Multidimensional Quantification of Exclusion Criteria to Reduce the Gap between Randomized Clinical Trial and Real-World Outcomes in Multiple Myeloma

Abstract Randomized clinical trials (RCTs) are considered the highest level of evidence to define the efficacy of newly developed treatments before their adoption into clinical practice. RCTs incorporate exclusion criteria that eliminate specific patient populations in order to reduce the incidence of serious adverse events and enhance the efficacy of a given anti-cancer strategy. However, exclusion criteria may lead to a significant gap between patients (pts) enrolled on RCTs and real world pt populations, which represent the ultimate stakeholders in cancer treatment. The analysis of real-world evidence to answer clinical questions has recently gained increased interest. Assessing different dimensions of this gap may help overcome barriers in trial recruitment and enhance the applicability of RCTs in daily practice. There has been significant advancement in treating multiple myeloma (MM) over the past two decades bringing multiple new mechanisms of action to the bedside. We selected ten recent RCTs: ASPIRE, TOURMALNE-MM01, ELOQUENT-2, ENDEAVOR, POLLUX and CASTOR, OCEAN, ICARIA, APOLLO and ELOQUENT-3 studies, which are pharma-sponsored landmark trials that provided the basis for FDA approval of anti-myeloma agents. Our objective was to quantify the gap in eligibility criteria between the ten RCTs and real world populations by examining these trials using a single institution database. Methods: Pts with relapsed MM that were initiated on a second (or later line) of therapy that were recognized, retrospectively. Eligibility criteria of the ten landmark RCTs was applied during the 21 day period before the index treatment date. Pts that received Len-containing regimens were tested as to be enrolled on trials with Len/Dex control arm, patients that received Bor-containing regimens were examined to be enrolled on Bor/Dex trials and subjects who had Pom-containing regimen were screened for Pom/Dex trials. Pts were then classified as "Trial eligible" or "Trial ineligible", accordingly and were monitored longitudinally from the index treatment date until death, loss to follow-up, or end of the follow up period. Ten commonly used eligibility criteria were examined (Fig. 1). Any cancer in the three years prior to the index treatment date was counted as "history of other malignancies", i.e., skin and prostate cancer were excluded. Concurrent infection was defined as use of any antibiotic other than acyclovir, ciprofloxacin or bactrim. To calculate area under the curve of the polygon graphs Shoelace algorithm was used. Results : 516 pts were studied between 2010 and 2020 and 153 were excluded due to missing values. 224, 136 and 98 pts were treated with Len-, Bor- or Pom-containing regimens, respectively. Overall, the trial-eligible cohort was more likely to have autologous stem cell transplant and to have had longer treatment-free period before index treatment date (p-value: 0.009). There was a substantial variation in the ineligibility rate for these ten RCTs among the study population (Fig. 1). The most common items that excluded a patient from a RCT were: other malignancy, current infection and renal dysfunction. Differences between trial-eligible and trial-ineligible pts stratified by trial are listed in Tables 1, 2 and 3 for trials with Len, Bor and Pom as control arms, respectively. The median follow-up for the Len, Bor and Pom cohorts was 31, 30 and 22 months, respectively. Trial-ineligible pts displayed a significantly worse OS (2-year rate 58% vs. 78%, p-value: 0.001) and 49% higher chance of death (HR 1.69, 90%, CI: 1.17-2.62) compared with trial-eligible cohort. Conclusion: Here, we assessed the multidimensional gap that exists between patient cohorts enrolled on RCTs and real world cohorts for ten landmark MM trials. We present a quantitative deviation score as a tool to calibrate the generalizability of these landmark trials against a single institution. Importantly, we show that trial-eligibility alone significantly correlates with superior OS across a variety of MM clinical trials across all ten MM RCTs. Furthermore, our results reveal that ineligibility rates were quite different among the ten trials which significantly limit cross-trial comparisons. We propose a uniform methodology to assess patient exclusion criteria and narrow the efficacy gap observed between RCTs and real world evidence. Figure 1 Figure 1. Disclosures Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau. Malek: Medpacto Inc.: Research Funding; Amgen: Honoraria; Janssen: Other: Advisory board ; Takeda: Honoraria; BMS: Honoraria, Research Funding; Cumberland Inc.: Research Funding; Bluespark Inc.: Research Funding; Sanofi: Other: Advisory Board.

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Patient Selection Bias Limits the Real World Efficacy of Randomized Clinical Trials in Multiple Myeloma

Blood ◽

10.1182/blood-2020-139856 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-2

Author(s):

Augusta Eduafo ◽

Leland Metheny ◽

James Driscoll ◽

Benjamin K. Tomlinson ◽

Kirsten M Boughan ◽

...

Keyword(s):

Real World ◽

Research Funding ◽

Randomized Clinical Trials ◽

Advisory Board ◽

P Value ◽

Exclusion Criteria ◽

Eligibility Criteria ◽

Current Infection ◽

Index Treatment

Randomized clinical trials (RCT) are imperative for testing novel cancer therapies and advancing the science of cancer care. Exclusion criteria are employed to minimize toxicity and maximize benefit. However, the selection process introduces a deviation between enrolled patients (pts) and the real world population. Estimating how much the selected population deviates from the MM cohort at large may increase inclusiveness and could help define barriers to recruiting to MM studies. There has been significant advancement in treating Multiple Myeloma (MM) during the last decade. Over 16 FDA-approved anti-myeloma regimens are now available. We selected the recent 6 RCTs (ASPIRE, TOURMALNE-MM01, ELOQUENT-2, ENDEAVOR, POLLUX and CASTOR studies) which were pharma-sponsored landmark trials that provided the basis for FDA approval of a new agent or established a new indication for formerly FDA-approved drug. We intended to quantify the gap between the trial population and real world by examining the eligibility criteria of these trials compared against a single institution database. Methods: Pts with relapsed MM initiating second or later line of therapy containing lenalidomide (Len) or bortezomib (Bor) were identified retrospectively. The 3-week period before the index treatment date was used to apply the eligibility criteria of the mentioned 6 trials. Pts who received Len-containing regimens were tested as to be enrolled on trials with Len/Dex control arm (ASPIRE, TOURMALINE-MM1, POLLUX, and ELOQUENT-2) and pts who had Bor-containing regimens were reviewed to be enrolled on Bor/Dex trials (CASTOR and ENDEAVOR). Pts were classified as "Trial eligible" or "Trial ineligible", accordingly. Pts were followed up longitudinally from the index treatment date until death, loss to follow-up, or the end of the study period (Jan, 2018). Ten frequently used eligibility criteria were studied (Fig-1). History of other malignancies, except skin and prostate cancer, was defined as any cancer requiring therapy other than anti-myeloma regimen in the 3 years prior to the index treatment date. Current infection referred to the use of any medication other than acyclovir, ciprofloxacin or Bactrim. Shoelace algorithm was used to calculate area under the curve of the polygon graphs. Results: 516 pts were studied between 2010 and 2018; 153 pts were excluded due to missing values, while 224 and 136 pts were treated with Len-containing and Bor-containing regimens, respectively. Overall, the trial-eligible cohort was more likely to have autologous stem cell transplant and to have had longer treatment-free period before index treatment date (p-value: 0.012). There was a substantial variation in the ineligibility rate for these 6 RCTs among the study population (Fig-1). The most common items that excluded a patient from a RCT were: Other malignancies, current infection and renal dysfunction. Within the Len cohort the trial-specific Glomerular Filtration Rate (GFR) threshold for renal function was highest in ASPIRE trial (Cr clearance> 50 ml/min) causing high rate of exclusion (29% vs. 8% in other trials). Only TOURMOULINE-MM01 and ASPIRE trials had bor-refractory status as the exclusion criteria leading to 36% ineligibility rate. The differences between the trial-eligible and trial-ineligible pts stratified by trial are listed in Table-1 and 2 for trials with Len and Bor as the control arms, respectively. The median follow-up for the Len and Bor cohort was 31 and 30 months, respectively. The trial-ineligible pts had significantly worse OS (2-year survival rate 69% vs. 82%, P-value: 0.001) and 43% higher chance of death (hazard ratio 1.43, 90% confidence interval (CI): 1.08-2.02) compared with trail-eligible cohort. Conclusion: Here we assessed the eligibility criteria of 6 landmark MM studies and showed that ineligibility rates were quite different amongst these trials suggesting significant limitations in cross-trial comparison. Furthermore, trial-eligibility per se was associated with improved survival. We therefore proposed a quantitative deviation score calibrating the generalizability of the results of these trials to a single institution cohort. Such a tool can lead to efforts to broaden eligibility criteria and possibly narrow the gap between reported clinical trial efficacy and the observed effectiveness in real-world MM pts. Disclosures de Lima: Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding. Malek:Medpacto: Research Funding; Takeda: Other: Advisory board , Speakers Bureau; Bluespark: Research Funding; Cumberland: Research Funding; Sanofi: Other: Advisory board; Janssen: Other: Advisory board, Speakers Bureau; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria.

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Utility of routinely collected electronic health records data to support effectiveness evaluations in inflammatory bowel disease: a pilot study of tofacitinib

BMJ Health & Care Informatics ◽

10.1136/bmjhci-2021-100337 ◽

2021 ◽

Vol 28 (1) ◽

pp. e100337

Author(s):

Vivek Ashok Rudrapatna ◽

Benjamin Scott Glicksberg ◽

Atul Janardhan Butte

Keyword(s):

Inflammatory Bowel Disease ◽

Pilot Study ◽

Disease Activity ◽

Real World ◽

Bowel Disease ◽

P Value ◽

Health Records ◽

Real World Evidence ◽

Inflammatory Bowel

ObjectivesElectronic health records (EHR) are receiving growing attention from regulators, biopharmaceuticals and payors as a potential source of real-world evidence. However, their suitability for the study of diseases with complex activity measures is unclear. We sought to evaluate the use of EHR data for estimating treatment effectiveness in inflammatory bowel disease (IBD), using tofacitinib as a use case.MethodsRecords from the University of California, San Francisco (6/2012 to 4/2019) were queried to identify tofacitinib-treated IBD patients. Disease activity variables at baseline and follow-up were manually abstracted according to a preregistered protocol. The proportion of patients meeting the endpoints of recent randomised trials in ulcerative colitis (UC) and Crohn’s disease (CD) was assessed.Results86 patients initiated tofacitinib. Baseline characteristics of the real-world and trial cohorts were similar, except for universal failure of tumour necrosis factor inhibitors in the former. 54% (UC) and 62% (CD) of patients had complete capture of disease activity at baseline (month −6 to 0), while only 32% (UC) and 69% (CD) of patients had complete follow-up data (month 2 to 8). Using data imputation, we estimated the proportion achieving the trial primary endpoints as being similar to the published estimates for both UC (16%, p value=0.5) and CD (38%, p-value=0.8).Discussion/ConclusionThis pilot study reproduced trial-based estimates of tofacitinib efficacy despite its use in a different cohort but revealed substantial missingness in routinely collected data. Future work is needed to strengthen EHR data and enable real-world evidence in complex diseases like IBD.

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Real World Evidence of Prescription Patterns and Effect of Oxbryta (voxelotor) for Patients with Sickle Cell Disease

Blood ◽

10.1182/blood-2020-143434 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-32

Author(s):

Nirmish Shah ◽

Ahmar Urooj Zaidi ◽

Michael U. Callaghan ◽

Darla Liles ◽

Clarissa E. Johnson ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Sickle Cell ◽

Real World ◽

Research Funding ◽

Cell Disease ◽

Advisory Committees ◽

Real World Evidence ◽

Disease Modifying

Background: Sickle cell disease (SCD) is a chronic illness characterized by anemia, recurrent severe pain and recurrent organ damage, affecting approximately 100,000 persons in the United States. Prior to November 2019, FDA approved SCD disease-modifying treatments included only hydroxyurea (HU) and L-glutamine. However, voxelotor (Oxbryta®) was recently approved under an accelerated approval based on the HOPE study for the treatment of adult and pediatric patients with SCD 12 years of age and older. We aimed to provide real world evidence of the types of patients prescribed voxelotor and preliminary evidence of potential treatment effects. Methods: Patient records were reviewed from five medical centers with comprehensive sickle cell care. All patients prescribed voxelotor from Nov 25, 2019 to July 31, 2020 were included in our analysis. Data reviewed included: patient demographics, hydroxyurea use, as well as pre- and post- voxelotor changes on red cell transfusion number, vaso-occlusive crisis (VOC) and hemoglobin (Hb) values. In addition, voxelotor dosage changes, side effects, and patients perception on impact on their health were recorded. Descriptive and summary statistics were used to provide results. Results: We reviewed data from 60 patients (18 pediatric and 42 adult), across the five centers, who were prescribed voxelotor. Mean age was 33 (SD 13.8) years old with 63% female patients. All patients were African-American/Black and 96% were HbSS (2% Hb SC and 2% HbSOArab). Eighty (80)% were on hydroxyurea, 20% were on chronic transfusions, and 10% were on erythropoietin stimulating agents when prescribed voxelotor. Mean baseline hemoglobin during the 3 months prior to initiation was 7.38 g/dL (SD 1.46) with all patients started at the recommended dose of 1500mg. Annualized VOC events for the year prior to starting voxelotor was 0.62 (SD) or 7.44 VOCs per year. Across all sites, 31 patients were prescribed voxelotor but had either not initiated drug, not returned for follow up labs at time of analysis, or refused to take drug once approved (n=1). Nine patients had only 1 month of follow labs to review and an additional 18 patients with 3 months of follow up labs. These 27 patients were followed for an average of 6.0 months (SD 7.7) on treatment with 4 patients (15%) requiring dose adjustment to 1000mg. Dose adjustments were for side effects including abdominal pain, diarrhea, loose stools and nausea/vomiting. One patient had dosing changed from daily to three times a day. Average hemoglobin during steady state after 1 and 3 months of treatment were 8.6 g/dL (SD 1.8) and 8.0 g/dL (SD 1.8), respectively. In addition, 52% increased by 1g/dL at 1 month (n=21) and 44% increased by 1g/dL at 3 months (n=18). The mean maximum hemoglobin obtained during the 3-month period following initiation of voxelotor was 8.9 (SD 2.1) g/dL. During follow up visits, several patients reported 'more energy' and improvement in 'morning achiness' and 'quality of life', while a few patients noted no change in stamina or well-being. Three patients (5%) had drug discontinued due to becoming pregnant, unexplained elevation of liver enzymes, and due to excessive abdominal pain and nausea. Annualized VOC rates after voxelotor initiation were numerically decreased, although limited by short follow up. Conclusion: We present real world evidence of prescribing patterns and initial outcomes from the use of newly approved voxelotor. We found the majority of patients prescribed voxelotor were the HbSS genotype, on hydroxyurea, and with a mean baseline Hb <7.5 g/dL, indicating an initial focus on more anemic patients. Interestingly, one-fifth of the prescribed patients where on chronic transfusions. Consistent with the HOPE trial, the average Hb levels was found to have increased at 1 month and 3-month follow up. Our preliminary results support an overall increase in hemoglobin in patients treated with voxelotor and we aim to continue following patients over a longer follow up period. This provides important real-world evidence for this newly approved disease-modifying therapy for SCD. Disclosures Shah: Alexion: Speakers Bureau; CSL Behring: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; Bluebird Bio: Consultancy. Zaidi:Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Emmaus Life Sciences: Consultancy, Honoraria; Imara: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria; Cyclerion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Callaghan:Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Research Funding; Sancillio: Other; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NovoNordisk: Other, Speakers Bureau; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Alnylum: Current equity holder in publicly-traded company; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hema Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Castro:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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CML Patients Outcome after TKI Discontinuation: A Single Institution Experience in the US

Blood ◽

10.1182/blood.v128.22.1923.1923 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1923-1923 ◽

Cited By ~ 1

Author(s):

Kamal Chamoun ◽

Hagop M. Kantarjian ◽

Mary Beth Rios ◽

Rita Assi ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Adverse Events ◽

Relapse Rate ◽

Research Funding ◽

Cytogenetic Response ◽

Advisory Board ◽

Treatment Discontinuation ◽

Molecular Response ◽

Single Institution ◽

Complete Cytogenetic Response

Abstract Chronic myeloid leukemia (CML) patients who achieve a complete cytogenetic response (CCyR) with tyrosine kinase inhibitor (TKI) have an expected survival rate comparable to that of the general population. It is practice to continue TKI therapy indefinitely. However, this chronic therapy may impact patient's lives either by its associated adverse events, or its influence on real-life events (eg. pregnancy, financial burden). Therefore, treatment discontinuation has been increasingly sought. Discontinuation of therapy for patients with sustained MR4.5 has been associated with 30-50% sustained molecular response in previous studies. However, patients may sometimes choose to discontinue therapy for various reasons regardless of the response. We retrospectively analyzed the outcome of 95 patients with CML who discontinued TKI therapy at a single institution. Median age at diagnosis was 50 years (range 26 - 75), 56 (59%) were females. Median follow up from diagnosis to treatment discontinuation was 120 months. TKI was the initial therapy in 62 patients (41 imatinib, 7 nilotinib, 12 dasatinib, 1 bosutinib, 1 ponatinib) and interferon in 33 patients (34%). At time of discontinuation, 67 patients (71%) were receiving their first TKI (48 imatinib, 6 nilotinib, 12 dasatinib, 1 ponatinib) while 25 (26%) and 3 (3%) patients were receiving their second and third TKI respectively. All patients achieved complete cytogenetic response (CCyR) and major molecular response (MMR) in a median of 3 (range 2-93) and 9 months (range 2-132) respectively. MR4.5 was achieved in 92 (97%) patients at a median of 17 months. Three patients had MMR as their best response. Patients received TKI for a median of 104 months (range 8-203) before discontinuation. Fifty two patients (54%) discontinued therapy due to adverse events, 27 (28%) electively due to sustained MR4.5, 7 (7%) due to pregnancy, 6 (6%) for financial reasons and 3 (3%) due to the occurrence of a second cancer. At time of discontinuation all patients were in CCyR; 90 patients (95%) were in MR4.5 and 5 patients (5%) in MMR. The median MR4.5 duration before discontinuation was 75 months (range 1-178); 84 had a sustained MR4.5 for at least 2 years and 59 for at least 5 years. After a median follow-up from treatment discontinuation of 23 months (0 to 113 months), 38 (40%) patients have lost their response at a median of 4 months (range 1-34) after discontinuation; 10 patients lost response after 12 months from discontinuation. Among patients with MR4.5 at discontinuation, molecular relapse occurred in 33 patients (37%) at a median of 4 months (range 1-34; 8 after 12 months from discontinuation). All 5 patients with MMR at discontinuation loss their response at a median of 8 months (range 2-14). Patients receiving imatinib, dasatinib or nilotinib had a median TKI treatment duration of 117, 64 and 65 months before discontinuation, and lost their response at a rate of 33%, 56% and 46%, respectively. Relapse rate for patients with MR4.5 sustained >2 years was 32%, whereas those with <2 years it was 82%; a similar analysis with cutoff of 5 years yielded a relapse rate of 15% and 77%, respectively. Among patients with b3a2 with MR4.5 at discontinuation, 35% lost response, compared to 33% for those with b2a2 and 53% for those with both b3a2 and b2a2. Twenty four relapsing patients were eventually retreated; 21 re-gained the response they had at the time of discontinuation in a median of 4.5 months after resumption of therapy. At last follow up, 82 (86%) patients were in MR4.5, 4 (4%) in MMR, 5 (5%) in CCyR, 3 (3%) in PCyR and 1 (1%) in mCyR. This analysis shows that patients with less than MR4.5 at time of discontinuation have higher risk of relapse. The lower percentage of relapse seen in patients who had been on imatinib likely represents the longer period of treatment before discontinuation compared to the 2nd generation TKIs. Late relapses (e.g., beyond a year) occur in a subset of patients. Although the majority of patients who lose their response after discontinuation respond to retreatment, treatment discontinuation is still not recommended outside clinical trials. Disclosures Jain: Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Research Funding; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Incyte: Research Funding; BMS: Research Funding. Daver:BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Research Funding; Kiromic: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. DiNardo:Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

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Real-World Outcomes for 205 Danish Patients with Chronic Lymphocytic Leukemia Treated with Ibrutinib

Blood ◽

10.1182/blood-2019-123011 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1767-1767

Author(s):

Kathrine Aarup ◽

Lisbeth Enggaard ◽

Robert Schou Pedersen ◽

Rasmus Heje Thomsen ◽

Olav Jonas Bergmann ◽

...

Keyword(s):

Clinical Trials ◽

Real World ◽

Cumulative Incidence ◽

Research Funding ◽

Population Based ◽

Advisory Board ◽

Lymphocytic Leukemia ◽

Travel Grant ◽

Tract Infections

Introduction Ibrutinib is an oral irreversible inhibitor of Bruton's tyrosine kinase for treatment of chronic lymphocytic leukemia (CLL). Ibrutinib has demonstrated superior efficacy for patients with TP53 aberration or relapsed/refractory (R/R) CLL; and more recently superior progression free survival (PFS) has been demonstrated compared to chemoimmunotherapy as first line therapy. However, knowledge about the outcomes and adverse events (AE) upon ibrutinib among patients at a population-based level are still limited. The aim of the here presented study is to explore outcomes of ibrutinib treatment in a population-based cohort of patients with CLL treated with ibrutinib in Denmark. Methods In this retrospective study, patients from 8 hospitals in Denmark, who were diagnosed with CLL and treated with ibrutinib from April 2014 until February 2019 were included. Medical records were retrospectively reviewed to obtain information. Patients receiving ibrutinib within clinical trials were excluded. Overall survival (OS) was defined as time from ibrutinib start to death from any cause while PFS was defined as time from ibrutinib start to progression or death from any cause. PFS and OS were analyzed with the Kaplan-Meier method while cumulative incidence was calculated with the Aalen-Johansen estimator. Results In total, 205 patients with CLL receiving ibrutinib treatment were identified from hospital records and registries. The median follow-up was 21.4 months (IQR, 11.9-32.8) and the median time on ibrutinib was 16.8 months (IQR, 6.0-28.1). The median age at treatment initiation was 72.8 years (IQR, 65.7-77.8), 128 (62.4%) were male, and 111 (63.4%) were Binet stage B/C at treatment initiation out of 175 with available information regarding clinical stage. Thirty-nine (19.0%) received ibrutinib as first-line, and 166 for R/R CLL with a median of 2 (range, 1-8) prior treatment regimens. Information on TP53 aberration was available for 149 and regarding IGHV mutation for 147 patients, 111 (74.5%) had TP53 aberration and 107 (72.8%) were IGHV unmutated. Eighty-six patients (42.0%) discontinued ibrutinib during follow-up with a median time until discontinuation of 9.3 months (IQR, 3.0-23.2). Forty-seven (54.7%) discontinued due to AEs, 19 (22.1%) due to progression (12 had progression of CLL and 7 had Richter's transformation) while the remaining 20 (23.2%) discontinued due to other reasons. The estimated cumulative incidence of discontinuation at 12 months was 24.8% (95% CI: 18.6-30.9). The estimated OS after 12 and 24 months was 88.8% (95%CI: 84.3-93.3) and 76.8% (95%CI: 70.4-83.2) and the estimated PFS after 12 and 24 months was 87.3% (95%CI: 82.5-92.1) and 72.4% (95%CI: 65.5-79.2). One hundred and eighty-eight (91.7%) experienced at least one AE, among these 45 (23.9%) experienced a grade 3+. The most common AEs were hemorrhage (tendency to bruise, epistaxis etc.) which occurred in 86 (42.0%) of all and musculoskeletal and connective tissue disorders (arthralgia, myalgia etc.) which occurred in 82 (40.0%). Thirty-one (15.1%) patients experienced atrial fibrillation while on ibrutinib and 14 (6.8%) developed hypertension. One hundred and thirty-seven patients (66.8%) had at least one infection and among these 80 (58.4%) were hospitalized with an infection. The most common infections were lower respiratory tract infections and urinary tract infections that occurred for 88 (42.9%) and 41 (20.0%). The estimated cumulative incidence for any infection was 58.9% (95%CI: 52.0-65.9) at 12 months. Conclusion This is the first study describing outcomes for a population-based cohort of CLL patients treated with ibrutinib in Denmark. Real-world studies are warranted, to confirm the results from clinical trials. In this study, patients appear to have comparable OS and types of AE compared with the RESONATE trial. Differences in frequency of AEs compared to the clinical trial may reflect the focus of clinicians in routine practice. Discontinuation in this cohort was higher compared to clinical trials but comparable to previously reported real-world studies. While ibrutinib can be safely managed in routine clinical practice, this study demonstrates that a quarter of patients discontinue treatment due to mainly AEs. Further patient training and information, and in some instances personalized treatment with other targeted agents based on adverse event profile, may improve treatment adherence. Disclosures Aarup: Research Committee, Rigshospitalet: Research Funding. Enggaard:Abbie: Other: Advisory board; Gilead: Other: Advisory board; Janssen: Other: Advisory board. Frederiksen:Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding; Novartis: Research Funding; Alexion: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; AstraZeneca: Consultancy, Other: Travel Grant, Research Funding; Sunesis: Consultancy; Acerta: Consultancy; CSL Behring: Consultancy; Roche: Other: Travel Grant; Janssen: Consultancy, Other: Travel Grant, Research Funding; Gilead: Other: Travel Grant; Abbvie: Consultancy, Other: Travel Grant, Research Funding.

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Efficacy of Daratumumab Containing Regimens Post Lenalidomide Maintenance in Transplant Eligible Patients: Real-World Experience from the Canadian Myeloma Research Group Database

Blood ◽

10.1182/blood-2020-133372 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 26-27

Author(s):

Hira S Mian ◽

Christine Eisfeld ◽

Christopher P. Venner ◽

Victor Jimenez-Zepeda ◽

Cyrus Khandanpour ◽

...

Keyword(s):

Stem Cell ◽

Real World ◽

Research Group ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

P Value ◽

Cell Transplant ◽

Second Line

Introduction Lenalidomide maintenance following autologous stem cell transplant (ASCT) remains a standard of care among transplant eligible patients with newly diagnosed multiple myeloma (NDMM). Many previous clinical trials done in patients following one prior line of therapy either excluded patients progressing on lenalidomide or included a very small proportion of these patients. Given the paucity of data in this setting, the optimal management of patients progressing on lenalidomide maintenance remains unknown. Daratumumab-containing triplet regimens have recently been introduced for these patients, typically in combination with pomalidomide (DPd), lenalidomide (DRd), or bortezomib (DVd). To our knowledge, there is no prospective data to allow comparison of the efficacy of these three regimens in patients progressing on lenalidomide maintenance, which is an increasingly common clinical scenario. Understanding the comparative efficacy, tolerability and toxicity of these regimens in patients progressing on lenalidomide maintenance in the 'real-world' is needed in order to help clinicians make appropriate decisions and guide future studies. Methods The Canadian Myeloma Research Group Database (formerly known as the Myeloma Canada Research Network Database, MCRN-DB) is a prospectively maintained disease specific database with over 7000 patients enrolled from 14 academic sites across Canada with legacy data collected from 2007. The Munster Myeloma database collects myeloma specific information in a German academic center and currently contains data from 800 patients collected from 2005. All consecutive patients treated with daratumumab based regimens in second line following relapse on lenalidomide maintenance were included in the analysis from the two databases analyzed up to 30/06/2020. Results A total of 1380 NDMM patients on lenalidomide maintenance post autologous stem cell transplant were identified in the two databases. From them, 73 patients were included in this analysis as they were treated with daratumumab containing regimen in second line. Specifically, 18 (24.7%) of these patients were treated with DPd, 32 (43.8%) patients with DRd, and 23 (31.5%) patients with DVd. The baseline characteristics, maintenance details, post-maintenance response rates and toxicity for each regimen are shown in Table 1. The median follow-up for the cohort from the time of daratumumab initiation was 8.3 months (range 0.4 - 40.0). Although, a higher proportion of patients in the DPd arm obtained a CR/VGPR compared to DRd or DVd, it did not reach statistical significance (p-value 0.06). The median PFS of the entire cohort was 16.96 months (95% CI 11.47-23.44). The median PFS of the individual regimens was as follows: DPd 17.65 months, DRd not reached and DVd 11.47 months as demonstrated in Figure 1 (p-value =0.46). Conclusion In summary, our results show that daratumumab-based regimens are effective among patients progressing on lenalidomide maintenance in the real world. Despite the small sample size, the results presented here are in line with recent sub-analyses of phase III studies examining the common daratumumab-based regimens used in this setting (CASTOR with median PFS of DVd between 7.8 months in all lenalidomide refractory patients and 27 months in all patients in first relapse; MM014 with median PFS of DPd after lenalidomide refractoriness of 21.8 months). The efficacy of DRd, in which daratumumab is added to an increased dose of lenalidomide, is notable and warrants further evaluation to identify which patients are most likely to benefit. Additional studies with longer follow-up are required to assess the optimal daratumumab-based regimen to be used in this growing population of patients relapsing after lenalidomide maintenance. Disclosures Mian: Janssen: Consultancy, Honoraria; Celgene: Consultancy; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy. Venner:Celgene, Amgen: Research Funding; Janssen, BMS/Celgene, Sanofi, Takeda, Amgen: Honoraria. Jimenez-Zepeda:Janssen, Celgene, Amgen, Takeda: Honoraria. McCurdy:Sanofi: Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Sebag:Celgene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding. Song:Celgene: Research Funding; Celgene, Janssen, Amgen, Takeda: Honoraria. Leblanc:Celgene: Research Funding; Celgene Canada; Janssen Inc.; Amgen Canada; Takeda Canada: Membership on an entity's Board of Directors or advisory committees. White:Karyopharm: Honoraria; Antengene: Honoraria; GSK: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Stakiw:Roche: Research Funding; Celgene: Honoraria; Lundbeck: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria. Louzada:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Kotb:Karyopharm: Current equity holder in publicly-traded company; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Merck: Honoraria, Research Funding; Sanofi: Research Funding. Reece:Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Amgen: Consultancy, Honoraria; Millenium: Research Funding; BMS: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding.

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Patient Characteristics, Treatment Outcomes and Healthcare Resource Utilization across Europe in Multiple Myeloma Patients Ineligible for Stem Cell Transplantation Who Received Lenalidomide- or Bortezomib-Based Regimens

Blood ◽

10.1182/blood-2019-123629 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4772-4772

Author(s):

Elena Zamagni ◽

Sujith Dhanasiri ◽

Adam Moore ◽

Arun Ghale ◽

Murielle Roussel

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Health Outcomes ◽

Real World ◽

Research Funding ◽

Healthcare Resource ◽

Healthcare Resource Utilization ◽

Advisory Board ◽

To Receive

BACKGROUND: ESMO guidelines (Moreau P, et al. Ann Oncol. 2017) recommend lenalidomide- (LEN) and bortezomib-based (BORT) regimens as first line (1L) treatment (tx) options for patients (pts) with multiple myeloma (MM) who are ineligible for stem cell transplantation (NSCT). The aim of this study was to determine tx outcomes and healthcare resource utilization (HCRU) for pts with NSCT MM receiving 1L LEN- or BORT-based regimens in 7 European countries. METHODS: Physicians from Austria, Belgium, France, Germany, Italy, Spain, and Netherlands abstracted retrospective data from medical records of pts with MM who received 1L LEN- or 1L BORT-based regimens between Jun 1 2015 and Nov 30 2016. Data were abstracted during Q1-2 2019 to allow adequate follow up time to assess outcomes of interest. Data collected included pt demographics, clinical characteristics, tx patterns, health outcomes (e.g. progression free survival [PFS], time to next tx [TTNT]), and HCRU (e.g. supportive tx, hospitalizations, healthcare professional [HCP] visits, monitoring tests). Health outcomes were compared for LEN- and BORT-based regimens using the Kaplan-Meier estimator. HCRU was calculated as means per month (mo), per usage type, to account for variation in tx duration. Patients with complete resource use data for an HCRU category were included in the analysis for that category. RESULTS: 59 physicians provided data on 453 pts. A total of 220 (48.6%) pts received 1L LEN- and 233 (51.4%) received 1L BORT-based regimens. The most common 1L LEN- and BORT-based regimens were LEN + dexamethasone (DEX; n = 194) and LEN + prednisone (PRED; n = 15), and BORT + melphalan + PRED (n = 94) and BORT + DEX (n = 82), respectively. Mean follow up time was similar for both regimens (38.2 vs 39.4 mo, respectively). Demographic profiles of pts receiving 1L LEN- or BORT-based regimens were similar (P > 0.05 for all demographic variables); time from diagnosis to start of 1L, performance status at first tx, comorbidities, CRAB criteria, bone lesions at diagnosis, or cytogenetic testing did not differ significantly. Within the follow up period, pts treated with 1L LEN-based regimens received significantly fewer lines of tx (mean [SD] 1.55 [0.64] vs 1.75 [0.69] lines; P < 0.01) vs pts treated with 1L BORT-based regimens. Of the 233 pts receiving 1L BORT-based regimens,142 went on to receive 2L tx, of whom 104 (73%) received a second-line (2L) LEN-based regimen. Of the 220 pts receiving 1L LEN-based regimens, 105 went on to receive 2L tx, of whom 50 (48%) received a 2L BORT-based regimen. Health outcomes: Significant differences in PFS (P < 0.01) were observed; the probability of maintaining PFS was higher for pts receiving 1L LEN- vs 1L BORT-based regimens at 12 (94% vs 85%) and 24 mo (76% vs 63%) post-1L initiation. A significantly longer TTNT (median 45.7 vs 36.5 mo; P < 0.01) was observed for pts receiving 1L LEN vs those receiving 1L BORT. A significantly longer time to third line (3L) tx was estimated for pts receiving 1L LEN- vs 1L BORT-based regimens: approximately 15% of 1L LEN pts had started 3L tx at 48 mo vs 22% of 1L BORT pts (P = 0.01). From a sequencing perspective, a trend toward longer time to 3L tx was observed for pts receiving 1L LEN followed by 2L BORT vs pts receiving 1L BORT followed by 2L LEN (P = 0.11). HCRU: Across the follow up period, no differences were observed, with low overall HCRU observed for each cohort. CONCLUSIONS: Following the approval of LEN in the 1L setting, physicians have more options when treating NDMM. The findings of this study suggest that in a real-world setting, health outcomes are significantly better for NSCT pts with NDMM who receive 1L LEN- vs 1L BORT-based regimens. A US claims database study also suggested that LEN-based tx is associated with longer TTNT (Chari A, et al Clin Lymphoma Myeloma Leuk). In this analysis, 1L LEN-based regimens extended the time to 3L tx, potentially delaying progression to use of and associated cost impact of expensive tx in later line settings. Longer duration on 1L tx may also be expected to reduce total per pt per mo (PPPM) costs, as reported by a US study (Arikian SR, et al. Curr Med Res Opin). In our study, routine tx-related HCP visits were not explicitly captured and so the data may not accurately reflect differences in HCRU for pts receiving 1L LEN- vs 1L BORT-based regimens. This study provides real-world evidence to support 1L LEN-based regimens as providing clinically meaningful benefits for pts. Disclosures Zamagni: Celgene Corporation: Honoraria, Other: Advisory board, Speakers Bureau; Janssen: Honoraria, Other: Advisory board, Speakers Bureau; Amgen: Honoraria, Other: Advisory board, Speakers Bureau; BMS: Honoraria, Other: Advisory Board, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Sanofi: Honoraria, Other: Advisory Board, Speakers Bureau. Dhanasiri:Celgene Corporation: Employment, Equity Ownership. Moore:Adelphi Real World: Employment. Ghale:Adelphi Real World: Employment. Roussel:Janssen: Honoraria, Other: travel fees, lecture fees, Research Funding; takeda: Other: travel fees, lecture fees, Research Funding; Amgen: Other: travel fees, lecture fees, Research Funding; Celgene Corporation: Consultancy, Other: travel fees, lecture fees, Research Funding.

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Response to Bridging Therapy (BT) before CAR-T Cell Infusion Predicts Outcomes for Relapsed/Refractory (R/R) Aggressive B-Cell Non-Hodgkin Lymphoma (NHL)

Blood ◽

10.1182/blood-2020-141058 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 30-30

Author(s):

Arushi Khurana ◽

Abdullah S. Al Saleh ◽

Sangeetha Gandhi ◽

Tuan A Truong ◽

Nabila Bennani ◽

...

Keyword(s):

Overall Survival ◽

B Cell ◽

Real World ◽

Research Funding ◽

Progressive Disease ◽

Case Series ◽

Advisory Board ◽

Bridging Therapy ◽

Car T

Background: Real world multi-institutional data of anti-CD19 CAR-T therapy from across the US shows similar response rates and toxicities as that of the registration trials. For axicabtagene ciloleucel (axi-cel), bridging therapy (BT) during CAR-T manufacturing was not allowed. Real world data shows that patients who received BT had lower complete remission (CR) rates, duraiton of response (DOR) and overall survival (OS). Whether the poorer outcome is due to the effect of the BT or the aggressive biology of the disease is unknown. Patients with lower disease burden had higher response rate in the registration study ZUMA-1 for axi-cel. We examined the impact of response to BT on CAR-T outcome. Specifically, we also describe our experience using polatuzumab vedotin, bendamustine and rituximab (Pola-BR), also a recently approved therapy for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), prior to CAR-T as salvage (ST) and BT. Methods: A retrospective review of 63 patients who received axi-cel for NHL from June 2016 - March 2020 at Mayo Clinic, Rochester was performed. ST was defined as the last therapy prior to leukapheresis and grouped into categories - autologous stem cell transplant (ASCT), and non-ASCT (chemotherapy and immunotherapy) . BT was defined as lymphoma-directed therapy given between leukapheresis and CAR-T infusion. Response to all lymphoma-directed therapy was evaluated using 2014 Lugano criteria. Event free survival (EFS) was defined as time from axi-cel infusion to progression, next treatment, or death. Overall survival (OS) was defined as time from axi-cel infusion to death. Results: Patients received BT if there were concerns for symptomatic progression of disease during CAR-T manufacturing that would reduce the likelihood of eligibility to receive CAR-T. The decision and choice of BT was at the discretion of the treating physician. Sixty-eight percent (n=43) of the patients received BT (19 chemo, 24 immunotherapy). Demographics of the patients based on their response to BT are shown in table 1. More patients in the BT responder group had received chemotherapy as type of bridge (58% vs. 33%). With a median follow up of 12-months for those still alive, significant improvement in EFS was seen in patients who had partial response (PR) or stable disease (SD) to BT than patients who continued to progress (median 12 months vs. 3 months, p = 0.01) [Figure 1A]. OS however, was not significant between the two groups (median OS 18 months - responders vs. 12 months non-responders, p = 0.19) [Figure 1B]. We also describe in the case series below 11 patients who received Pola-BR in salvage setting (ST) and/or BT (Table 2). Due to the lymphopenic effects of bendamustine, it was avoided before T-cell collection if possible. Two patients, however, received bendamustine as part of Pola-BR for salvage therapy as its need was determined per the managing physician. Axi-cel was successfully manufactured for all 10 patients. One patient did not have measurable disease after Pola-BR BT and remains on observation. A second patient died before CAR-T infusion from progressive disease. Four of the nine patients treated with CAR-T remained in response. Updated outcome will be presented. Conclusion: While patients who received BT have worse EFS than those who didn't, having some control of lymphoma after BT was associated with better EFS compared to patients who continued to have progressive disease after BT. Preliminary data from Pola-BR case series shows 60% (6/10) patients achieved PR/SD before CAR-T infusion, but requires longer follow up for its impact on survival. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding; Verastem: Other: Advisory Board. Ansell:AI Therapeutics: Research Funding; Takeda: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding; Trillium: Research Funding. Lin:Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Bluebird Bio: Consultancy, Research Funding; Juno: Consultancy; Legend BioTech: Consultancy; Merck: Research Funding; Takeda: Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy.

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Connected health for growth hormone treatment research and clinical practice: learnings from different sources of real-world evidence (RWE)—large electronically collected datasets, surveillance studies and individual patients’ cases

BMC Medical Informatics and Decision Making ◽

10.1186/s12911-021-01491-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Nea Boman ◽

Luis Fernandez-Luque ◽

Ekaterina Koledova ◽

Marketta Kause ◽

Risto Lapatto

Keyword(s):

Growth Hormone ◽

Observational Study ◽

Case Studies ◽

Real World ◽

Growth Disorders ◽

Injection Device ◽

Growth Outcomes ◽

Real World Evidence ◽

High Adherence

Abstract Background A range of factors can reduce the effectiveness of treatment prescribed for the long-term management of chronic health conditions, such as growth disorders. In particular, prescription medications may not achieve the positive outcomes expected because approximately half of patients adhere poorly to the prescribed treatment regimen. Methods Adherence to treatment has previously been assessed using relatively unreliable subjective methods, such as patient self-reporting during clinical follow-up, or counting prescriptions filled or vials returned by patients. Here, we report on a new approach, the use of electronically recorded objective evidence of date, time, and dose taken which was obtained through a comprehensive eHealth ecosystem, based around the easypod™ electromechanical auto-injection device and web-based connect software. The benefits of this eHealth approach are also illustrated here by two case studies, selected from the Finnish cohort of the easypod™ Connect Observational Study (ECOS), a 5-year, open-label, observational study that enrolled children from 24 countries who were being treated with growth hormone (GH) via the auto-injection device. Results Analyses of data from 9314 records from the easypod™ connect database showed that, at each time point studied, a significantly greater proportion of female patients had high adherence (≥ 85%) than male patients (2849/3867 [74%] vs 3879/5447 [71%]; P < 0.001). Furthermore, more of the younger patients (< 10 years for girls, < 12 years for boys) were in the high adherence range (P < 0.001). However, recursive partitioning of data from ECOS identified subgroups with lower adherence to GH treatment ‒ children who performed the majority of injections themselves at an early age (~ 8 years) and teenagers starting treatment aged ≥ 14 years. Conclusions The data and case studies presented herein illustrate the importance of adherence to GH therapy and how good growth outcomes can be achieved by following treatment as described. They also show how the device, software, and database ecosystem can complement normal clinical follow-up by providing HCPs with reliable information about patient adherence between visits and also providing researchers with real-world evidence of adherence and growth outcomes across a large population of patients with growth disorders treated with GH via the easypod™ device.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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