Select high risk genetic features predict earlier progression following chemotherapy in chronic lymphocytic leukemia: Prospective randomized trial (Intergroup E2997) to evaluate justification for risk-adapted therapy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6521-6521 ◽  
Author(s):  
M. R. Grever ◽  
G. W. Dewald ◽  
D. S. Neuberg ◽  
J. C. Reed ◽  
S. Kitada ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Progression Free Survival ◽  
Response Duration ◽  
Complete Response ◽  
P53 Mutation ◽  
Lymphocytic Leukemia ◽  
Clinical Staging ◽  
Interphase Cytogenetics ◽  
Mutational Status ◽  
Genetic Features

6521 Background: Genomic features including lack of IgVH mutations, del(11q), del(17p), and p53 mutations have been reported to predict clinical course and overall survival in CLL patients (pts). Bcl-2 family proteins and ZAP-70 have also been explored as predictors in CLL. Methods: We prospectively evaluated the prognostic significance of clinical features and laboratory variables on response and progression-free survival (PFS) following treatment with fludarabine (F, n=132) or fludarabine plus cyclophosphamide (FC, n=137) as part of the US Intergroup Trial E2997 for previously untreated CLL. Results: FC therapy had higher complete response (CR) (23.4% versus 4.6%), overall response (OR) (74.3% versus 59%), and median PFS (31.6 mos versus 19.2 mos) compared to F. CR and OR were not significantly different based on interphase cytogenetics, IgVH status, or p53 mutation. IgVH status or levels of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 proteins were not associated with clinical response or PFS. IgVH status and ZAP-70 levels were associated with time from diagnosis to treatment. Using a model including treatment arm, pts with del(17p) or (11q) had significantly shorter PFS (hazard ratios 3.54 and 2.05 respectively). In pts with a p53 mutation without del(17p) there was no enhancement of the model predicting poorer outcome, nor did IgVH status enter the model for predicting PFS. Conclusions: Combination chemotherapy is associated with a higher CR, OR, and PFS. Also, initiation of therapy for pts with Rai stages 0/1 resulted in a higher response rate. Del(17p) and del(11q) are highly predictive of shortened PFS with fludarabine-based chemotherapy. IgVH and p53 mutational status, as well as expression of ZAP-70, Bcl-2 family proteins, and CD38, did not predict response or PFS. ZAP-70 expression is associated with cytogenetic subsets predicted to have a worse overall prognosis, but did not identify pts who will do poorly with therapy. A combination of clinical staging and cytogenetics provide support for future risk-stratified treatment of CLL. Pts with a projected short response duration can be identified for future investigational strategies. No significant financial relationships to disclose.

Clinical significance of ZAP-70 protein expression in B-cell chronic lymphocytic leukemia

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 853-861 ◽  
Author(s):  
Maria Ilaria Del Principe ◽  
Giovanni Del Poeta ◽  
Francesco Buccisano ◽  
Luca Maurillo ◽  
Adriano Venditti ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Clinical Staging ◽  
Mutational Status ◽  
Staging Systems ◽  
Cell Chronic Lymphocytic Leukemia

Abstract The clinical course of B-cell chronic lymphocytic leukemia (B-CLL) is variable, and novel biologic parameters need to be added to the clinical staging systems to predict an indolent or aggressive outcome. We investigated the 70-kDa zeta-associated protein (ZAP-70), CD38, soluble CD23 (sCD23), and cytogenetics in 289 patients with B-CLL. Both a shorter progression-free survival (PFS) and overall survival (OS) were observed in ZAP-70+ (P < .001), in CD38+ (P < .001) and in sCD23+ patients (P < .001 and P = .013, respectively). ZAP-70+CD38+ or ZAP-70+ patients with an unmutated IgVH status showed both a shorter PFS (P < .001) and OS (P < .001 and P < .001, respectively) as compared with ZAP-70–/CD38– or ZAP-70– patients with mutated IgVH genes. Discordant patients showed an intermediate outcome. Note, ZAP-70+ patients even if CD38– or mutated showed a shorter PFS, whereas ZAP-70– patients even if CD38+ or unmutated had a longer PFS. Furthermore, ZAP-70 positivity was associated with a shorter PFS both within normal karyotype (P < .001) and within the poor-risk cytogenetic subset (P = .02). The predictive value of ZAP-70 expression was confirmed in multivariate analysis. Thus, ZAP-70 protein determined by flow cytometry improves the prognostic significance of cytogenetics and appears to be a better predictor of outcomes than IgVH gene mutational status. On this line, we recommend and are also interested in conducting a prospective randomized trial of early intervention versus observation for ZAP-70+ patients.

Select High-Risk Genetic Features Predict Earlier Progression Following Chemoimmunotherapy With Fludarabine and Rituximab in Chronic Lymphocytic Leukemia: Justification for Risk-Adapted Therapy

2006 ◽  
Vol 24 (3) ◽  
pp. 437-443 ◽  
Author(s):  
John C. Byrd ◽  
John G. Gribben ◽  
Bercedis L. Peterson ◽  
Michael R. Grever ◽  
Gerard Lozanski ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Prognostic Factors ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Interphase Cytogenetics ◽  
Mutational Status ◽  
The Impact

Purpose Several new prognostic factors predicting rapid disease progression in chronic lymphocytic leukemia (CLL) have been identified, including unmutated Ig VH mutational status, del(11)(q23), del(17)(p13.1), and p53 mutations. To date, the impact of these same prognostic factors have not been examined relative to treatment outcome with chemoimmunotherapy. Methods We examined the impact of these new prognostic factors on predicting treatment outcome in symptomatic, untreated CLL patients who received chemoimmunotherapy with fludarabine and rituximab as part of a completed, randomized phase II study, Cancer and Leukemia Group B (CALGB) 9712. Results Eighty-eight patients treated as part of CALGB 9712 had detailed prognostic factor assessment performed. Using Ig VH mutational status to classify risk, there was no association between complete response rate with either unmutated Ig VH mutational status or high-risk interphase cytogenetics. However, the median progression-free survival (PFS; P = .048) and overall survival (OS; P = .01) were shorter among the Ig VH unmutated patients as compared with the Ig VH mutated patients. Using the hierarchical classification of Döhner, PFS (P = .005) and OS (P = .004) were significantly longer as the classification moved from high risk [del (11)(q22.3) or del (17)(p13.1)] to low risk. Conclusion These data demonstrate that high-risk CLL patients characterized by Ig VH unmutated (≥ 98%) or high-risk interphase cytogenetics, including either del(17p) or del(11q), appear to have a shorter PFS and OS with chemoimmunotherapy. Larger prospective studies will be required to determine the independent influence of Ig VH mutational status and interphase cytogenetics on treatment outcome.

Clinical, Laboratory, and Treatment Outcome Characteristics of Chronic Lymphocytic Leukemia (CLL) Patients with p53 Mutations or del(17p) Enrolled on a Prospective Phase III Clinical Trial: Short Progression Free Survival, Irrespective of Fludarabine-Based Treatment Used.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 949-949 ◽  
Author(s):  
David M. Lucas ◽  
Gordon W. Dewald ◽  
Donna S. Neuberg ◽  
John C. Byrd ◽  
Gerard Lozanski ◽  
...  
Keyword(s):  
Cytogenetic Analysis ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
P53 Mutation ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Fish Analysis ◽  
Single Mutation ◽  
P53 Mutations ◽  
Free Survival

Abstract Deletions or mutations of the tumor suppressor p53 have been associated with more aggressive disease in many types of cancer including CLL, and are more commonly found in relapsed or refractory patients. We studied symptomatic patients (pts) enrolled on ECOG 2997, a randomized phase III trial of fludarabine monotherapy (F) versus fludarabine plus cyclophosphamide (CF) for previously untreated CLL. A total of 235 pretreatment samples were analyzed for p53 mutations in exons 5–9 using denaturing gradient gel electrophoresis (DGGE), followed by confirmation of mutations using automated sequencing. Cytogenetic analysis was also performed on 243 patient samples by Fluorescence In Situ Hybridization (FISH) using a probe to detect deletions in 17p13.1, the chromosomal location of the p53 gene. In the analysis by DGGE, a total of 25 pts (10.6%) were found to have p53 mutations. In 22 cases there was a single mutation, and in three cases there were two mutations. Mutations in exon 6 were the most common, and in each of the cases with two mutations, one of these was in exon 6. Results by exon are as follows: Exon 5 (1 pt, 0.4%), Exon 6 (15 pts, 6.4%), Exon 7 (5 pts, 2.1%), Exon 8 (3 pts, 1.3%), Exon 9 (4 pts, 1.7%). The interphase cytogenetic analysis included 24 of the 25 pts with a p53 mutation by DGGE. Of the 19 (7.8%) pts with del(17p13.1) as the leading cytogenetic anomaly, seven were cases that also had mutations in p53 by DGGE. The remaining 17 pts with mutations in p53 by DGGE had as leading cytogenetic anomaly: del(11q) (2 pts); trisomy 12 (3 pts), normal cytogenetics (2 pts), and del(13q) (10 pts). Results from both the DGGE and FISH analyses were combined to identify a group of 37 pts with either del(17p) or p53 mutation. This constituted 16% of the 230 pts in which either FISH or p53 mutational analysis was performed. Immunocytochemistry staining for p53 was performed on all pts, and no correlation was found between over-expression of p53 protein with mutation and/or deletion of this gene. The pts were then assessed by treatment arm for response and progression-free survival (PFS), relative to patients without p53 abnormality either by DGGE or FISH analysis. In the FC group: 13 pts had either a p53 mutation or del(17p), nine (69%) of whom achieved a CR or a PR, versus 56/74 (76%) of those with normal p53 (p=0.73). In the F group: 15 pts had either a p53 mutation or del(17p), of whom four (27%) achieved a CR or a PR, versus 38/70 (54%) of those with normal p53 (p=0.09). Pts with a detectable abnormality in p53 had a significantly reduced PFS, regardless of whether they received fludarabine alone (p=0.02) or fludarabine plus cyclophosphamide (p=0.005). This study suggests that routine immunocytochemistry staining should not be substituted for p53 mutational studies. While some short responses were observed in patients with p53 mutation and/or deletion receiving fludarabine and/or fludarabine cyclophosphamide, the time to progression was significantly shorter, emphasizing the prognostic significance of p53 abnormalities for this disease.

scholarly journals The Magnitude of Improvement in Progression-Free Survival with Targeted Therapy in Relapsed/Refractory Chronic Lymphocytic Leukemia Based on Genetic Risk: A Systematic Review and Meta-Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5568-5568
Author(s):  
Stefano Molica ◽  
Diana Giannarelli ◽  
Rosana Mirabelli ◽  
Luciano Levato ◽  
Tait D. Shanafelt
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Randomized Trials ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Advisory Board ◽  
Lymphocytic Leukemia ◽  
Mutational Status ◽  
Genetic Features ◽  
11Q Deletion

Abstract Background Currently, only genetic testing, del(17p) or TP53, determines choices of therapy in chronic lymphocytic leukemia (CLL) whereas mutational status of IGHV and 11q deletion are not recognized as reliable parameters for treatment selection (with exception for fludarabine, cyclophosphamide and rituximab [FCR] in mutated IGHV). To increase understanding of the predictive value of prognostic parameters in the novel therapy era, we conducted a systematic review and meta-analysis assessing the magnitude of improvement in progression-free survival (PFS) with B-cell receptor (BCR) or BCL2 pathway inhibitors based on the presence or absence of 17p deletion/TP53 mutations, 11q deletion and IGHV mutational status in relapsed refractory (R/R) CLL patients. Methods Randomized trials comparing BCR or BCL2 inhibitors to other treatment regimens were considered eligible for this analysis. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was utilized as a reporting guideline. The search strategy yielded 1184 records for screening with 97 full-text articles assessed for eligibility. Finally, seven randomized trials were included in the quantitative meta-analysis, all of which compared BCR or BCL2 inhibitors to a different comparator. Results Meta-analysis of seven randomized trials comprising 2415 patients with R/R CLL revealed that treatment with BCR or BCL2 pathway inhibitors improved OS compared with the combined comparator treatments [Hazard ratio (HR) 0.555;95% confidence interval (CI): 0.452-0.680;P=0.000]. Of note, the I2 statistic for heterogeneity (i.e.,8.8% [P=0.36] ) and Q values (i.e., 6.583) indicated a high level of homogeneity of results across studies. Similar results were obtained with PFS (HR, 0.196; 95% CI: 0.144-0.268; P=0.000) although significant statistical heterogeneity existed across the studies (I2 = 78.6%, P<0.00001;Q=28.08). Next, we evaluated the magnitude of improvement in PFS obtained with BCR or BCL2 pathway inhibitors in R/R CLL patients with high-risk genetic features (Fig 1). The risk of progression was lower for 17p deleted patients (n= 450) treated with BCR or BCL2 inhibitors in comparison to combined comparator treatments (HR, 0.206; 95% CI, 0.108-0.392; P = .000; I2 = 76%; P=0.001;Q=20.853). The same applied with the analysis of TP53 which included five studies enrolling 582 R/R CLL patients with mutated TP53 (HR, 0.231 (95% CI:0.1370.390;P=0.000;I2=75.8%,P=0.0002;Q=16.513). Data for PFS by 11q deletion status, restricted to 4 studies (3 of ibrutinib and one of venetoclax) including 433 patients , revealed a significantly higher risk of progression for 11q deleted patients treated with comparator treatments [HR,0.081; 95% CI: 0.054-0.121; I2= 0.0% (P=0.56), Q =2.06]. Finally, data for PFS by IGHV mutational status that relied on 6 studies including 1580 IGHV unmutated patients favoured treatment with BCR or BCL2 inhibitors ( HR, 0.172; 95% CI, 0.109-0.272; P=0.000; I2= 84.8%, P<0.0001; Q= 32.98). An additional pooled meta-analysis restricted to patients with low risk genetic features revealed that the benefit observed with BCR or BCL2 inhibitors in patients with high-risk genetic features may extend to former (data not shown). Of note, the interaction analysis comparing the magnitude of PFS improvement in patients with and without high risk genetic features, respectively, showed that the benefit was independent of mutational status of IGHV (HR,1.39; 95% CI,0.77-2.40;P=0.26), mutational status of TP53 (HR,1.06; 95% CI,0.56-2.00;P=0.43) and 17p deletion (HR,1.10;95% CI,1.10;95%CI, 0.52-2.35;P=0.40). Interestingly, R/R CLL patients who carried 11q deletion treated with BCR or BCL2 inhibitor fared significantly better in terms of the improvement of PFS than patients without 11q deletion (HR,0.39; 95% CI,0.25-0.62;P<0.0001) indicating the particular value of novel therapies in patients with this genetic defect. Conclusions The important information provided by present meta-analysis is that the improvement over traditional treatments observed with BCR or BCL2 pathway inhibitors is common to all patients with R/R CLL, including those patients with unfavorable and favourable prognostic parameters. BCR signal transduction and BCL2 inhibitors have broad utility and overcome many but not all of the traditional poor risk molecular features in CLL. Figure 1. Figure 1. Disclosures Molica: Gilead: Other: Advisory board; AbbVie: Other: Advisory board; Roche: Other: Advisory board; Jansen: Other: Advisory board. Levato:Novartis: Other: Advisory board. Shanafelt:Genentech: Research Funding; GlaxoSmithKline: Research Funding; Jansen: Research Funding; Pharmacyclics: Research Funding.

Mutational Status of the TP53 Gene As a Predictor of Response and Survival in Patients With Chronic Lymphocytic Leukemia: Results From the LRF CLL4 Trial

2011 ◽  
Vol 29 (16) ◽  
pp. 2223-2229 ◽  
Author(s):  
David Gonzalez ◽  
Pilar Martinez ◽  
Rachel Wade ◽  
Sarah Hockley ◽  
David Oscier ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Survival Data ◽  
Prognostic Value ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Tp53 Gene ◽  
Lymphocytic Leukemia ◽  
Tp53 Mutations ◽  
Mutational Status ◽  
Gene Tp53

Purpose TP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial. Patients and Methods We analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data. Results Mutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value. Conclusion TP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.

Outcome of Treatment with Fludarabine Versus Fludarabine and Cyclophosphamide in Chronic Lymphocytic Leukemia (CLL) Is Adversely Impacted by High Risk Genetic Features: Results from ECOG 2997.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3487-3487 ◽  
Author(s):  
Michael R. Grever ◽  
David M. Lucas ◽  
Gordon W. Dewald ◽  
Donna S. Neuberg ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
High Risk ◽  
P53 Mutation ◽  
Hazard Ratio ◽  
Phase Iii ◽  
P53 Mutations ◽  
Interphase Cytogenetics ◽  
Molecular Features ◽  
Mutational Status ◽  
Significant Difference ◽  
The Impact

Several prognostic factors including un-mutated VH mutational status, select interphase cytogenetic abnormalities [del(11q22.3), del(17p13.1)] and p53 mutations have been associated with shorter interval time from diagnosis to symptomatic disease requiring treatment, shortened progression-free survival (PFS) and overall survival (OS). Limited prospective data exists relative to the relevance of these biologic markers on PFS following treatment with modern therapies for CLL. E2997 is a randomized phase III trial of 278 previously untreated, symptomatic CLL patients who received fludarabine and cyclophosphamide (FC) versus fludarabine (F). We analyzed the response rates and PFS of the patients for whom interphase cytogenetics, VH mutational status, and p53 mutational status studies have been completed. FC therapy had a higher complete response (CR) (23% versus 5%, p<0.002), overall response [OR] (73% versus 50%, p<0.002), and median PFS (33.5 months versus 15 months, p<.0001) as compared to F. The CR and OR was not different based upon interphase cytogenetics or VH mutational status for the entire group of patients or when analyzed by arm of treatment. However, the OR for pts with del(17) or p53 mutations was lower in both the FC arm (69%, versus 76% in patients with normal p53) and F arm (27%, versus 54% in normal p53). Using the Dohner hierarchical classification [del(17p)>del(11q)>del(6q)>tri12>normal> del(13q14)], the relationship of interphase cytogenetics, VH mutational status and p53 mutational status with PFS is summarized below: Median PFS on FC (months) Median PFS on F (months) NR = median not reached; p53 mut+ = mutation present del(17p) 11.9 8.2 del(11q) 30.6 12.8 del(6q) 26.9 26.7 tri 12 NR 20.3 normal NR 11.2 del(13q) NR 21.2 del(17p)/p53 mut+ 11.9 8.9 no del(17p)/p53 mut+ NR 17.8 VH<98% NR 21.2 VH>98% 21.4 13.4 Using the interphase cytogenetic groups, there was a significant difference in PFS for both the FC (p=0.04) and F (p=0.01) treatment arms. Similarly, the presence of a p53 mutation or deletion [del(17p)] predicted for shorter PFS for both FC (p=0.005) and F (p=0.02) therapies. PFS did not statistically differ among VH mutational groups for either arm. We next investigated a Cox proportional hazards analysis to assess the impact of multiple molecular features and treatment arm on PFS. Treatment with F (hazard ratio 3.14, p<0.0001), presence of del(17p) or p53 mutation (hazard ratio 3.13, p=0.0001), and presence of del(11q) (hazard ratio 2.067, p=0.019) were highly significant in the model. Finally, VH unmutated status and del(11q) were highly associated. In conclusion, our data demonstrate that high risk genomic features including p53 mutations, del(17p), and del(11q) are highly predictive of shortened PFS. Our data provide support for a risk-stratified therapy approach for the treatment of CLL.

Rituximab Therapy for Autoimmune Hemolytic Anemia and Immune Thrombocytopenia: A Belgian Registry.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1737-1737
Author(s):  
Daan Dierickx ◽  
Philippe Mineur ◽  
Agnes Triffet ◽  
Alain Kentos ◽  
Carine Keppens ◽  
...  
Keyword(s):  
Platelet Count ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Hemoglobin Concentration ◽  
Progression Free Survival ◽  
Response Duration ◽  
Patient Characteristics ◽  
Complete Response ◽  
Free Survival ◽  
One Year

Abstract Background. Immune thrombocytopenic purpura (ITP) and autoimmune hemolytic anemia (AIHA) may respond to the chimeric anti-CD20 monoclonal antibody rituximab, even when refractory to conventional therapy. Aims. To collect data on Belgian patients given rituximab in the setting of ITP or AIHA in order to assess the response rate and the factors predictive for response in a multicenter study. Method. Belgian hematology centers were invited to fill a questionnaire specifying the major characteristics and quality of response of ITP and AIHA patients given rituximab. For ITP, complete response (CR) was defined as a platelet count &gt;150,000/μL, and a partial response (PR) as a platelet count 50–100,000/μL. For AIHA, Response (R) was defined as a 2g increase of the hemoglobin concentration and achievement of transfusion independence. Results. All the patients were given rituximab after relapse or after failing at least one previous line of treatment. Except in 10 cases, rituximab was given at the dose of 375mg/m2 weekly for 4 weeks. In 31 assessable episodes of ITP a CR was achieved in 18 patients (58%) and a PR in 2 patients (6%). In 53 episodes of AIHA, R was achieved 42 times (79%). In both ITP and AIHA patients we could find no significant correlation between response and sex, age, prior splenectomy, platelet count or hemoglobin concentration when rituximab was started, number of previous treatments, response to previous treatments, duration of disease before rituximab was given, presence of an underlying malignant or autoimmune condition. In patients with AIHA, response rates were similar in cold agglutinin disease (8/10) and in warm antibody mediated hemolysis (29/38). Progression-free survival in responding patients is presented graphically. At one year, 83% of ITP patients and 61% of AIHA patients were alive without progression. Conclusion. In this still open registry, we could confirm that rituximab induces responses in a majority of previously treated patients with ITP or AIHA. Responses could not be predicted from pre-treatment patient characteristics. In most patients response duration exceeded one year. Progression-free survival of responding patients Progression-free survival of responding patients

The Prognostic Significance of Cytopenia in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 746-746
Author(s):  
Clive S. Zent ◽  
Wei Ding ◽  
Karin F. Giordano ◽  
Susan M. Schwager ◽  
Tait D. Shanafelt ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Accurate Determination ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Clinical Staging ◽  
Early Stage Disease ◽  
Stage Disease ◽  
Staging Systems ◽  
Prognostic Importance ◽  
Worse Prognosis

Abstract Background: Historically, CLL patients with cytopenia were thought to have a poor prognosis and cytopenia is a key feature of CLL clinical staging systems. The implications of cytopenia in CLL could have changed because of improved diagnostic accuracy, increased recognition of early stage disease, and better treatments. Newer data suggest that the etiology of cytopenia determines its prognostic importance in CLL. Patients with cytopenia caused by autoimmune disease (AID) are less likely to have the poor prognosis associated with patients with bone marrow (BM) failure. To determine the prognostic significance of cytopenia in patients with CLL, we performed an observational study at Mayo Clinic Rochester (MCR). Methods: We studied all patients with CLL seen in the Division of Hematology at MCR from 1 January 1995 to 31 December 2004 (n = 1,750). Cytopenia (hemoglobin < 10 g/dL or platelet count < 100 × 09/L) was considered due to BM failure in patients with extensive BM involvement by CLL (< 20% residual myeloid tissue on BM biopsy) or reticulocytopenia without other causes persisting > 3 months after CLL therapy. Cytopenia was attributed to AID in patients with autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), pure red blood cell aplasia (PRCA), or autoimmune granulocytopenia (AIG). Results: Median age at diagnosis of CLL was 63.7 years (69% male). Cytopenia occured in 423 (24.2%) patients. In 303 patients, cytopenia was due to CLL (228 BM failure and 75 AID). In 120 patients cytopenia was due to CLL related factors (splenomegaly, n = 11; possible AID, n = 18; treatment of CLL, n = 16) or non CLL causes (other malignancy, n = 12; iron deficiency, n = 11; anemia of chronic disease, n = 10; renal failure, n = 6; drugs effect, n = 4; surgical blood loss n = 4). In 28 (6.6%) patients the cause of cytopenia was not definitively determined. Of the patients with BM failure, 97 (43%) had cytopenia at CLL diagnosis (70% male, median age 63.3 years [range 32–95]), The AID patients the median age of CLL diagnosis was 66.7 years (range 30–85) with 79% male. AID diagnoses were AIHA (n = 41), ITP (n= 35), PRCA (n=8), and AIG (n=3); 9 patients had > 1 AID. Survival from diagnosis of cytopenia was significantly better for patients with AID (median 9.1 years) than BM failure (median 4.4 years, p < 0.001). AID patients had a longer survival from diagnosis of CLL (median 12.4 years) versus the rest of the CLL population (median 9.5 years, p = 0.020) but patients with BM failure at diagnosis had a worse prognosis (median 6.2 years, p < 0.001). Conclusion: We show that the etiology of cytopenia in CLL patients determines its prognostic importance. Anemia and thrombocytopenia caused by BM failure, but not AID, are associated with a significantly worse prognosis. These data show the importance of accurate determination of the etiology of cytopenia in all patients with CLL. Cytopenia in patients with AID is not a marker of advanced stage disease; these patients often need different management compared to those with BM failure. Cytopenia due to AID versus BM failure can be difficult to distinguish and a BM study should be done in all patients considered for treatment. Patients with cytopenia due to AID cannot be meaningfully classified by current clinical staging systems. We believe that efforts to review the NCI-WG 96 criteria are timely and should consider the etiology of cytopenia in CLL patients.

Abnormal Serum Free Light Chain Ratios Are Associated with Earlier Time to First Treatment and Poor Survival in Patients with Chronic Lymphocytic Leukaemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3141-3141
Author(s):  
Guy Pratt ◽  
Graham Mead ◽  
Supratik Basu ◽  
Abe Jacobs ◽  
Roger Holder ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Female Ratio ◽  
Cox Regression Analysis ◽  
Serum Free ◽  
Kaplan Meier ◽  
Mutational Status ◽  
Time To First Treatment

Abstract Introduction: Serum free light chains (sFLC) have prognostic significance in plasma cell disorders. In B-cell chronic lymphocytic leukemia (CLL), a small study found 8/18 (44%) of patients to have abnormal FLC ratios but no assessment of prognostic value was published. The aim of the present study was to determine whether abnormal serum FLC concentrations are indicative of a poor prognosis in CLL patients. Methods: Sera were analysed from 381 previously diagnosed CLL patients (Stage A 307; B 30; C 26; 18 missing; male: Female Ratio 1.6:1, mean age 71 (29–98)) with samples taken before their first treatment (303) or after treatment (78). The study was approved by the Birmingham Heart of England NHS Trust Review Board. Patients were described using the Binet staging system and measured for prognostic markers including CD38, Zap70, mutational status, β2M and FLC. Kaplan Meier survival curves and Cox proportional hazards regression (age, sex, CD38, Zap 70, mutational status, β2M and sFLC) were calculated using SPSS v14. Results: 147/381 (39%) patient sera had abnormal sFLC ratios. Kaplan Meier analysis of all deaths showed abnormal ratios were significantly associated with worse survival (n=350, p&lt;0.001). Analysis of deaths attributed to CLL (n=30) also indicated that an abnormal FLC ratio was predictive of shorter survival (p=0.001). However, for deaths not attributed to CLL (n=32), the FLC ratio was not significantly predictive of outcome (p=0.112). For Cox regression analysis (n=228) of deaths attributed to CLL only, three significant, independent, prognostic factors were identified: CD38 (p&lt;0.001), abnormal ratio (p&lt;0.001) and Stage (p=0.027). Analysis of the untreated patient population (n=303), using Kaplan Meier analysis of time to first treatment, found that an abnormal lambda ratio (p=0.04) but not an abnormal kappa ratio (p=0.443) predicted earlier treatment. For patients with an abnormal lambda ratio, the mean time to first treatment was 38 months earlier than those patients with a normal ratio. Cox regression analysis (n=171) of time to first treatment, found 4 significant, independent factors predicting earlier treatment: Zap70 (p&lt;0.001), Age (p&lt;0.001), abnormal sFLC ratio (p=0.001) and Stage (p=0.027). Conclusions: As shown in other monoclonal gammopathies, abnormal sFLC ratios were associated with poorer outcomes in patients with CLL. Furthermore, in an untreated population, patients with an abnormal lambda sFLC ratio required earlier treatment, indicating a pathological mechanism which is as yet unclear but which warrants further investigation.

Absolute Monocyte Count and Serum CD14 As Prognostic Markers In Chronic Lymphocytic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5297-5297
Author(s):  
Daphne R. Friedman ◽  
Kathleen K. Harnden ◽  
Youwei Chen ◽  
Alicia D. Volkheimer ◽  
J. Brice Weinberg
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Risk Stratification ◽  
Clinical Outcomes ◽  
Prognostic Markers ◽  
Prognostic Significance ◽  
Hazard Ratio ◽  
Lymphocytic Leukemia ◽  
Monocyte Count ◽  
Interphase Cytogenetics ◽  
Mutation Status

Abstract Introduction Although chronic lymphocytic leukemia (CLL) is a generally indolent malignancy, there is a spectrum of disease aggressiveness. Clinical and molecular prognostic markers are helpful for the clinician and for the patient, in terms of disease management and life planning. Additional prognostic markers can help with further risk stratification, especially for CLL patients with “low-risk” disease. The prognostic value of absolute monocyte count (AMC) has been evaluated in various malignancies, including CLL where elevated AMC at diagnosis was shown to be associated with rapid time to first therapy (TTT), and in one series, inferior overall survival (OS). The mechanism by which elevated AMC is associated with worse treatment free survival is not known. However, CD14, which is secreted by monocytes, improves in vitro CLL cell survival, and is found at high levels in the serum of CLL patients. We hypothesized that elevated AMC at the time of CLL diagnosis is associated with inferior survival and that elevated serum CD14 is associated with high AMC and worse survival. Methods CLL patients followed at the Duke University and Durham VA Medical Centers and enrolled in an IRB approved protocol to collect clinical data and blood samples were evaluated. We selected patients for whom AMC was measured between three months prior to diagnosis to three months after diagnosis. We evaluated the correlation between AMC and TTT and OS, with AMC as a continuous and as a dichotomized variable. We also assessed the prognostic capability of AMC in relation to other clinical and molecular prognostic markers, such as Rai stage, race, interphase cytogenetics by FISH, CD38 and ZAP70 expression, and IGHV mutation status. We measured serum CD14 levels using an ELISA assay, and evaluated the correlation between CD14 levels and clinical outcomes or AMC. Cox proportional hazard models were used to evaluate time to event outcomes, Wilcoxon rank sum test and Kruskal-Wallis rank sum test were used to compare AMC to other prognostic markers, and Pearson’s correlation test was used to compare continuous variables. Results From a cohort of over 600 CLL patients, we selected 222 patients with AMC measured ± three months from the date of diagnosis. AMC ranged from 0 to 7.63 cells/mL. With a median follow up of 5.2 years (range 0.1 – 18.2), 102 patients (46%) had been treated, and 59 patients (27%) died. This was not significantly different from the entire cohort. Higher AMC was significantly correlated with shorter TTT (p = 0.002, hazard ratio 1.37, 95% CI 1.12 – 1.68) and inferior OS (p = 0.017, hazard ratio 1.39, 95% CI 1.06 – 1.83). There was no significant difference in AMC in patients stratified by Rai stage, race, interphase cytogenetics, CD38 or ZAP70 expression, or IGHV mutation status. When combined with molecular prognostic markers (IGHV mutation status, CD38 and ZAP70 expression, and interphase cytogenetics) in multivariate models, AMC retained significant prognostic power for TTT and OS. The serum soluble CD14 levels were measured in CLL patients from this cohort, with a mean CD14 level of 2.3 ug/mL. The prognostic significance of serum CD14 and correlation with AMC will be presented. Conclusions Absolute monocyte count at the time of CLL diagnosis is associated with inferior clinical outcomes – both TTT and OS. These results confirm and extend other reports evaluating the prognostic significance of circulating monocytes in CLL. Our evaluation of serum CD14, a monocyte-derived secreted protein that promotes CLL cell viability, in concert with AMC may provide a possible explanation for the associations identified in this cohort of patients. As an easily measured clinical marker, AMC can be readily used and/or combined with other prognostic markers to improve risk stratification and patient counseling at the time of diagnosis. Disclosures: No relevant conflicts of interest to declare.

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