microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5237-5245 ◽  
Author(s):  
Basile Stamatopoulos ◽  
Nathalie Meuleman ◽  
Benjamin Haibe-Kains ◽  
Pascale Saussoy ◽  
Eric Van Den Neste ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Disease Risk ◽  
Lymphocytic Leukemia ◽  
Aberrant Expression ◽  
Early Therapy ◽  
Disease Evolution ◽  
Binet Stage

Abstract Aberrant expression of microRNAs has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Although disease evolution can be predicted by several prognostic factors, a better outcome individualization in a given patient is still of utmost interest. Here, we showed that miR-29c and miR-223 expression levels decreased significantly with progression from Binet stage A to C were significantly lower in poor prognostic subgroups (defined by several prognostic factors) and could significantly predict treatment-free survival (TFS) and overall survival (OS). Furthermore, we developed a quantitative real-time polymerase chain reaction (qPCR) score combining miR-29c, miR-223, ZAP70, and LPL (from 0 to 4 poor prognostic markers) to stratify treatment and death risk in a cohort of 110 patients with a median follow-up of 72 months (range, 2-312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of greater than 312, of 129, 80, 36, and 19 months, respectively (hazard ratio, HR0/4 < 1/4 < 2/4 < 3/4 < 4/4 = 17.00, P < .001). Patients with a score of 0-1/4, 2-3/4, and 4/4 had a median OS of greater than 312, of 183 and 106 months, respectively (HR0/4 < 1/4 < 2/4 < 3/4 < 4/4 = 13.69, P = .001). This score will help to identify, among the good and poor prognosis subgroups, patients who will need early therapy and thus will require a closer follow-up.

MicroRNA-29c and 223 Are Powerful Prognostic Factors for Chronic Lymphocytic Leukemia and Improve Risk Stratification When Combined with ZAP70 and LPL in a qPCR Score.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1066-1066
Author(s):  
Basile Stamatopoulos ◽  
Nathalie Meuleman ◽  
Dominique Bron ◽  
Benjamin Haibe-Kains ◽  
Pascale Saussoy ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Noncoding Rna ◽  
Poor Prognosis ◽  
Lymphocytic Leukemia ◽  
Early Therapy ◽  
Mutational Status ◽  
Igvh Mutational Status ◽  
Binet Stage

Abstract Background: MicroRNAs (or miR) are a novel class of small noncoding RNA involved in gene regulation. Aberrant microRNA expression has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Currently, the heterogeneous evolution of this disease can be predicted by several prognostic factors. Nevertheless, a better individualization of the outcome in a given patient is still of utmost interest. Methods: In the current study, we investigated the expression of two microRNAs, miR-29c and miR-223, compared them to other biological or clinical markers and proposed a quantitative real-time PCR (qPCR) score to better assess CLL outcome. All cut-offs were calculated by ROC curve analysis maximising the correlation with the immunoglobulin variable heavy chain (IgVH) mutational status; statistical differences were evaluated by Mann Whitney test or Kruskal-Wallis test ; treatment-free (TFS) and overall (OS) survival differences were investigated by log-rank test or Cox proportional hazard ratio (HR). Results: miR-29c and miR-223 expression decreased significantly with progression along Binet Stage A to C (P=0.0010 and P=0.0183, respectively), and were significantly lower in poor prognosis subgroups defined by cytogenetic abnormalities, IgVH mutational status, lymphocyte doubling time, solubleCD23, β2-microglobulin, ζ-associated protein 70 (ZAP70), lipoprotein lipase (LPL) and CD38 expression. Furthermore, miR-29c and miR-223 could predict TFS (n=110, P=0.0015 and P&lt;0.0001, respectively) and OS (n=110, P=0.0234 and P=0.0008, respectively). Regarding all these results, we developed a qPCR score (from 0 to 4 poor prognostic markers) combining miR-29c, miR-223, ZAP70 and LPL in order to stratify treatment and death risk in a 110 patient cohort with a median follow-up of 72 months (range, 2–312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of &gt;312, 129, 80, 36 and 19 months, respectively (HR=17.00, P&lt;0.0001). Patient with a score of 0–1/4, 2–3/4 and 4/4 had a median OS of &gt;312, 183 and 106 months, respectively (HR=13.69, P=0.0001). Interestingly, during the first 50 months after diagnosis, only 10% of patients with a 0/4 score required a treatment, when compared to 100% of the 4/4. Furthermore, during the total follow-up (312 months), patients with a 4/4 score had a 27-fold higher risk to be treated and a 31-fold higher risk to die comparing to patients with a 0/4 score. This score was validated by a 10-fold cross-validation (prediction accuracy of 82%). Finally, in Binet stage A patients (n=77), this score remained relevant and significant for TFS and OS prediction (HR=18.56, P&lt;0.0001 and HR=12.5, P=0.0068, respectively). Conclusions: we showed that (i) miR-29c and miR-223 levels were decreased in poor prognosis patients regarding several well-known prognostic factors; (ii) a low level of these two microRNAs is thus associated to disease aggressiveness, tumor burden and poor clinical evolution; (iii) we also showed that these two microRNAs could predict TFS and OS; (iv) we proposed a qPCR score to better individualize evolution of a particular CLL patient. This score will help to identify patients who will need early therapy and require thus a closer follow-up.

Chemoimmunotherapy Improves Survival of Patients with Chronic Lymphocytic Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3908-3908
Author(s):  
Gabriela Ghita ◽  
Julio Delgado ◽  
Tycho Baumann ◽  
Ivan Dlouhy ◽  
Marta Aymerich ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Alkylating Agents ◽  
Lymphocytic Leukemia ◽  
Disease Evolution ◽  
Prognostic Features ◽  
Purine Analogs ◽  
Significant Difference ◽  
Binet Stage

Abstract Abstract 3908 INTRODUCTION Chemoimmunotherapy, namely the combination of fludarabine, cyclophosphamide and rituximab (FCR), results in a higher response rate and a longer progression-free survival in patients with chronic lymphocytic leukemia (CLL). There is also evidence coming from several historical comparisons, observational, and epidemiological studies and, above all, a large randomized clinical trial (German CLL Study Group – Hallek M et al, Lancet 2010) that FCR prolongs survival. Since additional randomized studies to validate the superiority of FCR over older therapies in CLL are difficult to envisage, other approaches to confirm this observation are worth to be considered. AIM The aim of this study was to ascertain whether chemoimmunotherapy given at any time over the course of the disease, independently of the treatment phase, prolonged survival in a group of unselected patients with CLL from the Hospital Clínic of Barcelona. MATERIALS AND METHODS Out of 1042 consecutive patients diagnosed and followed-up from 1980 to December 2010, we selected 484 patients who received at some point of their disease evolution: (1) alkylating agents and no purine analogs (PA) nor rituximab (R) (no PA no R) (n=211; of which 67 < 65 years). (2) purine analogs but no R (PA) (n=159). (3) PA plus rituximab (PA+R) (n=114). Clinical information (age, sex, Binet stage) and laboratory characteristics (β2-microglobulin, CD38, ZAP-70, genomic alterations, IGHV mutational status) at disease presentation, treatment, and follow-up was obtained from a database prospectively managed at our institution from the 1970s onwards. All treated patients were included in the analysis regardless of the number of cycles of therapy given and independently of whether they had participated in clinical trials or not. RESULTS The median age (range) of the whole series (n=340, 222M/118F) was 56 (24–84) years. The three groups were well balanced for key clinical characteristics such as age, sex, and Binet stage at treatment. It should be noted that patients older than 65 years were initially excluded from the analysis to avoid a bias in the results due to the general worse prognosis of older patients. On the other hand, patients from the PA and PA+R groups presented poorer risk prognosis factors such as a higher expression of CD38 (p=0.006), ZAP-70 (p=0.052), and adverse cytogenetic abnormalities (p=0.026) or unmutated IGHV genes (p=0.005) than those in the no PA no R group. After a median follow up of 9.4 years (range, 0.3–21), 148 (44%) patients remain alive. At 10 years, the overall survival of the PA+R group was 65% (95% CI, 53–77%) compared with 43% (35–51%) and 43% (31–54%) for the no PA no R and PA groups, respectively (p<0.001) (Figure 1). When all patients who did not receive PA or R were included in the study (n=211), the statistically significant difference was, not surprisingly, maintained (data not shown). In addition, patients from both the PA group and the PA+R group had poorer prognostic features. These data are in keeping with a conservative therapeutic approach in patients with low-risk disease and a poorer risk of patients treated with PA with or without R. This is also an additional argument in favor of the effectiveness of chemoimmunotherapy in high-risk patients. Interestingly, when survival of patients treated with PA+R was analyzed according to the time at which treatment was administered (first line, n=55 vs. ≥ second line, n=59), no differences were observed (p= 0.8) (Figure 2) CONCLUSION Chemoimmunotherapy prolongs survival of patients with CLL. Moreover, this effect could be independent of the phase of the disease at which chemoimmunotherapy is given. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Lymphocyte Doubling Time As A Key Prognostic Factor To Predict Time To First Treatment In Early-Stage Chronic Lymphocytic Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Fortunato Morabito ◽  
Giovanni Tripepi ◽  
Riccardo Moia ◽  
Anna Grazia Recchia ◽  
Paola Boggione ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Doubling Time ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Prognostic Role ◽  
Mutational Status ◽  
Binet Stage ◽  
Time To First Treatment

The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone’s biology was almost unknown. LDT was defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol (clinicaltrial.gov identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT &gt;12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT ≤ 12 months maintained a significant independent relationship with shorter TTFT along with IGHV unmutated (IGHVunmut) status, 11q and 17p deletions, elevated β2M, Rai stage I-II, and NOTCH1 mutations. Based on these statistics, two regression models were constructed including the same prognostic factors with or without the LDT. The model with the LTD provided a significantly better data fitting (χ2 = 8.25, P=0.0041). The risk prediction developed including LDT had better prognostic accuracy than those without LDT. Moreover, the Harrell’C index for the scores including LDT were higher than those without LDT, although the accepted 0.70 threshold exceeded in both cases. These findings were also confirmed when the same analysis was carried out according to TTFT’s explained variation. When data were further analyzed based on the combination between LDT and IGHV mutational status in the training and validation cohorts, IGHVunmut and LDT&gt;12months group showed a predominant prognostic role over IGHVmut LTD ≤ 12 months (P=0.006) in the O-CLL validation cohort. However, this predominance was of borden-line significance (P=0.06) in the Barcelona group, while the significant prognostic impact was definitely lost in the Novara group. Overall, in this study, we demonstrated that LDT could be re-utilized together with the more sophisticated prognostic factors to manage the follow-up plans for Binet stage A CLL patients.

scholarly journals Risk Factors Associated with Richter's Transformation in Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1697-1697 ◽  
Author(s):  
Yasmin Ben-Dali ◽  
Mariam Hussein Hleuhel ◽  
Michael Asger Andersen ◽  
Christian Brieghel ◽  
Erik Clasen-Linde ◽  
...  
Keyword(s):  
Risk Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Incidence Rate ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Univariate Analysis ◽  
Lymphocytic Leukemia ◽  
Increased Risk ◽  
Binet Stage

Abstract Background Richter's transformation (RT) refers to the development of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL). Roughly, 2-10 % of patients with CLL develop RT most often as diffuse large B-cell lymphoma (DLBCL) or Hodgkin lymphoma (HL). Aim This study aimed to assess the incidence rate and risk factors for RT for patients with CLL in a nationwide cohort. Furthermore, we want to assess prognostic risk factors for patients with RT. Methods All patients diagnosed with CLL in Denmark between 2008 and 2016 were included in this study. Clinical data was retrieved from the Danish National CLL Registry (DCLLR), whereas all histologically verified DLBCL, HL and/or transformation diagnoses for patients with CLL were retrieved from the Danish National Pathology Registry. Patients were followed from date of CLL diagnosis until date of RT, death or end of follow-up, whichever came first. The time to RT was estimated as cumulative incidence considering death as a competing risk. Stepwise Cox analysis with backward elimination was applied to identify independent risk factors for RT in patients with CLL. Results A total of 3771 CLL patients were identified, and followed for 14165 person-years. With a median follow-up of 4.3 (IQR (2.4;6.6)) years, 120 (3%) CLL patients had a transformation diagnosis, of which 4 patients were excluded due to misdiagnosis. DLBCL accounted for 78/116 (67%) cases, HL for 15/116 (13%) cases and one patient presented with both DLBCL and HL. In the remaining 22/116 (19%) cases the subtype of the transformation was either unspecified or unclassified RT. The median time to RT was 3.4 (IQR (1.8;5.7)) years from CLL diagnosis and the median overall survival (OS) after development of RT was 4.9 (IQR (0.7;8.4)) years. The cumulative incidence of RT, calculated by Aalen-Johansen estimator, at 5 and 8 years post-CLL diagnosis were 3.3% and 7.9% respectively (Figure 1). The annual crude incidence rate of RT was approximately 0.7% per year for all CLL patients. In all, 918 (24%) patients received CLL-related treatment, of whom 59 (6.4%) patients developed RT, resulting in a cumulative incidence of RT of 7% after 5 years and 11% after 8 years. At the time of CLL diagnosis, patients treated for CLL prior to RT diagnosis had a worse median OS (1.49 years) compared to RT patients who were untreated for CLL (6.16 years). In the univariate analysis, RT was significantly associated with male gender, advanced Binet stage (B or C), unmutated IGHV status (CLL-U), elevated beta-2-microglobulin (>3.5 mg/L) and elevated lactate dehydrogenase (>205 U/L). Of cytogenic aberration, deletion 13q (del(13q)) had a protective effect on the risk of RT, whereas deletion 11q (del(11q)) and deletion 17p (del(17p)) increased the risk. In the multivariable model, advanced Binet stage (HR 2.86 (1.82;4.51), p<0.001), del(17p) ((HR 3.74 (2.12;6.61), p<0.001) and CLL-U ((HR 2.30 (1.46;3.63), p<0.001) showed an independent correlation with development of RT. ZAP70 and CD38 were excluded from statistical analyses due to incomplete data and high inter-laboratory variation. Among RT patients, CLL-U, trisomy 12 and del(17p) at CLL diagnosis as well as ECOG Performance Status (PS) (i.e. PS≥1) at time of RT diagnosis correlated with poor OS in univariate analysis. Both del(17p) and PS≥1 were independently associated with an increased risk of death in a multivariable analysis (HR 2.9, (1.1;7.7), p=0.04 and HR 3.0, (1.0;3.1), p=0.05, respectively). Conclusions To the best of our knowledge, we here report the largest study on RT assessing nationwide data of consecutive patients diagnosed with CLL. The incidence of RT in this unselected population was 3.3% after 5 years while the median OS for patients from time of RT was 4.9 years. Advanced Binet stage, del(17p) and CLL-U were significantly and independently associated with an increased risk of RT. Del(17p) at CLL diagnosis and PS≥1 at RT diagnosis were significant predictors for death for patients with RT. For patients diagnosed with RT prior to any CLL treatment, a less severe disease course with a median OS of 6.16 years was demonstrated. Contrary, the median OS for patients receiving prior CLL treatment was 1.49 years. Thus, assessment of different treatment options for patients developing RT based on whether they have received prior CLL treatment or not is warranted. Figure 1. Figure 1. Disclosures Ben-Dali: Rigshospitalet: Research Funding. Hleuhel:Rigshospitalet: Research Funding. Brieghel:Arvid Nilson's Fund: Research Funding; Rigshospitalet, Denmark: Research Funding. Niemann:Danish Cancer Society: Research Funding; Novo Nordisk Foundation: Research Funding; Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; CSL Behring: Consultancy.

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

Blood ◽  
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.

A Prospective Study of Young Chronic Lymphocytic Leukemia (CLL) Patients Investigated at Diagnosis: Distribution and Clinical Significance of Prognostic Factors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3121-3121
Author(s):  
Ilaria Del Giudice ◽  
Francesca Romana Mauro ◽  
Maria Stefania De Propris ◽  
Simona Santangelo ◽  
Marilisa Marinelli ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
P53 Protein ◽  
Young Patients ◽  
P53 Gene ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
P53 Protein Expression ◽  
Binet Stage ◽  
Wbc Count

Abstract In chronic lymphocytic leukemia (CLL) the distribution and prognostic impact of genetic and molecular markers has been assessed on retrospective series of patients in different phases of the disease. Our aim was to assess the distribution and clinical significance of a comprehensive panel of clinical and biologic parameters prospectively evaluated at presentation in all young patients diagnosed with CLL at our Institution, taking advantage of the fact that in Italy individuals with a lymphocytosis are referred to the hematologist for the diagnostic work-up. From November 2002 to June 2008, 105 young CLL patients (&lt;60 years-old) were diagnosed with CLL and included in this study. There were 56 males and 49 females, with a median age of 52 years-old. 81% were in Binet stage A, 19% in stages B/C. Rai stage 0 was recorded in 63% of patients, I/II in 31%, III/IV in 6%. The median white blood cell (WBC) count was 18.8 × 109/L (range 5.8–236.6). Prognosis was evaluated as the time from diagnosis to first treatment (TFI, treatment-free interval), since only 3 patients died after a median follow-up of 32.4 months (range 1 to 88). The median TFI was 43.9 months. Clinical features included: gender, WBC count, Binet and Rai stage. Serological and biologic parameters included: beta2-microglobulin, LDH, IgG immunoglobulin levels, lymphocyte morphology, T-cell subsets, IgVH mutational status, CD38 and ZAP-70 expression, cytogenetic abnormalities evaluated by FISH, p53 protein expression and p53 gene sequencing (exon 5 to 8). The distribution of the prognostic markers is summarized in the table. Raised beta2-microglobulin and LDH were present only in 5% and 15% of cases, respectively. The CD4/CD8 ratio was normal in almost all cases. The proportion of unmutated IgVH, CD38 and ZAP-70 positive cases was about one third of the cohort of CLL patients at diagnosis. The incidence of del(17p) (cut off &gt;20% cells) and del(11q) (cut off &gt;10% cells) was 2% and 7%, respectively. Patients with del(17p) or del(11q) exclusively showed unmutated IgVH and ZAP-70+, and were mostly CD38+. p53 mutations were present in 4 cases, 3 with unmutated IgVH and del(17p) and 1 with mutated IgVH and no del(17p). In univariate analysis, the following variables resulted associated to a short TFI: advanced stage Binet B/C and Rai I/IV (&lt;0.0001), WBC count (&lt;0.0001), proportion of CD3+ cells &lt;16% (0.0002), raised beta2-microglobulin (&lt;0.0001) and LDH (&lt;0.0001), unmutated IgVH (&lt;0.0001), CD38+ (&lt;0.0001), ZAP-70+ (&lt;0.0018), adverse cytogenetic abnormalities (del(17p), del(11q), +12) (&lt;0.0001). Atypical CLL morphology showed a trend for significance (0.06). Multivariate analysis on TFI - including WBC count (as continuous variable), CD3 %, LDH, IgVH mutation status, ZAP-70 and CD38 expression and corrected with interaction between WBC and IgVH status - was focused on the 84 patients with Binet stage A. High WBC count, raised LDH, unmutated IgVH resulted as unfavorable prognostic factors, whilst the proportion of CD3+ cells was associated with a better outcome. Neither ZAP-70 or CD38 showed an independent prognostic value. In CLL cases with discordant expression of ZAP-70 and IgVH mutation status (25% of cases), the latter appeared to be more relevant than ZAP-70 in determining the TFI. In conclusion, unmutated IgVH, raised LDH, WBC count and a low proportion of CD3+ cells at diagnosis are significant predictors of TFI in early stage CLL. This group represents about one third of young patients at diagnosis. Adverse FISH abnormalities are present only in a small subgroup of cases in the early phases of the disease. Young CLL patients at diagnosis N° of cases % Raised beta2-microglobulin (&gt;3400 ng/l) 5/102 5% Raised LDH 16/105 15% Hypo IgG 21/98 21% Atypical morphology 27/104 26% CD3+ cells (&lt;16%) 60/105 57% CD4/CD8 (&lt;1) 3/101 3% IgVH mutated (≥98%) 67/103 65% IgVH unmutated (&lt;98%) 36/103 35% CD38 ≥7% 25/104 24% ZAP-70 ≥10% 39/100 39% Del(17p) &gt;20% 2/104 2% Del(11q) &gt;10% 7/104 7% +12 &gt;5% 7/104 7% Del(13q) &gt;5% isolated 59/104 57% Normal (none of the above) 29/104 28% p53 protein expression 3/100 3% p53 gene mutation 4/105 4%

Preliminary Results of a Phase II Open-Label, Randomized Study of the BH3 Mimetic Protein Navitoclax (ABT-263) with or without Rituximab for Treatment of Previously Untreated B-Cell Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 190-190 ◽  
Author(s):  
Herbert Eradat ◽  
Sebastian Grosicki ◽  
John Catalono ◽  
Walter Cosolo ◽  
Irina Dyagil ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase Ii ◽  
Research Funding ◽  
Response Rate ◽  
Response Assessment ◽  
Lymphocytic Leukemia ◽  
Preliminary Results ◽  
Binet Stage ◽  
Bh3 Mimetic

Abstract Abstract 190 Introduction: Overexpression of Bcl-2 in Chronic Lymphocytic Leukemia (CLL) is associated with enhanced CLL-cell resistance to spontaneous or chemotherapy-induced apoptosis. The BH3 mimetic protein navitoclax (ABT-263) specifically inhibits Bcl-2, and related proteins Bcl-xL and Bcl-w, and can induce apoptosis of CLL cells in vitro. Phase I evaluation in relapsed/refractory CLL patients demonstrated 35% overall response rate (Roberts, 2012). Dose-limiting thrombocytopenia due to Bcl-xL inhibition was mitigated using a lead-in dosing schedule to allow the bone marrow to achieve a compensatory increase in platelets prior to dose escalation to the MTD of 250 mg. Based on the promising single-agent data, a Phase II trial randomized trial compared the safety, pharmacokinetics, and biologic activity of treatment with navitoclax and rituximab (RTX) versus RTX alone. Methods: Patients with CLL who required initial treatment according to iwCLL criteria (Hallek et al, 2008) were stratified by Binet stage and high-risk cytogenetic features (17p deletion and/or 11q deletion), and randomized 1:1:1 to receive RTX weekly for 8 wks (375 mg/m2 wk 1, 500 mg/m2 wks 2–8) (Arm A), or RTX for 8 wks plus navitoclax daily for 12 wks (250 mg/day following a 7–14 day lead-in period of 100 mg/day) (Arm B), or RTX for 8 wks plus navitoclax daily as in Arm B, but continued treatment with navitoclax until disease progression, relapse, or unacceptable toxicity (Arm C). Arm A to Arm B crossover was permitted. Response rate was assessed by iwCLL CLL response criteria at week 12, and every 12 weeks during follow-up. The study was stopped after the last patient had completed ≥ 12 weeks of treatment and week-12 response assessment. Results: Baseline characteristics and prognostic factors for the 118 randomized patients were generally balanced among the three treatment arms. Median age was 63 years (range 38–94), and 55% were Binet stage B+C. Median baseline lymphocyte count was 53,000 mm3 (range 7,000–552,000/mm3). FISH analyses identified higher than expected rates of deletion of 11q or 17p in the CLL cells of 32% or 28% of patients, respectively. Median time on study was 32 weeks overall (24 wks for Arm A, 33 wks Arm B, and 44 wks Arm C). AEs of Grade 3–4 that were more common (> 5% greater) in a navitoclax-treated arm compared with the RTX arm included thrombocytopenia, neutropenia, leukopenia, anemia, GI symptoms (diarrhea, abdominal pain), chills, fatigue, ALT/AST/bilirubin elevations, and infusion-related reactions (to RTX). Thrombocytopenia, neutropenia, and hepatic enzyme elevations were generally reversible when navitoclax was stopped and/or dose-reduced; however, 12 patients (15%) discontinued navitoclax due to laboratory abnormalities (9 due to ALT elevations). Neutropenia responded to growth factors. One serious event of epistaxis occurred related to the thrombocytopenia. Two deaths occurred on study, one on the RTX-only arm due to a pulmonary embolus and one on Arm B due to hypotension and dyspnea related to a severe RTX infusion reaction. Investigator-assessed objective response (CR and PR) rate was 35% for Arm A, 55% for Arm B (p=0.19 vs A), and 70% for Arm C (p=0.0034 vs A). All responses were PRs except for 2 CRs in Arm C. All responses were confirmed by CT (and BM for CR) ≥ 8 wks after clinical response assessment. While the presence of 17p deletion appeared to result in a lower response rate to RTX alone (Arm A, ORR 18%, 2/11 pts), it did not appear to affect the response to ABT-263 and RTX (Arm B, ORR 73%, 8/11 pts); Arm C, ORR 50%, 5/10 pts. Limited PFS results appeared consistent with the responses by arm, with a longer PFS associated with the longer duration of ABT-263 treatment on Arm C; however, the magnitude of PFS differences could not be precisely quantified due to the limited follow-up and patient number. Preliminary pharmacokinetic analysis did not detect any drug interaction between navitoclax and RTX. Conclusions: Navitoclax in combination with RTX weekly × 8 was generally well-tolerated as initial therapy for CLL patients and demonstrated greater clinical activity than treatment with RTX alone as well as responses in patients with 17p deletion. The preliminary results of this study indicate that a BH3-mimetic inhibitor of Bcl-2 could be highly effective when used in combination with RTX for treatment of patients with CLL. Disclosures: Eradat: Genentech: Research Funding. Off Label Use: BH3 Mimetic Protein Navitoclax (ABT-263). Catalono:Genentech: Consultancy. Kipps:Genentech: Research Funding. Zheng:Genentech: Employment. Yalamanchili:Genentech: Employment. Sahasranaman:Genentech: Employment. Hurst:Genentech: Employment. Ho:Genentech: Employment.

scholarly journals Driver Mutations and Single Copy Number Abnormalities Identify Binet Stage A Patients with Chronic Lymphocytic Leukemia with Aggressive Progression

2020 ◽  
Vol 9 (11) ◽  
pp. 3695
Author(s):  
Ana P. Gonzalez-Rodriguez ◽  
Angel R. Payer ◽  
Juan J. Menendez-Suarez ◽  
Christian Sordo-Bahamonde ◽  
Seila Lorenzo-Herrero ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Copy Number ◽  
Statistical Significance ◽  
Single Copy ◽  
Lymphocytic Leukemia ◽  
Driver Mutations ◽  
Genetic Characteristics ◽  
Risk Of Progression ◽  
Binet Stage

The correlation between progression and the genetic characteristics of Binet stage A patients with chronic lymphocytic leukemia (CLL) detected by whole exome sequencing (WES) was analyzed in 55 patients. The median follow-up for the patients was 102 months. During the follow-up, 24 patients (43%) progressed. Univariate Cox analysis showed that the presence of driver mutations, the accumulation of two or more mutations, the presence of adverse mutations, immunoglobulin heavy chain genes (IGHV) mutation status and unfavorable single copy number abnormalities (SCNAs) were associated with a higher risk of progression. Particularly, the occurrence of an adverse mutation and unfavorable SCNAs increased the risk of progression nine-fold and five-fold, respectively. Nevertheless, only the occurrence of adverse mutations retained statistical significance in the multivariate analysis. All patients carrying an unfavorable mutation progressed with a median progression-free survival (PFS) of 29 months. The accumulation of two or more mutations also increased the risk of progression with a median PFS of 29 months. The median PFS of patients with unfavorable SCNAs was 38 months. Combining mutations and SCNAs, patients may be stratified into three groups with different prognostic outcomes: adverse (17% probability of five-year PFS), protective (86% probability of five-year PFS) and neither (62% probability of five-year PFS, p < 0.001). Overall, the analysis of the mutational status of patients with CLL at an early stage of the disease may allow the identification of patients with a high risk of progression. The feasibility of an early therapeutic intervention in these particular patients requires further investigation.

scholarly journals The complex karyotype landscape in chronic lymphocytic leukemia allows to refine the risk of Richter syndrome transformation

Haematologica ◽  
2021 ◽  
pp. 0-0
Author(s):  
Andrea Visentin ◽  
Laura Bonaldi ◽  
Gian Matteo Rigolin ◽  
Francesca Romana Mauro ◽  
Annalisa Martines ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Complex Karyotype ◽  
Biological Variables ◽  
Richter Syndrome ◽  
Binet Stage ◽  
The Impact

Complex karyotype (CK) at chronic lymphocytic leukemia (CLL) diagnosis is a negative biomarker of adverse outcome. Since the impact of CK and its subtypes, namely type-2 CK (CK with major structural abnormalities) or high-CK (CK with C5 chromosome abnormalities), on the risk of developing Richter syndrome (RS) is unknown, we carried out a multicenter reallife retrospective study to test its prognostic impact. Among 540 CLL patients, 107 harbored a CK at CLL diagnosis, 78 were classified as CK2 and 52 as high-CK. Twenty-eight patients developed RS during a median follow-up of 6.7 years. At the time of CLL diagnosis, CK2 and high-CK were more common and predicted the highest risk of RS transformation, together with advanced Binet stage, unmutated (U)-IGHV, 11q-, TP53 abnormalities. We integrated these variables into a hierarchical model: high-CK and/or CK2 patients showed a 10-year time to RS (TTRS) of 31%; U-IGHV/11q-/TP53 abnormalities/Binet stage B-C patients had a 10-year TTRS of 12%; while mutated (M)-IGHV without CK and TP53 disruption a 10-year TTRS of 3% (p<0.0001). We herein demonstrated that CK landscape at CLL diagnosis allows to refine the risk of RS transformation and we recapitulated clinico-biological variables into a prognostic model.

scholarly journals Chronic Lymphocytic Leukemia: Prognostic Factors at Presentation in a Resource-Limited Center

2021 ◽  
pp. 56-62
Author(s):  
Kaladada Ibitrokoemi Korubo ◽  
Uchechukwu Prince Okite ◽  
Sampson Ibekwe Ezeugwu
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Median Survival ◽  
Prognostic Markers ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Lymphocytic Leukemia ◽  
Resource Limited ◽  
Binet Stage ◽  
Wbc Count

PURPOSE Determining chronic lymphocytic leukemia (CLL) prognosis using the International Prognostic Index markers such as TP53 and immunoglobulin heavy-chain variable region gene mutation in a resource-limited setting is difficult to achieve because of cost and equipment unavailability. The aim of this study is to determine prognostic factors easily available to hematologists in low- or medium-income countries. MATERIALS AND METHODS This was a retrospective study conducted at the University of Port Harcourt Teaching Hospital, Nigeria. Data were retrieved from CLL patient records from January 2004 to December 2019 (15 years). Data collected were analyzed using SPSS software version 25. RESULTS A total of 46 records were reviewed, with a median age of 55 years and a male:female ratio of 1:1.2. All patients were symptomatic at presentation, with splenomegaly (91.3%), anemia (82.6%), and lymphadenopathy (76.1%) predominating. About 89.1% of the patients presented at Binet stage C and/or high-risk Rai (Rai stages III and IV) with 10.9% presenting at Binet stage B and/or intermediate-risk Rai (Rai stage II). Only 13% of the patients had immunophenotyping done with 6.5% being done for the Matutes CLL score. The 5-year overall survival (OS) was 15.7% with a median survival of 26 months. WBC count and absolute lymphocyte count (ALC) > 100 × 109/L were significant poor prognostic markers ( P = .013 and .021, respectively). Thirty-five (76.1%) received chemotherapy, and they had a better median survival than those who did not (26 v 17.5 months). The most common regimen used was cyclophosphamide, vincristine, and prednisolone for 15 (42.9%) patients. CONCLUSION WBC count and ALC > 100 × 109/L were poor prognostic markers. Patients who received chemotherapy had a better OS.

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