ABSTRACT
Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed at investigating this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age: 63 years). The overall response rate was 90% in responseevaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, highrisk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2 to 3 months prior to start of KRd treatment significantly decreased PFS and overall survival (OS) in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e.delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AEs) were observed in 56% of the patients, and non-fatal or fatal AE's that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.
ABSTRACT
FLT3 mutations are the most common genomic alteration detected in acute myeloid leukemia (AML) with a worse clinical prognosis. The highly frequent FLT3 mutations, together with the side effects associated with clinical prognosis, make FLT3 promising treatment targets and have provoked the advancement of FLT3 inhibitors. Recently, numerous FLT3 inhibitors were actively developed, and thus the outcomes of this aggressive subtype of AML were significantly improved. Recently, midostaurin and gilteritinib were approved as frontline treatment of AML and as therapeutic agents in the recurred disease by the United States Food and Drug Administration. Recently, numerous promising clinical trials attempted to seek appropriate management in frontline settings, in relapsed/refractory disease, or after stem cell transplantation in AML. This review follows numerous clinical trials about the usefulness of FLT3 inhibitors as frontline therapy, as relapsed/refractory conditioning, and as maintenance therapy of stem cell transplantation. The cumulative data of FLT3 inhibitors would be important clinical evidence for further management with FLT3 inhibitors in AML patients with FLT3 mutations.
Subject(s)
Antineoplastic Agents , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Humans , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Aniline Compounds/pharmacology , Mutation , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
Acute myeloid leukemia (AML) is a heterogenous hematopoietic neoplasm with various genetic abnormalities in myeloid stem cells leading to differentiation arrest and accumulation of leukemic cells in bone marrow (BM). The multiple genetic alterations identified in leukemic cells at diagnosis are the mainstay of World Health Organization classification for AML and have important prognostic implications. Recently, understanding of heterogeneous and complicated molecular abnormalities of the disease could lead to the development of novel targeted therapeutic agents. In the past years, gemtuzumab ozogamicin, BCL-2 inhibitors (venetovlax), IDH 1/2 inhibitors (ivosidenib and enasidenib) FLT3 inhibitors (midostaurin, gilteritinib, and enasidenib), and hedgehog signaling pathway inhibitors (gladegib) have received US Food and Drug Administration (FDA) approval for the treatment of AML. Especially, AML patients with elderly age and/or significant comorbidities are not currently suitable for intensive chemotherapy. Thus, novel therapeutic planning including the abovementioned target therapies could lead to improve clinical outcomes in the patients. In the review, we will present various important and frequent molecular abnormalities of AML and introduce the targeted agents of AML that received FDA approval based on the previous studies.
Subject(s)
Antineoplastic Agents/therapeutic use , Cell Proliferation/drug effects , Leukemia, Myeloid/drug therapy , Molecular Targeted Therapy/methods , Signal Transduction/drug effects , Acute Disease , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Humans , Leukemia, Myeloid/metabolism , Leukemia, Myeloid/pathology , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/metabolism , Sulfonamides/therapeutic use , United States , United States Food and Drug AdministrationABSTRACT
In tumor microenvironment, the programmed death 1 (PD-1) immune checkpoint has a crucial role of mechanism of T cell exhaustion leading to tumor evasion. Ligands of PD-1, programmed death ligand 1/2 (PD-L1/L2) are over-expressed in tumor cells and participate in prolonged tumor progression and survivals. Recently, clinical trials for patients who failed to obtain an optimal response prior to standardized chemotherapy in several solid cancers have been focused on targeting therapy against PD-1 to reduce disease progression rates and prolonged survivals. Since various inhibitors targeting the immune checkpoint in PD-1/PD-L1 pathway in solid cancers have been introduced, promising approach using anti-PD-1 antibodies were attempted in several types of hematologic malignances. In diffuse large B cell lymphoma (DLBCL) as the most common and aggressive B cell type of non-Hodgkin's lymphoma, anti-PD-1 and anti-PD-L1 antibodies were studies in various clinical trials. In this review, we summarized the results of several studies associated with PD-1/PD-L1 pathway as an immune evasion mechanism and described clinical trials about targeting therapy against PD-1/PD-L1 pathway in DLBCL.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , B7-H1 Antigen/immunology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/immunology , Programmed Cell Death 1 Receptor/immunology , Tumor Escape/drug effects , Animals , Antineoplastic Agents, Immunological/pharmacology , B7-H1 Antigen/analysis , B7-H1 Antigen/antagonists & inhibitors , Humans , Immunotherapy/methods , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/therapy , Molecular Targeted Therapy/methods , Programmed Cell Death 1 Receptor/analysis , Programmed Cell Death 1 Receptor/antagonists & inhibitors , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/pathologyABSTRACT
Chimeric antigen receptor (CAR) T-cell therapy has shown promising clinical impact against hematologic malignancies. CD19 is a marker on the surface of normal B cells as well as most B-cell malignancies, and thus has a role as an effective target for CAR T-cell therapy. In numerous clinical data, successes with cell therapy have provided anticancer therapy as a potential therapeutic option for patients who are resistant to standard chemotherapies. However, recent growing evidence showed the limitations of the treatment such as antigen-positive relapse due to poor CAR T-cell persistence and antigen-negative relapses associated with CAR-driven mutations, alternative splicing, epitope masking, low antigen density, and lineage switching. The understanding of the resistance mechanisms to the cell therapy has developed novel potential treatment strategies, including dual-targeting therapy (dual and tandem CAR), and armored and universal CAR T-cell therapies. In this review, we provide an overview of resistance mechanisms to CD19 CAR T-cell therapy in B-cell malignancies and also review therapeutic strategies to overcome these resistances.
Subject(s)
B-Lymphocytes/immunology , Drug Resistance, Neoplasm/physiology , Hematologic Neoplasms/immunology , Hematologic Neoplasms/therapy , Immunotherapy, Adoptive/methods , Antigens, CD19/immunology , Cell- and Tissue-Based Therapy , Epitopes, B-Lymphocyte , Humans , Leukemia, Lymphocytic, Chronic, B-Cell , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/immunologyABSTRACT
Myelofibrosis (MF) is a clinical manifestation of chronic BCR-ABL1-negative chronic myeloproliferative neoplasms. Splenomegaly is one of the major clinical manifestations of MF and is directly linked to splenic extramedullary hematopoiesis (EMH). EMH is associated with abnormal trafficking patterns of clonal hematopoietic cells due to the dysregulated bone marrow (BM) microenvironment leading to progressive splenomegaly. Several recent data have emphasized the role of several cytokines for splenic EMH. Alteration of CXCL12/CXCR4 pathway could also lead to splenic EMH by migrated clonal hematopoietic cells from BM to the spleen. Moreover, low Gata1 expression was found to be significantly associated with the EMH. Several gene mutations were found to be associated with significant splenomegaly in MF. In recent data, JAK2V617F homozygous mutation was associated with a larger spleen size. In other data, CALR mutations in MF were signigicantly associated with longer larger splenomegaly-free survivals than others. In addition, MF patients with ≥1 mutations in AZXL1, EZH1 or IDH1/2 had significantly low spleen reduction response in ruxolitinib treatment. Developments of JAK inhibitors, such as ruxolitinib, pacritinib, momelotinib, and febratinib enabled the effective management in MF patients. Especially, significant spleen reduction responses of the drugs were demonstrated in several randomized clinical studies, although those could not eradicate allele burdens of MF.
Subject(s)
Hematopoiesis, Extramedullary/physiology , Janus Kinases/genetics , Primary Myelofibrosis/genetics , Primary Myelofibrosis/pathology , Splenomegaly/genetics , Bone Marrow/pathology , Cell Movement , Chemokine CXCL12/metabolism , Hematopoiesis, Extramedullary/drug effects , Humans , Janus Kinase Inhibitors/pharmacology , Janus Kinase Inhibitors/therapeutic use , Mutation , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/physiopathology , Randomized Controlled Trials as Topic , Receptors, CXCR4/metabolism , Spleen/pathology , Splenomegaly/drug therapy , Splenomegaly/physiopathologyABSTRACT
The CIBMTR chronic graft-versus-host disease (cGVHD) risk score can be refined and improved for better prognostic stratification. Three hundred and seven consecutive patients diagnosed with cGVHD by the NIH consensus criteria were retrospectively reviewed and had the CIBMTR risk score applied and analyzed. The CIBMTR risk score was successfully validated in our cohort (n = 307). The 3-year overall survival (OS) rates in each risk group (RG) were 82.5 ± 11.3% (RG1), 79.4 ± 3.0% (RG2), 71.8 ± 6.3% (RG3), and 27.3 ± 13.4% (RG4). A significantly lower OS rate and higher non-relapse mortality (NRM) were noted in RG4 compared to the other RGs. However, there were no differences in OS or NRM among RG1 to 3. To improve prognostic stratification power of the CIBMTR risk score, we incorporated the absolute lymphocyte (ALC) and eosinophil count (EC) at time of cGVHD into the CIBMTR risk score. Lower ALC (<1.0 × 109/L, HR 1.94, p = 0.014) and lower EC (<0.5 × 109/L, HR 3.27, p = 0.014) were confirmed as adverse risk factors for OS. Patients were stratified into four revised risk groups (rRG). The 3-year OS rates were 93.3 ± 6.4% (rRG1, score 0-3), 84.9 ± 3.4% (rRG2, score 4-6), 70.9 ± 4.4% (rRG3, score 7-9), and 32.0 ± 1.1% (rRG4, score ≥ 10) (p < 0.001). The 3-year NRM rates were 0.0% (rRG1), 6.7 ± 0.4% (rRG2), 18.4 ± 0.7% (rRG3), and 57.7 ± 5.1% (rRG4) (p < 0.001). The revised CIBMTR risk score was superior to the original CIBMTR risk score for OS (p < 0.001). The revised CIBMTR risk score including ALC and EC at the onset of cGVHD improved the prognostic stratification power of the CIBMTR risk score for long-term outcomes.
Subject(s)
Eosinophils , Graft vs Host Disease/blood , Graft vs Host Disease/diagnosis , Leukocyte Count , Lymphocytes , Adolescent , Adult , Aged , Biomarkers , Chronic Disease , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Mortality , Premedication , Prognosis , Severity of Illness Index , Survival Analysis , Transplantation, Homologous , Young AdultABSTRACT
An increase in large granular lymphocytes (LGL) is frequently seen in patients following allogeneic hematopoietic cell transplantation (allo-HCT) and it has been associated with better outcomes in some reports. We assessed 826 consecutive patients at our institution with over 12 years of follow-up for the occurrence of LGL lymphocytosis after allo-HCT. The 3-year cumulative incidence of LGL lymphocytosis was 14.5% with a median duration of over 3.5 years. The development of LGL lymphocytosis was strongly correlated with CMV viremia and GVHD. The clinical course of patients with LGL lymphocytosis after allo-HCT was indolent, with the majority of these patients not displaying any clinical signs or symptoms related to the LGL proliferation. LGL lymphocytosis was associated with better outcomes, including higher overall survival (OS 86.6% vs 44.7% at 3 years), lower non-relapse mortality (NRM 5.5% vs 30.4% at 3 years), and lower risk of relapse (8.9% vs 22.9% at 3 years). A time-dependent multivariable analysis confirmed the favorable impact of LGL lymphocytosis on OS and NRM, but not on the risk of relapse. In multivariable analysis, a longer duration of LGL lymphocytosis was associated with better OS and NRM. Improved immunomodulatory properties of these cells, regulating GVHD and infections, may explain the observed favorable outcomes of patients who developed LGL lymphocytosis following allo-HCT.
Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Leukemia, Large Granular Lymphocytic/diagnosis , Leukemia, Large Granular Lymphocytic/mortality , Neoplasms, Second Primary/diagnosis , Neoplasms, Second Primary/mortality , Adolescent , Adult , Aged , Cytomegalovirus Infections/etiology , Female , Follow-Up Studies , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/methods , Humans , Immunophenotyping , Incidence , Leukemia, Large Granular Lymphocytic/epidemiology , Leukemia, Large Granular Lymphocytic/etiology , Male , Middle Aged , Neoplasms, Second Primary/epidemiology , Neoplasms, Second Primary/etiology , Prognosis , Risk Factors , Survival Analysis , Symptom Assessment , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methods , Transplantation, Homologous , Young AdultABSTRACT
Reduced-intensity conditioning (RIC) has been shown to have similar overall survival (OS) but higher relapse rates compared with myeloablative (MAC) regimens in patients with myeloid malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Using propensity score matching (PSM) analysis, well-balanced pairs of different variables can be compared effectively. We retrospectively compared allo-HSCT recipients with acute myeloid leukemia or myelodysplasia receiving a RIC regimen (FBT200; fludarabine 30 mg/m2/day for 4 days, busulfan 3.2 mg/kg/day for 2 days, and total body irradiation [TBI] 200 cGy) or MAC regimen (FBT400; fludarabine 50 mg/m2/day for 4 days, busulfan 3.2 mg/kg/day for 4 days, and TBI 400 cGy). A total of 248 patients (121 in the RIC group and 127 in the MAC group) were included in the analysis. No statistically significant difference was observed in 2-year OS (RIC group, 45.2 ± 5.0%; MAC group, 51.7 ± 5.2%; P = .541), nonrelapse mortality (NRM; RIC group, 28.7 ± 2.8% MAC group, 34.7 ± 4.6%; P = .368), and acute graft-versus-host disease (GVHD) (P = .171) or chronic GVHD (P = .605) at 1 year. The cumulative incidence of relapse (CIR) at 2 years was statistically significantly different between the 2 groups, however (RIC, 26.1 ± 2.6%; MAC, 14.2 ± 3.5%; P = .033). When PSM was applied to the study population, 42 case-control pairs were evenly matched. PSM analysis confirmed no statistically significant difference in 2-year OS (RIC, 49.0 ± 9.1%; MAC, 54.9 ± 7.7%; P = .718), NRM (RIC, 22.2 ± 2.3%; MAC, 33.3 ± 2.8%; P = .238), or CIR (RIC, 25.7 ± 2.6%; MAC, 9.5 ± 1.1%; P = .315) in the PSM pairs. Our findings demonstrate that after applying PSM, FBT 200 RIC conditioning has comparable OS, NRM, and CIR to FBT 400 MAC conditioning before allo-HSCT.
Subject(s)
Leukemia, Myeloid/therapy , Propensity Score , Transplantation Conditioning/methods , Adult , Aged , Busulfan/administration & dosage , Case-Control Studies , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Humans , Leukemia, Myeloid/complications , Leukemia, Myeloid/mortality , Male , Middle Aged , Myeloablative Agonists/therapeutic use , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/therapy , Recurrence , Retrospective Studies , Survival Analysis , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives , Whole-Body Irradiation , Young AdultABSTRACT
Arsenic compounds have been used in traditional medicine for several centuries. KML001 (sodium metaarsenite; NaAsO2) is an orally bio-available arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in lymphoid neoplasms. The aim of this study is to evaluate the anti-proliferative effect of KML001 in non-Hodgkin's lymphoma and to compare its efficacy with As2O3. KML001 inhibited cellular proliferation in all tested lymphoma cell lines as well as JurkatR cells (adriamycin-resistant Jurkat cells) in a dose-dependent manner, while As2O3 was not effective. Cell cycle regulatory protein studies have suggested that KML001 induces G1 arrest via p27-induced inhibition of the kinase activities of CDK2, 4, and 6. Treatment of KML001 induced apoptosis in Jurkat and JurkatR cells. The apoptotic process was associated with down-regulation of Bcl-2 (antiapoptotic molecule), up-regulation of Bax (proapoptotic molecule), and inhibition of caspase-3, -8, and -9. In addition, cell signaling including the STAT, PI3K/Akt, MAPK, and NF-κB signal pathways were inhibited in KML001-treated Jurkat and JurkatR cells. Furthermore, targeting the telomere by KML001 was observed in the Jurkat and JurkatR cells. The In vivo anti-tumoral activity of KML001 was confirmed in a xenograft murine model. Interestingly, partial responses were seen in two lymphoma patients treated with 10 mg/day (follicular lymphoma for 16 weeks and mantle cell lymphoma for 24 weeks) without severe toxicities. These findings suggest that KML001 may be a candidate agent for the treatment of de novo, refractory, and relapsed non-Hodgkin's lymphoma patients.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Arsenites/pharmacology , Lymphoma, Non-Hodgkin/drug therapy , Sodium Compounds/pharmacology , Aged , Animals , Antineoplastic Agents/administration & dosage , Arsenic Trioxide , Arsenicals/pharmacology , Arsenites/administration & dosage , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Down-Regulation/drug effects , Female , Humans , Jurkat Cells , Lymphoma, Non-Hodgkin/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Nude , Middle Aged , Oxides/pharmacology , Pilot Projects , Signal Transduction/drug effects , Sodium Compounds/administration & dosage , Up-Regulation/drug effects , Xenograft Model Antitumor AssaysABSTRACT
BACKGROUND: Iron is a crucial element for cell proliferation, growth, and metabolism. However, excess iron and altered iron metabolism are both associated with tumor initiation and tumor growth. Deferasirox is an oral iron chelator. Although some studies have indicated that deferasirox is a promising candidate for anti-cancer therapies, its effectiveness against gastric cancer has not yet been determined. This study was conducted to determine whether deferasirox exerts anti-tumor effects in gastric cancer cell lines and whether deferasirox and cisplatin act synergistically. METHODS: Four human gastric cancer cell lines (AGS, MKN-28, SNU-484, and SNU-638) were treated with various concentrations of deferasirox to determine the IC50 for each cell line. The effects of deferasirox on the cell cycle were evaluated by flow cytometry, and the effects of deferasirox on iron metabolism, the cell cycle, and apoptosis were assessed by Western blotting. To determine whether deferasirox enhances the effect of cisplatin, AGS cells were cultured in the presence and absence of cisplatin. RESULTS: Deferasirox inhibited the proliferation of all gastric cancer cell lines as assessed by MTT assays. Since the IC50 of deferasirox was the lowest (below 10 µM) in AGS cells, subsequent experiments were performed in this line. Deferasirox upregulated transferrin receptor 1 expression and decreased ferroportin expression. Moreover, deferasirox induced G1 arrest; upregulated p21, p27, and p53 expression; and downregulated cyclin D1, cyclin B, and CDK4 expression. Furthermore, deferasirox induced apoptosis, upregulated N-myc downstream regulated gene 1 (NDRG1), and downregulated p-mTOR and c-myc expression. It was also found to act synergistically with cisplatin. CONCLUSIONS: Our results suggest that deferasirox may exert anti-tumor effects in the context of gastric cancer. Deferasirox affects a number of different pathways and molecules; for instance, deferasirox upregulates NDRG1 expression, inhibits the cell cycle, downregulates mTOR and c-myc expression, and induces apoptosis. In addition, deferasirox appears to potentiate the anti-cancer effects of cisplatin. Although the efficacy of deferasirox remains to be tested in future studies, the results presented here indicate that deferasirox is a promising novel anti-cancer therapeutic agent.
Subject(s)
Apoptosis/drug effects , Benzoates/pharmacology , Cell Cycle/drug effects , Cell Proliferation/drug effects , Iron Chelating Agents/pharmacology , Stomach Neoplasms/drug therapy , Triazoles/pharmacology , Antineoplastic Agents/pharmacology , Blotting, Western , Cisplatin/pharmacology , Deferasirox , Drug Synergism , Humans , Stomach Neoplasms/pathology , Tumor Cells, CulturedABSTRACT
We retrospectively reviewed 242 patients who received related donor myeloablative peripheral blood hematopoietic cell transplantation. We compared patients who received mycophenolate (MMF)/cyclosporine (CSA) (n = 71), to historical controls who received methotrexate (MTX)/CSA (n = 172). There were no differences in overall survival, nonrelapse mortality, and relapse. The MMF/CSA group had significantly faster neutrophil and platelet engraftment: medians of 13 versus 18 days and 10 versus 14 days, respectively (P = 0.001). The cumulative incidence of acute graft versus host disease (GVHD) (Grades, 2-4) was significantly lower in the MMF/CSA group (45.1 vs. 74.4%, P < 0.001). The MMF/CSA group showed a lower incidence of skin (51.5 vs. 72.1%, P < 0.001) and liver acute GVHD (11.3 vs. 54.2%, P < 0.001) and a higher incidence of lung (42.2 vs. 19.0%, P = 0.045), eye (59.7 vs. 30.1%, P < 0.001), and mouth (72.8 vs. 56.4%, P = 0.001) chronic GVHD but only eye chronic GVHD was confirmed in propensity score matching (PSM) analysis. The incidence of cytomegalovirus (CMV) viremia was higher in the MMF/CSA group (55.8 vs. 39.6%, P < 0.001) but this was not confirmed in PSM analysis. MMF/CSA was identified as an independent favorable factor for acute GVHD (P < 0.001, hazard ratio, 0.41) but as a possible adverse risk factor for CMV viremia as this was not found to be statistically significant in PSM analysis. MMF/CSA in myeloablative matched related donor peripheral blood stem cell transplant is not inferior as GVHD prophylaxis in comparison with MTX/CSA and is associated with faster engraftment but a potentially higher risk of CMV viremia.
Subject(s)
Cytomegalovirus Infections/therapy , Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/therapy , Mycophenolic Acid/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Transplantation Conditioning , Adolescent , Adult , Antibiotics, Antineoplastic/therapeutic use , Cyclosporine/therapeutic use , Cytomegalovirus/immunology , Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/mortality , Cytomegalovirus Infections/pathology , Female , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Graft vs Host Disease/prevention & control , Humans , Immunosuppressive Agents/therapeutic use , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Male , Methotrexate/therapeutic use , Middle Aged , Myeloablative Agonists/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Recurrence , Retrospective Studies , Survival Analysis , Tissue Donors , Transplantation, HomologousABSTRACT
We evaluated the impact of age and remission status on 242 consecutive patients who underwent allogeneic hematopoietic cell transplantation for acute myeloid leukemia (AML) in our program between 1999 and 2011. Median age of all patients was 48 years (range, 18 to 71). Based on age and remission status, patients were divided into 4 groups: first complete remission (CR1) age <60 years (n = 116), second complete remission (CR2) age <60 years (n = 78), CR1 age ≥60 years (n = 32), and CR2 age ≥60 years (n = 16). Donors were matched related (n = 155, 64%) or matched unrelated (n = 87, 36%). Median follow-up of survivors was 65 months (range, 12 to 145). In a univariate analysis, 3-year overall survival rates of the 4 groups were 57%, 43%, 39%, and 16% (P = .003), respectively. In a multivariable analysis, hazard ratios of nonrelapse mortality and survival were 2.08 (P = .06) and 1.52 (P = .23), respectively, in patients ≥60 years in CR2 compared with ≥ 60 years in CR1. Although a plateau in survival was observed for patients ≥60 years in CR1 similar to those <60 years in CR1 and CR2, no long-term survivors were seen in patients ≥60 years in CR2. Our data suggest disappointing outcomes in AML patients ≥60 years of age transplanted in CR2. Therefore, if a transplant is indicated, early referral is recommended in patients ≥60 years with AML.
Subject(s)
Antineoplastic Agents/therapeutic use , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/therapy , Adolescent , Adult , Age Factors , Aged , Female , Histocompatibility Testing , Humans , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Remission Induction , Survival Analysis , Time Factors , Tissue Donors , Transplantation, HomologousABSTRACT
Graft-versus-host disease (GVHD) has no therapeutic benefit after hematopoietic cell transplantation (HCT) for patients with acquired aplastic anemia (AA), and its prevention is highly desirable. We designed a conditioning regimen using an intermediate dose of alemtuzumab (50 to 60 mg) and describe our institutional experience of 41 patients who underwent HCT for AA. The median age at HCT was 37 years (range, 17 to 59). The conditioning regimen was high-dose cyclophosphamide (n = 9) or fludarabine based (n = 32). Additional GVHD prophylaxis was with cyclosporine. With a median follow-up of 3.6 years, overall survival at 3 years was 85%. Survival in patients <40 years and ≥40 years was 96% and 67%, respectively (P = .04). Graft failure occurred in 4 (10%) patients; 2 primary and 2 secondary. The cumulative incidences of acute (grades 1 to 2) and chronic GVHD were 27% and 15%, respectively. No patients developed grade 3 to 4 acute GVHD or severe chronic GVHD. The following viral complications were frequent: cytomegalovirus reactivation (79%), herpes simplex (18%), varicella zoster (25%), and BK virus hemorrhagic cystitis (8%). The majority of patients had no significant long-term health issues. This intermediate-dose alemtuzumab-based conditioning regimen results in excellent survival with a favorable impact on GVHD and long-term health outcomes, but close monitoring for viral complications is important.
Subject(s)
Anemia, Aplastic/drug therapy , Anemia, Aplastic/therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/methods , Adolescent , Adult , Alemtuzumab , Anemia, Aplastic/mortality , Female , Humans , Male , Middle Aged , Survival Analysis , Treatment Outcome , Young AdultABSTRACT
A new severity grading system for graft-versus-host disease (GVHD) was established by the National Institutes of Health (NIH) consensus criteria (NCC). However, its prognostic value still needs to be validated. Four hundred twenty-five consecutive patients who survived beyond 100 days after allogeneic stem cell transplantation were reviewed and reclassified using NCC. GVHD-specific survival (GSS) and cumulative incidence of relapse were compared according to the NIH global score at the onset and peak of chronic GVHD (cGVHD). Of 346 patients with cGVHD diagnosed by the Revised Seattle Criteria, 317 patients were reclassified according to the NCC as classic cGVHD (n = 144) and overlap syndrome (n = 173). The NIH global scores at onset were mild (43.2%), moderate (42.3%), and severe (14.5%), whereas more moderate (55.5%) and severe (31.6%) cGVHD was observed at the peak of cGVHD. With a median follow-up duration of 34 months, the 5-year GSS was significantly worse for the severe group than the moderate/mild groups at onset and at peak: 50.9% ± 7.8% versus 89.7% ± 3.2% versus 93.5% ± 2.4% at onset (P < .001) and 69.1% ± 5.2% versus 93.2% ± 2.1% versus 97.3% ± 2.7% at peak (P < .001). Severe NIH global score at onset and peak were confirmed as a poor prognostic factor for GSS in multivariate analysis. The cumulative incidence of relapse did not differ among the severity groups at onset or peak. In conclusion, the new NIH global scoring system was shown to differentiate a high-risk group of patients (with severe grade cGVHD) in terms of long-term transplant outcomes.
Subject(s)
Graft vs Host Disease/diagnosis , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Severity of Illness Index , Transplantation Conditioning , Adolescent , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Chronic Disease , Consensus , Female , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Graft vs Host Disease/therapy , Hematologic Neoplasms/immunology , Hematologic Neoplasms/pathology , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Myeloablative Agonists/therapeutic use , National Institutes of Health (U.S.) , Recurrence , Transplantation, Homologous , United StatesABSTRACT
Sclerotic chronic graft-versus-host disease (sclGVHD) is associated with significant morbidity and a poor quality of life. We reviewed 502 patients diagnosed with chronic GVHD and analyzed the incidence and risk factors of sclGVHD and long-term outcomes and immunosuppressive therapy (IST) cessation in patients with sclGVHD. With a median onset at 18 months the cumulative incidence of sclGVHD was estimated at 22.6% at 5 years (95% confidence interval, 18.6% to 26.8%). Univariate and multivariate analysis identified 2 risk factors for sclGVHD: non-T cell depletion (hazard ratio [HR] 9.09, P < .001) and peripheral blood stem cell (HR 3.87, P < .001). Overall survival (OS) at 5 years was significantly better in the sclGVHD group (88.1%) compared with the non-sclGVHD group (62.7%; P < .001), as were nonrelapse mortality (7.3% versus 21.5% at 5 years) and relapse rates (9.1% versus 19.3% at 5 years). There was no difference in the rate of IST cessation at 5 years (44.8% versus 49.9%, P = .312), but there was a trend of longer IST duration in the sclGVHD group compared with the non-sclGVHD group (median 71.6 months versus 62.9 months). In conclusion, T cell depletion and graft source affect the risk of sclGVHD. SclGVHD did not adversely affect long-term outcomes or IST duration.
Subject(s)
Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Adolescent , Adult , Aged , Female , Graft vs Host Disease/epidemiology , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Humans , Incidence , Male , Ontario/epidemiology , Risk Factors , Transplantation, Homologous , Young AdultABSTRACT
Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myeloid leukemia (AML). Impact of lymphocyte recovery on post-transplant outcomes has been suggested but reports are conflicting. We evaluated the impact of lymphocyte recovery at 28 d post-HCT in 191 AML patients using peripheral blood stem cells as graft. Patients were divided into those with absolute lymphocyte count (ALC) ≥ 0.5 × 10(9) /L (n = 111, 58%; high ALC group) and those with ALC < 0.5 × 10(9) /L (n = 80, 42%; low ALC group), at day 28 post-transplant. With a median follow-up of 49 months, overall survival (OS) was significantly improved in the high ALC group (59% at 3 yr) vs. patients with low ALC (40% at 3 yr, P = 0.03). Cumulative incidence of relapse (CIR) was significantly lower in the high ALC group (16% at 3 yr) vs. low ALC group (36% at 3 yr, P = 0.001). Multivariable analysis for CIR demonstrated high ALC group as an independent factor decreasing relapse risk (P = 0.03, HR = 0.49, 95% CI = 0.26-0.92). Multivariable analysis for OS and non-relapse mortality did not demonstrate ALC ≥ 0.5 × 10(9) /L at 28 d post-transplant to be predictive. We conclude that lymphocyte recovery with ALC ≥ 0.5 × 10(9) /L at day 28 post-transplant is associated with less relapse in AML patients undergoing allogeneic peripheral blood HCT, but without survival benefit.
Subject(s)
Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/pathology , Lymphocyte Count , Adolescent , Adult , Aged , Female , Humans , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Neoplasm Recurrence, Local , Peripheral Blood Stem Cell Transplantation , Prognosis , Risk Factors , Time Factors , Transplantation Conditioning , Treatment Outcome , Young AdultABSTRACT
Allogeneic stem cell transplantation (allo-SCT) remains an option for patients who have disease progression post-autologous stem cell transplantation (ASCT) or who would not be eligible to ASCT for relapsed diffuse large B-cell lymphoma. Data with myeloablative or non-myeloablative allo-SCT demonstrate that allografts are safe and feasible with potential benefits including lack of tumour cell contamination and possible graft-versus-lymphoma (GVLY) effect although limited by high non-relapse mortality (NRM). However, the benefit of GVLY effect may be minimal or minimized by NRM. The current role of allo-SCT in DLBCL remains to be defined by prospective randomized controlled trials.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Lymphoma, Large B-Cell, Diffuse/surgery , Humans , Lymphoma, Large B-Cell, Diffuse/therapy , Transplantation, Homologous , Treatment OutcomeABSTRACT
The treatment outcomes of chronic myeloid leukemia in chronic phase (CML-CP) have dramatically improved with comparable life-expectancy to average of general population in tyrosine kinase inhibitor (TKI) era. However, less than a half of patients who started with TKI can remain on frontline TKI. The reasons of switching TKI can be either intolerance or the lack of efficacy. Although a kinase domain (KD) mutation can guide to select salvage TKI from the point of view on the efficacy of TKIs, many factors need to be considered before choosing next-line TKI such as the high-risk features of CML, the adverse events with prior TKI, and the comorbidities of patients. The therapeutic options for CML-CP after failing frontline TKI due to treatment failure or suboptimal responses will be reviewed including allogeneic hematopoietic stem cell transplantation.
ABSTRACT
BACKGROUND: The global TARGET survey examined real-world management of chronic myeloid leukemia (CML) compared with international guideline recommendations. This report focused on the responses of physicians from South Korea compared with those of physicians from the rest of the world (ROW). METHODS: The self-administered, online survey, comprising 23 questions and clinical case scenarios, was completed between April and August 2017. It was designed to gather information on practicing physicians and local practices for CML diagnosis, disease monitoring, treatment, and adverse event (AE) management. RESULTS: While there were similarities in the mutation analysis and treatment efficacy between Korea and the ROW, there were also differences in CML management. Initial diagnostic testing was more comprehensive in Korea than in the ROW, and there was significantly better access to standardized polymerase chain reaction testing. Assessment of BCR-ABL levels during the first 12 months of treatment was excellent in Korea, and there was greater frontline use of second-generation BCR-ABL tyrosine kinase inhibitors. Korean physicians were significantly less likely to switch therapy for hematologic AEs. Treatment-free remission was not an important goal of therapy among Korean or ROW physicians. CONCLUSION: This study identified some differences in the current CML management between Korea and the ROW; CML management in Korean patients was generally in line with the current guidelines.