SOHO 2019 | Update on chemotherapy-free treatments for R/R AML 

Chemotherapy resistance and relapse are two of the main causes of death in patients with acute myeloid leukemia (AML). Thus, the development of novel chemotherapy-free approaches is crucial for these patients. Such targeted antibody-based or cell-based therapies including; chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs) and dual affinity retargeting (DART) antibodies.

During the 2019 Society of Hematologic Oncology (SOHO) annual meeting, in Houston, TX, US, two presentations showcased chemotherapy-free approaches for the treatment of AML. Elizabeth Budde from City of Hope National Medical Center, Duarte, CA, US, presented the current landscape of CAR-T trials for AML¹, while, John DiPersio from Washington University School of Medicine in St. Louis, St. Louis, MO, US, spoke about the use of ADCs, DARTs and BiTEs in the clinical setting of AML.² We hereby provide a summary of these talks regarding the latest updates on these chemotherapy-free approaches for the treatment of AML.

CAR-T trial landscape in AML¹

One of the major challenges of CAR-T therapy for AML is the identification of a good CAR-T target, which should only or primarily be expressed by leukemic stem cells, so as to avoid CAR-T cell resistance and off-target toxicities. Such a target is yet to be identified with multiple options being evaluated pre-clinically (i.e. CD7, CD25, CD32, CD38, CD47 etc.). At the moment, the CAR-T constructs that have made it to the clinic target CD33, CD123, NKG2DL or LewisY.¹ Some of the ongoing clinical trials using the CAR-Ts mentioned above are shown in Table 1.

The speaker highlighted that CAR-T therapy for AML is still at early stages with multiple ongoing and planned trials worldwide on different molecular targets (Table 1). CD123 and NKG2D targeted CAR-T treatment has led to encouraging early data with regards to feasibility, tolerability and patient responses. As Elizabeth Budde pinpointed, the ways to improve the effectiveness of CAR-T therapies for AML involve the optimization not only of the manufacturing but also the CAR-T design and dosing. Moreover, combination treatments with immunomodulatory drugs and dual-targeting therapies carry great potential for AML patients and should be further investigated.¹

ADCs, DARTs & BiTEs for AML²

To date, there are eight clinical trials investigating the efficacy and safety of bispecific antibodies for the treatment of AML. These are shown in Table 2.²

Flotetuzumab²

The speaker presented preliminary data from the phase I trial of flotetuzumab (FLZ), the humanized DART that targets CD3 and CD123 as explained below.

• FLZ was administered intravenously to n= 50 patients with relapsed/refractory AML at the stepwise dosing schedule from 30ng/kg at Day one to 500 ng/kg and at Day seven (week one)
• During weeks 2-4, patients received 500ng/kg of FLZ per day of cycle one and a four days on/ three days off schedule for cycle two onwards
• The recommended phase II dose of FLZ was 500ng/kg per day administered as a seven day/week continuous intravenous infusion
• Among the patients with primary refractory AML (62%), 32% achieved a complete response (CR)
• FLZ was well tolerated especially due to the stepwise escalation with mild tp moderate CRS events of short duration with a median of one day (grade one: 82%; grade two: 76%; grade three: 8%; grade four: 0%)

Last but not least, the investigators showed that PD-L1 expression was linked to decreased FLZ activity, as patients who progressed early (< 15 days) had significantly higher PD-L1 expression. Further results are expected the expansion cohort and an additionally planned FLZ plus MGA012 (anti-PD1) cohort.

AMV564-101 trial²

• n= 40 enrolled patients with R/R AML, aged ³ 18 with high-risk disease
• Study design 3+3
• AMV564 was administered on a 14-day continuous stepwise dose escalation from 0.5-15mg on Day one to 450mg on Day 14
• Thirty-three patients have been dosed to date
• Treatment was well-tolerated with no donor lymphocyte infusions and grade 1-2 CRS events
• One long duration (7 months) CRi was observed and one stable disease at seven months
• AMV564 led to quick and selective depletion of leukemic blasts and myeloid-derived suppressor cells (MDSCs) was observed by flow cytometry
• Further results are expected from this ongoing trial in the near future

Conclusions

This is an exciting time for the clinical setting of R/R AML as numerous CAR-Ts, ADCs, BiTEs/DARTs are under pre-clinical and early clinical investigation. With many of these chemotherapy-free therapies showing promising activity and tolerability, it is certain that the future of patients with R/R AML seems more hopeful than ever.