scholarly journals Low Rates of CNS Relapse in High Risk DLBCL Patients Treated with R-CODOX-M and R-IVAC: Results from a Phase 2 UK NCRI/Bloodwise Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1855-1855 ◽  
Author(s):  
Elizabeth H Phillips ◽  
Amy A Kirkwood ◽  
Anthony Lawrie ◽  
Simon Rule ◽  
Russell Patmore ◽  
...  

Abstract Introduction: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) represents a major clinical challenge and is fatal in most patients. Recently Schmitz et al (J ClinOncol 2016), defined an effective risk model, the CNS-IPI, to identify those at highest risk of CNS relapse, based on the international prognostic index (IPI) score and presence of renal or adrenal involvement. For DLBCL patients receiving R-CHOP-like regimens +/- intrathecal methotrexate, the risk of CNS relapse for low, intermediate and high-risk patients was <1%, 3-4% and 10-12%, respectively. The optimum strategy for CNS prophylaxis, however, has yet to be defined. Aim: To assess CNS relapse rates in an intermediate-high risk cohort of patients with DLBCL treated with the R-CODOX-M R-IVAC regimen, incorporating multiple CNS-penetrating agents. Methods: Patients with newly diagnosed DLBCL and an IPI score ≥3 were enrolled in a prospective, multi-centre, phase 2 trial (McMillan et al, Hematol Oncol 2015; 31(S1), 130a) and treated with modified CODOX-M and IVAC, including high dose intravenous methotrexate, cytarabine, ifosfamide and etoposide with 8-12 intrathecal injections (Mead et al, AnnOncol 2002; 23(8):1264-74); plus 8 doses of rituximab. The primary endpoint was progression-free survival (PFS). CNS involvement was diagnosed according to neurological signs, radiological findings and/or demonstration of malignant lymphocytes within the cerebrospinal fluid. Involvement ofextranodal sites was prospectively documented at registration and at relapse. Presence of CNS, adrenal and renal involvement was confirmed using case report forms prior to this post hoc analysis. Results: 108 patients were treated at 32 UK sites between May 2008 and April 2013. Median age was 50 years (18-65 years). Eight patients (7.4%) had CNS involvement at baseline. Eighty-two patients (75.9%) received 4 cycles of treatment. At a median follow-up of 45 months, PFS and overall survival were 65.5% (95% CI: 55.5 - 73.8) and 73.7% (64.0 - 81.2), respectively. Progression or relapse within the CNS occurred in 5 patients (4.6%; Table 1) at a median of 5.5 months after registration (0.9-9.1 months). All patients died within 9 months of CNS relapse, 4 due to DLBCL and one treatment-related death. Excluding those with CNS involvement at baseline or incomplete information (n=4; 2 with missing baseline information (no CNS relapse) and 2 awaiting confirmation of CNS status at relapse), CNS-IPI was evaluable in 96 patients, of which 95% had an elevated LDH, 57% had a performance status of ≥2, and 8% were ≥60 years. All patients had stage III-IV disease, 76% had >1 extranodalsite and 27% had renal or adrenal involvement. Forty-one patients (43%) were intermediate risk (2-3 factors) and 55 (57%) were high risk (4-6 factors) for CNS relapse. 2-year CNS relapse rates were 0% for intermediate risk and 6.2% (2.0 - 18.1) for high risk patients (Figure 1). Of the 3 CNS relapses in high risk patients, 2 occurred concurrently with systemic relapse; there was only one episode of isolated CNS relapse. Of the 8 patients with CNS involvement at baseline, 2 (25%) developed CNS relapse, including 1 isolated CNS relapse. One further patient died of refractory DLBCL whilst 5 (62.5%) are alive and progression free with a minimum of 28 months follow-up. Conclusions: Inclusion of CNS-directed therapy intrinsic to the R-CODOX-M IVAC regimen resulted in very low rates of CNS relapse. Although patient numbers and low event rates make direct comparison difficult, results appear promising alongside historical results with R-CHOP chemotherapy. CNS relapse rates for both intermediate and high risk patients in this trial were below the 95% confidence intervals for CNS relapse reported in large training and validation cohorts by Schmitz et al (0% vs 2.2 - 4.4 and 2.3 - 5.5 for intermediate risk patients and 6.2% vs 6.3 - 14.1 and 7.9 - 16.1 for high risk). Of note, only 2 patients in the whole cohort progressed with isolated CNS disease, one of whom had CNS disease at diagnosis. Thus, where systemic disease was fully treated, treatment failure due to inadequate CNS penetration was rare. Reasonable outcomes were achieved in patients with CNS involvement at diagnosis but greater patient numbers are required to further evaluate this regimen in secondary CNS lymphoma. Table 1 PFS events and CNS relapse rates Table 1. PFS events and CNS relapse rates Figure 1 CNS relapse rates according to CNS-IPI and presence of CNS disease at baseline Figure 1. CNS relapse rates according to CNS-IPI and presence of CNS disease at baseline Disclosures Phillips: Roche: Consultancy. Patmore:Roche: Honoraria; Janssen Cilag: Honoraria. Ardeshna:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference Expenses, Research Funding. Montoto:Roche: Honoraria; Gilead: Research Funding.

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 18-19
Author(s):  
Ferdows Atiq ◽  
Esmee Wuijster ◽  
Moniek P.M. de Maat ◽  
Marieke J.H.A. Kruip ◽  
Marjon H. Cnossen ◽  
...  

Introduction Although large studies have recently provided valuable insights on the diagnosis, bleeding phenotype, and treatment outcomes of VWD patients, these aspects remain poorly understood in individuals with low VWF. Firstly, there is no clear evidence which cut-off value should be used to diagnose low VWF. Although 0.50 IU/mL is the most recommended cut-off value, some centers use the lower limit of normal (0.60 IU/mL). Secondly, the incidence of post-surgical bleeding, postpartum hemorrhage (PPH) and traumatic- or spontaneous bleeding after diagnosis of low VWF are still unknown. Lastly, it is hard to predict which individuals with low VWF have an increased bleeding risk. Therefore, we investigated the bleeding phenotype of individuals with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL, and the incidence of post-surgical bleeding, PPH and traumatic- and spontaneous bleeding after their initial diagnosis of "low VWF". Methods We performed a retrospective cohort study from January 2007 to November 2019 at the Erasmus MC, University Medical Center Rotterdam. All patients evaluated for the presence of a bleeding disorder with VWF antigen (VWF:Ag) and/or VWF activity (VWF:Act) and/or VWF collagen binding (VWF:CB) levels between 0.31-0.60 IU/mL, were included. Patients with VWF:Ag and/or VWF:Act and/or VWF:CB ≤0.30 IU/mL, acquired VWD and those with a concomitant bleeding disorder were excluded. For each individual we collected data from electronic patient files on baseline characteristics, reason for referral, family history of bleeding disorders, ISTH-BAT and laboratory measurements at diagnosis. Retrospective follow-up started from initial date of low VWF diagnosis through November 2019, during which we collected data on surgical procedures, pregnancies, and incidence of spontaneous- and traumatic bleeding. Results We included 439 patients; 269 patients with historically lowest VWF levels 0.31-0.50 IU/mL and 170 patients 0.51-0.60 IU/mL. Mean age at diagnosis was 28.8 ±17.7 years. Most patients were female (74.3%) and had blood group O (76.4%, Table 1). The bleeding score (BS) was similar in patients with historically lowest VWF levels of 0.31-0.50 IU/mL (3.7 ±3.0) and 0.51-0.60 IU/mL (4.0 ±2.9, p=0.209, Table 1). During the mean follow-up period of 6.3 ±3.7 years, 259 surgical procedures were performed in 146 patients, 81 deliveries in 56 women, and 109 spontaneous- or traumatic bleedings in 71 patients. The incidence of post-surgical bleeding was 7 (2.7%) during follow-up, whereas 8 deliveries (10%) were complicated by PPH. Overall, 65 out of 439 patients (14.8%) had a bleeding episode requiring treatment during follow-up, resulting in an incidence of bleeding requiring treatment of 0.5 ±1.9 per patient per decade. No difference was found in the incidence of bleeding requiring treatment between patients with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL (Figure 2A, p=0.154). We found that referral for a personal bleeding diathesis, a younger age at diagnosis and an abnormal BS at diagnosis were strong and independent risk factors for bleeding requiring treatment during follow-up, respectively HR=2.32 (95%CI: 1.16-4.63), HR=1.18 (95%CI: 1.01-1.38) and HR=1.77 (95%CI: 1.04-3.01). These risk factors were combined to develop a risk score to identify low VWF patients with an increased risk for bleeding requiring treatment (Figure 2B). The risk score performed excellent to differentiate in bleeding requiring treatment between low risk, intermediate risk and high risk patients (p&lt;0.001, Figure 2C). The number of patients with bleeding requiring treatment was 8/126 (6.3%) in patients with low risk, 18/143 (12.6%) in intermediate risk and 39/170 (22.9%) in high risk patients (p&lt;0.001). Likewise, the incidence of bleeding requiring treatment per patient per decade was 0.22 ±1.08 in low risk, 0.28 ±1.25 in intermediate risk and 0.87 ±2.61 in high risk patients (p=0.004, Figure 2D). Conclusion To conclude, there is no difference in the bleeding phenotype of individuals with historically lowest VWF levels of 0.31-0.50 IU/mL and 0.51-0.60 IU/mL. Therefore, the cut-off value to diagnose low VWF should be set at 0.60 IU/mL. Furthermore, the risk score developed in the current study may assist to identify low VWF patients with low, intermediate and high risk for future bleeding. Disclosures Atiq: SOBI: Other: travel grant; CSL Behring: Research Funding. Kruip:Boehringer Ingelheim: Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Daiichi Sankyo: Research Funding; SOBI: Research Funding; Bayer: Speakers Bureau. Cnossen:Takeda: Research Funding; Shire: Research Funding; Baxter: Research Funding; Bayer: Research Funding; Sobi: Research Funding; CSL behring: Research Funding; Nordic Pharma: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding. Leebeek:CSL Behring: Research Funding; Shire/Takeda: Research Funding; Uniqure: Consultancy; Shire/Takeda: Consultancy; Novo Nordisk: Consultancy; SOBI: Other: Travel grant; Roche: Other: DSMB member for a study.


Cardiology ◽  
2017 ◽  
Vol 137 (4) ◽  
pp. 207-217 ◽  
Author(s):  
Liefke C. van der Heijden ◽  
Marlies M. Kok ◽  
Marije M. Löwik ◽  
Peter W. Danse ◽  
Gillian A.J. Jessurun ◽  
...  

Objective: Limited data is available on the long-term outcome of patients with increased cardiovascular event risk, treated with newer-generation durable polymer drug-eluting stents (DES). Methods: We therefore assessed 3-year follow-up data of high-risk versus low- to intermediate-risk patients of the randomized DUTCH PEERS trial (NCT01331707). In both risk groups we also compared patients treated with Resolute Integrity versus Promus Element DES. Patients were categorized as “high-risk” if they met ≥1 of the following criteria: (1) diabetes (17.9%); (2) previous myocardial infarction (21.9%); (3) previous coronary revascularization (25.8%); (4) chronic renal failure (3.5%); (5) left ventricular ejection fraction ≤30% (1.5%); and (6) age ≥75 years (17.3%). Results: At the 3-year follow-up, the incidence of the composite endpoint target vessel failure (TVF) (13.2 vs. 7.5%; logrank p < 0.001) and 2 of its components - cardiac death (4.7 vs. 1.5%; logrank p < 0.001) and target vessel revascularization (7.3 vs. 4.7%; logrank p = 0.03) - was higher in high-risk (n = 957) versus low- to intermediate-risk patients (n = 854). Among high-risk patients, treatment with Resolute Integrity (n = 481) and Promus Element stents (n = 476) was similarly safe and efficacious (TVF: 13.3 vs. 13.1%; logrank p = 0.95; definite-or-probable stent thrombosis: 1.7 vs. 1.7%; logrank p = 1.00). Conclusions: The newer-generation Resolute Integrity and Promus Element stents showed similar results in terms of safety and efficacy for treating high-risk patients, who had significantly higher event rates than patients with low-to-intermediate risk.


Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5270-5270
Author(s):  
Juan-Manuel Sancho ◽  
Alberto Orfao ◽  
Olga García ◽  
Carlos Panizo ◽  
Elena Pérez ◽  
...  

Abstract Background and objective. Several studies have demonstrated that flow cytometry (FCM) improves the sensitivity of conventional cytology (CC) for the identification of leptomeningeal disease in aggressive lymphomas with high risk of central nervous system (CNS) involvement. A previous report from our group showed infiltration by FCM study in 27 out of 123 (22%) newly diagnosed aggressive B-cell lymphomas, while CC was positive in only 7 (6%). However, the clinical significance of the occult disease in CNS (FCM positive and CC negative) remains unknown. Patients and Methods. At the time of the analysis, 68 out of 123 patients of the previous study had adequate follow-up (median of follow-up for the alive patients [n=42] of 18 months [range 12–30]). In this cohort of patients the CNS involvement during follow-up was assessed according to CC and FCM results in cerebrospinal fluid at the time of diagnosis. Results. Three groups were defined according to the results of CC and CFM: Group 1, patients without CNS involvement (CC and FCM negatives, n=49); Group 2, patients with occult CNS disease (FCM positive and CC negative, n=11); Group 3, patients with CNS disease (CC and FCM positive, n=8). The groups were comparable for the main clinical and biological characteristics and histological subtypes of NHL. In the Group 1, 40 patients received intrathecal (IT) prophylaxis, 2 received CNS therapy due to the presence neurological symptoms and 7 did not receive any prophylaxis. In the Group 2, CNS prophylaxis was administered to 7 patients, whereas the 4 remaining received active therapy. The 8 patients of the Group 3 received active CNS therapy. Overall, 6 patients showed CNS relapse/progression, 2 in the Group 1 (4.1%) (both with diffuse large B cell lymphoma [DLBCL]) and 4 in the Group 3 (50%) (3 with Burkitt’s lymphoma and the remaining with DLBCL). None of the patients of the Group 2 showed CNS relapse or progression during follow-up. As expected, patients of Group 3 showed a significant increase in CNS relapse compared to those from Groups 1 (p&lt;0.001) and 2 (p=0.038). However, the incidence of CNS relapse in patients of Groups 1 and 2 was not statistically different (p=0.496). Conclusions. Up to now, and different from previous studies, the presence of occult CNS disease in our cohort of patients with NHL and high risk of CNS disease was not associated with a higher risk of CNS relapse. This feature could be due to the fact that most of the patients received adequate CNS prophylaxis, that could be sufficient to eliminate the occult disease.


Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3274
Author(s):  
Vinson Wai-Shun Chan ◽  
Wei Shen Tan ◽  
Aqua Asif ◽  
Alexander Ng ◽  
Olayinka Gbolahan ◽  
...  

External factors, such as the coronavirus disease 2019 (COVID-19), can lead to cancellations and backlogs of cancer surgeries. The effects of these delays are unclear. This study summarised the evidence surrounding expectant management, delay radical prostatectomy (RP), and neoadjuvant hormone therapy (NHT) compared to immediate RP. MEDLINE and EMBASE was searched for randomised controlled trials (RCTs) and non-randomised controlled studies pertaining to the review question. Risks of biases (RoB) were evaluated using the RoB 2.0 tool and the Newcastle–Ottawa Scale. A total of 57 studies were included. Meta-analysis of four RCTs found overall survival and cancer-specific survival were significantly worsened amongst intermediate-risk patients undergoing active monitoring, observation, or watchful waiting but not in low- and high-risk patients. Evidence from 33 observational studies comparing delayed RP and immediate RP is contradictory. However, conservative estimates of delays over 5 months, 4 months, and 30 days for low-risk, intermediate-risk, and high-risk patients, respectively, have been associated with significantly worse pathological and oncological outcomes in individual studies. In 11 RCTs, a 3-month course of NHT has been shown to improve pathological outcomes in most patients, but its effect on oncological outcomes is apparently limited.


2021 ◽  
Vol 24 (3) ◽  
pp. 680-690
Author(s):  
Michiel C. Mommersteeg ◽  
Stella A. V. Nieuwenburg ◽  
Wouter J. den Hollander ◽  
Lisanne Holster ◽  
Caroline M. den Hoed ◽  
...  

Abstract Introduction Guidelines recommend endoscopy with biopsies to stratify patients with gastric premalignant lesions (GPL) to high and low progression risk. High-risk patients are recommended to undergo surveillance. We aimed to assess the accuracy of guideline recommendations to identify low-risk patients, who can safely be discharged from surveillance. Methods This study includes patients with GPL. Patients underwent at least two endoscopies with an interval of 1–6 years. Patients were defined ‘low risk’ if they fulfilled requirements for discharge, and ‘high risk’ if they fulfilled requirements for surveillance, according to European guidelines (MAPS-2012, updated MAPS-2019, BSG). Patients defined ‘low risk’ with progression of disease during follow-up (FU) were considered ‘misclassified’ as low risk. Results 334 patients (median age 60 years IQR11; 48.7% male) were included and followed for a median of 48 months. At baseline, 181/334 (54%) patients were defined low risk. Of these, 32.6% were ‘misclassified’, showing progression of disease during FU. If MAPS-2019 were followed, 169/334 (51%) patients were defined low risk, of which 32.5% were ‘misclassified’. If BSG were followed, 174/334 (51%) patients were defined low risk, of which 32.2% were ‘misclassified’. Seven patients developed gastric cancer (GC) or dysplasia, four patients were ‘misclassified’ based on MAPS-2012 and three on MAPS-2019 and BSG. By performing one additional endoscopy 72.9% (95% CI 62.4–83.3) of high-risk patients and all patients who developed GC or dysplasia were identified. Conclusion One-third of patients that would have been discharged from GC surveillance, appeared to be ‘misclassified’ as low risk. One additional endoscopy will reduce this risk by 70%.


Author(s):  
Laura C. Blomaard ◽  
Bas de Groot ◽  
Jacinta A. Lucke ◽  
Jelle de Gelder ◽  
Anja M. Booijen ◽  
...  

Abstract Objective The aim of this study was to evaluate the effects of implementation of the acutely presenting older patient (APOP) screening program for older patients in routine emergency department (ED) care shortly after implementation. Methods We conducted an implementation study with before-after design, using the plan-do-study-act (PDSA) model for quality improvement, in the ED of a Dutch academic hospital. All consecutive patients ≥ 70 years during 2 months before and after implementation were included. The APOP program comprises screening for risk of functional decline, mortality and cognitive impairment, targeted interventions for high-risk patients and education of professionals. Outcome measures were compliance with interventions and impact on ED process, length of stay (LOS) and hospital admission rate. Results Two comparable groups of patients (median age 77 years) were included before (n = 920) and after (n = 953) implementation. After implementation 560 (59%) patients were screened of which 190 (34%) were high-risk patients. Some of the program interventions for high-risk patients in the ED were adhered to, some were not. More hospitalized patients received comprehensive geriatric assessment (CGA) after implementation (21% before vs. 31% after; p = 0.002). In 89% of high-risk patients who were discharged to home, telephone follow-up was initiated. Implementation did not influence median ED LOS (202 min before vs. 196 min after; p = 0.152) or hospital admission rate (40% before vs. 39% after; p = 0.410). Conclusion Implementation of the APOP screening program in routine ED care did not negatively impact the ED process and resulted in an increase of CGA and telephone follow-up in older patients. Future studies should investigate whether sustainable changes in management and patient outcomes occur after more PDSA cycles.


Author(s):  
Grischa Hoffmann ◽  
Christine Friedrich ◽  
Katharina Huenges ◽  
Rainer Petzina ◽  
Astrid-Mareike Vogt ◽  
...  

Abstract Background High-risk patients with multivessel disease (MVD) including a complex stenosis of the left anterior descending coronary may not be ideal candidates for guideline compliant therapy by coronary artery bypass grafting (CABG) regarding invasiveness and perioperative complications. However, they may benefit from minimally invasive direct coronary artery bypass (MIDCAB) grafting and hybrid revascularization (HCR). Methods A logistic European system for cardiac operative risk evaluation score (logES) >10% defined high risk. In high-risk patients with MVD undergoing MIDCAB or HCR, the incidence of major adverse cardiac and cerebrovascular events (MACCEs) after 30 days and during midterm follow-up was evaluated. Results Out of 1,250 patients undergoing MIDCAB at our institution between 1998 and 2015, 78 patients (logES: 18.5%; age, 76.7 ± 8.6 years) met the inclusion criteria. During the first 30 days, mortality and rate of MACCE were 9.0%; early mortality was two-fold overestimated by logES. Complete revascularization as scheduled was finally achieved in 64 patients (82.1%). Median follow-up time reached 3.4 (1.2–6.5) years with a median survival time of 4.7 years. Survival after 1, 3, and 5 years was 77, 62, and 48%. Conclusion In high-risk patients with MVD, MIDCAB is associated with acceptable early outcome which is better than predicted by logES. Taking the high-risk profile into consideration, midterm follow-up showed satisfying results, although scheduled HCR was not realized in a relevant proportion. In selected cases of MVD, MIDCAB presents an acceptable alternative for high-risk patients.


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