乌鸦传媒

The practical management of Richter transformation (RT) -- defined as the occurrence of an aggressive lymphoma in patients with a previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL) -- continues to use long-standing historical approaches to treatment while leveraging new targeted therapies. The primary goal of frontline treatment of RT is to achieve a complete response before transplant, using novel agents if needed.

As detailed in a review in the , although "unprecedented progress" has been made in the treatment of CLL, outcomes for patients with RT (also known as Richter's syndrome) unfortunately remain poor. Multiagent chemoimmunotherapy regimens, such as rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) have led to incremental progress against RT, although outcomes do not match the success with the same regimens used in de novo diffuse large B-cell lymphoma.

Targeted therapies approved for CLL, such as inhibitors of Bruton tyrosine kinase and B-cell leukemia/lymphoma-2 (BCL-2), have limited activity in RT as monotherapy, and initial promising activity with checkpoint blockade antibody monotherapy was also eventually found to be ineffective for most patients, explained the review's authors, Christine Ryan, MD, and Matthew Davids, MD, MMSc, both of Dana-Farber Cancer Center and Harvard Medical School in Boston.

They noted that as outcomes for patients with CLL have improved in recent years, there has been a growing focus on research into improving the biological understanding of the underlying pathophysiology of RT and on translating these new insights into rational combination strategies that are poised to improve therapeutic outcomes. The review, an overview of the biology and diagnosis of RT, summarized data supporting various therapies that have been recently studied in RT, as well as promising novel approaches under investigation.

In the following interview, Ryan and Davids elaborated on the information in their review.

What is the expectation for targeted monotherapies to improve outcomes for RT?

Ryan/Davids: Recently some targeted agents, including pirtobrutinib [Jaypirca], epcoritamab [Epkinly], and glofitamab [Columvi], have encouragingly shown promise as monotherapy. We await longer-term follow-up data from the initial studies investigating these agents to better understand the durability of the responses achieved.

Given the commonly aggressive nature of RT and how challenging it can be to treat, it is very possible that combination strategy approaches may ultimately prove to be a more effective therapeutic approach. The results of monotherapy studies provide valuable information regarding which combination approaches may be worthy of further investigation.

What is the role of immune checkpoint blockade in RT?

Ryan/Davids: While initial small studies with single-agent immune checkpoint blockade had very promising results, a larger when checkpoint blockade was used as a monotherapy. Recent studies combining immune checkpoint blockade with other targeted agents, such as ibrutinib or venetoclax, have demonstrated encouraging results.

Given that patients with RT have underlying CLL and given the known immune dysfunction associated with CLL, there is significant biological interest in further exploring immune checkpoint blockade in RT, particularly in combination regimens.

Which combination therapeutic approaches are currently being evaluated?

Ryan/Davids: There are several combination therapeutic approaches currently under investigation including:

• Combining targeted agents with traditional chemoimmunotherapy – venetoclax, acalabrutinib [Calquence], and polatuzumab vedotin [Polivy] are each being evaluated in combination with chemoimmunotherapy

• Combining BCL-2 inhibition with PI3 [phosphoinositide 3]- kinase inhibition

• Combining small molecule inhibitors with immune checkpoint blockade

These latter two approaches harness the unique mechanisms of action of various targeted agents with the aim of achieving improved clinical outcomes compared to a monotherapy approach.

What is your bottom-line message for practicing oncologists?

Ryan/Davids: While Richter's transformation continues to have a dismal prognosis, we are currently seeing significant efforts in the field to tackle this challenging disease.

New biological insights into the mechanisms of transformation and pathophysiology of this disease, coupled with the availability of many novel targeted agents for other B-cell malignancies, brings hope that we will make advancements in improving outcomes for patients with RT.

Given the limited efficacy of current standard-of-care treatments, patient enrollment in a clinical trial whenever possible remains a key priority in advancing the field.

Read the review here.