Front-Line Nonchemotherapy Regimens May Improve Long-Term Outcomes in CLL

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An assortment of agents has been approved in the United States for the first-line treatment of chronic lymphocytic leukemia (CLL), and all of them are effective, explained Richard Furman, MD, of Weill-Cornell Medical College, NewYork-Presbyterian Hospital, New York. In the modern era, most patients with CLL are treated with nonchemotherapy regimens.

“We have a great selection of drugs for the treatment of CLL, but there are few data on their relative effectiveness to each other. Head-to-head studies of these drugs would take too long to complete and probably not teach us a whole lot. When we select first-line treatment for CLL, we have to consider toxicities and patient biases,” Dr. Furman told attendees at the virtual edition of the 2020 Chemotherapy Foundation Symposium.1

Richard Furman, MD

Richard Furman, MD

“Since the formal approval of fludarabine/cyclophosphamide/rituximab (FCR, a chemotherapy option) for the front-line treatment of CLL in 2010, every agent approved has been nonchemotherapy. This is the mark of a new era for patients with CLL, with none of the front-line regimens recommended in the NCCN Guidelines being chemotherapy.” Preferred regimens include ibrutinib, acalabrutinib or acalabrutinib plus obinutuzumab, or venetoclax plus obinutuzumab.

Observations from various clinical trials show that in treatment-naive CLL patients over the age of 65, 80% of patients can achieve long-term disease control on ibrutinib. There are insufficient data on the value of adding an anti-CD20 agent (rituximab or obinutuzumab) to a BTK inhibitor, and the optimal duration of treatment for venetoclax (a BCL2 inhibitor) remains unclear.

Clinical Trial Data

“We have a plethora of trials comparing chemotherapy vs nonchemotherapy in CLL,” said Dr. Furman. However, two of the most informative studies were the ALLIANCE A041202 and ECOG-ACRIN 1912.

The ALLIANCE trial enrolled 519 elderly, treatment-naive patients; they were randomly assigned to bendamustine/rituximab, ibrutinib/rituximab or ibrutinib as a single agent.2 Patients with (del)17p were included (ie, those with a poor prognosis). A significant benefit in progression-free survival was observed with single-agent ibrutinib vs bendamustine/rituximab (P < .001) and with ibrutinib/rituximab vs bendamustine/rituximab (P < .001), but there was no significant difference between these regimens in overall survival.

“This study allowed crossover at disease progression on bendamustine/rituximab to single-agent ibrutinib, and that might negate finding an overall survival advantage,” Dr. Furman stated.

“We have a great selection of drugs for the treatment of CLL, but there are few data on relative effectiveness.”
— Richard Furman, MD

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The ECOG-ACRIN 1912 trial randomly assigned treatment-naive patients with CLL younger than age 70 to receive ibrutinib/rituximab vs FCR.2 Patients with (del)17p were not included. The 3-year progression-free survival and overall survival rates were significantly superior for ibrutinib/rituximab vs FCR (P < .001 for both).

An interesting commentary by the ACOG-ACRIN 1912 lead author, Tate Shanafelt, MD, suggested a significant difference in cardiac adverse events between the ibrutinib arms in these two trials, with a significant increase risk in those over 65. “For both trials, grade 3 and higher toxicities were an important focus, particularly cardiovascular disease and deaths,” he said. The risk of cardiovascular disease and death was higher with ibrutinib than with bendamustine/rituximab in the ALLIANCE trial. There were more hematologic toxicities with FCR, and nonhematologic toxicities were more common with ibrutinib/rituximab in the ECOG-ACRIN 1912 study.3

“We have to think about adverse events and how they factor into overall survival,” Dr. Furman said. “The median age of patients in the ECOG trial was 57 years, compared with 71 years in the ALLIANCE trial. Older patients have an increased risk of atrial fibrillation and hypertension compared with younger patients. We can see the significant impact of age on developing cardiovascular adverse events.”

Novel Agents in CLL

Three classes of novel agents have been approved for the front-line treatment of CLL:

  • BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib (for mantle cell lymphoma, but approval expected soon for CLL)
  • PI3K inhibitors (idelalisib, duvelisib)
  • BCL2 inhibitor (venetoclax).

These three BTK inhibitors have a similar mechanism of action. So, if patients experience disease progression on one, they cannot move on to another, noted Dr. Furman. “I believe [once zanubrutinib is approved], these three agents will have equal applicability, but they have important differences,” he commented. They have differential effects on BTK and non-BTK enzymes as well as different half-lives.

“Keep in mind that they are covalent inhibitors. Therefore, when the inhibitor is metabolized from the serum, the covalently bound enzymes remain inhibited,” he continued.

Toxicities appear to be different as well. The most mature data are for ibrutinib; some adverse events occur early in therapy, with the exception of hypertension and atrial fibrillation, which can occur later. Longer follow-up is needed to characterize more fully the toxicities of the other two BTK inhibitors.


  • There are many recommended chemotherapy-free options for the first-line treatment of CLL: ibrutinib or ibrutinib plus rituximab; acalabrutinib or acalabrutinib plus rituximab; and venetoclax plus obinutuzumab.
  • The optimal duration of venetoclax administration is not established, nor is the added benefit of a CD20 inhibitor (rituximab, obinutuzumab).

Treatment-naive patients older than age 65 seem to do well on ibrutinib, Dr. Furman noted. In one study of relapsed or refractory CLL, at 7 years, 88% were progression-free.4 The 6-year overall survival rate with ibrutinib was 88% for treatment-naive patients and 58% for patients with relapsed or refractory CLL.

Patients with CLL treated with ibrutinib have a 1.9% risk of disease progression at 4 years if older than 65, do not have complex karyotype and no (del)17p; younger patients with cytogenetic complexity and (del)17p have a 44% risk of disease progression at 4 years.5

According to the results of the phase III, multicenter, open-label ELEVATE-TN study of treatment-naive patients aged 65 or older with CLL, acalabrutinib with or without obinutuzumab significantly improved progression-free survival compared with chlorambucil/obinutuzumab chemoimmunotherapy.6 Acalabrutinib appears to have fewer side effects than ibrutinib, noted Dr. Furman, and it is a new treatment option for patients with treatment-naive symptomatic CLL. “The second-generation BTK inhibitor acalabrutinib is on track to match ibrutinib,” Dr. Furman said.


The BCL2 inhibitor venetoclax has achieved attention in CLL because of its ability to achieve minimal residual disease (MRD) in the blood and bone marrow. The CLL14 trial randomly assigned 432 patients with treatment-naive CLL and coexisting conditions to receive fixed-dose venetoclax/obinutuzumab for six cycles vs chlorambucil/obinutuzumab for six cycles.7 Significantly more patients treated with venetoclax achieved MRD negativity in the peripheral blood and bone marrow compared with chlorambucil (P < .001). Progression-free survival was also significantly better with venetoclax, especially in MRD-negative patients.

However, Dr. Furman noted some study limitations. Progression-free survival is the most important endpoint for patients, not response or MRD negativity. Additionally, they gave only 1 year of venetoclax. The optimal duration of venetoclax therapy is unknown. We may be denying patients benefit by limiting their treatment to 1 year,” he commented.

“Another point is some MRD-negative patients experience disease progression, so stopping therapy at the point when MRD negativity is observed does not mean all is well,” Dr. Furman told listeners. “The optimal duration of treatment with venetoclax remains unclear.”

“Some MRD-negative patients experience disease progression, so stopping therapy at the point when MRD negativity is observed does not mean all is well.”
— Richard Furman, MD

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In addition, venetoclax plus obinutuzumab have been associated with tumor-lysis syndrome, infusion reactions (obinutuzumab), diarrhea, and nausea.

Closing Thoughts

Dr. Furman emphasized that most patients with CLL treated with ibrutinib will experience long-term disease control. Those 80% of patients still progression-free at 7 years may not require additional therapy as there may be a plateau. The important question is whether combinations of novel agents will be all that is necessary for the remaining 20%, he said.

Dr. Furman concluded: “The data are insufficient regarding the benefit of adding a CD20 inhibitor to ibrutinib or acalabrutinib. These agents are approved in combination with CD20 because that is the way they were studied.” 

DISCLOSURE: Dr. Furman has received honoraria from Genentech/Roche and Janssen; has served as a consultant or advisor to AbbVie, Acerta Pharma, AstraZeneca, BeiGene, Genentech/Roche, Incyte, Janssen Biotech, Loxo, OncoTracker, Pharmacyclics, Sunesis Pharmaceuticals, TG Therapeutics, and Verastem; has received research funding from Acerta Pharma and TG Therapeutics; has provided expert testimony for AbbVie and Janssen Oncology; has been reimbursed for travel, accommodations, or other expenses by Janssen Oncology and TG Therapeutics; and has held other relationships with AbbVie, Incyte, and Janssen Biotech.


1. Furman R: Choosing first-line therapy for CLL. 2020 Chemotherapy Foundation Symposium. Presented November 4, 2020.

2. Woyach JA, Ruppert AS, Heerema NA, et al: Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 379:2517-2528, 2018.

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

4. Byrd JC, Furman RR, Coutre S, et al: Up to 7 years of follow-up of single-agent ibrutinib in the phase 1b/2 PCYC-1102 trial of first line and relapsed/refractory patients with chronic lymphocytic leukemia/small lymphocytic leukemia. 2018 ASH Annual Meeting & Exposition. Abstract 3133.

5. Woyach JA, Ruppert AS, Guinn D, et al: BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol 35:1437-1443, 2017.

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

7. Fischer K, Al-Sawaf O, Bahlo J, et al: Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med 380:2225-2236, 2019.