Tanya Siddiqi, MD, director of the Chronic Lymphocytic Leukemia Program at the Toni Stephenson Lymphoma Center, and an associate clinical professor of the Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation, at City of Hope, discusses the role of acalabrutinib (Calquence) as a frontline treatment for patients with chronic lymphocytic leukemia (CLL). 

Acalabrutinib was previously examined in a phase 3 ELEVATE-TN trial (NCT02475681) with or without obinutuzumab (Gazyva) vs chlorambucil-based therapy in combination with obinutuzumab, according to Siddiqi. Unsurprisingly, the acalabrutinib regimen yielded a significant improvement in outcomes, Siddiqi says.

Currently, the biggest question is how to decide between acalabrutinib and ibrutinib (Imbruvica), which has had longer follow-up and was approved by FDA. Both agents are good options for patients with CLL in the frontline setting, though acalabrutinib is beginning to be utilized more often, she says. This is because the agent may have fewer adverse effects (AEs), such as atrial fibrillation and hypertension.

Atrial fibrillation occurs in approximately 10% to 14% of patients treated with ibrutinib, whereas acalabrutinib has not yielded a notable amount of these AEs. This could reassure patients and doctors alike that acalabrutinib may be better tolerated, Siddiqi concludes.

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Tanya Siddiqi, MD, discusses the role of acalabrutinib as a frontline treatment for patients with chronic lymphocytic leukemia. 

Dr. Siddiqi on the Role of Acalabrutinib in Frontline CLL

Tanya Siddiqi, MD, an assistant clinical professor in the Department of Hematology and Hematopoietic Cell Transplantation at the City of Hope, discusses the rationale to evaluate CAR T-cell therapy in chronic lymphocytic leukemia (CLL). 

In diseases such as acute lymphoblastic leukemia, aggressive B-cell non-Hodgkin lymphomas such as diffuse large B-cell lymphoma, and mantle cell lymphoma, CD19-directed CAR T-cell therapy was introduced with the hope of addressing an immediate unmet clinical need, explains Siddiqi. As such, the utility of this modality in CLL went largely unknown as the need for the therapy in other disease types was greater than in this disease. 

However, with the growth of CAR T-cell therapy, the field of CLL is beginning to explore the modality for use in patients who have progressed on novel oral agents, such as ibrutinib (Imbruvica) or venetoclax (Venclexta), says Siddiqi. Currently, the field has limited salvage options for these patients, concludes Siddiqi. 

Tanya Siddiqi, MD, discusses the rationale to evaluate CAR T-cell therapy in chronic lymphocytic leukemia.  



Dr. Siddiqi on the Rationale to Evaluate CAR T-Cell Therapy in CLL 

Tanya Siddiqi, MD, assistant clinical professor, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, discusses the results of the TRANSCEND CLL 004 trial.

The TRANSCEND CLL 004 study treated patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with lisocabtagene maraleucel (liso-cel). The trial showed that the CAR T-cell therapy was well tolerated. One patient experienced grade 3 cytokine release syndrome (CRS), which was manageable/reversible and 3 patients experienced grade 3 neurological events.

The outcomes of the study were encouraging. At the first assessment, the overall response rate was 81.5% and the complete remission rate was 45.5%. Undetectable minimal residual disease testing was found in 65% in the marrow as well.

Tanya Siddiqi, MD, discusses the results of the TRANSCEND CLL 004 trial.
 

Dr. Siddiqi on the Results of the TRANSCEND CLL 004 Trial in CLL

Tanya Siddiqi, MD, director, Chronic Lymphocytic Leukemia Program, Toni Stephenson Lymphoma Center, associate clinical professor, Department of Hematology & Hematopoietic Cell Transplantation, and a hematologist/oncologist at City of Hope, discusses the rationale for the phase I/II TRANSCEND CLL 004 trial (NCT03331198) investigating the use of the CAR T-cell therapy lisocabtagene maraleucel (liso-cel; JCAR017) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). 

Although the introduction of chemoimmunotherapy into the treatment paradigm has improved patient responses, CLL remains an incurable disease, says Siddiqi. Novel agents like ibrutinib (Imbruvica) or venetoclax (Venclexta) may achieve undetectable minimal residual disease (MRD) in patients; however, fixed-duration treatment or monotherapy with these drugs will not reliably keep patients MRD-negative, adds Siddiqi.

With the TRANSCEND CLL 004 trial, investigators set out to answer the question of whether there was a way to help these patients achieve undetectable MRD and cure them of their disease, explains Siddiqi. 

Investigators set out to see whether they could create CAR T cells from the patients’ T-cells and modulate their immune systems to target CD19-positive CLL cells, explains Siddiqi, just as they had done for patients with aggressive lymphomas in the past.

Results from the trial showed that 88% of patients responded to the therapy 30 days into the study. The overall response rate was 83%, which was maintained for 6 months. Moreover, 67% of patients had undetectable MRD by day 30. Further follow-up data are anticipated later this year.

Tanya Siddiqi, MD, discusses the rationale for the phase I/II TRANSCEND CLL 004 trial investigating the use of the CAR T-cell therapy lisocabtagene maraleucel in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma. 
 

Dr. Siddiqi on Rationale for the TRANSCEND CLL 004 Trial in CLL/SLL

Tanya Siddiqi, MD, a hematologist/oncologist at City of Hope, discusses the safety profile of lisocabtagene maraleucel (liso-cel; JCAR017) in the phase I TRANSCEND CLL 004 trial.

Toxicities associated with CAR T-cell therapy were easily manageable in the TRANSCEND CLL 004 trial, says Siddiqi. The majority of grade ≥3 events were cytopenia from chemotherapy. However, events of cytokine release syndrome (CRS) and neurotoxicity were also reported. About 70% of patients had CRS, but only 2 of the 23 patients had grade 3 CRS. Furthermore, around 39% of patients experienced neurotoxicity, but there were only 5 cases of grade 3/4 events of neurotoxicity.

Four cases of tumor lysis syndrome (TLS) were also reported. TLS was not common in the lymphoma trial, but abnormal circulating CLL cells in the blood can trigger a greater risk, as has been observed in acute leukemia, says Siddiqi. These patients were either managed with allopurinol (Zyloprim) and pills or rasburicase. However, 1 patient needed dialysis as well.

 included severe hypertension around day 28. Investigators thought this to be a strange finding because CAR T cells generally cause hypotension, says Siddiqi. The other toxicity was neurotoxicity that lasted more than 7 days and became a DLT by definition, says Siddiqi. That patient also had grade 4 TLS, requiring dialysis.

Tanya Siddiqi, MD, a hematologist/oncologist at City of Hope, discusses the safety profile of lisocabtagene maraleucel (liso-cel; JCAR017) in the TRANSCEND CLL 004 trial.

Dr. Siddiqi on the Safety Profile of Liso-Cel in the TRANSCEND CLL 004 Trial

Tanya Siddiqi, MD, a hematologist/oncologist at City of Hope, discusses the CLL14 trial, which tested venetoclax (Venclexta) plus obinutuzumab (Gazyva) versus obinutuzumab plus chlorambucil in patients with previously untreated chronic lymphocytic leukemia and coexisting conditions.

Data from the open-label, phase III CLL14 trial presented at the 2019 ASCO Annual Meeting showed that the addition of venetoclax to obinutuzumab reducted the risk for disease worsening or death by 65% compared with obinutuzumab/chlorambucil. Furthermore, the trial met its primary endpoint of investigator-assessed progression-free survival (HR, 0.35; 95% CI, 0.23-0.53; 

 < .001). The results, according to Siddiqi, were expected, but the study provided necessary hard data supporting the use of the fixed-duration, chemotherapy-free regimen as an option for patients with comorbidities.

Siddiqi says that she has many patients who are interested in receiving a finite therapy as opposed to indefinite treatment with ibrutinib (Imbruvica). For these patients, venetoclax/obinutuzumab may serve as an alternative option, allowing them to receive 1 year of therapy, to take a break from treatment, and then to see what happens over time.

These data are among the most exciting that have been reported within the past year, concludes Siddiqi.

Dr. Siddiqi on the CLL14 Trial Results in CLL

Tanya Siddiqi, MD, a hematologist/oncologist at City of Hope in Duarte, CA, discusses the phase I/II TRANSCEND CLL 004 trial, which evaluated the efficacy of anti-CD19 CAR T cells in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

Patients who have relapsed/refractory CLL or SLL and fail ibrutinib (Imbruvica) or venetoclax (Venclexta) have an unmet need for appropriate therapy, says Siddiqi.

The TRANSCEND CLL 004 trial, an open-label, multicenter study, enrolled patients who had received ≥2 lines of therapy, including BTK inhibitors, to receive the investigational CAR T-cell product, lisocabtagene maraleucel (JCAR017). The best overall response rate in 15 evaluable patients was 87%, with 7 patients (47%) achieving complete response.

Eradication of minimal residual disease in the blood was also seen in 67% of patients by day 30, making this an excellent option for this patient population, Siddiqi concludes.

15th International Conference on Malignant Lymphoma

Tanya Siddiqi, MD, a hematologist/oncologist at City of Hope, discusses the phase I/II TRANSCEND CLL 004 trial, which evaluated the efficacy of anti-CD19 CAR T cells in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

Tanya Siddiqi, MD

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