Roeker Discusses the Important Data to Consider in Managing Newly Diagnosed CLL

Lindsey Roeker, MD

Hematologic Oncologist

Memorial Sloan Kettering Cancer Center

New York, NY

Targeted Oncology^TM: How do you assess risk for patients with newly diagnosed CLL? What is your approach toward cytogenetic and molecular testing at your institution?

ROEKER: Based on the National Comprehensive Cancer Network [NCCN] guidelines, before starting treatment, [we] test FISH, which for most panels includes trisomy 12 and deletion of [chromosomes] 17p, 11q, and 13q. Often they also include translocation of [chromosomes] 11 and 14 just to help with ensuring the diagnosis is correct. The TP53 and IGHV mutational testing is done through next-generation sequencing [NGS]. [Karyotyping of stimulated CLL cells is also part of the prognostic information for CLL.]¹

Is testing for TP53 the same as the FISH testing for del(17p)?

The deletion of 17p [testing] is looking for the absence of the TP53 gene, whereas the TP53 mutational testing is looking for that change in an existing gene. They are separate and there are patients who can have one or the other. They can also co-occur, so you can have deletion of 17p, meaning you only have 1 copy left but then that copy that’s left also can be mutated. The major way that I use these is in a [patient] who has high-risk disease and that just takes [frontline] chemoimmunotherapy fully off the table.

The informCLL disease registry was a big registry of a lot of different community practices that looked at how often [prognostic biomarker] testing was performed. In the frontline setting, 57% of [clinicians] seemed to not be doing FISH and then TP53 mutational testing isn’t being done for the majority, 81%.

[These tests are done] relatively infrequently, and I think part of the reason is [clinicians don’t know] how to send for testing if [they] don’t have a streamlined relationship with a laboratory. We all know that requisition tests can be very annoying, but this is a reminder that the standard approach would be doing both of those. This registry opened our eyes as a community to see that we can probably do some more of this testing upfront. The other thing to remember is IGHV mutational testing never changes over time, so you only do it once and then you’re good for the duration of the patient’s course.²

What are the study data and recommendations that guide therapy in the frontline setting?

Some of the frontline data come from the phase 3 RESONATE-2 study [NCT01722487].³ This was a study that looked at patients who were older, which was defined as older than 65 [years], but not that much older. Between the ages of 65 and 69 years, patients had to have a comorbidity that precluded fludarabine, cyclophosphamide, rituximab [(Rituxan) FCR], or they had to be [70 years or older].

They did not include patients with deletion of [chromosome] 17p. This was the first frontline study with no deletion-17p patients. They did not specify TP53 mutational status. Patients were stratified based on performance status and Rai stage, and they either received ibrutinib [Imbruvica] or chlorambucil [Leukeran]. The median age in this population was 72 years, and the primary end point was progression-free survival [PFS].^3,4

We now have 7 years of long-term follow-up from this study and the median PFS still has not been reached for the ibrutinib arm. There’s an 84% risk reduction in progression or death, and at the 6.5-year mark, 61% of patients treated with ibrutinib were still progression free and alive. The responses do seem to deepen, so the complete response [CR] seems to grow over time with ibrutinib.⁵

The prespecified subgroups they looked at were age, Rai stage, ECOG [performance status], bulky disease, and [if they were] high-risk, which were TP53 mutated, deletion of 11q, or unmutated IGHV. Across all the subgroups, ibrutinib was superior to chlorambucil, including in those with high-risk disease.⁵

There didn’t seem to be a significant difference based on IGHV mutational status in patients treated with ibrutinib, but for chlorambucil IGHV-mutated patients did better than unmutated [patients with chlorambucil]. For the overall survival [OS] after 7 years of follow-up, 78% of patients are alive and the 5-year OS rate was 83% in a group that was designed to be older and did have some comorbidities.

After 7 years of follow-up, notably, 47% of [patients] were still on ibrutinib, which means that 53% were not. Of those discontinuations, [approximately] half of them are due to adverse events [AEs]. This is just a reminder that [patients] stop ibrutinib for progression [and] also for the toxicity. It is important to remember that managing these AEs is an important part of putting [patients] on ibrutinib.

The concomitant medication for those in the study is a good reminder that so many patients need acid-blocking medications or use them at some point. For the total population of ibrutinib-treated patients, 65% at some point during treatment required an acid-reducing medication including 56% who took a proton pump inhibitor [PPI].

Are there other studies clinicians should consider?

The ELEVATE TN [NCT02475681] is a phase 3 frontline study that looked at acalabrutinib [Calquence]-containing regimens. It was in patients who were either aged over 65 years or under 65 years with comorbidities. Patients were stratified based on deletion of chromosome 17p, performance status, and geographic region. Patients were randomized to acalabrutinib with or without obinutuzumab [Gazyva] vs obinutuzumab with chlorambucil. Crossover was allowed from obinutuzumab plus chlorambucil to acalabrutinib. The primary end point was PFS.⁶

The investigator-assessed estimated PFS at 48 months for acalabrutinib monotherapy was 78%; for acalabrutinib with obinutuzumab it was 87%, and that is a significant difference. When talking about whether to add a CD20 into the regimen, [these are] the PFS data that I talk to patients about. It’s a significant change, but both regimens performed well. It’s obviously significantly better than obinutuzumab by itself.⁷

[For the PFS] stratified by IGHV mutational status, the unmutated IGHV patients have percentages that are similar to the overall population, so it doesn’t seem that there’s a significant detriment to having IGHV-unmutated disease. For deletion 17p or mutated TP53, the PFS at 48 months is closer to 75%, and these are the higher-risk patients.

The investigator-assessed OS showed no benefit between the acalabrutinib-containing arms and the obinutuzumab plus chlorambucil arm, although crossover was allowed, so we’ll see what happens with further follow-up but with that crossover, it is obviously challenging to demonstrate an OS benefit.⁶

What was the safety profile of this therapy?

For the safety profile of acalabrutinib, [approximately] 40% of patients with acalabrutinib plus obinutuzumab and 30% of patients with acalabrutinib alone experience some severe AEs with the most common one being pneumonia. The AEs of clinical interest include atrial fibrillation in [approximately] 3% to 4% of those treated in the acalabrutinib-containing arms.

Hypertension is a little more common at 7.3% for the acalabrutinib plus obinutuzumab arm vs 4.5% for acalabrutinib alone. Bleeding of any grade happens in [approximately] 40%, but major bleeding events are relatively rare at 2.8%.^6,8 The NCCN guidelines highlight the drug-drug interactions. Remember with acalabrutinib you must think about acid-blocking medications. If you’re going to have a patient on a H2-receptor blocker, it is a good idea to time it after the dose.

Also, chloroquinolines increase acalabrutinib levels: When we think about acalabrutinib vs ibrutinib, there have been different reports in terms of rates of hypertension and atrial fibrillation.¹

Please discuss how the CLL14 study [NCT02242942] affects your decision-making.

[This study] looked at patients with comorbidities—those with a cumulative illness rating scale greater than 6 or creatinine clearance under 70 mL/min. Patients were randomized to either venetoclax [Venclexta] plus obinutuzumab or chlorambucil plus obinutuzumab for 12 months, and the primary end point of the study was PFS.⁹

At 52.4 months, there was a significant PFS benefit for venetoclax plus obinutuzumab over chlorambucil plus obinutuzumab, and the minimal residual disease undetectable rate at a threshold of 10^-4 was 76% for the venetoclax plus obinutuzumab arm vs 35% for the chlorambucil plus obinutuzumab arm.

The PFS stratified by IGHV and TP53 mutational status showed that patients with mutated disease had some separation of the curves [at approximately] the 30-month mark.

That’s why for patients with TP53 aberrations, whether that’s deletion of 17p or mutated TP53, I do tend more toward the [Bruton tyrosine kinase]–based approach because of the inferior PFS. Although you could similarly argue that because of the high-risk disease, they [don’t do as] well. There haven’t been head-to-head comparison data, but I don’t think it’s necessarily wrong to use the CLL14 data now.¹⁰

Regarding AEs, 60% [of patients] had some cytopenia with venetoclax plus obinutuzumab, the most common one being neutropenia. Other AEs included infusion-related reactions in 9% and infections in [approximately] 18%. The neutrophil count decrease and neutropenia were complementary.⁹

_REFERENCES

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_{2. Mato AR, Barrientos JC, Ghosh N, et al. Prognostic testing and treatment patterns in chronic lymphocytic leukemia in the era of novel targeted therapies: results from the INFORM CLL registry. Clin Lymphoma Myeloma Leuk. 2020;20(3):174-183.e3. doi:10.1016/j.clml.2019.10.009}

_{3. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388}

_{4. 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}

_{5. Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210}

_{6. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab 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}

_{7. Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. Published online January 1, 2022. doi:10.1038/s41375-021-01485-x}

_{8. Calquence. Prescribing information. AstraZeneca Pharmaceuticals LP; 2019. Accsessed March 30, 2022. https://bit.ly/3D6nThH}

_{9. 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}

_{10. Al-Sawaf O, Zhang C, Lu T, et al. Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study. J Clin Oncol. 2021;39(36):4049-4060. doi:10.1200/JCO.21.01181}