CLL Research: Duvelisib and Venetoclax Show Early Promise in CLL/SLL or Richter’s Syndrome
Dr. Jennifer L. Crombie, M.D. is a Chronic Lymphocytic Leukemia (CLL) Specialist at the Dana-Farber Cancer Institute in Boston and an Instructor in Medicine at Harvard Medical School. In December, Dr. Crombie gave an oral poster presentation at the American Society of Hematology annual meeting (ASH 2020). The poster’s title is Updated Results from a Phase I/II Study of Duvelisib and Venetoclax in Patients with Relapsed or Refractory CLL/SLL or Richter’s Syndrome. (Abstract 3141) Dr. Crombie is one of the principal investigators (PI) for this trial. (NCT03534323)
Background – Duvelisib and Venetoclax Study
Several novel therapeutic agents have received approval for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the past seven years. These drugs can be effective as single agents; however, complete response (CR) rates are typically low, and those responses may not be durable for some patients. Treatment with novel agents as monotherapy such as ibrutinib (Imbruvica®) or acalabrutinib (Calquence®) generally requires indefinite treatment associated with prolonged side risks effects, the development of drug resistance, and high cost.
The MURANO study showed that venetoclax (Venclexta®) plus rituximab is an effective time-limited regimen for treating patients with relapsed or refractory (R/R) CLL. This regimen’s two potential drawbacks are a two-year treatment period, and rituximab is a product infused intravenously, requiring numerous visits to an infusion clinic.
To address these issues, and in the hope of developing a time-limited all-oral treatment regimen, the team at Dana-Farber established a multicenter phase I/II trial of duvelisib (Copiktra®), a small molecule dual inhibitor of PI3K-δ (delta), and PI3K-γ (gamma), plus venetoclax a BCL-2 inhibitor for patients with (R/R) CLL or SLL. Both duvelisib and venetoclax are FDA-approved individually for the treatment of R/R CLL/SLL. Both of these drugs are well-tolerated treatments that target pathways fundamental to CLL cell biology. Further, these drugs, when combined, provide an all-oral regiment with a convenient treatment schedule.
Methods – Can Duvelisib and Venetoclax Combination Provide a Time-Limited All-Oral Treatment Option?
This trial enrolled 22 patients as of July 19, 2020 (study data cutoff date). The median patient age was 69 (range, 50-78). A majority of patients in this group had one or more high-risk factors, including deletion(17p) 7/22 (32%), TP53 mutation 10/22 (45%), deletion (11q) 2/22 (9%), unmutated IGHV 20/22 (91%) and mutation in NOTCH1 10/22 (45%). The median number of prior treatments for this group was 3 (range, 1-6), including two patients who relapse after stem cell transplant and 15/22 (68%) previously treated with a BTK, such as ibrutinib (Imbruvica®) or acalabrutinib (Calquence®). Of those who had prior BTK exposure, seven had progressed on that therapy.
In the Phase 1 portion of this study, the primary aim is to evaluate the safety of the combination, the primary objective for all Phase 1 clinical trials. Secondary goals in Phase 1 are to determine if there are dose-limiting toxicities (DLT), to determine the maximum tolerated dose (MTD), and to ascertain the recommended Phase 2 dose (RP2D).
MTD is the highest dose of a drug or treatment that does not cause unacceptable side effects. Researchers find the MTD by testing increasing dosages on different groups until the highest dose with acceptable side effects is found.
The primary endpoints in the Phase 2 portion of this study are to determine the complete response rates (CR) and the rate of undetectable minimal residual disease (uMRD). Patients who achieve uMRD after at least one year of duvelisib and venetoclax combination therapy are given the option to discontinue treatment with close monitoring or remain on venetoclax. Patients who reach uMRD and stop duvelisib and venetoclax can restart venetoclax in the event of relapse.
MRD assessment used eight-color flow cytometry at the level of 10 to the minus 4th or less than one malignant cell among 10,000 lymphocytes in both peripheral blood (PB) and bone marrow (BM).
Results: Can Duvelisib and Venetoclax Combination Provide a Time-Limited All-Oral Treatment Option?
The median number of cycles was 7.5 (range, 1-22). The overall response rate (ORR) for patients treated with duvelisib and venetoclax for CLL/SLL was 94% (17/18). 56% of patients attained complete response (CR), and 39% reached partial response (PR). The one patient not counted in the ORR elected to undergo a stem cell transplant before an assessment of response could be made.
As of the data cutoff, 56% (10/18) of patients achieved uMRD. Four patients had not reached the point of evaluation. Of the patients who have completed 1-year duvelisib and venetoclax, 58% (7/12) had a CR with uMRD and stopped all treatment. This group included two deletion (17p) patients.
Hematologic side effects were the most common. Neutropenia or low neutrophil counts occurred in 78% of participants. Of those who developed neutropenia, 68% were the more severe grade 3 or higher. Seventy percent of patients who developed neutropenia required some form of active management such as administration of the growth-factor drugs filgrastim or pegfilgrastim.
The immune-mediated side effects associated with the PI3k class of drugs only occurred in three patients, with one each experiencing diarrhea, colitis, and liver inflammation.
Eleven patients held duvelisib treatment temporarily; nine patients had a duvelisib dose reduction, and six discontinued duvelisib due to toxicity issues.
Conclusions: Duvelisib and Venetoclax
The combination treatment strategy with duvelisib and venetoclax can potentially shift the paradigm in the management of CLL/SLL. More profound responses alleviate the need for lifelong therapy, thereby reducing the risk of side effects and possibly decreasing the chances of developing resistance to treatment.
In animal studies, the combination of duvelisib and venetoclax showed synergistic activity in Richter’s Syndrome (RS). All three patients with RS transformed to diffuse large B-cell lymphoma (DLBCL), the more common transformation. Only one patient attained a partial response from the combination of duvelisib and venetoclax. All three RS patients died, but this combination warrants further study for RS because of the promising pre-clinical efficacy reported at ASH-2019 (Ianello et al.)
Duvelisib plus venetoclax shows activity in patients with R/R CLL/SLL. The side effects are consistent with those associated with the individual drugs.
Follow-up data on this trial is ongoing, and we look forward to more data in the future.