The patient received ATO, steroid, and azacytidine; however, within 7 days he developed respiratory distress followed by cardiac arrest which proved fatal... STAT5B-RARa t(17;17) is a rare variant of APML. It exhibits diagnostic, therapeutic, and prognostic difference with the common PML-RARa positive APL and, hence, the need for its prompt identification. Our case demonstrates the valuable role of NGS in reaching a definite diagnosis of such challenging and rare malignancy.

over 1 year ago

Next-generation sequencing

BCR (BCR Activator Of RhoGEF And GTPase) • KIT (KIT proto-oncogene, receptor tyrosine kinase) • CD33 (CD33 Molecule) • PML (Promyelocytic Leukemia) • CD34 (CD34 molecule) • PTPRC (Protein Tyrosine Phosphatase Receptor Type C) • NCAM1 (Neural cell adhesion molecule 1) • STAT5B (Signal Transducer And Activator Of Transcription 5B) • GATA2 (GATA Binding Protein 2) • ANPEP (Alanyl Aminopeptidase, Membrane) • MPO (Myeloperoxidase)

STAT5b-RARA fusion • RARA positive

Oncomine Myeloid Assay GX

azacitidine

over1year

Factors associated with thrombo-hemorrhagic deaths in patients with Acute Promyelocytic Leukemia treated with Arsenic Trioxide and All-Trans Retinoic Acid (ISTH 2023)

The induction and consolidation therapy was with Arsenic Trioxide and All-trans Retinoic Acid without chemotherapy (except hydroxyurea). The median age of 248 patients (140 males, 108 females) was 32 years (Range- 12-73). Two hundred (80.6%) patients had bleeding at presentation. The most common site of bleeding was epistaxis/gum bleed (N=128; 51.6%)(Figure 1).

over 1 year ago

Clinical

RARA (Retinoic Acid Receptor Alpha)

RARA positive

arsenic trioxide • hydroxyurea

over1year

AML AND MDS WITH RARA OVEREXPRESSION: MOLECULAR AND CLINICAL FEATURES OF PATIENTS ENROLLED IN A PHASE 2 TRIAL EVALUATING TAMIBAROTENE-BASED THERAPY (EHA 2023)

AML and MDS with RARA overexpression present with molecular features similar to those described in published datasets. Notably, SRSF2 was the most common mutation in the ND older unfit AML cohort, consistent withpublished series. While the small number of RARA -positive MDS patients precludes definitive characterization of molecular profiles, data in AML patients suggest that RARA overexpression may be agnostic to known molecular features.

over 1 year ago

P2 data • Clinical

TP53 (Tumor protein P53) • NRAS (Neuroblastoma RAS viral oncogene homolog) • IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • NPM1 (Nucleophosmin 1) • DNMT3A (DNA methyltransferase 1) • RUNX1 (RUNX Family Transcription Factor 1) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • ETV6 (ETS Variant Transcription Factor 6) • PTPN11 (Protein Tyrosine Phosphatase Non-Receptor Type 11) • RARA (Retinoic Acid Receptor Alpha) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • CEBPA (CCAAT Enhancer Binding Protein Alpha) • STAG2 (Stromal Antigen 2)

SRSF2 mutation • U2AF1 mutation • RARA overexpression • RARA positive

Oncomine Myeloid Assay GX

Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)

over1year

Molecular Heterogeneity of Pediatric AML with Atypical Promyelocytes Accumulation in Children-A Single Center Experience. (PubMed, Genes (Basel))

These cases exhibited TBL1XR1::RARB and KMT2A::SEPT6 fusions as well as mutations, e.g., NPM1 insertion and non-recurrent chromosomal aberrations. Our findings demonstrate the genetic diversity of AML with APL-like morphological features, which is of high importance for successful therapy implementation.

over 1 year ago

Journal

NPM1 (Nucleophosmin 1) • KMT2A (Lysine Methyltransferase 2A) • SEPTIN6 (Septin 6) • TBL1XR1 (TBL1X Receptor 1)

NPM1 mutation • Chr t(15;17) • RARA positive

over1year

RARA-positive AML is a Novel Patient Subset with an Actionable Target for Treatment with SY-1425, an Oral, Selective RARα Antagonist (IASL 2023)

No abstract available

over 1 year ago

Clinical

RARA (Retinoic Acid Receptor Alpha)

RARA positive

Amnolake (tamibarotene)

2years

Targeting RARA Overexpression with Tamibarotene, a Potent and Selective RARα Agonist, is a Novel Approach in AML. (PubMed, Blood Adv)

The combination of oral tamibarotene plus azacitidine was evaluated in a Phase 2 clinical study in 51 newly diagnosed unfit AML patients identified as RARA-positive (N = 22) or RARA-negative (N = 29) for RARA mRNA overexpression in peripheral blasts with a blood-based biomarker test. These results support further evaluation of tamibarotene-based treatment strategies in AML and MDS patients with RARA overexpression to provide a targeted approach with the goal of improving patient outcomes. This trial is registered at www.clinicaltrials.gov as NCT02807558.

2 years ago

Journal

RARA (Retinoic Acid Receptor Alpha)

RARA overexpression • RARA positive

azacitidine • Amnolake (tamibarotene)

2years

FISH Signal Pattern for an APL Variant Translocation with a PRKAR1A-RARA Fusion. (PubMed, J Assoc Genet Technol)

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.

2 years ago

Journal

PRKAR1A (Protein Kinase CAMP-Dependent Type I Regulatory Subunit Alpha)

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

2years

Initial Results from SELECT-AML-1, a Phase 2 Study of Tamibarotene in Combination with Venetoclax and Azacitidine in RARA-Positive Newly Diagnosed AML Patients Ineligible for Standard Induction Chemotherapy (ASH 2022)

The triplet demonstrated an initial safety profile similar to ven/aza. Data from the safety lead-in will inform triplet dosing for the randomized portion of the study.

2 years ago

Clinical • P2 data • Combination therapy

IDH2 (Isocitrate Dehydrogenase (NADP(+)) 2) • RUNX1 (RUNX Family Transcription Factor 1) • RARA (Retinoic Acid Receptor Alpha) • SRSF2 (Serine and arginine rich splicing factor 2) • BCOR (BCL6 Corepressor) • CSF3R (Colony Stimulating Factor 3 Receptor)

IDH2 mutation • SRSF2 mutation • RARA overexpression • RARA positive

Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)

2years

STAT5B-RARa Fusion Positive Variant Acute Promyelocytic Leukemia: Role of Next-Generation Sequencing in Detection of a Rare Malignancy (AMP 2022)

The patient received ATO, steroid and azacytidine; however, within seven days he developed respiratory distress followed by cardiac arrest which proved fatal... STAT5B-RARa t(17; 17) is a rare variant of APML. It exhibits diagnostic, therapeutic, and prognostic difference with the common PML-RARa positive APL and hence the need for its prompt identification. Our case demonstrates the valuable role of NGS in reaching a definite diagnosis of such challenging and rare malignancy.

2 years ago

Next-generation sequencing

STAT5b-RARA fusion • RARA positive

Oncomine Myeloid Assay GX

azacitidine

2years

AML-108 SELECT-AML-1 Trial in Progress: A Phase 2 Study of Tamibarotene in Combination With Venetoclax and Azacitidine in Previously Untreated Adult Patients Selected for RARA-Positive AML who are Ineligible for Standard Induction Therapy. (PubMed, Clin Lymphoma Myeloma Leuk)

U.S. and France.

2 years ago

Clinical • P2 data • Clinical Trial,Phase II • Journal • Combination therapy

RARA (Retinoic Acid Receptor Alpha)

RARA positive

Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)

2years

MDS-110 SELECT-MDS-1 Trial in Progress: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Tamibarotene/Azacitidine Versus Placebo/Azacitidine in Newly Diagnosed Adult Patients Selected for RARA-Positive Higher-Risk MDS. (PubMed, Clin Lymphoma Myeloma Leuk)

Azacitidine will be administered at 75 mg/m IV/SC daily on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally on days 8-28 of each 28-day cycle. Response is assessed per the modified IWG MDS criteria (Cheson 2006).

2 years ago

Clinical • P3 data • Clinical Trial,Phase III • Journal

RARA (Retinoic Acid Receptor Alpha)

RARA overexpression • RARA positive

azacitidine • Amnolake (tamibarotene)

over2years

A novel RARA-SNX15 fusion in PML-RARA-positive acute promyelocytic leukemia with t(11;17;15)(q13;q21.2;q24.1). (PubMed, Int J Hematol)

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.

over 2 years ago

Journal

PML (Promyelocytic Leukemia)

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

over2years

A RANDOMIZED, DOUBLE-BLIND, PHASE 3 STUDY OF TAMIBAROTENE/AZACITIDINE VERSUS PLACEBO/AZACITIDINE IN NEWLY DIAGNOSED ADULT PATIENTS SELECTED FOR RARA-POSITIVE HR-MDS (SELECT-MDS-1) (EHA 2022)

Results Approximately 190 patients will be randomized 2:1 and stratified by IPSS-R risk group and geographic region, providing 90% power to detect the difference in CR rates between the experimental and control arms, respectively, with one-sided alpha of 0.025. Conclusion The SELECT-MDS-1 trial opened to enrollment in February 2021, recruitment is ongoing, with sites located in North America, Israel, and Europe (NCT04797780).

over 2 years ago

Clinical • P3 data

RARA (Retinoic Acid Receptor Alpha)

RARA overexpression • RARA positive

azacitidine • Amnolake (tamibarotene)

over2years

TAMIBAROTENE IN COMBINATION WITH VENETOCLAX AND AZACITIDINE IN PREVIOUSLY UNTREATED ADULT PATIENTS SELECTED FOR RARA-POSITIVE AML WHO ARE INELIGIBLE FOR STANDARD INDUCTION THERAPY (SELECT AML-1) (EHA 2022)

Results Response rates and 95% exact binomial confidence intervals will be calculated by treatment group. Conclusion The SELECT AML-1 trial ( NCT04905407) opened in July 2021 with ongoing enrollment.

over 2 years ago

Clinical • Combination therapy

RARA (Retinoic Acid Receptor Alpha)

RARA overexpression • RARA positive

Venclexta (venetoclax) • azacitidine • Amnolake (tamibarotene)

over2years

A Study for Improving the Outcome of Childhood Acute Promyeloid Leukemia (clinicaltrials.gov)

P4, N=176, Completed, South China Children's Leukemia Group | Enrolling by invitation --> Completed | Trial completion date: Sep 2022 --> Oct 2021

over 2 years ago

Trial completion • Trial completion date

PML (Promyelocytic Leukemia)

RARA positive

cytarabine • methotrexate • mitoxantrone • arsenic trioxide • mercaptopurine

3years

Assessment of Minimal/Measurable Residual Disease Testing in Acute Myeloid Leukaemia By Molecular Methods in an Interlaboratory Study (ASH 2021)

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.

3 years ago

NPM1 (Nucleophosmin 1) • RUNX1 (RUNX Family Transcription Factor 1) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • PML (Promyelocytic Leukemia)

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

3years

A Study for Improving the Outcome of Childhood Acute Promyeloid Leukemia (clinicaltrials.gov)

P4, N=162, Enrolling by invitation, South China Children's Leukemia Group | Trial primary completion date: Sep 2020 --> Dec 2021

3 years ago

Clinical • Trial primary completion date

PML (Promyelocytic Leukemia)

RARA positive

cytarabine • methotrexate • mitoxantrone • arsenic trioxide • mercaptopurine

over3years

Mutational profile of ZBTB16-RARA-positive acute myeloid leukemia. (PubMed, Cancer Med)

Our data suggest the association of mutations of the ARID1A gene and of the other members of the SWI/SNF chromatin remodeling complexes with ZBTB16-RARA+AMLs, where they may support the peculiar disease phenotype.

over 3 years ago

Journal

ARID1A (AT-rich interaction domain 1A) • SMARCA4 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 4) • ARID2 (AT-Rich Interaction Domain 2) • ZBTB16 (Zinc Finger And BTB Domain Containing 16)

ARID1A mutation • SMARCA4 mutation • RARA positive • ZBTB16-RARA fusion

over3years

Clinicopathological Evaluation of Acute Leukemias in a Tertiary Care Hospital: A Cross-Sectional Study. (PubMed, Turk Patoloji Derg)

The application of revised 4th edition WHO 2016 classification confers uniformity in reporting acute leukemia cases that aids in the treatment by using targeted therapies and helps in the prediction of prognosis. The WHO classification for acute leukemias is very objective, therapy oriented and the need of the hour.

over 3 years ago

Clinical • Observational data • Journal

NPM1 (Nucleophosmin 1) • RUNX1 (RUNX Family Transcription Factor 1) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • PML (Promyelocytic Leukemia) • CEBPA (CCAAT Enhancer Binding Protein Alpha)

NPM1 mutation • CEBPA mutation • RARA positive