European Collaborative Study of Treatment Outcomes in 347 Patients with Systemic AL Amyloidosis with Mayo Stage III Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 995-995 ◽  
Author(s):  
Ashutosh Wechalekar ◽  
Stefan O Schonland ◽  
Efstathios Kastritis ◽  
Philip N Hawkins ◽  
Meletios A. Dimopoulos ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Clinical Trials ◽  
High Risk ◽  
Cardiac Involvement ◽  
Staging System ◽  
Stage Iii ◽  
Al Amyloidosis ◽  
High Risk Factors ◽  
Intent To Treat

Abstract Abstract 995 N-terminal fragment of BNP (NT-proBNP) and cardiac troponin –T (TnT) or I (TnI) form a useful staging system in AL amyloidosis and poor outcomes have been reported in stage III patients treated before routine use of novel agents. These patients are routinely excluded from clinical trials and prospective outcome data is limited but recent studies suggest that some such patients may have better outcomes. We report the outcomes of 347 patients with Mayo stage III AL amyloidosis seen at the amyloid centres in London (UK), Pavia (Italy), Heidelberg (Germany) and Athens (Greece). Organ involvement and responses are defined according to 2005 amyloidosis consensus criteria. Presenting features were [n (%)/median (range)]: cardiac, renal and liver involvement in 338 (97%), 216 (62%) and 77 (22%) respectively, NT-proBNP 9106 ng/L (379–216187); TnI – 0.18 ng/ml (0.1–12); TnT −0.09 ng/ml (0.04–8.2) and IVS 15 mm (7–24). Treatments given were: Bortezomib combinations - 23 (7%), MDex - 150 (43%), thalidomide combinations - 96 (28%), lenalidomide combinations - 13 (4%). 30 (8%) were deemed too ill for treatment or died prior to treatment initiation. Only 37% completed the planned treatment course. The haematological responses on an intention to treat basis were seen in (Overall response rate/complete response (CR)/partial response (PR))(n(%)): MDex – 63(42%)/24 (16%)/39 (26%); Thalidomide combinations 31(32%)/11(12%)/20(21%), bortezomib combinations 10(43%)/6 (23%)/4 (17%), lenalidomide combination 5(38%)/0(0%)/5(38%). The median overall survival (OS) was 7.1 mos. The overall survival at 12 months from response evaluation was 74% for CR, 52% for PR and 18% for NR and from diagnosis was (median): CR – 59 mo, PR 28 mo, NR 10 mo and not assessable for response 2.9 mos. Stage III patients without echocardiographic evidence of cardiac involvement had excellent outcomes with 80% estimated 2 year OS. Using best fit cut-off, in multivariate model (including NT-proBNP., systolic blood pressure (SBP), ejection fraction, NYHA, ECOG, dFLC, LV wall thickness), NT-proBNP > 8000 ng/L (HR 2.3; p <0.0001) and SBP < 100 mm of Hg (HR 1.6; p<0.0001) were the only independent predictors of poor outcome. Using NT-proBNP >8000 ng/L and SPB <100 mm of Hg as high risk criteria, stage III patients can be further subdivided based on presence of none, one or two criteria with OS of 25 mo, 6 mo and 3 mo respectively. Using these criteria, on intent to treat basis, OS by CR/PR/NR was: no high risk factors – median not reached/69 mo/7 mo and one high risk factor - 59 mo/23 mo/4 mos respectively and too few patients for patients with two high risk factors making comparison unreliable. In conclusion, outcomes amyloidosis patients with stage III disease remain poor. However, stage III patients are heterogeneous and combination of NT-proBNP and SBP can usefully sub-classify these patients. Patients with abnormal biomarkers just due to renal failure in absence of cardiac involvement should be excluded from the current Mayo staging system. Although, treatment responses of stage III patients, on intent to treat basis, are poor with all regimes, it is encouraging that haematological responses improve outcomes and patients who achieve a CR have best outcomes. Clinical trials are urgently needed in patients with stage III disease to confirm these findings and define optimal treatment options. Disclosures: No relevant conflicts of interest to declare.

Efficacy and toxicity of postoperative external beam radiotherapy or chemoradiation for early-stage cervical cancer

2020 ◽  
Vol 30 (12) ◽  
pp. 1878-1886
Author(s):  
Mick J E van den Akker ◽  
Nanda Horeweg ◽  
Jogchum Jan Beltman ◽  
Carien L Creutzberg ◽  
Remi A Nout
Keyword(s):  
Risk Factors ◽  
Cervical Cancer ◽  
Overall Survival ◽  
Risk Factor ◽  
High Risk ◽  
Early Stage ◽  
Free Survival ◽  
High Risk Factors ◽  
Early Stage Cervical Cancer ◽  
Risk Factors For Recurrence

ObjectiveThe aim of this study was to assess the impact of the evolving role of the addition of chemotherapy to postoperative radiotherapy on oncological outcomes and toxicity in patients with early-stage cervical cancer after radical hysterectomy.MethodsRetrospective cohort study of patients with stage IB1–IIB FIGO 2009 cervical cancer treated from November 1999 to May 2015 by primary surgery and radiotherapy (46–50.4 Gy in 1.8–2.0 Gy fractions) with or without concurrent cisplatin (40 mg/m2, 5–6 weekly cycles) with or without a brachytherapy boost. Chemotherapy was allocated depending on the risk factors for recurrence. Incidences of all outcomes were calculated using Kaplan–Meier’s methodology and compared by log-rank tests. Risk factors for recurrence and survival were identified using Cox’s proportional hazards models.ResultsA total of 154 patients were included, median follow-up was 9.6 years (IQR: 6.1–12.8). Five-year pelvic recurrence-free survival was 75.3%; 74.7% in patients with high-risk factors treated with radiotherapy; and 77.3% in those treated with chemoradiation (P=0.43). Distant metastasis-free survival at 5 years was 63.4%; 63.6% in high-risk patients after radiotherapy; and 57.1% after chemoradiation (P=0.36). Five-year overall survival was 63.9%: 66.8% and 51.6% after radiotherapy and after chemoradiation in patients with high-risk factors (P=0.37), respectively. Large tumor size was a risk factor for vaginal and pelvic recurrence, ≥2 involved lymph nodes was a significant risk factor for para-aortic recurrence and death. Mild treatment-related late toxicity was observed in 53.9% of the patients. Five-year severe (grade 3–5) late rectal, bladder, bowel, and vaginal toxicities were, respectively, 1.3%, 0%, 3.4%, and 0.9%. Any late severe toxicity was observed in 5.5% of patients treated with radiotherapy and in 15.3% of those treated with chemoradiation (P=0.07).ConclusionPostoperative (chemo)radiation for early-stage cervical cancer patients with risk factors for recurrence yields adequate pelvic tumor control, but overall survival is limited due to distant metastasis.

Pre-Transplant Variables Affecting the Outcome of Submyeloablative Allogeneic HSCT in Uniformly Treated Patients with Hematologic Malignancies.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2324-2324
Author(s):  
Jayesh Mehta ◽  
S. Singhal ◽  
M. Tallman ◽  
S. Williams ◽  
J. Winter ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
Risk Factor ◽  
High Risk ◽  
Cox Model ◽  
Performance Status ◽  
Hematologic Malignancies ◽  
Current Treatment ◽  
Allogeneic Hsct ◽  
High Risk Factors

Abstract The outcome of 63 consecutive submyeloablative allografts (27–66 y, median 52) performed for hematologic malignancies after 100 mg/m2 melphalan without (n=21; prior autograft) or with (n=42; no prior autograft) 50 mg/kg cyclophosphamide was analyzed to study the effect of pre-transplant characteristics. GVHD prophylaxis comprised cyclosporine-mycophenolate (n=37; HLA-identical sibling donors) or tacrolimus-mycophenolate (n=26, 1-locus mismatched sibling or 9–10/10 allele-matched unrelated). No growth factors were administered routinely post-transplant and supportive care was uniform. 14 patients experienced transplant-related mortality (TRM), and 32 relapsed. 24 relapsing patients died, and 7 of the other 8 are alive in CR or with declining disease. The following factors were analyzed in a Cox model for their effect on TRM and relapse: chemosensitive (n=25) vs refractory disease (n=38), age ≤55 (n=44) vs >55 (n=19), normal (n=32) vs abnormal (n=31) LDH, HLA match (n=56) vs mismatch (n=7), prior autograft or not, performance status 0–1 (n=47) vs 2–3 (n=16). Outcome Favorable factor RR (95% CI) P TRM Age ≤55 0.20 (0.04–0.86) 0.03 HLA matched 0.21 (0.05–0.89) 0.04 Performance status 0-1 0.25 (0.06–0.99) 0.05 Relape Chemosensitive disease 0.28 (0.11–0.73) 0.01 Fig 1 shows TRM for patients with 0, 1 or 2 high-risk factors for TRM. Fig 1 shows TRM for patients with 0, 1 or 2 high-risk factors for TRM. Fig 2 shows overall survival (OS) for patients with 0 or 1 high-risk factors for TRM by disease chemosensitivity. Fig 2 shows overall survival (OS) for patients with 0 or 1 high-risk factors for TRM by disease chemosensitivity. Table 2 shows the causes of death by risk factors for TRM and disease chemosensitivity. Group (n) Alive TRM Death from disease A: 2 risk factors for TRM (7) 1 (14%) 5 (71%) 1 (14%) B: 1 risk factor for TRM + Refractory (19) 2 (11%) 6 (32%) 11 (58%) C: 1 risk factor for TRM + Sensitive (9) 5 (56%) 1 (11%) 3 (33%) D: 0 risk factor for TRM + Refractory (12) 3 (25%) 1 (8%) 8 (67%) E: 0 risk factor for TRM + Sensitive (16) 13 (81%) 1 (6%) 2 (13%) These data suggest that while the current treatment approach is optimal for patients falling in Group E, modified approaches are needed for other patients. Based on the causes of failure, the following modifications appear to be warranted. Group A: A completely non-ablative regimen to reduce toxicity. Group B: A completely non-ablative regimen to reduce toxicity with augmentation of graft-vs-tumor effects by elective donor leukocyte infusions and/or abbreviated immunosuppression. Group C: Augmentation of graft-vs-tumor effects by elective donor leukocyte infusions and/or abbreviated immunosuppression. Group D: Conventional-intensity rather than reduced-intensity allogeneic HSCT.

Allograft After Pediatric-Inspired Therapy Does Not Improve Young patient's Outcome with High Risk Philadelphia- Chromosome-Negative Acute Lymphoblastic Leukemia (Ph-ALL). A Single Center Report

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3528-3528
Author(s):  
Thibaut Leguay ◽  
Arnaud Pigneux ◽  
Reza Tabrizi ◽  
Mathieu Sauvezie ◽  
Krimo Bouabdallah ◽  
...  
Keyword(s):  
Risk Factors ◽  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Induction Chemotherapy ◽  
Fusion Transcript ◽  
Low Risk ◽  
Multicentric Study ◽  
High Risk Factors ◽  
The Impact

Abstract Abstract 3528 Allogeneic stem cells transplant (allo-SCT) is currently the preferred therapeutic option for young adults with Ph- ALL in first CR. However, the results of different studies suggested that pediatric-inspired therapy have markedly improved the outcome of these patients. In our monocentric study, we analyzed the impact of the allo-SCT on outcome in adults treated within these pediatric-inspired trials. Between April 2002 and March 2010, 75 young adult patients with Ph- ALL were treated in our clinical unit. 70 patients (49 men and 21 women) were in complete remission (CR) (93%) after induction chemotherapy (4 after two courses), 2 died before evaluation (3%) and 3 patients were refractory and died with progressive disease (4%). The median age of the population was 33 years (range, 16–59). Among the 70 patients in CR, 54 (77%) were considered at high-risk ALL and therefore eligible for allo-SCT after 1 or 2 consolidation courses. Baseline high-risk factors were: WBC count of ≥ 30 × 109/L for B-lineage ALL, clinical and/or morphologic CNS involvement, t(4;11) and/or MLL-AF4 fusion transcript, t(1;19) and/or E2A-PBX1 fusion transcript and low hypodiploidy and/or near-triploidy. Fourteen patients with low-risk ALL received chemotherapy alone with late intensification followed by maintenance therapy. With a median follow-up of 36.5 months, median overall survival (OS) for the entire population was not reached and the estimated OS at five years was 75% (70-80%). The high-risk factors as previously defined could separate two different groups with statistically different outcome. In the low-risk (LR) group, none patient died or relapsed during this study. While, in the high-risk (HR) group, 11 of 54 patients (20%) relapsed and 14 patients (26%) died. For the LR group and the HR group, the estimated OS at five years was respectively 100% and 69% (64-74%) (p=0.04) and the estimated disease free survival (DFS) was respectively 100% and 61% (56-66%) (p=0.02). In the HR group, 30 of the 54 patients (55.5%) had donor and had received allogeneic SCT, 28 of 30 patients after myeloablative conditioning regimen, 12 patients with related donor and 18 patients with unrelated donor. The 24 other patients without donor had received the same chemotherapy than patients in the LR group with late intensification and maintenance therapy. There was no difference between the two subgroups for death: 6 patients with donor (D+) and 8 without donor (D-). Nevertheless, there was more relapses in the subgroup D- (8 relapses) than in the subgroup D+ (3 relapses) (p=0.006). At five years, in the subgroup D+, the estimated OS and DFS were respectively 75 % (68-82) and 72 % (66-78). In the subgroup D-, the estimated OS and DFS were respectively 62 % (55-69) and 48 % (41-55). There was no difference between two subgroups D+ and D- for OS (p=0.4) and DFS (p=0.19). In addition, there was no difference for age, sex, risk factor and initial characteristic of the disease. These results suggest that allograft might not improve the outcome of patient with high-risk Ph- ALL. One explanation is that pediatric-inspired induction chemotherapy improves the outcome of the whole population (75% of overall survival) and this advantage decreases the impact of the allo-SCT. Nevertheless, allo-SCT decreased the risk of relapse but did not modify OS and DFS. However, more patients are necessary to confirm these results in a multicentric study. Disclosures: No relevant conflicts of interest to declare.

High-Dose Melphalan and Stem Cell Transplantation for Patients with AL Amyloidosis and Cardiac Involvement

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2043-2043
Author(s):  
Saulius Girnius ◽  
David C Seldin ◽  
Karen Quillen ◽  
Nancy T Andrea ◽  
John Mark Sloan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cardiac Involvement ◽  
Troponin I ◽  
Performance Status ◽  
Stage I ◽  
Stage Iii ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cardiac Biomarker ◽  
High Dose Melphalan

Abstract Abstract 2043 Treatment of AL amyloidosis (AL) with high dose melphalan and autologous stem cell transplant (HDM/SCT) results in a high rate of durable complete hematologic responses associated with clinical responses and improvement in survival. However, patients with cardiac involvement are at increased risk of treatment-related mortality (TRM). Recently, cardiac biomarkers, B-type natriuretic peptide (BNP) and troponins, have been used to predict survival for AL amyloidosis patients, including those undergoing treatment with HDM/SCT. Here we report on treatment-related mortality (TRM), overall survival, and time to next treatment (progression) and hematologic responses in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarker stage, treated with HDM/SCT. Eligibility for HDM/SCT was based upon strict functional and clinical criteria rather than upon staging based upon biomarkers, and required a Zubrod performance status <2, NYHA heart failure class < III, left ventricular ejection fraction (LVEF) >40%, and adequate cardiopulmonary reserve at a stair climb. Cardiopulmonary exercise testing was also used for some patients. Cardiac involvement was determined by electrocardiographic and echocardiographic abnormalities, as defined by Consensus Opinion of the 10th Symposium on Amyloid and Amyloidosis. A cardiac risk assessment or “cardiac staging” system incorporating biomarkers was used, with patients assigned to stage I (normal biomarkers, BNP < 100 pg/mL and troponin I < 0.1 ng/mL), II (one elevated biomarker) or III (both biomarkers elevated). Between 1/2008 and 10/2010, 35 patients with AL amyloidosis and cardiac involvement were treated with HDM/SCT. The median age was 58 years (range, 41–72). There were 17 males (49%) and 29 (83%) with lambda clonal plasma cell dyscrasia. All but one patient had multi-organ involvement and 80% (n=28) had renal involvement. Eleven percent (n=4) patients had cardiac biomarker stage I disease, 31% (n=11) had stage II disease, and 57% (n=20) had stage III disease. The median troponin I level was 0.121 ng/mL (range, 0.006 – 0.523), and the median BNP was 224 pg/mL (range, 18–923). The median interventricular septal thickness was 13 mm (range, 9–18) and the median LVEF was 60% (range, 40–70). Peripheral blood stem cells were mobilized using G-CSF alone at 10–16 m/kg/day for 3–4 days. The total dose of melphalan, administered over two consecutive days, depending on age, severity of cardiac disease and performance status. Forty % (n=14) received 200 mg/m2 HDM and 60% (n=21) received 140 mg/m2 HDM. TRM, defined as deaths within 100 days of SCT, occurred in 3 patients (9%), all cardiac stage III (3/20, 15% of the stage III patients); patients with cardiac stage I or II did not have any TRM. This compares to a TRM of 3% (n=1/30) in patients without cardiac involvement who were treated with HDM/SCT during the same time period (Fisher's exact test, p=0.6177). There were two additional deaths during the first year after HDM/SCT, one with cardiac stage II disease and one with stage III disease. Three-year overall survival for combined Stage I and II disease was 93%, for Stage III it was 76%, and for the cohort without cardiac involvement it was 96% (p=0.08). Three-year progression free survival for combined Stage I and II disease was 69%, for Stage III it was 45%, and without cardiac involvement it was 69% (p=0.0424). Median overall survival and progression free survivals have not been reached, with a median follow-up for 21 months. By intention-to-treat analysis, 23% (n=8) of patients achieved a hematologic complete response (CR) and 46% (n=16) a partial response (PR) at 1 year following HDM/SCT. Thirty % (n=11) required additional treatment by one year following HDM/SCT. While the cardiac biomarker stage III group clearly encompasses patients at high risk of early mortality from disease and complications of treatment, for patients that meet functional criteria for HDM/SCT, this therapeutic modality may offer the potential for effective treatment for selected stage III patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Analysis of classical high risk factors in stage III colon cancer: Experience at University Hospital Ramon y Cajal (UHRyC)

2018 ◽  
Vol 29 ◽  
pp. v67
Author(s):  
J. Serrano Domingo ◽  
R. Martín Huertas ◽  
A. Barquín García ◽  
E. Corral de la Fuente ◽  
C. Saavedra Serrano ◽  
...  
Keyword(s):  
Risk Factors ◽  
Colon Cancer ◽  
High Risk ◽  
University Hospital ◽  
Stage Iii ◽  
Stage Iii Colon Cancer ◽  
High Risk Factors ◽  
Cancer Experience ◽  
Ramón Y Cajal

scholarly journals The Effect of Cytogenetic Abnormalities on Organ Involvement and Survival in Patients with AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1833-1833
Author(s):  
Michael Ozga ◽  
Qiuhong Zhao ◽  
Don M. Benson ◽  
Patrick Elder ◽  
Nita Williams ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Plasma Cell ◽  
Cardiac Involvement ◽  
Response To Therapy ◽  
Al Amyloidosis ◽  
Prognostic Impact ◽  
Cytogenetic Abnormalities ◽  
Kidney Involvement ◽  
The Impact

Introduction: Systemic light chain amyloidosis (AL) is a clonal plasma-cell neoplasm that carries a poor prognosis. Efforts are being made at recognizing this disease earlier and developing better prognostic tools as AL is frequently diagnosed at an advanced stage. Cytogenetic analysis and its prognostic relevance have been well studied in multiple myeloma (MM), a related disorder, but remain relatively unknown and less widely reported in AL literature. Previous studies have demonstrated that AL amyloidosis exhibits an increased incidence of translocation t(11;14). However, with an extensive array of fluorescence-in-situ hybridization (FISH) probes now available, multiple other cytogenetic abnormalities are being identified in AL at diagnosis. In addition, it is well known that cardiac involvement in AL is an independent negative prognostic factor for these patients; however, the implications of cytogenetics for these high-risk patients remains largely unexplored. Finally, with the advent of novel non-transplant therapy options for AL patients, we look to evaluate the relevance of daratumumab in this setting. As such, the present study aims to a) determine the most relevant FISH abnormalities in AL patients and establish their importance as independent prognostic factors for response to therapy and in survival, b) assess the impact of cytogenetics on the survival of cardiac AL patients, and c) determine the effect of daratumumab on the survival of patients with AL. Methods: A retrospective chart review was performed on 140 consecutive AL patients treated at The Ohio State University. This cohort included 20 patients who received daratumumab. Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis. Hyperdiploidy was defined as trisomies of at least 2 chromosomal loci. Primary endpoints were progression free survival (PFS) and overall survival (OS), and Kaplan Meier curves were used to calculate PFS and OS. Results: The median age at diagnosis was 62 years (range: 33-88) and 55% were male. Median number of organs involved was 2, and 49% and 65% had cardiac and kidney involvement, respectively. Chromosomal abnormalities were detected in 86 (61%) patients. Translocation t(11;14) was the most prevalent (44%) aberration followed by hyperdiploidy (43%). We observed a statistically significant relationship between several FISH abnormalities and increased plasma cell burden (PC) (≥10%), including gain (+) 5p/5q (p=0.025), del13q (0.009), +11q (p<0.001), and hyperdiploidy (p<0.001). In addition, hyperdiploidy was associated with worsening of PFS (p=0.019) and OS (p=0.032) (Figure 1A). In multivariable analysis, hyperdiploidy was confirmed to be a poor prognostic marker after adjusting for other confounding variables. In patients with cardiac involvement, hyperdiploidy was also associated with worsening of PFS (p=0.0497) and OS (p=0.006) (Figure 1B). Del 13q was found to be associated with cardiac involvement (p=0.01) but showed no prognostic impact on survival. Conversely, survival benefit was seen among these patients with cardiac involvement who had no FISH abnormalities at diagnosis, both in terms of OS and PFS (p=0.019 and p=0.042, respectively). In addition, the overall presence of t(11;14) did not have any prognostic impact on OS (p=0.76) or PFS (p=0.41). However, on further stratification, we did observe a marginal difference in PFS (p=0.09) among four groups (Figure 1C), and more specifically, patients with presence of only t(11;14) did worse compared to those patients with normal FISH in terms of PFS (p=0.021). This potentially suggests that patients with t(11;14) only are at risk for earlier progression. Finally, we evaluated the efficacy of daratumumab, and observed a median OS of 6.1 years and median PFS 2.6 years. Of note, presence of gain 1q was associated with a trend toward better response to daratumumab. 100% of patients (5/5) with gain 1q achieved a hematologic partial response (PR) or better versus only 60% of patients without +1q. Conclusion: Our findings reveal the effect of hyperdiploidy on PC tumor burden, overall survival, and its importance within the high-risk cardiac AL patient population. The results with daratumumab in our patient subset with gain 1q is intriguing in its own right but identification of the mechanism by which the effect of this mutation is abrogated merits further exploration as its use only continues to grow. Disclosures Rosko: Vyxeos: Other: Travel support. Efebera:Takeda: Honoraria; Akcea: Other: Advisory board, Speakers Bureau; Janssen: Speakers Bureau.

Elevated Serum Levels Of Von Willebrand Factor (vWF) Predict For Early Death and Shorter Survival In Patients With Primary Systemic Light Chain (AL) Amyloidosis Independently Of Cardiac Biomarkers

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3194-3194
Author(s):  
Efstathios Kastritis ◽  
Ioannis Papassotiriou ◽  
Evangelos Terpos ◽  
Alexandra Gougoutsi ◽  
Nikolaos Simos ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
High Risk ◽  
Cardiac Involvement ◽  
Early Death ◽  
Cardiac Biomarkers ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Initiation Of Therapy

Abstract Organ dysfunction in systemic light chain (AL) amyloidosis is caused by the deposition of amyloid fibrils composed of immunoglobulin light chains in tissue microcirculation. vWF is mainly produced, stored and secreted by endothelial cells (ECs) and it is critical for thrombus formation. The secretion of vWF by ECs is triggered by several conditions and it has been proposed that changes in the levels of circulating vWF may reflect a state of “stimulation” of the endothelium. Cardiac involvement is the main determinant of prognosis in AL amyloidosis, but the role of endothelium in this disease has not been extensively studied and no marker of endothelial dysfunction has been evaluated, as yet. Thus, we studied the prognostic role of vWF in patients with AL amyloidosis who were treated with novel agents. The vWF antigen (vWFag) levels were measured using a latex particle-enhanced immunoturbidimetric assay (HemosIL vWF antigen) with an automated coagulometer (ACL Top 3G, Instrumentation Laboratory, Lexington, MA, USA). The inter- and intra-assay CVs were 2% and 3% at a concentration of 123.5 U/dL, respectively, and the lower limit of detection was 2.2 U/dL. The analysis included 81 consecutive patients with newly diagnosed AL amyloidosis who were treated in a single center (Department of Clinical Therapeutics, University of Athens, Greece) from 2005 to 2012. Median age of the patients was 68 years (range 42-82 years) and the median number of involved organs was 2; heart was involved in 62%, kidneys in 74%, peripheral nerve in 24%, liver in 9% and soft tissue in 21% of patients. Median NTproBNP level was 2,318 pg/mL (range 33-75,000 pg/mL); 36% had NTproBNP levels ≥4,000 pg/mL and 28%, 38% and 34% of patients had Mayo stage -1, -2 and -3, respectively. Primary therapy based on bortezomib was given in 52% of patients, on lenalidomide in 44%, while 4% received MDex. Median survival of the cohort was 47 months; 3- and 6-month mortality was 12% and 20%, respectively. The median serum level of vWFag in patients with AL amyloidosis was 181 (range 20-557) U/dL and was significantly higher than that measured in healthy controls (median: 84 U/dL, range 48-124; p <0.001). There was no significant association of vWFag levels with renal, cardiac, nerve or liver involvement. There was no significant correlation of vWFag levels with the levels of NTproBNP (or BNP) or Mayo stage and there was no significant correlation with the degree of renal dysfunction, serum albumin levels or proteinuria. Levels of involved free light chains did not have any correlation with vWFag levels either. We then examined the prognostic significance of vWFag and we found that levels of vWFag within the top quartile (≥230 U/dL) were associated with a very poor outcome (median survival 4 months vs. 47 months, p=0.001). Because the most important predictor of early death in patients with AL amyloidosis is cardiac involvement, we performed a multivariate analysis which included NTproBNP levels: vWFag levels ≥230 U/dL were independently associated with survival (HR: 2.64, 95% CI 1.2-5.8, p=0.01), along with NTproBNP levels ≥4,000 pg/ml (HR: 4.17, 95% CI 1.98- 8.8, p<0.001). Because the survival curves indicated that patients with vWFag ≥230 U/dL had a significant probability of early death, we performed an analysis to identify whether vWFag is a significant predictor of early death, adjusting for the levels of NTproBNP ≥4000 pg/mL. Thus, in multivariate analysis, vWFag ≥230 U/dL was independent predictor of death within 6 months from initiation of therapy (HR: 15, 95% CI 2.6-84, p=0.002) together with NTproBNP ≥4,000 pg/mL (HR: 16.8, 95% CI 3- 94, p=0.001). A combination of the two risk factors was able to identify patients at a very high risk of early death: 75% of patients with both risk factors present died within 3 months from initiation of therapy (figure). In conclusion, vWFag levels are elevated in patients with AL amyloidosis but are not correlated with other features of the disease, such as pattern of organ involvement and cardiac biomarkers. For the first time, we found that high levels of vWFag are associated with a high risk of early death and shorter survival in patients with AL amyloidosis, independently of cardiac biomarkers. In addition, wWFag levels improve the prognostic ability of cardiac biomarkers in patients with AL amyloidosis. Our data also justify the investigation of the role of endothelial dysfunction in AL amyloidosis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Integrated Analysis of B-Cell Maturation Antigen-Specific CAR T Cells (CT053) in Relapsed and Refractory Multiple Myeloma Subjects By High-Risk Factors

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1751-1751
Author(s):  
Chengcheng Fu ◽  
Songfu Jiang ◽  
Jie Jin ◽  
Wenming Chen ◽  
Siguo Hao ◽  
...  
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
Phase 1 ◽  
Stage Iii ◽  
Efficacy And Safety ◽  
Car T Cells ◽  
High Risk Factors ◽  
B Cell Maturation ◽  
Car T ◽  
Grade 3

Abstract Background: For relapsed and refractory multiple myeloma (RRMM), various clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor (CAR) T-cell clinical trials are under way. For one such treatment, CT053, the Phase 1 investigator-initiated CG studies (NCT03380039, NCT03716856, NCT03302403) and the Phase 1 LUMMICAR STUDY 1 (NCT03975907) demonstrated deep and durable responses in heavily pretreated subjects with RRMM. Here we report integrated efficacy and safety of CT053 in Chinese subjects with RRMM based on high-risk factors. Methods: All subjects had received ≥2 prior therapies, including at least an immunomodulatory drug and a proteasome inhibitor. Subjects also could have had exposure to an anti-CD38 antibody. All subjects were refractory to the last therapy per International Myeloma Working Group criteria. After lymphodepletion, subjects received a dose of 0.5 (n=1), 1.0 (n=4), 1.5 (n=32), or 1.8 (n=1) ×10 8 CAR+ T cells. We performed an integrated subgroup analyses of efficacy and safety in subjects stratified by high-risk characteristics, including extramedullary disease (EMD), high-risk cytogenetics [del(17p), t(4;14), t(14;16), t(14;20) and gain 1q], and International Staging System (ISS) stage III. Results: A total of 38 subjects (LUMMICAR STUDY 1: n=14; CG studies: n=24) were treated with CT053 in Phase I studies in China. Of these, 31.6% subjects (12/38) had EMD, 47.4% (18/38) had high-risk cytogenetics, and 28.9% (11/38) had ISS stage III disease. After a median follow-up of 13.9 months, the objective response rate (ORR), complete response (CR) rate, median duration of response (mDOR) and median progression-free survival (mPFS) were 92.1%, 78.9%, 24.0 months [95% CI 13.3 months-not reached (NR)] and 22.7 months (95% CI 13.3 months-NR), respectively. The ORRs for subjects with EMD, high-risk cytogenetics, and ISS stage III were 91.7% (95% CI 0.62-1.00), 83.3% (95% CI 0.59-0.96), and 81.8% (95% CI 0.48-0.98), respectively. A lower CR rate and poorer mDOR and mPFS were observed in subjects with EMD compared to subjects without EMD (58.3% vs 88.5%, 9.2 months vs 24.0 months, and 9.3 months vs 25.0 months, respectively). Although high-risk cytogenetics and ISS stage III disease at baseline did not substantially affect the CR rate, they seemed to negatively impact the DOR and PFS. The mDOR and mPFS were 14.8 months (95% CI 8.5 months-NR) and 15.6 months (95% CI 6.2-25.0 months) respectively for subjects with high-risk cytogenetics, and 13.3 months (95% CI 7.6 months-NR) and 13.3 months (95% CI 0.9 months-NR), respectively for subjects with ISS stage III. The median DOR and median PFS had not been reached in subjects without these two high-risk factors (Figure 1). No dose limiting toxicity or CT053 treatment-related death occurred. The incidence of Grade 1/2 cytokine release syndrome (CRS) was 73.7%, and no ≥Grade 3 CRS occurred. Generally, CRS cases fully resolved after supportive care or tocilizumab. Only one subject with ISS stage III and EMD developed Grade 3 CAR T-cell-related encephalopathy syndrome (CRES), which fully resolved after methylprednisolone treatment. No other grade of CRES was observed in the studies. Conclusions: The results demonstrate that CT053 represents a promising treatment option for subjects with RRMM, including those with high-risk disease. Phase 2 trials are actively enrolling. Figure 1 Figure 1. Disclosures LI: CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in publicly-traded company. Wang: CARsgen Therapeutics Corp: Current Employment. Zhao: CARsgen Therapeutics Corp: Current Employment.

scholarly journals Perineural Invasion Should Be Regarded as an Intermediate-Risk Factor for Recurrence in Surgically Treated Cervical Cancer: A Propensity Score Matching Study

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Ting Wan ◽  
Hua Tu ◽  
Lili Liu ◽  
He Huang ◽  
Yanling Feng ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cervical Cancer ◽  
Overall Survival ◽  
Risk Factor ◽  
High Risk ◽  
Propensity Score ◽  
Cancer Patients ◽  
Perineural Invasion ◽  
Intermediate Risk ◽  
High Risk Factors

Background. Perineural invasion (PNI) is considered as a poor prognostic factor in cervical cancer, but there has been no postoperative adjuvant therapy for it, because whether it belongs to high- or intermediate-risk factors has not been determined, this study intends to provide evidences to solve this problem. Methods. We conducted a retrospective analysis of cervical cancer patients who underwent radical surgery and be reported PNI from January 2012 to June 2017 at the Sun Yat-sen University Cancer Center. After 1 : 1 propensity score matching (PSM), a group of patients without PNI was matched according to the clinical pathological features. Postoperative pathological parameters and prognosis were evaluated between the PNI and the matched groups. Results. 1836 patients were screened, of which 162 (8.8%) diagnosed as stages IB1 to IIB reported PNI. Comparing to the matched group, more PNI (+) patients had deep outer cervix stromal invasion, cervical tunica adventitia invasion, positive lymph nodes, and positive margins. Among patients without high-risk factors, PNI (+) patients had worse 3-year overall survival (90.8% vs. 98.1%, P = 0.02 ), PNI (+) patients with single intermediate-risk factor and PNI (-) patients who meet with SEDLIS criteria had similar progress free survival ( P = 0.63 ) and overall survival ( P = 0.63 ), even similar survival curves. Conclusion. PNI is related to a worse overall survival among cervical cancer patients without high-risk factors and play the role as an intermediate-risk factor.

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