scholarly journals The Impact of Molecular and Cytogenetic Clonal Evolution on Survival in Relapsed/Refractory AML

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4452-4452
Author(s):  
Ian M. Bouligny ◽  
Keri R. Maher
Keyword(s):  
Overall Survival ◽  
Conflicts Of Interest ◽  
Clonal Evolution ◽  
Clonal Diversity ◽  
Risk Category ◽  
Refractory Disease ◽  
Real World Data ◽  
Primary Induction ◽  
Induction Failure ◽  
The Impact

Abstract Background: Clonal diversity and evolution in acute myeloid leukemia (AML) are consequences of disease progression and play a pivotal role in the development of drug resistance and refractoriness to therapy. Much work has been done with characterizing clonal architecture in bulk tumors samples or single-cell DNA sequencing, but real-world data observing the impact of clonal evolution and responses to therapy remains scarce in the relapsed and refractory settings. Therefore, the purpose of this study was to analyze the impact of observed clonal evolution on survival. Patients & Methods: We retrospectively analyzed 81 patients with AML with relapsed or refractory disease from June 2018 to December 2020. Cytogenetic and molecular data were obtained at the time of diagnosis and the time of primary induction failure or relapse, when available. We identified a total of 24 patients that demonstrated evidence of clonal evolution following induction or salvage therapy. Baseline patient demographics were obtained, including cytogenetic risk and next-generation sequencing molecular profiling at diagnosis and throughout treatment alongside dates and types of induction regimens. We compared the survival of those with evidence of clonal evolution to matched groups without. The groups with and without clonal evolution were compared for baseline statistical differences using an unpaired t-test with Welch's correction and Kaplan-Meier survival analyses were computed and compared with log-rank tests using GraphPad Prism. The event for calculating the overall survival was the date of death with patients otherwise censored at the date of last contact. Results: Of the 24 patients with evidence of clonal evolution, we detected that evolution occurred in four (16.7%) patients at the time of primary induction failure (refractory to first induction), 19 (70.8%) at the time of first relapse, and 3 (12.5%) at the time of second relapse. The median age of patients with clonal evolution was 63 years (range: 23 - 74) with 17 (70.8%) males and 7 (29.2%) females. The most commonly occurring mutations were NPM1 (25.0%), FLT3-ITD (20.8%), and TP53 (20.8%). At the time of initial diagnosis, cytogenetic risk was favorable in one (4.2%), intermediate in 7 (29.2%), and adverse in 16 (66.7%). The majority (79.2%) of patients underwent first induction with 7+3 and 8 (33.3%) patients underwent allogenic SCT. At the time of clonal evolution and ignoring the adverse prognosis associated with relapse, one patient with favorable cytogenetics remained favorable, only one (14.3%) patient with intermediate cytogenetics shifted to adverse, and one (6.3%) patient in the adverse category shifted to intermediate by ELN criteria. Three (12.5%) patients out of 24 acquired FLT3-ITD and three (12.5%) acquired an additional cooperating mutation (NRAS, KRAS, or KIT) for a total of 25.0% acquiring a signaling pathway mutation. Out of 10 patients with either mutated TP53 or MLL, three (27.3%) acquired a cooperating mutation in FLT3 or RAS. We then compared the clonal evolution cohort with the 57 remaining relapsed/refractory patients without evidence of clonal evolution. There was no difference between the groups with respect to baseline characteristics, including age (p = 0.989), ECOG status at diagnosis (p = 0.4689), Charlson Comorbidity Index (CCI) score (p = 0.6454), or prior SCT (p = >0.999). The median overall survival (OS) of the clonal evolution group was 227 days and compared to 382 days in the non-evolution cohort (p = 0.843). Conclusion: We did not detect a significant OS difference between those with clonal evolution and those without. Independent of the adverse prognosis associated with relapsed or refractory disease, cytogenetic risk category appeared to remain the same with clonal evolution. Common trends during clonal evolution included acquisition of one or several cooperating mutations in FLT3 or RAS, both with and without the presence of mutated TP53 and MLL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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

Prognostic Indices in Older DLBCL Patients Receiving R-CHOP: An Analysis of the U.S. Intergroup Study (E4494, CALGB 9793).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 813-813
Author(s):  
R.H. Advani ◽  
H. Chen ◽  
T.M. Habermann ◽  
V.A. Morrison ◽  
E. Weller ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Univariate Analysis ◽  
Risk Groups ◽  
Low Risk ◽  
Risk Category ◽  
Free Survival ◽  
Prognostic Tool ◽  
The Impact ◽  
The U.S

Abstract Background: We reported that addition of rituximab (R) to chemotherapy significantly improves outcome in DLBCL patients (pt) >60 years (JCO24:3121–27, 2006). Although the IPI is a robust clinical prognostic tool in DLBCL, Sehn et al (ASH 2005: abstract 492) reported that a revised (R) IPI more accurately predicted outcome in pt treated with rituximab-chemotherapy. Methods: We evaluated outcomes of the Intergroup study with respect to the standard IPI, R-IPI, age-adjusted (aa) IPI for evaluable pt treated with R-CHOP alone or with maintenance rituximab. We further assessed a modified IPI (mIPI) using age ≥ 70 y as a cutoff rather than age 60 y. Results: The 267 pt in this analysis were followed for a median of 4 y. Pt characteristics were: age > 70 (48%) (median=69), male 52%, stage III/IV 75%, >1 EN site 30%, LDH elevated 60%, PS ≥2 15%. On univariate analysis all of these characteristics were significant for 3 y failure-free survival (FFS) and overall survival (OS). The IPI provided additional discrimination of risk compared to the R-IPI with significant differences in FFS and OS for 3 vs 4–5 factors. The aa-IPI defined relatively few pt as low or high risk. The impact of age was studied using a cut-off of 70 years in a modified IPI, yielding 4 risk groups as shown below. Conclusions: For pt ≥ 60 treated with rituximab-chemotherapy the distinction between 3 vs 4,5 factors in the IPI was significant.The IPI also provided additional discrimination of risk compared to the R-IPI. In this older group of pt, use of an age cutoff ≥70 y placed more patients in the low risk category. It is of interest to apply the mIPI in other datasets with DLBCL pt >60 y. Group # Factors # Pt % 3y FFS* % 3y OS* *All risk groups significantly different; logrank p < 0.001 **95 % CI: FFS (0.46,0.66), OS (0.58,0.78) ***95 % CI: FFS (0.21,0.45), OS (0.31,0.55) L: Low, LI: Low Intermediate, HI: High Intermediate, H; High IPI L 0–1 12 78 83 LI 2 28 70 80 HI 3 33 56** 68** H 4–5 37 33*** 43*** R-IPI Very Good 0 0 - - Good 1–2 40 72 81 Poor 3–5 60 46 57 aa-IPI L 0 12 78 83 LI 1 35 68 78 HI 2 44 47 59 H 3 9 31 35 mIPI (age ≥ 70) L 0–1 27 77 86 LI 2 28 62 74 HI 3 29 47 58 H 4–5 16 28 36

Increased Expression of Macrophage Migration Inhibitory Factor (MIF) Receptor CD74 Is Associated with Inferior Outcome in Younger Patients (Pts) with Cytogenetically Normal Acute Myeloid Leukemia (CN-AML): a Cancer and Leukemia Group B (CALGB) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1616-1616 ◽  
Author(s):  
Eyal C. Attar ◽  
Kati Maharry ◽  
Krzysztof Mrózek ◽  
Michael D. Radmacher ◽  
Susan P. Whitman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Advanced Pancreatic Cancer ◽  
Disease Free Survival ◽  
Prognostic Impact ◽  
Free Survival ◽  
Expression Levels ◽  
The Impact ◽  
Disease Free

Abstract Abstract 1616 Poster Board I-642 CD74 is a type II integral membrane protein receptor that binds its ligand MIF to induce phosphorylation of the extracellular signal-regulated kinase-1/2 (ERK-1/2) and drive cellular proliferation via nuclear factor-kappa B (NF-kB) activation. CD74 expression has been identified in human solid tumors, and its expression is associated with adverse prognosis in advanced pancreatic cancer. As CD74 is expressed and NF-kB constitutively activated in myeloblasts, we hypothesized that CD74 expression might also be associated with adverse outcome in AML. To investigate the prognostic impact of CD74 expression in the context of other predictive molecular markers in CN-AML, we assessed CD74 expression levels by Affymetrix HG-U133 Plus 2.0 microarray in 102 younger [<60 years (y)] adults with primary CN-AML, treated on the front-line CALGB 19808 trial with an induction regimen containing daunorubicin, cytarabine, etoposide and, in some cases, the inhibitor of multidrug resistance valspodar, and consolidation with autologous stem cell transplantation. Microarray data were analyzed using the Robust Multichip Average method, making use of a GeneAnnot chip definition file, which resulted in a single probe-set measurement for CD74. At diagnosis, CD74 expression, when assessed as a continuous variable, was significantly associated only with extramedullary disease involvement (P=.006) among clinical features, and with none of the molecular prognostic variables tested, including NPM1, WT1, CEBPA, FLT3 (FLT3-ITD and FLT3-TKD) mutations, MLL partial tandem duplication, or differential BAALC and ERG expression levels. Although CD74 expression levels were not associated with achievement of complete remission (CR; 83% vs 81%), higher levels of CD74 were associated with shorter disease-free survival [DFS; P=.046, hazard ratio (HR) 1.85, 95% confidence interval (CI) 1.12-3.08] and with shorter overall survival (OS; P=.02, HR 1.32, CI 1.04-1.67). In multivariable analyses, higher CD74 expression was independently associated with shorter DFS (P=.045, HR 1.98, CI 1.16-3.40), after adjusting for WT1 mutations (P<.001) and FLT3-TKD (P=.04), and shorter OS (P=.01, HR 1.58, CI 1.11-2.25) after adjusting for FLT3-TKD (P=.02), WT1 mutations (P=.007), BAALC expression levels (P=.02), white blood counts (P=.007), and extramedullary involvement (P=.04). As quartiles 2-4 had similar expression levels distinct from the lowest quartile, to display the impact of CD74 expression levels on clinical outcome only, pts were dichotomized into low (the lowest quartile) and high (the top three quartiles) CD74 expressers. The Kaplan-Meier curves for DFS and OS (Figures 1 and 2) are shown below. In conclusion, our study identifies elevated CD74 expression as associated with adverse prognosis in younger CN-AML pts. Since we previously reported that higher CD74 expression was favorably associated with achievement of CR in AML patients receiving chemotherapy plus bortezomib, an inhibitor of the proteasome and NF-kB (Attar et al., Clin Cancer Res, 2008;14:1446-54), it is possible that in future studies elevated CD74 levels can be used not only for prognostication, but also to stratify CN-AML pts to study of bortezomib-containing chemotherapy regimens. Figure 1 Disease free survival Figure 1. Disease free survival Figure 2 Overall survival Figure 2. Overall survival Disclosures No relevant conflicts of interest to declare.

TIMP-1 and TIMP-2 Levels Are Directly Correlated with Neoangiogenesis and Are Prognostic Factors in Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4866-4866
Author(s):  
Luciana Correa Oliveira de Oliveira ◽  
Juliana Alves Uzuelli ◽  
Ana Paula Alencar de Lima Lange ◽  
Barbara Amelia Aparecida Santana-Lemos ◽  
Marcia Sueli Baggio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Bone Disease ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4866 Background Multiple myeloma (MM) is an incurable malignant disease, characterized by increased angiogenesis in the bone marrow (BM) microenvironment and aberrant BM metabolism. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases implicated in tumour progression, invasion, metastasis and angiogenesis, via proteolytic degradation of extracellular matrix. MMPs are inhibited by tissue inhibitors of metalloproteinase (TIMP). Although recent studies have implicated MMP 9 in MM bone disease, little is known about the role of the TIMPs. Objectives a) to compare levels of sRANKL, OPG, MMP-2, MMP-9, TIMP-1, TIMP-2, VEGF, bFGF, microvessel density (MVD) between newly diagnosed MM patients and healthy controls; b) to determine the association of these molecules with disease progression, bone disease and neoangiogenesis and c) to evaluate the impact of these variables on survival. Patients and Methods As of July 2009 38 newly diagnosed and untreated multiple myeloma patients were enrolled in the study. The median age was 61years-old (range 39-91) with 24 (63%) males. Patients were diagnosed and categorized according The International Myeloma Working Group criteria and ISS, respectively. Bone involvement was graded according to standard X-ray: patients with no lesions, or with one/ two bones involved or diffuse osteoporosis were classified as low score, whereas patients with lesions in more than two bones or presence of bone fracture were classified as high score. MMP-2 and MMP-9 were determined by PAGE gelatin zymography from plasma as previously described. MMP-9, TIMP-1 and TIMP-2, OPG and sRANKL concentrations were measured by ELISA. The levels of VEGF, bFGF were obtained using cytometric bead array. Ten healthy volunteers were used as controls. Bone marrow MVD measured in hotspots was evaluated in 26 out of 38 patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Comparisons among groups were analyzed by ANOVA and the correlation by the Spearman's correlation coefficient. Cox regression were performed for overall survival (OS) analysis. Results Patients with MM had elevated TIMP-1, TIMP-2 and OPG values compared with controls. No significant difference was found between plasma sRANKL, pro-MMP2, pro-MMP9 and MMP-9 levels. We found that plasma TIMP-1 levels correlated positively with bFGF, VEGF, MVD, beta-2 microglobulin (B2M) and OPG (r: 0.514, p=0,001, r: 0.350, p=0,031; r: 0.610, p<0.0001; r: 0.760, p<0.0001 and r: 0.701, p<0.0001, respectively) and TIMP-2 levels with bFGF, DMV, B2M and OPG (r: 0.512, p=0.002; r: 0.595, p<0.0001; r: 0.587, p<0.0001 and r: 0.552, p<0.0001, respectively). TIMP-1 and TIMP-2 levels correlated with the ISS stage (p<0.0001, p=0.006, respectively). The only variables that correlated with clinical bone disease staging were hemoglobin, B2M and albumin levels, whereas TIMP-1, TIMP-2, bFGF, VEGF and OPG correlated with DMV. On the univariate analyses, age, gender, proMMP2, TIMP-1, TIMP-2, creatinine, B2M and MVD were significantly associated with overall survival. In Cox regression model, TIMP-1, TIMP-2 and B2M levels remained to be significantly associated with OS. In conclusion, our results suggest that TIMP-1 and TIMP-2 levels are strongly associated with neoangiogenesis and are independent prognostic factors in MM. Disclosures No relevant conflicts of interest to declare.

6 Year Experience of Treatment by Imatinib in CML CP Patientsin 6 Million Population Region of Russia(Saint-Petersburg and Leningrad region)with Impact On Time and Kind of Pretreatment.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4278-4278
Author(s):  
Kudrat Abdulkadirov ◽  
Elza Lomaia ◽  
Vasiliy Shuvaev ◽  
Alla Abdulkadirova ◽  
Vera Udalieva ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Median Time ◽  
Conflicts Of Interest ◽  
Clonal Evolution ◽  
Leningrad Region ◽  
Imatinib Treatment ◽  
Saint Petersburg ◽  
Late Group ◽  
Early Late

Abstract Abstract 4278 Imatinib(IM) has become the “gold standard” for the treatment of CML CP. In clinical trials the majority of pts obtain complete hematologic (CHR) and complete cytogenetic (CCyR) responses. The aim of the study was to evaluate the results of treatment by IM in CML CP pts in general practice (outside clinical trials). Patients and methods There are 335 pts with CML in databases in Saint-Petersburg and Leningrad region. Most of them (283/335-84,5%) are ever treated with IM. Disease phases at the time of the start of IM therapy by ELN (from 268/283 evaluable pts) and MDACC (from 256/283 evaluable pts) criteria were: CP – 232 and 215, AP – 28 and 33, BP - 8 and 8 respectively. All 232 pts in CML CP (by ELN criteria) treated since 2001 by IM were included in the study. Before IM 91/232(39%), 114/232(49%) and 17/232 (7,3%) pts were pretreated by hydroxyurea, interferon-alfa with or without hydroxyurea and busulfan. 12/335(4%) pts were undergone alloSCT(6 alive, 6 dead due to progression or TRM) There were 134/232(58%) pts in early (duration before Im ≤ 12 mos) and 98/232(42%) pts in late CP (> 12 mos). In early and late CP, there were 49/123 and 50/89, 40/123 and 23/89, 34/123 and 16/89 evaluable pts with low, intermediate and high Socal score respectively. The predominance of low Sokal score in late CP pts could to be related to survival benefit before imatinib.. The median time before Im for the whole group, for early and late CP pts were 7,4 mos(from 7 days to 132 mons), 1,8 mons (form 7 days to 12 mons) and 39 mons (from 12,1 mos to 132 mos) respectively. Median time of Im therapy was 33 mos (1 - 75 mos) in whole group, 24mons (1 - 73mos) in early and 34mos(2 - 75mos) in late CP pts respectivel Results Estimated overall survival by 6 years was 94,2% in whole group, 97% and 87% in early and late CP pts resp. Only 14/228(6,1%) of evaluable patients died due to CML: 4/130(3%) in early and 10/98(10,2%) in late CP group. 4 pts, resistant to IM, were transplanted: 1 in early CP and 3 in BP. Deathes were due to TRM or disease progression. CHR was achieved by 3 mons in most cases: 82/110(74,5%) and 36/64(56%) pt, in early and late CP, resp. Patients (39 in hole group, 12 in early and 27 in late CP) with CHR before IM were excluded from these analyses. The probability of CCyR by 6 years was 98% in early CP and 82% in late CP (p=0.002). The rate of CCyR was 75% 80/107) vs 31% (14/75) in patients with or without CHR by 3 mons (p=0.00). The same differences were found in early and late CP. CCyR in patients with CHR before IM was the same as in patients with newly obtained CHR by 3 mons on IM. Thereafter we have divided group of pts with late CP according to its duration before IM (very early -<6mons, early late - 6-60 mons and very late ≥60 mons) and compared CCyR in early CP with different subgroups of late CP. Achievement of CCyR was higher in pts in very early(69.1%) and early –late(68.2%) than in very late group(34.6%)(p=0.09) Further subdivisions of the period of 6-60 mos did not reveal any differences. Moreover, when we deleted the patients pretreated with busulfan, the differences were found only between early and early-late phases. We have separately analyzed very late group, it appeared that pretreatment with busulfan severely decreases CCyR (22% vs 81% in with (12 pts) or without (7 pts) busulfan pretreatment, p=0,002. Probably, patients in very late CP is a specific group of patients with preformed very good prognosis. Clonal evolution before treatment (8 pts in early CP and 7 in late CP) did not influence CCyR achievement. The probability of progression to AP/BP was slightly higher in late (6%) than in early CP (3%) (p=0.05). The appearance of clonal evolution was higher in late than in early CP (p=0,0002). Progression to AP/BP was 1% vs 11% in pts with or without CHR by 3 mos resp. (p=0.003). Conclusions Imatinib is efficacious drug in general hematological practice with very high probability of overall survival, CCyR and low risk of progression to AP/BP. CHR is an early and very important predictor for further successful treatment. Achievement of CCyR strongly depends on CHR by 3 mons. Patients with CHR before imatinib have similar CCyR in patients with CHR by 3 mons on imatinib. Pretreatment period predispose patients to clonal evolution on imatinib treatment. Busulfan pretreatment severely decreases probability of CCyR. Disclosures: No relevant conflicts of interest to declare.

Evolution of Human BCR-ABL1 lymphoblastic Leukaemia-Initiating Cells.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1023-1023
Author(s):  
Faiyaz Notta ◽  
Charles Mullighan ◽  
Jean Wang ◽  
Armando G Poeppl ◽  
Sergei Doulatov ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Genetic Diversity ◽  
Lymphoblastic Leukaemia ◽  
Copy Number ◽  
Copy Number Alteration ◽  
Conflicts Of Interest ◽  
Clonal Diversity ◽  
Poor Patient ◽  
Growth Properties ◽  
The Impact

Abstract Abstract 1023 Many tumour types are composed of genetically diverse cells, however little is known of how diversity evolves or the impact that diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR-ABL1 acute lymphoblastic leukaemia, we demonstrate that genetic diversity occurs in functionally defined leukaemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct subclones. Reconstruction of the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multiclonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, while in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A/CDKN2B, and poor patient outcome. Our findings link clonal diversity with function and underscore the importance of developing therapies that eradicate all subclones. Disclosures: No relevant conflicts of interest to declare.

Statins Use Improves the Clinical Outcomes of Salvage Therapy in Relapsed/Refractory CLL

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3931-3931
Author(s):  
Long Xuan Trinh ◽  
Young Kwang Chae ◽  
Preetesh Jain ◽  
Ohad Benjamini ◽  
Xuemei Wang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Elderly Patients ◽  
Clinical Outcomes ◽  
Salvage Therapy ◽  
Older Patients ◽  
Conflicts Of Interest ◽  
Young Patients ◽  
The Other ◽  
Concurrent Use ◽  
The Impact

Abstract Abstract 3931 Introduction - Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase. In addition, statins possess anti-inflammatory, immunomodulatory, antioxidant, and cell growth inhibitory properties. In B- CLL cells, statins induce in-vitro apoptosis (Daphne Chapman-Shimshon et-al), suggesting that statins might possess properties. We noticed a high prevalence of dyslipidemia in patients with chronic lymphocytic leukemia (CLL). However the impact of dyslipidemia and its modulation by statins on clinical outcomes of patients with CLL remains unclear. Therefore, we conducted a retrospective analysis to assess the effect of statins in patients with CLL who received salvage (fludarabine, cyclophosphamide and rituximab) FCR chemotherapy. Methods - We analyzed the clinical outcome of relapsed/refractory patients with CLL (n=284) who underwent FCR salvage therapy at our institution between 1999 and 2012. Patients who were uninterruptedly treated with statins at least one month prior to and during salvage therapy (n=35) were assigned to the statins arm, whereas the other arm consisted of 249 patients who were not treated with statins. The Cox proportional hazards regression model was used to assess the association between patient characteristics and progression-free survival (PFS) and overall survival (OS). Actual survival and PFS were estimated using the method of Kaplan-Meier, and OS and PFS were compared among two groups of patients using log-rank test. Results - All pretreatment characteristics of the patients with concurrent use of statins were similar to those who were not treated with statins except for their age. Patients in the statins arm were older: 21 patients (60%) were older than 65 compared to 74 patients of 249 (30%) in the other group (p<0.05). The median OS and PFS of all 284 patients were 3.9 years (95% CI: 3.4–4.5) and 1.74 years (95% CI: 1.6–2.3), respectively. PFS was significantly longer in patients treated with statins. Fifteen of the 35 statin-treated patients (43%) as opposed to only 36 of 249 (14%) in the non-statins group experience no disease progression. Concurrent use of statins significantly prolonged PFS. The median PFS for statin-treated v/s. untreated was 4.6 and 1.7 years, respectively (p<0.05). This significantly improved PFS was consistent in young and elderly patients. In young patients (age < 65) with statins, the median PFS was not reached whereas in patients who were not treated with statins it was 2 years (p<0.05). In older patients (age ≥ 65), PFS was significant longer with concurrent use of statins than without statins; estimated PFS were 2 and 1.6 years, respectively (p<0.05). With the median follow-up of 5 years, the median overall survival was significantly longer in patients treated with statins, with 17 of 35 (49%) patients of the statins group and 59 (24%) of 249 in patients who were not treated with statins alive at the end of study. Concurrent use of statins significantly prolonged OS with an estimated median OS for the two groups of 6.9 years and 3.9 years, respectively (p<0.05). This significantly improved OS was consistent in young and elderly patients. Young patients (age <65) with statins had a significant prolonged survival with an estimated OS of 8.6 years whereas estimated OS in young patients without statins (p<0.05) was only 4 years. In older patients (age ≥65) the median OS was significantly longer with the concurrent use of statins than without statins; estimated OS in the two subgroups were 6.9 and 2.6 years respectively, (p<0.05). Conclusions - In conclusion, concurrent use of statins significantly improved OS, PFS in relapsed/refractory CLL patients treated with salvage FCR therapy. Further studies to determine the role of statins and mechanism of action in patients with CLL are warranted. Disclosures: No relevant conflicts of interest to declare.

ASXL1 Mutations in AML: Molecular Biomarker for Secondary AML?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2343-2343
Author(s):  
Jingmei Hsu ◽  
Anita J. Kumar ◽  
Martin P. Carroll ◽  
Noelle V. Frey ◽  
Nirav N. Shah ◽  
...  
Keyword(s):  
Overall Survival ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Myeloproliferative Neoplasm ◽  
Molecular Characteristics ◽  
Intermediate Risk ◽  
Kaplan Meier ◽  
The Impact

Abstract Background: Additional sex combs like transcription factor 1 (ASXL1) is a member of the polycomb group protein. ASXL1 mutation has been implicated in myeloid malignancy transformation. It is hypothesized that mutated ASXL1 leads to the loss of polycomb repressive complex 2 (PRC2) mediated gene repression and subsequent transforming events. Recent studies identify ASXL1 mutation as a poor prognostic marker in patients (pts) with de novo acute myeloid leukemia (AML) who present with intermediate–risk cytogenetic lesions (Patel, NEJM 2012; Schnittger, Leukemia2013). To study the impact of ASXL1 mutations in an unselected AML population, we analyzed clinical and molecular characteristics of patients with untreated AML who express ASXL1 mutation at presentation. Methods: Using next generation sequencing, 254 adult patients with AML seen at the Hospital of the University of Pennsylvania were analyzed for mutations, including ASXL1, using a 33-gene hematologic malignancy panel. Clinical characteristics were obtained from retrospective chart review. Kaplan-Meier estimates were used to calculate overall survival (OS) from time of diagnosis. Living patients were censored at date last seen. Results: ASXL1 mutations were detected in 36/254 (14%) AML pts. There were 29 known pathologic mutations, 1 benign, 1 probable pathologic, and 9 variants of unknown clinical significance (VUS). In 6/36 (16.7%) pts, ASXL1 was the sole mutation identified. Of the 30 pts with additional mutations (Figure 1), 6/30 (20%) pts harbored 2 independent ASXL1 mutations. When the 27 patients with pathologic ASCL mutations were analyzed for co-mutations, TET2 (13/27, 48%) was the most frequent ASXL1 co-mutation. FLT3 (0/27, 0%) and NPM1 (1/27, 3.7%) were notable for their absence. Median age of pts at diagnosis was 69 years (range 23-80). Prior myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN) was noted in 9/36 (25%) and 11/36 (30.6%) pts, respectively. Four pts (11.1%) had received chemotherapy and/or radiation therapy for a prior non-myeloid neoplasm. Karyotype was normal in 18/36 (50%) pts, and 7 additional pts had intermediate cytogenetic lesions. There were 7 pts (19.4%) with unfavorable cytogenetics (complex karyotype (3 pts), 7q- (3 pts), and 5q- (1 pt)). Four pts (11.1%) had a favorable karyotype, with t(8;21) in 3 pts and t(15;17) in 1 pt. At presentation, median white blood cell count (WBC) was 6.4x103/uL (1.0 x -103). In pts whose AML transformed from prior MPN, median WBC was 50 X103/uL (3.3-140). Standard induction chemotherapy with an anthracycline and cytarabine was given to 17/36 (47%) pts. An additional 3/36 (8.3%) pts underwent induction therapy with clofarabine. Complete remission (CR) was documented in 14/20 (70%) evaluable pts. Of the remaining pts, 11 received a hypomethylating agent, and 5 received other therapies. Thirty-day treatment mortality for all 36 pts and for 27 pts with known ASXL1 pathologic mutation was 13.4% and 18.5% respectively. Kaplan-Meier estimate showed a median overall survival of 349 days (median follow up of 107 days (range 15-1570)). For the 27 pts with a pathologic ASXL1 mutation, the OS was 276 days (Figure 2, median follow up of 145 days (range 18-1570)). Conclusion: ASXL1 mutations in de novo AML with intermediate-risk cytogenetics is associated with poor clinical outcome in cooperative group trials. Strikingly we demonstrate in a single institution, retrospective analysis that 66.7% of pts who present with ASXL1 mutations in the setting of previously untreated AML had documented MDS, MPN and/or prior chemotherapy/radiation. Further studies are necessary to evaluate if ASXL1 mutation has independent prognostic significance in AML or if it is primarily a marker for secondary leukemia. Figure 1: ASXL1 and co-mutations Figure 1:. ASXL1 and co-mutations Figure 2: Overall survival for AML patients with ASXL1 pathologic mutation Figure 2:. Overall survival for AML patients with ASXL1 pathologic mutation Disclosures No relevant conflicts of interest to declare.

An Analysis of CNS2 Patients with AML: Do They Require Additional Intrathecal Therapy? a Report from Children’s Oncology Group Protocols AAML0531 and 03P1 and St Jude Children’s Research Hospital Protocol AML02

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 277-277 ◽  
Author(s):  
Donna Johnston ◽  
Jeffrey E Rubnitz ◽  
Todd A. Alonzo ◽  
Robert B. Gerbing ◽  
Richard Aplenc ◽  
...  
Keyword(s):  
Overall Survival ◽  
Conflicts Of Interest ◽  
White Blood Cells ◽  
Study Entry ◽  
Intrathecal Therapy ◽  
Oncology Group ◽  
Research Hospital ◽  
Cns Disease ◽  
Cns Relapse ◽  
The Impact

Abstract Introduction: Pediatric patients with acute myeloid leukemia (AML) require central nervous system (CNS) directed chemotherapy to minimize CNS relapse. Patients with AML who have CNS disease at diagnosis, defined as >5 white blood cells (WBC) with positive blast in cytospin, require more intensive CNS directed therapy to clear CNS disease and prevent CNS relapse. Those with <5 WBC but with a positive cytospin are designated as CNS2 disease. Those without any blast (negative cytospin) are designated as CNS1. The need for extra CNS therapy for CNS2 patients varies among treatment protocols, and consensus has not been reached as to the best CNS directed therapy for these patients. We studied the impact of intensive vs. standard management of CNS2 patients by comparing patients treated on the two most recent Children’s Oncology Group (COG) trials to those treated on the St Jude Children’s Research Hospital AML02 trial, where COG trials managed those with CNS2 disease more intensively, similar to CNS3, and AML02 treated such patients similar to CNS1. Both trials used a similar MRC-based chemotherapy backbone. This backbone gave intrathecal (IT) cytarabine at the beginning of each cycle of therapy except Capizzi II therapy, and on the AML02 protocol most patients received IT triple therapy. On both backbones, patients with CNS3 disease, and those on COG trials with CNS2 disease, received twice weekly IT cytarabine until the CSF was clear of blasts plus 2 additional treatments with a minimum of 4 IT treatments given. Thus, this analysis is the first comparison of outcome of CNS2 patients examining the variable of additional CNS directed therapy. Methods: Disease characteristics and clinical outcome for children who were CNS2 treated with intensive or standard intrathecal chemotherapy were compared across COG and SJCRH studies and compared to those who were CNS1 or CNS3. Results: Among the 1361 eligible patients enrolled on AAML03P1 and AAML0531 with available data for CNS status, 247 had CNS2 status. Of the 200 eligible patients enrolled on AML02, 47 patients had CNS2 status. On all protocols, patients with CNS2 status had a significantly higher incidence of Inv(16) compared to CNS1 patients (p<0.001 for both protocols). As well, patients with CNS2 status had a higher incidence of M4 FAB classification compared to CNS1 patients (p<0.001 for COG protocols and p=0.002 for AML02). On both protocols, patients who were CNS2 had similar incidence of Inv(16) compared to patients who were CNS3. In contrast, on the COG protocols the incidence of M4 FAB was similar among CNS2 and CNS3 patients, while on the AML02 protocol the incidence of M4 FAB was significantly higher in CNS2 compared to CNS3. The event free survival (EFS) for patients treated on COG protocols showed significant differences according to CNS status, with CNS1 patients having superior EFS compared to CNS2 and CNS3 patients (p=0.005), while on AML02, the EFS for CNS2 patients was significantly higher than CNS3 patients (p=0.04) and higher, but not significantly, than CNS1 patients (p=0.06). The overall survival (OS) for CNS2 patients treated on COG protocols was not significantly different from that of CNS1 and CNS3 patients (p=0.32), while on AML02, the OS was significantly higher for CNS2 patients compared to CNS1 (p=0.05) and CNS3 patients (p=0.02)(Figures 1 and 2). However, for the AML02 protocol, the Cox analysis showed that CNS status was not independently associated with EFS, OS, or cumulative incidence of relapse On the COG protocols there were 101 patients with relapse involving CNS, of which 34 were CNS1, 32 CNS2 and 34 CNS3 with a 5 year CNS refractory/relapse rate of 4%, 13% and 28% respectively (p<0.001). One patient with CNS relapse was unknown for CNS group. Of the 101 patients who relapsed involving CNS: 34% were CNS1, 32% were CNS2, and 34% were CNS3. Conclusions: Patients with AML who have <5 white cells with blasts present in the cerebrospinal fluid at diagnosis may not require extra IT therapy but may be able to be treated in the same fashion as patients with no blasts in the CSF at diagnosis. Additional analyses will assist in determining which, if any, CNS2 patients require extra IT therapy. Figure 1 Figure 1. – Overall Survival From Study Entry for Patients on COG AAML03P1 and AAML0531 Figure 2 Figure 2. – Overall Survival from Study Entry for Patients on SJCRH AML02 Disclosures No relevant conflicts of interest to declare.

scholarly journals High Cumulative Illness Rating Scale (CIRS) Score in CLL Correlates with Short CLL Telomere Length and Decreased Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4362-4362
Author(s):  
Lin Yang ◽  
Sara Beiggi ◽  
Yunli Zhang ◽  
Sara Kost ◽  
Robert Schmidt ◽  
...  
Keyword(s):  
Overall Survival ◽  
Telomere Length ◽  
Rating Scale ◽  
Conflicts Of Interest ◽  
Tumor Biology ◽  
Leukemia Cell ◽  
Surrogate Marker ◽  
The Elderly ◽  
Lymphocytic Leukemia ◽  
The Impact

Abstract The impact of chronic disease on the development and progression of cancer is increasingly recognized. Chronic lymphocytic leukemia (CLL) is a disease of the elderly and many of these patients have multiple comorbidities, which could shorten an individual's life, either directly or by enhancing CLL progression. In normal cells, including buccal cells (BC), it is known that chronic illness and age can shorten telomere length and this is a surrogate marker of overall survival. In the present study, we have examined the relationship between comorbidities and BC telomere length in CLL patients and determined whether these features can predict patient survival and disease aggressiveness. Telomere length in isolated genomic DNA from buccal and CLL cells of 196 CLL patients was measured at the time of diagnosis, using multiplex quantitative real-time PCR. Comorbidities were measured by the Cumulative Illness Rating Scale (CIRS) and CLL aggressiveness by leukemia cell telomere length. The median age of patients at diagnosis was 66 years (range, 39-89). With a median follow-up of 4.86 years (range, 0.05-7.69 years), approximately half the patients have progressed and one quarter have died. The median CIRS score of these patients was 3 (range, 0-12); a score of ≥7 was considered high. In patients with an elevated CIRS score, a direct correlation was found with increasing age (P<0.0001, r=0.42). In addition, independent of the effects of age, an increased CIRS score was found to correlate with poor overall survival (P=0.048, r=0.18). The median BC relative telomere length (T/S) of 2.01 (range, 0.70-5.66) was longer than the median CLL T/S of 0.53 (range, 0.07-2.48). There was no correlation between buccal and CLL telomere lengths (P=0.21). BC telomere lengths shortened with increasing age (P=0.011), but showed no association with markers of CLL disease, survival or high CIRS scores (P=0.08, r=-0.16). Meanwhile, patients with shorter CLL telomeres showed more aggressive disease with unmutated IGHVstatus (P<0.0001), higher Rai stage (P=0.02), shorter lymphocyte doubling time (P=0.004), earlier time to treatment (P<0.0001) and shorter overall survival (P=0.02). More importantly, short CLL telomere lengths occurred independent of increasing age (P=0.47), and significantly correlated with high CIRS scores (P=0.03, r=-0.18). In summary, while BC telomere lengths shorten with age in CLL cases, it is not predictive of survival or comorbidities in CLL. In contrast, independent of age, short CLL telomeres correlate with increasing CIRS scores and both predict poor survival. These results suggest that comorbidities in CLL may affect tumor biology, enhancing disease progression. This finding may partly explain the more aggressive clinical course of CLL in the elderly. Whether altering comorbidities in CLL can influence disease aggressiveness and survival requires further study. Disclosures No relevant conflicts of interest to declare.

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