Patients with chronic lymphocytic leukemia (CLL) with low-risk genomic features, such as mutated IGHV gene, were able to achieve long-term remissions when treated with fludarabine, cyclophosphamide, and rituximab (FCR), according to long-term follow-up results from a study initiated at the MD Anderson Cancer Center in 1999.
In fact, the long-term data showed that patients with mutated IGHV were more likely to die from causes other than CLL, according to a study published in Blood by Philip A. Thompson, MBBS, of Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues.
In the single-arm study, 300 patients with progressive or advanced CLL were treated with FCR as initial therapy. Of these patients, 88 had mutated IGHV, 126 unmutated, and 86 status unknown.
With a median follow-up of 19.0 years, median progression-free survival (PFS) was 6.4 years. Among patients with IGHV-mutated CLL, the median PFS was 14.6 years compared to 4.2 years for those with IGHV-unmutated CLL.
At 15 years follow-up, about half (48.7%) of patients with IGHV-mutated CLL were alive and progression-free compared to 8.3% of patients with non-IGHV-mutated CLL. Seventeen percent of the patients in remission at 10 years follow-up subsequently progressed; however, only four of 45 (9%) patients with IGHV-mutated CLL progressed after 10 years.
Median overall survival (OS) was 12.7 years. The 15-year OS rate was about double for patients with IGHV-mutated CLL compared with unmutated disease (63.1% vs. 32.0%, respectively). Patients with IGHV-mutated CLL were less likely to die from progressive refractory CLL than they were from other causes.
About one-third (32%) of patients developed other malignancies; 6.3% developed therapy-related myeloid neoplasms (tMNs), and 84% of these were fatal.
According to Dr. Thompson, there currently are no robust tools in CLL that predict tMNs.
“In other malignancies, such as follicular lymphoma, the presence of clonal hematopoiesis in pre-chemotherapy samples has been shown to be a risk factor for later development of tMNs. It’s tempting to extrapolate from these data, and perhaps to avoid chemoimmunotherapy in patients with clonal hematopoiesis, especially given the availability of highly active targeted agents,” Dr. Thompson said. “This is a very active area of research, with ever-increasing understanding of the relative risks of different mutations in different genes and applied to different populations of patients. However, I would stress that more research needs to be done in this area before such an approach could be routinely recommended outside of a clinical trial.”
Ideally, prospective data — randomized, if possible — would need to demonstrate that choosing a non-chemotherapy approach reduces the risk of tMN development, Dr. Thompson said, acknowledging that doing a randomized trial in this setting would be very challenging.
Given the increased risk for tMN, a risk-benefit assessment was recommended when counseling patients about FCR. Dr. Thompson said he discusses FCR only with fit, young (aged <65) patients with a life expectancy of at least 15 years who have highly favorable genomics defined as mutated IGHV and the absence of del(17p), del(11q), IGHV3-21, and subset 2 utilization TP53 mutation.
“If all these criteria are met, I discuss long-term results of FCR with the patient and stress that no novel agent has yet demonstrated the ability to replicate these results,” Dr. Thompson said. “I discuss that venetoclax plus obinutuzumab as firstline therapy has shown higher rates of undetectable [measurable] residual disease in the GAIA-CLL13 trial, but we are yet to see whether this translates into very long-term remissions analogous to those seen with FCR.”
Dr. Thompson also discusses the risks of chemoimmunotherapy, which include tMNs — many of which will be fatal — myelosuppression, immunosuppression, and infection. However, venetoclax plus obinutuzumab is also associated with immunosuppression, neutropenia, and infection; and indefinitely administered Bruton tyrosine kinase inhibitors carry risk for cardiac arrhythmias, bleeding, and immunosuppression.
“Most patients are more comfortable taking the risk of unclear durability of response with venetoclax plus obinutuzumab than the risk of tMN and will opt for venetoclax plus obinutuzumab,” Dr. Thompson said, “but I feel either is a reasonable option for this highly selected group of patients.”
One limitation to this study was incomplete follow-up of all patients, which could result in underestimation of incidence of relapse, later adverse events, and mortality.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Thompson PA, Bazinet A, Wierda WG, et al. Sustained remissions in CLL after frontline FCR treatment with very long-term follow-up [published online ahead of print, 2023 Aug 18]. Blood. doi: 10.1182/blood.2023020158.