The stem cell mobilizing capacity of patients with acute myeloid leukemia in complete remission correlates with relapse risk: results of the EORTC-GIMEMA AML-10 trial.

Variable numbers of CD34+ cells can be harvested from the blood of AML patients in CR after G-CSF supported mobilization following consolidation chemotherapy. We hypothesized that a decreased ability to mobilize stem cells reflects a chemotherapy-induced reduction in the number of normal and leukemic stem cells. We therefore analyzed whether the mobilizing capacity of these patients was of prognostic significance. 342 AML-patients in first CR received daily G-CSF from day 20 of the consolidation course and underwent 1-6 aphereses to obtain a minimum dose of 2 x 10(6) CD34+ cells/kg. Afterwards they were randomized for autologous bone marrow (BM) or blood SCT. As a surrogate marker for the mobilizing capacity, the highest yield of CD34+ cells of a single apheresis was adopted. Patients could be categorized into four groups: no harvest (n = 76), low yield (<1 x 10(6) CD34+/kg; n = 50), intermediate yield (1-6.9 x 10(6) CD34+ cells/kg; n = 128) and high yield (> or = 7 x 10(6) CD34+ cells/kg; n = 88). The median follow-up was 3.4 years; 163 relapses and 16 deaths in CR were reported. Autologous blood or BM SCT was performed in 36%, 64%, 81% and 88%, respectively, of the patients assigned to the no harvest, low, intermediate and high CD34+ yield group. The 3-year disease-free survival rate was 46.7%, 65.0%, 50.4% and 26.9% (P = 0.0002) and the relapse incidence was 47.5%, 30.1%, 43.1% and 71.9% (P < 0.0001). Multivariate Cox's proportional hazards model showed that the CD34+ yield was the most important independent prognostic variable (P = 0.005) after cytogenetics. Patients with the highest mobilizing capacity have a poor prognosis due to an increased relapse incidence.     

Patterns and outcome of relapse after autologous stem cell transplantation for mantle cell lymphoma

BACKGROUND:

Autologous stem cell transplantation (autoSCT) has improved the outcome of patients with mantle cell lymphoma (MCL) considerably. However, little is known about the patterns and outcome of MCL recurrence after autoSCT.

METHODS:

The authors conducted a retrospective study of 118 patients with MCL who underwent autoSCT from August 1992 to August 2008 at 3 different referral centers in Germany.

RESULTS:

Fifty‐two relapses occurred for a cumulative incidence of 46% after 5 years. Only 3 patients relapsed after 5 years (at 90 months, 91 months, and 171 months) after undergoing autoSCT. A Cox regression analysis of the incidence of relapse identified not receiving rituximab before autoSCT and undergoing salvage autoSCT as predictive factors for relapse, whereas cytosine arabinoside intensification; a total body irradiation‐based, high‐dose regimen; patient age; and year of transplantation had no influence. The median overall survival (OS) after relapse was 23 months. Twenty patients (39%) underwent allogeneic stem cell transplantation (alloSCT) for relapse, and 11 of those patients remained in ongoing complete remission at the time of the current report. It is noteworthy that there were 4 long‐term survivors who lived for >5 years after relapse even without undergoing alloSCT. A Cox regression analysis of OS after relapse revealed that the response duration after autoSCT was an adverse predictor of OS, whereas alloSCT was associated with a significantly longer OS after relapse.

CONCLUSIONS:

The current results indicated that autoSCT was capable of inducing long‐term remission up to 16 years after treatment, but the outcome of patients with MCL who relapsed after autoSCT was poor, especially if their response duration after autoSCT was short. However, for a subset of patients with relapsed MCL, alloSCT may offer the possibility of durable survival, and individual patients can enjoy long‐term survival after relapse even without undergoing alloSCT. Cancer 2011. © 2010 American Cancer Society.     

自体外周血干细胞移植患者粒细胞缺乏期并发感染的临床分析

目的:综合分析肿瘤患者经自体外周血干细胞移植(APBSCT)治疗后出现粒细胞缺乏伴感染发热的特点、危险因素及预后。方法:对89例进行APBSCT治疗的患者进行回顾性调查研究,收集其粒细胞缺乏期的相关临床资料并分析其感染情况。结果:89例行APBSCT治疗患者均在干细胞回输后4d(0～15d)出现粒细胞缺乏,持续时间6d(3～27d)。粒细胞缺乏期感染发生率为78.7%(70/89),发热中位时间为3d(1～20d),无感染相关性死亡。发热患者使用抗生素治疗,其中44例(66.7%)初始治疗有效。34例(38.2%)患者的预防性抗感染用药中含抗真菌药物,但其中仍有25例(73.5%)出现发热。结论:感染是APBSCT粒细胞缺乏期主要并发症,粒细胞缺乏时间是感染的高危因素,预防性应用抗真菌药物未能降低感染发生率,早期、足量广谱抗生素治疗效果良好。     

Poor mobilization of peripheral blood stem cells is a risk factor for worse outcome in lymphoma patients undergoing autologous stem cell transplantation

The effect of poor blood stem cells mobilization on the outcome of autologous stem cell transplantation (ASCT) has not been well studied. Our aim is to evaluate poor mobilization as a prognostic factor in lymphoma patients undergoing ASCT. We analyzed 90 consecutive patients with Hodgkin's (HD) and non-Hodgkin's lymphoma (NHL) who underwent ASCT. Poor mobilization was defined as the inability to obtain > or = 1 x 10(6) CD34+ cells/kg ideal body weight with two large volume aphereses. Patients were divided into 2 groups: group 1 = poor mobilizers, and group 2 = good mobilizers. The poor mobilizers received lower median transplant CD34+ cell dose (2 x 10(6) vs. 4.5 x 10(6)/kg for good mobilizers, P = 0.001), were more heavily pretreated (P = 0.01), and required higher number of aphereses for PBSC collection (P = 0.0006). The median progression-free survival (PFS) in groups 1 and 2 was 10 and 41 months (P = 0.04), while the median overall survival (OS) was 38 months and not reached (P = 0.02), respectively. Univariate analysis showed that > or = 3 pre-transplant treatments, CD34+ cell dose < or = 2 x 10(6), elevated LDH before transplant, and poor mobilization were significant prognostic factors for poor PFS, while only the first three were significant for worse OS. Multivariate analysis using these same four factors revealed that number of pre-transplant treatments (HR = 6.03, P = 0.001), CD34+ cell dose (HR = 0.1, P = 0.0007) were the only independent predictive factors for worse overall outcome. In conclusion, our data show that poor mobilization could indicate poor outcome in lymphoma patients undergoing ASCT, however, it is more likely to be a reflection of the heavy pre-transplant therapy and lower CD34+ cell dose re-infused in this group of patients.     

Re-infused autologous graft natural killer cells correlates with absolute lymphocyte count recovery after autologous stem cell transplantation

Early absolute lymphocyte count (ALC) has been reported to be a powerful prognostic indicator of survival after autologous stem cell transplantation (ASCT). One possible source affecting ALC recovery includes the re-infused autologous graft lymphocytes (AGL). To assess if the re-infused AGL correlate with ALC recovery post-ASCT, we conducted a pilot study to identify which of the re-infused AGL subsets is most associated with day 15 ALC recovery in three patients with multiple myeloma and four patients with non-Hodgkin's lymphoma. Using the Spearman rank correlation coefficient analysis ( r ), we compared absolute numbers of CD3, CD4, CD8, CD19, and CD16+/CD56+ cells/kg of body weight from the apheresis product with ALC (cells/ μl) at day 15 post-ASCT. The main lymphocyte subsets identified in the apheresis product were T cells and NK cells. There was no strong correlation between T or B cells from the apheresis product compared with the ALC at day 15 post-ASCT (CD3, r =0.21; CD4, r =0.32; CD8, r =0.39; and CD19, r =0.14 ). However, there was good correlation between NK cells from the apheresis product compared with ALC at day 15 post-ASCT (CD16+/CD56+/CD3 -, r =0.77 ). These data provide preliminary evidence that the number of re-infused autologous graft NK cells in the apheresis product significantly affect ALC recovery early post-ASCT. However, given the small sample size, our results are primarily hypothesis generating and subject of further research.     

Intra-cerebral relapse following prolonged remission after autologous stem cell transplantation for multiple myeloma

Central nervous system (CNS) myeloma is a rare phenomenon, especially so after high-dose therapy (HDT) and stem cell transplantation. We describe a case of isolated CNS relapse of myeloma post autologous transplantation that followed a prolonged progression-free interval. Issues regarding the pathophysiology and management of this unusual complication are discussed.     

急性白血病患者异基因造血干细胞移植术后复发危险因素分析

目的 探讨急性白血病(AL)患者异基因造血干细胞移植(allo-HSCT)术后复发危险因素.方法 回顾性分析郑州大学第一附属医院造血干细胞移植中心自2003年12月至2013年12月行allo-HSCT的157例AL患者的临床资料,应用Cox回归法分析受者年龄、性别、疾病类型、初诊白细胞计数、诱导疗程数、人类白细胞抗原(HLA)配型、急性移植物抗宿主病(aGVHD)、慢性移植物抗宿主病(cGVHD)、移植物来源、巨细胞病毒(CMV)感染与移植后复发的关系.结果 157例患者中32例在移植后24个月内复发.单因素分析结果示:初诊白细胞计数(P=0.023)、诱导疗程数(P=0.074)、移植物来源(P=0.044)、cGVHD(P=0.033)是allo-HSCT后复发的影响因素.多因素Cox回归分析结果示:诱导疗程数(P=0.027)、cGVHD(P=0.011)是allo-HSCT后复发的独立影响因素.结论 诱导疗程数多、未发生cGVHD是allo-HSCT后复发的危险因素.     

复发/难治性淋巴瘤患者自体干细胞移植后巩固化疗的疗效分析

背景与目的：目前,大剂量化疗+自体造血干细胞移植(autologous stem cell transplantation,auto-HSCT)是部分复发/难治淋巴瘤的首选治疗方案,但其再次复发率仍较高。因此我院血液科骨髓移植病区尝试对自体干细胞移植治疗后高危复发的难治性患者进行巩固化疗,并对其临床疗效进行比较分析。方法：回顾性分析38例接受auto-HSCT治疗的复发/难治性淋巴瘤患者的临床资料。将auto-HSCT治疗后给予巩固化疗的19例患者作为治疗组,与仅接受auto-HSCT治疗的19例进行对照(对照组)。巩固化疗方案为Mini-BEAM或减低剂量CBV,每次化疗间隔2～3个月,共2个疗程。以auto-HSCT为随访起点,比较2组患者无进展生存期(progression-free survival,PFS)和总体生存期(overall survival,OS)的差异。结果：治疗组及对照组中位随访时间分别为17.2和7.5个月。意向性分析显示2组中位PFS分别为24.7和7.8个月,治疗组明显优于对照组(P=0.029)。OS呈现一定差异的趋势(P=0.055)。完成治疗分析显示2组中位PFS分别为24.7和5.2个月,治疗组亦优于对照组(P=0.01)。结论：针对高危恶性淋巴瘤患者,在自体移植基础上进一步予以巩固化疗,可延迟疾病复发、降低复发率,延长患者生存时间。     

PD-1hiTIM-3+ T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation

Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1^hiTIM-3⁺ cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1^hiTIM-3⁺ T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing T_N and T_EMRA subsets. Importantly, increase of PD-1^hiTIM-3⁺ cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation.     

Delirium in patients undergoing hematopoietic stem cell transplantation

BACKGROUND: Delirium is common in patients with malignant disease and is associated with significant morbidity. Studies have not examined the epidemiology of delirium in patients undergoing hematopoietic stem cell transplantation (HSCT). The objectives of this study were to determine the prevalence, incidence, severity, and duration of delirium in the acute phase of HSCT and to determine the pretransplantation risk factors for the occurrence and severity of delirium during this period. METHODS: Ninety adult patients with malignancies who were admitted to the Fred Hutchinson Cancer Research Center for their first HSCT were assessed prospectively from 1 week pretransplantation to 30 days posttransplantation. Delirium occurrence using the Delirium Rating Scale (DRS) and severity using the Memorial Delirium Assessment Scale (MDAS) were assessed three times per week. Pretransplantation risk factors were assessed by patient self-report, charts, and computerized records. RESULTS: The cumulative posttransplantation incidence of delirium events (DRS score > 12) was 66 (73%), and the incidence of delirium episodes (DRS score > 12 for 2 of 3 consecutive assessments) was 45 (50%). The mean +/- standard deviation duration of delirium episodes was 4.8 +/- 2.8 assessments (approximately 10 days). Pretransplantation risk factors for having a delirium episode were lower cognitive functioning (Trailmaking B test [a standardized test of visual conceptual and visuomotor tracking and cognitive flexibility]; P = 0.0008), higher blood urea nitrogen (P = 0.002), higher alkaline phosphatase (P = 0.008), lower physical functioning (SF-12 [self report questionnaire that is a general measure of functioning]; P = 0.03), and higher magnesium (P = 0.03). Pretransplantation risk factors for higher delirium severity scores were higher creatinine (P < 0.0001), the presence of total body irradiation (P = 0.0001), higher magnesium (P = 0.0003), lower Mini-Mental State Examination score (P = 0.002), malignancy diagnosis category (P = 0.002), female gender (P = 0.008), higher alkaline phosphatase (P = 0.02), older age (P = 0.03), and prior alcohol or drug abuse (P = 0.046). CONCLUSIONS: Half of patients who undergo HSCT experience a delirium episode during the 4 weeks posttransplantation. Pretransplantation risk factors can assist in identifying patients who are more likely to develop delirium posttransplantation.     

自体造血干细胞移植可使中国高危多发性骨髓瘤患者获益更多

目的 评价自体造血干细胞移植（ASCT）对初治多发性骨髓瘤（MM）的疗效.方法 选取诱导治疗后获得部分缓解（PR）及以上疗效的42例初治MM患者进行ASCT,中位随访34.2个月后,观察患者的疗效、无进展生存（PFS）和总生存（OS）.选择同时期的49例诱导治疗后获得PR及以[上疗效的初治MM患者,进入非移植组（non-ASCT）,经巩固维持治疗后观察疗效、PFS和OS,比较两组的差异,分析ASCT在MM中的作用.结果 与non-ASCT组相比,ASCT可明显延长患者的OS（未达到/37.2个月,P=O.000）,而且对PFS也有延长趋势（33.9个月/39.8个月,P=0.133）.ASCT可明显改善DSⅢ期（P=0.009）和ISSⅢ期（P=0.049）患者PFS,但对DSⅠ /Ⅱ期和ISS Ⅰ/Ⅱ期患者的PFS改善不明显.ASCT可明显改善诱导治疗后获得CR患者的PFS（P=0.016）,对非常好的PR （VGPR） /PR患者的PFS改善不明显;不同年龄患者OS均明显改善（≤55岁,P=0.039;＞ 55岁,P=0.000）.ASCT可明显改善不同ISS分期患者的OS（Ⅰ/Ⅱ期,P=0.003;Ⅲ期,P=0.012）,对DSⅢ期患者的OS也有明显改善作用（P=0.000）,但对DSⅠ/Ⅱ期患者OS的作用不明显（P=0.446）.诱导治疗后获得CR和VGPR/PR的患者进行移植后,OS可进一步得到改善（CR,P=0.004; VGPR/PR,P=0.004）.结论 ASCT可明显改善初治MM患者的生存,使高龄和分期预后不良的MM患者获益更多.     

Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma

BackgroundHigh-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined.Patients and methodsIn this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation.ResultsMR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24–0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23–0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed.ConclusionsThese data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.     

The pretransplant Follicular Lymphoma International Prognostic Index is associated with survival of follicular lymphoma patients undergoing autologous hematopoietic stem cell transplantation

We retrospectively evaluated the association of the Follicular Lymphoma International Prognostic Index (FLIPI) and other characteristics with survival following high-dose therapy and autologous stem cell transplantation (ASCT) in 207 consecutive follicular lymphoma (FL) patients. The FLIPI was associated with OS both when evaluated as a categorical variable (0 - 1 vs. 2 vs. 3 vs. 4, p = 0.01, global test) and a continuous linear variable (p = 0.002). The association of FLIPI with survival appeared to be more relevant for patients who received standard conditioning regimens compared to those that were treated with high-dose radioimmunotherapy (p = 0.004). Among all patients, mortality was also associated with chemosensitive disease (HR = 0.47, p = 0.01) or untreated relapse (HR = 0.20, p = 0.0002) vs. chemoresistant disease, and ≥2 extranodal sites (HR = 2.82, p = 0.03) after adjusting for FLIPI. These data suggest that the FLIPI and select non-FLIPI factors after adjustment for the FLIPI are associated with survival in FL patients undergoing ASCT.     

82例恶性血液病患者异基因造血干细胞移植后复发的危险因素分析

目的 探讨异基因造血干细胞移植(allo-HSCT)后复发的危险囚素.方法 总结82例接受allo-HSCT治疗的血液病患者的临床资料,分析供受者年龄、供受者性别、供受者血型异同、供者类型、疾病状态、HLA配型、预处理方案、移植物抗宿主病(GVHD)的有无、回输CD34+细胞数量、有无巨细胞病毒感染等与移植后复发的关系.结果 16例患者在移植后2～28个月复发.单因素分析结果显示,疾病状态(P=0.013)、疾病诊断到移植的时间(P=0.042)、预处理方案(P=0.046)、急性GVHD(P=0.022)、慢性GVHD(P=0.002)与allo-HSCT后复发有关.Cox多因素回归分析结果显示,疾病状态(OR=2.58,95%CI为1.26～5.01)、疾病诊断到移植的时间(OR=1.98,95%CI为1.11～3.63)和慢性GVHD(OR=3.74,95%CI为1.96～7.97)是allo-HSCT后复发的独立影响因素.结论 复发仍是allo-HSCT失败的首要原因,疾病状态、疾病诊断到移植的时间以及无慢性GVHD是移植后复发的主要危险因素.

Abstract：

Objective To explore the risk factors for relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and the measures of prophylaxis and treatment.Methods We summarized the clinical data of 82 patients with hematologic malignancies who were treated in our hospital from August 2003to December 2008.Factors including age, sex, ABO blood group disparity of donor and recipient as well as the type of donor, status of disease, HLA-match, conditioning regimen, whether or not having developed acute GVHD and chronic GVHD, infusion number of CD34 + cells, relationship between CMV infection and relapse post-transplantation were considered and analyzed.Results Single factor analysis indicated that there were five independent risk factors related with the disease relapse ( P ＜ 0.05 ), including status of disease, time of diagnosis to transplantation, acute graft versus host disease (aGVHD), conditioning regimen, and chronic graft versus host disease (cGVHD).Simultaneously, the type of donor was a substantial factor (P ＜ 0.01 ), determined by multi-factor Cox regression analysis.Cox regression analysis determined that disease status ( OR = 2.58, 95% CI 1.26-5.01, P = 0.01 ), time from diagnosis to treatment ( OR = 1.98, 95% CI 1.11-3.63, P = 0.025 ) and cGVHD ( OR = 3.74, 95% CI 1.96-7.97,P ＜0.001 ) were major factors for relapse of the patients who had undergone transplantation.Conclusions Relapse remains the primary cause of failure after allo-HSCT.Status of disease, time from diagnosis to treatment and not cGVHD are the major risk factors.Effective prevention and treatment of relapse after engraftment can improve the efficacy of HSCT.