New Therapies Research Articles

Relinf Registry-Based Analysis Shows Overall Survival Improvement with New Therapies for Relapsed or Refractory Large B-Cell Lymphoma: A Study from the Geltamo Group

Introduction: Several new therapeutic agents have been approved in recent years for the treatment of relapsed/refractory (R/R) Large B cell lymphoma (LBCL) (diffuse large B cell lymphoma [DLBCL] and high-grade B cell lymphomas [HGBCL]), such as new monoclonal antibodies (MA), bispecific antibodies (BA) and CAR-T cell therapy. The objective of our study was to evaluate the epidemiology and the use of these new therapies (NT) in Spain and to analyze the impact on survival. Methods: We present a multicenter retrospective study based on the GELTAMO (Spanish lymphoma group) RELINF platform. From 60 centers actively registering on the platform, 17 university hospitals accepted to participate, and 5 of them were CAR-T therapy providers. Participating centers completed a short questionnaire on disease relapse and the use of new drugs in their registered patients. The histologies included were DLBCL, HGBCL not otherwise specified (NOS), and double hit (DH). Results: From 3270 patients with ABCL registered, 2853 patients were included in the present analysis; 738 patients experienced R/R disease, 492 (67%) were refractory or had early relapse (up to 1 year from the first line), and 246 (33%) late relapses, half of them (54%) during the second year. In both early and late relapse groups, about a third of patients were older than 80 years. Early relapses were significantly higher in double/triple hit HGL (34%) and T-cell-rich DLBCL (29%) compared to DLBCL or HGL NOS (16%) (p<0.001). The median number of lines among relapsed patients was 2 (1-10). 236 patients received NT, with the following distribution: CAR-T, n=144, BA, n=68, polatuzumab-based, n=92, and tafasitamab-lenalidomide, n=14. Most patients who received only 2 lines (n=376) were treated with conventional treatments, although 11 patients (3%) received CAR-T, 11 (3%) BM, 15 (4%) polatuzumab-based, and 5 (1%) tafasitamab-lenalidomide. Among 354 patients who received more than 2 lines of treatment, 130 (37%) received CAR-T cell therapy, 75 (21%) polatuzumab, 9 (2%) tafasitamab-lenalidomide, 55 (15%) BA, and 160 (45%) of these patients did not receive any NT. In the overall series, with a median follow-up of 49 months (95%CI: 47-51), median progression-free survival (PFS) was 54 months (95%CI: 48-61), and median overall survival (OS) was 82 months (95%CI: 74-90). Considering only the R/R patients, with a median follow-up of 40 months since the first relapse, the median OS2 (mOS2) was 16.8 (IC95%: 14.5-19) months. Survival analysis is shown in Table 1. The mOS2 for the early relapse group was 13.5 (95%CI: 11.5-15.5) months vs 31.1 (95%CI: 22.5-39.8) months for late relapses. Median OS2 for relapsed patients treated with NT was 31.1 months (95%CI: 22.5-39.7) compared with 11.9 months (95%CI: 9.2-14.6) for the group of standard treatment (p<0.001)) (Figure 1). Interestingly, OS2 was longer in patients treated in CAR-T provider centers than in non-CAR-T centers, in both early relapse group (mOS: 18.3 months [95%CI: 14.1-22.5] vs. 8.6 months [95%CI: 6.2-11]: p<0.001) and late relapse group (37.9 months [95%CI: 24.2-51.5] vs. 18.7 months [95%CI: 13.9-23.4], p=0.001). This difference was not found when we evaluated high complexity institutions (those that perform allogeneic transplant) vs. those that are no. In multivariate analysis, early relapse (HR 1.68, 95%CI 1.37-2.06, p<0.001), age over 65 years (HR 1.91, 95%CI: 1.23-2.98, p=0.004), treatment with CAR-T cell therapy (HR 0.68, 95%CI: 0.51-0.90, p=0.007) and treatment in a CAR-T cell provider center (HR 0.7, 95%CI: 0.58-0.85, p<0.001) independently influenced OS2. Conclusions: Our real-world analysis confirms the negative impact on OS of factors like age or early relapse in patients with R/R LBCL. According to our results, the introduction in recent years of NT has markedly improved OS, especially CAR-T cell therapy.

Impact on Survival of the Introduction of New Therapies for Relapsed-Refractory Aggressive B-Cell Lymphoma, Based on the Relinf Registry: A Study By the Spanish Geltamo Group

Introduction. Treatment of relapsed-refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBCL) has changed substantially in recent years, due to the incorporation (in a commercial setting or in the context of clinical trials) of new therapeutic options such as new monoclonal antibodies (MA), antibody-drug conjugates (ADC), bispecific antibodies (BA) or CAR-T cell therapy. The main objective of our study was to evaluate the frequency of use of these new therapies (NT) in Spain, and their impact on overall survival (OS). Methods. This is a multicenter retrospective study. Patients with DLBCL and HGBCL were identified from the RELINF platform, where GELTAMO investigators register all patients with lymphoma diagnosed in each center from January 2014. Finally, 15 centers (2 out of 15 CAR-T cell providers) accepted to participate in the study, who were asked to complete additional information related with relapse and NT. Patients were divided in 2 cohorts according to date of documentation of relapse / refractory disease: 2014-2017 (first period) and 2018-2021 (second period). The use of NT in both periods and their impact on OS were analyzed. Results We included 2162 patients in the analysis, 1891 DLBCL (51% germinal centre B-cell phenotype, 41% activated B-cell phenotype, 8% indeterminate), and 271 HGBCL (45% of them double/triple hit). Median age was 69 y/o, 72% were ≥ 70 y/o at diagnosis, and 49.8% were female. Four hundred and ninety four patients had relapsed or refractory disease, 183 in the 1st period, and 311 in the 2nd period. Median number of lines for r/r patients was 3 (2-7). NT were used in 353 patients, 30 in the 1st period and 111 in the 2nd period. New MA were used in 88 (28%) patients, being polatuzumab vedotin the most frequently used antibody (47, 54%) (tafasitamab 7, loncastuximab 5, brentuximab 11, others 10), and BA in 28 (9%), all of them within clinical trials. Twenty patients received NT in 1st relapse, 14 MA and 7 BA. From 211 patients who received > 2 lines of treatment, 128 were in the 2nd period, and 60 (47%) of them received CAR-T cell therapy, whereas 39 (30%) of these patients did not receive any NT. Five-year progression free survival (PFS) for the entire cohort was 71% (95% CI 69-74), and median overall survival (OS) was 90 months (95% CI: 76-NR). Median OS for r/r patients was 22 months (95% CI: 19 - 26), and for the group of patients who received > 2 lines was 23 months (95% CI; 19-27). With a median follow up of 25 months (50 months for the 1st period and 20 months for the 2nd period) OS was superior for patients relapsed in the 2nd period (26 months [95% CI: 22-38]), compared with those relapsed in the 1st period (18 months [IC: 16-22], p= 0.016) (Figure 1, A). Median OS since first relapse for patients pre-treated with > 2 lines who received CAR-T cells was 31 months vs 11 months for patients who did not receive CART (p= 0.002) (Figure 1, B). Conclusion: The OS of patients with r/r DLBCL and HGBCL has improved in recent years, probably in relation to the incorporation of NT, although the use of these NT in Spain has been lower than expected for this population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

REAL WORLD MULTIPLE MYELOMA REGISTRY FROM JORDAN, A DEVELOPING COUNTRY.

Background and objectiveScanty reports from the middle east and north Africa (MENA) region have been published on multiple myeloma (MM). Multiple myeloma registry has been established at Jordan University Hospital (JUH) since 2009. Our work aims to review this Multiple Myeloma registry with data from 113 patients diagnosed with MM at JUH and analyze their management and course.MethodsThis is a non-interventional and retrospective analysis of the MM registry from 2009-to 2016 involving 113 patients at JUH. Statistical analysis was done using the Statistical Package for the Social Sciences (SPSS). Overall survival (OS) was analyzed with the Kaplan-Meier method. P-value was considered significant if it was (<0.05).ResultsWe found no gender difference in this registry. The median age is 62 years. Most patients are in ISS stage II and III (36.28% for each). Immunoglobulin type G Kappa is the dominant subtype. Bone pain is the most common presenting symptom. The most common laboratory finding is anemia (45.6%). Most of our patients (85.2%) had received thalidomide and dexamethasone, while only 14.8% received bortezomib, thalidomide, and dexamethasone. Our patients' mean overall survival (OS) was 74 months, and the median survival was 38 months. For ISS stages I, II, and III, median OS was 96, 46, and 16 months.ConclusionMM in a developing country presents a challenging disease compared to industrial countries in both epidemiology and management. An improved road map in the care of MM in these countries is needed. The use of three or four drugs combination upfront is warranted. However, this is limited because of the high cost of these drugs. We expect the following decade to show better survival and quality of life for MM patients once these drugs are widely used.

PCN371 A REVIEW OF SWEDISH HEALTH TECHNOLOGY ASSESSMENTS BASED ON INDIRECT COMPARISONS OF HOSPITAL DRUGS IN ONCOLOGY

Randomized controlled trials (RCTs) with head-to-head comparisons remain the gold standard for demonstrating relative treatment efficacy and for use in cost-effectiveness models (CEMs), which serve as an important part of health technology assessment (HTA) submissions in Sweden. However, such comparative evidence is not always available. Recent Swedish HTA submissions were thus reviewed to understand the acceptability of different types of comparative evidence with a focus on oncology. HTAs of hospital drugs subject to national managed introduction by the New Therapy (NT) Council in Sweden were identified. The methodology used in the accompanying CEMs and the NT Council decisions were assessed. The Dental and Pharmaceutical Benefits Agency (TLV) website was searched for published HTAs of hospital drugs in oncology between January 2015 and April 2019. HTAs in which CEMs included comparative efficacy estimates other than head-to-head clinical trials were reviewed, including the method(s) used, the corresponding comments on the method(s) and the NT Council recommendations associated with the HTA. Of the 32 HTAs identified, 23 were based on direct treatment comparisons, while nine were based on indirect comparisons. Of these, three utilized a network meta-analysis, with one positive, one restricted and one negative recommendation. The other six used alternative methods (e.g. matching-adjusted indirect comparison, naïve indirect comparison). Of these, four recommendations were positive, one was restricted, and one was negative. Of the 23 HTAs that were based on direct comparisons, 13 of the recommendations were positive, four were restricted, five were negative and one had no published recommendation. Although HTA evidence based on indirect comparisons are generally considered by TLV as having a high level of uncertainty, some still result in positive recommendations. In general, products with cost per quality-adjusted life year below one million SEK per TLV assessment were likely to receive positive recommendations.

Animal models of infantile spasms

Infantile spasms(IS), an age-dependent epileptic encephalopathy seen in infancy, is characterized by unique electro-clinical features and pharmacological reactions.Most conventional antiepileptic drugs are ineffective for IS.Hormonal treatment(including adrenocorticotropic hormone ACTH, and oral steroids)and vigabatrin(VGB)now widely used as first-line treatments for IS, have certain effects on IS, but the effect of these two options on long-term outcomes has not been established.The etiology of IS is variable.It is unclear that how a wide variety of conditions result a common phenotype.Ideal animal models can help to understand pathogenesis of disease and explore new therapies to improve the ultimate outcome.This review summarizes the research status of animal models of IS. Key words: Infantile spasm; Animal model; Pathogenesis; New drug therapy

PIN77 - A Cost-Effectiveness Evaluation for a New Therapy in HIV Treatment

PIN77 A Cost-EffECtIvENEss EvAluAtIoN for A NEw thErAPy IN hIv trEAtmENt Malhan S.1, Kockaya G.2, Elbir Zengin T.2, Dalgic C.2, Yenilmez F.B.3, Cerci P.3, Oksuz E.1, Tayfun K.2, Unal S.3 1Baskent University, Ankara, Turkey, 2Gilead Science, Istanbul, Turkey, 3Hacettepe University, Ankara, Turkey Objectives: Economical evaluation of Stribild in Turkey, which is a single tablet regimen indicated for the treatment of HIV-1 infection in adults aged 18 years and over who are antiretroviral treatment naive or are infected with HIV-1 without known mutations associated with resistance to any of the three antiretroviral agents in it. MethOds: STRIBILDTM was compared with various treatment options; tenofovir DF+emtricitabine+efavirenz (FTC/TDF+EFV), tenofovir DF+emtricitabine+ ritonavir+lopinavir (FTC/TDF+LPV/r), tenofovirDF+emtricitabine+nevirapine (FTC/ TDF+NVP), tenofovir DF+emtricitabine+darunavir (FTC/TDF+DRV+r), tenofovir DF+emtricitabine+raltegravir (FTC/TDF+RAL), lamivudine+zidovudine+efavirenz (3TC/AZT+EFV), lamivudine+zidovudine+ritonavir+lopinavir (3TC/AZ+LPV/r), lam ivudine+zidovudine+nevirapine (3TC/AZT+NVP). The adherence rates were calculated from the increase rate in CD4 cell count and the risk of hospitalization as the effectiveness values. The data were taken from patient files from Hacettepe University that consists of 252 patients and 12 year follow-ups with an outpatient clinic, interventions, laboratory and imaging tests, medication usage, side effects, comorbidity’s diseases and their treatments and complications. The costs of treatment of diseases were calculated by cost of disease methodology. Average annual cost per patient is calculated for health care technologies. Health technology effectiveness values are found from the literature review. Incremental cost-effectiveness ratio (ICER) was used for the comparison. Results: According to comparison of rate of compliance to treatment, STRIBILDTM was cost effective against 3TC/AZT+EFV (2157.2 TL), FTC/TDF+LPV/r (612.7 TL), FTC/TDF+NVP (951.9 TL), FTC/TDF+DRV+r (544.28 TL) and cost saving aganist FTC/TDF+RAL (-166,22 TL). According to the rate of risk of hospitalization, STRIBILDTM was cost effective against 3TC/AZT+EFV (517.7 TL), FTC/TDF+LPV/r (318.6 TL), FTC/TDF+NVP (495 TL), FTC/TDF+DRV+r (283 TL), 3TC/ AZT+EFV (632,4 TL), 3TC/AZ+LPV/r (425.6 TL), 3TC/AZT+NVP (591.2 TL). According to the increase rate in CD4 cell count and over 95% of compliance rate, STRIBILDTM was cost effective against FTC/TDF+EFV (392.2 TL) and cost saving against FTC/TDF+RAL (-308.7 TL), respectively. cOnclusiOns: HIV is a life-threatening disease with in terms of major public health problem globally.. In this study, STRs in comparison of combination treatment strategies, has higher compliance rates, better outcomes and lower health care costs.

COX‐LOX INHIBITION: CURRENT EVIDENCE FOR AN EMERGING NEW THERAPY

SUMMARYSafe and effective drug treatment is an important objective of all doctors. In the treatment of arthritis, non‐steroidal anti‐inflammatory drugs offer effective treatment but safety is significantly limited, largely due to gastrointestinal toxicity. Attention has recently focused on exploiting increased knowledge of metabolism of arachidonic acid to allow the development of safer anti‐inflammatory drugs. Dual inhibitors of cyclo‐oxygenase and lipoxygenase are planned. These drugs may inhibit formation of both prostaglandins and leukotrienes. This review outlines the salient features of cyclo‐oxygenase and lipoxygenase metabolism of arachidonic acid. The role of the eicosanoids in mediating inflammation and gastrointestinal integrity is delineated. Evidence is presented regarding action of licofelone, one COX/LOX inhibitor that is currently in advanced stages of clinical trials. This review examines the hypothesis that licofelone is an effective anti‐inflammatory agent that does not cause peptic damage.

Growth Factors Promote High-Dose Chemotherapy

NEW THERAPY that endows the immune and hematopoietic systems with impressive resilience following chemotherapy has allowed oncologists to surpass the "bone marrow barrier," the dose-limiting factor that has historically determined the maximum chemotherapeutic dose. The therapy calls for patients to be given hematopoietic growth factors in combination with autologous peripheral blood progenitor immune cells immediately following high-dose chemotherapy. Advances in leukapheresis now allow progenitor cells, which develop into the entire spectrum of blood cells, to be drawn from the patient's peripheral blood prior to high-dose chemotherapy. Previously, these cells had to be removed from the bone marrow to achieve the quantities necessary to overcome myelosuppression. In clinical trials that determined the safety and feasibility of the protocol, patients receiving growth factors demonstrated faster neutrophil and platelet recovery than controls who received no growth factors. They also experienced fewer episodes of fever and infection, and fewer days in the hospital. Oncologists

The Empirical Basis for the Discovery of New Therapies

THE EMPIRICAL BASIS FOR THE DISCOVERY OF NEW THERAPIES JAMES S. GOODWIN* It is commonly held that a major change in the search for new therapies took place some time in the early decades of this century. Therapies used before that time, whether efficacious or not, are considered to have been derived on empirical grounds, while many therapies introduced in the past half-century are seen as the product of scientific reasoning. It is said that we have now entered the age of "rational drug design" [1, 2]. Indeed, "empirical" has become something of a dirty word in pharmacology [3]. Such a broad dichotomy as empirical versus scientific or rational does have some validity for understanding how therapies are introduced, but the usefulness of this distinction is limited. Empirical is defined as "relying or based solely on experiment and observation rather than theory" [4]. In this article, I will argue that the discovery of new therapies has always been and will continue to be an empirical science. The vast majority of efficacious ancient and modern drugs were discovered and initially used without any understanding of how they work. To the extent that we deny or ignore that reality in our future attempts to discover new therapies, we risk fostering a system wherein potentially efficacious treatments may be overlooked while inefficacious therapies are accepted [5]. I shall propose five patterns by which we understand how new therapies are discovered. These patterns apply to both ancient and modern times. Each of the five ways has resulted in important advances in therapeutics , and each is still a valuable path for the discovery of new therapies . Two major goals in the search for new therapies are to avoid The preparation of this manuscript was supported by a grant from the Dreyfus Medical Foundation. The author thanks Drs. Shirley Murphy, Tom Anderson, Barry Blackwell, Daniel McCarty, Shrinivas Murthy, Frederick Goodwin, and Jean Goodwin for their comments and suggestions, and welcomes suggestions or corrections from interested readers. *Department of Medicine, University of Wisconsin Medical School, Milwaukee Clinical Campus, 950 North 12th Street, Milwaukee, Wisconsin 53233.© 1991 by The University of Chicago. All rights reserved. 0031-5982/92/3501-0750$1.00 20 James S. Goodwin ¦ Discovery ofNew Therapies accepting useless treatments, or placebos, and to avoid rejecting potentially efficacious treatments, a process we have previously termed the tomato effect [5]. A third goal in the search for new therapies, to adequately access toxicities related to the treatments, does not differ among the five paths of new drug discovery and will not be considered here. Each of the five ways of discovering new therapies has different strengths and weaknesses with respect to accepting useless treatments and missing useful ones. Five Ways New Therapies Are Discovered The classification proposed is arbitrary, and there are many examples of overlap, where the discovery process for a given therapy fits into more than one category. There are surely other ways of categorizing the discovery of new therapies. This represents one attempt at ordering that process. New therapies can be seen as resulting from one or more of the following processes: 1.An unpremeditated or unexpected finding. 2.Mass screening. 3.Copycat or me-too variation on existing drugs or treatment. 4.Understanding how a previously discovered, efficacious drug works. 5.Breakthrough in understanding a physiologic or pathophysiologic process. As mentioned earlier, all of these have contributed important new therapies; none should be disparaged. I hope to show that overreliance on any one of these processes to the detriment of the others results in a less than optimal atmosphere for the discovery of new therapeutics. In particular, a bias against the "empirical" methods of drug discovery would be inappropriate. UNPREMEDITATED FINDINGS The word "serendipity" is often used to describe unpremeditated findings, but the derivation of that word does not reflect the creativity and rigor required to turn unpremeditated findings into scientific discovery . Pasteur's comment that chance favors only the prepared mind is often quoted but perhaps not fully appreciated—most people leave out the word "only." Unpremeditated findings most often contribute to the discovery of new therapies in the context of ongoing rigorous scientific investigation [6]. It is important to remember...

A NEW THERAPY IN MYASTHENIA GRAVIS

Acta Psychiatrica ScandinavicaVolume 25, Issue s59 p. 122-132 A NEW THERAPY IN MYASTHENIA GRAVIS A preliminary report of 9 cases treated with methylene blue in small dosages. Tore Patrick Störtebecker M. D., Tore Patrick Störtebecker M. D. Oslo, Norway.Search for more papers by this author Tore Patrick Störtebecker M. D., Tore Patrick Störtebecker M. D. Oslo, Norway.Search for more papers by this author First published: April 1950 https://doi.org/10.1111/j.1600-0447.1950.tb09411.xCitations: 2AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume25, Issues59April 1950Pages 122-132 RelatedInformation

NEW THERAPY OF OPHIDIASIS.

Australian Journal of Experimental Biology and Medical ScienceVolume 26, Issue 2 p. 153-162 Original Article NEW THERAPY OF OPHIDIASIS. ER Trethewie, ER Trethewie Institute of Medical and Veterinary Science, Adelaide, and the Department of Experimental Medicine, University of AdelaideSearch for more papers by this authorAllan J Day, Allan J Day Institute of Medical and Veterinary Science, Adelaide, and the Department of Experimental Medicine, University of Adelaide This work was aided by a grant from the National Health and Medical Research Council.Search for more papers by this author ER Trethewie, ER Trethewie Institute of Medical and Veterinary Science, Adelaide, and the Department of Experimental Medicine, University of AdelaideSearch for more papers by this authorAllan J Day, Allan J Day Institute of Medical and Veterinary Science, Adelaide, and the Department of Experimental Medicine, University of Adelaide This work was aided by a grant from the National Health and Medical Research Council.Search for more papers by this author First published: 01 March 1948 https://doi.org/10.1038/icb.1948.15Citations: 10 AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume26, Issue2March 1948Pages 153-162 Journal of the Australian and New Zealand Society for Immunology RelatedInformation