Trisomy 8 Defines a Distinct Subtype of Myeloproliferative Neoplasms Driven by the MYC-Alarmin Axis.

Despite advances in understanding the genetic abnormalities in myeloproliferative neoplasms (MPNs) and the development of JAK2 inhibitors, there is an urgent need to devise new treatment strategies, particularly for triple negative myelofibrosis (MF) patients who lack mutations in the JAK2 kinase pathway and have very poor clinical outcomes. Here we report that MYC copy number gain and increased MYC expression frequently occur in triple negative MF, and that MYC-directed activation of S100A9, an alarmin protein that plays pivotal roles in inflammation and innate immunity, is necessary and sufficient to drive development and progression of MF. Notably, the MYC-S100A9 circuit provokes a complex network of inflammatory signaling that involves numerous hematopoietic cell types in the bone marrow microenvironment. Accordingly, genetic ablation of S100A9 or treatment with small molecules targeting the MYC-S100A9 pathway effectively ameliorates MF phenotypes, highlighting the MYC-alarmin axis as a novel therapeutic vulnerability for this subgroup of MPNs.

Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes.

BACKGROUND: Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms. About 90% of cases are driven by constitutive activation of 1 of 3 genes impacting the JAK/STAT pathway: JAK2, CALR, and MPL. Triple-negative myelofibrosis (TN-MF) accounts for only 5%-10% of cases and carries the worst outcomes. Little has been described about this subset of disease. Given the marked heterogeneity surrounding disease biology, clonal architecture, clinical presentation, and poor outcomes in TN-MF, identification of features of interest and assessment of treatment response are areas in need of further investigation. PATIENTS AND METHODS: We collected and evaluated baseline clinical and molecular parameters from 626 patients with a diagnosis of myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa (Florida, US) between 2003 and 2021 and compared them based on presence or absence of the three classical phenotypic driver mutations. RESULTS: A small proportion of patients (6%) harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival time compared to the non-TN cohort (mOS 37.4 months vs. 85.7 months; P = .009) and higher rates of leukemic transformation. More pronounced thrombocytopenia and anemia, lower LDH, EPO levels, as well as lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (P < .05). Similarly, patients with TN-MF had higher risk disease per DIPSS+ and GIPSS. Mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL, and GNAS, were more commonly seen among those lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was significantly higher in TN-MF as was trisomy 8. TN patients had fewer responses (46.2% vs. 63.4%) and shorter duration of response to ruxolitinib. CONCLUSION: TN-MF is invariably associated with significantly decreased survival and more aggressive clinical behavior with higher rates of leukemic transformation and shorter duration of response to ruxolitinib. Mutations impacting RNA splicing, epigenetic modification and signaling (SRSF2, SETBP1, IDH2, CBL, and GNAS) are more common in TN-MF, which likely drive its aggressive course and may account for suboptimal responses to JAK inhibition.

Mutations highly specific for secondary AML are associated with poor outcomes in ELN favorable risk NPM1-mutated AML.

ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous malignancy with outcomes largely predicted by genetic abnormalities. Mutations of NPM1 are common in AML, occurring in ∼30% of cases, and generally considered a favorable risk factor. Mutations highly specific for secondary AML (sMut) have been shown to confer poor prognosis, but the overall impact of these mutations in the setting of favorable-risk AML defined by mutant NPM1 remains unclear. In this multicenter study of patients with AML (n = 233) with NPM1 mutation at diagnosis, we observed that patients with sMut had worse overall survival (OS) than those without sMut (15.3 vs 43.7 months; P = .002). Importantly, this finding persisted in the European LeukemiaNet (ELN) 2017-defined favorable risk subset (14.7 months vs not reached; P < .0001). Among patients who achieved NPM1 measurable residual disease (MRD) negativity, longer OS was observed in the entire cohort (P = .015) as well as in both the sMut subset (MRD negative: median OS (mOS) 73.9 months vs MRD positive: 12.3 months; P = .0170) and sMut ELN 2017-favorable subset (MRD negative: mOS 27.3 vs MRD positive: 10.5 months; P = .009). Co-occurrence of sMut and mutant NPM1 confers a poor prognosis in AML.

Transcriptional Plasticity Drives IMiD and p300 Inhibitor Resistance in Multiple Myeloma.

SUMMARY: In this issue of Blood Cancer Discovery, Neri, Barwick, and colleagues and Welsh, Barwick, and colleagues performed RNA sequencing, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and genetic studies to characterize the underlying mechanisms of immunomodulatory drug (IMiD) resistance in multiple myeloma. They demonstrated that IMiD resistance is driven by sustained expression of MYC and IRF4 via transcriptional plasticity that involves induction of ETV4 and BATF proteins, the binding of these proteins to their super-enhancers, and the recruitment of BRD4 and p300. Finally, these studies suggest IMiD and p300 inhibitor combination as a promising therapeutic strategy in multiple myeloma. See related article by Neri, Barwick, et al., p. 56 (9). See related article by Welsh, Barwick, et al., p. 34 (10).

Young patients with myelofibrosis have distinct clinicomolecular features, favorable prognosis, and commonly exhibit inflammatory comorbidities.

Myelofibrosis (MF) is commonly diagnosed in older individuals and has not been extensively studied in young patients. Given the infrequent diagnosis in young patients, analyzing this cohort may identify factors that predict for disease development/progression. We retrospectively analyzed clinical/genomic characteristics, treatments, and outcomes of patients with MF aged 18-50 years (YOUNG) at diagnosis. Sixty-three YOUNG patients were compared to 663 patients diagnosed at 51 or older (OLDER). YOUNG patients were more likely to be female, harbor driving CALR mutations, lack splicing gene mutations, and have low-risk disease by dynamic international prognostic scoring system (DIPSS) at presentation. Thirty-six patients (60%) presented with incidental lab findings and 19 (32%) with symptomatic disease. Median time to first treatment was 9.4 months (mo). Fourteen (22%) YOUNG patients underwent allogeneic hematopoietic stem cell transplant (median 57.4 mo post-diagnosis). Five (8%) developed blast-phase disease (median 99 mo post-diagnosis). Median overall survival (OS) for YOUNG patients was not reached compared to 62.8 mo in OLDER cohort (p < 0.001). The survival advantage for YOUNG patients lost significance when compared to OLDER patients lacking splicing mutations (p = 0.11). Thirty-one (49%) had comorbidities predating MF diagnosis. Presence of a comorbidity correlated with increased disease risk as measured by serial DIPSS (p=0.02). Increased disease risk correlated with decreased OS (p = 0.05). MF is rare in young adults, has distinct clinical/molecular correlates, and a favorable prognosis. The high frequency of inflammatory comorbidities and their correlation with progression of disease risk clinically highlights the role of inflammation in MF pathogenesis.

Drivers of deep molecular response and long-term outcomes in patients with core binding factor acute myeloid leukemia.

A swimmer plot on clinical course of patients undergoing allogeneic stem cell transplant for core binding factor acute myeloid leukemia.

Nonhealing Cutaneous Ulcers in a Patient With Myelodysplastic Syndrome.

A 75-year-old man with myelodysplastic syndrome that has been well controlled with lenalidomide develops multiple nonhealing cutaneous ulcers. What is your diagnosis?

Clinicopathologic characteristics, genetic features, and treatment options for acute lymphoblastic leukemia with JAK2 rearrangement-A 10-case study and literature review.

JAK2 rearrangement (JAK2-R) in acute lymphoblastic leukemia (ALL) is rare and often categorized as B-ALL with BCR::ABL1-like features based on the World Health Organization classification. We report 10 patients with JAK2-R ALL, 9 males and 1 female, with a median age 40.5 years. Eight patients presented with marked leukocytosis (median WBC, 63 × 10 9/L) and hypercellular (>95%) bone marrow with increased lymphoblasts (72%-95%). There was no evidence of bone marrow fibrosis or hypereosinophilia. Immunophenotypic analysis showed 9 B-cell and 1 T-cell neoplasms. Using fluorescence in situ hybridization (FISH) and RNA sequencing analysis, JAK2 partners were identified for 7 cases and included PCM1 (n = 4), ETV6 (n = 2) and BCR (n = 1). All patients received upfront polychemotherapy. Additionally, 2 patients received ruxolitinib, 2 received allogeneic stem cell transplant, and 1 received CAR-T therapy. The 1- and 3-year overall survival rates were 55.6% and 22.2%, respectively. A literature review identified 24 B-ALL and 4 T-ALL cases with JAK2-R reported, including 16 males, 6 females and 6 gender not stated. Many JAK2 partner-genes were reported with the most common being PAX5 (n = 7), ETV6 (n = 5), BCR (n = 4) and PCM1 (n = 2). Survival data on 13 reported cases showed 1- and 3-year overall survival rates of 41.7% and 41.7%, respectively. In summary, JAK2-R ALL occurs more often in adult males, are mostly of B-cell lineage, and associated with an aggressive clinical course. Absence of eosinophilia and bone marrow fibrosis and no evidence of preexisting/concurrent JAK2-R myeloid neoplasms distinguish JAK2-R ALL from other myeloid/lymphoid neoplasms with eosinophilia and JAK2-R.

Clinical Response to Upfront Targeted Tyrosine Kinase Inhibitors among Patients with Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Gene Fusion.

INTRODUCTION: Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusion (MLN-TK) is an entity encompassed of a heterogeneous group of rare hematopoietic neoplasms that are driven by gene fusion involving PDGDRA/B, FGFR1, JAK2, FLT3 or ETV6::ABL1. Though patients presenting with chronic phase MLN-TK with PDGFRA fusion display a favorable outcome in response to upfront TK inhibitor (TKI) therapy, the outcomes of MLNs driven by other TK fusions are not well described. In this study, we aimed to critically analyze the treatment outcomes of patients with MLN-TK, focusing on the role of upfront TKIs in both chronic- and blast-phase diseases. METHODS: The retrospective study included patients with confirmed MLN-TK from 3 centers and assessed demographic and clinical variables, treatment, and outcomes. RESULTS: Forty-two patients with confirmed MLN-TK [PDGFRA (n = 22), PDGFRB (n = 4), FGFR1(n = 10), JAK2 (n = 2); and FLT3 (n = 3)] were included. Fifteen of 25 (60%) chronic-phased patients received upfront TKI therapy had a long-term remission. Nine of 16 (60%) blast-phase patients with upfront TKIs also achieved complete remission and remained alive at a median follow-up of 20 months. All 3 patients with blast phase disease who received upfront chemotherapy without positive response did not respond to subsequent TKI therapy, emphasizing the importance of initiating TKI therapy early. Upfront TKI therapy was associated with longer overall survival in univariate analyses (HR, 0.054 [95% CI, 0.007-0.42]) and multivariate analyses (HR, 0.03 [95% CI, 0.002-0.47]). CONCLUSION: The outcomes of upfront TKI therapy are excellent for MLN-TK in both chronic and blast phases, regardless of gene abnormalities.

Disease-related thrombocytopenia in myelofibrosis is defined by distinct genetic etiologies and is associated with unique prognostic correlates.

BACKGROUND: Thrombocytopenia in patients with myelofibrosis (MF) is prognostically detrimental and poses a therapeutic challenge. MF patients with thrombocytopenia are considered high-risk by most prognostic models and their distinct phenotype has given rise to the emerging concept of cytopenic MF. Yet, the mechanisms underlying thrombocytopenia in MF are poorly understood. METHODS: This study aimed to highlight the genetic mechanisms driving low platelet counts in treatment-naive MF patients, establish their phenotypic correlates, and assess prognostic factors specific to this group of patients. RESULTS: The authors found that most patients presenting with low platelets had a clear thrombocytopenia-specific genetic abnormality involving a U2AF1 Q157 mutation, deletion 20q, molecular complexity (three or more mutations), or high-risk karyotype. Etiologic clustering did not correlate with prognosis; however, thrombocytopenic patients were found to have unique prognostic variables including low serum albumin and mutations of SRSF2 and TP53. This led to the proposal of a prognostic model (SRSF2, albumin, TP53 score) that stratifies thrombocytopenic patients as low, intermediate, or high-risk with corresponding median survivals of 93.5, 29.5, and 7.2 months, respectively. CONCLUSIONS: This study demonstrates that thrombocytopenia in MF is driven by different genetic mechanisms and is not uniformly high-risk. As novel agents with improved hematologic safety profiles enter the treatment landscape, thoughtful, risk-adapted therapeutic decisions will be required for MF patients with thrombocytopenia. LAY SUMMARY: A significant minority of patients with myelofibrosis (MF) present with low platelets. Historically, these patients have been viewed as having "high-risk" disease, but this may not be uniformly true. Our study shows that there are various different causes for low platelets in MF, some of which represent high-risk disease whereas others do not. Additionally, our study shows that genetic mutations affecting the genes SRSF2 and TP53 are uniquely problematic in this group, as is a low serum albumin level. This study helps to risk-stratify MF patients with thrombocytopenia, thereby providing more information to guide informed and individualized treatment decisions.

Gilteritinib Combined with Azacitidine as Salvage Therapy for B/Myeloid Mixed Phenotype Acute Leukemia.

Mixed phenotype acute leukemia (MPAL) is a rare group of acute leukemias with blasts that co-express antigens of more than one lineage or separate populations of blasts of different lineages. Though treatment guidelines are not well established, the standard of care in treating MPAL remains the acute lymphoblastic leukemia (ALL)-derived chemotherapeutic regimen of hyper-cyclophosphamide, vincristine, doxorubicin (also known by its trade name, Adriamycin), and dexamethasone (CVAD) followed by allogeneic stem-cell transplant (ASCT). Beyond induction chemotherapy, evidence-based treatments remain to be investigated, especially regarding patients who relapse prior to ASCT. This case report illustrates a patient with relapsed MPAL following induction hyper-CVAD who was not immediately eligible for ASCT. After brief treatment with gilteritinib alone, the patient was started on gilteritinib and azacitidine as salvage therapy and achieved and maintained complete remission with incomplete count recovery (CRi) for eight months. Targeted therapy is a novel approach to improve survival rate, but unfortunately, there have been very few studies in the context of MPAL. We report a patient with relapsed FLT3-mutant MPAL who achieved remission using a combination approach with targeted therapy.

Comparison of Different Treatment Strategies for Blast-Phase Myeloproliferative Neoplasms.

INTRODUCTION: Up to 20% of patients with myeloproliferative neoplasms (MPN) will progress to blast phase (MPN-BP). Outcomes are dismal, with intensive chemotherapy providing little benefit. Low-intensity therapy is preferred due to better tolerability, but the prognosis remains poor. Allogeneic stem cell transplant (AHSCT) is still the only potential for long term survival. PATIENTS AND METHODS: To better evaluate the initial treatment approach in MPN-BP, we performed a single-institution retrospective analysis of 75 patients with MPN-BP treated at Moffitt Cancer Center between 2001 and 2021. Patients were stratified by initial treatment: best supportive care (BSC), hypomethylating agent (HMA)-based therapy or intensive chemotherapy (IC). RESULTS: Median overall survival (mOS) for the entire cohort was 4.8 months (BSC 0.8 months, HMA 4.7 months, and IC 11.4 months). Among IC patients, improved survival was evident in those that received AHSCT (mOS 40.8 months vs. 4.9 months, p < .01). Most patients that underwent AHSCT were initially treated with IC (p < .01). All patients that underwent AHSCT had achieved complete response (CR) or CR with incomplete hematological recovery (CRi). On multivariate analysis, factors associated with improved survival were receipt of therapy (HMA or IC) (P = .017), CR/CRi (P = .037) and receipt of AHSCT (p < .001). CONCLUSION: We show that active treatment with IC improves survival, but it is mostly tied to receipt of AHSCT. IC is a reasonable approach in appropriate patients as it can provide an effective bridge to AHSCT. Other treatment strategies such as molecularly targeted therapy and novel agents are desperately needed.

Disrupting the MYC-TFEB Circuit Impairs Amino Acid Homeostasis and Provokes Metabolic Anergy.

MYC family oncoproteins are regulators of metabolic reprogramming that sustains cancer cell anabolism. Normal cells adapt to nutrient-limiting conditions by activating autophagy, which is required for amino acid (AA) homeostasis. Here we report that the autophagy pathway is suppressed by Myc in normal B cells, in premalignant and neoplastic B cells of Eµ-Myc transgenic mice, and in human MYC-driven Burkitt lymphoma. Myc suppresses autophagy by antagonizing the expression and function of transcription factor EB (TFEB), a master regulator of autophagy. Mechanisms that sustained AA pools in MYC-expressing B cells include coordinated induction of the proteasome and increases in AA transport. Reactivation of the autophagy-lysosomal pathway by TFEB disabled the malignant state by disrupting mitochondrial functions, proteasome activity, AA transport, and AA and nucleotide metabolism, leading to metabolic anergy, growth arrest, and apoptosis. This phenotype provides therapeutic opportunities to disable MYC-driven malignancies, including AA restriction and treatment with proteasome inhibitors. SIGNIFICANCE: MYC suppresses TFEB and autophagy and controls amino acid homeostasis by upregulating amino acid transport and the proteasome, and reactivation of TFEB disables the metabolism of MYC-driven tumors.

MYC overexpression is associated with an early disease progression from MDS to AML.

Recent studies demonstrated that MYC epigenetically regulates AML cell survival and differentiation by suppressing IDH1/2-TET2-5hmC signaling and that MYC overexpression is associated with poor survival outcomes in multiple AML patient cohorts. However, the oncogenic roles of MYC in MDS remain to be explored. A total of 41 patients with de novo MDS were retrospectively identified using the Total Cancer Care database at the Moffitt Cancer Center. A total of 61 % of patients had low MYC expression and 39 % of patients had high MYC expression defined as MYC reactivity by immunohistochemical staining in ≥5% of bone marrow (BM) cells at the time of MDS diagnosis. The median MDS-to-AML progression free survival (PFS) was significantly shorter in the high MYC group (median PFS 9.3 vs. 17.7 months, HR = 2.328, p = 0.013). Further, overall survival (OS) was also shorter in the high MYC patients (median OS 19.7 vs. 51.7 months, HR = 2.299, p = 0.053). Multivariate analyses demonstrated that high MYC expression is an independent poor prognostic factor for the MDS-to-AML progression (HR = 2.275, p = 0.046). Our observations indicate that MYC may play a crucial role in MDS transformation to AML and the underlying mechanisms of MYC-driven MDS clonal expansion and leukemic transformation require further investigation.

TFEB links MYC signaling to epigenetic control of myeloid differentiation and acute myeloid leukemia.

MYC oncoproteins regulate transcription of genes directing cell proliferation, metabolism and tumorigenesis. A variety of alterations drive MYC expression in acute myeloid leukemia (AML) and enforced MYC expression in hematopoietic progenitors is sufficient to induce AML. Here we report that AML and myeloid progenitor cell growth and survival rely on MYC-directed suppression of Transcription Factor EB (TFEB), a master regulator of the autophagy-lysosome pathway. Notably, although originally identified as an oncogene, TFEB functions as a tumor suppressor in AML, where it provokes AML cell differentiation and death. These responses reflect TFEB control of myeloid epigenetic programs, by inducing expression of isocitrate dehydrogenase-1 (IDH1) and IDH2, resulting in global hydroxylation of 5-methycytosine. Finally, activating the TFEB-IDH1/IDH2-TET2 axis is revealed as a targetable vulnerability in AML. Thus, epigenetic control by a MYC-TFEB circuit dictates myeloid cell fate and is essential for maintenance of AML.

Baseline and serial molecular profiling predicts outcomes with hypomethylating agents in myelodysplastic syndromes.

Hypomethylating agents (HMAs) are widely used in the treatment of myelodysplastic syndromes (MDSs), yet identifying those patients unlikely to benefit remains challenging. We assessed response and overall survival (OS) in 247 patients molecularly profiled by next-generation sequencing (NGS) before first-line HMA therapy, and a subset of 108 patients were sequenced serially during treatment. The most common mutations included TP53 (33.1%), ASXL1 (19%), TET2 (16.5%), DNMT3A (14.1%), and SRSF2 (12.1%). The overall response rate was 42.1%, with the composite TET2-mutant/ASXL1 wild-type genotype representing the strongest predictor of response (overall response rate, 62.1%; complete remission rate, 34.5%). The median OS for the cohort was 15 months, and the number of mutations detected by NGS (hazard ratio [HR], 1.22; P = .02), as well as mutations in TP53 (HR, 2.33; P = .001) and EZH2 (HR, 2.41; P = .04) were identified as independent covariates associated with inferior OS in multivariable analysis. Serial molecular profiling revealed that clearance of TP53 mutations during HMA therapy was associated with superior OS (HR, 0.28; P = .001) and improved outcome in patients proceeding to allogeneic hematopoietic cell transplantation. These data support baseline molecular profiling by NGS in MDS patients treated with HMAs and provide novel observations of sequential profiling during therapy that provide particular value in TP53-mutated disease.

Prognostic significance of serial molecular annotation in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (sAML).

The implementation of next-generation sequencing (NGS) has influenced diagnostic, prognostic, and therapeutic decisions in myeloid malignancies. However, the clinical relevance of serial molecular annotation in patients with myelodysplastic syndrome (MDS) undergoing active treatment is unknown. MDS or secondary acute myeloid leukemia (sAML) patients who had at least two NGS assessments were identified. Outcomes according to mutation clearance (NGS-) on serial assessment were investigated. Univariate and multivariate Cox regression models were used to evaluate the prognostic impact of NGS trajectory on overall survival (OS). A total of 157 patients (MDS [n = 95]; sAML [n = 52]; CMML [n = 10]) were identified, with 93% of patients receiving treatment between NGS assessments. Magnitude of VAF delta from baseline was significantly associated with quality of response to treatment. Patients achieving NGS- had significantly improved OS compared to patients with mutation persistence (median OS not reached vs. 18.5 months; P = 0.002), which was confirmed in multivariate analysis (HR,0.14; 95%CI = 0.03-0.56; P = 0.0064). Serial TP53 VAF evaluation predicts outcomes with TP53 clearance representing an independent covariate for superior OS (HR,0.22; 95%CI = 0.05-0.99; P = 0.048). Collectively, our study highlights the clinical value of serial NGS during treatment and warrants prospective validation of NGS negativity as a biomarker for treatment outcome.

Retrospective Analysis of the Clinical Use and Benefit of Lenalidomide and Thalidomide in Myelofibrosis.

INTRODUCTION: Anemia in myelofibrosis (MF) occurs frequently, is poorly addressed by US Food and Drug Administration-approved JAK inhibitors, and negatively impacts quality of life. Immunomodulatory imide agents (IMiDs) such as thalidomide and lenalidomide are among the limited treatment options that have demonstrated anemia benefit in single-arm studies. PATIENTS AND METHODS: To better understand the comparative impact of lenalidomide and thalidomide in MF patients, we analyzed 176 consecutive MF patients who received lenalidomide or thalidomide for at least 4 weeks. We sought to understand the variability in patient populations receiving lenalidomide versus thalidomide, to assess the efficacy of these agents, and to investigate clinical or genomic features that predict response. RESULTS: Clinical benefit (CB) was assessable in 83 lenalidomide- and 67 thalidomide-treated patients. Thalidomide-treated patients were more likely to have thrombocytopenia (P < .001) and high-risk disease (P = .02). Forty-one (49%) lenalidomide-treated patients were deemed to have CB, predominantly due to anemia benefit. Similarly, 28 (42%) of thalidomide-treated patients had CB attributable to anemia benefit. Overall survival was similar for lenalidomide- and thalidomide-treated patients (P = .51). Lenalidomide-treated patients with CB had longer overall survival than those who did not (P = .01). High-risk mutations were found in 12 (41%) of 29 and 20 (57%) of 35 patients treated with lenalidomide and thalidomide, respectively (P = .32). Splicing mutations were common in both cohorts, though thalidomide-treated patients were more likely to have a high-risk SRSF2 or U2AF1 Q157 mutation (P = .01). CONCLUSION: Overall, in this retrospective analysis, lenalidomide and thalidomide showed similar rates of CB in a cohort of MF patients that frequently harbored splicing mutations.

Survival outcomes in blastic plasmacytoid dendritic cell neoplasm by first-line treatment and stem cell transplant.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with dismal clinical outcomes. Conventional chemotherapies such cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) and hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose cytarabine and methotrexate (CVAD) have been commonly used for the BPDCN treatment until a recent study showed promising outcomes in patients treated with SL-401 (Tagraxofusp). In this single-institution retrospective study, we identified a total of 49 consecutive BPDCN patients. Among 42 patients who received treatment, hyper-CVAD regimen was associated with higher complete response rate compared with CHOP-based regimens or SL-401 (91% vs 50% vs 50%), although the difference did not achieve statistical significance. Furthermore, there was no significant overall survival (OS) difference between patients treated with SL-401 vs other chemotherapies as their first-line treatment (hazard ratio = 1.597; 95% CI, 0.460-5.548; P = .431). Of note, patients who received allogeneic stem cell transplant (allo-SCT) had significantly longer OS (hazard ratio = 0.160; 95% CI, 0.0453-0.56; P = .041). Extent of disease (skin vs bone marrow vs both) or younger age (<60 years old) did not have significant prognostic impact on OS. Collectively, our study confirmed the survival benefit of allo-SCT and suggests that conventional and intensive chemotherapies such as CHOP and hyper-CVAD as well as SL-401 would be comparable first-line choice for the BPDCN patients.