The cumulative amount of serum-free light chain is a strong prognosticator in chronic lymphocytic leukemia (original) (raw)
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Blood, 2011
Free light chains (FLCs) are the most commonly detected paraproteins in chronic lymphocytic leukemia (CLL). We examined the types of FLC abnormalities and prognostic utility of the FLC assay compared with standard prognostic biomarkers in a prospective cohort of 339 patients with newly diagnosed CLL. Three types of FLC abnormalities were identified: monoclonal elevated FLC (elevated κ and/or λ with abnormal FLC ratio), polyclonal elevated FLC (elevated κ and/or λ with normal FLC ratio), and ratio-only FLC abnormality (normal range κ and λ with abnormal FLC ratio). One hundred sixty-five patients (49%) had a FLC abnormality with approximately equal distribution among monoclonal elevation, polyclonal elevation, and ratio-only abnormality. All FLC abnormalities were associated with poor time to first treatment: monoclonal FLC (hazard ratio [HR], 4.99; 95% confidence interval [CI], 2.94-8.48), polyclonal FLC (HR, 2.40; 95% CI, 1.24-4.64), ratio-only FLC (HR, 2.57; 95% CI, 1.40-4.69). Mo...
Prognostic Significance of Serum Free Light Chains in Chronic Lymphocytic Leukemia
Advances in Hematology, 2013
Background. Serum free light chains (sFLC), the most commonly detected paraprotein in CLL, were recently proposed as useful tools for the prognostication of CLL patients. Objective. To investigate the prognostic implication of sFLC and the summated FLCkappa plus FLC-lambda in a CLL patients' series. Patients and Methods. We studied 143 CLL patients of which 18 were symptomatic and needed treatment, while 37 became symptomatic during follow-up. Seventy-two percent, 18%, and 10% were in Binet stage A, B and C, respectively. Median patients' followup was 32 months (range 4-228). Results. Increased involved (restricted) sFLC (iFLC) was found in 42% of patients, while the summated FLC-kappa plus FLC-lambda was above 60 mg/dL in 14%. Increased sFLC values as well as those of summated FLC above 60 were related to shorter time to treatment ( = 0.0005 and = 0.000003, resp.) and overall survival ( = 0.05 and = 0.003, resp.). They also correlated with 2-microglobulin ( = 0.009 and = 0.03, resp.), serum albumin ( = 0.009 for summated sFLC), hemoglobin ( < 0.001), abnormal LDH ( = 0.037 and = 0.001, resp.), Binet stage ( < 0.05) and with the presence of beta symptoms ( = 0.004 for summated sFLC). Conclusion. We confirmed the prognostic significance of sFLC in CLL regarding both time to treatment and survival and showed their relationship with other parameters.
Clinical and molecular predictors of disease severity and survival in chronic lymphocytic leukemia
American Journal of Hematology, 2007
Several parameters may predict disease severity and overall survival in chronic lymphocytic leukemia (CLL). The purpose of our study of 190 CLL patients was to compare immunoglobulin heavy chain variable region (IgV H ) mutation status, cytogenetic abnormalities, and leukemia cell CD38 and Zap-70 to older, traditional parameters. We also wanted to construct a simple, inexpensive prognosis score that would significantly predict TTT and survival in patients at the time of diagnosis and help practicing clinicians. In univariate analyses, patients with higher clinical stage, higher leukocyte count at diagnosis, shorter leukocyte doubling time, elevated serum lactate dehydrogenase (LDH), unmutated immunoglobulin heavy chain variable region (IgV H ) genes, and higher CD38 had a shorter overall survival and time-to-treatment (TTT). CLL cell Zap-70 expression was higher in patients with unmutated IgV H , and those with higher Zap-70 tended to have shorter survival. IgV H 4-34 or IgV H 1-69 was the most common IgV H genes used (16 and 12%, respectively). Of those with IgV H 1-69, 86% had unmutated IgV H and had a significantly shorter TTT. A cytogenetic abnormality was noted in 71% of the patients tested. Patients with 11q22 del and 17p13 del or complex abnormalities were significantly more likely to have unmutated IgV H . We found that a prognostic score constructed using modified Rai stage, cellular CD38, and serum LDH (parameters easily obtained clinically) significantly predicted TTT and survival in patients at the time of diagnosis and performed as well or better than models using the newer markers. Am.
Clinical Lymphoma Myeloma and Leukemia, 2015
In a series of 608 patients with chronic lymphocytic leukemia (CLL), we identified the best biologic prognostic markers (fluorescence in-situ hybridization analysis, IGHV mutational status, and CD38 expression), and in a cohort of 212 subjects, we combined them in a new and easy scoring system, the integrated CLL scoring system (ICSS). Introduction: Several prognostic factors have been identified to predict the outcome of patients with chronic lymphocytic leukemia (CLL), but only a few studies analyzed more markers together. Patients and Methods: Taking advantage of a population of 608 patients, we identified the strongest prognostic markers of survival and, subsequently, in a cohort of 212 patients we integrated data of cytogenetic lesions, IGHV mutational status, and CD38 expression in a new and easy scoring system we called the integrated CLL scoring system (ICSS). ICSS defines 3 groups of risk: (1) low risk (patients with 13q À or normal fluorescence in-situ hybridization analysis results, mutated IGHV, and CD38) (2) high risk (all 11q À or 17p À patients and/or all unmutated IGHV and CD38 þ patients); and (3) intermediate risk (all remaining patients). Results: Using only these 3 already available prognostic factors, we were able to properly redefine patients and better predict the clinical course of the disease. Conclusion: ICSS could become a useful tool for CLL patients' management.
Haematologica, 2018
Chronic lymphocytic leukemia patients with differential somatic hypermutation status of the immunoglobulin heavy variable genes, namely mutated or unmutated, display fundamental clinicobiological differences. Considering this, we assessed prognosis separately within mutated and unmutated chronic lymphocytic leukemia in 3015 patients, hypothesizing that the relative significance of relevant indicators may differ between these two categories. Within Binet-A mutated chronic lymphocytic leukemia patients, besides TP53 abnormalities, trisomy 12 and stereotyped subset #2 membership were equivalently associated with the shortest time-to-first-treatment and a treatment probability at 5- and 10-years after diagnosis of 40% and 55%, respectively; the remaining cases exhibited 5-year and 10-year treatment probability of 12% and 25%, respectively. Within Binet-A unmutated chronic lymphocytic leukemia patients, besides TP53 abnormalities, del(11q) and/or SF3B1 mutations were associated with the ...
Leukemia & Lymphoma, 2013
Chronic lymphocytic leukemia (CLL) is a clinically and biologically heterogeneous disease where the majority of patients have an indolent disease course, while others may experience a far more aggressive disease, treatment failure and poor overall survival. During the last two decades, there has been an intense search to fi nd novel biomarkers that can predict prognosis as well as guide treatment decisions. Two of the most reliable molecular prognostic markers, both of which are off ered in routine diagnostics, are the immunoglobulin heavy chain variable ( IGHV ) gene mutational status and fl uorescence in situ hybridization (FISH) detection of prognostically relevant genomic aberrations (e.g. 11q ؊ , 13q ؊ , ؉ 12 and 17p ؊ ). In addition to these markers, a myriad of additional biomarkers have been postulated as potential prognosticators in CLL, on the protein (e.g. CD38, ZAP70, TCL1), the RNA (e.g. LPL , CLLU1 , micro-RNAs) and the genomic (e.g. TP53 , NOTCH1 , SF3B1 and BIRC3 mutations) level. Eff orts are now being made to test these novel markers in larger patient cohorts as well as in prospective trials, with the ultimate goal to combine the " best " markers in a " CLL prognostic index " applicable for the individual patient. Although it is clear that these studies have signifi cantly improved our knowledge regarding both prognostication and the biology of the disease, there is still an immediate need for recognizing biomarkers that can predict therapy response, and eff orts should now focus on addressing this pertinent issue. In the present article, we review the extensive literature in the fi eld of prognostic markers in CLL, focus on the most clinically relevant markers and discuss future directions regarding biomarkers in CLL.
Prognostic markers in chronic lymphocytic leukemia: A comprehensive review
Blood Reviews, 2009
The clinical course of individual CLL patients is highly variable, with life expectancies ranging from months to decades. Importantly, a significant subset of patients presents with low grade CLL, but will nevertheless develop a more aggressive and life-threatening disease. As these patients may potentially benefit from early treatment, it is crucial to assess patients' prognosis at diagnosis, allowing individual risk-adapted therapy. Reliable predictions of prognosis in an early stage of the disease have long been lacking in the clinical workup of CLL patients. During the last decades many efforts have been made to identify prognostic markers in CLL, resulting in a plethora of reports describing the predictive value of different parameters with regard to overall survival, disease progression and response to therapy.
Defining the prognosis of early stage chronic lymphocytic leukaemia patients
British Journal of Haematology, 2012
Approximately 70% of chronic lymphocytic leukaemia (CLL) patients present with early stage disease, therefore defining which patients will progress and require treatment is a major clinical challenge. Here, we present the largest study of prognostic markers ever carried out in Binet stage A patients (n = 1154) with a median follow-up of 8 years. We assessed the prognostic impact of lymphocyte doubling time (LDT), immunoglobulin gene (IGHV) mutation status, CD38 expression, ZAP-70 expression and fluorescence in situ hybridization (FISH) cytogenetics with regards to time to first treatment (TTFT) and overall survival (OS). Univariate analysis revealed LDT as the most prognostic parameter for TTFT, with IGHV mutation status most prognostic for OS. CD38 expression, ZAP-70 expression and FISH were also prognostic variables; combinations of these markers increased prognostic power in concordant cases. Multivariate analysis revealed that only LDT, IGHV mutation status, CD38 and age at diagnosis were independent prognostic variables for TTFT and OS. Therefore, IGHV mutation status and CD38 expression have independent prognostic value in early stage CLL and should be performed as part of the routine diagnostic workup. ZAP-70 expression and FISH were not independent prognostic markers in early stage disease and can be omitted at diagnosis but FISH analysis should be undertaken at disease progression to direct treatment strategy.