ABSTRACT
Cancer patients are at a higher risk to develop severe COVID-19 symptoms after SARS-CoV-2 infection compared to the general population and regularly show an impaired immune response to SARS-CoV-2 vaccination. In our oncological center, 357 patients with hematological and oncological diseases were monitored for neutralizing antibodies from October 2021 over 12 months. All patients had received three anti-SARS-CoV-2 vaccinations with an mRNA-(Comirnaty/BionTech or Spikevax/Moderna) or a vector vaccine (Vakzevria/AstraZeneca or JCOVDEN/Johnson&Johnson). Neutralizing anti-SARS-CoV-2 IgG antibodies in the patients' sera were detected within 3 months before, 3-10 weeks and 5-7 months after the booster vaccination (third vaccination). 112 patients developed a breakthrough SARS-CoV-2 infection during the observation period. High anti-SARS-Cov-2 antibody levels before infection significantly protected against symptomatic Covid-19 disease (p = .003). The median antibody titer in patients with asymptomatic Covid-19 disease was 2080 BAU/ml (binding antibody units per Milliliter) and 765 BAU/ml in symptomatic patients. 98% of the solid tumor patients reached seroconversion after the booster vaccination in comparison to 79% of the hematological patients. High antibody titers of >2080 BAU/ml after the booster vaccination were detected in 61% of the oncological and 34.8% of the hematological patients. 7-10 months after the booster vaccination, the anti-SARS-CoV-2 antibody titer declined to an average of 849 BAU/ml. Considering the heterogenous humoral immune response of cancer patients observed in this study, an individual vaccination strategy based on regular measurement of anti-SARS-CoV-2 antibody levels should be considered in contrast to fixed vaccination intervals.
ABSTRACT
OBJECTIVE: Fluconazole or posaconazole is a standard of care in antifungal prophylaxis for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). However, many patients need to interrupt standard prophylaxis due to intolerability, drug-drug interactions, or toxicity. Micafungin has come to prominence for these patients. However, the optimal biological dose of micafungin stays unclear. METHODS: We retrospectively evaluated the efficacy of micafungin as antifungal prophylaxis in HSCT patients. Micafungin was applied as bridging in patients who were not eligible to receive oral posaconazole. Micafungin was either given at a dose of 100 mg or 50 mg SID. RESULTS: A total of 173 patients received micafungin prophylaxis, 62 in the 100 mg and 111 in the 50 mg dose group. The incidence of probable or proven breakthrough IFDs during the observation period was one in the 100 mg and one in the 50 mg group. Fungal-free survival after 100 days was 98% and 99% (P = .842), and overall survival after 365 days was 60% and 63% (P = .8) respectively. In both groups, micafungin was well tolerated with no grade 3 or 4 toxicities. CONCLUSION: In this retrospective analysis, which was not powered to detect non-inferiority, micafungin is effective and complements posaconazole as fungal prophylaxis in HSCT.
Subject(s)
Antifungal Agents/therapeutic use , Hematopoietic Stem Cell Transplantation , Micafungin/therapeutic use , Mycoses/prevention & control , Adolescent , Adult , Aged , Antifungal Agents/administration & dosage , Female , Humans , Male , Micafungin/administration & dosage , Middle Aged , Retrospective Studies , Transplantation, Homologous , Young AdultABSTRACT
AFM13 is a bispecific, tetravalent chimeric antibody construct (TandAb) designed for the treatment of CD30-expressing malignancies. AFM13 recruits natural killer (NK) cells via binding to CD16A as immune effector cells. In this phase 1 dose-escalation study, 28 patients with heavily pretreated relapsed or refractory Hodgkin lymphoma received AFM13 at doses of 0.01 to 7 mg/kg body weight. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, antitumor activity, and pharmacodynamics. Adverse events were generally mild to moderate. The maximum tolerated dose was not reached. Pharmacokinetics assessment revealed a half-life of up to 19 hours. Three of 26 evaluable patients achieved partial remission (11.5%) and 13 patients achieved stable disease (50%), with an overall disease control rate of 61.5%. AFM13 was also active in brentuximab vedotin-refractory patients. In 13 patients who received doses of ≥1.5 mg/kg AFM13, the overall response rate was 23% and the disease control rate was 77%. AFM13 treatment resulted in a significant NK-cell activation and a decrease of soluble CD30 in peripheral blood. In conclusion, AFM13 represents a well-tolerated, safe, and active targeted immunotherapy of Hodgkin lymphoma. A phase 2 study is currently planned to optimize the dosing schedule in order to further improve the therapeutic efficacy. This phase 1 study was registered at www.clinicaltrials.gov as #NCT01221571.
Subject(s)
Antibodies, Bispecific/administration & dosage , Hodgkin Disease/drug therapy , Immunotherapy/methods , Adult , Aged , Antibodies, Bispecific/pharmacokinetics , Dose-Response Relationship, Drug , Female , Humans , Ki-1 Antigen/immunology , Male , Middle Aged , Receptors, IgG/immunology , Recurrence , Young AdultABSTRACT
Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/MDS) represent severe late effects in patients treated for Hodgkin lymphoma (HL). Because more recent data are scarce, we retrospectively analyzed incidence, outcome, and risk factors for the development of t-AML/MDS after HL. A total of 11,952 patients treated for newly diagnosed HL within German Hodgkin Study Group trials between 1993 and 2009 were considered. At a median follow-up of 72 months, t-AML/MDS was diagnosed in 106/11,952 patients (0.9%). Median time from HL treatment to t-AML/MDS was 31 months. The median age of patients with t-AML/MDS was higher than in the whole patient group (43 vs 34 years, P < .0001). Patients who received 4 or more cycles of BEACOPP(escalated) had an increased risk to develop t-AML/MDS when compared with patients treated with less than 4 cycles of BEACOPP(escalated) or no BEACOPP chemotherapy (1.7% vs 0.7% vs 0.3%, P < .0001). The median overall survival (OS) for all t-AML/MDS patients was 7.2 months. However, t-AML/MDS patients proceeding to allogeneic stem cell transplantation had a significantly better outcome with a median OS not reached after a median follow-up of 41 months (P < .001).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Hematopoietic Stem Cell Transplantation , Hodgkin Disease/drug therapy , Leukemia, Myeloid, Acute/chemically induced , Myelodysplastic Syndromes/chemically induced , Neoplasms, Second Primary , Adolescent , Adult , Aged , Bleomycin/adverse effects , Cyclophosphamide/adverse effects , Doxorubicin/adverse effects , Etoposide/adverse effects , Female , Follow-Up Studies , Germany , Hodgkin Disease/pathology , Humans , Incidence , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Myelodysplastic Syndromes/mortality , Prednisone/adverse effects , Procarbazine/adverse effects , Prognosis , Retrospective Studies , Survival Rate , Vincristine/adverse effects , Young AdultABSTRACT
NKG2D, an activating receptor expressed on NK cells and T cells, is critically involved in tumor immunosurveillance. In this study, we explored the potential therapeutic utility of the NKG2D ligand ULBP2 for the treatment of colon carcinoma. To this end we designed a fusion protein consisting of human ULBP2 and an antibody-derived single chain targeting the tumor carcinoembryonic antigen (CEA). The bispecific recombinant fusion protein re-directed NK cells towards malignant cells by binding to both, tumor cells and NK cells, and triggered NK cell-mediated target cell killing in vitro. Moreover, tumor growth was significantly delayed in a syngeneic colon carcinoma mouse model in response to immunoligand treatment. The anti-tumor activity could be attributed to the stimulation of immune cells with an elevated expression of the activation marker CD69 on NK, T and NKT cells and the infiltration of CD45+ immune cells into the solid tumor. In summary, it was demonstrated that immunoligands provide specific tumor targeting by NK cells and exert anti-tumor activity in vitro and in vivo. This technology represents a novel immunotherapeutic strategy for solid tumors with the potential to be further developed for clinical applications.
Subject(s)
Carcinoembryonic Antigen/immunology , Colonic Neoplasms/immunology , Colonic Neoplasms/therapy , Intercellular Signaling Peptides and Proteins/therapeutic use , NK Cell Lectin-Like Receptor Subfamily K/immunology , Natural Killer T-Cells/immunology , Adoptive Transfer , Animals , Antigens, CD/metabolism , Antigens, Differentiation, T-Lymphocyte/metabolism , Carcinoembryonic Antigen/genetics , Cell Line, Tumor , Disease Models, Animal , GPI-Linked Proteins/therapeutic use , HEK293 Cells , Humans , Immunotherapy, Adoptive , Killer Cells, Natural/immunology , Killer Cells, Natural/transplantation , Lectins, C-Type/metabolism , Leukocyte Common Antigens/metabolism , Mice , Mice, Inbred C57BL , Recombinant Fusion Proteins/therapeutic use , Single-Chain Antibodies/genetics , Single-Chain Antibodies/immunologyABSTRACT
Hodgkin lymphoma (HL) relapsing after allogeneic stem cell transplantation (alloSCT) presents a major clinical challenge. In the present investigation, we evaluated brentuximab vedotin, a CD30-directed Ab-drug conjugate, in 25 HL patients (median age, 32 years; range, 20-56) with recurrent disease after alloSCT (11 unrelated donors). Patients were > 100 days after alloSCT, had no active GVHD, and received a median of 9 (range, 5-19) prior regimens. Nineteen (76%) had refractory disease immediately before enrollment. Patients received 1.2 or 1.8 mg/kg of brentuximab vedotin IV every 3 weeks (median, 8 cycles; range, 1-16). Overall and complete response rates were 50% and 38%, respectively, among 24 evaluable patients. Median time to response was 8.1 weeks, median progression-free survival was 7.8 months, and the median overall survival was not reached. Cough, fatigue, and pyrexia (52% each), nausea and peripheral sensory neuropathy (48% each), and dyspnea (40%) were the most frequent adverse events. The most common adverse events ≥ grade 3 were neutropenia (24%), anemia (20%), thrombocytopenia (16%), and hyperglycemia (12%). Cytomegalovirus was detected in 5 patients (potentially clinically significant in 1). These results support the potential utility of brentuximab vedotin for selected patients with HL relapsing after alloSCT.
Subject(s)
Antineoplastic Agents/administration & dosage , Hematopoietic Stem Cell Transplantation , Hodgkin Disease/drug therapy , Immunoconjugates/administration & dosage , Neoplasm Recurrence, Local/drug therapy , Adult , Antineoplastic Agents/adverse effects , Brentuximab Vedotin , Combined Modality Therapy , Female , Graft vs Host Disease/mortality , Hematopoietic Stem Cell Transplantation/adverse effects , Hodgkin Disease/mortality , Humans , Immunoconjugates/adverse effects , Infections/mortality , Male , Middle Aged , Neoplasm Recurrence, Local/mortality , Prospective Studies , Transplantation, Homologous , Treatment Outcome , Young AdultABSTRACT
The CD30-targeting Ab-drug conjugate brentuximab vedotin (SGN-35) was recently approved for the treatment of relapsed Hodgkin lymphoma and anaplastic large-cell lymphoma by the Food and Drug Administration. In the present study, we report the experience of the German Hodgkin Study Group with brentuximab vedotin as single agent in 45 patients with refractory or relapsed CD30(+) Hodgkin lymphoma who were treated either in a named patient program (n = 34) or in the context of a safety study associated with the registration program of this drug. In these very heavily pretreated patients, an objective response rate of 60%, including 22% complete remissions, could be documented. The median duration of response was 8 months. This retrospective analysis supports the previously reported excellent therapeutic efficacy of brentuximab vedotin in heavily pretreated CD30(+) malignancies.
Subject(s)
Antineoplastic Agents/therapeutic use , Hematologic Neoplasms/drug therapy , Hodgkin Disease/drug therapy , Immunoconjugates/therapeutic use , Ki-1 Antigen/metabolism , Retrospective Studies , Adult , Brentuximab Vedotin , Clinical Trials, Phase I as Topic , Disease-Free Survival , Female , Germany , Humans , Kaplan-Meier Estimate , Male , RecurrenceABSTRACT
Natural killer (NK) cells represent a key component of the innate immune system against cancer. Nevertheless, malignant diseases arise in immunocompetent individuals despite tumor immunosurveillance. Hodgkin lymphoma (HL) is characterized by CD30(+) tumor cells and a massive infiltration of immune effector cells in affected lymph nodes. The latter obviously fail to eliminate the malignant cell population. Here, we tested for functional NK cell defects in HL and suggest an improvement of NK function by therapeutic means. We demonstrate that peripheral NK cells (pNK) from patients with HL fail to eliminate HL cell lines in ex vivo killing assays. Impaired NK cell function correlated with elevated serum levels of soluble ligands for NK cell receptors NKp30 (BAG6/BAT3) and NKG2D (MICA), factors known to constrict NK cell function. In vitro, NK cell cytotoxicity could be restored by an NKG2D/NKp30-independent bispecific antibody construct (CD30xCD16A). It artificially links the tumor receptor CD30 with the cytotoxicity NK cell receptor CD16A. Moreover, we observed that NK cells from patients treated with this construct were generally activated and displayed a restored cytotoxicity against HL target cells. These data suggest that reversible suppression of NK cell activity contributes to immune evasion in HL and can be antagonized therapeutically.
Subject(s)
Antibodies, Bispecific/therapeutic use , Hodgkin Disease/therapy , Killer Cells, Natural/immunology , Antibodies, Bispecific/pharmacology , Cell Line, Tumor , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Humans , ImmunohistochemistryABSTRACT
Antibody engineering and protein design have led to the creation of a new era of targeted anti-inflammatory therapies in rheumatology. Recombinant DNA technologies have enabled the selection and humanization of specific antibody fragments in order to develop therapeutic reagents of any specificity that can be 'armed' to deliver effective anti-inflammatory 'payloads'. Antibodies and antibody-like proteins provide the opportunity to block key soluble mediators of inflammation in their milieu, or alternatively to block intracellular inflammation-triggering pathways by binding to an upstream cell-surface receptor. These designer proteins can be tuned for desired pharmacokinetic and pharmacodynamic effects, and represent tools for specific therapeutic intervention by delivering precisely the required immunosuppressive effect. The extent of desired and undesired effects of a particular biologic therapy, however, can be broader than initially predicted and require careful evaluation during clinical trials. This Review highlights advances in recombinant technologies for the development of novel biologic therapies in rheumatology.
Subject(s)
Antibodies/therapeutic use , Drug Design , Recombinant Proteins/therapeutic use , Rheumatic Diseases/drug therapy , Rheumatology/trends , Animals , Antibodies/chemistry , Humans , Molecular Structure , Protein Engineering , Recombinant Proteins/chemistryABSTRACT
Display technologies are fundamental to the isolation of specific high-affinity binding proteins for diagnostic and therapeutic applications in cancer, neurodegenerative, and infectious diseases as well as autoimmune and inflammatory disorders. Applications extend into the broad field of antibody (Ab) engineering, synthetic enzymes, proteomics, and cell-free protein synthesis. Recently, in vitro display technologies have come to prominence due to the isolation of high-affinity human antibodies by phage display, the development of novel scaffolds for ribosome display, and the discovery of novel protein-protein interactions. In vitro display represents an emerging and innovative technology for the rapid isolation and evolution of high-affinity peptides and proteins. So far, only one clinical drug candidate produced by in vitro display technology has been approved by the FDA for use in humans, but several are in clinical or preclinical testing. This review highlights recent advances in various engineered biopharmaceutical products isolated by in vitro display with a focus on the commercial developments.
Subject(s)
Biopharmaceutics/methods , Combinatorial Chemistry Techniques , Protein Engineering/methods , Protein Interaction MappingABSTRACT
Engineered antibodies have become an invaluable source of biopharmaceuticals against a wide range of diseases. About 200 antibody-based biologicals have been tested in clinical trials. Single chain variable fragments of antibodies (scFvs) provide binding specificity and offer an increased ease of in vitro display selection. Here, we present the generation of a human scFv library from peripheral blood lymphocyte RNA of a patient with relapsed T-cell non-Hodgkin lymphoma (T-NHL) who experienced a rare case of "spontaneous" remission. Antibodies against human T-cell antigen CD28, a co-stimulatory protein that influences the immune response by amplification of the transcriptional effects of T-cell receptors, might have contributed to the patient's remission. The scFv library was panned against CD28 using ribosome display and further subjected to affinity maturation. Isolated scFv were assessed for binding specificity and affinity and may provide the basis for the development of novel immunotherapeutic strategies. This work demonstrates the selection of a fully human antibody fragment from a patient-derived gene pool by in vitro ribosome display technology.
Subject(s)
Antibodies, Monoclonal/immunology , CD28 Antigens/immunology , Immunoglobulin Fc Fragments/immunology , Lymphoma, Non-Hodgkin/immunology , Peptide Library , Receptors, Antigen, T-Cell/immunology , Ribosomes/immunology , CD28 Antigens/isolation & purification , Humans , Immunoassay/methods , Lymphoma, Non-Hodgkin/pathologyABSTRACT
IVC (in vitro compartmentalization) provides a complete cell-free approach for the production of novel targeted proteins. IVC uses aqueous droplets, which contain DNA and components for protein production, within water-in-oil emulsions. Recent advances in the composition and formation, as well as the detection, sorting and recovery, of the droplets enable the evolution of the encoded protein. Furthermore, IVC technology permits the step-wise addition of reagents into the droplets, making them suitable for high-throughput applications - where synthetic enzymes with substrate specificity are selected for catalytic activity, binding and regulation. In the broad field of in vitro display, developments such as the incorporation of unnatural amino acids and the production of cell toxic proteins expand the diverse spectrum of future applications for IVC.
Subject(s)
Cell-Free System/chemistry , DNA/chemistry , Directed Molecular Evolution , Drug Design , Emulsions/chemistry , Protein Engineering/methods , Proteins/chemical synthesis , Biomimetics , Cell CompartmentationABSTRACT
Engineered antibodies and their fragments are invaluable tools for a vast range of biotechnological and pharmaceutical applications. However, they are facing increasing competition from a new generation of protein display scaffolds, specifically selected for binding virtually any target. Some of them have already entered clinical trials. Most of these nonimmunoglobulin proteins are involved in natural binding events and have amazingly diverse origins, frameworks, and functions, including even intrinsic enzyme activity. In many respects, they are superior over antibody-derived affinity molecules and offer an ever-extending arsenal of tools for, e.g., affinity purification, protein microarray technology, bioimaging, enzyme inhibition, and potential drug delivery. As excellent supporting frameworks for the presentation of polypeptide libraries, they can be subjected to powerful in vitro or in vivo selection and evolution strategies, enabling the isolation of high-affinity binding reagents. This article reviews the generation of these novel binding reagents, describing validated and advanced alternative scaffolds as well as the most recent nonimmunoglobulin libraries. Characteristics of these protein scaffolds in terms of structural stability, tolerance to multiple substitutions, ease of expression, and subsequent applications as specific targeting molecules are discussed. Furthermore, this review shows the close linkage between these novel protein tools and the constantly developing display, selection, and evolution strategies using phage display, ribosome display, mRNA display, cell surface display, or IVC (in vitro compartmentalization). Here, we predict the important role of these novel binding reagents as a toolkit for biotechnological and biomedical applications.
Subject(s)
Peptide Library , Proteins/chemistry , Proteins/metabolism , Animals , Combinatorial Chemistry Techniques , Humans , Protein Binding/physiology , Protein Interaction Mapping , Proteins/isolation & purificationABSTRACT
BACKGROUND: While recent data show that crizotinib is highly effective in patients with ROS1 rearrangement, few data is available about the prognostic impact, the predictive value for different treatments, and the genetic heterogeneity of ROS1-positive patients. PATIENTS AND METHODS: 1137 patients with adenocarcinoma of the lung were analyzed regarding their ROS1 status. In positive cases, next-generation sequencing (NGS) was performed. Clinical characteristics, treatments and outcome of these patients were assessed. Overall survival (OS) was compared with genetically defined subgroups of ROS1-negative patients. RESULTS: 19 patients of 1035 evaluable (1.8%) had ROS1-rearrangement. The median OS has not been reached. Stage IV patients with ROS1-rearrangement had the best OS of all subgroups (36.7 months, p < 0.001). 9 of 14 (64.2%) patients had at least one response to chemotherapy. Estimated mean OS for patients receiving chemotherapy and crizotinib was 5.3 years. Ten patients with ROS1-rearrangement (52.6%) harbored additional aberrations. CONCLUSION: ROS1-rearangement is not only a predictive marker for response to crizotinib, but also seems to be the one of the best prognostic molecular markers in NSCLC reported so far. In stage IV patients, response to chemotherapy was remarkable high and overall survival was significantly better compared to other subgroups including EGFR-mutated and ALK-fusion-positive NSCLC.
Subject(s)
Adenocarcinoma/genetics , Lung Neoplasms/genetics , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/enzymology , Adenocarcinoma of Lung , Adult , Aged , Female , Gene Rearrangement , Genetic Variation , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , Male , Middle Aged , Prognosis , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Survival Analysis , Treatment OutcomeABSTRACT
We report the results of rituximab monotherapy in 21 patients with refractory or relapsed aggressive non Hodgkin s lymphoma (NHL). The majority of the patients (16/21) were refractory to conventional treatment and not eligible for high dose chemotherapy. Responses (1 complete and 6 partial) were achieved in some of these patients and their median overall survival was 8 months.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Adolescent , Adult , Aged , Antibodies, Monoclonal, Murine-Derived , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , RituximabABSTRACT
Isolation of cell-surface specific antibodies prerequisites the functional expressing of antigens on intact cells, which are maintained routinely by cell culturing. However, long-term culturing of tumor cells could alter their antigen expression patterns and stable fixation of whole cells is not guaranteed on plastic surfaces during stringent screening procedures. We prepared functional breast cancer cell-membrane fractions that express surface molecules in their native conformation. Specific binding phages were isolated from phage antibody libraries constructed from the spleen messenger RNA of mice immunized with breast cancer cell-membrane fractions. After negative selection on non-mammary carcinoma cells and four rounds of positive selection on breast carcinoma cell lines, phage antibodies were enriched that bound specifically to breast cancer cell lines as confirmed by phage enzyme linked immunosorbent assay (ELISA) using 96-well plates coated with breast cancer cell membranes. The isolated phage antibodies were highly specific for the breast cancer cell line 8701-BC but not on other carcinoma such as the Hodgkin-derived cell line L540Cy as demonstrated by ELISA and flow cytometry. This report describes a rapid and more versatile method for isolating antibody fragments compared to whole cell screening procedures. One single membrane preparation can be stored for at least 15 months at -80 degrees C and used to immunize mice or for screening of antibody libraries. The selection and screening strategy used should be generally applicable to identify novel cell-surface antigens and their corresponding antibodies.
Subject(s)
Immunoglobulin Fragments/immunology , Immunoglobulin Variable Region/immunology , Peptide Library , Vaccination , Animals , Antibody Formation/immunology , Breast Neoplasms/immunology , Female , Flow Cytometry , Humans , Mice , Tumor Cells, CulturedABSTRACT
Targeted treatment of cancer with monoclonal antibodies has added to the beneficial outcome of patients. In an attempt to improve anti-tumor activity of monoclonal antibodies, multi-specific antibodies have entered the research arena. To date, only a few multi-specific constructs have entered phase III clinical trials, in contrast to classical monoclonal antibodies, which are the standard first-line therapy in several tumor entities. In this review, we will assess selected multi-specific antibodies in pre-clinical and clinical development that may be new treatment options for cancer patients in the very near future. We will further evaluate therapy modalities including the timely distribution or the combination of various therapeutic approaches and assess the potential role of multi-specific antibodies in cancer treatment.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Immunotherapy/methods , Neoplasms/therapy , Animals , Antibodies, Monoclonal/pharmacology , Clinical Trials as Topic , Humans , Neoplasms/immunologyABSTRACT
Brentuximab vedotin has emerged as a possible treatment option in patients suffering from relapsed and refractory Hodgkin lymphoma (HL). We investigated the role of 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for monitoring treatment response to brentuximab vedotin in patients with relapsed and refractory HL. Twelve consecutive, heavily pretreated patients with relapsed and refractory HL treated with brentuximab vedotin were available for analysis. FDG-PET/CT studies were performed early during treatment after a median of 3 cycles (range, 2-5 cycles), and were analyzed visually using a 5-point scale (5PS) and quantitatively using the maximum standardized uptake value (SUV(max)) and the three-dimensional (3D) isocontour at 50% of the maximum pixel value (SUV(50)) in the hottest single lesion. The median follow-up in our study cohort was 16 months (range, 5-30 months). The median progression-free survival (PFS) was 12.5 months and PFS at 12 months was 58%. Patients treated with brentuximab vedotin and negative interim FDG-PET/CT assessed by visual or quantitative analysis demonstrated a significantly prolonged PFS compared to patients with positive interim FDG-PET/CT. The 1-year PFS was 100% in patients with negative interim FDG-PET/CT assessed by visual analysis, whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 38% (p = 0.033). The 1-year PFS was 75% in patients with negative interim FDG-PET/CT assessed by quantitative analysis using the SUV(50), whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 25% (p = 0.017) Interim FDG-PET/CT might be a suitable diagnostic approach to predict response to brentuximab vedotin in relapsed and refractory HL.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fluorodeoxyglucose F18 , Hodgkin Disease/diagnosis , Hodgkin Disease/drug therapy , Positron-Emission Tomography , Tomography, X-Ray Computed , Adolescent , Adult , Brentuximab Vedotin , Female , Hematopoietic Stem Cell Transplantation , Hodgkin Disease/mortality , Humans , Immunoconjugates/administration & dosage , Male , Middle Aged , Prognosis , Recurrence , Retrospective Studies , Transplantation, Autologous , Transplantation, Homologous , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: In acute myeloid leukemia (AML), the MDS1 and EVI1 complex locus - MECOM, also known as the ecotropic virus integration site 1 - EVI1, located in band 3q26, can be rearranged with a variety of partner chromosomes and partner genes. Here we report on a 57-year-old female with AML who presented with the rare translocation t(3;10)(q26;q21) involving the MECOM gene. Our aim was to identify the fusion partner on chromosome 10q21 and to characterize the precise nucleotide sequence of the chromosomal breakpoint. METHODS: Cytogenetic and molecular-cytogenetic techniques, chromosome microdissection, next generation sequencing, long-range PCR and direct Sanger sequencing were used to map the chromosomal translocation. RESULTS: Using a combination of cytogenetic and molecular approaches, we mapped the t(3;10)(q26;q21) to the single nucleotide level, revealing a fusion of the MECOM gene (3q26.2) and C10orf107 (10q21.2). CONCLUSIONS: The approach described here opens up new possibilities in characterizing acquired as well as congenital chromosomal aberrations. In addition, DNA sequences of chromosomal breakpoints may be a useful tool for unique molecular minimal residual disease target identification in acute leukemia patients.
ABSTRACT
INTRODUCTION: Rheumatoid arthritis (RA) is a systemic disease and the most prevalent of all autoimmune disorders. Here we review recent advances in the development and availability of biologic agents with a focus on monoclonal antibody or smaller formats of targeted engineered therapeutics including novel, non-antibody-based therapeutics. AREAS COVERED: Today an array of biologics blocking either proinflammatory cytokines or lymphocyte activation/survival are available that enable a substantial improvement over conventional disease-modifying antirheumatic drugs (DMARDs). We review the engineering process of antibody-based biologics, their preclinical and clinical application, and current efforts to treat RA by interfering with B-cell function (notable targets covered are CD20, CD38, B-cell activating factor, transmembrane activator and calcium-modulating and cyclophilin interactor), with T-cell function (CD3, CD4, CD28), with bone erosion (RANKL), and with cytokines or growth factors (tumor necrosis factor, interleukin-1 [IL-1], IL-6, IL-17, VEGF). Future treatment choices might encompass the blockade or modulation of danger-associated molecular patterns such as HMGB1, pattern recognition receptors, messenger RNAs or noncoding RNAs, histone acetylation, and inflammasome components. EXPERT OPINION: Although current therapies can reduce the signs and symptoms of RA for many patients, the quest for a cure (or a more complete blockade of the structural damage) in RA is still ongoing and will need treatment approaches, which are not exclusively confined to blocking a particular cytokine, receptor, or autoreactive B or T cell involved in disease progression. To this end exciting treatment alternatives and drug targets are on the horizon that may become available to patients in the future.