Profiling CLL Patients Likely to Progress on Available Agents

Richard R. Furman, MD

The next frontier in advancing the field of chronic lymphocytic leukemia (CLL) is identifying patients who will not experience long-term progression-free survival (PFS) on novel agents, according to Richard Furman, MD.

These patients will need new approaches beyond currently available treatments, which include ibrutinib (Imbruvica), venetoclax (Venclexta), idelalisib (Zydelig), and others, said Furman.

The 4 primary causes of treatment failure for patients with CLL are disease progression, Richter’s transformation, adverse events, and secondary cancers, including myelodysplastic syndrome and acute myeloid leukemia. Furman, director of the CLL Research Center at Weill Cornell Medicine, focused on the first two causes in a discussion at the 35th Annual CFS.^®

Furman first discussed the current standard of care in CLL. Although the FCR regimen (fludarabine, cyclophosphamide, and rituximab) may be a viable option for some patients, 5-year follow-up data from the phase Ib/II PCYC-1102 trial presented at the 2016 ASH Annual Meeting further established ibrutinib as the new standard of care.¹

Among 31 treatment-naïve patients aged >65, the median PFS and overall survival (OS) were not reached, and the 5-year PFS and OS rates were both 92%. The 2 treatment-naïve patients who did progress both had del(17p). Among 101 relapsed/refractory patients (all ages), the median PFS was 52 months and the median OS was not reached, with 5-year PFS and OS rates of 43% and 57%, respectively.

“So, in essence, for the treatment-naïve patients, we may have found exactly what our patients need, and they need nothing else—except for those del(17p) patients—but obviously, we need to do better for our relapsed/refractory patients,” said Furman.

An analysis published in the Journal of Clinical Oncology assessed resistance to ibrutinib in a cohort of 308 patients with CLL enrolled across 4 clinical trials.² Among these patients, 237 received ibrutinib alone.

At a median follow-up of 3.4 years (range, 0.3-5.9 years), 136 patients (44%) remained on therapy, 14 patients (4.5%) had received transplantation or therapy elsewhere, and 158 patients (51%) had discontinued ibrutinib.

Among the patients who discontinued, 83 (52.5%) did so due to disease progression. Of these patients, 55 (66%) experienced progression of CLL and 28 (34%) had Richter’s transformation.

Furman noted that in patients with CLL that responds to ibrutinib and then progresses, “the progression is commonly associated with single-based paramutations that make ibrutinib not effective.” The mutation either effects the binding of ibrutinib (BTK: C481S, C481F, C481R, C481A) or it’s an activating mutation of phospholipase C gamma 2 (S707Y, S707P, S707F,R665W and L845F, L845 del, D993Y) that bypasses the need for BTK activity.

Furman said that the multitrial analysis showed that these mutations are responsible for about 87% of the patients with progressive CLL. He also noted that emerging data are showing that these single-based paramutations exist in the patient before ibrutinib treatment is started. “The mutations are just able to grow out,” said Furman.

The researchers on the multitrial analysis drilled deeper and found that among the 55 CLL progressors, variables associated with discontinuation included complex karyotype (≥3 abnormalities), del(17p), and age.

The investigators were able to determine that at 4 years, the risk for CLL progression for patients receiving ibrutinib was 1.9% for patients aged ≥65 with no complex karyotype and no del(17p). However, for patients aged <65 with a complex karyotype and del(17p), the risk for CLL progression was 44%.

“The del(17p) and complex karyotype are probably responsible for what I call ‘genomic instability,’ and it’s this genomic instability that really leads to the mutations developing in the marrow before the patient gets treated,” said Furman.

Focusing on Richter’s transformation, Furman said in the multitrial analysis, variables linked to ibrutinib discontinuation among the patients with Richter’s transformation were complex karyotype and MYC abnormalities.

Beyond these findings, Furman said another analysis showed that prior treatment with the combination of purine analogues and alkylating agents led to a 3-fold increase in the risk of developing Richter’s transformation (odds ratio, 3.26; P = .0003).³ Other factors associated with developing Richter’s transformation include NOTCH1 and IGHV 4-39 mutations.

Looking ahead, Furman said advancing CLL care requires identifying patients with these high-risk factors for CLL progression and Richter’s transformation, and developing new approaches and/or therapies to either prevent resistance to available agents or treat patients when resistance occurs.

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. Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443. doi: 10.1200/JCO.2016.70.2282.
3. Parikh SA, Rabe KG, Call TG, et al. Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients. Br J Haematol. 2013 Sep;162(6):774-82. doi: 10.1111/bjh.12458.