The Bottom Line:
The first interim analysis of the Phase 2 HOVON 158/Next Step Trial was conducted halfway through a 15-month course of treatment with ibrutinib and venetoclax. As compared to baseline, PET-CT scanning showed a decrease in metabolic activity in all but one patient. However, despite the decrease in metabolic activity and, in some cases, normal metabolic activity on PET-CT scans, several patients had persistently enlarged lymph nodes. In addition, fine-needle aspiration (FNA) identified malignant cells in these lymph nodes with levels more significant than those in the peripheral blood. This suggests the lymph node is a sanctuary for chronic lymphocytic leukemia (CLL) cells.
Who Performed the Research and Where Was it Presented:
Dr. Mark-David Levin, a hematologist in the Department of Internal Medicine at Albert Schweitzer Hospital, Dordrecht, Netherlands, and colleagues presented the results of the Exploratory Results of PET-CT and Residual Lymph Node Fine Needle Aspiration of Patients Treated with First-Line Venetoclax and Ibrutinib for CLL / SLL; First Interim Analysis of the Phase 2 HOVON 158/Next STEP Trial at the American Society for Hematology (ASH) Annual Meeting in December 2022.
Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a disease of the peripheral blood (PB), bone marrow (BM), and lymph node (LN), the latter of which may serve as a safe harbor for CLL cells to proliferate and often develop resistance. The past decade has seen the introduction of venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), and obinutuzumab, an anti-CD20 monoclonal antibody as effective treatments for CLL / SLL. Ibrutinib works through the B-cell receptor signaling pathway to promote cell death, but rarely, it results in undetectable measurable residual disease (MRD) activity. Venetoclax blocks the pro-survival protein BCL-2 found in CLL cells to cause cell death. When used in combination with venetoclax, Ibrutinib is a powerful combination, often resulting in undetectable MRD and complete response (CR) because the two agents work through different mechanisms and because ibrutinib also forces CLL cells from the LN where they can be exposed to the effects of venetoclax. However, there remain many individuals at the end of time-limited therapy who have evidence of MRD in the PB or BM, or even despite reaching undetectable MRD in these sites, have enlarged lymph nodes. The LN compartment can be more challenging to access than PB or BM, and not as much is known about how disease in the LN responds to treatment as compared to PB and BM.
The HOVON 158/NEXT STEP trial is designed to evaluate the efficacy of extending and intensifying treatment by an additional six months with ibrutinib and obinutuzumab, a drug that works through a distinctly different pathway than the other two agents, for those individuals who have not reached undetectable MRD or a CR at the end of the first 15 cycles of ibrutinib and venetoclax. Furthermore, the trial also studies whether persistently enlarged lymph nodes contain malignant cells utilizing two surveillance methods and compares how the LN compartment, in contrast to the PB and BM, responds during treatment. The first of the two methods employed for LN analysis is positron emission tomography/computed tomography (PET/CT). This technique uses CT to visualize enlarged lymph nodes and PET to measure cellular metabolic activity, which is increased with malignancy. However, not being a commonly used method in CLL / SLL, the correlation between PET/CT findings and actual LN involvement is not clear. The second technique is FNA, a form of biopsy using a small needle to withdraw a tissue sample from an LN located in an easily accessible body area.
Following the presentation at ASH, Dr. Brian Koffman interviewed Dr. Mark-David Levin, also Vice-President of the Dutch CLL Working Group, to gain further insights into this research.
Methods and Participants:
- HOVON 158/NEXT STEP trial is an open-label, single-arm phase 2 study.
- Eligible patients with untreated CLL or SLL are treated with three 28 days cycles of ibrutinib followed by 12 cycles of combined ibrutinib and venetoclax.
- Patients are assessed for CR as defined by the International Workshop on Chronic Lymphocytic Leukemia (IwCLL) criteria and are tested for MRD by bone marrow biopsy after cycle 15. Patients achieving CR with undetectable MRD at a <10-4, less than one malignant cell per 10,000 cells may stop treatment.
- Intensification with an additional six cycles of ibrutinib combined with obinutuzumab is administered to patients with MRD positivity and/or less than a CR.
- After cycle 8, exploratory analysis is done with PET-CT scanning. If at the end of cycle 8, an LN > 1.5 cm is present on physical examination or CT scan and located in the cervical, axillary, or inguinal regions, a fine needle aspiration by ultrasound is completed. The sampled cells are analyzed by flow cytometry.
- 30 patients were enrolled.
- In the first 8 cycles, one patient withdrew due to adverse events. There were no progression events, death, or safety concerns.
- Based on MRD testing by flow cytometry of PB and CT scanning,100% of patients showed a response to treatment at the end of cycle 8.
- PET scans at baseline were positive in 18 (60%) patients and, after 8 cycles, showed a decrease in disease activity in all but one patient.
- 9 of the 13 patients with an enlarged lymph node after cycle 8 underwent FNA.
- Adequate samples for interpretation were obtained by FNA in 5 of the 9 biopsied patients, and CLL cells were found by flow cytometry in the samples of these five patients.
- In 4 of the 5 patients, levels of CLL cells were higher in the lymph node than in the peripheral blood.
- Two patients with CLL cells detected by FNA had no evidence of increased metabolic activity by PET scanning.
After three cycles of ibrutinib followed by five cycles of ibrutinib and venetoclax, all patients responded to treatment based on MRD testing of PB and CT scanning, and all but one patient had a decrease in metabolic uptake on PET-CT scan. However, despite a decrease in metabolic activity in the lymph nodes on PET-CT and, in 2 cases, normal metabolic activity on PET scanning, persistent CLL cells were detected in enlarged lymph nodes by FNA and in concentrations more significant than those in peripheral blood, suggesting that the residual LN serves as a sanctuary for CLL.
Often patients focus on the amount of CLL in the peripheral blood or marrow, but it is essential to remember that CLL can hide out and grow in the protective niches in the lymph nodes. Therefore, curative therapies will need to clear cancer from all three compartments where lymphocytes are found, namely the blood, bone marrow, and lymph nodes.
Links and Resources:
You can watch our interview with Dr. Mark-David Levin here:
You can read the actual ASH abstract here:
Exploratory Results of PET-CT and Residual Lymph Node Fine Needle Aspiration of Patients Treated with First-Line Venetoclax and Ibrutinib for CLL / SLL; First Interim Analysis of the Phase 2 HOVON 158/Next STEP Trial
We share in this journey together,
Kim Davidson, MD
CLL patient and physician