Huang Y

Control study of melphalan instead of cyclophosphamide as a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation for treatment of myeloid malignancies

目的 评价以马法兰(Mel)替代改良白消安(Bu)＋环磷酰胺(Cy)(Bu/Cy)方案中Cy的预处理方案在异基因造血干细胞移植(allo-HSCT)治疗恶性髓系血液病中的有效性及安全性。 方法 分析94例进行allo-HSCT的恶性髓系血液病患者临床资料，其中48例采用Bu+Cy＋氟达拉滨(Flu)＋阿糖胞苷(Ara-C)(BCFA)方案预处理，46例采用Bu+Mel+Flu+ Ara-C (BMFA)方案预处理。移植后观察比较两组预处理方案相关不良反应、植入率、移植物抗宿主病(GVHD)、感染发生、非复发死亡(NRM)率以及总生存(OS)率。 结果 两组患者均获得中性粒细胞成功植入。BMFA组Ⅲ~Ⅳ度口腔溃疡以及腹泻发生率均高于BCFA组(P<0.05)，BMFA组急性GVHD(aGVHD)发生率较高，但差异无统计学意义(36.5％对56.5%，P=0.100)。中位随访42个月，BCFA组和BMFA组NRM率分别为12.5％和19.6% (P=0.400)。BMFA组复发率显著低于BCFA组，分别为4.3％和25.0%(P=0.009)。两组OS率分别为(71.8±6.7)％和(76.1±6.3)%(P=0.852)，无病生存(DFS)率分别为(67.8±8.9)％和(76.1±6.3)%(P=0.567)，BCFA组均略低于BMFA组，但差异均无统计学意义。 结论 应用Mel替代Cy的预处理方案治疗恶性髓系血液病复发率较低，并获得较满意的DFS率，但应注意预处理相关毒性的预防及aGVHD的治疗和干预。OBJECTIVE To evaluate melphalan instead of cyclophosphamide in modified busulfancyclophosphamide regimen as a new myeloablative conditioning regimen for the treatment of myeloid malignancies patients receiving allogeneic hematopoietic stem cell transplantation （HSCT）. METHODS The clinic data of 94 myeloid malignancies patients undergoing allogeneic HSCT were analyzed, of which 48 patients received Bu+Cy+Flu+Ara-C, 46 cases Bu+Mel+Flu+Ara-C regimens. Rregimen-related toxicity, engraftment, graft- versus-host disease（GVHD）, infection condition, non- relapse mortality, and overall survival were compared between the two groups. RESULTS All patients achieved neutrophil engraftment. The incidence of grade Ⅲ-Ⅳ oral mucositis and diarrhea in BMFA group was higher than in BCFA group（P<0.05）. The incidence of acute GVHD in BMFA group was also higher than in BCFA group but without statistically significant difference（36.5% over 56.5%, P=0.100）. With a median follow up of 42 months, the incidence of no relapse mortality in BCFA group was 12.5% and 19.6% in BMFA group（P=0.400）. The relapse rate in BMFA group（4.3%）was significantly lower than in BCFA group （25.0%, P=0.009）. The overall survival rates were（71.8±6.7）% and（76.1±6.3）%（P=0.852）, and diseasefree survival rates were（67.8±8.9）% and（76.1±6.3）%（P=0.567）were comparable between BCFA group and BMFA group. CONCLUSION Melphalan instead of cyclophosphamide as a new myeloablative conditioning regimen had lower relapse and satisfied disease-free survival rates, but the risk of regimenrelated toxicity and GVHD should be taken into consideration.

[Outcomes of adults with Ph-negative B-cell acute lymphoblastic leukemia after autologous hematopoietic stem cell transplantation and the significance of minimal residual disease].

目的 探讨自体造血干细胞移植（auto-HSCT）在成人Ph染色体阴性急性B淋巴细胞白血病（B-ALL）中的地位及其预后因素。 方法 回顾性分析1996年1月至2014年2月86例首次行auto-HSCT患者的疗效。 结果 5年总生存（OS）和无病生存（DFS）率分别为（63.8±5.6）％和（60.9±5.6）%，5年累积无复发死亡（NRM）率和复发率分别为（4.70±0.05）％和（34.40±0.31）%。年龄≥35岁、诊断时乳酸脱氢酶水平高、高白细胞起病、首次诱导治疗第15天骨髓原始细胞比例≥5%、第1次完全缓解（CR1）至移植时间间隔>6个月及回输物中CD34+细胞数≥3.8×106/kg均为不良预后因素。且CR1至移植时间间隔>6个月是影响预后的独立不良因素。34例患者具有微小残留病（MRD）检测结果，显示移植前MRD阳性（MRD≥0.01 %）、首次诱导化疗后MRD未转阴或巩固化疗过程中MRD转阳均提示不良预后，且巩固化疗中MRD转阳是影响DFS的独立不良因素。 结论 auto-HSCT联合维持化疗是成人B-ALL治疗的可选方案。由于移植前及化疗过程中MRD阴性结果提示更好的结局，故MRD可能在指导成人B-ALL移植治疗中具有重要意义。OBJECTIVE To better understand predictive factors and role of autologous hematopoietic stem cell transplantation (auto-HSCT)in the post-remission therapy for adult Ph-negative B-cell acute lymphoblastic leukemia (B-ALL)patients. METHODS Outcomes of 86 adult patients with B-ALL who received auto-HSCT in our center from January 1996 to February 2014 were retrospectively analyzed. RESULTS Overall survival (OS)and disease free survival (DFS)at 5 years for the cohort were (63.8 ± 5.6)% and (60.9 ± 5.6)%, respectively. The cumulative non-relapse mortality (NRM)and relapse at 5 years were (4.70 ± 0.05)% and (34.40 ± 0.31)%. For DFS, age ≥ 35 years, high lactate dehydrogenase at diagnosis, high initial WBC count, blast cell proportion ≥ 5% on 15th day of the first induction therapy, complete remession (CR)1 to HSCT interval >6 months and CD34⁺ cells in graft ≥ 3.8 × 10⁶/kg were the poor prognostic factors. CR1 to HSCT interval >6 months was the independently undesirable factors in COX regression model. For 34 patients who had results of minimal residual disease (MRD), positive pretransplantation MRD (MRD≥0.01%), positive post-induction MRD or MRD positive again during the chemotherapy indicated poor prognosis, and the last one was the independent adverse prognostic factor. CONCLUSION Auto-HSCT combined with post-transplantation maintenance chemotherapy could be an optional approach for adult B-ALL patients. MRD plays a significant role in the treatment choice for adult Ph-negative B-ALL patients.

Comparison of outcomes of adult acute lymphoblastic leukemia patients underwent autologous and allogeneic hematopoietic stem cell transplantation

目的 对比分析成人急性淋巴细胞白血病(ALL)自体造血干细胞移植(auto-HSCT)和异基因造血干细胞移植(allo-HSCT)疗效差异。 方法 研究纳入2007年1月至2010年12月进行造血干细胞移植(HSCT)的106例成人ALL患者，其中auto-HSCT 50例，首次完全缓解(CR1)46例，第2次CR(CR2)4例，高危组21例，移植前检测微小残留病(MRD)均阴性；allo-HSCT患者56例，CR151例，CR25例，高危组44例，移植前14例MRD阳性。 结果 106例患者移植后中位随访22.9(0.8~63.3)个月，29例血液学复发。其中auto-HSCT、allo-HSCT患者3年累积复发率(RR)分别为(29.9±8.0)%和（32.7±6.8）%（P=0.402）。标危组患者auto-HSCT和allo-HSCT后RR差异无统计学意义（P=0.554），高危组患者auto-HSCT和allo-HSCT后RR差异亦无统计学意义（P=0.967）。allo-HSCT患者2年累积非复发死亡率(NRM)[(22.3±6.0)%]显著高于auto-HSCT患者(0)(P=0.001)。标危组患者auto-HSCT和allo-HSCT后3年总生存(OS)率分别为（77.1±13.2）%和(90.9±8.7)%（P=0.739）。高危组患者auto-HSCT和allo-HSCT后3年OS率分别为（68.7±10.8）%和(45.2±8.5)%(P=0.094)。 结论 成人ALL患者auto-HSCT和allo-HSCT同样有效，如果患者MRD持续阴性，auto-HSCT可成为allo-HSCT的有效替代治疗手段。OBJECTIVE To compare the outcomes of adult patients with acute lymphoblastic leukemia (ALL) who underwent autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS From Jan 2007 to Dec 2010, 106 adult ALL patients were retrospectively divided into two groups, 50 in auto-HSCT group and 56 in allo-HSCT group. Auto-HSCT group included 21 patients with high-risk, 46 patients in CR1 and 4 cases in CR2. All the 50 patients had negative minimal residual disease (MRD) prior to HSCT. Allo-HSCT group included 44 patients with high risk, 51 patients in CR1 and 5 cases in CR2, 15 patients with positive MRD before allo-HSCT. response, regulatory T cells (Treg), cytokines levels and treatment-related adverse effects were observed. RESULTS Of the total 106 patients, 29 patients relapsed at a medium follow-up of 22.9(0.8-63.3) months. The 3-year cumulative relapse rate (RR) was (29.9±8.0) % in auto-HSCT group and (32.7±6.8) % in allo-HSCT group. There were no significant differences in RR and overall survival (OS) between auto-HSCT and allo-HSCT groups, even of stratified risk groups. In standard risk group, 3-year OS was (77.1±13.2) % in auto-HSCT group and (90.9±8.7) % in allo-HSCT group (P=0.739). In high-risk group, 3-year OS was (68.7±10.8) % after auto-HSCT and (45.2±8.5) % after allo-HSCT (P=0.094). CONCLUSION Due to acceptable RR and OS, adult ALL patients with no MRD before HSCT showed favorable survival. Auto-HSCT may be a considerable choice for adult ALL patients with negative MRD when lacking of donors for allo-HSCT.

[IL-18 single nucleotide polymorphisms in hematologic malignancies with HLA matched sibling donor allogeneic hematopoietic stem cell transplantation].

OBJECTIVE To explore the impact of interleukin-18 (IL-18) single nucleotide polymorphisms on outcomes of hematologic malignancies with HLA-matched sibling donor hematopoietic stem cell transplantation (allo-HSCT). METHODS Single- nucleotide polymorphisms in IL-18 promoter was detected by PCR-sequence-specific primer analysis (PCR-SSP) in 93 recipients and their HLA matched sibling donors. Hematopoietic reconstitution, incidences of graft versus host disease (GVHD) and infections, transplant related mortality (TRM), and disease free survival (DFS) were analyzed. RESULTS In comparison with -137 G/C+C/C donor genotype, patients with -137 G/G donor genotype had shorter duration of neutrophil recovery [15(11-23) days vs 17(11-24) days, P=0.01], higher incidence of extensive chronic GVHD (20.6% vs 3.3%, P=0.029), but no difference in the interval of platelet recovery [20(11-46) days vs 20(7-38) days, P=0.844]. The incidence of extensive chronic GVHD in -607 C/C donor genotype (31.6%) was significantly higher than that (10.8%) in C/A + A/A donor genotype (P=0.024). Recipients with -607 C/C genotype also had higher incidence (33.3%) of extensive chronic GVHD than those with C/A+A/A genotype (10.7%, P=0.016). There were no differences in acute GVHD, TRM, and DFS between different genotypes. CONCLUSION IL-18 -137 G homozygous genotype in donor facilitated neutrophil reconstitution, but increased the risk of extensive chronic GVHD in patients with allo-HSCT.

Outcome analysis of alternative donor allogeneic hematopoietic cell transplantation in the treatment of 19 severe aplastic anemia patients

OBJECTIVE To evaluate the efficacy of alternative donor allogeneic hematopoietic stem cell transplantation (AD allo-HSCT) in the treatment of severe aplastic anemia (SAA). METHODS Retrospective analysis of the clinical data of 19 SAA patients received AD allo-HSCT from May 2003 to December 2012. Of them, 12 received haploidentical HSCT (haplo-HSCT), 7 received unrelated donor transplantation. The conditioning regimen was CY+ATG+Flu±Ara-C±Bu/Mel, the GVHD preventing regimen was MMF+MTX+CSA/FK506; the median reinfusion quantity of CD34+ was 3.10(2.11-4.38)×10⁶/kg in allo-BMT and 4.90(2.08-6.88)×10⁶/kg in allo-PBSCT. RESULTS Hematopoiesis reconstitution was achieved in all 19 patients. Twelve patients developed acute graft-versus-host disease (aGVHD), and 7 developed chronic GVHD (cGVHD). Graft rejection (GR) was occurred in one patient. The median follow-up time was 13(3-115) months. Thirteen patients survived, and the prospective 5-year overall survival rate is (67.5±11.0)%. CONCLUSION AD allo-HSCT can be used as an alternative therapy for SAA patients without HLA matched sibling donor.

[Analyses of risk factors for intestinal acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation].

OBJECTIVE To investigate the risk factors of intestinal acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS The clinical data of 534 cases of 533 patients undergoing allo-HSCT during Jan 2004 and Sep 2012 were retrospectively analyzed. The effects of donor-recipient HLA mismatching, recipient age, donor age, donor-recipient sex combination, donor-recipient relationship, HSC source, conditioning regimen with or without total body irradiation (TBI) and HLA loci on intestinal aGVHD with different severity were analyzed by Logistic regression. RESULTS Intestinal aGVHD occurred in 123(23.0%) cases, with 86(16.1%) cases of stage 1 intestinal aGVHD(16.1%) and 37(6.9%) cases of stage 2 to 4 intestinal aGVHD. Multivariate analysis showed that donor-recipient HLA mismatching (OR=2.519, P=0.002), increasing donor age (OR=1.034, P=0.003), female donor for male recipient (OR=1.855, P=0.007) were risk factors for intestinal aGVHD, HLA-B38 (OR=0.256, P=0.032) was its protective factor. Donor-recipient HLA mismatching (OR=2.799, P=0.011), increasing donor age (OR=1.045, P=0.012), HLA-A1 (OR=4.157, P=0.002), A30 (OR=3.143, P=0.005) were risk factors for stage 2 to 4 intestinal aGVHD. CONCLUSION Occurrence of intestinal aGVHD and its severity are associated with donor-recipient HLA mismatching, donor age, donor-recipient sex relationships and some HLA loci.

[Prophylaxis of invasive fungal infection with different administration regimens of itraconazole in patients with acute myeloid leukemia: a report from a randomized, controlled trial].

OBJECTIVE To evaluate the efficacy and safety of antifungal prophylaxis of itraconazole in patients with acute myeloid leukemia (AML) to probe the relationship of the antifungal effect and the adverse events with serum concentration. METHODS From April 2009 to May 2011, a total of 310 courses from 112 patients referred to our institute were enrolled in this study; of them, 297 courses were eligible for analysis. Eligible cases were randomized into oral group and injection/oral group according to different chemotherapy of induction and consolidation. Blood samples were collected at different time points for measurements of serum itraconazole levels. The morbidity of IFI and the adverse events were analyzed. RESULTS The morbidities of IFI in injection/oral and oral groups were 10.1% and 20.9%, respectively (P=0.010). 7 and 9 cases in injection/oral and oral groups, respectively were withdrawn from the study because of adverse events, and the difference between these two groups was of no significance. Serum itraconazole levels of injection/oral and oral groups were 672(299-1097) μg/L and 534(210-936) μg/L, respectively (P<0.01). CONCLUSION Antifungal prophylaxis with itraconazole in AML patients was effective and safe. Prophylactic effect with injection/oral itraconazole was superior to oral itraconazole solution; moreover, prophylactic effect of itraconazole was highly correlated with its serum level.