Seema A. Bhat, MD, a hematologist specializing in chronic lymphocytic leukemia (CLL) at The Ohio State University Comprehensive Cancer Center–James, discusses the results of the phase 3 ELEVATE-TN trial in patients with treatment-naïve CLL.

Results of the ELEVATE-TN trial showed that after a median follow-up of 28 months, the median progression-free survival (PFS) for the acalabrutinib (Calquence)-containing arms was not reached. In the chlorambucil plus obinutuzumab (Gazyva) arm, however, the median PFS was 22.6 months, says Bhat. The 2-year PFS rates were 93%, 87%, and 47% for acalabrutinib/obinutuzumab, single-agent acalabrutinib, and chemoimmunotherapy, respectively.

The comparison made between the 2 acalabrutinib-containing arms was not a preplanned analysis; however, in a post-hoc analysis, some separation between the curves was seen, Bhat adds. Additionally, the complete response (CR) rates were higher in the acalabrutinib/obinutuzumab arm at 13% compared with 1% patient in single agent acalabrutinib arm. Yet, results from the RESONATE-2 study indicated that CR rates with 

ibrutinib (Imbruvica), tend to increase 

over time. Long-term follow-up from the ELEVATE-TN are needed, but nonetheless, these are highly encouraging data, concludes Bhat.

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Seema A. Bhat, MD, discusses the results of the phase 3 ELEVATE-TN trial in patients with treatment-naïve CLL.

Dr. Bhat on ELEVATE-TN Results in Treatment-Naïve CLL

Seema A. Bhat, MD, a hematologist specializing in chronic lymphocytic leukemia (CLL) at The Ohio State University Comprehensive Cancer Center–James, discusses the approval of acalabrutinib (Calquence) in CLL based on data from the phase 3 ELEVATE-TN trial.

The ELEVATE-TN study was an international study conducted in older or younger patients with comorbidities. Patients enrolled in the study were randomized 1:1:1 to 3 arms, says Bhat. The standard arm was comprised of chlorambucil plus obinutuzumab (Gazyva), which was given in a standard fashion for 6 cycles. The 2 experimental arms included acalabrutinib monotherapy and acalabrutinib plus obinutuzumab.

Notably, obinutuzumab was started on cycle 2 and given for a total of 6 cycles, while acalabrutinib was given indefinitely. This trial permitted crossover from the chlorambucil/obinutuzumab arm to the acalabrutinib/obinutuzumab arm upon disease progression. The study met its primary end point of progression-free survival, which led to the FDA’s decision to approve acalabrutinib for patients with CLL or small lymphocytic lymphoma in November 2019, concludes Bhat.

Seema A. Bhat, MD, discusses the approval of acalabrutinib in chronic lymphocytic leukemia based on data from the phase 3 ELEVATE-TN trial.

Dr. Bhat on the FDA Approval of Acalabrutinib in CLL


Seema A. Bhat, MD, hematologist, The Ohio State University Comprehensive Cancer Center–James, discusses the potential for time-limited combination regimens in chronic lymphocytic leukemia (CLL).

With the introduction of targeted therapy, CLL continues to be a rapidly evolving field, says Bhat.

Targeted therapies are given indefinitely, which can add toxicity and financial burden and decrease compliance, Bhat explains.

However, combining targeted agents may induce better and deeper remissions, which could allow for time-limited options, says Bhat.

Time-limited combinations could reduce the long-term adverse effects and financial toxicity that are associated with indefinite treatment, concludes Bhat.

Seema A. Bhat, MD, discusses the potential for time-limited combination regimens in chronic lymphocytic leukemia.  



Dr. Bhat on the Potential for Time-Limited Combinations in CLL 

Seema A. Bhat, MD, a hematologist specializing in chronic lymphocytic leukemia (CLL) at The Ohio State University Comprehensive Cancer Center–James, discusses emerging targeted therapies in chronic lymphocytic leukemia.

The armamentarium in CLL is expanding, Bhat explains. Currently, the covalently bound BTK inhibitors ibrutinib (Imbruvica) and acalabrutinib (Calquence) are approved. However, patients can develop resistance to these agents over time. 

As such, reversible BTK inhibitors, such as LOXO-305 and ARQ 531, are in development, Bhat says.

Zanubrutinib (Brukinsa), which is another covalently bound BTK inhibitor, is also be evaluated in an ongoing head-to-head clinical trial with ibrutinib, Bhat says. 

Additionally, the next-generation PI3K inhibitor umbralisib is being evaluated in combination with CD20-directed monoclonal antibodies and other targeted agents, Bhat says. If approved, the agent would add to the current approvals of idelalisib (Zydelig) and duvelisib (Copiktra). 

Seema A. Bhat, MD, emerging targeted therapies in chronic lymphocytic leukemia.  



Dr. Bhat on Emerging Targeted Therapies in CLL 

Seema A. Bhat, MD, a hematologist specializing in chronic lymphocytic leukemia (CLL) at The Ohio State University Comprehensive Cancer Center–James, discusses the rationale to evaluate acalabrutinib (Calquence) in chronic lymphocytic leukemia (CLL).

The international phase 3 ASCEND trial randomized patients with previously treated CLL to receive acalabrutinib monotherapy or rituximab (Rituxan) in combination with idelalisib (Zydelig) or bendamustine.

Acalabrutinib is a next-generation BTK inhibitor that, like ibrutinib (Imbruvica), is covalently binding, Bhat explains. 

Moreover, in November 2019, acalabrutinib was granted regulatory approval by the FDA for the treatment of patients with CLL or small lymphocytic lymphoma based on findings from the ASCEND trial, as well as results from the phase 3 ELEVATE-TN trial, concludes Bhat.

Seema A. Bhat, MD, discusses the rationale to evaluate acalabrutinib in chronic lymphocytic leukemia.  



Dr. Bhat on the Rationale to Evaluate Acalabrutinib in CLL 

Seema A. Bhat, MD, a hematologist specializing in chronic lymphocytic leukemia (CLL) at The Ohio State University Comprehensive Cancer Center–James, discusses the combination of ibrutinib (Imbruvica) plus fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR) in young patients with treatment-naïve CLL.

In the phase 3 E1912 study, investigators examined the regimen in the up-front treatment of younger patients with CLL, says Bhat. Ibrutinib was already approved by the FDA for the treatment of patients with CLL in the frontline setting when the E1912 trial began; however, the approval was somewhat controversial, according to Bhat, as the partner arm in the phase 3 RESONATE-2 study received chlorambucil, which is rarely used in young fit patients. The E1912 study compared ibrutinib with the standard of care at the time for younger patients with CLL, which was FCR based on data from the CLL10 study, adds Bhat.

The E1912 study included treatment-naïve patients who were under 70 years; those with high-risk with del(17p) CLL were excluded. In the trial, participants were randomized 2:1 to receive ibrutinib plus rituximab versus FCR given in the standard fashion for 6 cycles. The primary end point of the trial was progression-free survival (PFS), which was met. Ibrutinib plus rituximab significantly improved PFS compared with FCR. Longer follow-up data showed that ibrutinib plus rituximab led to a 3-year PFS rate of 89.4% versus 72.9% with FCR, concludes Bhat.

Seema A. Bhat, MD, discusses the combination of ibrutinib plus fludarabine, cyclophosphamide, and rituximab in young patients with treatment-naïve CLL.

Dr. Bhat on the Combination of Ibrutinib Plus FCR in Treatment-Naïve CLL

Seema A. Bhat, MD, hematologist, The Ohio State University Comprehensive Cancer Center–James, discusses the role of targeted therapies in chronic lymphocytic leukemia (CLL).

Historically, ibrutinib (Imbruvica) has played a key role in the ​treatment of patients with CLL, ​Bhat says. However, newer options such as ​the second-generation BTK inhibitor acalabrutinib (Calquence), as well as PI3K inhibitors​, ​have expanded the CLL armamentarium. 

Notably, the phase 3 ELEVATE CLL R/R trial (NCT02477696) is evaluating ibrutinib versus acalabrutinib in a head-to-head trial in the relapsed/refractory setting, says Bhat.

Targeted therapies can have some limitations, particularly with regard to safety, cost, and patient adherence to treatment. As the field​ accelerates forward, these factors must be addressed, Bhat concludes.

Seema A. Bhat, MD, hematologist, discusses the role of targeted therapies in chronic lymphocytic leukemia.

Seema A. Bhat, MD

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