Chidamide combined with a modified Bu-Cy conditioning regimen improves survival in patients with T-cell acute lymphoblastic leukemia/lymphoma undergoing allogeneic hematopoietic stem cell transplantation.

This study aimed to evaluate the efficacy and safety of chidamide (Chi) combined with a modified Busulfan-Cyclophosphamide (mBuCy) conditioning regimen for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only in the same period. The leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse-related mortality (NRM) were evaluated. Patients in the Chi group were associated with lower 2-year CIR (19.0 vs. 41.4%, P = 0.030), better 2-year LFS (76.1 vs. 48.1%, P = 0.014), and had no significant difference in 2-year OS (80.5 vs. 66.4%, P = 0.088). Patients with minimal residual disease (MRD) positive before HSCT in the Chi group exhibited an advantage in 2-year LFS and a trend towards better 2-year OS (75.0 vs. 10.2%, P = 0.048; 75.0 vs. 11.4%, P = 0.060, respectively). Multivariable analysis showed that the chidamide intensified regimen was independently associated with better LFS (HR 0.23; 95%CI, 0.08-0.63; P = 0.004), and showed no significant impact with OS for all patients (HR 0.34, 95%CI, 0.11-1.07; P = 0.064). The cumulative incidence rates of grade II-IV aGVHD were similar (36.4 vs. 38.6%, P = 0.858). 20 patients in Chi group evinced an elevation in γ-glutamyltransferase, as compared to the mBuCy group (90.9 vs. 65.9%, P = 0.029). No transplantation-related mortality was documented within the first 100 days after transplantation. The results demonstrate that the chidamide intensified regimen may be an effective and acceptable safety option for T-ALL/LBL undergoing allo-HSCT, and further validation is needed.

Decitabine in combination with fludarabine and cyclophosphamide as a lymphodepletion regimen followed by CD19/CD22 bispecific targeted CAR T-cell therapy significantly improves survival in relapsed/refractory B-ALL patients.

Relapse is a major limitation of chimeric antigen receptor (CAR) T-cell therapy. Here, we speculated that decitabine (DAC) in combination with fludarabine and cyclophosphamide (FC) as a lymphodepletion regimen may improve the efficacy of CD19/CD22 CAR T-cell therapy. Fourteen of 26 patients with relapsed/refractory B cell acute lymphoblastic leukemia (r/r B-ALL) without remission before lymphodepletion treatment were treated with DAC (total dose 100 mg/m2 in 3 days) followed by the FC regimen (DAC group), while twelve patients received the FC regimen (CON group). On Day 28 after CAR T-cells infusion, no significant differences in complete remission (CR) and minimal residual disease negative CR rates were found between both groups. However, there were significant differences in overall survival (OS) and leukemia-free survival (LFS) between two groups: 3-year OS, 92.3% (DAC) versus 41.7% (CON), P = 0.005 and 3-year LFS, 92.9% (DAC) versus 27.3% (CON), P < 0.001. There was no significant difference in the incidence of cytokine release syndrome between both groups. Median time to platelet and neutrophil counts recovery was similar in both groups. All adverse events were reversible and manageable. In conclusion, DAC in combination with the FC lymphodepletion regimen may be a new treatment option that can improve the efficacy of CAR T-cell therapy in r/r B-ALL.

Case report: Rare persistent complete donor chimerism and GVHD following micro-transplantation from HLA haplotype homozygous donors.

HLA-mismatched hematopoietic stem cell micro-transplantation (MST) is an effective treatment for older patients (≥60 years) with acute myeloid leukemia. Donor selection for MST is broad, ranging from HLA fully mismatched unrelated donors to HLA partially matched related donors. However, the influence of HLA haplotype homozygous donors such donors on MST has not been studied. Such donors has been reported to be associated with a higher risk of graft-versus-host disease (GVHD) in transfusion and cord blood transplantation (CBT). Additionally, sustained complete donor chimerism is rare in MST and usually accompanied by severe acute GVHD and death. Herein, we report the first case of MST using an HLA haplotype homozygous donor. The patient developed persistent complete donor chimerism (donor cells>95%) for 7 months and prolonged isolated thrombocytopenia (PT) for 3 months, after receiving MST from his HLA homozygous son. Grade I acute GVHD presented on day 12 post-MST and it was controlled by timely immunosuppressive treatment. Then he maintained complete molecular remission, complete donor chimerism and mild GVHD for 5 months. However, moderate overlapping GVHD with skin, oral, eyes, and intestinal involvement developed after he self-discontinued Tacrolimus treatment. Fortunately, the GVHD was controlled after intensive anti-rejection therapy and Tacrolimus is now being continued for prophylaxis. This case underscores that HLA haplotype homozygous donors might not be a good choice for MST and GVHD prophylactic should be administrated if such donors have to be selected.

Successful application of PD-1 knockdown CLL-1 CAR-T therapy in two AML patients with post-transplant relapse and failure of anti-CD38 CAR-T cell treatment.

Patients with relapsed/refractory acute myeloid leukemia (R/R AML) often show resistance to chemotherapy and have dismal outcomes. Therefore, it is urgent to develop new treatment strategies to address this problem. With tremendous achievement of chimeric antigen receptor T cells (CAR-T) therapy against B-cell malignancies, many efforts have been devoted to developing CAR-T therapy for R/R AML but with limited success, in part owing to a lack of specific targets. C-type lectin-like molecule-1 (CLL-1) is highly expressed on AML blasts with no expression on normal hematopoietic stem cells, which makes it an ideal target of immunotherapy for AML. Here, we report 2 R/R AML patients who relapsed after allogeneic stem cell transplantation and failed multiline salvage therapies including anti-CD38 CAR-T therapy, but were successfully treated with PD-1 silenced anti-CLL-1 CAR-T therapy. Both patients achieved molecular complete remission with incomplete hematologic recovery at 28 days of evaluation after CLL-1 CAR-T cell infusion. Cytokine release syndrome in cases 1 and 2 were grade 1 and 2, respectively. At the last follow-up, cases 1 and 2 had maintained continuous remission for 8 and 3 months, respectively. Our results demonstrated that CLL-1 CAR-T cells might be an effective and safe salvage therapy for AML patients with posttransplant relapse.

Low-dose decitabine as part of a modified Bu-Cy conditioning regimen improves survival in AML patients with active disease undergoing allogeneic hematopoietic stem cell transplantation.

Relapse is the major cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Effective preventive intervention in high-risk AML may be crucial. In this study, we investigated the clinical efficacy and safety of low dose decitabine (DAC) as part of a modified Busulfan-Cyclophosphamide (Bu-Cy) regimen for high-risk AML patients undergoing allo-HSCT to reduce relapse rate. Fifty-nine patients received DAC (20 mg/m2/d, i.v.) for 5 days, followed by modified Bu-Cy (DAC group). A matched-pair control (CON) group of 177 patients (matched 1:3) received modified Bu-Cy only. The differences were more substantial among patients with active disease: 2-year OS, 80.7% (DAC) versus 43.5% (CON), P = 0.011 and 2-year LFS, 64.9% (DAC) versus 39.2% (CON), P = 0.024. Median time to relapse was 8 months (DAC) versus 5 months (CON) for the entire groups and 6.5 months (DAC) versus 3.5 months (CON) for patients with active disease. In summary, our data indicated that the conditioning regimen containing low dose DAC may confer a survival advantage in high-risk AML patients with active disease undergoing allo-HSCT, and a prospective randomized trial is warranted to confirm these observations.

Bloodstream infections in pediatric patients with acute leukemia: Emphasis on gram-negative bacteria infections.

BACKGROUND/PURPOSE: Acute leukemia is the most common pediatric hematological malignancy. Bloodstream infections (BSIs) are severe complications in these patients during chemotherapy. This study aims to explore clinical features, laboratory, and microbiological characteristics of BSIs in acute leukemic children. METHODS: Patients aged < 18 years, diagnosed with acute myeloid leukemia or acute lymphocytic leukemia with BSIs from January 2004 to December 2013 were enrolled. BSIs was defined as positive isolate(s) of blood culture and associated with clinical findings. Clinical presentations, demographic features, and microbiological findings were retrospectively reviewed. RESULTS: In total, 126 isolates of 115 episodes of BSIs were identified from 69 patients (acute lymphocytic leukemia 56; acute myeloid leukemia 13). Gram-negative bacteria (GNB), gram-positive cocci, and fungi constituted 56.3%, 42.3%, and 2.4% of the pathogens, respectively. Eighty-three and a half percent of BSIs occurred along with neutropenia, and 73% had severe neutropenia. GNB was the leading pathogen of BSIs. The major GNBs were Escherichia coli, Klebsiella pneumonia, and Pseudomonas aeruginosa. White blood cell counts, absolute neutrophil counts, and platelet counts were significantly lower in patients of BSIs caused by GNB than gram-positive cocci. Plasma level of C-reactive protein was significant high in patients of GNB BSIs (179.8 mg/L vs. 127.2 mg/L; p = 0.005). Eighty-two percent of patients of E. coli, K. pneumonia, and P. aeruginosa BSIs had sepsis related organ failure or organ dysfunction. P. aeruginosa BSIs had the highest case-mortality (40%). CONCLUSION: Neutropenia was the major risk factor of BSIs in pediatric leukemic patients. BSIs of GNB were associated with severe neutropenia, systemic inflammatory responses, and high mortality.

The trend of macrolide resistance and emm types of group A streptococci from children at a medical center in southern Taiwan.

BACKGROUND: Group A streptococcus (GAS) is a common pathogen in children. Macrolide resistance in GAS has been described worldwide. The aims of this study are to analyze macrolide resistance of GAS isolates in southern Taiwan and to clarify the relationship of emm typing and macrolide resistance in the past decade. METHODS: All GAS isolated from patients younger than 18 years at a single tertiary center in southern Taiwan were collected from 2000 to 2012. Antibiotics susceptibility to erythromycin, azithromycin, and clindamycin were determined by agar dilution method, and were interpreted by Clinical and Laboratory Standards Institute (CLSI) standards. emm typing was performed by polymerase chain reaction (PCR). RESULTS: A total of 301 isolates were collected during the period of 13 years. Scarlet fever (38.5%) and acute pharyngitis (32.2%) were the most common diagnosis. Decreased resistance rate of erythromycin from 53.1% in 2000 to 0% in 2010 was found, but it increased rapidly to 65% in 2011. The resistance rate of azithromycin was the lowest (4.2%) in 2005, but was higher than 15% after 2006. The involvement of the erythromycin resistance genes were mefA (53.1%), ermB (35.9%), and ermTR (10.9%). The resistance of clindamycin also increased since 2011. emm12 was the most common serotype and accounted for 44.9% of all isolates. Compared with the non-emm12 group, resistance to erythromycin, azithromycin, and clindamycin were more frequently detected in the emm12 group. CONCLUSION: Increased resistance of GAS to macrolide and clindamycin was found in recent years. emm12 was the main serotype for macrolide resistance.

Clinical and epidemiological characteristics in children with community-acquired mycoplasma pneumonia in Taiwan: A nationwide surveillance.

BACKGROUND: Community-acquired pneumonia (CAP) is the leading cause of hospitalization of children. Mycoplasma pneumoniae is one of the most common pathogens. The disease severity is diverse, and the diagnosis remains a challenge to clinical pediatricians. The aims of this study are to provide a nationwide surveillance of the epidemiology and clinical manifestations of community-acquired mycoplasma pneumonia (CAMP) in children in Taiwan. METHODS: The medical records of children enrolled by the Taiwan Pediatric Infectious Disease Alliance (TPIDA) project during 2010-2011 were reviewed. Hospitalized children with segmental or lobar pneumonia were included. The demographic, clinical, laboratory and radiographic data were analyzed. Nasopharyngeal swabs, pleural effusion, and serum were collected for multiplex viral and bacterial polymerase chain reaction (PCR), mycoplasma immunoglobulin M (IgM), or paired immunoglobulin G (IgG) titer. RESULTS: There were overall 127 children with CAMP. Among them, 16 (12.6%) children had PCR and IgM positivity, 74 (58.3%) children had a positive serologic study, 34 (27.8%) children had positive PCR detection, and three (2.4%) children had paired IgG above a four-fold increase. Enrolled patients were divided into two groups before and after the age of 5 years. Children younger than 5 years or younger had a significantly longer hospitalization, higher intensive care unit (ICU) admission rates, and more complications. They were more frequent to receive oxygen supplementation and even surgical intervention. The white blood cell counts and C-reactive protein levels were higher in children 5 years old or younger. CONCLUSION: Mycoplasma pneumoniae is an important etiology of CAP in children 5 years or younger. They had a longer length of hospitalization, higher inflammatory responses, and more complications, compared to children older than 5 years.