INTEGRATED ANALYSIS: OUTCOMES OF IBRUTINIB-TREATED PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LEUKEMIA (CLL/SLL) WITH HIGH-RISK PROGNOSTIC FACTORS

Abstract Abstract 4860 Backgroud: Chronic lymphocytic leukemia (CLL) is one of the most frequent chronic lymphoproliferative disorders in Europe. It is characterized by persistent monoclonal lymphocitosis with localized or generalized lymphadenopathy. Despite the initial clinical presentation, it has a heterogeneous natural history, with the majority of patients living 10–12 years, but with some patients dying rapidly, within 2–3 years of diagnosis. Beside clinical prognostic factors, novel cytogenetic markers are recognized to be useful in predicting disease free and overall survival in CLL. AIMS: In a retrospective study throughout 10 years (1999-2009), we analyzed the clinical and biological presentation and compared the evolution and survival of patients with B-CLL using different cytogenetic markers. METHODS: We identified 112 cases (63 males and 49 females) of B-CLL with cytogenetic study by fluorescence in situ hybridization (FISH). RESULTS: Amongst 112 patients, the male to female (M/F) ratio was 1.3:1 and the median age was 70 (43-96) years. At diagnosis, the median lymphocyte count was 15.5 G/L (5.4-173). Fifty five patients (49%) had lymphadenopathies and seventeen (15%) had splenomegaly and/or hepatomegaly at presentation. By the revised Rai staging system seventy (63%) patients were included in low risk group, thirty (27%) in intermediate risk group and twelve (10%) in high risk group. The expression of ZAP-70 and CD38 by flow citometry was performed in 75 patients and revealed 13 (17%) patients CD38+ and 12 (16%) ZAP70+. The study of chromosomal aberrations with FISH showed thirty six patients (32%) with no abnormality, thirty six (32%) with isolated 13q deletion, fifteen (14%) with 12 trisomy, twelve (11%) with 11q deletion and thirteen (11%) with 17p deletion. Forty (36%) patients showed progressive disease in a median time of sixteen months (0-120), thirteen with 13qdel, seven with 17pdel and five with 12 trisomy. After treatment two patients showed progressive disease, six maintain a stable disease and thirty two obtain a remission, nine in complete remission. The Overall Survival (OS) at ten years was 70%. By the revised Rai staging system the OS at ten years was 80% for low risk, 70% for intermediate risk and all the high risk patients died during follow up. The OS at five years for the del13q-, 12 trisomy, del11q- and del17p- was 90%, 88%, 58% and 60%, respectively. SUMMARY: Chronic lymphocytic leukemia is currently considered a chronic disorder with a favourable outcome, but with a variable evolution to progressive disease. This retrospective study allowed the characterization of patient with CLL in our department and the acknowledgement that our results are quite similar to the published data. Disclosures: No relevant conflicts of interest to declare.

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The role of prognostic factors in assessing ‘high-risk’ subgroups of patients with chronic lymphocytic leukemia

Leukemia ◽

10.1038/sj.leu.2404802 ◽

2007 ◽

Vol 21 (9) ◽

pp. 1885-1891 ◽

Cited By ~ 67

Author(s):

N E Kay ◽

S M O'Brien ◽

A R Pettitt ◽

S Stilgenbauer

Keyword(s):

Prognostic Factors ◽

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia

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Occurrence of Chromosomal Translocations as Independent Prognostic Factor in Chronic Lymphocytic Leukemia.

Blood ◽

10.1182/blood.v108.11.2084.2084 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2084-2084

Author(s):

Christine Mayr ◽

Cathrine Schulz ◽

Stephan Stilgenbauer ◽

Alexander Kröber ◽

Hartmut Döhner ◽

...

Keyword(s):

Risk Factor ◽

Prognostic Factors ◽

High Risk ◽

Prognostic Factor ◽

Chronic Lymphocytic Leukemia ◽

Prognostic Significance ◽

Lymphocytic Leukemia ◽

Chromosomal Translocations ◽

Study Cohort ◽

Binet Stage

Abstract Background: The course of chronic lymphocytic leukemia (CLL) is highly variable. Therefore, there is a need for prognostic factors that are readily performed and have a high predictive power. Methods: The occurrence of translocations, a recently identified prognostic factor in CLL (Blood2006;107:742–751), was studied in 148 previously untreated, mostly early-stage patients and compared with respect to treatment-free survival (TFS) to several prognostic factors (Binet stage, mutational status of immunoglobulin genes, CD38, thymidine kinase serum concentration and cytogenetic aberrations detected by interphase FISH). To investigate chromosomal translocations, we applied a new method, CpG oligodeoxynucleotide stimulation that allows efficient preparation of metaphase spreads from CLL cells. Results: The occurrence of translocations classified the majority of patients with poor prognosis. If translocations were investigated in addition to the currently used prognostic factors they identified those patients who were classified to be in a low-risk group based on traditionally used criteria, who had in fact a high risk for progression. Vice versa, patients in the high-risk groups for progression who did not have translocations had a long TFS. There was a substantial overlap of patients who had translocations and additional risk factors. But when we omitted patients who had translocations in addition to a given risk factor, we found that the respective risk factor lost its prognostic significance for the remaining patients. The two factors that retained their prognostic power in these patients were translocations and the Binet stage. This could suggest that the prognostic significance of the currently used factors derives from their frequent co-occurrence with translocations. Finally, multivariate analyses demonstrated that Binet stage (p=0.02) and translocations (p=0.0005) are the factors with the highest impact on TFS in our study cohort. Conclusion: We present a method for efficient preparation of metaphase spreads in CLL cells in order to investigate chromosomal translocations. The occurrence of translocations is an independent prognostic marker in CLL. Finally, translocations occur not as a late event in the course of the disease and may define a new biological subgroup in this disease entity.

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Characteristic Proinflammatory Serum Cytokine Profiles In Patients with B-Cell Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood.v116.21.3595.3595 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3595-3595

Author(s):

James J. Harding ◽

Raymond Yeh ◽

Yan Nikhamin ◽

Mark Frattini ◽

Nicole Lamanna ◽

...

Keyword(s):

Prognostic Factors ◽

High Risk ◽

Chronic Lymphocytic Leukemia ◽

B Cell ◽

Serum Levels ◽

Lymphocytic Leukemia ◽

Regulatory Role ◽

Healthy Controls ◽

Β2 Microglobulin ◽

Cd38 Expression

Abstract Abstract 3595 Background: Cytokines are posited to play a critical regulatory role on the survival of the B-cell neoplastic clone in Chronic Lymphocytic Leukemia (CLL). AIM: The primary goals of this study were 1) to define additional relevant cytokines, growth factors and chemokines in CLL pathophysiology and 2) to correlate abnormal cytokine levels with disease stage, relevant hematological data and multiple prognostic factors. METHODS: A novel bead-based protein array system was employed to simultaneously measure 38 proinflammatory cytokines in the sera of CLL patients (N=116) and healthy age and sex matched controls (N=30). These results were correlated with Rai stage, β2-microglobulin level, LDH, CD38 expression and cytogenetic abnormalities. RESULTS: We first confirmed previous observations that TNFα, IL-1α, IL-1RA, IL-10, sIL-2Rα, VEGF and sCD40 ligand are significantly elevated in patients with CLL as compared with healthy controls. Expanding on the current literature, we demonstrated perturbations in an additional 15 serum cytokines in affected individuals. Compared to healthy controls, CLL patients had an increase in serum levels of IL-3 (p=0.002), IL-7 (p=0.008), INF-2α (p<0.0001), MCP-1 (p<0.0001), MIP-1β (p=0.002), MDC (p<0.0001), Fractakine (p<0.0001), EGF (p<0.0001), FGF-2 (p<0.0001), GRO (p<0.0001), Eotaxin (p<0.0001) and FLT-3 ligand (p<0.0001). Patients with CLL also exhibited significantly lower levels of INF-γ (p<0.01), IL-6 (p<0.005) and IL-8 (p<0.002) when compared to healthy individuals. Advanced Rai stage and high risk chromosomal abnormalities (del 11q and del 17p) strongly correlated with higher serum levels of TNFα, soluble IL-2Rα, IL-10, MCP-1, MIP-1α, MIP-1β and IP-10. Finally, serum levels of TNFα, MIP-1α and MIP-1β correlated with other adverse prognostic markers, including total white blood cell count, serum β2-microglobulin and LDH levels as well as CD38 expression. CONCLUSION: We have demonstrated numerous previously unrecognized cytokine abnormalities in patients with CLL and described a unique cytokine signature associated with advanced disease. Supported by the current understanding of cytokine biology and CLL pathophysiology, our observations suggest an important regulatory role for hematopoietic cytokines, such as IL-3 and IL-7, in promulgating survival of the aberrant B-cell clone. Likewise, the profoundly high levels of chemokines (i.e. MCP-1, MIP-1α, MIP-1β, IP-10) and their association with high risk prognostic factors argue for their role in sustaining the neoplastic microenvironment. Finally, the altered levels of IL-10, IL-6 and INF-γ observed in patients with CLL likely contribute to the immunosuppressive phenotype of the disease state. Disclosures: No relevant conflicts of interest to declare.

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

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.1021 ◽

2006 ◽

Vol 24 (3) ◽

pp. 437-443 ◽

Cited By ~ 184

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.

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Up to 6.5 years (median 4 years) of follow-up of first-line ibrutinib in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and high-risk genomic features: integrated analysis of two phase 3 studies

Leukemia & Lymphoma ◽

10.1080/10428194.2021.2020779 ◽

2022 ◽

pp. 1-12

Author(s):

Jan A. Burger ◽

Tadeusz Robak ◽

Fatih Demirkan ◽

Osnat Bairey ◽

Carol Moreno ◽

...

Keyword(s):

High Risk ◽

Chronic Lymphocytic Leukemia ◽

Lymphocytic Leukemia ◽

Integrated Analysis ◽

Small Lymphocytic Lymphoma ◽

First Line ◽

Phase 3 ◽

Two Phase ◽

Genomic Features

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Complex analysis of prognostic factors in chronic lymphocytic leukemia

Orvosi Hetilap ◽

10.1556/oh.2007.27943 ◽

2007 ◽

Vol 148 (16) ◽

pp. 737-743

Author(s):

Béla Kajtár ◽

Pál Jáksó ◽

László Kereskai ◽

Ágnes Lacza ◽

Gábor Méhes ◽

...

Keyword(s):

Prognostic Factors ◽

Chronic Lymphocytic Leukemia ◽

Complex Analysis ◽

Lymphocytic Leukemia

Bevezetés: Az utóbbi években felfedezett számos új prognosztikai faktor segítséget nyújthat a várható túlélés meghatározásához krónikus lymphocytás leukémia esetében. Célok: Jelen tanulmány célja e prognosztikai faktorok gyakoriságának, valamint egymással való összefüggésének meghatározása volt 419 beteg mintáin. Módszerek: 160 esetben végezték el az immunglobulin-nehézláncgén mutációs vizsgálatát. Eredmények: Az esetek 62%-ában nem mutált immunglobulin gént találtak, a nehézlánc géncsaládok használata különbözött a mutációs státusz függvényében. A CD38 expresszió 78%-os konkordanciát mutatott a mutációs státusszal, a ZAP-70-expresszió tekintetében korrelációt nem figyeltek meg. Citogenetikai abnormalitást 76%-ban láttak, a leggyakoribb eltérések a del(13q) (57%), a 12-es triszómia (15%), a del(11q) (12%) és a del(17p) (6%) voltak. A del(11q)-t hordozó esetek 95%-a nem mutált, az egyedül del(13q)-t hordozó esetek 74%-a mutált IgH-gént tartalmazott. Következtetések: A vizsgált paraméterek nem függetlenek egymástól, ezért alkalmazásuk a klinikai gyakorlatban gondos tervezést igényel.

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