Prognosis value of S45F mutation of CTNNB1 in desmoid-type fibromatosis (DF): Prospective analysis of 500 consecutive patients (pts) from ALTITUDES trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11510-11510
Author(s):  
Nicolas Penel ◽  
Sylvie Bonvalot ◽  
André-Michel Bimbai ◽  
Sébastien Salas ◽  
Francois Le Loarer ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Abdominal Wall ◽  
Cox Model ◽  
Standard Of Care ◽  
Front Line ◽  
Poor Prognostic Factor ◽  
Mutational Status ◽  
Systemic Treatments ◽  
Ctnnb1 Mutation

11510 Background: DF rare locally aggressive fibroblastic non-metastasizing tumor, with an unpredictable course. Its management remains challenging, there is a current shift in standard of care from large surgical resection (SR) to active surveillance (AS). Most of DF display somatic mutation of CTNNB1, with three major hotpots: S45F, T41A and S45P. The poor prognosis of S45F is a matter of debate (Timbergen et al. Ann Surg 2019). Methods: ALTITUDES (NCT02867033) is a nationwide prospective registry of DF, diagnosed from January 2016 to December 2020 and confirmed by central pathological review. CTNNB1 mutations were identified by NGS. Primary endpoint was event-free survival (including disease progression or relapse). We have selected pts managed by AS, SR or systemic treatments as front-line. Pt undergoing R2 resection and then managed by follow-up were part of AS group. Prognostic factors were assessed using univariate and multivariate Cox Model. Results: From the 630-pts enrolled in ALTITUDES, 500 (79.3%) were eligible for the present analysis. Exclusion criteria were diagnosis before 2016 in 13 pts, multiple DF in 33 pts, 39 pts without CTNNB1 mutation analysis, and 45 pts receiving other treatments. The study population included 349 females (69.8%), the median age was 40 years (range 1-89). Abdominal wall was the predominant primary site: 161 pts (32.2%). In 430 (86.0%) cases, there was a CTNNB1 mutation, including, S45F in 56 cases (11.2%). In 70 cases (14.0%), we did not identify CTNNB1 mutation. The front-line managements were AS in 361 pts (72.2%), SR with R0/R1 margins in 57 cases (11.4%) and systemic treatments in 82 pts (16.5%). The median follow-up was 23 months (Range, 0.4-55). Overall, progression or relapse occurred in 128 pts (25.6%). We observed a significant EFS-difference between treatment groups, both in univariate and multivariate analysis with, compared to AS, a better outcome in patients with SR and worse outcome in patients who had received a systemic treatment (p = 0.01 in multivariate analysis). The risk of event was significantly associated with the tumor size, with a HR = 1.46 in tumors larger than 50 mm compared to smaller tumors (95%CI, 1.01-2.10, p = 0.04). We did not observe any significant association between the CTNNB1 mutational status and the outcome: compared to patients with another mutation, the hazard ratio associated with a S45F mutation was HR = 0.84 (95%CI, 0.48-1.46, p = 0.53) in multivariate analysis. Age, gender, location (abdominal wall versus other) were not associated with EFS. Conclusions: In this large prospective study, S45F was not an independent poor prognostic factor in DF. Size and front-line treatment drive both the outcome. The understanding and prediction of natural course of DF require further studies.

Preoperative uracil/tegafur and concomitant radiotherapy in locally advanced rectal (LAR) cancer: Updated results with a median follow-up of 5 years and analysis of prognostic factors (PF)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3573-3573 ◽  
Author(s):  
C. Fernandez-Martos ◽  
I. Romero ◽  
J. Aparicio ◽  
C. Bosch ◽  
R. Girones ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Residual Disease ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Locally Advanced ◽  
Standard Of Care ◽  
Complete Information ◽  
Risk Groups ◽  
Attractive Alternative

3573 Background: Preop chemoradiotherapy (CRT) with CI 5-FU is a standard of care for LAR cancer. Oral fluoropyrimidines, an attractive alternative to intravenous 5-FU, are perceived by patients as more convenient. Methods: We performed a phase II study in patients with potentially resectable tumors, localized in middle or distal rectum, ultrasonographically staged as T3 or T4 or N+ who were treated with UFT (400 mg/m2/d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Pts underwent surgery 5 to 6 weeks later followed by four cycles of 5-FU/LV (Mayo Clinic Scheme). Early end points of efficacy (pCR, downstaging, sphincter preserving surgery) and toxicity have already been reported (JCO 2004;22:3016). We now present data on secondary objectives (RFS, DFS and OS) and univariate and multivariate analysis of clinical and pathological PF. Results: 94 patients were included and complete information on 88 (94%) is availablewith a median follow-up of 5 years (60.4 months). Actuarial Kaplan-Meier DFS, RFS and OS are 61%, 66%, and 70 %. Patterns of failure are 7% pelvic and 25% distant. Univariate analysis results are shown in the table . Survival rate was also higher among patients with no or few residual disease after CRT but did not reach statistical significance. In Cox multivariate analysis both ypT and ypN are independent PF for DFS and RFS but only ypT is an independent PF for OS. Conclusions: This approach with preop UFT/RT reproduces the results that have been accomplished with 5-FU. ypT and ypN could be helpful to identify different risk groups and to select adjuvant treatments. [Table: see text] No significant financial relationships to disclose.

Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemotherapy) collaboration.

2017 ◽  
Vol 35 (18_suppl) ◽  
pp. LBA1-LBA1 ◽  
Author(s):  
Qian Shi ◽  
Alberto F. Sobrero ◽  
Anthony Frank Shields ◽  
Takayuki Yoshino ◽  
James Paul ◽  
...  
Keyword(s):  
Cox Model ◽  
Disease Free Survival ◽  
Standard Of Care ◽  
Pooled Analysis ◽  
Phase Iii ◽  
Stage Iii ◽  
Differential Outcomes ◽  
Phase Iii Trials ◽  
Stratified Cox Model

LBA1 Background: Since 2004, 6 months (m) of oxaliplatin (oxali)-based treatment has been the standard of care as adjuvant therapy for stage III CC. Since oxali is associated with cumulative neurotoxicity, shorter duration of adjuv therapy could spare pts toxicity and lead to substantial saving in health expenditures. Methods: A prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials (SCOT, TOSCA, Alliance/SWOG 80702, IDEA France (GERCOR/PRODIGE), ACHIEVE, HORG) was performed to evaluate the non-inferiority (NI) of 3m compared with 6m (ref) of adjuv FOLFOX/XELOX. The primary endpoint was disease-free survival (DFS), defined as time from enrolment to relapse, 2nd CRC, and death (all causes). NI was to be declared if the 2-sided 95% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.12. NI was examined within regimen and stage subgroups as pre-planned. Results: The analysis included 12,834 pts from 12 countries, accrued from 6/07 to 12/15. Stage distribution: 13% T1-2, 66% T3, 21% T4; 28% N2; 40% received XELOX. G3+ neurotoxicity was higher in the 6m v 3m arm (16 v 3% FOLFOX, 9 v 3% XELOX, p<0.0001). With a median follow-up of 39 mos, 3263 DFS events were observed. Overall, the 3 year DFS rate was 74.6% (3m) and 75.5% (6m), with estimated DFS HR of 1.07 (95%CI, 1.00-1.15). The 3m v 6m DFS HRs were 1.16 (95%CI, 1.06-1.26) and 0.95 (95% CI, 0.85-1.06) for FOLFOX and XELOX treated pts, respectively. The 3m v 6m DFS HRs were 1.01 (95%CI, 0.90-1.12) in T1-3 N1, and 1.12 (95%CI, 1.03-1.23) for T4 or N2 pts. Conclusions: While NI was not established for the overall cohort, NI of 3m v 6m oxali-based adjuv therapy was supported for XELOX. As each IDEA trial treated varying proportions of pts with XELOX (0 to 75%), the regimen interaction likely produced the differential outcomes observed between individual studies. Certain substages (T1-3 N1) also showed NI for 3m v 6m. These data provide a framework for discussions on risks and benefits of individualized adjuv therapy approaches. Support: U10CA180821, U10CA180882, U10CA180888, U10CA180835, INCA, PHRC2009, EME 09/800/34, HTA 14/140/84, CRUK C1348/A15960, JFMC. Clinical trial information: NCT01150045.

IMbrave150: Exploratory analysis to examine the association between treatment response and overall survival (OS) in patients (pts) with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4071-4071
Author(s):  
Michel Ducreux ◽  
Andrew X. Zhu ◽  
Ann-Lii Cheng ◽  
Peter R. Galle ◽  
Masafumi Ikeda ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Cox Model ◽  
Objective Response ◽  
Geographic Region ◽  
Exploratory Analysis ◽  
Primary Analysis ◽  
Recist 1.1 ◽  
Kaplan Meier ◽  
Ecog Ps

4071 Background: Based on IMbrave150 (NCT03434379) results, atezo + bev has been approved in > 60 countries for pts with unresectable HCC who have not received prior systemic therapy (Finn RS, NEJM 2020). OS and objective response rate (ORR) improvements with atezo + bev vs sor were maintained with an additional 12 mo of follow up since primary analysis. Updated median OS was 19.2 mo with atezo + bev vs 13.4 mo with sor (stratified HR, 0.66; 95% CI: 0.52, 0.85). Updated ORR was 30% with atezo + bev vs 11% with sor by independently-assessed (IRF) RECIST 1.1 (Finn RS, ASCO GI 2021). Here, we report an exploratory analysis examining the association of response by RECIST 1.1 with OS and independent predictors of survival. Methods: Pts in this Ph III study were systemic treatment–naive with unresectable HCC, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1. Pts were randomized 2:1 to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. ORR was determined by IRF RECIST 1.1. Kaplan-Meier analyses of OS by response status were conducted without landmark and with 4- and 6-mo landmarks. Multivariate analysis was conducted using Cox modeling with time-dependent covariate (responder [yes/no]) with backwards elimination. These analyses only included pts treated with atezo + bev. Results: IMbrave150 enrolled 501 pts, including 336 treated with atezo + bev. Median follow-up was 15.6 mo. OS was longer in pts with confirmed response per RECIST 1.1 (responders, CR + PR) vs non-responders by Kaplan-Meier analyses without landmark and with 4- and 6-mo landmarks (Table). By multivariate analysis, in addition to responder (yes/no), 5 of the 10 initially included predictors of OS remained in the final Cox model ( P< 0.10): ECOG PS (0/1), geographic region (Asia excluding Japan/rest of the world), etiology (hepatitis B/hepatitis C/non-viral), macrovascular invasion and/or extrahepatic spread (yes/no), and baseline alpha-fetoprotein ( < 400 ng/mL/≥400 ng/mL). Conclusions: Atezo + bev is the new standard of care for pts with previously untreated, unresectable HCC. Here we showed that in IMbrave150 pts treated with atezo + bev, response by RECIST 1.1 was associated with OS, suggesting that confirmed response is an independent predictor of OS in these pts. Clinical trial information: NCT03434379. [Table: see text]

Survival Advantage for Patients (pts) with Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP) Treated with Imatinib.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1006-1006
Author(s):  
Jorge Cortes ◽  
Moshe Talpaz ◽  
Susan O’Brien ◽  
Guillermo Garcia-Manero ◽  
Farhad Ravandi-Kashami ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Median Survival ◽  
Clonal Evolution ◽  
Standard Of Care ◽  
Cytogenetic Response ◽  
Survival Advantage ◽  
Control Group ◽  
Significant Prognostic Factor ◽  
Hematologic Response

Abstract When treated with imatinib, pts with CML in AP have a hematologic response rate of over 80%, and 25% achieve a major cytogenetic (CG) response. These results are superior to any other therapy available and have established imatinib as the standard of care for AP CML. However, a survival benefit was not defined in these single-arm studies. With longer follow-up of pts in AP treated with imatinib, we investigated whether imatinib therapy led to a survival advantage over other therapies that have been used for this disease. For this analysis, AP was defined as the presence of any of the following: blasts ≥15%, blasts + promyelocytes ≥30%, basophils ≥20%, platelets (plts) &lt;100 x109/L unrelated to therapy, or clonal evolution. Since 1982, 395 pts with AP have been treated at MDACC: 177 (45%) with imatinib and 218 (55%) with other therapies including IFN-α-based therapy (n=102), homoharringtonine (n=36), decitabine (n=47), daunorubicin + ara −C (n=24), or others (n=9). The rate of complete hematologic response was 82% with imatinib and 38% with others (p &lt; 0.0001), and major cytogenetic response was 48% and 13%, respectively (p &lt;0.0001). The median follow-up is 41 months (mo) (range, 3 – 206): 38 mo (3 to 63) for the imatinib group and 82 mo (3 to 206) for the others. A total of 249 pts have died: 67 in the imatinib cohort and 182 in the control group. The median survival was 21 months for the control group, and has not been reached for the imatinib cohort (estimated rate 53% at 3 yrs). Clinical characteristics adversely affecting survival (p&lt;0.05) included time from diagnosis to treatment &gt;36 mo, splenomegaly, Hgb &lt;10 g/dl, plts &lt;100 x109/L, peripheral or marrow blasts ≥5%, marrow basophils &gt;5%, blasts + promyelocytes &gt;5%, clonal evolution, and treatment with imatinib. Pts treated with imatinib were older, but had fewer pts with splenomegaly, high blasts or clonal evolution than the control group. By multivariate analysis, the independent pre-treatment characteristics associated with survival (p&lt;0.05) were splenomegaly, anemia, presence of peripheral blood blasts, and disease duration &gt;1 yr. After adjusting for these differences in a multivariate analysis, treatment with imatinib was the most significant prognostic factor associated with improved survival (p&lt;0.0001). We conclude that treatment with imatinib has changed the natural history of AP CML with an expected median survival in excess of 3 years.

scholarly journals Cachexia at Diagnosis adversely predicts outcomes in patients with Aggressive B-Cell NHL receiving standard of care treatment: A Prospective Observational Study from India

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2907-2907
Author(s):  
Vivek S Radhakrishnan ◽  
Reena Nair ◽  
Anwesha Patra ◽  
Saurabh Jayant Bhave ◽  
Jeevan Kumar Garg ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Observational Study ◽  
B Cell ◽  
Research Funding ◽  
Prospective Observational Study ◽  
Univariate Analysis ◽  
Standard Of Care ◽  
High Grade ◽  
Actuarial Survival

Background and Objectives:Cancer associated malnutrition and cachexia is an important determinant of the patient's short and long term outcomes. This prospective study was conducted to determine the association between cachexia at diagnosis and overall survival of patients with aggressive B-cell non-Hodgkin's Lymphoma (ABNHL) Methods:This investigator initiated single centre prospective observational study was conducted at the Tata Medical Center, Kolkata, India between Jan 2015 and Mar 2019 after IRB approval. Patients diagnosed with ABNHL receiving standard of care chemo-immunotherapy were eligible. This study was supported by an educational research grant from Baxter to our institution. All patients who consented to participate were screened for cachexia at entry using a modified Subjective Global Assessment (SGA) tool (1). Baseline clinical factors of prognostic importance including stage, IPI score, etc. were recorded. All statistical analysis was carried out using EpiInfo-ver.7 software. Results:239 patients diagnosed with high grade B-NHL were recruited. The study group included 89 women and 150 men, and 77 (32.1%) were older than 65 years. 130 (54.3%) patients received private care. 88(36.8%) had IPI stage high-intermediate plus high grade; 136 (56.9%) had Ann Arbor stage III plus IV disease; 40 (16.7%) had extra-nodal NHL; 96 (40.1%) had weight loss and 107(44.7%) had reduced food intake. Cachexia scores estimated by the modified SGA tool was SGA-A in 101, SGA-B in 120 and SGA-C in 18 patients. Only 37 (15.4%) had been subjected to screening for malnutrition prior to cancer treatment. 44 (20.5%) patients experienced neutropenic sepsis during treatment. At a median follow up of 457 days, 69% achieved complete remission at the end of initial therapy, 50 (20.9%) patients died during the study period. In univariate analysis, SGA, IPI, Stage and age groups were statistically significant prognostic markers. The 2-year actuarial survival of all patients adjusted for SGA, IPI and Stage was 72%. The two-year actuarial survival in the SGA-A, SGA-B, and SGA-C groups were respectively 80%, 68% and 45% (p<0.001). In a multivariate analysis using cox proportional hazards method the hazard ratio for SGA B was 1.67 (0.94-2.97), and SGA-C was 3.65, after adjusting for IPI and stage groups (p=0.0137).The follow up is continuing and final multivariate analysis will be done when sufficient events have occurred. Conclusions:Cachexia at diagnosis is an important independent prognostic biomarker in patients with ABNHL. The role of routine screening for cachexia before initiating treatments and providing individualized medical nutrition therapy along with physical therapy during chemotherapy to prevent worsening of cachexia and improve survival needs evaluation. References: 1.Shirodkar M etal, Indian J Gastroenterol.2005; 24:246-50 Figure Disclosures Patra: Baxter: Research Funding. Mallath:Otsuka Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; GlaxoSmithKline: Research Funding; Baxter: Research Funding; Otsuka Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Bayer-Zydus Pharma: Honoraria; Sayre-Therapeutics: Honoraria.

Clinical Relevance of JAK2V617F Allele Burden in Primary and Post-Polycythemic/Post-Thrombocythemic Myelofibrosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2799-2799
Author(s):  
Paola Guglielmelli ◽  
Giovanni Barosi ◽  
Alessandro Pancrazzi ◽  
Giovanni Longo ◽  
Elisabetta Antonioli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Clinical Relevance ◽  
Leukocyte Count ◽  
Group Analysis ◽  
Hemoglobin Level ◽  
Jak2v617f Mutation ◽  
Risk Category ◽  
Allele Burden ◽  
Mutational Status

Abstract The JAK2V617F mutation is found in 60% of patients (pts) with primary myelofibrosis (PMF) and &gt;90% with post-polycythemia vera MF (PPV-MF); few pts with post-essential thrombocythemia MF (PET-MF) have been reported. There are conflicting results about clinical relevance of V617F mutational status and/or burden in PMF, while no study specifically addressed this point yet in PPV/PET-MF. An association of mutation with poorer survival in PMF has been reported (Campbell P et al, Blood, 2006), while Tefferi A et al (Leukemia, 2008) found a reduced survival only for pts with lowest allele burden. Barosi G et al (Blood, 2007) found that JAK2V617F mutation independently predicted evolution towards large splenomegaly, splenectomy and leukemic transformation. We separately evaluated 2 groups of pts, 240 pts with PMF and 65 pts with secondary forms of MF (PPV-MF n=43, PET-MF n=22); the V617F allele burden was measured in granulocytes by RT-PCR. Diagnosis of PMF satisfied the 2008 WHO criteria, and that of PPV- or PET-MF the IWG-MRT criteria. PMF: 150 pts (63%) were JAK2V617F-pos, median V617F allele burden 45% (range, 1–100%); percentage of pts in the four allele quartiles was 16%, 50%, 15%, and 19%. Median interval from diagnosis to genotyping was 21 months. In multivariate analysis, JAK2V617F mutated patients had significantly higher leukocyte count (P=.02) and hemoglobin level (P&lt;.0001), that were both positively correlated with V617F burden (P= .03 and P=.01, respectively). Pts with Hb &lt;10g/dL were significantly less among JAK2V617-pos (12% vs 26%; P&lt;.007), accounting for a significantly greater proportion of mutated pts in the Lille low risk category (P=.04). Nor a mutated JAK2 genotype nor the V617F burden had any influence on presence or degree of palpable splenomegaly, thrombosis, hemorrhage, AML evolution, or cytoreductive treatment. 29 pts died (12.0%); survival was independent of JAK2 genotype, and was associated (multivariate analysis) only with age (95% CI, 1.07–1.18) and leukocyte count (95% CI, 1.02–1.10). Since we previously observed a time-dependent accumulation of mutated alleles in PMF, we performed a sub-group analysis in 90 pts in whom quantitation of V617F burden was performed within six months from diagnosis: 56 pts (62%) were mutated, median V617F burden was 36% (range, 10–100%); percentage of pts in the four allele quartiles was 27%, 50%, 16%, and 7%. Similar to the whole pts series, the only parameters significantly associated with allele burden were hemoglobin level, (P=.03), leukocyte count (P=.04) and low Lille score (P=.04). However, we found a statistically significant association (multivariate analysis) of lowest V617F burden quartile with shortened survival compared to patients having greater than 25% V617F allele or to JAK2V671F unmutated patients, corroborating finding from Tefferi et al (Leukemia, 2008). Using Cox analysis, reduced survival was associated with low V617F burden (P=.008), leukocytosis (P=−003) and age (P=.03). These findings indicate that a low V617F burden, measured at the time of diagnosis, has a negative impact on survival, and might represent a novel criterion for risk stratification in PMF. PPV/PET-MF: 49 pts (75.3%) were JAK2V617F mutated, median V617F allele burden 73% (10–100%). All 43 PPV-MF were mutated compared to 6/22 (27%) of PET-MF (P&lt;.01). Median V617F burden was significantly greater in PPV-MF than in 173 control PV pts (72% vs 52%; P&lt;.01), as well as in PET-MF (57% vs 26% in 200 control ET pts; P&lt;.001), supporting that accumulation of V617F alleles is a mechanism of evolution toward MF in JAK2V617F-positive PV or ET pts. However, since JAK2V617F mutation frequency was significantly lower in PET-MF pts (27.2%) than in ET pts (63.4%; P&lt;.01), genetic mechanisms other than JAK2V617F may have a dominant role in MF transformation of ET. A part for lower platelet count (P=.04) in JAK2V617F-pos PPV/PET-MF pts no other difference with unmutated pts was found. In the analysis of quartiles, we found a correlation of allele burden with age, leukocyte count and circulating CD34+ cell count (all P&lt;.05), while there was no impact on clinical characteristics including spleen size, thrombosis, hemorrhage, AML transformation or overall survival (median follow-up, 40 months). Therefore, both presence and burden of JAK2V617F seem to have little influence on disease phenotype in pts with PPV- or PET-MF, although larger series and longer follow-up might be warranted.

Autologous Stem Cell Transplantation (ASCT) in CLL. Results of a Phase III Randomized Multicenter Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 878-878 ◽  
Author(s):  
Laurent Sutton ◽  
Sylvie Chevret ◽  
Karim Maloum ◽  
Olivier Tournilhac ◽  
Marine Diviné ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Conditioning Regimen ◽  
Response Duration ◽  
Phase Iii ◽  
Fish Analysis ◽  
Safe Procedure ◽  
Mutational Status

Abstract Abstract 878 Introduction: We investigated, in a prospective randomized study, the place of ASCT in the frontline treatment of CLL. Patients and methods: From March 2001 to December 2007, 241 patients were included in the trial. Eligibility criteria were previously untreated stage B and C CLL patients under 66 years, characterized by Matutes score 4-5, absence of cyclin D1 expression, baseline flow assessment of ZAP 70 and CD38 expression, karyotype and FISH analysis, IgHv mutational status (centralized). Preceding randomization, initial chemotherapy consisted of 3 monthly courses of mini CHOP regimen as previously described, followed by 3 monthly courses of fludarabine, IV or oral. Patients achieving CR (NCI 1996 criteria plus normal CT scan) were randomized between observation and ASCT. Non CR patients were offered cisplatin/cytosine-arabinoside/dexamethasone (DHAP) rescue and randomized whatever the response between ASCT or 3 subsequent monthly IV courses of Fludarabine-Cyclophosphamide (FC). Conditioning regimen for ASCT consisted of cyclophosphamide IV (60 mg/sqm d-5-4) and fractionated total body irradiation (10 Gy). The primary end-point of the study was event-free survival at 3 years. Responses after initial treatment (i.e.before randomization) and after completion of therapy, overall survival, side effects, prognostic significance of clinical and biological characteristics at baseline were other endpoints. Results: Baseline characteristics were: gender (M/F: 3), age (median 56.4 years, range 33.3-66), stage B (185 patients) or C (56 patients). All enrolled cases but five (236 patients) started the treatment. Among them, 206 completed the six planned courses of initial chemotherapy. For the 236 patients, CR rate was 43.6%, and overall response was 89.8%. Forty two patients were not randomized because of treatment failure (19) or patient/physician decisions (23). After an observed median follow-up of 40.2 months (Q1-Q3, 17.9-47.9) at the reference date (1/1/2009), the overall survival for the 241 patients was 87.8% (95% CI, 83.3-92.6) at 3 years and 75.4% (95% CI, 66.2-88.6) at 5 years. For the 199 randomized patients, the overall survival was 90.9% (95% CI, 86.7-95.3) at 3 years. Among them 105 patients were in CR after initial treament and were allocated to ASCT (53 patients) or observation (52 patients) with a 3 years EFS of respectively 78.7% (95% CI, 67.7-91.4) and 31.3% (95% CI, 20.1-48.8) (p<0.00001). The median EFS from the start of the studied treatment was 26.2 months in the observation arm (not reached in the ASCT arm). Randomization (p=0.0001), mutational status (p<0.00001) and 11q deletion (p=0.001) remained independent prognostic factors for EFS in a multivariate analysis. There was no difference between ASCT and observation arms in terms of overall survival with 98% (95% CI, 94.3-100) and 97.5% (95% CI, 92.2-100)respectively. For the 94 patients not achieving CR and rescued with DHAP, the EFS at 3 years was 46.5% (95% CI, 33.6-66.3) in the ASCT arm (46 patients) and 43.2% (95% CI, 29.8-62.5) in the FC arm (48 patients). There was not statistical difference between these 2 arms but for the 34 patients actually autografted the EFS was 57.8% (95% CI, 41.7-80.2). The overall survival was not different for ASCT and FC arms: 81,2% (95% CI, 70.3-93.9) and 85,4% (95% CI, 75.1-97) respectively. In multivariate analysis, the only prognostic factor influencing the EFS (p=0.0001) and the overall survival (p=0.04) was the 17p deletion. The mutational status (non mutated) and the 17p deletion remained adverse prognostic factors in patients actually autografted. For the whole study, 28 patients allocated to ASCT did not receive this treatment mainly because of mobilisation failures (14 pts). Four MDS were recorded within the follow-up frame. Conclusions: ASCT is a safe procedure which significantly improves response duration in patients attaining CR after a first line treatment. For patients not in CR, ASCT or consolidation with 3 FC courses provide similar results on response duration but ASCT could be considered in patients without 17p deletion or with mutated IGHV gene. Disclosures: Van Den Neste: Roche: Research Funding.

Prognostic factors and therapeutic options for epithelioid hemangioendothelioma (EHE): A multicenter analysis of a series of fifty-seven cases.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11062-11062
Author(s):  
Aurore Vozy ◽  
Audrey Simonaggio ◽  
Philippe Terrier ◽  
Valerie Paradis ◽  
Nicolas Penel ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Prognostic Factor ◽  
Active Surveillance ◽  
Soft Tissues ◽  
Cox Model ◽  
Univariate Analysis ◽  
Poor Prognostic Factor ◽  
Free Survival ◽  
The Impact

11062 Background: EHE is a rare vascular mesenchymal tumor for which there is currently no standard for treatment particularly for metastatic disease. EHE often present metastatic evolution but metastases are not a poor prognostic factor. The aim of this study was to improve knowledge of outcome of EHE patients and see the impact of active surveillance on outcome for metastatic EHE patients. Methods: Patients with EHE treated at three centers in France were included in this retrospective cohort. Univariate analysis of prognostic factors was performed using the Cox model. Survival was estimated using the Kaplan-Meier method and long rank analysis. Results: Fifty-seven patients with EHE were collected in this analysis: 27 (47%) women and 30 (53%) men, with a median age at diagnosis of 39 years (range, 12-83). At diagnosis, 17 (29.8%) patients had a localized tumor, while 40 (70.2%) patients had synchronous metastases. The most commonly affected organs were liver (29.8%), bones (14.0%), skin, lungs and soft tissues (10.5% each). For the 17 patients with localized EHE, the median distant recurrence-free survival after resection of primary was 64.6 months, 95% CI [29.4, NA], (median follow-up of 62.7 months, range, 12.5-234.8). For the 40 patients with metastatic EHE, the median progression-free survival (PFS) was 59.0 months, 95% CI [21.3, NA], (median follow-up of 121.1 months, range, 1.0-202.0). No prognostic factor was identified for localized EHE. For metastatic EHE, age was associated with progression (p = 0.019), and presence of pleural/ascites/pericarditis effusion adversely affected overall survival (OS) (p = 0.002). An initial “wait and see” attitude was proposed to 23 patients (57.5%) while 17 patients (42.5%) were treated at diagnosis with local or systemic treatment (monotherapy or combination of chemotherapy with anthracyclin, taxane, cyclophosphamide). OS were similar in both groups of patients, 174months and 121months for chemotherapy treated patients and active surveillance patients respectively (p = 0.56). Conclusions: Presence of effusion was a significant poor prognostic factor in metastatic EHE patients. Active surveillance could be proposed for asymptomatic patients without effusion but this strategy need to be confirmed in largest or prospective randomized trials.

Low expression of gamma-glutamyl transpeptidase 1 is an independent poor prognostic factor in ovarian clear cell carcinoma, in relation to up-regulation of immune suppressive genes and EMT-related genes.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6042-6042
Author(s):  
Hiroshi Asano ◽  
Ryosuke Matsuoka ◽  
Kanako C Hatanaka ◽  
Daisuke Endo ◽  
Ayako Nozaki ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Cell Carcinoma ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Ovarian Clear Cell Carcinoma ◽  
Poor Prognostic Factor ◽  
Gsh Metabolism ◽  
Low Expression

6042 Background: Ovarian clear cell carcinoma (OCCC) is a distinct entity from other epithelial ovarian cancers such as the most prevalent high-grade serous cancer (HGSC), and often exhibit less sensitivity to platinum-based chemotherapy. Several studies using cell lines have reported that glutathione (GSH) metabolism plays an important role in chemo-resistance of OCCC. Here, we aimed to correlate the prognosis of OCCC and the expression of gamma-glutamyltransferase 1 (GGT1), one of the key enzymes in GSH metabolism. Methods: We prepared a FFPE-tissue microarray, and analyzed 56 OCCC patients with the follow-up periods over 3 years. Expression level of GGT1 was evaluated by immunohistochemistry (IHC) using H-score (0-300), and was correlated with clinical outcomes. The prognostic significance was assessed by multivariate analysis using Cox regression model. To investigate the possible related pathways, we performed transcriptome analysis using Ion AmpliSeq Transcriptome Human Gene Expression Kit (Thermo Fisher Scientific) from the frozen tissue specimens collected from 33 ovarian cancer patients including 15 OCCC patients and 18 HGSC patients. Results: The OCCC patients were divided into two populations in the histogram of H-score in IHC staining, and the cut-off value was 90; 44 cases showed GGT1-high, and remaining 12 cases were GGT1-low. Follow-up periods, FIGO stage, and optimal surgery rate were not significantly different between two groups. However, platinum-resistant recurrent rate was significantly higher (42% vs. 14%, p=0.027), and overall survival (OS) was significantly shorter (5-year OS; 42% vs. 72%, p=0.0226) in GGT1-low OCCC. Multivariate analysis revealed that low expression of GGT1 was one of the independent poor prognostic factors as well as platinum-drug resistance. In enrichment analysis, the genes related to GSH metabolism, such as SLC3A1, GGT1, CSE, and GPX3 were up-regulated and positively correlated with HNF1B expression in OCCC. The expression level of GGT1 was inversely correlated with that of immune suppressive genes (TGF-b, IFNG, IL10, FOXP3, PD-L1, CTLA4) and epithelial-mesenchymal transition (EMT)-related genes (CDH2, VIM, TWIST1, ZEB1, ZEB2) in OCCC samples. Conclusions: Low expression of GGT1 is an independent poor prognostic factor probably in part due to suppression of tumor immunity and induction of EMT in OCCC.

scholarly journals Outcomes of older patients with NPM1-mutated AML: current treatments and the promise of venetoclax-based regimens

2020 ◽  
Vol 4 (7) ◽  
pp. 1311-1320 ◽  
Author(s):  
Curtis A. Lachowiez ◽  
Sanam Loghavi ◽  
Tapan M. Kadia ◽  
Naval Daver ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Older Patients ◽  
Type I Error ◽  
Cox Model ◽  
Standard Of Care ◽  
Complete Response ◽  
Type I ◽  
Risk Of Death ◽  
Beneficial Impact ◽  
Count Recovery

Abstract Nucleophosmin-1 mutations (NPM1+) occur in ∼30% of acute myeloid leukemia (AML) patients. Although typically associated with favorable prognosis, the beneficial impact of NPM1+ decreases with increasing age in patients treated with standard intensive chemotherapy (IC) or hypomethylating agents (HMAs). This retrospective analysis compared outcomes of NPM1+ AML patients treated with 1 of 3 induction approaches: HMA plus BCL-2 inhibitor venetoclax (VEN), HMA, or IC therapy. Composite complete response (CRc: CR + CR with incomplete count recovery) was seen in 96% (27/28), 36% (17/47), and 89% (204/228) of HMA + VEN, HMA, and IC patients, respectively (HMA + VEN vs HMA, P &lt; .001; HMA + VEN vs IC, P = .10). Older patients (age &gt;65 years) treated with HMA + VEN, HMA, or IC had CR rates of 88%, 28%, and 56%, respectively (HMA + VEN vs HMA, P &lt; .001; HMA + VEN vs IC, P = .01). Significant improvement in overall survival (OS) was seen in patients age &gt;65 years treated with HMA + VEN vs HMA (not reached [NR] vs 0.4 years; P &lt; .001) or IC (NR vs 0.93 years; P = .001). Older patients treated with HMA + VEN had OS of 80% after median 1-year follow-up, with estimated 2-year OS of 70%. In the multivariable Cox model analysis, HMA + VEN was associated with a 69% lower risk of death compared with IC (hazard ratio, 0.31; 95% confidence interval, 0.12-0.83; type I error–adjusted P = .038). HMA + VEN combinations demonstrated impressive results compared with traditional standard-of-care regimens in older patients with NPM1+ AML.

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