Cytogenetic Progression in Patients with Multiple Myeloma As Assessed By Serial Bone Marrow Biopsy Is Associated with Worse Outcome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4209-4209
Author(s):  
Catherine Randall Paschal ◽  
Jens C Eickhoff ◽  
Aric C Hall ◽  
Jennifer Laffin ◽  
Natalie Scott Callander ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
High Risk ◽  
Risk Group ◽  
Clonal Evolution ◽  
Intermediate Risk ◽  
Disease Course ◽  
Cytogenetic Abnormalities ◽  
Standard Risk

Abstract Background:Multiple Myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal, mutated plasma cells, which ultimately leads to multi-organ damage and in most cases death. Despite improved treatments, clinical heterogeneity remains, with some patients succumbing to disease within 1-2 years. Certain cytogenetic and FISH abnormalities at diagnosis confer a higher likelihood of poor outcomes (Mikhael et al., 2013). Still, the utility of repeated cytogenetic assessment over the course of disease is unknown. Methods: We performed a retrospective review to identify MM patients with cytogenetics (CG) performed at diagnosis who had two or more bone marrow (BM) examinations performed during follow up over a five year period at UW Carbone Cancer Center. We reviewed the pathology and CG results from each BM sample. CG data was categorized into risk groups using the mSMART stratification criteria: High risk - deletion 17p13, t(14;16), t(14;20); intermediate risk - t(4;14), hypodiploid, deletion 13, gain of 1q21; standard risk - hyperdiploidy and all other abnormalities, and normal CG. CG progression over disease course was categorized based on stability or change in CG risk group. We measured survival from date of diagnosis to death or last follow up. Results: 130 patients with CG at diagnosis were identified over the five year period of the study. These patients had 365 follow-up bone marrow (BM) aspirates, 341 with repeat CG study. Initial cytogenetics were as follows: 90 (69%) of 130 patients had normal CG at diagnosis, 13 (10%) standard risk CG, 16 (13%) intermediate risk CG, and 11 (8%) high risk CG. Serial CG studies showed both development of new CG abnormalities in patients with previously normal studies, and clonal evolution with CG abnormal patients acquiring additional abnormalities on repeat testing. 24 (27%) of 90 patients with normal CG at diagnosis developed abnormal CG during disease course: 12 had intermediate risk CG and 9 high risk CG, the latter all due to p53 deletion. Clonal evolution and drift among initially CG abnormal patients were also common. Of the 34 patients with abnormal CG results on diagnosis and subsequent bone marrow samples, clonal evolution was identified in 19 patients (56%) and 4 (12%) patients developed new CG abnormalities unrelated to the prior clone, while 11 (32%) showed stable CG. Despite this high rate of change, only two patients with abnormal CG at diagnosis moved from a lower to a higher cytogenetic risk group. When we correlated CG at diagnosis with survival, we found that patients with high risk CG at diagnosis appeared to have shorter median overall survival at 3.8 yrs (range 1-12 yrs) compared with 7.4 yrs (range 2-12 yrs) for intermediate risk, 8.5 yrs (range 2-9 yrs) for standard risk, and 8.2 yrs (range 1-12 yrs) for normal CG. Comparison among all four groups was not statistically significant however, possibly due to the small proportion of high risk CG patients. When we examined the effect of acquiring CG abnormalities, we found that development of abnormal CG in patients with normal CG at diagnosis was associated with shorter median OS (4.0 yrs) compared to either persistent normal CG (11.3 yrs) or any CG abnormality at diagnosis (7.4 yrs), overall comparison p = 0.0048. Conclusion: Our longitudinal study of 130 unselected patients with MM revealed a cohort who showed cytogenetic progression. In patients with normal CG at diagnosis, the presence of cytogenetic abnormalities in follow-up BM specimens was associated with inferior overall survival. This finding indicates that serial testing may facilitate the detection of a higher risk patient cohort. Further analysis is underway to identify clinical parameters that underlie a higher risk of clonal evolution or development of new cytogenetic abnormalities. The results of our study will help elucidate the optimal prognostic utility of cytogenetic analysis in patient care. Disclosures No relevant conflicts of interest to declare.

scholarly journals Increasing Chemotherapy Intensity Improves Relapse Rate and Not Overall Survival in AML Patients: A Single Center Experience

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4899-4899
Author(s):  
Fousia Alsobhi ◽  
Muhammad Matloob Alam ◽  
Mohamed Bayoumy ◽  
Ibraheem Abosoudah
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Relapse Rate ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Intermediate Risk ◽  
Group 3 ◽  
Acute Myeloid ◽  
Case Distribution

Abstract BACKGROUND Acute Myeloid Leukemia (AML) represents 15%-20% of all leukemia in children less than 14 years. Over the last few years' treatment modification, intensification, introduction of new chemotherapeutic agents, targeted therapy and concomitant haematopoietic stem cell transplantation (HSCT) in high risk patients has improved overall survival in children with AML up to 50-60 %. METHODOLOGY: The aim of this single center retrospective study is to describe the clinic-pathological features and outcome of chemotherapy and HSCT in patients admitted with diagnosis of AML between 2005 and 2014 at King Faisal Specialist Hospital and Research Centre (KFSH&RC)-Jeddah, Saudi Arabia. RESULTS: A total of 32 acute myeloid leukemia patients was admitted and treated at our institute during this study periods. Out of them male were 18 (56.3%). Mean age of study population was 6.5 +/- 5 years. Fever was the most common presenting complaints 32 (100%) followed by lymphadenopathy 31 (97%), pallor 30 (94%), hepato-splenomegally 29 (91%) and bleeding 19 (60%). Four patients have Down syndrome (12.5%) and CNS involvement were documented in 3 (9.4%). Regarding etiology majority of the patients have De Novo 30 (93.7%) and remaining 2 (96.3%) cases have MDS. Case distribution according to FAB classification was as follow M1 (n=1; 3.1%), M2 (n=7; 21.9%), M3 (n=4; 12.5%), M4 Eo (n=1; 3.1%), M5 (n=8; 25%), M6 (n=4; 12.5%), M7 (n=4; 12.5%), and no information (n=3; 9.4%). Cytogenetic were normal in most cases 18 (56.3%) and abnormal cytogenetic was recorded in remaining 14 (23.8%) cases. Out of, complex cytogenetic (n=2; 6.3%), FLT3/ITD (n=2; 6.3%), Monosomy 7 (n=3; 9.4%), t(15;17) in (n=4; 12.5%) and t(8;21) in (n=3; 9.4%). Risk group classification was as followed; High risk (n=10; 31.3%), Intermediate (n=10; 31.3%) and low risk (n=11; 34.4%) and not done in (n=1; 3.1%). Case distribution according to the chemotherapy protocol used for treatment were POG 8498 protocol (n=15; 46.9%) and AAML 0531 protocol (n=13, 40.6%). Remaining 4 (n=4, 12.5%) patients with diagnosis of APL were treated with C9710 protocol. Complete remission after 2 cycle of induction chemotherapy was achieved in 23 (71.3%) cases, 6 (18.8%) cases experienced induction failure and another 3 (9.4%) patients expired during induction chemotherapy and/or lost to follow up. Fungal infection was observed in two cases (n=2; 6.3%), one had is documented Candida infection and this patients did not recover and expired. Sixteen patients received allogeneic HSCT after chemotherapy (8 belongs to high risk, 6 intermediate risk and 2 low risk group), out of them 12 were in complete remission and 4 patients were not in remission at the time of transplantation. Out of 8 patients who belongs to high risk group 3 were relapsed and 1 expired and out of 6 patients who belongs to intermediate risk group, 3 were relapsed and 1 expired after HSCT. Overall relapse rate in group of patients treated with AAML 0531 and POG 8497 were (n=6/28; 21.4%) with mean duration of relapse 26 +/- 27 months. Relapse rate in patients treated with AAML 0531 protocol was much lower than those who treated with POG 8497 protocol (15% vs 27%). Overall mortality rate was (n=8/32; 25%) mean timing of expiry from diagnosis is 37 +/- 32 months with mean duration of follow up is 48 +/- 6.5 months. Mortality rate in both group of patients who were treated with AAML 0531 protocol or POG 8497 protocol was comparable (31% vs 27%). CONCLUSION: We observed better event free survival in our patients treated with AAML 0531 protocol, however, the overall survival was comparable with patients treated with POG 8497 protocol. Further large scale, multicenter and long-term follow up study will be required to validate these findings. Disclosures No relevant conflicts of interest to declare.

Prognostic Factors for Survival After 2-CdA-Based Therapy for Symptomatic Waldenström Macroglobulinemia (WM) Stratify Patients Into Low- and High-Risk Groups.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1668-1668
Author(s):  
Sheeba K Thomas ◽  
Lei Feng ◽  
Kay B Delasalle ◽  
Michael Wang ◽  
Jatin J Shah ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Retrospective Studies ◽  
Risk Group ◽  
Stage I ◽  
Stage Ii ◽  
Stage Iii ◽  
Primary Therapy ◽  
Intermediate Risk

Abstract Abstract 1668 Poster Board I-694 Introduction Retrospective studies performed by others between 2001-2009, have identified various prognostic factors for survival among patients with symptomatic WM. These include hemoglobin, platelet count, albumin, and β2-micrglobulin (β2M) at varied cutoffs, as well as gender, age, IgM level, monoclonal (M) protein level, hyperviscosity syndrome, prior therapy, presence of splenomegaly/organomegaly, stage as defined by the International Staging System for multiple myeloma (ISSMM) and risk score as defined by the International prognostic scoring system for Waldenström macroglobulinemia (IPSSWM). Methods We retrospectively analyzed our experience with 80 previously untreated patients with symptomatic WM who participated on one of four 2-chlorodeoxyadenosine (2-CdA)-based clinical trials between 3/90-5/02, to identify factors predicting overall survival. Patients received either 2 consecutive 4-6 week courses of 2-CdA at 1.5 mg/m2 subcutaneously three times daily for 7 days (d) alone (10 patients), with prednisone (Pred) at 60 mg/m2 orally (po) d1-7 (21 patients), with cyclophosphamide (Cy) at 40 mg/m2 po twice daily (bid) for 7d (31 patients), or with Cy at 40 mg/m2 po bid for 7d + rituximab (Rit) at 375 mg/m2 intravenously weekly for 4 weeks (18 patients). Overall survival (OS) from the start of therapy was censored as of April 1, 2009. Predictive factors identified by multivariate analysis in other retrospective studies, as well as other clinically relevant factors, were evaluated. Results Median age of patients was 62.1 years (range 35.9-80.1), and 41 were male. Median hemoglobin was 10 g/dL (5.6-15.6), platelet count was 243 K/μL (26-654), albumin was 4.1 g/dL (2.5-5.4), and β2M was 3.3 mg/L (1.4-15.9). Splenomegaly and lymphadenopathy (≥ 2 cm) were present in 29.1% and 28.8% of patients, respectively. By ISSMM, 38 patients were Stage I, 29 were Stage II, and 13 were Stage III. By IPSSWM, 24 patients were low-risk, 45 were intermediate-risk, and 11 were high-risk. With a median follow-up of 9.9 years (yrs; range 0.9-16.8), median OS for all patients was 8.9yrs (0.1 yrs-not reached (NR)). By univariate analysis, age <65y, primary therapy (2CdA/Cy/Rit >2CdA/Cy > 2CdA >2CdA/Pred), albumin ≥3.5 g/dL, B2M <3.5 mg/L vs. 3.5-5.5 mg/L vs. >5.5 mg/L, ISSMM and IPSSWM, were all significant (p< 0.05). In multi-covariate models, primary therapy (2CdA/Cy/Rit vs. other 2CdA regimens), age, ISSMM, and IPSSWM remained significant. Removing the 2CdA/Pred cohort (which had the poorest OS) from the analysis of primary therapy, the trend toward superior OS with 2CdA/Cy/Rit vs. 2CdA+2CdA/Cy persisted (NR vs. 9.2 yrs), but did not reach statistical significance (p=0.12). Median OS for patients of age <65 yrs was 15.4 yrs compared with 6.2 yrs for those age ≥65 yrs (p=0.03). ISSMM stage I disease was associated with a median OS of 12.5 yrs, while stage II was 6.3 yrs, and stage III was 6.0 yrs (p=0.02). By comparison, median OS has not yet been reached among those classified as having low-risk disease by IPSSWM, while the intermediate-risk group has a median OS of 6.5 yrs, and the high-risk group has a median OS of 5.8 yrs (p=0.03). Conclusion Both ISSMM and IPSSWM are predictive of overall survival among patients with symptomatic WM treated first-line with 2CdA-based regimens. In our experience, rates of 10 year OS were better stratified by age, <65 yrs (62%) vs. ≥65 yrs (30%), and IPSSWM risk score, low (63%) vs. intermediate (46%) vs. high (24%), than by ISSMM stage (stage I [58%] vs. stage II [49%] vs. stage III [0%]). Novel therapeutic strategies are needed to improve the survival of patients with WM who are of older age, or who have high-risk IPSSWM or higher stage ISSMM disease. Longer follow-up is needed to confirm the trend toward improved survival seen with the addition of rituximab to 2CdA-based therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Association between Immunoglobulin Isotypes and Cytogenetic Risk Groups in Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5585-5585
Author(s):  
Ramya Muddasani ◽  
Albert Ho ◽  
Meredith Akerman ◽  
Shahidul Islam ◽  
Mitchel Polak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Risk Group ◽  
Clonal Evolution ◽  
Prognostic Significance ◽  
Risk Groups ◽  
Categorical Variables ◽  
Intermediate Risk ◽  
Immunoglobulin Isotypes ◽  
Standard Risk

Abstract Introduction: Cytogenetic abnormalities (CAs) in multiple myeloma (MM) have prognostic significance and predict the risk of clonal evolution, disease progression, and response to treatment. The Revised International Scoring System (R-ISS) was recently updated to incorporate high risk CAs, including del(17p), t(14:16), and t(14:20), the presence of which confer a poorer prognosis. Prior studies have demonstrated the prognostic value of specific CAs and MM immunoglobulin isotypes, for example, non-IgG isotypes having been associated with poorer prognosis. However, data showing a link between cytogenetic risk groups and MM isotypes are limited. Thus, we determined whether a relationship exists between higher-risk CAs and MM isotypes, as well as the degree of malignant plasma cell infiltration of the bone marrow (BM). Methods: We performed a retrospective analysis of a multi-institutional commercial pathology repository of 442 MM patients identified according to the International Myeloma Working Group criteria that included assessment of BM infiltration (BM%), MM isotype, CA, and cytogenetic risk group. The study protocol was approved in accordance with IRB standards. As per the R-ISS, the high risk CAs included del(17p), t(14:16), and t(14:20), intermediate risk CAs included t(4;14), del(13q), dup(1q), and hypodiploidy, and standard risk CAs included t(6;14), t(11;14), and hyperdiploidy. Patients with CAs that included more than one risk group were considered to be in the higher risk category. Associations between categorical variables were made using the chi-squared test or Fisher's exact test. The Mann-Whitney test was used to compare groups (MM isoytpe, CAs, or cytogenetic risk group). Statistical significance was considered at p<0.05. Analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC). Results: Among the 442 MM patients, isotype groups included 42% IgG, 16% IgA and 42% light chain-only (LCO). There were 184 patients (42%) who had CAs associated with known MM cytogenetic risk groups, of which 34% were standard-risk, 61% were intermediate-risk, and 5% were high-risk. The median BM% of clonal plasma cells was 50% (range 1-95%). When examining the relationship between any CA and BM%, del(13q14), dup(1p32), dup(1q21), t(4;14), trisomy(11q13), and monosomy(16q23) were associated with a significantly higher BM% than patients who were lacking those respective CAs. For example, the median BM% for patients with t(4;14) was 60% compared with 15% in patients lacking this translocation (p<0.0001). LCO isotype was associated with a lower BM% (p<0.04), however there was no significant correlation between IgG/IgA isotypes and BM%. There was a higher median BM% seen in the intermediate risk group (50%, p<0.0001) compared to standard risk group (20%, p<0.04). The high risk group was not significantly associated with BM%. When comparing isotypes to cytogenetic risk groups, IgA isotype was significantly associated with intermediate risk cytogenetics (p<0.03). Conversely, there was a significantly lower rate of standard risk CAs among IgA isotypes (p<0.01). There was no significant correlation between IgG/LCO and cytogenetic risk. IgA isotype correlated with specific CAs, including del(13q) (p<0.02) and del(16q23) (p<0.04). There was a higher rate of t(11:14) in the non-IgA isotype groups. Additionally, IgG isotype was associated with a trisomy(11q13) (p<0.03). LCO isotype also corresponded with a higher rate of del(17p) (p<0.03), t(11:14) (p<0.03), and a lower rate of t(4:14) (p<0.04) and trisomy (11q13) (p<0.01). Conclusions: In MM, CAs are valuable in risk stratifying patients and predicting treatment responses. In this study, data suggest that the IgA isotype is significantly associated with intermediate-risk cytogenetics, including del(13q) and hypodiploidy, and LCO disease correlates with high risk cytogenetics, including del(17p). When taken together this may explain the previously known association of these isotypes with poorer prognosis, and suggests divergent clonal evolution among MM isotypes. Associations between clinical parameters and disease responses remain ongoing. Disclosures No relevant conflicts of interest to declare.

scholarly journals A Comparison of 1 or 2 Courses of High Dose Cytarabine As Consolidation in Younger Patients with AML: First Results of the UK NCRI AML17 Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 221-221
Author(s):  
Nigel H. Russell ◽  
Robert K Hills ◽  
Sylvie Freeman ◽  
Steven Knapper ◽  
Lars Kjeldsen ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Risk Group ◽  
Wild Type ◽  
Younger Patients ◽  
Protocol Amendment ◽  
Poor Risk ◽  
The Uk ◽  
Standard Risk

Abstract On behalf of the UK NCRI AML Working Party Introduction Outcomes in younger patients with AML have steadily improved over the last 4 decades. However, the question of the optimal chemotherapy schedule remains open. As outcomes improve attention turns from survival to survivorship: can similar - or better - outcomes be obtained with less cost to the patient. We have previously shown in our MRC AML12,15 trials that a fifth course of chemotherapy did not improve outcomes in these younger patients. A retrospective analysis of patients who received 3 or 4 courses of treatment showed that, while patients with poor risk disease had better outcomes with four courses, any effect of a fourth course was much less clear for patients with good or standard risk disease. Methods The UK NCRI AML17 trial (ISRCTN: 55675535) was designed for patients with AML or high risk MDS up to the age of 60. Following their first course of treatment, patients were allocated a risk group based upon a validated score (comprising cytogenetics, WBC, age, secondary disease and blast response to course 1)[1]; additionally, patients who failed to achieve at least a 50% reduction in blasts were considered poor risk. A protocol amendment included patients who were otherwise standard risk, but were FLT-3 ITD mutant/NPM1c wild type in the poor risk group. Remaining adults who were either good or standard risk could be randomised after 2 courses of treatment (DA or ADE, with or without GO at 3/6 mg/m2) to receive 1 or 2 courses of consolidation (3 or 4 courses in total). Before mid-2010 patients were randomised between MACE/MidAC vs MACE; based on the results of AML15 [2], a protocol amendment changed consolidation to 1 or 2 courses of Ara-C 3g/m2/d for 5 days. Follow-up is complete to 1st March 2015, with median follow-up of 28.8 months (range 0.1-68.2). Results From July 2009 to June 2015, 1017 patients were randomised. Median age was 48 (range 16-72); 45% were male; 24% had core binding factor leukaemia; 76% intermediate risk disease; 1% had secondary disease, and 3% high risk MDS; WHO PS was 2+ in 4% of patients. Overall survival at 5 years was 57%. An additional course of consolidation reduced relapse (CIR 53% vs 57%; HR 0.81 (0.67-0.99) p=0.04), with no difference in death in remission (7% vs 6%; HR1.10 (0.61-2.00) p=0.8), leading to some evidence of improved relapse free survival (41% vs 37%, HR 0.84 (0.70-1.01) p=0.06). Survival however, did not differ significantly between the arms (58% vs 55%, HR 0.90 (0.71=1.14) p=0.4), reflecting the effect of salvage: 3 year survival from relapse was 32% vs 31% (HR 0.97 (0.75-1.26) p=0.8). In stratified analyses, there was no difference in the effect of the extra course by cytogenetics (p-values for interaction between cytogenetics and treatment p=1.0 for survival); while relapse was reduced more in CBF leukaemias (HR 0.63 (0.40-1.00), p=0.05) than in others (HR 0.91 (0.73-1.13) p=0.4), the test for interaction was not significant (p=0.16). Information on minimal residual disease (by immunophenotype to a sensitivity of up to 1 in 104) was available for 353 patients post course 1 and 265 patients post course 2. There was no evidence of a differential effect of an extra course of consolidation by MRD status after either course (p=1.0 for survival post course 1; p=0.3 for survival post course 2). In stratified analyses, there was no interaction between treatment and age, sex, performance status or diagnosis. However, there was a significant benefit for FLT3-ITD WT patients (OS: 63% vs 54%, HR 0.75 (0.57-0.99) p=0.04), which was not present for ITD mutant patients (41% vs 58%; HR 1.38 (0.84-2.26) p=0.2; p=0.04 for interaction), and evidence of greater benefit for 4 courses in patients with lower WBC at diagnosis (p=0.04 for trend). There was no heterogeneity by induction therapy (p=0.7), in particular the use of gemtuzumab ozogamicin or not (p=0.2). Conclusions These data in good and standard risk patients (as defined comprising 63% of patients diagnosed) suggests no overall survival benefit of a 4th course of chemotherapy in younger patients with AML, although relapse was significantly reduced. With respect to subgroups, there was a suggestion that 4 courses of treatment was beneficial for FLT3 wild type patients. Attention now turns to whether the use of more intensive induction regimens such as FLAG-Ida can improve outcomes while delivering fewer courses. [1] Burnett et al. Blood 2006:108 (11): Abstract 18 [2] Burnett et al. JCO 2013: 31(27);3360-8 Disclosures Russell: Therakos: Other: shares. Cavenagh:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau.

A Novel Risk Classification Model Predicts Overall Survival and Locoregional Surgery Benefit in Colorectal Patients with Distant Metastasis at the Initial Diagnosis

2020 ◽  
Author(s):  
Mo Chen ◽  
Tian-en Li ◽  
Pei-zhun Du ◽  
Junjie Pan ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Distant Metastasis ◽  
Cox Regression ◽  
Risk Group ◽  
Risk Groups ◽  
Risk Classification ◽  
Low Risk ◽  
Classification Model ◽  
Intermediate Risk

Abstract Background and aims: In this research, we aimed to construct a risk classification model to predict overall survival (OS) and locoregional surgery benefit in colorectal cancer (CRC) patients with distant metastasis.Methods: We selected a cohort consisting of 12741 CRC patients diagnosed with distant metastasis between 2010 and 2014, from the Surveillance, Epidemiology and End Results (SEER) database. Patients were randomly assigned into training group and validation group at the ratio of 2:1. Univariable and multivariable Cox regression models were applied to screen independent prognostic factors. A nomogram was constructed and assessed by the Harrell’s concordance index (C-index) and calibration plots. A novel risk classification model was further established based on the nomogram.Results: Ultimately 12 independent risk factors including race, age, marriage, tumor site, tumor size, grade, T stage, N stage, bone metastasis, brain metastasis, lung metastasis and liver metastasis were identified and adopted in the nomogram. The C-indexes of training and validation groups were 0.77 (95% confidence interval [CI] 0.73-0.81) and 0.75 (95% CI 0.72-0.78), respectively. The risk classification model stratified patients into three risk groups (low-, intermediate- and high-risk) with divergent median OS (low-risk: 36.0 months, 95% CI 34.1-37.9; intermediate-risk: 18.0 months, 95% CI 17.4-18.6; high-risk: 6.0 months, 95% CI 5.3-6.7). Locoregional therapies including surgery and radiotherapy could prognostically benefit patients in the low-risk group (surgery: hazard ratio [HR] 0.59, 95% CI 0.50-0.71; radiotherapy: HR 0.84, 95% CI 0.72-0.98) and intermediate risk group (surgery: HR 0.61, 95% CI 0.54-0.68; radiotherapy: HR 0.86, 95% CI 0.77-0.95), but not in the high-risk group (surgery: HR 1.03, 95% CI 0.82-1.29; radiotherapy: HR 1.03, 95% CI 0.81-1.31). And all risk groups could benefit from systemic therapy (low-risk: HR 0.68, 95% CI 0.58-0.80; intermediate-risk: HR 0.50, 95% CI 0.47-0.54; high-risk: HR 0.46, 95% CI 0.40-0.53).Conclusion: A novel risk classification model predicting prognosis and locoregional surgery benefit of CRC patients with distant metastasis was established and validated. This predictive model could be further utilized by physicians and be of great significance for medical practice.

scholarly journals Pre-Enucleation Chemotherapy in Advanced Intraocular Retinoblastoma. Central America Follow Up: AHOPCA II

2016 ◽  
Vol 2 (3_suppl) ◽  
pp. 75s-75s
Author(s):  
Sandra Luna-Fineman ◽  
Soad L. Alabi ◽  
Mauricio E. Castellanos ◽  
Yessika Gamboa ◽  
Ligia Fu ◽  
...  
Keyword(s):  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Central America ◽  
Conflicts Of Interest ◽  
Risk Group ◽  
High Risk Group ◽  
Globe Rupture ◽  
Neo Adjuvant Chemotherapy ◽  
Standard Risk

Abstract 57a Purpose: A significant percentage of patients in Central America present with buphthalmos, carrying a high risk of globe rupture and orbital contamination. In 2007, AHOPCA introduced chemotherapy before enucleation in children with buphthalmos. Methods: Patients with advanced intraocular disease were considered standard-risk and underwent enucleation. Those with diffuse invasion of choroid, postlaminar optic nerve, or anterior chamber invasion received 4-6 cycles of adjuvant chemotherapy (vincristine, carboplatin, etoposide). Patients with buphthalmos or perceived to be at risk for abandonment were considered high-risk, given 2-3 cycles of chemotherapy before enucleation to compete 6 cycles regardless of pathology. All cases were discussed via online meetings. Results: From 2007 to 2014, 396 patients were enrolled; 240 had IRSS stage I (174 unilateral). 143 had upfront enucleation, 95 had pre-enucleation chemotherapy, 1 is pending enucleation and 1 abandoned before enucleation. The standard-risk group 69 had risk pathology and 76 had no risk factors; 125 had no events, 5 abandoned 11 relapsed/progressed and 2 died of toxicity. Of 95 high-risk group, 8 abandoned, 20 relapse/progressive, 6 had toxic deaths and 61 are alive at last follow-up (median time of 4 years). Of high risk group, 55 were unilateral, 82% are alive. At 7 years OS (abandonment-censored) was 95±0.02 and 79±0.04 for standard-risk and high-risk (p=0.008). Conclusion: AHOPCA addressed advanced intraocular disease with an innovative approach. In eyes with buphthalmos and patients with risk of abandonment, neo-adjuvant chemotherapy is effective, when followed by post-enucleation chemotherapy. This approach avoids ocular rupture and intensified therapy, and reduces refusal/abandonment rate. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: No COIs from the authors.

Frequency of Clonal Evolution by FISH in Untreated, Early Stage Patients with CLL: A Prospective, Longitudinal Study with Long Clinical Follow-Up.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2098-2098 ◽  
Author(s):  
Tait D. Shanafelt ◽  
Stephanie Fink ◽  
Tom E. Witzig ◽  
Sarah F. Paternoster ◽  
Stephanie Smoley ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Time ◽  
Early Stage ◽  
Clonal Evolution ◽  
Normal Karyotype ◽  
Risk Category ◽  
Fish Analysis ◽  
Cytogenetic Abnormalities ◽  
Study Participants

Abstract Background: Using fluorescent in-situ hybridization (FISH), a number of investigators have identified specific cytogenetic abnormalities that identify CLL patients with a more aggressive (17p-, 11q-) or indolent (13q-) disease course. Some have suggested patients who initially have a normal karyotype may acquire new chromosome abnormalities during the course of their disease. Since patients with specific cytogenetic abnormalities (17p-, 11q-) are less likely to respond to purine nucleoside analogues, such clonal evolution has potential implications for treatment as well as prognosis. No study has prospectively investigated the frequency of clonal evolution in a cohort of patients with newly diagnosed untreated CLL. Methods: Between 1994 and 2000, we enrolled 167 patients with previously untreated CLL seen at Mayo Clinic in a prospective trial evaluating the prognostic importance of cytogenetic abnormalities and clonal evolution detected by FISH. All patients provided a baseline blood specimen for FISH testing and follow-up specimens over the following 24 months. Other research samples from later timepoints were tested where available. Study participants were contacted by mail in 2004 to update vital and treatment status. Of 83 living responders, 70 (84%) indicated they would be willing to provide an additional follow-up sample for cytogenetic analysis of whom 48 have returned a sample to date. Results of clinical FISH testing during the follow-up interval were also abstracted. FISH was performed on interphase nuclei from blood as we have previously described (BJH 121:287). Results: Median age at diagnosis was 64. Median time from diagnosis to study enrollment was 3.3 months. 94% of patients had early stage disease at enrollment (88 Rai 0; 48 Rai I, 18 Rai II, 2 Rai III; 8 Rai IV). Median follow-up time from diagnosis for all 164 eligible study participants was 8.5 years (range: 0.33–22.9 yrs). As of last follow-up, 48% of patients have received treatment and 57 (35%) have died. 75% of patients had chromosome abnormalities on FISH testing at baseline. The frequency of individual cytogenetic abnormalities on baseline FISH analysis along with overall survival by hierarchical FISH risk category are shown in Table I. 106 patients had sequential samples for FISH analysis at least 2 years apart, 61 had samples at least 5 years apart, and 22 had samples at least 10 years apart. 15 patients had evidence of clonal evolution during follow up as evidenced by a new FISH anomaly not present on the baseline specimen. No clonal evolution was observed in the first 2 years of follow-up (n=106), however of 61 patients with samples at least 5 years apart, 14 (23%) had evidence of clonal evolution. Median time for development of a new cytogenetic abnormality among these patients was 9.3 years. Conclusions: Clonal evolution occurs during the course of disease for approximately 25% of patients with early stage CLL. Clonal evolution appears to occur at low frequency during the first 2 years of follow-up but increases in frequency after 5 years. This finding has potentially significant implications for prognosis and treatment of patients with CLL. FISH Risk Category* N (Baseline) Median Overall Survival (Years) * Difference between groups significant p=0.0038 13q- x 1 37 14.4 13q- x2 35 17 Normal Karyotype 40 13.2 12+ 24 11.1 11q- 12 8.6 17p- 10 10.5 6q- 2 4.1 Other 2 Not reached

Chronic Lymphocytic Leukemia: Evaluation of Cytogenetic Markers as Prognostic Factors

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4860-4860
Author(s):  
Jose Carda ◽  
Patricia Sousa ◽  
Patricia Olim ◽  
Emília Magalhães ◽  
Luis Rito ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Retrospective Study ◽  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Progressive Disease ◽  
Risk Group ◽  
Staging System ◽  
Lymphocytic Leukemia ◽  
Intermediate Risk

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.

Patients with FLT3 Negative Acute Myeloid Leukemia and Normal Cytogenetic who Have the Combination Mutations (NPM1-/CEBPA-) Have Better Survival Than Patients Who Have the Combination Mutations (NPM1+/CEBPA+)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4874-4874
Author(s):  
Shamail Butt ◽  
Pascal Akl ◽  
Himanshu Bhardwaj ◽  
Samer A Srour ◽  
Terry Dunn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Mutation Analysis ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Intermediate Risk ◽  
Cebpa Mutations ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract Abstract 4874 Introduction: Acute Myeloid Leukemia (AML) is the most common type of acute leukemia in adults. About 50% of patients with AML have normal karyotype, and are categorized as intermediate risk group. However, the clinical behavior and response to treatment in this group is heterogeneous. As a result, there is strong interest in characterizing molecular genetic features in the intermediate-risk AML patients that might rectify their stratification risk. In this group, FLT3-ITD (Internal Tandem Duplication) and FLT3-TKD (Tyrosine Kinase Domain) mutations are known to confer unfavorable risk whereas NPM1 and CEBPA mutations are known to be favorable risk markers. The purpose of this study is to analyze the combination of NPM1 and CEBPA mutations in presence or absence of FLT3 mutations on prognosis of AML patients referred to the State's largest tertiary care center over a period of 10 years for the treatment of leukemia. Patients and Method: We performed a retrospective chart review of all patients with AML evaluated at University of Oklahoma Health Sciences Center between January 2000 and December 2010. Patient's age, gender, race, laboratory and clinical data as well as bone marrow biopsy and aspirate findings were reported. PCR and Fragment Analysis were conducted on all available DNA preserved bone marrow materials to test the FLT3, NPM1 and CEBPA mutations. For statistical analysis, Kaplan-Meyer curve was used. Results: A total of 239 patients were evaluated. Male to female ratio was 2/1. Median age at diagnosis was 46y. 21 out of the 239 patients were less than 18 year old. DNA samples were present on 132 patients and mutation analysis for FLT3, CEBPA and NPM1 was performed. Correlation between mutations and AML prognosis was determined. 67/132 (50.8 %) patients were categorized into intermediate risk group (majority of patients had normal cytogenetics). 14/67 (20.9%) pts were FLT3+ (FLT3-ITD or FLT3-TKD mutation). 17/67 (23.9%) were NPM1+. 7/67 (10.4%) were CEBPA +. Kaplan-Meier curve was used to identify cumulative proportion surviving over time. FLT3 presence or absence itself was not identified to be statistically significant (p 0.416) in terms of overall survival. Interestingly, presence or absence of combined NPM1/CEBPA mutation in FLT3 negative patients, among intermediate risk group, was found to be statistically significant (p<0.05) in determining overall survival. In this subgroup, presence of NPM1/CEBPA combination (NPM1+/CEBPA+) was associated with poor prognosis (figure 2, lower curve), while absence of NPM1/CEBPA combination (NPM1-/CEBPA-) carries a better prognosis (figure 2, upper curve). Conclusion: Results of our study highlight the importance of performing combinations of mutation analysis in evaluation of overall prognosis in AML patients. FLT3-/NPM1+ profile in patients with normal cytogenetics is thought to confer a favorable prognosis. We demonstrated in this study that using combination mutation analysis in patients with FLT3- can change the risk stratification in patients with intermediate risk group and might affect therapeutic interventions in this patient population. Larger prospective studies are needed in the future for further validation of our findings. Disclosures: No relevant conflicts of interest to declare.

Clinical Features of Chinese Refractory Cytopenia of Childhood: Lower Overall Survival and Higher Possibillity of Clonal Evolution Than Nsaa Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4947-4947
Author(s):  
Wenbin An ◽  
Zhanqi Li ◽  
Shuchun Wang ◽  
Xiaojuan Chen ◽  
Wenyu Yang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Survival Time ◽  
Clinical Features ◽  
Bone Marrow Biopsy ◽  
Lymphocyte Count ◽  
Clonal Evolution ◽  
Scoring Model ◽  
Erythroblastic Island

Abstract Abstract 4947 Objective: To analyze the clinical features and survival time in patients with refractory cytopenia of childhood (RCC), and to develop a new diagnostic scoring system for RCC. Methods: The clinical information, laboratory findings at primary diagnosis and survival time in 97 non-severe aplastic anemia (NSAA) children diagnosed in August, 2000 to June, 2006 were analyzed retrospectively. According to the criteria for RCC proposed in the 2008 edition of the World Health Organization classification of hematopoietic and lymphoid tissues, diagnosis of these NSAA patients was reassessed. Results: 37/97 cases (38. 1%) were reassessed as RCC, 60/97 cases (61. 9%) were still diagnosed as NSAA. There was no significant differences in distribution of age, gender and chromosomal abnormalities, absolute neutrophil count, PLT, MCV, absolute reticulocyte count, the number of cytopenias and duration from onset to starting treatmeat between RCC and NSAA. All patients received the treatment of CsA and androgen. There was no significant differences in distribution of treatment response. The overall survival (OS) of RCC patients was significantly lower than NSAA patients (P=0. 041) in long-term follow-up. The former had 91. 5% of 6-year prospective survival (PS) and the latter had 96. 5% of 6-year PS. At a median follow-up of 93 months (range 6–138), 2 patients reassessed as RCC progressed into AML-M5 and PNH respectively, while no NSAA patient progressed into clonal diseases. There was significant differences in the distribution of HGB<11g/dl at onset and lymphocyte count<3×109/L, dysplastic megakarycytes≥10% (CD41 monoclonal antibogy immunohistochemical staining) and periodic acid schiff (PAS) staining (+) in bone marrow aspirate between RCC and NSAA (P=0. 034, 0. 025, 0. 032, 0. 029). Compared with NSAA, there was significant differences in the distribution of bone marrow cellularity down to 10% of the normal age matched value, dysplastic erythroblastic island, number of erythroblastic mitoses and micromegakaryocytes in bone marrow biopsy of RCC(P< 0. 0001, 0. 0001, 0. 0001, 0. 0001). Using Logistic regression, a new diagnostic scoring model including increased dysplastic erythroblastic island, having micromegakaryocytes in bone marrow biopsy, and lymphocyte count<3×109/L in peripheral blood was developed. By ROC curve analysis, score≥2 points was identified as a cut-off value with sensitivity of 70. 3% and specificity of 95%. Conclusion: RCC patients had similar clinical features with NSAA patients but had lower OS and higher possibillity of clonal evolution. This new diagnostic scoring model had significance to differentiate diagnose RCC and NSAA. Disclosures: No relevant conflicts of interest to declare.

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