Curating Novel Combinations in CLL

Partner | Cancer Centers | <b>City of Hope</b>

Tanya Siddiqi, MD, discusses the novel agents that have emerged in the treatment paradigm for patients with chronic lymphocytic leukemia.

Tanya Siddiqi, MD

In what was once considered an incurable disease, multiple targeted therapies have emerged for patients with chronic lymphocytic leukemia (CLL), with the goal of providing deep remissions and improvements in overall survival (OS), explained Tanya Siddiqi, MD.

In a presentation during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Siddiqi, an associate professor and director of the Chronic Lymphocytic Leukemia Program at City of Hope, discussed the novel agents that have emerged in the treatment paradigm for patients with CLL.

Findings from the CLL11 trial had shown obinutuzumab (Gazyva) to be a favorable combination partner for chlorambucil in the frontline setting for elderly patients.1 Hoping to extract the most benefit from obinutuzumab and confirm the viability of a nonchemotherapy combination, the monoclonal antibody was tested in combination with the BCL-2 inhibitor venetoclax (Venclexta) in the phase III CLL14 trial.2

In the trial, treatment-naïve patients with coexisting medical conditions were randomized to receive either fixed-duration venetoclax/obinutuzumab (n = 216) or chlorambucil/obinutuzumab (n = 216). A key aspect of the trial was that treatment was not given indefinitely, stressed Siddiqi. Rather, patients were evenly randomized to receive 12 months of venetoclax alongside 6 months of obinutuzumab or 6 months of obinutuzumab followed by 6 months of chlorambucil.

The majority of patients had either unmutated IGHV, a TP53 abnormality, or del(17p), which is representative of a poor-risk population. Even so, the combination of venetoclax/obinutuzumab reduced the risk of progression or death by 65% versus chlorambucil/obinutuzumab (HR, 0.35; 95% CI, 0.23-0.53; P <.0001). The overall response rate (ORR) was 85% (95% CI, 79%-89%) with venetoclax/obinutuzumab versus 71% (95% CI, 65%-77%) in the control arm (P = .0007). Although this failed to translate to an OS benefit, venetoclax was approved for use in combination with obinutuzumab as frontline therapy in May 2019.

The complete results of the study were presented at the 2019 ASCO Annual Meeting and showed that higher rates of minimal residual negativity (MRD) in both blood and bone marrow were achieved early and were more sustainable with the venetoclax arm compared with the control arm.3 Specifically, 81% of patients who received venetoclax/obinutuzumab were MRD-negative 12 months after treatment completion versus 27% of patients who were given chlorambucil/obinutuzumab.

Grade 3/4 treatment-emergent adverse events (AEs) were comparable between arms, the most common being neutropenia and infections. However, investigators reported a greater number of fatalities with venetoclax after patients had completed therapy.

“That has to be vetted further to see whether it had to do with patient age or happened by chance,” said Siddiqi.

Although this combination has a lot of appeal for use in elderly patients, ibrutinib (Imbruvica) could also be considered after having demonstrated a superior progression-free survival (PFS) benefit over bendamustine/rituximab (BR; Rituxan) in the phase III ALLIANCE A041202 trial.4 This shift toward non-chemotherapy regimens is also evident among younger patients, added Siddiqi, as combinations of ibrutinib/rituximab and ibrutinib/obinutuzumab have become preferred regimens.

“The bottom line is that chemotherapy is largely dead in CLL. We knew it for a long time, but now it has been proven,” said Siddiqi.

Within the past year, several additional novel combinations have emerged, such as the combination of ibrutinib and venetoclax, which is being evaluated in the phase II CAPTIVATE trial.5

In the trial, fit treatment-naïve patients under the age of 70 are being randomized to a 3-month lead-in with ibrutinib to establish disease control, after which venetoclax is introduced for an additional 12 cycles of treatment. If patients are MRD-negative after 1 year of therapy, they are randomized to receive either ibrutinib maintenance or placebo. In the context of MRD-positivity, patients are randomized to continue therapy with the combination or to receive ibrutinib maintenance.

Preliminary results have shown a 77% undetectable MRD rate in peripheral blood after 6 cycles of ibrutinib plus venetoclax; the undetectable MRD rate in bone marrow was 86% after 12 cycles of the combination.

Common AEs included arthralgia and headache but fell within the parameters of the known toxicity profiles of both drugs. Although no grade 3/4 AEs were reported with the combination, some dose reductions were implemented to account for drug interactions, explained Siddiqi.

In the relapsed/refractory setting, the second-generation BTK inhibitor acalabrutinib was evaluated as monotherapy versus investigator’s choice of idelalisib (Zydelig) and rituximab or BR in the phase III ASCEND trial.6 Notably, patients in the combination arms were allowed to cross over after confirmed disease progression. The majority of patients had received ≤2 prior lines of therapy but were constitutive of a high-risk patient population.

Results presented at the 2019 European Hematology Association Congress showed that 12-month PFS rates were 88% with acalabrutinib versus 68% with physician’s choice, while 12-month OS rates were 94% and 91%, respectively. Additionally, an 81% ORR was observed in the acalabrutinib arm versus 75% in the physician’s choice arms (P = .22), although this difference was not found to be statistically significant.

However, the entrance of this agent into the frontline setting may be imminent, added Siddiqi, according to topline findings from the phase III ELEVATE-TN trial. The trial investigated the frontline use of acalabrutinib/obinutuzumab and acalabrutinib monotherapy, each versus obinutuzumab/chlorambucil; results showed that both acalabrutinib arms met the primary endpoint of PFS.7 Specifically, acalabrutinib in combination with obinutuzumab showed a statistically significant and clinically meaningful improvement in PFS versus obinutuzumab/chlorambucil.

Another area of excitement is CAR T-cell therapy, which is being evaluated across several hematologic malignancies and CLL is no exception, said Siddiqi. In the phase I TRANSCEND CLL 004 trial, patients with relapsed/refractory disease are receiving the CD19-directed CAR T-cell therapy lisocabtagene maraleucel (liso-cel; JCAR017) after lymphodepletion with fludarabine and cyclophosphamide.

Notably, inclusion criteria were more stringent among patients with good-risk features, requiring them to have failed ≥3 prior lines of therapy, whereas patients with poor-risk features only had to have failed ≥2 prior lines of therapy. The majority of patients had high-risk features. Moreover, 100% of the population had been previously exposed to ibrutinib and 50% had received prior venetoclax.

Due to the manufacturing time required for the product, patients were allowed to receive bridging therapy.

At a median follow-up of 9 months, the best ORR was attained in 81.8% of the study population (n = 22; 95% CI, 56.7-94.8).8 Interestingly, a higher proportion of patients achieved a complete response at a dose level of 50 x 106 CAR T cells as opposed to 100 x 106 CAR T cells. Undetectable MRD was achieved in 75% (n = 15) of patient’s blood and 65% (n = 13) of patient’s bone marrow samples by day 30.

“Most of this happened in the very first month of assessment,” said Siddiqi, adding that responses have only deepened over time and the majority have been sustained.

Although cytokine release syndrome and neurotoxicity manifested in a majority of patients, it did so at a low grade, said Siddiqi. Few progressions have been reported, but those that have been are due to Richter’s transformation, she added.

The phase II portion of the study as well as an extended cohort of the phase I trial where liso-cel will be evaluated in combination with ibrutinib are currently enrolling.

“There are multiple novel agents that we are evaluating in CLL,” concluded Siddiqi. “We have many building blocks, and now we have to figure out the best way to put them together to find a cure for a historically incurable disease.”


  1. Goede V, Fischer K, Dyer MJS, et al. Overall survival benefit of obinutuzumab over rituximab when combined with chlorambucil in patients with chronic lymphocytic leukemia and comorbidities: final survival analysis of the CLL11 study. Presented at: 2018 European Hematology Association Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S151.
  2. FDA Prescribing Information for Venetoclax. Published July 2019. Accessed September 5, 2019.
  3. Fischer K, Al-Sawaf O, Bahlo J, et al. Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD-) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. J Clin Oncol. 2019;37(15 suppl; abstr 7502). doi: 10.1200/JCO.2019.37.15_suppl.7502.
  4. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528. doi: 10.1056/NEJMoa1812836.
  5. Wierda WG, Siddiqi T, Flinn I, et al. Phase 2 CAPTIVATE results of ibrutinib (ibr) plus venetoclax (ven) in first-line chronic lymphocytic leukemia (CLL). J Clin Oncol. 2018;36(15 suppl; abstr 7502). doi: 10.1200/JCO.2018.36.15_suppl.7502.
  6. Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, Netherlands. Abstract LB2606.
  7. Calquence phase III ELEVATE-TN trial met primary endpoint at interim analysis in previously-untreated chronic lymphocytic leukaemia [news release]. AstraZeneca. Published June 6, 2019. Accessed September 5, 2019.
  8. Siddiqi T, Dorritie KA, Soumerai JB. TRANSCEND CLL 004: minimal residual disease after lisocabtagene maraleucel in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Presented at: 15th International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 065.