Myeloablative Conditioning allo-SCT Research Articles

Allogeneic stem cell transplant outcomes between TBI-containing reduced intensity and myeloablative conditioning regimens for ALL in complete remission

Total-body irradiation (TBI)-based conditioning regimen is preferred in acute lymphoblastic leukemia (ALL). We retrospectively evaluated allogeneic stem cell transplant (alloSCT) outcomes of 86 adult ALL patients in complete remission (CR) who received TBI-containing reduced intensity (RIC) (Flu/Mel/TBI = 31) and myeloablative conditioning (MAC) (VP16/TBI = 47; CY/TBI = 8) between January 2005 and December 2019. All patients received peripheral blood allografts. Patients in the RIC group were older than the MAC group (61 years old versus 36 years, p < .001). Donor was 8/8 HLA-matched in 83% and unrelated in 65% of patients. Three-year survival was 56.04% for RIC and 69.9% for MAC (HR 0.64; p = .19). Propensity score-based multivariable Cox analyses (PSCA) did not demonstrate any difference in grade III–IV acute graft versus host disease (GVHD) (SHR 1.23, p = .91), chronic GVHD (SHR 0.92, p = .88), survival (HR 0.94, p = .92), and relapse-free survival (HR 0.66, p = .47) between both groups, while relapse rate was lower (SHR 0.21, p = .02) for MAC compared to RIC. Our study did not demonstrate any difference in survival for TBI-containing RIC and MAC alloSCT for adult ALL in CR.

Outcomes of AML Patients Undergoing Reduced Intensity Allogeneic Stem Cell Transplantation with Adverse Risk Disease By European Leukemianet Classification: A Single Center Retrospective Analysis

Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults with a median age at diagnosis of close to 70 years. (Juliusson G, et al. Blood, 2011;119(17):3890-3899) The majority of patients with AML require allogeneic stem cell transplant (Allo-SCT) in order to achieve cure. European LeukemiaNET (ELN) published risk stratifications for AML patients according to cytogenetics in 2010 and then updated risk categories in 2017 to incorporate molecular abnormalities as well. The ELN adverse risk category predicts for a higher risk of relapse and worse overall survival (OS) compared to favorable and intermediate risk patients. (Döhner H, et al. Blood, 2017;129(4):424-447) Older patients are more likely than younger patients to have adverse risk disease. (Mrozek K, et al. JCO, 2012;30(36):4515-4523). In addition, older patients are typically not considered for myeloablative conditioning (MAC) regimens due to the high risk of non-relapse mortality (NRM). Thus, a significant proportion of AML patients who are candidates for Allo-SCT have adverse risk disease by ELN criteria and are only candidates for RIC Allo-SCT, both of which increase the risk of relapse. A recent randomized trial in AML and MDS patients noted a trend toward improved OS and statistically significant improvement in relapse free survival (RFS) favoring MAC over RIC (Scott BL, et al. JCO, 2017; 35(11): 1154-1161). Despite this, studies have shown durable remissions and long term disease free survival with RIC Allo-SCT in AML patients with high risk features. (Tauro S, et al. JCO, 2005; 23(36):9387-9393) However, to our knowledge no study has investigated the use of RIC Allo-SCT exclusively in patients who have adverse risk by 2017 ELN criteria. Thus, we reviewed AML patients with adverse risk disease by 2017 ELN criteria at diagnosis who underwent RIC Allo-SCT at our institution. Methods: We conducted a single center retrospective study of high risk adult AML patients by ELN criteria who underwent RIC Allo-SCT at MUSC from 3/20/2010 to 2/20/2018. Adverse risk disease was defined by the 2017 ELN criteria. Baseline demographic, clinical, laboratory, pathology, and outcomes data were collected by retrospective chart review. Kaplan Meier was utilized for time to event analysis. Results: A total of 42 patients with adverse risk AML received RIC Allo-SCT. The median follow up was 16.6 months. Clinical characteristics were collected for each patient and are included in table 1. The median age was 62 with 16 patients (38%) ≥ 65 years of age. Twenty-three patients had a HCT-CI score ≥ 3 (54%) with 9 patients (21%) having a HCT-CI score ≥ 5. Complete remission (CR) was defined as bone marrow blasts &lt; 5% without known molecular evidence of persistent/relapsed AML. CR and CR with incomplete count recovery (CRi) was not able to be defined. Thirty-one patients (73%) were in CR1 at transplant, 7 patients (16%) were in CR2+ defined as CR necessitating ≥ 2 treatment regimens. Four patients (9%) never achieved a CR and were labelled as primary induction failure (PIF), and one patient (3%) received prior MAC Allo-SCT before receiving RIC Allo-SCT and was labeled as Relapse. Four of the five patients with disease status of PIF or relapse were deceased within 13 months of Allo-SCT. The non-relapse mortality (NRM) at 1 year was 26.2%. Relapse-free survival (RFS) at 1, 2, and 3 years was 57.1%, 45.2%, and 35.7% respectively. The overall survival (OS) at 1, 2, and 3 years was 66.7%, 50.0%, and 40.5% respectively. A subset analysis of the patients in CR1 or CR2+ prior to RIC-Allo SCT noted a NRM at 1 year of 27% along with a RFS at 1, 2, and 3 years of 59.5%, 48.7%, and 40.5% respectively. Cause of death included relapse (33%), infection (29%), acute GVHD (25%), and chronic GVHD (3%). Conclusion: This provides evidence that although adverse risk disease by ELN criteria and reduced intensity conditioning both increase the incidence of relapse in patients with AML, that RIC Allo-SCT for this high risk patient population can provide long term disease free survival. In addition, the favorable outcomes for patients in CR1 and CR2+ prior to RIC-Allo are promising. It would be interesting to investigate a larger multi-center series of patients with adverse risk disease by ELN in CR prior to RIC Allo-SCT. Minimal residual disease by myeloid molecular panel and/or flow in this patient population prior to transplant would be of great interest as well. Disclosures Edwards: Genzyme: Consultancy.

Better early outcome with enteral rather than parenteral nutrition in children undergoing MAC allo-SCT

There is no consensus on the type of nutritional support to introduce in children undergoing allogeneic stem cell transplantation (allo-SCT) after myeloablative conditioning (MAC). This retrospective, multicenter, observational study compared the early administration of enteral nutrition (EN group, n=97) versus parenteral nutrition (PN group, n=97) in such patients with matching for important covariates. The primary endpoint was the study of day 100 overall mortality. The early outcome at day 100 was better in EN group regarding mortality rate (1% vs. 13%; p=0.0127), non relapse mortality (1% vs. 7%; p=0.066), acute GVHD grades II-IV (37% vs. 54%; p=0.0127), III-IV (18% vs. 34%; p=0.0333) and its gut localization (16% vs. 32%; p=0.0136). Platelet engraftment was better in EN group than in PN group for the threshold of 20G/L (97% vs. 80% p<0.0001) and 50G/L (92% vs. 78%, p<0.0001). The length of stay was shorter in EN group (28 vs. 52 days, p<0.0001). There were no differences between the two groups regarding the polynuclear neutrophil engraftment, infection rate or mucositis occurrence. These results suggest that, in children undergoing MAC allo-SCT, PN should be reserved to the only cases when up-front EN is insufficient or impossible to perform.

High incidence of chronic graft-versus-host disease after myeloablative allogeneic stem cell transplantation for chronic lymphocytic leukemia in Sweden: graft-versus-leukemia effect protects against relapse

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment option for eligible patients with chronic lymphocytic leukemia (CLL). However, it is known that cure of CLL is only possible if a graft-versus-leukemia effect is present. Between 1994 and 2007, 48 adults underwent allo-SCT for poor-risk CLL in Sweden. Of these, ten (21%) patients aged 24-53 years (median: 46 years) received myeloablative conditioning (MAC), based on TBI and cyclophosphamide. All MAC patients had refractory, poorly controlled CLL before allo-SCT (partial remission in 9/10 patients and progressive disease in one). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II-IV was 30%. Nine patients developed chronic GVHD; extensive in four. Rates of nonrelapse mortality at 1, 3 and 10 years were 0, 10 and 20%, respectively. Two patients relapsed 36 and 53 months after transplantation. Six patients were still alive after a median follow-up time of 11.5 years (range 5.9-13.7). The probabilities of relapse-free and overall survival from 1, 3 and 5 years after transplantation were 100, 90 and 70%, and 100, 90 and 80%, respectively. Nevertheless, our analysis of long-term outcome after MAC allo-SCT for CLL suggests that younger patients with poorly controlled CLL may benefit from MAC allo-SCT.

Reduced-intensity conditioning allogeneic stem cell transplantation in malignant lymphoma: current status.

Allogeneic stem cell transplantation (allo-SCT) is a potential cure for patients with malignant lymphoma that is based on the graft-versus-lymphoma (GVL) effect. Myeloablative conditioning allo-SCT is associated with high mortality and morbidity, particularly in patients older than 45 years, heavily pretreated patients (prior hematopoietic stem cell transplantation or more than two lines of conventional chemotherapy) or patients affected by other comorbidities. Therefore, conventional allo-SCT is restricted to younger patients (<50 to 55 years) in good physical condition. Over the last decade, allo-SCT with reduced-intensity conditioning (RIC-allo-SCT) has been increasingly used to treat patients with lymphoma. This treatment is associated with lower toxicity and substantial decrease in the incidence of transplant-related mortality, and has the potential to lead to long-term remissions. Therefore, patients who are not suitable to undergo conventional allo-SCT can benefit from the potentially curative GVL effects of allo-SCT. Although RIC-allo-SCT has improved the survival of lymphoma patients, high post-transplant relapse rates or disease progression mainly results in treatment failure. Thus, further improvement is clearly needed. The role and timing of RIC-allo-SCT in the treatment of lymphoma remains unclear. Therefore, more prospective studies should clarify the effectiveness of this method. In this article, we review the recent literature on RIC-allo-SCT as a treatment for major lymphoma subtypes. Areas that require further investigation in the context of clinical trials are also highlighted.

Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation for Adult Patients with T-Cell Acute Lymphoblastic Leukemia: A Survey From the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

AbstractAbstract ▪356▪This icon denotes a clinically relevant abstract Background:T-cell acute lymphoblastic leukemia (T-ALL) comprises about 25% of all adult ALL. Although allogeneic hematopoietic stem cell transplantation (allo-SCT) exerts a graft versus leukemia effect, very few large series exist on the outcome of adult T-ALL patients allografted with a myeloablative conditioning regimen. Patients and methods:adult cases of T-ALL patients who underwent related or unrelated (6/6) allo-SCT with a myeloablative regimen between 2000 and 2010 were extracted from the EBMT registry. Patients with a prior autologous or allogeneic SCT and those who received cord blood allo-SCT were excluded from analysis. Primary goal of the study was to evaluate overall survival (OS), leukemia-free survival (LFS), non-relapse mortality (NRM) and relapse incidence (RI) for T-ALL patients in first (CR1), second or subsequent remission (CR2+) and in relapse or refractory disease (advanced). Results:886 patients were included in this study. The median follow-up was 43 months. The median age was 29 (range: 18–63) and 649 patients (73%) were males. Allo-SCT characteristics are described in table 1.Among patients (n=561) allografted in CR1, 25% had a white blood cell count (WBC) ≥100 G/L, and a complex karyotype was identified in 43 cases (16%, available data = 268). 4-year OS and 4-year LFS were 58% (standard deviation (SD) 2%) and 55% (SD 2%), respectively, whereas 4-year NRM and RI were 19% (SD 2%) and 26% (SD 2%), respectively. In univariate analysis, age < median age (60% versus 50%, p = 0.02) and use of total-body-irradiation (TBI) (57% versus 42%, p = 0.04) were associated with an improved 4-year LFS. In a multivariate analysis including age, use of TBI, donor type and donor sex, age <median age (Hazard Ratio (HR)= 0.71 [95% CI: 0.55–0.92], p=0.01) and use of TBI (HR = 0.67 [0.48–0.93], p=0.02) were associated with an improved LFS.In the CR2+ T-ALL group (n=151), 4-year OS and 4-year LFS were 25% (SD 4%) and 24% (SD 4%), respectively. 4-year NRM was 27% (SD 4%) whereas 4-year RI was 49% (SD 4%). In univariate analysis, use of TBI was associated with an improved 4-year LFS (29% versus 8%, p = 0.02). In a multivariate analysis including age, patient sex, use of TBI and donor type, use of TBI was associated with an improved LFS (HR = 0.57 [0.37–0.88], p=0.01).Finally, in the advanced T-ALL group (n=174), 4-year OS and 4-year LFS were 15% (SD 3%) and 12% (SD 3%), respectively. 4-year NRM was 30% (SD 4%), whereas 4-year RI was 58% (SD 4%). In univariate analysis, use of TBI was associated with an improved 4-year LFS (16% versus 3%, p= 0.002). In a multivariate analysis including age, use of TBI and donor type, use of TBI was again associated with an improved LFS (HR=0.56 [0.38–0.82], p=0.003). Conclusion:This large series demonstrates that myeloablative conditioning allo-SCT is followed by a relatively favorable outcome in patients with T-ALL transplanted in CR1, and might be an option for subgroups of patients in more advanced phase of the disease. Of note, use of TBI as part of the conditioning regimen is associated with an improved LFS in all disease stages.Table 1Allo-SCT characteristicsCR1 N = 561CR2 N = 151Advanced N = 174Donor typeIdentical sibling351 (62%)79 (52%)104 (60%)Matched unrelated donor210 (38%)72 (48%)70 (40%)Stem cell sourceBone marrow205 (37%)42 (28%)39 (22%)Peripheral blood356 (63%)109 (72%)135 (78%)TBI-based regimen476 (85%)104 (69%)131 (75%) Disclosures:No relevant conflicts of interest to declare.

Better Outcome of Patients Undergoing Enteral Tube Feeding After Myeloablative Conditioning for Allogeneic Stem Cell Transplantation

Parenteral nutrition (PN) is still widely preferred to enteral nutrition (EN) in malnourished patients undergoing allogeneic stem-cell transplantation (allo-SCT) after myeloablative conditioning (MAC). The purpose was to determine whether EN improves early outcome after MAC allo-SCT. Early outcome was prospectively assessed in patients undergoing MAC allo-SCT. A total of 121 consecutive patients undergoing a first MAC allo-SCT for acute leukemia, myelodysplastic syndrome, or myeloproliferative syndrome were included. Patients who received cord blood were excluded. Enteral nutrition was systematically offered, although PN was provided when EN had been refused or was poorly tolerated. Among the patients, 94 received EN (EN group) and 27 did not (non-EN group). Overall survival (OS), cumulative incidence of engraftment and acute graft-versus-host disease (aGVHD) within the first 100 days after transplantation were studied. Because EN and PN treatment assignments were not random, propensity score adjustments were performed on patient outcomes. Outcome was better in the EN group than in the non-EN group for OS (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.04-0.42; P=0.0008), neutrophil (HR, 2.07; 95% CI, 1.26-3.39; P=0.004), and platelet (HR, 1.93; 95% CI, 1.004-3.70; P=0.049) engraftments and aGVHD development (HR, 0.12; 95% CI, 0.04-0.39; P=0.0004). In Cox model analysis, EN demonstrated a protective effect (HR, 0.20; 95% CI, 0.05-0.77; P=0.019) on OS, whereas demonstrated a detrimental impact (HR, 4.18; 95% CI, 1.02-17.12; P=0.047). Enteral nutrition was found to be an independent factor in neutrophil engraftment (HR, 2.17; 95% CI, 1.24-3.81; P=0.007), whereas PN delayed platelet engraftment (HR, 0.57; 95% CI, 0.33-0.99; P=0.046). Enteral nutrition was the only factor that was protective against grades 3 to 4 aGVHD development (HR, 0.19; 95% CI, 0.05-0.72; P=0.01). Routine use of EN is preferable to upfront PN in these patients.

Enteral nutrition: a first option for nutritional support of children following allo-SCT?

Parenteral nutrition (PN) is the treatment of choice for nutritional support of patients undergoing allo-SCT following myeloablative conditioning (MAC). Here we prospectively assessed the outcomes of early enteral nutrition (EN) in a paediatric cohort. From 2003 to 2010, all 65 consecutive children undergoing MAC allo-SCT at our referral centre began EN the day after transplantation. Post-transplant and nutritional outcomes of patients receiving only EN (EN group, n=50) were compared with those of patients requiring additional PN (EN-PN group, n=15). In the EN group time to platelet recovery (P=0.01) and length of hospitalisation (P<0.001) were shorter, while in the EN-PN group the proportion of unrelated donors (P=0.02) and the frequency of severe acute GVHD (aGVHD; P=0.004) were higher. All patients were alive at day 100. PN was started 14 days after transplant because of poor digestive tolerance to EN or severe gut aGVHD. The body mass index Z-score in the EN-PN group decreased from transplant to discharge (P=0.02). In only 23% of cases was PN required for severely ill patients. Our results suggest that EN might be considered to be an option for nutritional support in children undergoing MAC allo-SCT, while PN should be used only as a rescue option, possibly in combination with EN.

Reduced Intensity Conditioning Regimens Do Not Offer a Survival Advantage to Myeloma Patients Receiving Allogeneic Stem Cell Hematopoietic Transplantation: A Societe Française De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC) Registry Study,

Abstract 4113 Purpose:Despite the raise of major new drugs in the management of multiple myeloma (MM), it is still an incurable disease and allogeneic stem cell transplantation (alloSCT) is currently the sole potential curative therapy mediated by a graft-versus-myeloma (GVM) effect. For over ten years, reduced intensity conditioning regimens (RIC) in alloSCT has been developed to maintain the GVM effect and to decrease the high transplanted related mortality (TRM) associated with myeloablative conditioning (MAC) in myeloma patients. Yet, as numerous studies have assessed RIC alloSCT versus autologous SCT, only few data provides a comparison between RIC and MAC for MM in large series. Our study aims to compare RIC and MAC alloSCT for MM on a large retrospective French cohort. Methods:We report a retrospective multicenter study based on the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) registry, evaluating the outcome of patients undergoing alloSCT for MM. Between 1995 and 2009, 811 patients allografted for MM were registered. Data concerning disease characteristics and the allograft procedure were screened using the French Promise® database; computerized discrepancy errors and data verification of every single file ensure data quality, important missing data were directly retrieved in each centre.We assign the type of conditioning regimen for each patient according to the registry’s data reported by the local physician and check this information according to the following rules. We consider as myeloablative (MAC) all regimens containing > 8 mg/kg oral busulfan, > 600 cGY TBI, ≥ 200 mg/kg cyclophosphamide or combinations as BEAM like regimens. All other chemotherapy combinations with or without TBI are defined as RIC regimens generally including fludarabine. Patients were excluded when major data or conditioning information were not available; 566 patients (70% of the entire cohort) were finally eligible for analysis, 478 RIC and 88 MAC.Chi-squared test and T-test were used for comparisons. Survival analyses (Overall survival, OS; progression-free survival, PFS) are made using the Kaplan-Meier curve and log rank test. Multivariate analysis is made using the Cox proportional hazards model. Results:The RIC and MAC populations were statistically different regarding age (respectively 53 versus 46 years, p<.0001), number of prior transplant (> 1 prior transplant in 94% RIC versus 77% MAC, p<.0001), time to transplantation (<12 months after diagnosis in 22% RIC versus 38% MAC, p=.001) and stem cell source (peripheral blood 84% RIC versus 52% MAC, p<.0001, and bone marrow 10% RIC versus 45% MAC, p<.0001).The 2-year OS is 69.5% after RIC and 79.9% after MAC (p<.0001); 5-year OS is 49.7% after RIC and 60.2% after MAC (p<.0001, fig.1). The 2 year PFS is 49.3% and 70.1% and 5-year PFS is 29.6% and 40.8% after RIC and MAC respectively (p<.0001, fig.2).Factors associated with better OS and PFS in multivariate analysis are the following in the whole cohort: < 12 months between diagnosis and alloSCT (p=.0078 and p=.0037, respectively); disease status at transplantation (at least partial response, p=.0409 and p=.0026); no or limited acute graft-versus-host disease (GvHD) (p<.0001 and p=.0094) and presence of chronic GvHD (p<.0001 and p<.0001). On multivariate analysis, the intensity of conditioning regimen (RIC vs MAC) do not appear statistically significant for OS (p = 0.64) and PFS (p = 0.17). For patients transplanted between 2006 and 2009, neither high risk-cytogenetic nor bortezomib use before transplantation seems to affect the outcome in multivariate analysis. [Display omitted] Conclusions: In the French practice, MAC regimens have had more limited indications due to their higher toxicity. This study suggests that the outcome after MAC-alloSCT is comparable to that after RIC-alloSCT with a trend to a better OS in the late follow-up (after 5 years) after MAC. The aspect of flattening in the survival curves suggests that the anti-tumoral action of the conditioning regimen remains essential on the anti-myeloma effect after alloSCT and that should be considered in the transplantation procedure. Disclosures:No relevant conflicts of interest to declare.

Risk Factors Associated with Kidney Injury and the Impact of Kidney Injury on Overall Survival in Pediatric Recipients Following Allogeneic Stem Cell Transplant

Pediatric allogeneic stem cell transplant (AlloSCT) patients are at substantial risk of developing kidney injury (KI), and KI contributes to transplant-related morbidity and mortality. We compared the estimated creatinine clearance (eCrCl) at 1, 3, 6, 9, and 12 months post-AlloSCT in 170 patients following reduced toxicity conditioning (RTC) versus myeloablative conditioning (MAC) to baseline. eCrCl was calculated using the Schwartz equation. Patients with ≥ 50% drop in eCrCl from the baseline were considered to have KI. Patients received tacrolimus and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. The logistic regression model was used for assessing risk factors for KI. Seventy-six patients (median age = 10.6 years) received RTC AlloSCT; 94 patients (median age = 8.5 years) received MAC AlloSCT. The incidence of KI at 1 month post-AlloSCT was significantly higher in MAC versus RTC AlloSCT (43/94 [45.7%] versus 13/76 [17.1%] P < .0001). There was no statistical difference in KI at 3, 6, 9, and 12 months post-AlloSCT between the 2 conditioning groups. On multivariate analysis, only MAC was a significant risk factor for KI (odds radio [OR] 3.44, 95% confidence interval [CI] 1.59-7.42, P = .002). In multivariate analysis for risk factors affecting overall survival (OS), the following were statistically significant: MAC versus RTC (hazard ratio [HR] 2.66, P = .0008), average versus poor-risk disease status (HR 2.09, P = .004), matched sibling donor (MSD) and matched unrelated donor (MUD) versus umbilical cord blood (UCB) (HR 2.31, P = .013), no KI versus KI (HR 2.00, P = .005). In children, MAC is associated with significant risk of KI in the first month after transplant, and KI in the first month post-AlloSCT is associated with a significantly decreased OS.

Incidence of Viral and Fungal Infections following Busulfan-Based Reduced-Intensity versus Myeloablative Conditioning in Pediatric Allogeneic Stem Cell Transplantation Recipients

Reductions in the duration and nadir of neutropenia have translated into a significant decrease in bacteremia in adult recipients of allogeneic stem cell transplantation (allo-SCT) with reduced-intensity conditioning (RIC) during the first 30 days after transplantation. It remains to be determined whether RIC allo-SCT also will result in a decrease in systemic viral infections (SVIs) and invasive fungal infections (IFIs), which are more dependent on alterations in cellular immunity. We compared the incidence of SVIs and IFIs in children receiving busulfan-based RIC allo-SCT and in children receiving myeloablative conditioning (MAC) allo-SCT for various malignant and nonmalignant diseases. Allo-SCT recipients at risk for cytomegalovirus (CMV) received ganciclovir/foscarnet, and most of the patients received antifungal prophylaxis with liposomal amphotericin B until day +100. Eighty-six patients (median age, 7.5 years; 70% with malignant disease, 30% with nonmalignant disease; 80% average risk, 20% poor risk) were evaluated. The probability of developing grade II-IV acute graft-versus-host disease (aGVHD) was 29.1% (95% confidence interval [CI]=16.7%-41.6%) in RIC allo-SCT versus 40.3% (95% CI=23.9%-56.6%) in MAC allo-SCT (P=.23), and that of chronic GVHD (cGVHD) was 28.9% (95% CI=14.7%-43.0%) in RIC allo-SCT versus 28.4% (95% CI=10.5%-46.3%) in MAC allo-SCT (P=.73). The overall probability of developing an SVI was 58%, and that of developing an IFI was 15%. These probabilities did not differ significantly by conditioning intensity. In a multivariate Cox regression model, the following were identified as independent risk factors for invasive fungal infection: older age (hazard ratio [HR]=1.3; 95% CI=1.1-1.6; P=< .01), poor risk status (HR=6.5; 95% CI =1.1-37.4; P=.03), and CMV-positive recipient (high vs low CMV risk group, HR=26.7; 95% CI=3.4-210.8; P=< .01). Overall infection-related mortality was only 1.1% (1/86) for SVIs and 2.3% (2/86) for IFIs. Our data indicate that RIC allo-SCT does not carry a lower risk of SVIs and IFIs than MAC allo-SCT in pediatric recipients.

Antithymocyte Globulins (ATG) as Part of the Myeloablative Conditioning (MAC) Regimen Can Reduce the Risk of Severe Graft-Vs.-Host Disease (GVHD) after Allogeneic Stem Cell Transplantation (allo-SCT) from Matched-Unrelated Donors (MUD).

The use of ATG in the setting of standard MAC allo-SCT is still controversial. Some studies, however, suggested a beneficial effect of ATG in preventing acute GVHD. Here, we report the results of a large multicenter retrospective study analyzing the effect of ATG, incorporated within the MAC regimen for MUD-transplants in leukemic patients compared to patients not receiving ATG. The purpose of the study was to compare the incidence and severity of acute and chronic GVHD as well as non-relapse mortality (NRM), leukemiafree and overall survivals (LFS, OS). The study included 171 adult patients with acute leukemia and MDS (73% standard risk and 27% more advanced disease) reported to the registry of the SFGM-TC between 1998 and 2004, and for whom detailed allelic HLA typing (4 digits) for the recipient and the donor was available. Patients' characteristics were as follow: median age: 33 (range, 15–67), 57% male recipients, 35% female donors, 44% AML, 43% ALL, 11% MDS and 2% unclassified leukemia. The stem cell source was bone marrow in 72.5% of patients, while PBSCs were used in 27.5% of cases. 81% of patients were transplanted from 10/10 allelic MUD, and 19% from a MUD with at least one allelic difference. A high dose TBI-based MAC regimen was used in 84% of cases, while 16% received a high-dose chemotherapy containing MAC regimen. 85% of the patients received the classical CsA and short course methotrexate GVHD prophylaxis regimen. In this series, 120 patients (70%) did not receive ATG (“no-ATG” group), while 51 patients received ATG (“ATG” group; Thymoglobuline*-Genzyme in all cases; total ATG dose: ≤5 mg/Kg, n=13; >5 and <10 mg/Kg, n=17; ≥10 mg/Kg, n=21) as part of the MAC regimen. Except for a significantly higher number of allelic differences between recipient and donor (33% vs. 13%; P=0.002), the “no-ATG” and “ATG” groups were strictly comparable as for patients, disease and transplant characteristics. 95% of patients had a sustained engraftment at a median of 20 (range, 9–41) days after allo-SCT with no significant differences between the 2 groups. With a median followup of 30.3 (range, 2.6–68.1) months after allo-SCT, grade 0–1 and 2–4 acute GVHD occurred in 74 (46%) and 88 patients (54%) respectively, with grade 3–4 acute GVHD being significantly lower in the “ATG” group as compared to the “no-ATG” group (18% vs. 32%; P=0.04). In this series, 142 patients (83%) were evaluable for chronic GVHD. Limited and extensive chronic GVHD were observed in 22 and 25% of assessable patients respectively, with extensive chronic GVHD being significantly lower in the “ATG” group as compared to the “no-ATG” group (5% vs. 33%; P=0.001). Interestingly, patients from the “ATG” group had a higher incidence of limited chronic GVHD (33% vs. 18%; P=0.06). The use of ATG was not associated with a higher risk of infections: infection-related mortality was comparable between both groups (23% vs. 27%, P=NS). Also, NRM was comparable between both groups (30% vs. 29%; P=NS). In multivariate analysis including all relevant risk factors tested in the univariate analysis, we found that an HLA allelic mismatch and the non-use of ATG were associated with an increased risk of severe grade 3–4 acute GVHD (RR=2.80, 95%CI, 1.5–5.3), P=0.001; and RR=2.4, 95%CI, 1.1–5.0, P=0.02 respectively). Similarly, multivariate analysis showed that the absence of use of ATG was the unique and strongest parameter associated with an increased risk of extensive chronic GVHD (RR=6.9; 95%CI, 1.7–29.0, P=0.008). Finally, LFS and OS at 2 years were not significantly different between the “no-ATG” and “ATG” group (48.8% vs. 41.3%, P=NS; and 53.6% vs. 54.3%, P=NS; respectively) Despite its retrospective nature, these results strongly indicate a global long-term beneficial effect of ATG when used as part of the MAC regimen prior to allo-SCT from MUD (especially in the HLA mismatch setting). Though prospective studies are needed to assess the optimal ATG dosing and administration schedule, such protective effect of ATG against severe acute and chronic GVHD, can be likely achieved without an increased risk of infections or leukemia recurrence.