Allogeneic Stem Cell Transplantation in Refractory Acute Myeloid Leukaemia.

Refractory acute myeloid leukaemia is very difficult to treat and represents an unmet clinical need. In recent years, new drugs and combinations of drugs have been tested in this category, with encouraging results. However, all treated patients relapsed and died from the disease. The only curative option is allogeneic transplantation through a graft from a healthy donor immune system. Using myeloablative conditioning regimens, the median overall survival regimens is 19%. Several so-called sequential induction chemotherapies followed by allogeneic transplantation conditioned by reduced intensity regimens have been developed, improving the overall survival to 25-57%. In the allogeneic transplantation field, continuous improvements in practices, particularly regarding graft versus host disease prevention, infection prevention, and treatment, have allowed us to observe improvements in survival rates. This is true mainly for patients in complete remission before transplantation and less so for refractory patients. However, full myeloablative regimens are toxic and carry a high risk of treatment-related mortality. In this review, we describe the results obtained with the different modalities used in more recent retrospective and prospective studies. Based on these findings, we speculate how allogeneic stem cell transplantation could be modified to maximise its therapeutic effect on refractory acute myeloid leukaemia.

Philadelphia chromosome-positive acute myeloid leukemia successfully treated by allogeneic hematopoietic stem cell transplantation: A case report and review of the literature.

RATIONAL: The Philadelphia chromosome (Ph) is seen in most patients with chronic myeloid leukemia and some patients with acute lymphoblastic leukemia. However, Ph-positive acute myeloid leukemia (Ph + AML) is a rare entity with a poor prognosis and a short median survival period. To date, there have been few clinical reports on this disease. And the treatment regimen of this disease has not been uniformly determined. PATIENT CONCERNS: We report a case of a Ph + AML. A 32-year-old male who was admitted to our hospital with weakness for 2 months. DIAGNOSIS: Philadelphia chromosome-positive acute myeloid leukemia. INTERVENTIONS: The patient achieved complete remission by the administration of a tyrosine kinase inhibitor, combined with low-intensity chemotherapy and a B-cell lymphoma 2 inhibitor. Then, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from his sister was successfully performed. OUTCOMES: The patient has been in a continuous remission state for 6 months after transplantation. LESSONS: We reported a rare Ph + AML case, successfully treated with allo-HSCT. This case provided strong support for treating Ph + AML with allo-HSCT.

Recent advances in CAR-T cell therapy for acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is a fatal and refractory haematologic cancer that primarily affects adults. It interferes with bone marrow cell proliferation. Patients have a 5 years survival rate of less than 30% despite the availability of several treatments, including chemotherapy, allogeneic haematopoietic stem cell transplantation (Allo-HSCT), and receptor antagonist drugs. Allo-HSCT is the mainstay of acute myeloid leukaemia treatment. Although it does work, there are severe side effects, such as graft-versus-host disease (GVHD). In recent years, chimeric antigen receptor (CAR)-T cell therapies have made significant progress in the treatment of cancer. These engineered T cells can locate and recognize tumour cells in vivo and release a large number of effectors through immune action to effectively kill tumour cells. CAR-T cells are among the most effective cancer treatments because of this property. CAR-T cells have demonstrated positive therapeutic results in the treatment of acute myeloid leukaemia, according to numerous clinical investigations. This review highlights recent progress in new targets for AML immunotherapy, and the limitations, and difficulties of CAR-T therapy for AML.

Haploidentical hematopoietic cell transplantation with or without an unrelated cord blood unit for adult acute myeloid leukemia: a multicenter, randomized, open-label, phase 3 trial.

Coinfusion of unrelated cord blood (UCB) units in haploidentical hematopoietic cell transplantation (haplo-HCT) (haplo-cord HCT) for hematopoietic malignancies showed promising results in previous reports, but the efficiency of haplo-cord HCT in acute myeloid leukemia (AML) still lacks sufficient evidence. This multicenter, randomized, phase 3 trial (ClinicalTrials.gov NCT03719534) aimed to assess the efficacy and safety of haplo-cord HCT in AML patients. A total of 268 eligible patients aged 18-60 years, diagnosed with measurable residual disease in AML (excluding acute promyelocytic leukemia), with available haploidentical donors and suitable for allotransplantation, were randomly allocated (1:1) to receive haplo-cord HCT (n = 134) or haplo-HCT (n = 134). The 3-year overall survival (OS) was the primary endpoint in this study. Overall median follow-up was 36.50 months (IQR 24.75-46.50). The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group (80.5%, 95% confidence interval [CI]: 73.7-87.9 vs. 67.8% 95% CI 60.0-76.5, p = 0.013). Favorable progression-free survival (70.3%, 95% CI 62.6-78.8 vs. 57.6%, 95% CI 49.6-67.0, p = 0.012) and cumulative incidence of relapse (12.1%, 95% CI 12.0-12.2 vs. 30.3%, 95% CI 30.1-30.4, p = 0.024) were observed in haplo-cord HCT group. Grade 3-4 adverse events (AEs) within two years posttransplantation in the two groups were similar. Haplo-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery (p = 0.026) and increased T-cell reconstitution in the early period posttransplantation. Haplo-cord HCT can improve OS in AML patients without excessive AEs, which may exert additional benefits for recipients of haplo-HCT.

Higher TIGIT+ γδ TCM cells may predict poor prognosis in younger adult patients with non-acute promyelocytic AML.

Introduction: γδ T cells recognize and exert cytotoxicity against tumor cells. They are also considered potential immune cells for immunotherapy. Our previous study revealed that the altered expression of immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on γδ T cells may result in immunosuppression and is possibly associated with a poor overall survival in acute myeloid leukemia (AML). However, whether γδ T-cell memory subsets are predominantly involved and whether they have a relationship with clinical outcomes in patients with AML under the age of 65 remain unclear. Methods: In this study, we developed a multicolor flow cytometry-based assay to monitor the frequency and distribution of γδ T-cell subsets, including central memory γδ T cells (TCM γδ), effector memory γδ T cells (TEM γδ), and TEM expressing CD45RA (TEMRA γδ), in peripheral blood from 30 young (≤65 years old) patients with newly diagnosed non-acute promyelocytic leukemia (also known as M3) AML (AMLy-DN), 14 young patients with AML in complete remission (AMLy-CR), and 30 healthy individuals (HIs). Results: Compared with HIs, patients with AMLy-DN exhibited a significantly higher differentiation of γδ T cells, which was characterized by decreased TCM γδ cells and increased TEMRA γδ cells. A generally higher TIGIT expression was observed in γδ T cells and relative subsets in patients with AMLy-DN, which was partially recovered in patients with AMLy-CR. Furthermore, 17 paired bone marrow from patients with AMLy-DN contained higher percentages of γδ and TIGIT+ γδ T cells and a lower percentage of TCM γδ T cells. Multivariate logistic regression analyses revealed the association of high percentage of TIGIT+ TCM γδ T cells with an increased risk of poor induction chemotherapy response. Conclusions: In this study, we investigated the distribution of γδ T cells and their memory subsets in patients with non-M3 AML and suggested TIGIT+ TCM γδ T cells as potential predictive markers of induction chemotherapy response.

Continuously improving outcome over time after second allogeneic stem cell transplantation in relapsed acute myeloid leukemia: an EBMT registry analysis of 1540 patients.

Second allogeneic stem cell transplantation (alloSCT2) is among the most effective treatments for acute myeloid leukemia (AML) relapse after first alloSCT (alloSCT1). Long-term EBMT registry data were used to provide large scale, up-to-date outcome results and to identify factors for improved outcome. Among 1540 recipients of alloSCT2, increasing age, better disease control and performance status before alloSCT2, more use of alternative donors and higher conditioning intensity represented important trends over time. Between the first (2000-2004) and last (2015-2019) period, two-year overall and leukemia-free survival (OS/LFS) increased considerably (OS: 22.5-35%, LFS: 14.5-24.5%). Cumulative relapse incidence (RI) decreased from 64% to 50.7%, whereas graft-versus-host disease and non-relapse mortality (NRM) remained unchanged. In multivariable analysis, later period of alloSCT2 was associated with improved OS/LFS (HR = 0.47/0.53) and reduced RI (HR = 0.44). Beyond, remission duration, disease stage and patient performance score were factors for OS, LFS, RI, and NRM. Myeloablative conditioning for alloSCT2 decreased RI without increasing NRM, leading to improved OS/LFS. Haploidentical or unrelated donors and older age were associated with higher NRM and inferior OS. In summary, outcome after alloSCT2 has continuously improved over the last two decades despite increasing patient age. The identified factors provide clues for the optimized implementation of alloSCT2.

Effective delivery of anti-PD-L1 siRNA with human heavy chain ferritin (HFn) in acute myeloid leukemia cell lines.

Because of the high biocompatibility, self-assembly capability, and CD71-mediated endocytosis, using human heavy chain ferritin (HFn) as a nanocarrier would greatly increase therapeutic effectiveness and reduce possible adverse events. Anti-PD-L1 siRNA can downregulate the level of PD-L1 on tumor cells, resulting in the activation of effector T cells against leukemia. Therefore, this study aimed to produce the tumor-targeting siPD-L1/HFn nanocarrier. Briefly, the HFn coding sequence was cloned into a pET-28a, and the constructed expression plasmid was subsequently transformed into E. coli BL21. After induction of Isopropyl ß-D-1-thiogalactopyranoside (IPTG), HFn was purified with Ni-affinity chromatography and dialyzed against PBS. The protein characteristics were analyzed using SDS-PAGE, Western Blot, and Dynamic light scattering (DLS). The final concentration was assessed using the Bicinchoninic acid (BCA) assay. The encapsulation was performed using the standard pH system. The treatment effects of siPD-L1/HFn were carried out on HL-60 and K-562 cancer cell lines. The RT-PCR was used to determine the mRNA expression of PD-L1. The biocompatibility and excretion of siPD-L1/HFn have also been evaluated. The expression and purity of HFn were well verified through SDS-PAGE, WB, and DLS. RT-PCR analyses also showed significant siRNA-mediated PD-L1 silencing in both HL-60 and K-562 cells. Our study suggested a promising approach for siRNA delivery. This efficient delivery system can pave the way for the co-delivery of siRNAs and multiple chemotherapies to address the emerging needs of cancer combination therapy.

Graft failure after allogeneic hematopoietic stem cell transplantation in pediatric patients with acute leukemia: autologous reconstitution or second transplant?

BACKGROUND: Graft failure (GF) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of graft failure remains the most advisable approach as there is no clear recommendation for the best strategies for reversing this complication. Administration of growth factor, additional hematopoietic progenitor boost, or a salvage HSCT are current modalities recommended for the treatment of GF. Autologous recovery without evidence of disease relapse occurs rarely in patients with GF, and in the absence of autologous recovery, further salvage transplantation following a second conditioning regimen is a potential treatment option that offers the best chances of long-term disease-free survival. The preconditioning regimens of second HSCT have a significant impact on engraftment and outcome, however, currently there is no consensus on optimal conditioning regimen for second HSCT in patients who have developed GF. Furthermore, a second transplant from a different donor or the same donor is still a matter of debate. OBSERVATIONS: We present our experience in managing pediatric patients with acute leukemia who encountered graft failure following stem cell transplantation. CONCLUSIONS AND RELEVANCE: Although a second transplantation is almost the only salvage method, we illustrate that some pediatric patients with acute leukemia who experience graft failure after an allogeneic stem cell transplant using Myeloablative conditioning (MAC) regimen may achieve long-term disease-free survival through autologous hematopoiesis recovery.

Transformation of Severe Aplastic Anemia into Donor Cell Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: A Rare Case Report.

BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important treatment for severe aplastic anemia (SAA). It is known that SAA can evolve into malignant clonal diseases, such as acute myeloblastic leukemia (AML) or myelodysplastic syndrome. However, the transformation of SAA into AML after allo-HSCT is a rare phenomenon. Here, we report a case of SAA transformed into AML after patient received human leucocyte antigen (HLA)-matched sibling peripheral blood stem cell transplantation. CASE REPORT A 51-year-old female patient presented with petechiae and fatigue and received a diagnosis of idiopathic SAA. The immunosuppressive therapy combined with umbilical cord blood transplantation failed for this patient. Then, she received HLA-matched sibling allogeneic peripheral blood stem cell transplantation (allo-PBSCT). However, 445 days after allo-PBSCT, the patient had a diagnosis of AML by bone marrow puncture. Donor-recipient chimerism monitoring and cytogenetic analysis confirmed that the leukemia was donor cell origin. Notably, a new HOXA11 mutation was detected in the peripheral blood of the patient after transplantation by whole-exome sequencing, which was the same gene mutation detected in the donor. The patient received 1 cycle of induction chemotherapy with azacytidine and achieved complete remission. However, the leukemia relapsed after 2 cycles of consolidation chemotherapy. Unfortunately, the patient died of leukemia progression 575 days after allo-HSCT. CONCLUSIONS The mechanism of how normal donor hematopoietic cells transform to leukemia in the host remains unclear. Donor cell leukemia provides a unique opportunity to examine genetic variations in donors and hosts with regards to the progression to malignancy.

Redefining hyperviscosity in acute leukemia: Potential implications for red cell transfusions in the microvasculature.

Hyperleukocytosis is an emergency of acute leukemia leading to blood hyperviscosity, potentially resulting in life-threatening microvascular obstruction, or leukostasis. Due to the high number of red cells in the circulation, hematocrit/hemoglobin levels (Hct/Hgb) are major drivers of blood viscosity, but how Hct/Hgb mediates hyperviscosity in acute leukemia remains unknown. In vivo hemorheological studies are difficult to conduct and interpret due to issues related to visualizing and manipulating the microvasculature. To that end, a multi-vessel microfluidic device recapitulating the size-scale and geometry of the microvasculature was designed to investigate how Hct/Hgb interacts with acute leukemia to induce "in vitro" leukostasis. Using patient samples and cell lines, the degree of leukostasis was different among leukemia immunophenotypes with respect to white blood cell (WBC) count and Hct/Hgb. Among lymphoid immunophenotypes, severe anemia is protective against in vitro leukostasis and Hct/Hgb thresholds became apparent above which in vitro leukostasis significantly increased, to a greater extent with B-cell acute lymphoblastic leukemia (ALL) versus T-cell ALL. In vitro leukostasis in acute myeloid leukemia was primarily driven by WBC with little interaction with Hct/Hgb. This sets the stage for prospective clinical studies assessing how red cell transfusion may affect leukostasis risk in immunophenotypically different acute leukemia patients.

Household income and health-related quality of life in children receiving treatment for acute myeloid leukemia: Potential impact of selection bias in health equity research.

OBJECTIVE: Examine the influence of household income on health-related quality of life (HRQOL) among children with newly diagnosed acute myeloid leukemia (AML). DESIGN: Secondary analysis of data prospectively collected from pediatric patients receiving treatment for AML at 14 hospitals across the United States. EXPOSURE: Household income was self-reported on a demographic survey. The examined mediators included the acuity of presentation and treatment toxicity. OUTCOME: Caregiver proxy reported assessment of patient HRQOL from the Peds QL 4.0 survey. RESULT: Children with AML (n = 131) and caregivers were prospectively enrolled to complete PedsQL assessments. HRQOL scores were better for patients in the lowest versus highest income category (mean ± SD: 76.0 ± 14 household income <$25,000 vs. 59.9 ± 17 income ≥$75,000; adjusted mean difference: 11.2, 95% CI: 2.2-20.2). Seven percent of enrolled patients presented with high acuity (ICU-level care in the first 72 h), and 16% had high toxicity (any ICU-level care); there were no identifiable differences by income, refuting mediating roles in the association between income and HRQOL. Enrolled patients were less likely to be Black/African American (9.9% vs. 22.2%), more likely to be privately insured (50.4% vs. 40.7%), and more likely to have been treated on a clinical trial (26.7% vs. 18.5%) compared to eligible unenrolled patients not enrolled. Evaluations of potential selection bias on the association between income and HRQOL suggested differences in HRQOL may be smaller than observed or even in the opposing direction. CONCLUSIONS: While primary analyses suggested lower household income was associated with superior HRQOL, differential participation may have biased these results. Future studies should partner with patients/families to identify strategies for equitable participation in clinical research.

Validation of the 2022 European LeukemiaNet risk stratification for acute myeloid leukemia.

This study aimed to validate the 2022 European LeukemiaNet (ELN) risk stratification for acute myeloid leukemia (AML). A total of 624 newly diagnosed AML patients from 1998 to 2014 were included in the analysis. Genetic profiling was conducted using targeted deep sequencing of 45 genes based on recurrent driver mutations. In total, 134 (21.5%) patients had their risk classification reassessed according to the 2022 ELN risk stratification. Among those initially classified as having a favorable risk in 2017 (n = 218), 31 and 3 patients were reclassified as having intermediate risk or adverse risk, respectively. Among the three subgroups, the 2022 ELN favorable-risk group showed significantly longer survival outcomes than the other groups. Within the 2017 ELN intermediate-risk group (n = 298), 21 and 46 patients were reclassified as having favorable risk or adverse risk, respectively, and each group showed significant stratifications in survival outcomes. Some patients initially classified as having adverse risk in 2017 were reclassified into the intermediate-risk group (33 of 108 patients), but no prognostic improvements were observed in this group. A multivariable analysis identified the 2022 ELN risk stratification, age, and receiving allogeneic hematopoietic cell transplantation as significant prognostic factors for survival. The 2022 ELN risk stratification enables more precise decisions for proceeding with allogeneic hematopoietic cell transplantation for AML patients.

[The Role of NK Cells in Allogeneic Hematopoietic Stem Cell Micro-Transplantation for Acute Myeloid leukemia].

OBJECTIVE: To explore the role of NK cells in allogeneic hematopoietic stem cell micro-transplantation(MST) in the treatment of patients with acute myeloid leukemia(AML). METHODS: Data from 93 AML patients treated with MST at our center from 2013-2018 were retrospectively analyzed. The induction regimen was anthracycline and cytarabine combined with peripheral blood stem cells transplantation mobilization by granulocyte colony stimulating factor (GPBSC), followed by 2-4 courses of intensive treatment with medium to high doses of cytarabine combined with GPBSC after achieving complete remission (CR). The therapeutic effects of one and two courses of MST induction therapy on 42 patients who did not reach CR before transplantation were evaluated. Cox proportional hazards regression analysis was used to analyze the impact of donor NK cell dose and KIR genotype, including KIR ligand mismatch, 2DS1, haplotype, and HLA-Cw ligands on survival prognosis of patients. RESULTS: Forty-two patients received MST induction therapy, and the CR rate was 57.1% after 1 course and 73.7% after 2 courses. Multivariate analysis showed that, medium and high doses of NK cells was significantly associated with improved disease-free survival (DFS) of patients (HR=0.27, P =0.005; HR=0.21, P =0.001), and high doses of NK cells was significantly associated with improved overall survival (OS) of patients (HR=0.15, P =0.000). Donor 2DS1 positive significantly increases OS of patients (HR=0.25, P =0.011). For high-risk patients under 60 years old, patients of the donor-recipient KIR ligand mismatch group had longer DFS compared to the nonmismatch group (P =0.036); donor 2DS1 positive significantly prolonged OS of patients (P =0.009). CONCLUSION: NK cell dose, KIR ligand mismatch and 2DS1 influence the therapeutic effect of MST, improve the survival of AML patients.

From code to care: Clinician and researcher perspectives on an optimal therapeutic web portal for acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML), a rapidly progressing cancer of the blood and bone marrow, is the most common and fatal type of adult leukemia. Therapeutic web portals have great potential to facilitate AML research advances and improve health outcomes by increasing the availability of data, the speed and reach of new knowledge, and the communication between researchers and clinicians in the field. However, there is a need for stakeholder research regarding their optimal features, utility, and implementation. METHODS: To better understand stakeholder perspectives regarding an ideal pan-Canadian web portal for AML research, semi-structured qualitative interviews were conducted with 17 clinicians, researchers, and clinician-researchers. Interview guides were inspired by De Laat's "fictive scripting", a method where experts are presented with scenarios about a future technology and asked questions about its implementation. Content analysis relied on an iterative process using themes extracted from both existing scientific literature and the data. RESULTS: Participants described potential benefits of an AML therapeutic portal including facilitating data-sharing, communication, and collaboration, and enhancing clinical trial matchmaking for patients, potentially based on their specific genomic profiles. There was enthusiasm about researcher, clinician, and clinician-researcher access, but some disagreement about the nature of potential patient access to the portal. Interviewees also discussed two key elements they believed to be vital to the uptake and thus success of a therapeutic AML web portal: credibility and user friendliness. Finally, sustainability, security and privacy concerns were also documented. CONCLUSIONS: This research adds to existing calls for digital platforms for researchers and clinicians to supplement extant modes of communication to streamline research and its dissemination, advance precision medicine, and ultimately improve patient prognosis and care. Findings are applicable to therapeutic web portals more generally, particularly in genomic and translational medicine, and will be of interest to portal end-users, developers, researchers, and policymakers.

[Veno-venous extracorporeal membrane oxygenation for capillary leak syndrome during induction chemotherapy in acute myeloid leukemia].

A 44-year-old woman was diagnosed with acute myeloid leukemia (RUNX1::RUNX1T1 translocation) and received induction chemotherapy with idarubicin hydrochloride and cytosine arabinoside. The pneumonia that had been present since admission worsened, and a drug-induced skin rash appeared. On day 17, she presented with respiratory failure and shock, complicated by hemoconcentration and hypoalbuminemia. This was considered capillary leak syndrome due to pneumonia and drug allergy, so she was started on pulse steroid therapy and IVIG, and was intubated on the same day. On day 18, venovenous-extracorporeal membrane oxygenation (VV-ECMO) was started due to worsening blood gas parameters despite ventilatory management. Bronchoalveolar lavage fluid was serous, and both blood and sputum cultures yielded negative. The patient was weaned from VV-ECMO on day 26 as the pneumonia improved with recovery of hematopoiesis. She was disoriented, and a CT scan on day 28 revealed cerebral hemorrhage. Her strength recovered with rehabilitation. After induction chemotherapy, RUNX1::RUNX1T1 mRNA was not detected in bone marrow. The patient received consolidation chemotherapy, and has maintained complete remission. Severe respiratory failure during induction chemotherapy for acute leukemia can be fatal, but VV-ECMO may be lifesaving.

Innovations in conditioning and post-transplant maintenance in AML: genomically informed revelations on the graft-versus-leukemia effect.

Acute Myeloid Leukemia (AML) is the prototype of cancer genomics as it was the first published cancer genome. Large-scale next generation/massively parallel sequencing efforts have identified recurrent alterations that inform prognosis and have guided the development of targeted therapies. Despite changes in the frontline and relapsed standard of care stemming from the success of small molecules targeting FLT3, IDH1/2, and apoptotic pathways, allogeneic stem cell transplantation (alloHSCT) and the resulting graft-versus-leukemia (GVL) effect remains the only curative path for most patients. Advances in conditioning regimens, graft-vs-host disease prophylaxis, anti-infective agents, and supportive care have made this modality feasible, reducing transplant related mortality even among patients with advanced age or medical comorbidities. As such, relapse has emerged now as the most common cause of transplant failure. Relapse may occur after alloHSCT because residual disease clones persist after transplant, and develop immune escape from GVL, or such clones may proliferate rapidly early after alloHSCT, and outpace donor immune reconstitution, leading to relapse before any GVL effect could set in. To address this issue, genomically informed therapies are increasingly being incorporated into pre-transplant conditioning, or as post-transplant maintenance or pre-emptive therapy in the setting of mixed/falling donor chimerism or persistent detectable measurable residual disease (MRD). There is an urgent need to better understand how these emerging therapies modulate the two sides of the GVHD vs. GVL coin: 1) how molecularly or immunologically targeted therapies affect engraftment, GVHD potential, and function of the donor graft and 2) how these therapies affect the immunogenicity and sensitivity of leukemic clones to the GVL effect. By maximizing the synergistic action of molecularly targeted agents, immunomodulating agents, conventional chemotherapy, and the GVL effect, there is hope for improving outcomes for patients with this often-devastating disease.