21 research outputs found
Antiretroviral activity of 5-azacytidine during treatment of a HTLV-1 positive myelodysplastic syndrome with autoimmune manifestations
Myelodysplastic syndromes (MDS) are often accompanied by autoimmune phenomena. The underlying mechanisms for these associations remain uncertain, although T cell activation seems to be important. Human T-lymphotropic virus (HTLV-1) has been detected in patients with myelodysplastic syndromes, mostly in regions of the world which are endemic for the virus, and where association of HTLV-1 with rheumatological manifestation is not rare. We present here the case of a 58 year old man who presented with cytopenias, leukocytoclastic vasculitis of the skin and glomerulopathy, and was diagnosed as MDS (refractory anemia with excess blasts - RAEB 1). The patient also tested positive for HTLV-1 by PCR. After 8 monthly cycles of 5-azacytidine he achieved a complete hematologic remission. Following treatment, a second PCR for HTLV-1 was carried out and found to be negative. This is the first report in the literature of a HTLV-1-positive MDS with severe autoimmune manifestations, which was treated with the hypomethylating factor 5-azacitidine, achieving cytogenetic remission with concomitant resolution of the autoimmune manifestations, as well as HTLV-1-PCR negativity. HTLV-1-PCR negativity may be due to either immune mediated clearance of the virus, or a potential antiretroviral effect of 5-azacytidine. 5-azacytidine is known for its antiretroviral effects, although there is no proof of its activity against HTLV-1 infection in vivo
Atypical Chronic Myelogenous Leukemia, BCR-ABL1 Negative: Diagnostic Criteria and Treatment Approaches
Atypical chronic myelogenous leukemia (aCML), BCR/ABL1 negative is a
rare myelodysplastic/myeloproliferative neoplasm, usually manifested
with hyperleukocytosis without monocytosis or basophilia, organomegaly,
and marked dysgranulopoiesis. In this review, we will discuss the
classification and diagnostic criteria of aCML, as these have been
formulated during the past 30 years, with a focus on the recent advances
in the molecular characterization of the disease. Although this entity
does not have a definitive molecular profile, its molecular
characterization has contributed to a better understanding and more
accurate classification and diagnosis of aCML. At the same time, it has
facilitated the identification of adverse prognostic factors and the
stratification of patients according to their risk for leukemic
transformation. What is more, the molecular characterization of the
disease has expanded our therapeutic choices, thoroughly presented and
analyzed in this review article
Challenges in the treatment of melanoma with BRAF and MEK inhibitors in patients with sickle cell disease: case report and review of the literature
Patients with sickle cell disease (SCD) suffer from complications due to anemia, inflammation, and vaso-occlusion. Factors that trigger sickling and/or inflammation may initiate such complications, while treatment with hydroxyurea (HU) reduces their emergence and prolongs survival. On the contrary, inhibition of the BRAF-MEK-ERK pathway with BRAF and MEK inhibitors (BRAF/MEKi) has revolutionized treatment of melanoma but their use has been correlated with inflammatory adverse events. Thus, treatment of patients with SCD with BRAF/MEKi may be quite challenging and pyrexia in those patients should be managed as a medical emergency. In this article, intrigued by the case of a 36-year-old female patient with S/β-thal under HU who was treated with dabrafenib and trametinib for melanoma, we analyze the mechanisms underlying inflammation and vaso-occlusion in SCD, the mechanisms of pyrexia and inflammation induced by BRAF/MEKi, their potential interconnections, the shared role of the inflammasome in these two entities, and the protective effect of HU in SCD. Since SCD is the most common inheritable blood disorder, the administration of BRAF/MEKi for melanoma in patients with SCD may be a rather common challenge. Thus, proper treatment with HU may pave the way for an uneventful management of such patients
PARP1 as a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome
Poly(ADP-ribose) polymerase 1 (PARP1) is a key mediator of various forms
of DNA damage repair and plays an important role in the progression of
several cancer types. The enzyme is activated by binding to DNA
single-strand and double-strand breaks. Its contribution to chromatin
remodeling makes PARP1 crucial for gene expression regulation.
Inhibition of its activity with small molecules leads to the synthetic
lethal effect by impeding DNA repair in the treatment of cancer cells.
At first, PARP1 inhibitors (PARPis) were developed to target breast
cancer mutated cancer cells. Currently, PARPis are being studied to be
used in a broader variety of patients either as single agents or in
combination with chemotherapy, antiangiogenic agents, ionizing
radiation, and immune checkpoint inhibitors. Ongoing clinical trials on
olaparib, rucaparib, niraparib, veliparib, and the recent talazoparib
show the advantage of these agents in overcoming PARPi resistance and
underline their efficacy in targeted treatment of several hematologic
malignancies. In this review, focusing on the crucial role of PARP1 in
physiological and pathological effects in myelodysplastic syndrome and
acute myeloid leukemia, we give an outline of the enzyme's mechanisms of
action and its role in the pathophysiology and prognosis of
myelodysplastic syndrome/acute myeloid leukemia and we analyze the
available data on the use of PARPis, highlighting their promising
advances in clinical application
PARP1-Driven Apoptosis in Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is considered a malignancy resulting from defects in apoptosis. For this reason, targeting apoptotic pathways in CLL may be valuable for its management. Poly [ADP-ribose] polymerase 1 (PARP1) is the main member of a family of nuclear enzymes that act as DNA damage sensors. Through binding on DNA damaged structures, PARP1 recruits repair enzymes and serves as a survival factor, but if the damage is severe enough, its action may lead the cell to apoptosis through caspase activation, or necrosis. We measured the PARP1 mRNA and protein pretreatment levels in 26 patients with CLL and the corresponding posttreatment levels in 15 patients after 3 cycles of immunochemotherapy, as well as in 15 healthy blood donors. No difference was found between the pre- and posttreatment levels of PARP1, but we found a statistically significant relative increase of the 89 kDa fragment of PARP1 that is cleaved by caspases in the posttreatment samples, indicating PARP1-related apoptosis in CLL patients after treatment. Our findings constitute an important step in the field, especially in the era of PARP1 inhibitors, and may serve as a base for future clinical trials with these agents in CLL
The diagnosis and management of sarcoid-like reactions in patients with melanoma treated with BRAF and MEK inhibitors. A case series and review of the literature
Sarcoidosis and sarcoid-like reactions (SLR) have been repeatedly
reported in patients with melanoma treated with BRAF and MEK inhibitors.
In the current study we present three patients that developed SLR under
treatment with BRAF and mitogen-activated protein kinase (MEK)
inhibitors for melanoma. Two patients developed mediastinal
lymphadenitis with histological features of an SLR while on targeted
therapy in the adjuvant setting, whereas one patient with metastatic
melanoma developed granulomatous nephritis while receiving combination
treatment with BRAF/MEK inhibitors and atezolizumab. In addition, we
review the published literature on the pathogenesis, clinical
characteristics, histologic features, imaging findings, and other
potential useful diagnostic tools. We also address the need for a common
terminology for these cases and propose an algorithm for the accurate
diagnosis of BRAF/MEK inhibitor-induced SLR. We also review the
currently available data on the treatment of these patients and suggest
a treatment approach for SLR in patients with melanoma, as well as for
the management of melanoma when SLR emerges
Immunogenicity and Safety of the BNT162b2 mRNA COVID-19 Vaccine in Patients with Melanoma Treated with Immunotherapy
The BNT162b2 vaccine against SARS-CoV-2 has a proven efficacy and a favorable safety profile. In cancer patients under immunotherapy in the form of immune-checkpoint inhibitors (ICIs), the efficacy of the vaccine has not been thoroughly studied, while a theoretical concern has also been raised about triggering immune-related adverse events (irAEs) by the vaccine. We conducted a prospective, non-interventional study on the immunogenicity and safety of the BNT162b2 vaccine in patients with advanced or metastatic melanoma treated with ICIs. Blood samples were obtained 0–4 days before the first dose and 12–21 days after the second dose of the vaccine for the quantification of the SARS-CoV-2 anti-spike antibody using an ELISA and immunophenotyping of the T and myeloid cell subpopulations. The active recording of AEs for a two-month period was conducted. Forty patients were included in the study. All but one (97.3%) achieved seroconversion after two doses of the vaccine and no correlations of the antibody titers with any of the studied parameters (age, gender, stage and duration of the disease, type of ICI, previous treatment, etc.) were found. Moreover, no differences in the subpopulations of the T cells (including the T-regulatory cells) or the myeloid cells were found pre- and post-vaccination. All AEs were low-grade, while one case of arthritis exacerbation was noted. The seroconversion rate in the studied population was high and was comparable to that of healthy subjects, while no major safety issues were raised during the safety follow-up. Finally, no derangements in the subpopulations of T cells or myeloid cells were noted. This is the first study focusing on the immunogenicity, safety, and effect of anti-SARS-CoV-2 vaccines on the blood-cell immunophenotype status of patients with melanoma treated with ICIs
Progressive multifocal leukoencephalopathy in the context of newer therapies in hematology and review of new treatment strategies
Progressive multifocal leukoencephalopathy (PML) is a rare, often fatal
demyelinating disease of the central nervous system (CNS) caused by the
reactivation of JC polyomavirus in the CNS. We present a case of a
54-year-old man with follicular lymphoma diagnosed with PML after being
treated with anti-CD20 monoclonal antibody-based regimens for several
years. Due to the lack of effective treatment choices for PML, the
patient was treated with nivolumab, based on recent reports, but
succumbed to his disease a few months after diagnosis. In this paper, we
focus on reviewing the literature of PML cases correlated with newer
agents used in hematology, possible factors affecting disease prognosis,
as well as the available data on upcoming therapeutic options for
patients with PML. Though newer promising treatments such as anti-PD1
monoclonal antibodies arise, a definitive treatment option is yet to be
found. Vigilance, early detection, and prompt intervention play a
crucial role in the prognosis of PML in patients with hematological
malignancies
The Role of Methylation in Chronic Lymphocytic Leukemia and Its Prognostic and Therapeutic Impacts in the Disease: A Systematic Review
Epigenetic regulation has been thoroughly investigated in recent years and has emerged as an important aspect of chronic lymphocytic leukemia (CLL) biology. Characteristic aberrant features such as methylation patterns and global DNA hypomethylation were the early findings of the research during the last decades. The investigation in this field led to the identification of a large number of genes where methylation features correlated with important clinical and laboratory parameters. Gene-specific analyses investigated methylation in the gene body enhancer regions as well as promoter regions. The findings included genes and proteins involved in key pathways that play central roles in the pathophysiology of the disease. Τhe application of these findings beyond the theoretical understanding can not only lead to the creation of prognostic and predictive models and scores but also to the design of novel therapeutic agents. The following is a review focusing on the present knowledge about single gene/gene promoter methylation or mRNA expression in CLL cases as well as records of older data that have been published in past papers