Health-related quality of life in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation

Reduced-intensity conditioning allogeneic HSCT (RIC) has less regimen-related morbidity and mortality than myeloablative allogeneic HSCT (MT) offering allogeneic transplantation to patients otherwise excluded. Whether these advantages improve health-related quality of life (HRQL) is unknown. We examined the HRQL effects of RIC and MT in patients with hematological diseases pre-transplant (baseline), days 0, 30, 100, 1 and 2 years following HSCT. HRQL was measured using the Short Form-36 Health Survey and the Functional Assessment of Cancer Therapy - General and BMT. Data were analyzed using mixed linear modeling adjusting for baseline HRQL differences. Patients (RIC=41, MT=35) were predominately male (67%), in remission/stable disease (65%) with an Eastern Cooperative Oncology Group status 相似文献   

更昔洛韦胶囊在造血干细胞移植患者巨细胞病毒血症中的应用

目的 探讨更昔洛韦(ganciclovir,DHPG)胶囊治疗造血干细胞移植(HSCT)后患者巨细胞病毒(CMV)血症的疗效和安全性.方法 选择2006年2月至5月在北京大学血液病研究所行HSCT的30例移植后CMV血症患者进行前瞻性研究.CMV感染预防采用更昔洛韦10 mg/(kg·d),分2次静脉滴注,移植前第9天至移植前第2天,连续8 d.移植后应用定量多聚酶链反应(PCR)定期进行病毒DNA检测,CMV-DNA定量＞6.0×102拷贝/mL或＜1×105拷贝/mL的患者应用更昔洛韦胶囊1 g每日3次治疗.结果 HSCT后发生CMV血症的中位时间为移植后42 d,诊断时CMV-DNA中位数4.626×103拷贝/mL.更昔洛韦胶囊治疗的总有效率为90%,14 d转阴率66.67%,转阴中位时间10 d.4例(13.3%)出现不良事件,程度为轻至中度,表现为血细胞计数减少3例,转氨酶升高1例.结论 更昔洛韦胶囊用于治疗HSCT后CMV血症患者安全有效.     

Treosulfan-based conditioning regimen for allogeneic haematopoietic stem cell transplantation in patients with thalassaemia major

The safety and efficacy of a preparation with treosulfan/thiotepa/fludarabine were explored in 20 thalassaemia patients given allogeneic marrow transplantation. Seventeen patients were transplanted from unrelated donors after receiving anti-thymocyte globulin. The regimen was well tolerated. Two patients experienced secondary graft failure; one died of acute graft-versus-host disease. Cumulative incidence (95% confidence interval, CI) of transplantation-related mortality and graft failure was 5% (95% CI, 0-34%) and 11% (95% CI, 3-43%), respectively. Two-year probability of survival and thalassaemia-free survival was 95% (95% CI, 85-100%) and 85% (95% CI, 66-100%), respectively. This regimen might find elective application in patients at high risk of developing life-threatening complications.     

Fludarabine-based conditioning for allogeneic stem cell transplantation for multiply transfused patients with Fanconi's anemia

A fludarabine-based protocol (fludarabine (25 mg/m(2)/day x 6 days), cyclophosphamide (10 mg/kg/day x 2 days) and ATG (ATGAM 10 mg/kg/day x 4 days)) was used in four multiply transfused Fanconi's anemia (FA) patients aged 5-15 years to reduce rejection during allogeneic bone marrow transplantation (BMT). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mini methotrexate. The graft source was G-CSF-stimulated bone marrow or peripheral blood stem cells (PBSC) in two patients each. All patients engrafted with median time to ANC>500/mm(3) being 14 days (range: 12-17) and unsupported platelet count >20 ,000/mm(3) being 13 days (range: 11-18). One patient had secondary graft rejection on day 56 and expired on day 69 due to fungal pneumonia. One patient who developed acute myeloid leukemia on day 56 underwent successful induction with cytosine and daunorubicin followed by peripheral blood stem cell (PBSC) rescue on day 70 and is presently in remission with complete donor chimerism and grade I GVHD. At a median follow-up of 13 months (range: 4-21), three patients (75%) are well with complete donor chimerism. Addition of fludarabine to the conditioning regimen for BMT in FA can provide additional immunosuppression for engraftment without increasing toxicity.     

Non-overt disseminated intravascular coagulation in patients during treatment with antithymocyte globulin for unrelated allogeneic hematopoietic stem cell transplantation

We assessed the effect of rabbit antithymocyte globulin manufactured by Fresenius (ATG-F) on the hemostatic system in patients (n=12) with various hematological malignancies undergoing hematopoietic stem cell transplantation (HSCT) from HLA-matched unrelated donors. For this purpose, we monitored different parameters of coagulation before, during and after the administration of ATG-F. As a control group, we recruited patients (n=10) undergoing HSCT from their HLA-identical siblings who did not receive ATG-F as part of their preparative regimens. At 24 and 48 h after ATG-F treatment had been initiated, we found a temporary rise in D-Dimer, tissue factor, soluble thrombomodulin and thrombin-antithrombin III complex levels and a significant decrease of platelet counts in patients treated with ATG-F as compared to the control group. No differences between the two groups could be detected with regard to global coagulation tests as well as the incidence of bleeding manifestations, thromboembolic complications or the development of vascular-occlusive-disease of the liver. This temporary state of a stressed but compensated coagulation system under ATG-F therapy can be addressed as nonovert disseminated intravascular coagulation (DIC). The effect was independent from the different conditioning regimens and eased off after cessation of ATG-F. We conclude that ATG-F can induce nonovert DIC in patients receiving antithymocyte globulin as part of their conditioning regimen for HSCT.     

Double lumen port access in patients receiving allogeneic blood stem cell transplantation.

We performed a prospective trial investigating the feasibility of a double lumen port access in 26 patients with hematological malignancies or solid tumors receiving either standard conditioning (n = 9, median age 49 years (range 19-65)) or dose-reduced conditioning (n = 17, median age 56 years (range 35-66)) followed by allogeneic blood stem cell transplantation. The port system was implanted within 3 months (n = 20, range 7-91 days) before transplantation or as indicated at different time points after transplantation (n = 6, range 28-680 days). Most infusions, including the graft itself and all blood drawings, were performed via the port. Over a cumulative duration of 5622 days (1310 days after standard conditioning (range 56-349) and 4431 days after dose-reduced conditioning (range 49-489)) two port systems of patients receiving standard conditioning were removed due to early postimplantation pocket infection on day 6 and 8 after insertion, respectively. In the dose-reduced conditioning group only one late removal (day 287) of a port was required. Most of the patients in both groups reported less pain and a higher degree of comfort compared to peripheral or central venipuncture. The use of double lumen port access during conditioning and in an outpatient setting after allogeneic hemopoietic stem cell transplantation is feasible and advantageous for both patient and medical staff. Implantation several weeks before the start of conditioning might help in avoiding early infectious complications after conventional myeloablative conditioning.     

Platelet flow cytometric findings in patients undergoing conditioning therapy for allogeneic hematopoietic stem cell transplantation

The conditioning regimen preceding hematopoietic stem cell transplantation (HSCT) causes a rapid decrease in the platelet count and signs of disseminated intravascular coagulation, possibly indicating platelet activation. As impacts during the conditioning regimen may predict later transplantation-associated complications, we investigated changes in platelet membrane glycoproteins (GP) and the liberation of microparticles. Platelet receptors and granules of 49 patients undergoing HSCT were evaluated by flow cytometric analysis before and after the different phases of the conditioning regimen [chemotherapy, total body irradiation (TBI), therapy with antithymocyte globulin (ATG)] and final transplantation. Following chemotherapy a high surface expression of CD62P, a low mepacrine staining, and a reduced surface expression of CD42b (part of the GP Ib/V/IX complex) were found, indicating an irreversible activation of platelets. In addition, elevated levels of circulating microparticles were observed, which may reinforce the thrombosis risk in these patients. Treatment with ATG leads to an elevated surface expression of PAC-1 epitopes, which are neoepitopes appearing after activation of GP IIb/IIIa. However, a significant degranulation was not detectable, which may be the consequence of inhibitory influences on platelets during ATG-induced cytokine release syndrome. TBI and transplantation itself had no influence on platelets. This study was able to demonstrate activating effects on platelets by certain phases of the conditioning regimen in patients receiving HSCT. Chemotherapy, in particular, leads to a strong and irreversible platelet activation and a generation of microparticles, which may cause an increased thrombosis risk. Our findings underline the impact of platelets on the pathogenesis of hemostatic complications during HSCT.     

Conventional versus reduced-intensity conditioning regimen for allogeneic stem cell transplantation in patients with hematological malignancies

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA)-compatible sibling donors is a potential curative treatment for hematological and non-hematological malignancies. Nevertheless, high mortality rates may be associated with this therapy, especially in older patients, those with other comorbidities or who receive a second HSCT. PATIENTS AND METHODS: We analyzed the factors associated with transplant-related mortality (TRM) and overall survival in 157 consecutive adult patients (104 males and 53 females) who received a HSCT [29 bone marrow (BM) transplantation and 128 peripheral blood (PB) transplantation] from a HLA-identical sibling between January 1995 and March 2002 in our institution. One hundred patients received a standard conditioning prior to HSCT (STAND) and 57 patients received a reduced-intensity conditioning (RIC) HSCT. Fifty-eight patients were in an early phase at transplant and 99 in a non-early phase. Median age was 46 yr (16-66), and 90 patients (57%) were >45 yr of age. RESULTS: Patients in the RIC group were older than those in the STAND group, and had a higher proportion of non-early disease phases including a prior autologous HSCT in 39%. Median follow-up for survivors was 28 and 15 months in the STAND and RIC groups (P < 0,001), respectively. Cumulative incidence of TRM at 2 yr was 30% [95% confidence interval (CI) 22-41%] for the STAND group and 22% (95% CI 13-37%) for the RIC group [non-significant (NS)]. Factors associated with a higher TRM in multivariate analysis were: STAND vs. RIC conditioning regimen [relative risk (RR) 5.4; 95% CI 2.3-12.8; P < 0.001]; age > or =45 yr vs. <45 yr (RR 5; 95% CI 2.4-10.8, P < 0.001); second vs. first HSCT (RR 2.8, 95% CI 1.3-6.3, P = 0.01) and non-T-cell-depleted vs. T-cell-depleted graft (RR 2.7, 95% CI 1.3-5.8, P = 0.009). Overall survival (OS) at 2 yr was 52.5 +/- 10.4% for STAND group and 59 +/- 16.8% in RIC group. Factors associated with poorer OS in multivariate analysis were: STAND vs. RIC conditioning regimen (RR 3.4, 95% CI 1.7-6.9, P = 0.001); age > or =45 vs <45 yr (RR 2.5, 95% CI 1.4-4.5, P = 0.002) and diagnosis [other than chronic myeloid leukemia (CML) vs. CML] (RR 2.6, 95% CI 1.2-5.7 P = 0.02). CONCLUSIONS: Our results indicate that the introduction of RIC allogeneic HSCT for patients at high risk for TRM (advanced age, prior HSCT and non-T-cell depletion) leads to a reduction in the TRM and improvement in the OS.     

Cataracts in patients receiving stem cell transplantation after conditioning with total body irradiation

One hundred and ninety-three patients with hematological malignancies and a follow-up > or =1 year, treated with stem cell transplantation (45 autologous, 99 allogeneic T cell-depleted matched, 49 allogeneic T cell-depleted mismatched) from July 1985 to May 1998, were considered evaluable for the development of cataracts. Total body irradiation (TBI), administered either according to a hyperfractionated scheme (HTBI) or in a single dose (STBI), was employed in the conditioning regimens. HTBI was prescribed in 94% of patients undergoing allogeneic matched transplant, while STBI was used in 71% of patients receiving allogeneic mismatched and in all patients undergoing autologous transplant. The median follow-up was 7.56 years in the HTBI and 3.02 years in the STBI group. Among the different risk factors analyzed by univariate analysis only the TBI scheme and type of transplant reached statistical significance (P < 0.0001 and P < 0.001, respectively). By multivariate analysis only the TBI scheme was an independent factor for cataract development (STBI vs HTBI RR 7.2; P < 0.01). Our results showed that STBI is more cataractogenic than HTBI. The incidence of cataract we observed was among the lowest described in the literature. T cell depletion, because it prevents graft-versus-host disease and reduces the protracted use of post-transplant steroids, explains the results we obtained.     

Tecelac as antithymocyte globulin in conditioning for childhood allogeneic stem cell transplantation

Antithymocyte globulin (ATG) preparations in allogeneic stem cell transplantation are used in various conditioning regimens both to prevent graft rejection and reduce the incidence and severity of graft-versus-host disease. Tecelac (RATG) is a highly purified ATG preparation with high specific activity. The high specific antibody content implies the need for lower doses, with reduced side-effects in comparison to other ATGs. Here, we report on the first 10 patients worldwide who received RATG as part of conditioning. Patients were heterogeneous with regard to diagnoses and graft characteristics. RATG was given in cases of matched unrelated donors, mismatched family donors, reduced conditioning, or high risk for graft failure. Mostly mild allergic reactions toward RATG were seen. All of the patients engrafted in due time. Two died within 2 months of transplant of pulmonary complications not related to RATG. Two developed GVHD grade I, no chronic GVHD was seen to date. Viremia occurred in two, with no viral disease developed. Of the eight patients surviving, one suffered relapse of acute leukemia, one shows impending graft failure. The others are well. Using RATG in conditioning is feasible.     

改良BU/CY预处理方案行异基因造血干细胞移植治疗恶性血液病的临床研究

异基因造血干细胞移植(Allo-HSCT)是目前治疗恶性血液病的有效方法,致力于提高植入率和无病存活率,降低移植相关毒性及移植相关病死率,其预处理方案的优化设计是造血干细胞移植的重点.现将我院应用改良BU/CY预处理方案治疗恶性血液病的临床及长期观察情况报道如如下.     

Pure red cell aplasia after allogeneic stem cell transplantation with reduced conditioning

Conditioning regimens with reduced intensity are used increasingly for allogeneic stem cell transplantation in elderly or extensively pretreated patients. Two cases of pure red cell aplasia after fludarabine-based conditioning and during immunosuppression with cyclosporin are described. Both patients received ABO-mismatched stem cells and had anti-donor isoagglutinins. Red cell recovery occurred after extended immunosuppression when isoagglutinins had disappeared. Colony assays indicated serologic suppression of the erythrocyte lineage in one patient. Since reduced conditioning permits donor cell engraftment primarily by suppression of host T cells, antibody-mediated immunological complications may occur more frequently than after 'classical' conditioning.     

Multilineage hematopoietic engraftment after allogeneic peripheral blood stem cell transplantation without conditioning in SCID patients

Successful stem cell transplantation for patients with severe combined immunodeficiency (SCID) from matched family donors without conditioning results in engraftment of T lymphocytes. B lymphocytes engraft in only 50% of the cases, while myelopoiesis and erythropoiesis remain of host origin. Full hematopoietic engraftment was reported in one case after bone marrow transplantation without conditioning for a SCID patient. We studied three SCID patients who were transplanted with unmodified mobilized peripheral blood from HLA-identical family sex-mismatched members. They received megadoses of stem cells (18-23 x 10(6)CD34/kg). In contrast to the expected mixed chimerism that usually occurs in the absence of conditioning, we found in our patients 100% donor cell engraftment based on fluorescence in situ hybridization (FISH) and microsatellite techniques. Subset analysis of the engrafted cells using a multiparametric system enabling a combined analysis of morphology, immunophenotyping and FISH showed that both T and B lymphocytes and myeloid cells were of donor origin in two patients, while T lymphocytes and myeloid cells were of donor origin in the third. In the two cases with ABO incompatibility, erythroid engraftment was evidenced by blood group conversion from recipient to donor type. Multilineage donor engraftment is possible in SCID patients even without conditioning.     

Reduced-toxicity conditioning prior to allogeneic stem cell transplantation improves outcome in patients with myeloid malignancies

The introduction of reduced intensity/toxicity conditioning regimens has allowed allogeneic hematopoietic cell transplantation to be performed in patients who were previously considered too old or otherwise unfit. Although it led to a reduction in non-relapse mortality, disease control remains a major challenge. We studied the outcome of 165 patients with acute myeloid leukemia (n=124) or myelodysplastic syndrome (n=41) transplanted after conditioning with fludarabine (30 mg/m²/day for 5 days), intravenous busulfan (either 260 mg/m²: reduced intensity conditioning, or 390–520 mg/m²: reduced toxicity conditioning), and rabbit anti-thymoglobulin (2.5 mg/kg/day for 2 days). The median age of the patients at transplantation was 56.8 years. The 2-year relapse incidence was 29% (23% versus 39% for patients transplanted in first complete remission and those transplanted beyond first complete remission, respectively; P=0.008). The 2-year progression-free survival rate was 57% (95% CI: 49.9–65). It was higher in the groups with favorable or intermediate cytogenetics than in the group with unfavorable cytogenetics (72.7%, 60.5%, and 45.7%, respectively; P=0.03). The cumulative incidence of grades 2–4 and 3–4 acute graft-versus-host disease at day 100 was 19.3% and 7.9%, respectively. The cumulative incidence of chronic graft-versus-host disease at 1 year was 21.6% (severe forms: 7.8%). Non-relapse mortality at 1 year reached 11%. The 2-year overall survival rate was 61.8% (95% CI: 54.8–69.7). Unfavorable karyotype and disease status beyond first complete remission were associated with a poorer survival. This well-tolerated conditioning platform can lead to long-term disease control and offers possibilities of modulation according to disease stage or further development.     

伊曲康唑在异基因造血干细胞移植患者真菌感染中的应用

目的观察伊曲康唑治疗异基因造血干细胞移植患者的真菌感染的疗效。方法2002年10月至2005年10月诊断真菌感染的患者75例,其中确定诊断4例,临床诊断22例,拟诊49例。全部病例均于诊断后给予伊曲康唑注射液治疗,125～200mg／次,第1、2天给予2次／d,以后1次／d,病情稳定后改为口服胶囊或口服液治疗。结果总有效率为76．0％（57／75）;确诊病例3例有效（3／4）、临床诊断病例有效率为81．8％（18／22）、拟诊病例为73．5％（36／49）。临床诊断病例和拟诊病例的疗效之间差异无统计学意义（P=0．446）。结论伊曲康唑治疗异基因造血干细胞移植患者的真菌感染是有效的。     

Intravenous busulphan for conditioning before autologous or allogeneic human blood stem cell transplantation

This study was undertaken to evaluate the toxicity and pharmacokinetics of a dimethyl sulphoxide (DMSO)-based intravenous formulation of busulphan in the conditioning of 45 patients undergoing allogeneic or autologous stem cell transplantation (SCT). Busulphan was given as a single daily dose. In 15 patients a single dose of intravenous busulphan, given over 3 h in 1 d, was combined with additional oral (single daily) doses. Thirty patients received all four daily doses intravenously. Busulphan plasma levels were analysed using high performance liquid chromatography. There was no major acute toxicity with daily intravenous doses of 2.8-3.1 mg/kg infused over 3 h. No veno-occlusive disease (VOD) was seen in 30 patients receiving busulphan as an intravenous formulation over 4 d. In the group of 15 patients receiving three oral doses and one intravenous single daily dose, one patient experienced mild VOD. Pharmacokinetic samples were taken over at least 2 d of treatment in 44 patients. The area under the concentration time curve (AUC) values normalized for a dose of 1 mg/kg were 7000 ng/ml x h on d 1 and 5890 ng/ml x h on d 4, thus showing a moderate decrease over time. This was accompanied by a moderate increase of the clearance from 2.6 to 3.0 ml/min/kg. Administration of busulphan as a DMSO-based intravenous formulation was well tolerated. The total dose of busulphan can be given in four (rather than the typical 16) doses. With such a regimen, the intravenous administration becomes feasible on an outpatient basis.