Young Low-risk Patients Research Articles

Conduction Abnormalities after Transcatheter Aortic Valve Implantation: Incidence, Impact and Management Using CT Data Interpretation.

The demonstrated safety and effectiveness of transcatheter aortic valve implantation (TAVI) among low surgical risk patients opened the road to its application in younger low-risk patients. However, the occurrence of conduction abnormalities and need for permanent pacemaker implantation remains a frequent problem associated with adverse outcomes. The clinical implications may become greater when TAVI shifts towards younger populations, highlighting the need for comprehensive strategies to address this issue. Beyond currently available clinical and electrocardiographic predictors, patient-specific anatomical assessment of the aortic root using multi-sliced CT (MSCT) imaging can refine risk stratification. Moreover, leveraging MSCT data for computational 3D simulations to predict device-anatomy interactions may help guide procedural strategy to mitigate conduction abnormalities. The aims of this review are to summarise the incidence and clinical impact of new left bundle branch block and permanent pacemaker implantation post-TAVI using contemporary transcatheter heart valves; and highlight the value of MSCT data interpretation to improve the management of this complication.

Bicuspid Aortic Valve, from the Unknown till the Perfection of the Species.

The bicuspid aortic valve (BAV) is the most common congenital cardiac abnormality. Though most often isolated, BAV may be associated with other cardiovascular malformations. BAV-related aortopathy is the most common, sharing genetic alterations and phenotypic heterogeneity characteristics. Sometimes silent for a lifetime, BAV may manifest as aortic valve dysfunction, aortic aneurysm, or more emergent situations, such as endocarditis or aortic dissection. Its embryological origin and the characterization of the genes involved, as well as the histopathological and hemodynamic aspects of its natural history, are becoming increasingly clear. In addition, emerging evidence of rhythm disorders associated with BAV has been identified. A new international nomenclature and classification has been introduced to interpret all the advances made in recent years for the comprehension of this condition. In the guidelines, more attention has been paid to the diagnosis of BAV and related aortopathy, together with surveillance, and family screening. Surgical treatment remains the gold standard, especially in young low-risk patients, and valve repair techniques have been shown to be effective and durable. Finally, the new era of transcatheter techniques is also being applied to dysfunctional BAV, allowing the treatment of patients at high surgical risk, with increasingly promising results, and the possibility of expanding indications through the introduction of more advanced devices. This review aims to comprehensively describe the BAV conundrum, focusing on anatomy, pathophysiology, genetics, diagnosis of BAV-related disorders, and the different treatment options available in the transcatheter era.

Feasibility of Coronary Access Following Redo-TAVR for Evolut Failure: A Computed Tomography Simulation Study.

Coronary accessibility following redo-transcatheter aortic valve replacement (redo-TAVR) is increasingly important, particularly in younger low-risk patients. This study aimed to predict coronary accessibility after simulated Sapien-3 balloon-expandable valve implantation within an Evolut supra-annular, self-expanding valve using pre-TAVR computed tomography (CT) imaging. A total of 219 pre-TAVR CT scans from the Evolut Low-Risk CT substudy were analyzed. Virtual Evolut and Sapien-3 valves were sized using CT-based diameters. Two initial Evolut implant depths were analyzed, 3 and 5 mm. Coronary accessibility was evaluated for 2 Sapien-3 in Evolut implant positions: Sapien-3 outflow at Evolut node 4 and Evolut node 5. With a 3-mm initial Evolut implant depth, suitable coronary access was predicted in 84% of patients with the Sapien-3 outflow at Evolut node 4, and in 31% of cases with the Sapien-3 outflow at Evolut node 5 (P<0.001). Coronary accessibility improved with a 5-mm Evolut implant depth: 97% at node 4 and 65% at node 5 (P<0.001). When comparing 3- to 5-mm Evolut implant depth, sinus sequestration was the lowest with Sapien-3 outflow at Evolut node 4 (13% versus 2%; P<0.001), and the highest at Evolut node 5 (61% versus 32%; P<0.001). Coronary accessibility after Sapien-3 in Evolut redo-TAVR relates to the initial Evolut implant depth, the Sapien-3 outflow position within the Evolut, and the native annular anatomy. This CT-based quantitative analysis may provide useful information to inform and refine individualized preprocedural CT planning of the initial TAVR and guide lifetime management for future coronary access after redo-TAVR. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02701283.

Lifetime Management of Aortic Stenosis: Transcatheter Versus Surgical Treatment for Young and Low-Risk Patients.

Transcatheter aortic valve replacement is now indicated across all risk categories of patients with symptomatic severe aortic stenosis and has been proposed as first line option for the majority of patients >74 years old. However, median age of patients enrolled in the transcatheter aortic valve replacement low-risk trials is 74 years and transcatheter aortic valve replacement has never been systematically investigated in young low risk patients. Although the long-term data in surgical aortic valve replacement in young patients (age <75) are well known, such data remain lacking in transcatheter aortic valve replacement. In the absence of clear guideline recommendations in patients with challenging anatomies (eg, hostile calcium, bicuspid), it is important to know the potential advantages and disadvantages of each treatment and to consider how they might integrate with each other in the lifetime management of such patients. In this review, we discuss current outstanding issues on the management of severe aortic stenosis from a lifetime management perspective, particularly in terms of initial intervention and future reinterventions.

Transcatheter Aortic Valve Replacement in Young Low-Risk Patients With Severe Aortic Stenosis: A Review.

In the last decades, transcatheter aortic valve replacement (TAVR) revolutionized the treatment of symptomatic severe aortic stenosis. The efficacy and safety of TAVR were first proven in inoperable and high-risk patients. Then, subsequent randomized clinical trials showed non-inferiority of TAVR as compared to surgical aortic valve replacement also in intermediate- and low-risk populations. As TAVR was progressively studied and clinically used in lower-risk patients, issues were raised questioning its opportunity in a younger population with a longer life-expectancy. As long-term follow-up data mainly derive from old studies with early generation devices on high or intermediate surgical risk patients, results can hardly be extended to most of currently treated patients who often show a low surgical risk and are treated with newer generation prostheses. Thus, in this low-risk younger population, decision making is difficult due to the lack of supporting data. The aim of the present review is to revise current literature regarding TAVR in younger patients.

COVID-19 and its implications on patient selection for TAVI and SAVR: Are we heading into a new era?

COVID-19 and its implications on patient selection for TAVI and SAVR: Are we heading into a new era?

Impact of Transcatheter Aortic Valve Durability on Life Expectancy in Low-Risk Patients With Severe Aortic Stenosis.

Recent clinical trial results showed that transcatheter aortic valve replacement (TAVR) is noninferior and may be superior to surgical aortic valve replacement (SAVR) for mortality, stroke, and rehospitalization. However, the impact of transcatheter valve durability remains uncertain. Discrete event simulation was used to model hypothetical scenarios of TAVR versus SAVR durability in which TAVR failure times were varied to determine the impact of TAVR valve durability on life expectancy in a cohort of low-risk patients similar to those in recent trials. Discrete event simulation modeling was used to estimate the tradeoff between a less invasive procedure with unknown valve durability (TAVR) and that of a more invasive procedure with known durability (SAVR). Standardized differences were calculated, and a difference >0.10 was considered clinically significant. In the base-case analysis, patients with structural valve deterioration requiring reoperation were assumed to undergo a valve-in-valve TAVR procedure. A sensitivity analysis was conducted to determine the impact of TAVR valve durability on life expectancy in younger age groups (40, 50, and 60 years). Our cohort consisted of patients with aortic stenosis at low surgical risk with a mean age of 73.4±5.9 years. In the base-case scenario, the standardized difference in life expectancy was <0.10 between TAVR and SAVR until transcatheter valve prosthesis failure time was 70% shorter than that of surgical prostheses. At a transcatheter valve failure time <30% compared with surgical valves, SAVR was the preferred option. In younger patients, life expectancy was reduced when TAVR durability was 30%, 40%, and 50% shorter than that of surgical valves in 40-, 50-, and 60-year-old patients, respectively. According to our simulation models, the durability of TAVR valves must be 70% shorter than that of surgical valves to result in reduced life expectancy in patients with demographics similar to those of recent trials. However, in younger patients, this threshold for TAVR valve durability was substantially higher. These findings suggest that durability concerns should not influence the initial treatment decision concerning TAVR versus SAVR in older low-risk patients on the basis of current evidence supporting TAVR valve durability. However, in younger low-risk patients, valve durability must be weighed against other patient factors such as life expectancy.

Addition of rituximab to CHOP-like chemotherapy in first line treatment of primary mediastinal B-cell lymphoma

BackgroundThe addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) -like therapy has improved survival in primary mediastinal B-cell lymphoma (PMBCL) patients. However, these results were obtained in young low risk patients and a reevaluation in an unselected patient cohort is warranted.MethodsIn this study, we analyzed 80 PMBCL patients treated with a CHOP-based regimen with and without rituximab.ResultsIn the non-rituximab cohort 10-year progression free survival (PFS) was 67% and 10-year overall survival (OS) was 72% versus a PFS of 95% and a OS of 92% in the rituximab group, PFS P = 0.001, OS P = 0.023. A subgroup PFS analysis by international prognostic index (IPI) risk revealed that all risk groups benefit from addition of rituximab to induction chemotherapy. In addition, OS probability was higher in the group of non-low risk patients who were treated with rituximab compared to those patients who did not receive rituximab (P = 0.035). In multivariate analysis, only addition of rituximab to induction chemotherapy and reaching complete remission (CR) after first line therapy had a beneficial effect on both PFS and OS, whereas IPI, age, upfront high dose (HD) chemotherapy/autologous blood stem cell transplantation (ABSCT) and rituximab maintenance had no impact on survival.ConclusionsOur data demonstrate a survival benefit in unselected PMBCL patients treated with CHOP-like induction regimen and additional rituximab independently of the IPI risk score.

Matched sibling donor hematopoietic stem cell transplantation for thalassemia.

Bone marrow transplantation is the only curative treatment for severe thalassemia. Since its successful first report in 1981, more than 4000 patients with this disease worldwide underwent bone marrow transplantation. The purpose of this review is to update the most recent reports of matched sibling donor hematopoietic stem cell transplantation in thalassemia. Advanced and improved transplant techniques result in the improved outcomes in those transplants from a matched sibling donor with transplant-related mortality less than 5%. Class 3 patients aged at least 7 years and liver enlargement at least 5 cm have a very high risk of graft rejection and regimen-related toxicity. This subset of patients require innovative approaches to overcome the morbidity and mortality. Those include the addition of hydroxyurea, azathioprine, and fludarabine as preconditioning to busulfan, thiotepa, and cyclophosphamide. Novel conditioning consisting of pretransplant immunosuppression with two cycles of fludarabine and dexamethasone followed by reduced intensity conditioning with fludarabine, busulfan, and thymoglobulin has been developed. Bone marrow transplantation in young low-risk (class 1 and 2) patients should be performed as soon as possible. For class 3 severe thalassemia, novel conditioning regimens have been developed to overcome graft rejection and regimen-related toxicity. Hematopoietic stem cell transplantation in adults who have been well chelated should be offered with clinical trials.

Time to Explore Transcatheter AorticValveReplacement in Younger,Low-Risk Patients.

During the last decade transcatheter aortic valve replacement (TAVR) has been established as a treatment for patientswith severe aortic stenosis, who are at particularly high surgical risk. As compared with surgical aortic valve replacement (SAVR), TAVR has been associated with lower early risk of mortality, atrial fibrillation, acute kidney injury, and bleeding. Furthermore, device and periprocedural improvements have addressed most of the initial limitations forTAVR, including the Achilles' heel, paravalvular leakage. Supported by this as well as preliminary data among lower-risk patients, TAVR is currently being evaluated in prospective randomized trials against SAVR in younger low-riskpatients. Although durability of the TAVR device may be of concern in younger patients given their longer lifeexpectancy, intermediate-term controlled data does not reveal any difference between TAVR and SAVR devices.

Immune Mechanisms in Myelodysplastic Syndrome.

Myelodysplastic syndrome (MDS) is a spectrum of diseases, characterized by debilitating cytopenias and a propensity of developing acute myeloid leukemia. Comprehensive sequencing efforts have revealed a range of mutations characteristic, but not specific, of MDS. Epidemiologically, autoimmune diseases are common in patients with MDS, fueling hypotheses of common etiological mechanisms. Both innate and adaptive immune pathways are overly active in the hematopoietic niche of MDS. Although supportive care, growth factors, and hypomethylating agents are the mainstay of MDS treatment, some patients—especially younger low-risk patients with HLA-DR15 tissue type—demonstrate impressive response rates after immunosuppressive therapy. This is in contrast to higher-risk MDS patients, where several immune activating treatments, such as immune checkpoint inhibitors, are in the pipeline. Thus, the dual role of immune mechanisms in MDS is challenging, and rigorous translational studies are needed to establish the value of immune manipulation as a treatment of MDS.

High Rate of Initial Treatment Failure in Patients with Primary Mediastinal B-Cell Lymphoma Treated with R-CHOP

Abstract 1601 Introduction:Primary Mediastinal B-cell Lymphoma (PMBCL) is an uncommon variant of Diffuse Large B-cell Lymphoma (DLBCL). Given the rarity of this disease, data guiding management is extrapolated from DLBCL trials, or from small retrospective analyses limited to PMBCL. Prospective evaluation of R-CHOP in the MiNT trial showed excellent results in PMBCL, but this trial was limited to young low risk patients. We present the largest retrospective series to date of R-CHOP for PMBCL in all risk groups. Methods:We identified cases of PMBCL at our institution using a comprehensive clinicopathologic database derived from tumor registry data. Natural language processing software was used to search pathology reports for terms of “mediastinal lymphoma,” “mediastinal large cell lymphoma,” “mediastinal large B-cell lymphoma,” as well as “lymphoma” in mediastinal biopsy specimens. Cases were included if they met clinicopathologic criteria for PMBCL, defined as a large B-cell lymphoma with typical features for PMBCL presenting with a dominant anterior mediastinal mass. All patients had to have been treated with R-CHOP. Progression-free survival (PFS) and overall survival (OS) are calculated by the Kaplan-Meier method and univariate analysis is performed to assess predictors of outcome. Results:Fifty-eight cases from 2000–2011 met inclusion criteria and are included in the analysis. The median age was 38 years (range 20–82) and 60% were male. Forty-four patients (76%) presented at limited Ann Arbor stage and 12 patients (21%) at advanced stage; presenting stage could not be discerned in 2 patients. Fifty-five percent of patients presented with mediastinal bulk ≥10cm in size; median size was 11cm (range 5–17cm). LDH was elevated at diagnosis in 60% of patients, normal in 21%, and unknown in 19%. By revised IPI score, 19% were low-risk (0 risk factors), 60% were intermediate risk (1–2 risk factors) and 12% were high-risk (≥3 risk factors). R-CHOP was given for a median of 6 cycles (range 1–8); 51 of 58 patients received 6 or 8 cycles. Among patients who achieved initial remission, 78% underwent consolidative radiotherapy and the remainder were observed after chemotherapy alone.The overall response rate was 81% (90%CI [71%–89%]) with 72% complete responses and 9% partial responses. Ten patients (17%) had primary refractory disease defined as progression on treatment or within 3 months of completion of therapy. Among 46 patients who achieved a response, 5 (11%) subsequently relapsed. Two patients, both elderly, died during treatment. Among the 10 patients with primary refractory disease, 6 have died from progressive lymphoma, 2 patients are alive with active disease undergoing salvage therapy, 1 is alive and free of disease greater than 8 years from diagnosis, and 1 was lost to follow-up. Among 5 patients with relapsed disease, 2 are alive without disease at last follow-up, while 3 have died of progressive lymphoma. Median follow-up for the entire series is 58 months. Five-year PFS is 68% (95% CI, 55% to 80%) and 5-year OS is 76% (95% CI, 65% to 88%). On univariate analysis, advanced Ann Arbor stage and high R-IPI score were associated with inferior PFS and OS. (p=0.006 and p<0.001, respectively for PFS, p=0.005 and p<0.001 for OS, log-rank test). Conclusion:PMBCL treated with R-CHOP carries an overall favorable prognosis, though primary refractory disease occurs in a significant number of patients, and is rarely curable with second line therapy. Advanced stage disease and high R-IPI scores are associated with inferior outcome. Novel treatment approaches warrant evaluation in high-risk patients. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Stress testing in young low-risk patients with potential acute coronary syndromes

ObjectiveYoung patients are at low risk for an acute coronary syndrome (ACS); however, many of these patients still enter a “rule-out ACS” pathway and receive stress testing. We hypothesized that stress testing in patients younger than 40 years without known coronary disease will not identify patients at high risk for 30-day adverse cardiovascular events. MethodsWe conducted a cohort study of patients younger than 40 years evaluated in the emergency department for potential ACS. Patients were excluded if they used cocaine, had known cardiac disease, or had an abnormal electrocardiogram. Patients were followed up in-house; follow-up was performed by direct telephone contact and medical record review. The main outcome was a composite of death, acute myocardial infarction (AMI), and revascularization at 30 days. Comparisons between patients with and without stress testing were done using χ2 or t test, as appropriate; 95% confidence intervals were reported for the main outcomes. ResultsOf 8816 patient visits, 1144 patients met inclusion criteria. Within 30 days, 82 patients (7.2%) received stress testing, 2 of whom led to cardiac catheterization. Death (n = 2), AMI (n = 3), and revascularization (n = 1) were not different between patients who did and did not receive stress testing (2.4% [0.2%-8.5%] vs 0.4% [0.1%-1.0%]). ConclusionThe 30-day cardiovascular complication rate is not different between young patients without known heart disease who do and do not receive stress testing when they present with symptoms of a potential ACS. Testing of young patients at low risk for disease should be reconsidered.

The Risk of Vascular and Thromboembolic Events Is Increased In Young Low-Risk Germ Cell Cancer Patients by Cisplatin Containing Chemotherapy

AbstractAbstract 5119 Introduction:It has been previously reported that both short and long term vascular and thromboembolic events (TEE) occur following cisplatin containing chemotherapy for germ-cell cancer (GCC) (Bokemeyer et al. 1998, Weijl et al. 2000, Diekmann et al. 2010). It has also been shown that patients with GCC are at higher risk of TEE than patients with non-GCC, while on cisplatin-based chemotherapy (Piketty et al. 2005). Method:We reviewed all GCC patients treated in our department from 2008 until 2010 with cisplatin-based chemotherapy and assessed the incidence of TEE. Cases were analyzed with respect to risk factors for vascular events (obesity, diabetes, nicotine abuse, prior cardiovascular disease, prior TEE), tumor characteristics (low- vs. intermediate/high-risk GCC) and age. In addition, further analysis of hemostasis laboratory tests of these patients is being performed. Result:Eight patients (8/50=16%) treated with cisplatin-containing chemotherapy developed TEE. Of these TEE, two were myocardial infarctions, four pulmonary embolisms, one patient showed thrombosis of the jugular vein and one a peripheral (femoral) arterial thrombosis. TE-risk factors included: nicotine abuse in two patients, obesity and nicotine abuse in one patient and no identifiable factors in the others (hemostasis laboratory tests are currently being performed). The median age of these 8 patients was 42 years (range 16–61). Patients were treated with PEB (cisplatin, etoposide, bleomycin) or PIV (cisplatin, ifosfamide, etoposide) initially applying continuous heparin prophylaxis with 15000IE/day (d), d1-5 only during PEB or PIV, but no low-molecular weight heparin (LMWH-) and/or aspirin (ASS-) medication for venous and arterial TEE prophylaxis thereafter. With these clinically very relevant and severe TEEs, we have adapted our PEB- and PIV protocols, adding a LMWH prophylaxis (enoxaparin 40mg d6-21 after chemotherapy). Conclusion:We observed an increased risk of major thromboembolic and vascular events with an incidence rate of 16% in GCC patients after cisplatin-containing chemotherapy. Prior studies have identified TEE-risks in GCC and with cisplatin-chemotherapy, albeit LMWH- and/or ASS-prophylaxis - without clinical trials - has not been recommended as yet. Prospective studies investigating thrombosis prophylaxis measures are currently performed in order to achieve the best standard of care for these patients. Currently an extensive hemostasis diagnostic testing from all patients with TEE is being performed. Disclosures:No relevant conflicts of interest to declare.

Randomised Intergroup Trial of First line Treatment for young Low-Risk Patients (

AbstractAbstract 111 Background:The addition of rituximab to CHOP-21 significantly improved clinical outcome in elderly patients with DLBCL (Coiffier et al., 2002). The MInT trial, randomized young good-prognosis patients to receive a CHOP-like regimen or the same CHOP-like regimen plus rituximab, and was stopped early because of superiority of the rituximab arm, and results were published with a median follow-up of 34 months (Pfreundschuh et al., Lancet Oncology 2006; 379-91). Objective:Because the MInT study was the first study to show a survival benefit with the addition of rituximab to a CHOP-like regimen in young good-prognosis patients, extended follow-up is important to determine whether the survival benefit is maintained over time and whether a definitive effect on cure rates can be shown. Methods:In a phase III intergroup study with participating cooperative groups from 18 countries, previously untreated patients (18-60 years) with low-risk DLBCL (age-adjusted IPI 0 or 1, stages II-IV and stage I with bulky disease) were randomized to receive 6 cycles of a CHOP-like regimen (CHEMO) or the same chemotherapy plus rituximab 375 mg/m2, given on day 1 of each 3-week regimen and on days 1, 22, 43, 64, 85 and 106 of the 2-week regimens, respectively (R-CHEMO). Radiotherapy (30-40 Gy) was planned to sites of initial bulky disease and/or extranodal involvement. The primary endpoint was event-free survival (EFS) with events defined as failure to achieve complete remission, progressive disease, relapse, death or additional therapy. The trial was powered to show a 10% difference in EFS rate after 3 years. Results:Between 05/2000 and 10/2003 a total of 823 patients were recruited of whom 396 were allocated to receive CHOP-21, 361 to CHOEP-21, 34 to MACOP-B, and 32 to PMitCEBO with or without rituximab. Toxicity, incidence of adverse events and severe adverse events in the CHEMO and the R-CHEMO arms were not significantly different. After a median follow-up of 70 (0.03-117) months, patients assigned to chemotherapy and rituximab had increased 6-year event-free survival compared with those assigned to chemotherapy alone (74.0% [95% CI 69.0–78.3] vs 55.7% [50.3-60.8]; log-rank p<0·0001), increased 6-year progression-free survival (79.9% [75.1 - 83.8%] vs 63.8% [58.2-68.8]; log-rank p<0.001) and increased overall survival (89.8% [86.0-92.6] vs 80.0% [75.3-83.9; log rank p=0.001). In a multivariate analysis event-free survival was affected by the addition of rituximab (hazard ratio [HR] 0.49, p< 0.001), age-adjusted IPI (HR 1.73, p<0.001), and bulky disease (HR 1.43, p=0.004). Similar effects were observed for OS, while PFS was affected by treatment arm (HR 0.49, p<0.001) and age-adjusted IPI (HR 1.8, p<0.001). As a consequence, a very favorable subgroup (aaIPI=0, no bulky) can be distinguished from a less favorable subgroup (aaIPI=1 and/or bulky disease) among good-prognosis patients treated with rituximab. There were 10 late (>60 months) events after CHEMO (61.4 to 96.1 months), including 4 in the very favorable subgroup, while all 8 late events (67.5 to 105.7 months) after R-CHEMO occurred in the less favorable subgroup only, and none in the very favorable subgroup. Conclusion:Addition of rituximab to a CHOP-like regimen leads to a significant improvement of the outcome in young patients with good-prognosis diffuse large B-cell lymphoma, with significant survival benefit maintained during a 6-year follow-up. However, except in the very favorable subgroup after R-CHEMO, late relapses after 5 years occur. While reduction of treatment in a randomized study like the FLYER trial of the DSHNHL is justified, further progress, e.g. by dose densification (UNFOLDER trial of the DSHNHL) and/ or dose escalation is still warranted for the less favorable subgroup. Supported by Roche, Deutsche Krebshilfe and KML. Disclosures:Pfreundschuh:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Trneny:Roche: Honoraria, Research Funding. Walewski:Roche: Honoraria, Research Funding. Pettengell:Roche: Honoraria. Jäger:Roche: Honoraria, Research Funding. Lopez-Guillermo:Roche: Consultancy.

Rituximab Does Not Improve Progression Free (PFS) or Overall Survival (OS) in Patients with Limited Stage Diffuse Large B Cell Lymphoma (DLBCL).

Abstract 3755Poster Board III-691 IntroductionDiffuse Large B Cell Lymphoma (DLBCL) is the most common lymphoid malignancy accounting for approximately 33% of all newly diagnosed NHLs. Three randomized trials and multiple retrospective analyses have demonstrated both progression-free (PFS) and overall survival (OS) benefit to the addition of the anti-CD20 monoclonal antibody rituximab to anthracycline-containing chemotherapy in older advanced-stage patients, and in young low-risk patients with DLBCL. Approximately half of newly diagnosed patients with DLBCL present in limited stage and the benefit of rituximab containing chemotherapy regimens for these patients remains uncertain. MethodsWe used an IRB-approved clinicopathologic database, derived from comprehensive tumor registry data at the Massachusetts General Hospital, Dana Farber Cancer Institute and Brigham and Women's Hospital, to identify all patients 18 years or older diagnosed with limited stage DLBCL between 2000 and 2006. We included all patients treated with 3 or more cycles of anthracycline containing chemotherapy with curative intent. We excluded primary DLBCL of the CNS. We determined the impact of the use of rituximab on OS and PFS. PFS and OS were calculated from the date of initial diagnosis. ResultsA total of 138 patients met eligibility criteria and are included in the analysis. Median age was 51 years (range 18-89 years). 30% of patients were above 60 years of age, and less than 3% had an IPI score of 3 or higher. One hundred and six patients received CHOP + rituximab (RCHOP) and 32 received CHOP alone. Of the 106 patients receiving RCHOP, 48 were irradiated and 58 were not. Of the 32 patients receiving CHOP, 20 received radiation and 12 did not. At a median follow-up of 35 months (range 3-109 months), PFS and OS for the entire cohort are 86.2% and 90.6%, respectively. On univariate analysis of outcome, the addition of rituximab to CHOP did not improve PFS (81.3% vs. 87.7%,p=0.817, Logrank Test) or OS (84.4% vs. 92.5%, p=0.411, Logrank Test). ConclusionThe outcome of an unselected series of patients with limited stage DLBCL is excellent. In this retrospective cohort of patients with limited stage DLBCL, the use of rituximab in conjunction with standard chemotherapy did not improve PFS or OS. The results we obtained are very similar to those reported by SWOG (Persky et al. JCO 2008). The overlapping confidence intervals for PFS and OS between SWOG 0014 and 8736 patients and our data suggest that a large multicenter trial will be needed to show a benefit of rituxan in this extremely good prognosis population.CHOPRCHOPmedian Age49 (18-89)51.5 (19-85)>608 (25%)33 (31%)% IPI 034%30%% IPI 122%26%% IPI 29%10%% IPI 33%3%Radiation20 (63%)48 (45%) Disclosures:Hochberg:Genentech: Speakers Bureau; Biogen-Idec: Speakers Bureau; Enzon: Speakers Bureau; Amgen: Speakers Bureau.

Treatment of diffuse large B-cell lymphomas

Over 30 years ago, the combination of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was demonstrated to induce complete remissions and long-term disease-free survival in a considerable proportion of lymphoma patients. Since then many attempts to improve results by modifications of CHOP using escalated doses, additional drugs or the alternative use of putatively non-cross resistant chemotherapy regimens failed in randomized trials. While dose escalation strategies including high-dose approaches necessitating stem cell support have not yet unequivocally been demonstrated to be superior to a base-line CHOP-21, dose-dense bi-weekly modifications (CHOP-14) with growth factor support (G-CSF) improved the outcome of young and elderly patients with aggressive lymphomas compared to CHOP-21. A substantial improvement of treatment results has also been achieved by the implementation of rituximab into treatment protocols. Although not formally established in young patients with poor-prognosis, the combined immuno-chemotherapy with CHOP and rituximab has become an accepted standard for the treatment of diffuse large B-cell lymphoma (DLBCL) worldwide. For patients >60 years of age 6 courses CHOP-14 using G-CSF with rituximab (R-CHOP-14) followed by two additional courses of rituximab yielded the best treatment results without a relevant increase in toxicity compared with CHOP-21. For younger low-risk patients (aaIPI 0,1) 6 courses R-CHOP-21 are the standard treatment. Young high-risk patients (aaIPI ≥ 2) should be treated with dose-dense regimens within clinical trials.

Telephonic management of rectal bleeding in young adults – a prospective randomized controlled trial

The majority of young adults referred with rectal bleeding to a colorectal specialist clinic have a very low risk of serious disease such as cancer, and a high chance of gaining symptom relief by simple dietary changes. To determine whether young low-risk patients with rectal bleeding can be managed with a structured telephonic interview and dietary advice, rather than an outpatient visit. A single-blinded, prospective, randomized controlled trial was performed in two stages. Patients under 40 years with rectal bleeding only were offered inclusion. Part-I trial: Patients were interviewed on telephone by the colorectal nurse specialist (CNS) and randomized to receive dietary advice (Advice Group) or not (Control Group). All patients were seen in clinic 6 weeks later by a doctor 'blinded' to their trial status. Part-II trial: Patients were interviewed on telephone by the CNS and again randomized to an Advice Group or a Control Group. The Control Group were seen in clinic 6 weeks later. The Advice Group were telephoned again 6 weeks later, and if their bleeding had stopped, were not brought to clinic. All patients were tracked for a year after the study to ensure no adverse diagnoses came to light. Part-I trial: 63 of 89 eligible patients were contactable and none refused the study. Seventy per cent of the Advice Group compared with 33% (P = 0.001) of the Control Group had symptomatic improvement when seen in clinic. Approximately 30% of each group required further treatment. Part-II trial: 54 of 94 eligible patients were contactable. However a further nine declined to enter the trial; 90% of patients in the Advice Group had improved at 6 weeks as judged by telephone interview compared with 56% of patients in the Control Group (P = 0.024) who were seen in clinic. The 90% of patients who improved in the Advice Group did not need to come to clinic to be seen. In both parts of the trial, the CNS identified a small number of patients with urgent symptoms at interview and brought them to clinic. The majority had anal fissures or haemorrhoids although in Part-II, one patient had ulcerative colitis and one had colorectal cancer. Telephonic consultation is an effective way of identifying those patients with urgent symptoms among a cohort of young adults referred to the hospital with rectal bleeding. Telephonic dietary advice leads to resolution of rectal bleeding in the majority of patients without urgent symptoms.

Comparison of Outcome of Unselected Patients with Diffuse Large B-Cell Lymphoma Diagnosed before and after Approval of Rituximab in France in This Indication.

Two randomized-controlled trials had demonstrated improved outcome with adding rituximab to CHOP for elderly patients and young low-risk patients with DLBCL (Coiffier et al., NEJM 2002 and Pfreundschuh et al., ASH 2004, abstr #88). It seemed interesting to assess whether this was confirmed in daily practice in an unselected patient population. We compared the outcome of newly diagnosed patients treated in our department between two time periods, before and after approval of rituximab for treatment of DLBCL in France, in March 2002. Patients with primary cerebral lymphoma, secondary transformation of indolent lymphoma or HIV positivity were excluded of the study but no selection was made on type of initial treatment or therapeutic intent (palliative or curative) to conform with daily clinical practice. 229 patients were identified, with median age 61 years (range, 20–90), elevated LDH (66%), extranodal sites >1 (26%), stage III-IV (57%), poor performance status >1 (24%), IPI score 0–1 (37%), 2 (20%), 3(21%), 4–5 (22%). 148 patients were diagnosed between 01/1996 and 03/2004 (time period 1) and 81 between 04/2002 and 07/2004 (time period 2). Patient characteristics did not differ between the two time periods (median age, performance status, stage, elevated LDH, extra-nodal involvement, IPI distribution). 11% of patients received rituximab as part of initial treatment in time period 1, and 93% in time period 2. Response rates at the end of treatment for time periods 1 and 2 were CR/CRu 71% and 79% (p=0.1), PR 6% and 10% (p=0.3), progression 17% and 9% (p=0.08), toxic death 6% and 2% (p=0.2), respectively. At the time of this abstract, the follow-up for living patients was 60 and 18 months for time periods 1 and 2 respectively, with no difference in terms of progression-free survival (PFS), event-free survival (EFS) and overall survival (OS). The lack of outcome difference between the two cohorts could be due to short follow-up of time period 2 and efficiency of rituximab in the patients treated in time period 1. In fact, PFS is significantly improved for patients under rituximab compared to patients not treated with rituximab (see survival outcomes in table). In conclusion, this global evaluation of treatment with rituximab in an unselected population of DLBCL patients before and after date of approval of rituximab requires further follow-up for validation of outcome benefit. [Display omitted]

First Analysis of the Completed Mabthera International (Mint) Trial in Young Patients with Low-Risk Diffuse Large B-Cell Lymphoma (DLBCL): Addition of Rituximab to a CHOP-Like Regimen Significantly Improves Outcome of All Patients with the Identification of a Very Favorable Subgroup with IPI=O and No Bulky Disease.

Rituximab has been shown to improve outcome in elderly patients with DLBCL (Coiffier et al., NEJM, 2002), but there is only limited data for young low-risk patients. In an intergroup study conducted in 18 countries, untreated patients (18–60 years) with low-risk CD20+ DLBCL (IPI 0 or 1, stages II-IV and stage I with bulk) were randomized to receive 6 cycles of a CHOP-like regimen (CHEMO) or the same chemotherapy plus rituximab 375 mg/m2 given on days 1, 22, 43, 64, 85, and 106 (R-CHEMO). Radiotherapy was planned to sites of initial bulk and/or extranodal involvement. The primary endpoint was time to treatment failure (TTF). Between 05/2000 and 10/2003, 824 patients were recruited. A first planned interim analysis was performed on 326 evaluable patients in November 2003 and let the independent review committee recommend the early stopping of the MInT trial on Dec 5, 2003, with 59 patients still under chemotherapy (28 CHEMO; 31 R-CHEMO). These were censored for this analysis. We here present the first full-set analysis on 823 evaluable patients (410 CHEMO; 413 R-CHEMO) with data base status as of Aug 2nd, 2004.Patient characteristics were: median age 47 years; IPI=1: 57%; stages III/IV: 28%; elevated LDH: 29%; bulky disease: 49%. Toxicity was not different in the two arms. After a median time of observation of 22 months, R-CHEMO patients had a significantly longer TTF (p<0.00001), with estimated 2-year TTF rates of 60% (CHEMO) vs 76% (R-CHEMO). Complete remission (CR) rates of evaluable patients (CR) were significantly different (67% CHEMO vs 81% R-CHEMO, p<0.0001) as were the rates of progressive disease during treatment (15% vs 4% , p<0.00001). Similarly, overall survival was significantly different (p<0.001), with 2-year survival rates of 87% (CHEMO) and 94% (R-CHEMO), respectively. The rate of lymphoma-associated deaths was reduced by two thirds with R-CHEMO. Using a Cox proportional hazard model for the primary endpoint TTF, treatment arm (p<0.00001), bulky disease (p<0.0001) and IPI (p<0.001) were significantly associated with the risk of an event. The benefit of R-CHEMO was demonstrated for all patients irrespective of these risk factors. However, 2-year TTF after R-CHEMO in patients with bulky disease and/or IPI=1 was significantly worse (p<0.001) than in patients with IPI=0 and no bulk (71% vs 90%, respectively), proposing two novel subgroups of young low-risk patients with a favorable and less favorable outcome in the era of combined rituximab/CHOP-like chemotherapy. The combination of 6 cycles of a CHOP-like chemotherapy with rituximab sets the standard for young low-risk patients with CDD20+ DLBCL. While further improvement will be difficult to demonstrate for the favorable (IPI=0, no bulk) subgroup, it is still warranted with regard to TTF for the less favorable subgroup (IPI=1 and/or bulk).