Application of omics in the diagnosis, prognosis, and treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most frequent leukemia in adults with a high mortality rate. Current diagnostic criteria and selections of therapeutic strategies are generally based on gene mutations and cytogenetic abnormalities. Chemotherapy, targeted therapies, and hematopoietic stem cell transplantation (HSCT) are the major therapeutic strategies for AML. Two dilemmas in the clinical management of AML are related to its poor prognosis. One is the inaccurate risk stratification at diagnosis, leading to incorrect treatment selections. The other is the frequent resistance to chemotherapy and/or targeted therapies. Genomic features have been the focus of AML studies. However, the DNA-level aberrations do not always predict the expression levels of genes and proteins and the latter is more closely linked to disease phenotypes. With the development of high-throughput sequencing and mass spectrometry technologies, studying downstream effectors including RNA, proteins, and metabolites becomes possible. Transcriptomics can reveal gene expression and regulatory networks, proteomics can discover protein expression and signaling pathways intimately associated with the disease, and metabolomics can reflect precise changes in metabolites during disease progression. Moreover, omics profiling at the single-cell level enables studying cellular components and hierarchies of the AML microenvironment. The abundance of data from different omics layers enables the better risk stratification of AML by identifying prognosis-related biomarkers, and has the prospective application in identifying drug targets, therefore potentially discovering solutions to the two dilemmas. In this review, we summarize the existing AML studies using omics methods, both separately and combined, covering research fields of disease diagnosis, risk stratification, prognosis prediction, chemotherapy, as well as targeted therapy. Finally, we discuss the directions and challenges in the application of multi-omics in precision medicine of AML. Our review may inspire both omics researchers and clinical physicians to study AML from a different angle.

High hyperdiploid karyotype with ≥ 49 chromosomes represents a heterogeneous subgroup of acute myeloid leukemia with differential TP53 mutation status and prognosis: a single-center study from China.

High hyperdiploid karyotype with ≥ 49 chromosomes (which will be referred to as HHK) is rare in acute myeloid leukemia (AML). The European leukemia network (ELN) excluded those harboring only numerical changes (with ≥ 3 chromosome gains) from CK and listed them in the intermediate risk group, while the UK National Cancer Research Institute Adult Leukaemia Working Group classification defined ≥ 4 unrelated chromosome abnormalities as the cutoff for a poorer prognosis. Controversies occurred among studies on the clinical outcome of HHK AML, and their molecular characteristics remained unstudied. We identified 1.31% (133/10,131) HHK cases within our center, among which 48 cases only had numerical changes (NUM), 42 had ELN defined adverse abnormalities (ADV) and 43 had other structural abnormalities (STR). Our study demonstrated that: (1) No statistical significance for overall survival (OS) was observed among three cytogenetic subgroups (NUM, STR and ADV) and HHK AML should be assigned to the adverse cytogenetic risk group. (2) The OS was significantly worse in HHK AML with ≥ 51 chromosomes compared with those with 49-50 chromosomes. (3) The clinical characteristics were similar between NUM and STR group compared to ADV group. The former two groups had higher white blood cell counts and blasts, lower platelet counts, and mutations associated with signaling, while the ADV group exhibited older age, higher chromosome counts, higher percentage of myelodysplastic syndrome (MDS) history, and a dominant TP53 mutation.

Molecular characteristics in Chinese with chronic lymphocytic leukemia by next-generation sequencing: A single-center retrospective analysis.

INTRODUCTION: Although the prevalence of Asian chronic lymphocytic leukemia (CLL) patients is not as high as that of Caucasians, there are more atypical CLLs in Asia whose genetic characteristics and their clinical significance are distinct and remain unclear. METHODS: A retrospective analysis of 85 CLL samples in our center was conducted from 2019 to 2022. We used next-generation sequencing with a 172 gene panel to explore the multi-gene mutational data and the mutational status of immunoglobulin heavy variable (IGHV) gene. RESULTS: MYD88 (20.0%) was the most frequently mutated gene, much higher than in Europe, followed in order by TP53 (18.8%), NOTCH1 (14.1%), IGLL5 (11.8%), and DNMT3A (8.2%). In addition, the incidence of ATM and SF3B1 mutations was relatively lower in our centre compared to Europe. Mutated (M)-IGHV patients were more likely to have a cooccurrence of MYD88 mutation, while complex karyotype and DNMT3A mutation were more common in the unmutated (U)-IGHV group. MYD88 mutated CLL was characterized by prevalence in young males in high-risk staging, with isolated 13q deletion and concomitant mutation of IGLL5. CLL patients with MYD88 and TP53 mutation showed an unfavorable prognosis. CONCLUSION: These results would be valuable in helping to understand the characteristics and significance of cytogenetic genetics in Chinese patients with CLL.

Mutation spectrum of FLT3 and significance of non-canonical FLT3 mutations in haematological malignancy.

Fms-like tyrosine kinase 3 (FLT3) is frequently mutated in haematological malignancies. Although canonical FLT3 mutations including internal tandem duplications (ITDs) and tyrosine kinase domains (TKDs) have been extensively studied, little is known about the clinical significance of non-canonical FLT3 mutations. Here, we first profiled the spectrum of FLT3 mutations in 869 consecutively newly diagnosed acute myeloid leukaemia (AML), myelodysplastic syndrome and acute lymphoblastic leukaemia patients. Our results showed four types of non-canonical FLT3 mutations depending on the affected protein structure: namely non-canonical point mutations (NCPMs) (19.2%), deletion (0.7%), frameshift (0.8%) and ITD outside the juxtamembrane domain (JMD) and TKD1 regions (0.5%). Furthermore, we found that the survival of patients with high-frequency (>1%) FLT3-NCPM in AML was comparable to those with canonical TKD. In vitro studies using seven representative FLT3-deletion or frameshift mutant constructs showed that the deletion mutants of TKD1 and the FLT3-ITD mutant of TKD2 had significantly higher kinase activity than wild-type FLT3, whereas the deletion mutants of JMD had phosphorylation levels comparable with wild-type FLT3. All tested deletion mutations and ITD were sensitive to AC220 and sorafenib. Collectively, these data enrich our understanding of FLT3 non-canonical mutations in haematological malignancies. Our results may also facilitate prognostic stratification and targeted therapy of AML with FLT3 non-canonical mutations.

Rapid molecular response to dasatinib in Ph-like acute lymphoblastic leukemia patients with ABL1 rearrangements: case series and literature review.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype with a poor prognosis under conventional chemotherapy. Ph-like ALL has a similar gene expression profile to Philadelphia chromosome-positive (Ph+) ALL, but is highly heterogeneous in terms of genomic alterations. Approximately 10-20% of patients with Ph-like ALL harbor ABL class (e.g. ABL1, ABL2, PDGFRB, and CSF1R) rearrangements. Additional genes that form fusion genes with ABL class genes are still being researched. These aberrations result from rearrangements including chromosome translocations or deletions and may be targets of tyrosine kinase inhibitors (TKIs). However, due to the heterogeneity and rarity of each fusion gene in clinical practice, there is limited data on the efficacy of tyrosine kinase inhibitors. Here, we report three cases of Ph-like B-ALL with ABL1 rearrangements treated with the dasatinib backbone for the CNTRL::ABL1, LSM14A::ABL1, and FOXP1::ABL1 fusion genes. All three patients achieved rapid and profound remission with no significant adverse events. Our findings suggest that dasatinib is a potent TKI for the treatment of ABL1-rearranged Ph-like ALL and can be used as a first-line treatment option for such patients.

RUNX1 together with DAT mutations predicted poor outcome in acute myeloid leukemia.

We retrospectively explored the prognostic impact of DAT mutations at diagnosis in 122 RUNX1mut AML patients. RUNX1 missense mutation was dominant in the RUNT domain, and frameshift mutation was dominant in the TAD domain. DAT mutations occurred in 38.5% of RUNX1mut AML. After propensity score matching, DATpos patients had worse two-year relapse-free survival (RFS) than DATneg patients (p = .041). Moreover, RUNX1high (VAF ≥ 37.6%) patients showed poorer two-year overall survival (OS) and RFS than RUNX1low (VAF < 37.6%) patients (OS, p = .033; RFS, p = .027), especially in the RUNX1highDATpos group. Additionally, multivariate analysis confirmed that DAT mutations at diagnosis were an independent adverse factor for RFS. There were no significant differences in two-year OS and RFS between DATpos and DATneg patients or between RUNX1high and RUNX1low patients who undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Collectively, DAT mutations at diagnosis were adverse factors for RFS, and allo-HSCT could likely improve the poor outcomes of these patients.

CAR-T cell therapy followed by allogenic hematopoietic stem cell transplantation yielded comparable outcome between Ph like ALL and other high-risk ALL.

It was previously believed that patients with Ph-like ALL had poorer prognosis compared with other B-ALL subgroups due to resistance to conventional chemotherapy and lack of targeted drugs. CAR-T therapy has been successfully applied in the treatment of relapsed and refractory B-ALL. Currently, there are few data on whether CAR-T therapy can alter the outcome of Ph-like ALL. Here we included 17 Ph-like, 23 Ph+ and 51 other B-ALL patients, who received autologous CAR T-cell therapy and subsequently allogenic stem cell transplantation. Patients in the Ph-like group and B-ALL-others group were younger that those in the Ph+ group (P=0.001). Ph-like and Ph+ ALL patients showed higher white blood cell counts at diagnosis (P=0.025). The percentage of patients with active disease before receiving CAR T-cells infusion was 64.7%, 39.1% and 62.7% in the Ph-like, Ph+ and B-ALL-others groups. The response rates to CAR-T therapy were 94.1% (16/17), 95.6% (22/23) and 98.0% (50/51) in the Ph-like, Ph+ and B-ALL-others groups. Measurable residual disease negative CR was achieved in 64.7% (11/17), 60.9% (14/23) and 54.9% (28/51) in the Ph-like, Ph+ and B-ALL-others groups, respectively. The estimated rates of 3-year overall survival (65.9%±16.5%, 59.7%±10.5% and 61.6%±7.3%, P=0.758) and 3-year relapse-free survival (59.8%±14.8%, 63.1%±10.5% and 56.3%±7.1%, P=0.764) were comparable among the Ph-like, Ph+ and B-ALL-others groups. Estimated 3-year cumulative relapse rate was 7.8%±0.6%, 23.4%±0.9% and 29.0%±0.4% (P=0.241). Our findings suggest that CART followed by allo-HSCT results in a comparable prognosis in Ph-like ALL and other high-risk B-ALL.Trial registration ClinicalTrials. gov, NCT03275493, Registered on September 7, 2017, prospectively registered and NCT03614858, Registered on August 3, 2018, prospectively registered.

Insights from a rare myeloproliferative neoplasm with coexisting BCR-ABL1 fusion gene, CALR, and TET2 mutations treated with nilotinib and ruxolitinib.

Myeloproliferative neoplasms (MPNs) with concurrent BCR-ABL1 fusion gene and CALR mutation are especially rare. We report a patient with coexisting BCR-ABL1 fusion gene, CALR, and TET2 mutations who was treated with the combination of the second-generation TKI nilotinib and JAK1/JAK2 inhibitor ruxolitinib.

Integrative genomic and transcriptomic profiling reveals distinct molecular subsets in adult mixed phenotype acute leukemia.

Mixed phenotype acute leukemia (MPAL) is a subtype of leukemia in which lymphoid and myeloid markers are co-expressed. Knowledge regarding the genetic features of MPAL is lacking due to its rarity and heterogeneity. Here, we applied an integrated genomic and transcriptomic approach to explore the molecular characteristics of 176 adult patients with MPAL, including 86 patients with T-lymphoid/myeloid MPAL (T/My MPAL-NOS), 42 with Ph+ MPAL, 36 with B-lymphoid/myeloid MPAL (B/My MPAL-NOS), 4 with t(v;11q23), and 8 with MPAL, NOS, rare types. Genetically, T/My MPAL-NOS was similar to B/T MPAL-NOS but differed from Ph+ MPAL and B/My MPAL-NOS. T/My MPAL-NOS exhibited higher CEBPA, DNMT3A, and NOTCH1 mutations. Ph+ MPAL demonstrated higher RUNX1 mutations. B/T MPAL-NOS showed higher NOTCH1 mutations. By integrating next-generation sequencing and RNA sequencing data of 89 MPAL patients, we defined eight molecular subgroups (G1-G8) with distinct mutational and gene expression characteristics. G1 was associated with CEBPA mutations, G2 and G3 with NOTCH1 mutations, G4 with BCL11B rearrangement and FLT3 mutations, G5 and G8 with BCR::ABL1 fusion, G6 with KMT2A rearrangement/KMT2A rearrangement-like features, and G7 with ZNF384 rearrangement/ZNF384 rearrangement-like characteristics. Subsequently, we analyzed single-cell RNA sequencing data from five patients. Groups G1, G2, G3, and G4 exhibited overexpression of hematopoietic stem cell disease-like and common myeloid progenitor disease-like signatures, G5 and G6 had high expression of granulocyte-monocyte progenitor disease-like and monocyte disease-like signatures, and G7 and G8 had common lymphoid progenitor disease-like signatures. Collectively, our findings indicate that integrative genomic and transcriptomic profiling may facilitate more precise diagnosis and develop better treatment options for MPAL.

Case report: CD38-directed CAR-T cell therapy: A novel immunotherapy targeting CD38- positive blasts overcomes TKI and chemotherapy resistance of myeloid chronic myeloid leukemia in blastic phase.

Resistance to tyrosine kinase inhibitor (TKI) is a tough problem in the treatment of chronic myeloid leukemia in blastic phase (CML-BP), which was often associated with acquired mutations in the kinase domain and not eliminating the leukemic stem cells. The efficacy of TKI or combination with chemotherapy in CML-BP remains unsatisfactory. Chimeric antigen receptor T (CAR-T) cell immunotherapy may overcome TKI and chemotherapy resistance. However, lack of ideal targetable antigens is a major obstacle for treating patients with myeloid malignancies. CD38 is known to be expressed on most (acute myeloid leukemia) AML cells, and its lack of expression on hematopoietic stem cells renders it as a potential therapeutic target for myeloid CML-BP. We develop a CD38-directed CAR-T cell therapy for AML, and two patients with myeloid CML-BP were enrolled (NCT04351022). Two patients, harboring E255K and T315I mutation in the ABL kinase domain, respectively, were resistant to multiple TKIs (imatinib, dasatinib, nilotinib, and ponatinib) and intensive chemotherapy. The blasts in the bone marrow of two patients exhibited high expression of CD38. After tumor reduction chemotherapy and lymphodepletion chemotherapy, 1 × 107 CAR-T-38 cells per kilogram of body weight were administered. They achieved minimal residual disease-negative and BCR::ABL1-negative complete remission and experienced grade II cytokine release syndrome manifesting as fever. Our data highlighted that CAR-T-38 cell therapy may overcome TKI and chemotherapy resistance in patients with myeloid CML-BP.

Clinical characteristics and prognostic analysis of acute myeloid leukemia patients with PTPN11 mutations.

OBJECTIVES: Little is known about the clinical impact of germline/somatic mutations of PTPN11 in acute leukemia. The aim of this study was to investigate the clinical characteristics and prognostic impact of PTPN11 mutations in patients with acute myeloid leukemia (AML). METHODS: Seventy-four patients with PTPN11 mutation-positive AML treated at our institution were enrolled in this study. The prevalence of PTPN11 mutations was examined using targeted next-generation sequencing technology, and patients with AML and PTPN11 mutations were screened. Clinical characteristics, prognostic impact, and association between PTPN11 mutations and other mutations were analyzed retrospectively. RESULTS: PTPN11 mutations co-occurred more commonly with DNMT3A, NPM1, and FLT3 internal tandem duplication mutations. Compared with PTPN11 wild-type (WT) patients, PTPN11 mutation-positive AML patients presented with higher white blood cell (WBC) and platelet (PLT) counts. In 74 PTPN11 positive AML patients, PTPN11 mutations had an adverse effect on overall survival (OS) (62.5%) and a negative prognostic effect on event-free survival (EFS) (50%). Allo-hematopoietic stem cell transplantation (HSCT) abrogated the negative effect of mutations in PTPN11; the OS and EFS of AML patients with PTPN11 mutations who received transplantation were longer than those of AML patients with PTPN11 mutations who did not undergo allo-HSCT (P = 0.001, EFS; P < 0.001, OS). Discussion: Newly diagnosed PTPN11 mutation-positive AML patients with high WBC and PLT counts or presenting no remission after first induction chemotherapy suffer from high mortality rates. CONCLUSION: Given the lack of targeted therapies for PTPN11 mutations, timely HSCT is necessary for patients.

CD7-directed CAR T-cell therapy: a potential immunotherapy strategy for relapsed/refractory acute myeloid leukemia.

Relapsed/refractory acute myeloid leukemia (AML) patients generally have a dismal prognosis and the treatment remains challenging. Due to the expression of CD7 on 30% AML and not on normal myeloid and erythroid cells, CD7 is an attractive target for immunotherapy of AML. CD7-targeted CAR T-cells had demonstrated encouraging efficacy in xenograft models of AML. We report here on the use of autologous CD7 CAR T-cells in the treatment of a relapsed/refractory AML patient with complex karyotype, TP53 deletion, FLT3-ITD mutation, and SKAP2-RUNX1 fusion gene. Before the CAR T-cell therapy, the patient achieved partial remission with IA regimen and attained complete remission after reinduction therapy (decitabine and venentoclax). Relapse occurred after consolidation (CLAG regimen). Then she failed CLIA regimen combined with venetoclax and exhibited resistance to FLT3 inhibitors. Bone marrow showed 20% blasts (CD7+ 95.6%). A total dose of 5 × 106/kg CD7 CAR T-cells was administered after the decitabine +FC regimen. Seventeen days after CAR T-cells infusion, she achieved morphologic leukemia-free state. The patient developed grade 3 cytokine release syndrome. No severe organ toxicity or immune effector cell-associated neurotoxicity syndrome was observed. In summary, the autologous CD7 CAR T-cell therapy could be considered a potential approach for AML with CD7 expression (NCT04762485).Trial registration Clinical Trials.gov, NCT04762485. Registered on February 21, 2021, prospectively registered.

Molecular genetic and clinical characterization of acute myeloid leukemia with trisomy 8 as the sole chromosome abnormality.

INTRODUCTION: The aim of the study was to determine molecular genetic and clinical characterization of acute myeloid leukemia (AML) with trisomy 8 as the sole chromosome abnormality, a recurrent but rare chromosomal abnormality in AML. METHODS: Interphase fluorescence in situ hybridization, reverse transcriptase-quantitative polymerase chain reaction for gene rearrangement and next-generation sequencing (NGS) were performed on sole trisomy 8 AML patients. RESULTS: A total of 35 AML patients with trisomy 8 as the sole chromosome abnormality were screened. The most frequently mutated genes were DNMT3A(37.1%), RUNX1(28.6%), FLT3-ITD(28.6%), IDH2(22.9%), NPM1(17.1%), and ASXL1 (14.3%). The sole +8 AML patients exhibited more mutations in RUNX1 (28.6% vs. 4.8%, P = 0.001) and ASXL1 (14.3% vs. 4.8%, P = 0.039) by comparing with normal karyotype AML (NK AML) patients(n = 63). The sole +8 AML patients(n = 35) with RUNX1 or IDH2 mutations showed significantly lower WBC counts, while FLT3-ITD showed higher white blood cell (WBC) counts as compared to the corresponding wild-type groups. Total of 45.7% patients achieved complete remission (CR) after the first induction therapy. The CR rate of patients with FLT3-ITD or IDH1 mutation was significantly lower than that in the corresponding wild-type cases (P = 0.047, 0.005, respectively). The median overall survival (OS) and disease-free survival (PFS) were 18.0 (95% CI: 10.8-25.2) and 10 (95% CI: 6.7-13.3) months, respectively. FLT3-ITD mutations and allogeneic hematopoietic stem cell transplantation (allo-HSCT) were independent prognostic markers for OS in multivariable analysis. CONCLUSION: The results suggest a possible association between trisomy 8 and additional mutations that may influence clinical feature and prognosis.

Successful application of PD-1 knockdown CLL-1 CAR-T therapy in two AML patients with post-transplant relapse and failure of anti-CD38 CAR-T cell treatment.

Patients with relapsed/refractory acute myeloid leukemia (R/R AML) often show resistance to chemotherapy and have dismal outcomes. Therefore, it is urgent to develop new treatment strategies to address this problem. With tremendous achievement of chimeric antigen receptor T cells (CAR-T) therapy against B-cell malignancies, many efforts have been devoted to developing CAR-T therapy for R/R AML but with limited success, in part owing to a lack of specific targets. C-type lectin-like molecule-1 (CLL-1) is highly expressed on AML blasts with no expression on normal hematopoietic stem cells, which makes it an ideal target of immunotherapy for AML. Here, we report 2 R/R AML patients who relapsed after allogeneic stem cell transplantation and failed multiline salvage therapies including anti-CD38 CAR-T therapy, but were successfully treated with PD-1 silenced anti-CLL-1 CAR-T therapy. Both patients achieved molecular complete remission with incomplete hematologic recovery at 28 days of evaluation after CLL-1 CAR-T cell infusion. Cytokine release syndrome in cases 1 and 2 were grade 1 and 2, respectively. At the last follow-up, cases 1 and 2 had maintained continuous remission for 8 and 3 months, respectively. Our results demonstrated that CLL-1 CAR-T cells might be an effective and safe salvage therapy for AML patients with posttransplant relapse.

Companion gene mutations and their clinical significance in AML with double or single mutant CEBPA.

INTRODUCTION: We report the co-mutations in AML with CEBPAsm or CEBPAdm and their clinical features in a large cohort (n = 302) of CEBPAmut AML patients. MATERIALS AND METHODS: We retrospectively sequenced 112 genes in 302 patients with CEBPAmut using NGS, and studied the spectrum and clinical impact of co-mutations in CEBPAdm and CEBPAsm. RESULTS: ① The average number of mutations in CEBPAsm and CEBPAdm AML was comparable, but not significant (P = 0.17). ② CEBPAdm patients exhibited more mutations in CSF3R (P = 0.037), GATA2 (P = 0.022), and WT1 (P = 0.046). In contrast, CEBPAsm patients more frequently harbored mutations in NPM1 (P = 0.000), FLT3-ITD (P = 0.025) and NOTCH2 (P = 0.043), as well as mutations in signaling pathways and spliceosomes (P = 0.064, P = 0.027, respectively). ③ Patients with CEBPAsm/TET2mut or CEBPAsm /GATA2mut had higher platelet counts (both P = 0.011), while patients with CEBPAdm /TET2mut had significantly higher hemoglobin levels (P = 0.009). The CR rate of patients with FLT3-ITD mutations was significantly lower in the CEBPAsm group than the CEBPAdm group (P = 0.028). CONCLUSIONS: CEBPAsm and CEBPAdm AML are each associated with their own complex co-mutation cluster. Some co-mutations influence the clinical features and CR rate differently in patients with different CEBPA mutational status.

Clinical and molecular features of sacrum chordoma in Chinese patients.

Background: Chordoma is a rare malignant bone tumor with high recurrence and metastasis rates. Little is known about the mutational process of this incurable disease. The aim of our research was to explore the potential driver genes and signal pathways in the pathogenesis of chordoma and provide a new idea for the study of molecular biological therapy of chordoma. Methods: We performed whole-exome-sequencing (WES) on 8 sacrum chordoma tissue samples (matched to peripheral blood samples that had been drawn from patients before surgery) to identify genetic alterations in Chinese patients. We analyzed the sequencing data from known driver genes, pathway enrichment analysis and significantly mutated genes (SMGs) after quality control of sequencing, comparison of reference genomes, analysis of mutations and identification of somatic mutations. Immunohistochemistry staining, Sanger sequencing and GeneChip were used to verify the related genes obtained from the analysis of sequencing data. Results: The driver genes Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA), Phosphoinositide-3-Kinase Regulatory Subunit 1 (PIK3R1), and Phosphatase And Tensin Homolog (PTEN) were enriched in the Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway and could be potential therapeutic targets for the treatment of sacrum chordoma. The significantly mutated gene Claudin 9 (CLDN9) may play a critical role in the development and progression of sacrum chordoma. Conclusions: Collectively, our results identified the genetic signature of sacrum chordoma and could be used to develop a potential promising therapeutic strategy for the treatment of sacrum chordoma in Chinese patients.

Clinical Response to Venetoclax and Decitabine in Acute Promyelocytic Leukemia With a Novel RARA-THRAP3 Fusion: A Case Report.

Variant acute promyelocytic leukemia (APL) showed quite different aspects, and the current treatments remained challenged at present. Venetoclax, a selective inhibitor of B-cell lymphoma 2 (BCL-2), is a small molecule that has been studied in several hematologic malignancies as both monotherapy and in combination with other agents. However, there is little of its use in the treatment of APL or variant APL. In this report, we identified THRAP3 as novel RARA fusion in resembling APL, which was resistant to all-trans retinoic acid (ATRA) combined arsenic trioxide (ATO) chemotherapy. Then, the patient was salvaged by low-dose venetoclax and decitabine. The treatment in this case demonstrates the potential ability of venetoclax in variant APL, thus providing a new treatment option for all kinds of APL.