Chemotherapy Poised to Have Minor Role in Future CLL Treatment

The day is approaching that chemotherapy may be unnecessary for the treatment of patients with chronic lymphocytic leukemia.

Matthew S. Davids, MD, MMSc

The day is approaching that chemotherapy may be unnecessary for the treatment of patients with chronic lymphocytic leukemia (CLL), but “we’re not quite there yet,” said Matthew S. Davids, MD, MMSc, in a presentation addressing the issue at the 23rd Annual International Congress on Hematological Malignancies® held in Miami, Florida.1

Fludarabine, cyclophosphamide, and rituximab (Rituxan), or FCR, is a compelling option in frontline CLL, Davids said, basing that on long-term data from a study of 300 patients given FCR. At the median follow-up of 12.8 years, the progression-free survival (PFS) rate was 30.9% (median PFS, 6.4 years). However, the 12.8-year PFS rate was 53.9% for patients with mutated IGHV and 8.7% for patients with unmutated IGHV.2

Davids, who is the associate director of the CLL Center at Dana-Farber Cancer Institute and assistant professor of medicine at Harvard Medical School, noted that bendamustine/rituximab (BR) is highly active as frontline therapy and is widely used in community practice. However, he cautioned that randomized data from CLL10 showed a median PFS of 55.2 months for FCR-mutated IGHV and 41.7 months for BR-mutated IGHV (P <.001) and a median overall survival (OS) rate at 36 months of 91% and 92% for FCR and BR, respectively (P = .897).3 “There’s very good PFS in the frontline for FCR as opposed to BR, particularly in the IGHV group, and that’s the group where you want to think about FCR if they’re young enough and fit enough to tolerate it,” Davids said.

Obinutuzumab (Gazyva) plus chlorambucil shows activity and is well tolerated as frontline therapy for older, frail patients, based on data from CLL11. Improvements in response, depth of response, and some minimal residual disease negativity translated into a significant PFS rate of 50% at 29.2 months, he noted.4 “The time-to-next-treatment is [42.7 months]. You can actually get durable benefit from 6 months of therapy, although without the risks that we see with other agents.”

In terms of novel agent frontline options, 4-year updated data from the RESONATE-2 trial of ibrutinib (Imbruvica) versus chlorambucil showed that the median PFS was not reached in the ibrutinib cohort versus 15 months for chlorambucil (HR, 0.137; 95% CI, 0.090-0.210). Notable was that PFS was “excellent” in high-risk patients with del(11q) or unmutated IGHV. Discontinuation due to adverse events (AEs) decreased over time, with 65% of patients treated with ibrutinib continuing daily treatment.5 However, Davids noted, in this analysis, only about two-thirds of patients on ibrutinib remained on the drug due to progression and tolerability issues.

Davids also reviewed data presented late last year from the E1912 study of patients under the age of 70 with previously untreated CLL randomized to either ibrutinib with rituximab (IR) or standard-of-care FCR. The IR regimen was given for about 6 months and then ibrutinib as monotherapy until disease progression or tolerability issues. The study excluded patients with del(17p). AE incidence between the IR (n = 352) and FCR (n = 158) arms included neutropenia 22.7% and 43.7%, respectively; anemia, 2.6% and 12.0%; thrombocytopenia, 2.9% and 13.9%; and any infection, 7.1% versus 19.0%.6

Davids noted “dramatic” improvements in PFS. At a median follow-up of 33.4 months, the hazard ratio (HR) for PFS favored IR over FCR (HR, 0.352; 95% CI, 0.223-0.558; P <.00001). The HR for OS also favored the IR arm (HR, 0.168, 95% CI 0.053-0.538; P = .0003). IR also delivered superior results for IGHV unmutated disease (HR, 0.262; 95% CI; 0.137-0.498; P <.00001) but not IGHV mutated (HR, 0.435; 95% CI, 0.140-0.1350; P = .07).

“I think we were all surprised by the significant OS benefit for IR that was observed relatively early in this frontline study. It’s quite striking, actually, and our initial thought was, could these be [due to] infectious issues from FCR.” But according to the investigators it was CLL progression events in the FCR-treated patients, and so “that does give us pause to think about which specific patients may benefit from FCR.”

Davids also discussed the Alliance North American Intergroup Study A041202 of ibrutinib alone or in combination with rituximab versus BR in untreated older patients with CLL. Fresh data from this trial were presented at the 2018 ASH Annual Meeting. This population included del(17p) and TP53 mutation—positive patients. About 60% of patients had IGHV-unmutated disease.7

There were 2 deaths (1%) in the BR arm, 7 (4%) in the ibrutinib arm, and 4 (2%) in the IR arm. “We know that there are cardiovascular risks with ibrutinib and that does speak to patient selection in terms of who we are putting on ibrutinib,” Davids said.

PFS was the primary endpoint, and the 24-month estimated PFS rate was 74% for BR; 87%, ibrutinib; and 88%, IR. Both of the ibrutinib regimens were dramatically better by this measure, or ≤14 percentage points higher than with BR, Davids noted. “The other interesting thing was there was no benefit from a PFS perspective to adding rituximab.”

For the IGVH-mutated subgroup, the respective 24-month estimated PFS numbers were 87% (n = 52), 86% (n = 45), and 88% (n = 45) for BR, ibrutinib, and IR, respectively.

A third study Davids highlighted from the ASH meeting was iLLUMINATE, which randomized patients ≥65 years of age with previously untreated CLL to ibrutinib/obinutuzumab versus chlorambucil/obinutuzumab. Patients with del(17p) or TP53 mutation were included. Superior PFS was seen with ibrutinib/obinutuzumab by independent review. Estimated PFS rate was 79% with ibrutinib/obinutuzumab versus 31% with chlorambucil/obinutuzumab. Even after excluding patients with del(17p), a 74% reduction was seen in the risk of progression or death with ibrutinib/obinutuzumab.8

In the high-risk population, which included patients with unmutated IGHV, del(11q), del(17p) and TP53 mutation, an 85% reduction in risk of progression or death was seen with ibrutinib/obinutuzumab and an 84% reduction in risk of progression or death with ibrutinib/obinutuzumab among high-risk patients with CLL without del(17p). An 85% reduction in risk of progression or death with ibrutinib/obinutuzumab was seen in unmutated IGHV patients without del(17p). Median PFS for the patients treated with ibrutinib/obinutuzumab versus patients treated with chlorambucil/obinutuzumab was not reached versus 14.7 months at a median follow-up of 31.3 months (HR, 0.154; 95% CI, 0.087-0.270; P <.0001).


  1. Davids MS. Choosing frontline therapy in chronic lymphocytic leukemia: no more chemotherapy? Presented at: 23rd Annual International Congress on Hematologic Malignancies®; February 28-March 1, 2019; Miami Beach, FL.
  2. Thompson PA, Tam, CS, O’Brien, SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303-309. doi: 10.1182/blood-2015-09-667675.
  3. Eichhorst B, Fink AM, Bahlo J, et al; international group of investigators; German CLL Study Group. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17(7):928-942. doi: 10.1016/S1470-2045(16)30051-1.
  4. Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015;29(7):1602-1604. doi: 10.1038/leu.2015.14.
  5. Burger J, Barr P, Robak T, et al. Ibrutinib for first-line treatment of older patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): a 4-year experience from the RESONATE-2 study. Presented at: 2018 European Hematology Association; June 14-17, 2018; Stockholm; Sweden. Abstract PF343.
  6. Shanafelt TD, Wang S, Kay NE, et al. A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912). Presented at: 2018 American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract LBA-4.
  7. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib Alone or in Combination with Rituximab Produces Superior Progression Free Survival (PFS) Compared with Bendamustine Plus Rituximab in Untreated Older Patients with Chronic Lymphocytic Leukemia (CLL): Results of Alliance North American Intergroup Study A041202. Presented at: 2018 American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 6.
  8. Moreno C, Greil R, Demirkan F, et al. Ibrutinib + Obinutuzumab Versus Chlorambucil + Obinutuzumab As First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results from Phase 3 iLLUMINATE. Presented at: 2018 American Society of Hematology Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 691.

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