470 research outputs found
Setting Fire to ESA and EMA Resistance: New Targeted Treatment Options in Lower Risk Myelodysplastic Syndromes
During the last decade, substantial advances have been made in the understanding of
the complex molecular, immunological and cellular disturbances involved in the initiation as well
as evolution of myelodysplastic syndromes (MDS). In 85% of the mainly frail and older patient
population, anemia is present at the time of diagnosis and is thus a major therapeutic challenge.
High rates of primary resistance to erythropoiesis-stimulating agents (ESAs), the currently only
approved standard therapy to treat anemia in lower-risk MDS, demand the development of novel
and effcient drugs with a good safety profile. Luspatercept, a ligand trap of activin receptor II, is able
to promote late stage erythropoiesis even in patients failing prior ESA treatment. The presence of
ring sideroblastic phenotype defines a subgroup of patients with higher response rates. Additionally,
recent developments in clinical research using HIF-1 or telomerase modulation by roxadustat or
imetelstat are promising. Other areas of translational research involve targeting the inflammasome
by anti-inflammatory drugs in order to improve anemia. These efforts will hopefully pave the way
for new targeted treatment options for anemic low-risk MDS patients
Production and Application of CAR T Cells: Current and Future Role of Europe
Rapid developments in the field of CAR T cells offer important new opportunities
while at the same time increasing numbers of patients pose major challenges. This
review is summarizing on the one hand the state of the art in CAR T cell trials with a
unique perspective on the role that Europe is playing. On the other hand, an overview
of reproducible processing techniques is presented, from manual or semi-automated
up to fully automated manufacturing of clinical-grade CAR T cells. Besides regulatory
requirements, an outlook is given in the direction of digitally controlled automated
manufacturing in order to lower cost and complexity and to address CAR T cell products
for a greater number of patients and a variety of malignant diseases
Clinical Challenges and Consequences of Measurable Residual Disease in Non-APL Acute Myeloid Leukemia
The ability to detect residual levels of leukemic blasts (measurable residual disease, MRD)
has already been integrated in the daily routine for treatment of patients with chronic myeloid and
acute lymphoblastic leukemia. In acute myeloid leukemia (AML), a variety of mostly retrospective
studies have shown that individuals in AML remission who tested positive for MRD at specific
time-points or had increasing MRD levels are at significantly higher risk of relapse and death
compared to MRD-negative patients. However, these studies differ with respect to the “MRD-target”,
time-point of MRD determination, material analyzed, and method applied. How this probably
very valuable MRD information in individual patients may be adapted in the daily clinical routine,
e.g., to separate patients who need more aggressive therapies from those who may be spared
additional—potentially toxic—therapies is still a work-in-progress. With the exception of MRD
assessment in acute promyelocytic leukemia (APL), the lack of randomized, prospective trials renders
MRD-based decisions and clinical implications in AML a difficult task. As of today, we still do
not have proof that early intervention in MRD-positive AML patients would improve outcomes,
although this is very likely. In this article, we review the current knowledge on non-APL AML MRD
assessment and possible clinical consequences
Reduction of 5-azacitidine induced skin reactions in MDS patients with evening primrose oil
The Effect of Lenalidomide on Health-Related Quality of Life in Patients With Lower-Risk non-del(5q) Myelodysplastic Syndromes: Results From the MDS-005 Study
Abstract Background The phase III MDS-005 study compared lenalidomide versus placebo in red blood cell transfusion-dependent (RBC-TD) patients with lower-risk non-del(5q) myelodysplastic syndromes (MDS), ineligible/refractory to erythropoiesis-stimulating agents. Lenalidomide-treated patients were more likely to achieve transfusion independence (TI) ≥ 8 weeks (26.9% vs. 2.5%; P Patients and Methods Patients were randomized 2:1 to oral lenalidomide 10 mg once daily or placebo once daily (both on 28-day cycles). Patients with creatinine clearance 40 to 60 mL/min were given lenalidomide 5 mg once daily. Health-related quality of life (HRQoL), a predefined secondary end point, was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 questionnaire at baseline, week 12, week 24, every 12 weeks thereafter, and at discontinuation. Results At week 24, lenalidomide was associated with benefit versus placebo across all 5 preselected questionnaire scales (fatigue, dyspnea, global quality of life, physical functioning, and emotional functioning). After adjustment for baseline scores, only emotional functioning achieved significance ( P = .047). Further improvement versus baseline was observed for patients who continued lenalidomide after week 24. In post hoc analyses, achievement of TI ≥ 8 weeks was associated with significant improvements across all scales ( P P Conclusion Lenalidomide did not adversely affect HRQoL in RBC-TD patients with lower-risk non-del(5q) MDS and response to lenalidomide was associated with significant improvements in HRQoL
Case Report: ANXA2 Associated Life-Threatening Coagulopathy With Hyperfibrinolysis in a Patient With Non-APL Acute Myeloid Leukemia
Patients with acute promyelocytic leukemia (APL) often present with potentially lifethreatening
hemorrhagic diathesis. The underlying pathomechanisms of APLassociated
coagulopathy are complex. However, two pathways considered to be APLspecific
had been identified: 1) annexin A2 (ANXA2)-associated hyperfibrinolysis and 2)
podoplanin (PDPN)-mediated platelet activation and aggregation. In contrast, since
disseminated intravascular coagulation (DIC) is far less frequent in patients with non-
APL acute myeloid leukemia (AML), the pathophysiology of AML-associated hemorrhagic
disorders is not well understood. Furthermore, the potential threat of coagulopathy in non-
APL AML patients may be underestimated. Herein, we report a patient with non-APL AML
presenting with severe coagulopathy with hyperfibrinolysis. Since his clinical course
resembled a prototypical APL-associated hemorrhagic disorder, we hypothesized
pathophysiological similarities. Performing multiparametric flow cytometry (MFC) and
immunofluorescence imaging (IF) studies, we found the patient’s bone-marrow
mononuclear cells (BM-MNC) to express ANXA2 - a biomarker previously thought to be
APL-specific. In addition, whole-exome sequencing (WES) on sorted BM-MNC (leukemiaassociated
immunophenotype (LAIP)1: ANXAlo, LAIP2: ANXAhi) demonstrated high intratumor
heterogeneity. Since ANXA2 regulation is not well understood, further research to
determine the coagulopathy-initiating events in AML and APL is indicated. Moreover,
ANXA2 and PDPN MFC assessment as a tool to determine the risk of life-threatening DIC
in AML and APL patients should be evaluated
Graft-versus-Host disease Prophylaxis with Everolimus and Tacrolimus Is Associated with a High Incidence of Sinusoidal Obstruction Syndrome and Microangiopathy: Results of the EVTAC Trial
AbstractA calcineurin inhibitor combined with methotrexate is the standard prophylaxis for graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Everolimus, a derivative of sirolimus, seems to mediate antileukemia effects. We report on a combination of everolimus and tacrolimus in 24 patients (median age, 62 years) with either myelodysplastic syndrome (MDS; n = 17) or acute myeloid leukemia (AML; n = 7) undergoing intensive conditioning followed by HSCT from related (n = 4) or unrelated (n = 20) donors. All patients engrafted, and only 1 patient experienced grade IV mucositis. Nine patients (37%) developed acute grade II-IV GVHD, and 11 of 17 evaluable patients (64%) developed chronic extensive GVHD. Transplantation-associated microangiopathy (TMA) occurred in 7 patients (29%), with 2 cases of acute renal failure. The study was terminated prematurely because an additional 6 patients (25%) developed sinusoidal obstruction syndrome (SOS), which was fatal in 2 cases. With a median follow-up of 26 months, the 2-year overall survival rate was 47%. Although this new combination appears to be effective as a prophylactic regimen for acute GVHD, the incidence of TMA and SOS is considerably higher than seen with other regimens
The Evolving Landscape of Biomarkers for Anti-PD-1 or Anti-PD-L1 Therapy
The administration of antibodies blocking the immune checkpoint molecules programmed
cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) has evolved as a very promising
treatment option for cancer patients. PD-1/PD-L1 inhibition has significantly enhanced expansion,
cytokine secretion, and cytotoxic activity of CD4+ and CD8+ T lymphocytes, resulting in enhanced
antitumor responses. Anti-PD-1 or anti-PD-L1 therapy has induced tumor regression and improved
clinical outcome in patients with different tumor entities, including melanoma, non-small-cell lung
cancer, and renal cell carcinoma. These findings led to the approval of various anti-PD-1 or anti-PD-L1
antibodies for the treatment of tumor patients. However, the majority of patients have failed to
respond to this treatment modality. Comprehensive immune monitoring of clinical trials led to
the identification of potential biomarkers distinguishing between responders and non-responders,
the discovery of modes of treatment resistance, and the design of improved immunotherapeutic
strategies. In this review article, we summarize the evolving landscape of biomarkers for anti-PD-1
or anti-PD-L1 therapy
Risk Stratification, Measurable Residual Disease, and Outcomes of AML Patients with a Trisomy 8 Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Background: For most patients with acute myeloid leukemia (AML) harboring a trisomy 8 an allogeneic hematopoietic stem cell transplantation (HSCT) is a suitable and recommended consolidation therapy. However, comparative outcome analyses between patients with and without trisomy 8 undergoing allogeneic HSCT have not been performed so far. Methods: We retrospectively analyzed clinical features, outcomes, and measurable residual disease (MRD) of 659 AML (12%, n = 81, with a trisomy 8) patients subjected to allogeneic HSCT as a consolidation therapy. Results: The presence of a trisomy 8 associated with a trend for higher age at diagnosis, AML of secondary origin, lower white blood cell counts at diagnosis, worse ELN2017 genetic risk, wild-type NPM1, and mutated IDH1/2 and JAK2. Outcomes after allogeneic HSCT in the entire cohort did not differ between patients with a sole trisomy 8, trisomy 8 with additional cytogenetic aberrations or without a trisomy 8. A trisomy 8 did not affect outcomes within the three ELN2017 risk groups. In accordance with findings in unselected patient cohorts, persistent MRD at allogeneic HSCT in patients with a trisomy 8 identified individuals with a higher risk of relapse following allogeneic HSCT. Conclusions: Outcomes of trisomy 8 patients after allogeneic HSCT did not compare unfavorably to that of other AML patients following allogeneic HSCT. Rather than the presence or absence of a trisomy 8, additional genetic aberrations and MRD at HSCT define outcome differences and aid in informed treatment decisions
Case Report: Graft Versus Tumor Effect After Non-Myeloablative Allogeneic Stem-Cell Transplantation in a Patient With Brentuximab-Vedotin Refractory Sezary Syndrome
Sezary Syndrome (SS) is a rare leukemic variant of primary cutaneous T-cell lymphoma.
Relapsed or refractory disease is generally considered incurable by conventional
therapeutic approaches, although durable responses can be achieved with novel
monoclonal antibodies. Allogeneic hematopoietic stem cell transplantation (alloHSCT)
may have potential value by inducing graft vs-lymphoma (GvL) effects, but there is
currently no consensus regarding the timing of alloHSCT or type of conditioning
regimen. Here we present the case of a male patient who achieved a complete
remission (CR) of primary refractory SS after non-myeloablative alloHSCT. Patient: Two
years prior to HSCT, the patient had been refractory to CHOEP-based chemotherapy,
interferon, extracorporeal photopheresis (ECP), and bexarotene. Directly prior to
alloHSCT brentuximab-vedotin (BV) was applied resulting in a partial remission of the
skin compartment and overall in a stable disease. Prior to HSCT, flow cytometry of the
bone marrow and peripheral blood showed an infiltration with T-cells positive for CD5,
CD4, low CD3, low CD2 and negative for CD7, CD38, HLA-DR and CD8. The trephine
biopsy showed a 7% infiltration of SS cells. The CD4:CD8 ratio in peripheral blood (pb)
was massively increased at 76.67, with 63.5% of white blood cells expressing a SS
immune phenotype. The conditioning regimen included 30 mg/m2 fludarabine on days -5,
-4 and -3 and total body irradiation with 2 Gy on day -1. Immunosuppression consisted of
cyclosporine A from day-1 and mycophenolate mofetil from day 0. The patient received
6.55x106 CD34+ cells and 1.11x108 CD3+ cells/kg body weight. Bone marrow
evaluation on day 28 still showed persistent SS cells by flow cytometry. After tapering
immunosuppression until day 169, the CD4:CD8 ratio in pb normalized. CR was
documented on day 169 after alloHSCT and is now ongoing for almost 3 years after
alloHSCT. Conclusions: We confirm that an alloHSCT can be a curative option for
refractory patients with SS. The achievement of a CR after tapering the
immunosuppressive therapy indicates a significant role of the GvL effect. In present
treatment algorithms for patients with SS, the timing of an alloHSCT and the intensity of
conditioning should be further explored
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