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Time-to-Progression after Chemotherapy Increased in Unmutated IgVh CLL
Abstract & Commentary
By Andrew S. Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: Unmutated immunoglobulin variable heavy chain (IgVh) in patients with chronic lymphocytic leukemia is associated with worse outcome. Lin et al explored the role of IgVh mutational status on outcome after fludarabine, cyclophosphamide, and rituximab for CLL in 177 patients. They found that complete remission rates were similar at 73% and 83% for unmutated and mutated IgVh, respectively (p = 0.12). Among those achieving CR, time-to-progression was considerably shorter for unmutated IgVh (p < 0.001) and the results were maintained after adjustment. Survival was not different by mutational status after adjustment. Unmutated IgVh in CLL is associated with more rapid disease progression after CR.
Source: Lin K, et al. Relevance of the immunoglobulin VH somatic mutation status in patients with chronic lymphocytic leukemia treated with fludarabine, cyclophosphamide, and rituximab (FCR) or related chemoimmunotherapy regimens. Blood. 2009;113:3168-3171.
Chronic lymphocytic leukemia (CLL) is a common lymphoproliferative disorder. As with most cancers, the disease is highly heterogeneous, with extremely varied survival. Somatic mutations in the immunoglobulin variable heavy chain (IgVh) has been described in around 50% of CLL patients,1,2 and are of considerable prognostic importance. For patients with CLL cells that use unmutated IgVh, survival is poor relative to patients having CLL cells using mutated IgVh. Whether this higher mortality relates to lower response to induction, higher relapse or both is not clear.
Investigators from MD Anderson Cancer Center evaluated the pre-treatment IgVh mutational status from samples of 177 CLL patients treated with fludarabine, cyclophosphamide, and rituximab (FCR). In some patients, the treatment protocol employed FCR augmented by higher doses of rituximab, mitoxantrone, or alemtuzumab. Mutated IgVh was defined as detecting greater than 2% mutations (< 98% homology to germline status).
Mutational status showed 59% having unmutated IgVh and 41% having mutated IgVh. As expected, unmutated IgVH was associated with higher white blood cell count at treatment, elevated beta-2-microglobulin, and abnormal karyotype. Restricting results to FCR-only patients, complete remission (CR) rate was 73% for unmutated and 83% for mutated CLL (p = 0.12), respectively. Flow-cytometry negative CR rates were 57% for unmutated and 67% for mutated (p = 0.21), respectively. Protocols with FCR as a base protocol and incorporating other treatment showed similar trends with a marginal trend of lower initial CR (p = 0.46).
Time-to-progression (TTP) among those who achieved CR was inferior for unmutated IgVh compared to mutated at 47% vs. 82%, respectively (p < 0.001). The results were maintained when only considering those with a flow-cytometry negative CR. In a multivariate analysis, only unmutated IgVh status was strongly associated with TTP (HR = 3.8, p < 0.001), whereas standard factors such as older age, elevated beta-2 microglobulin, cytogenetic abnormalities, elevated white blood cell count, CD38 positivity, and time interval before treatment were not statistically significant.
Six-year overall survival was 71% in CLL patients having an unmutated IgVh compared to 82% in those without such a mutation (p = 0.05). In multivariate analysis, unmutated status was no longer significant, whereas older age and higher beta-2 microglobulin did predict for worse survival.
Because of the heterogonous nature of CLL, the optimal timing for treatment and regimen remain controversial and must be individualized. Somatic mutations in the immunoglobulin variable heavy chain (IgVh) have emerged as an adverse prognostic factor that can be identified in around half of the patients. Poor prognostic biologic factors can impair outcome through resistance to therapy, higher risk of relapse once remission is attained, or a combination of both. Lin et al suggest in this study that the adverse influence of unmutated IgVh is primarily attributable to disease relapse rather than low remission rates. Specifically, among patients who received the FCR regimen, complete remission rates were not statistically different by mutational status, whereas time-to-progression after complete remission was much shorter among patients having unmutated IgVh. The shorter time-to-progression was confirmed in multivariate analysis. Lin et al suggest that more aggressive remission strategies be considered in CLL patients harboring unmutated IgVh.
The data provided herein are particularly useful in demonstrating the prognostic relevance of IgVh after FCR, an aggressive regimen often used for younger patients where the goal is optimal and prolonged disease control. Still, the findings should be considered preliminary rather than confirmatory, and the conclusions may be premature. First, the remission rates, although statistically similar, were 10% lower in absolute terms in patients with unmutated IgVh. If this difference is true, it would be significant in a larger cohort, and suggests both remission rates and relapse after remission are influenced by IgVh mutational status. Second, overall survival was lower for unmutated IgVh in univariate analysis, but not after adjusting for other factors. It would be difficult to attribute the lack of a survival difference to only an inadequately powered sample since time-to-progression was markedly worse in the unmutated patients. Even though TTP was shorter with unmutated disease, these data raise an intriguing hypothesis that FCR mitigated part of the adverse influence of unmutated IgVh.
While IgVh mutational status may become clinically useful, we need considerably more data before we can make treatment decisions, such as more intensive consolidation, based on this test, such as more intensive consolidation. While higher stage still is the most widely used clinically tool to determine prognosis and treatment, a dizzying array of novel prognostic markers have been studied for CLL. A non-inclusive list includes lymphocyte doubling time, CD38 positivity, zeta chain associated protein 70 (ZAP 70), karyotypic abnormalities, bone marrow histology, and beta-2 microglobulin, as well as IgVh mutational status. Unmutated IgVh appears to be a strong adverse prognostic factor in most studies.1,2 Still, the optimal prognostic marker remains unknown, and some markers, such as ZAP-70, may be better or additive to IgVh.3 Most likely, a panel of markers will be needed to supplement clinical information such as stage, age, and health status.
Technical issues also warrant discussion. Assessing IgVh is technically difficult and not clinically available. Further, a gold-standard definition for unmutated status is lacking, although recent studies suggest > 97% sequence homology to the somatic genotype should define unmutated IgVH.4 In this study, > 98% sequence homology was used to defined unmutated.
In conclusion, mutated IgVh among CLL patients treated with FCR was associated with a shorter time-to-progression after remission. Further studies will be needed to determine whether treatment decisions should be influenced by IgVh mutational status.
1. Damle RN, et al: Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999;94:1840-1847.
2. Hamblin TJ, et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848-1854.
3. Rassenti LZ, et al: ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004;351:893-901.
4. Hamblin TJ, et al. Determination of how many immunoglobulin variable region heavy chain mutations are allowable in unmutated chronic lymphocytic leukaemia long-term follow up of patients with different percentages of mutations. Br J Haematol. 2008; 140:320-323.