Prognostic Relevance of Cytogenetics in Childhood Acute Lymphoblastic Leukaemia (ALL): Final Results From MRC ALL97.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 88-88
Author(s):  
Anthony V Moorman ◽  
Hannah M Ensor ◽  
Lucy Chilton ◽  
Sue M Richards ◽  
Sally E Kinsey ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Chromosomal Abnormalities ◽  
Risk Index ◽  
Univariate Analysis ◽  
Chromosome 21 ◽  
Independent Effect ◽  
Childhood All ◽  
Prognostic Relevance ◽  
Risk Of Relapse

Abstract Abstract 88 Chromosomal abnormalities in childhood ALL are important disease markers and predictors of prognosis. Virtually all modern protocols recommend that patients with t(9;22), MLL translocations and haploidy (<30 chromosomes) receive intensive therapy. However, there is less consensus regarding the prognostic relevance of other abnormalities, e.g. t(1;19), intrachromosomal amplification of chromosome 21 (iAMP21), dic(9;20), abnormal 9p, CDKN2A deletions and low hypodiploidy (30–39 chromosomes). Furthermore, the long term prognosis and independent effect of some abnormalities, especially t(12;21)/ETV6-RUNX1, has been questioned. We investigated the prognostic relevance of cytogenetics among 1,934 children treated on MRC ALL97. Patients with t(9;22), haploidy, low hypodiploidy and those aged <2yrs with a MLL translocation were treated as high risk. In order to focus on the intrinsic aggressiveness of the leukemic clone, we used relapse-free survival (RFS) as our primary endpoint. In addition, we constructed a cytogenetic based risk index to assess the utility of cytogenetics as a whole in predicting relapse. The 5yr RFS of the whole cohort was 81% (95% CI 79–82%) with a median follow-up of 8.2yrs. Univariate analysis revealed 5 abnormalities that were significantly associated with relapse: t(12;21) Hazard ratio (HR)=0.50 (95% CI 0.36, 0.68); high hyperdiploidy (51–65 chromosomes): 0.58 (0.45, 0.74); iAMP21: 5.51 (3.57, 8.50); t(9;22): 3.31 (2.06, 5.32); other MLL translocations [not t(4;11)]: 2.70 (1.39, 5.25); and 17p loss [del(17p)]: 2.13 (1.35, 3.34) (all p<0.003). Moreover, all abnormalities, except other MLL translocations, retained their significance in multivariate analysis. The following abnormalities were not predictive of relapse: t(4;11), t(1;19), dic(9;20), CDKN2A deletions, −7 and abnormal 9p. There were too few haploid and low hypodiploid patients to be formally tested but 10/18 (56%) relapsed. Further analysis of high hyperdiploid patients revealed that there was no difference in RFS for those with (n=218) and without (n=200) triple trisomy (+4, +10 and +17) [HR=0.81 (0.49, 1.34), p=0.4]. However, high hyperdiploid patients with a +18 (n=396) had a lower risk of relapse [HR=0.44 (0.26, 0.74) (p=0.002)] than other patients (n=86). Among 369 t(12;21) patients 47 (13%) suffered a relapse. The timing of these relapses was different to the rest of the cohort with fewer early relapses (within 6 months of the end of treatment) in the t(12;21) cohort: 9/47 (19%) versus 170/285 (59%), p<0.001. The 5yr and 7yr cumulative risk of relapse for t(12;21) patients was 11% (95% CI 8–15%) and 13% (9–17%) respectively compared to 24% (22–28%) and 27% (24–30%), respectively for other patients. A total of 54/1596 (3.4%) patients had del(17p) by cytogenetics: i(17q) (n=18), del(17)(p) (n=7), monosomy 17 (n=8) and unbalanced translocations (n=21). It is a secondary abnormality co-existing with high hyperdiploidy (n=21), t(12;21) (n=6), MLL translocations (n=2) and t(9;22) (n=1). Overall, these patients had an inferior RFS (64%, (49%–75%), p=0.004). However, the presence of del(17p) did not abrogate the good outcome of patients with t(12;21) and high hyperdiploidy [HR=1.70 (0.75, 3.87) p=0.206] but did represent a strong marker of relapse among other patients [HR=2.96 (1.68, 5.20) p<0.001]. We classified 1,733 patients into three cytogenetic risk groups: good (GRG) [t(12;21), high hyperdiploidy] n=928 (54%); poor (PRG) [t(9;22), t(4;11), other MLL, t(17;19), haploidy, low hypodiploidy, iAMP21, del(17p)] n=153 (9%); standard (SRG) [all other cases] n=652 (38%). The 5 year RFS were GRG 88% (85–90%), SRG 79% (75–82%) and PRG 49% (40–57%). In multivariate analysis, patients in the GRG or PRG were less or more likely to relapse compared to patients in the SRG: HR=0.65 (0.50–0.83), p=0.001 and HR=2.67 (2.01–3.53), p<0.001, respectively. Moreover, there was a strong correlation between cytogenetic risk group and the BFM risk classification of relapses, based on immunophenotype, timing and site of relapse. Among GRG patients who relapsed, only 11/130 (8.5%) suffered a high risk relapse; whereas 36/76 (47%) PRG patients who relapsed had a high risk relapse. These data clarify the prognostic relevance of several chromosomal abnormalities in the context of a modern childhood ALL therapy and provide further evidence that cytogenetics is a powerful and independent indicator of relapse risk. Disclosures: No relevant conflicts of interest to declare.

Effect of the Number of Prognostically Relevant Mutated Genes on Survival and Leukemia Progression in Primary Myelofibrosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 104-104
Author(s):  
Paola Guglielmelli ◽  
Terra L. Lasho ◽  
Flavia Biamonte ◽  
Johannah Score ◽  
Carmela Mannarelli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Risk Stratification ◽  
Validation Cohort ◽  
Univariate Analysis ◽  
Primary Myelofibrosis ◽  
Risk Category ◽  
Prognostic Relevance ◽  
High Risk Category ◽  
Risk Categories

Abstract Background The median survival (OS) of patients with primary myelofibrosis (PMF; 6.5y) is significantly shortened compared to reference population (Cervantes et al, JCO 2012; 30:2981). OS is predicted by the four risk categories of IPSS, Dynamic-IPSS and DIPSS-plus score, nevertheless pts heterogeneity persists within these categories, necessitating improved risk stratification. We recently reported that pts harboring mutations in any one of the prognostically relevant ASXL1, EZH2, IDH1/2 and SRSF2 genes constitute a IPSS-and DIPPS-plus independent Molecular High Risk category (MHR+) characterized by significant reduction of OS and leukemia free survival (LFS) (Vannucchi et al, Leukemia 2013). The aim of this work was to analyze the impact of the number of prognostically relevant mutated genes on OS and LFS in PMF. Patients and methods Two independent cohorts are included, a “test cohort” from Europe, analyzed at diagnosis, and a “validation cohort” from Mayo Clinic, analyzed at any time after diagnosis. Mutation analysis was performed in DNA from whole blood or granulocytes using RTQ-PCR, HRM and direct sequencing; all mutations were confirmed at least twice. The prognostic value of the molecular variables with regard to OS and LFS was analyzed by Cox regression. Test cohort It included 490 pts (median age 61y; males = 301) risk stratified by IPSS into high (n=74, 15%), intermediate-2 (n=93, 19% ), intermediate-1 (n=147, 30%) and low (n=176, 36%). The median follow-up was 3.63y (95% CI, 0.06-28.33); 161 pts died (33.0%), of whom 76 (15.6%) had progressed to acute leukemia after a median of 3.4y (0.04-28.3) from diagnosis. One hundred forty-six pts (29.8%) presented at least one of the four aforementioned mutated genes and were classified as MHR+. The OS of MHR+ pts was significantly reduced compared to patients with no mutations (n=344): 80.7 vs 148.9 mo (HR 2.2, CI95% 1.6-3.03). One hundred twelve (22.8%) pts had 1 mutation and 34 (6.9%) had 2 or more mutations. In univariate analysis presence of 2 or more mutated genes was significantly more detrimental for OS (29.5mo; HR 4.12, IC95% 2.6-6.4) than having 1 mutated gene (84.2mo; HR 1.8, IC95% 1.2-2.5) compared with having no mutations (148.9mo). Multivariate analysis results adjusted for IPSS indicated that having two or more mutations was an independent prognostic factor for OS (HR 2.9, 95% CI 1.8-4.5). Notably, the prognostic relevance of harboring two or more mutations involved both lower (low and intermediate-1; HR 1.87, 95% CI 1.3-2.6) and higher (intermediate-2 and high; HR 1.6, 95% CI 1.2-2.1) categories of IPSS. Also LFS resulted significantly shorter (129mo; HR 3.1, 95%CI 1.9-4.8) in MHR+ pts compared with pts with no adverse mutations (323mo). Having 2 or more mutations correlated with greater reduction of LFS (79.6mo; HR 7.02, CI95% 3.9-12.6) than having one mutation only (133.9mo; HR 2.2, IC95% 1.3-3.7) as compared with no mutations (323.2mo). Multivariate analysis showed that IPSS high risk category (HR 4.5; 95% CI 2.3-8.8) and two or more mutated genes (HR 5.3; 95% CI 2.9-9.8) predicted independently for a significant reduction in LFS. The negative impact on LFS of having 2 or more mutated genes compared to one or no mutations was maintained in the lower (HR 6.4, 95% CI 2.6-15.2) and higher (HR 5.5, 95% CI 2.3-12.8) risk categories. Validation cohort Validation cohort included 262 patients (median age 64 years; males = 167) risk stratified by DIPSS-plus into high (n=89, 34%), intermediate-2 (n=92, 35%), intermediate-1 (n=46, 18%) and low (n=34, 13%). One hundred forty-six pts (56%) displayed none of the four aforementioned mutations, 93 (36%) harbored one mutation whereas 23 (9%) harbored two or more mutations. In univariate analysis, having two or more mutations (HR 3.7; 95% CI 2.2-6.1) was significantly more detrimental for OS than having no mutations, which is more favorable than having one mutation (HR 1.9; 95% CI 1.4-2.7). When adjusted for DIPSS-plus, the presence of two or more mutations retained its significance (HR 2.1; 95% CI 1.3-3.6) and outperformed ASXL1 mutation alone in its prognostic relevance Conclusions Overall, these results show that the number of prognostically relevant mutated genes correlate with OS and LFS in pts with PMF, suggesting that screening for these mutations might help to improve risk stratification. Disclosures: No relevant conflicts of interest to declare.

Allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: impact of conditioning regimen without total-body irradiation--a report from the Société Française de Greffe de Moelle.

1994 ◽  
Vol 12 (6) ◽  
pp. 1217-1222 ◽  
Author(s):  
G Michel ◽  
E Gluckman ◽  
H Esperou-Bourdeau ◽  
J Reiffers ◽  
J L Pico ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multivariate Analysis ◽  
Bone Marrow Transplantation ◽  
High Risk ◽  
Complete Remission ◽  
Total Body Irradiation ◽  
Conditioning Regimen ◽  
Total Body ◽  
First Complete Remission ◽  
Risk Of Relapse

PURPOSE To analyze the French experience of chemotherapeutic preparation before human leukocyte antigen (HLA)-identical bone marrow transplantation (BMT) in children with acute myeloblastic leukemia (AML) in first complete remission (CR). PATIENTS AND METHODS The data base used for this study was a French BMT registry for childhood AML. Twenty-three children were conditioned with busulfan and 120 mg/kg cyclophosphamide (Bu-Cy 120 group). Nineteen received busulfan and 200 mg/kg cyclophosphamide (Bu-Cy200 group). During the same time period, 32 patients were prepared with total-body irradiation (TBI group) most often in combination with 120 mg/kg of cyclophosphamide. RESULTS The probability of relapse was 54%, 13%, and 10% for the Bu-Cy120, Bu-Cy200, and TBI groups, respectively (P < .05 in the univariate analysis, log-rank test, 2 df). In the multivariate analysis, a conditioning regimen with Bu-Cy120 was significantly associated with a higher risk of relapse (P = .02; relative risk, 3.62). The probability of transplant-related mortality (TRM) was 0% for Bu-Cy120, 5% for Bu-Cy200, and 10% for TBI. Kaplan-Meier estimations of event-free survival (EFS) were 46% +/- 24%, 82% +/- 18%, and 80% +/- 14%, respectively, for the three groups, with median follow-up durations of 28 months (range, 3 to 78), 31 months (4 to 68), and 48 months (2 to 73). In the multivariate analysis, two factors adversely affected EFS: a conditioning regimen with Bu-Cy120 (P = .07) and a long interval from diagnosis to BMT (> or = 120 days, P = .08). CONCLUSION Bu-Cy120 is a well-tolerated preparation, but results in a high risk of relapse for children with AML in first CR. This high risk of relapse is not observed when the dose of cyclophosphamide is increased to 200 mg/kg.

Long-Term Follow-Up of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) with Fludarabine and Melphalan (FM) Reduced Intensity Conditioning (RIC) for High-Risk AML/MDS.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 838-838
Author(s):  
B. Oran ◽  
R. Saliba ◽  
S. Giralt ◽  
D. Couriel ◽  
A. Carrasco-Yalan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
High Risk ◽  
Disease Progression ◽  
Disease Status ◽  
Independent Effect ◽  
Donor Type

Abstract RIC with FM has extended the use of HSCT to patients otherwise not eligible for this treatment. Longer follow-up and larger number of patients now allow for more robust evaluation of risk factors and outcomes. Herein are the results of such an evaluation. Patients and Methods: We evaluated outcomes of 112 patients with high-risk AML/MDS treated from August 1996 to December 2003 with FM (fludarabine 100–180 mg/m2 and melphalan 100–180 mg/m2) and unmanipulated HSCT. Eligibility included age &gt;54 yrs. or comorbidity precluding an ablative preparative regimen. Disease status at HSCT was relapsed/refractory (n=43, 38.4%), primary induction failure (n=32, 28.6%), untreated (n=7, 6.3%) or complete remission (CR, n=30, 26.8). Cytogenetic risk was intermediate (n=59, 53%), high (n=47, 42%), low (n=3, 2.5%) or unknown (n=3, 2.5%). Donors were HLA matched related (MRD; n=59) or unrelated (UD; n=53). GVHD prophylaxis was tacrolimus based in all but one patient. Anti-thymocyte-globulin was added in 31 UD HSCT. Stem cell sources were bone marrow (n=56) or peripheral blood (n=57). Median age was 55 (range 22–74). Evaluated were the following variables and their influence on disease progression and overall survival: - age, donor type, duration of first CR, disease status at transplant (categorized as CR, No CR with (NoCR/CB) and without circulating blasts (NoCR/NoCB)), cytogenetics, acute and chronic GVHD (time dependent variables), and blood counts on day 30 (lymphocytes, monocytes and platelets). We used a Cox’s regression analysis. Results: Median time of follow up among survivors (n=43) was 28.4 mo (3.3–88.9). CR rate at day 30 post transplant was 87% (n=97), 8 patients died early and 7 did not respond. 25 (26%) of 97 patients progressed after day 30. All but 3 patients relapsed within the first year post HSCT, and only one relapsed more than 2 years after HSCT. In a landmark analysis, disease status at transplant was the only significant risk factor for progression among these 97 patients (HR of 3.7 for the NoCR/CB group compared to the CR group). 69 of 112 patients died with a median survival of 4.6 mo. Seven deaths (10% of all deaths) were observed more than 2 yrs. after HSCT, due to GVHD (n=3), infection (n=2), relapse (n=1) and unknown causes (n=1). Two-year OS and PFS was 44% and 69% respectively. Disease status at HSCT and grade II-IV aGVHD were the only significant predictors of OS on univariate and multivariate analysis. Blood counts on day 30 were associated with disease status at transplant, donor type and aGVHD. Their independent effect on outcome could not be evaluated given sample size. Conclusion: A significant portion of older patients with high-risk AML/MDS may achieve long-term PFS, but early relapses are the major cause of treatment failure in this context. Prognostic factors for event-free and overall survival Variables Multivariate analysis for disease progression CB=circulating blasts Disease status n Events (n) HR 95% CI p 2-yr PFS CR 30 6 1.0 57% (39–72) NoCR/NoCB 41 7 1.1 0.4–3.2 0.9 46% (30–60) NoCR/CB 26 12 3.7 1.4–9.8 0.001 22% (9–38) Multivariate analysis for overall survival (OS) Disease status HR 95% CI p 2-yr OS CR 30 12 1.0 66% (48–80) NoCR/NoCB 49 29 1.8 0.9–3.5 0.06 40% (26–53) NoCR/CB 34 28 2.8 1.4–3.5 0.002 23% (11–37) gd II-IV aGVHD 2.8 1.8–4.6 &lt;0.001

Favorable Leukemia-Free Survival (LFS) for Adults and Children Undergoing Myeloablative Umbilical Cord Blood (UCB) Transplantation with Cyclophosphamide (CY), Fludarabine (FLU) and Total Body Irradiation (TBI): A Single Center Analysis of 194 Patients.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1957-1957 ◽  
Author(s):  
Claudio Brunstein ◽  
Daniel Weisdorf ◽  
Todd DeFor ◽  
Jeffrey S. Miller ◽  
Philip B. McGlave ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Disease Risk ◽  
Negative Impact ◽  
Lymphoblastic Leukemia ◽  
Univariate Analysis ◽  
Chronic Phase ◽  
Relapse Risk ◽  
Cell Dose

Abstract We evaluated the outcomes in 194 consecutive patients (pts) transplanted with UCB after a myeloablative therapy for acute myeloid leukemia (AML,n=86), acute lymphoblastic leukemia (ALL,n=89), chronic myeloid leukemia (CML,n=13), and myelodysplastic syndrome (MDS,n=6) between 1995 and 2007. Methods: Pts were assigned to 3 treatment groups (Table 1): Cy 120mg/kg, TBI 1320 cGy and equine anti-thymocyte globulin (ATG) 90mg/kg with one UCB unit (CyTBI, 1995–2000; n=65; median age 9 yrs, r 0.5–52); CyTBI and Flu 75mg/m2/day with one UCB unit (CYFluTBI-1, 2000–2007; n=36; median age 8yrs, r 2–44); and Cy/Flu/TBI with two UCB units (CyFluTBI-2, 2001–2007; n=93; median age 25yrs, r 9–45). All received cyclosporine A (CsA) with either short course methylprednisolone (2 mg/kg/days; days +5 to +19) or mycophenolate mofetil (days -3 to +30). Pts were classified as standard (acute leukemia in CR1-2 or CML in first chronic phase, n=138) or high risk (n=56) for relapse. Median follow-up for survivors is 2.8 years (r: 0.7–9.2). Pts received a 0–1 HLA-mismatched graft in 81% for CyFluTBI-1, 47% for CyTBI, and 36% for CyFluTBI-2 (p&lt;.01). The total nucleated cell dose infused in recipients of CyFluTBI-1 was 3.6 (2.1–13.9), CyTBI 3.0 (0.9–14.0), and CyFluTBI-2 3.6 (1.7–6.5) x 107/kg (p=.01). Results: Engraftment was not significantly different for the 3 groups (CyFluTBI-1 97% (92–100) vs. CyTBI 89% (82–96) vs. CyFluTBI-2 87% (80–94) (p=.06). Patients receiving a total CD34+ cell dose &gt; 2.5 x 106/kg had significantly better engraftment (&lt;2.5, 80% [74–94], 2.5–3.8, 88% [80–98], 3.9–6.5, 94% [88–100], &gt;6.5, 98% [94–100], p&lt;.01). Incidence of grades II-IV GVHD was higher after CyFluTBI-2 (51% [40–62]) as compared to CyFluTBI-1 (25% [11–39]) or CyTBI 37% (25–49) (p&lt;.01) in univariate, but not in multivariate analysis after adjusting for age and disease risk. While treatment-related mortality (TRM) at 2 yrs was similar in univariate analysis (CyFluTBI-1, 11% [1–21] vs. CyFluTBI–2, 32% [22–42] vs. CyTBI 32% [22–42], p=.07), after adjusting for age and disease risk TRM was higher for the CyTBI (RR 3.5 [1.1–9.2], p=.03) vs. CyFluTBI-1. The relapse risk at 4 yrs for CyFluTBI-1 was 37% (19–55), CyFluTBI-2 19% (10–28), and CyTBI 28% (18–38) (p=.19). The LFS at 4 yrs for CyFluTBI-1 was 52% (34–70), CyFluTBI-2 49% (38–60), and CyTBI 37% (25–49) (p=.46). In multivariate analysis, only high risk disease was associated with higher relapse risk (RR 2.0;95%CI,1.0–3.9;p=.05) and mortality (RR 2.2;95%CI,1.4–3.4;p&lt;.01). Notably, cell dose and HLA match had no effect on any outcome in multivariate analysis. Conclusions: Use of two partially HLA matched UCB units has increased the applicability of UCB particularly in adult recipients. As a result all UCB grafts contain &gt;2.5 x 107 nucleated cells/kg at cryopreservation, limiting the negative effect of low cell dose on engraftment and survival and reducing the negative impact of HLA mismatch previously reported.

An Automated and Quantitative Protein Expression-Based Classification System to Identify High Risk Multiple Myeloma Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 735-735
Author(s):  
Alex Klimowicz ◽  
Paola Neri ◽  
Adnan Mansoor ◽  
Anthony Magliocco ◽  
Douglas A. Stewart ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
High Risk ◽  
Protein Expression ◽  
Classification System ◽  
Risk Group ◽  
Univariate Analysis ◽  
High Risk Group ◽  
Group Classification ◽  
Low Risk ◽  
High Expression

Abstract Background: Autologous stem cell transplantation (ASCT) has dramatically improved the survival of myeloma patients; however, this approach has significant toxicities and nearly 25% of MM patients progress within one year from their transplant. While gene expression profiling-based (GEP) molecular classification has permitted the identification of unresponsive high-risk patients, these approaches have proven too costly and complex to translate into clinical practice. Less expensive and more readily available methods are needed clinically to identify, at the time of diagnosis, MM patients who may benefit from more aggressive or experimental therapies. While protein-based tissue arrays offer such alternative, biases introduced by the “observer-dependent” scoring methods have limited their wide applicability. Methods: We have designed a simplified, fully automated and quantitative protein expression based-classification system that will allow us to accurately predict survival post ASCT in a cost effective and “observer-independent” manner. We constructed tissue microarrays using diagnostic bone marrow biopsies of 82 newly diagnosed MM patients uniformly treated with a dexamethasone based induction regimen and frontline ASCT. Using the HistoRx PM-2000 quantitative immunohistochemistry platform, coupled with the AQUA analysis software, we have examined the expression of the following proteins: FGFR3 which is associated with t(4;14), cyclin B2 and Ki-67 which are associated with cellular proliferation, TACI which is associated with maf deregulation, and phospho-Y705 STAT3 and p65NF-κB, which are associated with myeloma cell growth and survival. For FGFR3, patients were divided into FGFR3 positive and negative groups based on hierarchical clustering of their AQUA score. For all other proteins examined, based on AQUA scores, the top quartiles or quintiles of patients were classified as high expression groups. Based on the univariate analysis, patients were further classified as “High Risk” MM if they had been identified as high expressers of either TACI, p65NF-κB or FGFR3. The Kaplan-Meier method was used to estimate time to progression and overall survival. Multivariate analysis was performed using the Cox regression method. Results: 82 patients were included in this study. In univariate analysis, FGFR3 and p65NF-κB expression were associated with significantly shorter TTP (p=0.018 and p=0.009) but not OS (p=0.365 and p=0.104). TACI expression levels predicted for worse OS (p=0.039) but not TTP (p=0.384). High expression of Ki67 or phospho-Y705 STAT3 did not affect survival. Of the 82 cases, 67 were included in the multivariate analysis since they had AQUA scores available for all markers: 26 (38.8%) were considered as High Risk by their AQUA scores and had significantly shorter TTP (p=0.014) and OS (p=0.006) compared to the Low Risk group. The median TTP for the Low and High Risk groups was 2.9 years and 1.9 years, respectively. The 5-years estimates for OS were 60.6% for the High Risk group versus 83.5% for the Low Risk group. Multivariate analysis was performed using del13q and our risk group classification as variables. Both our risk group classification and del13q were independent predictors for TTP, having 2.4 and 2.3 greater risk of relapse, respectively. Our risk group classification was the only independent predictor of OS with the High Risk group having a 5.9 fold greater risk of death. Conclusions: We have found that the expression of FGFR3, TACI, and p65NF-κB, in an automated and fully quantitative tissue-based array, is a powerful predictor of survival post-ASCT in MM and eliminates the “observer-dependent” bias of scoring TMAs. A validation of this “High Risk” TMA based signature is currently underway in larger and independent cohorts. Figure Figure

Clinical, Pathological, and Prognostic Characteristics Of Mature Nodal Or Extranodal T-Cell and NK-Cell Non-Hodgkin´s Lymphoma (NHL) In a Single Mexican Institution

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1763-1763
Author(s):  
Gladys P Agreda-Vásquez ◽  
Erick Crespo-Solis ◽  
Gustavo J Ramos-Blas ◽  
Cesar Lara-Torres ◽  
Carmen Lome-Maldonado ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
T Cell ◽  
High Risk ◽  
Nk Cell ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
Prognostic Index ◽  
T Cell Lymphoma ◽  
Number Of Patients ◽  
Who 2008

Abstract Background Mature nodal or extranodal T-cell and NK-cell NHL are a rare and heterogeneous group of NHL with aggressive behavior and poor clinical outcome. Their incidence varies according to geographical region and racial characteristics. Mexico is included in those countries known to have a high incidence of extranodal T/NK-cell lymphoma, type nasal (NKTCL). Objective To evaluate the outcome and prognosis of patients with mature nodal or extranodal T-cell or NK-cell NHL in a single institution in Mexico City. Methods Clinicopathological characteristic, treatment, outcome, and prognosis of patients admitted to our institution between August, 1991 and December 2009 were analyzed. Prognostic Index T-cell (PIT) was used in all subtypes of lymphomas except in NKTCL subtype. All tissue biopsies and immunophenotypic markers were reviewed by an expert hematopathologist and reclassified according to the WHO 2008 classification. Univariate analysis using log-rank test was used to determine the correlation between clinical features and overall survival (OS). Multivariate analysis using Cox proportional hazard models were performed. A p value < 0.05 was considered significant. Results A total of 67 patients were analyzed. Median age was 37 years. B symptoms were presented in 83.6%, 74.6% had at least one site with extranodal disease, 73.1% advanced clinic stage, 32.8% high risk by International Prognostic Index (IPI) and 47.5% high risk by PIT. According to WHO 2008 classification the most common subtype was peripheral T-cell lymphoma not otherwise (PTCL NOS) specified in 38 patients (56.7 %), angioimmunoblastic T-cell lymphoma (AITL) and NKTCL were the second most common subtypes with 8 cases in each group (11.9 %), anaplastic large cell lymphoma (ALCL) kinase-positive (ALK-positive) was identified in 3 patients (4.5 %), ALCL ALK-negative in 2 cases (3.0 %), lymphoblastic lymphoma and subcutaneous panniculitis-like T-cell lymphoma (SPTCL) with 3 patients in each group (4.5 %), hepatosplenic T-cell lymphoma (HSTL) and aggressive NK-cell leukemia with one case in each group (1.5 %). CHOP-like therapy was used in 71.6 % of patients. Nine percent of patients did not receive treatment. The response was evaluated in 53 patients in whom overall response was 71.7 % with 44.8 % achieving complete remission (CR). Median OS was 2760 days (CI 95 % 1153.145-4366.855). Histopathology subtype did not predict OS. Both prognostic scores, IPI and PIT, were able to identify 4 groups of patients with different outcomes. The analysis failed to demonstrate any advantage of adding etoposide to the chemotherapy schedule. Multivariate analysis showed that, IPI, PIT, and CR were predictive for OS (Table 1). Conclusion Previous publications in Mexican population, with larger number of patients included, were particularly focus on clinical characteristics and prognosis of NKTCL. Our series provides data of mature nodal or extranodal T-cell and NK-cell NHL in Mexico. The current study confirms the poor prognosis of aggressive forms of mature nodal or extranodal T-cell and NK-cell NHL regardless of the chemotherapy schedule employed. Disclosures: No relevant conflicts of interest to declare.

Comparison Between Related T-Cell Depleted HLA-Haploidentical Stem Cell Transplantation (TCD-Haplo) and Umbilical Cord Blood Transplantation (UCBT) in Pediatric Patients with Acute Leukemia, a Eurocord, PDWP-EBMT Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1215-1215
Author(s):  
Franco Locatelli ◽  
Myriam Labopin ◽  
Gerard Michel ◽  
Rupert Handgretinger ◽  
Cristina Diaz de Heredia ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Acute Leukemia ◽  
Advanced Disease ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Gvhd Prophylaxis ◽  
Risk Of Relapse

Abstract Both TCD-Haplo and UCBT are used for treating children with either acute lymphoblastic (ALL) or myeloid (AML) leukemia in need of an allograft and lacking a suitable donor. Although both these types of HSCT have been shown to be effective in curing children with acute leukemia, to date, no study has compared the outcomes of these two types of transplant. We performed a retrospective registry-based study on children (less than 18 years) with either ALL or AML, receiving, after a myeloablative conditioning regimen, a TCD-Haplo (CD34+ cell positive selection, CD3+ negative or TCR alpha/beta+ cell depletion) or single unit UCBT. Patients given pharmacological graft-versus-host disease (GVHD) prophylaxis after graft infusion in haplo HSCT were excluded. Transplants were performed from 2001 to 2012 in EBMT centers; 1067 patients received single UCBT and 266 TCD-Haplo for AML (n=478) or ALL (n=855). Median follow up was 28 (range 1-150) and 20 (range 1-152) months for UCBT and TCD-Haplo, respectively. Compared to TCD-Haplo, UCBT recipients were younger (median age 5.96 years vs 9.6 years, p=<0.0001), were transplanted more frequently in CR1 (42% vs 24%, p=<0.001), less frequently in advanced disease (10% vs 21%, p=<0.001) and had more often negative cytomegalovirus (CMV) serology (45% vs 31%, p=<0.001). Conditioning regimen was mainly total body irradiation (TBI)-based, 56% versus 50% for TCD-Haplo and UCBT, respectively. For UCBT, patients CSA+steroids was the most commonly used (72%) GVHD prophylaxis. A higher proportion of patients transplanted with TCD-Haplo received ATG in the conditioning regimen (90% vs 74%, p=<0.001). Acute GVHD (grade II-IV) incidence was 16% and 28% (p<0.001) while that of chronic GVHD was 14% and 16%, (p=0.40) for TCD-Haplo and UCBT respectively. Since diagnosis was the most important factor influencing outcome, the analysis was performed separately for patients with ALL and AML. For ALL (n=855) in univariate analysis, the 2-year probability of leukemia-free survival (LFS) was 35% and 43% (p=0.08), for TCD-Haplo and UCBT, respectively. The cumulative incidence (CI) of non-relapse mortality (NRM) was 28% and 29% (p=0.57), and relapse incidence (RI) was 36% and 28% (p=0.01) for TCD-Haplo and UCBT, respectively. According to disease status, for patients in CR1 (n=300), 2-year RI was 21% versus 20%, p=0.75; NRM 30% versus 24%, p=0.59; and 2- year LFS 49% versus 56%, p=0.87; for TCD-Haplo and UCBT, respectively. For patients in CR2 (n=478), 2-year RI was 34% versus 29%, p=0.75; NRM 28% versus 32%, p=0.29; and 2- year LFS 38% versus 39%, p=0.63, for TCD-Haplo and UCBT, respectively. For patients in advanced disease (n=77), 2-year LFS was 5% versus 8%, p=0.08 for TCD-Haplo and UCBT, respectively. For patients with AML (n=478), 2-year probability of LFS was 21% and 58% (p=<0.0001), for TCD-Haplo and UCBT, respectively. CI of NRM was 43% and 19% (p=<0.001), and RI was 36% and 23% (p=0.01) for TCD-Haplo and UCBT, respectively. According to disease status, for patients in CR1 (n=207), 2-year RI was 31% versus 14%, p=0.06; NRM 45% versus 16%, p=0.002; and 2-year LFS 24% versus 69%, p=<0.001; for TCD-Haplo and UCBT, respectively. For patients in CR2 (n=180), 2-year RI was 28% versus 24%, p=0.49; NRM 44% versus 21%, p=0.004; and 2- year LFS 28% versus 55%, p=0.0005, for TCD-Haplo and UCBT, respectively. For patients in advanced disease status (n=91), 2-year LFS was 10% versus 22%, p=0.44 for TCD-Haplo and UCBT, respectively. In multivariate analysis adjusted for differences between the 2 groups, for patients with ALL, no statistically significant differences were observed according to the graft source. Disease status was the only factor associated with better LFS (HR 4.84, p<0.0001). TCD-Haplo was associated with greater risk of RI (HR 1.58, p=0.01). For AML, in multivariate analysis, TCD-Haplo was associated with greater risk of relapse (HR 1.67, p=0.05) and of NRM (HR= 1.94; p=<0.001), and worse LFS (HR 1.94, p=<0.001) when compared to UCBT. Advanced disease at transplantation (HR 2.89, p=<0.001) was the other factor associated with LFS and RI. This retrospective analysis demonstrates that children with ALL have comparable probability of LFS after either UCBT or TCD-Haplo. By contrast, in children with AML, UCBT is associated with lower risk of relapse and NRM than TCD-Haplo, this translating into better LFS. These results may help guide physician choices for transplanting children with acute leukemia. Disclosures No relevant conflicts of interest to declare.

The Disease Risk Index Predicts Outcomes Including Relapse and Survival in CD34-Selected Allogeneic HCT for Acute Leukemia and Myelodysplastic Syndrome

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3498-3498
Author(s):  
Christina Cho ◽  
Patrick Hilden ◽  
Jonathan U. Peled ◽  
Scott T. Avecilla ◽  
Pere Barba ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cumulative Incidence ◽  
Disease Risk ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Univariate Analysis ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Donor Type ◽  
Very High

Abstract INTRODUCTION: T-cell depleted allogeneic peripheral blood stem cell transplant (TCD PBSCT) using CD34 selection achieves relapse rates comparable to those of unmodified grafts (Pasquini et al., JCO 2012), but disease-related predictors of outcome have not been fully characterized in the TCD setting. We evaluated the prognostic utility of the refined Disease Risk Index (DRI; Armand et al., Blood 2014) in TCD PBSCT. METHODS: This was a retrospective analysis of patients who underwent first allogeneic HCT with TCD PBSCT for AML, ALL, or MDS at a single center between 1/2000 and 12/2015. Overall survival (OS), relapse-free survival (RFS), and chronic GVHD/relapse-free survival (CRFS) were estimated by the Kaplan-Meier method. Cumulative incidence of relapse, non-relapse mortality (NRM), acute GVHD (aGVHD), and chronic GVHD (cGVHD) were estimated using the cumulative incidence method for competing risks. The univariate association between variables of interest and OS/RFS/CRFS was evaluated using the log-rank test; Cox regression models assessed the adjusted effect of significant covariates on OS and RFS. Given only 1 patient with very high DRI, the high/very high DRI groups were combined. Similarly, given few patients with low DRI, the low/intermediate groups were combined in multivariate analysis. RESULTS: The analysis comprised a total of 519 patients. Median age was 55 years (range 18-73). There were 302 patients (58%) transplanted for AML, 144 (28%) for MDS, and 73 (14%) for ALL. Seventeen patients had low DRI scores (3%), 431 intermediate (83%), and 71 high/very high (14%). Median follow-up among survivors was 53.1 months (range 4.6-171.0). Two-year estimates for outcomes of interest were OS 62.8% (95% CI 58.5, 66.9), RFS 58.1% (95% CI 53.7, 62.3), and CRFS 54.0% (95% CI 49.5, 58.2). The cumulative incidence of relapse at 2 years was 17.3% (95% CI 14.2, 20.7). There were 0 relapse events in patients with low DRI, whereas intermediate and high/very high DRI scores were associated with a significantly increased incidence of relapse (p &lt; 0.001), with 2 year estimates 14.7% (95% CI 11.5, 18.3) and 37.1% (95% CI 25.8, 48.4), respectively. The cumulative incidence of NRM was 24.6% (95% CI 20.9, 28.4) at 2 years. The cumulative incidence of aGVHD at 100 days was 12.5% (95% CI 9.8, 15.5) for grade 2-4 and 2.5% for grade 3-4 (95% CI 1.4, 4.1); with a cumulative incidence of cGVHD of 4.7% (95% CI 3.1, 6.7) at 1 year. NRM, aGVHD, and cGVHD did not vary with DRI. In univariate analysis, DRI was associated with significant differences in OS, RFS, and CRFS (Table 1; Figure). Additional factors associated with poorer OS in univariate analysis were HCT-CI score &gt; 0, KPS &lt; 90, donor type (matched unrelated or mismatched vs. matched related donor), and age &gt; the median of 55.3 years; HCT-CI and KPS also correlated with significant differences in RFS. On multivariate analysis (Table 2), high/very high DRI corresponded to significantly greater risk of death (HR 1.72 for OS, [95% CI 1.24, 2.40]) and relapse or death (HR 1.86 for RFS [95% CI 1.35, 2.55]), compared with low/intermediate DRI. Multivariate analysis also showed that KPS &lt; 90 was associated with worse OS and RFS, as did a higher HCT-CI score. Neither age nor donor type was significantly associated with OS in multivariate analysis. CONCLUSION: In a large cohort of patients undergoing first TCD PBSCT at a single center for acute leukemia or MDS, DRI score significantly correlated with relapse incidence as well as OS, RFS, and CRFS. We have previously shown that the HCT-CI score, which incorporates patients' baseline comorbidities, is also predictive of outcomes after TCD PBSCT. Combining these prognostic tools will serve to better select appropriate patients for TCD PBSCT, a transplant approach currently under investigation in a multicenter phase 3 trial (BMT CTN 1301). Disclosures Koehne: Atara Biotherapeutics: Consultancy.

scholarly journals Investigating Ethnic Differences in Toxicities of Childhood ALL Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5989-5989
Author(s):  
Yasmin Rawlins ◽  
Jemily Malvar ◽  
Richard Sposto ◽  
Etan Orgel ◽  
Deepa Bhojwani
Keyword(s):  
Quality Of Life ◽  
Risk Factor ◽  
High Risk ◽  
Age At Diagnosis ◽  
Primary Therapy ◽  
Childhood All ◽  
Hispanic Ethnicity ◽  
Hispanic Patients ◽  
Risk Of Relapse

Abstract Introduction Acute lymphoblastic leukemia (ALL) is the most common childhood cancer with an excellent survival rate due to advancements in therapy. However, significant chemotherapy treatment-related toxicities (TRTs) are associated with the intensity of such treatments, which can affect quality of life, preclude the ability to provide optimal therapy, and impact survival. Further, outcomes are worse among certain minority populations, including Hispanic patients. At this single institution with a predominately Hispanic population, we sought to review several TRTs and determine whether Hispanic ethnicity may be a risk factor for increased severe, short-term TRTs and to explore the effects of TRTs on event-free survival (EFS). Methods This study is a retrospective chart-review of patients diagnosed with ALL at Children's Hospital Los Angeles from January 2008 to December 2010. Infants, patients with Down's syndrome and those who transferred to another institution during therapy were excluded from this study. Demographic and TRT information were collected from the electronic medical record, from the start of treatment until 30 days after the end of primary therapy, relapse, transplant, or death. TRTs were graded per the Common Terminology Criteria for Adverse Events version 4.0; only toxicities severe enough to negatively effect patients' quality of life, chemotherapy continuation, and survival were included. The specific TRTs were fractures, osteonecrosis, and peripheral neuropathy of ≥ grade 2, fungal and culture-positive bacterial infections, thrombosis, pancreatitis, and hyperbilirubinemia ≥ grade 3, and hepatic transaminitis ≥ grade 4. The X2 test was used to compare the proportions of Hispanic and non-Hispanic patients with and without the selected TRTs. Univariable and multivariable Cox regression models were used to examine the association of patient demographics with EFS and time to TRT. All analyses were performed using a 2-sided test and completed using the statistical software Stata. Results Of the 172 patients diagnosed with ALL between 2008 and 2010, 138 patients are included in this study, 124 with B-cell ALL and 14 with T-cell ALL. Among the 138 patients, 57.2% were male, 24.6% were obese, 76.1% were Hispanic, and 58% were classified as high-risk by the NCI Rome criteria. The median age at diagnosis was 7.9 years (range 1.1 to 20). All patients were treated according to ongoing Children's Oncology Group therapeutic studies. During the course of therapy, 23 patients relapsed, 3 developed secondary malignancy, and 2 patients died from infection. There were 156 TRTs observed in 85 patients, with 61.6% of patients experiencing one or more of the selected TRTs. The most common TRTs were infectious and gastrointestinal/hepatobiliary events. While Hispanic patients had 2.2 times higher frequency of pancreatitis than non-Hispanic patients and 1.8 times more hyperbilirubinemia, there were no statistically significant differences in the incidence of any TRTs by ethnicity. NCI high risk and older age were the only significant predictors of any TRT (p<0.001). Obesity was significantly associated with the development of pancreatitis and hyperbilirubinemia (p=0.01). Ethnicity, NCI risk, and ages were all predictive of EFS in the univariable analysis, with Hispanic ethnicity associated with 3.4-fold increase in risk of relapse and death when compared to non-Hispanics (p = 0.047). In the multivariable setting, NCI risk was the only significant predictor of EFS, although there was a trend in increased risk of relapse and death among Hispanic patients. Discussion In this relatively small cohort of patients, we did not identify ethnicity as a risk factor for increased TRTs during therapy for ALL, although certain TRTs such as pancreatitis and hyperbilirubinemia may be more common among Hispanic patients. As expected, Hispanic ethnicity, NCI risk, and age at diagnosis were risk factors for increased relapse and death. These results may suggest that additional factors, such as genetics, disease biology, or medication compliance, may play a more significant role in worse outcomes for Hispanic patients, rather than difference in tolerance of the treatment itself. Analyses of a larger cohort of patients are ongoing to confirm these results and to comprehensively analyze the determinants of pancreatitis and hepatic toxicity, and their interaction with obesity in Hispanic patients with ALL. Disclosures Bhojwani: Amgen: Other: Blinatumumab global pediatric advisory board 2015.

Survival Benefit with Decitabine Compared to Historical Experience with Intensive Chemotherapy in Patients with Higher Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2652-2652
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Jorge Cortes ◽  
William G. Wierda ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Survival Benefit ◽  
Chromosomal Abnormalities ◽  
Independent Effect ◽  
Poor Performance Status ◽  
Study Group ◽  
Intensive Chemotherapy ◽  
Historical Experience ◽  
Group A ◽  
Group B

Abstract Background Decitabine is a hypomethylating agent, approved by the FDA for treating MDS. Intensive chemotherapy is one treatment option in higher risk MDS. The comparative efficacy of these two strategies, decitabine vs. intensive chemotherapy, has not been evaluated. Study Aims Compare the results of decitabine in MDS with contemporary historical experience with intensive chemotherapy (as used in AML) in patients with higher risk MDS. Study Group and Treatment The study group treated with decitabine included 115 patients with higher risk MDS treated on our decitabine frontline study. (Kantarjian, Blood 2006; First Edition Online). The contemporary historical experience included two cohorts: Group A: 115 patients receiving intensive chemotherapy from 1995–2005 and matched for age, IPSS and cytogenetics; and Group B: All 376 patients treated with intensive chemotherapy from 1995–2005 with similar entry criteria as the decitabine study. Patients received decitabine 20 mg/m2 IV/D x 5 every four weeks. Response was evaluated by the modified IWG criteria (Cheson, Blood 108:419, 2006) In comparing decitabine to Group B, a multivariate analysis was conducted to assess the independent effect of decitabine vs. intensive chemotherapy. Results 115 patients were treated with decitabine; median age 64 years (range 37–89 years). IPSS risk groups: intermediate-1 17%, intermediate-2 30%, high 15%, not assessable 39%. Decitabine was given for a median of 7 courses (range 1 to 23); number of decitabine courses 3 or more in 81/89 patients (91%) followed on study for at least 6 months. Hemoglobin <10 g/dL in 76%; thrombocytopenia <100 x 109/L in 72%; ANC <1.0 x 109/L in 47%; chromosomal abnormalities in 63%; prior therapy for MDS in 54%; marrow blast 5% or more in 79%. Overall, 80 patients (70%) achieved IWG response: CR 40 (35%), PR 2 (2%), marrow CR +/− other hematologic improvements (HI) 26 (23%), other HI 12 (10%). Median remission duration was 20 months; median survival was 21 months. The CR rates by AML criteria (Cheson JCO21:4642, 2003) were 43% with decitabine and 46% with intensive chemotherapy in Group A, and 52% with intensive chemotherapy in Group B. Mortality at 6 weeks was 3% with decitabine vs. 12% with intensive chemotherapy (p=0.002); the 3-month mortality was 7% with decitabine vs. 22% with intensive chemotherapy. The survival was better with decitabine versus intensive chemotherapy in Group A (median 22 month vs. 11 month; estimated 2-year survival rate 47% vs. 25%, p<0.001). A multivariate analysis for survival in all 491 patients receiving decitabine or intensive chemotherapy (Group B) identified the following to be independent adverse factors for survival: abnormal cytogenetics, older age, anemia, thrombocytopenia, and poor performance status. Entering decitabine vs. intensive chemotherapy after accounting for the effect of other prognostic factors selected decitabine as an independent favorable prognostic factor for survival (pvalue 0.002; hazard risk 0.76). Conclusions Compared with intensive chemotherapy decitabine is associated with a survival benefit in higher risk MDS.

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