Post-transplantation cyclophosphamide (PT-Cy) alone or in combination with other immunosuppressive drugs has emerged as a promising strategy in the setting of allogeneic hematopoietic stem cell transplantation. Improved survival rate was reported in lymphoid malignancies following PT-Cy strategy compared with myeloid disease in non-myeloablative bone marrow transplant setting. Thus, we aimed to evaluate the safety and efficacy of PT-Cy combined with cyclosporine as graft-versus-host disease (GVHD) prophylaxis after myeloablative conditioning and T cell-replete peripheral stem cell transplantation in lymphoid malignancies. This single-arm phase II clinical trial (NCT01435447) involving 31 adult patients was conducted from January 2013 to June 2018. The donor-type neutrophil engraftment rate was 100%, and the overall incidence of grade II to IV and grade III to IV acute GVHD was 39% and 24%, respectively. The cumulative incidence rates of chronic GVHD (35%), including moderate to severe forms (10%), were reduced compared with those of the historical group (P = 0.03 and P = 0.04, respectively). With a median follow-up of 18 months, the estimated 2-year overall and event-free survival was 64.8% (95% confidence interval: 47.8%-86.7%) and 58.4% (95% CI: 41.9%-81.7%), respectively. The 2-year cumulative incidence rate of relapse was 19.5% (95% CI: 9.0%-35.8%), whereas the non-relapse mortality rate was 21.8% (95% CI: 11.3%-38.1%). These results demonstrated the feasibility of PT-Cy as GVHD prophylaxis in this clinical setting. This strategy could significantly reduce the incidence of chronic GVHD and its moderate to severe forms but not of acute GVHD and results in similar survival outcomes compared with the historical group. A prospective study with additional patients is warranted to confirm the role of PT-Cy in lymphoid malignancy.
Adult ; Busulfan/therapeutic use* ; Cyclophosphamide/therapeutic use* ; Graft vs Host Disease/prevention & control* ; Hematopoietic Stem Cell Transplantation ; Humans ; Neoplasms ; Peripheral Blood Stem Cell Transplantation ; Pharmaceutical Preparations ; Prospective Studies ; Transplantation Conditioning ; Vidarabine/analogs & derivatives*

OBJECTIVE: To investigate effect and mechanism of miR-214 in fludarabine resistance of chronic lympho-cytic leukemia (CLL). METHODS: A total of 10 patients with CLL resistante to fludarabine (Flu) and 10 healthy persons admitted to Hematology Department of our hospital in August 2014 - July 2018 were selected. Expression level of miR-214 in mononuclear cells in patients with CLL and healthy persons were determined by RT-PCR. Primary CLL cells from patients with CLL were divided into normal control group (control group), negative control group (miR-214-NC group) and viral transinfection group (miR-214-ASO group). After 24 h-transfection, CLL cells were cultured with different con-centration of Flu for 48 h, then the cell proliferation and apoptosis were detected, and the levels of down-stream genes and proteins releted with PTEN and PI3K/AKT signialing pathway were determined. RESULTS: The expression level of miR-214 in mononuclear cells of CLL patients significantly increased in comparison with healthy persons(P<0.05); the expression level of miR-214 in miR-214-ASO group significantly decreased (P<0.05); Absorbance in control group at Flu concentration of 3, 10 and 30 μmol/L was significantly decreased (P<0.05). Apoptosis rate in miR-214-ASO group at Flu concentration of 10 mmol/L significantly increased (P<0.05). At Flu concentration of 10 mmol/L, mRNA levels PTEN and BAD in miR-214-ASO group significantly increased (P<0.05), but mRNA levels of MDM2 and NF-κB significantly decreased (P<0.05). At Flu concentration of 10 mmol/L, protein levels of PTEN and p-BAD in miR-214-ASO group significantly increased (P<0.05), but protein levels of MDM2 and NF-κB significantly decreased (P<0.05). CONCLUSION Inhibition of miR-214 can enhance the sensitivity of drug-resistant CLL cells to fludarabine, which may be raleted with the promotion of cell apotosis and regulation of down-stream molecules expression of PTEN/AKT signaling pathway.
Apoptosis ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell ; drug therapy ; MicroRNAs ; Phosphatidylinositol 3-Kinases ; Vidarabine ; analogs & derivatives ; genetics ; therapeutic use

Objective: To evaluate the efficacy of reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC-allo-HSCT) for patients with myelofibrosis (MF). Methods: The clinical data of 10 patients with myelofibrosis (MF) who underwent RIC-allo-HSCT. Results: Of all 10 patients, 6 were male and 4 women, with a median age of 28.5 (22-54). Using fludarabine/busulfan plus total body irradiation (FB+TBI) pretreatment scheme based. Hematopoiesis reconstitution was achieved in 9 patients (90%). The median time of neutrophil and platelet engraftment was 13.5 (10-22) day and 16.5 (13-40) day, respectively. Acute GVHD occurred in 4 cases while chronic GVHD in 5 cases. The prospective OS for 3 years was (90.0±8.5)% after a median follow-up time of 17 months. Transplant related mortality was 1 case. Conclusion: RIC-HSCT with FB+TBI is a feasible and effective alternative for MF patients.
Adult ; Busulfan ; Female ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Male ; Middle Aged ; Primary Myelofibrosis ; Prospective Studies ; Transplantation Conditioning ; Vidarabine ; Young Adult

Objective: To summarize and investigate the characteristics, prognosis and treatments of chronic lymphocytic leukemia (CLL) patients with trisomy 12 by using FISH (CEP12). Methods: Clinical data of 330 CLL patients were analyzed retrospectively by using FISH (CEP12) to detect trisomy 12 from May 2003 to April 2015. The clinical data and laboratory characteristics of CEP12 positive patients (70 cases) were compared with those CEP12 negative patients (260 cases). Results: Compared with CEP12 negative CLL patients, the proportion of hepatomegaly (13.6% vs 4.0%, P=0.011) and LDH>247 U/L (43.3% vs 18.5%, χ(2)=15.892, P<0.001) in CEP12 positive CLL patients were much higher, respectively. There were no significant differences between age, sex, clinical stage, β(2)-microglobulin level, IGHV mutation ratio and splenomegaly/lymphadenopathy in these two subgroups. However, compared with CEP12 negative patients, CEP12 positive patients had higher ratio of FMC7 (23.8% vs 12.7%, χ(2)=4.730, P=0.030), and lower ratio of CD23 (95.2% vs 99.6%, P=0.033). The overall response rates (ORR) in Fludarabine (without Rituximab), Rituximab (with or without Fludarabine) and the traditional chemotherapy group (chlorambucil, CHOP or CHOP-like) were 77.5% (31/40), 84.8% (56/66) and 45.4% (50/110), respectively. The ORR of the traditional chemotherapy group was lower than that of the Fludarabine group and Rituximab group. For CEP12 positive patients, the ORR was inferior to CEP12 negative patients when only using Fludarabine (P<0.05). However, when using Rituximab, the difference could be eliminated, and the ORR was even a little higher in CEP12 negative patients (91.7% vs 81.0%, P=0.306). Compared with CEP12 negative patients, there were no significant differences in progression-free survival (PFS) (χ(2)=0.410, P=0.478) and overall survival (OS) (χ(2)=0.052, P=0.180) for CEP12 positive patients whom the median time from diagnosis to start treatment and OS time was 22.6 (95%CI 15.4-31.7) and 118.5 (95%CI 74.5-162.4) month while the 5-year PFS and OS were (52.9±7.6)% and (74.8±6.6)%. Conclusions: CEP12 positive CLL patients are more common in hepatomegaly and higher level of LDH. The traditional chemotherapy treatment had the lowest efficacy, and the curative effect of single use of fludarabine is not as good as that of CEP12 negative patients, however, when using Ritaximab, the efficacy could be comparable.
Antibodies, Monoclonal, Murine-Derived ; Antineoplastic Combined Chemotherapy Protocols ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell ; Retrospective Studies ; Rituximab ; Trisomy ; Vidarabine

OBJECTIVETo investigate the safety and effectiveness of HLA-mismatched allogeneic hematopoietic stem cell transplantation (allo-HSCT) combined with related haploidentical bone marrow infusion for treatment of hematologic malignancies and to explore the mathod for reduction of aGVHD incidence and clinical significance.

METHODSA total of 30 patients with hematologic malignancies (8 cases of AML, 17 AML, 2 MDS and 3 Mix-AL) received related haploidentical and unrelated HLA-mismatched allo-HSCT combined with related haploidentical bone marrow infusion. Among them 20 cases received related haploidentical transplantation of the first donor, 10 cases received unrelated HLA-mismatched treaplantation. The new conditioning regimen for the patients underwent allo-HSCT consisted of fludarabine, busulfan, Me-CCNU and cyclophosphamide. The drugs for GVHD prophylaxis included cyclosporine A and methotrexate, while mycophenolate mofetil and rabbit anti-T-lymphocyte globulin (ATG) were used.

RESULTSAll the patients achieved full engraftment. The median time for neutrophils to reach over 0.5 × 10(9)/L was 14 days (8-26 days), while the median time for platelets to reach over 20 × 10(9)/L was 11.5days (10-24 days). The incidence of I-II grade of aGVHD at 100 d was 22.28% (95% CI 9.9%-34.7%), the incidences of II-IV and III-IV grade of aGVHD were 22.7% (95% CI, 10%-35.4%) and 12.7% (95% CI 6.9%-15.5%) respectively. The incidences of I-II and III-IV cGVHD were 13.3% (95% CI, 1.4%- 26.8%) and 3.3 % (95% CI, 0%-12.2%), one case (3.3%) was in extensive cGVHD. DFS and OS of 2 years were 81.1% (95% CI, 66.0%-96.2%) and 68.2% (95% CI 51.0%-85.4%).

CONCLUSIONThese data suggest that the incidence of grade II-IV grade of aGVHD in recipients of 2 partially HLA-matched units was lower, co-infusion of haplo-BM and partially matched units in allogeneic transplantation is safe and effective for reducing the incidence of aGVHD and improving the survival in DFS.

Antilymphocyte Serum ; therapeutic use ; Busulfan ; therapeutic use ; Cyclosporine ; therapeutic use ; Graft vs Host Disease ; prevention & control ; HLA Antigens ; genetics ; Hematologic Neoplasms ; therapy ; Hematopoietic Stem Cell Transplantation ; Humans ; Incidence ; Leukemia ; therapy ; Mycophenolic Acid ; analogs & derivatives ; therapeutic use ; Stem Cell Transplantation ; Tissue Donors ; Transplantation Conditioning ; Transplantation, Homologous ; Vidarabine ; analogs & derivatives ; therapeutic use

OBJECTIVETo analyze the treatment outcome of a consecutive series of 100 leukemia patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT).

METHODSThe clinical data of leukemia patients received allo-HSCT were analyzed retrospectively, the therapeutic efficacy was summarized. 100 evaluable cases of leukemia included 47 cases of AML, 33 cases of ALL, 2 cases of AL (biphenotypic), 16 CML and 2 CMML. Before transplantation, 76 cases were in first complete remission, 9 cases in second or greater complete remission and 15 cases in non-remission or relapse. All the patients received peripheral blood hematopoietic stem cell transplantation (PBHSCT). The conditioning regimen of human leukocyte antigen (HLA)-matched allo-HSCT group was modified BuCy, but in HLA-mismatched group Fludarabine and anti-human thymocyte globulin (ATG) was added. CsA+MTX regimen was used for prophylaxis of graft-versus-host disease (GVHD) in HLA-identical allo-HSCT, while additional MMF was added in HLA-mismatched group. The average time of follow-up was 13 months.

RESULTSAt the last follow-up, 66.0% (66/100) patients survived, 53.0% (53/100) patients survived without leukemia, 28.0% (28/100) patients relapsed and 34.0% (34/100) patients died, 44.1% patients of them died from infectious pulmonary complications. During transplantation, 65.0% of the patients were suffered from lung infection. The overall survival (OS) and disease-free survival (DFS) of all cases was 60.9% and 48.8%, respectively. The recurrence rate was significantly higher in non-remission (66.7%) than in CR (21.2%) patients (P < 0.05). The cumulative incidence of GVHD in HLA-mismatched transplantation was 60.8%, which was significantly higher than that of HLA-matched transplantation (38.8%) (P < 0.05).

CONCLUSIONAllo-HSCT can cure a significant proportion of leukemia patients, especially for those in CR status. Since the incidence of infectious pulmonary complications after allo-HSCT is still high, much more attention should be paid to it. The comprehensive prognosis of HLA-matched transplantation is better than the HLA-mis-matched transplantation.

Antilymphocyte Serum ; therapeutic use ; Disease-Free Survival ; Graft vs Host Disease ; prevention & control ; HLA Antigens ; genetics ; Humans ; Incidence ; Leukemia ; therapy ; Peripheral Blood Stem Cell Transplantation ; Recurrence ; Retrospective Studies ; Transplantation Conditioning ; Treatment Outcome ; Vidarabine ; analogs & derivatives ; therapeutic use

OBJECTIVETo explore the clinical efficacy and safety of rituximab combined with fludarabine and cyclophosphamide for the treatment of the chronic lymphocytic leukemia (CLL).

METHODSForty cases of CLL patients treated in our hospital from March 2010 to March 2014 years were selected and divided into the observation group (20 cases) and control group (20 cases) by random number table method. The patients in control group were treated with CHOP chemotherapy, the patients in observation group were treated with rituximab combined with fludarabine, cyclophosphamide treatment. The therapeutic efficacy of patients in 2 groups was analyzed according to the peripheral hemogram indexes, symptom and sign disappeared time as well as adverse reaction incidence.

RESULTSthe remission rate in observation group was 90.00%, which was significantly higher than that in control group (70.00%) (P < 0.05); the peripheral hemogram indexes in 2 groups before treatment showed no significant difference (P > 0.05), and were significantly improved after treatment, but the white blood cell count and lymphocyte absolute number were significantly lower in observation group as compared to the control group (P < 0.05); symptom and sign disappeared time in observation group were significantly shorter as compared with the control group (P < 0.05); adverse reaction incidence in obseovation group was significantly lower as compared with control group (P < 0.05).

CONCLUSIONapplication of rituximab combined with fludarabine and cyclophosphamide in the treatment of CLL shows the higher curative effect, can effectively improve the symptoms and reduce the incidence of adverse reactions. It is worthy to be popularized.

Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Cyclophosphamide ; administration & dosage ; therapeutic use ; Doxorubicin ; therapeutic use ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell ; drug therapy ; Prednisone ; therapeutic use ; Rituximab ; administration & dosage ; therapeutic use ; Treatment Outcome ; Vidarabine ; administration & dosage ; analogs & derivatives ; therapeutic use ; Vincristine ; therapeutic use

OBJECTIVETo evaluate the efficacy of FLAG regimen for treating patients with refractory/relaspse AML and their progonistic factors.

METHODSThe 38 patients with median age 40.5 (range 13-69) were treated with FLAG regimen from July 2006 to July 2013 in hospital. According to disease status, all the patiens were divided into 4 different groups: early relapse group (3 patients), late relapse group (12 patients), first induction failure group (16 patients) and second induction failure group (7 patients); meanwhile, based on risk status, all above-mentioned patients were stratified into better (8 patients), intermediate (26 patients) and poor (4 patients) groups, respectively.

RESULTSTwenty two cases achieved complete remission, 5 cases achieved partial remission among 38 patients. The complete remission (CR) rate was 57.9% and the overall response (OR) rate was 71.7%. The CR rate was higher in first induction failure group (12/16, 75%) than that in second induction failure group (3/7, 42.9%) and late relapse group (6/12, 50%). In better group and intermediate group, the CR rates (5/8, 62.5%; 16/26, 61.5%) were higher than that in poor group (1/4, 25%). The risk status was associated with the CR rate (P = 0.03) [OR = 25.9(95% CI 1.2-545.4)]. The intermediate risk was favorable factor to CR. Out of 22 patients with CR, 12 patients received allogenetic hematopoietic stem cell transplantation (allo-HSCT) and 10 patients received large dose of cytarabine or other regimens as consolidation treatments, 6 patients who accepted allo-HSCT are still alive. The overall survival (OS) was 25 months. The univariate analyses showed that the response to FLAG was accociated with OS [HR = 0.246, CR vs NR (95% CI 0.07-0.79) P = 0.03]. The 2-year cumulative survial rates in CR group and PR group were 62% and 48%, respectively. The 18- month cumulative survival rate was 73% in better group, 52% in intermediate group, 36% in poor group (P = 0.17); and 65% in first induction failure group and 32% in second induction failure group (P = 0.19).

CONCLUSIONThe efficacy of FLAG regimen has been confirmed to be effective for patients with refractory and relapse AML. The patients who achieved remission could acquire benefit from following HSCT or other consolidation chemotherapy, and their survials could be improved.

Adolescent ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Chronic Disease ; Cytarabine ; therapeutic use ; Granulocyte Colony-Stimulating Factor ; therapeutic use ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; Middle Aged ; Recurrence ; Remission Induction ; Survival Rate ; Treatment Outcome ; Vidarabine ; analogs & derivatives ; therapeutic use ; Young Adult

OBJECTIVETo enrich our national database with data of rare diseases by analyzing molecular diagnosis and hematopoietic stem cell transplantation (HSCT) in children with inherited bone marrow failure syndromes (IBMFS).

METHODNext-generation sequencing (NGS)-based genetic diagnosis panel was applied for the clinical diagnosis and management of IBMFS. Retrospective analysis was performed on clinical and genetic data of 17 consecutive children who received HSCT over a long time interval (November. 2005-June 2015).

RESULTThree patients were diagnosed only by clinical manifestation before 2012. After that NGS-based genetic diagnosis panel was used to identify IBMFS-related genes in 12/14.IBMFS patients (except two Diamond-Blackfan anemia (DBA) patients). Two Fanconi anemia (FA) patients were confirmed to be new variations through family-genotype-analysis and 3 families accepted prenatal diagnosis to avoid birth of affected fetuses. Seventeen IBMFS patients (10 FA,5 DBA and 2 dyskeratosis congenital (DKC)) were treated with HSCT from matched sibling donors (n=2), matched unrelated donors (n=8) or mismatched unrelated donors (n=7). The source of stem cells for transplantation included peripheral blood (n=12) and cord blood (n=5). With regard to the conditioning regimens, FA and DKC patients received fludarabine-based reduced intensity conditioning, while DBA patients received classical busulfan-based myeloablative conditioning. Median age at the time of HSCT was 36 months (7-156 months). The number of infused mononuclear cells and CD34⁺ cells was (10.6 ± 6.7) × 10⁸ and (5.9 ± 7.0) × 10⁶ per kilogram of recipient body weight, respectively. The median number of days to neutrophil recovery was 13 days after HSCT (range: 10-19 days). Platelet recovery was faster in the PBSCT group than in the CBT group ((16.3 ± 6.0) days vs. (30.0 ± 17.1) days,t=-2.487,P=0.026). During a median follow-up of 17 months (range: 2-114 months), except one FA patient who was transplanted with HLA-matched unrelated cord blood (CB) died from pneumonia and heart failure because of engraftment failure, other 16 children are alive after the successful HSCT. The failure-free survival rate of the patients three years after HSCT was 94%.

CONCLUSIONNGS-based molecular diagnosis technology and effective HSCT have significantly facilitated the treatment of children with IBMFS in our country, and our national database about this rare disease is to be further exploited.

Anemia, Aplastic ; Anemia, Diamond-Blackfan ; therapy ; Bone Marrow Diseases ; Child ; Dyskeratosis Congenita ; therapy ; Fanconi Anemia ; therapy ; Fetal Blood ; Hematopoietic Stem Cell Transplantation ; Hemoglobinuria, Paroxysmal ; diagnosis ; genetics ; therapy ; Humans ; Retrospective Studies ; Siblings ; Survival Rate ; Transplantation Conditioning ; Unrelated Donors ; Vidarabine ; analogs & derivatives ; therapeutic use

OBJECTIVETo explore the efficacy of unrelated umbilical cord blood transplantation (UCBT) in the treatment of Gaucher disease.

METHODThe clinical characteristics of three children with Gaucher disease underwent UCBT in our hospital between April 2013 and September 2014 were retrospectively analyzed. Literature on allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of Gaucher disease was searched at Wanfang and Pubmed databases between 1983 and 2015 and was reviewed and summaried.

RESULTThree children with Gaucher disease, all were female, received UCBT. These patients' age at receiving transplantation was 3.8 years, 7.1 years and 2.6 years, respectively. The second case received the second transplantation. The first and third case received splenectomy before UCBT. The pretreatment regimen was busulfan (Bu)/fludarabine (Flu)/cyclophosphamide (CTX)/antithymocyte globulin (ATG), and for the patient received the second transplantation melphalan was added to the myeloablative conditioning regimen of Bu/Flu/CTX/ATG. Cyclosporine and mycophenolate mofetil (MMF) wee used for prophylaxis of acute graft versus host disease (aGVHD). The dose of cord blood stem cell nucleated cell counts was 9.7 × 10⁷ /kg,11.9 × 10⁷ /kg and 7.6 × 10⁷/kg respectively. The dose of cord blood stem cell CD34⁺ cell counts was 5.4 × 10⁵/kg , 3.5 × 10⁵/kg and 3.2 × 10⁵/kg respectively. The day of granulocytes exceeding 0.5 × 10⁹/L was day 11, 12 and 19 after transplantation, respectively. The day of platelets exceeding 20 × 10⁹/L was day 14, 33 and 74 after transplantation, respectively. At one month after transplantation the rate of chimerism was over 95% and all patients got donor complete chimerism. The level of β-glucocerebrosidase recovered to normal at one month after transplantation. During transplantation, all patients developed cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia. In case 1 immune thrombocytopenia occurred at five month after transplantation unresponding to steroids and mesenchymal stem cells infusion was administered and his platelet in routine blood test recovered to normal. But the patient died because she was infected with varicella-zoster virus out of hospital at nine month after transplantation and the level of β-glucocerebrosidase was normal before death and chronic GVHD (cGVHD) was not found. The case 2 is now in 19th month after transplantation and his level of β-glucocerebrosidase was normal. cGVHD was not found. The patient is currently free of disease. The case 3 was in 9th month after transplantation and his level of β-glucocerebrosidase was normal. cGVHD was found at 112 day after transplantation and was localized and could be controlled by hormonal therapy. The patient is currently free of disease. Three patients' size of liver was significantly reduced after their level of β-glucocerebrosidase ecovered. There were 50 cases with Gaucher disease who were treated with allo-HSCT in the literature and none of them were reported from China. Disease-free survival rate of patients treated with allo-HSCT for Gaucher disease was 85%. In all reports, there were 31 cases who had information of typing of Gaucher disease, of whom 22 cases had type 1 and 9 cases had type 3. Twenty-nine cases had information of survival, of whom 24 cases survived and 5 cases died of infection. Fifteen cases had data of engraftment, 2 of whom had graft failure and one had late graft failure.Glucocerebrosidase recovered to normal in 25 of 31 cases who had relevant data, in one of whom with late graft failure the enzyme recovered to normal 3 month after transplantation, but his enzyme decreased to the initial level 9 month after transplantation. Along with enzyme level's recovery to normal, in a part of cases bone pain and hepatomegaly were relieved and growth delay was improved.

CONCLUSIONThe unrelated UCBT may be a form of treatment that offers the potential of permanent cure and a procedure with possible long-term benefits in patients with Gaucher disease.

Antilymphocyte Serum ; therapeutic use ; Busulfan ; therapeutic use ; Child ; Child, Preschool ; China ; Cyclophosphamide ; therapeutic use ; Cyclosporine ; therapeutic use ; Disease-Free Survival ; Female ; Gaucher Disease ; therapy ; Graft vs Host Disease ; Hematopoietic Stem Cell Transplantation ; Humans ; Mycophenolic Acid ; analogs & derivatives ; therapeutic use ; Retrospective Studies ; Transplantation Conditioning ; Vidarabine ; analogs & derivatives ; therapeutic use