Chronic Lymphocytic Leukemia: New Treatments Achieve Deeper Remissions

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At the National Comprehensive Cancer Network® (NCCN®) 2020 Virtual Congress: Hematologic Malignancies, William Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center, Houston, reviewed current data on chronic lymphocytic leukemia (CLL), including promising new combinations of modern therapies that achieve deep remissions. He even hinted at the possibility of a cure for CLL in the future.1

“There has been a lot of progress [in CLL]. We have refocused on minimal residual disease [MRD] as an endpoint. We still have lot of work to do, but we expect long remissions and long treatment-free intervals with combinations of drugs we already have, and I am optimistic about curing these patients,” said Dr. Wierda.

William Wierda, MD, PhD

William Wierda, MD, PhD

“Treatment goals are changing,” he explained. “For progress in CLL, we would like to eliminate chemoimmunotherapy and replace it with combinations of small-molecule inhibitors with the goal of achieving deep remission. We are interested in refractory CLL and how to manage it. Immune reconstitution is important because patients with CLL are at higher risk for infections and second cancers,” he told listeners.

Minimal Residual Disease

Achieving undetectable MRD status was a goal of the treatment of CLL for many years when the standard treatment was chemoimmunotherapy, mainly rituximab plus chemotherapy. Then came the era of Bruton’s tyrosine kinase (BTK) inhibitors, where achieving MRD became less important because these drugs rarely achieve undetectable MRD. However, BCL2 inhibitors (ie, venetoclax) can achieve deep remission, and, as these agents are integrated into CLL regimens, the focus is back on MRD.

CLL is a multicompartmental disease that is present in the blood, lymph nodes, spleen, liver, and secondary lymphoid tissue. MRD can be detected in these compartments with standard multicolor flow cytometry, and molecular tests are also used. The U.S. Food and Drug Administration recently approved the ClonoSEQ assay to detect MRD.

“In a number of clinical trials in CLL, MRD status at the end of treatment correlated with progression-free survival and overall survival,” Dr. Wierda said.

The FCR300 trial showed that patients with mutated IGHV (a good prognostic feature) and undetectable MRD have significantly improved progression-free and overall survival with the chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab (FCR).2

“The goal is to achieve undetectable MRD in the bone marrow,” Dr. Wierda noted. “Patients who achieve this are potentially cured.”

Newly Diagnosed CLL

Essential tests for initiating treatment in newly diagnosed CLL include fluorescence in situ hybridization for detecting the percentage of cells with the del(17p) aberration, TP53 mutation status (which can change over time), and IGHV status (which does not change over time).

Six randomized phase III trials have compared BTK inhibitor–based therapy vs chemoimmunotherapy as first-line treatment:

  • RESONATE-2 (age > 65 years)
  • ILLUMINATE (all ages, with comorbidities)
  • Alliance A041202 (age > 65 years)
  • ECOG E1912 (age < 70 years, non–del[17p])
  • ELEVATE-TN (age ≥ 65 years, or > 18 years and < 65 years with cumulative illness rating scale score > 6 or creatinine clearance of 30–69 mL/min)
  • CLL14 (age ≥ 18 years, with cumulative illness rating scale > 6 or creatinine clearance of 30–69 mL/min).

All six trials were positive and showed improved progression-free survival with the BTK inhibitor–based treatment—ibrutinib or acalabrutinib—over chemoimmunotherapy. “These six studies showed superior outcomes with BTK inhibitors, and now they are used as first-line treatment,” Dr. Wierda told listeners.

In RESONATE-2, front-line ibrutinib overcame poor prognosis factors of del(11q) and unmutated IGHV vs chlorambucil.3 “11q is a high-risk feature with chemoimmunotherapy,” Dr. Wierda explained.

He said that outcomes are similar with chemoimmunotherapy regardless of IGHV status, but ibrutinib is superior in unmutated IGHV compared with chemoimmunotherapy. “Ibrutinib also has activity among patients with (del)17p and TP53 mutation. We still consider del(17p) a higher-risk feature, but patients with this genetic abnormality do remarkably better on BTK inhibitor therapy than with chemotherapy or chemoimmunotherapy,” he told the audience.

ECOG E1912 showed improved progression-free survival for ibrutinib/rituximab vs chemoimmunotherapy with FCR in newly diagnosed patients aged 70 years or younger.4

Acalabrutinib is a newer BTK inhibitor that has fewer off-target effects compared with ibrutinib, which is assumed to translate to an improved toxicity profile. Acalabrutinib is approved in CLL for the front-line and relapsed settings.

In the phase III ELEVATE-TN trial, acalabrutinib plus obinutuzumab was compared with chlorambucil plus obinutuzumab as front-line therapy.5 Estimated progression-free survival at 24 months was 93% with acalabrutinib/obinutuzumab, 87% with acalabrutinib monotherapy, and 47% with chlorambucil/obinutuzumab (P < .0001 for both regimens vs chlorambucil/obinutuzumab).

“We need further follow-up of this trial, and we need to determine whether continuous and indefinite treatment is needed. There is controversy about whether the CD20 antibody [ie, obinutuzumab] adds benefit to acalabrutinib in front-line treatment,” Dr. Wierda commented.

The CLL14 trial enrolled a frail population treated with venetoclax plus obinutuzumab vs chlorambucil plus obinutuzumab.6 At 18 months of follow-up, the venetoclax-based arm had undetectable MRD status in 47.2% of patients vs 7.4% for the control arm. “Venetoclax also converted patients from MRD-positive to MRD-negative. You can achieve a deeper remission with venetoclax,” he stated.

First-Line Treatment Choices for CLL

The choice of first-line treatment for CLL is guided by patient characteristics and the goals of treatment. Dr. Wierda’s stated preferences follow:

For patients with del(17p)/TP53 mutations, the goal is durable disease control. Do not use chemoimmunotherapy; use a BTK inhibitor with or without obinutuzumab. Reserve BCL2 inhibitor–based therapy for debulking.

For older unfit patients, the goal is durable control vs deep remission. For those with unmutated IGHV, consider patient preference and comorbidities. Continuous BTK inhibitor therapy with or without obinutuzumab is the first choice. For older unfit patients with mutated IGHV, a fixed-duration BCL2 inhibitor plus obinutuzumab is the first choice.

For young, fit patients (who comprise about 20% of all patients with CLL), the goals are durable control and deep remission. For unmutated IGHV, a fixed-duration BCL2 inhibitor plus obinutuzumab is recommended. For those with mutated IGHV, FCR-based chemoimmunotherapy is the best choice.

“I hope venetoclax will become standard therapy, but more follow-up is needed,” he said. Venetoclax is being studied as consolidation therapy after BTK inhibitor–based therapy in patients with newly diagnosed high-risk CLL. In that study, venetoclax is added if the patient is on a BTK inhibitor for more than 1 year.7 The primary endpoint is undetectable MRD in bone marrow after consolidation with venetoclax. At 12 months, 67% of patients had undetectable MRD status.

The benefit of adding a CD20 antibody (such as obinutuzumab) to venetoclax is not clear. Studies are evaluating this strategy. In the phase II CLL2-GIVE trial, 68% of patients with high-risk del(17p) and TP53 mutations had undetectable MRD at 18 months of follow-up on first-line treatment with a triplet combination of ibrutinib, obinutuzumab, and venetoclax.8

“For progress in CLL, we would like to eliminate chemoimmunotherapy and replace it with combinations of small-molecule inhibitors with the goal of achieving deep remission.”
— William Wierda, MD, PhD

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Relapsed or Refractory CLL

The rationale for combining ibrutinib and venetoclax is based on their nonoverlapping mechanisms of action and toxicity profiles. Ibrutinib clears CLL cells from the lymph nodes, whereas venetoclax clears the blood, and synergy has been seen in preclinical studies. Studies are ongoing with this combination. “We continue to see consistently good, deep, long-lasting responses,” he said.

The CAPTIVATE study, conducted in patients younger than age 70, evaluated MRD in patients with relapsed or refractory disease following chimeric antigen receptor T-cell therapy and treated them with ibrutinib plus venetoclax.9 At the end of 12 months, 72% had undetectable MRD in the bone marrow and 75% had undetectable MRD in the peripheral blood.

In the RESONATE phase III study, patients with relapsed CLL were treated with ibrutinib vs ofatumumab.10 Progression-free survival was superior with ibrutinib on long-term follow-up, but median overall survival was not significantly different between the two arms. Median progression-free survival was 88 months for those without del(17p) compared with 25 months for those with a complex karyotype and del(17p). “Even with the superior results for ibrutinib, we still worry about patients with the 17p deletion,” Dr. Wierda noted.

Other combinations are being studied in relapsed or refractory CLL. The ASCEND trial is evaluating acalabrutinib vs idelalisib or bendamustine/rituximab.11 Thus far, acalabrutinib appears to improve progression-free survival compared with the other two regimens; 12-month progression-free survival was 88% with acalabrutinib vs 68% with investigator’s choice.

The MURANO trial compared the combination of venetoclax given for 2 years and rituximab given for 6 months vs bendamustine/rituximab for 6 months in 389 patients with relapsed or refractory CLL.12 “Results were impressive in MURANO, with 60% of patients achieving undetectable MRD status. That is unexpectedly high for relapsed or refractory CLL,” Dr. Wierda said.

In the VENICE-1 trial, a lower rate of undetectable MRD status was observed in patients with relapsed or refractory CLL treated with venetoclax monotherapy: 26.9% in those previously treated with BTK inhibitors and 36% in those naive to BTK inhibitors.13 “In patients who are refractory to BTK inhibitors, relapses tend to be associated with specific mutations,” Dr. Wierda noted.

M14-032 is the first prospective study of a treatment for patients with CLL progression on a BTK inhibitor. In this study, venetoclax was active after ibrutinib therapy with durable clinical activity and favorable tolerability.14 Patients enrolled in this trial had a mean of four prior therapies, and 44% had del(17p). The objective response rate was 65%, and the complete response rate was 9%.

LOXO-305 is a highly selective BTK inhibitor designed to reverse the acquired resistance that develops in patients treated with BTK inhibitors. A small study showed that LOXO-305 achieved responses in patients previously treated with BTK inhibitors, including those with deleterious mutations.15 Dr. ­Wierda said he is looking forward to hearing an update of this study at the 2020 American Society of Hematology Annual Meeting & Exposition. 

DISCLOSURE: Dr. Wierda has served as a consultant or advisor to Sanofi and has received research funding from AbbVie, Acerta Pharma, Cyclacel, Emergent BioSolutions, Genentech, Gilead Sciences, GlaxoSmithKline/Novartis, Janssen, Juno Therapeutics, Karyopharm Therapeutics, Kite Pharma, Loxo, miRagen Therapeutics, Oncternal Therapeutics, Pharmacyclics, Sunesis Pharmaceuticals, and Xencor.


1. Wierda W: Updates in the management of chronic lymphocytic leukemia/small lymphocytic lymphoma: Sequencing therapy and the role of MRD testing. NCCN 2020 Virtual Congress: Hematologic Malignancies. Presented October 9, 2020.

2. Thompson PA, Tam CS, O’Brien S, et al: Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 127:303-309, 2016.

3. 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 34:787-798, 2020.

4. Shanafelt TD, Wang XV, Kay NE, et al: Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med 381:432-443, 2019.

5. Sharman JP, Egyed M, Jurczak W, et al: Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukemia (ELEVATE-TN): A randomized, controlled, phase 3 trial. Lancet 395:1278-1291, 2020.

6. Al-Sawaf O, Zhang C, Tandon M, et al: Fixed-duration venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukaemia: Follow-up of efficacy and safety results from the multicenter, open-label, randomized phase 3 CLL14 trial. European Hematology Association Virtual Congress 2020. Abstract S155. Presented June 12, 2020.

7. Thompson PA, Keating MJ, Jain N, et al: Venetoclax added to ibrutinib in high-risk CLL achieves a high rate of undetectable MRD. Blood 134(suppl 1):358, 2019.

8. Huber H, Edenhofer S, von Tresckow J, et al: CLL2-GIVE: A prospective, open-label, multicenter phase-II trial of obinutuzumab, ibrutinib, plus venetoclax in untreated patients with CLL with 17p deletion/TP53 mutation. European Hematology Association Virtual Congress 2020. Abstract S157. Presented June 12, 2020.

9. Tam CS, Siddiqi T, Allan JN, et al: Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the MRD cohort of the phase 2 CAPTIVATE study. Blood 134(suppl 1):35, 2019.

10. Byrd JC, Hillmen P, O’Brien S, et al: Long-term follow-up of the RESONATE phase 3 trial of ibrutinib vs ofatumumab. Blood 133:2031-2042, 2019.

11. Ghia P, Pluta A, Wach M, et al: ASCEND: Phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 38:2849-2861, 2020.

12. Seymour JF, Kipps TJ, Eichhorst B, et al: Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl Med 378:1107-1120, 2018.

13. Kater AP, Arslan O, Demikran F, et al: Efficacy of venetoclax in patients with relapsed/refractory chronic lymphocytic leukemia: Primary endpoint analysis of the international phase 3B trial (VENICE-1). European Hematology Association Virtual Congress 2020. Abstract S156. Presented June 17, 2020.

14. Jones JA, Mato AR, Wierda WC, et al: Venetoclax for chronic lymphocytic leukemia progressing after ibrutinib: An interim analysis of a multicenter, open-label, phase 2 trial. Lancet Oncol 19:65-75, 2018.

15. Mato AR, Flinn IW, Pagel JM, et al: Results from a first-in-human proof-of-concept phase 1 trial in pretreated B-cell malignancies for Loxo-305, a next-generation, highly selective, non-covalent BTK inhibitor. Blood 134(suppl 1):501, 2019.