CD123 overexpression

In addition, we present best practices and real-world insights from clinicians in academic and community settings in the US on how they use tagraxofusp to treat BPDCN. Several case studies illustrate the efficacy of tagraxofusp and discuss its safety profile, as well as the prevention, mitigation, and management of anticipated adverse events.

The complexity of the phenotypic signature of lymphoblasts at diagnosis of B ALL is illustrated by the variability in the expression of LAP antigens. Knowledge of the expression levels of these markers in normal leukocytes and during normal B differentiation is crucial for an optimal interpretation of diagnostic cytometry results and serves as a basis for the biological follow-up of B ALL.

Standard of care treatments for BPDCN patients are intense chemotherapy or tagraxofusp (Elzonris®)...Pivekimab sunirine was granted orphan drug and Breakthrough Therapy designation and is currently being tested for the treatment of BPDCN patients as monotherapy and, as a triplet therapy in combination with azacitidine and venetoclax for the treatment of AML patients...Pivekimab sunirine is a potent ADC targeting CD123 and is highly efficacious against an aggressive BPDCN cell line model. This finding reinforces the importance of its use for the treatment of BPDCN patients.

Tagraxofusp was able to effectively eliminate pDCs and blasts to a lesser extent as a single agent. High expression of BCL-2 in blasts supports the consideration of tagraxofusp in combination with venetoclax as an effective combination therapy to eradicate both blasts and pDCs in AML-PDC patient samples.

Conclusion Vibecotamab was safe and active in low-blast, high-risk myeloid diseases, with a response rate of 64% in MDS/CMML after HMA failure and 25% in MRD-positive AML. The clinical activity of vibecotamab, including in pts with prior venetoclax exposure and/or HSCT, and its lack of clinically significant myelosuppression provide rationale to combine it with other agents in AML, MDS, and CMML.

In this small subgroup, there is evidence that TAG has efficacy in first-line treatment of BPDCN with PCHM. High response rates were observed and consistent in patients with and without PCHM. The safety profile was manageable and predictable; PCHM did not appear to predispose patients to different TRAEs.

Furthermore, our study revealed that the USP9X/CDC123 axis promotes the occurrence and development of breast cancer through regulating the cell cycle, and suggests that it may be a potential target for breast cancer intervention. In conclusion, our study demonstrates that USP9X is a key regulator of CDC123, providing a novel pathway for the maintenance of CDC123 abundance in cells, and supports USP9X/CDC123 as a potential target for breast cancer intervention through regulating the cell cycle.

BPDCN currently has 1 approved therapy, tagraxofusp (TAG), with a median age of 68, CR/CRc rate of 57% and mOS of 15.8 mos (n=65; Pemmaraju JCO 2022). PVEK demonstrates compelling activity in frontline and R/R BPDCN pts, including durable responses in the R/R setting for pts who received prior TAG. PVEK safety was manageable with primarily low-grade IRRs and edema and no new safety signals were observed. Enrollment continues in the pivotal de novo frontline BPDCN cohort (NCT03386513) Antibody targeting, Monoclonal antibody, Myeloid malignancies

Some of these agents have shown promising results at the clinical level, including tagraxofusp (CD123 conjugated with diphtheria toxin) for the treatment of BPDCN and IMGN632 (anti-CD123 drug-conjugate), and flotetuzumab (bispecific anti-CD123 and anti-CD3 monoclonal antibody) for the treatment of AML. However, the therapeutic efficacy of CD123-targeting treatments is still unsatisfactory and must be improved through new therapeutic strategies and combined treatments with other antileukemic drugs.

Our data indicate the feasibility of an innovative off-the-shelf therapeutic strategy based on CAR.CD123-NK cells, characterized by remarkable efficacy and an improved safety profile compared to CAR.CD123-T cells. These findings open a novel intriguing scenario not only for the treatment of refractory/resistant AML patients but also to further investigate the use of CAR-NK cells in other cancers characterized by highly difficult targeting with the most conventional T effector cells.

While the numbers of pts are low, there is evidence that TAG has efficacy in 1L pts with BPDCN who had PCHM. High rates of response, similar to those reported in pts with no PCHM, were observed. TAG did enable 1 of the 8 pts with PCHM to be bridged to SCT.

Results N/A Conclusion Phase 2 expansion cohorts for patients with untreated /frontline and relapsed AML are enrolling to further characterize the safety profile and assess the antileukemic activity. NCT04086264

Results N/A Conclusion Enrollment continues in the pivotal cohort for frontline/untreated BPDCN patients. CADENZA, https:// BPDCNtrial.com, NCT03386513

In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD+ to MRD- and RFS in both fit and unfit AML subpopulations (NCT04086264). IMGN632 is also being tested as a monotherapy in a pivotal cohort for adults with frontline BPDCN (NCT03386513, https://BPDCNtrial.com).

An additional cohort is enrolling patients with relapsed/refractory BPDCN, which may have had up to 3 prior lines of therapy, including CD123-targeted therapies and prior hematopoietic stem cell transplant (after 120 days) and may have CNS involvement (if cleared with intrathecals), but who must not have prior history of veno-occlusive disease of the liver, or history of grade 4 capillary leak syndrome or non-cardiac grade 4 edema, and other eligibility. Both cohorts are enrolling patients at the RP2D (0.045 mg/kg IV Q 3 weeks) in the US and EU (NCT03386513, https://BPDCNtrial.com).

Since inhibition of FLT3 leads to upregulation of surface FLT3 expression, future experiments will explore combinatorial FLT3 inhibition with CART-FLT3. If successful, these experiments will provide a strong rationale for a combination clinical trial in AML where leukemia control by small molecules is followed by a coup-de-grace delivered by CART cells.

With a manageable safety profile in this R/R AML population, the novel IMGN632 triplet demonstrated compelling anti-leukemia activity. Ongoing escalation cohorts aim to optimize safety and efficacy of the triplet therapy. Expansion proof-of-concept cohorts are planned in both relapsed and frontline AML patients (NCT04086264).

Targeting these metabolic abnormalities could prevent HR-MDS from progressing to AML. Strikingly, in low risk-MDS-SC, the expression of ribosomal proteins is decreased, which may be accompanied by a reduction in protein synthesis.

In addition to several therapies currently undergoing clinical trials, Tagraxofusp-erzs (Stemline Therapeutics, Inc., NY) is a single FDA-approved option available for treatment of adults and children over 2 years of age suffering from BPDCN...However, off-label use of venetoclax (AbbVie Inc, IL and Genentech-USA, CA), a Bcl2 inhibitor currently in a Phase I clinical trial, resulted in a satisfactory clinical outcome, nearly complete resolution of a right knee tumor lesion, and deferment of bone marrow transplant...20(5):550-551. doi:10.36849/JDD.5373.

Lentiviral vector expressing CD123-CLL1 has been successfully constructed, and K562 leukemia cell line stably expressing CD123 and CLL-1 has been successfully obtained.

CD200 and CD123 both had a negative influence on clinical presentation and treatment outcome, which remarkably worsened when both were concomitantly overexpressed. CD200 and CD123 can therefore be used as markers of MRD in AML and may also serve as therapeutic targets.