Graft versus host disease after stem cell allotransplantation with low-dose total body irradiation, fludarabine, and antithymocyte globulin

BACKGROUND: We previously showed that antithymocyte globulin (ATG) given with total body irradiation (TBI) 200 cGy and fludarabine results in high rate of donor engraftment. Its influence on acute and chronic graft versus host disease (GVHD) and on graft versus tumor effect is less known. METHODS: Sixty-five patients underwent nonmyeloablative stem cell transplant with ATG, TBI 200 cGy, and fludarabine. GVHD prophylaxis was mycophenolate mofetil and cyclosporine. Forty-two patients (pts) (65%) had match related donors, 18 (27%) match unrelated, 1 (1.5%) mismatch related, and 4 (6%) mismatch unrelated donors. RESULTS: At a median follow-up of 862 days, 24 patients (37%) developed GVHD. The median age of the patients with and without GVHD was 56 years respectively. Acute GVHD grade II-IV developed in 19 pts (29%). Fatal GVHD of liver and/or gut occurred in nine pts (14%). Forty-one pts survived more than 100 days. Five pts (12%) had chronic GVHD, two had extensive, and three had limited involvement. Relapsed disease was observed in 22 pts (34%). Infections occurred in 15 pts (23%) and were fatal in 13 (20%). CONCLUSIONS: The addition of ATG to TBI 200cGy and fludarabine resulted in a modest incidence of GVHD. The best transplant outcomes were observed in pts with lymphoid malignancies.     

High-dose busulfan and the risk of pulmonary mortality after autologous stem cell transplant

The non-relapse mortality of autologous stem cell transplant is low enough that the procedure has been extended to older patients with non-Hodgkin's lymphoma. We treated 537 non-Hodgkin's lymphoma patients with high-dose chemotherapy consisting of busulfan, cyclophosphamide, and etoposide followed by autologous stem cell transplant. Sixteen patients were identified who died of pulmonary complications at a five-year incidence of 3.6%. Risk factors for pulmonary mortality included older age and lower baseline D(CO) and FEV1. We conclude that high-dose busulfan is associated with pulmonary mortality after autologous transplant, particularly in older patients.     

A high antithymocyte globulin dose increases the risk of relapse after reduced intensity conditioning HSCT with unrelated donors

The study included 110 consecutive patients with hematological malignancies receiving fludarabine‐based reduced intensity conditioning (RIC) and hematopoietic stem cell transplantation (HSCT) from matched unrelated donors. The median age was 55 yr (range 11–68) and all but 15 patients received peripheral blood stem cell grafts. Antithymocyte globulin (ATG) (Thymoglobulin, Genzyme) at a total dose of 6 mg/kg (n = 66) or 8 mg/kg (n = 44) was given to all patients according to protocol. The ATG dose did not affect time‐to‐neutrophil or platelet engraftment. The incidences of acute GVHD grades II–IV were 34% and 18% (p = 0.11) and of chronic GVHD were 40% and 26% (p = 0.46) in patients receiving 6 and 8 mg/kg of ATG, respectively. The five‐yr relapse‐free survival (RFS) was 61% and 36% (p = 0.14) in patients, given low and high ATG dose, respectively. In patients given low‐dose ATG, the incidence of relapse was lower compared to those given high‐dose ATG, 19% vs. 41% (p = 0.04). In multivariate analysis, age >50 yr (p < 0.001), absence of acute (p < 0.001) and chronic GVHD (p = 0.001) were correlated to relapse, and low‐dose ATG was associated with improved RFS (p < 0.05). A high dose (8 mg/kg) of ATG in RIC HSCT with unrelated donors increased the risk for relapse and reduced the RFS.     

Long‐term outcomes of antithymocyte globulin in patients with hematological malignancies undergoing myeloablative allogeneic hematopoietic cell transplantation: a systematic review and meta‐analysis

Antithymocyte globulin (ATG) has shown efficacy in preventing acute GVHD (aGVHD) in allogeneic hematopoietic cell transplantation (allo‐HCT), but its efficacy in chronic GVHD (cGVHD) and long‐term outcomes remains controversial. We conducted a systematic review and meta‐analysis to evaluate potential benefit and risk of prophylactic ATG use in myeloablative HCT. We searched Pubmed, EMBASE, Cochrane databases, and included 10 trials (two RCTs and eight retrospective) comparing ATG use vs. control with a total of 1859 patients. The median follow‐ups were over two yr. Outcomes assessed included overall cGVHD, extensive cGVHD, overall survival (OS), disease‐free survival, relapse, and causes of death. Our results showed ATG significantly decreased overall cGVHD (RR = 0.59; 95% CI: 0.53–0.66, p < 0.00001), extensive cGVHD (RR = 0.34; 95% CI: 0.25–0.47, p < 0.00001). Pooled results also showed ATG use was associated with a marginal increased risk of relapse (RR = 1.28; 95% CI: 1.01–1.63, p = 0.04), and a non‐inferior OS (HR = 0.86; 95% CI: 0.74–1.01, p = 0.06). We conclude prophylactic use of ATG exerts a favorable effect in reducing cGVHD without survival impairment in a long term, although a higher relapse rate is a major threat.     

减低强度预处理造血干细胞移植联合低剂量环孢素A治疗恶性血液病

目的 探讨以减低强度的氟达拉滨、白消安(Bu)和环磷酰胺(CTX)为预处理方案的异基因外周血造血干细胞移植(HSCT)联合低剂量环孢素A(CsA)的疗效及并发症发生情况.方法 恶性血液病患者11例,接受同胞间HSCT,供、受者问HLA配型,HLA全相合10例.5个抗原相合1例.预处理包括移植前第9～4天给予氟达拉滨30～35 mg·m-2·d-1,移植前第4、3天给予白消安3.2 mg·kg-1·d1,移植前第2、1天给予CTX 60mg·kg1·d-1.移植后联合使用CsA和短程甲氨蝶呤(MTX)预防移植物抗宿主病(GVHD),供者细胞植入后,降低CsA用量.结果 移植后早期11例造血功能均获得重建,骨髓细胞为完全供者型.随访3～17个月,9例并发急性GVHD,主要侵犯肝脏和皮肤;9例并发慢性GVHD,均侵犯口腔和肝脏,其中1例为广泛性慢性GVHD,其余为局限性慢性GVHD.增加CsA用量或者加用甲泼尼龙后,急、慢性GVHD均能得到控制,仅1例需加用霉酚酸脂.11例中,2例的原发病复发,其中1例病情得到控制,1例失访.结论 HSCT时采用氟达拉滨、白消安和环磷酰胺(CTX)预处理方案,并将白消安的用量减为常用剂量的一半,移植后采用低剂量CsA,细胞的植入率高;急、慢性GVHD的发生率较高,但对糖皮质激素和CsA的治疗反应良好.     

Comparative outcomes of reduced intensity and myeloablative allogeneic hematopoietic stem cell transplantation in patients under 50 with hematologic malignancies

We have conducted a direct comparison of the outcomes of reduced intensity and myeloablative conditioning in younger adults with hematological malignancies<50 yr. One hundred and five patients received transplants from human leukocyte antigen (HLA)-matched donors, via either reduced intensity (n=35) or myeloablative conditioning (n=70). The median ages of the reduced intensity and myeloablative groups were 36 and 33 yr (p=0.014). Neutrophil engraftment (i.e. time to absolute neutrophil count>0.5x10(9)/L) occurred more rapidly in the reduced intensity group (median: 10 d; range: 0-21 d) than in the myeloablative group (median: 18 d; range: 11-38 d; p<0.0001). The incidence of grades 2-4 acute graft-vs.-host disease were similar between the reduced intensity and myeloablative groups, at 17% vs. 24% respectively (p=0.40). The cumulative incidence of day 100 non-relapse mortality was 18% in the reduced intensity group, and 21% in the myeloablative group (p=0.88). The overall two-yr survival rates were 43% in the reduced intensity group, and 35% in the myeloablative group (p=0.72). In conclusion, reduced intensity transplantation yielded outcomes comparable with those of myeloablative transplantation in patients under 50 with hematological malignancies.     

包含氟达拉滨和阿糖胞苷的预处理方案在异基因造血干细胞移植中的应用

目的 探讨异基因造血干细胞移植(allo-HSCT)时采用含氟达拉滨(Flu)和阿糖胞苷(Ara-C)的白消胺+环磷酰胺方案(BuCy方案)的预处理效果及不良反应.方法 60例髓系恶性血液病患者在allo-HSCT前接受含Flu和Ara-C的BuCy方案预处理,按Bu使用天数(2、3和4 d)将患者分为2d组、3d组及4d组,于移植前第4、3、2天输注Flu,剂量为30 mg·m-2·d-1,在Flu输注完毕后4h开始滴注Ara-C,剂量为2 mg·m-2·d-1.观察预处理相关毒性、植入情况、移植相关并发症、原发病复发、移植相关死亡、受者的无病存活率(DFS)、总存活率及影响疗效的相关因素等.结果 所有受者均获得造血重建,中性粒细胞＞0.5×109/L的时间为移植后14d(中位数),血小板＞20×109/L的时间为18 d(中位数).预处理相关毒性有肝功能异常40例,腹泻20例,口腔红斑和溃疡21例,心功能损害4例,经相关处理后缓解.移植相关并发症有严重感染20例,出血性膀胱炎6例,急性移植物抗宿主病(GVHD)10例,慢性GVHD22例,肝静脉闭塞症1例.原发病复发8例,4例经甲磺酸伊马替尼联合供者淋巴细胞输注治疗后获得持续分子生物学缓解,4例死亡.移植相关死亡15例,其中2例死于100d内,除1例死于肝静脉闭塞症外,其余病例死于GVHD.受者的3年DFS、移植相关死亡率及慢性GVHD累积发生率分别为66.6％、27.2％和42.9％.2d组和3d组的3年累积复发率分别为21.0％和1 1.1％(P＞0.05),DFS分别为72.4％和72.2％ (P＞0.05),移植相关死亡率分别为17.9％和23.3％(P＞0.05).4d组的移植相关死亡率明显高于其他两组(P＜0.05),而原发病复发率为0.结论 在BuCy基础上联合应用Flu和Ara-C进行预处理,髓外毒性小,原发病复发率低,疗效确切,且严重GVHD发生率较低.     

Cardiac allograft survival in rhesus primates treated with combined total lymphoid irradiation and rabbit antithymocyte globulin.

Eighteen abdominal heterotopic cardiac allografts were performed in outbred rhesus primates. For immunosuppression seven animals received six 100-rad/day total lymphoid irradiation (TLI) doses the week preceding transplant and three 3-mg/kg i.m. rabbit antithymocyte globulin (RATG) doses on postoperative days -1, 0, and +1; five animals were given this RATG dose but no irradiation; three were given TLI alone; and three were given no immunosuppressive therapy. Circulating T lymphocyte counts were monitored in all animals (rosettes). Graft survival in the combined TLI-RATG therapy group (169 +/- 15 days) was significantly greater than in untreated (11 +/- 1 days), RATG alone (22 +/- 12 days), or TLI alone (38 +/- 6 days) treated animals (P less than 0.001, 0.0001, and 0.001, respectively). The animals receiving combined TLI-RATG therapy also achieved significantly greater and more prolonged T lymphopenia than that obtained in the other three groups. Six of seven cardiac allografts placed in animals receiving TLI-RATG therapy were removed electively before cessation of electrical activity; however, in four of these rejection pathology was noted. Thus, it seems that combined TLI-RATG therapy may be of benefit in the management of transplant recipients, but its use will probably not abolish these patients' requirements for immunosuppressive maintenance measures.     

Renal transplantation after myeloablative and non-myeloablative hematopoietic cell transplantation from the same donor

Hematopoietic cell transplantation is a key treatment to prolong patient survival for many hematological disorders. Renal impairment is well recognized as a significant complication of hematopoietic cell transplantation, which can progress to end-stage renal disease. Herein, we report our experience of two patients who underwent renal transplantation from the same donor who provided cells for the preceding hematopoietic cell transplantation. One patient had undergone peripheral blood stem cell transplantation with a non-myeloablative conditioning regimen, whereas the other had received bone marrow transplantation with a myeloablative regimen. Chronic immunosuppressive therapy was not needed in either one to maintain the kidney graft function. Not only bone marrow transplantation with a myeloablative conditioning regimen, but also peripheral blood stem cell transplantation with a non-myeloablative regimen can confer immunological tolerance.     

Analysis of infusion‐site reactions in renal transplant recipients receiving peripherally administered rabbit antithymocyte globulin as compared with basiliximab

Antithymocyte globulin rabbit (r‐ATG) has been used for the treatment and prevention of acute rejection in renal transplant recipients (RTR). Current manufacturer recommendations for r‐ATG dictate the need for administration through a high‐flow vein (central line). Previous studies have shown peripheral administration of r‐ATG to be safe; however, these studies suggest the co‐administration of heparin and hydrocortisone and did not compare the infusion‐site reaction rates to a control group. A retrospective analysis was conducted of adult RTR receiving r‐ATG or basiliximab between January 2004 and October 2006. Each agent was administered through a dedicated peripheral line. The primary endpoint was the incidence of infusion‐site reactions. Other endpoints included the need to replace the intravenous catheter and the incidence of systemic thrombosis within 1 month of transplantation. During the study period, 152 peripheral infusions of r‐ATG and 92 peripheral infusions of basiliximab were administered. No difference in infusion‐site reactions was noted between the groups. There was also no difference either in the need for peripheral line replacement or the rates of systemic thrombosis. Peripheral administration of r‐ATG is safe and can be infused without concomitant heparin and hydrocortisone. This method of r‐ATG infusion was shown to be as safe as peripherally administered basiliximab.     

Clostridium difficile‐associated disease in allogeneic hematopoietic stem‐cell transplant recipients: risk associations,protective associations,and outcomes

Dubberke ER, Reske KA, Srivastava A, Sadhu J, Gatti R, Young RM, Rakes LC, Dieckgraefe B, DiPersio J, Fraser VJ. Clostridium difficile‐associated disease in allogeneic hematopoietic stem‐cell transplant recipients: risk associations, protective associations, and outcomes.
Clin Transplant 2009. DOI: 10.1111/j.1399‐0012.2009.01035.x
© 2009 John Wiley & Sons A/S. Abstract:  The purpose of this study was to evaluate risk factors, protective factors, and outcomes associated with Clostridium difficile‐associated disease (CDAD) in allogeneic hematopoietic stem‐cell transplant (HSCT) recipients. A case–control study was performed with 37 CDAD cases and 67 controls. In the multivariable logistic regression analysis, receipt of a third or fourth generation cephalosporin was associated with increased risk of CDAD (OR = 4.6, 95% CI 1.6–13.1). Receipt of growth factors was associated with decreased risk of CDAD (OR=0.1, 95% CI 0.02–0.3). Cases were more likely to develop a blood stream infection after CDAD than were controls at any point before discharge (p < 0.001). CDAD cases were more likely than controls to develop new onset graft‐vs.‐host disease (GVHD) (p < 0.001), new onset severe GVHD (p < 0.001), or new onset gut GVHD (p = 0.007) after CDAD/discharge. Severe CDAD was a risk factor for death at 180 d in multivariable Cox proportional hazards regression (HR=2.6, 95% CI 1.1–6.2). CDAD is a significant cause of morbidity and mortality in allogeneic HSCT patients, but modifiable risk factors exist. Further study is needed to determine the best methods of decreasing patients’ risk of CDAD.     

Hematopoietic stem cell transplantation in patients with chronic kidney disease

Patients with significant medical comorbidities such as chronic kidney disease (CKD) traditionally have been excluded from hematopoietic stem cell transplantation (HSCT) because of unacceptably high transplant-related morbidity and mortality, an exclusion that can have enormous consequences for patients with CKD from myeloma in particular. Much of the excess HSCT-related morbidity among CKD patients relates to the toxic effects of conditioning regimens, which have a narrow therapeutic index even in patients with normal renal function. Common posttransplant complications are more challenging to prevent and manage in patients with CKD. In selected centers, autologous HSCT is performed with some frequency in patients with advanced CKD and even dialysis-dependent end-stage renal disease (ESRD), with acceptable outcomes, but cure from malignancy rarely is obtained. Allogeneic transplants using reduced-intensity conditioning regimens are being used with increasing frequency in patients with CKD, for both nonmalignant and malignant conditions, relying in the latter case on a graft-versus-malignancy effect to eliminate residual malignancy. In patients with ESRD from myeloma who have suitable donors, simultaneous allogeneic HSCT and kidney transplantation from a human leukocyte antigen-identical sibling provides the opportunity to treat both the malignant condition and the ESRD, avoiding the risks of posttransplant care in a dialysis-dependent patient and freeing the patient of the subsequent burdens of both ongoing dialysis and immunosuppression.     

Histopathologic features of transplant glomerulopathy associated with response to therapy with intravenous immune globulin and rituximab

Transplant glomerulopathy (TG) is associated with poor long‐term allograft survival and is often accompanied by microcirculation inflammation. Histopathologic scoring may inform prognosis and help guide therapy. We retrospectively assessed 33 patients with biopsy‐proven TG. All biopsies were given a glomerulitis (g) and peritubular capillaritis (ptc) score. We determined allograft survival and serum creatinine stability in three different score groups: g < 2 and ≥ 2, ptc < 2 and ≥ 2, and (g + ptc) < 4 and ≥ 4. We assessed the impact of treatment with intravenous immune globulin (IVIG) and rituximab on outcomes. Graft survival and serum creatinine stability did not differ in each of the histopathologic score groups. Higher‐score groups were associated with the presence of concomitant antibody‐mediated rejection and were more likely to receive IVIG and rituximab. Treatment with IVIG and rituximab resulted in stability of serum creatinine within the higher‐score groups, but not in the lower‐score groups. Stabilization of serum creatinine was associated with an improvement in donor‐specific antibody. Histopathologic scoring in kidney allograft biopsies with TG may help guide treatment. The combination of IVIG and rituximab appears to be beneficial in patients whose biopsies have moderate or severe microvascular injury.     

A rare complication after allogeneic stem cell transplantation: post‐transplant erythrocytosis

Post‐transplant erythrocytosis is an infrequent complication and has been reported after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in aplastic anemia, acute myeloid leukemia, and chronic myeloid leukemia. The pre‐disposing factors and treatment are not clearly defined. We present 11 post‐transplant erythrocytosis cases. More studies should be conducted to distinguish the pathogenesis and follow‐up for this rare complication.     

Assessment and prevention of cytomegalovirus infection in allogeneic hematopoietic stem cell transplant and in solid organ transplant: A multidisciplinary consensus conference by the Italian GITMO,SITO, and AMCLI societies

Cytomegalovirus (CMV) remains a major cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (allo‐HSCT) and solid organ transplantation (SOT) recipients. In view of the uncertainties on the assessment and prevention of CMV infection in both transplant procedures, three Italian scientific societies for HSCT and SOT and for Clinical Microbiology appointed a panel of experts to compose a framework of recommendations. Recommendations were derived from a comprehensive analysis of the scientific literature and from a multidisciplinary consensus conference process. The lack of adequate clinical trials focused on certain diagnostic procedures, and antiviral intervention forced the panel to use the methods of consensus for shaping some recommendations. Recommendations concerning the two types of transplant were given for the following issues: assessment of pretransplant CMV serostatus, immunological monitoring after transplant, CMV prophylaxis with antivirals, CMV preemptive strategy, and CMV prophylaxis with immunoglobulin infusion and with adoptive immunotherapy. The questions raised by and the recommendations resulting from this consensus conference project may contribute to the improvement of certain crucial aspects of the management of CMV infections in allo‐HSCT and in SOT populations.     

Relationship between antithymocyte globulin,T cell phenotypes,and clinical outcomes in pediatric kidney transplantation

Depletional induction using antithymocyte globulin (ATG) reduces rates of acute rejection in adult kidney transplant recipients, yet little is known about its effects in children. Using a longitudinal cohort of 103 patients in the Immune Development in Pediatric Transplant (IMPACT) study, we compared T cell phenotypes after ATG or non-ATG induction. We examined the effects of ATG on the early clinical outcomes of alloimmune events (development of de novo donor specific antibody and/or biopsy proven rejection) and infection events (viremia/viral infections). Long-term patient and graft outcomes were examined using the Scientific Registry of Transplant Recipients. After ATG induction, although absolute counts of CD4 and CD8 T cells were lower, patients had higher percentages of CD4 and CD8 memory T cells with a concomitant decrease in frequency of naïve T cells compared to non-ATG induction. In adjusted and unadjusted models, ATG induction was associated with increased early event-free survival, with no difference in long-term patient or allograft survival. Decreased CD4⁺ naïve and increased CD4⁺ effector memory T cell frequencies were associated with improved clinical outcomes. Though immunologic parameters are drastically altered with ATG induction, long-term clinical benefits remain unclear in pediatric patients.