Availability Of Novel Drugs Research Articles

Real-world data for precision cancer medicine-A European perspective.

Leveraging real-world data (RWD) for drug access is necessary to overcome a key challenge of modern precision oncology: tackling numerous low-prevalence oncogenic mutations across cancers. Withholding a potentially active medication in patients with rare mutations for the sake of control chemotherapy or "best" supportive care is neither practicable nor ethically justifiable anymore, particularly as RWD could meanwhile be used instead, according to scientific principles outlined by the US Food and Drug Administration, European Medicines Agency and other stakeholders. However, practical implementation varies, with occasionally opposite recommendations based on the same evidence in different countries. In the face of growing need for precision drugs, more transparency of evaluation, a priori availability of guidance for the academia and industry, as well as a harmonized framework for health technology assessment across the European Union (EU) are imperative. These could in turn trigger infrastructural changes in national and pan-European registries, cancer management guidelines (e.g., frequency of routine radiologic restaging, inclusion of patient-reported outcomes), and the health data space, to ensure conformity with declared standards and facilitate extraction of RWD sets (including patient-level data) suitable for approval and pricing with minimal effort. For an EU-wide unification of precision cancer medicine, collective negotiation of drug supply contracts and funding solidarity would additionally be required to handle the financial burden. According to experience from pivotal European programs, off-label use could potentially also be harmonized across EU-states to accelerate availability of novel drugs, streamline collection of valuable RWD, and mitigate related costs through wider partnerships with pharmaceutical companies.

559. A Nationwide Survey of COVID-19 Management in the Dominican Republic Over the Course of the Pandemic

BackgroundCOVID-19 was declared a global Public Health Emergency by the WHO in January 2020. Limited treatment options existed early in the pandemic. As COVID-19 spread across the globe and new therapeutics emerged, different interpretations of the literature grew, and major societies relayed conflictive recommendations. There is a paucity of data on COVID-19 management in low- and middle-income countries. As a result, we performed a nationwide survey of local treatment practices in the Dominican Republic (DR).MethodsWe performed an anonymous survey of infectious diseases specialists in the DR and US. The survey collected hospital characteristics and COVID-19 management protocols during different quarters of 2020-21. Management was categorized by drug and disease severity based on supplemental oxygen requirements. A convenience sample in the US representing community and academic sites was surveyed for point comparison between the US and DR.ResultsThe survey was completed by physicians from a total of 11 sites located in 4 cities of the DR: Santo Domingo (3), Santiago (4), La Vega (2) and San Francisco (2). These cities were representative of all regions in the country. The survey included 7 (64%) hospitals with < 200 beds, 3 (27%) with 201-300 beds, and 1 (9%) with >400 beds. Seven (47%) were private, 2 (13%) public, and 6 (40%) were teaching hospitals. In the US, 2 academic hospitals with >400 beds and 2 community hospitals with < 200 beds in a major city were surveyed. Management of COVID-19 at sites in the DR and US throughout the pandemic is plotted in Figure 1. Remdesivir use by disease severity is plotted in Figure 2.Figure 1. Management of COVID-19 at sites in the US and DR throughout the COVID-19 pandemic FIgure 2. Remdesivir use by disease severity at sites in the US and DR throughout the COVID-19 pandemic ConclusionThroughout the pandemic, as therapeutic options evolved, hospitals and physicians had to adapt to changing guidelines and availability of novel drugs. Variability between countries and sites emerged. The use of hydroxychloroquine and convalescent plasma waned more rapidly in the US. Dexamethasone was widely used at all sites. Tocilizumab and remdesivir were used more liberally in the DR. Antimicrobial stewardship limited these agents at US sites to more narrow therapeutic windows which could explain the discrepancies seen between the US and DR. Uncertainty of benefit in certain disease states, limited availability, and cost may also play a role.Disclosures All Authors: No reported disclosures

Impact of the Availability of Novel Drugs on Overall Survival of Multiple Myeloma Patients: A Real-World Study

Introduction: Multiple myeloma is an incurable hematologic malignancy. However, many novel drugs (lenalidomide, carfilzomib, daratumumab, elotuzumab and ixazomib) have recently been approved in Brazil for this disease. Proving that the availability of these drugs increases survival is not straightforward, since pivotal trials with these drugs were designed to show benefit in progression-free survival and not in overall survival. Hypothesis: We have hypothesized that the availability of novel drugs would reduce the risk of death. Methods: This is a real-world, unicenter analysis that included patients with multiple myeloma treated between 1993 and 2017. The availability of novel drugs (lenalidomide, carfilzomib, daratumumab, elotuzumab and ixazomib) was treated as a time-dependent covariate and analyzed by Cox model. The analysis was controlled for the International Staging System (ISS) and for age. Results: With a median follow-up of 6 years, we included 151 patients with multiple myeloma. Fourty percent had ISS-I, 34% ISS-II and 26% ISS-III. Mean age was 60.5 y/o (SD: 12.2). There has been 51 deaths, and 5-y overall survival was 90% for ISS-I, 80% for ISS-II and 54% for ISS-III (p=0.0004). In multivariable analysis, age (HR=1.06, p&amp;lt;0.0001) and ISS-III (HR=4.51, p&amp;lt;0.0001) were risk factors for death, while the availability of two or more novel drugs was protective (HR=0.31, p=0.006). The availability of a single novel drug was also protective (HR=0.58), although it did not reach statistical significance (p=0.13). Adjusted Simon-Makuch survival plot is in figure 1 (adjusted for ISS III and 60 y/o). Discussion: Our results show that the availability of two or more novel drugs increases overall survival in multiple myeloma. This is an important finding, since the pivotal trials were designed to show advantages in progression-free survival and, once achieved, the experimental drug was offered to the control group, hampering overall survival analyses. Overall survival benefit, therefore, are more likely to be seen in real-world studies. We included the availability of novel drugs as a time-dependent, and the interpretation of our results is that patients alive when two novel drugs became available had benefit in overall survival. Our study has two weaknesses. Two or more novel drugs were more likely to be available for patients from a more recent time. This difference could be due to changes in supportive care, but there has been no major change in supportive care for multiple myeloma patients. Another weakness is that patient alive in the more recent years may have not received novel drug-based treatment. Considering that multiple myeloma is an incurable disease, this is unlikely for the majority of patients. In conclusion, the availability of two or more novel drugs for multiple myeloma improves survival. Figure Disclosures No relevant conflicts of interest to declare.

Access to Novel Drugs for Non-Small Cell Lung Cancer in Central and Southeastern Europe: A Central European Cooperative Oncology Group Analysis.

BackgroundTreatment of non‐small cell lung cancer (NSCLC) improved substantially in the last decades. Novel targeted and immune‐oncologic drugs were introduced into routine treatment. Despite accelerated development and subsequent drug registrations by the European Medicinal Agency (EMA), novel drugs for NSCLC are poorly accessible in Central and Eastern European (CEE) countries.Material and MethodsThe Central European Cooperative Oncology Group conducted a survey among experts from 10 CEE countries to provide an overview on the availability of novel drugs for NSCLC and time from registration to reimbursement decision in their countries.ResultsAlthough first‐generation epidermal growth factor receptor tyrosine kinase inhibitors were reimbursed and available in all countries, for other registered therapies—even for ALK inhibitors and checkpoint inhibitors in first‐line—there were apparent gaps in availability and/or reimbursement. There was a trend for better availability of drugs with longer time from EMA marketing authorization. Substantial differences in access to novel drugs among CEE countries were observed. In general, the availability of drugs is not in accordance with the Magnitude of Clinical Benefit Scale (MCBS), as defined by the European Society for Medical Oncology (ESMO). Time spans between drug registrations and national decisions on reimbursement vary greatly, from less than 3 months in one country to more than 1 year in the majority of countries.ConclusionThe access to novel drugs for NSCLC in CEE countries is suboptimal. To enable access to the most effective compounds within the shortest possible time, reimbursement decisions should be faster and ESMO MCBS should be incorporated into decision making.

Management of NK/T-Cell Lymphoma, Nasal Type.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is a rare peripheral T-cell lymphoma associated with Epstein-Barr virus. It most often presents as limited-stage disease in patients of East Asian descent with a palatal deformity caused by erosion of the tumor through the hard palate. Limited-stage disease is often curable with the use of l-asparaginase-based chemotherapy and high-dose radiation therapy. Obtaining an accurate diagnosis is essential, because treatment with standard lymphoma regimens and omission of radiation severely compromise the likelihood of long-term survival. Conversely, patients with advanced disease have a poor prognosis and are recommended for asparaginase-based chemotherapy followed by consolidation with autologous transplantation as a potentially curative approach. Progress often has been hampered by the rarity of this disease. However, discovery of common genetic alterations in pathways that promote growth and inhibit apoptosis, and actionable markers such as CD30 (among others), have begun to broaden the availability of novel drugs (eg, targeted therapies). There is also cautious optimism about immunotherapies, such as checkpoint blockade and novel cellular therapies that target Epstein-Barr virus. Advances in treatment and understanding of the genetic landscape of this disease offer hope for improved treatment outcomes.

Mucormycosis of the Central Nervous System.

Mucormycosis involves the central nervous system by direct extension from infected paranasal sinuses or hematogenous dissemination from the lungs. Incidence rates of this rare disease seem to be rising, with a shift from the rhino-orbital-cerebral syndrome typical of patients with diabetes mellitus and ketoacidosis, to disseminated disease in patients with hematological malignancies. We present our current understanding of the pathobiology, clinical features, and diagnostic and treatment strategies of cerebral mucormycosis. Despite advances in imaging and the availability of novel drugs, cerebral mucormycosis continues to be associated with high rates of death and disability. Emerging molecular diagnostics, advances in experimental systems and the establishment of large patient registries are key components of ongoing efforts to provide a timely diagnosis and effective treatment to patients with cerebral mucormycosis.

Drug Sensitivity Screening on Multiple Myeloma for Precision Cancer Therapy

Abstract Introduction Multiple Myeloma (MM) is considered incurable and MM patients eventually relapse despite use of many promising approved drugs in standard-of-care treatment. It has been challenging to design precision medicine protocols to tailor personalized treatment for MM patients that relapse despite availability of novel drugs. In-vitro drug screening has been hampered by lack of in-vitro culture protocols that mimic tumor microenvironment and that accommodates for low cell number. Here, we report our novel MM proliferation protocol along with an in-vitro functional screening platform, that allow us to assess drug sensitivity on MM patient samples with a customized panel of 30 myeloma drugs. Using our novel drug sensitivity screening platform, we aim to identify efficient drugs for individual patients with progressive disease and select the best treatment option. Methods Previously, we have established culture settings that mimic the tumor microenvironment for MM (Wang D. et al Leukemia 2017). Here, we implemented a novel protocol that allowed primary MM cells to proliferate in a 384 well-format. Stimulated CD138+ MM cells were tested against a customized library of 30 clinically approved drugs including proteasome inhibitors (PI) and drugs that are in clinical trials. CD138+ MM cells were cultured in 384-well format in the presence of individual drugs in a concentration range over 6 logs for 72 hours (3 days). To define drugs that inhibit malignant plasma cell growth, we used the cell-based assays CellTiter-Glo® luminescent cell viability assay and CellTox™ green cytotoxicity assay as readouts by assessing drug sensitivity at day 3. We performed MM drug screening on 18 patient samples and 6 healthy B-cell (BC) control samples. We performed drug screening on myeloma cells SK-MM2 (patient derived cell line) for 527 drugs at 5 concentrations. We are currently performing drug screening on 11 MM cell lines which represents diverse cancer stage. For each patient sample, a Drug Sensitivity Score (DSS) was calculated for every drug using the IC50 value, slope and the area under the curve (AUC). Next, DSS values for the full MM patient cohort were compared to those of healthy controls to generate a selective DSS (sDSS) for each drug (sDSS = DSSpatient - average DSShealthy). Drugs which had sDSS &gt;5 were considered clearly more effective for patient samples in the in vitro test. MM patient samples were assessed for sDSS score using our screening data and we ranked all the drugs by their sDSS score. We have generated sDSS score for both CTG (cell viability) and CTxG (cell toxicity) datasets. Results and conclusion To date we have performed MM drug sensitivity screening on 18 MM patient samples and 6 healthy B cells donors. We adopted a quantitative scoring approach using sDSS to rank drugs that are selective and effective in inhibiting myeloma cells. Based on our drug sensitivity analysis, proteasome inhibitors such as bortezomib and carfilzomib were more effective in inhibiting myeloma cell proliferation compared to other drugs in all 18 patient samples as well as in the 6 healthy donors. Surprising, doxorubicin showed the highest average sDSS score in 10 patients with score 12.96 followed by prednisolone with average sDSS score 6.73 (Figure 1), while proteasome inhibitor bortezomib showed average sDSS score of 4.14 and carfilzomib showed average sDSS score of 1. In addition, we observed that samples from dexamethasone-treated patients showed lower sDSS score for dexamethasone in the in vitro drug screening compared to samples from untreated patients (MM0905 and MM0706). Based on the screening data and clustering analysis, we concluded that the observed diversity in drug effectiveness between patient samples supports the hypothesis of tumor heterogeneity and creates a basis for exploring the possibility to individualize treatment choices. Figure 1: Selective Drug Sensitivity Screening (sDSS) score for 30 drugs for 13 MM patient samples. HB, Healthy donor B cells (Euclidean distance, Ward linkage method) Disclosures Schjesvold: Novartis: Honoraria; Oncopeptides: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Bayer: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria.

Immune Profiling of Cancer Patients Treated with Immunotherapy: Advances and Challenges.

The recent advances in immunotherapy and the availability of novel drugs to target the tumor microenvironment have dramatically changed the paradigm of cancer treatment. Nevertheless, a significant proportion of cancer patients are unresponsive or develop resistance to these treatments. With the aim to increase the clinical efficacy of immunotherapy, combinations of agents and standard therapies with complementary actions have been developed mostly on an empirical base, since their mechanisms of actions are not yet fully dissected. The characterization of immune responsiveness and its monitoring along with the treatment of cancer patients with immunotherapy can provide insights into the mechanisms of action of these therapeutic regimens and contribute to the optimization of patients’ stratification and of combination strategies and to the prediction of treatment-related toxicities. Thus far, none of the immunomonitoring strategies has been validated for routine clinical practice. Moreover, it is becoming clear that the genomic and molecular make-up of tumors and of the infiltrating immune system represent important determinants of the clinical responses to immunotherapy. This review provides an overview of different approaches for the immune profiling of cancer patients and discusses their advantages and limitations. Recent advances in genomic-based assays and in the identification of host genomic relationships with immune responses represent promising approaches to identify molecular determinants and biomarkers to improve the clinical efficacy of cancer immunotherapy.

Risk Stratification and Targets in Multiple Myeloma: From Genomics to the Bedside.

In the past 15 years, significant improvements in overall survival have been observed in multiple myeloma (MM), mainly due to the availability of novel drugs with variable mechanisms of action. However, these improvements do not benefit all patients, and some of them, defined as high risk, still display short survival. The most important risk factors are the genetic abnormalities present in the malignant plasma cells. The most important high-risk features are the del(17p), the del(1p32), the t(4;14), and 1q gains. Assessing these markers is mandatory at diagnosis and at least at first relapse, since it has been clearly shown that the lenalidomide-dexamethasone combination is not efficient in these high-risk patients. In contrast, a triplet combination adding a proteasome inhibitor or a monoclonal antibody to the lenalidomide-dexamethasone backbone clearly improves the survival. Another way to improve the outcome would be to specifically target genetic abnormalities with specific inhibitors. The sequencing of more than 1,000 MM exomes revealed again a huge heterogeneity. The most frequent mutations involve the KRAS and NRAS genes (20%-25% each). However, to date, no good RAS-inhibitors are clinically available, preventing targeted therapy. The only drugable target is the V600E BRAF mutation. Unfortunately, this specific mutation is present in only 3% of the patients. Finally, it has been recently reported a specific efficiency of the BCL2-inhibitor venetoclax in patients with the t(11;14) translocation, which is found in 20% of the patients.

Time trends in antithrombotic management of patients with atrial fibrillation treated with coronary stents: Results from TALENT-AF (The internAtionaL stENT - Atrial Fibrillation study) multicenter registry.

Antithrombotic management of patients with atrial fibrillation (AF) requiring percutaneous coronary intervention (PCI) is highly variable; limited evidence-based guidelines exist to influence practice. Patient characteristics and availability of novel drugs may have contributed to practice variability. We undertook an international multicenter retrospective registry of AF patients treated with PCI. The primary measures of interest were antiplatelet and OAC prescriptions at discharge. We compared temporal trends between Prior (2010-2012) and Recent (2013-2015) cohorts and investigated variables associated with OAC prescription. We identified 488 cases (140 Prior, 348 Recent). Median CHADS2 and HAS-BLED scores were 2 (IQR, 1-3) and 2 (IQR, 2-3). Clinical characteristics were similar between cohorts, with high (85%) prevalence of ACS. More patients in the Recent cohort, compared with Prior, received OAC (56.9% vs 44.3%; P = 0.01) and NOAC (27.3% vs 3.6%; P < 0.01) at baseline. Triple therapy at discharge was not different between the cohorts. Clinical presentation with ACS and consequent use of potent P2Y12 inhibitors were associated with reduced odds of OAC prescription at discharge (OR: 0.57, P = 0.045 and OR: 0.38, P = 0.023, respectively). Despite little change over time in clinical characteristics of AF patients undergoing PCI, significantly more patients received OAC at presentation. However, triple therapy was not more frequent in the Recent cohort, and ACS presentation was associated with lack of OAC at discharge. We underscore the need for trial evidence and use of updated guidelines to assist clinicians in balancing ischemic and bleeding risks.

Asymptomatic and Treatment-requiring Multiple Myeloma - Data from the Czech Registry of Monoclonal Gammopathies.

Monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) are premalignant stages of multiple myeloma (MM). MM is a malignancy of plasma cells, which is associated with a median overall survival of 5 to 7 years. MM accounts for approximately 10% of hematological malignancies. Descriptive analysis of data from 19 Czech centres collected in the Registry of Monoclonal Gammopathies (RMG) was performed. Over the last 10 years of prospective collection of data, together with retrospectively recorded data on patients diagnosed before the registry establishment, data on 7,467 patients with either asymptomatic or symptomatic form of MM have been gathered. Validation criteria for the analysis were met by 2,506 MGUS patients, 400 SMM patients and 4,738 MM patients. The median duration of follow-up was 4.3 years in MGUS patients and 2.4 years in SMM patients. The overall risk of progression from MGUS to malignancy was 1.7% per year. The risk of progression from SMM to MM was highest in the 1st years after diagnosis: overall, this risk was 16.6% per year. The median duration of follow-up was 2.8 years in MM patients. The median overall survival from the diagnosis was 5.7 years. The median OS from treatment initiation/progression-free survival decreased from 60.5/21.0 months in the 1st line therapy to 34.3/12.4 months in the 2nd line therapy, 22.6/8.9 months in the 3rd line therapy and 13.8/5.8 months in the 4th or higher line therapies. Thanks to the availability of novel drugs for MM treatment in the Czech Republic, treatment strategies have changed dramatically over the last decade. RMG is a registry designated for the collection of data on diagnosis, treatment, treatment results and survival of patients with monoclonal gammopathies in the long-term follow-up. RMG is a valuable source of data from real clinical practice.Key words: registries - monoclonal gammopathy of undetermined significance - smouldering multiple myeloma - multiple myeloma - progression - treatment - survival.

Allogeneic Stem Cell Transplantation for Relapsed/Refractory B Cell Lymphomas: Results of a Multicenter Phase II Prospective Trial including Rituximab in the Reduced-Intensity Conditioning Regimen

The treatment of patients with refractory/relapsed B cell non-Hodgkin lymphoma (NHL) is evolving because of the availability of novel drugs. Allogeneic stem cell transplantation (alloSCT) can be curative, but its morbidity and mortality remain a matter of concern. We conducted a multicenter prospective phase II trial to evaluate the benefit of including only 1 dose of rituximab in the conditioning regimen before alloSCT. The primary endpoint was progression-free survival. The study enrolled 121 patients with relapsed/refractory B cell lymphomas. The conditioning regimen consisted of thiotepa, cyclophosphamide, fludarabine, and rituximab (500 mg/m2). Rabbit antithymocyte globulin was administered only in case of unrelated donors. Sixty-seven (55%) and 54 (45%) patients received grafts from related and unrelated donors, respectively. The crude cumulative incidence (CCI) of nonrelapse mortality (NRM) was 21% at 3 years. The CCIs of chronic graft-verus-host disease (GVHD) at 3 years were 54% and 31% in recipients of matched sibling and unrelated grafts, respectively. At a median follow-up of 41 months, the estimated 3-year progression-free and overall survival were 50% and 61%, respectively. Long-term outcome was also evaluated with the composite endpoint of GVHD-free and relapse-free survival (GRFS). This is the first work evaluating the GRFS in a prospective trial of lymphoma patients: the 1-year and 3-year GRFS were 40% and 34%, respectively. AlloSCT can cure a fraction of patients with rather low NRM and an encouraging PFS and GRFS.

Use of Bevacizumab in the Management of Potentially Resectable Colorectal Liver Metastases: Safety, Pathologic Assessment and Benefit

Liver metastases are a frequent and commonly lethal complication of colorectal cancer. Surgical resection of limited liver disease offers currently the best chance of long-term survival, but surgery is not feasible for a rather significant proportion of patients with hepatic metastases. Despite the overall improvement in the medical management of patients with metastatic colorectal cancer, whose median survival has been substantially prolonged with the availability of novel drugs, long-term outcomes remain rather poor if a combined onco-surgical strategy cannot be implemented. Nonetheless, newer chemotherapy schedules have become more frequently, rapidly and deeply active, improving hepatic lesions’ downsizing, hence extending the pool of patients amenable to secondary liver surgery. Here, we summarize available data on the efficacy and safety of bevacizumab, an anti-VEGF monoclonal antibody indicated for the treatment of metastatic colorectal cancer, as a conversion chemotherapeutic option in the management of patients with liver metastases.

Treatment, Outcome and Prognostic Factors in Renal Cell Carcinoma - A Single Center Study (2000-2010).

In Switzerland efficient availability of novel drugs for renal cell cancer (RCC) has been granted early. Since the advent of the targeted agents for RCC the usage of these drugs has been reported to improve progression free survival. Here, we find that patients who are able to receive sequential targeted therapy, including tyrosine kinase inhibitors (TKI) and mTOR inhibitors (mTORi), have a largely better outcome than those who have less exposure to these agents. The value of the prognostic scores developed by Motzer and Heng is fully reflected by the outcomes according to prognostic risk groups in our unselected patient cohort. Also, the use of surgical intervention appears to be an important prognostic factor, however with a somehow diminished effect by novel systemic therapies. The importance of multiple lines of targeted therapies is underlined by this retrospective analysis. For patients with metastatic RCC not receiving targeted therapy the median OS was 22.6 months compared to those with one TKI 25.4 months. Patients receiving a second-line therapy (median overall survival 27.6 months) and those patients with three or more lines of therapy (43.8 months) have the greatest benefit. Also, exposure to a mTORi improves survival versus non-exposure to mTORi (63.3 vs. 22.3 months, p=0.038). In conclusion a trend towards improved survival is confirmed for an unselected population when the full variety of therapeutic options is available and can be used for the individual patient.

Front-line lenalidomide therapy in patients with newly diagnosed multiple myeloma.

The availability of novel drugs with different and innovative mechanisms of action such as proteasome inhibitors such as bortezomib and immunomdulatory agents as thalidomide and lenalidomide have changed the landscape of the treatment of patients with newly diagnosed multiple myeloma, allowing the development of several new therapeutic regimens both for transplant-eligible and -ineligible patients. Among these new agents, lenalidomide has become one of the most commonly used in these patients. In this article, we review the current state-of-the-art of different induction and maintenance lenalidomide-containing regimens administered in transplant-eligible and -ineligible patients with newly diagnosed multiple myeloma. We also discuss the safety profile and potential long-term side effects of this drug and analyze its utility in certain subgroups of patients like those with high-risk disease or different degrees of renal impairment.

Early mortality in multiple myeloma

The life expectancy of patients diagnosed with multiple myeloma (MM) in the US has improved substantially over the last two decades, a phenomenon affecting predominantly, but not exclusively, younger patients.1 This improvement in survival has been attributed to the broader use of autologous hematopoietic progenitor cell transplantation (AHPCT)2 and increasing availability of novel drugs both in the newly diagnosed and relapsed setting,1 as well as improved supportive care. The impact of these interventions in early mortality (EM, henceforth defined as death in the first year after the diagnosis) is less well known.

Trends in Utilization and Outcomes of Autologous Transplantation as Early Therapy for Multiple Myeloma

The impact of novel drugs for treating multiple myeloma (MM) on the utilization and outcomes of autologous hematopoietic progenitor cell transplantation (AHPCT) is unknown. We reviewed characteristics and outcomes of 20,278 patients who underwent AHPCT within 12 months of diagnosis of MM in the United States and Canada and registered at the Center for International Blood and Marrow Transplant Research (CIBMTR) in 3 time cohorts reflecting the increasing availability of novel drugs: 1995 to 1999 (n = 2226), 2000 to 2004 (n = 6408), and 2005 to 2010 (n = 11,644). In the United States, the number of AHPCTs performed increased at a greater rate than new MM cases. Patients in recent cohorts were older, less likely to have stage 3 MM, and more likely to have received previous thalidomide, lenalidomide, or bortezomib. On multivariate analysis, AHPCT in the 2000 to 2004 cohort (HR = 0.77) or in the 2005 to 2010 cohort (HR = 0.68) were associated with lower risk of death. Survival at 60 months post-AHPCT improved from 47% in 1995 to 1999 to 55% in 2000 to 2004 and to 57% in 2005 to 2010, owing less to improvement in progression-free survival (50% versus 55% versus 57% at 24 months) than to postrelapse/progression survival (58% versus 65% versus 72% at 24 months). AHPCT and new biological agents are complementary, nonredundant therapies and should be combined in the management of MM in suitable patients.

Trends in Utilization and Outcomes of Autologous Hematopoietic Cell Transplantation (AHCT) in the Upfront Management of Patients with Multiple Myeloma: A Cibmtr Analysis

AbstractAbstract ▪596▪This icon denotes a clinically relevant abstract BackgroundLarge population-based studies have demonstrated a significant improvement in survival (OS) for patients (pts) with multiple myeloma (MM) over time since the mid-1990s. The improvement has mostly affected younger patients suggesting a beneficial impact of AHCT. The availability of novel drugs within the last decade and their impact on the utilization and outcomes of AHCT recipients is unknown. MethodsWe retrospectively reviewed the characteristics and outcomes of 20,278 patients undergoing AHCT within 12 months of diagnosis in USA and Canada and reported to CIBMTR in the periods of 1995–1999 (n=2226), 2000–2004 (n=6408) and 2005–2010 (n=11644) including a subgroup of 4373 individuals with detailed patient, disease and treatment information. We subsequently compared survival and analyzed patient, disease and treatment characteristics across the three periods with the time period serving as a surrogate for pre- and post-transplant exposure to novel agents. ResultsAcross the 3 time periods, there was a marked increase in the number of upfront transplants across all age groups (Figure 1a). Patients receiving upfront HSCT in the more recent period were older, less likely to have stage 3 MM at diagnosis and more likely to have received thalidomide (<1 % vs. 22% vs. 52%), lenalidomide (0% vs. <1% vs. 21%) or bortezomib (0% vs. 2% vs. 35%) and have chemosensitive disease at the time of AHCT. The proportion of African-American patients remained low and stable across the three periods (14 vs. 13 vs. 15%). Over the 3 periods, there was a decrease in chemotherapy based stem cell mobilization and increase of single agent G-CSF based mobilization (24% vs. 24% vs. 41%). The use of single agent Melphalan conditioning increased from 54% in 1995–1999 to nearly 100% in the latest period concomitant with near disappearance of total body irradiation-based and multi-drug conditioning regimens. Compared with 1995–99 cohort, survival was superior in the 2000–04 and 2005–09 cohorts at 24 (72% vs. 79% vs. 84%, P<0.001), 48 (54% vs. 60% vs. 64%, P<0.001) and 60 months (47% vs. 52% vs. 55%, P<0.001) (Figure 1b). In multivariate analysis, we found that transplant in the 2000–04 period (HR=0.77, 95% C.I. 0.67–0.89) or in the 2005–10 period (HR=0.68, 95% C.I. 0.59–0.79) along with Karnofsky performance score of 80–100 (HR=0.59, 95% CI 0.51–0.70) and chemosensitivity (HR= 0.76, 95% C.I. 0.66–0.87) were associated with lower risk of death. Factors associated with higher risk of death were age 50–65 (HR=1.29 95% 1.13–1.47), age 65–80 (HR=1.45, 1.23–1.72), Durie-Salmon or ISS stage III at diagnosis (HR 1.56, 95% C.I. 1.39–1.76) and more than one prior line of therapy (HR=1.15, 95% C.I. 1.03–1.28). In comparison to patients transplanted in 1995–99, post relapse survival was superior for patients transplanted in 2000–04 and 2005–10 at 24 months (58% vs. 65% vs. 72%, P=0.005 and <0.001 respectively) and 48 months (33% vs. 39% vs. 40%, P=0.023 and 0.033 respectively). The use of maintenance therapy has changed with 27% in 1995–99 receiving planned interferon vs. 23% in 2005–09 receiving planned thalidomide, lenalidomide or bortezomib maintenance. ConclusionsUtilization of upfront AHCT is increasing in the USA, particularly in older patients. Improvement in survival for MM patients seen in population studies results not only from greater utilization of AHCT but also from the improvement in outcomes after AHCT and a significant recent improvement in post-relapse survival. Pre- and post-transplant exposure to novel agents likely contributes to survival. AHCT and novel agents are complementary and should be combined for the optimal management of newly diagnosed MM. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Adaptive immunity in rheumatic diseases – Bystander or pathogenic player?

Rheumatic diseases comprise a wide spectrum of different conditions. Some are caused by disturbances of the adaptive immune system, while defects in innate immune responses have been identified for others. In between are a variety of multifactorial diseases for which the evidence for a causative involvement of the adaptive immune system is still controversial. In these cases, availability of novel drugs that target key players of the adaptive immune system have improved our understanding of the relevance of adaptive immunity to the disease process, but it has also generated unprecedented findings. Rheumatoid arthritis (RA) is a prototypic example of a disease in which the relative contribution of adaptive immunity to disease pathogenesis is incompletely understood. Although numerous markers have been identified that reflect an activated adaptive immune system, several caveats render interpretation of these findings difficult. For one, the very early immune responses initiating disease are likely to take place before an individual is identified as a patient, and are thus difficult to study in the human. Furthermore, increasing evidence points to pathogenetically distinct subgroups within the clinical diagnosis RA, offering the possibility that adaptive immune responses might be relevant to one subgroup but not the other. In addition, many indications for an adaptive immune system involvement are based on associations for which the underlying mechanism is often unknown. Finally, therapeutic interventions targeting the adaptive immune system have generated heterogeneous results. The present review addresses these issues by placing adaptive immune responses in the context of rheumatic diseases, and by reviewing the evidence for a contribution of adaptive immunity to RA.

MRD-Directed Post-Remissional Therapy Dramatically Improves Outcome of Adult Patients with High Risk AML by Implementing Allogeneic Transplant Option

AbstractAbstract 2702Despite improvements in supportive care and wider availability of novel drugs, the outcome of young adult with AML still remains unsatisfactory with a long term survival of 30–40%. Such a dismal outlook is due to the contribution of several reasons. Among these, we believe that risk-category allocation based on the sole definition of pre-treatment biological features (genetics/cytogenetics) may fail to distinguish some high-risk patients which consequently are not timely addressed to intensive treatments. Furthermore, proper treatment of patients with poor prognosis may be hampered by the limited availability of HLA full compatible sibling donors (30% of patients). For the same reasons, some low-risk patients may be misclassified and over-treated (e.g. by giving them allotransplant for the simple reason that they have a full related compatible donor) with an excessive rate of treatment related mortality. Minimal residual disease (MRD) detection promises to be a strong predictive factor in adult AML when measured after the [induction-consolidation] phase and in fact, we have demonstrated (Venditti Blood 2000, Maurillo JCO 2008, Buccisano Blood 2010) that it refines the upfront genetic/cytogenetic risk classification. Thus, we designed a risk-directed pilot study which took into account: 1) an adjusted risk-stratification based on pretreatment genetics/cytogenetics and MRD status at the end of consolidation; and 2) a fast prospective assignment of all high-risk patients to allogeneic stem cell transplantation (alloSCT) in the form of HLA full compatible sibling, matched unrelated donor, umbilical cord blood or full haploidentical donor transplant. By applying this adjusted risk-stratification, we were able to discriminate two discrete category of patients: 1) Low-risk: good and intermediate-risk karyotype (K) that were MRD negative after consolidation (MRDneg good/int-K); and 2) High-risk: adverse-risk K, FLT3-ITD mutated cases and good/intermediate-risk K that were MRD positive after consolidation (MRDpos good/int-K). We also analyzed the outcome of a matched historical cohort of high-risk patients whose post-consolidation treatment was oriented according to a “genetic randomization”: alloSCT for those with a HLA full compatible sibling and autologous stem cell transplant (auSCT) for those lacking this option. Results achieved in this retrospective cohort were compared with those generated in the analysis of the prospective one. The prospective cohort included 25 high risk patients (4 MRDpos good-K, 9 MRDpos int-K, 4 adverse-karyotype and 8 FLT3-ITD). Five of them relapsed early being 20 evaluable for this analysis. The retrospective cohort accounted for 52 high-risk patients (8 MRDpos good-K, 33 MRDpos int-K, 1 adverse-karyotype and 10 FLT3-ITD). Ten of them relapsed early being 42 evaluable for this analysis. Even though the median follow-up of the prospective cohort is still short (18 months) survival estimates were dramatically superior as compared to the retrospective one (DFS 70% vs. 20%, p=0.00047; OS 69% vs. 24%, p=0.046). Accordingly, the prospective cohort also showed a lower relapse rate (20% vs. 52%, p=0.003). The 2 cohorts were well balanced in terms of frequency of FLT3-ITD, adverse-K and treatment related mortality rate, therefore, we believe that the improvement in survival estimates is related to the higher percentage of patients who were able to receive alloSCT. In fact, in the prospective cohort 21/20 (95%) of patients entering the post-consolidation phase underwent alloSCT as compared to 12/42 (30%) in the retrospective cohort (p<0.001). Notably, in the prospective cohort, only 8/21 patients had an HLA full compatible sibling whereas in 6 and 7 an haploidentical or MUD/UCB donor was found, respectively. We conclude that: 1) risk-assessment combining upfront genetics/cytogenetics with post-consolidation MRD status improves identification of high-risk category of patients who share a very poor prognosis if not selectively submitted to alloSCT; 2) the actual risk of disease recurrence should guide alloSCT option according to a “transplant vs no transplant” rather than “donor versus no donor” approach. This implies that once high-risk patients are identified they should receive alloSCT whatever the source of stem cell and, in our experience, this is feasible in the large majority of patients. Disclosures:No relevant conflicts of interest to declare.