造血干细胞移植预处理中静脉马利兰的应用

背景：马利兰常用于骨髓或外周血干细胞移植预处理,其主要在肝脏代谢。 目的：评价静脉应用马利兰预处理在造血干细胞移植治疗恶性血液病中的有效性及安全性。 方法：纳入43例患者预处理方案采用静脉剂型马利兰,观察其造血干细胞移植预处理中马利兰治疗相关毒性(肝脏、神经系统、口腔黏膜炎)造血干细胞植活时间、急性移植物抗宿主病、总生存率、白血病复发情况。 结果与结论：静脉应用马利兰后,谷丙转氨酶升高72%(31/43),发生不典型肝静脉闭塞综合征5%(2/43),有1例发生双手麻木。口腔黏膜炎发生率60%(26/43)。中性粒细胞植活时间16 d,血小板植活时间12 d,2例自体造血干细胞移植患者血小板延迟植活。Ⅰ~Ⅱ度急性移植物抗宿主病发生63%(24/38)。总生存率72%(31/43)。复发率23%(10/43)。提示造血干细胞移植预处理方案中应用静脉马利兰给药,患者耐受性好,方法安全有效。     

Improved outcomes in intermediate- and high-risk aggressive non-Hodgkin lymphoma after autologous hematopoietic stem cell transplantation substituting intravenous for oral busulfan in a busulfan, cyclophosphamide, and etoposide preparative regimen.

Forty-nine patients with intermediate- and high-risk aggressive non-Hodgkin lymphoma underwent autologous hematopoietic stem cell transplantation (autoHSCT) using the regimen of busulfan (Bu), cyclophosphamide (Cy), and etoposide (E) that was originally developed for allogeneic HSCT. Eighteen patients treated before 1999 received Cy 2.5 g/m2 on days -3 to -2 and E 1800 mg/m2 on day -3 after oral (PO) administration of Bu 1 mg/kg every 6 hours x 4 days for a total of 16 doses beginning on day -7. After April 1999, 31 patients similar in all pretransplantation risk assessments received the same regimen except that intravenous (IV) Bu was substituted for PO Bu and pharmacokinetic-directed (PKD) dosing was attempted to achieve an area under the concentration time curve of 1000-1500 micromol/min for each dose. Nonrelapse mortality was 28% for PO Bu patients versus 3% for the IV PKD group (P = .01, chi-square test). Actuarial 5-year overall survivals were 28% for patients who received the PO Bu regimen and 58% for patients who received the IV Bu regimen (P = .010, log-rank test), and progression-free survivals were 17% and 50%, respectively (P = .008, log-rank test). After substitution of PKD IV Bu in the BuCyE regimen, we observed lower nonrelapse mortality with increased overall and progression-free survivals in patients with intermediate- and high-risk aggressive non-Hodgkin lymphoma who underwent autoHSCT.     

非清髓性异基因造血干细胞移植预处理方案的毒性比较

背景：选择高效低毒的预处理方案是提高造血干细胞移植成功率的关键。氟达拉滨和抗胸腺细胞球蛋白,均属于强效免疫抑制剂,常用于非清髓性造血干细胞移植预处理中。 目的：对采用氟达拉滨或抗胸腺细胞球蛋白为基础的非清髓性异基因造血干细胞移植预处理方案患者,在预处理中及移植后早期毒性进行比较。 方法：32例血液系统恶性肿瘤患者中,按照非清髓性预处理方案中的免疫抑制剂分成两组即氟达拉滨组和抗胸腺细胞球蛋白组,预处理方案均为氟达拉滨或抗胸腺细胞球蛋白联合减低化疗强度的白消安/环磷酰胺,或者马法兰。抗胸腺细胞球蛋白组在形成混合性嵌合体后进行供者淋巴细胞输注。对两组患者预处理中出现的器官毒性进行统计学分析,毒性分级参照Bearman等制订的预处理相关毒性(RRT)分级标准。 结果与结论：两组无因预处理相关毒性而死亡。氟达拉滨组转氨酶发生率、腹泻发生率与和抗胸腺细胞球蛋白组比较差异均无显著性意义(P > 0.05);氟达拉滨组肝脏毒性发生率、黏膜炎发生率均显著低于抗胸腺细胞球蛋白组(P < 0.05);血液学毒性方面,氟达拉滨组白细胞达最低值、血小板≥50×109 L-1的时间、输注红细胞量、输注血小板的量均低于抗胸腺细胞球蛋白组(P < 0.05)。     

Iron overload manifesting as apparent exacerbation of hepatic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Iron overload presenting as exacerbation of hepatic graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation has not been previously described. We report 6 patients with established hepatic GVHD in whom iron overload (median serum ferritin, 7231 mug/dL; median transferrin saturation, 77%) resulting from a lifetime median of 20 units of packed red blood cell transfusions was manifested by worsening of liver function. Liver biopsies performed in 4 patients confirmed severe iron overload and also hepatic GVHD. Analysis for the C282Y and H63D hemochromatosis gene mutation was negative for the homozygous state in all 6 patients. Erythropoietin-assisted phlebotomy resulted in normalization of liver function at a median of 7 months and of serum ferritin at a median of 11 months. Immunosuppressive therapy was successfully tapered in all 4 patients who completed the phlebotomy program, and this supported the impression that iron overload, rather than GVHD, was the principal cause of liver dysfunction. At a median follow-up of 50 months (range, 18-76 months) from the transplantation and 25 months (range, 5-36 months) from ferritin normalization, all 4 patients require maintenance phlebotomy. We conclude that iron overload can mimic GVHD exacerbation, thus resulting in unnecessary continuation or intensification of immunosuppressive therapy for GVHD, and that maintenance phlebotomy is necessary after successful iron-reduction therapy.     

Cyclophosphamide following targeted oral busulfan as conditioning for hematopoietic cell transplantation: pharmacokinetics, liver toxicity, and mortality.

The pharmacokinetics of cyclophosphamide (CY) and its metabolites hydroxycyclophosphamide and carboxyethylphosphoramide mustard were determined in 75 patients receiving targeted oral busulfan followed by i.v. CY ((T)BU/CY) and in 147 patients receiving i.v. CY followed by total body irradiation (CY/TBI) in preparation for hematopoietic cell transplantation (HCT). In the (T)BU/CY patients only, the association of the pharmacokinetic data with liver toxicity, relapse, and survival was evaluated. CY was infused at 60 mg/kg/day over 1 or 2 hours on 2 consecutive days; the majority of patients had BU levels targeted to a steady state plasma concentration (Css) of 800-900 ng/mL. Systemic exposure (i.e., area under the concentration-time curve [AUC]) of CY, hydroxycyclophosphamide, and carboxyethylphosphoramide mustard was measured. Liver toxicity was assessed as the development of hepatic sinusoidal obstruction syndrome (SOS). CY metabolism was highly variable and age dependent. (T)BU/CY-treated patients had lower AUC(CY) (P < .0001), higher AUC(HCY) (P < .0001), and higher AUC(CEPM) (P = .15) than CY/TBI-conditioned patients. Among patients receiving (T)BU/CY, 17 (23%) developed SOS, and there were no statistically significant associations between the AUC of CY or its metabolites and SOS, nonrelapse mortality, relapse, or survival (all P >.15). In conclusion, CY exhibits conditioning-regimen dependent pharmacokinetics and pharmacodynamics, suggesting that lowering CY doses is unlikely to improve outcomes to (T)BU/CY. Alternative strategies, such as administering i.v. busulfan or CY before BU, should be explored.     

Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy.

Reduced conditioning intensity has extended the option of allogeneic hematopoietic stem cell transplantation to patients who cannot tolerate fully myeloablative regimens. However, relapse and graft-versus-host disease (GVHD) continue to be major causes of morbidity and mortality. We prospectively tested whether a moderate reduction of the intensity of the preparative regimen would lead to significant reduction in regimen-related toxicity without compromising tumor control in a cohort of 44 patients ineligible for conventional hematopoietic stem cell transplantation. Patients were conditioned with fludarabine, busulfan, mycophenolate, and total lymphoid irradiation. Tacrolimus and methotrexate were given as prophylaxis for GVHD. Donors were 5 of 6 or 6 of 6 matched family members. The median age was 61 years. Eleven patients had comorbid conditions that precluded conventional myeloablative transplantation. Fatal regimen-related organ toxicity occurred in 3 patients. The cumulative incidence of grade 2 to 4 or grade 3 to 4 acute GVHD by day 100 was 38% (95% confidence interval [CI] = 25%, 55%) and 20% (95% CI = 10%, 39%), respectively, with a median time to onset of 66 days. For the entire cohort, 1-year overall survival, disease-free survival, and relapse rates were 54% (95% CI = 41%, 71%), 47% (95% CI = 35%, 65%), and 37% (95% CI = 19%, 51%), respectively. Outcomes differed based on stage of disease at time of transplantation, advanced (n = 19) versus nonadvanced (n = 25). Median survival times were 138 days and 685 days for subjects with advanced and nonadvanced disease, respectively (P =.005). After adjusting for age and comorbidity, disease stage continued to be significantly associated with overall survival (P =.005). In conclusion, a moderate reduction in conditioning dose intensity resulted in delayed onset of acute GVHD (compared with historical controls). A reduction in conditioning intensity is associated with poor survival for patients with advanced-stage disease, highlighting the importance of the conditioning regimen for tumor control.     

Interleukin 12 is associated with reduced relapse without increased incidence of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Interleukin (IL)-12 has antitumor effects in murine studies. To evaluate this clinically, we investigated whether high levels of circulating IL-12 in patients after allogeneic hematopoietic stem cell transplantation (HSCT) are associated with improved relapse-free survival. We prospectively studied 134 patients undergoing HSCT. Median follow-up was 1158 days (range, 70-1792 days). Plasma IL-12 levels were measured before transplantation and on days 0, +4, +7, and +14 after transplantation. The highest levels were seen on days +4 and +7 and were categorized by a cluster analysis of the logarithmically transformed IL-12 concentrations, which were then correlated with relapse-free survival. Forty-six patients had low levels of IL-12 (median, 2 pg/mL; range, 0-6.5 pg/mL), 49 patients had medium levels (median, 20.5 pg/mL; range, 7-75.5 pg/mL), and 25 patients had high levels (median, 181 pg/mL; range, 84-623 pg/mL). Patients with high IL-12 levels before transplantation had the highest increase after transplantation. With a multivariate Cox model for relapse onset, with the low IL-12 level as the reference, patients in the high-IL-12 group had an adjusted hazard ratio of 0.27 (95% confidence interval, 0.09-0.79), and medium group patients had a hazard ratio of 0.65 (95% confidence interval, 0.31-1.36). The incidences of relapse at 500 days by Kaplan-Meier analysis by IL-12 group were 23.0% (high group), 40.3% (medium group), and 48.8% (low group). There was no association between IL-12 levels and the risk of acute graft-versus-host disease (GVHD; P = .51) or chronic GVHD (P = .28). In conclusion, high IL-12 levels after HSCT are associated with improved relapse-free survival without increasing the risk for GVHD. Patients with high pretransplantation IL-12 levels have an increased likelihood of higher posttransplantation IL-12 levels, possibly because of a host-graft interaction, and this may predispose to better clinical outcomes.     

HLA-DRB1*09 is associated with increased incidence of cytomegalovirus infection and disease after allogeneic hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) infection is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT); however, we have little information on the clinical association of various human leukocyte antigen (HLA) alleles with CMV infection. We reviewed medical records of 60 patients who underwent allo-HSCT. The effect of the 7 most frequent HLA alleles on the incidence of CMV infection and disease was analyzed, including HLA-A*02, A*11, A*24, B*13, B*40(60), DRB1*15, and DRB1*09. All the patients were monitored for CMV infection at least once weekly within 3 months. CMV infection was found in 38 (63.3%) patients on a median of day 36 (range: 16-89). Diagnosis of CMV disease was established in 6 (10.0%) patients, comprising pneumonia (n = 2), enterocolitis (n = 2), and hemorrhagic cystitis (n = 2). CMV disease was successfully treated using ganciclovir or foscarnet combined with immune globulins in 4 patients. The other 2 patients died without improvement of CMV disease. In multivariate analysis, grade II-IV acute graft-versus-host disease (aGVHD), CMV seronegative donors, and HLA-DRB1*09 were associated with increased incidence of CMV infection and disease after allo-HSCT. We suggest that more cautions should be taken to prevent CMV infection in patients with HLA-DRB1*09 after allo-HSCT.     

Comparison of itraconazole,voriconazole, and posaconazole as oral antifungal prophylaxis in pediatric patients following allogeneic hematopoietic stem cell transplantation

Oral antifungal prophylaxis with extended-spectra azoles is widely used in pediatric patients after allogeneic hematopoietic stem cell transplantation (HSCT), while controlled studies for oral antifungal prophylaxis after bone marrow transplantation in children are not available. This survey analyzed patients who had received either itraconazole, voriconazole, or posaconazole. We focused on the safety, feasibility, and initial data of efficacy in a cohort of pediatric patients and adolescents after high-dose chemotherapy and HSCT. Fifty consecutive pediatric patients received itraconazole, 50 received voriconazole, and 50 pediatric patients received posaconazole after HSCT as oral antifungal prophylaxis. The observation period lasted from the start of oral prophylactic treatment with itraconazole, voriconazole, or posaconazole until two weeks after terminating the oral antifungal prophylaxis. No incidences of proven or probable invasive mycosis were observed during itraconazole, voriconazole, or posaconazole treatment. A total of five possible invasive fungal infections occurred, two in the itraconazole group (4 %) and three in the voriconazole group (6 %). The percentage of patients with adverse events potentially related to clinical drugs were 14 % in the voriconazole group, 12 % in the itraconazole group, and 8 % in the posaconazole group. Itraconazole, voriconazole, and posaconazole showed comparable efficacy as antifungal prophylaxis in pediatric patients after allogeneic HSCT.     

A study of a reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation for patients with hematologic malignancies using Campath-1H as part of a graft-versus-host disease strategy.

Nonmyeloablative transplantation (NMT) is intended to be less toxic than traditional allografts, but such regimens as fludarabine/melphalan still pose a significant risk of graft-versus-host disease (GVHD). We used Campath-1H in an attempt to reduce the risk of GVHD in NMT. Patients with hematologic malignancies suitable for allogeneic transplantation underwent transplantation using a regimen of fludarabine 30 mg/m(2) on days -5 to -2 (total, 120 mg/m(2)), total body irradiation of 200 cGy on day -1, and Campath-1H 20 mg/day on days -7 to -3 (total dose, 100 mg). After loss of graft in 5 of the first 6 patients, the protocol was amended by decreasing the Campath-1H dose to 20 mg on days -4 and -3 and 10 mg on day -2 (total dose, 50 mg) for all subsequent patients. GVHD prophylaxis consisted of only cyclosporine, due to the immunosuppressive effect of Campath-1H. Patients received prophylactic acyclovir, fluconazole, and a quinolone. Other requirements included creatinine clearance > or = 25 mL/min, diffusing capacity > or = 45% of predicted, and cardiac ejection fraction > or = 40%. Twenty-five patients with hematologic malignancies entered the study. The median age was 40 years (range, 26-71 years). Median time to engraftment (defined as a neutrophil count of 500 mm(3) and a platelet count of 20,000 mm(3) without platelet support on at least 2 days) was 19 days (range, 9-32 days). All patients who were treated after the amendment engrafted with 90%-100% donor cells by day 100 except for 2 early deaths. Acute GVHD developed in 40% of the patients. Patients who underwent related transplants developed GVHD after donor lymphocyte infusions for poor engraftment or relapse whereas those undergoing unrelated transplants developed GVHD de novo. Two patients (8%) developed chronic GVHD, and 48% had cytomegalovirus reactivation, which was easily managed medically. Nonrelapse mortality within the first 12 months was 12%; 32% of the patients survived at a median of 269 days. We conclude that Campath-1H, fludarabine, and melphalan is a reasonable preparative regimen for reduced-intensity transplantation with a low nonrelapse mortality, but that issues of GVHD remain problematic, due to either the use of donor lymphocyte infusions or the use of volunteer unrelated donors.     

Non‐specific interstitial pneumonia as a manifestation of graft‐versus‐host disease following pediatric allogeneic hematopoietic stem cell transplantation

Bronchiolitis obliterans (BO) is generally believed to be a marker of pulmonary manifestation of graft‐versus‐host disease (GVHD) in patients who have undergone bone marrow transplantation for hematological malignancy. Pulmonary manifestations reported as GVHD (other than BO) include lymphocytic bronchiolitis with cellular interstitial pneumonia, lymphoid interstitial pneumonia, veno‐occlusive disease, and diffuse alveolar damage. Morphological reactions in the lungs of bone marrow transplant recipients associated with interstitial pneumonia have not been described systematically. Reported herein is a fibrosing non‐specific interstitial pneumonia (NSIP) pattern together with BO in both lungs in an 8‐year‐old girl following a second allogeneic hematopoietic stem cell transplantation for relapsed neuroblastoma of adrenal origin. The course was complicated by bilateral pneumothoraces, and the patient underwent lung transplantation 3 years after the second stem cell transplantation. Because the patient had chronic GVHD of the skin and the liver preceeded by the development of pulmonary involvement, NSIP may represent one of the facets of pulmonary GVHD.     

A Phase I study of gemtuzumab ozogamicin (GO) in combination with busulfan and cyclophosphamide (Bu/Cy) and allogeneic stem cell transplantation in children with poor-risk CD33+ AML: a new targeted immunochemotherapy myeloablative conditioning (MAC) regimen

Children with high-risk acute myelogenous leukemia (AML) (induction failure [IF], refractory relapse [RR], third complete remission [CR3]) have dismal outcomes. Over 80% of AML patients express CD33, a target of gemtuzumab ozogamicin (GO). GO is an active drug in childhood AML but has not been studied in a myeloablative conditioning regimen. We sought to determine the safety of GO in combination with busulfan/cyclophosphamide (Bu/Cy) conditioning before allogeneic hematopoietic stem cell transplantation (alloSCT). GO was administered on day -14 at doses of 3.0, 4.5, 6.0, and 7.5 mg/m(2), busulfan on days -7, -6, -5, -4 (12.8-16.0 mg/kg), and cyclophosphamide on days -3 and -2 (60 mg/kg/day). GVHD prophylaxis consisted of tacrolimus and mycophenolate mofetil. We enrolled 12 patients: 8 IF, 3 RR, 1 CR3; median age: 3 years (1-17); median follow-up: 1379 days (939-2305). Nine received umbilical cord blood (UCB), 2 matched unrelated donors (MUDs) and 1 HLA-matched sibling donor: 3 patients each at GO doses of 3.0, 4.5, 6.0, or 7.5 mg/m(2). No dose-limiting toxicities secondary to GO were observed. Day 100 treatment-related mortality (TRM) was 0%. Myeloid and platelet engraftment was observed in 92% and 75% of patients at median day 22 (12-40) and 42 (21-164), respectively. Median day +30 donor chimerism was 99% (85%-100%). The probability of grade II-IV acute graft-versus-host disease (aGVHD) was 42% and chronic GVHD (cGVHD) was 28%. One-year overall survival (OS) and event-free survival (EFS) was 50% (95% confidence interval [CI], 20.8-73.6). GO combined with Bu/Cy regimen followed by alloSCT is well tolerated in children with poor-risk AML. GO at 7.5 mg/m(2) in combination with Bu/Cy is currently being tested in a phase II study.