Novel Agents, Earlier Diagnosis Driving Survival Gains in CLL

Richard R. Furman, MD

The median overall survival (OS) for patients with chronic lymphocytic leukemia (CLL) has more than tripled since the 1970s, primarily due to an ever-expanding armamentarium of novel agents and earlier diagnosis, said Richard Furman, MD, director of the Weill Cornell Medicine CLL Research Center, at the 36th Annual CFS^®.

There have been several novel agents approved for CLL, since the introduction of fludarabine, cyclophosphamide, and rituximab (FCR) in 2010. Leading the pack was the anti-CD20 monoclonal antibody obinutuzumab (Gazyva), which was approved for frontline treatment with chlorambucil in 2013. This was followed in 2014 by the BTK inhibitor ibrutinib (Imbruvica), PI3K inhibitor idelalisib (Zydelig), and the BCL-2 inhibitor venetoclax (Venclexta) in 2016, among other agents.

Another emerging category are the spleen tyrosine kinase (Syk) class of inhibitors, which includes entospletinib (GS-9973). Another drug to watch closely is umbralisib (TGR-1202), an oral PI3K delta inhibitor that targets the delta isoform, Furman said. It is distinct from other PI3K agents, such as idelalisib and duvelisib (Copiktra), which recently gained FDA approval “because it has a different backbone it may have a different toxicity profile, and this is going to be something very important to keep an eye on,” he said.

The introduction of ibrutinib was a game-changer in the CLL space. In long-term findings from a phase Ib/II study, the 5-year PFS was high for treatment naïve patients (92%) and relapsed/refractory (R/R) patients (43%) treated with ibrutinib. The same was seen for 5-year OS rates (92% vs 57%).¹

“Patients who are treatment naïve and >65 years have an excellent chance of remaining free from regression at 5 years. The people who did progress were del17p patients. So, for a subgroup of patients, in theory, BTK is all that they need,” Furman said. “The challenge is to figure out what to do for others who will need more than that; and predicting who those people are going to be is the second part of that challenge,” he added.

It’s important to consider how agents affect patients over the long term, Furman said. For example, after 5 years of FCR, the risk of myelodysplastic syndrome is about 8%. “I think we’re approaching a time when we could start thinking about CLL patients living 20 to 30 years after they start treatment.”

One advantage of ibrutinib is that the risk of adverse events does not significantly increase beyond the 2-year point, except for hypertension, which is treatable, Furman said. “Beyond 24 months on ibrutinib, you’re not going to be at increased risk of developing atrial fibrillation. Also, we see an improvement in our infectious risks.”

Deciding who will do well with BTK inhibitors is aided by looking at where failures have occurred with these agents. For example, Richter’s transformation can develop early for some (median, 1.8 years), often prior to chemotherapy, and genomic instability is a cause of progression, Furman said, with complex karyotypes, del17p, and age each contributing. However, he said, “if you have a stable genome, you’re going to do incredibly well on ibrutinib,” he said.

For patients >65 years of age with no complex karyotypes or del17p who are treated with ibrutinib, the risk of CLL progression at 4 years is 1.9% as opposed to a 44% risk for those <65 with complex karyotypes or del17p, Furman said.²

Richter’s transformation is another factor impacting OS. In a study by patient clonal relatedness conducted in 2011, the median OS was 62.5 months for clonally unrelated and 14.2 months for clonally related.³ “I think the greatest limitation to the clonally unrelated patients doing well is primarily the fact that the marrow is infiltrated with CLL and they might not be able to tolerate or receive full delivery of chemotherapy, but in theory these patients should do just as well as those with all other de novo diffuse large b cell lymphomas,” Furman said.

Also clarifying is the distinction between patients with Richter’s transformation who have NOTCH1 mutations (15-year OS, 45%) versus those who are NOTCH1 wild-type (15-year OS, 4.6%).⁴ “The numbers actually really indicate that the vast majority of risk is demonstrated by year 5.” This makes this another useful risk factor for therapy selection, Furman said.

While single-agent ibrutinib is sufficient for many patients, those with Richter’s transformation, del17p, complex karyotypes, or age below 65 years, may be ideal for an experimental combination strategy. For these patients, Furman encouraged enrollment in a clinical trial.

References

1. O’Brien SM, Furman RR, Coutre SE, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia. Presented at: 58th American Society of Hematology Annual Meeting; San Diego, CA; December 3-6, 2016. Abstract 233.
2. BTK^C481S-Mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443. doi: 10.1200/JCO.2016.70.2282.
3. Rossie D, Spina V, Deambrogi C, et al. The genetics of Richter syndrome reveals disease heterogeneity and predicts survival after transformation. Blood. 2011;117(12):3391-3401. doi: 10.1182/blood-2010-09-302174.
4. Rossi D, Rasi S, Spina V, et al. Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndrome. BJH. 2012;158(3):426-9. Br J Haematol. doi: 10.1111/j.1365-2141.2012.09155.x