Survival and Response Outcomes to Different Treatment Schedules in CML Patients Starting Therapy with Imatinib. Results from the CML Spanish Registry (RELMC)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1237-1237
Author(s):  
Luis Felipe Casado ◽  
Isabel Massague ◽  
Pilar Giraldo ◽  
Manuel Perez-Encinas ◽  
Raquel De Paz ◽  
...  
Keyword(s):  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
The Other ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
High Risk Patients ◽  
Advisory Boards ◽  
Best Response ◽  
Risk Patients

Abstract Abstract 1237 Background: The RELMC is a multicentric, 17-hospitals-based cancer registry whose aim is to describe the treatments received by patients with CML, their outcomes, and the variables that influence treatment choices. Aim: To study the response and survival outcomes, in newly diagnosed CML patients treated with Imatinib (Im) as first line treatment. Patients and methods: 249 newly diagnosed CML patients have been included. They are distributed in the following subgroups according to treatments received Im400. 166 patients received only Im400. Result: A summary of response and outcome is included in Table 1. Complete cytogenetic response with regards to the best response, the CCyR rate was lower in patients with Im400-HDIm-2GTKI (60%) and Im400-2GTKI (62%). The rates were 84% in Im400, 83% in Im400-HDIm and 85% in HDIm; P Chi2 8,381(a) p=0,079. The CCyR cumulative incidence was also lower in patients with Im400-HDIm-2GTKI and Im400-2GTKI in comparison to the other groups, although second line response was faster in patients who changed to 2GTKI after Im400. The frequency of CCyR as best response in the Hasford high risk patients was low in all groups (66%,50%,50%,50&55%). Major molecular response MMR as best response was lower in patients with Im400-HDIm-2GTKI (50%) and Im400-2GTKI (47%). The rates were 83%, 81% and 77% in the Im400, Im400-HDIm and HDIm groups respectively; P Chi2 19,4(a)p=0,001. The MMR cumulative incidence was higher in the HDIm group, lower in those treated with Im400-HDIm-2GTKI, and intermediate and similar in the other three groups. MMR as best response in the Hasford high risk patients was also low in all groups (60%, 75%, 50%, 50% & 33%). Complete molecular response regarding best response, the CMR rate was lower in patients with Im400-HDIm-2GTKI (37,5%), Im400-2GTKI (31,6%) and Im400-HDIm (34%). In the other groups, the rate was 48% (Im400), and 72% (HDIm); P Chi2 17,4(a) p=0,002. The CMR cumulative incidence was higher in the HDIm group, and nil in those treated with Im400-HDIm-2GTKI. Salvage therapy after suboptimal response (SR) or Failure (F). Two-thirds of patients with SR or F were able to obtain an optimal response and avoid transformation with a timely therapy change. All but one of the options (Im400-HDIm-2GTKI group) were similarly effective. Survival: 6 patients progressed (2,4%) (4 AP, 2 BC), and died; 6 patients changed to allo BMT and were censored; 6 patients died of non-CML related causes. Conclusion: Disclosures: Palomera: Janssen Cilag: Honoraria. Steegmann:Bristol-Myers Squibb: Honoraria, Participated in advisory boards, Research Funding; Novartis: Participated in advisory boards, Research Funding.

Randomized Comparison of Imatinib 800 Mg Vs. Imatinib 400 Mg +/- IFN in Newly Diagnosed BCR/ABL Positive Chronic Phase CML: Analysis of Molecular Remission at 12 Months; The German CML-Study IV.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 339-339 ◽  
Author(s):  
Rudiger Hehlmann ◽  
Susanne Jung-Munkwitz ◽  
Michael Lauseker ◽  
Armin Leitner ◽  
Nadine Pletsch ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Standard Dose ◽  
Chronic Phase ◽  
Study Group ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Molecular Remission ◽  
High Risk Patients ◽  
Risk Patients

Abstract Abstract 339 Initial reports that high dose imatinib results in better responses more rapidly than standard dose imatinib remain controversial. The German CML Study Group therefore compared imatinib 800 mg (IM 800) with standard dose imatinib +/- IFN (IM 400, IM 400 + IFN) in newly diagnosed, not pretreated CML with regard to molecular response at 12 months and survival in a randomized clinical trial. By April 30, 2009, 1026 chronic phase CML patients have been randomized (326 for IM 400, 338 for IM 800, 351 for imatinib + IFN). Comparison was for molecular and cytogenetic remissions, overall (OS) and progression free (PFS) survival and toxicity. 1015 patients were evaluable at baseline, 904 for survival analysis (294 for IM 400, 286 for IM 800, 324 for IM 400+IFN), 790 for cytogenetic (analysis of at least 20 metaphases required) and 823 for molecular response. The three treatment groups were similar regarding median age, sex, median values of Hb, WBC, platelets and distribution according to the EURO score. Median follow-up was 25 months in the imatinib 800 mg arm and 42 months in the imatinib 400 mg +/-IFN arms. The difference is due to the fact that at first the IM 800 arm was designed for high risk patients only and opened up to all risk groups in July 2005. The median daily doses of imatinib were 626 mg (209- 800 mg) in the IM 800 arm and 400 mg (184- 720 mg) in the IM 400 +/- IFN arms. Of 218 patients receiving imatinib 800 mg and evaluable for dosage at 12 months, 100 (45.9%) received more than 700 mg/day, 27 (12.4%) 601-700 mg, 37 (17.0%) 501-600 mg, 48 (22.0%) 401-500 mg and only 6 (2.8%) 400 mg/day or less. The cumulative incidences at 12 months of complete cytogenetic remission (CCR) were 52.3%, 64.9% and 50.6%, and of major molecular remission (MMR) 30.2%, 54.3% and 34.6% with IM 400, IM 800 and IM 400 +IFN, respectively. The cumulative incidences of achieving CCR and MMR with IM 400, IM 800 and IM 400+IFN at 6, 12, 18 and 24 months after start of treatment are summarized in the table. MMR at 12 months was reached faster with IM 800 than with IM 400 (p=0.0003) or IM400+IFN (p=0.0131). Optimal molecular response (OMR=<0.01% BCR-ABL according to the international scale) was reached with IM 800 after a median of 31.3 months vs. 47.5 and 42.5 months with IM 400 +/- IFN. Also CCR was reached faster with IM 800 (p<0.01). The more rapid achievement of MMR with IM 800 was observed in low and intermediate risk patients with little or no difference in high risk patients. In an analysis “as treated” patients receiving more than 600 mg/day reached remissions faster than those receiving lower dosages (CCR after a median of 7.8 vs. 8.9 months, MMR after a median of 10.4 vs. 12.9 months). At the time of this evaluation, OS (92% at 5 years) and PFS (88% at 5 years) showed no difference. Type and severity of adverse events (AE) at 12 months did not differ from those expected (all grades and grades III/IV). Hematologic (thrombocytopenia 7% vs. 4%) and non-hematologic AEs (gastrointestinal 35% vs. 15-24% and edema 29% vs. 16-19%) were more frequent with IM 800, fatigue (14% vs. 7-13%) and neurological problems (15% vs. 6-7%) more frequent with IM 400 + IFN (all grades). These data show a significantly faster achievement of MMR at 12 months with IM 800 as compared to IM 400 +/-IFN. So far, this faster response rate did not translate into better OS or PFS. Hence IM 400 should still be considered as standard of care. With some individual dose adjustments tolerability of IM 800 was good. Longer observation is required to determine whether this more rapid achievement of MMR and CCR will have a long term impact or not. Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; European LeukemiaNet: Research Funding; Kompetenznetz Leukämie: Research Funding; Roche: Research Funding; Essex: Research Funding.

scholarly journals RVD induction and autologous stem cell transplantation followed by lenalidomide maintenance in newly diagnosed multiple myeloma: a phase 2 study of the Finnish Myeloma Group

2019 ◽  
Vol 98 (12) ◽  
pp. 2781-2792 ◽  
Author(s):  
Sini Luoma ◽  
Pekka Anttila ◽  
Marjaana Säily ◽  
Tuija Lundan ◽  
Jouni Heiskanen ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Maintenance Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
High Risk Patients ◽  
Risk Patients

Abstract Autologous stem cell transplantation (ASCT) combined with novel agents is the standard treatment for transplant-eligible, newly diagnosed myeloma (NDMM) patients. Lenalidomide is approved for maintenance after ASCT until progression, although the optimal duration of maintenance is unknown. In this trial, 80 patients with NDMM received three cycles of lenalidomide, bortezomib, and dexamethasone followed by ASCT and lenalidomide maintenance until progression or toxicity. The primary endpoint was the proportion of flow-negative patients. Molecular response was assessed if patients were flow-negative or in stringent complete response (sCR). By intention to treat, the overall response rate was 89%. Neither median progression-free survival nor overall survival (OS) has been reached. The OS at 3 years was 83%. Flow-negativity was reached in 53% and PCR-negativity in 28% of the patients. With a median follow-up of 27 months, 29 (36%) patients are still on lenalidomide and 66% of them have sustained flow-negativity. Lenalidomide maintenance phase was reached in 8/16 high-risk patients but seven of them have progressed after a median of only 6 months. In low- or standard-risk patients, the outcome was promising, but high-risk patients need more effective treatment approach. Flow-negativity with the conventional flow was an independent predictor for longer PFS.

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.

Long Term Outcome of Patients with Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid, Arsenic Trioxide with or without Gemtuzumab Ozogamicin

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3776-3776
Author(s):  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
Guillermo Garcia-Manero ◽  
Elihu Estey ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Low Risk ◽  
Newly Diagnosed ◽  
Term Outcome ◽  
Long Term Outcome ◽  
High Risk Patients ◽  
Risk Patients

Abstract Background - Combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) for the initial treatment of patients with low and intermediate risk acute promyelocytic leukemia (APL) has been shown to be superior to ATRA plus chemotherapy but there is limited available long-term follow up on the "chemotherapy-free" combinations. Methods - We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on three consecutive prospective clinical trials of the combination of ATRA and ATO with or without gemtuzumab ozogamicin (GO) (ID01-014; NCT01409161; NCT00413166). Initially patients received ATRA 45 mg/m2 in two divided doses daily and beginning 10 days later, ATO 0.15 mg/kg daily. With subsequent studies, the schedule was modified for all patients to receive concomitant therapy with ATRA and ATO from day 1. Patients with WBC > 10 x 109/L and patients whose WBC rose to greater than 10 x 109/L during therapy also received a dose of GO 9 mg/m2. Standard supportive care as well as steroids for prophylaxis for differentiation syndrome were administered to all patients. A bone marrow exam to assess response was performed between days 21 and 28 and, if necessary, repeated weekly. Once in CR, patients received consolidation with ATO 0.15 mg/kg daily 5 days/week for 4 weeks every 8 weeks for a total of 4 cycles and ATRA 45 mg/m2 daily for 2 weeks every 4 weeks for a total of 8 months. Bone marrow assessment was performed every 3 months for 1 year and if PCR for PML-RARA was confirmed positive, a dose of GO would be administered. Results - From July 2002 to May 2015, 183 patients have been enrolled into the three trials. During the same period a total of 235 patients with newly diagnosed APL were seen at our institution. Reasons for not being enrolled in the studies were: insurance/socio-economic in 39 (75%) and died within 48 hours of presentation in 13 (25%). Median age of the study patients was 50 years (range, 14-84). 52 (28%) were older than 60 years. Median WBC at presentation was 2.2 x 109/L (range, 0.3-187.9). 52 (28%) had high risk disease with WBC > 10 x 109/L and 131 (72%) had low risk disease with a WBC ≤ 10 x 109/L. Cytogenetics were t(15;17) alone in 117 (64%), t(15;17) plus other in 48 (26%), other, not done, or insufficient in 18 (10%). PCR was positive for PML-RARA in all patients (100%) with the long isoform in 104 (57%), short in 78 (43%), and both in 1 (<1%). Overall 176 (96%) achieved CR with CR rate of 96% for low risk patients and 96% for high risk patients. Early death (occurring within 1 month of study entry) occurred in 7 (4%) and was due to 1 infection/multi-organ failure (MOF), 3 hemorrhage, 3 MOF/hemorrhage/infection. Differentiation syndrome was diagnosed in 21 (11.5%) Other toxicities included QT prolongation in 14 (7.7%), infections in 44 (24.0%), and hemorrhagic events in 10 (5.5%). The median duration of follow-up is 39.6 months (range, 0.8 - 138.8). Six patients (3%) have relapsed including 2 (1%) with extramedullary (both CNS) relapse. The median event-free (EFS), disease-free (DFS) and overall survival (OS) have not yet been reached. The 5-year EFS is 85%, DFS is 96%, and OS is 87% (Figures 1). The 5-year DFS and OS for low risk patients is 99% and 88%, respectively and for the high risk patients 87% and 85%, respectively (figure 2). Conclusion - The combination of ATRA and ATO, with and without GO is effective and associated with excellent long-term DFS and OS in both low and high risk patients with newly diagnosed APL. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Cortes: Teva: Research Funding; BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Jabbour:Pfizer: Consultancy, Research Funding. Faderl:Celator: Research Funding; Astellas: Research Funding; Seattle Genetics, Inc.: Research Funding; Karyopharm: Consultancy, Research Funding; Onyx: Speakers Bureau; Ambit: Research Funding; BMS: Research Funding; JW Pharma: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding. Wierda:Glaxo-Smith-Kline Inc.: Research Funding; Celgene Corp.: Consultancy. DiNardo:Novartis: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

scholarly journals Molecular Treatment Stratification for Newly Diagnosed High-Risk Myeloma, Including Plasma Cell Leukemia - Feasibility Results of the Ukmra Optimum: MUK9 Trial (NCT03188172)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3162-3162 ◽  
Author(s):  
Matthew Jenner ◽  
Amy L Sherborne ◽  
Andrew Hall ◽  
Vallari Shah ◽  
Katrina Walker ◽  
...  
Keyword(s):  
High Risk ◽  
Plasma Cell ◽  
Primary Endpoint ◽  
Research Funding ◽  
Plasma Cell Leukemia ◽  
Newly Diagnosed ◽  
Cell Leukemia ◽  
High Risk Patients ◽  
High Risk Disease ◽  
Risk Patients

Background High-risk myeloma patients have unsatisfactory outcomes with current treatments and are in urgent need of improved diagnostic and therapeutic strategies. We have recently validated specific markers predicting high-risk disease in newly diagnosed MM (NDMM), in particular double-hit with presence of ≥2 consensus high-risk markers t(4;14), t(14;16), t(14;20), del(1p), gain(1q), del(17p) (Shah V, et al., Leukemia 2018) and diagnostic GEP SKY92 high risk signature (Sherborne A, et al., IMW 2017). Diagnostic tests for these markers were implemented in the UK multi-center OPTIMUM: MUK9 trial to prospectively stratify therapy for high-risk NDMM. Trial design OPTIMUM: MUK9 is a phase 2 trial for transplant eligible NDMM, consisting of two inter-related protocols: a molecular screening protocol (MUK9A) and an interventional trial (MUK9B) for high-risk MM identified in MUK9A. Patients with suspected or confirmed MM fit for intensive therapy enrolled in MUK9A have central molecular profiling at ICR, London, of CD138-selected BM MM cells for translocations, copy number aberrations (qRT-PCR; MLPA P425, MRC Holland) and SKY92 signature status (MMprofiler; SkylineDx). If clinically indicated SOC therapy (VTD, max. 2 cycles) can be given whilst central results are generated. Patients found to have high-risk MM by double-hit and/or SKY92 are offered enrolment into MUK9B. All other patients receive SOC (VTD, HD-MEL+ASCT) for which clinical data is collected. Patients diagnosed with plasma cell leukemia (PCL) can be enrolled directly in MUK9B. MUK9B treatment consists of quintuplet daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction (up to 6 cycles), bortezomib-augmented single HD-MEL+ASCT, Dara-VRd consolidation 1 (6 cycles), Dara-VR consolidation 2 (12 cycles) and Dara-R maintenance (until PD). Dose adjustments are permitted in order to maximize tolerability of long-term therapy. Patient reported outcomes (PRO) are recorded at baseline and throughout treatment. Response and MRD are centrally assessed (Birmingham, Leeds). Primary endpoint for MUK9A is feasibility of central molecular testing within 56 days turnaround time, which we report on here. Primary endpoint of MUK9B is treatment efficacy, comparing MUK9B PFS to near-concurrent molecularly matched high-risk patient outcomes from UK NCRI Myeloma XI using a Bayesian design. Secondary endpoints include safety, PFS2, MRD and OS and study of molecular evolution in high-risk disease. Results The protocol recruited 29/Sep/17 - 31/Jul/19 at 39 UK sites, achieving the recruitment target of 105 high-risk patients treated on MUK9B ahead of projections. At the time of analysis (12/Jul/19), 430 patients with suspected or confirmed NDMM have been recruited to MUK9A across 39 UK NHS hospitals. Of these, 376 (87%) patients were confirmed to have symptomatic MM (60.9% male; median age 61y (range 29-79)) as per updated IMWG diagnostic criteria (2014), including 9 (2%) PCL patients, with the remainder diagnosed as SMM/MGUS (31; 7%) or other (14; 3%). For 371 of the 376 symptomatic MM patients BM was received by the central laboratory and was of sufficient quality for profiling in 331 (89%) patients. Repeat samples were requested for all others and a sufficient sample received for 20/45 (44%). Central results were successfully reported within the pre-specified 56 day interval for all patients (median 17 days; IQR 13-22). Of 346 patients with a reported result, 128 (37.0%) have high-risk MM, with molecular characteristics mirroring Myeloma XI patients (Figure 1). PCL patients show expected characteristics as listed in Table 1. Basic demographics were not different between high-risk vs. non-high-risk. 101 high-risk patients have or are planning to enter MUK9B, 10 pending decision; 17 high-risk patients did not enter MUK9B, the majority due to ineligibility. 92 patients have started Dara-CVRD therapy. There are currently no safety concerns, the majority of patients are completing induction successfully; 1 patient stopped induction therapy due to adverse events. Updated results will be presented. Discussion Our data demonstrate feasibility of multi-center molecular stratified trial delivery for high-risk NDMM patients. These early trial results strongly support accelerated trial strategies for MM patient groups with high unmet need and rational drug development specifically for high-risk MM. Disclosures Jenner: Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Walker:Janssen, Celgene: Other: Research funding to Institution. Croft:Celgene: Other: Travel expenses. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Drayson:Abingdon Health: Consultancy, Equity Ownership. Owen:Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses; Celgene, Janssen: Honoraria. Pratt:Binding Site, Amgen, Takeda, Janssen, Gilead: Consultancy, Honoraria, Other: Travel support. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Kaiser:Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses.

Prediction of Molecular Response of Chronic Phase CML Patients by the EUTOS Score: Results of the Randomized CML-Study IV,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3762-3762
Author(s):  
Susanne Saussele ◽  
Michael Lauseker ◽  
Verena Hoffmann ◽  
Ulrike Proetel ◽  
Benjamin Hanfstein ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Low Risk ◽  
Molecular Response ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
High Risk Patients ◽  
Risk Patients ◽  
Eutos Score

Abstract Abstract 3762 Introduction: The EUTOS Score was developed and validated as a prognostic tool for the achievement of complete cytogenetic response (CCR) at 18 months for chronic phase (CP) CML patients under imatinib therapy. The score identifies high-risk patients not reaching CCR at 18 months with a positive predictive value of 34% and a specificity of 92% using only two variables, peripheral blood basophils and spleen size at diagnosis (Hasford et al. Blood 2011). We sought to evaluate the clinical impact of the EUTOS score to predict molecular response. Therefore, we analyzed the EUTOS score with patients from the German CML-Study IV, a randomized 5-arm trial (imatinib 400 mg vs. imatinib 800 mg vs. imatinib in combination with interferon alpha vs. imatinib in combination with araC vs. imatinib after interferon failure). Results: From July 2002 to December 2010, 1,502 patients with BCR-ABL positive CML in CP were randomized. 129 patients with imatinib after interferon alpha and 36 other patients had to be excluded (14 due to incorrect randomization or withdrawal of consent, 22 with missing baseline information). 1,337 patients were evaluable for overall and progression-free survival (OS and PFS), 1,252 for molecular responses. 749 of these patients were part of the score development sample. Therefore cytogenetic analyses are not described here. By EURO score, 36% of patients (n=475) were low risk, 51% (n=681) intermediate risk, and 12% (n=167) high risk. The EUTOS score was low risk in 88% (n=1163) and high risk in 12% (n=160). The high-risk patients differed between the two scores: EUTOS high-risk patients were classified according to EURO score in 12% as low (n=19), in 45% as intermediate (n=68) and in 43% as high risk (n=73). Patients with high, intermediate, and low risk EURO score achieved MMR in 22, 16, and 13 months and CMR4 (BCR-ABL <=0.01%) in 59, 41, and 34 months. P-values for low vs. intermediate risk groups were borderline only (0.03 for MMR and 0.04 for CMR4), whereas p-values for high vs. low/intermediate risk groups were for both molecular response levels <0.001. At 12 months the proportion of patients in MMR was 38%, 46%, 54% for high, intermediate, and low risk patients, respectively. Similar results were observed with the Sokal score. Patients with high risk EUTOS score achieved deep molecular responses (MMR and CMR4) significantly later than patients with low risk EUTOS score (MMR: median 21.0 vs. 14.8 months, p<0.001, Fig. 1a; CMR4: median 60.6 vs. 37.2 months, p<0.001, Fig. 1b). The proportions of patients achieving MMR at 12 months were significantly lower in the EUTOS high-risk group than in the EUTOS low-risk group (30.8% vs. 50.6%, p<0.001). OS after 5 years was 85% for high and 91% for low risk patients (p=n.s.), PFS was 85% and 90%, respectively. Conclusions: The EUTOS score clearly separates CML patients also according to MMR and CMR4 (MR4). The new EUTOS score should be used in future trials with tyrosine kinase inhibitors in CML. Disclosures: Neubauer: Novartis: Honoraria, Research Funding; Roche: Research Funding. Kneba:Hoffmann La Roche: Honoraria. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hochhaus:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.

scholarly journals Trial-in-Progress: Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma (NCT#03269669): SWOG S1608

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2425-2425
Author(s):  
Paul M. Barr ◽  
Hongli Li ◽  
Brian K. Link ◽  
Christopher R. Flowers ◽  
Richard Burack ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Clinical Factors ◽  
High Risk Patients ◽  
Cytotoxic Treatment ◽  
Additional Chemotherapy ◽  
Risk Patients ◽  
The Impact

Abstract While the majority of follicular lymphoma (FL) patients have an overall survival of nearly 2 decades, a subset of patients has a markedly inferior survival. Across randomized studies, 20% of patients will respond poorly to first-line chemoimmunotherapy and account largely for the early deaths in the larger FL population. This group represents the largest unmet need in FL, for which a precision approach to therapy must be developed. With the development of newer monoclonal antibodies, immunomodulatory agents, therapies targeting molecules downstream of the B-cell receptor and novel cellular strategies, non-cytotoxic treatment has the potential to improve outcomes for patients with early progressing FL. There are several validated clinical factors known to correlate with disease outcome in newly diagnosed FL including age, lactate dehydrogenase, β2-microglobulin and disease extent that have been incorporated in prognostic systems such as FLIPI and FLIPI2. More recently, genetic biomarkers have been identified, including MLL2, EZH2, IRF4, CREPPB, and EPHA7 which reflect the disease biology as well as the impact of the lymphoma microenvironment. The addition of these molecular aberrations to clinical factors has led to the development of the M7-FLIPI as well as a 23-gene score, improving risk prognostication for newly diagnosed FL patients. However, such systems have shown a limited ability to predict progression or relapse within 2 years of chemotherapy. As such, identification of these patients at diagnosis or prior to therapy is currently not possible. S1608 was developed to 1) enable identification of high-risk patients using clinical and molecular markers by validating the m7-FLIPI prognostic system and to 2) identify the novel therapeutic approaches most active in this population. This study is enrolling high-risk patients, refractory to chemoimmunotherapy, and in randomized fashion, comparing novel regimens against additional chemotherapy to identify the most active non-chemotherapeutic strategies for this population. Eligible patients must be 18 years or older with grade 1, 2 or 3a FL and have relapsed or progressed with 2 years of finishing their first course of chemoimmunotherapy. Previous chemotherapy must have been CHOP or bendamustine based. Patients are eligible regardless of anti-CD20 therapy used, whether radiation therapy had been administered and whether or not maintenance therapy was utilized. Note that patients are required to have evidence of progressive disease within 2 years but do not have to be registered within 2 years. These high-risk patients are randomized to 12 months of lenalidomide, umbralisib or additional chemotherapy (for 6 months), all combined with 12 months of obinutuzumab. The primary clinical endpoint is CR rate after 6 cycles, allowing responding patient to proceed with consolidative cellular therapies if desired by the treating physician. Biopsies from diagnosis and at the time of relapse as well as circulating tumor DNA are being collected to prospectively evaluate the m7-FLIPI and to identify additional predictive markers. S1608 is a collaborative effort amongst the SWOG, Alliance and ECOG-ACRIN cooperative groups. The study represents one of the only prospective efforts to characterize early progressing FL and the only randomized trial comparing treatment strategies for this group of follicular lymphoma patients most in need of alternative therapies. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820, U10CA180821; and TG Therapeutics, Inc. Figure 1 Figure 1. Disclosures Barr: Genentech: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Beigene: Consultancy; Abbvie/Pharmacyclics: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Gilead: Consultancy. Link: Novartis, Jannsen: Research Funding; MEI: Consultancy; Genentech/Roche: Consultancy, Research Funding. Flowers: Cellectis: Research Funding; Nektar: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; BeiGene: Consultancy; 4D: Research Funding; Karyopharm: Consultancy; Morphosys: Research Funding; Guardant: Research Funding; Bayer: Consultancy, Research Funding; Genmab: Consultancy; Eastern Cooperative Oncology Group: Research Funding; SeaGen: Consultancy; Genentech/Roche: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Adaptimmune: Research Funding; Janssen: Research Funding; Iovance: Research Funding; Acerta: Research Funding; Kite: Research Funding; Allogene: Research Funding; EMD: Research Funding; Amgen: Research Funding; Celgene: Consultancy, Research Funding; Ziopharm: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; National Cancer Institute: Research Funding; Xencor: Research Funding; Spectrum: Consultancy; Gilead: Consultancy, Research Funding; Epizyme, Inc.: Consultancy; Biopharma: Consultancy; Denovo: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding. Weigert: Janssen: Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. Herrera: ADC Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Karyopharm: Consultancy; Kite, a Gilead Company: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Research Funding; Merck: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Takeda: Consultancy; Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Weinstock: SecuraBio: Consultancy; ASELL: Consultancy; Bantam: Consultancy; Abcuro: Research Funding; Verastem: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Consultancy; Travera: Other: Founder/Equity; Ajax: Other: Founder/Equity. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. Kahl: Abbvie, BeiGene, AstraZeneca, Acerta: Research Funding; Research to Practice: Speakers Bureau; Abbvie, ADCT, AstraZeneca, Beigene, Celgene, Teva, Janssen, MTEM, Bayer, InCyte, Adaptive, Genentech, Roche, MEI, KITE, TG Therapeutics, Epizyme, Takeda: Consultancy. Smith: Celgene, Genetech, AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Friedberg: Novartis: Other: DSMC ; Acerta: Other: DSMC ; Bayer: Other: DSMC .

scholarly journals Uptake and detection rate of a stepwise cardiometabolic disease detection program in primary care—a cohort study

2019 ◽  
Vol 30 (3) ◽  
pp. 402-407
Author(s):  
Daphne M Stol ◽  
Monika Hollander ◽  
Ilse F Badenbroek ◽  
Mark M J Nielen ◽  
François G Schellevis ◽  
...  
Keyword(s):  
Risk Factors ◽  
Primary Care ◽  
Cohort Study ◽  
High Risk ◽  
Newly Diagnosed ◽  
Additional Risk ◽  
High Risk Patients ◽  
Detection Program ◽  
Risk Patients

Abstract Background Early detection and treatment of cardiometabolic diseases (CMD) in high-risk patients is a promising preventive strategy to anticipate the increasing burden of CMD. The Dutch guideline ‘the prevention consultation’ provides a framework for stepwise CMD risk assessment and detection in primary care. The aim of this study was to assess the outcome of this program in terms of newly diagnosed CMD. Methods A cohort study among 30 934 patients, aged 45–70 years without known CMD or CMD risk factors, who were invited for the CMD detection program within 37 general practices. Patients filled out a CMD risk score (step 1), were referred for additional risk profiling in case of high risk (step 2) and received lifestyle advice and (pharmacological) treatment if indicated (step 3). During 1-year follow-up newly diagnosed CMD, prescriptions and abnormal diagnostic tests were assessed. Results Twelve thousand seven hundred and thirty-eight patients filled out the risk score of which 865, 6665 and 5208 had a low, intermediate and high CMD risk, respectively. One thousand seven hundred and fifty-five high-risk patients consulted the general practitioner, in 346 of whom a new CMD was diagnosed. In an additional 422 patients a new prescription and/or abnormal diagnostic test were found. Conclusions Implementation of the CMD detection program resulted in a new CMD diagnosis in one-fifth of high-risk patients who attended the practice for completion of their risk profile. However, the potential yield of the program could be higher given the considerable number of additional risk factors—such as elevated glucose, blood pressure and cholesterol levels—found, requiring active follow-up and presumably treatment in the future.

scholarly journals Open-Labeled, Multicenter Phase II Study of Bortezomib for Maintenance Therapy in Patients with High Risk Diffuse Large B Cell Lymphoma (DLBCL): Borma Trial from Consortium for Improving Survival of Lymphoma (CISL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2884-2884
Author(s):  
Jae-Cheol Jo ◽  
Ho Sup Lee ◽  
Cheolwon Suh ◽  
Hye Jin Kang ◽  
Won Seog Kim ◽  
...  
Keyword(s):  
High Risk ◽  
Maintenance Therapy ◽  
B Cell ◽  
Research Funding ◽  
Maintenance Treatment ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Risk Patients ◽  
Large B Cell Lymphoma ◽  
Risk Patients

Background: High-intermediate or high risk in international prognostic index (IPI) has a long-term chance of cure in the range about 50% in patients with diffuse large B cell lymphoma (DLBCL) treated by R-CHOP. These high risk patients should be considered for additional new treatment to standard R-CHOP or investigational approaches in the context of clinical trials that are designed to ensure that potentially curative therapy. Bortezomib inhibits NF-κB activation through proteasome inhibition, providing rationale for its use in cells that constitutively express NF-κB. Non-germinal center B cell (GCB) DLBCL has a worse survival after upfront chemotherapy and is characterized by constitutive activation of the antiapoptotic NF-κB pathway, which can inhibit chemotherapy. There is no study of bortezomib as maintenance therapy after treated with R-CHOP in high risk patients with DLBCL. So we applied additional bortezomib as maintenance therapy in order to assess improving efficacy and survival rates in high risk patients with non-GCB DLBCL who had been confirmed complete response (CR) after treated with R-CHOP. Methods: Patients with newly diagnosed stage II(bulky)-IV DLBCL with high or high intermediate IPI score of 3 to 5, and patients achieving a CR at the end of 6 or 8 cycles of R-CHOP21 were eligible for enrollment. Non-GCB DLBCL according to Hans criteria confirmed by central review was need before enrollment. Bortezomib maintenance treatment was consisted of bortezomib 1.3mg/m2 subcutaneously administration day 1 and day 15 per 28-day cycle with a total of 12 cycles. The primary endpoint was 3-year progression-free survival (PFS). Secondary endpoints were 3-year overall survival (OS), and toxicites. Toxicity was graded according to the Common Terminology Criteria for Adverse Events v4.0. Results: Fifty-nine patients were enrolled between May 2014 and Oct 2018. The type of Non-GCB DLBCL in all patients was confirmed by the central pathology review. The median age was 65 years (range: 27-86 years), and 60% were > 61 years. The baseline clinical features were as follows: female sex, 45.8%; ECOG >1, 10.2%; stage II bulky (>10cm), 6.8%; stage III/IV, 93.2%. At the time of analysis, 29 patients completed 12-cycles of bortezomib maintenance, and 3 patients is ongoing. Seven patients did not finished maintenance therapy due to toxicities (fatigue, atrial flutter, neuropathy, pleural effusion, thrombocytopenia), and withdrawal of informed consent (n=4). Sixteen patients experienced disease progression during bortezomib maintenance treatment. With a median follow-up of 25.1 months, 3-year PFS rate was 56.9% and 3-year OS rate was 86.4% (Figure 1). Toxicity was assessed in 489 cycles of bortezomib maintenance in all 59 patients. There was no treatment-related death and febrile neutropenia. Conclusion: Bortezomib maintenance showed 3-year PFS rate of 56.9% with acceptable toxicities in patients with high risk DLBCL achieving a CR at the end of 6 or 8 cycles of R-CHOP21. Figure 1 Disclosures Kim: Celltrion: Research Funding; Novartis: Research Funding; J + J: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

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