Chr t(15;17)/PML-RARA fusion

This is the first report of an insertional PML::RARA fusion into the RARA gene on 17q detected by OGM. OGM has demonstrated its utility in a clinical cytogenetics environment, allowing for clearer characterization and diagnosis of various neoplasms.

However, the results of the present study confirmed that they may also be present in APL. Thus, these findings suggested a possible signaling pathway that involves the PML/RARA oncoprotein in APL.

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.

P1, N=16, Suspended, Syros Pharmaceuticals | N=24 --> 16 | Recruiting --> Suspended | Trial primary completion date: Apr 2024 --> Jan 2024

RT-PCR for PML-RARA was positive for the bcr-3 transcript and FISH was positive for t(15;17) (q24;q21). The take home point from our case is to look for the presence of cells with bundle of Auer rods whenever there is pancytopenia with the presence of myelocyte-like cells with prominent granulations.

The use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is highly effective making this now the most curable subtype of AML...On COG AAML1331, pediatric patients with HR APL were enrolled on a treatment arm that included the anthracycline idarubicin only in induction using a ATO-ATRA based regimen without maintenance therapy...Standard risk APL using a cytotoxic free ATO-ATRA induction also frequently results in hyperleukocytosis (elevated white blood cell count from blast differentiation) requiring cytoreduction. Thus, careful monitoring of these potential complications and aggressive supportive care to correct coagulopathy and treat differentiation syndrome and/or hyperleukocytosis is critical to prevent early death and ensure excellent cure rates.

P1, N=24, Recruiting, Syros Pharmaceuticals | Trial completion date: Mar 2023 --> Apr 2024 | Trial primary completion date: Mar 2023 --> Apr 2024

P2, N=165, Completed, National Cancer Institute (NCI) | Active, not recruiting --> Completed

After ATRA and ATO dual induction and chemotherapy consolidation, the patient achieved complete remission (CR) with undetectable PML/RARα. However, the JAK2 V617F remained positive, and the patient developed MPN (PV/ET) 22 months later, which responded well to interferon therapy.AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; ATO, arsenic trioxide; BM, bone marrow; CR, complete remission; ET, essential thrombocythemia; Hb, hemoglobin; JAK2, Janus-associated kinase 2; MPN, myeloproliferative neoplasms; PLT, platelets; PMF, primary myelofibrosis; PML/RARα; PV, polycythemia vera; WBC, white blood cells.

The typical signal pattern for a positive RARA break-apart probe is one red, one green, and one fusion. In this study, we report a rare APL case with a PRKAR1A-RARA fusion gene with a signal pattern distinct from that of t(15;17) and its other variants.

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

FISH studies revealed five copies of RUNX1. Amplification of RUNX1 is a rare event in AML with only a few cases reported in the literature (mainly therapy related AML) and it is usually associated with poor prognosis.

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

Oral arsenic trioxide plus ATRA was associated with fewer early deaths and better long-term survival than ATRA plus chemotherapy, with shorter hospital stays and outpatient treatment as distinct health-care advantages.

Further studies are needed to evaluate the biological significance of RARA-SNX15L in APL. In conclusion, this is the first report of APL with a complex chromosomal rearrangement involving SNX15.

Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Taking into consideration the identified cytogenetic abnormalities AML patients were classified by risk groups . Presence of the additional/secondary chromosomal aberrations in leukemic cells or new cells clones with multiple structural and numerical changes at AML relapse is the one sign of clonal evolution and progression of disease .

This would have significant consequences clinically, with NPM1 marker false-positivity potentially committing patients to unneeded additional chemotherapy and/or transplant with the attendant risk of morbidity and mortality which highlights the need for ongoing EQA in this area. UK NEQAS LI will work with laboratories advocating they undertake a root cause analysis process to identify the source(s) of error contributing to false positive NPM1 marker results and support their subsequent corrective actions; sharing any educational findings with all participants.

We aimed to assess the value of MRD monitoring by RT-qPCR in patients with APL treated with ATRA and arsenic trioxide +/- GO...Time to relapse was 7.9-12.4 months in 6 patients, and one patient relapsed after 79.5 months. These data show that MRD monitoring may be important for the detection of relapse in patients treated with this regimen within one year after completing therapy, however, since late molecular relapse is rare, our data suggest a low value of MRD monitoring beyond that first year.

By using the EPIDEM model, with its emphasis on local context, culture, and resources, improved communication and workflow changes enabled us to reduce the time needed to diagnose APL to 0.64 days and identify potential locally derived screening cutoffs.

In these two patients, whole exome and transcriptome profiling via the MI-ONCOSEQ platform identified a PRKAR1A-RARα fusion in one patient and ZBTB16-RARα fusion in another patient. These cases illustrate the utility of whole exome and transcriptome profiling in diagnosing variant translocations in patients in whom there is a high clinical suspicion for APL based on hematopathology review.

CD56 expression was the most common aberrancy seen in more than 25% cases. CD34negativeHLADR negative is highly associated with NPM1 mutation.

The improvement of APL outcome is mainly due to two agents, which target the typical translocation t(15;17) and its fusion transcript PML-RARα responsible for initiating and maintaining the disease: all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)...Disease relapse is infrequent and can be cured with ATRA-ATO rechallenging, with or without subsequent transplantation depending on the interval between complete remission and relapse. New therapeutic landscapes contemplate the use of an oral chemo-free ATRA-ATO combination, implementing treatment as outpatient care, thus increasing quality of life and decreasing medical costs.

Additional chromosome aberrations had adverse effects on the prognosis in APL.

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.

He was treated with ATRA, arsenic trioxide andGO (Figure)...Our patient presented with EM in the form of GS of the softtissue tissue in the lateral of the right 3-4 th intercostal area, there was noinvolvement in the bone marrow. We treated him with ATRA+ATO and GO.Neurological side effects stopped when we ceased ATO.

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.

Greater awareness should be attained as towards the risks of thromboembolic events in APML cases, especially in the early periods of the disease. Management remains centred on treating the underlying cause and offering standard treatments as per estab- lished guidelines. 1.

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.

More than 95% of patients with this disease belong to typical APL, which express PML-RARA and are sensitive to differentiation induction therapy containing all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), and they exhibit an excellent clinical outcome...If ATRA-sensitive RARA rearrangement was identified, ATRA could be added back for re-induction of differentiation. Through this review, we hoped to provide one integrated view on the genetic landscape of variant APL and helped to remove the barriers for managing this type of disease.

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.

The treatment was successful with chemotherapy for both AML and ALL with daunorubicin, cytarabine (DA) and vincristine, prednisone (VP). We reported here this suggestive MPAL case of rare disease condition and effective treatment, in order to provide experience for the early diagnosis and treatment of similar patients.

The evolution of PET/CT imageries was compared to the quantification of PML-RARα fusion gene by RQ-PCR. In promyelocytic sarcoma medical care, 18F-FDG PET/CT appears to be an attractive tool for finding targets for biopsy, for the primary staging, for assessing therapeutic response and for detecting early relapse.

The fusion confers a selective sensitivity to the targeted drugs, arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA), with response rates over 90% (PMID: 31635329)...Predicting non-response to ATO and ATRA in patients with PML-RARA fusion up-front could prevent ineffective treatment, avoid unnecessary adverse events and reduce treatment costs. Additionally, computational modeling can identify new mechanisms of resistance and suggest alternative regimens for non-responding patients by targeting the patient-specific disease biomarkers unique to each.

Moreover, the complexity of aberrations (including cytogenetics) emphasizes that in this group of patients AML arises from a stepwise mutation acquisition model. In contrast, AYA-AML are typically characterized by favorable cytogenetic translocations and less clonal instability, dominated by the enrichment in myeloid leukemia driver gene mutations such as WT1.