Authored by Dr. Brian Koffman
The Bottom Line:
An accelerated five-day venetoclax in hospital ramp-up, called SAVE (Safe Accelerated Venetoclax Escalation), can be done safely for most chronic lymphocytic leukemia (CLL) patients with an acceptably low risk of tumor lysis syndrome (TLS).
Who Performed the Research and Where Was it Presented:
Jennifer Leigh Crombie and several colleagues from Dana Farber in Boston presented these results at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago in 2023.
Venetoclax is an extremely effective therapy for CLL, but its use in the community outside of academic centers may have been slowed by the cumbersomeness of the five-week ramp up recommended to lower the risk of TLS and the need for careful blood monitoring with each dose increase. Moreover a few patients may have rapidly accelerating CLL and may not have the luxury of waiting five weeks. A safe shorter ramp up would be welcome.
As a reminder, TLS is best thought of as “too much of a good thing” where large numbers of cancer cells are rapidly killed releasing into the blood stream excesses of their intracellular contents including potassium, phosphates and uric acid that the body, specifically the kidneys, cannot safely handle. TLS can be and tragically was fatal early in the development of venetoclax when it was not recognized just how quickly and powerfully venetoclax killed CLL cells. The 5-week ramp up now in place was a response to the safety concerns raised by early deaths from TLS.
Methods and Participants:
This is an ongoing phase Ib trial for patients with treatment naïve (TN) and relapsed/refractory (R/R) CLL. To qualify one needed a diagnosis of CLL requiring treatment and adequate renal function. The primary endpoint was looking for the highest risk TLS group that can safely tolerate an accelerated venetoclax ramp-up. Risk of TLS is determined primarily by the amount of CLL (tumor burden) and the adequacy of renal function. Patients are treated in-patient with a five-day daily venetoclax ramp-up schedule (20-50-100-200-400 mg). TLS labs are monitored pre-dose and at 4, 8, 12, and 24 hours following each dose. Rituximab or obinutuzumab are given as per standard of care.
- As of the time of reporting, 20 patients have been treated
- 19 patients received obinutuzumab with venetoclax, and one patient received venetoclax monotherapy.
- All patients completed an accelerated venetoclax ramp-up with no one developing clinical TLS.
- One with medium TLS risk had lab results (but no symptoms) suggesting TLS (increased phosphates and uric acid peaked at 8.7 mg/dL) after the first venetoclax 400 mg dose, which required treatment and prolonged the ramp-up to six days.
- The median inpatient time was six days (range 5-8).
- Adverse events:
- 45% developed a low neutrophil count.
- 35% had low platelets.
- One patient died two months into treatment due to complications of a bowel obstruction unrelated to study treatment.
- Overall response rate (ORR) after three months was 89% in 19 evaluable patients including two complete remissions (CRs). Among the 19 evaluable patients after three months, 74% and 42% had undetectable measurable residual disease (uMRD) in the peripheral blood and the bone marrow, respectively.
We already knew venetoclax was a very effective and generally well tolerated therapy in TN and RR CLL. Now these early results suggest that an accelerated five-day veneoclax ramp-up is feasible in CLL with a low risk of developing TLS. Due to the frequent lab tests required (pre-dose and at 4, 8, 12, and 24 hours following each dose) this accelerated ramp-up needs to be done in hospital. For patients who would be better served by more quickly getting to a therapeutic dose or who are bothered by the inconvenience and logistics of the slow ramp-up, there is reason to hope that this accelerated inpatient approach will be a safe option and offer an option for patients away from academic centers who could benefit from treatment with venetoclax.
Links and Resources:
Watch my monologue on the ASCO abstract:
To read more details found in the actual ASCO abstract, click on: SAVE (Safe Accelerated Venetoclax Escalation): Initial results of a prospective, phase Ib study of venetoclax with an accelerated dose ramp-up in patients with CLL.
Stay strong. We are all in this together.
Brian Koffman MDCM (retired) MS Ed (he, him, his)
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.