Evolving Data for CLL Set Stage for Frontline Therapy

William G. Wierda, MD, PhD

In the past 3 years, novel agents have shaken up the treatment landscape for patients with chronic lymphocytic leukemia (CLL). Deciding between agents in the first-line setting has become increasingly complex, as data for pathway inhibitors, specifically Bruton tyrosine kinase inhibitors (BTKis) and BCL-2 inhibitors, show promising therapeutic response. While individual patient risk factors such as comorbidities and age at diagnosis remain a key stratification factor, cytogenetic abnormalities including 17p deletions (del[17p]) and TP53 and IGHV mutations are reliable prognostic tools to identify patients with CLL who may be at a higher risk of early progression.¹

“Selection and choice of first-line therapy is an important decision to make for patients with CLL,” moderator William G. Wierda, MD, PhD, said. “We have options, and we have a lot of data to support our decisions. We also have prognostic factors to help us prioritize and select frontline therapy.” In a recent OncLive Peer Exchange^®, a panel of hematologic experts discussed the paradigm shift in frontline therapy options for patients with CLL. The panelists focused on the latest data for novel BTKis and discussed progress in overcoming acquired resistance to BCL-2 inhibitors.

Advances in BTKis

“There has been a very rapid shift in therapies for CLL. There have been many new approvals,” Nicole Lamanna, MD, said. She noted that FDA-approved BTKis now include ibrutinib (Imbruvica) and acalabrutinib (Calquence), which can be used as monotherapy or in combination with a CD20 monoclonal antibody in the first- and subsequent-line settings, and that she expects zanubrutinib (Brukinsa) to be approved as well.

Nicole Lamanna, MD

The recently published follow-up results from arm C of the SEQUOIA trial (NCT03336333), in which treatmentnaïve patients with the high-risk cytogenetic marker del(17p) received zanubrutinib, showed an overall response rate of 94.5% at a median follow-up of 18.2 months, with 3.7% achieving a complete response or complete response with incomplete bone marrow recovery, 87.2% a partial response (PR), 3.7% a PR with lymphocytosis, 4.6% stable disease, and 0.9% progressive disease.2 The estimated 18-month progression-free survival (PFS) rate was 88.6%, and the estimated overall survival rate was 95.1%. Treatment was generally well tolerated, with only 4 patients (3.7%) discontinuing treatment because of an adverse effect (AE). The most common AEs, occurring in at least 10% of treated patients, included contusion, upper respiratory tract infection, decreased neutropenia/neutrophil count, gastrointestinal effects including diarrhea, nausea, constipation, rash, back pain, cough, arthralgia, and fatigue.²

“We all would agree that for patients with a 17p or a TP53 abnormality, these are patients who should receive a novel agent. Our longest data happen to be with BTK inhibitors in this subgroup, but certainly there are data for venetoclax-based combinations as well in this poor prognostic group of patients. That’s an important factor to know about prior to treating your patient,” Lamanna said.

She also emphasized that patients’ chromosomal abnormalities may change following various treatments, making it important to assess patients’ cytogenetic markers before starting any subsequent treatments.

New and Emerging Venetoclax Combinations

Considerable progress has also been made with venetoclax, the first selective, orally bioavailable BCL-2 inhibitor. It has shown good therapeutic responses as a monotherapy in patients with CLL irrespective of the presence of adverse clinical or genetic features, including in patients with relapsed or refractory CLL.³ A challenge, however, has been that most patients ultimately become resistant to this treatment, which has led to the investigation of a variety of venetoclax combination approaches.³

“Recently, we had the [approval of] the BCL-2 inhibitor venetoclax in combination with obinutuzumab,” Lamanna said (Table⁴ ). Approval was based on data from CLL14 (NCT02242942), a randomized, multicenter, open label, actively controlled trial, which randomly assigned 432 patients with previously untreated CLL with coexisting medical conditions 1:1 to venetoclax (Venclexta) plus obinutuzumab (Gazyva) (VenG; n = 216) or obinutuzumab plus chlorambucil (GClb; n = 216).⁴ The primary end point was investigator-assessed PFS. Data from an updated analysis presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showed that after a median follow-up of 39.6 months, the median PFS was not reached in the VenG arm versus 35.6 months in the GClb arm (HR, 0.31; 95% CI, 0.22-0.44; P < .001). The estimated 3-year PFS rate was significantly higher in the VenG arm than in the GClb arm at 81.9% versus 49.5%, respectively. Benefit was observed regardless of high-risk cytogenetic features, including TP53 deletion/mutation or the presence of unmutated immunoglobulin heavy-chain variable region genes.⁴

Table. Trial Snapshot⁴

“The CLL14 study, in my opinion, is one of the most important studies for CLL,” Mazyar Shadman, MD, MPH, said. “Basically, it introduced time limits and chemotherapy-free treatment in the first-line setting. The benefit was seen in all the known risk groups for CLL, including those with TP53 abnormality or unmutated IGHV gene. So here, because we are talking about the fixed-duration therapy, the depth of response becomes very important and one of the secondary end points of this study was the rate of MRD [minimal residual disease] eliminations.” Three months after treatment completion, a higher rate of undetectable MRD (10^-4) was observed in the VenG arm (75.5%) versus in the GClb arm (35.2%; P < .001). Further, at 18 months after treatment, 47.2% of patients in the VenG arm had undetectable MRD compared with 7.4% in the GClb arm.⁴

Mazyar Shadman, MD, MPH

“This data is very impressive because we know from venetoclax-based therapies that the duration of response and progression-free survival are directly correlated with the depth of response, meaning that if you receive that undetectable MRD, the PFS would be longer,” Shadman said.

Additionally, venetoclax is showing promise combined with BTKis. “I should give credit to The University of Texas MD Anderson Cancer Center for publishing data that show for the first time the preclinical synergy between BTK inhibitors and BCL-2 inhibitors. We are seeing this now translate to clinical efficacy as well, not just additive properties between these drugs. We can utilize the modulation of different pathways and then hit them hard with both drugs,” John N. Allan, MD, said.

John N. Allan, MD

In a phase 2 study (NCT02756897) that assessed ibrutinib plus venetoclax in 80 previously untreated high-risk older patients with CLL who had del(17p), mutated TP53, 11q deletion, or unmutated IGHV, 88% had complete remission or complete remission with incomplete count recovery and 61% had remission with undetectable MRD after 12 cycles of combined treatment.⁵ Responses were observed across all risk groups. No new safety concerns were observed. Three patients had laboratory evidence of tumor lysis syndrome, but none developed clinical evidence of this complication or had to cease treatment because of it.

The panelists were particularly excited about upcoming updates from the phase 2 CAPTIVATE trial (NCT02910583), which they noted has 2 particularly well-designed cohorts that will enable cross-study comparisons to help answer some key questions in CLL.⁶ “We will find out if a patient population seems to benefit from maintenance. We’re going to start to learn what to do with MRD,” said Allan, who is an investigator on the trial. “The 25% of patients who don’t achieve MRD are randomized to monotherapy ibrutinib versus continuing the doublet of venetoclax and ibrutinib followed by a period of continual ibrutinib. That will be an interesting group to see who is not reaching MRD and then how well they do.” Allan explained this will help investigators determine if there is potential for MRD to deepen in those patients over time. “Right now, a lot of the data show that patients either reach MRD negativity or don’t within the first year or two. After the second year, MRD doesn’t seem to deepen. There is something about the biology of CLL that keeps MRD from deepening,” he said.

After this Peer Exchange, data from CAPTIVATE supported the fixed-duration treatment regimen of ibrutinib plus venetoclax in patients who had confirmed undetectable MRD, defined as undetectable in both peripheral blood and bone marrow serially over at least 3 cycles. Patients 70 years or younger received 3 cycles of lead-in ibrutinib followed by 12 cycles of ibrutinib plus venetoclax. The primary end point of disease-free survival (DFS) in these patients was defined as survival without progression or MRD relapse.

Of 149 randomized patients, 86 (58%) had confirmed undetectable MRD and were randomized to placebo (n = 43) or maintenance ibrutinib (n = 43). The 1-year DFS rate was not significantly different for patients who received placebo (95.3%; 95% CI, 82.7%- 98.8%) versus those who received ibrutinib (100%; 95% CI, 100%-100%; P = .1475).⁶

Full results will be presented at the 2020 American Society of Hematology Annual Meeting and Exposition.

What makes the ibrutinib and venetoclax combination particularly exciting is that it is a completely oral, once-daily, chemotherapy-free regimen, which is convenient for patients. Thus far, results from the MRD cohort that received 12 cycles of ibrutinib plus venetoclax prior to MRD-guided randomized treatment discontinuation showed high rates of undetectable MRD in peripheral blood and bone marrow.⁶

Other trials the panelists were excited about included A041702 (NCT03737981) and EA9161 (NCT03701282).^7,8 A041702 is a randomized phase 3 trial led by the Alliance for Clinical Trials in Oncology comparing ibrutinib plus obinutuzumab with an ibrutinib, obinutuzumab, and venetoclax triplet in previously untreated older adults (≥70 years) with CLL in need of therapy.⁸ The trial is still enrolling patients through the National Cancer Institute’s National Clinical Trials Network. Similarly, EA9161 is a randomized phase 3 trial comparing the same combinations in younger patients (≤ 69 years).⁸

“We are limited in terms of understanding the benefit of that anti-CD20, whether it is going to help or not. We’ll start to see MRD rates, and these are all very similar patient populations, so we will be able to make comparisons across studies to see if these MRD rates are any different or can have an additive effect,” Allan said, noting that these trials will help answer the question of whether patients can achieve an 80% bone marrow disease-negative state with the addition of an anti-CD20 to a BTKi and BCL-2 doublet.

Selecting Optimal First-Line Therapy

The panelists agreed that choosing between BTKi and BCL-2 inhibitor therapy in the firs line are highly individualized decisions. “The choice in my mind is probably going to be a BTK inhibitor versus venetoclax/obinutuzumab,” John M. Burke, MD, said. “The choice for me doesn’t have as much to do with the disease, the biology, the gene mutation, etc. A lot of it comes down to 2 other factors related to the patient and the patient’s preferences. For example, venetoclax/obinutuzumab is a 1-year fixed duration therapy. That’s a big difference from indefinite therapy with a BTK inhibitor,” he said.

John M. Burke, MD

The other factor is a patient’s comorbidities, such as the presence of underlying cardiac issues, atrial fibrillation, or use of an anticoagulation therapy, which will play a role in therapeutic selection based on the toxicity profiles of the agents, Burke added. “For the patient who doesn’t have an obvious contraindication, it comes down to patient preference.”

One notable exception is in patients who receive a diagnosis under aged 65 years, are deemed fit, or have an IGHV mutation and no del(17p) or TP53 aberrancy according to fluorescence in situ hybridization results. “That is a group of patients that seems to have a particularly good outcome with FCR [fludarabine, cyclophosphamide and rituximab (Rituxan)] and chemotherapy,” Burke said. “A significant percentage of this subset of patients treated with FCR continue to be disease free well beyond 10 years now. So I think the FCR regimen or something similar to that still comes into play as an option for those patients.”

References

1. NCCN Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic leukemia, version 1.2021. Accessed November 11, 2020. https://www.nccn.org/ professionals/physician_gls/pdf/cll.pdf
2. Brown JR, Roback T, Ghia P, Azhar A, Baig M. Efficacy and safety of zanubrutinib in patients with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with del(17p): follow-up results from arm C of the SEQUOIA (BGB-3111-304) trial. Blood. 2020;136(suppl 1):11- 12. doi:10.1182/blood-2020-134280
3. Tariq S, Tariq S, Khan M, et al. Venetoclax in the treatment of chronic lymphocytic leukemia: evidence, expectations, and future prospects. Cureus. 2020;12(6):e8908. doi:10.7759/cureus.8908
4. Al-Sawaf O, Zhang C, Tandon M, et al; CLL14 Study Investigators. Fixed-duration venetoclax-obinutuzumab for previously untreated patients with 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
5. Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380(22):2095-2103. doi:10.1056/NEJMoa1900574
6. Wierda WG, Tam CS, Allan JN, et al. Ibrutinib (Ibr) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 1-year disease-free survival (DFS) results from the MRD cohort of the phase 2 CAPTIVATE study. Blood. 2020;136(suppl 1):16-17. doi:10.1182/blood-2020-134446
7. Woyach J, Ruppert AS, Perez G, et al. Alliance A041702: a randomized phase III study of ibrutinib plus obinutuzumab versus ibrutinib plus venetoclax and obinutuzumab in untreated older patients (≥ 70 years of age) with chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):1751. doi:10.1182/ blood-2019-127102
8. EA9161 educational material. ECOG-ACRIN Cancer Research Group. Accessed November 11, 2020. https://ecog-acrin. org/clinical-trials/ea9161-educational-materials