ABSTRACT
Immune effector cell (IEC) therapy is emerging as a promising approach in the field of cancer immunotherapy. Clinical IEC trials, predominantly using chimeric antigen receptor (CAR) T cells, have shown excellent responses in CD19+ B cell malignancies and multiple myeloma. In solid tumors, preclinical data are encouraging, but clinical data are in their infancy, and there are challenges in using CAR T therapy in this setting, including (1) on-target off-tumor toxicity, (2) optimal target identification, (3) effective trafficking into bulky tumor tissue, and (4) resistance to tumor immune evasion mechanisms. Novel techniques and modifications are being explored in both the preclinical and clinical settings, aiming to improve treatment efficacy and address the aforementioned obstacles to successful CAR T therapy in solid tumors. Here we review these challenges in a clinically oriented approach and summarize published clinical trials using CAR T therapy in a variety of solid tumors.
Subject(s)
Immunotherapy, Adoptive , Neoplasms , Antigens, CD19 , Humans , Lymphocytes , Neoplasms/therapy , Receptors, Antigen, T-Cell , Tumor MicroenvironmentABSTRACT
BACKGROUND: Despite the well-defined role of minimal residual disease (MRD) monitoring by real-time quantitative polymerase chain reaction (RT-PCR) for RUNX1/RUNX1T1 and CBFB-MYH11 transcripts in core binding factor (CBF) acute myeloid leukemia (AML) after intensive chemotherapy, there has been a paucity of data assessing the utility of MRD monitoring at and after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: Patients with CBF AML who underwent HSCT in complete remission (first or second) from January 2007 through December 2018 were included in this analysis. RESULTS: MRD by polymerase chain reaction at HSCT was assessed in 50 of 76 patients, and 44 (88%) had evidence of MRD (MRDpos). MRDpos patients had 3-year overall survival (OS) and leukemia-free survival (LFS) rates of 69.3% and 66.3%, respectively. Six MRD-negative patients had 3-year OS and LFS rates of 100% and 100%, respectively. Thirty-five of the 70 evaluable patients (50%) had a day +100 MRD assessment by RT-PCR, and 14 (40%) were MRDpos. The presence of MRD by RT-PCR on day +100 was not associated with lower estimates of LFS (75% vs 82.2%; P = .3) but was associated with a higher relapse incidence, although the difference did not reach statistical significance (27.6% vs 9.7%; P = .2). CONCLUSIONS: Durable complete remissions can be achieved in patients with CBF AML with HSCT even if they are MRDpos by RT-PCR at HSCT. The clinical impact of frequent MRD monitoring for identifying a group at high risk for early relapse and then for determining the best time point for therapeutic interventions to prevent impending relapse warrants investigation in prospectively designed clinical trials.
Subject(s)
Core Binding Factors/genetics , Leukemia, Myeloid, Acute/diagnosis , Neoplasm, Residual/diagnosis , Real-Time Polymerase Chain Reaction/methods , Adult , Core Binding Factor Alpha 2 Subunit/genetics , Core Binding Factor beta Subunit/genetics , Female , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Myosin Heavy Chains/genetics , Neoplasm, Residual/genetics , Neoplasm, Residual/therapy , Oncogene Proteins, Fusion/genetics , Prognosis , RUNX1 Translocation Partner 1 Protein/genetics , Transplantation, HomologousABSTRACT
Hypomethylating agents (HMAs) are standard of care for higher-risk myelodysplastic syndromes (MDS). However, less than half of patients achieve objective responses and most eventually lose their response. Pracinostat is a pan-histone deacetylase inhibitor with demonstrated activity in advanced myeloid malignancies. This phase II study explored the benefit of adding pracinostat to HMAs in MDS patients who did not respond to single-agent HMA treatment. The goal was to estimate the clinical improvement rate [complete remission (CR), marrow CR, partial response (PR) and haematological improvement]. Group 1 included patients with primary/secondary HMA failures; Group 2 included those who did not achieve response but had stable disease (SD) after single-agent HMAs. Forty-five patients (39 Group 1, 6 Group 2) received a median of 3 cycles. Among all patients, 1 (2%) had CR, 7 (16%) had marrow CR and 18 (40%) had SD; disease progression occurred in 3 (7%). Median overall survival was 5·7/5·6 months for Group 1/2. Grade ≥3 adverse events occurred in 38 patients (84%) leading to treatment discontinuation in 12 (33%). Adding pracinostat to HMAs did not improve outcomes in patients previously treated with HMAs. Frequent dose modifications/early discontinuation resulted in suboptimal drug exposure. A reduced pracinostat dose may improve tolerability and efficacy.
Subject(s)
Benzimidazoles/administration & dosage , Histone Deacetylase Inhibitors/administration & dosage , Myelodysplastic Syndromes/drug therapy , Aged , Aged, 80 and over , Bone Marrow/metabolism , Bone Marrow/pathology , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Myelodysplastic Syndromes/metabolism , Myelodysplastic Syndromes/pathologyABSTRACT
BACKGROUND: The addition of midostaurin to induction chemotherapy improves survival in younger patients with newly diagnosed, FLT3-mutated acute myeloid leukemia (AML). Sorafenib is a potent multikinase inhibitor with efficacy when given as monotherapy. The authors investigated whether the addition of sorafenib to intensive induction chemotherapy improves outcomes in patients with FLT3-internal tandem duplication (ITD)-mutated AML. METHODS: In total, 183 patients who were newly diagnosed with FLT3-ITD-mutated AML between February 2001 and December 2017 were identified. Of these, 79 patients (43%) underwent intensive chemotherapy with the addition of sorafenib, and 104 (57%) received intensive chemotherapy alone. Propensity score matching identified 42 patients in each cohort. RESULTS: The overall response rate was 98% in the sorafenib cohort and 83% in the intensive chemotherapy cohort (P = .057). The median follow-up was 54 months. The median event-free survival was 35 months in the sorafenib cohort and 8 months in the intensive chemotherapy cohort (P = .019), and the median overall survival was 42 and 13 months, respectively (P = .026). With censoring at the time of allogeneic stem cell transplantation, the median event-free survival was 31 and 8 months in the sorafenib and intensive therapy cohorts, respectively (P = .031), and the median overall survival was not reached and 10 months, respectively (P = .001). Multivariate Cox proportional hazards models confirmed that treatment with sorafenib was a favorable prognostic factor (P = .009; hazard ratio, 0.558; 95% CI, 0.360-0.865). CONCLUSIONS: The addition of sorafenib improves survival in patients with FLT3-ITD-mutated AML regardless of whether they undergo allogeneic stem cell transplantation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid/therapy , Mutation , Tandem Repeat Sequences/genetics , fms-Like Tyrosine Kinase 3/genetics , Acute Disease , Adult , Cohort Studies , Combined Modality Therapy , Female , Humans , Induction Chemotherapy/methods , Kaplan-Meier Estimate , Leukemia, Myeloid/genetics , Male , Middle Aged , Remission Induction , Sorafenib/administration & dosage , Staurosporine/administration & dosage , Staurosporine/analogs & derivatives , Transplantation, Homologous , Young AdultABSTRACT
Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 gene (FLT3) confer a poor prognosis in adult AML. Studies have reported that a higher mutant allelic burden is associated with a worse prognosis. Adult patients with FLT3-ITD mutated AML treated at our institution were identified. Patients were assigned into 2 groups; patients who received idarubicin and cytarabine (IA, group one) containing induction, and who received sorafenib in addition to IA containing regimens at induction (group two). The optimal FLT3-ITD mutant allele cut-off was defined as the cut-off to divide the whole cohort with the highest statistical significance. A total of 183 patients including 104 (57%) in group one and 79 (43%) in group two were identified. The complete remission (CR)/CR with incomplete hematologic recovery (CRi) for group one and group two were 85% and 99%, respectively (P = .004). The median relapse free survival (RFS) for group one and two were 12 and 45 months, respectively (P = .02). The median overall survival (mOS) was 17 months in group one, and has not been reached in group two (P = .008). The optimal FLT3-ITD mutant allele cut-off for OS was 6.9% in group one, there was no optimal cut-off in group two. On multivariate analysis, poor performance status (PS) (P = .003), sorafenib (P = .01), and presenting white blood cells (WBC) (P < .001) were independent predictors of OS. Higher FLT3-ITD allele burden is associated with a worse outcome in patients treated with IA-based chemotherapy. Addition of sorafenib to chemotherapy not only nullifies the negative prognostic impact of higher allele burden, but also improves outcome of FLT3-ITD mutated AML patients regardless of the allele burden.
Subject(s)
Alleles , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Leukemia, Myeloid, Acute , Mutation , Tandem Repeat Sequences , fms-Like Tyrosine Kinase 3 , Adolescent , Adult , Aged , Cytarabine/administration & dosage , Disease-Free Survival , Female , Follow-Up Studies , Humans , Idarubicin/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Retrospective Studies , Sorafenib/administration & dosage , Survival Rate , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
Given the increasing incidence of chronic graft-versus-host disease (cGVHD) and its rapidly escalating costs due to many lines of drug treatments, we aimed to perform a meta-analysis to assess the comparative effectiveness of various treatment options. Using these results, we then conducted a cost-effectiveness analysis for the frequently utilized agents in steroid-refractory cGVHD. We searched for studies examining tacrolimus, sirolimus, rituximab, ruxolitinib, hydroxychloroquine, imatinib, bortezomib, ibrutinib, extracorporeal photopheresis, pomalidomide, and methotrexate. Studies with a median follow-up period shorter than 6 months and enrolling fewer than 5 patients were excluded. Meta-analysis for overall and organ system-specific GVHD response (overall response [ORR], complete response [CR], and partial response [PR]) was conducted for each intervention. Cost per CR and cost per CR + PR were calculated as the quotient of the 6-month direct treatment cost by CR and CR + PR. Forty-one studies involving 1047 patients were included. CR rates ranged from 7% to 30% with rituximab and methotrexate, respectively, and ORR ranged from 30% to 85% with tacrolimus and ruxolitinib, respectively. Cost per CR ranged from US$1,187,657 with ruxolitinib to US$680 with methotrexate. Cost per ORR ranged from US$453 for methotrexate to US$242,236 for ibrutinib. The most cost-effective strategy was methotrexate for all of the organ systems. Pomalidomide was found to be the least cost-effective treatment for eye, gastrointestinal, fascia/joint, skin, and oral GVHD, and imatinib was found to be the least cost-effective treatment for liver and extracorporeal photopheresis for lung GVHD. We observed huge cost-effectiveness differences among available agents. Attention to economic issues when treating cGVHD is important to recommend how treatments should be sequenced, knowing that many patients will cycle through available agents.
Subject(s)
Cost-Benefit Analysis/trends , Graft vs Host Disease/economics , Chronic Disease , Female , Health Care Costs , Humans , MaleABSTRACT
Therapy related myeloid neoplasms (t-MN) including therapy related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML) are associated with aggressive disease biologies and poor outcomes. In this large (n = 497) and informative (inclusive of molecular and cytogenetic information) chronic myelomonocytic leukemia (CMML) patient cohort, we demonstrate key biological insights and an independent prognostic impact for t-CMML. T-CMML was diagnosed in 9% of patients and occurred approximately 7 years after exposure to prior chemotherapy and/or radiation therapy. In comparison to de novo CMML, t-CMML patients had higher LDH levels, higher frequency of karyotypic abnormalities and had higher risk cytogenetic stratification. There were no differences in the distribution of gene mutations and unlike t-MDS/AML, balanced chromosomal translocations, abnormalities of chromosome 11q23 (1%) and Tp53 mutations (<2%) were uncommon. Molecularly integrated CMML prognostic models were not effective in risk stratifying t-CMML patients and responses to hypomethylating agents were dismal with no complete responses. Median overall (OS) and leukemia free survival (LFS) was shorter for t-CMML in comparison to d-CMML (Median OS 10.9 vs 26 months and median LFS 50 vs 127 months) and t-CMML independently and adversely impacted OS (P = .0001 HR 2.1 95% CI 1.4-3.0). This prognostic impact was retained in the context of the Mayo Molecular Model (P = .001, HR 2.4, 95% CI 1.5-3.7) and the GFM prognostic model (P < .0001, HR 2.15, 95% CI 1.5-3.7). In summary, we highlight the unique genetics and independent prognostic impact of t-CMML, warranting its inclusion as a separate entity in the classification schema for both CMML and t-MN.
Subject(s)
Cytogenetics/methods , Leukemia, Myelomonocytic, Chronic/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Leukemia, Myelomonocytic, Chronic/genetics , Male , Middle Aged , Prognosis , Young AdultABSTRACT
Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogenic hematopoietic cell transplantation (HCT). Corticosteroids are the first-line treatment; however, less than one-half of patients achieve durable remission. Studies suggest that TNF-α, a cytokine released from the bone marrow during conditioning, is involved in the pathogenesis of aGVHD. We retrospectively evaluated the outcome of anti-TNF-α therapy with infliximab in 35 patients with steroid refractory (SR) aGVHD. Infliximab was administered intravenously at 10 mg/kg for a median of 4 doses (range, 1 to 6) on a weekly basis. The overall response rates were 40% (17% complete response [CR], 23% partial response [PR]) at 4 weeks, 23% (9% CR, 14% PR) at 8 weeks, and 17% (all CR) at 12 weeks. Twenty-nine (83%) patients had infectious complications within 12 weeks of initiation of infliximab. These infections included 40 bacterial infections, 6 invasive fungal infections, and 5 viral reactivations. Twelve patients (34%) died secondary to infections. Overall survival at 12 weeks and 6 months from the start of infliximab therapy was 37% (13 of 35) and 17% (6 of 35), respectively; with most deaths secondary to complications from GVHD and infections. In conclusion; the use of infliximab therapy in patients with SR-aGVHD is associated with a modest poorly sustained response along with a heightened risk of severe infections. Future studies with more effective and less toxic therapies are needed for these patients.
Subject(s)
Graft vs Host Disease/therapy , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Infliximab/administration & dosage , Myeloablative Agonists/adverse effects , Transplantation Conditioning/adverse effects , Acute Disease , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Bacterial Infections/etiology , Bacterial Infections/immunology , Bacterial Infections/mortality , Bacterial Infections/pathology , Bone Marrow/drug effects , Bone Marrow/immunology , Bone Marrow/pathology , Drug Administration Schedule , Female , Graft vs Host Disease/immunology , Graft vs Host Disease/mortality , Graft vs Host Disease/pathology , Hematologic Neoplasms/immunology , Hematologic Neoplasms/mortality , Hematologic Neoplasms/pathology , Humans , Infliximab/adverse effects , Injections, Intravenous , Male , Middle Aged , Mycoses/etiology , Mycoses/immunology , Mycoses/mortality , Mycoses/pathology , Retrospective Studies , Survival Analysis , Transplantation, Homologous , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesis , Tumor Necrosis Factor-alpha/immunology , Virus Diseases/etiology , Virus Diseases/immunology , Virus Diseases/mortality , Virus Diseases/pathologyABSTRACT
Patients with multiple myeloma (MM) who undergo high-dose chemotherapy and autologous hematopoietic cell transplantation (Auto-HCT) have an increased risk of developing therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). We retrospectively reviewed the medical records of all MM patients who underwent an Auto-HCT at our institution between 1 January and 31 December 2018 and later developed t-MDS/AML. Among the 2982 patients who underwent at least 1 Auto-HCT, 55 (2%) developed t-MDS/AML (MDS, n = 52; AML, n = 3). The median age at t-MDS/AML diagnosis was 66 years (range 43-83 years), and the median time from Auto-HCT to t-MDS/AML diagnosis was 58.5 months (range 6-206 months). At diagnosis, all 3 patients with tAML and 65% of those with therapy-related myelodysplastic syndrome (tMDS) had high-risk disease, per 2022 European LeukemiaNet and R-IPSS, respectively, and 62% had TP53 gene mutations. Patients who developed tMDS/AML were older at MM diagnosis (median 61 versus 59 years; P = .06), more often were male (73% versus 58%; P = .029), received more than 2 years of lenalidomide maintenance (57% versus 39%; P = .014), and experienced complete remission more frequently after Auto-HCT compared to those who did not develop t-MDS/AML (56% versus 40%; P = .012). In a multivariable model, male gender, advanced age at MM diagnosis, experiencing complete remission after Auto-HCT, and lenalidomide maintenance were independent predictors of developing t-MDS/AML. Among the patients who developed t-MDS/AML, 14 (25%) underwent allogeneic hematopoietic stem transplantation (Allo-HCT). After a median follow-up of 9.9 months from t-MDS/AML diagnosis, the median overall survival (OS) after t-MDS/AML diagnosis was 11.8 months for all patients, and 18.2 months versus 11.1 months for Allo-HCT recipients versus nonrecipients, respectively (P = .25). On univariate analysis, receiving an alkylator as induction for MM (hazard ratio [95% confidence interval]: 2.9 [1.3-6.3]; P = .009), age > 60 years (3.1 [1.2-8.2]; P = .025), and higher-risk R-IPSS (2.7 [1.3-6.0]; P=0.011) predicted worse OS after t-MDS/AML diagnosis. None of these retained significance in the multivariable analysis. T-MDS/AML after Auto-HCT for MM is associated with aggressive disease characteristics, including high-risk cytogenetics and TP53 mutations. The outcomes of patients remain poor, even with Allo-HCT. A better understanding of disease biology and novel therapeutic approaches is warranted.
Subject(s)
Leukemia, Myeloid, Acute , Multiple Myeloma , Myelodysplastic Syndromes , Humans , Male , Adult , Middle Aged , Aged , Aged, 80 and over , Female , Multiple Myeloma/therapy , Lenalidomide/adverse effects , Retrospective Studies , Leukemia, Myeloid, Acute/chemically induced , Leukemia, Myeloid, Acute/therapy , Myelodysplastic Syndromes/etiology , Myelodysplastic Syndromes/therapyABSTRACT
Background: Cytogenetic findings are important prognostic factors in acute myeloid leukemia. Large systematic data about chromosomal characteristics of Turkish AML patients have not been reported to date. Objectives: The karyotypic profiles of 157 adult AML patients were evaluated retrospectively and compared with other reports from different populations. Methods: Cytogenetics analyses were performed on bone marrow samples using G-banding. Patients were categorized according to their cytogenetic results into four groups with the addition of a normal karyotyped group to the favorable, intermediate and adverse groups of European Leukemia Network. Results: Cytogenetic analyses were carried out successfully in 138 patients (88%). Abnormal karyotypes were found in 79 (57.2%) patients of which 13 (9.4%) were in favorable, 37 (26.8%) in intermediate and 29 (21%) in adverse groups. t(8;21) (5%) was the most common favorable abnormality while monosomal karyotypes (15.9%) in adverse group. Conclusion: This single center study is the most comprehensive study about the cytogenetic profile of acute myeloid leukemia in Turkey with comparison of other population-based studies. While there were similarities and differences with different publications, our results did not show a marked tendency to the findings of any specific geographic region.
Subject(s)
Leukemia, Myeloid, Acute , Humans , Adult , Retrospective Studies , Turkey , Karyotyping , Cytogenetic Analysis , Prognosis , Chromosome AberrationsABSTRACT
INTRODUCTION: This study estimated the comparative efficacy of ciltacabtagene autoleucel (cilta-cel; CARTITUDE-1), a chimeric antigen receptor (CAR)-T-cell therapy, versus 3 non-CAR-T therapies (belantamab mafodotin [DREAMM-2], selinexor plus dexamethasone [STORM Part 2], and melphalan flufenamide plus dexamethasone [HORIZON]), each with distinct mechanisms of action, for the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were triple-class exposed to an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 monoclonal antibody. PATIENTS AND METHODS: Pairwise matching-adjusted indirect treatment comparisons (MAICs) were conducted using patient-level data for cilta-cel from CARTITUDE-1 and summary level data for each comparator (2.5 mg/kg cohort in DREAMM-2, modified intention-to-treat population in STORM Part 2, and triple-class refractory patients in HORIZON). Treated patients from CARTITUDE-1 who satisfied the eligibility of the comparator trial were included. MAICs adjusted for imbalances in important prognostic factors between CARTITUDE-1 and the comparator populations. Comparative efficacy of cilta-cel versus each therapy was estimated for overall response rate, complete response or better rate, progression-free survival, and overall survival. RESULTS: After adjustment, patients treated with cilta-cel demonstrated at least a 3.1-fold and at least a 10.3-fold increase in the likelihood of achieving an overall response or complete response or better, respectively, at least a 74% reduction in the risk of disease progression or death, and at least a 47% reduction in the risk of death. These results were statistically significant. CONCLUSION: Cilta-cel showed improved efficacy over each comparator for all outcomes, demonstrating its potential as an efficacious treatment for patients with triple-class exposed RRMM.
Subject(s)
Multiple Myeloma , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Dexamethasone/pharmacology , Dexamethasone/therapeutic use , Humans , Hydrazines , Melphalan/pharmacology , Melphalan/therapeutic use , Multiple Myeloma/drug therapy , Multiple Myeloma/etiology , TriazolesABSTRACT
Relapse after allogeneic hematopoietic cell transplantation (HCT) leads to poor survival in patients with acute myeloid leukemia (AML). A second HCT (HCT2) may achieve durable remission. To determine the outcomes of patients who received an HCT2 for relapsed AML and to evaluate the predictors of overall survival (OS) and progression-free survival (PFS). We retrospectively reviewed medical records of adult patients who underwent an HCT2 for relapsed AML at our institution during 2000 to 2019. Ninety-one patients were identified with a median age of 44 years (range 18-73) at HCT2. Donor types were HLA-identical sibling (n = 37 [41%]), HLA-matched-unrelated (n = 34 [37%]), haploidentical (n = 19 [21%]), and cord blood (n=1 [1%]). Donors were different at HCT2 in 53% of patients. The majority of patients received reduced intensity conditioning (n = 71 [78%]) and were in remission (n = 56 [61%]) at HCT2. The median remission duration after HCT1 was 8.4 months (range 1-70) and the median time between transplants was 14 months (range 3-73). The median follow-up of surviving patients after HCT2 was 66 months (range 2-171), with 32% alive at time of analysis. The most common cause of death was disease recurrence (n = 45 [73%]). At 2 years, the rates of OS, PFS, progression, and nonrelapse mortality were 36%, 27%, 42%, and 18%, respectively. The development of chronic graft-versus-host disease (GVHD) after first HCT and HCT comorbidity index (HCT-CI) ≥2 at HCT2 were associated with inferior PFS and OS after HCT2. A second HCT is feasible in selected patients with AML who have relapsed after HCT1. Long-term survival benefit is possible in patients without chronic GVHD after HCT1 and HCT-CI <2 at HCT2.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Adolescent , Adult , Aged , Humans , Leukemia, Myeloid, Acute/therapy , Middle Aged , Retrospective Studies , Transplantation Conditioning , Young AdultABSTRACT
The Endothelial Activation and Stress Index (EASIX) score, defined as [(creatinine × lactate dehydrogenase [LDH])/platelets], is a marker of endothelial activation that has been validated in the allogeneic hematopoietic stem cell transplant setting. Endothelial activation is one of the mechanisms driving immune-mediated toxicities in patients treated with chimeric antigen receptor-T (CAR-T)-cell therapy. This study's objective was to evaluate the association between EASIX and other laboratory parameters collected before lymphodepletion and the subsequent onset of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) those patients. Toxicity data were collected prospectively on 171 patients treated with axicabtagene ciloleucel (axi-cel) for large B-cell lymphoma (LBCL). CRS grades 2 to 4 were diagnosed in 81 (47%) patients and ICANS grades 2 to 4 in 84 (49%). EASIX combined with ferritin (EASIX-F) identified 3 risk groups with CRS grades 2 to 4 cumulative incidence of 74% (hazards ratio [HR], 4.8; 95% confidence interval [CI], 2.1-11; P < .001), 49% (HR, 2.3; 95% CI, 1.02-5; P = .04), and 23% (reference), respectively. EASIX combined with CRP and ferritin (EASIX-FC) identified 3 risk groups with an ICANS grade 2 to 4 cumulative incidence of 74% (HR, 3.6; 95% CI, 1.9-6.9; P < .001), 51% (HR, 2.1; 95% CI, 1.1-3.9; P = .025), and 29% (reference). Our results indicate that common laboratory parameters before lymphodepletion correlate with CAR-T-related toxicities and can help support clinical decisions, such as preemptive toxicity management, hospitalization length, and proper setting for CAR-T administration.
Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma, Large B-Cell, Diffuse , Receptors, Chimeric Antigen , Cytokine Release Syndrome , Ferritins , HumansABSTRACT
OBJECTIVES: Immune thrombocytopenia (ITP) is an autoimmune disease with heterogeneous background. FCGR2C mutations were defined in one third of the patients but genetic players have not been fully elucidated yet. Although childhood ITP present as benign, ITP in adulthood is chronic disease with treatment challenges. This study aimed to focus on adult ITP patients using a whole genome genotyping that is valuable approach to identify the responsible genomic regions for the disease. METHODS: Herein 24 adult primary-refractory for ITP patients were evaluated using HumanCytoSNP12BeadChip,Illumina. Forty-six age and sex matched healthy individuals, and ptients awith nonhematological conditions were analyzed as controls. Identified CNV regions were verified by qRTPCR. T-cell receptor beta and delta (TCRB/TCRG) clonality were assessed by heteroduplex analysis in mosaic cases. RESULTS: Several CNV losses and gains were defined (losses:2q,7q,17q,19p, and gains: 1q,2p,3q,4q,7q,10q,12p,13q,14q,15q,17p,20q,21p,22q,Xp). Mosaic changes of different sizes (0.2-17.77Mb) were identified in five patients and three of them showed clonality. CNV regions that were unique to ITP patients were identified for the first time and among these genes, those related to immune regulation, and cellular trafficking were noteworthy. Conclusion: Identified CNV regions harbor several candidate genes, the functions of which might shed light on the pathogenesis of chronic ITP.
Subject(s)
DNA Copy Number Variations , Purpura, Thrombocytopenic, Idiopathic/genetics , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Aged, 80 and over , Case-Control Studies , Chronic Disease , Clone Cells , Drug Resistance , Female , Gene Rearrangement, T-Lymphocyte , Genetic Association Studies , Humans , Male , Middle Aged , Mosaicism , Purpura, Thrombocytopenic, Idiopathic/drug therapy , Purpura, Thrombocytopenic, Idiopathic/surgery , Real-Time Polymerase Chain Reaction , Receptors, Antigen, T-Cell, alpha-beta/genetics , Receptors, Antigen, T-Cell, gamma-delta/genetics , Splenectomy , T-Lymphocytes, Cytotoxic/chemistry , T-Lymphocytes, Cytotoxic/immunology , Young AdultABSTRACT
FLT3-ITD mutations in newly diagnosed acute myeloid leukemia (AML) are associated with worse overall survival (OS). FLT3-ITD diversity can further influence clinical outcomes. Addition of FLT3 inhibitors to standard chemotherapy has improved OS. The aim of this study is to evaluate the prognostic impact of FLT3 diversity and identify predictors of efficacy of FLT3 inhibitors. We reviewed prospectively collected data from 395 patients with newly diagnosed FLT3-ITD mutant AML. 156 (39%) patients received FLT3 inhibitors combined with either high or low intensity chemotherapy. There was no statistically significant difference in clinical outcomes among patients treated with FLT3 inhibitors based on FLT3 numerical variation (p = 0.85), mutation length (p = 0.67). Overall, the addition of FLT3 inhibitor to intensive chemotherapy was associated with an improved OS (HR = 0.35, 95% CI: 0.24-0.5, p = 0.0005), but not in combination with lower intensity chemotherapy (HR = 0.98, 95%CI: 0.7-1.36, p = 0.85). A differential effect of FLT3 inhibitor on OS was more pronounced in younger patients with FLT3 allelic ratio ≥0.5 (HR = 0.41, 95% CI: 0.25-0.66, p < 0.001), single ITD mutation (HR = 0.55, 95% CI: 0.34-0.88, p = 0.01), diploid cytogenetics (HR = 0.52, 95% CI: 0.35-0.76, p = 0.001), NPM1 co-mutation (HR = 0.35, 95% CI: 0.19-0.67, p = 0.001). Our analysis identifies predictors of survival among diverse FLT3 related variables in patients treated with FLT3 inhibitor.
Subject(s)
Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Protein Kinase Inhibitors/therapeutic use , fms-Like Tyrosine Kinase 3/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Alleles , Cytogenetics , Female , Humans , Leukemia, Myeloid, Acute/diagnosis , Male , Middle Aged , Mutation/drug effects , Nucleophosmin , Prognosis , Survival Analysis , Treatment Outcome , Young AdultSubject(s)
Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Leukemia, Myeloid, Chronic-Phase/drug therapy , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Humans , Imatinib Mesylate , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Treatment OutcomeABSTRACT
Apoptosis, the process of programmed cell death, occurs normally during development and aging. Members of the B-cell lymphoma 2 (BCL2) family of proteins are central regulators of apoptosis, and resistance to apoptosis is one of the hallmarks of cancer. Targeting the apoptotic pathway via BCL2 inhibitors has been considered a promising treatment strategy in the past decade. Initial efforts with small molecule BH3 mimetics such as ABT-737 and ABT-263 (navitoclax) pioneered the development of the first-in-class Food and Drug Administration (FDA)-approved oral BCL2 inhibitor, venetoclax. Venetoclax was approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, and is now being studied in a number of hematologic malignancies. Several other inhibitors targeting different BCL2 family members are now in early stages of development.
Subject(s)
Antineoplastic Agents/therapeutic use , Hematologic Neoplasms/drug therapy , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Aniline Compounds/therapeutic use , Apoptosis/drug effects , Biphenyl Compounds/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Drug Approval , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Molecular Targeted Therapy , Nitrophenols/therapeutic use , Piperazines/therapeutic use , Proto-Oncogene Proteins c-bcl-2/metabolism , Sulfonamides/therapeutic use , United States , United States Food and Drug AdministrationABSTRACT
BACKGROUND: Enhancement of natural killer cell activity by blocking interactions between killer immunoglobulin (Ig)-like receptors (KIRs) and human leukocyte antigen-C (HLA-C) molecules can improve outcomes in myeloid malignancies. Lirilumab is a human IgG4 monoclonal antibody that blocks KIR/HLA-C interaction. We designed a study to evaluate the safety and efficacy of lirilumab as a single agent and in combination with azacitidine in patients with myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Adult patients with MDS who had not received previous hypomethylating agents were included. Lower-risk MDS patients received single-agent lirilumab (3 mg/kg); higher-risk patients received azacitidine (75 mg/m2/day for 7 days) in combination with lirilumab (3 mg/kg, on day 7), in a 28-day cycle. Responses were evaluated according to 2006 International Working Group criteria. RESULTS: A total of 10 patients including 8 with higher and 2 with lower-risk enrolled. The median age was 70 (range, 50-84) years and 4 (40%) had complex cytogenetics. Baseline molecular mutations included TP53 (n = 5), TET2 (n = 3), and NRAS (n = 2). Patients received a median of 4 (range, 2-13) and 9 (range, 5-14) cycles of treatment with azacitidine with lirilumab and single-agent lirilumab, respectively. Two patients achieved complete remission (CR), 5 marrow CR, and 3 had stable disease. The median event-free survival for the entire cohort was 8 months (95% confidence interval, 4 months to not reached), and the median overall survival has not yet been reached. Five patients experienced 8 episodes of Grade ≥3 adverse events attributable to study drug, with the most frequent being infection or neutropenic fever (75%). CONCLUSION: Lirilumab either as a single agent as well as used in combination with azacitidine has clinical activity in patients with MDS. Further studies are needed to confirm our findings.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antimetabolites, Antineoplastic/therapeutic use , Azacitidine/therapeutic use , Myelodysplastic Syndromes/drug therapy , Aged , Aged, 80 and over , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myelodysplastic Syndromes/pathology , Pilot Projects , Prognosis , Receptors, KIR/antagonists & inhibitors , Survival RateABSTRACT
OBJECTIVES: Newer tyrosine kinase inhibitors (TKIs) (bosutinib, ponatinib) and allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be utilized as a salvage therapy in patients with chronic myeloid leukemia (CML) who failed two lines (imatinib â nilotinib or imatinib â dasatinib) of TKI therapy. However, these TKIs are not available in many countries and not all patients can undergo allo-HSCT. METHODS: In this study, CML patients who received dasatinib or nilotinib as a third-line treatment were retrospectively evaluated. RESULTS: Out of 209 patients, third-line dasatinib/nilotinib was administered in 21. During the follow-up, 16 out of 21 patients gained and/or maintained an optimal response, and 4 patients died due to progression. Seventeen patients were alive at the time of the analysis, of which 13 were still on TKI, whereas 4 patients quit treatment. DISCUSSION: In patients failing two lines of TKI, dasatinib or nilotinib can be beneficial and safely administered as a third-line treatment especially in nations with restricted resources.
Subject(s)
Dasatinib/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Adult , Aged , Female , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Middle Aged , Retrospective Studies , Young AdultABSTRACT
Somatic mutations contribute to the heterogeneous prognosis of chronic myelomonocytic leukemia (CMML). Hypomethylating agents (HMAs) are active in CMML, but analyses of small series failed to identify mutations predicting response or survival. We analyzed a retrospective multi-center cohort of 174 CMML patients treated with a median of 7â¯cycles of azacitidine (nâ¯=â¯68) or decitabine (nâ¯=â¯106). Sequencing data before treatment initiation were available for all patients, from Sanger (nâ¯=â¯68) or next generation (nâ¯=â¯106) sequencing. Overall response rate (ORR) was 52%, including complete response (CR) in 28 patients (17%). In multivariate analysis, ASXL1 mutations predicted a lower ORR (Odds Ratio [OR]â¯=â¯0.85, pâ¯=â¯0.037), whereas TET2mut/ASXL1wt genotype predicted a higher CR rate (ORâ¯=â¯1.18, pâ¯=â¯0.011) independently of clinical parameters. With a median follow-up of 36.7â¯months, overall survival (OS) was 23.0â¯months. In multivariate analysis, RUNX1mut (Hazard Ratio [HR]â¯=â¯2.00, pâ¯=â¯.011), CBLmut (HRâ¯=â¯1.90, pâ¯=â¯0.03) genotypes and higher WBC (log10(WBC) HRâ¯=â¯2.30, pâ¯=â¯.005) independently predicted worse OS while the TET2mut/ASXL1wt predicted better OS (HRâ¯=â¯0.60, pâ¯=â¯0.05). CMML-specific scores CPSS and GFM had limited predictive power. Our results stress the need for robust biomarkers of HMA activity in CMML and for novel treatment strategies in patients with myeloproliferative features and RUNX1 mutations.