However, the patient died on d 56 with severe graft versus host disease (GVHD) and multi-organ failure.51 As mentioned previously, CD123 is often upregulated in cases of CD19-negative relapsed B-cell ALL after failing CD19-targeted immunotherapies. and the PSI expression is stronger in cases with hypodiploidy while weaker in cases transporting the rearrangement.5 In one study, the expression of CD123 by flow cytometry was noted at higher intensity in B-cell ALL compared to AML.3 Likewise, CD123 is expressed by a subset of immature T-cell ALL (~40%),4,6,7 with the expression of CD123 more frequent in early T-cell precursor (ETP) cases (~85%).4,7 PSI CD123 is also expressed by other less common hematological malignancies. For example, up to 95% of cases of vintage hairy cell leukemia express CD123.3,8 CD123 expression is considered the hallmark and one of the characteristic findings in BPDCN, and it is observed in almost all cases.9 Additionally, CD123 is expressed frequently by systemic mastocytosis (SM) (64%), with higher frequency among aggressive subtypes (100%) compared to indolent cases (61%), SM with associated hematological neoplasm (57%) and mast cell leukemia (0%).10 CD123 is also expressed by a large subset of Hodgkins lymphoma ReedCSternberg cells (~60%) but less frequently by non-Hodgkins lymphomas.11 Of notice, CD123 is preferentially overexpressed in LSC as compared to normal hematopoietic stem cells.12C14 This differential expression Mouse monoclonal to FUK allows for the selective eradication of PSI LSC and leukemic blasts through targeting of CD123, with less potential impact on hematopoietic cells.15 Intriguingly, the level of CD123 expression and the percentage of blasts expressing CD34+CD38(low/-)CD123+ in AML was found to correlate with treatment response, relapse and survival.16,17 Likewise, there was a correlation between CD123 expression and inferior relapse-free survival among patients with T-cell ALL in one study,4 likely due to the stem cell-like properties of leukemia progenitors in the poor-risk ETP subtype. Lastly, a subset of patients with B-cell ALL treated with CD19-targeted immunotherapies will lose CD19 expression at the time of relapse or progression,18,19 and among these patients with CD19-unfavorable relapsed ALL, CD123 expression PSI is usually managed and upregulated.14 Together, the growth and survival advantages conferred by expression of CD123, the overexpression of CD123 by different subtypes of acute leukemia, and the differential expression of CD123 by hematological malignancies versus normal hematopoietic stem cell (HSC) have led to therapeutic targeting of CD123. The following discussion highlights the successes and limitations of the major therapeutic modalities that have been thus far tested in clinical trials. Table 1 compares the main therapeutic modalities and Table 2 summarizes the ongoing clinical trials for CD123-targeted therapies. Table 1. A comparison of CD123-targeting therapies =?.44).23 Tagraxofusp (Stemline Therapeutics), formerly known as SL-401, is a recombinant fusion protein consisting of human IL-3 fused to a truncated diphtheria toxin (DT) payload. Tagraxofusp binds to CD123 and is subsequently internalized to release DT into the leukemia cell, which results in inhibition of protein synthesis and apoptosis of the targeted cells.24 In an open-label multi-center study that enrolled patients with newly diagnosed and relapsed or refractory (r/r) BPDCN, tagraxofusp produced a response rate of 90% (CR?=?72%) in newly diagnosed patients (n?=?29) and 67% in r/r patients (n?=?15). The most common adverse events were transaminitis and hypoalbuminemia, with 19% of patients developing capillary leak syndrome (CLS).25 Tagraxofusp was granted FDA approval for the treatment of BPDCN in adults and children older than 2 y of age on December 21, 2018.24 Tagraxofusp is given by intravenous infusion on d 1 to 5 of every 21-d cycle. For patients who have clinical benefit, tagraxofusp is given indefinitely. In a pivotal cohort (stage III) from your STML-401-0114 study (n?=?13), the CR/clinical CR rate of treatment-na?ve patients with BPDCN was 54% using the BPDCN response criteria, with a median duration of response not reached (median follow up of.