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.

Table 1. Ongoing CAR-T trials in AML¹ CAR-T target Clinical trial ID CAR T cell source Patient age (years) Lymphodepletion CAR-T dose Efficacy & safety CD33 NCT01864902 China Lentivirus 4-1BB Auto or allo 5-90 None in one patient 4.25x10⁸ in one patient One patient with transient blast reduction>50% at week 2
Fevers and hyperbilirubinemia   NCT03126864 Lentivirus 4-1BB Auto 1-80 Fludarabine (Flu) Cytarabine (Cy) N/A N/A   NCT02958397China N/A Auto 14-75 yes N/A N/A   NCT02799680China Lentivirus Allo ≥ 50 Idarubicin                  Cy N/A N/A LewisY NCT01716364 RetrovirusCD28 Auto ≥ 18 Fludarabine (Flu)Cytarabine (Cy) 1.48-9.2x10⁸ One patient achieved cytogenic complete response (CR) NKG2DL NCT03018405

RetrovirusDAP10 Auto ≥ 18 None 3x10⁸-3x10⁹ 3/8 patients responded41% CRS3/10 grade 3-4 CRS CD123

Lentivirus     CD28 Auto or allo ≥ 12 Flu/Cy 50-500x10⁶ N/A  

mRNA electroporation    4-1BB Auto ≥ 18 None or Cy 4x10⁶/kg x 4 4x10⁶/kg x 6 No anti-AML activityGrade1-4 CRS but no neurotoxicity or hematological toxicity   NCT03190278 Lentivirus      4-1BB Universal donor 18-75 Flu/Cy 6.25x10⁴/kg 6.25x10⁶/kg One patient death; trial reopened 11.2017   NCT03766126 Lentivirus      4-1BB Auto ≥ 18 Flu/Cy 2x10⁶/kg N/A (opened 02.2019)

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

Table 2. Bispecific DART antibodies in clinical trials for AML² * Preliminary data are described below Dual targets Clinical trial ID Drug name Sponsor Status CD123 & CD3 NCT02715011 JNJ-63709178 Janssen Suspended   NCT02730312 XmAb14045 Xencor Recruiting   NCT02152956 Flotetuzumab* MacroGenics Recruiting CD33 & CD3 NCT02520427 AMG 330 Amgen Recruiting   NCT03224819 AMG 673 Amgen Recruiting   NCT03144245 AMV564* Amphivena Recruiting   NCT03516760 GEM333 GEMoaB Recruiting CLL1 & CD3 NCT03038230 MCLA-117 Merus Recruiting

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.