Lancet, Jeffrey E.

Abstract Background: Chronic myelomonocytic leukemia (CMML) is a universally fatal adult myeloid neoplasm with a median survival of 32 months and no approved therapies that alter its natural history. Although most patients initially present asymptomatically, disease progression (DP) is inevitable and its biological triggers remain poorly understood. Anecdotes and small case series suggest that acute inflammatory events (AIE) may precipitate hyperleukocytosis and DP in some patients, but fragmented care in the U.S. has hindered large-scale retrospective analyses. To address this gap, we launched a prospective, multi-institutional observational study to systematically evaluate the relationship between AIEs and DP. Our aim is to identify modifiable, cell-extrinsic stressors that contribute to disease destabilization and inform strategies for prolonging the indolent phase of CMML. Methods: We enrolled patients with WHO-defined CMML in a clinically asymptomatic state, defined by: (1) MPN-SAF TSS <20, (2) no CMML-directed therapy, (3) no symptomatic splenomegaly, and (4) transfusion independence. Key exclusions included active malignancy, uncontrolled infection, or inability to attend monthly visits. Over 24 months, participants underwent monthly interviews to document AIEs, including flares of chronic illness e.g. gout, infections, surgery procedures, cardiovascular events, and trauma. AIE severity was graded by hospitalization status. Blood samples were collected at each visit, with bone marrow collected when clinically indicated. Cytokine profiling was performed using Olink Reveal assays, and genomic data were integrated to assess mutation-specific inflammatory patterns. DP was defined by worsening symptoms (MPN-SAF TSS ≥20 with ≥50% increase), new transfusion needs, therapy initiation, symptomatic splenomegaly, or transformation to CMML-2/AML. Descriptive statistics summarized baseline and AIE data. Progression-free (PFS) and overall survival (OS) were analyzed using Kaplan–Meier and Cox regression models. Results: A total of 102 patients were enrolled over 2 years, with a median follow-up of 1 year (range, 0.5–1.5). The median age was 72 years; 71 were male and 31 female. By FAB criteria, 38 had myeloproliferative-type CMML, and 8 met WHO 2022 criteria for CMML-2. CPSS-Mol risk distribution was: 49.0% low, 26.5% intermediate-1, 37.3% intermediate-2, and 3.99% high. A total of 260 AIE were recorded in 77 patients. The most common AIEs were surgical procedures (n=115 events in 53 patients), flares of chronic disease (n=99 in 38), and infections (n=87 in 47). DP occurred in 28 patients: 18 met symptom-defined criteria, 13 met disease-defined criteria, and 3 met both. Longitudinal labs showed significant post-AIE increases in WBC (6.29 → 7.73 ×10⁹/L, p = 0.02) and platelets (112 → 131 ×10⁹/L, p = 0.03), with no change in hemoglobin (p = 0.27). Progressors had significantly lower hemoglobin than non-progressors (11.6 vs. 12.7 g/dL, p = 0.037), with no differences in WBC or platelet counts (p > 0.5). Among those with DP, 25 of 28 had at least one AIE. AIE presence was significantly associated with DP (OR 3.76, p = 0.04). Flares of chronic disease conferred a threefold increased risk of DP (OR 3.37, p = 0.008) and remained an independent risk factor after adjusting for CPSS-Mol risk (OR 3.6, p = 0.009). Severe AIEs requiring hospitalization trended toward higher risk but were not statistically significant (OR 2.3, p = 0.09). Among the 44 patients with genomic data, all AIE-positive patients (29/29) harbored at least one epigenetic regulator mutations (TET2, DNMT3A, ASXL1, IDH1/2), compared to 12/15 AIE-negative patients (p = 0.034). Signaling mutations (JAK2, CBL, NRAS, KRAS) were also enriched in AIE-positive cases (11/29 vs. 1/15, p = 0.035). No significant differences were found in spliceosome or tumor suppressor mutations. No genomic features distinguished progressors from non-progressors, regardless of whether there was an AIE. Conclusion: In this interim analysis of a prospective multi-institutional CMML cohort, AIE were significantly associated with DP. Ongoing work is aimed at sequentially annotating genomic alterations and profiling secreted factors before and after AIEs. While this study continues to accrue and mature, these findings support inflammation as a modifiable driver to CMML biology and progression and lay the groundwork for future studies investigating inflammatory or supportive interventions to delay disease evolution.

Abstract Background and Significance: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy with overlapping dysplastic and proliferative features, a high risk of leukemic transformation, and no disease-modifying therapies. Patients with proliferative CMML often present with symptomatic monocytosis, leukocytosis, splenomegaly, and systemic inflammation, which contribute to shortened survival and impaired quality of life. Hydroxyurea (HU), the standard cytoreductive agent, provides transient control of leukocytosis but has no known disease modifying properties. In the phase 3 DACOTA trial (Itzykson et al., JCO 2022), decitabine modestly delayed leukemic transformation compared to HU but did not improve event-free or overall survival and was associated with increased early mortality. HU achieved a clinical benefit rate (CBR) of approximately 15% (excluding stable disease), highlighting the urgent need for safer and more effective therapies. Pacritinib is a potent and selective multikinase inhibitor with a kinome profile that targets key mediators of clonal proliferation and inflammatory signaling relevant to CMML. It inhibits JAK2 (IC₅₀ = 6 nM) and IRAK1 (IC₅₀ = 13.6 nM)—critical drivers of cytokine-mediated growth and monocytic skewing—while sparing JAK1, potentially reducing myelosuppressive toxicity. Pacritinib also inhibits CSF1R (IC₅₀= 39.5 nM) which is involved in monocytic differentiation. Preclinical models demonstrate that dual inhibition of JAK2 and IRAK1 suppresses CMML colony formation and prolongs survival in xenografts. Furthermore, CSF1R inhibition may reduce monocyte-lineage bias in leukemic clones. Clinically, pacritinib is FDA-approved for intermediate- or high-risk myelofibrosis with severe thrombocytopenia (platelets <50 × 10⁹/L) based on evidence of significant spleen volume and symptom reduction with limited hematologic toxicity. These mechanistic and clinical data provide a strong rationale for evaluating pacritinib in advanced proliferative CMML, a setting characterized by both cytokine-driven proliferation and treatment-limiting cytopenias. Study Design and Methods PROSPERA (NCT07033598) is a collaborative multicenter, open-label, randomized phase 2 trial. Sixty-six patients with WHO-defined CMML-1 or CMML-2 will be enrolled. Eligible patients must have proliferative features (WBC ≥13 × 10⁹/L) and advanced disease as defined by ≥5 cm palpable splenomegaly, symptom burden (Myeloproliferative Neoplasm-Symptom Assessment Form Total Symptom Score MPNSAF-TSS ≥20), or thrombocytopenia (platelets <100 × 10⁹/L). Prior JAK inhibitor therapy is not allowed. The trial will be conducted at approximately six sites across the United States and United Kingdom, with enrollment anticipated to begin by the end of 2025. Participants will be randomized 2:1 to receive either pacritinib (200 mg orally twice daily) or HU (dosed as per investigator discretion) for 48 weeks. Patients in the HU arm may cross over to pacritinib at Week 24 if, in the opinion of the treating physician, they are not deriving clinical benefit (after assessment of the primary endpoint). Randomization will be stratified by prior cytoreductive therapy (none vs. prior HU or hypomethylating agents). The primary endpoint is CBR at Week 24, defined by modified IWG MDS/MPN criteria incorporating hematologic improvement, spleen volume reduction, and symptom response. Secondary endpoints include CBR at any time, duration of response, event-free survival, leukemia-free survival, and overall survival. Correlative studies will assess treatment-related changes in clonal dynamics, cytokine signaling, and hematopoietic composition using longitudinal peripheral blood and bone marrow sampling. Single-cell transcriptomic and immunophenotypic profiling will be employed to characterize pacritinib's impact on both the malignant clone and the surrounding immune microenvironment.

Background: Menin, a protein involved in transcriptional regulation, plays a role in the genesis of multiple cancers. Preclinical data from BMF-219, an investigational, highly selective, oral small-molecule inhibitor of menin, show sustained potent abrogation of menin-dependent oncogenic signaling. BMF-219 is the first and only covalent menin inhibitor in clinical development and is being evaluated in multiple hematologic malignancies, solid tumors, and diabetes mellitus. COVALENT-101 (NCT05153330) is a Phase I dose-escalation and -expansion study of BMF-219 in R/R AL (Cohort 1), DLBCL (Cohort 2), MM (Cohort 3), and CLL (Cohort 4). Here we report preliminary safety, PK and anticancer activity data from Cohort 1 (AL). Methods: Doses of BMF-219 are escalated independently for each indication, initially in single-subject cohorts followed by a “3 + 3” design. Eligible patients (pts) include adults with R/R AL ineligible for standard therapy. Initially pts were enrolled agnostic to molecular status. A subsequent amendment introduced quotas for KMT2Ar (MLL1r), NPM1 and other known menin-dependent mutations: CEBP/A, MLL1-PTD, MN1, NUP98, NUP214, PICALM-AF10, SETBP1. Prior exposure to reversible menin inhibitor therapy is permitted. Subjects receive BMF-219 daily for continuous 28-day cycles until progression/intolerability. There are 2 parallel dose-escalation arms: pts not taking (Arm A) or taking (Arm B) moderate or strong CYP3A4 inhibitors. The study is ongoing and accruing in the escalation. Expansion cohorts will enroll pts to obtain further safety and efficacy data at the OBD/RP2D. Results: As of data cutoff of 7/24/2023, 26 pts with R/R AL (24 AML; 2 ALL) are enrolled; 7 remain on study treatment. Baseline characteristics include 17(65%) males and 9(35%) females with a median age of 57.5 years (range 33-84). There is a median of 4 (range 1-8) prior lines of therapy and 11 (42%) with prior HSCT(s). Six pts (23%) had KMT2Ar, 3 (12%) KMT2A-PTD, 4 (15%) NPM1, and 13 (50%) WT for KMT2A and NPM1. Dosing began with single-patient cohorts at 100 mg QD (Arm A) and 25 mg QD (Arm B) and has been escalated through 4 dose levels. Thus far, pts have been dosed up to 500 mg QD (Arm A) and 125 mg QD (Arm B). BMF-219 exposures were comparable between arms, with ~2-4-fold higher exposures observed with co-administration of a moderate or strong CYP3A4 inhibitor. At the highest dose (DL4) in which PK was evaluated, Arm A (500 mg QD) and Arm B (125 mg QD), pts on average achieved ~50% of target exposure (2000 ng*hr/mL) with some pts surpassing it. Higher QD dosing or corresponding BID dosing is expected to achieve desired exposure. BMF-219 has generally been well tolerated with no DLTs observed and no discontinuations due to treatment-related toxicities. No related QTc prolongation was observed. At the time of data cutoff, 23 of 26 pts were included in the safety population. Common TRAEs (≥10%) include vomiting 13% (3) and Differentiation Syndrome (DS) 13% (3). No Grade 5 TRAEs were reported. The only common Grade ≥3 TRAE (≥5%) was DS 13% (3). The efficacy evaluable population includes AML pts who meet the following criteria: dosed at or near predicted efficacious dose (500 mg or above [Arm A]; 125 mg or above [Arm B]), had known menin-dependent mutations, and completed at least one scheduled response assessment (or had a minimum of 7 doses if discontinued prematurely). Thus far, 2 of 5 efficacy evaluable patients achieved a complete remission (1 CR; 1 CRi) and both continue BMF-219 treatment. Patient A: 39/M, NUP98-NSD1, ECOG=0, 500 mg QD, Arm A, 4 prior lines of treatment including intensive chemotherapy and allo-HSCT. At C1D27, marrow blasts were reduced to 6% from 13% at study entry. The patient achieved CR at C2D28 with 0% blasts.Patient B: 70/F, NPM1m, ECOG=1, 125 mg QD, Arm B, 1 prior line of treatment with decitabine and an investigational agent. At C1D28, marrow blasts were reduced to 34% from 52% at study entry. The patient achieved CRi with 3% blasts at C2D28. Conclusion: BMF-219 is generally well tolerated with no DLT observed (and able to be taken with and without CYP3A4 inhibitors) with no pts discontinuing therapy due to toxicity. BMF-219 dose escalation is ongoing and approaching target exposure. BMF-219 demonstrates early signs of clinical activity in different genomic subgroups. The trial is ongoing and includes enrollment for pts diagnosed with AL, DLBCL, MM and CLL.

Background. The inclusion of gene mutations and chromosomal abnormalities in the 2022 WHO and ICC Classifications of MDS has enhanced diagnostic precision and is expected to improve clinical decision-making process. Although these two systems share similarities, clinically relevant discrepancies still exist and potentially cause inconsistency in their adoption in a clinical setting. In this study on behalf of the International Consortium for MDS (icMDS), we adopted a data-driven approach to provide a harmonization roadmap between the 2022 WHO and ICC classification for MDS. A modified Delphi Process consensus approach is currently ongoing among icMDS experts to finalize a harmonized MDS classification scheme. Methods. We analyzed retrospective international cohorts of patients with a diagnosis of MDS (n=7017) and AML (n=1002) according to WHO 2016 criteria. Hierarchical Dirichlet Processes were applied to define clusters capturing broad dependencies among all gene mutations and cytogenetic abnormalities. To investigate the features of importance and their impact on the clustering process, we employed the SHapley Additive exPlanations approach (SHAP). This allowed to define harmonized labels for each clinical entity. The clinical relevance of the unsupervised clustering was assessed through the analysis of phenotypic features and outcomes among each group. ( Blood 2022;140: 9828-9830) Results. Patients' characteristics are summarized in Table 1. We identified 9 clusters, defined by specific genomic features. The cluster of highest hierarchical importance was characterized by biallelic inactivation of TP53 (biTP53). According to SHAP analysis, bi TP53 was defined as 2 or more TP53 mutations, or 1 mutation with copy number loss or cnLOH. Most patients assigned to bi TP53 cluster had TP53 VAF>10% (77.9%) and complex karyotype (70.1%). Assignment to bi TP53 cluster was irrespective of blast count. Patients with monoallelic TP53 mutation segregated into other clusters. Hierarchically, the second cluster included patients with del(5q). SHAP analysis highlighted 5q deletion alone, or with one other chromosomal abnormality other than -7, and absence of bi TP53, as the most relevant features. Most of these patients had blast counts <5% (88.1%). The third distinct cluster included patients with SF3B1 mutations (in the absence of concurrent del(7q), abn3q26.2, complex karyotype or RUNX1 mutation). Most patients with MDS and SF3B1 mutation had <5% blasts (94.2%). Common co-mutated variants in the SF3B1 cluster included mutant DNMT3A (25.2%) and TET2 (38.3%). Morphologically defined MDS cases (i.e., not meeting criteria for bi TP53, del(5q) or SF3B1) were preferentially assigned to the following additional clusters: SF3B1 and concurrent higher-risk mutations (e.g., RUNX1 and ASXL1); SRSF2 and concomitant TET2 mutations; U2AF1 mutations with del(20q), del(7q) or -7; SRSF2 with TET2 mutations and co-mutational patterns including RUNX1 and ASXL1; and AML-like genomic signatures. Our analyses suggest that morphologically defined MDS is characterized by a large heterogeneity in terms of mutation profiles, not entirely captured by the presence of unilineage versus multilineage dysplasia, percentage of bone marrow blasts, and presence of hypocellularity and fibrosis. To better investigate the continuum between high risk MDS (i.e., patients with ≥10% blasts) and AML, an exploratory comparison was made using a cohort of AML (defined according to WHO 2016) patients analyzed using the same statistical methods. Only a partial overlap in genetic signatures was observed between MDS with ≥10% blasts and AML. However, similarities were observed between the AML-like MDS clusters (characterized by mutant NPM1, bZIP CEBPA, and Core Binding Factor abnormalities) and AML clusters defined by the same genetic signature, thus supporting the classification of these entities as AML, irrespective of blast count. Conclusion. Our study demonstrated the utility of a data-driven approach based on advanced statistical methods to generate a harmonized classification for MDS. Table 2 shows a provisional, hierarchical classification algorithm. Further refinement of entity labels and classification criteria is the subject of the ongoing modified Delphi Process consensus approach among icMDS experts.

Abstract Purpose: Preclinical studies in myeloid neoplasms have demonstrated efficacy of bromodomain and extra-terminal protein inhibitors (BETi). However, BETi demonstrates poor single-agent activity in clinical trials. Several studies suggest that combination with other anticancer inhibitors may enhance the efficacy of BETi. Experimental Design: To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and patient-derived xenograft models of disease. We used standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models. Results: We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Furthermore, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy. Conclusions: Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data support further clinical investigation of this combination.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with dismal clinical outcomes. Conventional chemotherapies were previously shown to have some clinical efficacy, however, long-term outcomes of BPDCN patients remain poor. In a recent clinical trial, SL-401 demonstrated an overall response rate (ORR) of 90% in previously untreated BPDCN patients. Despite promising outcomes observed in SL-401 studies, there remains a lack of data regarding the optimal first-line therapy. In this single institution retrospective study, we explored the survival outcomes based on front-line treatment and allogeneic stem cell transplant (allo-SCT). A total of 49 patients with confirmed diagnosis of BPDCN were included in the study. Median age at diagnosis was 71.4 (32.0-91.4) years with a male predominance (82%). Among these, 11 (22%) patients had concurrent hematologic neoplasms at the time of BPDCN diagnosis. The most common site of disease involvement was skin (n=42, 86%) followed by bone marrow (BM) (n=32, 65%), lymph node (LN) (n=13, 27%), and nasopharynx (n=2, 4%) with 14 (29%) and 5 (10%) patients having skin and BM involvement only, respectively. Of note, 17 (35%) patients had both skin and BM disease and 8 (16%) had simultaneous skin, BM, and LN involvement. In the front-line setting, CHOP-based regimens, hyper-CVAD, and SL-401 were used in 10 (20%), 11 (22%), and 12 (24%) patients, respectively. The median cycle number of SL-401 treatment was 6 (1-73). Allo-SCT was performed in 10 (20%) patients and 4 (8%) patients received autologous stem cell transplant (auto-SCT). Transplant was performed following first-line therapy in 11 patients (CR, n=10; PR, n=1) and second-line therapy in 3 patients (CR, n=3). Among 21 vs. 12 patients who received chemotherapy vs. SL-401 as their first-line therapy, a total of 11 (52%) and 3 (25%) patients underwent transplant. A total of 23 (55%), 13 (31%), and 6 (14%) patients achieved a complete response (CR), partial response (PR), and progressive disease (PD), respectively. CR rate was higher in patients who were treated with hyper-CVAD compared to others, however, it was not statistically significant (50% in CHOP-based regimens vs. 91% in hyper-CVAD, P=0.064; 50% in SL-401 vs. 91% in hyper-CVAD, P=0.069). The median PFS was 9.9 months and the median OS was not reached when all patients were included for the analyses. In the subgroup analyses, patients who were treated with hyper-CVAD had longest PFS compared to patients treated with CHOP-based regimens (HR=0.217, 95%CI=0.050-0.933, P=0.003) or SL-401 (HR=0.385, 95%CI=0.126-1.179, P=0.075) although the PFS difference between hyper-CVAD and SL-401 did not reach the statistical significance. There was no PFS difference between SL-401 and CHOP-based regimen treated groups (HR=0.931, 95%CI=0.321-2.70, P=0.894). In the OS analysis based on first-line therapy, there was no difference between patients treated with SL-401 compared to patients treated with chemotherapy regimens (HR=1.597, 95%CI=0.460-5.548, P=0.431). Further, there was no OS difference between individual types of front-line therapies (P=0.678). In contrast, patients who received allo-SCT showed significantly longer OS outcomes compared to patients with no transplant (HR=0.160, 95%CI=0.0453-0.56, P=0.041). Additional OS analyses based on age (<60 vs. ≥60) (HR=0.481, 95%CI=0.146-1.582, P=0.258), ASXL1 mutation (HR=1.705, 95%CI=0.2773-10.48, P=0.5649), or presence of previous or concurrent hematologic malignancy (HR=2.97, 95%CI=0.65-13.57, P=0.1602) did not show any statistical difference. In a multivariate Cox model (adjusting for age, front-line therapy, gender, and transplant) allo-SCT was significant factor for OS (HR=0.137, 95%CI=0.020-0.959, P=0.045). In conclusion, our study supports current recommendations of using SL-401 or hyper-CVAD as the first-line treatments followed by consolidation with allo-SCT in the eligible responders to induction therapy to further improve survival outcomes in BPDCN patients. Disclosures Lancet: Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy. kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy. Sokol:Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Abstract 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.