Acute myeloid leukemia (AML) is a heterogeneous disease linked to a broad spectrum of molecular alterations, and as such, long-term disease control requires multiple therapeutic approaches. Driven largely by an improved understanding and targeting of these molecular aberrations, AML treatment has rapidly evolved over the last 3–5 years. The stellar successes of immunotherapies that harness the power of T cells to treat solid tumors and an improved understanding of the immune systems of patients with hematologic malignancies have led to major efforts to develop immunotherapies for the treatment of patients with AML. Several immunotherapies that harness T cells against AML are in various stages of preclinical and clinical development. These include bispecific and dual antigen receptor-targeting antibodies (targeted to CD33, CD123, CLL-1, and others), chimeric antigen receptor (CAR) T-cell therapies, and T-cell immune checkpoint inhibitors (including those targeting PD-1, PD-L1, CTLA-4, and newer targets such as TIM3 and STING). The current and future directions of these T-cell-based immunotherapies in the treatment landscape of AML are discussed in this review.

Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with FLT3-mutated acute myeloid leukemia (AML) treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next-generation sequencing (NGS) at relapse identified emergent mutations involving on-target FLT3, epigenetic modifiers, RAS/MAPK pathway, and less frequently WT1 and TP53. RAS/MAPK and FLT3-D835 mutations emerged most commonly following type I and II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment RAS-mutated patients, pretreatment cohort-level variant allelic frequencies for RAS were higher in nonresponders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in FLT3-mutated AML treated with type I versus II FLT3i. Significance: Sequential NGS-based mutational analysis at relapse after FLT3i-based therapies showed distinct pathways of secondary resistance between type I and II FLT3i. FLT3 mutations may be lost at relapse after FLT3i-based therapies. Pretreatment RAS/MAPK mutations may also be associated with primary resistance in patients treated with type I FLT3i. See related commentary by Shastri et al., p. 113.

Cryopreservation of grafts has been established in autologous and cord blood transplantation, yet there is little experience regarding the effect of cryopreservation with sibling and unrelated grafts. We evaluated the effect of cryopreservation of grafts on allogeneic transplant outcomes using related, unrelated and haploidentical donors, including 958 patients, age 18-74 years (median 55) and using PBSC for various hematologic malignancies. Fresh grafts were received by 648 (68%) patients, 310 (32%) received cryopreserved. There was no difference between fresh vs cryopreserved grafts for neutrophil engraftment (P = .09), platelet engraftment (P = .11), graft failure (5.6% vs 6.8%, P = .46) and grade II-IV acute graft-vs-host disease (GVHD) (P = .71), moderate/severe chronic GVHD was observed in 176 (27%) vs 123 (40%) patients, respectively (P < .001). Multivariable analysis demonstrated no difference between fresh vs cryopreserved for OS (P = .39) and CIR (P = .08) while fresh grafts demonstrated borderline increased NRM (HR 1.27, 95% CI 1.02-1.59, P = .04). Of note, for patients with no or mild chronic GVHD, CIR was less for fresh compared to cryopreserved (HR = 0.67 for fresh, 95% CI 0.48-0.92, P = .01). We conclude there were no differences in engraftment and survival between fresh and cryopreserved grafts for allogeneic HCT, thus establishing cryopreservation to be a safe option for allogeneic HCT.