Oncology
Chronic Lymphocytic Leukemia
IGHV Gene Mutational Status in Prognostic Testing for Chronic Lymphocytic Leukemia
Overview
Today, prognostic testing in chronic lymphocytic leukemia (CLL) is used not only to develop the prognosis, but also to help to direct therapy. In particular, assessment of the immunoglobulin heavy chain variable region (IGHV) gene mutational status and the application of fluorescence in situ hybridization (FISH) cytogenetic techniques to detect 17p deletion (del[17p]) or TP53 mutation are cited as crucial. Such factors help to distinguish between patients who are likely to respond to chemoimmunotherapy with long remissions versus those who would be much better suited for the novel agents.
Expert Commentary
Jan A. Burger, MD, PhD
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In our clinical practice, the 2 most important prognostic factors that speak to both possible treatments and expected outcomes are as follows: (1) the mutational status of the IGHV portion of the B-cell receptor and (2) the profile generated by FISH cytogenetic testing. We distinguish between IGHV-unmutated versus -mutated CLL, as the unmutated status is an adverse predictor of outcome in patients who receive standard chemoimmunotherapy. The cytogenetic workup using the FISH panel for patients with CLL provides essential information, especially about whether del(17p) is present. Based on those 2 key parameters, we then discuss with patients who need treatment the best options available for them. We currently use IGHV mutational status as a stratifying factor to determine whether patients would be candidates for chemoimmunotherapy. If they are mutated, we have long-term experience with fludarabine, cyclophosphamide, and rituximab (FCR), and we know that approximately 60% of patients remain in remission beyond 10 years if they have the lower-risk feature of mutated CLL. And for those patients, we still offer the FCR program, although, currently, we make efforts to reduce the number of administered chemoimmunotherapy cycles. Thus, IGHV mutation status is currently the key stratifying factor to either discuss or discard the prospect of chemoimmunotherapy as a treatment possibility in the front-line setting. |
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“IGHV mutation status is currently the key stratifying factor to either discuss or discard the prospect of chemoimmunotherapy as a treatment possibility in the front-line setting.”
The cytogenetic markers are also helpful in assessing the risk of eventually relapsing after treatment with either chemoimmunotherapy or novel agents. Some of the genetic anomalies have significant implications in these areas. For instance, del(17p) status is very important when selecting treatment because you do not want to use chemoimmunotherapy for patients with del(17p). And if you treat these patients with novel agents, they have a higher risk of progressing, particularly in the relapse setting. Therefore, del(17p) should also be considered when deciding about the use of cellular therapy such as allogeneic hematopoietic stem cell transplantation or chimeric antigen receptor T-cell therapy. Another factor detected with the CLL FISH cytogenetic panel is 11q deletion (del[11q]). Patients with del(11q) are often younger male patients who are IGHV unmutated, and such individuals have shorter than average remission durations with chemoimmunotherapy, hence this, again, favors the use of novel agents over chemoimmunotherapy.
References
Garg R, Wierda W, Ferrajoli A, et al. The prognostic difference of monoallelic versus biallelic deletion of 13q in chronic lymphocytic leukemia. Cancer. 2012;118(14):3531-3537.
Hallek M, Cheson BD, Catovsky D, et al. Guidelines for diagnosis, indications for treatment, response assessment and supportive management of chronic lymphocytic leukemia. Blood. 2018 Mar 14. pii: blood-2017-09-806398. doi: 10.1182/blood-2017-09-806398. [Epub ahead of print]
Hallek M, Shanafelt TD, Eichhorst B. Chronic lymphocytic leukaemia. Lancet. 2018;391(10129):1524-1537.
Itchaki G, Brown JR. Experience with ibrutinib for first-line use in patients with chronic lymphocytic leukemia. Ther Adv Hematol. 2018;9(1):3-19.
Kipps TJ. Outcomes of ibrutinib-treated patients with chronic lymphocytic leukemia/small lymphocytic leukemia with high-risk prognostic factors in an integrated analysis of 3 randomized phase 3 studies. XVII International Workshop on Chronic Lymphocytic Leukemia; May 12-15, 2017; New York, NY.
Nabhan C, Raca G, Wang YL. Predicting prognosis in chronic lymphocytic leukemia in the contemporary era. JAMA Oncol. 2015;1(7):965-974.
O’Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016;17(10):1409-1418.
Parikh SA, Strati P, Tsang M, West CP, Shanafelt TD. Should IGHV status and FISH testing be performed in all CLL patients at diagnosis? A systematic review and meta-analysis. Blood. 2016;127(14):1752-1760.
The International CLL-IPI Working Group. An international prognostic index for patients with chronic lymphocytic leukemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 2016;17(6):779-790.
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