Uy GL, Aldoss I, Foster MC, et al. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia. Blood. 2021; 137: 751762.

Immunotherapy in the form of allogeneic hematopoietic stem cell transplantation (allo HSCT) has been a foundation of curative therapy in acute myeloid leukemia (AML) since the 1970s when Dr. E. Donnall Thomas and colleagues reported that patients with refractory acute leukemia could achieve long-term leukemia-free survival with high-dose chemotherapy followed by human leukocyte antigen (HLA)–identical sibling marrow transplantation.1-4  This approach has been successful, and significant advances have decreased transplant-related mortality (TRM) during the past 40 years due to the use of better drugs for prophylaxis of graft-versus-host disease and infections, reduced intensity or nonmyeloablative conditioning (RIC) regimens, improved HLA matching, and the development of the comorbidity index; however, relapse after transplant remains the major cause of treatment failure in AML and substantial TRM (2-year TRM is 25-39% in adults aged >40 years with AML)5  remains a barrier to transplant utilization in AML. Accordingly, nontransplant immunotherapy approaches such as targeted antibody-based therapy and chimeric antigen receptor T-cell therapy, which are exceedingly successful in acute lymphoblastic leukemia, have been enthusiastically pursued as potential therapeutic strategies to harness the potency of cell-based immune therapy, but with greater target selectivity in AML. The development of such therapies, however, has been limited to the approval of only a single antibody-targeted therapy for AML, the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin.6  The major hurdle to the development of antibody-based therapy is related to the few suitable cell surface antigen targets that can differentiate AML blasts from normal hematopoietic progenitor cells.

CD123, the interleukin 3 (IL-3) receptor α chain (IL3RA), is a promising tumor-associated antigen target for AML and one that appears amenable to immunotherapy due to its high expression on the surface of AML blasts and leukemia stem cell populations,7  as well as its limited expression on normal hematopoietic stem and progenitor cells and other normal myeloid tissues (i.e., plasmacytoid dendritic cells, monocytes, and basophils).8  Early attempts of therapeutics targeting CD123 included a diphtheria toxin IL-3 fusion protein9  and a monoclonal antibody to CD123 (CSL-360)10  and demonstrated antileukemia activity in vitro and/or in vivo, but when tested in phase I clinical trials, both agents lacked clinical activity in AML. In contrast, flotetuzumab, a drug that has shown promising preclinical activity, is an investigational dual affinity retargeting (DART) antibody that targets both CD123-positive AML cells and CD3-expressing T lymphocytes to form an artificial immunologic synapse, and then induces T-cell activation, T-cell expansion, and T-cell–mediated CD123 targeted killing.11-13 

In the current article, Dr. Geoffrey Uy and colleagues report the results of a first in-human phase I/II single arm, multicenter study of flotetuzumab in 88 patients with relapsed or refractory (R/R) AML. The primary objective of the study was to determine the maximum tolerated dose (MTD) and schedule of flotetuzumab and to characterize the toxicity profile. Secondary objectives included pharmacokinetic and pharmacodynamic profile and the antitumor activity of flotetuzumab. The trial enrolled 42 patients to the phase I dose-finding cohort, and 46 patients were enrolled onto the phase II dose-expansion cohort. The recommended phase II dose (RP2D) of flotetuzumab is 500 ng/kg/day administered as a continuous infusion in 28-day cycles, following a "lead-in dose" phase during week 1 of treatment. Ninety-six percent of patients treated at the RP2D experienced infusion-related reactions/cytokine release syndrome (IRR/CRS), though the majority (81%) had mild to moderate signs/symptoms (grade 2). Seven patients (8%) experienced grade 3 IRR/CRS, and no grade 4/5 events occurred. Most IRR/CRS events (32%) occurred during the first week of treatment with the "lead-in dose" phase, and the IRR/CRS events decreased throughout the 28-day cycle. The IRR/CRS events were managed with drug interruptions and/or tocilizumab. Neurologic events were infrequent overall, with the most common event being headache (grade 1 or 2 in 10%). Two patients experienced grade 3 neurologic events: one headache and one episode of delirium. Both patients recovered from these events. Importantly, flotetuzumab at the RP2D did not appear to result in prolonged myelosuppression. The overall complete response rate (ORR) for the RP2D was 24 percent (12 of 50), and the complete response with or without complete hematologic recovery (CR/CRh) was 18 percent (9 of 50). The median time-to-first response was 0.84 months (range, 0.8-2.1 months), and median overall survival (OS) was 3.2 months (95% CI, 2.10-6.47).

Exploratory subgroup analysis revealed that patients with primary induction failure (PIF) or early relapse occurring within six months after initial treatment (ER) had higher response rates (43%; 12 of 28) than patients with late relapse (LR; 14%; 1 of 7) or prior treatment with a hypomethylating agent (30%; 3 of 10). The six- and 12-month survival rates for patients with PIF/ER treated at the R2PD were 42 percent and 20 percent, respectively.

Previously, the authors described the immune architecture of AML marrow specimens from pediatric and adult patients and identified distinct immune subtypes — immune-infiltrated and immune-depleted — and reported significant differences in the immune gene expression profiles. Importantly, these subtypes were predictive of the response and/or resistance to cytotoxic chemotherapy and immune targeted therapy.14  In the current study, the authors extended their prior results and examined the role of immune gene-signatures and response to flotetuzumab in a subgroup of 38 patients. Specifically, they confirmed that patients with the immune-infiltrated subtype were less likely to have responded to cytotoxic chemotherapy (i.e., patients met criteria for PIF/ER), but more likely to respond to immunotherapy. Consistent with this observation, patients with PIF/ER showed higher tumor immune infiltration scores when compared to patients with LR, and response to flotetuzumab was correlated with high immune infiltration scores. Additionally, the authors identified a 10 gene-expression signature that was associated with CR to flotetuzumab, and the genes in the signature reflected an immune infiltrated marrow microenvironment.

In summary, flotetuzumab is an effective targeted immunotherapy with a manageable safety profile for R/R AML. Noteworthy clinical activity of flotetuzumab in the primary refractory and early relapse patients is promising, and the clinical trial discussed here is continuing with a focus on these patient subgroups (NCT02152956). The gene expression data reveal a complex immune microenvironment within the marrow that may predict response to this therapy. If the primary refractory and early relapse patient populations prove to be the bullseyes for this DART, improved patient outcomes will follow. Whether flotetuzumab can also induce minimal residual disease–negative remissions in these patient populations is unknown but will surely be the focus of future clinical trials and another important target for this DART.

Dr. O'Dwyer and Dr. Torres indicated no relevant conflicts of interest

1.
Thomas
ED
,
Storb
R
,
Clift
RA
, et al
Bone-marrow transplantation (first of two parts)
.
N Engl J Med
.
1975
;
292
:
832
843
.
2.
Thomas
ED
,
Storb
R
,
Clift
RA
, et al
Bone-marrow transplantation (second of two parts)
.
N Engl J Med
.
1975
;
292
:
895
902
.
3.
Thomas
ED
,
Buckner
CD
,
Banaji
M
, et al
One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation
.
Blood
.
1977
;
49
:
511
533
.
4.
Thomas
ED
,
Flournoy
N
,
Buckner
CD
, et al
Cure of leukemia by marrow transplantation
.
Leuk Res
.
1977
;
1
:
67
-
70
.
5.
McClune
BL
,
Weisdorf
DJ
,
Pedersen
TL
, et al
Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome
.
J Clin Oncol
.
2010
;
28
:
1878
-
1887
.
6.
Norsworthy
KJ
,
Ko
CW
,
Lee
JE
, et al
FDA approval summary: Mylotarg for treatment of patients with relapsed or refractory CD33-positive acute myeloid leukemia
.
Oncologist
.
2018
;
23
:
1103
-
1108
.
7.
Jordan
CT
,
Upchurch
D
,
Szilvassy
SJ
, et al
The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells
.
Leukemia
.
2000
;
14
:
1777
1784
.
8.
Agis
H
,
Füreder
W
,
Bankl
HC
, et al
Comparative immunophenotypic analysis of human mast cells, blood basophils and monocytes
.
Immunology
.
1996
;
87
:
535
-
543
.
9.
Frankel
A
,
Liu
JS
,
Rizzieri
D
, et al
Phase I clinical study of diphtheria toxin-interleukin 3 fusion protein in patients with acute myeloid leukemia and myelodysplasia
.
Leuk Lymphoma
.
2008
;
49
:
543
-
553
.
10.
He
SZ
,
Busfield
S
,
Ritchie
DS
, et al
A phase 1 study of the safety, pharmacokinetics and anti-leukemic activity of the anti-CD123 monoclonal antibody CSL360 in relapsed, refractory or high-risk acute myeloid leukemia
.
Leuk Lymphoma
.
2015
;
56
:
1406
-
1415
.
11.
Johnson
S
,
Burke
S
,
Huang
L
, et al
Effector cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion
.
J Mol Biol
.
2010
;
399
:
436
-
449
.
12.
Chichili
GR
,
Huang
L
,
Li
H
, et al
A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: preclinical activity and safety in nonhuman primates
.
Sci Transl Med
.
2015
;
7
:
289ra82
.
13.
Al-Hussaini
M
,
Rettig
MP
,
Ritchey
JK
, et al
Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform
.
Blood
.
2016
;
127
:
122
-
131
.
14.
Vadakekolathu
J
,
Minden
MD
,
Hood
T
, et al
Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia
.
Sci Transl Med
.
2020
;
12
:
eaaz0463
.