Mazyar Shadman, MD, a physician and associate professor in the Divisions of Medical Oncology and Clinical Research at Seattle Cancer Care Alliance, discusses continuous vs time-limited treatments for patients with chronic lymphocytic leukemia (CLL).

When the field shifted away from chemotherapy approaches toward BTK inhibitors, CLL treatment became continuous; the disease becoming more of a chronic illness, Shadman says. This method has proven to be extremely effective and is supported by long-term data, Shadman explains. Venetoclax (Venclexta) brought back the possibility of a time-limited option for patients.

Now that there is a drug capable of yielding deep remissions, it is worth considering combinations with another class of drug or more, thus achieving the best possible remission, Shadman says. This would be determined through minimal residual disease detection.

By achieving a deep and sustained remission in which patients with CLL may not relapse for a long time, or potentially ever, it may be possible to achieve cure, Shadman concludes.

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Mazyar Shadman, MD, discusses continuous vs time-limited treatments for patients with chronic lymphocytic leukemia.

Dr. Shadman on Continuous Vs Time-Limited Treatments in CLL

Mazyar Shadman, MD, a physician and associate professor in the Divisions of Medical Oncology and Clinical Research at Seattle Cancer Care Alliance, discusses the role of minimal residual disease (MRD) in chronic lymphocytic leukemia (CLL).

In the post-chemotherapy era, MRD primarily applies to venetoclax (Venclexta)-based regimens, according to Shadman. However, it's important to understand that standard treatment strategies are not based on MRD status, Shadman adds; however, there is currently a lot of academic interest in the marker, so its role in the paradigm may become more pronounced in the future.

Currently, in a clinical setting, Shadman utilizes FDA-approved standards of care. For example, when using a combination of venetoclax and obinutuzumab (Gazyva) in the frontline setting, treatment should be stopped at 1 year, Shadman explains. Although data from the phase 3 CLL14 trial (NCT02242942) indicated that MRD may have predictive value, it shouldn't currently be changing treatment approaches, Shadman concludes.

Mazyar Shadman, MD, discusses the role of minimal residual disease in chronic lymphocytic leukemia.

Dr. Shadman on the Role of MRD in CLL

Mazyar Shadman, MD, a physician and associate professor in the Divisions of Medical Oncology and Clinical Research at Seattle Cancer Care Alliance, discusses the potential for CAR T-cell therapy in patients with high-risk chronic lymphocytic leukemia (CLL).

CAR T is currently being examined in several studies being conducted in patients with CLL, such as the TRANSCEND CLL 004 (NCT03331198), according to Shadman. Additionally, 2 ongoing studies have been presented, including 1 with lisocabtagene maraleucel (liso-cel) monotherapy, as well as a study with liso-cel in patients who received ibrutinib (Imbruvica) concurrently.

This treatment approach appears to be effective in patients with high-risk disease, according to Shadman. With this modality, it's possible to achieve high rates of complete remissions, some of which are durable if the patient has no detectable minimal residual disease, Shadman says. Although the follow-up is short, this is still an important treatment for patients with high-risk CLL, Shadman explains. 

Additionally, the combination of ibrutinib and liso-cel appears to be safe, but larger studies are needed to determine whether the CAR T-cell products contributes to the efficacy or toxicity of the regimen, Shadman says. Although this modality is not currently approved by the FDA for use in patients with CLL, when and if it is, it should be viewed as an important part of the treatment paradigm, especially in the high-risk population, Shadman concludes.

Mazyar Shadman, MD, discusses the potential for CAR T-cell therapy in patients with high-risk chronic lymphocytic leukemia.

Dr. Shadman on the Potential for CAR T-Cell Therapy in High-Risk CLL

Mazyar Shadman, MD, a physician and associate professor in the Divisions of Medical Oncology and Clinical Research at Seattle Cancer Care Alliance, discusses the potential utility of LOXO-305 in chronic lymphocytic leukemia (CLL).

LOXO-305 is a third-generation, highly selective BTK inhibitor that inhibits wild-type and 

-mutant BTK, says Shadman. The agent is non-covalent and, therefore, can reversibly bind BTK. As such, LOXO-305 may be effective in treating patients with CLL who progress on ibrutinib (Imbruvica) or acalabrutinib (Calquence), Shadman explains. Additionally, because LOXO-305 is highly selective for BTK, the agent could provide an option to patients who are intolerant to other BTK inhibitors, Shadman says. 

During the 2020 ASH Annual Meeting and Exposition, findings from the phase 1/2 BRUIN study showed promising efficacy with LOXO-305 in heavily pretreated patients with CLL or small lymphocytic lymphoma who had poor prognoses. Moreover, the efficacy was not limited to patients with 

 mutations. Although LOXO-305 is in the early stages of clinical development, combination approaches or moving the agent into earlier lines of treatment may be on the horizon, concludes Shadman. 

Mazyar Shadman, MD, discusses the potential utility of LOXO-305 in chronic lymphocytic leukemia.  



Dr. Shadman on the Potential Utility of LOXO-305 in CLL 

Mazyar Shadman, MD, a physician and associate professor in the Divisions of Medical Oncology and Clinical Research at Seattle Cancer Care Alliance, shares treatment considerations for patients with chronic lymphocytic leukemia (CLL).

When forming a treatment strategy, it is important to consider comorbidities, social and supportive factors, and disease characteristics, Shadman explains. Moreover, factors such as Functional Independence Score in Hemophilia and 

 mutational status, should also be taken into account.

The majority of patients will receive a BTK inhibitor or a venetoclax (Venclexta)-based regimen. However, there is a small patient population who can benefit from chemoimmunotherapy, which has been a focus of discussion in the field, Shadman says. The fludarabine, cyclophosphamide, and rituximab (Rituxan) regimen is not often utilized by Shadman, although he notes that occasionally a patient may be a good candidate for the approach, provided that they understand the risks. These risks include the possibility of developing acute myeloid leukemia or myelodysplastic syndrome.

For most patients, treatment with a BTK inhibitor or venetoclax is recommended, according to Shadman. However, fixed-duration therapy with venetoclax is appealing compared with continuous treatment with BTK inhibitors, Shadman concludes.

Mazyar Shadman, MD, shares treatment considerations for patients with chronic lymphocytic leukemia.

Dr. Shadman on Treatment Considerations in CLL

Mazyar Shadman, MD, MPH, assistant member, Fred Hutchinson Cancer Research Center, discusses next steps for CAR T-cell therapy in diffuse large B-cell lymphoma (DLBCL).

CAR T-cell therapy has made a large impact in relapsed/refractory DLBCL, where there are 2 FDA-approved products targeting CD19. Long-term follow-up data suggest these therapies are inducing durable responses. Now, ongoing studies are looking at the feasibility of bringing CAR T-cell therapy into an earlier setting, says Shadman.

In the second-line setting of DLBCL, patients are typically treated with induction chemoimmunotherapy, followed by intensive therapy and autologous stem cell transplant. The question is whether CAR T-cell therapy can demonstrate better outcomes. Lisocabtagene maraleucel (liso-cel; JCAR017) is one product that is being tested in this setting.

Furthermore, axicabtagene ciloleucel (axi-cel; Yescarta) is being studied in the frontline setting for patients with high-risk DLBCL who don’t achieve a complete response to induction therapy, says Shadman.

Mazyar Shadman, MD, MPH, assistant member, Fred Hutchinson Cancer Research Center, discusses next steps for CAR T-cell therapy in diffuse large B-cell lymphoma.

Mazyar Shadman, MD, MPH

Articles

Dr. Shadman on Continuous Vs Time-Limited Treatments in CLL

Dr. Shadman on the Role of MRD in CLL

Dr. Shadman on the Potential for CAR T-Cell Therapy in High-Risk CLL

Dr. Shadman on the Potential Utility of LOXO-305 in CLL

Dr. Shadman on Treatment Considerations in CLL

Dr. Shadman on Next Steps for CAR T-Cell Therapy in DLBCL