The long road:improving outcome in elderly "unfit" AML?

In this issue of Blood, Wei et al(1) report the results of a prospective randomized placebo-controlled trial that presents formal evidence of an overall survival benefit of adding venetoclax to low-dose cytarabine (LDAC) in elderly patients with newly diagnosed acute myeloid leukemia (AML) not considered eligible for intensive cytotoxic treatment

Treatment of AML in Older Patients

Acute myeloid leukaemia (AML) is a disease mostly diagnosed in older adults. Treatment of older patients with AML remains challenging with higher rates of intrinsic chemotherapeutic resistance and decreased treatment tolerance. Indeed AML in older patients has different clinical and biologic characteristics compared to younger patients. Several treatment options are available for treatment of AML in older patients, namely conventional intensive chemotherapy (‘3 + 7’), low-dose cytarabine, and hypomethylating agents. Combinations with new drugs have been recently approved or are in advanced stages of clinical testing, namely venetoclax, midostaurin, glasdegib. Clinical decision making should take into account disease characteristics (e.g. cytogenetic and molecular abnormalities, white blood cell count), patient characteristics (e.g. performance, comorbidities, geriatric assessment) and patients’ preference when considering which treatment option is most suitable for the older patient. Allogeneic haematopoietic cell transplantation (HCT) as post-remission strategy should also be considered for older patients with AML. Allogeneic HCT following reduced-intensity conditioning or non-myeloablative conditioning has made this treatment option more suitable for older patients with a reduction in treatment-related mortality

Inhibition of Autophagy Does Not Re-Sensitize Acute Myeloid Leukemia Cells Resistant to Cytarabine

Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease

Paradoxical down-regulation of p16INK4a mRNA with advancing age in Acute Myeloid Leukemia

Aging is generally considered to be the consequence of stem cell attrition caused by the activity of tumor suppressor pathways that censor potentially malignant clones by eliciting apoptosis or senescence. An important effector of aging is the cyclindependent kinase inhibitor p16INK4a, which is also a known suppressor of cancer. The expression of p16INK4a is very low or absent in young organisms but increases with advancing age. We recently showed that, unlike healthy cells, acute myeloid leukemia (AML) derived blasts show a down-regulation of p16INK4a mRNA with increasing age. Based on this observation we hypothesize that suppression of defense mechanisms which protect older cells against cellular and DNA damage might facilitate oncogenesis in older individuals

Characteristics, primary treatment, and survival of MDS/MPN with neutrophilia:a population-based study

Myelodysplastic and myeloproliferative neoplasms (MDS/MPN) with neutrophilia, until recently called atypical chronic myeloid leukemia (aCML), being part of the MDS/MPN is a very rare disease with poor prognosis. Although emerging data reveal its cytogenetic and molecular profile, integrated survival and treatment data remain scarce. We analyzed a cohort of 347 adult patients diagnosed with MDS/MPN with neutrophilia, registered in the Netherlands Cancer Registry between 2001 and 2019. Our demographic baseline data align with other cohorts. We observed cytogenetic aberrations exclusively in patients aged &gt;65 years, with trisomy 8 being the most common abnormality. We identified 16 distinct molecular mutations, with some patients (16/101) harboring up to 3 different mutations; ASXL1 being the most frequent one (22%). In a multivariable Cox regression analysis, only age, hemoglobin level and allogeneic hematopoietic stem cell transplant (alloHSCT) were associated with overall survival (aged &gt;65 years; hazard ratio [HR] 1.85; P = .001 and alloHSCT HR, 0.51; P = .039). Because no other treatment modality seemed to affect survival and might cause toxicity, we propose that all patients eligible for alloHSCT should, whenever possible, receive an allogeneic transplant. It is imperative that we strive to improve outcomes for patients who are not eligible for alloHSCT. Tackling this challenge requires international collaborative efforts to conduct prospective intervention studies.</p

The Novel Immune Checkpoint GPR56 Is Expressed on Tumor-Infiltrating Lymphocytes and Selectively Upregulated upon TCR Signaling

High levels of tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment (TME) are associated with a survival benefit in various cancer types and the targeted (re)activation of TILs is an attractive therapeutic anti-cancer approach that yields curative responses. However, current T cell targeting strategies directed at known immune checkpoints have not increased objective response rates for all cancer types, including for epithelial ovarian cancer (EOC). For this reason, the identification of new immune checkpoints that regulate T cell immunity remains of great interest. One yet largely uninvestigated checkpoint of potential interest is the G protein-coupled receptor 56 (GPR56), which belongs to the adhesion GPCR family. GPR56 was originally reported to function in cerebral cortical development and in anti-depressant response, but also in cancer. Recently, GPR56 was identified as an inhibitory receptor expressed on human NK cells that by cis-interaction with the tetraspanin CD81 attenuated the cytotoxic activity of NK cells. This NK cell checkpoint could be blocked by an GPR56 antibody, leading to increased cytotoxicity. Interestingly, GPR56 expression has also been reported on cytokine producing memory CD8 T lymphocytes and may thus represent a T cell checkpoint as well. Here, GPR56 mRNA expression was characterized in the context of TILs, with GPR56 expression being detected predominantly in tumor infiltrating CD8 T cells with a cytotoxic and (pre-)exhausted phenotype. In accordance with this mRNA profile, TILs from ovarian cancer patients expressed GPR56 primarily within the effector memory and central memory T cell subsets. On T cells from healthy donors the expression was limited to effector memory and terminally differentiated T cells. Notably, GPR56 expression further increased on TILs upon T cell receptor (TCR)-mediated stimulation in co-cultures with cancer cells, whereas GPR56 expression on healthy primary human T cells did not. Further, the ectopic expression of GPR56 significantly reduced the migration of GPR56-positive T cells. Taken together, GPR56 is a potential immune-checkpoint in EOC found on (pre-)exhausted CD8 TILs that may regulate migratory behavior

The IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis.

Upregulation of the plasma membrane receptor IL1RAP in Acute Myeloid Leukemia (AML) has been reported but its role in the context of the leukemic bone marrow niche is unclear. Here, we studied the signaling events downstream of IL1RAP in relation to leukemogenesis and normal hematopoiesis. High IL1RAP expression was associated with a leukemic GMP-like state, and knockdown of IL1RAP in AML reduced colony-forming capacity. Stimulation with IL1β resulted in the induction of multiple chemokines and an inflammatory secretome via the p38 MAPK and NFκB signaling pathways in IL1RAP-expressing AML cells, but IL1β-induced signaling was dispensable for AML cell proliferation and NFκB-driven survival. IL1RAP was also expressed in stromal cells where IL1β induced expression of inflammatory chemokines and cytokines as well. Intriguingly, the IL1β-induced inflammatory secretome of IL1RAPexpressing AML cells grown on a stromal layer of mesenchymal stem cells affected normal hematopoiesis including hematopoietic stem/progenitor cells while AML cell proliferation was not affected. The addition of Anakinra, an FDA-approved IL1 receptor antagonist, could reverse this effect. Therefore, blocking the IL1-IL1RAP signaling axis might be a good therapeutic approach to reduce inflammation in the bone marrow niche and thereby promote normal hematopoietic recovery over AML proliferation after chemotherapy

A luminescence-based method to assess antigen presentation and antigen-specific T cell responses for in vitro screening of immunomodulatory checkpoints and therapeutics

Investigations into the strength of antigen-specific responses in vitro is becoming increasingly relevant for decision making in early-phase research of novel immunotherapeutic approaches, including adoptive cell but also immune checkpoint inhibitor (ICI)-based therapies. In the latter, antigen-specific rapid and high throughput tools to investigate MHC/antigen-specific T cell receptor (TCR) activation haven't been implemented yet. Here, we present a simple and rapid luminescence-based approach using the human papillomavirus 16 (HPV16) E7 11-20 peptide as model antigen and E7-TCR transgenic Jurkat.NFAT- luciferase reporter cells. Upon E7 peptide pulsing of HLA-A2 + cell lines and macrophages, an effector to target ratio dependent increase in luminescence compared to non-pulsed cells was observed after co-incubation with E7-TCR expressing Jurkat, but not with parental cells. Analogous experiments with cells expressing full-length HPV16 identified that E7-specific activation of Jurkat cells enabled detection of endogenous antigen processing and MHC-I presentation. As proof of concept, overexpression of established checkpoints/inhibitory molecules (e.g., PD-L1 or HLA-G) significantly reduced the E7-specific TCR-induced luminescence, an effect that could be restored after treatment with corresponding targeting antagonistic antibodies. Altogether, the luminescence-based method described here represents an alternative approach for the rapid evaluation of MHC-dependent antigen-specific T cell responses in vitro. It can be used as a rapid tool to evaluate the impact of the immunosuppressive tumor microenvironment or novel ICI in triggering effective T cell responses, as well as speeding up the development of novel therapeutics within the immune-oncology field. </p

Extranodal Natural Killer/T-cell Lymphoma, Nasal Type:Diagnosis and Treatment

The aggressive lymphoma, extranodal natural killer/T-cell lymphoma-nasal type, is strongly associated with Epstein-Barr virus (EBV) and is most common in Asia and in South and Central America. By contrast, incidence is low in the United States and Europe, where extranodal natural killer/T-cell lymphoma represents only 0.2%-0.4% of all newly diagnosed non-Hodgkin lymphomas. At diagnosis, it is important to test for EBV DNA in plasma by polymerase chain reaction and to carry out positron emission tomography/computer tomography and magnetic resonance imaging of the nasopharynx. In stage I/II disease, radiotherapy is the most important treatment modality, but in high-risk stage I/II disease (stage II, age > 60 y, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance score ≥2, primary tumor invasion), it should be combined with chemotherapy. The most optimal responses are reached with nonmultidrug resistance-based therapy (eg, asparaginase- or platinum-based therapy). Therapeutic approaches consist of either platinum-based concurrent chemoradiotherapy or sequential chemoradiotherapy. The minimum dose of radiotherapy should be 50-56 Gy. Treatment of stage III/IV disease consists of 3 cycles of chemotherapy followed by autologous hematopoietic cell transplantation. Allogeneic hematopoietic cell transplantation should only be considered in case of relapsed disease or after difficulty reaching complete remission. During treatment and follow-up, plasma EBV levels should be monitored as a marker of tumor load