Dr Kadia on Targeting the IRAK4 Pathway in AML

Tapan M. Kadia, MD, professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses targeting the IRAK4 pathway in patients with acute myeloid leukemia (AML) and highlights the importance of utilizing targeted therapies in the treatment of patients with hematologic malignancies.

The IRAK4 pathway, initially targeted in the management of myelodysplastic syndrome, is now gaining traction in AML due to its analogous nature, Kadia begins. Although studies in AML are in early stages, their potential impact remains promising, as the IRAK4 pathway contains a loop of inflammatory cytokines, he states. The optimal targeting of this pathway in patients with newly diagnosed or relapsed AML is still unfolding, and ongoing studies aim to provide insights into the efficacy of IRAK4-targeted agents, Kadia explains. Overall, when anticipating the future of AML management, targeted therapies emerge as pivotal players, he notes.

Targeted therapy benefits patients with AML because it is generally less intense and toxic than traditional therapies, Kadia says. One such therapy is the class of IDH1 inhibitors, Kadia continues. A strategic combination of lower intensity therapy with these inhibitors yields response rates comparable, if not superior, to those observed with traditional intensive chemotherapy, he emphasizes. To harness the potential of targeted therapies, comprehensive characterization of leukemia at the outset through next-generation sequencing is imperative, Kadia imparts.

Understanding mutations and cytogenetics informs the selection of therapies tailored to specific AML subsets. FLT3 inhibitors, such as midostaurin (Rydapt) and quizartinib (Vanflyta), showcase advancements in frontline AML management, providing new treatment options for patients, Kadia expands. Exploring the extended use of quizartinib reveals promising results, especially for patients with minimal residual disease–positive disease, he explains. The evolving landscape emphasizes a dynamic approach, continuously assessing the disease from diagnosis, adapting therapies to its changing nature, and investigating whether lower intensity treatment options can match the efficacy of intensive chemotherapy in newly diagnosed patients, Kadia states.

Although low-intensity therapy is currently reserved for older or unfit patients, ongoing trials are exploring its effectiveness compared with intensive chemotherapy in various patient populations, he says. Despite the current standard of care favoring intensive chemotherapy, the tailored approach recognizes exceptions, such as younger patients with 

 mutations or high-risk disease, in whom low-intensity therapy is deemed appropriate, Kadia concludes.

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Tapan M. Kadia, MD, discusses targeting the IRAK4 pathway in patients with acute myeloid leukemia and highlights the importance of utilizing targeted therapies in the treatment of patients with hematologic malignancies.


Treated secondary acute myeloid leukemia AML (TS-AML) that arises after prior treatment of MDS with hypomethylating agents (HMAs) is associated with very poor prognosis (complete remission [CR] rates, 15%-30%; median overall survival [OS], 6-8 months).

E-selectin ligand is highly expressed on AML blasts in the leukemic microenvironment, and it may be a marker of cell survival and resistance to chemotherapy.

Exposure of leukemic blasts to HMAs has been shown to increase their expression of the E-selectin ligand.

Uproleselan is an E-selectin antagonist that overcomes resistance to chemotherapy in AML.

We studied the combination of low-intensity chemotherapy with cladribine plus LDAC (CLAD/LDAC) with uproleselan to overcome local and microenvironmental resistance and improve outcomes in this difficult patient subset.

This is Phase Ib/II clinical trial (NCT04848974) to evaluate the safety, tolerability, and explore the efficacy of Uproleselan added to Cladribine and LDAC.

A 3+3 dose-escalation approach was implemented to evaluate 2 different dose levels for Cladribine (CLAD)+ LDAC; each 4-week cycle consists of Uproleselan (at a fixed dose of 800mg intravenously [IV]) added to IV CLAD 5 days (3.75mg/m2 and 5mg/m2; level -1 and 1, respectively) and subcutaneous LDAC twice daily 10 days (15mg, and 20mg; level -1 and 1, respectively) during induction; consolidation was similar except it was with 3-days of CLAD, for up to 6 cycles.

Pts aged ≥18 years with a diagnosis of TS-AML with adequate organ function, who have not received therapy for their AML were enrolled. TS-AML is defined as AML arising from a previously treated myeloid neoplasm.

Presence of the E-selectin ligand was assessed using Flow Cytometry (FC).

Ten patients have been treated, with 9 patients currently evaluable (gender, 6 men [67%]; median age, 68 years [range, 58-80 years]). At the start of therapy, the median concentration of bone marrow blasts was 33% (range, 1%-78%), median white blood count was 2.2 × 103/µL (range, 0.6-20.1 × 103/µL), median platelet count was 18 × 103/µL (4-305 × 103/µL), and median creatinine level was 0.98 mg/dL (range, 0.67-1.52 mg/dL).

Patients had received a median of 1 treatment (range, 1-2 treatments) prior to AML transformation.

Prior diagnoses were: therapy-related Myelodysplastic Syndrome (t-MDS), Chronic Myelomonocytic Leukemia (CMML), MDS and MDS/MPN in 3 (33%), 3 (33%), 2 (22%) and 1 (11%) respectively; all had received HMA, 5 (56%) additionally had Ven and 3 (33%) had stem cell transplantation (SCT) prior to enrolling.

All pts had unfavorable features by ELN 2017.

The most frequent mutations were: SXL1, TP53 and TET2 in 4 pts each (44%), SRSF2 and NRAS in 3 patients each (33%) and SETBP1, RUNX1 and EZH2 in 2 patients each (22%). 6 pts were evaluable for E-selectin ligand expression; the median expression was 59% (42%-95%) and median MFI was 20.5 (13-262).

The most common SAEs were ≥ grade 3 neutropenic fever (70%), (including 2 grade 5 events), grade 3 bleeding (10%), and grade 2 thrombosis (5%)

There were no dose-limiting toxicities observed on dose levels -1 or 1.

Two pts treated on dose level -1 die during the study follow-up due to sepsis within the first 4-weeks during induction.

Median time to 0.5x109/L neutrophil and 50x109/L platelets recovery was 29 (17-39) and 38 (33-48) days respectively.

The median follow-up is 4+ months. 8 pts were evaluable for response at the time of analysis. The ORR was 62% (5/8), including 2 (25%) PR, 1 (13%) CRi, 1 (13%) CRp and 1 (13%) MLFS.

There was a reduction in BM blasts in 6 pts (75%). 5 pts were taken off protocol due to progression, 2 for death, 1 for allogeneic SCT and 1 continued onto maintenance in remission.

The one pt who achieved negative MRD, underwent SCT and is still alive. Median OS and EFS were 4.7 and 1.3 months respectively; 4-month RFS (CRi, CRp, and MLFS) was 67%.

The median cycles received was 1 (1-3), median cycles at which the best response was achieved was 1 (1-2).

The 4-month OS were 100% and 60% among responders vs. non-responders, respectively (

=0.27), and the 4-month EFS were 50% and 0% respectively (

=0.85) among pts who had prior Ven exposure or prior SCT, respectively.

The combination of Cladribine + LDAC with Uproleselan was overall well tolerated with few treatment-related AEs.

The combination produced an ORR of 62% in a high-risk, refractory population whose prognosis is very dismal.

The relationship of E-selectin ligand expression, response to treatment, and outcomes is being analyzed.

Huante EA, Kantarjian H, Chien KS, et al. 1448 Uproleselan added to cladribine plus low-dose cytarabine (LDAC) in patients with treated secondary acute myeloid leukemia (TS-AML).Abstract presented at: 2022 American Society of Hematology, December 10, 2022; New Orleans, LA. Abstract 1448. Accessed December 14, 2022. 

https://ash.confex.com/ash/2022/webprogram/Paper169670.html

Tapan M. Kadia, MD evaluates the use of uproleselan, an E-selectin antagonist, in combination with LDAC and Cladribine in patients with treated secondary acute myeloid leukemia. 

Uproleselan Added to Cladribine Plus Low-Dose Cytarabine (LDAC) In Patients with Treated Secondary Acute Myeloid Leukemia (TS-AML)

Tapan M. Kadia, MD, associate professor, Department of Leukemia, The University of Texas MD Anderson Cancer Center, discusses the use of E-selectin as a target for treatment in acute myeloid leukemia (AML).

E-selectin is a marker that is present in the tumor microenvironment for patients with AML, Kadia says. E-selectin serves as a marker that binds to leukemia cells, protecting them by activating cell survival and growth pathways and promoting resistance to chemotherapy in AML, Kadia explains.

By disrupting the interaction of E-selectin and leukemia cells in the tumor microenvironment, AML cells can become more sensitive to chemotherapy, Kadia notes. Uproleselan, a novel E-selectin antagonist, is designed to bind to E-selectin to make AML cells more vulnerable to systemic treatments, potentially leading to better outcomes, response rates, and long-term survival for patients with AML, Kadia concludes.

Tapan M. Kadia, MD, discusses the use of E-selectin as a target for treatment in acute myeloid leukemia.

Dr. Kadia on E-selectin as a Target in the Treatment of AML

Tapan M. Kadia, MD, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses the utilization of uproleselan (GMI-1271) with chemotherapy in relapsed/refractory acute myeloid leukemia (AML).

The rationale of adding uproleselan to chemotherapy in a phase 1/2 trial (NCT02306291) was to block E-selectin, thereby sensitizing resistant leukemic blasts to chemotherapy in patients with relapsed/refractory AML, particularly in the salvage setting, Kadia says. Uproleselan, an E-selectin antagonist, was combined with mitoxantrone, etoposide, and cytarabine (MEC) chemotherapy in the patient population, Kadia explains.

A separate cohort of patients aged 60 years or older who had newly diagnosed AML and were eligible for intensive chemotherapy received uproleselan with cytarabine and idarubicin, Kadia adds.

Patients who achieved remission were eligible for uproleselan with their consolidation chemotherapy, which consisted of MEC consolidation or intermediate-dose, cytarabine-based consolidation, Kadia concludes.

Tapan M. Kadia, MD, discusses the utilization of uproleselan with chemotherapy in relapsed/refractory acute myeloid leukemia.


Tapan M. Kadia, MD

Articles

Dr Kadia on Targeting the IRAK4 Pathway in AML

Uproleselan Added to Cladribine Plus Low-Dose Cytarabine (LDAC) In Patients with Treated Secondary Acute Myeloid Leukemia (TS-AML)

Dr. Kadia on E-selectin as a Target in the Treatment of AML

Dr. Kadia on the Utilization of Uproleselan with Chemotherapy in R/R AML