Myeloid Neoplasms Research Articles

Isolated intracranial myeloid sarcoma as an acute myeloid leukemia relapse: A case report

Abstract Introduction/Objective Adequate assessment during intraoperative consultation on a patient with a brain mass is imperative to provide critical information that will direct the therapeutic approach during surgery. Methods/Case Report The patient is a 67-year-old female with acute myeloid leukemia (AML) on maintenance therapy and in remission for the past 2 years that developed altered mental status and seizures. Imaging revealed a diffuse intra-axial mass within the corpus callosum and right hypothalamic region. A brain stereotactic biopsy was performed. Blood work showed mild leukopenia (3.63x109/L), thrombocytopenia (platelet count of 82x109/L), and an essential normal hemoglobin level of 11.9 g/dL. A frozen section assessment during intraoperative consultation revealed an infiltration of small blue cells, suggesting a hematolymphoid process. Further histological assessment showed small to intermediate-sized monomorphic cells in sheets and around the vessels with open fine chromatin, prominent nuclei, and scant cytoplasm admixed with tingible body macrophages. Differential diagnoses included high- grade B-cell lymphoma, Burkitt lymphoma, mantle cell lymphoma blastoid variant, lymphoblastic lymphoma, and myeloid sarcoma (MS). The tumor cells were positive for CD34, CD43, and MPO (subset) and negative for CD20, PAX5, TdT, CD3, and AE1/AE3 by immunohistochemical staining, consistent with MS. Concurrent bone marrow biopsy with flow cytometric evaluation showed progressive trilineage hematopoiesis without evidence of residual leukemia. Results (if a Case Study enter NA) NA Conclusion Intracranial MS is extremely rare, and literature reviews are limited to primarily case reports. MS can occur before, during, or after the initial presentation of AML. Interestingly, this patient had an isolated intracranial myeloid sarcoma as an AML relapse without bone marrow involvement. We aim to increase the awareness of isolated recurrence of AML in the form of an intracranial MS; this disease warrants consideration in patients with a history of a myeloid neoplasm who present with neurological symptoms despite the absence of peripheral disease.

Different inflammatory, fibrotic, and immunologic signatures between pre-fibrotic and overt primary myelofibrosis.

Primary myelofibrosis (PMF) is a myeloid proliferative neoplasm (MPN) characterized by bone marrow (BM) fibrosis. Pre-fibrotic PMF (pre-PMF) progresses to overt PMF. Megakaryocytes (MKs) play a primary role in PMF; however, the functions of MK subsets and those of other hematopoietic cells during PMF progression remain unclarified. Therefore, we analyzed BM aspirates in pre-PMFs, overt PMFs, and other MPNs using single-cell RNA sequencing (scRNA-seq). We identified 14 cell types with subsets, including hematopoietic stem and progenitor cells (HSPCs) and MKs. HSPCs in overt PMF were MK-biased and inflammation/fibrosis-enriched. Among MKs, the epithelial-mesenchymal transition (EMT)-enriched subset was abruptly increased in overt PMF. MKs in non-fibrotic/non-PMF MPN were MK differentiation-enriched, whereas those in fibrotic/non-PMF MPN were inflammation/fibrosis-enriched. Overall, the inflammation/fibrosis signatures of the HSPC, MK, and CD14+ monocyte subsets increased from pre-PMF to overt PMF. Cytotoxic and dysfunctional scores also increased in T and NK cells. Clinically, MK and HSPC subsets with high inflammation/fibrosis signatures were frequent in the patients with peripheral blood blasts ≥1%. scRNA-seq predicted higher cellular communications of MK differentiation, inflammation/fibrosis, immunologic effector/dysfunction, and tumor-associated signaling in overt PMF than pre-PMF. However, no decisive subset emerged during PMF progression. Our study demonstrated that HSPCs, monocytes, and lymphoid cells contribute to PMF progression, and subset specificity existed regarding inflammation/fibrosis and immunologic dysfunction. PMF progression may depend on multiple cell types' alterations, and EMTenriched MKs may be potential targets for the diagnosis and therapy of the progression.

Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications.

Myeloid neoplasms with and without preexisting platelet disorders frequently develop in association with an underlying germline predisposition. Germline alterations affecting ANKRD26, CEBPA, DDX41, ETV6, and RUNX1 are associated with nonsyndromic predisposition to the development of myeloid neoplasms including acute myeloid leukemia and myelodysplastic syndrome. However, germline predisposition to myeloid neoplasms is also associated with a wide range of other syndromes, including SAMD9/9L associated predisposition, GATA2 deficiency, RASopathies, ribosomopathies, telomere biology disorders, Fanconi anemia, severe congenital neutropenia, Down syndrome, and others. In the fifth edition of the World Health Organization (WHO) series on the classification of tumors of hematopoietic and lymphoid tissues, myeloid neoplasms associated with germline predisposition have been recognized as a separate entity. Here, we review several disorders from this WHO entity as well as other related conditions with an emphasis on the molecular pathogenesis of disease and accompanying somatic alterations. Finally, we provide an overview of establishing the molecular diagnosis of these germline genetic conditions and general recommendations for screening and management of the associated hematologic conditions.

B-232 One Year Post-Implementation Experience Using a Custom Designed DNA Contamination Detection Module for a Clinical Myeloid Neoplasm Next Generation Sequencing Assay

Abstract Background In complex automated clinical laboratory Next Generation Sequencing (NGS) workflows, numerous opportunities exist for contamination events to occur. For oncology testing applications, detection of these events is crucial for accurate results reporting. A contamination detection module (MICon) using microhaplotype (MH) regions and an in-house designed analysis model was developed for use in a NGS assay for myeloid neoplasms (NGSHM) [1]. Variant detection for NGSHM has a validated analytical sensitivity of 2% variant allele frequency (VAF). Gross contamination events can potentially cause erroneous false positive variant detection whereas true low VAF mutations may be masked and evade detection. The following study was performed to evaluate MICon module performance on samples processed over the course of a year. Methods MH regions contain highly conserved tandem single nucleotide polymorphisms (SNPs) with high global heterogeneity occurring within a 300-nucleotide span. From the work of Kidd et al [2], 27 MH regions covering 92 SNPs and spanning 16 chromosomes were selected for inclusion in the 47 gene NGSHM target-capture panel. Sequencing was performed on a NovaSeq 6000 and analyzed through an internal bioinformatics pipeline, which incorporates the MICon module. MICon uses a binary classification model incorporating VAFs from MH regions, number of MH genotypes, and the contamination estimation score from verifyBamID to compute a single value on a 0-100 scale. Scores <50 are classified as non-contaminated and scores ≥50 require further investigation. Results The dataset was comprised of 10,990 samples. A total of 10,232 patient cases (93.1%) had non-contaminated MICon scores <50. Control replicates accounted for 261 samples (2.4%). There were 497 patient cases (4.5%) with MICon scores ≥50. Of the 497 patient cases, 137 (27.6%) had undergone hematopoietic stem cell transplantation (HSCT) and 114 (22.9%) contained gross chromosomal abnormalities, representing iatrogenic or tumor biological factors. An additional 135 (27.2%) of cases were contaminated from laboratory processing errors, 45 (9.1%) occurred due to chemistry failures during run processing, and 66 (13.2%) had an undetermined cause for a high score, representing laboratory-related and unknown factors. Overall, the 135 laboratory processing errors detected accounted for 1.3% of patient cases analyzed by the laboratory. These cases were repeated, and the non-contaminated results were accurately reported. Conclusions Herein it was shown the implementation of MICon has improved patient safety over the course of a year. The 1.3% of patient cases identified as arising from laboratory processing errors were successfully reprocessed. While the overall rate of laboratory processing errors appears low, the absolute number can be significant in a high-volume test setting, despite reliance on highly automated processes. Value is added by MICon through identifying errors that could result in the release of inaccurate patient results. By detecting previously unrealized errors, MICon has become an invaluable asset to the NGSHM assay by enhancing patient laboratory testing safety.

Beyond myeloid neoplasms germline guidelines: Validation of the thresholds criteria in the search of germline predisposition variants

AbstractIntroductionGermline predisposition to myeloid neoplasms can be suspected in patients younger than 50 years or when harboring mutations with a variant allele frequency (VAF) higher than 30% for point mutations in specific genes. To investigate the VAF thresholds’ accuracy we have explored the prevalence of germline variants below the 30% VAF threshold.MethodsA total of 40 variants with VAF lower than 30% in bone marrow samples of myeloid neoplasm patients were selected and studied in CD3+ cells.ResultsAll the selected variants were not found in CD3+ cells except one variant in the SF3B1 gene. However, the whole series was found somatic. Selected variants were also evaluated with our previously studied series of 52 variants with VAF higher than 30%.ConclusionOur study suggests that variants with VAF below 30% are strong somatic candidates but the variants with VAF higher than 30% cannot be considered of germline origin.

Tattoos and Risk of Hematologic Cancer: A Population-Based Case-Control Study in Utah.

Approximately one-third of US adults have a tattoo, and the prevalence is increasing. Tattooing can result in long-term exposure to carcinogens and inflammatory and immune responses. We examined tattooing and risk of hematologic cancers in a population-based case-control study with 820 cases diagnosed 2019-2021 and 8200 frequency-matched controls, ages 18-79 years. We calculated odds ratios (OR) and 95% confidence intervals (CI) using multivariable-adjusted logistic regression models. The prevalence of tattooing was 22% among Hodgkin lymphoma (HL) cases, 11% among non-Hodgkin lymphoma (NHL) cases, 16% among myeloid neoplasm cases, and 15% among controls. Though there were no clear patterns of associations between ever receiving a tattoo and risk of HL, NHL, or myeloid neoplasms overall, in analyses restricted to ages 20-60 years, ever receiving a tattoo (OR 2.06 [95% CI 1.01, 4.20]) and receiving a tattoo 10+ years prior (OR 2.64 [95% CI 1.23, 5.68]) were associated with an aggregated group of rarer mature B-cell NHLs. We also observed elevated risks for a 10+ year latency for myelodysplastic syndromes and chronic myeloid leukemia (OR 1.48 [95% CI 0.40, 5.41], and OR 1.24 [95% CI 0.45, 3.43], respectively). Though estimates were imprecise, we found some suggestive evidence that tattooing may be associated with an increased risk of certain hematologic cancer subtypes. With an estimated 46% prevalence of tattooing in US individuals ages 30-49, additional studies are needed to understand the degree to which these exposures may be associated with hematologic cancer risk.

Clonal hematopoiesis and hematological malignancy.

Clonal hematopoiesis (CH), the expansion of hematopoietic stem cells and their progeny driven by somatic mutations in leukemia-associated genes, is a common phenomenon that rises in prevalence with advancing age to affect most people older than 70 years. CH remains subclinical in most carriers, but, in a minority, it progresses to a myeloid neoplasm, such as acute myeloid leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm. Over the last decade, advances in our understanding of CH, its molecular landscape, and the risks associated with different driver gene mutations have culminated in recent developments that allow for a more precise estimation of myeloid neoplasia risk in CH carriers. In turn, this is leading to the development of translational and clinical programs to intercept and prevent CH from developing into myeloid neoplasia. Here, we give an overview of the spectrum of CH driver mutations, what is known about their pathophysiology, and how this informs the risk of incident myeloid malignancy.

A-149 For something completely different: granuloma annulare-like histiocytosis as skin specific manifestation of ETV6::SYK rearranged myeloid neoplasm with eosinophilia

A-149 For something completely different: granuloma annulare-like histiocytosis as skin specific manifestation of ETV6::SYK rearranged myeloid neoplasm with eosinophilia

Rare Non-Cryptic NUP98 Rearrangements Associated With Myeloid Neoplasms and Their Poor Prognostic Impact.

NUP98 rearrangements (NUP98r), associated with various hematologic malignancies, involve more than 30 partner genes. Despite their clinical significance, reports on the clinicopathological characteristics of rare NUP98r remain limited. We investigated the characteristics of patients with myeloid neoplasms harboring NUP98r among those identified as having 11p15 translocation in chromosomal analysis. We retrospectively reviewed results from bone marrow chromosomal analyses conducted between 2011 and 2023 and identified 15 patients with 11p15 translocation. Subsequently, NUP98r were evaluated using FISH and/or reverse transcription PCR, and clinical and laboratory data of the patients were analyzed. NUP98r were identified in 11 patients initially diagnosed as having AML (N=8), myelodysplastic syndrome (N=2), or chronic myelomonocytic leukemia (N=1), with a median age of 44 yrs (range, 4-77 yrs). Three patients had a history of chemotherapy. In total, five NUP98 fusions were identified: NUP98::DDX10 (N=3), NUP98::HOXA9 (N=2), NUP98::PSIP1 (N=2), NUP98::PRRX1 (N=1), and NUP98::HOXC11 (N=1). Patients with NUP98r exhibited a poor prognosis, with a median overall survival of 12.0 months (95% confidence interval [CI], 3.4-29.6 months) and a 5-yr overall survival rate of 18.2% (95% CI, 5.2%-63.7%). Our study revealed the clinical and genetic characteristics of patients with myeloid neoplasms harboring rare and non-cryptic NUP98r. Given its association with poor prognosis, a comprehensive evaluation is crucial for identifying previously underdiagnosed NUP98r in patients with myeloid neoplasms.

Myeloid neoplasm post cytotoxic treatment in patients with multiple myeloma.

Myeloid neoplasm post cytotoxic treatment in patients with multiple myeloma.

Comprehensive Genomic Profiling in Non-Myeloid Hematologic Malignancies Identifies Variants That Can Alter Clinical Practice.

Comprehensive genomic profiling (CGP) is frequently adopted to direct the clinical care of myeloid neoplasms and solid tumors, but its utility in the care of lymphoid and histiocytic cancers is less well defined. In this study, we aimed to evaluate the frequency at which mutations identified by CGP altered management in non-myeloid hematologic malignancies. We retrospectively examined the CGP results of 105 samples from 101 patients with non-myeloid hematologic malignancies treated at an academic medical center who had CGP testing between 2014 and 2021. CGP revealed one or more pathogenic or likely pathogenic variant in 92 (88%) of samples and 73 (72%) of tested patients had one or more mutations with diagnostic, prognostic, or therapeutic significance. The identification of a resistance variant resulted in the suspension of the active treatment or affected subsequent treatment choice in 9 (69%) out of 13 patients. However, the presence of a therapy sensitizing variant only led to consideration of a biomarker-directed therapy in 6 (10%) out of 61 patients. Overall, CGP of non-myeloid hematologic malignancies identified clinically significant variants in 72% of patients and resulted in a change in management in 22% of patients.

Sarcomatoid Morphology in Pediatric Langerhans Cell Neoplasm Does Not Always Predict Aggressive Clinical Course.

Langerhans cell sarcoma (LCS), a rare malignant neoplasm in the general category of myeloid neoplasms characterized by overtly malignant Langerhans cells (LC) with conspicuous mitotic activity including atypical forms. Although most cases occur in adults, rare examples of LCS have been reported in children with variable clinical outcome. We present 2 childhood cases of Langerhans cell neoplasm with high grade sarcomatous features and OSBPL9::BRAF fusion and BRAF V600E mutation.

Characterisation and prognostic impact Of ZRSR2 mutations in myeloid neoplasms.

Characterisation and prognostic impact Of ZRSR2 mutations in myeloid neoplasms.

Genomic Landscape of Myelodysplastic/Myeloproliferative Neoplasms: A Multi-Central Study.

The accurate diagnosis and classification of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) are challenging due to the overlapping pathological and molecular features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). We investigated the genomic landscape in different MDS/MPN subtypes, including chronic myelomonocytic leukemia (CMML; n = 97), atypical chronic myeloid leukemia (aCML; n = 8), MDS/MPN-unclassified (MDS/MPN-U; n = 44), and MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T; n = 12). Our study indicated that MDS/MPN is characterized by mutations commonly identified in myeloid neoplasms, with TET2 (52%) being the most frequently mutated gene, followed by ASXL1 (38.7%), SRSF2 (34.7%), and JAK2 (19.7%), among others. However, the distribution of recurrent mutations differs across the MDS/MPN subtypes. We confirmed that specific gene combinations correlate with specific MDS/MPN subtypes (e.g., TET2/SRSF2 in CMML, ASXL1/SETBP1 in aCML, and SF3B1/JAK2 in MDS/MPN-RS-T), with MDS/MPN-U being the most heterogeneous. Furthermore, we found that older age (≥65 years) and mutations in RUNX1 and TP53 were associated with poorer clinical outcomes in CMML (p < 0.05) by multivariate analysis. In MDS/MPN-U, CBL mutations (p < 0.05) were the sole negative prognostic factors identified in our study by multivariate analysis (p < 0.05). Overall, our study provides genetic insights into various MDS/MPN subtypes, which may aid in diagnosis and clinical decision-making for patients with MDS/MPN.

Perspectives on drug development in chronic myelomonocytic leukemia: changing the paradigm

AbstractDrug development for chronic myelomonocytic leukemia (CMML) has failed to parallel the recent success observed in related myeloid neoplasms. To address these shortcomings, the US Food and Drug Administration (FDA) held a “Mini-symposium on CMML: Current State of the Art and Trial Design” in September 2023. This symposium brought together a panel of key FDA regulators and academic experts in CMML drug development to discuss challenges and provide perspectives on future drug development for this disease. The panel explored unique challenges that underlie the lack of therapeutic advances in CMML to date and discussed relevant topics such as clinical trial design, study end points, and key regulatory considerations. This article summarizes the key points of discussion from this symposium to facilitate advancements in the field.

Site-discordant expression of myeloid cell nuclear differentiation antigen in blastic plasmacytoid dendritic cell neoplasm

Abstract Objectives Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic neoplasm that can show clinical, morphologic, and immunophenotypic overlap with acute myeloid leukemia. Myeloid cell nuclear differentiation antigen (MNDA) is a nuclear protein expressed by myelomonocytic cells previously reported to be reliably absent in BPDCN and proposed as a useful adjunct for the distinction of BPDCN and acute myeloid leukemia. We encountered a case of BPDCN that showed strong nuclear expression of MNDA in bone marrow and breast samples and weak to absent expression in skin samples, prompting us to reevaluate the expression of MNDA in BPDCN. Methods We collected all available BPDCN cases from the Stanford University archives collected in the past 10 years and subjected them to MNDA immunohistochemistry. In select cases, molecular profiling by next-generation sequencing was performed. Results We found 4 cases (of 8 total examined [50%]) with convincing site-discordant MNDA expression. This expression was seen in 3 of 6 (50%) bone marrow samples, 1 of 2 (50%) breast soft tissue samples, and 3 of 14 (up to 21%) skin samples and was not obviously predicted by age, sex, history of myeloid neoplasm, or treatment history. In 2 cases, MNDA was strongly expressed in 2 distinct sites (breast/bone marrow, skin/bone marrow) and negative in subsequent samples. Conclusions Our findings suggest that MNDA expression in BPDCN is anatomic site dependent and transient, with noncutaneous infiltrates showing more frequent expression than cutaneous infiltrates. These results caution against the use of MNDA to exclude BPDCN when considering the differential diagnosis of a blastic extramedullary infiltrate.

Standardized bone marrow assessment, risk variables, and survival in dogs with myelodysplastic syndrome and acute myeloid leukemia.

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are heterogeneous neoplasms of hematopoietic stem cells that are challenging to diagnose, differentiate, and prognosticate. Cytogenetic and mutational analyses are useful in humans but unavailable for dogs, where diagnosis and classification still rely largely on hematologic and morphologic assessment. The objectives of this study were to apply a classification scheme to myeloid neoplasms and to assess outcome in relation to predictor variables. Keyword search of a laboratory database, application of sequential exclusion criteria, and consensus from 3 reviewers yielded 70 cases of myeloid neoplasia with hematology results, and cytologic (11), histologic (14), or both (45) types of marrow specimens. Based on blast percentage and morphology, 42 cases were classified as MDS and 28 as AML. Dogs with MDS had significantly lower body weights, hemoglobin concentrations and blood blasts, and higher red blood cell size variability and platelet numbers than dogs with AML. Estimates of median survival using Kaplan-Meier curves for dogs with MDS and AML were 384 and 6 days, respectively (P < .001). The instantaneous risk of death for dogs with MDS was approximately 5× lower than that of dogs with AML. Significant predictor variables of survival were body weight, white blood cell count, platelet count, and percent blood blasts (P < .05). Hazard ratios (HRs) derived from best-fitting Cox regression models were 1.043, 0.998, and 1.061 for increased neutrophils, decreased platelets, and increased blood blasts, respectively. Findings from this study suggest that hematologic and morphologic variables are useful to predict outcomes in myeloid neoplasia.

Association between ABO blood groups and hematological myeloid neoplasms in adolescents and adults.

Prior research suggests a potential link between ABO blood types and susceptibility to various malignancies. The correlation between ABO blood types and hematological myeloid neoplasms, however, remains inadequately explored. This study investigates the association between ABO blood groups and the incidence of hematological myeloid neoplasms in adolescents and adults. In this retrospective clinical study, 1,022 adolescent and adult cases of myeloid neoplasms diagnosed at our institution were initially considered. After excluding conditions potentially linked to ABO blood types from prior studies, 792 eligible cases were analyzed. These cases were categorized based on disease subtypes and compared with a control group for blood type distribution. Our findings reveal a significantly higher prevalence of blood type A in patients with myeloid neoplasms compared to the control group, except for chronic myelocytic leukemia and myeloproliferative neoplasms. Conversely, the prevalence of blood type AB in myeloid neoplasms was notably lower than in the control group. The study suggests a potential association between ABO blood types and the risk of developing hematological myeloid neoplasms in adolescents and adults. Further research is warranted to elucidate the underlying mechanisms of this relationship.

Complete morphologic response to gilteritinib in ALK-rearranged acute myeloid leukemia

The cytogenetic abnormality inv(2)(p23q13) in acute myeloid leukemia (AML) results in a fusion of RANBP2 with ALK. This fusion makes ALK constitutively active and acts as a driver for the proliferation of AML cell lines. Gilteritinib, a FLT3 inhibitor approved in AML, also can inhibit ALK among other receptor tyrosine kinases. A 75-year-old-woman with a history of essential thrombocythemia (ET) and a presumed germline DDX41 mutation developed ALK-fusion positive AML and despite standard therapies was transfusion-dependent and globally declining. The patient has been on gilteritinib with an ongoing response of more than one year with near normal blood counts and no evidence of AML. The fact that she was found to harbor a presumed germline DDX41 alteration may account for why she developed, and yet survived, two myeloid neoplasms (ET and AML). Additionally, this demonstrates that gilteritinib is clinically active as an ALK inhibitor, and could be considered for use in any AML patient presenting with an inv(2(p23q13)) translocation. Finally, it is an example of using a disease-agnostic, precision medicine approach to arrive at a beneficial treatment.

Therapy-related myeloid neoplasms following curative treatment of acute promyelocytic leukemia: incidence, correlation with therapeutic regimen, and future directions.

All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) have revolutionized the treatment of acute promyelocytic leukemia (APL), offering a cure rate of > 80%. Along with improved survival, the long-term consequences of anti-APL therapy are becoming increasingly apparent, including potential therapy-related myeloid neoplasms (t-MNs). T-MNs are well known to arise after cytotoxic chemotherapy, but the leukemogenic potential of regimens utilizing only ATRA/ATO is not well established. The objective of this study is to examine the incidence, long-term risk, and clinicopathologic features of t-MNs arising after anti-APL therapy and how they correlates with the therapeutic regimen employed. We retrospectively collected treated APL patients between 01/2001 and 02/2021, categorized them into ATRA/ATO + chemo and ATRA/ATO groups based on the regimen used, and evaluated for the development of t-MN. A total of 110 APL patients were identified, including 67 (61%) treated with ATRA/ATO + chemo and 43 (39%) treated with ATRA/ATO only. Overall, 4/110 (3.6%) patients developed t-MNs, with all four emerging in the ATRA/ATO + chemo group. Ultimately, the incidence of t-MN in ATRA/ATO + chemo group was significantly higher compared with ATRA/ATO only group(5.97% vs. 0.0%, respectively; p = 0.0289). Our data spanning over two decades suggests that conventional chemotherapy for APL is associated with a small but significant risk of t-MN, whereas ATR/ATO does not carry this risk. This takes on new significance, considering several recent and ongoing trials have shown that a chemotherapy-free approach might become feasible for all risk APL types in the near future. Consequently, the omission of leukemogenic and arguably unnecessary chemotherapy from APL regimens may reduce the incidence of t-MNs in long-term survivors without sacrificing their cure rates.