PML-RARA fusion

The robust detection of PML/RARA fusion gene from human serum samples validates the reliability and potential of this platform in the screening, diagnosis, and prognosis of APL cases. Our findings present an approach that holds significant potential for the further development of the robust CRISPR/Cas sensor system, offering a rapid and adaptable paradigm for APL diagnosis.

In Iranian APL patients, bcr1 predominates, while bcr3 correlates with higher WBC counts, high-risk categorization, additional chromosomal abnormalities, and faster CHR. Survival is negatively impacted by old age, relapse, lower PLT counts, higher WBC counts, and leukocytosis.

In the context of acute myeloid leukemia (AML) specifically, several efficacious combination therapies have been approved for specific patient subsets, such as all-trans retinoic acid (ATRA) plus arsenic trioxide in the PML-RARA fusion acute promyelocytic subtype and Midostaurin plus Cytarabine and Daunorubicin in FLT3-mutant AML. Strong established hits in our screen include ATR inhibition plus Gemcitabine treatment as well as several combinations involving the BCL-2 inhibitor Venetoclax with chemotherapies (Decitabine and Daunorubicin), Quizartinib, Idasanutlin, and mTOR inhibitors. Thus, we have developed an efficient and cost-effective high throughput drug combinations profiling system that has uncovered candidate therapies that may expand treatment options for patients afflicted by AML.

All 12 patients received ATRA+ATO for induction: 9 patients received idarubicin, 1 received daunorubicin, and 2 received gemtuzumab ozogamicin. In addition, 2 patients received hydroxyurea and cytarabine for cytoreduction... High-risk APL patients can be successfully treated with ATRA/ATO- based induction and consolidation without maintenance therapy, thus avoiding the long-term toxicities of maintenance therapy.

Background: Acute promyelocytic leukemia (APL) is characterized by the formation of a PML-RARa fusion gene and almost curable disease with the use of all-trans retinoic acid (ATRA) and arsenicals, including arsenic trioxide (ATO) and Realgar-Indigo naturalis formula (RIF)... After the application of arsenicals (ATO and RIF), the level of arsenic concentration in tissues would be higher than normal for a period of time, and gradually return to normal. Moreover, arsenic residue in the tissues was not afactor affecting the quality of life in children suffering from APL treated with arsenicals. Fig.1 Arsenic concentrations in the plasma (A), urine (B), hair (C) and nail (D) samples obtained from the different groups.

Quantitative reverse-transcription polymerase chain reaction analysis revealed WT1 and PML-RARA fusion transcripts in both the peripheral blood and bone marrow samples. Thus, the determination of peripheral blood WT1 expression may be sufficiently sensitive for detecting a small number of circulating APL cells.

Then they were randomized to receive consolidation therapy including ATRA plus ATO or ATRA plus RIF. Interim results of this study proved efficacy of ATRA plus RIF was non-inferior to ATRA plus intravenous ATO for consolidation therapy in standard-risk APL. The toxicity is almost equivalent except slightly advantage of ATRA-RIF group on coagulation. No relapses may be attributed to simultaneous administer of ATRA and ATO/RIF.

Combination therapy with ATRA and arsenic trioxide cures the vast majority of APL patients, however the underlying molecular mechanism(s) by which PML-RARA initiates APL are not yet clear...Blood. 2021; 138(13):1148-1161.

The complex karyotype with clonal evolution and mutations in KMT2A, KRAS, NRAS, and SUZ12 indicates a poor prognosis. We hypothesize that the CA detected may be a cause of the unique pathological features of this case. More reports can help test this hypothesis and confirm if the CA may be markers for diagnosis, prognosis, and treatment of this type of tumor.

Patients with low-risk APL are successfully treated using a chemotherapy-free combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). In this review, we explore the work that has gone into the modern-day diagnosis and highly successful treatment of this once devastating leukemia.

P3, N=276, Completed, Gruppo Italiano Malattie EMatologiche dell'Adulto | Active, not recruiting --> Completed

The all-trans-retinoic acid (ATRA) and Arsenic Trioxide (ATO) only regimens have demonstrated success in treating low- and intermediate-risk patients. However, induction with ATRA/ATO only regimens have been showing increased incidence of differentiation syndrome (DS), a potentially lethal complication, traditionally treated with dexamethasone...The lengths of hospital stay in patients receiving ATRO/ATO only was 38 days (n = 7), and in patients receiving combination therapy was 14 days (n = 17) (P = 0.0007). In conclusion, adding adjuvant chemotherapy to ATRA/ATO only protocol may reduce the duration of DS and the length of hospital stay during APL induction treatment.

P3, N=280, Active, not recruiting, Technische Universität Dresden | Trial primary completion date: Jul 2022 --> Jan 2025 | Recruiting --> Active, not recruiting

Interestingly, miR-125b expression led to low peripheral white cell counts to bone marrow blast percentage ratio, confirming the clinical observation in acute promyelocytic leukemia patients. This study suggests that dysregulated miR-125b expression is actively involved in disease progression and pathophysiology of acute promyelocytic leukemia, indicating that targeting miR-125b may represent a new therapeutic option for acute promyelocytic leukemia.

However, early clinical trials in which cancer patients were treated either with 1,25D or with analogs did not lead to conclusive results. Recent results have shown that AML types with certain mutations, such as isocitrate dehydrogenase (IDH) mutations, may be the right targets for differentiation therapy using 1,25D, due to upregulation of vitamin D receptor (VDR) pathway.

Resembling acute promyelocytic leukemia (APL) is a unique subtype of APL who sharing clinical, morphological, and immunophenotypic features with typical APL, but lacking evidence of PML-RARA fusion gene and usually insensitive to arsenic trioxide (ATO) and all-trans retinoic acid (ATRA)...They usually were resistant to ATO and ATRA but partially sensitive to anthracycline-based chemotherapy...The patient with RARG-HNRNPM was benefited from a combined chemotherapy homoharringtonine, cytarabine, and aclacinomycin (HAA) regimen with no relapse. RARG rearrangement resembling APL are various. The treatment should be switched from ATRA/ATO to AML combined chemotherapy regimen early.

Aims To report on the use of arsenic trioxide (ATO) combined with ATRA in a pediatric patient with very late APL extramedullary relapse. Therefore, she received the association ATO-ATRA in second line, obtaining the second complete remission with a chemo-free regimen. This case shows that the association ATO-ATRA as single therapy in pediatric patients is safe and effective also for relapses and that the best second line therapeutic regimen should be chosen considering the treatment history of each patient.

P3, N=280, Recruiting, Technische Universität Dresden | Trial completion date: Jan 2022 --> Mar 2025 | Trial primary completion date: Nov 2021 --> Jul 2022

Several studies have demonstrated a preclinical activity of the current available PARPi, olaparib, rucaparib, niraparib, veliparib and talazoparib, as single agent and/or in combination with cytotoxic, hypomethylating or targeted drugs in acute leukemia, thus encouraging the development of clinical trials. These data, along with the warning coming from the observation of cases of therapy-related myeloid malignancies among patients receiving PARPi for solid tumors treatment, indicate that PARPi represents a promising strategy in a personalized medicine setting. The characterization of the clonal and subclonal genetic background and of the DDR functionality is crucial to select acute leukemia patients that will likely benefit of PARPi-based therapeutic regimens.

Adhering to a systematically planed treatment course is essential for acquiring rapid remission and reduction of relapse. Treatment compliance should be paid attention to guaranteed, especially during the oral administration courses outside the hospital.

Our findings suggest JADE2 as a novel myeloid player involved in retinoic acid-induced differentiation. Despite lacking a rearranged RARA, our findings implicate that altered retinoic acid signaling by JADE2 disruption may underlie the APL-like features in our case, corroborating the importance of this signaling in APL pathogenesis.

Later, the development of ATRA, chemotherapy, and arsenic trioxide combinations turned APL into a highly curable malignancy. In this review, we summarize the evolution of APL therapy, focusing on key milestones that led to the standard-of-care APL therapy available today and discuss treatment algorithms and management tips to minimize induction mortality.

On confirmation of the diagnosis, the patient was initiated on ATRA and idarubicin...The patient was immediately started on intravenous dexamethasone 10 mg every 12 hours for treatment of both DS and myocarditis, and demonstrated resolution of symptoms as well as normalization of cardiac enzymes. She was advised to continue a prolonged prednisone tapering regimen after completion of dexamethasone for 14 days...We postulate that myocarditis although rare, is likely to be a constituent of the amalgam of pathologies involved in DS. Cardiac MRI may be a more accurate non-invasive diagnostic test to confirm myopericarditis after ATRA induction.

On confir- mation of the diagnosis, the patient was initiated on ATRA and idarubicin...The patient was immediately started on intravenous dexamethasone 10 mg every 12 hours for treatment of both DS and myocarditis, and demonstrated res- olution of symptoms as well as normalisation of cardiac enzymes. She was advised to continue a prolonged prednisone tapering regimen after completion of dexamethasone for 14 days...We postulate that myocarditis although rare, is likely to be a constituent of the amal- gam of pathologies involved in DS. Cardiac MRI may be a more accurate non-invasive diagnostic test to confirm myopericarditis after ATRA induction.

We identified TNRC18-RARA as novel RARA fusion in resembling APL. Our study highlights the importance of combining multiple molecular techniques to characterize and optimally manage APL lacking classic t(15;17)(q24;q12)/PML-RARA fusion.

Thus, although HF diet and obesity accelerate the onset of APL in B6.mCG-PML-RARα mice, sexual dimorphism remains, with females showing extended latency compared to males under conditions of both HF and LF diets. Overall, our studies provide a robust mouse model to study the mechanisms by which sex impacts leukemia latency, as well as demonstrate that obesity accelerates leukemia development without affecting sexual dimorphism.

No abstract available

Ligation-dependent reverse transcription polymerase chain reaction was used for validation and was shown to be a fast and reliable method for fusion detection. We conclude that a next-generation sequencing-based approach can replace conventional CCA for karyotyping, provided that efforts are made to cover lowly expressed fusion transcripts.

These modifications to the 100 000 Genomes Project GeCAP should significantly increase the utility of WGS in a clinical setting. This will allow patients with AML & ALL to fully benefit from the potential diagnostic and therapeutic opportunities afforded by WGS as we move towards implementation in the NHS Genomic Medicine service.

On the third day, chemotherapy was started based on AML-BFM 2008, without Idarubicin, and support for tumor lysis syndrome... the control of bleeding is essential during the induction therapy of AML patients. Chemotherapy can improve the DIC outcome by controlling leukemia, always associated with sources of fibrinogen replacement and agents that convert protein C into the activated form, not widely available in our country. Although the incidence of DIC is rare in non-APL AML, this knowledge is important, which allows the immediate recognition and treatment of this condition, allowing a better outcome for these patients.