Persky Reviews Therapies for Treatment-Naïve Chronic Leukocytic Leukemia

Daniel O. Persky, MD

During a virtual Targeted Oncology Case-Based Roundtable event, Daniel O. Persky, MD, professor of Medicine and associate Director, Clinical Investigations at University of Arizona Cancer Center, reviewed the case of a 61-year-old patient with chronic lymphocytic leukemia (CLL).

Targeted Oncology^TM: What do you think of these poll results?

PERSKY: Half chose ibrutinib [Imbruvica] and then the rest were split between 3 options: ibrutinib with anti-CD20 monoclonal, acalabrutinib [Calquence] with anti-CD20 monoclonal, and venetoclax [Venclexta] with anti- CD20 monoclonal, equally so. That’s interesting, which points out that we don’t have a standard of care in frontline CLL treatment.

How was the RESONATE-2 [NCT01722487] study designed to assess ibrutinib in the frontline setting for patients with CLL?

[Patients on the trial were] treatment naive had active disease and were over the age of 65.1 They had no deletion of the 17p gene and were stratified by performance status and Rai stage. There was 1:1 randomization to either standard ibrutinib 420 mg daily until disease progression, then conversion to extension study, or chlorambucil, on days 1 and 15 of 28-day cycle, up to 12 cycles. And then, allowing crossover, 55 patients crossed over to ibrutinib. This was first reported in 2015,1 and then there was an update this year.²

What were the key results of the study?

Progression-free survival [PFS] was looked at by an independent review committee. At 18 months follow-up, PFS was not reached versus follow up at 18.9 months, but both were clinically and statistically significant.¹ At 5-year follow-up, however, the difference in PFS has maintained itself.²

What other study assessed potential frontline treatments that could be used for this patient with CLL?

ECOG-E1912 [NCT02048813] was reported at the ASH [American Society of Hematology] meeting in 2018 and published shortly thereafter.³ This study looked at younger patients under the age of 70—that’s how they defined it— requiring treatment by International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Patients had good performance status; creatinine clearance over 40; were able to tolerate FCR [fludarabine, cyclophosphamide, rituximab (Rituxan)], importantly; and had no deletion of 17p, with a 2:1 randomization.

Arm A of the studywas ibrutinib with rituximab, and rituximab was introduced with cycle 2, eventually going up to 500 mg/m^2. After the first 7 cycles until progression, patients continued ibrutinib. Arm B was standard FCR for 6 cycles. The primary end point overall was PFS.

What key findings of this study might affect a treatment decision?

The initial report of the study was at 34 months. There was a significant difference both in PFS and overall survival [OS]. The 3-year PFS was 89.4% versus 72.9% [for ibrutinib/rituximab vs. chemoimmunotherapy]. Then 3-year OS was 98.8% versus 91.5%.³ These are great overall survival numbers.

In the IGHV-mutated [population], the PFS missed that statistical significance, and clinically, it was 88% versus 82%, so these are our favorable patients.⁴ Not much of a difference. However, for IGHV-unmutated [patients], there was a significant difference [89% vs 65%]. So this is a higher-risk group to consider treating.

What other combinations might be considered for this patient?

ELEVATE TN [NCT02475681] was reported at the last ASH 2019 and published in Lancet.⁵ This is a study that asked the question of whether adding an anti-CD20 monoclonal antibody to a BTK [Bruton tyrosine kinase] inhibitor makes a difference. These were treatment-na.ve patients with CLL, 65 or older, or younger but with significant comorbidities. [Patients had a] CIRS [Cumulative Illness Rating Scale] score—which is a fairly complicated assessment—of more than 6. [Investigators allowed patients with] deletion 17p, but stratified for it, and also stratified by performance status and geographic region. There was a 1:1:1 randomization to acalabrutinib 100 mg by mouth twice a day versus acalabrutinib plus obinutuzumab [Gazyva], starting with cycle 2, versus obinutuzumab with chlorambucil, 6 cycles.

The primary end point was independent review committee [IRC]–assessed PFS of acalabrutinib/obinutuzumab versus obinutuzumab/chlorambucil. Crossover from chlorambucil to acalabrutinib was allowed after progression.

Please describe the efficacy of these regimens.

With a median follow-up of 28 months—and this is IRC-assessed PFS primary end point—there was a superiority of acalabrutinibcontaining arms versus chlorambucil-based therapy. The acalabrutinib monotherapy was fairly comparable with acalabrutinib/ obinutuzumab, although the obinutuzumab-containing [Kaplan-Meier] curve was a little bit better.

The advantage [of acalabrutinib] versus chlorambucil pretty much persisted in all subgroups—about age, gender, Rai stage, performance status, and bulky disease as defined by 5-cm cutoff. Hard to see how to interpret the arms where it’s a little bit smaller of a group. Only for the IGHV-mutated population, acalabrutinib was not statistically significant.

Best overall response rate [was mostly] partial responses, but with longer exposure to inhibitors like BTK inhibitors and other novel agents, usually the response keeps improving. That’s why I think it’s important to look at the median follow-up. There was a greater proportion of complete response in the acalabrutinib/obinutuzumab arm compared with the other arms. There was significant crossover. The acalabrutinib/obinutuzumab versus obinutuzumab/chlorambucil [OS], clinically, is becoming significant.

There was bit more pneumonia in the acalabrutinib/obinutuzumab arm. Febrile neutropenia rates were fairly similar. If anything, chlorambucil had a bit more. Also interesting, [chlorambucil had] more tumor lysis syndrome. Any-grade atrial fibrillation was 3% to 4% for acalabrutinib and less than 1% for chlorambucil. There was more hypertension in the acalabrutinib/obinutuzumab arm.

Bleeding, as you would have expected, is going to be higher with a BTK inhibitor, at about 40% in those arms versus 12% with chlorambucil. Major bleeding was a lot less, but again, a bit higher with acalabrutinib-containing arms. Infections [were also] more with acalabrutinib.

What was another relevant trial of obinutuzumab?

The CLL14 trial [NCT02242942] investigated fixedduration venetoclax plus obinutuzumab. [Inclusion criteria were] elevated CIRS or reduced creatinine clearance.⁶ There was 1:1 randomization of obinutuzumab/venetoclax, with venetoclax starting after obinutuzumab, versus oral chlorambucil for 12 cycles, obinutuzumab for 6 cycles for 12 months.

There was superiority of PFS [with] venetoclax versus chlorambucil. This was persistent on the recent update, which was almost 40 months’ median follow-up.⁷

This study incorporated a lot of minimal residual disease [MRD] assessment at 3-month intervals. And, typically, undetectable MRD is a bit harder to reach in the bone marrow than peripheral blood. There was, again, significant difference [between the arms]. Patients who were MRD-negative had better PFS—not surprisingly. Even MRD-negative patients receiving chlorambucil/obinutuzumab had better PFS.

Cytopenias and febrile neutropenia were fairly similar [in both arms]. Most of the toxicities appeared to be fairly similar.

_References:

_{1. 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}

_{2. 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}

_{3. 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}

_{4. Shanafelt TD, Wang V, Kay NE, et al. Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 Trial. Blood. 2019;134(suppl 1):33. doi:10.1182/blood-2019-126824}

_{5. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-na.ve 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}

_{6. 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}

_{7. Al-Sawaf O, Zhang C, Tandon M, et al. Fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: follow-up of efficacy and safety results from the multicenter, open-label, randomized phase III CLL14 trial. J Clin Oncol. 2020;38(suppl 15):8027. doi:10.1200/JCO.2020.38.15_suppl.8027}