To explore the functional consequences of possible cross-talk between the CXCR4/CXCL12 and the sphingosine-1-phosphate (S1P) pathways in multiple myeloma (MM) cells and to evaluate the effect of S1P ...targeting with the FTY720 modulator as a potential anti-MM therapeutic strategy.
S1P targeting with FTY720 induces MM cell apoptosis. The combination of FTY720 with the SPHK1 inhibitor SKI-II results in synergistic inhibition of MM growth. CXCR4/CXCL12-enhanced expression correlates with reduced MM cell sensitivity to both FTY720 and SKI-II inhibitors, and with SPHK1 coexpression in both cell lines and primary MM bone marrow (BM) samples, suggesting regulative cross-talk between the CXCR4/CXCL12 and SPHK1 pathways in MM cells. FTY720 was found to directly target CXCR4. FTY720 profoundly reduces CXCR4 cell-surface levels and abrogates the CXCR4-mediated functions of migration toward CXCL12 and signaling pathway activation. Moreover, FTY720 cooperates with bortezomib, inducing its cytotoxic activity and abrogating the bortezomib-mediated increase in CXCR4 expression. FTY720 effectively targets bortezomib-resistant cells and increases their sensitivity to bortezomib, promoting DNA damage. Finally, in a recently developed novel xenograft model of CXCR4-dependent systemic MM with BM involvement, FTY720 treatment effectively reduces tumor burden in the BM of MM-bearing mice. FTY720 in combination with bortezomib demonstrates superior tumor growth inhibition and abrogates bortezomib-induced CXCR4 increase on MM cells.
Altogether, our work identifies a cross-talk between the S1P and CXCR4 pathways in MM cells and provides a preclinical rationale for the therapeutic application of FTY720 in combination with bortezomib in patients with MM.
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Background and Objectives
The COVID‐19 pandemic has led to a growing interest in hospital‐at‐home programmes, including home transfusion services. We studied whether the pandemic had influenced ...patients' perception of home transfusions.
Materials and Methods
We conducted a survey among haematology patients who receive transfusions in the hospital day care facility. Patients were asked about the burden of day care transfusions and whether they would prefer receiving home transfusions. The survey was conducted during the COVID‐19 pandemic, and the results were compared with a survey performed before the pandemic (baseline).
Results
Sixty patients were included in the COVID‐19 cohort and 31 patients in the baseline cohort. There was a non‐significant decrease in the proportion of patients willing to receive home transfusions during the pandemic compared with baseline (35% vs. 47%, respectively, p = 0.28). More patients in the COVID‐19 cohort were afraid to receive home transfusions (60% compared with 48% at baseline, p = 0.29), and fewer patients believed that hospital transfusion impaired their quality of life (19% compared with 36% at baseline, p = 0.09). These unexpected results may be partly attributed to the shorter time needed to arrive at the hospital during the pandemic and a greater fear of having transfusion‐related adverse effects at home.
Conclusions
Our results show that the pandemic did not increase the willingness of patients to receive home transfusions, with a non‐significant drift towards refusal of home transfusions. Patients' opinions should be taken into consideration when planning for future home transfusion services, by creating a comprehensive approach to patients' needs.
Acute leukemia is an aggressive blood malignancy with low survival rates. A high expression of stem-like programs in leukemias predicts poor prognosis and is assumed to act in an aberrant fashion in ...the phenotypically heterogeneous leukemia stem cell (LSC) population. A lack of suitable genome engineering tools that can isolate LSCs based on their stemness precludes their comprehensive examination and full characterization. We hypothesized that tagging endogenous stemness-regulatory regions could generate a genome reporter for the putative leukemia stemness-state. Our analysis revealed that the ERG + 85 enhancer region can serve as a marker for stemness-state and a fluorescent lentiviral reporter was developed that can accurately recapitulate the endogenous activity. Using our novel reporter, we revealed cellular heterogeneity in several leukemia cell lines and patient-derived samples. Alterations in reporter activity were associated with transcriptomic and functional changes that were closely related to the hematopoietic stem cell (HSC) identity. Notably, the differentiation potential was skewed towards the erythro-megakaryocytic lineage. Moreover, an ERG + 85
fraction of AML cells could regenerate the original cellular heterogeneity and was enriched for LSCs. RNA-seq analysis coupled with in silico drug-screen analysis identified 4HPR as an effective inhibitor of ERG + 85
leukemia growth. We propose that further utilization of our novel molecular tool will identify crucial determinants of LSCs, thus providing a rationale for their therapeutic targeting.
Purpose: CT-011 is a humanized IgG1 monoclonal antibody that modulates the immune response through interaction with PD-1, a protein
belonging to the B7 receptor family present on lymphocytes. The ...objectives of this phase I study were to assess the dose-limiting
toxicities, to determine the maximum tolerated dose, and to study the pharmacokinetics of CT-011 administered once to patients
with advanced hematologic malignancies.
Experimental Design: Seventeen patients were treated with escalating doses of CT-011 ranging from 0.2 to 6 mg/kg. For pharmacokinetic analysis,
blood samples were withdrawn from the patients before and immediately after treatment and at 24 hours, 48 hours, and on days
7, 14, and 21. CT-011 blood levels were assessed with a specific ELISA and derived concentrations were used to calculate pharmacokinetic
parameters. Activation of the immune system was assessed by measuring peripheral blood CD4 + , CD8 + , and CD69 + lymphocytes.
Results: The study showed the antibody to be safe and well tolerated in this patient population. No single maximum tolerated dose
was defined in this study. Clinical benefit was observed in 33% of the patients with one complete remission. Pharmacokinetic
analyses show that serum C max and the AUC of CT-011 increased proportionally with dose. The median t 1/2 of CT-011 ranged from 217 to 410 hours. Sustained elevation in the percentage of peripheral blood CD4 + lymphocytes was observed up to 21 days following CT-011 treatment.
Conclusions: A single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in patients with advanced hematologic malignancies.
Despite improvement in survival of newly diagnosed adult precursor B-acute lymphoblastic leukemia/lymphoma (B-ALL), the results of relapsed/refractory disease are poor. Blinatumomab, a bispecific ...monoclonal antibody directed against CD19/CD3 show clinical activity against relapsed/refractory B-ALL and in minimal residual disease (MRD)-positive patients.
We report our “real-world” experience with blinatumomab in patients with relapsed/refractory B-ALL.
Twenty-one patients, at a median age 52 years with median disease duration of 10 months, were included. Indications for treatment were hematological relapse (
n
= 17), MRD positivity (
n
= 2), inability to continue intensive chemotherapy (
n
= 1), and bridging to a second alloSCT (
n
= 1). Blinatumomab was given as first salvage in 11 patients and after at least one prior salvage treatment in eight.
Complete response (CR) was newly achieved in 47% and was maintained in 75% of patients with baseline CR. At a median follow-up of 12.4 months, 13 patients were alive, and 11 in CR. Median leukemia-free survival was 8.7 months, and median overall survival was 15.2 months. Median leukemia-free survival and overall survival were not reached in patients proceeding to alloSCT compared to 5.1 and 15.2 months, respectively, for patients who did not receive stem cell transplantation.
Treatment was well tolerated with neurological events reported in two patients (10%) and GI events in three patients (14%). Cytokine storm was reported in four patients (19%).
In conclusion, treatment with blinatumomab is effective and tolerable in adult patients with relapsed/refractory B-ALL outside of a clinical trial stetting.
Multiple myeloma, a plasma cell malignancy, is the second most common blood cancer. Despite extensive research, disease heterogeneity is poorly characterized, hampering efforts for early diagnosis ...and improved treatments. Here, we apply single cell RNA sequencing to study the heterogeneity of 40 individuals along the multiple myeloma progression spectrum, including 11 healthy controls, demonstrating high interindividual variability that can be explained by expression of known multiple myeloma drivers and additional putative factors. We identify extensive subclonal structures for 10 of 29 individuals with multiple myeloma. In asymptomatic individuals with early disease and in those with minimal residual disease post-treatment, we detect rare tumor plasma cells with molecular characteristics similar to those of active myeloma, with possible implications for personalized therapies. Single cell analysis of rare circulating tumor cells allows for accurate liquid biopsy and detection of malignant plasma cells, which reflect bone marrow disease. Our work establishes single cell RNA sequencing for dissecting blood malignancies and devising detailed molecular characterization of tumor cells in symptomatic and asymptomatic patients.
Abstract
The COVID‐19 pandemic continues to pose challenges to the treatment of hemato‐oncology patients. Emergence of COVID‐19 variants, availability of vaccine boosters and antiviral treatments ...could impact their outcome. We retrospectively studied patients with hematologic malignancies and confirmed COVID‐19 during the Omicron outbreak. Of 116 evaluated patients, 16% developed severe or critical COVID‐19. Diagnosis of chronic lymphocytic leukemia (CLL) was significantly associated with severe COVID‐19 (
p
= 0.01). The vaccine effectiveness was related to the timing of the vaccine, with patients who received a mRNA vaccine within 7–90 days prior to COVID‐19 being less likely to develop severe disease compared to all other patients (
p
= 0.019). There was no correlation between disease severity and antiviral therapies. Importantly, 45% of patients undergoing active hematological treatment had to interrupt their treatment due to COVID‐19. In conclusion, patients with hematologic malignancies are at a considerable risk for severe COVID‐19 during the Omicron outbreak, with patients with CLL being the most vulnerable. mRNA vaccines have the potential to protect hematological patients from severe COVID‐19 if administered within the previous 3 months. Hematological treatment interruption is a frequent adverse outcome of COVID‐19 infection.
This study investigated the impact of COVID‐19 on patients with hematologic malignancies during the Omicron outbreak. Of the 116 patients evaluated, 16% developed severe or critical COVID‐19. chronic lymphocytic leukemia (CLL) was found to be significantly associated with severe COVID‐19, while mRNA vaccines administered within 7–90 days prior to COVID‐19 reduced the likelihood of severe disease. Additionally, 45% of patients undergoing active hematological treatment had to interrupt their treatment due to COVID‐19.
Neural stem cells are currently being investigated as potential therapies for neurodegenerative diseases, stroke, and trauma. However, concerns have been raised over the safety of this experimental ...therapeutic approach, including, for example, whether there is the potential for tumors to develop from transplanted stem cells.
A boy with ataxia telangiectasia (AT) was treated with intracerebellar and intrathecal injection of human fetal neural stem cells. Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm. We compared the tumor cells and the patient's peripheral blood cells by fluorescent in situ hybridization using X and Y chromosome probes, by PCR for the amelogenin gene X- and Y-specific alleles, by MassArray for the ATM patient specific mutation and for several SNPs, by PCR for polymorphic microsatellites, and by human leukocyte antigen (HLA) typing. Molecular and cytogenetic studies showed that the tumor was of nonhost origin suggesting it was derived from the transplanted neural stem cells. Microsatellite and HLA analysis demonstrated that the tumor is derived from at least two donors.
This is the first report of a human brain tumor complicating neural stem cell therapy. The findings here suggest that neuronal stem/progenitor cells may be involved in gliomagenesis and provide the first example of a donor-derived brain tumor. Further work is urgently needed to assess the safety of these therapies.
Information regarding the significance of platelet (PLT) count on outcome of atrial fibrillation (AF) patients who are treated with anticoagulants is limited.
We conducted a monocentric observational ...retrospective cohort study of AF patients treated with either warfarin (n = 6287) or non-vitamin K antagonist oral anticoagulants (NOACs) (n = 5240). Patient were divided into 3 subgroups; low, normal and high PLT for counts < 150 K/ μl, 150-450 K/ μl and > 450 K/ μl, respectively. A multivariate Cox-regression was used to evaluate the association between PLT subgroups and clinical outcomes.
During follow-up median = 40.6 months (IQR 17.6-60), mortality (HR 1.36, 95 CI 1.1-1.74, p = 0.01) and rate of myocardial infarction (MI) (HR 2.4, 95 CI 1.28-4.57, p = 0.007) were higher in patients with high compared to normal PLT. Transient ischemic attack or cerebrovascular accident (TIA/CVA) rate was lower in patients with low compared to normal PLT (HR 0.69, 95 CI 0.51-0.93, p = 0.02). A comparison between NOACs and warfarin demonstrated a significantly better clinical outcome for patients on NOACs in both the low (lower mortality rates) and normal PLT subgroup (lower mortality, TIA/CVA and systemic emboli rates). For patients on NOACs, low and high compared to normal PLT were associated with a higher combined outcome (HR 1.12, 95 CI 1-1.38, p = 0.047), and a higher systemic emboli rate (HR 7.07, 95 CI 1.66-30.25, p = 0.008), respectively.
Abnormal PLT count is associated with different clinical outcome of AF patients on anticoagulants. Further studies are needed in order assess whether PLT level should influence strategies of anticoagulation.
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