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- Johns Hopkins School of Medicine (3)
- Center for Interdisciplinary Clinical Research, Würzburg University, Würzburg, Germany (2)
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- Department of Laboratory Medicine and Medicine Huddinge, Karolinska Institutet and University Hospital, Stockholm, Sweden (1)
- Department of Medicine A, University Hospital of Münster, Münster, Germany (1)
- Early Clinical Trial Unit, Comprehensive Cancer Center Mainfranken (1)
- Experimentelle Tumorimmunologie, Frauenklinik, Universität Würzburg (1)
- Interdisciplinary Center for Clinical Research (IZKF), Würzburg, Germany (1)
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- N-2030-2015 (1)
Background
A significant number of oncological patients are heavily burdened by psychosocial stress. Doctors recommending or referring their patients to psycho-oncologists in the course of routine consultations can positively influence psycho-oncological care. The aim of this study was to analyze the frequency and predictors of such recommendations and to examine the use of these services by patients.
Methods
4,020 cancer patients (mean age 58 years; 51% women) were evaluated in a multicenter, cross-sectional study in Germany. Data was gathered about doctors’ referral practices, patients’ utilization of psycho-oncological care services, and disease-related symptoms. The PHQ-9 depression scale and the GAD-7 anxiety scale were used to measure psychological burden. Descriptive data analysis was conducted on the basis of subgroup comparisons and multivariable analysis was done using binary logistical regression.
Results
21.9% of the respondents reported having been given a recommendation or referral for psycho-oncological care by a doctor within the course of their cancer diagnosis and treatment. This comprises 29.5% of the patients identified by screening as being psychologically burdened. Nearly half of the patients who received a recommendation or referral (49.8%) acted on it. Predictors for seeking out psycho-oncological care included: patient desire (OR = 2.0), previous experience with psycho-oncological care (OR = 1.59), and female gender (OR = 1.57). Multivariable analysis indicated that patients’ level of psychological burden (depression, anxiety) had no effect on whether doctors gave them a recommendation or referral.
Conclusions
Along with examining the degree to which patients are burdened (e.g. using screening instruments), determining whether or not patients would like to receive psycho-oncological care is an important aspect of improving referral practices and, by extension, will allow important progress in the field of psycho-oncological care to be made.
According to the updated International Myeloma Working Group criteria, smoldering multiple myeloma (SMM) is an asymptomatic plasma cell disorder characterized by an M-component >3 g/dL, bone marrow plasma cell infiltration >10% and <60%, and absence of any myeloma-defining event. Active multiple myeloma is preceded by SMM, with a median time to progression of approximately 5 years. Cases of SMM range from the extremes of “monoclonal gammopathy of undetermined significance-like”, in which patients never progress during their lifetimes, to “early multiple myeloma”, in which transformation into symptomatic disease, based on genomic evolution, may be rapid and devastating. Such a “split personality” makes the prognosis and management of individual patients challenging, particularly with regard to the identification and possible early treatment of high-risk SMM. Outside of clinical trials, the conventional approach to SMM generally remains close observation until progression to active multiple myeloma. However, two prospective, randomized trials have recently demonstrated a significant clinical benefit in terms of time to progression, and of overall survival in one of the two studies, for some patients with higher-risk SMM treated with lenalidomide ± dexamethasone, raising the question of whether such an approach should be considered a new standard of care. In this paper, experts from the European Myeloma Network describe current biological and clinical knowledge on SMM, focusing on novel insights into its molecular pathogenesis, new prognostic scoring systems proposed to identify SMM patients at higher risk of early transformation, and updated results of completed or ongoing clinical trials. Finally, some practical recommendations for the real-life management of these patients, based on Delphi consensus methodology, are provided.
The advances in cancer immunotherapy come with several obstacles, limiting its widespread use and benefits so far only to a small subset of patients. One of the underlying challenges remains to be the lack of representative nonclinical models that translate to human immunity and are able to predict clinical efficacy and safety outcomes. In recent years, immunocompetent Cancer-on-Chip models emerge as an alternative human-based platform that enables the integration and manipulation of complex tumor microenvironment. In this review, we discuss novel opportunities offered by Cancer-on-Chip models to advance (mechanistic) immuno-oncology research, ranging from design flexibility to multimodal analysis approaches. We then exemplify their (potential) applications for the research and development of adoptive cell therapy, immune checkpoint therapy, cytokine therapy, oncolytic virus, and cancer vaccines.
Background
In the phase 3 ALCYONE study, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) versus bortezomib/melphalan/prednisone (VMP) significantly improved progression-free survival (PFS) and overall survival (OS) in transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. We present a subgroup analysis of ALCYONE by patient frailty status.
Patients and Methods
Frailty assessment was performed retrospectively using age, Charlson comorbidity index, and baseline Eastern Cooperative Oncology Group performance status score. Patients were classified as fit (0), intermediate (1), or frail (≥2); a nonfrail category combined fit and intermediate patients.
Results
Among randomized patients (D-VMP, n = 350; VMP, n = 356), 391 (55.4%) were nonfrail (D-VMP, 187 [53.4%]; VMP, 204 [57.3%]) and 315 (44.6%) were frail (163 [46.6%]; 152 [42.7%]). After 40.1-months median follow-up, nonfrail patients had longer PFS and OS than frail patients, but benefits of D-VMP versus VMP were maintained across subgroups: PFS nonfrail (median, 45.7 vs. 19.1 months; hazard ratio [HR], 0.36; P < .0001), frail (32.9 vs. 19.5 months; HR, 0.51; P < .0001); OS nonfrail (36-month rate, 83.6% vs. 74.5%), frail (71.4% vs. 59.0%). Improved greater than or equal to complete response and minimal residual disease (10−5)-negativity rates were observed for D-VMP versus VMP across subgroups. The 2 most common grade 3/4 treatment-emergent adverse events were neutropenia (nonfrail: 39.2% [D-VMP] and 42.4% [VMP]; frail: 41.3% and 34.4%) and thrombocytopenia (nonfrail: 32.8% and 36.9%; frail: 36.9% and 39.1%).
Conclusion
Our findings support the clinical benefit of D-VMP in transplant-ineligible NDMM patients enrolled in ALCYONE, regardless of frailty status.
Zusammenfassend lässt sich sagen, dass diese prospektive Studie sowohl den prognostischen als auch den prädiktiven Nutzen eines Tumormarker-Abfalls von CA19- 9 auf eine Induktionschemotherapie bei Patienten mit LAPC bestätigt. Nicht die Ausgangswerte des Tumormarkers vor Therapie sollten zur Planung des weiteren Vorgehens herangezogen werden, sondern die Werte nach Abschluss der Induktionschemotherapie bzw. der Abfall unter der Induktionschemotherapie. Das biochemische Ansprechen von CA19-9 ist ein bedeutender Indikator für den Behandlungserfolg und verbessert die diagnostische Genauigkeit bei der Auswahl von Patienten für eine chirurgische Exploration. Sowohl die Betrachtung des biochemischen Ansprechens allein als auch in Kombination mit dem radiologischen Ansprechen verbessert Sensitivität und Spezifität hinsichtlich einer möglichen R0-Resektion. Kombiniert man bei Patienten mit einer SD in Woche 16 ein gutes biochemisches Ansprechen (Rückgang von CA19-9 > 55%), so wird eine Sensitivität von 100% hinsichtlich der möglichen R0-Resektion erreicht. Zur Abschätzung des Gesamtüberlebens von Patienten mit LAPC sollten dagegen eher die absoluten Werte von CA19-9 nach Induktionschemotherapie verwendet werden und nicht der relative Rückgang des Markers. So zeigen Patienten, welche in Woche 16 einen CA19-9 Wert < 50 U/ml aufweisen mit 27,8 Monaten das beste mediane Gesamtüberleben.
Emerging data demonstrate that the activity of immune cells can be modulated by microbial molecules. Here, we show that the short-chain fatty acids (SCFAs) pentanoate and butyrate enhance the anti-tumor activity of cytotoxic T lymphocytes (CTLs) and chimeric antigen receptor (CAR) T cells through metabolic and epigenetic reprograming. We show that in vitro treatment of CTLs and CAR T cells with pentanoate and butyrate increases the function of mTOR as a central cellular metabolic sensor, and inhibits class I histone deacetylase activity. This reprogramming results in elevated production of effector molecules such as CD25, IFN-γ and TNF-α, and significantly enhances the anti-tumor activity of antigen-specific CTLs and ROR1-targeting CAR T cells in syngeneic murine melanoma and pancreatic cancer models. Our data shed light onto microbial molecules that may be used for enhancing cellular anti-tumor immunity. Collectively, we identify pentanoate and butyrate as two SCFAs with therapeutic utility in the context of cellular cancer immunotherapy.
Background
Gastric pull-up (GPU) procedures may be complicated by leaks, fistulas, or stenoses. These complications are usually managed by endoscopy, but in extreme cases multidisciplinary management including reoperation may be necessary. Here, we report a combined endoscopic and surgical approach to manage a failed secondary GPU procedure.
Case summary
A 70-year-old male with treatment-refractory cervical esophagocutaneous fistula with stenotic remnant esophagus after secondary GPU was transferred to our tertiary hospital. Local and systemic infection originating from the infected fistula was resolved by endoscopy. Hence, elective esophageal reconstruction with free-jejunal interposition was performed with no subsequent adverse events.
Conclusion
A multidisciplinary approach involving interventional endoscopists and surgeons successfully managed severe complications arising from a cervical esophago-cutaneous fistula after GPU. Endoscopic treatment may have lowered the perioperative risk to promote primary wound healing after free-jejunal graft interposition.
The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients.
We compared the feasibility of 4 cytomegalovirus (CMV)- and Aspergillus-reactive T-cell immunoassay protocols in allogenic stem cell transplant recipients. While enzyme-linked immunospot performed best overall, logistically advantageous whole blood–based assays performed comparably in patients with less severe lymphocytopenia. CMV-induced interferon-gamma responses correlated strongly across all protocols and showed high concordance with serology.
Neutrophils are key components of the innate immune response, providing host defence against infection and being recruited to non-microbial injury sites. Platelets act as a trigger for neutrophil extravasation to inflammatory sites but mechanisms and tissue-specific aspects of these interactions are currently unclear. Here, we use bacterial endotoxin in mice to trigger an innate inflammatory response in different tissues and measure neutrophil invasion with or without platelet reduction. We show that platelets are essential for neutrophil infiltration to the brain, peritoneum and skin. Neutrophil numbers do not rise above basal levels in the peritoneum and skin and are decreased (~60%) in the brain when platelet numbers are reduced. In contrast neutrophil infiltration in the lung is unaffected by platelet reduction, up-regulation of CXCL-1 (2·4-fold) and CCL5 (1·4-fold) acting as a compensatory mechanism in platelet-reduced mice during lung inflammation. In brain inflammation targeting platelet receptor GPIbα results in a significant decrease (44%) in platelet-mediated neutrophil invasion, while maintaining platelet numbers in the circulation. These results suggest that therapeutic blockade of platelet GPIbα could limit the harmful effects of excessive inflammation while minimizing haemorrhagic complications of platelet reduction in the brain. The data also demonstrate the ability to target damaging brain inflammation in stroke and related disorders without compromising lung immunity and hence risk of pneumonia, a major complication post stroke. In summary, our data reveal an important role for platelets in neutrophil infiltration to various tissues, including the brain, and so implicate platelets as a key, targetable component of cerebrovascular inflammatory disease or injury.
Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single-agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single-agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients.
Bei Patienten mit invasiver Aspergillose fanden sich gegenüber gesunden Probanden deutlich erhöhte Werte A. fumigatus spezifischer CD154+/CD4+ Zellen. Die Anwendbarkeit dieses Assays im klinischen Routinebetrieb und bei gegenüber A. fumigatus epxonierten Probanden und Patienten sollte in dieser translationalen Arbeit untersucht werden.
Für den vorbeschriebenen Assay zur Bestimmung CD154+/CD4+ Zellen aus aufgereinigten PBMCs zeigt diese Arbeit eine signifikant reduzierte Detektionsrate nach Blutprobenlagerung von über 2 Stunden. In der Literatur beschriebene Verfahren zur verlängerten Lagerungszeit von heparinisierten Blutproben mittels vorhergehender Dilution und Agitation ermöglichen keine Verlängerung präanalytischer Lagerungszeiten über 6 Stunden. Die Kryokonservierung frisch aufbereiteter PBMCs bei −20 C vor Bestimmung A. fumigatus spezifischer T-Zellen wird als Versandmöglichkeit in einem multizentrischen Setting gezeigt. Um die klinische Anwendbarkeit zu verbessern, wird ein Vollblutprotokoll zur Detektion A. fumigatus spezifischer CD154+/CD4+ Zellen demonstriert, das die Verwendung von bettseitig mit Vollblut beimpften Blutmonovetten mit vorgelegtem A. fumigatus-Lysat ermöglicht.
Die Anwendung des Assays zur Bestimmung A. fumigatus spezifischer T-Zellen wurde bei hämatoonkologischen Patienten vor und drei Monate nach Stammzelltransplantation untersucht. Insbesondere eine reduzierte Zellzahl der gemessenen Lymphozyten ist hier ein limitierender Faktor der erfolgreichen Messung. Aufgrund der generell nied- rigen Erfolgsrate von 20 % bzw. 54 % vor bzw. nach HSCT ist die Anwendbarkeit des Assays in diesem Kollektiv fraglich. Die Erhebung von Expositionsfaktoren gesunder Probanden gegenüber A. fumigatus ermöglicht die Einteilung in eine schwach und stark gegenüber A. fumigatus exponierte Gruppe mit signifikant erhöhtem Anteil A. fumigatus spezifischer CD154+/CD4+ Zellen. Hierzu trägt insbesondere das Vorliegen antigenspezifischer T-Gedächtniszellen als Korrelat einer langfristigen Exposition bei. Retrospektiv fand sich auch nach kurzfris- tiger beruflicher Exposition ein Anstieg CD154+/CD4+ spezifischer T-Zellen. Dies legt eine Verwendung CD154+/CD4+ spezifischer T-Zellen als Biomarker in Bereichen der umweltmedizinischen Abklärung von Schimmelpilzexposition oder der Diagnostik allergischer Erkrankungen nahe.
Quantitative nuclear magnetic resonance imaging (MRI) shifts more and more into the focus of clinical research. Especially determination of relaxation times without/and with contrast agents becomes the foundation of tissue characterization, e.g. in cardiac MRI for myocardial fibrosis. Techniques which assess longitudinal relaxation times rely on repetitive application of readout modules, which are interrupted by free relaxation periods, e.g. the Modified Look-Locker Inversion Recovery = MOLLI sequence. These discontinuous sequences reveal an apparent relaxation time, and, by techniques extrapolated from continuous readout sequences, a putative real T1 is determined. What is missing is a rigorous analysis of the dependence of the apparent relaxation time on its real partner, readout sequence parameters and biological parameters as heart rate. This is provided in this paper for the discontinuous balanced steady state free precession (bSSFP) and spoiled gradient echo readouts. It turns out that the apparent longitudinal relaxation rate is the time average of the relaxation rates during the readout module, and free relaxation period. Knowing the heart rate our results vice versa allow to determine the real T1 from its measured apparent partner.
In dieser Arbeit wurde ein modulares Zelllinienmodell zur Visualisierung klonaler Evolutionsmechanismen etabliert. Hierfür wurden unterschiedlich fluoreszierende Proteine (LSSmKate2, EGFP, mTagBFP2) durch Anwendung eines Sleeping Beauty basierten Vektorsystems in unterschiedliche Sublinien der Myelom Zelllinie L363 eingebracht. Diese vier Sublinien beinhalten jeweils eine von drei aus primären Patientenproben gewonnenen Mutationen in IKZF1 (A152T, E170D, R439H) oder den IKZF1 WT. Die Anwendung von immunmodulatorischen Medikamenten (IMiDs) führt zu einer Ubiquitinierung des Transkriptionsfaktors IKZF1 durch die E3-Ubiquitin-Protein-Ligase (CRBN-CUL4). Durch Mutationen in IKZF1 kommt es zu Störungen in diesem Prozess und damit zu einer Überexpression von IKZF1. Dies wirkt sich wachstumsfördert auf die Myelomzellen aus. Die Auswirkungen der einzelnen Mutationen in IKZF1 ist aufgrund dessen ein klinisch relevantes Forschungsthema.
In dieser Arbeit wurden jeweils zwei Sublinien mit Zellen des IKZF1 WT und Zellen mit einer IKZF1 Mutation mit jeweils unterschiedlich fluoreszierenden Proteinen markiert. Diese wurden gemeinsam unter Behandlung mit verschiedenen Konzentrationen von Lenalidomid inkubiert. Somit konnte das Selektionsverhalten mittels Durchflusszytometrie-Auswertungen visualisiert werden. Es konnte gezeigt werden, dass die IKZF1 Mutation A152T einen deutlichen Selektionsvorteil für die Myelomzellen darstellt. Bei den IKZF1 Mutationen E170D und R439H konnte kein Selektionsvorteil gegenüber dem IKZF1 WT beobachtet werden.
Objectives
Early diagnosis of invasive aspergillosis (IA) remains challenging, with available diagnostics being limited by inadequate sensitivities and specificities. Triacetylfusarinine C, a fungal siderophore that has been shown to accumulate in urine in animal models, is a potential new biomarker for diagnosis of IA.
Methods
We developed a method allowing absolute and matrix-independent mass spectrometric quantification of TAFC. Urine TAFC, normalized to creatinine, was determined in 44 samples from 24 patients with underlying hematologic malignancies and probable, possible or no IA according to current EORTC/MSG criteria and compared to other established biomarkers measured in urine and same-day blood samples.
Results
TAFC/creatinine sensitivity, specificity, positive and negative likelihood ratio for probable versus no IA (cut-off ≥ 3) were 0.86, 0.88, 6.86, 0.16 per patient.
Conclusion
For the first time, we provide proof for the occurrence of TAFC in human urine. TAFC/creatinine index determination in urine showed promising results for diagnosis of IA offering the advantages of non-invasive sampling. Sensitivity and specificity were similar as reported for GM determination in serum and bronchoalveolar lavage, the gold standard mycological criterion for IA diagnosis.
Background & Aims
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are increasingly a cause of cirrhosis and hepatocellular carcinoma globally. This burden is expected to increase as epidemics of obesity, diabetes and metabolic syndrome continue to grow. The goal of this analysis was to use a Markov model to forecast NAFLD disease burden using currently available data.
Methods
A model was used to estimate NAFLD and NASH disease progression in eight countries based on data for adult prevalence of obesity and type 2 diabetes mellitus (DM). Published estimates and expert consensus were used to build and validate the model projections.
Results
If obesity and DM level off in the future, we project a modest growth in total NAFLD cases (0–30%), between 2016–2030, with the highest growth in China as a result of urbanization and the lowest growth in Japan as a result of a shrinking population. However, at the same time, NASH prevalence will increase 15–56%, while liver mortality and advanced liver disease will more than double as a result of an aging/increasing population.
Conclusions
NAFLD and NASH represent a large and growing public health problem and efforts to understand this epidemic and to mitigate the disease burden are needed. If obesity and DM continue to increase at current and historical rates, both NAFLD and NASH prevalence are expected to increase. Since both are reversible, public health campaigns to increase awareness and diagnosis, and to promote diet and exercise can help manage the growth in future disease burden.
Lay summary
Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis can lead to advanced liver disease. Both conditions are becoming increasingly prevalent as the epidemics of obesity and diabetes continue to increase. A mathematical model was built to understand how the disease burden associated with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis will change over time. Results suggest increasing cases of advanced liver disease and liver-related mortality in the coming years.
Objectives
Novel formulations (gastro-resistant tablet and intravenous solution) of posaconazole (POS) have been approved in prophylaxis and therapy of invasive fungal diseases (IFDs). Study aim was to analyze treatment strategies and clinical effectiveness.
Methods
We set up a web-based registry on
www.ClinicalSurveys.net
for documentation of comprehensive data of patients who received novel POS formulations. Data analysis was split into two groups of patients who received novel POS formulations for antifungal prophylaxis (posaconazole prophylaxis group) and antifungal therapy (posaconazole therapy group), respectively.
Results
Overall, 180 patients (151 in the posaconazole prophylaxis group and 29 in the posaconazole therapy group) from six German tertiary care centers and hospitalized between 05/2014 – 03/2016 were observed. Median age was 58 years (range: 19 – 77 years) and the most common risk factor for IFD was chemotherapy (n = 136; 76%). In the posaconazole prophylaxis group and posaconazole therapy group, median POS serum levels at steady-state were 1,068 μg/L (IQR 573–1,498 μg/L) and 904 μg/L (IQR 728–1,550 μg/L), respectively (P = 0.776). During antifungal prophylaxis with POS, nine (6%) probable/proven fungal breakthroughs were reported and overall survival rate of hospitalization was 86%. The median overall duration of POS therapy was 18 days (IQR: 7 – 23 days). Fourteen patients (48%) had progressive IFD under POS therapy, of these five patients (36%) died related to or likely related to IFD.
Conclusions
Our study demonstrates clinical effectiveness of antifungal prophylaxis with novel POS formulations. In patients treated for possible/probable/proven IFD, we observed considerable mortality in patients receiving salvage treatment and with infections due to rare fungal species.
Anthocyanins are flavonoids that have been suggested to provide beneficial health effects. The biological activity of anthocyanins is influenced by their pharmacokinetic properties, but anthocyanins are associated with limited bioavailability in humans. In the presented study, we investigated how the encapsulation of bilberry extract (BE), a source of anthocyanins, with either whey protein or citrus pectin influences the bioavailability and intestinal accessibility of anthocyanins in humans. We performed an intervention study that analyzed anthocyanins and their degradation products in the urine, plasma, and ileal effluent of healthy volunteers and ileostomists (subjects without an intact colon). We were able to show, that whey protein encapsulation modulated short-term bioavailability and that citrus pectin encapsulation increased intestinal accessibility during passage through the small intestine and modulated the formation of the degradation product phloroglucinol aldehyde (PGAL) in human plasma.
Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation (alloHSCT) have a poor prognosis, and alternative therapies are needed for this patient population. Blinatumomab, a bispecific T cell engager immunotherapy, was evaluated in an open-label, single-arm, phase II study of adults with R/R Philadelphia chromosome-negative B cell precursor ALL and resulted in a rate of complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh) of 43% within 2 treatment cycles. We conducted an exploratory analysis to determine the efficacy and safety of blinatumomab in 64 patients who had relapsed following alloHSCT before enrollment in the phase II study. Forty-five percent of the patients (29 of 64) achieved a CR/CRh within the first 2 cycles of treatment, 22 of whom had a minimal residual disease (MRD) response (including 19 with a complete MRD response). After 1 year and 3 years of follow-up, the median relapse-free survival was 7.4 months for patients who achieved CR/CRh in the first 2 cycles, and the median overall survival was 8.5 months; overall survival rate (Kaplan-Meier estimate) was 36% at 1 year and 18% at 3 years. Grade 3 and 4 adverse events were reported in 20 patients (31%) and 28 patients (44%), respectively, with grade 3 and 4 neurologic events in 8 and 2 patients, respectively, and grade 3 cytokine release syndrome in 2 patients. Eight patients had fatal adverse events, including 5 due to infections. Seven patients had grade ≤ 3 graft-versus-host disease during the study, none of which resulted in the discontinuation of blinatumomab or hospitalization. Our data suggest that blinatumomab is an effective salvage therapy in this patient population.