Novel Agents, Approaches Advancing CLL Paradigm

Jessica Hergert

Farrukh T. Awan, MD, an associate professor in the Department of Internal Medicine at UT Southwestern Medical Center
Farrukh T. Awan, MD
There has been an explosion of new therapeutics that have become available in the paradigm of chronic lymphocytic leukemia (CLL), such as next-generation BTK inhibitors, explained Farrukh Awan, MD.

For example, in November 2019, acalabrutinib (Calquence) received FDA approval for the treatment of adult patients with CLL or small lymphocytic leukemia. The decision was based on results from the phase III ELEVATE-TN trial, which looked at patients with previously untreated CLL, as well as the phase III ASCEND trial of patients with relapsed/refractory disease.

"Acalabrutinib is an option for patients who are intolerant of ibrutinib (Imbruvica)," said Awan. "In most situations, patients who stop ibrutinib [because of toxicity] can safely continue on acalabrutinib."

At the 2019 ASH Annual Meeting, results of the ELEVATE-TN trial demonstrated a 90% reduction in risk of disease progression or death with acalabrutinib in combination with obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil for treatment-naïve patients with CLL (HR, 0.10; 95% CI, 0.06-0.17; P <.0001).1

Additionally, single-agent acalabrutinib demonstrated a statistically significant improvement in progression-free survival (PFS) over obinutuzumab/chlorambucil (HR, 0.20; 95% CI, 0.13-0.30; P <.0001).

In the ASCEND trial, the median PFS with acalabrutinib was not reached compared with 16.5 months for investigator's choice of bendamustine/rituximab (Rituxan; BR) or rituximab/idelalisib (Zydelig) in patients with previously treated CLL (HR, 0.31; 95% CI, 0.20-0.49; P <.0001).2

In an interview during the 2020 OncLive® State of the Science Summit™ on Hematologic Malignancies, Awan, an associate professor in the Department of Internal Medicine, at Harold C. Simmons Comprehensive Cancer Center, of UT Southwestern Medical Center, discussed the introduction of acalabrutinib into the CLL armamentarium as well as other paradigm-shifting advances with BTK inhibitors, novel combinations, and emerging agents.

OncLive: What is the utility of BTK inhibitors in CLL?

Awan: This has been an exciting time for CLL. Over the past 3 years, we have had a tremendous explosion of new drugs that have substantially improved outcomes for patients.

One theme we have seen is that chemotherapy is [being phased out] in CLL. Two landmark studies have compared the BTK inhibitor ibrutinib with chemotherapy in patients with untreated CLL, in both the younger and older patient populations. Ibrutinib was compared with either fludarabine/cyclophosphamide/rituximab (FCR) or BR.

In both studies, investigators observed a substantial improvement with ibrutinib. Further investigation is needed to determine whether certain subgroups of patients will benefit from time-limited therapy with 6 months of chemotherapy versus lifelong therapy with ibrutinib.

Some patients in this untreated population have mutated IGHV and tend to do well with 6 months of FCR. However, every other subgroup benefited more from BTK inhibitors.

We hope we can see BTK inhibitors prevail [for patients with IGHV mutations] with longer follow-up data. Overall, the field is moving toward chemotherapy-free regimens.

How has the introduction of acalabrutinib affected this space?

In relapsed/refractory CLL, acalabrutinib [demonstrated superiority] to both BR and rituximab/idelalisib. In [treatment-naïve patients], acalabrutinib by itself or in combination with obinutuzumab has good efficacy.

Should BTK inhibitors be combined with CD20-targeted antibodies, such as obinutuzumab?

At this point, if [that combination is used], most of us would prefer to use obinutuzumab as our CD20-directed antibody of choice rather than rituximab. That said, the data need longer follow-up to definitively say either way.

Many patients do not want to take lifelong treatment. Although we get good responses with BTK inhibitors, they are not deep responses. Essentially, the patient will continue on therapy until progression. We have not come up with a useful stopping rule, though we are trying to develop different strategies to limit the duration of therapy.

As such, venetoclax (Venclexta) has been shown to be better in a time-limited manor versus a number of different comparators. The CLL14 trial established the superiority of venetoclax for untreated patients, whereas the MURANO trial established the agent for relapsed/refractory patients. Essentially, both trials [gave us] a time-limited option of 12 or 24 months that we can use to get deep remissions for our patients. I hope that those remissions will last a long time and that our patients will not need chemotherapy at all.

How may combination regimens further shift the CLL treatment paradigm?

So much work is being done to combine these agents in a rational manner using minimal residual disease as an endpoint. If you get patients into a deep remission in the peripheral blood or bone marrow, they can discontinue therapy and, hopefully, sustain their remission for an extended period. That is exciting for us and for our patients, but we need more follow-up. What happens when the disease comes back? Can you use these [therapies] to salvage them?

What novel drugs have emerged in this space?

The improvement has been established not just in drugs like BTK inhibitors and BCL-2 inhibitors. We have so many other agents making their way up the treatment algorithm.

Duvelisib (Copiktra) is now approved as a PI3K inhibitor for patients with relapsed/refractory CLL [after at least 2 prior lines of therapy]. We also have alternative BTK inhibitors in clinical trials that may be utilized if a patient develops resistance to ibrutinib or acalabrutinib.

What other treatment strategies are being explored?

At UT Southwestern Medical Center, we have access to some trials looking at triplet therapies and CAR T-cell therapy. CAR T-cell therapy is a huge advancement in CLL, and emerging data look promising. These are patients who have failed [all prior therapies] and historically, had dismal outcomes.

Currently, the numbers are small and follow-up is short, so more data are needed. Cellular therapy is exciting because it [spares patients] from allogeneic stem cell transplant, but it is potentially curative. Historically, transplant was only an option for a small group of patients as most patients with relapsed/refractory CLL are older and ineligible for transplant.


  1. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (o) or alone versus o plus chlorambucil (clb) in patients (pts) with treatment-naïve chronic lymphocytic leukemia (CLL): results from ELEVATE-TN. Blood. 2019;134(suppl 1):31. doi: 10.1182/blood-2019-128404.
  2. Ghia P, Pluta A, Wach M, et al. Acalabrutinib vs rituximab plus idelalisib (IdR) or bendamustine (BR) by investigator choice in relapsed/refractory (RR) chronic lymphocytic leukemia: phase 3 ASCEND study. Hematol Oncol. 2019;37(S2):86-87. doi: 10.1002/hon.54_2629.
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