Donor-derived CD19 CAR-T Cells versus Chemotherapy Plus Donor Lymphocyte Infusion for Treatment of Recurrent CD19-positive B-ALL After Allogeneic Hematopoietic Stem Cell Transplantation.

OBJECTIVE: This study aimed to compare the efficacy of anti-CD19 chimeric antigen receptor T cells (CAR-T cells) versus chemotherapy plus donor lymphocyte infusion (chemo-DLI) for treating relapsed CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: Clinical data of 43 patients with B-ALL who relapsed after allo-HSCT were retrospectively analyzed. Twenty-two patients were treated with CAR-T cells (CAR-T group), and 21 with chemotherapy plus DLI (chemo-DLI group). The complete remission (CR) and minimal residual disease (MRD)-negative CR rates, leukemia-free survival (LFS) rate, overall survival (OS) rate, and incidence of acute graft-versus-host disease (aGVHD), cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were compared between the two groups. RESULTS: The CR and MRD-negative CR rates in the CAR-T group (77.3% and 61.5%) were significantly higher than those in the chemo-DLI group (38.1% and 23.8%) (P=0.008 and P=0.003). The 1- and 2-year LFS rates in the CAR-T group were superior to those in the chemo-DLI group: 54.5% and 50.0% vs. 9.5% and 4.8% (P=0.0001 and P=0.00004). The 1- and 2-year OS rates in the CAR-T versus chemo-DLI group were 59.1% and 54.5% vs. 19% and 9.5% (P=0.011 and P=0.003). Six patients (28.6%) with grade 2-4 aGVHD were identified in the chemo-DLI group. Two patients (9.1%) in the CAR-T group developed grade 1-2 aGVHD. Nineteen patients (86.4%) developed CRS in the CAR-T group, comprising grade 1-2 CRS in 13 patients (59.1%) and grade 3 CRS in 6 patients (27.3%). Two patients (9.1%) developed grade 1-2 ICANS. CONCLUSION: Donor-derived anti-CD19 CAR-T-cell therapy may be better, safer, and more effective than chemo-DLI for B-ALL patients who relapse after allo-HSCT.

Poor pretransplantation minimal residual disease clearance as an independent prognostic risk factor for survival in myelodysplastic syndrome with excess blasts: A multicenter, retrospective cohort study.

BACKGROUND: Minimal residual disease (MRD) is an important prognostic factor for survival in adults with acute leukemia. The role of pretransplantation MRD status in myelodysplastic syndrome with excess blasts (MDS-EB) is unknown. This study retrospectively analyzed the relationship between pretransplantation MRD status and long-term survival. MATERIALS AND METHODS: Patients with MDS-EB who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) from March 5, 2005, to November 8, 2020, were included. The relationship between pretransplantation MRD status and long-term survival was analyzed using univariate and multivariate logistic regression models. RESULTS: Of 220 patients with MDS-EB who underwent allo-HSCT, 198 were eligible for inclusion in this multicenter, retrospective cohort study. Complete remission was attained in 121 (61.1%) patients, and 103 patients underwent detection of MRD pretransplantation, with 67 patients being MRD-positive and 36 patients being MRD-negative. The median follow-up time was 16 months, the median age was 41 years (6-65 years), and 58% of the patients were men. The 3-year disease-free survival (DFS) and overall survival (OS) probabilities for all patients were 70.1% and 72.9%, respectively. For patients in complete remission, the 3-year DFS and OS probabilities were 72.2% and 74.8%, respectively. Further analysis found that the 3-year DFS rates of MRD-negative and MRD-positive patients were 85.6% and 66.5% (p = .045), respectively, whereas the 3-year OS rates were 91.3% and 66.4% (p = .035), respectively. Univariate and multivariate analyses showed that poor pretransplantation MRD clearance was an independent prognostic risk factor for DFS and OS. CONCLUSION: Poor pretransplantation MRD clearance is an independent prognostic risk factor for long-term survival after allo-HSCT for patients with MDS-EB. PLAIN LANGUAGE SUMMARY: Poor minimal residual disease clearance pretransplanation is an independent prognostic risk factor for long-term survival after allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome with excess blasts.

Developing and validating a mortality prediction model for ICH in ITP: a nationwide representative multicenter study.

Intracranial hemorrhage (ICH) is a rare and life-threatening hemorrhagic event in patients with immune thrombocytopenia (ITP). However, its mortality and related risk factors remain unclear. Herein, we conducted a nationwide multicenter real-world study of ICH in adult ITP patients. According to data from 27 centers in China from 2005 to 2020, the mortality rate from ICH was 33.80% (48/142) in ITP adults. We identified risk factors by logistic univariate and multivariate logistic regression for 30-day mortality in a training cohort of 107 patients as follows: intraparenchymal hemorrhage (IPH), platelet count ≤10 × 109/L at ICH, a combination of serious infections, grade of preceding bleeding events, and Glasgow coma scale (GCS) level on admission. Accordingly, a prognostic model of 30-day mortality was developed based on the regression equation. Then, we evaluated the performance of the prognostic model through a bootstrap procedure for internal validation. Furthermore, an external validation with data from a test cohort with 35 patients from 11 other centers was conducted. The areas under the receiver operating characteristic (ROC) curves for the internal and external validation were 0.954 (95% confidence interval [CI], 0.910-0.998) and 0.942 (95% CI, 0.871-1.014), respectively. Both calibration plots illustrated a high degree of consistency in the estimated and observed risk. In addition, the decision curve analysis showed a considerable net benefit for patients. Thus, an application (47.94.162.105:8080/ich/) was established for users to predict 30-day mortality when ICH occurred in adult patients with ITP.

High-dose Chemotherapy Combined with Autologous Hematopoietic Stem Cell Transplantation as Frontline Therapy for Intermediate/High-risk Diffuse Large B Cell Lymphoma.

The role of autologous hematopoietic stem cell transplantation (auto-HSCT) following high-dose chemotherapy has been validated and accepted as a standard treatment for patients with relapsed diffuse large B-cell lymphoma (DLBCL). However, its clinical efficacy as frontline therapy remains to be elucidated. This study aimed to examine the feasibility of frontline auto-HSCT for newly diagnosed intermediate/high-risk DLBCL patients. We retrospectively reviewed the data of 223 patients treated with frontline auto-HSCT or chemotherapy alone (year 2008-2014) from four hospitals. The median follow-up time was 29.4 months. Between the two treatment arms among the intermediate/high-risk DLBCL patients, the 3-year overall survival (OS) and progression-free survival (PFS) rates of patients given frontline auto-HSCT were 87.6% and 81.9%, respectively, and the chemotherapy-alone group showed 3-year OS and PFS rates of 64.9% and 59.59%, respectively. Compared with the chemotherapy-alone group, the frontline auto-HSCT could eliminate the adverse impact of non-germinal center B-cell (GCB) type. In addition, in the frontline auto-HSCT group, patients who achieved complete response (CR) at auto-HSCT had a longer survival time than those who did not achieve CR. Our results suggested that frontline auto-HSCT could improve the prognosis of intermediate/high-risk DLBCL patients.

[Clinical Efficiency of Rituximab Combined with Autologous Hematopoietic Blood Stem Cell Transplantation for Treatment of CD20+ B non.Hodgkin Lymphoma].

AbstractObjective: To investigate the effeciency of autologous hematopoietic stem cell transplantation (auto.HSCT) combined with rituximab(R) to treat CD20+ B non.Hodgkin lymphoma(B.NHL). METHODS: From January 2005 to December 2013, 83 patients with refractory/recurrent CD20+ B.NHL who were treated with auto.HSCT in our department were enrolled. The patients were divided into 2 groups: 57 patients in Rituximab group, and 26 patients in control group(without Rituximab). All the patients received chemotherapy and auto.HSCT. For the patients in treatment group, Tituximab was used before transplantation of the stem cells, and for some patients Rituximab was used after transplantation. For the patients in control group, the induction, enhancement and transplantation were the same as those in treatment group. The clinical efficiency of the patients in treatment group according to the time and frequency of R was analyzed in subgroups and compared with the control group. The deadline of follow.up was April 30 2014. RESULTS: All the patient achieved complete response. The median follow.up time was 39 months. Both the two groups collected peripheral blood stem cells successfully, and had no difference in hematopoietic reconstitution time. Three patients in treatment group and six patients in control group relapsed and the three year overall survival and EFS in treatment group was significantly higher than that in control group, that is（93.0% vs 73.1%, P=0.037） and （89.5% vs 65.4%, P=0.034）, respectively. Subgroup analysis showed that: compared with the treatment group in which using R in the whole courses(before and after transplantation, and collection of stem cells) was superior to the control group in both OS and EFS, with the OS 97% vs 87.5% (P>0.05) and EFS 97% vs 76.2% (P=0.05) respectively. While stratified by the different courses of rituximab, the OS was 88.9% (1-2 courses, 9 cases), 93.1% (3-4 courses, 29 cases), 94.7%(more than 5 courses,19 cases), and EFS was 77.8%, 89.7% and 94.7%, respectively. CONCLUSION: For the patients with refractory/recurrent CD20+ B.NHL, the combination of R and inducing chemotheraphy, purify in body before transplantation, as well as continue with R after auto.HSCT could obviously improve the OS and EFS of patients. For the patients who with R before and after transplantation, their EFS is better than the patients with R before transplantation only.

Donor-derived CD19 CAR-T cell therapy of relapse of CD19-positive B-ALL post allotransplant.

Safety and efficacy of allogeneic anti-CD19 chimeric antigen receptor T cells (CAR-T cells) in persons with CD19-positive B-cell acute lymphoblastic leukemia (B-ALL) relapsing after an allotransplant remain unclear. Forty-three subjects with B-ALL relapsing post allotransplant received CAR-T cells were analyzed. 34 (79%; 95% confidence interval [CI]: 66, 92%) achieved complete histological remission (CR). Cytokine release syndrome (CRS) occurred in 38 (88%; 78, 98%) and was ≥grade-3 in 7. Two subjects died from multiorgan failure and CRS. Nine subjects (21%; 8, 34%) developed ≤grade-2 immune effector cell-associated neurotoxicity syndrome (ICANS). Two subjects developed ≤grade-2 acute graft-versus-host disease (GvHD). 1-year event-free survival (EFS) and survival was 43% (25, 62%). In 32 subjects with a complete histological remission without a second transplant, 1-year cumulative incidence of relapse was 41% (25, 62%) and 1-year EFS and survival, 59% (37, 81%). Therapy of B-ALL subjects relapsing post transplant with donor-derived CAR-T cells is safe and effective but associated with a high rate of CRS. Outcomes seem comparable to those achieved with alternative therapies but data from a randomized trial are lacking.

Risk stratification and outcomes of intracranial hemorrhage in patients with immune thrombocytopenia under 60 years of age.

Intracranial hemorrhage (ICH) is a devastating complication of immune thrombocytopenia (ITP). However, information on ICH in ITP patients under the age of 60 years is limited, and no predictive tools are available in clinical practice. A total of 93 adult patients with ITP who developed ICH before 60 years of age were retrospectively identified from 2005 to 2019 by 27 centers in China. For each case, 2 controls matched by the time of ITP diagnosis and the duration of ITP were provided by the same center. Multivariate analysis identified head trauma (OR = 3.216, 95%CI 1.296-7.979, P =.012), a platelet count ≤ 15,000/µL at the time of ITP diagnosis (OR = 1.679, 95%CI 1.044-2.698, P =.032) and severe/life-threatening bleeding (severe bleeding vs. mild bleeding, OR = 1.910, 95%CI 1.088-3.353, P =.024; life-threatening bleeding vs. mild bleeding, OR = 2.620, 95%CI 1.360-5.051, P =.004) as independent risk factors for ICH. Intraparenchymal hemorrhage (OR = 5.191, 95%CI 1.717-15.692, P =.004) and a history of severe bleeding (OR = 4.322, 95%CI 1.532-12.198, P =.006) were associated with the 30-day outcome of ICH. These findings may facilitate ICH risk stratification and outcome prediction in patients with ITP.

Successful Treatment of Veno-occlusive Disease, Transplantation-Associated Thrombotic Microangiopathy, and Acute Graft-vs-Host Disease in a Patient with Relapsed Epstein-Barr Hemophagocytic Lymphohistiocytosis After Haploidentical Hematopoietic Stem Cell Transplantation: A Case Report.

BACKGROUND: Allogenic hematopoietic stem cell transplantation may be the best currently available method to treat relapsed hemophagocytic lymphohistiocytosis (HLH) related to Epstein-Barr virus. The high rate of transplantation-related complications was initially the main obstacle preventing the wider adoption of this protocol; however, the previously more common complications, such as infection and graft failure, have fallen to very low levels with the development of new drugs and methods. Some other complications, such as veno-occlusive disease and transplantation associated thrombotic microangiopathy, are rare after allogenic hematopoietic stem cell transplantation, but the morbidity and mortality associated with them are very high. CASE PRESENTATION: A patient with relapsed HLH related to Epstein-Barr virus showed the sequential severe complications of veno-occlusive disease, transplantation-associated thrombotic microangiopathy, and acute graft-vs-host disease after haploidentical transplantation. This patient was successfully treated by stopping administration of calcineurin inhibitors and instead treating with defibrotide, rituximab, CD25 monoclonal antibody, atorvastatin calcium tablets, methylprednisolone, budesonide, continuous plasma exchange, and bedside ultrafiltration. At the last follow-up, the patient had been living disease free for 2 years without any other complications. CONCLUSION: Epstein-Barr virus related-HLH patients have severe clinical features and currently poor prognosis. Allogenic hematopoietic stem cell transplantation may be the best way to treat this disease; however, the management of related complications is vital in the improvement of long-term survival.

Preventive infusion of donor-derived CAR-T cells after haploidentical transplantation: Two cases report.

RATIONALE: Relapse is the main cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, there are no efficient methods to prevent relapse after allo-HSCT. Chimeric antigen receptor T (CAR-T) cells have achieved favorable outcomes in the treatment of refractory/relapsed acute lymphoblastic leukemia (ALL) because of their strong anti-leukemia activity. However, it is unclear whether the CAR-T cells constructed using viral systems can be used as preventive infusions to prevent relapse after haploidentical HSCT. PATIENT CONCERNS: Two patients with ALL with high risk received haploidentical HSCT. DIAGNOSES: Two patients were diagnosed with ALL with high risk. INTERVENTIONS: Patients received preventive infusion of donor-derived CAR-T cells constructed using viral systems on day 60 after haploidentical HSCT. OUTCOMES: The CAR-T cells were continually detected, and no graft versus host disease developed. The two patients survived with disease-free for 1 year and 6 months, respectively. LESSONS: Preventive infusion of donor-derived CAR-T cells after haploidentical HSCT may be safe and that immunosuppressors may not affect the proliferation of CAR-T cells.

Donor-derived CAR-T Cells Serve as a Reduced-intensity Conditioning Regimen for Haploidentical Stem Cell Transplantation in Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia: Case Report and Review of the Literature.

BACKGROUND: Reduced-intensity conditioning (RIC) regimens with low tolerable toxicities have been used for allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the relapse rate by this treatment is high. Treatment of CD19 B-cell relapsed/refractory acute lymphoblastic leukemia (r/r ALL) with allogeneic chimeric antigen receptor-modified T (CAR-T) cells is safe and effective. Use of allogeneic CD19-CAR-T cells as a part of RIC regimens for treatment of r/r ALL patients with haploidentical HSCT has not been investigated yet. CASE PRESENTATION: A 12-year-old girl with CD19 r/r ALL underwent haploidentical HSCT. The patient received fludarabine, busulfan, and cyclophosphamide combined with haploidentical donor-derived CD19-CAR-T cells as the conditioning regimen. Granulocyte colony-stimulating factor-mobilized peripheral blood stem cells and granulocyte colony-stimulating factor-mobilized bone marrow were infused on days 1 and 2, respectively. Mycophenolate mofetil and tacrolimus were administered on day 1, antithymocyte globulin was administered on days +14 and +15, and a short course of methotrexate was administered to prevent graft-versus-host disease. The time of peak CAR-T cell proliferation was detected after the first infusion of CAR-T cells on day 7. The patient's engraftment and full-donor cell engraftment were established. The disease was in complete remission with minimal residual disease, which was undetectable by flow cytometry. No graft-versus-host disease or serious cytokine-release syndrome was found. CONCLUSIONS: Treatment of r/r ALL with RIC including CD19-CAR-T cells followed by allo-HSCT was safe and effective, which suggest that CAR-T cells can be used as a part of RIC regimens in the treatment of r/r ALL in haploidentical HSCT.

Targeting of the leukemia microenvironment by c(RGDfV) overcomes the resistance to chemotherapy in acute myeloid leukemia in biomimetic polystyrene scaffolds.

The bone marrow microenvironment provides a relative sanctuary from cytotoxic drugs for leukemia cells. The present niche models concentrate on a two-dimensional (2D) co-culture system in vitro, which does not imitate the in vivo environment, while the 3D scaffolds are more reflective of this. Osteopontin (Opn) secreted by bone marrow osteoblasts, may participate in protecting leukemia cells from apoptosis by binding to its receptor αvß3, which can be expressed on the surface of the leukemia MV4-11 cell line. However, the association between the Opn/αvß3 axis and leukemia cells is unknown. In the present study, experiments were conducted on 3D polystyrene scaffolds coated with osteoblasts and leukemia cells. The cells were exposed to cyclo(Arg-Gly-Asp-d-Phe-Val) [c(RGDfV)] (35 nmol/ml), which blocks αvß3, for a period of 24 h. Cytarabine was applied 24 h later. The adhesion, migration and apoptosis rates, and the cell cycle of the leukemia cells were analyzed after incubation for 24 and 48 h. In contrast to the 2D culture system, the stromal cells in the scaffolds secreted significantly more alkaline phosphatase and Opn (P<0.05). c(RGDfV) disrupted the adhesion and migration between the tumor cells and the matrix, induced the leukemia cells to leave the protective microenvironment and increased their sensitivity to cell cycle-dependent agents (P<0.05). In summary, the data certified that the 3D scaffolds are suitable for the growth of cells, and that c(RGDfV) inhibits the adhesion and migration abilities of leukemia cells in the endosteal niche. Therefore, blocking the function of Opn may be beneficial in the treatment of acute myeloid leukemia.

AMD3100 and G-CSF disrupt the cross-talk between leukemia cells and the endosteal niche and enhance their sensitivity to chemotherapeutic drugs in biomimetic polystyrene scaffolds.

BACKGROUND: The multidrug resistance of leukemia cells is closely related to the microenvironment. The present leukemia microenvironment models focus on two-dimensional co-culture system in vitro which does not mimic the in vivo cell growth, while the 3D polystyrene (PS) scaffolds have the advantage. Stromal cell derived factor-1 may be involved in the shielding of endosteal niche from leukemia cells by binding to its receptor CXCR4, but the relationship between SDF-1/CXCR4 axis and leukemia cells is unclear. DESIGN AND METHODS: The experiments were built on the 3D PS scaffolds coated with osteoblasts. Stromal cells and MV4-11 cells were plated on the scaffolds. Then G-CSF, AMD3100 and cytarabine were added. Adhesive rate, SDF-1 level, migration state, apoptosis rate, and cell cycle of leukemia cells were observed after incubation at 24h and 48h. RESULTS: G-CSF decreased the level of SDF-1 and inhibited the expression of CXCR4 and promoted stationary phase leukemia cells to enter the mitotic phase and enhanced the killing effect of chemotherapeutic drugs. AMD3100 disrupted the interaction between tumors and matrix, mobilized the leukemia cells to keep away from the protective microenvironment and strengthened the cytotoxic effect of Ara-C. The combination of G-CSF and AMD3100 had stronger effects on killing the leukemia cells induced by Ara-C. CONCLUSION: It demonstrates that AMD3100 and G-CSF may inhibit adhesion and migration abilities of leukemia cells with the bone marrow niche. Both of them inhibit the role of SDF-1/CXCR4 directly or indirectly. Thus inhibiting SDF-1/CXCR4 axis may be helpful to the treatment of refractory AML.

Are there any new insights for G-CSF and/or AMD3100 in chemotherapy of haematological malignants?

AML is a common life-threatening blood system malignancy. The treatment of AML continues to face greater challenges. An abnormal haematopoietic niche with high adhesion and proliferation might be the root cause of resistance and relapse. Most leukaemia cells are stored in the endosteal niche and recess in the G0 phase, and they are not sensitive to varieties of radiotherapies and chemotherapies. G-CSF and AMD3100 are increasingly used in priming chemotherapy. G-CSF can promote leukaemia cells to the cell cycle, which improves the complete remission rate of leukaemia patients. AMD3100, the novel CXCR4 antagonist, could also potentially promote leukaemia cells to cell cycle and improve the susceptibility of leukaemia cells to chemotherapeutic agents. The combination of them enhances anti-leukaemia effect. So in this review, we explore the function of G-CSF and/or AMD3100 in the priming chemotherapy of haematological malignants.

Extramedullary T-lymphoblastic blast crisis in chronic myelogenous leukemia: A case report of successful diagnosis and treatment.

Extramedullary T-lymphoblastic blast crisis of chronic myelogenous leukemia (CML) is uncommon and the prognosis is poor. It was usually misdiagnosed as the co-existence of T-lymphoblastic lymphoma (T-LBL) and CML. In the present study, we report a patient with CML, who developed extramedullary T-lymphoblastic blast crisis and was successfully treated with human leukocyte antigen (HLA)-mismatched stem cell transplantation. The patient was a 44-year-old man who presented with lymphadenectasis and leucocytosis prior to diagnosis. The bone marrow smear, biopsy and fluorescence in situ hybridization (FISH) of Breakpoint Cluster Region/ Abelson murine leukaemia (BCR/ABL) supported the diagnosis of CML in the chronic phase, while the immunohistochemistry of lymph nodes supported the diagnosis of T-LBL. The FISH test for BCR/ABL in lymph node blast cells was performed and the result was positive; therefore, the patient was diagnosed with extramedullary T-lymphoblastic blast crisis of CML. After several courses of combined chemotherapy, the patient was treated with HLA-mismatched stem cell transplantation and obtained continuous remission for 51 months until the present (September 2013).

Is splenectomy necessary for immune thrombocytopenic purpura? The role of rituximab in patients with corticosteroid resistance in a single-center experience.

BACKGROUND: Corticosteroid therapy followed by splenectomy for immune thrombocytopenic purpura (ITP) is the standard practice. Rituximab is mostly used in patients with chronic refractory ITP who have failed multiple previous treatments, including splenectomy. OBJECTIVE: We explored the potential role of rituximab as an early therapeutic option for patients with corticosteroid-resistant ITP who preferred to avoid splenectomy in favor of other treatment. METHODS: Twenty-five patients with corticosteroid-resistant ITP were treated with rituximab between May 1, 2009, and June 30, 2012, at a single center. Rituximab was administered at 100 mg/m(2) on days 7, 14, 21, and 28. The response to rituximab therapy and adverse effects were observed. RESULTS: Complete remission was achieved in 19 patients (76%), partial remission in 3 patients (12%), and minimal response in none of the patients; 1 patient was considered a treatment failure (4%). Two patients (8%) were lost to follow-up. Twenty-two patients (88%) achieved a platelet count >50 × 10(9)/L. The median time from administration of the first rituximab dose to partial remission was 2 months (range, 0.7-3 months) for all the patients. Response classified as sustained was achieved in 21 patients (84%). No serious adverse effects were observed during rituximab therapy. CONCLUSIONS: Rituximab therapy is effective and safe for patients with corticosteroid-resistant ITP before splenectomy, resulting in high complete remission and overall response rates. A multicenter study with a larger sample should be performed to further explore the role of rituximab therapy.

High-dose methotrexate in the mobilization of hematopoietic stem cells for patients with non-Hodgkin's lymphoma: a twelve-year study in a single center.

BACKGROUND: High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is a promising approach for non-Hodgkin's lymphoma (NHL). Higher cell doses have been associated with a faster blood count recovery and a reduction in transfusion requirements, infection rates, and hospitalization times. Mobilization failure constitutes one of the main reasons for avoiding auto-HSCT. The role of high-dose methotrexate (MTX) as mobilization regimen is still unclear. STUDY DESIGN AND METHODS: The effect of high-dose MTX as a mobilization regimen for 67 adult patients with NHL who received auto-HSCT was studied between January 2001 and October 2012. The stem cells were mobilized using combination chemotherapy including MTX plus granulocyte-colony-stimulating factor (G-CSF) in 33 patients (Group A), and the stem cells of the other 34 patients were mobilized using the same combination chemotherapy plus G-CSF without MTX (Group B). RESULTS: All of the patients were successfully mobilized in Group A; however, two patients failed in Group B. The median numbers of CD34+ cells collected were 14.36 × 10(6) and 5.3 × 10(6) cells/kg for Groups A and B, respectively (p < 0.05). All of the patients experienced a stable neutrophil and platelet (PLT) engraftment. The times to white blood cell engraftment were 8.0 days in Group A and 11.0 days in Group B, and the times to PLT engraftment were 12.0 days in Group A and 13.0 days in Group B (p < 0.05 for both variables). CONCLUSION: High-dose MTX is a powerful regimen component for stem cell mobilization in adult patients with NHL.

Features and clinical outcomes in 40 patients with mixed-lineage acute leukemia in a single center.

Mixed-lineage acute leukemia (MAL) is characterized as acute leukemia involving acute myeloid cells and lymphoid cells at the same time. It is easily misdiagnosed because of the dual characteristics involving both lymphoid and myeloid cells and has a poor prognosis. We retrospectively analyzed the features and treatment effectiveness in a single center in 40 patients with MAL. The morphology was consistent with acute lymphoblastic leukemia (ALL) (47.5%) or acute myeloid leukemia (AML) (20%) or was inconclusive (32.5%). Twenty-two patients were characterized as B/myeloid, and 18 patients as T/myeloid. Cytogenetics showed t(9;22)/(Ph(+)) (12.5%) and 11q23/MLL rearrangements (6.25%). The rate of first complete remission for patients undergoing chemotherapy based on the features of both ALL and AML and of either ALL or AML was 71.4 and 42.9%, respectively. The 1-year overall survival rates were 37.5 and 60.0% for chemotherapy and chemotherapy followed by haploidentical hematopoietic stem cell transplantation (HSCT), respectively. The 1-year disease-free survival rates were 25.0 and 50.0% for chemotherapy and chemotherapy followed by HSCT, respectively. These results showed that MAL is confirmed to be a poor-risk disease. The chemotherapy for remission induction should be based on both myeloid cells and lymphoid cells. Transplantation should be performed after the first remission.

Comparison of total body irradiation before and after chemotherapy in pretreatment for hematopoietic stem cell transplantation.

OBJECTIVE: To explore the best time to carry out total body irradiation (TBI) in hematopoietic stem cell transplantation (HSCT) pretreatment. METHODS: Retrospective analysis was applied in 88 cases of HSCT using TBI as pretreatment from March 2001 to June 2009 in our hospital. Using 8 MV X-ray, all the patients were irradiated by linear accelerator in 2 consecutive days, with a total dose of 7-11 Gy and an instantaneous dose rate ranging between 4.0 and 5.0 cGy/min. Of the 88 cases, 40 cases were given traditional high-dose chemotherapy before TBI (Group CT/TBI), and 48 cases were given TBI before chemotherapy (Group TBI/CT) instead. RESULTS: Eighty-seven cases of transplantation were successful, with no serious complications, including radiation pneumonia. Compared with Group CT/TBI, Group TBI/CT showed similar incidence of complications (p=0.08), similar recent chemotherapy toxicity (p=0.833), and significantly lower recent radiation toxicity (p=0.000). CONCLUSIONS: TBI in the pretreatment of HSCT is safe and effective. Using TBI before the high-dose chemotherapy can maintain the same pretreatment effect, effectively reduce apparent immediate reaction/discomfort during TBI, reduce preparation workload of radiotherapy, and lower radiation side-effects. Further research is needed to expand its clinical application.

Factors influencing engraftment in HLA-haploidentical/mismatch related transplantation with combined granulocyte-colony stimulating factor-mobilized peripheral blood and bone marrow for patients with leukemia.

Unmanipulated HLA-haploidentical/mismatch related transplantation with combined granulocyte-colony stimulating factor-mobilized peripheral blood stem cells (G-PBSCs) and granulocyte-colony stimulating factor-mobilized bone marrow (G-BM) has been used as an alternative transplantation strategy for patients without an HLA-matched donor. In this transplantation setting, factors associated with hematopoietic recovery have not been defined completely. The aim of this study was to investigate the factors influencing the engraftment in this transplantation setting for patients with leukemia. The study group comprised 104 patients with leukemia who underwent transplantation at a single institution between 2005 and 2008. Factors correlating with neutrophil and platelet engraftment post-transplantation were analyzed retrospectively. All patients achieved an absolute neutrophil count of 500/µL with a mean time of 13.6days (range 8-20days) and a platelet count over 20×10(9)/L with a mean time of 20.2days (range 16-26days). In univariate analysis, donor and age were associated with increased risk of neutrophil engraftment, but their significance was lost upon multivariate analysis. The sex, age, donor, CD34(+) cell dose, conditioning regimen, mismatched locus, ABO mismatched and diagnosis have no effect on platelet engraftment. Our results suggest that it is an ideal approach to treat patients with leukemia with HLA-haploidentical/mismatched related transplantation with combined G-PBSCs and G-BM for a high level of stem cells without delayed engraftment.

Regulation of acute graft-versus-host disease by human umbilical cord blood derived stromal cells in haploidentical stem cell transplantation in mice through very late activation antigen-4.

Human umbilical cord blood derived stromal cells (hUCBDSCs), a novel resource isolated by our laboratory, have been shown to exert an immunologic regulation. Very late activation antigen-4 (VLA-4) has been associated with graft-versus-host disease (GVHD). This study aimed to investigate the possible mechanism by in vitro co-cultured splenocytes of donor mice with hUCBDSCs and in haploidentical stem cell transplantation in mice with acute GVHD. Both hUCBDSCs and human bone marrow stromal cells (hBMSCs) elicited decreased lymphocyte expression of VLA-4, but this decrease was stronger with hUCBDSCs than with hBMSCs (p<0.05). Cotransplantation of bone marrow with hUCBDSCs significantly decreased the expression of VLA-4 compared with control mice (p<0.05). A significant reduction of VLA-4 labeling in the target organs of GVHD was evident in haploidentical mice cotransplanted with hUCBDSCs. Our study shows that hUCBDSCs may protect mouse recipients of haploidentical stem cell transplantation from aGVHD via downregulating the expression of VLA-4.