc Hoffman, MD

During a Targeted Oncology Case Based Peer Perspective event, Marc Hoffman, MD, assistant professor, Division of Hematologic Malignancies and Cellular Therapies, University of Kansas Medical Center in Kansas City, KS, reviewed the case of a 53-year-old woman with relapsed chronic lymphocytic leukemia (CLL) and evaluates how he would make his treatment considerations for this patient case, including the Bruton's tyrosine kinase (BTK) inhibitors.

Targeted Oncology™: What therapy options are there for this patient with del(17p) and TP53-mutated CLL?

HOFFMAN: In terms of suggested therapy for del(17p) or TP53-mutated disease, acalabrutinib [Calquence], ibrutinib [Imbruvica], and venetoclax [Venclexta] versus rituximab are all category 1 [recommendations from the National Comprehensive Cancer Network guidelines for CLL].¹ The longest [clinical] experience is certainly with ibrutinib in this setting. It has been approved the longest and had approval [for TP53 mutations and del(17p)] since being approved, broad spectrum, for all up-front therapy.² All the other regimens have been tested in this setting, and the PI3K inhibitors, idelalisib [Zydelig] and duvelisib [Copiktra], have activity here.

Which data support the use of ibrutinib, which has the longest clinical experience in patients such as this one?

The RESONATE trial [NCT01578707] is what I was referring to earlier. This is the trial with ibrutinib versus ofatumumab, and this was in the relapse setting. Ofatumumab largely fell out of fashion. It was broadly similar to rituximab in terms of the activity level at the time that this study was designed; it was a reasonable comparator. Crossover was permitted in this particular study, and patients were allowed to have del(17p).³

I don’t think I am giving you any [new information] here that ibrutinib is better than ofatumumab. In this particular study in the relapse setting, there was an overall survival [OS] benefit that was seen in spite of the fact that patients were allowed to cross over. With 6 years of follow-up data, [progression-free survival (PFS) was superior with ibrutinib, and] the ofatumumab arm was not particularly interesting [HR, 0.133; 95% CI, 0.099-0.178]. It is interesting that when you look at the long-term follow-up, even in the relapse setting, you’re getting a long-term and robust activity with persistent disease control in these patients [on ibrutinib]. [In patients with] mutated versus unmutated IGHV, it’s the same story that we have been seeing; the ibrutinib-treated population is going to do just as well [HR, 0.808; 95% CI, 0.430- 1.518]. In terms of the del(17p) or deletion 11q [del(11q)], the ibrutinib-treated patients [with] del(17p) still do a bit worse. The patients with del(11q) do a bit better, which is an interesting finding. I think this is largely just a numbersbased phenomenon.

In terms of the OS, there was a benefit for the initiation of ibrutinib over ofatumumab. The [Kaplan-Meier curve for survival] started to come back together, and a lot of this was probably due to crossover. But there was an early survival advantage. If you want your patients to live longer, ibrutinib is certainly a better drug than ofatumumab.

What are the adverse effects (AEs) of therapy associated with ibrutinib based on the data from RESONATE?

The long-term AEs [are] broadly consistent with what we see with the experience with ibrutinib. Most of the toxicities that you see are going to present within the first 6 months. There have been a couple of publications on this. The 1 exception to this is hypertension, which is a more long-term phenomenon. [There was] a later treatment emergence of hypertension in these patients. It is generally not severe or uncontrollable, but it is something that is worthwhile to look into.

Would you consider using acalabrutinib to treat this patient instead? What data support this regimen?

The ASCEND trial [NCT02970318] was looking into acalabrutinib versus rituximab plus idelalisib [IdR] or bendamustine [BR]. This was given at the investigator’s discretion. The primary end point was PFS, and patients with del(17p) were allowed. The majority of patients in the BR and IdR arm were given the idelalisib and not BR.⁴ The PFS shows an advantage for acalabrutinib over IdR and BR [HR, 0.31; 95% CI, 0.20-0.49; P <.0001]. This is a study looking at acalabrutinib versus idelalisib. The number of patients who received BR was only around 30. There is a clear PFS advantage to giving BTK [Bruton tyrosine kinase] inhibition in this setting.

The forest plot [showed that] pretty much under any circumstances you are going to do better [with acalabrutinib]. In this particular case presentation, in a patient that does have del(17p), you do have a significant advantage compared with the IdR or BR.

What safety data came out of ASCEND?

The BR-arm safety analyses were only 6 months, whereas for the IdR and acalabrutinib groups, AEs were reported for the duration of the treatment. There are some unique AEs of acalabrutinib. The AE-grade headache will emerge in the first 6 to 8 weeks if a patient does get it. Typically, you counsel them that this is an expected AE. The hematologic toxicities associated with idelalisib are significantly greater than those of acalabrutinib. For those [clinicians] who do have some experience with it, I don’t think that is surprising. In terms of idelalisib versus BR, the chemotoxicities are broadly similar, but there are a fair number of other low-grade toxicities that patients get at a broadly similar rate in the acalabrutinib and idelalisib arms.

What do you think of the answers to this poll?

I agree [with the responses]. Fortunately, we will have headto- head data in terms of ibrutinib versus acalabrutinib. I don’t think any of us are going to be particularly keen on looking at the efficacy data because it’s broadly considered that these drugs don’t differ a lot. But I think that having a true objective assessment of their safety profiles on a long-term basis in patients on a rigorous clinical trial will be extremely helpful for everyone to sort this out.

Are there other agents besides BTK inhibitors that could be considered for this patient?

The MURANO trial [examined] venetoclax plus rituximab versus BR [NCT02005471]. Patients were randomized in a 1:1 fashion, and this was in relapsed patients. Specifically, patients with del(17p) were allowed, much to the consternation of some of us, but that is the way that the study was designed. [Patients could] have up to 3 prior lines of therapy.5 In terms of the 4-year analysis, which was presented at the most recent ASH [American Society of Hematology Annual Meeting], the long-term data—and if you recall the venetoclax was given for 2 years and BR was given in the standard fashion—[show] a clear PFS benefit to giving rituximab and venetoclax in this setting [HR, 0.19; 95% CI, 0.13-0.28; P <.0001].

The OS [rate at 4 years] is greater if you give the venetoclax and rituximab versus BR [85.3% vs 66.8%, respectively]. This is compelling and it nails the coffin on BR, at least in the relapsed setting. You should not be giving this in the relapse setting. The hazard ratio [for OS] is 0.41; it’s a rather compelling hazard ratio in favor of survival for venetoclax. In terms of the subgroup analysis, there is a similar forest plot to what we’ve seen previously in a lot of the other settings. [Data indicate that] regardless of what baselines characteristics patients have, they do better with a venetoclax-based combination; del(17p) is no exception. In terms of secondary end points, there was the MRD [minimal residual disease] analysis that was performed. The MRD negativity rates were higher in patients that had a venetoclaxbased therapy versus BR, which I don’t think was surprising to a lot of us. Again, the CR [complete remission] rates are a bit less than you see with the MRD negativity rates. At the 4-year follow-up, the patients who did achieve MRD negativity frequently did not progress. Typically, if we get a patient to MRD negativity, they are a lot less likely to progress than if [we] didn’t. An interesting research question is [regarding] the 11 patients who had undetectable MRD status and did progress. What is going on with those patients? We are not sure. That is definitely an unmet need here.

What are the AEs associated with venetoclax?

In terms of the AEs here, you must keep in mind that the venetoclax arm was on treatment for 2 years and the BR arm was on treatment for 6 months. There was neutropenia. In terms of TLS [tumor lysis syndrome], there is a considerable risk with the drug. It almost died in production due to significant TLS that was seen. You do need to...do a dose-expansion strategy in order to mitigate against the TLS risk.

Richter’s transformation is indifferent [to either therapy], and the [incidence of] second primary malignancies was higher in the venetoclax arm. Keep in mind, this is a group of patients with CLL that have a high risk of getting secondary cancers. The venetoclax arm was on treatment for 2 years and the BR arm was on treatment for 6 months, so I don’t necessarily know that that is an adequate comparison of [this incidence].

_References

_{1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 4.2020. Accessed December 20, 2019. http://bit.ly/3jemRoI}

_{2. U.S. FDA approves Imbruvica (ibrutinib) for first-line treatment of chronic lymphocytic leukemia. News release. Janssen Biotech Inc. March 4, 2016. Accessed August 25, 2020. http://bit.ly/3leAq9f}

_{3. 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}

_{4. 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). Abstract presented at: 24th European Hematology Association Congress; June 13-15, 2020; Amsterdam, Netherlands. Accessed August 26, 2020. http://bit.ly/2Eskpfj}

_{5. Seymour JF, Kipps TJ, Eichorst BF, et al. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia - results from pre-planned interim analysis of the randomized phase 3 MURANO study. Blood. 2017;130 (suppl 1):LBA-2. doi:10.1182/blood.V130.Suppl_1.LBA-2}