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Cureus Apr 2024Myelodysplastic syndrome (MDS) represents a group of hematologic disorders marked by abnormal cellular development in the bone marrow, while monoclonal gammopathy of...
Myelodysplastic syndrome (MDS) represents a group of hematologic disorders marked by abnormal cellular development in the bone marrow, while monoclonal gammopathy of undetermined significance (MGUS) involves abnormal plasma cells without symptomatic manifestations. This paper presents a compelling case of a 74-year-old Hispanic female diagnosed with a rare combination of high-risk MDS characterized by a complex karyotype and TP53 mutation, alongside IgG lambda MGUS. The patient's clinical presentation included a spectrum of symptoms such as body aches, rash, fever, dyspnea, and bloody watery diarrhea. Initial diagnostic evaluations yielded no significant findings, but subsequent investigations revealed abnormalities in both bone marrow and peripheral blood, indicative of coexisting MDS and MGUS. Chromosomal analysis further confirmed the presence of a complex karyotype with multiple aberrations, notably including 5q deletion. This case underscores the rarity of simultaneous high-risk MDS and MGUS, particularly with the additional complexity of a TP53 mutation and complex karyotype. It underscores the imperative for continued research efforts to elucidate the underlying mechanisms and optimal management strategies for such intricate cases. Moreover, it highlights the therapeutic challenges posed by concurrent MDS and plasma cell disorders, advocating for more aggressive interventions such as stem cell transplantation as potential avenues for improved patient outcomes.
PubMed: 38765410
DOI: 10.7759/cureus.58451 -
Dermatology and Therapy Jun 2024Biological drugs (BD) and Janus kinase inhibitors (JAKi) have revolutionized the treatment of diverse dermatoses. However, there are concerns regarding their safety,... (Review)
Review
INTRODUCTION
Biological drugs (BD) and Janus kinase inhibitors (JAKi) have revolutionized the treatment of diverse dermatoses. However, there are concerns regarding their safety, especially the risk of cancer and opportunistic infections. Here, we discuss the risk of cancer associated with the BD and JAKi used in dermatology.
METHODS
A narrative review was carried out. All relevant articles evaluating the risk of cancer associated with BD or JAKi and published between January 2010 and February 2024 were selected.
RESULTS
Multiple large studies have evaluated the association between BD, JAKi and cancer risk. However, there is a lack of prospective, comparative studies. Overall, patients undergoing BD and JAKi present a cutaneous cancer incidence similar to that in the general population. The drugs more strongly associated with non-skin cancer risk were anti-tumor necrosis factor (anti-TNFs) agents and JAKi (especially tofacitinib and oral ruxolitinib). This risk appears to increase with age, the presence of other factors (such as chronic immunosuppression from previous drugs or other comorbidities), and specific diseases such as rheumatoid arthritis (RA) and myelodysplastic syndrome. Conversely, BD such as interleukin (IL)-17 and IL-23 inhibitors may even reduce the risk of some visceral and hematological malignancies. In patients with dermatological conditions such as psoriasis and atopic dermatitis, the risk of malignancies may be lower than in other subgroups, and probably comparable to the general population.
CONCLUSIONS
The incidence of cancer in patients undergoing BD or JAKi is generally low. This incidence can be higher in elderly patients with RA or myelodysplastic syndrome, and in those undergoing prolonged therapy with tofacitinib or ruxolitinib (oral), or anti-TNF agents.
PubMed: 38763966
DOI: 10.1007/s13555-024-01166-4 -
Frontiers in Pharmacology 2024Current clinical research has reported the effectiveness and safety of venetoclax in combination with hypomethylating agents (VEN-HMA) in patients with myelodysplastic...
A real-world experience of venetoclax combined with hypomethylating agents vs. monotherapy hypomethylating agents in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia patients.
INTRODUCTION
Current clinical research has reported the effectiveness and safety of venetoclax in combination with hypomethylating agents (VEN-HMA) in patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Thus, this study aimed to examine the effectiveness and safety of VEN-HMA therapy in patients with MDS and CMML and compared its short-term and long-term therapeutic effects with HMA monotherapy.
METHOD
We analyzed data from our center, comprising 19 patients with MDS and CMML who received VEN-HMA therapy, compared to 32 patients treated with HMA monotherapy.
RESULTS
The overall response rate (ORR) in the VEN-HMA group was 73.7%, compared to 59.4% in the HMA group. The survival analysis revealed that the median overall survival (mOS) time in the VEN-HMA group was 16 months, with a median progression-free survival (mPFS) time of 9 months, both of which were longer than those observed in the HMA group ( < 0.05). Key adverse events (AEs) included grade 3-4 neutropenia (89.5% in VEN-HMA group vs. 87.5% in HMA group), grade 3-4 thrombocytopenia (73.7% vs. 71.9%), and anemia (73.7% vs. 90.6%). Infection of grade 3 or higher occurred in 63.2% of patients in the VEN-HMA group and 65.6% of patients in the HMA group.
DISCUSSION
Our study has confirmed the effectiveness and safety of the combined treatment of HMAs and venetoclax, which offers significant advantages to patients due to the relatively high and rapid response rates.
PubMed: 38756378
DOI: 10.3389/fphar.2024.1265840 -
HemaSphere May 2024Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings...
Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing "immune classes" among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune "risk factors." By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.
PubMed: 38756352
DOI: 10.1002/hem3.64 -
Cureus Apr 2024We herein describe a case of a 79-year-old male who presented with severe aortic stenosis with myelodysplastic syndrome. He was hospitalized to undergo presurgical...
We herein describe a case of a 79-year-old male who presented with severe aortic stenosis with myelodysplastic syndrome. He was hospitalized to undergo presurgical evaluation and puncture of pericardiocentesis. After the placement of pericardial drainage, he developed bacterial pericarditis. His heart failure had worsened due to new onset of atrial fibrillation and pericardial constriction. Methicillin-sensitive was identified as the pathogen from the puncture. A pericardial windowing was performed so that his circulatory status was stabilized. An aortic valve replacement as well as resection of pericardial fibrosis was finally performed, and he was discharged without any sequela.
PubMed: 38752068
DOI: 10.7759/cureus.58290 -
EClinicalMedicine Jun 2024Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline...
Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial.
BACKGROUND
Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline mutation (gm) status, in NORA. This analysis reports final data on overall survival (OS).
METHODS
This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 10/μL at baseline and 300 mg/day otherwise. OS was a secondary endpoint.
FINDINGS
Totally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients.
INTERPRETATION
Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gm status.
FUNDING
Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].
PubMed: 38745967
DOI: 10.1016/j.eclinm.2024.102629 -
Frontiers in Oncology 2024Secondary acute lymphoblastic leukemia (s-ALL) refers to acute lymphoblastic leukemia that occurs after a previous malignant tumor, including therapy-related acute...
Secondary acute lymphoblastic leukemia (s-ALL) refers to acute lymphoblastic leukemia that occurs after a previous malignant tumor, including therapy-related acute lymphoblastic leukemia (t-ALL) and prior malignant tumor acute lymphoblastic leukemia (pm-ALL). We report a case of a 51-year-old female patient who developed acute lymphoblastic leukemia 14 years after being diagnosed with diffuse large B-cell lymphoma (DLBCL). The patient was unresponsive to conventional chemotherapy for acute lymphoblastic leukemia (ALL) and achieved remission with a combination of sorafenib and decitabine based on the molecular biology characteristics of her B-ALL.
PubMed: 38737911
DOI: 10.3389/fonc.2024.1329279 -
Leukemia Jun 2024
Topics: Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Trisomy; Chromosomes, Human, Pair 6; Genomics; Prognosis; Multiomics
PubMed: 38734787
DOI: 10.1038/s41375-024-02268-w -
Experimental Hematology & Oncology May 2024Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for myeloid malignancies such as some acute myeloid leukemias (AML) and...
BACKGROUND
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for myeloid malignancies such as some acute myeloid leukemias (AML) and high-risk myelodysplastic syndromes (MDS). It aims to eradicate the malignant clone using immunocompetent donor cells (graft-versus-leukemia effect, GVL). Unfortunately, relapse is the primary cause of transplant failure mainly related on HLA loss or downregulation and upregulation of inhibitory ligands on blasts which result in donor immune effector dysfunctions.
METHODS
Between 2018 and 2021, we conducted a monocentric prospective study including 61 consecutive patients transplanted for AML or high-risk MDS. We longitudinally investigated immune cells at days + 30, + 90 and + 180 post-transplant from bone marrow and peripheral blood. We assessed the dynamics between myeloid derived suppressor cells (MDSCs) and T-cells.
RESULTS
Among the 61 patients, 45 did not relapse over the first 12 months while 16 relapsed during the first year post-transplant. Through months 1 to 6, comparison with healthy donors revealed an heterogenous increase in MDSC frequency. In all recipients, the predominant MDSC subset was granulocytic with no specific phenotypic relapse signature. However, in relapsed patients, in vitro and in vivo functional analyses revealed that MDSCs from peripheral blood were highly immunosuppressive from day + 30 onwards, with an activated NLRP3 inflammasome signature. Only circulating immunosuppressive MDSCs were statistically correlated to circulating double-positive Tim3+LAG3+ exhausted T cells.
CONCLUSION
Our simple in vitro functional assay defining MDSC immunosuppressive properties might serve as an early biomarker of relapse and raise the question of new preventive treatments targeting MDSCs in the future. Trial registration NCT03357172.
PubMed: 38734654
DOI: 10.1186/s40164-024-00516-4 -
Biomedicine & Pharmacotherapy =... Jun 2024Myelodysplastic syndromes (MDS) encompass a collection of clonal hematopoietic malignancies distinguished by the depletion of peripheral blood cells. The treatment of...
Myelodysplastic syndromes (MDS) encompass a collection of clonal hematopoietic malignancies distinguished by the depletion of peripheral blood cells. The treatment of MDS is hindered by the advanced age of patients, with a restricted repertoire of drugs currently accessible for therapeutic intervention. In this study, we found that ES-Cu strongly inhibited the viability of MDS cell lines and activated cuproptosis in a copper-dependent manner. Importantly, ferroptosis inducer IKE synergistically enhanced ES-Cu-mediated cytotoxicity both in vitro and in vivo. Of note, the combination of IKE and ES-Cu intensively impaired mitochondrial homeostasis with increased mitochondrial ROS, MMP hyperpolarized, down-regulated iron-sulfur proteins and declined oxygen consumption rate. Additionally, ES-Cu/IKE treatment could enhance the lipoylation-dependent oligomerization of the DLAT. To elucidate the specific order of events in the synergistic cell death, inhibitors of ferroptosis and cuproptosis were utilized to further characterize the basis of cell death. Cell viability assays showed that the glutathione and its precursor N-acetylcysteine could significantly rescue the cell death under either mono or combination treatment, demonstrating that GSH acts at the crossing point in the regulation network of cuproptosis and ferroptosis. Significantly, the reconstitution of xCT expression and knockdown of FDX1 cells have been found to contribute to the tolerance of mono treatment but have little recovery impact on the combined treatment. Collectively, these findings suggest that a synergistic interaction leading to the induction of multiple programmed cell death pathways could be a promising approach to enhance the effectiveness of therapy for MDS.
Topics: Ferroptosis; Myelodysplastic Syndromes; Humans; Drug Synergism; Animals; Copper; Piperazines; Mice; Cell Survival; Imidazoles; Reactive Oxygen Species; Mitochondria; Cell Line, Tumor; Glutathione
PubMed: 38733771
DOI: 10.1016/j.biopha.2024.116727