Testing for Prognostic Markers Is a Necessity for Optimized CLL Care

Deborah M. Stephens, DO

The identification of prognostic markers at diagnosis in chronic lymphocytic leukemia (CLL) is critical, said Deborah M. Stephens, DO, who explained that the results of testing for these markers can be used to educate patients on their prognosis, tailor therapy accordingly, and enroll eligible patients on clinical trials.

The clinical presentation of CLL is heterogeneous. Some patients can receive active surveillance for a period before starting therapy, whereas others require immediate treatment. Prognostic factors, such as immunoglobulin variable heavy chain (IGHV), fluorescence in situ hybridization (FISH), and TP53, can indicate whether a patient has more aggressive or indolent disease and inform whether a traditional chemoimmunotherapy regimen, such as fludarabine, cyclophosphamide, and rituximab (Rituxan; FCR), or targeted therapy is more appropriate.

“In CLL, we really do have to consider both clinical risk and molecular risk,” said Stephens, director of the CLL and Lymphoma Program at Huntsman Cancer Institute, in a presentation on the evolving role of prognostic markers in CLL in the era of novel agents during the 39th Annual Chemotherapy Foundation Symposium Innovative Cancer Therapy for Tomorrow® (CFS®), a program hosted by the Physicians’ Education Resource^® (PER^®), LLC.¹

Association Between Prognostic Factors and Targeted Therapy Benefit

IGHV

IGHV status can influence whether to recommend targeted therapy, explained Stephens.

“I have a very strong preference for using targeted therapy in patients with unmutated IGHV,” said Stephens, who is also an assistant professor within the Division of Hematology and Hematologic Malignancies at the University of Utah.

The marker itself represents DNA sequencing for homology to the most similar germline gene; if the gene has at least 98% homology, IGHV is unmutated.

Patients with unmutated IGHV, which comprise approximately 50% of the CLL population, have a median overall survival (OS) of approximately 9 years vs approximately 25 years in patients with mutated IGHV.²

“A good thing about this risk factor is that it doesn’t change over time, so you can check IGHV once,” said Stephens.

In providing an example of why IGHV is important to evaluate, Stephens cited the phase 3 EA1912 trial (NCT02048813), which evaluated frontline ibrutinib (Imbruvica) plus rituximab vs FCR. The study showed that among patients with unmutated IGHV, the 3-year progression-free survival (PFS) rate was 90.7% with ibrutinib/rituximab vs 62.5% with FCR (HR, 0.26; 95% CI, 0.14-0.50), indicating that the ibrutinib-based therapy was far superior to chemoimmunotherapy in patients with the poor-risk marker.³

Similarly, the results of the phase 3 CLL14 trial (NCT02242942), which evaluated the frontline combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) vs chlorambucil and obinutuzumab, showed an improvement in PFS with venetoclax/obinutuzumab vs chlorambucil/obinutuzumab, regardless of IGHV status (HR, 1.16; P = .73; HR, 3.45; P < .01, respectively).⁴ The findings indicate that targeted agents are favored drugs for patients with unmutated IGHV.

“When comparing the IGHV-unmutated and -mutated patients, the venetoclax arms did exactly the same,” said Stephens. “IGHV status is very important in the likelihood and timing of treatment, and IGHV can be used to tailor the frequency of clinic visits,” said Stephens.

FISH

FISH testing has been around for some time, said Stephens, explaining that it’s used to probe for common and significant mutations in CLL, including deletion 13q, trisomy 12, deletion 11q, and deletion 17p, the latter of which is associated with particularly poor prognosis. Notably, FISH can change over time and should be reevaluated at the time of subsequent therapy.

With ibrutinib monotherapy, patients with deletion 17p had a median PFS of approximately 3 years vs approximately 1 year with chemoimmunotherapy in the phase 3 CLL-8 trial (NCT00281918).^5,6

In the CLL14 trial, patients without deletion 17p had improved PFS regardless of whether they received venetoclax/obinutuzumab or chlorambucil/obinutuzumab (HR, 4.42; P < .01; HR, 4.64; P < .01, respectively).⁴ However, venetoclax/obinutuzumab is still favorable vs chlorambucil/obinutuzumab, regardless of mutational status, said Stephens.

Stephens also addressed deletion 11q, which has historically been a poor prognostic marker. However, in a meta-analysis of 3 randomized studies of ibrutinib vs a comparator, the 42-month PFS rate was prolonged in patients with deletion 11q vs without, at 70% vs 65%, respectively (P = .02).⁷

“The authors suggested that deletion 11q should no longer be considered an adverse prognostic factor when patients are treated with ibrutinib,” Stephens said.

TP53

TP53 aberrations, or tumor suppressor proteins, are often associated with deletion 17p and are found in approximately 10% of patients with CLL at diagnosis, said Stephens.⁶

In the CLL14 trial, patients without a TP53 mutation had improved PFS regardless of whether they received venetoclax/obinutuzumab or chlorambucil/obinutuzumab (HR, 3.08; P = .01; HR, 2.74; P < .01, respectively).⁴ However, because patients with the aberration have poor PFS with standard chemoimmunotherapy and improved PFS with both ibrutinib and venetoclax/obinutuzumab, Stephens stated that either targeted approach would be better than chemoimmunotherapy in these patients.

Also associated with these aberrations is complex karyotype, which is defined as more than 3 abnormalities. Complex karyotype is currently associated with poor prognosis, even in ibrutinib-treated patients. However, a recent analysis indicated that the definition should be amended after the results showed that at least 5 chromosomal aberrations were found to be a novel, independent prognosticator.⁸

“These chromosomal abnormalities are highly inter-related and have a high impact on survival, [which has led to my] strong preference for targeted therapy in these patients,” Stephens said.

Combining Molecular Risk With Clinical Risk

The CLL International Prognostic Index (CLL-IPI) combines molecular risk factors like deletion 17p and TP53 and IGHV status with clinical risk factors, such as age and Rai stage, to determine whether a patient has low-, intermediate-, high-, or very high–risk disease. The tool is helpful not only in understanding a patient’s survival probability, but also in estimating their time to first treatment.

According to a paper published in Lancet Oncology, the CLL-IPI model estimated that the 5-year OS rates of patients with low-, intermediate-, high-, or very high–risk disease were 91%, 80%, 53%, and 19%, respectively.⁹ The 10-year OS rates were 87%, 40%, 16%, and 0%, respectively.

Regarding time to first treatment, a study published in the American Journal of Hematology indicated that, when stratified by low-, intermediate, and high-risk according to the CLL-IPI, the 5-year time to first treatment rates were 75%, 39%, and 23%, respectively.¹⁰

In conclusion, Stephens highlighted the ongoing phase 3 EVOLVE CLL Study/SWOG 1925 trial (NCT04269902) as a potential clinical trial for asymptomatic patients with newly diagnosed CLL who undergo molecular testing and are found to have a CLL-IPI score of at least 4, and/or complex cytogenetics. The study is evaluating early vs delayed treatment with venetoclax and obinutuzumab. Patients will be stratified by high-risk vs very high–risk CLL.

“This trial is a great benefit to patients because, in both of these arms, the drugs are completely paid for and [the results] will answer an important question of whether these high-risk patients should be treated early,” Stephens concluded.

References

1. Stephens DM. The evolving role of prognostic markers for CLL in the era of novel agents: putting data to practice. Presented at: 39th Annual CFS®; November 3-5, 2021; virtual.
2. Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848-1854. doi:10.1182/blood.V94.6.1848
3. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443. doi:10.1056/NEJMoa1817073
4. Tausch E, Schneider C, Robrecht S, et al. Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax. Blood. 2020;135(26):2402-2412. doi:10.1182/blood.2019004492
5. Byrd JC, Furman RR, Coutre SE, et al. Ibrutinib treatment for first-line and relapsed/refractory chronic lymphocytic leukemia: final analysis of the pivotal phase Ib/II PCYC-1102 study. Clin Cancer Res. 2020;26(15):3918-3927. doi:10.1158/1078-0432.CCR-19-2856
6. Stilgenbauer S, Schnaiter A, Paschka P, et al. Gene mutations and treatment outcome in chronic lymphocytic leukemia: results from the CLL8 trial. Blood. 2014;123(21):3247-3254. doi:10.1182/blood-2014-01-546150
7. Kipps TJ, Fraser G, Coutre SE, et al. Long-term studies assessing outcomes of ibrutinib therapy in patients with del(11q) chronic lymphocytic leukemia. Clin Lymph Myel Leuk. 2019;19(11):715-722. doi:10.1016/j.clml.2019.07.004
8. Baliakas P, Jeromin S, Iskas M, et al. Cytogenetic complexity in chronic lymphocytic leukemia: definitions, associations, and clinical impact. Blood. 2019;133(11):1205-1216. doi:10.1182/blood-2018-09-873083
9. International CLL-IPI Working Group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779-790. doi:10.1016/S1470-2045(16)30029-8
10. Molica S, Shanafelt TD, Giannarelli D, et al. The chronic lymphocytic leukemia international prognostic index predicts time to first treatment in early CLL: Independent validation in a prospective cohort of early stage patients. Am J Hematol. 2016;91(11):1090-1095. doi:10.1002/ajh.24493