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<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 >312, 129, 80, 36 and 19 months, respectively (HR=17.00, P<0.0001). Patient with a score of 0–1/4, 2–3/4 and 4/4 had a median OS of >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<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.

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.

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.

Correlative Study of ZAP-70 Gene Expression by Quantitative PCR and CD-38 Surface Marker in Patients with Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4796-4796
Author(s):  
Melissa L. Larson ◽  
Jamile M. Shammo ◽  
Sari H. Enschede ◽  
Parameswaran Venugopal ◽  
Daniel Russell ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Stage I ◽  
Cd38 Expression ◽  
Mutational Status ◽  
Multiple Treatments

Abstract Patients with chronic lymphocytic leukemia have heterogeneous clinical courses. Many possible prognostic factors have been evaluated as a way to predict each patient’s future course. Two such prognostic factors are IgVH gene mutational status and CD38 expression. Recently, ZAP-70 expression has been found to correlate with IgVH gene mutation, but little is known about the correlation between ZAP-70 and CD 38 expression. We sought to evaluate the concordance between the two. METHODS: A procedure was developed at our institution to evaluate ZAP-70 transcripts by PCR. The results were then confirmed by flow cytometry. The blood or bone marrow samples of 14 patients diagnosed with CLL were analyzed by PCR for ZAP-70 transcripts and flow cytometry for ZAP-70 protein expression and CD38 expression. The results of the ZAP-70 transcripts and CD38 expression were then correlated to the clinical courses of the patients. RESULTS: Of the 14 patients analyzed, the majority had Rai Stage I disease at diagnosis (4 Stage 0, 8 Stage I, and 2 Stage II). There was a median follow-up of 28 months. The median number of treatments for these patients was one (range 0–6). Overall, the results for ZAP-70 and CD38 expression were concordant in eight with CD38 data unavailable for 2 patients. In the four patients with discordant results, 3 of them had high CD38 expression and low ZAP-70. However, patients with high ZAP-70 were more likely to require multiple treatments once treatment was indicated. Patients with high CD38 were also more likely to be treated. Cytogenetic data was available for 9 patients with the following results: 5 with normal cytogenetics, 1 with deletion of 11q, 1 with deletion of 13q, and 2 with deletion of 17p. Five of the nine patients had high ZAP-70 expression. CONCLUSIONS: In our institution, the results of ZAP-70 and CD38 expression were concordant 67% of the time. Longer follow-up is necessary and may further delineate the roles of cytogenetics, ZAP-70 expression, and CD38 expression on prognosis in CLL.

Prognostic Factors of Chinese Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4387-4387
Author(s):  
Jianyong Li ◽  
Wei Xu ◽  
Chun Qiao ◽  
Yu-Jie Wu ◽  
Kourong Miao ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Gene Families ◽  
Lymphocytic Leukemia ◽  
High Expression ◽  
Chinese Patients ◽  
Cytogenetic Abnormalities ◽  
Western Countries ◽  
Mutational Status ◽  
Clinical Stages

Abstract Abstract 4387 Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies in the Western countries, however, infrequent in Asian populations. Although the median survival is around 10 years, CLL is a disease with an extremely variable clinical course with overall survival times ranging from months to decades; some patients never need treatment, while others require intensive treatment early after diagnosis. Some factors, such as clinical stages, IGHV mutational status, cytogenetic abnormalities, ZAP-70, and the expression of CD38 in leukaemic cells, were strong indicator of prognosis in CLL. However, the prognostic factors of Chinese patients with CLL compared with the Western countries have not yet been clarified. The aim of this study was to explore the influence of factors on the prognosis of Chinese patients with CLL. One hundred and twenty-nine patients with CLL were enrolled in this study. Multiplex PCR and sequencing, fluorescence in situ hybridization (FISH), and flow cytometry were used to detect IGHV mutational status, cytogenetic abnormalities, and the expression of ZAP-70 and CD38, respectively. A panel of FISH probes included 13q14 (D13S319), 17p13 (p53 gene), 11q23 (ATM gene), 6q23(MYB gene), the centromere of chromosome 12 (D12Z3) and 14q32 (IGHC/IGHV). In 129 CLL patients, according to the Binet clinical staging system, 65 (50.4 %) patients were in Binet A, 28 (21.7 %) in Binet B and 36 (27.9 %) in Binet C. Eighty-four (65.1%) patients had mutated IGHV, and 45 (34.9%) had unmutated IGHV. The most frequently expressed VH gene family was found to be VH3 (50.4%) followed by VH4 (32.6%), VH1 (10.9%), VH2 (2.3%), VH5(2.3%) and VH7 (1.6%), with no expression of VH6 gene families. VH1-69 and VH3-21 which commonly overused in Western CLL patients were very low in our cohort (0.8% and 3.1%, respectively). Molecular cytogenetic aberrations were found in 94 patients (72.9%) and 36 patients (27.9%) with more than two abnormalities. The most frequent abnormalities detected in our patients was del(13q14), with an incidence of 53.0%, followed by 14q32 translocation of 20.2%, +12 of 18.3%, del(11q23) of 10.8%, del(17p13) of 10.o%, and del(6q23) of 6.1%. Forty-one patients (31.8%) were positive for ZAP-70 (≥20%), and 51 patients (39.5%) were positive for CD38 (≥30%). With a median follow-up of 32 months (range, 4-58 months), eight patients (6.2%) died (CLL-related deaths). In univariate analysis for survival, advanced Binet stage (P=0.023), unmutated IGHV status (P=0.002), deletions of 17p13 or 11q23 (P=0.003), high expression of ZAP-70 (P=0.034), and high expression of CD38 (P=0.046) were poor prognostic factors. The prognostic factors with statistical significance were further used in a two-variables Cox analysis, which comparing unmutated IGHV status to other prognostic factors individually to show prognostic independence. The unmutated IGHV status were the independent prognostic factors and strongly associated with OS. This study demonstrates that the frequencies of IGHV gene families indicated significant difference in Chinese CLL patients compared with Western patients, suggesting involvement of ethnic and/or environmental factors in CLL disease initiation. The unmutated IGHV status, Binet clinical stages, Chromosomal aberrations of del(17p13) and del(11q23), high expression of ZAP-70 and CD38 have been shown highly predictive prognostic value for Chinese patients with CLL. Disclosures: No relevant conflicts of interest to declare.

Single-Agent Rituximab in Treatment-Refractory or Poor Prognosis Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2380-2380
Author(s):  
Giridhar U. Adiga ◽  
Peter H. Wiernik
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Poor Prognosis ◽  
Single Agent ◽  
Lymphocytic Leukemia ◽  
Weekly Dose ◽  
Mantle Cell ◽  
Binet Stage ◽  
Treatment Refractory ◽  
Cell Variant

Abstract Abstract 2380 Poster Board II-357 Background: Rituximab in combination with fludarabine and cyclophosphamide (R-FC) is the new standard therapy for patients with chronic lymphocytic leukemia (CLL). Rituximab in combination with FC or any other chemotherapy is indicated for first-line treatment of patients with CLL by the EMEA. However, the FC component of this treatment is myelosuppressive, and patients with CLL who refuse or are not candidates for myelosuppressive therapy have few treatment options. We investigated the effect of single-agent rituximab in patients with treatment-refractory or poor prognosis CLL. Method: 23 patients with progressing CLL received single-agent rituximab at an initial weekly dose of 375 mg/m2. Patients were progressively escalated to 3 g/m2 at the fourth weekly dose and remained on this dose for the remainder of their treatment cycle. Clinical responses, adverse events and treatment history were recorded and analyzed. A patient with mantle cell variant CLL was included in this series but is omitted from the group analysis. Results: 13 previously treated patients received a median of 1.5 (range 1–6) prior lines of therapy; 8 of these patients were fludarabine refractory. Nine patients had received no previous treatment for CLL. Overall response rate (ORR) and complete response (CR) rate were 90.9% and 54.5%, respectively. Even in patients who were fludarabine refractory ORR was 75% with 37.5% CR. Responses by population are summarized in table 1. As of August 2009, median progression-free survival (PFS) was 12.5 months (range 0-48), with a median response duration (DR) of 8.5 months (range 0-46) (fludarabine-refractory median PFS = 8 months). Patients with high-risk Binet stage C disease had less durable responses and shorter PFS compared with Binet stage A/B patients (DR= 8 vs. 9 months, PFS= 8 vs. 17 months). Patients ≥65 years had more durable responses and longer PFS compared with patients <65 years (DR= 11.5 vs. 5 months, PFS= 16 vs. 8 months). Four patients received rituximab as maintenance therapy (375mg/m2 weekly for 4 weeks, every 6 months). All experienced CR or partial response (PR) and had a PFS which was considerably longer than the overall population (48, 36, 34 and 33 months); all 4 patients were still in remission as of August 2009. The patient with mantle cell variant CLL achieved a CR and is still in molecular remission with a DR of 94 months and PFS of 96 months as of August 2009. No unexpected adverse events were observed. Conclusions: Single-agent rituximab was an effective treatment for treatment-refractory or poor prognosis CLL, and was well tolerated. High ORR and CR rates were seen even in patients who were fludarabine refractory. Encouraging responses were seen with rituximab maintenance and in older patients. These data suggest that there is a role for single-agent rituximab in the treatment of patients with difficult-to-treat CLL, and that the concept should be studied further. Disclosures: Off Label Use: Rituximab is a monclonal antibody licenced for the treatment of NHL as a single-agent. Rituximab is CLL currently under review by the FDA as treatment for relapsed/refractory CLL in combination with chemotherapy. Here it is used as a single-agent treatment for CLL.

A Phase II Study of Chlorambucil Plus Rituximab Followed by Maintenance Versus Observation In Elderly Patients with Previously Untreated Chronic Lymphocytic Leukemia: Results of the First Interim Analysis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2462-2462 ◽  
Author(s):  
Robin Foa ◽  
Stefania Ciolli ◽  
Francesco Di Raimondo ◽  
Giovanni Del Poeta ◽  
Francesco Lauria ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Interim Analysis ◽  
Overall Response Rate ◽  
Response Rate ◽  
Lymphocytic Leukemia ◽  
Induction Phase ◽  
First Line ◽  
Mutational Status ◽  
Igvh Mutational Status ◽  
Binet Stage

Abstract Abstract 2462 Background: Two of the largest trials ever conducted in patients with chronic lymphocytic leukemia (CLL) have shown that the addition of rituximab to fludarabine plus cyclophosphamide (R-FC) significantly improves outcome. However, myelotoxicity and immunosuppression limit the use of this regimen in patients with impaired performance status and pre-existing co-morbidities, predominantly in the elderly. Chlorambucil (CLB) remains a first-line treatment option for such patients. The use of CLB in combination with R is thus an attractive therapeutic option in view of the potentially increased activity compared to CLB alone and the likely good tolerability. This study was designed to determine whether the R-CLB combination is feasible and beneficial as first-line treatment for elderly patients with CLL and to define the role of maintenance R. Patients and Methods: Between October 2008 and January 2010, 97 elderly patients with untreated CD20+ CLL requiring therapy according to the IWCLL criteria were enrolled into the protocol. CLB treatment was administered every 28 days for up to 8 courses at a dose of 8 mg/m2/day p.o. on days 1–7 combined with 375 mg/m2 R for cycle 3 and 500 mg/m2 for cycles 4–8. Responsive patients were randomized to R maintenance (375 mg/m2 every 2 months for 2 years) versus observation. At baseline, blood samples were taken for FISH analysis, IgVH mutational status and expression of Zap-70 and CD38. Minimal residual disease (MRD) was planned to be evaluated on peripheral blood (PB) and bone marrow (BM) cells by four-color flow cytometry and, when required, by PCR. The primary endpoint was the overall response rate at the end of the induction phase defined according to the IWCLL 2008 on the intention-to-treat (ITT) population (all enrolled patients who received at least 1 dose of R). Secondary endpoints included the adverse event (AE) profile, progression-free and overall survival. Results: These are the data of the planned interim analysis based on the first 54 evaluable patients from 19 Italian centers, including tumor response at the end of the induction phase and safety. The median age of patients was 70.5 years (range 61–84): 14.8% were between 61 and 64, 31.5% between 65 and 69, 31.5% between 70 and 74, 16.7% between 75 and 79, and 5.6% were ≥80 years; thus, 53.8% of patients were over the age of 70; 70.4% were males; 25.9% were Binet stage A, 57.4% stage B and 16.7% stage C. The overall incidences of trisomy 12 and abnormalities of 13q, 11q23 and 17p13 were 24.5%, 52.8%, 20.8% and 5.7%, respectively; 7.5% of patients had p53 mutations. Of the 51/54 patients analyzed for the IgVH mutational status, 64.7% were unmutated; of the 53/54 patients studied, 39.6% were CD38+ and 71.7% were Zap-70+. The overall response rate on an ITT analysis was 81.4% (44/54 patients); a CR assessed by CT scan and trephine immunohistochemistry was found in 16.7% of cases (9 patients: 4 in Binet stage A, 3 in stage B and 2 in stage C), a CRi in 3.7% (2 patients), a nPR in 1.9% (1 patient) and a PR in 59.3% (32 patients). Eight of the 9 CR cases were investigated for MRD by flow cytometry and all proved positive: 6/8 had MRD levels <10−3 in the PB and 2/8 in the BM. A progressive disease was recorded in 2 patients (4%) and a stable disease in 2 (4%). Six patients (11%) were not evaluable for response: 1 investigator's decision, 2 AEs (1 R infusion-related reaction and 1 unrelated episode of dyspnea) and 3 SAEs (1 CLB-related anemia, 1 endometrial in situ carcinoma and 1 anaplastic oligoastrocytoma). Seven SAEs occurred in 7 patients during courses 3–8. Only 1 SAE was related to treatment (1 CLB-related anemia). The most common toxicities were neutropenia (31.5% of patients, 8.9% of cycles) and thrombocytopenia (14.8% of patients, 5.7% of cycles). Grade III-IV neutropenia was present in 16.7% of patients and in 3.8% of cycles. No grade III-IV infections occurred. A median of 85.4 R-CLB courses was administered with 85.1% of patients completing the planned treatment; 15.3% of cycles needed a CLB dose reduction (12.9% due to toxicity, mainly neutropenia and thrombocytopenia). Conclusions: Overall, the results of the interim analysis indicate that R-CLB is active and well tolerated in elderly patients with previously untreated CLL. Disclosures: Foa: Roche: Consultancy, Speakers Bureau. Montillo: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Runggaldier: Roche S.p.A. Monza: Employment. Gamba: Roche S.p.A. Monza: Employment.

Disruption of TP53 function by Point Mutations and Deletions Is Associated with An Increased Risk of Disease Progression within Previously Treated, Relapsed Chronic Lymphocytic Leukemia Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2445-2445
Author(s):  
Annika Dufour ◽  
Stefan K Bohlander ◽  
Evelyn Zellmeier ◽  
Gudrun Mellert ◽  
Karsten Spiekermann ◽  
...  
Keyword(s):  
Disease Progression ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Lymphocytic Leukemia ◽  
Dominant Negative ◽  
Tp53 Mutations ◽  
Mutational Status ◽  
Igvh Mutational Status ◽  
Binet Stage ◽  
Previously Treated

Abstract Abstract 2445 Chronic lymphocytic leukemia (CLL) patients with a deletion of the TP53 tumor supressor gene located at 17p13 have a poor prognosis in first line chemotherapy regimens. Recent studies indicated somatic TP53 mutations as a prognostic factor in CLL independent of 17p13 deletion status. We aimed to further characterize the prognostic value and the impact of TP53 mutations on progression-free survival (PFS) in the presence and absence of a 17p13 deletion in previously treated and relapsed CLL patients within an international phase III clinical study comparing Fludarabine and Cyclophosphamide with or without Rituximab (FC versus R-FC: REACH trial). We analyzed 457 patients at diagnosis for mutations in the TP53 gene using a combination of a microarray-based resequencing assay (AmpliChip p53 Test, Roche Molecular Systems, USA.) and Sanger sequencing of TP53 exons 2–10. The data were correlated with clinical and biologic markers as well as with interphase fluorescence in situ hybridization (FISH) and with PFS. Association of the clinical data with PFS was assessed by Cox proportional hazard models. To estimate the functional significance of the individual TP53 mutations we used the IARC TP53 database. TP53 mutations (n=60) were detected in 52 of 457 patients (11.4%) and included 42 missense, 4 nonsense, 8 frameshift mutations, 2 in-frame deletions and 4 mutations in splice sites. Among other clinical variables, only 17p13 deletion was associated with TP53 mutations: 27 of 52 TP53 mutated patients had a 17p13 deletion (concordance rate: 52%, Fisher's test p<0.001). Median PFS for patients with TP53 mutations (n=52, 13 months, HR=1.9 (1.4–2.7), p<0.001) was significantly shorter as compared to patients without TP53 mutations (n=480, 27 months). In a sub-group analysis, chemoimmunotherapy including Rituximab did not significantly improve the PFS of patients with TP53 mutations. Multivariate analysis including treatment arm, Binet stage, age, IGVH mutational status, 17p13 deletion and TP53 mutation status confirmed TP53 mutation status (HR-TP53=1.7 (1.1–2.6), p=0.009) as a prognostic factor for PFS independent of 17p13 deletion status (HR-17p=1.7 (1.1–2.7), p=0.024) and with a similar effect size. The other independent prognostic factors were treatment (HR=0.61 (0.48–0.76), p<0.001), Binet stage (HR=1.64 (1.3–2.1), p<0.001) and IGVH mutational status (HR=2.4 (1.85–3.1), p<0.001). To further dissect the contribution of TP53 mutation and 17p13 deletion on PFS, we considered a multivariate analysis comparing patients with both TP53 mutation and 17p13 deletion (n=28), with only 17p13 deletion (n=9), with a dominant negative TP53 mutation or multiple TP53 mutations (n=8) or with a single TP53 mutation (n=16) against patients without TP53 abnormalities (n=271), adjusted for treatment, Binet stage, age and IGVH mutational status. Patients with a predicted biallelic disruption of TP53 either by a TP53 mutation in combination with a 17p13 deletion (HR: 2.8 (1.8,4.2), p=<0.001) or patients with a dominant negative TP53 mutation as predicted by the IARC TP53 database or multiple TP53 mutations (HR=3.26 (1.5,7.1), p=0.003) had a risk similar in size and which was quite high for disease progression (the reference to calculate the risk, here and in the following, is always the group of patients without TP53 abnormalities). The risk slightly decreased for patients with only a deletion 17p13 (HR=2.2, (1.1–4.3), p=0.021). Very interestingly, single TP53 mutations showed a much lower risk for disease progression (in this case not even significant) (HR=1.61 (0.9–2.8), p=0.084) especially compared to the risk conferred by a biallelic disruption. In this large cohort of previously treated CLL patients, complete disruption of TP53 function (by a combination of a 17p13 deletion and a TP53 mutation, through dominant negative TP53 mutations or through multiple TP53 mutations) was associated with a higher risk for disease progression. Prognosis of patients with a single TP53 mutation was not significantly different from patients without TP53 aberrations. It remains to be shown whether CLL patients with a single TP53 mutation are at a higher risk of acquiring additional mutations of TP53 during disease progression. Prognostic stratification of previously treated CLL patients should include a routine molecular TP53 mutational analysis in addition to deletion analysis of the TP53 locus by FISH. Disclosures: Dufour: Roche: Research Funding. Bohlander:Roche: Research Funding. Spiekermann:Roche: Research Funding. Schneider:Roche: Research Funding. Hiddemann:Roche: Research Funding. Truong:Roche: Employment. Patten:Roche: Employment. Wu:Roche: Employment. Dmoszynska:Mundipharma:; Roche: Honoraria. Robak:Centocor Ortho Biotech Research & Development: Research Funding. Geisler:Roche: Speakers Bureau. Dornan:Genentech: Employment. Lin:Genentech: Employment. Yeh:Genentech: Employment. Weisser:Roche: Employment. Duchateau-Nguyen:Roche: Employment. Palermo:Roche: Employment.

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.

scholarly journals The Combination of Complex Karyotypes' Subtypes and IGHV Mutational Status Provides Prognostic and Predictive Information in Chronic Lymphocytic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1844-1844
Author(s):  
Andrea Visentin ◽  
Laura Bonaldi ◽  
Gian Matteo Rigolin ◽  
Francesca Romana Mauro ◽  
Annalisa Martines ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Board Member ◽  
Advisory Board ◽  
Lymphocytic Leukemia ◽  
Rank Test ◽  
Predictive Information ◽  
Excellent Outcome ◽  
Mutational Status

Abstract INTRODUCTION. Complex karyotype (CK), defined by the presence of at least 3 chromosomal abnormalities, is a heterogeneous cytogenetic category associated with adverse prognosis in several hematologic malignancies. Recently, Rigolin et al. provided evidence that CK with major structural abnormalities (CK2) at chronic lymphocytic leukemia (CLL) diagnosis negatively impact on the time to first treatment (TTFT) and overall survival (OS) (Rigolin GM, BJH 2018). However, it is unknown whether the prognostic strength of CK could be implemented when combined with stable markers such as the IGHV mutational status. In the present study, we assessed the prognostic and predictive role of the combination of CK subtypes and IGHV status in a large CLL series. METHODS. Stimulated cytogenetics with CpG+IL2 was performed in 736 CLL patients in 3 referenced Italian hematological centers. According to Rigolin et al, CK2 cases included unbalanced translocations, addition, insertion, derivative and marker chromosomes. All other CK were classified as type 1 (CK1). An IGHV gene sequence homology >98% was considered as unmutated (U-IGHV), as opposed to mutated (M-IGHV). Treatment was initiated according to the iwCLL guidelines. TTFT and OS were calculated from diagnosis to first treatment or death, respectively, or last known follow-up. Survival curves were compared with the log-rank test and p<.05 was considered as significant. Harrell concordance index (c-index) was used to compare our prognostic model with Dohner's and FISH-IGHV models. RESULTS. We focused on 520 out of the 736 patients with cytogenetic and IGHV status assessed within 12 months from diagnosis. The median age at diagnosis was 63 years, 322 (62%) were males, 68% at Binet A stage, 45% U-IGHV, 48 harbored TP53 abnormalities, 99 a CK (28 CK1 and 71 CK2), 232 received at least one line of therapy (31% FCR, 16% BR, 8% ibrutinib, 5% chlorambucil-antiCD20, 40% other treatments) and 80 died over a median follow-up of 5.8 years. 71 (14%) harbored CK2, 214 (41%) CK1 or U-IGHV and 235 (45%) M-IGHV without CK2. The former group were characterized by a higher prevalence TP53 (38% vs 8% vs 3%, p<0.0001) and cytogenetics abnormalities but lower cases with low-risk FISH (i.e. 13q or normal; 38% vs 54% vs 91%, p<0.0001) as compared with others two groups. We observed that subjects with CK2 had a shorter TTFT (median years 1.97, 3.40 and 19.1, p<0.0001) and 5 years OS (67%, 85%, 93%, p<0.0001) compared to cases with CK1/U-IGHV, or M-IGHV without CK. These data were confirmed in multivariate analysis. The worse prognosis of CK2 patients was independent of TP53 status (p values 0.0770 and 0.8122 for TTFT and OS, respectively). The c-indexes for our model were 69% and 68% for TTFT and OS, respectively, and were not inferior to those calculated with Dohner's (64% and 61%) and FISH-IGHV (69% and 63%) models. The combination of these two markers also provides predictive information after first-line therapy (p<0.0001 for both TTFT and OS). In particular, among 107 patients treated with FCR or BR just one of the M-IGHV cases relapsed but none died after a median follow-up of 43 months as compared with the other two subgroups (3-year PFS 92%, 69% and 23%, p<0.0001; 3-year OS: 100%, 94%, 62%, p<0.0001). CONCLUSIONS. In this study, we demonstrated that the combination of CK subtypes and IGHV status provides important prognostic and predictive data in CLL. Moreover, our model was not inferior to other commonly used prognostic scores. While patients with M-IGHV without any subtypes of CK showed an excellent outcome with chemoimmunotherapy, new alternative therapies should be explored for patients with CK2. Disclosures Visentin: janssen: Consultancy, Honoraria. Rigolin:Gilead: Research Funding. Mauro:abbvie: Other: board member; janssen: Other: board member. Foà:JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELTRION: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau. Cuneo:Roche: Other: advisory board, Speakers Bureau; Gilead: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau. Trentin:Gilead: Research Funding; Janssen: Research Funding; Abbvie: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees.

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