Huiying Qiu

Partially Matched Related Hematopoietic Stem Cell Transplantation without Ex Vivo T Cell Depletion Compared with Matched Unrelated Transplantation in Adult Patients with Hematologic Malignancies

The optimal alternative donor for adult hematopoietic stem cell transplantation (HSCT) candidates who lack an ideal histocompatible sibling remains controversial. We studied the clinical outcomes of 88 adult patients with hematologic malignancies who received a partially matched related donor (PMRD) transplant (n=36) or a matched unrelated donor (MUD) transplant (n=52) with a uniform myeloablative protocol without ex vivo T cell depletion. Age and other characteristics were comparable in the 2 groups, except that the PMRD group had a higher proportion of bone marrow (BM) grafts. Primary engraftment was achieved in nearly 98% of the whole cohort. The incidences of acute grade III-IV and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 15% and 16% in the PMRD group and 16% and 14% in the MUD group. Although treatment-related mortality (TRM) was 42% in the PMRD group and 31% in the MUD group (P=.29), the relapse rate was<11% for the whole cohort. With a median follow-up of 30 months, no statistically significant difference was observed in 3-year overall survival (OS) and event-free survival (EFS) between the PMRD group (45% and 38%) and the MUD group (54% and 50%). These data demonstrate that HSCT performed with PMRD can be an alternative option for treating adult patients with hematologic malignancies.

Outcomes of CAG Regimen for Refractory Biphenotypic Acute Leukemia Patients

OBJECTIVE To evaluated the efficiency of low-dose cytosine arabinoside plus aclarubicin with concurrent administration of granulocyte colony-stimulating factor (CAG) regimen for refractory biphenotypic acute leukemia (BAL). METHODS We treated 5 refractory BAL patients by CAG regimen (10 mg x m(-2) cytosine arabinoside subcutaneously administrated every 12 hours, day 1-14; 5-7 mg x m(-2) aclarubicin intravenously administrated daily, day 1-8; and concurrently used 200 microg x m(-2) x d(-1) granulocyte colony-stimulating factor subcutaneously) from November 2002 to April 2007. The efficacy of the regimen was evaluated by response rate, and the side effects were also measured. RESULTS The complete remission rate was 80%, median duration of absolute neutrophil count < 5.0 x 10(8)/L and platelet count < 2.0 x 10(10)/L was day 13 and day 1, respectively; and the infection rate was low (III-IV infection rate, 20.00%). CONCLUSION CAG regimen as remission induction chemotherapy for BAL patients is effective with a high remission rate and low toxicity.

Successful treatment of a patient with acquired haemophilia A with a combination of a low-dose rituximab and recombinant human FVIIa.

Acquired haemophilia A (AHA) is a rare bleeding disorder with a high potential for severe bleeding and an inhibitor-related mortality rate of 7.9–22%, which might be associated with pregnancy, autoimmune diseases, malignancy, infections or medication and occurs most commonly in the elderly. Effective treatment of actual bleeding episodes and eradication of Factor VII inhibitor are the two important aspects in treatment [1]. Here, we present an AHA case that was successfully treated with a combination of low-dose rituximab and recombinant human FVII a (rh FVIIa). A 58-years-old man was admitted for intramuscular bleeding. Lab tests showed a prolonged activated partial thromboplastin time (APTT) of 93.2 s, FVIII level less than 1% and FVIII inhibitor titre of 21.8 BU. No evidence of malignancy, tuberculosis or autoimmune disorders was found. The patient did not take any new drug before admission. Moreover, an acquired von Willebrand’s disease was excluded with normal vWF:Ag and vWF:Rco. Mixture of the patient’s plasma with normal control plasma did not correct the prolonged APTT. Based on clinical manifestation and lab tests, AHA was diagnosed. Intramuscular bleeding progressed with rapid fall of haemoglobin. Fresh plasma, human FVIII and prothrombin complex concentrates injection did not alleviate bleeding. Bleeding was resolved following infusion with rh FVIIa (90 lg kg 1 3 h 1 9 8 times). Prednisone (0.8 mg kg 1 day ) and Cyclophosphamide (CTX) (0.4 g 4 days 1 9 4 times) was given on day 1 while the FVIII remained less than 1% and the FVIII inhibitor titre >14 BU for the next 2 weeks. Low dose of rituximab (100 mg week 1 9 4 weeks) was administrated on day 11, and the antibodies were progressively decreased and finally disappeared on day 21. Oral Cyclosporine (250 mg day ) plus prednisone (0.5 mg kg 1 day ) were given outside hospital and serum level of CSA (150– 250 ng mL ) was monitored to avoid side effect. With 7 months follow-up, the patient showed no antibodies and normal FVIII (range 60–98%) with oral cyclosporine (100 mg day ). (Fig. 1). AHA occurs as a result of auto-antibodies against coagulation factor VIII (FVIII) which neutralize its procoagulant function and lead to life-threatening bleeding. Approximately 50% of the patients are idiopathic with no known underlying pathological conditions. Clinical manifestations include spontaneous haemorrhages into the skin, muscles or soft tissues or excessive bleeding during surgery. The diagnosis of AHA is based on the isolated prolongation of APTT which is not normalized after the addition of normal plasma along with reduced FVIII levels. Early therapy directed towards achieving haemostasis and inhibitor eradication can be life saving [2]. Acute bleeding episodes in patients with low-titre auto-antibodies can be treated with plasma-derived or recombinant human FVIII. However, by-passing activated prothrombin complex or recombinant human FVIIa is recommended for patients with high-titre auto-antibodies [3]. Initiating recommended rh FVIIa dose was 90– 120 lg kg 1 and repeated every second or third hour in serious bleedings. In this case, rapid haemostatic effect was achieved following rh FVIIa (90 lg kg 1 3 h 1 9 8) injection. Patients with AHA should undergo immediate inhibitor eradication to restore normal haemostasis. Prednisone with or without CTX is generally the treatment of choice, while the reported median time to response is lengthy [4]. For the patients with an up-regulated inhibitor level and serious bleeding could receive rituximab in combination with prednisone and it was reported that rituximab has been used as first line or salvage therapy with durable response rates of up to 84% and rapid onset of action with minimal toxicity [3,5]. In this case, rituximab induced durable remissions and was of particular benefit as the patient was refractory to conventional immunosuppressant therapy. However, the doses and the duration of rituximab treatment in patients with AHA remain still unclear. Wermke M et al. reported that 100 mg rituximab could achieve complete B-cell depletion and suggested that low-dose regimen rather than the classical lymphoma-dose (e.g. 375 mg m ) in the treatment

The value of monitoring minimal residual disease in the patients with donor lymphocyte infusion as intervention of relapsed/refractory acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation

Treatment of acute lymphoblastic leukemia (ALL) has achieved significant progress, however the long-term disease free survival (DFS) of adult ALL patients still does not exceed 20%38% [1-3]. Allogeneic HSCT (allo-HSCT) has been proved to be the most effective treatment for a variety of hematologic malignancies, but the benefits were limited [4]. Although donor lymphocyte infusion (DLI) could restore complete remission (CR) in many patients after transplantation, patients received prophylactic DLI with the risk of fatal graft versus host disease (GVHD). Monitoring minimal residual disease (MRD) allowed for the early detection of trance amount of tumor cells in ALL patients[56]. Whereas, the value of monitoring MRD in relapsed/refractory ALL patients with DLI as intervention after allo-HSCT remains to be evaluated. In this investigation, we reported monitoring MRD in 47 cases of relapsed/refractory ALL after allo-HSCT for 43 months in median and observed that among them 19 patients with a high risk for disease relapse after allo-HSCT were treated with DLI under the guidance of monitoring MRD. Notably, 6 among the 19 cases had no leukemic progression after DLI, suggesting that MRD monitoring has a value in the treatment of relapsed/refractory ALL patients using DLI as intervention after allo-HSCT.

Prognostic analysis of DLBCL patients and the role of upfront ASCT in high-intermediate and high-risk patients

The role of autologous stem cell transplantation (ASCT) as a frontline treatment in patients with diffuse large B cell lymphoma (DLBCL) who are in their first remission has not been fully elucidated in the rituximab era. We analyzed 272 DLBCL patients who received 4–6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) or R-CHOP followed by ASCT, from January 2005 to June 2013 in our institution. Multivariate analysis showed the none germinal center B cell (non-GCB) subtype (P=0.014, P=0.012) and International Prognostic Index (IPI) (3–5) (P=0.004, P=0.016) were independent unfavorable predictors of overall survival (OS) and progression-free survival (PFS), respectively. To investigate the treatment effect of upfront ASCT, we selected 94 high-intermediate and high-risk DLBCL patients who achieved complete remission after R-CHOP, with 41 in the ASCT and 53 in the non-ASCT groups. Survival analysis revealed patients who received upfront ASCT compared with those who did not had better OS (3-year OS: 74.5% vs. 50.4%, P=0.029) or PFS (3-year PFS: 59.6% vs. 32.1%, P=0.004), suggesting up-front ASCT following R-CHOP could improve the outcome of high-intermediate and high-risk DLBCL patients.The role of autologous stem cell transplantation (ASCT) as a frontline treatment in patients with diffuse large B cell lymphoma (DLBCL) who are in their first remission has not been fully elucidated in the rituximab era. We analyzed 272 DLBCL patients who received 4-6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) or R-CHOP followed by ASCT, from January 2005 to June 2013 in our institution. Multivariate analysis showed the none germinal center B cell (non-GCB) subtype (P=0.014, P=0.012) and International Prognostic Index (IPI) (3-5) (P=0.004, P=0.016) were independent unfavorable predictors of overall survival (OS) and progression-free survival (PFS), respectively. To investigate the treatment effect of upfront ASCT, we selected 94 high-intermediate and high-risk DLBCL patients who achieved complete remission after R-CHOP, with 41 in the ASCT and 53 in the non-ASCT groups. Survival analysis revealed patients who received upfront ASCT compared with those who did not had better OS (3-year OS: 74.5% vs. 50.4%, P=0.029) or PFS (3-year PFS: 59.6% vs. 32.1%, P=0.004), suggesting up-front ASCT following R-CHOP could improve the outcome of high-intermediate and high-risk DLBCL patients.

High Tim-3 expression on AML blasts could enhance chemotherapy sensitivity

T-cell immunoglobulin and mucin domain-containing molecule3 (Tim-3) represents a novel mechanism of T-cell dysfunction and exhaustion. Tim-3 has also been identified in various solid tumors. However, the role of Tim-3 expression on blast cells in acute myeloid leukemia (AML) is not well understood. In this study, we aimed to explore the role of Tim-3 in patients with de novo AML, and the correlation between Tim-3 and clinicopathological prognosis. The study cohort consisted of 76 patients with de novo non-M3 AML. These patients’ bone marrow samples were collected and then bone marrow mononuclear cells (BMCs) were isolated for flow cytometry to detect Tim-3 expression on blasts. According to FAB type, 76 diagnosed AML patients included in this study were: M0 (n=2), M1 (n=16), M2 (n=20), M4 (n=20), M5 (n=16), and M6 (n=2). A positive expression (>20%) of Tim-3 was found in 87% (66/76) of patients with AML. The average percentage of Tim-3(+) blasts in these AML patients was 58.26 ± 29.23%. Moreover, the frequency of Tim-3 high expression was higher in M4 patients than that in other AML patients according to FAB type (P=0.004). Tim-3 high expression was also closely associated with inv(16) (P=0.01) and C/EBPA mutation (P=0.03). The mutations of the following six genes, i.e., FLT3-ITD, NPM1, C-KIT, IDH1/IDH2, DNMT3A, were independent of the Tim-3 expression. Additionally, it is more likely to find higher levels of Tim-3 in the low-risk group than in the intermediate- and high-risk groups (P=0.02). The expression of Tim-3 was positively correlated with CD13 (r=0.36, P=0.001), CD34 (r=0.41, P=0.000), and CD7 (r=0.27, P=0.02) in AML patients. AML patients with high Tim-3 expression achieved significantly high complete remission (CR) rate (P=0.01), while their Tim-3 expression significantly decreased after CR (P=0.01). Blockade of Tim-3 expression on AML blasts significantly reduced the Idarubicin (IDA)-mediated suppression of cell growth and reduction of cell apoptosis in vitro. Collectively, our study suggests that high Tim-3 expression on AML blasts could enhances chemotherapy sensitivity.