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Blood Cancer Journal Mar 2024Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world...
Despite an increasing desire to use historical cohorts as "synthetic" controls for new drug evaluation, limited data exist regarding the comparability of real-world outcomes to those in clinical trials. Governmental cancer data often lacks details on treatment, response, and molecular characterization of disease sub-groups. The Australasian Leukaemia and Lymphoma Group National Blood Cancer Registry (ALLG NBCR) includes source information on morphology, cytogenetics, flow cytometry, and molecular features linked to treatment received (including transplantation), response to treatment, relapse, and survival outcome. Using data from 942 AML patients enrolled between 2012-2018, we assessed age and disease-matched control and interventional populations from published randomized trials that led to the registration of midostaurin, gemtuzumab ozogamicin, CPX-351, oral azacitidine, and venetoclax. Our analyses highlight important differences in real-world outcomes compared to clinical trial populations, including variations in anthracycline type, cytarabine intensity and scheduling during consolidation, and the frequency of allogeneic hematopoietic cell transplantation in first remission. Although real-world outcomes were comparable to some published studies, notable differences were apparent in others. If historical datasets were used to assess the impact of novel therapies, this work underscores the need to assess diverse datasets to enable geographic differences in treatment outcomes to be accounted for.
Topics: Humans; Neoplasm Recurrence, Local; Treatment Outcome; Cytarabine; Gemtuzumab; Hematopoietic Stem Cell Transplantation; Leukemia, Myeloid, Acute; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38531863
DOI: 10.1038/s41408-024-00996-x -
Molecules (Basel, Switzerland) Feb 2024Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development... (Review)
Review
Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics.
Topics: Humans; Antineoplastic Agents; Biological Products; Leukemia, Myeloid, Acute; Drug Discovery; Aquatic Organisms
PubMed: 38474445
DOI: 10.3390/molecules29050933 -
Leukemia Apr 2024We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia...
We identified 71 patients with AdvSM (aggressive SM [ASM], SM with an associated hematologic neoplasm [SM-AHN, e.g., acute myeloid leukemia, SM-AML], mast cell leukemia [MCL]) in two national registries (DRST/GREM) who received an allogeneic hematopoietic cell transplantation (alloHCT) performed in Germany from 1999-2021. Median overall survival (OS) of ASM/SM-AHN (n = 30, 45%), SM-AML (n = 28, 39%) and MCL ± AHN (n = 13, 19%) was 9.0, 3.3 and 0.9 years (P = 0.007). Improved median OS was associated with response of SM (17/41, 41%; HR 0.4 [0.2-0.9], P = 0.035) and/or of AHN (26/43, 60%, HR 0.3 [0.1-0.7], P = 0.004) prior to alloHCT. Adverse predictors for OS included absence of KIT D816V (10/61, 16%, HR 2.9 [1.2-6.5], P < 0.001) and a complex karyotype (9/60, 15%, HR 4.2 [1.8-10.0], P = 0.016). HLA-match, conditioning type or transplantation at centers reporting above-average alloHCTs (≥7) had no impact on OS. Taking into account competing events at years 1, 3 and 5, relapse-related mortality and non-relapse mortality rate were 15%/23%, 20%/30% and 23%/35%, respectively. Irrespective of subtype, subsequent treatment response was achieved in 13/30 (43%) patients and was highest on midostaurin/avapritinib (7/9, 78%). We conclude that outcome of alloHCT in AdvSM is more affected by disease phenotype and treatment response prior to transplant than by transplant characteristics.
Topics: Humans; Mastocytosis, Systemic; Retrospective Studies; Leukemia, Mast-Cell; Hematopoietic Stem Cell Transplantation; Leukemia, Myeloid, Acute
PubMed: 38448757
DOI: 10.1038/s41375-024-02186-x -
BioRxiv : the Preprint Server For... Jan 2024The venetoclax BCL2 inhibitor in combination with hypomethylating agents represents a cornerstone of induction therapy for older AML patients, unfit for intensive...
The venetoclax BCL2 inhibitor in combination with hypomethylating agents represents a cornerstone of induction therapy for older AML patients, unfit for intensive chemotherapy. Like other targeted therapies, venetoclax-based therapies suffer from innate and acquired resistance. While several mechanisms of resistance have been identified, the heterogeneity of resistance mechanism across patient populations is poorly understood. Here we utilized integrative analysis of transcriptomic and drug response data in AML patients to identify four transcriptionally distinct VEN resistant clusters (VR_C1-4), with distinct phenotypic, genetic and drug response patterns. VR_C1 was characterized by enrichment for differentiated monocytic- and cDC-like blasts, transcriptional activation of PI3K-AKT-mTOR signaling axis, and energy metabolism pathways. They showed sensitivity to mTOR and CDK inhibition. VR_C2 was enriched for mutations and associated with distinctive transcriptional suppression of expression. VR_C3 was characterized by enrichment for mutations and higher infiltration by cytotoxic T cells. This cluster showed transcriptional expression of erythroid markers, suggesting tumor cells mimicking erythroid differentiation, activation of JAK-STAT signaling, and sensitivity to JAK inhibition, which in a subset of cases synergized with venetoclax. VR_C4 shared transcriptional similarities with venetoclax-sensitive patients, with modest over-expression of interferon signaling. They were also characterized by high rates of mutations. Finally, we projected venetoclax-resistance states onto single cells profiled from a patient who relapsed under venetoclax therapy capturing multiple resistance states in the tumor and shifts in their abundance under venetoclax selection, suggesting that single tumors may consist of cells mimicking multiple VR_Cs contributing to intra-tumor heterogeneity. Taken together, our results provide a strategy to evaluate inter- and intra-tumor heterogeneity of venetoclax resistance mechanisms and provide insights into approaches to navigate further management of patients who failed therapy with BCL2 inhibitors.
PubMed: 38352538
DOI: 10.1101/2024.01.27.577579 -
Journal of Clinical Oncology : Official... May 2024Crenolanib is a second-generation tyrosine kinase inhibitor with activity against - and -mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in...
PURPOSE
Crenolanib is a second-generation tyrosine kinase inhibitor with activity against - and -mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in adults with newly diagnosed -mutant AML.
METHODS
Eligible patients were 18 years and older. Induction chemotherapy consisted of cytarabine (100 mg/m) continuous infusion on days 1-7 and anthracycline (daunorubicin 60-90 mg/m or idarubicin 12 mg/m, once daily) on days 1-3 followed by consolidation with high-dose cytarabine (1-3 g/m twice daily on days 1, 3, 5) and/or allogeneic transplant. Crenolanib (100 mg thrice a day) was given from day 9 until 72 hours before the next cycle, after consolidation, and for 12 months after consolidation or transplant.
RESULTS
Forty-four patients (median age, 57; range, 19-75 years) were enrolled. Thirty-six had , and 11 had mutations. European LeukemiaNet 2017 disease risk was favorable in 34%, intermediate in 30%, and adverse in 36%. The overall response rate was 86% (complete remission [CR], 77%; CR with incomplete count recovery [CRi], 9%): 90% in patients 60 years and younger and 80% in older patients. Measurable residual disease-negative CR/CRi rates were 89% and 45%, respectively. With a 45-month follow-up, median overall survival has not been reached and the median event-free survival was 44.7 months. Among younger patients, the estimated 3-year survival was 71.4% with 15% cumulative incidence of relapse. Treatment-related serious adverse events included febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL and absolute neutrophil count ≥1,000/µL during induction was 29 and 32 days, respectively. No new -mutant clones were detected at relapse in patients completing consolidation.
CONCLUSION
Crenolanib plus intensive chemotherapy in adults with newly diagnosed -mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.
Topics: Humans; fms-Like Tyrosine Kinase 3; Middle Aged; Adult; Female; Male; Aged; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Mutation; Young Adult; Piperidines; Benzimidazoles; Induction Chemotherapy; Cytarabine
PubMed: 38324741
DOI: 10.1200/JCO.23.01061 -
Journal of Oncology Pharmacy Practice :... Feb 2024While continual advancements in acute myeloid leukemia have augmented response rates and survival, outcomes in clinical trials may not correlate with real-world practice...
INTRODUCTION
While continual advancements in acute myeloid leukemia have augmented response rates and survival, outcomes in clinical trials may not correlate with real-world practice as trials may underrepresent individuals with comorbidities, decreased performance status, and older age. Additionally, clinical trials may underrepresent certain ethnicities, and disparities based on ethnicity, socioeconomic status, and insurance have been demonstrated in acute myeloid leukemia.
METHODS
We performed a retrospective chart review of adult patients with acute myeloid leukemia who were treated at Harbor-UCLA from 2014 to 2022 to examine patient characteristics, management patterns, and outcomes in a safety net hospital setting.
RESULTS
The median age was 56 years old (range 18-84). In regards to risk stratification, 22%, 33%, and 41% had favorable, intermediate, and adverse risk acute myeloid leukemia, respectively. The most common induction regimens included 7 + 3 (55%), azacitidine (10%), azacitidine + venetoclax (7%), and 7 + 3 + midostaurin (7%). The complete remission rate was 51%. Among patients who received intensive induction chemotherapy, 15% underwent re-induction with a second cycle, 51% received consolidation therapy, and 5% received maintenance therapy with a targeted agent. Overall, 12% of patients received allogeneic stem cell transplant. Median overall survival was 12.2 months, and 5-year overall survival was 18%.
CONCLUSIONS
Suboptimal response rates and survival in this population may be related to low rates of re-induction and allogeneic transplant in addition to high rates of adverse cytogenetics, secondary acute myeloid leukemia, and supportive care only. Efforts to increase access to clinical trials, novel therapies, and transplants for diverse and underinsured populations are essential.
PubMed: 38321873
DOI: 10.1177/10781552231225398 -
Biomedicines Dec 2023Single-cell DNA sequencing can address the sequence of somatic genetic events during myeloid transformation in relapsed acute myeloid leukemia (AML). We present an...
Single-cell DNA sequencing can address the sequence of somatic genetic events during myeloid transformation in relapsed acute myeloid leukemia (AML). We present an -mutated AML patient with an initial low ratio of -ITD (low-risk ELN-2017), treated with midostaurin combined with standard chemotherapy as front-line treatment, and with salvage therapy plus gilteritinib following allogenic stem cell transplantation after relapse. Simultaneous single-cell DNA sequencing and cell-surface immunophenotyping was used in diagnostic and relapse samples to understand the clinical scenario of this patient and to reconstruct the clonal composition of both tumors. Four independent clones were present before treatment: (63.9%), (13.9%), (13.8%), as well as a wild-type clone (8.3%), but only the minor clone with -ITD survived and expanded after therapy, being the most represented one (58.6%) at relapse. -ITD was subclonal and was found only in the myeloid blast population (CD38/CD117/CD123). Our study shows the usefulness of this approach to reveal the clonal architecture of the leukemia and the identification of small subclones at diagnosis and relapse that may explain how the neoplastic cells can escape from the activity of different treatments in a stepwise process that impedes the disease cure despite different stages of complete remission.
PubMed: 38255173
DOI: 10.3390/biomedicines12010066 -
Case Reports in Hematology 2024Systemic mastocytosis is defined by the clonal proliferation of abnormal mast cells. The clinical course can range from indolent forms with normal life expectancy to...
Systemic mastocytosis is defined by the clonal proliferation of abnormal mast cells. The clinical course can range from indolent forms with normal life expectancy to advanced mast cell leukemia with dismal prognosis. An association with other diseases, including myeloproliferative neoplasia, has been described. We present a case of a 75-year patient with a history of cutaneous mastocytosis who was diagnosed with mast cell leukemia more than 9 years ago and did not receive treatment. The patient presented to our clinic with acute kidney failure because of renal extramedullary hematopoiesis. Bone marrow histopathology revealed extensive fibrosis and 50% infiltration by mast cells with a c D816V mutation. No mutations supporting primary myelofibrosis were identified. Treatment with midostaurin was started, and the patient was discharged after improvement of renal function. Here, we discuss diagnostic challenges between different forms of mast cell leukemia and overlaps with other hematological malignancies.
PubMed: 38213502
DOI: 10.1155/2024/3502887 -
Diagnostics (Basel, Switzerland) Dec 2023Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm characterised by the accumulation of neoplastic mast cells (MCs) in various organs, resulting in... (Review)
Review
Advanced systemic mastocytosis (AdvSM) is a rare haematological neoplasm characterised by the accumulation of neoplastic mast cells (MCs) in various organs, resulting in organ dysfunction and reduced life expectancy. The subtypes include aggressive SM (ASM), SM with an associated haematological neoplasm (SM-AHN) and mast cell leukaemia (MCL). The gain of function D816V mutation is present in most cases. The availability of tyrosine kinase inhibitors (TKIs) has revolutionised the treatment landscape for patients with this life-limiting disease. Patients are now able to achieve molecular remission, improved quality of life and improved overall survival. This review focuses on the targeted therapies currently available in clinical practice and within the clinical trial setting for AdvSM. This review also highlights possible future therapeutic targets and discusses therapeutic strategies for this multimutated and clinically heterogeneous disease.
PubMed: 38201389
DOI: 10.3390/diagnostics14010080 -
Frontiers in Pharmacology 2023ARLs, which are a class of small GTP-binding proteins, play a crucial role in facilitating tumor tumorigenesis and development. ARL4C, a vital member of the ARLs...
ARLs, which are a class of small GTP-binding proteins, play a crucial role in facilitating tumor tumorigenesis and development. ARL4C, a vital member of the ARLs family, has been implicated in the progression of tumors, metastatic dissemination, and development of resistance to therapeutic drugs. Nevertheless, the precise functional mechanisms of ARL4C concerning tumor prognosis and immunotherapy drug susceptibility remain elusive. By combining the GTEx and TCGA databases, the presence of ARL4C was examined in 33 various types of cancer. Immunohistochemistry and immunofluorescence staining techniques were utilized to confirm the expression of ARL4C in particular tumor tissues. Furthermore, the ESTIMATE algorithm and TIMER2.0 database were utilized to analyze the tumor microenvironment and immune infiltration associated with ARL4C. The TISCH platform facilitated the utilization of single-cell RNA-seq datasets for further analysis. ARL4C-related immune escape was investigated using the TISMO tool. Lastly, drug sensitivity analysis was conducted to assess the sensitivity of different types of tumors to compounds based on the varying levels of ARL4C expression. The study found that ARL4C was highly expressed in 23 different types of cancer. Moreover, the presence of high ARL4C expression was found to be associated with a poor prognosis in BLCA, COAD, KIRP, LGG, and UCEC. Notably, ARL4C was also expressed in immune cells, and its high expression was found to be correlated with cancer immune activation. Most importantly, the drug sensitivity analysis revealed a positive correlation between ARL4C expression and the heightened sensitivity of tumors to Staurosporine, Midostaurin, and Nelarabine. The findings from our study indicate that the expression level of ARL4C may exert an influence on cancer development, prognosis, and susceptibility to immunotherapy drugs. In addition, the involvement of ARL4C in the tumor immune microenvironment has expanded the concept of ARL4C-targeted immunotherapy.
PubMed: 38178862
DOI: 10.3389/fphar.2023.1288492