Sequential Treatment with Rituximab and CHOP Chemotherapy in B-Cell PTLD - Moving Forward to a First Standard of Care: Results From a Prospective International Multicenter Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 100-100 ◽  
Author(s):  
Ralf Trappe ◽  
Sylvain Choquet ◽  
Stephan H.K. Oertel ◽  
Veronique Leblond ◽  
Daan Dierickx ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Risk Stratification ◽  
Disease Progression ◽  
Early Treatment ◽  
Interim Analysis ◽  
Research Funding ◽  
Low Risk ◽  
Sequential Treatment ◽  
Risk Patients

Abstract Abstract 100 Purpose: This trial aimed to investigate the efficacy and safety of sequential treatment with rituximab and CHOP-21 in patients with PTLD unresponsive to reduction of immunosuppression. Methods: An ongoing prospective, multicenter, international phase II trial was initiated in January 2003. Initially patients were treated with a fixed sequence of rituximab at days 1, 8, 15 and 22 (4R) followed by four cycles of CHOP-21 combined with G-CSF support starting 4 weeks after the last dose of rituximab (sequential treatment, ST). Based on the results of an earlier interim analysis showing that the response to rituximab predicts OS the trial was amended in 2007 introducing risk stratification according to the response to 4R (risk stratified sequential treatment, RSST). In RSST patients achieving a complete remission after 4R (low risk) continue with four 3-weekly courses of rituximab monotherapy while patients in PR, SD or PD (high risk) are followed by four cycles of R-CHOP-21 + G-CSF. Results: This is a scheduled interim analysis after inclusion of a total of 104 patients. The median follow up is 34.0 months for ST (64 pts.) and 9.1 months for RSST (40 pts.). 61 ST and 35 RSST patients were diagnosed with monomorphic PTLD, 3/5 with polymorphic PTLD. 27/23 patients were kidney, 3/0 kidney+pancreas, 15/8 liver, 13/6 heart, 6/3 lung or heart+lung transplant recipients. Median age at diagnosis of PTLD was 53/60 years (mean age: 48/56 years). 59%/58% of patients had an advanced stage of disease (Ann Arbor III/IV) and 49%/47% of tumors were EBV positive. 75%/75% of patients had late PTLD (i.e. later than 1 year after transplantation). LDH was elevated in 71%/64% of patients, respectively. The overall response rate (ORR) to 4 initial courses of rituximab monotherapy (4R, N=104) was 54% with a CR-rate of 32% and the subsequent completion of treatment with CHOP or R-CHOP allowed a clear increase of the response (p<0.0001, Fig. 1). With ST the final ORR was 89% (CR rate: 69%). 86%, 75% and 75% of patients were without disease progression at one, two and three years, respectively (Fig. 2a). Disease free survival was 87%, 78% and 70% at one, two and three years. There were 6 early treatment associated deaths (9%) resulting from infections (1 from CMV-colitis, 1 from PcP-pneumonia, 1 from fulminant hepatitis, 3 from sepsis) and 2/64 patients died from refractory PTLD. Two further patients died due to hemorrhage during treatment. With RSST the ORR was 90% and 73% achieved a complete remission. 90% of patients were without disease progression at one year (Fig. 2a). There was one early treatment related death due to infection (2.5%). This patient died from sepsis secondary to intestinal perforation in response to R-CHOP treatment. 2/40 patients died from refractory PTLD. With 1 event in 16 patients in both, the ST and the RSST-arms, subsequent consolidation with rituximab monotherapy (RSST) seems not to be inferior to consolidation with 4 cycles of CHOP (ST) in patients with a CR after 4R. Up to now there is no difference in toxicity between CHOP and R-CHOP in ST/RSST. Patients failing to achieve a complete remission with 4R (72 patients) seem to benefit from the subsequent escalation from CHOP to R-CHOP (Fig. 2b). Conclusions: This is the largest prospective study in PTLD. Sequential treatment with rituximab and CHOP-21 + G-CSF is well tolerated and highly effective with a treatment related mortality of less than 10% and an efficacy of up to 90%. In comparison to historic series of rituximab monotherapy, significantly more patients achieve a CR with sequential treatment and time to progression (TTP) is very much prolonged. In comparison to historic series of CHOP, sequential treatment is much better tolerated. This may result from a lower tumor burden and a better patient fitness at the time chemotherapy is applied. Introduction of risk stratification according to the response to 4 courses of rituximab monotherapy might further improve these results restricting chemotherapy related toxicity to high risk patients while these data suggest that low risk patients can effectively be treated with extended rituximab monotherapy. Thus, risk stratified sequential treatment (RSST) might further improve OS in this difficult to treat disease. Disclosures: Trappe: Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding; AMGEN GmbH: Research Funding. Choquet:Hoffmann La Roche Ltd.: Consultancy, Honoraria. Oertel:Hoffmann La Roche Ltd.: Employment, Equity Ownership. Leblond:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding. Ekman:Hoffmann La Roche Ltd.: Honoraria. Dührsen:Hoffmann La Roche Ltd.: Honoraria, Research Funding. Salles:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding. Morschhauser:Hoffmann La Roche Ltd.: Honoraria. Riess:Hoffmann La Roche Ltd.: Consultancy, Honoraria, Research Funding; AMGEN GmBH: Consultancy, Honoraria, Research Funding.

Genetic Risk Stratification to Minimize Inhibitor Risk with the Use of Recombinant Factor VIII Concentrates: A Sippet Analysis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 325-325
Author(s):  
Frits Rosendaal ◽  
Roberta Palla ◽  
Isabella Garagiola ◽  
Piermannuccio Mannucci ◽  
Flora Peyvandi
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Factor Viii ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Risk Difference ◽  
Low Risk ◽  
Inhibitor Development ◽  
High Risk Patients ◽  
Risk Patients

Abstract Background The development of neutralizing antibodies against factor VIII is a common and serious complication of replacement therapy, occurring mainly in the early stages of treatment. Meta-analyses of observational studies have suggested a higher risk of inhibitor development with concentrates produced by recombinant technologies (rFVIII) than with those derived from human plasma (pdFVIII) containing von Willebrand factor, which was recently confirmed in a randomized trial. In this trial cumulative incidences of inhibitor development were 44.5% for rFVIII and 26.8% for pdFVIII, for a hazard ratio (HR) of 1.87 (95% confidence interval (CI95) 1.17-2.96). Given the particularly high risk with rFVIII , it has been suggested to restrict the use of rFVIII to low risk patients, and treat high-risk patients with pdFVIII. We investigated such a strategy in a post-hoc analysis of the SIPPET study, in which we used the FVIII genotype (F8 gene mutation) to classify patients by prior risk. Methods SIPPET is an open label international randomized trial on which 251 previously untreated (n=142) or minimally treated (less than five exposure to blood components other than concentrate or cryoprecipitate, n=109) in 42 centers to be treated exclusively with a concentrate from the class of rFVIII or pdFVIII. Patients were tested for inhibitors before entry and at regular intervals during 50 exposure days, 3 years or the development of an inhibitor of at least 0.4 Bethesda units (BU). The trial ran from 2010 to 2014 and was terminated when the prespecified number of patients was included. Patients who had not reached 50ED by that time were censored. Patients were classified at high risk when they carried a null mutation (inversion, large deletion, frameshift, nonsense mutation) in the F8 gene and as low risk when they carried another causative variant (missense, splice site, polymorphisms, no mutation). We estimated cumulative incidences, hazard ratios and numbers needed to harm (NNH) for rFVIII vs pdFVIII for high- and low risk patients. Results Among 251 patients, 76 developed an inhibitor (all > 0.7 BU) of which 50 were high- titer (> 5 BU). Among 197 patients classified as high risk, 65 developed an inhibitor (cumulative incidence 38.2%, CI95 30.8-45.6), whereas among the 38 patients classified as low risk 7 developed an inhibitor (cumulative incidence 23.9%, CI95 8.2-39.6). High and low risk patients were equally distributed over the two arms of the trial, i.e., 96 out of 126 treated with rFVIII were high risk, and 101 out of 125 treated with pdFVIII. Among high risk patients, cumulative incidence was 30.7% when treated with pdFVIII , and 46.5% when treated with rFVIII (risk difference 15.8%). Among low risk patients, no inhibitors developed with pdFVIII, whereas the cumulative incidence was 43.2% with rFVIII (risk difference 43.2%). This implies that the Number Needed to Harm was 5.6 overall, 6.3 for high-risk patients, and 2.3 in low risk patients. Conclusion Risk stratification by the type of F8 mutation does not identify previously untreated patients with hemophilia A who have a low inhibitor risk when exposed to rFVIII. Other means need to be found to reduce the occurrence of inhibitors with rFVIII. Disclosures Palla: Pfizer: Other: travel support . Mannucci:NovoNordisk: Speakers Bureau; Kedrion: Speakers Bureau; Grifols: Speakers Bureau; Bayer: Speakers Bureau. Peyvandi:Bayer: Speakers Bureau; SOBI: Speakers Bureau; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Octapharma: Consultancy; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; CSL Behring: Speakers Bureau; LFB: Consultancy; Grifols: Speakers Bureau; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau.

Risk Stratification for the Development of Venous Thromboembolism in Hospitalized Patients with Cancer

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4728-4728 ◽  
Author(s):  
Arabesque Parker ◽  
Erica A. Peterson ◽  
Agnes Y. Y. Lee ◽  
Carine de Wit ◽  
Marc Carrier ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
High Risk ◽  
Risk Stratification ◽  
Board Of Directors ◽  
Cancer Patients ◽  
Major Bleeding ◽  
Research Funding ◽  
Low Risk ◽  
Advisory Committees ◽  
Risk Patients

Abstract Introduction: No method of venous thromboembolism (VTE) risk stratification exists for hospitalized cancer patients. The Khorana score is a validated tool in outpatients with cancer. The objective of this study was to assess the Khorana score for predicting development of VTE in cancer patients during admission to hospital. Methods: We conducted a retrospective analysis of data collected from healthcare records of consecutive, medically-ill cancer patients hospitalized between January and June 2010 in 3 academic medical centers in Canada. Objectively diagnosed symptomatic VTE during hospitalization, anticoagulant thromboprophylaxis (TP), and Khorana score variables were collected for every patient. Patients receiving therapeutic anticoagulation at admission, and those with incomplete data were excluded. The risk of VTE based on Khorana score category was evaluated using logistic regression. Continuous data were compared using a Student's t-test and expressed using the means and standard deviations. Categorical data were compared using the Pearson Chi-square test and were expressed as percentages. Statistical significance was defined as alpha less than 0.05. Results: 1398 patients were included. Mean age was 61.6 years, 51.2% were male, and mean BMI was 25.9 kg/m2. The most frequent tumor types were non-small cell lung carcinoma (12.7%) followed by lymphoma (10.9%). The median length of stay was 6 days (range 0-114 days). The most frequent reasons for hospitalization were chemotherapy (22.3%) followed by pain and palliation (21.4%). 34.5% received anticoagulant TP (n = 483/1398). The incidence of VTE was 2.9% (41/1398) overall, 5.4% (9/166) in high, 3.2% (26/817) in moderate, and 1.4% (6/415) in low Khorana score risk groups. High risk patients were significantly more likely than low risk patients to have VTE (p=0.016; OR 3.9, 95% CI 1.4-11.2). There was no difference in VTE incidence between patients who received anticoagulant TP and those who did not (3.5% vs 2.6%, p = 0.345). Patients with high risk Khorana score were more likely to receive anticoagulant TP than those with low risk Khorana score (46.4% vs. 23.9%, p <0.001, OR 2.8, 95% CI 1.9-4.0). Total incidence of major bleeding was 1.8% (25/1398). There was no difference in major bleeding between patients who received anticoagulant TP and those who did not (1.7% vs. 1.9%, p = 0.787). Conclusion: The Khorana score is predictive of VTE development in cancer patients who are hospitalized for medical illness and may be a useful tool for tailoring inpatient anticoagulant prophylaxis. Disclosures Lee: LEO: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bristol Myers-Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Carrier:BMS: Research Funding; Leo Pharma: Research Funding. Wu:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Leo Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

scholarly journals Pre-hospital risk assessment in suspected non-ST-elevation acute coronary syndrome: A prospective observational study

2018 ◽  
Vol 9 (1_suppl) ◽  
pp. 5-12 ◽  
Author(s):  
Dominique N van Dongen ◽  
Rudolf T Tolsma ◽  
Marion J Fokkert ◽  
Erik A Badings ◽  
Aize van der Sluis ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
High Risk ◽  
Risk Stratification ◽  
Risk Group ◽  
High Risk Group ◽  
Low Risk ◽  
Heart Score ◽  
Coronary Syndrome ◽  
Risk Patients ◽  
St Elevation

Background: Pre-hospital risk stratification of non-ST-elevation acute coronary syndrome (NSTE-ACS) by the complete HEART score has not yet been assessed. We investigated whether pre-hospital risk stratification of patients with suspected NSTE-ACS using the HEART score is accurate in predicting major adverse cardiac events (MACE). Methods: This is a prospective observational study, including 700 patients with suspected NSTE-ACS. Risk stratification was performed by ambulance paramedics, using the HEART score; low risk was defined as HEART score ⩽ 3. Primary endpoint was occurrence of MACE within 45 days after inclusion. Secondary endpoint was myocardial infarction or death. Results: A total of 172 patients (24.6%) were stratified as low risk and 528 patients (75.4%) as intermediate to high risk. Mean age was 53.9 years in the low risk group and 66.7 years in the intermediate to high risk group ( p<0.001), 50% were male in the low risk group versus 60% in the intermediate to high risk group ( p=0.026). MACE occurred in five patients in the low risk group (2.9%) and in 111 (21.0%) patients at intermediate or high risk ( p<0.001). There were no deaths in the low risk group and the occurrence of acute myocardial infarction in this group was 1.2%. In the high risk group six patients died (1.1%) and 76 patients had myocardial infarction (14.4%). Conclusions: In suspected NSTE-ACS, pre-hospital risk stratification by ambulance paramedics, including troponin measurement, is accurate in differentiating between low and intermediate to high risk. Future studies should investigate whether transportation of low risk patients to a hospital can be avoided, and whether high risk patients benefit from immediate transfer to a hospital with early coronary angiography possibilities.

Interim analysis of the largest prospective trial to date in adult CD20-positive post-transplant lymphoproliferative disorder (PTLD): Introducing risk-stratified sequential treatment (RSST).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8030-8030 ◽  
Author(s):  
Ralf Ulrich Trappe ◽  
Daan Dierickx ◽  
Petra Reinke ◽  
Ruth Neuhaus ◽  
Franck Morschhauser ◽  
...  
Keyword(s):  
High Risk ◽  
Overall Response Rate ◽  
Prospective Trial ◽  
Low Risk ◽  
Sequential Treatment ◽  
Tumor Control ◽  
Transplant Recipients ◽  
Risk Patients ◽  
Related Mortality

8030 Background: The prospective, multicenter international phase II PTLD-1 trial of sequential treatment (ST, 4 cycles of weekly rituximab followed by 4 cycles of CHOP-21 + G-CSF) in adult CD20-positive PTLD demonstrated excellent efficacy (90% overall response rate, ORR) and safety (11% treatment-related mortality, TRM). As the response to rituximab predicted overall survival (OS), the trial was amended in 2007 introducing risk-stratified sequential treatment (RSST) according to the response to rituximab (NCT00590447). Methods: Following rituximab on days 1, 8, 15 and 22, RSST consisted of 4 3-weekly courses of rituximab monotherapy for patients (pts) in complete remission (CR, low risk) while all others (high risk) received 4 cycles of R-CHOP-21 + G-CSF. Key exclusion criteria were CNS involvement, HIV infection, severe organ dysfunction not related to PTLD, and ECOG > 2. Primary endpoint was ORR. This is an analysis of the first 91 patients treated with RSST. Results: 79/91 pts had monomorphic, 12 polymorphic PTLD. 41/91 pts were kidney, 27 liver, 12 heart, 7 lung or heart+lung, 3 heart+kidney and 1 kidney+pancreas transplant recipients. Median age at diagnosis was 60 years (range 20-82). 73/91 pts had late PTLD and 39/85 PTLDs were EBV-associated. 1 pt died before initiation of treatment; 5 pts discontinued treatment after 4 cycles rituximab. TRM of RSST was 7/90 (8%) including 5 deaths with unknown remission status. ORR was thus 74/80 (93%, 95%CI: 84-97%; CR: 62/80 [78%]). 24/90 pts (27%) achieved CR with 4 cycles of rituximab. After a median follow up of >3 years, relapse rate in low risk pts was not increased by rituximab consolidation in RSST compared to CHOP consolidation in ST (3/23 vs. 5/14, p=0.104]). In patients in PD after rituximab, R-CHOP was more effective than CHOP in achieving CR (15/23 vs. 3/11, p=0.038). OS at 3 years was higher with RSST (70%, 95% CI: 60-82%) compared to ST (61%, 95%CI 49-72%) but this difference was not significant. Conclusions: With RSST 27% of pts were classified as low risk and achieved durable tumor control without chemotherapy while R-CHOP seems more efficient than CHOP in in high risk patients.

scholarly journals Clinical Relevance of Morphologic and Molecular Complete Remission in AML Patients Undergoing Reduced Intensity or Non-Myeloablative Conditioning

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Madlen Jentzsch ◽  
Dominic Brauer ◽  
Juliane Grimm ◽  
Marius Bill ◽  
Donata Backhaus ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Risk Stratification ◽  
Genetic Risk ◽  
Research Funding ◽  
Myeloablative Conditioning ◽  
Remission Status ◽  
Active Disease ◽  
Reduced Intensity

Introduction: For most acute myeloid leukemia (AML) patients (pts) an allogeneic stem cell transplantation (HSCT) offers the best chance for relapse-free long-term survival. Evaluation of measurable residual disease (MRD) at HSCT allows risk stratification additionally to genetic risk at diagnosis. Pts with active AML or with positive MRD status (MRD+) pre-HSCT have similar and dismal outcomes following myeloablative conditioning. Reduced intensity (ric) or non-myeloablative (nma) conditioning regimes have been developed to allow HSCT also in AML pts with higher age or comorbidities. Here, we analyzed and compared the clinical relevance of morphologic and MRD-based remission status in AML pts prior to nma- or ric-HSCT. Methods: We analyzed 345 AML pts who received an allogeneic peripheral blood HSCT at a median age of 63 (range 21-77) years with active disease (34%), or in first (49%) or second (17%) complete remission (CR, 87% of pts in remission) or CR with incomplete peripheral recovery (CRi, 13% of pts in remission) after nma (75%) or ric (25%) conditioning. Donors were HLA matched related (11%), matched unrelated (67%), antigen mismatched unrelated (21%) or haploidentical related (1%). At diagnosis, cytogenetics and the mutation status of CEBPA, NPM1 and presence of FLT3-ITD were assessed. Using a next-generation targeted amplicon sequencing approach we analyzed a panel comprising 54 recurrently mutated genes in myeloid malignancies on the MiSeq platform (Illumina). Pre-HSCT morphologic remission status as well as MRD status in pts in morphologic CR/CRi based on NPM1 mutations, BAALC, MN1 and WT1 expression were evaluated. MRD+ pts were defined by being positive for any of the analyzed markers. Median follow up after HSCT was 2.2 years. Results: Pts transplanted with active disease differed from pts in remission with or without MRD pre-HSCT: they were less likely to have de novo AML (P=.02 & P=.09, respectively) and had higher genetic risk including a higher frequency of an abnormal (P=.001 & P&lt;.001, respectively), a complex (P=.06 & P=.04, respectively) or a monosomal karyotype (P&lt;.001 & P=.003, respectively), a lower frequency of NPM1 mutations (P&lt;.001 & P&lt;.001, respectively) and worse ELN genetic risk (P&lt;.001 & P&lt;.001, respectively). They were also more likely to receive ric-HSCT (P&lt;.001 & P&lt;.001) because pts with active AML were frequently transplanted after FLAMSA conditioning. Pre-HSCT MRD- pts only differed from pre-HSCT MRD+ pts regarding a lower white blood count (P=.006) and lower circulating blasts at diagnosis (P=.05) while the proportion of pts transplanted in CR or CRi did not differ between MRD- and MRD+ AML pts. Also the number of applied chemotherapy cycles prior to HSCT did not differ between the three pts groups. Pre-HSCT MRD- pts had a significantly lower cumulative incidence of relapse/progression (CIR) compared to both MRD+ pts (P&lt;.001) and pts transplanted with active disease (P&lt;.001) while CIR did not differ between MRD+ pts and pts transplanted with active disease (P=.24, Figure 1A). Pre-HSCT MRD- pts had longer overall survival (OS) than pre-HSCT+ pts (P=.04) who again had longer OS than pts transplanted with active disease (P=.01, Figure 1B). In multivariate analyses, the MRD corrected remission status prior to HSCT remained a significant factor for CIR (Hazard Ratio 1.65, Confidence interval [CI] 1.31-2.06) after adjustment for ELN risk and for OS (Odds Ratio 0.63, CI 0.49-0.84) after adjustment for ELN risk, hemoglobin and platelet count at diagnosis. Conclusion: AML pts transplanted with active disease showed a variety of high-risk diagnostic parameters compared to pre-HSCT MRD- or MRD+ pts, as secondary disease and adverse genetic risk. In contrast, pre-HSCT MRD- and MRD+ pts could not be discriminated by high risk factors at diagnosis, underlining the importance of a dynamic risk stratification during remission. Both pts with active disease or a MRD+ status in CR/CRi prior to nma- or ric-HSCT showed dismal outcomes with higher CIR and shorter OS than MRD- pts. However, while CIR was comparable in pts with molecular or morphologic detectable disease, OS was worst in pts transplanted with active disease, indicating that MRD+ pts might still be salvageable after suffering relapse and able to achieve long-term outcomes. Figure Disclosures Jentzsch: JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria. Platzbecker:AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Geron: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Schwind:Pfizer: Honoraria; JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding.

scholarly journals A Novel Prognostic Model That Is Superior to FLIPI-1 and FLIPI-2 and Integrates Clinical and Treatment Factors to Predict Progression-Free Survival and Early Treatment Failure in Patients with Follicular Lymphoma in the GALLIUM Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2872-2872 ◽  
Author(s):  
Farheen Mir ◽  
Andrew Grigg ◽  
Michael Herold ◽  
Wolfgang Hiddemann ◽  
Robert Marcus ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Prognostic Model ◽  
Low Risk ◽  
Prognostic Variables ◽  
Advisory Committees ◽  
High Risk Disease ◽  
Risk Patients ◽  
Equity Ownership

Abstract Introduction: Progression of disease within 24 months of initial therapy (POD24) is associated with poor survival in patients with follicular lymphoma (FL). Existing prognostic models, such as FLIPI-1 and FLIPI-2, show poor sensitivity for POD24, and are derived from cohorts lacking bendamustine-treated patients. More accurate predictive models based on current standard therapies are needed to identify patients with high-risk disease. The Phase III GALLIUM trial (NCT01332968) compared the safety and efficacy of standard chemotherapy regimens plus rituximab (R) or obinutuzumab (G) in patients with previously untreated FL. Using GALLIUM data, we developed a novel risk stratification model to predict both PFS and POD24 in FL patients after first-line immunochemotherapy. Methods: Enrolled patients were aged ≥18 years with previously untreated FL (grades 1-3a), Stage III/IV disease (or Stage II with bulk), and ECOG PS ≤2, and required treatment by GELF criteria. Patients were randomized to receive either G- or R-based immunochemotherapy, followed by maintenance with the same antibody in responders. The chemotherapy arm (CHOP, CVP, or bendamustine) was selected by each study center. POD24 was defined as progressive disease or death due to disease within 24 months of randomization (noPOD24 = no progression or lymphoma-related death in that period). The most strongly prognostic variables, based on PFS hazard ratios, were estimated using penalized multivariate Cox regression methodology via an Elastic Net model. Selected variables were given equal weights, and a clinical score was formed by summating the number of risk factors for each patient. Low- and high-risk categories were determined using a cut-off that provided the best balance between true- and false-positives for PFS. PFS correlation and sensitivity to predict POD24 were assessed. The data used are from an updated GALLIUM efficacy analysis (data cut-off: April 2018; median follow-up: 57 months). Results: 1202 FL patients were enrolled. Based on data availability and biological plausibility (i.e. could reasonably be linked with high-risk disease), 25 potential clinical and treatment-related prognostic variables were entered into the Elastic Net model (Table). A model containing 11 factors was retained by the methodology and chosen as the best model (Table). Patients were categorized as 'low risk' if they scored between 0 and 3 (n=521/1000 patients with complete data) and as 'high risk' if they scored between 4 and 11 (n=479/1000 patients). At 2 years, the PFS rate was 84.5% in the whole FL population. Using our model, 2-year PFS for high-risk patients was 77% compared with 79.9% for FLIPI-1 and FLIPI-2. In low-risk patients, 2-year PFS was 92% compared with 87.9% for FLIPI-1 and 87.6% for FLIPI-2 (low-intermediate-risk patients). Our model increased the inter-group difference in 2-year PFS rate from 8% (FLIPI-1) and 7.7% (FLIPI-2) to 15%. At 3 years, the inter-group difference increased from 6.9% (FLIPI-1) and 9% (FLIPI-2) to 17% (Figure). Sensitivity for a high-risk score to predict POD24 was 73% using our model compared with 55% for FLIPI-1 and 52% for FLIPI-2 (based on 127 POD24 and 873 noPOD24 patients with complete data). Excluding patients who received CVP, which is now rarely used, resulted in an inter-group difference in PFS of 15% at 2 years and 16.8% at 3 years. A sensitivity analysis showed that inclusion of the 9 clinical factors only (i.e. removal of CVP and R treatment as variables) formed a more basic scoring system (low-risk patients, 1-3; high-risk patients, 4-9); the inter-group difference in PFS was 16.5% at 2 years and 17.6% at 3 years. However, sensitivity for POD24 decreased to 56%. Conclusion: Our clinical prognostic model was more accurate at discriminating patients likely to have poor PFS than either FLIPI-1 or FLIPI-2, and its prognostic value was sustained over time. Our model also identified the FL population at risk of POD24 with greater sensitivity. Variables such as age and bone marrow involvement were not retained by our model, and thus may not have a major impact in the current era of therapy. Factors such as sum of the products of lesion diameters were included, as this captures tumor burden more accurately than presence of bulk disease. Future studies will aim to improve the accuracy of the model by considering gene expression-based prognostic markers and DNA sequencing to form a combined clinico-genomic model. Disclosures Mir: F. Hoffmann-La Roche: Employment. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:F. Hoffman-La Roche: Other: Travel support and lecture fees; Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy. Seymour:Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bolen:Roche: Other: Ownership interests PLC*. Knapp:Roche: Employment. Launonen:Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Roche: Employment, Other: Travel, accommodation, expenses. Mattiello:Roche: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Oestergaard:Roche: Employment, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Casulo:Gilead: Honoraria; Celgene: Research Funding.

scholarly journals Evaluation of the International Prognostic Index for Chronic Lymphocytic Leukemia (CLL-IPI) and Validation of a Proposed Novel Risk Model (BALL Score) in Real-World Relapsed/Refractory (R/R) CLL Patients Receiving Idelalisib and Rituximab

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5485-5485
Author(s):  
Massimo Gentile ◽  
Gianluigi Reda ◽  
Francesca Romana Mauro ◽  
Paolo Sportoletti ◽  
Luca Laurenti ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Low Risk ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Scientific Advisory Board ◽  
Scientific Advisory

The CLL-IPI score, which combines genetic, biochemical, and clinical parameters, represents a simple worldwide model able to refine risk stratification for CLL patients. This score, developed in the era of chemo-immunotherapy, has not been gauged extensively in R/R-CLL patients treated with novel targeted agents, such as BCR and BCL2 inhibitors. Soumerai et al (Lancet Hematol 2019) assembled a novel risk model for OS in the setting of R/R-CLL receiving targeted therapies in clinical trials. This model, consisting of four accessible markers (β2M, LDH, Hb, and time from initiation of last therapy; BALL score), is able to cluster 3 groups of CLL patients with significantly different OS. This multicenter, observational retrospective study aimed to validate the proposed Soumerai (BALL) and/or CLL-IPI scores for R/R-CLL real-world patients treated with idelalisib and rituximab (IDELA-R). The primary objectives were to determine whether: i) the CLL-IPI retains its prognostic power also in R/R patients treated with IDELA-R; ii) the BALL score is of prognostic value for IDELA-treated R/R-CLL patients, and iii) the BALL score is predictive of PFS. This study, sponsored by Gilead (ISR#IN-IT-312-5339), included CLL patients collected from 12 Italian centers, who received IDELA-R (idelalisib 150 mg b.i.d. and a total of 8 rituximab infusions intravenously) outside clinical trials as salvage therapy with available data for the calculation of the CLL-IPI and BALL scores at the time of treatment start. OS was estimated for all subgroups of both scores. Additionally, risk-specific PFS was assessed. Kaplan-Meier curve, log-rank test, and Cox regression analyses were performed. The prognostic accuracy of the predictive model was assessed by Harrell's C-index. Overall, 120 CLL patients were included in this analysis. The majority of patients were Binet stage B and C (94.2%). The median age was 75 years and 83 cases (69.2%) were male. The median number of previous therapies was 3 (range 1-9) Baseline patient features are listed in Table 1. After a median follow-up of 1.6 years (1 month to 5.8 years), 33 patients had died and 39 experienced an event (death or progression). CLL-IPI scoring (115/120 evaluable cases) indicated that 6 patients (5.2%) were classified as low-risk, 24 (20.9%) as intermediate-risk, 58 (50.4%) as high-risk, and 27 (23.5%) as very high-risk. Stratification of patients according to the CLL-IPI score did not allow prediction of significant differences in OS. Thus, low-risk patients had a 2-year OS probability of 75% (HR=1), with an intermediate-risk of 68% (HR=2.9, 95%CI 0.37-23.3, P=0.3), high-risk of 83% (HR=1.58, 95%CI 0.2-12.5, P=0.66), and very high-risk of 63% (HR=5.9, 95%CI 0.78-45.2, P=0.86). Next, we tested a modified CLL-IPI by assigning a more balanced score to the original CLL-IPI variables (Soumerai et al, Leukemia Lymphoma 2019), partially overlapping previous results. Specifically, modified CLL-IPI high-risk group showed a significantly different OS as compared with intermediate- and low-risk groups. However, differently from the original report no difference was observed between low- and intermediate-risk). According to the BALL score (120/120 evaluable cases), 33 patients (27.5%) were classified as low-risk, 68 (56.7%) as intermediate-risk, and 19 (15.8%) as high-risk. Stratification of patients according to the BALL score predicted significant differences in terms of OS. Thus, low-risk patients had a 2-year OS probability of 92% (HR=1), intermediate-risk of 76% (HR=5.47, 95%CI 1.3-23.7, P=0.023), and high-risk of 54% (HR=15.1, 95%CI 3.4-67, P<0.0001) (Figure 1). Harrell's C-statistic was 0.68 (P<0.001) for predicting OS. To note, BALL score failed to significantly stratify patients in terms of PFS. As for Soumerai et al (Leukemia Lymphoma 2019), the original CLL-IPI score did not retain discriminative power in term of OS in R/R-CLL patients receiving IDELA-R. The modified CLL-IPI failed to stratify low- and intermediate-risk groups, likely due to the number of cases analysed in the current cohort and the heterogeneous IDELA-containing regimens included in the Soumerai study (Soumerai et al, Leukemia Lymphoma 2019). The CLL-IPI was designed for CLL patients treated with first-line chemo-immunotherapy. Herein, we confirm the prognostic power of the BALL score in this real-world series for OS, while losing the predictive impact of patient outcomes in terms of PFS. Disclosures Mauro: Gilead: Consultancy, Research Funding; Jannsen: Consultancy, Research Funding; Shire: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Coscia:Abbvie: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Varettoni:ABBVIE: Other: travel expenses; Roche: Consultancy; Janssen: Consultancy; Gilead: Other: travel expenses. Rossi:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Other: Scientific advisory board; Janseen: Honoraria, Other: Scientific advisory board; Roche: Honoraria, Other: Scientific advisory board; Astra Zeneca: Honoraria, Other: Scientific advisory board. Gaidano:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesys: Consultancy, Honoraria; Astra-Zeneca: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Real-World Treatments and Thrombotic Events in Polycythemia Vera Patients: A Retrospective Analysis between 2018-2019 in US Population

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Srdan Verstovsek ◽  
Ariel Han ◽  
Karin Chun Hayes ◽  
Tracy Woody ◽  
Frank Valone ◽  
...  
Keyword(s):  
High Risk ◽  
Real World ◽  
Blood Cells ◽  
Initial Treatment ◽  
Research Funding ◽  
Treatment Initiation ◽  
Low Risk ◽  
High Risk Patients ◽  
Risk Patients

BACKGROUND Polycythemia Vera (PV) is a rare myeloproliferative neoplasm associated with an increased production of red blood cells, white blood cells, and platelets. Most frequent treatment includes phlebotomy, hydroxyurea, interferon, and ruxolitinib. Current NCCN guideline recommends managing HCT levels to below 45%. The objective of this study was to determine real-world standards of care and patient characteristics, and to observe how treatment decisions vary by HCT level and thrombosis risk. METHODOLOGY We conducted a retrospective study using Symphony Health's longitudinal transactional healthcare claims database that includes prescription, medical and hospital claims across &gt; 4,900 US payers representing 86% of US lives. Eligible patients had at least one ICD-10 diagnosis code for PV and at least one of the treatments including phlebotomy, hydroxyurea, busulfan, interferon, and ruxolitinib between Jan 1, 2018 and Dec 31, 2019 (index period). For eligible patients, all prior treatment history initiated as far back as January 2010 was used to report therapy changes. Patients were also required to have at least one PV diagnosis within a year of treatment initiation and at least 2 HCT lab results during the index period. PV treatment changes and characteristics were studied. RESULTS Out of 28,306 patients with PV, 4,264 patients had HCT lab data for 2 years (index period). Median duration of follow-up was 854 days (range 98-3,373days). Patient therapy duration was from 1 to 9 years. Median patient age was 65 (range 11-94), with 1,451 (34%) patients aged less than 60, 2,813 (66%) 60 years or older, and a substantial male predominance (62% vs 38%). 1,247 (29%) patients were classified as Low Risk (age&lt; 60 with no TE history) and 3,017 (71%) patients as High Risk. Within the High-Risk group, 2,224 (52%) were age&gt;60 without prior TE, 204 (5%) were age&lt;60 with prior TE and 589 (14%) were age&gt;60 with prior TE. For Low Risk patients' initial treatment was phlebotomy alone (85%) and a total of 73% of all Low Risk patients remained on phlebotomy alone. For High Risk patients' initial treatment was phlebotomy alone (60%) and 43% all of High-Risk patients remained on phlebotomy alone (Figure 1). The median HCT prior to treatment initiation was 52.9% and 48% during treatment. 936 (22%) patients achieved NCCN treatment guidelines with HCT levels always remaining under 45%, and 1,226 (29%) patients had HCT levels controlled between 45% and 50%. However, 2,102 (49%) patients had some or all HCT levels&gt; 50% (Figure 2). With the most recent lab test, 2,180 (51%) of patients still had HCTs above 45% and 804 (19%) were still above 50%. In a sub-cohort of 653 High Risk patients with a prior TE and up to 5 years of follow up, 236 (36%) had at least one other TE; for the 1,774 High Risk patients who did not have the history of thrombosis, 161(9%) had at least one TE (Table 2). The most common TE since treatment began in patients with prior TE were deep vein thrombosis (n= 92 patients, 14%) and stroke (n= 95 patients, 15%). Among High Risk patients (n=397) who had another thrombotic event, 180 (45%) were treated by phlebotomy only and never switched to any other therapies. CONCLUSIONS Despite currently available treatments in US, patients' HCT level after treatment were higher than recommended as per guidelines. Failure to maintain HCT less than 45% increases the risk of future thrombotic events as shown by 36% of patients with prior TE experiencing another TE within the next 5 years. Disclosures Verstovsek: Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; CTI Biopharma Corp: Research Funding. Han:Protagonist Therapeutics: Consultancy. Chun Hayes:Protagonist: Consultancy. Woody:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Gupta:Protagonist: Current Employment.

Comparison Of Conventional, FISH and GEP Prognostic Factors In Multiple Myeloma: Introducing a Novel Risk Stratification

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3092-3092 ◽  
Author(s):  
Rowan Kuiper ◽  
Martin van Vliet ◽  
Annemiek Broyl ◽  
Yvonne de Knegt ◽  
Bronno van der Holt ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Risk ◽  
Partial Likelihood ◽  
Data Sets ◽  
Advisory Committees ◽  
Risk Patients

Abstract Introduction Multiple Myeloma (MM) is a heterogeneous disease with highly variable survival. Gene expression profiling (GEP) classifiers, such as the EMC-92, can consistently distinguish high risk patients from standard risk patients. Other prognostic factors for MM include the international staging system (ISS) and FISH. Here we present a comparison of prognostic factors and introduce a novel stratification based on EMC-92 and ISS. Methods Scores were calculated for the GEP classifiers EMC-92, UAMS-70, UAMS-17, UAMS-80 and MRC-IX-6 for the following five studies: HOVON-65/GMMG-HD4 (n=328; GSE19784), MRC-IX (n=247; GSE15695), UAMS-TT2 (n=345; GSE2658), UAMS-TT3 (n=238; E-TABM-1138 and GSE2658) and APEX (n=264; GSE9782; for details, see Kuiper R, et al. Leukemia (2012) 26: 2406–2413). FISH data were available for the HOVON-65/GMMG-HD4 trial and the MRC-IX trial. ISS values were available for all datasets except UAMS-TT2. Univariate associations between markers and overall survival (OS) were investigated in a Cox regression analysis, using Bonferroni multiple testing correction. For pair wise analysis of markers, the significance in the increase of partial likelihood was calculated. In order to find the strongest combination (defined as the highest partial likelihood) of GEP-ISS, we compared these pair-wise on the same data. Training sets of classifiers were excluded for those analyses in which that specific classifier was tested. All survival models have been stratified for study. The calculations were done in R using the package survival. Results Prognostic value of FISH, GEP and serum markers was determined in relation to overall survival (Figure 1). GEP classifiers generally performed much better than FISH markers. Of 6 FISH markers with known adverse risk, del(17p), t(4;14), t(14;20) and del(13q) demonstrated a significant association only in one of two data sets with available FISH (HOVON-65/GMMG-HD4). GEP classifiers, on the other hand, are much more robust. Classifiers EMC-92, UAMS-70 and UAMS-80 significantly identify a high-risk population in all evaluated data sets, whereas the UAMS-17 and the MRC-IX-6 classifiers predict high-risk patients in three of four datasets. As expected, ISS staging demonstrated stable and significant hazard ratios in most studies (three out of four). Indeed, when evaluating a merged data set, both ISS and all evaluated GEP classifiers are strong prognostic factors independent of each other. Markers with additive value to each other include all combinations of GEP classifiers as well as the combination of GEP classifiers together with ISS. Tested in independent sets, the EMC-92 classifier combined with ISS is the best combination, as compared to other classifier-ISS combinations tested on the same independent data sets. The strongest risk stratification in 3 groups was achieved by splitting the EMC-92 standard risk patients into low risk, based on ISS stage I, and intermediate risk, based on ISS stage II and III. This stratification retains the original EMC-92 high-risk group, and is robust in all cohorts. The proportions of patients defined as low, intermediate and high risk for this combined EMC-92-ISS classifier are 31% / 47% / 22 % (HOVON-65/GMMG-HD4), 19% / 61% / 20 % (MRC-IX), 46% / 39% / 15 % (UAMS-TT3) and 32% / 55% / 13 % (APEX). Variability in low risk proportion is caused by the variable incidence of ISS stage I. Conclusions We conclude that GEP is the strongest predictor for survival in multiple myeloma and far more robust than FISH. Adding ISS to EMC-92 results in the strongest combination of any of the GEP classifier-ISS combinations. Stratification in low risk, intermediate and high risk may result in improved treatment and ultimately in longer survival of MM patients. This research was supported by the Center for Translational Molecular Medicine (BioCHIP project) Disclosures: van Vliet: Skyline Diagnostics: Employment. Mulligan:Millennium Pharmaceuticals: Employment. Morgan:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Goldschmidt:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van Beers:Skyline Diagnostics: Employment. Sonneveld:Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding.

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