Time-Limited Therapy Takes Center Stage in Frontline and Relapsed/Refractory CLL

Fixed-duration treatment that leads to deep treatment-free remissions has become the prioritized strategy for patients with chronic lymphocytic leukemia, made possible by agents such as venetoclax, umbralisib, and lisocabtagene maraleucel.

Fixed-duration treatment that leads to deep treatment-free remissions has become the prioritized strategy for patients with chronic lymphocytic leukemia (CLL), made possible by agents such as venetoclax (Venclexta), umbralisib (Ukoniq), and lisocabtagene maraleucel (liso-cel; Breyanzi), according to William G. Wierda, MD, PhD.

Time-Limited Combinations Confer Improved Survival

BCL-2–based combinations have demonstrated sustained long-term remissions in the frontline and relapsed/refractory settings, evidenced by updated data from the phase 3 CLL14 and MURANO trials, explained Wierda, who is the D. B. Lane Cancer Research Distinguished Professor, section chief of Chronic Lymphocytic Leukemia, and center medical director in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, in a presentation during a 2021 Institutional Perspectives in Cancer webinar on hematologic malignancies.

In CLL14, previously untreated patients with comorbidities were randomized to 6 cycles of combination therapy with venetoclax and obinutuzumab (Gazyva) followed by another 6 cycles of venetoclax, or chlorambucil plus obinutuzumab followed by chlorambucil in the same schedule. At a median follow-up of 52.4 months, the median progression-free survival (PFS) had not been reached with venetoclax/obinutuzumab vs 36.4 months with obinutuzumab/chlorambucil (HR, 0.33; 95% CI, 0.25-0.45; P < .0001). The 4-year PFS rate was 74.0% and 35.4%, respectively.1

“We’re seeing very long remissions in the frontline setting with a fixed-duration of 1 year of treatment with venetoclax and obinutuzumab,” said Wierda, who is also the executive medical director of The University of Texas MD Anderson Cancer Center.

Moreover, the rate of undetectable minimal residual disease (MRD) status at the end of treatment at a sensitivity of 10-4 was more than doubled in the venetoclax/obinutuzumab arm, at 74% vs 32% with obinutuzumab/chlorambucil.

“The rate and kinetics of MRD relapse was more rapid for patients who received chlorambucil-based treatment compared with venetoclax-based treatment, which is important because completely eliminating chemoimmunotherapy from treatment for patients with CLL is an objective,” said Wierda.

In MURANO, patients with relapsed/refractory disease were randomized to 2 years of venetoclax plus 6 cycles of rituximab (Rituxan) or 6 cycles of bendamustine and rituximab (BR).

According to the 5-year analysis of the study, the median PFS was 53.6 months with venetoclax/rituximab vs 17.0 months with BR (HR, 0.19; 95% CI, 0.15-0.26; P < .0001).2 The 5-year PFS rate was 37.8% and not evaluable (NE), respectively. The median overall survival (OS) was NE in either arm (HR, 0.40; 95% CI, 0.26-0.62; P < .0001). However, the 5-year OS rate was 82.1% in the venetoclax/rituximab arm vs 62.2% in the BR arm.

Additionally, the median time from end of treatment to MRD conversion was 19.4 months, and the median time from MRD relapse to progressive disease was 25.2 months.

“These patients are achieving a very deep remission, with a long time in the relapsed setting to MRD relapse and an even longer time to clinical relapse and progression of disease,” said Wierda.

Fixed-duration treatment with ibrutinib (Imbruvica) and venetoclax has also shown deep remissions in previously untreated patients in the phase 2 CAPTIVATE study. In the trial, patients who achieved confirmed undetectable MRD after 12 cycles of combined treatment with ibrutinib and venetoclax were randomized to placebo or ibrutinib, and patients who were MRD positive were randomized to ibrutinib or continued ibrutinib/venetoclax.

At a median follow-up of 16.6 months, the 1-year disease-free survival rate was 95.3% in the placebo arm vs 100% in the ibrutinib arm (P = .1475),3 supporting the use of fixed-duration treatment as a means of achieving undetectable MRD and durable treatment-free remissions, explained Wierda.

Among patients who were MRD positive after 12 cycles of combined treatment with ibrutinib/venetoclax, the rate of MRD negativity was higher with continued ibrutinib/venetoclax vs ibrutinib alone, respectively (bone marrow: 34% vs 10%; peripheral blood: 19% vs 0%).

PI3K Inhibition Leads to Improved PFS

PI3K inhibitors are also showing improved depth and durability of responses compared with traditional chemoimmunotherapy, explained Wierda. In the phase 3 UNITY CLL trial, patients with previously untreated and relapsed/refractory disease were randomized to the PI3K inhibitor umbralisib plus ublituximab or obinutuzumab/chlorambucil for 6 cycles.

At a median follow-up of 36.7 months, the median PFS was 31.9 months with umbralisib/ublituximab vs 17.9 months with obinutuzumab/chlorambucil (HR, 0.546; 95% CI, 0.413-0.720; P < .0001). The 2-year PFS rates were 60.8% and 40.4%, respectively.4

In the treatment-naïve population, the median PFS was 38.5 months with umbralisib/ublituximab vs 26.1 months with obinutuzumab/chlorambucil (HR, 0.482; 95% CI, 0.316-0.736; P < .001). The 2-year PFS rates were 76.6% and 52.1%, respectively.

In the relapsed/refractory population, the median PFS was 19.5 months with umbralisib/ublituximab vs 12.9 months with obinutuzumab/chlorambucil (HR, 0.601; 95% CI, 0.415-0.869; P < .01). The 2-year PFS rates were 41.3% and 24.8%, respectively.

Despite these improvements in PFS compared with chemoimmunotherapy, umbralisib/ublituximab led to shorter survival than would be expected with BTK- or BCL-2–based therapy in the frontline and relapsed/refractory settings, which coupled with the regimen’s safety profile, leaves its role in question.

“There is a bit better tolerability with umbralisib compared with what we’ve seen with the other PI3 kinase inhibitors, idelalisib [Zydelig] and duvelisib [Copiktra], but we still see some of the same in-class toxicities, such as transaminitis and colitis that we have struggled with historically with this category of drugs,” said Wierda.

Taking Stock of CAR T-cell Therapy in the Refractory Setting

The CD19-directed CAR T-cell therapy liso-cel demonstrated encouraging activity as monotherapy in the phase 1/2 TRANSCEND CLL 004 trial, and findings from the combination portion of the study showed that the addition of ibrutinib to liso-cel resulted in durable remissions in patients with refractory disease.5

At a median follow-up of 10 months, the overall response rate was 63%, with an undetectable MRD rate of 89% in the blood and bone marrow at a sensitivity of at least 10-4. Moreover, 38% and 20% of patients experienced long-term T-cell persistence at 6 and 12 months, respectively.

“In terms of kinetics of expansion, the peak or Cmax of cell expansion of 128,000 copies/ug appeared to be higher than what was reported in the monotherapy arm, so there may be an advantage to using liso-cel plus ibrutinib in this setting,” concluded Wierda.


  1. Al-Sawaf O, Zhang C, Robrecht S, et al. Clonal dynamics after venetoclax–obinutuzumab therapy: novel insights from the randomized, phase 3 CLL14 trial. Blood. 2020;136(suppl 1):22-23. doi:10.1182/blood-2020-136977
  2. Kater AP, Kipps TJ, Eichhorst B, et al. Five–year analysis of Murano study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia (R/R CLL) patients following fixed-duration venetoclax–rituximab (VenR) therapy (Tx). Blood. 2020;136(suppl 1):19-21. doi:10.1182/blood-2020-136109
  3. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib (Ibr) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Blood. 2020;134(suppl 1):35. doi:10.1182/blood-2020-121424
  4. Gribben JG, Jurczak W, Jacobs RW, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 Unity-CLL study. Blood. 2020;134(suppl 1):37-39. doi:10.1182/blood-2020-134783
  5. Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Blood. 2020;136(suppl 1):39-40. doi:10.1182/blood-2020-140622