First pediatric experience of SL-401, a CD123-targeted therapy, in patients with blastic plasmacytoid dendritic cell neoplasm: report of three cases

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematological malignancy that primarily involves bone marrow (BM) and/or skin; secondary sites include lymph nodes, soft tissue, and central nervous system [1, 2]. BPDCN is derived from the precursors of plasmacytoid dendritic cells and characterized by the expression of CD123, CD4, and CD56, and the absence of other lineage markers [1, 2]. BPDCN typically affects elderly patients; however, it can be present at any age [3]. Pediatric patients are exceedingly rare with an unclear clinical course [3, 4]. Currently, no standardized therapeutic approach has been established, although an acute lymphoblastic leukemia (ALL) type of treatment appears to be more effective in those patients who are able to tolerate aggressive chemotherapy [2‐4]. The prognosis of BPDCN is extremely poor. Most adult patients relapse in less than 2 years, and the median overall survival is 9–13 months [2, 5]. Allogeneic stem cell transplant (SCT) in the first remission could produce durable remission in adult patients [6]. The role of SCT in children is not clear [3, 7, 8].

CD123, interleukin 3 (IL-3) receptor α chain, is ubiquitously expressed at high level on the surface of BPDCN blasts, making it an attractive therapeutic target [1]. As a targeted therapy directed to CD123, SL-401 is a recombinant fusion protein that links IL-3 to a truncated diphtheria toxin (DT) payload (IL-3 replaces the native binding domain of DT) [9]. After binding to CD123, SL-401 becomes internalized, the catalytic domain of DT translocates to the cytoplasm, leading to inhibition of protein synthesis and cell death [9]. In the largest adult trial in BPDCN, SL-401 was generally effective and well tolerated as reported at American Society of Hematology Annual Meeting 2017 [10]. The most common treatment-related adverse events (AEs) were transient transaminitis (50–52%), hypoalbuminemia (50%), thrombocytopenia (38%), fever (29%), and chills (29%). Capillary leak syndrome (CLS) occurred in 19% of patients [9]. At the optimal dose of 12 μg/kg/day, there were 2/119 (1.7%) grade 5 events of CLS across all SL-401 trials (BPDCN, acute leukemia, myeloproliferative neoplasms, and multiple myeloma) [9]. In the ongoing BPDCN phase 2 trial, the overall response rate (ORR) at a dose of 12 μg/kg/day was 90% (26/29) with a 72% rate of CR + CRc + CRi (CR = complete response; CRc = clinical CR [CR with minimal residual skin abnormality]; CRi = CR with incomplete hematologic recovery) in newly diagnosed patients. In patients with relapsed and/or refractory (R/R) disease, the ORR was 69% (9/13) with a 38% rate of CR + CRc + CRi. In addition, 45% (13/29) of patients in the first remission were subsequently bridged to SCT after receiving SL-401 [11].

Up to date, no pediatric patients with BPDCN using SL-401 have been reported. Here, we report the first experience of three children with BPDCN treated with SL-401 at City of Hope (COH) (Table 1). All patients received a 5-day infusion of 12 μg/kg/day SL-401 every 2–3 weeks. Each patient received single patient IND approval. All signed an informed consent/assent. This retrospective study has been approved by an institutional review board of COH.

BPDCN is a highly aggressive hematological malignancy. In the past, despite intensive combination chemotherapy, most adult patients die within 2 years of diagnosis [2, 5]. The published reports in children are extremely limited. One small case series reported 61% progression-free survival [3]. No consensus on the treatment options has been established.

SL-401, a targeted therapy directed to CD123, has demonstrated a tolerable safety profile and robust activity in adult patients with BPDCN. Here, we report the first pediatric experience with SL-401. Similar to adults, we observed mild, transient infusion-related AEs that were easily manageable. One patient with large tumor burden development hypoalbuminemia and weight gain, suggesting possible development of CLS. Despite that, this patient tolerated more frequent dosing. Another patient was able to maintain an excellent quality of life and attended school full time. Overall, the therapy is very well tolerated.

Two of the three patients responded to SL-401. None of them achieved CR. Unlike in adults where single-agent SL-401 activity is quite robust and durable; the response was transient, and the growth of soft tissue mass was observed in-between cycles in both responding patients who had large tumor burden. It is not clear why the response was less durable in our patients when compared to what was observed in adults. We speculate that there might be underlying biological differences between children and adults, and additional studies with more patients are needed. Our experience suggests that in children, SL-401 might be considered for combination therapy; albeit this study represents very few patients to draw definitive conclusions on single agent versus combination.

Of note, tumors from patient #1 and #3 remained to be CD123 positive despite clinical evidence of disease progression. This was consistent with what was observed in the adult study, suggesting that the mechanism of resistance was not due to the loss or decreased expression of CD123 [14] Recently, Stephansky et al. demonstrated that azacitidine could reverse the acquired resistance and synergize with SL-401 in the pre-clinical study [14]. This hypothesis is currently tested in an investigator-initiated trial [14]. Additionally, it has been reported that BPDCN blast is dependent on BCL2 and is sensitive to venetoclax [15]. It may be beneficial to evaluate whether the combination of SL-401 with azacitidine, BCL2 inhibitors, or other chemotherapy or using a more intensive treatment schedule such as every 2 weeks is tolerated and generate a more durable response in children. In addition, administering SL-401 to patients with low disease burden, as a bridging therapy prior to SCT or as maintenance therapy, needs to be further investigated.

In summary, this is the first report of SL-401 in pediatric patients with BPDCN. SL-401 was well tolerated and can produce a promising response. Further testing this agent in children is warranted.