scholarly journals Is There a Place for PD-1-PD-L Blockade in Acute Myeloid Leukemia?

2021 ◽  
Vol 14 (4) ◽  
pp. 288
Author(s):  
Laura Jimbu ◽  
Oana Mesaros ◽  
Cristian Popescu ◽  
Alexandra Neaga ◽  
Iulia Berceanu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Tumor Burden ◽  
Hematopoietic Stem ◽  
Classic Hodgkin Lymphoma ◽  
Acute Myeloid

Checkpoint inhibitors were a major breakthrough in the field of oncology. In September 2014, based on the KEYNOTE-001 study, the Food and Drug Administration (FDA) approved pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, for advanced or unresectable melanoma. Up until now, seven PD-1/PD-ligand(L)-1 inhibitors are approved in various solid cancers and hundreds of clinical studies are currently ongoing. In hematology, PD-1 inhibitors nivolumab and pembrolizumab were approved for the treatment of relapsed/refractory (R/R) classic Hodgkin lymphoma, and later pembrolizumab was approved for R/R primary mediastinal large B-cell lymphoma. In acute myeloid leukemia (AML), the combination of hypomethylating agents and PD-1/PD-L1 inhibitors has shown promising results, worth of further investigation, while other combinations or single agent therapy have disappointing results. On the other hand, rather than in first line, these therapies could be useful in the consolidation or maintenance setting, for achieving minimal residual disease negativity. Furthermore, an interesting application could be the use of PD-1/PD-L1 inhibitors in the post allogeneic hematopoietic stem cell transplantation relapse. There are several reasons why checkpoint inhibitors are not very effective in treating AML, including the characteristics of the disease (systemic, rapidly progressive, and high tumor burden disease), low mutational burden, and dysregulation of the immune system. We here review the results of PD-1/PD-L1 inhibition in AML and discuss their potential future in the management of this disease.

scholarly journals Neoantigen-Specific T-Cell Immune Responses: The Paradigm of NPM1-Mutated Acute Myeloid Leukemia

2021 ◽  
Vol 22 (17) ◽  
pp. 9159
Author(s):  
Fabio Forghieri ◽  
Giovanni Riva ◽  
Ivana Lagreca ◽  
Patrizia Barozzi ◽  
Francesca Bettelli ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Checkpoint Inhibitors ◽  
Specific Antigen ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Promising Therapeutic Approach ◽  
Acute Myeloid

The C-terminal aminoacidic sequence from NPM1-mutated protein, absent in normal human tissues, may serve as a leukemia-specific antigen and can be considered an ideal target for NPM1-mutated acute myeloid leukemia (AML) immunotherapy. Different in silico instruments and in vitro/ex vivo immunological platforms have identified the most immunogenic epitopes from NPM1-mutated protein. Spontaneous development of endogenous NPM1-mutated-specific cytotoxic T cells has been observed in patients, potentially contributing to remission maintenance and prolonged survival. Genetically engineered T cells, namely CAR-T or TCR-transduced T cells, directed against NPM1-mutated peptides bound to HLA could prospectively represent a promising therapeutic approach. Although either adoptive or vaccine-based immunotherapies are unlikely to be highly effective in patients with full-blown leukemia, these strategies, potentially in combination with immune-checkpoint inhibitors, could be promising in maintaining remission or preemptively eradicating persistent measurable residual disease, mainly in patients ineligible for allogeneic hematopoietic stem cell transplant (HSCT). Alternatively, neoantigen-specific donor lymphocyte infusion derived from healthy donors and targeting NPM1-mutated protein to selectively elicit graft-versus-leukemia effect may represent an attractive option in subjects experiencing post-HSCT relapse. Future studies are warranted to further investigate dynamics of NPM1-mutated-specific immunity and explore whether novel individualized immunotherapies may have potential clinical utility in NPM1-mutated AML patients.

scholarly journals Post-transplantation cyclophosphamide reduces the incidence of acute graft-versus-host disease in patients with acute myeloid leukemia/myelodysplastic syndromes who receive immune checkpoint inhibitors after allogeneic hematopoietic stem cell transplantation

2021 ◽  
Vol 9 (2) ◽  
pp. e001818 ◽  
Author(s):  
Chantal Saberian ◽  
Noha Abdel-Wahab ◽  
Ala Abudayyeh ◽  
Hind Rafei ◽  
Jacinth Joseph ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Checkpoint Inhibitors ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

BackgroundImmune checkpoint inhibitors (ICIs) are being used after allogeneic hematopoietic stem cell transplantation (alloHCT) to reverse immune dysfunction. However, a major concern for the use of ICIs after alloHCT is the increased risk of graft-versus-host disease (GVHD). We analyzed the association between GVHD prophylaxis and frequency of GVHD in patients who had received ICI therapy after alloHCT.MethodsA retrospective study was performed in 21 patients with acute myeloid leukemia (n=16) or myelodysplastic syndromes (n=5) who were treated with antiprogrammed cell death protein 1 (16 patients) or anticytotoxic T lymphocyte-associated antigen 4 (5 patients) therapy for disease relapse after alloHCT. Associations between the type of GVHD prophylaxis and incidence of GVHD were analyzed.ResultsFour patients (19%) developed acute GVHD. The incidence of acute GVHD was associated only with the type of post-transplantation GVHD prophylaxis; none of the other variables included (stem cell source, donor type, age at alloHCT, conditioning regimen and prior history of GVHD) were associated with the frequency of acute GVHD. Twelve patients received post-transplantation cyclophosphamide (PTCy) for GVHD prophylaxis. Patients who received PTCy had a significantly shorter median time to initiation of ICI therapy after alloHCT compared with patients who did not receive PTCy (median 5.1 months compared with 26.6 months). Despite early ICI therapy initiation, patients who received PTCy had a lower observed cumulative incidence of grades 2–4 acute GVHD compared with patients who did not receive PTCy (16% compared with 22%; p=0.7). After controlling for comorbidities and time from alloHCT to ICI therapy initiation, the analysis showed that PTCy was associated with a 90% reduced risk of acute GVHD (HR 0.1, 95% CI 0.02 to 0.6, p=0.01).ConclusionsICI therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after alloHCT may be a safe and feasible option. PTCy appears to decrease the incidence of acute GVHD in this cohort of patients.

scholarly journals Prognostic Impacts of D816V KIT Mutation and Peri-Transplant RUNX1–RUNX1T1 MRD Monitoring on Acute Myeloid Leukemia with RUNX1–RUNX1T1

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 336
Author(s):  
Byung-Sik Cho ◽  
Gi-June Min ◽  
Sung-Soo Park ◽  
Silvia Park ◽  
Young-Woo Jeon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Poor Survival ◽  
Hematopoietic Stem ◽  
Kit Mutation ◽  
Time Points ◽  
Post Transplant ◽  
Acute Myeloid

The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1–RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1–RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1–RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches.

scholarly journals Chimeric antigen receptor T cell therapies for acute myeloid leukemia

2020 ◽  
Vol 14 (6) ◽  
pp. 701-710
Author(s):  
Bin Gu ◽  
Jianhong Chu ◽  
Depei Wu
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Antigen Receptor ◽  
Target Antigen ◽  
Hematopoietic Stem ◽  
Car T ◽  
Acute Myeloid

AbstractChimeric antigen receptor T cell (CAR T) therapies have achieved unprecedented efficacy in B-cell tumors, prompting scientists and doctors to exploit this strategy to treat other tumor types. Acute myeloid leukemia (AML) is a group of heterogeneous myeloid malignancies. Relapse remains the main cause of treatment failure, especially for patients with intermediate or high risk stratification. Allogeneic hematopoietic stem cell transplantation could be an effective therapy because of the graft-versus-leukemia effect, which unfortunately puts the patient at risk of serious complications, such as graft-versus-host disease. Although the identification of an ideal target antigen for AML is challenging, CAR T therapy remains a highly promising strategy for AML patients, particularly for those who are ineligible to receive a transplantation or have positive minimal residual disease. In this review, we focus on the most recent and promising advances in CAR T therapies for AML.

Donor Lymphocyte Infusion in the Treatment of First Hematological Relapse After Allogeneic Stem-Cell Transplantation in Adults With Acute Myeloid Leukemia: A Retrospective Risk Factors Analysis and Comparison With Other Strategies by the EBMT Acute Leukemia Working Party

2007 ◽  
Vol 25 (31) ◽  
pp. 4938-4945 ◽  
Author(s):  
Christoph Schmid ◽  
Myriam Labopin ◽  
Arnon Nagler ◽  
Martin Bornhäuser ◽  
Jürgen Finke ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Tumor Burden ◽  
Donor Lymphocyte Infusion ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Purpose To evaluate the role of donor lymphocyte infusion (DLI) in the treatment of relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). Patients and Methods We retrospectively analyzed the data of 399 patients with AML in first hematological relapse after HSCT whose treatment did (n = 171) or did not (n = 228) include DLI. After correction for imbalances and established risk factors, the two groups were compared with respect to overall survival. Further, a detailed analysis of risk factors for survival among DLI recipients was performed. Results Median follow-up was 27 and 40 months, respectively. Estimated survival at 2 years (± standard deviation) was 21% ± 3% for patients receiving DLI and 9% ± 2% for patients not receiving DLI. After adjustment for differences between the groups, better outcome was associated with age younger than 37 years (P = .008), relapse occurring more than 5 months after HSCT (P < .0001), and use of DLI (P = .04). Among DLI recipients, a lower tumor burden at relapse (< 35% of bone marrow blasts; P = .006), female sex (P = .02), favorable cytogenetics (P = .004), and remission at time of DLI (P < .0001) were predictive for survival in a multivariate analysis. Two-year survival was 56% ± 10%, if DLI was performed in remission or with favorable karyotype, and 15% ± 3% if DLI was given in aplasia or with active disease. Conclusion Although further evidence for a graft-versus-leukemia effect by DLI is provided, our results confirm, that the clinical benefit is limited to a minority of patients. Strategies to reduce tumor burden before DLI, as well as alternative treatment options should be investigated in adults with relapsed AML after HSCT.

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