Dr Awan on the Evolving Role of Bispecific Antibodies Treatment in DLBCL

Farrukh Awan, MD, professor, Department of Internal Medicine, UT Southwestern Medical Center, member, Division of Hematology and Oncology, Harold C. Simmons Comprehensive Cancer Center, discusses the evolving role of bispecific antibodies in the treatment paradigm of relapsed diffuse large B-cell lymphoma (DLBCL).

Despite the success of frontline therapy in curing a substantial proportion of patients with DLBCL, a significant subset of these patients will experience relapse, Awan begins. Historically, treatment options for relapsed disease were limited to salvage chemotherapy, immunotherapy, or CAR T-cell therapy. However, CAR T-cell therapy poses its own unique challenges. For example, the lengthy time that is often needed for manufacturing, which causes a higher risk of disease progression during this period, makes this treatment option inaccessible for individuals in need of immediate intervention, Awan explains.

Awan notes that bispecific antibodies offer a promising alternative in this context, serving as an off-the-shelf immunotherapy option that can be administered without the delay associated with CAR T-cell production, he continues. These agents work by simultaneously engaging T cells and tumor cells, facilitating direct immune-mediated cytotoxicity, Awan explains. Initially introduced for patients in the third-line setting or those who were ineligible for CAR T-cell therapy, bispecific antibodies have demonstrated significant efficacy in these populations, providing an immediate treatment option for those with aggressive disease progression, he reports.

Awan emphasizes that as access to these therapies grows, they are becoming a key component of the treatment landscape for relapsed DLBCL, particularly for patients who are unsuitable for CAR T-cell therapy or those who experience relapse after CAR T-cell therapy treatment, Awan continues. Bispecific antibodies represent a critical advancement in the management of relapsed DLBCL, offering a viable and timely therapeutic alternative that bypasses the manufacturing delays associated with CAR T-cell therapy while maintaining efficacy in this difficult-to-treat patient population, he concludes.

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Farrukh Awan, MD, discuses the evolving role of bispecific antibodies in the treatment paradigm of diffuse large B-cell lymphoma.

Farrukh Awan, MD, professor, Department of Internal Medicine, UT Southwestern Medical Center, member, Division of Hematology and Oncology, Harold C. Simmons Comprehensive Cancer Center, compares the efficacy and safety of BTK inhibitors in the management of mantle cell leukemia (MCL).

After gaining approval in the frontline treatment of patients with chronic lymphocytic leukemia (CLL), the BTK inhibitors ibrutinib (Imbruvica), zanubrutinib (Brukinsa) and acalabrutinib (Calquence) were assessed in MCL, Awan begins. Several trials have reported efficacy data on the individual use of BTK inhibitors; however, Awan states there have been limited data comparing the 3 BTK inhibitors head to head.

Preliminary toxicity data on the use of ibrutinib vs acalabrutinib vs zanubrutinib show that these agents are similarly well tolerated in MCL, which allows patients to choose from several options, Awan says.

If an agent leads to poorly tolerated adverse effects (AEs) for an individual patient, they can choose another effective therapy, he adds.

According to toxicity data, the incidence of AEs appears to have increased with ibrutinib in MCL compared with CLL, Awan notes. However, ibrutinib is often administered at a higher dose level in MCL, he explains.

Although there are no direct efficacy comparisons of these options, zanibrutinib appears nominally more effective than acalabrutinib and ibrutinib, Awan continues. Early efficacy data show that the agent has a high response rate and elicits a median progression-free survival (PFS) of 18 to 36 months, Awan details.

In addition to BTK inhibitor monotherapies the administration of BTK inhibitors in combination with standard chemotherapy is also being investigated as a first-line treatment for MCL, Awan says. Ibrutinib plus bendamustine and rituximab (Rituxan) followed by rituximab maintenance was investigated in the phase 3 SHINE trial (NCT01776840) of elderly patients with MCL. The addition of ibrutinib to this regimen significantly prolonged PFS when compared with bendamustine and rituximab alone, Awan concludes. The regimen’s safety profile was also deemed consistent with known toxicities for each individual agent.

Editor's Note: Dr. Awan reports serving as a consultant or in an advisory role

for AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, Bristol-Myers Squibb, Cardinal Health, Celgene, Dava Oncology, Epizyme, Genentech, Gilead Sciences, Incyte, Janssen, Johnson & Johnson, Karyopharm, Kite Pharma, MEI Pharma, Merck, Pharmacyclics, Verastem, Caribou Biosciences, Cellecter; he received research funding from AbbVie/Pharmacyclics.

Farrukh Awan, MD, discusses the potential use of BTK inhibitors in the management of mantle cell leukemia.

 

Dr. Awan Discusses Distinguishes Among Available BTK Inhibitors in MCL

Farrukh Awan, MD, professor, the Department of Internal Medicine, UT Southwestern Medical Center, member, the Division of Hematology and Oncology, Harold C. Simmons Comprehensive Cancer Center, discusses the current use of BTK inhibitors in the management of chronic lymphocytic leukemia (CLL) and important factors to consider when determining the best treatment strategy.

Cross-trial comparisons of several studies on BTK inhibitors show that ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa) appear to have similar efficacy in the frontline setting. Considering this, clinicians need to evaluate the differences in toxicity between these 3 agents to select the appropriate treatment for their patients. The absence of head-to-head, first-line comparative studies can make this comparison challenging, but extrapolating data from these studies in the relapsed setting can help clinicians predict the performance of these therapies in the frontline.

Although all 3 drugs were shown to be well tolerated in this patient population, data indicatethat newer agents, specifically acalabrutinib, appear to have a slightly lower risk of toxicity compared with the older agent ibrutinib. Moreover, newer agents may have less cardiotoxicity and provide a lower risk of hypertension. Bleeding risks appear to be similar in all 3 drugs, while atrial fibrillation and ventricular arrhythmias are generally highest with ibrutinib, and progressively decline with acalabrutinib and zanubrutinib.

More long-term follow-up data are needed to conclusively distinguish between these 3 agents in clinical practice.

Farrukh Awan, MD, discusses the current use of BTK inhibitors in the management of chronic lymphocytic leukemia and important factors to consider when determining the best treatment strategy.


Dr. Awan on Selecting BTK Inhibitors for CLL Management

Farrukh Awan, MD, professor, the Department of Internal Medicine, UT Southwestern Medical Center, member, the Division of Hematology and Oncology, Harold C. Simmons Comprehensive Cancer Center, discusses the evolution of treating frontline chronic lymphocytic leukemia (CLL).

The development of additional frontline treatment options for patients with CLL over the past decade has created a limited role for chemotherapy, Awan explains, adding that BTK inhibitors are now the drug of choice for the majority of patients requiring treatment. Additionally, venetoclax (Venclexta) and other BCL-2 inhibitor–based regimens are promising time-limited treatment options for patients with CLL, Awan adds.

The 3 BTK inhibitors approved by the FDA in the frontline setting include ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa), Awan continues. Although head-to-head comparative studies have evaluated these agents in the relapsed/refractory setting of CLL, no head-to-head data are currently available for the frontline setting, Awan concludes.

Farrukh Awan, MD, discusses the evolution of treating frontline chronic lymphocytic leukemia.


Dr. Awan on the Evolution of Treating Frontline CLL

Farrukh Awan, MD, an associate professor in the Department of Internal Medicine at UT Southwestern Medical Center (UTSW), and a member of the Division of Hematology and Oncology at UTSW's Harold C. Simmons Comprehensive Cancer Center and William P. Clements Jr. University Hospital, discusses the importance of risk stratification in chronic lymphocytic leukemia (CLL). 

Patients with CLL should be risk stratified before making any treatment decisions, Awan says. In the frontline setting, risk stratification may inform whether a patient should receive time-limited treatment with a BCL-2 inhibitor or indefinite treatment with a BTK inhibitor.

Patients should undergo flow cytometry to confirm their diagnosis of CLL, fluorescence in situ hybridization, IGHV testing, and 

 mutation analysis to further stratify their risk, Awan explains. With the results of those tests, a treatment strategy can be planned accordingly. 

Additionally, age and performance status may inform treatment selection, says Awan.

Taken collectively, these factors can determine how frequently a patient needs to be seen in the clinic, what treatments they are eligible for, and how likely they are to respond to a particular therapy, concludes Awan.

Farrukh Awan, MD, discusses the importance of risk stratification in chronic lymphocytic leukemia.  



Dr. Awan on the Importance of Risk Stratification in CLL  

Farrukh Awan, MD, an associate professor in the Department of Internal Medicine at UT Southwestern Medical Center (UTSW), and a member of the Division of Hematology and Oncology at UTSW's Harold C. Simmons Comprehensive Cancer Center and William P. Clements Jr. University Hospital, discusses treatment options in the first relapsed setting in patients with chronic lymphocytic leukemia (CLL).

Treating patients with relapsed CLL depends on the therapy the patient has relapsed on, says Awan. Is it chemotherapy, a BTK inhibitor, or a BCL-2 inhibitor? With the current trials that are ongoing, the other considerations are whether the patient has had a time-limited option, if they were off treatment, or whether they relapsed while actively undergoing treatment. These are important factors to consider when talking about the treatment of patients in the relapsed setting.

Looking at chemoimmunotherapy specifically, a patient could have received bendamustine/rituximab (Rituxan); fludarabine plus cyclophosphamide and rituximab; or rituximab alone. If the patient has relapsed following chemoimmunotherapy, then it is an open discussion for next steps, similar to the untreated setting, adds Awan. A BCL-2 inhibitor or a BTK inhibitor can be used, though PI3K inhibitors should be avoided in this setting, Awan explains. Data suggest that acalabrutinib (Calquence) as a single agent may be more effective than the combination ofidelalisib (Zydelig) and rituximab.

If a patient cannot tolerate a BTK inhibitor, then that is a separate issue, Awan says. For those patients, another option is the BCL-2 inhibitor venetoclax (Venclexta). Time-limited duration and comorbid conditions all help make a decision between BCL-2 and BTK inhibitors in the first relapsed setting, concludes Awan.

Farrukh Awan, MD, discusses treatment options in the first relapsed setting in patients with chronic lymphocytic leukemia.

Dr. Awan on Treatment Options in the First Relapsed Setting of CLL

Farrukh Awan, MD, associate professor in the Department of Internal Medicine, UT Southwestern Medical Center (UTSW), and a member of the Division of Hematology and Oncology at UTSW's Harold C. Simmons Comprehensive Cancer Center and William P. Clements Jr. University Hospital, discusses remaining questions regarding the use of BTK inhibitors and CD20-directed monoclonal antibodies in chronic lymphocytic leukemia (CLL).

When determining whether to give a patient with CLL a BTK inhibitor alone or in combination with a CD20-directed antibody, it is important to have a discussion with patients, says Awan. During that conversation, the first question that is considered has to do with what benefit the patient can potentially derive from the addition of the CD20-directed antibody to the BTK inhibitor. Early data indicate that, at least with the addition of rituximab (Rituxan) to ibrutinib (Imbruvica), outcomes were not necessarily better than those observed with ibrutinib alone, says Awan. It should not be automatically assumed that the addition of a CD20-directed antibody to a BTK inhibitor will lead to longer remissions for patients, adds Awan.

In contrast, data from the CLL11 trial showed that obinutuzumab (Gazyva) outperformed rituximab, says Awan. As such, examining combinations with obinutuzumab made sense to examine in a clinical trial. Some emerging data suggest that there might be a trend toward improved outcomes when obinutuzumab is combined with acalabrutinib (Calquence) and possibly with ibrutinib. The field does not have the right trials to answer that specific question yet, concludes Awan.

Farrukh Awan, MD, discusses remaining questions regarding the use of BTK inhibitors and CD20-directed monoclonal antibodies in chronic lymphocytic leukemia.

Dr. Awan on Remaining Questions With BTK Inhibitors and Anti-CD20 Combos in CLL

Farrukh Awan, MD, associate professor, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, discusses the future of combination therapies in chronic lymphocytic leukemia (CLL).

The advent of combination regimens in CLL was a popular topic of discussion at the 2019 ASH Annual Meeting, says Awan. The idea with all these studies, such as those evaluating the combination of venetoclax (Venclexta) and ibrutinib (Imbruvica) or venetoclax and acalabrutinib (Calquence), is to combine all these agents in a rational manner and use minimal residual disease as an end point.

If patients can be brought into a deep remission, in the peripheral blood or bone marrow, then those patients can discontinue therapy and, hopefully, sustain their remission for an extended period of time, explains Awan. This idea is very exciting but more follow-up is needed. Specifically, investigators want to understand what should be done if the disease returns. Can these agents be used as salvage therapy?

Some exciting emerging data suggest that there are ways to manage those patients safely, says Awan. The key takeaway is that all these options are in the process of being developed further, especially the combinations, and hopefully these efforts will result in the use of all these treatments either sequentially or concurrently to improve outcomes, concludes Awan.

Farrukh Awan, MD, discusses questions regarding combination therapies in chronic lymphocytic leukemia.

Dr. Awan on Future of Combo Regimens in CLL Treatment Paradigm

Farrukh Awan, MD, associate professor in the Department of Internal Medicine at UT Southwestern (UTSW) Medical Center, and member, Division of Hematology and Oncology at UTSW’s Harold C. Simmons Comprehensive Cancer Center and William P. Clements Jr. University Hospital, discusses novel approaches under investigation in relapsed/refractory chronic lymphocytic leukemia (CLL).

Many drugs are slowly making their way through the treatment pipeline, says Awan. For example, duvelisib (Copiktra) received approval from the FDA for use in adult patients with relapsed/refractory CLL or small lymphocytic leukemia who had received at least 2 prior therapies, says Awan.

Additionally, alternative BTK inhibitors are being explored in clinical trials. The rationale behind that research is that those drugs would be utilized in patients who develop resistance to ibrutinib (Imbruvica) or acalabrutinib (Calquence), explains Awan. This concept is particularly exciting because even if a patient progresses on a BTK inhibitor, that does not necessarily mean that other BTK inhibitors would not be effective options for them, says Awan.

Furthermore, UT Southwestern Medical Center has access to some trials examining triplets and CAR T-cell therapy. CAR T-cell therapy is a huge advancement in the CLL treatment paradigm, says Awan, and emerging data with this approach look promising. Ongoing trials are evaluating CAR T-cell therapy in patients who have failed all prior treatment; historically, this patient population has had dismal outcomes, says Awan.

This approach is particularly exciting because patients can potentially be cured without having to undergo an allogeneic stem cell transplant, says Awan. Although patients with relapsed/refractory disease are experiencing favorable responses with CAR T-cell therapy, more follow-up will be needed, concludes Awan.

Farrukh Awan, MD, discusses novel approaches under investigation in relapsed/refractory chronic lymphocytic leukemia.

Dr. Awan on Novel Strategies Under Exploration in Relapsed/Refractory CLL

Farrukh Awan, MD, associate professor, Department of Internal Medicine, UT Southwestern (UTSW) Medical Center, and member, Division of Hematology and Oncology, Harold C. Simmons Comprehensive Cancer Center and William P. Clements Jr. University Hospital, discusses the utilization of acalabrutinib (Calquence) in patients with chronic lymphocytic leukemia (CLL).

The phase III ASCEND trial compared acalabrutinib with chemoimmunotherapy in the relapsed/refractory setting and data showed that acalabrutinib was superior, explains Awan. Furthermore, for patients with treatment-naïve CLL, the phase III ELEVATE-TN trial compared acalabrutinib alone versus acalabrutinib plus obinutuzumab (Gazyva), versus obinutuzumab plus chlorambucil. The study showed that acalabrutinib alone or in combination with obinutuzumab has positive efficacy was superior to chlorambucil/obinutuzumab.

Acalabrutinib can be utilized in patients who may not be tolerant of ibrutinib (Imbruvica), according to Awan. Research has shown that patients who stop ibrutinib (Imbruvica) due to adverse events can safely continue on acalabrutinib in most situations, Awan concludes.

Farrukh Awan, MD, discusses the utilization of acalabrutinib in patients with chronic lymphocytic leukemia.

Dr. Awan on Utilizing Acalabrutinib in CLL

Farrukh Awan, MD, associate professor, Department of Internal Medicine, UT Southwestern (UTSW) Medical Center, and member, Division of Hematology and Oncology, Harold C. Simmons Comprehensive Cancer Center and William P. Clements Jr. University Hospital, UTSW, discusses the need for time-limited treatments in patients with chronic lymphocytic leukemia (CLL).

Many patients with CLL do not want to take lifelong treatment, says Awan. The issue with BTK inhibitors is that although these agents induce very good responses in patients with CLL, the responses are not deep; this means that patients will need to continue on therapy indefinitely until their disease stops progressing. A stopping rule for BTK inhibitors in CLL does not exist, says Awan, although strategies to limit the duration of therapy are currently under investigation.

One of the major advances made in CLL in recent years has been the introduction of venetoclax (Venclexta) into the treatment paradigm. This agent has proved to perform better in a time-limited setting compared with other drugs, according to Awan.

For example, the phase III CLL14 trial demonstrated the superiority of fixed-duration treatment with venetoclax plus obinutuzumab (Gazyva) versus chlorambucil/obinutuzumab in untreated patients with CLL. Additionally, the phase III MURANO trial showed that when the agent was used in combination with rituximab (Rituxan), patients with relapsed/refractory disease had significantly higher rates of progression-free survival compared with bendamustine plus rituximab.

These data suggest that venetoclax can be used as a time-limited option in patients with CLL. Depending on the situation, patients will only have to receive treatment for 12 or 14 months rather than indefinitely. Not only does this option induce very deep responses in the vast majority of patients, but it is also results in deep remissions, says Awan. The hope is that the remissions will last a long time and patients will not need to receive chemotherapy at all, concludes Awan.

Farrukh Awan, MD, discusses the need for time-limited treatments in patients with chronic lymphocytic leukemia.

Dr. Awan on Time-Limited Treatments in CLL

Farrukh Awan, MD, associate professor, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, discusses the role of chemotherapy in the treatment of patients with chronic lymphocytic leukemia (CLL).

There has been a tremendous explosion of new drugs in CLL that have substantially improved outcomes for patients, says Awan. Novel therapies have reduced the need for chemotherapy. For example, in the phase III Alliance A041202, older patients with treatment-naïve CLL were randomized to receive bendamustine plus rituximab (Rituxan; BR), ibrutinib (Imbruvica), or ibrutinib plus rituximab. The results showed a substantial improvement in progression-free survival (PFS) with ibrutinib versus BR. Additionally, in the phase III E1912 trial, the combination of ibrutinib and rituximab improved PFS and overall survival versus fludarabine, cyclophosphamide, and rituximab in younger patients with newly diagnosed disease.

However, certain subgroups of patients may derive more benefit from chemotherapy versus continuous therapy with ibrutinib, says Awan. For example, patients with mutated IGHV tend to do well with chemotherapy.

With further follow-up, researchers might discover that BTK inhibitors are the preferred treatment in CLL.

Farrukh Awan, MD, discusses the role of chemotherapy in the treatment of patients with chronic lymphocytic leukemia (CLL).
 
 

Farrukh Awan, MD

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