Optimizing Transplant Approaches and Post-Transplant Strategies for Patients With Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is the commonest indication for allogeneic stem cell transplantation (allo-SCT) worldwide. The increasingly important role of allo-SCT in the management of AML has been underpinned by two important advances. Firstly, improvements in disease risk stratification utilizing genetic and Measurable Residual Disease (MRD) technologies permit ever more accurate identification of allo-mandatory patients who are at high risk of relapse if treated by chemotherapy alone. Secondly, increased donor availability coupled with the advent of reduced intensity conditioning (RIC) regimens has substantially expanded transplant access for patients with high risk AML In patients allografted for AML disease relapse continues to represent the commonest cause of transplant failure and the development of novel strategies with the potential to reduce disease recurrence represents a major unmet need.</p

Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia:Who, When, and How?

Although the majority of patients with acute myeloid leukemia (AML) treated with intensive chemotherapy achieve a complete remission (CR), many are destined to relapse if treated with intensive chemotherapy alone. Allogeneic stem cell transplant (allo-SCT) represents a pivotally important treatment strategy in fit adults with AML because of its augmented anti-leukemic activity consequent upon dose intensification and the genesis of a potent graft-versus-leukemia effect. Increased donor availability coupled with the advent of reduced intensity conditioning (RIC) regimens has dramatically increased transplant access and consequently allo-SCT is now a key component of the treatment algorithm in both patients with AML in first CR (CR1) and advanced disease. Although transplant related mortality has fallen steadily over recent decades there has been no real progress in reducing the risk of disease relapse which remains the major cause of transplant failure and represents a major area of unmet need. A number of therapeutic approaches with the potential to reduce disease relapse, including advances in induction chemotherapy, the development of novel conditioning regimens and the emergence of the concept of post-transplant maintenance, are currently under development. Furthermore, the use of genetics and measurable residual disease technology in disease assessment has improved the identification of patients who are likely to benefit from an allo-SCT which now represents an increasingly personalized therapy. Future progress in optimizing transplant outcome will be dependent on the successful delivery by the international transplant community of randomized prospective clinical trials which permit examination of current and future transplant therapies with the same degree of rigor as is routinely adopted for non-transplant therapies.</p

Identification of common and distinct epigenetic reprogramming properties of core-binding factor fusion proteins

RUNX1, also known as CBFa, is a master regulator of haematopoiesis. In Acute Myeloid Leukaemia (AML) it is frequently disrupted by translocations to different epigenetic regulators, resulting in the expression of core-binding factor fusion proteins. We compared the chromatin landscape of t(8;21) and t(3;21) AML which express RUNX1-ETO and RUNX1-EVI1, respectively. We found that the diverse clinical outcomes of patients with these two forms of AML are reflected in fundamental differences in gene expression and chromatin landscape. Despite both fusion proteins sharing a RUNT DNA binding domain, we show that RUNX1-EVI-1 targets a more immature stem cell-related gene expression program of genes as compared to RUNX1-ETO. Despite the differences in the epigenomic landscape of t(3;21) and t(8;21) leukaemia, knockdown of either core-binding factor fusion protein activates a common myeloid differentiation program involving up regulation of C/EBPa. By blocking C/EBPa DNA binding through a dominant negative partner, we showed that this factor is required for the downstream effects of RUNX1-EVI-1 knockdown. Even in the continued presence of RUNX1-EVI-1, ectopic expression of C/EBPa. is sufficient to initiate myeloid differentiation in t(3;21) cells. Overall, this suggests that deregulation of C/EBPa is a common pathway in the development of both t(8;21) and t(3;21) AML

Strategies to reduce relapse risk in patients undergoing allogeneic stem cell transplantation for acute myeloid leukaemia

Allogeneic stem cell transplantation is a centrally important curative strategy in adults with acute myeloid leukaemia; however, relapse occurs in a significant proportion of patients and remains the leading cause of treatment failure. The prognosis for patients who relapse post‐transplant remains poor, and the development of new strategies with the ability to reduce disease recurrence without increasing transplant toxicity remains a priority. In this review, within the context of our understanding of disease biology and the graft‐versus‐leukaemia (GVL) effect, we will discuss established, evolving and novel approaches for increasing remission rates, decreasing measurable residual disease pretransplant, future methods to augment the GVL effect and the opportunities for post‐transplant maintenance. Future progress depends upon the development of innovative trials and networks, which will ensure the rapid assessment of emerging therapies in prospective clinical trials

Identification of Glycopeptides as Posttranslationally Modified Neoantigens in Leukemia

Abstract Leukemias are highly immunogenic, but they have a low mutational load, providing few mutated peptide targets. Thus, the identification of alternative neoantigens is a pressing need. Here, we identify 36 MHC class I–associated peptide antigens with O-linked β-N-acetylglucosamine (O-GlcNAc) modifications as candidate neoantigens, using three experimental approaches. Thirteen of these peptides were also detected with disaccharide units on the same residues and two contain either mono- and/or di-methylated arginine residues. A subset were linked with key cancer pathways, and these peptides were shared across all of the leukemia patient samples tested (5/5). Seven of the O-GlcNAc peptides were synthesized and five (71%) were shown to be associated with multifunctional memory T-cell responses in healthy donors. An O-GlcNAc-specific T-cell line specifically killed autologous cells pulsed with the modified peptide, but not the equivalent unmodified peptide. Therefore, these posttranslationally modified neoantigens provide logical targets for cancer immunotherapy. Cancer Immunol Res; 5(5); 376–84. ©2017 AACR.</jats:p

Arginine dependence of acute myeloid leukaemia blast proliferation: a novel therapeutic target

Acute myeloid leukemia (AML) is one of the most common acute leukemias in adults and children, yet significant numbers of patients relapse and die of disease. In this study, we identify the dependence of AML blasts on arginine for proliferation. We show that AML blasts constitutively express the arginine transporters CAT-1 and CAT-2B, and that the majority of newly diagnosed patients' blasts have deficiencies in the arginine-recycling pathway enzymes argininosuccinate synthase and ornithine transcarbamylase, making them arginine auxotrophic. BCT-100, a pegylated human recombinant arginase, leads to a rapid depletion in extracellular and intracellular arginine concentrations, resulting in arrest of AML blast proliferation and a reduction in AML engraftment in vivo. BCT-100 as a single agent causes significant death of AML blasts from adults and children, and acts synergistically in combination with cytarabine. Using RNA sequencing, 20 further candidate genes which correlated with resistance have been identified. Thus, AML blasts are dependent on arginine for survival and proliferation, as well as depletion of arginine with BCT-100 of clinical value in the treatment of AML

C/EBPα overrides epigenetic reprogramming by oncogenic transcription factors in acute myeloid leukemia

Key Points C/EBPα directly represses the leukemia maintenance program; however, the pattern of repressed genes is specific for each type of AML. Overexpression of C/EBPα does not globally displace these proteins from their binding sites, but overrides their repressive activity.</jats:p

Posttransplant MRD and T-cell chimerism status predict outcomes in patients who received allografts for AML/MDS

Allogeneic stem-cell transplant allows for the delivery of curative graft-versus-leukemia (GVL) in patients with acute myeloid leukemia/myelodysplasia (AML/MDS). Surveillance of T-cell chimerism, measurable residual disease (MRD) and blast HLA-DR expression may inform whether GVL effectiveness is reduced. We report here the prognostic impact of these biomarkers in patients allografted for AML/MDS. One hundred eighty-seven patients from FIGARO, a randomized trial of reduced-intensity conditioning regimens in AML/MDS, were alive and relapse-free at the first MRD time-point and provided monitoring samples for flow cytometric MRD and T-cell chimerism, requested to month+12. Twenty-nine (15.5%) patients had at least 1 MRD-positive result posttransplant. MRD-positivity was associated with reduced overall survival (OS) (hazard ratio [HR], 2.18; P = .0028) as a time-varying Cox variable and remained significant irrespective of pretransplant MRD status in multivariate analyses (P < .001). Ninety-four patients had sequential MRD with T-cell chimerism results at months+3/+6. Patients with full donor T-cell chimerism (FDTC) had an improved OS as compared with patients with mixed donor T-cell chimerism (MDTC) (adjusted HR=0.4; P = .0019). In patients with MDTC (month+3 or +6), MRD-positivity was associated with a decreased 2-year OS (34.3%) vs MRD-negativity (71.4%) (P = .001). In contrast, in the group with FDTC, MRD was infrequent and did not affect the outcome. Among patients with posttransplant MRD-positivity, decreased HLA-DR expression on blasts significantly reduced OS, supporting this as a mechanism for GVL escape. In conclusion, posttransplant MRD is an important predictor of the outcome in patients allografted for AML/MDS and is most informative when combined with T-cell chimerism results, underlining the importance of a GVL effect in AML/MDS

Combination romidepsin and azacitidine therapy is well tolerated and clinically active in adults with high‐risk acute myeloid leukaemia ineligible for intensive chemotherapy

Azacitidine (AZA) is important in the management of patients with acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. Romidepsin (ROM) is a histone deacetylase inhibitor which synergises with AZA in vitro. The ROMAZA trial established the maximum tolerated dose (MTD) of combined ROM/AZA therapy in patients with AML, as ROM 12 mg/m2 on Days 8 and 15, with AZA 75 mg/m2 administered for 7/28 day cycle. Nine of the 38 (23·7%) patients treated at the MTD were classified as responders by Cycle 6 (best response: complete remission [CR]/incomplete CR n = 7, partial response n = 2). Correlative next‐generation sequencing studies demonstrated important insights into therapy resistance