Jul 19, · Acute fractures are usually due to trauma, although they can be related to bone cancer. "Fractures are very dependent on patient demographics," Apr 16, · Bone marrow is found inside the central part of bones and produces white blood cells, red blood cells and platelets. Bone marrow disorders include leukemia, anemia, myeloproliferative neoplasms and myelodysplastic syndromes Although most cases of MDS or acute leukemia are sporadic diseases, it is becoming clear that a subgroup of cases is associated with germ line mutations and is familial. 74 A major change to the revision of the WHO classification is the addition of a section on myeloid neoplasms with germ line predisposition, which includes cases of MDS
Immunotherapy in Acute Myeloid Leukemia: Where We Stand
Try out PMC Labs and tell us what you think. Learn More. In the past few years, our improved knowledge of acute myeloid leukemia AML pathogenesis has led to the accelerated discovery of new drugs and the development of innovative therapeutic approaches. The role of the immune system in AML development, growth and recurrence has gained increasing interest.
A better understanding of immunological escape and systemic tolerance induced by AML blasts has been achieved. The extraordinary successes of immune therapies that harness the power of T cells in solid tumors and certain hematological malignancies have provided new stimuli in this area of research. Accordingly, major efforts have been made to develop immune therapies for the treatment of AML patients.
The persistence of leukemia stem cells, representing the most relevant cause of relapse, even after allogeneic stem cell transplant allo-SCTremains a major hurdle in the path to cure for AML patients. Combining clinical results with biological immunological findings, possibly coupled with the discovery of biomarkers predictive for response, will hopefully allow us to determine the best approaches to immunotherapy in AML.
Acute myeloid leukemia AML is a clonal disease characterized by the rapid proliferation of immature myeloid cells in the bone marrow with impaired differentiation 1. Despite major progresses in AML therapy and high rates of complete remission CR after intensive chemotherapy, many patients will eventually relapse and die from the disease.
At present, there is no curative therapy for patients who relapse, except for a small proportion who are cured by allogeneic stem cell transplant allo-SCT in second CR.
Recently, bone density in acute leukemia, the identification of disease-specific molecular aberrations has triggered the development of targeted therapies e. Furthermore, bone density in acute leukemia, the new frontier of BCL-2 inhibition with venetoclax has brought new hopes, with improved CR rates, prolonged event-free survival EFS and OS in the newly diagnosed elderly population 24 — 7.
Nevertheless, relapse still remain a major flaw, on the one hand due to the clonal evolution of the disease leading to disease recurrence 1on the other hand due to the immunosuppressive milieu of the bone marrow microenvironment leading to immune escape 48 — In recent years, the importance of the fine-tuned interplay between AML blasts, the hematopoietic niche bone density in acute leukemia, and the cells of the immune system for AML development and growth has been demonstrated 8 We have better understood the mechanisms underlying the ability of AML cells to induce immunological escape and systemic tolerance 9 Such tolerogenic pathways, which create an immunosuppressive bone density in acute leukemia, have been suggested to both critically hamper anti-leukemia immune responses and to negatively impact the anti-leukemia efficacy of conventional and experimental therapies.
Clinically relevant, some of these pathways could be targeted by new drugs, such as immune checkpoint and macrophage checkpoint inhibitors, resulting in increased anti-tumor immunity. Given the molecular heterogeneity of AML 9 and the natural diversity of AML blasts, the best strategy to beat AML will eventually be to combine or sequentially apply chemotherapy, immunotherapy and molecular therapy, designing a three-headed chimera hopefully able to control the disease and avoid its recurrence.
Moreover, the use of novel techniques for monitoring of the minimal residual disease MRDbone density in acute leukemia, to identify possible recurring clones at an early time-point, together with biomarkers of early response and genomic profiling 12are required to increase the cure rate of AML.
CD33, CD, CLL1, TIM3, and CD are ubiquitously expressed on AML bulk cells and, often, in leukemic stem cells LSCsboth at diagnosis and relapse, bone density in acute leukemia, irrespective of genetic characteristics and leukemic clonal evolution.
Accordingly, they have been considered as ideal targets for AML immunotherapy Monoclonal antibodies treatments include naked antibodies against AML surface antigens such as CD33 e. lintuzumab or CD38 e. daratumumabantibodies conjugated to toxins in various anti-CD33 gemtuzumab ozogamicin, SGN33A, IMGN and anti-CD IMGN, SL, SGN-CDA formulations, antibodies conjugated to radioactive particles such as Iodine or Actinium-labeled anti-CD33 or anti-CD45 antibodies, and multiple bispecific antibodies Table 1.
An increasing number of different types and classes of monoclonal antibodies have proven their efficacy and have been approved for indications in several hematological malignancies, comprising AML. Ingemtuzumab ozogamicin GOa humanized anti-CD33 monoclonal antibody conjugated with calicheamicin, was granted accelerated approval by the United States US Food and Drug Administration FDA However, the promising results of the phase II study conducted in relapsed, older adults with AML 1516 were not confirmed in the randomized phase III S trial, evaluating GO versus no GO during induction and post-consolidation therapy in younger AML Therefore, the drug was voluntary withdrawn from the US market in by the company, basing on an unfavorable safety-efficacy profile.
Moreover, when OS was analyzed according to cytogenetic profile, the beneficial effect of GO was documented most clearly in patients with favorable risk AML, followed by a smaller benefit intermediate-risk AML, but no benefit in adverse-risk. Remission rates were not increased, but by significantly reducing the risk of relapse, the overall survival at 5 years was improved irrespective of patient age The survival benefit was particularly clear in those with favorable cytogenetics Patients with adverse karyotype did not benefit on the overall analysis, nor individually within any of the five trials.
Initial studies with GO in AML demonstrated an increased risk of VOD, reported to occur after SCT in patients who received GO before SCT. GO bone density in acute leukemia now reported in product labeling to pose risks for VOD based on clinical trial data. The example of GO showed how long and winding the road may be to develop and successfully commercialize a monoclonal antibody in AML. Preclinical studies suggest that GO would be most effective for AML with high CD33 expression 22even in the absence of reproducible cut-offs among different laboratories Although GO does not appear bone density in acute leukemia benefit the non-CBF AML patients with the lowest CD33 expression, a higher GO dose may be more effective in CDlow but not CDhigh younger adults In the setting of elderly patients, unfit for intensive chemotherapy, receiving single-agent GO, low or minimal CD33 expression was associated with inferior outcome 24 However, this issue remains controversial because other trials, particularly those in which GO was used in combination with chemotherapy, failed to identify a correlation between CD33 expression and clinical outcome 18 Given the vicissitudes of GO, several other antibodies targeting the CD33 antigen were developed in the last 10 years.
Lintuzumab HuM is a humanized monoclonal antibody that targets CD33, inducing antibody-dependent cell-mediated cytotoxicity and fixing human complement in vitro Other clinical trials with lintuzumab, alone or in combination with cytarabine in relapsed AML patients have been disappointing, mainly due to lack of efficacy 28 The anti-CD33 lintuzumab has been used as backbone for the development of immune-conjugated antibodies.
The median response duration was 6 months range, 2—12 In lintuzumab Ac the anti-CD33 antibody is conjugated with an bone density in acute leukemia emitting isotope, bone density in acute leukemia, Ac This regimen may represent a safe and potentially effective therapy for medically fit RR-AML pts, particularly as a bridge to allo-SCT 30 Combining 0.
SGN-CD33A is a humanized anti-CD33 antibody conjugated to a highly potent, synthetic DNA cross-linking pyrrolo-benzodiazepine dimer via a protease-cleavable linker. A subsequent randomized phase III study evaluating azacitidine with or without SGN-CD33A CASCADE study was prematurely terminated due to increased early mortality in the SGN-CD33A arm, and this agent is no longer being developed in AML.
Tagraxofusp formerly SL is an intravenously administered CDdirected cytotoxin composed of human interleukin-3 and a truncated diphtheria toxin payload that was approved in December by the US FDA for the treatment of blastic plasmacytoid dendritic cell neoplasm BPDCN. In vitrotagraxofusp induced potent cytotoxic activity against CDpositive AMLs and myelodysplastic syndrome blast cells In preclinical models, tagraxofusp improved the survival of immunodeficient animals xenografted with primary AML cells The results of a phase I clinical trial performed on 45 AML patients showed that the maximum tolerated dose was Tagraxofusp was safe, but efficacy data are not yet available bone density in acute leukemia CSL is a recombinant, chimeric IgG1, anti-CD monoclonal antibody that neutralizes IL-3, with anti-leukemic activity in vitro.
However, the trial failed to demonstrate anti-leukemic activity in most patients To improve clinical efficacy, CSL talacotuzumaba fully humanized antibody, was developed, containing specific Fc-domain point modifications to enhance binding affinity with Fcγ receptors 46 and increase anti-leukemic activity via antibody-dependent cellular cytotoxicity ADCC against leukemic blasts and leukemic stem cells In AML xenografts models in immune-deficient mice, CSL did not show any activity when administered as single agent, but was able to enhance the antileukemic effect induced by daunorubicin and cytarabine A second phase I study NCT enrolling high risk AML patients in first or second remission, who were not candidate for allo-SCT 45showed preliminary activity of CSL, with a relatively high conversion rate to negative minimal residual disease 49 or disease eradication in some patients More recently, talacotuzumab was given to elderly, high-risk AML or MDS patients who have failed treatment with hypomethylating agents Five of 24 AML patients achieved hematological improvement, providing the rationale to test the efficacy and safety bone density in acute leukemia decitabine plus talacotuzumab versus decitabine alone in newly diagnosed AML patients ineligible for intensive chemotherapy Unfortunately, the randomized multicenter study testing decitabine with or without talacotuzumab was terminated early due to lack of efficacy.
As whole, immunotherapy based on naked anti-CD moAb appears to have limited benefits, probably due to the compromised immune profile of these patients reduced mature NK cells, increased expression of inhibitory NK-cell receptors IMGN is a CDtargeting antibody-drug conjugate ADCin which a novel anti-CD antibody is coupled, via a peptide linker, bone density in acute leukemia, to a unique DNA-alkylating cytotoxic payload of the recently developed IGN indolinobenzodiazepine pseudodimer class.
IMGN reduced viability in AML cell lines and patient-derived samples, both in vitro and in vivo xenograft models, in the absence of or with limited myelosuppression Basing on these initial findings from the BPDCN cohort, IMGN was granted an FDA breakthrough designation for BPDCN in November 16th, IMGN was generally well tolerated. Another approach to immunotherapy in AML is retargeting the effector cells T-cells, NK-cells, macrophages to provide rapid activation, robust and durable cytotoxic responses, and potentially generate immunologic memory In this scenario, the class of bispecific antibodies bsAbsalso known as dual-targeting molecules, includes antibodies or single chain variable fragments scFv derived from the Fab fragment of the IgG immunoglobulin, composed of the VH and VL domains attached with a linker, to physically bridge two or more cells Several formats of bsAbs have been investigated in AML: BiTe Bispecific T-cell engagerbone density in acute leukemia, BiKe Bispecific killer cell engagerTriKe Trispecific killer cell engagerTandem Diabodies TandAbsand dual affinity retargeting antibodies DARTs 5759 — In the BiTe and BiKe molecules, binding domains are two single-chain variable fragment scFv regions, arisen from mAbs, joined by a flexible peptide linker with affinities for both a selected leukemia associated antigen e.
CD33, CD19 as well as a selected target on an effector immune cell, like CD3 expressed on T-cells in BiTes or CD16 expressed on NK-cells in BiKes Binding between effector cells and tumor cells facilitates the formation of cytolytic synapses inducing the apoptosis of the tumor cells and under specific circumstances the release of cytokines to amplify the immunological response by involving other immune cells or induce T cells proliferation 56 — 58 AMG is a human BiTe tandem single-chain antibody with the N-terminal specific for human CD33 and the C-terminal directed towards CD3Ԑ.
Recently, a new approach based on the combination of T-cell engagers with immune checkpoint blockade in a single molecule, using a bifunctional checkpoint inhibitory T cell-engaging Bone density in acute leukemia antibody that combines T-cell redirection to CD33 on AML cells with locally restricted immune checkpoint blockade has been proposed In vitrothe PD-1 attachment increases T-cell activation 3.
In a murine xenograft model, the CiTE induced complete AML eradication without infusion-related adverse events, as measured by body weight loss Ex vivoAMG showed a potent dose- and effector to target cell ratio, dependent activity against human AML cell lines 64 AMG cytotoxicity was neither affected by common CD33 single nucleotide polymorphisms nor by expression of the adenosine triphosphate-binding cassette ABC transporter proteins, P-glycoprotein or breast cancer resistance proteins Unlike bivalent CD33 antibodies, AMG did not reduce surface CD33 expression In vivodaily intravenous administration of AMG significantly prolonged the bone density in acute leukemia of immune-deficient mice adoptively transferred with human MOLM AML cells and human T-cells In the update presented at ASCOAMG exhibited dose-dependent increase in steady state exposures over the studied dose range with clinical PK profile consistent with continuous IV administration.
AMG was administered to patients on an intra-patient step-up strategy of up to µg, allowing the delivery of much higher doses of AMG to the patients while lowering the risk for cytokine release syndrome CRS, bone density in acute leukemia. CRS is an emerging side effect of immune-therapy, bone density in acute leukemia, manifesting as clinical syndrome characterized by a widespread immune inflammatory response due to the bone density in acute leukemia of cytokines.
The median response duration was 40 days range: 14— Responding patients were allowed to proceed to allo-SCT. AMG is a new anti-CD33x anti-CD3 Bone density in acute leukemia antibody construct, that binds both CD33 and CD3 and is genetically fused to the N-terminus of a single-chain IgG Fc region, thereby potentially increasing the half-life to 7 days which permits weekly dosing of the agent.
Currently, G is tested in the ongoing clinical trial NCTT No data are available up to now. Tandem diabodies combine two scFVs for each target connected with a single polypeptide target.
This allows them to maintain the avidity of a bivalent antibody as well as have a molecular weight that exceeds the renal clearance threshold AMV is a tetravalent anti-CD33 × anti-CD3 TandAb with a kDa molecular weight avoiding first pass renal clearance and resulting in a longer half-life in comparison to BiTEs.
Preliminary results presented at the EHA in showed evidence of T-cell activation by increased cytokine levels and expression of antigen markers of T-cell activation. Dual affinity retargeting antibodies DARTs consist of variable domains of two antigen-binding specificities linked to two independent polypeptide bone density in acute leukemia. Each variable domain is formed by associating one VL segment on one chain with a VH segment on a second chain, covalently linked via disulfide bridge The first-in-class DART with clinical activity in AML is flotetuzumab MGD or Sbased on two independent polypeptides fusing the heavy-chain variable domain of one antibody to the light-chain variable domain of the other to connect CD3 and CD In vitro studies demonstrated a dose-dependent killing of AML cells
The Acute Leukemias
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Jul 19, · Acute fractures are usually due to trauma, although they can be related to bone cancer. "Fractures are very dependent on patient demographics," Apr 04, · Treatment outcomes for acute lymphoblastic leukemia (ALL) in children are 1 of the tremendous successes of combination chemotherapy in oncology, with high survival rates of 80% to 90%. 1 In contrast, treatment of adults with ALL has been much less successful, with overall survival (OS) rates of only 30% to 40%, despite equivalent complete remission (CR) rates >90%. To better May 01, · Leukemia is a clonal proliferation of hematopoietic stem cells in the bone marrow. The four broad subtypes most likely to be encountered by primary care physicians are acute lymphoblastic, acute
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