Xutao Guo

Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study

ObjectiveWe conducted a prospective, randomized, open-label, multicenter study to compare busulfan plus fludarabine (BuFlu) with busulfan plus cyclophosphamide (BuCy) as the conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML) in first complete remission (CR1).MethodsTotally 108 AML-CR1 patients undergoing allo-HSCT were randomized into BuCy (busulfan 1.6 mg/kg, q12 hours, -7 ~ -4d; cyclophosphamide 60 mg/kg.d, -3 ~ -2d) or BuFlu (busulfan 1.6 mg/kg, q12 hours, -5 ~ -2d; fludarabine 30 mg/m2.d, -6 ~ -2d) group. Hematopoietic engraftment, regimen-related toxicity (RRT), graft-versus-host disease (GVHD), transplant related mortality (TRM), and overall survival were compared between the two groups.ResultsAll patients achieved hematopoietic reconstitution except for two patients who died of RRT during conditioning. All patients obtained complete donor chimerism by day +30 post-transplantation. The incidence of total and III-IV RRT were 94.4% and 81.5% (P = 0.038), and 16.7% and 0.0% (P = 0.002), respectively, in BuCy and BuFlu group. With a median follow up of 609 (range, 3–2130) days after transplantation, the 5-year cumulative incidence of TRM were 18.8 ± 6.9% and 9.9 ± 6.3% (P = 0.104); the 5-year cumulative incidence of leukemia relapse were 16.5 ± 5.8% and 16.2 ± 5.3% (P = 0.943); the 5-year disease-free survival and overall survival were 67.4 ± 7.6% and 75.3 ± 7.2% (P = 0.315), and 72.3 ± 7.5% and 81.9 ± 7.0% (P = 0.177), respectively in BuCy and BuFlu group.ConclusionCompared with BuCy, BuFlu as a myeloablative condition regimen was associated with lower toxicities and comparable anti-leukemic activity in AML-CR1 patients undergoing allo-HSCT.

Utility of FDG PET/CT in guiding antifungal therapy in acute leukemia patients with chronic disseminated candidiasis.

In this study, we report the results of using fluorine deoxyglucose positron emission tomography/computed tomography (FDG PET/CT) to guide the antifungal therapy against chronic disseminated candidiasis in patients with acute leukemia. Three adult patients were enrolled in this study. All patients underwent a series of PET/CT scans during the course of antifungal therapy. Antifungal therapy was modified based on the change of the FDG activity in the known sites of the fungal infection. With the guidance of FDG PET/CT, all 3 patients achieved favorable outcomes with long-term follow-up. FDG PET/CT appeared to be a valuable modality in designing proper antifungal therapy against chronic disseminated candidiasis in patients with acute leukemia.

Spectrum of Epstein-Barr virus-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation.

Background Epstein-Barr virus (EBV) infection may result in a spectrum of diseases in recipients of transplant. The aim of this study is to investigate the incidence, clinical characteristics, and prognosis of the spectrum of EBV-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods A total of 263 recipients undergoing allo-HSCT were prospectively enrolled. The blood EBV-DNA loads were regularly monitored by quantitative real-time polymerase chain reaction. Results The 3-year cumulative incidence of total EBV-associated diseases, posttransplantation lymphoproliferative diseases (PTLD), EBV fever, and EBV end-organ diseases (pneumonia, encephalitis/myelitis, and hepatitis) were 15.6%±2.5%, 9.9%±2.0%, 3.3%±1.3%, and 3.3%±1.2% (2.2%±1.0%, 1.6%±0.8%, and 0.9%±0.6%), respectively. Fever was the most common symptom of EBV-associated diseases. Patients with PTLD had better response rate to rituximab-based treatments compared with those with EBV end-organ diseases (including PTLD accompanied by EBV end-organ diseases) (P=0.014). The 3-year overall survival was 37.3%±13.7%, 100.0%, and 0.0%±0.0% in patients with PTLD, EBV fever, and EBV end-organ diseases (P=0.001). Conclusions EBV-associated diseases other than PTLD are not rare in the recipients of allo-HSCT. The clinical manifestations of EBV end-organ diseases are similar to PTLD. EBV end-organ diseases had poorer response to rituximab-based therapy compared with PTLD.

Triptolide, a Chinese herbal extract, enhances drug sensitivity of resistant myeloid leukemia cell lines through downregulation of HIF-1α and Nrf2

AIM To explore whether triptolide (TPL) can enhance drug sensitivity of resistant myeloid leukemia cell lines through downregulation of HIF-1α and Nrf2. MATERIALS & METHODS HL60/A and K562/G cells were subjected to different treatments and thereafter an methyl thiazole tetrazolium bromide assay, flow cytometry, western blot and real-time PCR were used to determine IC₅₀, apoptotic status and expression of Nrf2, HIF-1α and their target genes. RESULTS Doxorubicin- or imatinib-induced apoptosis was enhanced when anticancer agents were used in combination with TPL. When combined with TPL, both doxorubicin and imatinib downregulate Nrf2 and HIF-1α expression at protein and mRNA levels. Genes downstream of Nrf2, for example, NQO1, GSR and HO-1, as well as target genes of HIF-1α, for example, BNIP3, VEGF and CAIX are also downregulated at the mRNA level. CONCLUSION TPL is able to enhance drug sensitivity of resistant myeloid leukemia cell lines through downregulation of HIF-1α and Nrf2.

shRNA-Mediated BAALC knockdown affects proliferation and apoptosis in human acute myeloid leukemia cells

Abstract Brain and acute leukemia, cytoplasmic (BAALC) is a novel molecular marker indicating an inferior outcome in acute myeloid leukemia (AML) with normal cytogenetics. The biological function of BAALC is largely unknown. In this study, BAALC gene expression in an acute myeloid leukemia cell line KG1a was knocked down by a small hairpin RNA (shRNA). The expression of BAALC mRNA and protein in the knockdown cells was significantly inhibited. The proliferation and apoptosis status in the knockdown cells were investigated. The growth curves and FACS analysis demonstrated that BAALC gene knockdown resulted in decreased proliferation and enhanced apoptosis in KG1a cells. These results indicated that BAALC may act as an adverse prognostic factor through prompting proliferation and inhibiting apoptosis in leukemia cells.

Sequential intensified conditioning followed by prophylactic DLI could reduce relapse of refractory acute leukemia after allo-HSCT

The major obstacle is leukemia relapse for refractory leukemia undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We previously introduced a strategy of sequential intensified conditioning and early rapid immunosupressant withdrawal for refractory leukemia undergoing allo-HSCT, with 5-year overall survival (OS) and 3-year relapse rate of 44.6% and 33.3%. To reduce leukemia relapse, prophylactic donor lymphocyte infusion (DLI) was administered based on our historical strategy. A total of 153 refractory advanced acute leukemia patients were enrolled in this prospective study. According to the availability of donor lymphocytes and the criteria for DLI, 144 patients surviving day +60 were divided into two groups (80 DLI versus 64 non-DLI). The relapse rate was less and OS was better in patients receiving DLI than in those not receiving DLI (22.7% vs 33.9%, P=0.048; 58.1% vs 54.9%, P=0.043). The non-relapse mortality (NRM) was similar between DLI and non-DLI groups (P=0.104). Overall, the 5-year overall and disease-free survival post-transplantation were 51.1%±5.7% and 49.2%±5.3%. The 5-year relapse rate and NRM were 27.3%±4.4% and 29.7%±5.3%. Multivariate analysis revealed that lower bone marrow blasts on day 0, DLI and chronic graft-versus-host disease were associated with less relapse and better OS. The strategy of sequential intensified conditioning followed by early immunosupressant withdrawal and DLI could reduce relapse of refractory acute leukemia after allo-HSCT and improve survival.

Idarubicin is superior to daunorubicin in remission induction of de novo acute myeloid leukemia patients with high MDR1 expression.

AIM To investigate whether idarubicin in a cytarabine-based induction regimen was superior to daunorubicin in de novo acute myeloid leukemia patients expressing high MDR1. PATIENTS & METHODS The clinicopathological data were analyzed in 125 patients receiving daunorubicin or idarubicin with cytarabine for remission induction. Median MDR1 mRNA expression in pretreated bone marrow cells was used as the cutoff point for high and low MDR1 expression. RESULTS A total of 59.7% high and 77.8% low MDR1 expressers achieved complete remission (CR; p = 0.029). Idarubicin yielded a higher CR rate than daunorubicin in high MDR1 expressers (82.1 vs 41.2%; p = 0.001), it also demonstrated a higher CR rate than daunorubicin (p < 0.05) in high MDR1 expressers exhibiting favorable or intermediate risk, while there was no difference between the two treatment arms in low MDR1 expressers exhibiting either favorable or intermediate risk. CONCLUSION Idarubicin is associated with better remission induction of de novo acute myeloid leukemia patients with high MDR1 expression.

Low-dose decitabine enhances chidamide-induced apoptosis in adult acute lymphoblast leukemia, especially for p16-deleted patients through DNA damage.

AIM To investigate the combined action of decitabine (DAC) with chidamide (CS055) on acute lymphoblastic leukemia (ALL) cells. MATERIALS & METHODS ALL cell lines as well as primary cells from 17 ALL patients were subjected to different treatments and thereafter cell counting Kit-8 (CCK-8) assay, flow cytometry and western blot were employed to determine IC50, apoptosis and checkpoint kinase 1 and γH2A.X expression. RESULTS Low-dose DAC combined with CS055 could effectively kill ALL cells by the reduction of cell viability and induction of apoptosis. This was also observed in primary cells from 17 ALL patients, especially for those with p16 gene deletion. Suppression of checkpoint kinase 1 phosphorylation and upregulation of γH2A.X expression was demonstrated to participate in DAC plus CS055-induced apoptosis. CONCLUSION Low-dose DAC could enhance chidamide-induced apoptosis in adult ALL, especially for patients with p16 gene deletion through DNA damage.

Allogeneic hematopoietic stem cell transplantation improves the prognosis of p16-deleted adult patients with acute lymphoblastic leukemia

AIM The prognostic value of CDKN2A inactivation in adult patients with acute lymphoblastic leukemia (ALL) is still under debate, and the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for adult ALL with p16 deletion remains to be evaluated. MATERIALS & METHODS This study analyzed the clinical implications of p16 deletion in adult ALL and investigated the efficacy of allo-HSCT in patients with p16 deletion. RESULTS Deletion of p16 was identified in 38.4% of the adult ALL patients, and the prevalences of hemizygous deletion, homozygous deletion and mixed hemi/homozygous of p16 were 22.1, 11.6 and 5.5%, respectively. The prevalence of p16 deletion was 39.7% in B-lineage ALL and 33.3% in T-lineage ALL. Deletion of p16 was significantly associated with higher white blood cell count (p = 0.032) and lower platelets (p = 0.023) but was not related to age, sex, percentage of bone marrow blasts, hepatosplenomegaly, CNS leukemia rate, first complete remission and relapse rate (p > 0.05). Deletion of p16 was significantly correlated with poor outcome in terms of event-free survival (EFS; p = 0.028) and overall survival (OS; p = 0.033). Twenty-two of the 33 patients with p16 deletion received allo-HSCT treatment. Patients with p16 deletion after allo-HSCT experienced higher EFS and OS than those without (52.9 vs 0%, p < 0.001; 46.8 vs 29.1%, p = 0.01, respectively). Multivariate analysis found CNS leukemia and poor response to induction chemotherapy to be the risk factors for EFS and OS, whereas no deletions of p16 and allo-HSCT were favorable factors. CONCLUSION Deletion of p16 is a strong adverse prognostic factor in adult ALL. Testing for p16 alterations at diagnosis may help in risk stratification, and we propose to implement testing for p16 deletion in future treatment protocols.

A retrospective comparison of Escherichia coli and polyethylene glycol‑conjugated asparaginase for the treatment of adolescents and adults with newly diagnosed acute lymphoblastic leukemia

Data from clinical trials suggest that polyethylene glycol-conjugated asparaginase (PEG asparaginase) should be recommended as a replacement for Escherichia coli (E. coli) asparaginase in the treatment of pediatric acute lymphoblastic leukemia (ALL) due to its prolonged effect, similar safety profile and convenience. The present study investigated the efficacy and safety of PEG asparaginase in adolescents and adults with newly diagnosed ALL. The clinical data of 122 patients, ≥14 years old with de novo ALL, who received either PEG asparaginase or E. coli asparaginase as part of an induction regimen, were retrospectively analyzed. The results revealed that PEG asparaginase had a comparable complete remission rate (95.65 vs. 90.79%), median overall survival time (14.07 vs. 16.29 months) and median relapse-free survival time (10.00 vs. 8.57 months) with E. coli asparaginase. In addition, patients <35 years old receiving PEG asparaginase obtained a higher median RFS time compared with those receiving E. coli asparaginase (10.93 vs. 8.97 months; P=0.037). Patients treated with E. coli asparaginase exhibited a significantly higher incidence of central nervous system leukemia (CNSL) compared with those treated with PEG asparaginase (27.63 vs. 10.87%; P=0.028) during the consolidation phase. Toxic events, including allergy, grade III–IV liver dysfunction, renal function damage and pancreatic lesions were similar between the two groups. A longer duration of coagulation dysfunction (9.80±5.51 vs. 6.80±4.21 days; P=0.002) and agranulocytosis (18.89±8.79 vs. 12.03±8.34 days; P<0.01), and a higher incidence of grade IV–V infections (22.73 vs. 7.25%; P=0.018) were observed in the PEG asparaginase group. However, these did not increase bleeding events or infection-associated mortalities. When taking the convenience and superior efficacy in preventing CNSL into consideration, PEG asparaginase is a candidate for first-line treatment of adolescent and adult ALL. A larger prospective clinical trial is required to further confirm this point of view.