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Relapse after allogeneic hematopoietic cell transplantation (HCT) leads to poor survival in patients with acute myeloid leukemia (AML). A second HCT (HCT2) may achieve durable remission. To determine the outcomes of patients who received an HCT2 for relapsed AML and to evaluate the predictors of overall survival (OS) and progression-free survival (PFS). We retrospectively reviewed medical records of adult patients who underwent an HCT2 for relapsed AML at our institution during 2000 to 2019. Ninety-one patients were identified with a median age of 44 years (range 18-73) at HCT2. Donor types were HLA-identical sibling (n = 37 [41%]), HLA-matched–unrelated (n = 34 [37%]), haploidentical (n = 19 [21%]), and cord blood (n=1 [1%]). Donors were different at HCT2 in 53% of patients. The majority of patients received reduced intensity conditioning (n = 71 [78%]) and were in remission (n = 56 [61%]) at HCT2. The median remission duration after HCT1 was 8.4 months (range 1-70) and the median time between transplants was 14 months (range 3-73). The median follow-up of surviving patients after HCT2 was 66 months (range 2-171), with 32% alive at time of analysis. The most common cause of death was disease recurrence (n = 45 [73%]). At 2 years, the rates of OS, PFS, progression, and nonrelapse mortality were 36%, 27%, 42%, and 18%, respectively. The development of chronic graft-versus-host disease (GVHD) after first HCT and HCT comorbidity index (HCT-CI) ≥2 at HCT2 were associated with inferior PFS and OS after HCT2. A second HCT is feasible in selected patients with AML who have relapsed after HCT1. Long-term survival benefit is possible in patients without chronic GVHD after HCT1 and HCT-CI

Fluid overload (FO) grade ≥2 (more than 10% weight gain from baseline) has recently been recognized as an important toxicity associated with a high rate of nonrelapse mortality in recipients of allogeneic hematopoietic cell transplantation (AHCT). The causes for FO remain unclear. We hypothesized that endothelial damage, possibly due to treatments received prior to AHCT, may be associated with this toxicity and sought to determine whether the Endothelial Activation and Stress Index (EASIX) (defined as lactate dehydrogenase [U/L] × creatinine [mg/dL]/platelets [109 cells/L]) correlates with grade ≥2 FO in 2 cohorts of recipients of AHCT at our institution. We tested our hypothesis in a cohort of 145 consecutive recipients (study cohort) of AHCT transplant from HLA-haploidentical donors and validated the findings in a cohort of 449 (validation cohort) recipients of AHCT from HLA-matched donors who underwent transplantation between 2010 and 2015. Predictors of grade ≥2 FO were evaluated using competing risks regression in univariate analysis and classification and regression tree (CART) analysis in multivariate analysis. The cumulative incidence of grade ≥2 FO was estimated considering death as a competing risk. EASIX scores were evaluated based on log2-transformed values. Optimal predictive EASIX cutoff values were determined based on receiver operating characteristics curve analysis. Grade ≥2 FO occurred in 21% and 6% of the study and validation cohorts, respectively, with the majority of these cases being diagnosed before the day of AHCT. Median log2 EASIX score at admission was 2.4 (interquartile range [IQR], 1.3, 3.7) and 2.5 (IQR, 1.4, 3.9) in the 2 respective cohorts. In univariate analysis, high EASIX at admission was a significant predictor of grade ≥2 FO in the study (cutoff: 4.4, hazard ratio [HR] = 4.8, P 60 years (HR = 9.6, P = .04) in the validation cohort. At admission, the prevalence of EASIX score of >4.3 (18% versus 17%, P = .9) was not different between the diabetics and nondiabetics. EASIX score at admission is a significant predictor of grade ≥2 FO in recipients of AHCT from HLA-haploidentical or HLA-matched donors. Independently of EASIX, older patients with low weight were associated with increased risk of grade ≥2 FO for recipients of HLA-haploidentical transplants. For the HLA-matched cohort, diabetes and older age were associated with increased FO risk. These findings require validation in external cohorts.

Tailings dams have been built since 3000 BCE and despite the advancement of construction methods, mainly in the second half of the 21st century, their ruptures were still recorded. The main direct impacts are related to the loss of human lives, impairment of physical structures and changes in water quality. In this review, different dam failure events were critically analyzed considering their social and environmental impacts, besides the gaps in current regulations framework to appropriately charge the companies involved. These aspects differ the current review paper from those currently available, which also present advancements in the discussion of actions taken after the ruptures, the impacts on water quality, and the challenges related to the water supply. It has been noticed a lack of studies and methodologies capable to predict the water quality under scenarios of tailings contamination. Studies covering that aspect would be an important tool for planning emergency responses by stakeholders. With that in mind, the article discloses the pathway toward an effective strategy in scenarios of tailing dam failure that would mitigate the impacts on water quality and guarantee access to safe water.

Adapted from the haploidentical hematopoietic stem cell transplantation (HCT) literature, post-transplantation cyclophosphamide (PTCy) is being used increasingly with HLA-matched donors, generally with a calcineurin inhibitor, such as tacrolimus (Tac), and with or without mycophenolate mofetil (MMF). Owing to its immunosuppressive and potentially antitumor and antimicrobial properties, MMF is an attractive drug; the benefit gained when it is used with PTCy/Tac remains unclear, however. To assess this, we compared PTCy/Tac (n = 242) and PTCy/Tac/MMF (n = 144) regimens in recipients of HLA-matched donor transplantation. In multivariate analysis, the PTCy/Tac/MMF group had a significantly higher risk of grade II-IV acute graft-versus-host disease (aGVHD) (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.6 to 2.8; P.001), and steroid-refractory/dependent aGVHD (HR, 4.8; 95% CI, 2.4 to 9.6; P.001), yet a significantly lower risk of relapse (HR, .5; 95% CI, .3 to .9; P = .009) and better progression-free survival (PFS) (HR, .7; 95% CI, .5 to .9; P = .04). There were no differences in the risk of grade III-IV aGVHD, chronic graft-versus-host disease (cGVHD), nonrelapse mortality, or overall survival. MMF was associated with prolonged neutrophil engraftment by 2 days and an elevated risk of bacterial infection. In an exploratory stool microbiome analysis (n = 16), we noted a higher relative abundance of β-glucuronidase-producing bacteria in the MMF group, which may have a role in the pathogenesis of MMF-related GVHD. Our data suggest that the addition of MMF to PTCy/Tac for HLA-matched donor HCT does not provide any advantage for GVHD prevention. Further studies are needed to decipher this mechanism and understand its role with PTCy-based prophylaxis.

With the availability of immunomodulatory imide drugs (IMiDs) and proteasome inhibitors (PI), most patients with immunoglobulin light chain amyloidosis (AL) receive induction therapy before autologous hematopoietic stem cell transplantation (auto-HCT). In this study we evaluated the type of induction therapy and its impact on the outcome of auto-HCT in AL. We identified 128 patients with AL who underwent high-dose chemotherapy and auto-HCT at our institution between 1997 and 2013. Patients were divided into 3 groups: no induction, conventional chemotherapy (CC)-based induction (melphalan, steroids), and IMiD/PI-based induction (thalidomide, lenalidomide, or bortezomib). The hematologic response (HR) and organ response were defined according to the established criteria. Median age at auto-HCT was 58 years (range, 35 to 75). Twenty patients (15.5%) received no induction, 25 (19.5%) received CC, and 83 (65%) received IMiDs/PIs. One, 2, or 3 or more organs were involved in 90 (70%), 20 (16%), and 18 (14%) patients, respectively. After auto-HCT 12 of 20 (60%), 15 of 24 (62%), and 72 of 83 (87%) assessable patients achieved HR at 100 days in no induction, CC, and IMiD/PI groups, respectively (P = .001). Organ response at 1 year after auto-HCT was seen in 7 of 18 (39%), 14 of 24 (58%), and 37 of 79 (47%) assessable patients in no induction, CC, and IMiD/PI groups, respectively (P = .3). Achieving a hematologic complete response was associated with a significantly higher probability of achieving an organ response (P = .02). After a median follow-up of 26 months, rates of 2-year progression-free survival were 67%, 56%, and 73% in no induction, CC, and IMiD/PI groups, respectively (P = .07; hazard ratio, .5; 95% confidence interval [CI], .3 to 1.1). Rates of 2-year overall survival were 73%, 76%, and 87% in no induction, CC, and IMiD/PI groups, respectively (P = .05; hazard ratio, .4; 95% CI, .2 to .9). On multivariate analysis a low β2-microglobulin (P = .01; hazard ratio, .3; 95% CI, .1 to .7) and induction therapy with IMiD/PI (P = .01; hazard ratio, .3; 95% CI, .1 to .7) were associated with a better overall survival. Induction therapy with either CC or IMiDs/PIs is safe and feasible in selected patients with AL. IMiD/PI-based induction is associated with a longer overall survival compared with patients who received no induction or CC before auto-HCT.

We studied if the inclusion of early post–stem cell transplantation (SCT) minimal residual disease (MRD) assessments improved prognostication in patients with acute myeloid leukemia (AML). Two hundred sixty-nine AML patients in morphological complete remission (CR) who underwent a first SCT were included if they had evaluable pre-SCT MRD assessment by multiparametric flow cytometry. Post-SCT MRD assessments were performed at days +30, +100, and +180. The primary outcome was 1-year relapse incidence (RI). Of 269 patients in CR, 83 (30.8%) had detectable MRD pre-SCT. Post-SCT, during routine disease assessment time points, 9 of 241 evaluable patients (3.7%) at day +30, 6 of 191 evaluable patients (3.1%) at day +100, and 4 of 133 evaluable patients (3%) at day +180 were MRD positive while in CR. MRD positivity at day +30 predicted the highest risk of relapse at 1 year (group 1, 1-year RI 78%). Among MRD-negative patients at day +30, either adverse risk category by European Leukemia Net (ELN) or intermediate risk who were aged ≥60 years and/or pre-SCT MRD-positive represented the intermediate-risk group (group 2, 1-year RI 29%). The remaining patients represented the low-risk group (group 3, 1-year RI 5%). For patients in CR beyond day +30 post-SCT, detectable MRD at any time point predicted impending relapse within 2 months. Early post-SCT MRD assessment—combined with pre-SCT MRD assessment, ELN risk category, and age—improves risk stratification for relapse in AML patients post-transplant. Studies aimed at preventing impending relapse in this high-risk population are urgently needed.

In the coronavirus disease 19 (COVID-19) pandemic era, the number of haploidentical hematopoietic cell transplantations (HCTs) with peripheral blood (PB) grafts increased significantly compared with HCTs with bone marrow (BM) grafts, which may be associated with adverse outcomes. We compared outcomes of HCT in BM graft and PB graft recipients age ≥18 years with hematologic malignancies who underwent T cell- replete haploidentical HCT and received graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Among the 264 patients, 180 (68%) received a BM graft and 84 (32%) received a PB graft. The median patient age was 50 years in both groups. The majority (n = 199; 75%) received reduced-intensity conditioning. The rate of acute leukemia or myelodysplastic syndrome was higher in the BM graft recipients compared with the PB graft recipients (85% [n = 152] versus 55% [n = 46]; P < .01). The median times to neutrophil and platelet engraftment and the incidence of grade II-IV and grade III-IV acute GVHD (aGVHD) were comparable in the 2 groups. Among the patients with grade II-IV aGVHD, the rate of steroid-refractory aGVHD was 9% (95% confidence interval [CI], 5% to 18%) in the BM group versus 32% (95% CI, 19% to 54%) in the PB group (hazard ratio [HR], 3.7, 95% CI, 1.5 to 9.3; P = .006). At 1 year post-HCT, the rate of chronic GVHD (cGVHD) was 8% (95% CI, 4% to 13%) in the BM group versus 22% (95% CI, 14% to 36%) in the PB group (HR, 3.0; 95% CI, 1.4-6.6; P = .005), and the rate of systemic therapy-requiring cGVHD was 2.5% (95% CI, 1% to 7%) versus 14% (95% CI, 7% to 27%), respectively (HR, 5.6; 95% CI, 1.7 to 18; P = .004). The PB group had a significantly higher risk of bacterial and viral infections, with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, nonrelapse mortality, or survival. Our data suggest a benefit of the use of BM grafts over PB grafts for haplo-HCT.

The impact of age at diagnosis on outcomes of patients with Hodgkin lymphoma (HL) undergoing autologous hematopoietic transplantation (auto-HCT) is unclear. We retrospectively evaluated the impact of age on outcomes of 310 consecutive patients with relapsed/refractory HL who underwent auto-HCT between January 1996 and December 2010 with carmustine, etoposide, cytarabine, and melphalan conditioning therapy. Patients were stratified into ≤ 55 and >55-year-age groups based on age at diagnosis. At a median follow-up of 80 (range, 1 to 180) months, progression-free survival was similar between both age groups. However, age older than 55 years at diagnosis was associated with significantly poor overall survival with a hazard ratio [HR] of 2.3 (P = .003) from higher rate of second malignancies (HR, 3.8; P = .015) compared with patients 55 years or younger. In conclusion age > 55 years at diagnosis increases risk of second malignancies after auto-HCT.

Introduction PTCy-based GVHD prophylaxis has emerged as an effective method in Allo-HCT. Cyclophosphamide has historically been associated with increased rates of cardiac toxicities. This potential complication plays a role in the choice of optimal GVHD prophylaxis. The cardiac toxicity profile of PTCy compared with non-PTCy GVHD prophylaxis in HLA-matched Allo-HCT setting is unclear. Methods We performed a retrospective analysis to evaluate cardiac toxicities after HLA-matched Allo-HCT between October 1, 2016 and April 1, 2019. Cardiac toxicity was defined as any documented arrhythmia, heart failure, cardiac event (cardiac arrest or myocardial infarction), pericarditis, or pericardial effusion that occurred between Day 0 and 100. Results A total of 585 consecutive adult patients met eligibility (Table 1). 38 unique patients developed a total of 52 cardiac toxicities. The median time to cardiac toxicity was 20 days in the PTCy and 15 days in the non-PTCy groups. Toxicities (Table 2) included arrhythmias (40%), heart failure (27%), pericardial effusions (19%), and cardiac events (13%). This distribution and severity of toxicity was comparable between groups. Similarly the cumulative incidence of cardiac toxicity was comparable between the PTCy and non-PTCy groups (7 vs. 6%, p=0.4). Predictors of cardiac toxicity are shown in table 1. In univariate analysis, the cardiac comorbidity composite (defined as the presence of arrhythmia, cardiac, or heart valve comorbidities obtained via HCT-CI score) was found to be the most significant predictor for the development of cardiac toxicity (p In multivariate analysis, the cardiac comorbidity composite maintained significance and this effect was augmented by the presence of diabetes and infection. Patients with the cardiac comorbidity composite who also had diabetes or infection had the highest incidence (37%, p Conclusion Our results demonstrate a low incidence of cardiac toxicity. Baseline cardiac comorbidities are associated with higher incidence of developing cardiac toxicities after Allo-HCT. PTCy-based GVHD prophylaxis does not appear to impact the development of cardiac toxicities after HLA-matched Allo-HCT and may be associated with survival benefit in patients who do experience toxicity.

Introduction Haploidentical (HAPLO) stem cell transplantation (SCT) has been shown to be associated with lower incidence of severe acute graft-versus-host (aGVHD) compared with 8/8 HLA-matched unrelated donor (MUD) SCT. However, no information is available regarding aGVHD characteristics comparing these 2 donor sources. Methods We aimed to compare aGVHD characteristics and non-relapse mortality (NRM) in adult patients with grade 2-4 aGVHD after HAPLO (N=758) or MUD (N=2586) SCT that were reported to the Center for International Blood and Marrow Transplant Research (Table 1). GVHD prophylaxis included a calcineurin inhibitor (CNI), mycophenolate mofetil (MMF), and post-transplant cyclophosphamide (PTCy) in HAPLOs, and CNI with MMF or methotrexate in MUDs. Results The 6-m cumulative incidence (CumInc) of grade 2-4 aGVHD (35 vs 45%, 2 organs involved, stage 4 skin (1 vs 5%, p=0.01), and stage 3-4 liver (4 vs 7%, p=0.04) or LGI (14% vs 21%, p=0.01). The 2-yrs and overall CumInc of NRM since aGVHD was 18% (95% CI 14-23) and 19% (95% CI 14-24) in HAPLOs; and 30% (95% CI 27-33) and 51% (95% CI 30-68) in MUDs. In multivariate analysis, grade 2-4 aGVHD in HAPLOs was associated with significantly lower NRM, but this effect was limited to donor-recipient pairs [CumInc: 15 vs 30%, HR=0.5, p=0.002] that were not sex-mismatched (female to male). In sex-mismatched pairs [CumInc: 30% vs 26%, HR=1.2, p=0.6], NRM was comparable between HAPLOs and MUDs. Subset analyses in recipients (N=718) ≥60 years also showed HAPLOs (N=92) to have a lower 6-m CumInc of grade 2-4 (29 vs 44%, p Conclusions Compared with 8/8 HLA-matched unrelated SCT with standard GVHD prophylaxis, aGVHD tends to be less severe and associated with lower NRM after HAPLO SCT with PTCy GVHD prophylaxis. This effect is more pronounced in recipients ≥60 years of age.

Background Older patients undergoing allogeneic stem cell transplant (SCT) have inferior outcomes. They have limited physiological reserves, which makes them more susceptible to toxic effects of conditioning regimens. Supportive care directed at maintaining and augmenting their limited functional reserve may reduce non-relapse mortality (NRM). We studied impact of a multidisciplinary supportive care and prehabilitation program (ER-SCT) and compared one-year NRM with a historical control group. Methods Between 1/1/15 and 9/30/18, 204 patients ≥ 65 years old underwent allogeneic SCT at our institution. ER-SCT program started on 10/1/17 and 57 of 64(89%) eligible patients participated during the first year. All 64 patients were included in the ER-SCT cohort, while patients treated between 1/1/15-9/30/17 were in the control group. ER-SCT program consisted of a prehabilitation phase prior to admission. Patients were evaluated by a multidisciplinary team consisting of a geriatrician, physical medicine and rehabilitation physician, physical therapist, occupation therapist, dietician, nurse, and a pharmacist specializing in SCT. Preexisting chronic conditions were optimized and recommendations were made for nutrition, exercise, and coping strategies. During hospitalization, fluid usage and medication choice / doses were optimized for older patients to prevent side effects such as fluid overload and delirium. Physical therapy, occupational therapy and nutrition counselling was continued. The team continued to follow and intervene as needed after discharge from the hospital. Results Median age was 68 (65-79) with 36 (18%) patients >than 70 years. Diagnoses included AML 96 (47%), MDS 57(28%), MPD 26 (13%), ALL 8(4%), and other 17 (8%). 103 (51%) had high or very high disease risk index (DRI). HCT-CI score was >3 in 80 (39%). Donor types included 127 (62%) matched unrelated, 57(28%) matched related and 20(10%) haploidentical. The NRM at 1 year was 13% in ER-SCT cohort vs 26% (p=0.03) in the control cohort. Multivariate analysis adjusting for GVHD prophylaxis and conditioning regimen, age, DRI, HCT-CI, donor type and graft source showed that ER-SCT HR=0.4 (0.2-0.9, P=0.02), comorbidity score Conclusion Although the data from this retrospective sequential cohort analysis cannot be conclusive, they do suggest that a multidisciplinary supportive care program (ER-SCT) may reduce NRM in older patients undergoing allogeneic SCT.

Numerous genetic abnormalities affect treatment outcomes in multiple myeloma. The role of coexistent trisomy or hyperdiploidy and high-risk cytogenetic abnormalities (CGAs) is not well defined. We assessed the influence of overlapping genetic abnormalities in patients who received frontline autologous stem cell transplantation. A total of 491 consecutive patients between January 2009 and January 2016 were identified. High-risk CGAs included del(17p), t(4;14), t(14;16), and gain 1q21 by fluorescence in situ hybridization and del(13) by conventional cytogenetics. Thirty-two percent had a trisomy, 27% had a high-risk CGA, and 11% had both. Among patients with any trisomy, 3-year progression-free survival (PFS) and overall survival (OS) were 60% and 90%, respectively, compared to 25% and 65%, respectively, for patients with any high-risk CGA. Patients with co-existent trisomy and high-risk CGAs had 3-year PFS and OS of 43% and 89%, respectively, whereas those with isolated high-risk CGAs without trisomy had 3-year PFS and OS of 13% and 49%, respectively. The PFS (hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.1 to 3.3; P = .02) and OS (HR, 4.5; 95% CI, 1.5 to 13; P = .006) were worse for high-risk CGAs without versus those with concurrent trisomies. Our findings suggest a protective impact of trisomies in patients with high-risk CGAs and a potential need for revised risk stratification assessments to account for overlapping genetic abnormalities.

Forty patients (median age, 31 years; range, 20 to 63) with Hodgkin lymphoma underwent an allogeneic stem cell transplant with the gemcitabine–fludarabine–melphalan reduced-intensity conditioning regimen. Thirty-one patients (77%) had undergone a prior autologous stem cell transplant, with a median time to progression after transplant of 6 months (range, 1 to 68). Disease status at transplant was complete remission/complete remission, undetermined (n = 23; 57%), partial remission (n = 14; 35%), and other (n = 3; 8%). Twenty-six patients (65%) received brentuximab vedotin before allotransplant. The overall complete response rate before allotransplant was 65% in brentuximab-treated patients versus 42% in brentuximab-naive patients (P = .15). At the latest follow-up (October 2015) 31 patients were alive. The median follow-up was 41 months (range, 5 to 87). Transplant-related mortality rate at 3 years was 17%. Pulmonary, skin toxicities, and nausea were seen in 13 (33%), 11 (28%), and 37 (93%) patients, respectively. At 3 years, estimates for overall and progression-free survival were 75% (95% CI, 57% to 86%) and 54% (95% CI, 36% to 70%). Overall incidence for disease progression was 28% (95% CI, 16% to 50%). We believe the gemcitabine–fludarabine–melphalan regimen allows moderate dose intensification with acceptable morbidity and mortality. The inclusion of gemcitabine affected nausea, pulmonary, and likely skin toxicity. Exposure to brentuximab vedotin allowed more patients to reach allogeneic stem cell transplantation in complete remission. With over 50% of patients progression-free at 3 years, allogeneic stem cell transplantation with reduced-intensity conditioning remains an effective and relevant treatment option for Hodgkin lymphoma in the brentuximab vedotin era.

Context Relapse after allogeneic hematopoietic cell transplantation (allo-HCT1) leads to poor survival in patients with acute myeloid leukemia (AML). A second allo-HCT can achieve durable remission in a subset of patients. Objective To assess outcomes of patients who underwent allo-HCT2 for relapsed AML and identify risk factors associated with survival. Design We reviewed consecutive medical records of 91 adult patients (age >18 years) with AML who underwent allo-HCT2 for relapsed disease at our institution from January 2000 until August 2019. Results At allo-HCT2, median age was 43 (range, 18–67), donor types were HLA-identical sibling 41%, HLA-matched-unrelated 35%, haploidentical 21%, and cord-blood 1%. Donors were different at allo-HCT2 in 53% patients. The majority of patients received reduced intensity conditioning (78%) and were in remission (58%) at allo-HCT2. The median remission duration after allo-HCT1 was 8.4 months (range, 1–70); median time between transplants 13.6 months (range, 2.6–73). The median follow-up of surviving patients after allo-HCT2 was 25 months (range, 4–70), with 32% alive at time of analysis; the most common cause of death was disease recurrence (87%). At 2-years, progression-free-survival, overall survival, and cumulative incidence of relapse were 30% (95% CI, 18–37%), 36% (95% CI, 26–47%) and 42% (95% CI, 32–54%), respectively. The cumulative incidence of grades II–IV acute and chronic GVHD were 35% and 18%, respectively. In multivariate analysis, persistent disease at time of allo-HCT1 and allo-HCT2, along with high leukemia burden at allo-HCT2 (defined as BM blast >10%) [HR,2.4; p=0.006], development of cGVHD after allo-HCT1 [HR,3.1; p 2) [HR, 2.1; p=0.01] were associated with inferior PFS after allo-HCT2. These factors also predicted for OS. A total of 19, 55, and 17 patients had neither, one, or more than one adverse factors, respectively. Two-year OS was 60%, 40%, and 0%, and PFS was 47%, 28%, and 0% in these 3 respective groups. Conclusions Long-term survival benefit is possible after allo-HCT2 in patients with AML who relapsed after allo-HCT1. This can be achieved in patients without cGVHD after allo-HCT1 who are fit and in remission at time of allo-HCT1, along with

Background Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than the standard four day regimen. (Popat et al Lancet Haematology 2018). Subsequently, we added post-transplant cyclophosphamide (PTCy) GVHD prophylaxis to our fractionated regimen with a hypothesis that it will reduce GVHD and improve outcomes. Herein, we report the results of our retrospective analysis comparing outcomes of patients with AML who received fractionated busulfan myeloablative conditioning and PTCy versus standard tacrolimus (Tac) and methotrexate (Mtx) GVHD prophylaxis. Methods Patients with AML between 18-70 years of age with adequate organ function and 8/8-HLA matched related or unrelated donor, who were treated on 4 consecutive protocols using fractionated busulfan were included in the analysis. All patients received two fixed doses of busulfan 80mg/m2 as outpatient either on days -13 and -12, or on days -20 and-13 followed by busulfan on day -6 to -3 dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. Fludarabine ± cladribine were given on day -6 to -3. GVHD prophylaxis was PTCy 50mg/kg on days 3 and 4 and Tac ± mycophenolate mofetil in PTCy cohort (n=53), or standard Tac+ Mtx (n=53). Patients in both the cohorts were matched 1:1 by propensity score. Results Baseline characteristics were similar between the PTCy and Tac/Mtx cohorts. The median age was 60 (range, 18-70) and 58 (range, 24-70) years, respectively, (P=0.3). Forty-nine percent were in CR, and 30% had comorbidity index >3 in each arm. Similar proportion of patients had ELN adverse risk in both arms (43% vs 40%, respectively P=0.7). The median follow up was 19 months (range, 3-36) in the PTCy and 46 months (range, 14-73) in Tac/Mtx cohort. Overall survival at 2-year was 78% vs 58% (P=0.03), non-relapse mortality was 6% vs 13% (P=0.2), incidence of grade 3-4 acute GVHD at 1-year was 6% vs 19% (P=0.07) and chronic GVHD at 2-year was 10% vs 29% (P=0.03) [Table 1 and figure 1]. The median time to neutrophil engraftment was prolonged by 3 days (15 vs 12 days; P Conclusion As compared to Tac/Mtx, PTCy-based GVHD prophylaxis not only reduced severe acute GVHD and chronic GVHD, but also improved overall survival in AML patients up to the age of 70 years who received myeloablative fractionated busulfan conditioning. Prospective randomized trial is warranted to validate these findings.

Background Fluid overload (FO) grade ≥ 2 (more that 10% weight gain from baseline) has recently been recognized as an important toxicity associated with non-relapse mortality in recipients of allogeneic stem cell transplantation (alloSCT).1 The causes for fluid accumulation remain unclear. We hypothesized that endothelial damage due to treatments received prior to alloSCT may be associated with this toxicity and sought to determine whether the Endothelial Activation and Stress Index2 (EASIX), (defined as lactate dehydrogenase (U/L) × creatinine (mg/dL)/ thrombocytes (109 cells per L), correlates with grade ≥ 2 FO and overall survival (OS) in 2 cohorts of recipients of alloSCT at our institution. The first cohort included 145 recipients of haploidentical (haplo) transplantation, and the second 449 recipients of alloSCT from HLA-matched donors, as previously described.1 Methods Predictors (listed in table) of grade ≥ 2 FO and 6-months OS were evaluated using Cox's proportional hazards regression analysis on univariate analysis, and classification and regression tree (CART) analysis on multivariate (MV) analysis. EASIX scores were evaluated based on log2 transformed values. Results Median log2 EASIX score in the 2 cohorts was 2.4 (IQR: 1.3, 3.7) and 2.5 (IQR 1.4, 3.9) at admission, and 3.1 (IQR 2.2, 3.9) and 2.8 (IQR 1.7, 3.9) at transplant, respectively. CART analysis identified EASIX > 4.4 at admission to be an independent predictor of grade ≥ 2 FO in the haplo (HR=7.5, p 55 years recipients in the haplo cohort, and diabetes (HR=35, p=0.001) and age >60 years (HR=8.1, p=0.06) in the matched cohort. In patients with grade ≥ 2 FO, EASIX >4.4 at SCT was the only significant predictor of OS (HR=4.1, p=0.002). This effect was consistent in both cohorts (Figure A). In patients with grade 0-1 FO, MV analysis showed EASIX >3, comorbidity index score >3, and active disease at SCT to be independent adverse predictors of OS. OS was lowest (60%, reference) in patients with EASIX> 3 and comorbidity score >3, and this effect was consistent in both cohorts (Figure B). OS was significantly higher in patients with EASIX >3 and comorbidity score ≤3 (73%, p

Background Post transplant cyclophosphamide (PTCy), tacrolimus, and MMF GvHD prophylaxis makes transplantation from haploidentical donors feasible without T cell depletion. In matched donor transplant recipients, cumulative incidences of grades II-IV acute, grades III-IV acute, and chronic GVHD were 51%, 15%, and 14%, respectively when single agent PTCy was used (Kanakry et al JCO 2014 32:3497-3505). However; as a single agent it was inferior to tacrolimus and methotrexate in another study (Alousi etal BBMT 2015, 906-912). We therefore hypothesized that addition of tacrolimus to PTCy may be needed to prevent severe acute GVHD and improve transplant outcomes. Methods All patients with AML undergoing first allogeneic transplant from matched sibling or at least 9/10 matched unrelated donor between 1/1/2011 to 4/30/2018 were eligible for this retrospective study if they received a melphalan or timed sequential busulfan (course AUC 20,000 umol/min) based conditioning regimen. GVHD prophylaxis consisted of tacrolimus and methotrexate 5mg/m2 on day 1, 3, 6, and 11 in the Tac/MTX cohort (n=140); and cyclophosphamide 50mg/kg given on days 3 and 4 and tacrolimus in the PTCy cohort (n=76). Results Patient characteristics were similar in both cohorts except that patients in PTCy cohort were younger with a median age of 59 years versus 63.5 years (P Outcomes and results of univariate analysis are summarized in Table1. Conclusion Tacrolimus and PostCy based GVHD prophylaxis reduces severe GVHD and improves survival.

Background The cell of origin (COO) classification has been shown to predict survival outcomes in de-novo diffuse large B-cell lymphoma (DLBCL), however, it is unclear if this holds true following high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) in relapsed DLBCL patients. The current analysis aims to compare survival outcomes based on COO classification in relapsed DLBCL patients who received auto-HCT. Methods This retrospective study includes relapsed/refractory DLBCL patients, aged 18 and above, who received auto-HCT with standard of care conditioning from January 2007 to December 2016 at our institution. Hans algorithm using CD10, BCL6 and MUM1 markers was performed to classify patients as per COO into the GCB and non-GCB types. Kaplan Meier method was used to estimate progression free survival (PFS) and overall survival (OS). Results A total of 122 DLBCL (71 GCB, 51 non-GCB) patients were analyzed. Detailed patient characteristics are provided in Table 1. Except for GCB cohort being older (64 vs. 58 years, p 70 (HR=2.9, p=0.03) and IPI score 0 (HR=0.3, p=0.005) were significant variables in predicting PFS. After adjusting for these variables, no significant differences were seen in PFS between two groups. The median OS has not yet been reached in both groups therefore a difference in OS cannot be analyzed. Conclusion Our results suggest that cell of origin is not prognostic for patients with relapsed/refractory DLBCL treated with high dose chemotherapy followed by auto-SCT.

Introduction Graft-versus-host disease (GVHD) of the lung, also known as bronchiolitis obliterans syndrome (BOS), is associated with high mortality, but treatment with the combination of fluticasone, azithromycin, and montelukast (FAM) stabilizes lung function in the majority of patients. Recently, a randomized controlled trial evaluating azithromycin given at the time of conditioning for GVHD prevention was closed prematurely due to an increased risk of cancer relapse in azithromycin recipients. We evaluated whether exposure to azithromycin after allogeneic hematopoietic cell transplantation (allo-HCT), primarily for treatment of BOS, was also associated with a higher rate of cancer progression. Methods We conducted a retrospective study of patients who underwent allo-HCT and experienced a significant decline in pulmonary function from pre-HCT values (decrease in forced expiratory volumes in 1 second of ≥10% OR mid-flow rates of ≥25%) between 2005 and 2015. Risk factors for cancer progression were examined using cause-specific univariate and multivariate Cox regression analysis with azithromycin exposure evaluated as a time-dependent covariate. Results Among 672 eligible allo-HCT recipients with pulmonary decline, 9% (n=63) received azithromycin, including 41 patients for BOS and 22 patients for chronic treatment for mycobacterial infection or bacterial prophylaxis. Table 1 shows characteristics of the entire study cohort. No patients with chronic lymphocytic or myeloid leukemia (n=13) or lymphoma (n=12) who were exposed to azithromycin experienced cancer progression during the study period. Therefore, we evaluated the impact of azithromycin exposure on the rate of cancer progression in the subset of patients with acute myeloid leukemia or myelodysplastic syndrome (AML/MDS, n-327) or acute lymphoblastic leukemia (ALL, n=91). The median follow-up since allo-HCT in this subgroup was 73 months (range 5-148 months). 38 of these patients were exposed to azithromycin at a median time of 25 months (interquartile range 11-46 months) after allo-HCT. In multivariate analysis, azithromycin (HR 3.7, 95% CI 1.5-9.4, p=0.005) and unfavorable cytogenetics (HR 1.7, 95% CI 1.2-2.5, p=0.004) were associated with increased rates of cancer progression. Median time to cancer progression from time of allo-HCT was 8 months (range 1-98 months) for the entire cohort, while the median time to cancer progression was later in those exposed to azithromycin (median 21 months, range 4-25 months). The median time to cancer progression after exposure to azithromycin was 51 days (range 17-847 days). Conclusion Our findings show that recipients of allo-HCT for treatment of AML/MDS or ALL, exposure to azithromycin for BOS or infections is associated with an increased rate of cancer progression.

Chimerism testing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represents a promising tool for predicting disease relapse, although its precise role in this setting remains unclear. We investigated the predictive value of T lymphocyte chimerism analysis at 90 to 120 days after allo-HSCT in 378 patients with AML/MDS who underwent busulfan/fludarabine-based myeloablative preparative regimens. Of 265 (70%) patients with available T lymphocyte chimerism data, 43% of patients in first or second complete remission (CR1/CR2) at the time of transplantation had complete (100%) donor T lymphocytes at day +90 to +120 compared with 60% of patients in the non-CR1/CR2 cohort (P = .005). In CR1/CR2 patients, donor T lymphocyte chimerism ≤ 85% at day +90 to +120 was associated with a higher frequency of 3-year disease progression (29%; 95% confidence interval [CI], 18% to 46% versus 15%; 95% CI, 9% to 23%; hazard ratio [HR], 2.1; P = .04). However, in the more advanced, non-CR1/CR2 cohort, mixed T lymphocyte chimerism was not associated with relapse (37%; 95% CI, 20% to 66% versus 34%; 95% CI, 25% to 47%; HR, 1.3; P = .60). These findings demonstrate that early T lymphocyte chimerism testing at day +90 to +120 is a useful approach for predicting AML/MDS disease recurrence in patients in CR1/CR2 at the time of transplantation.

We studied the roles of autologous (A) and allogeneic (allo) stem cell transplantation (SCT) in the treatment of 134 patients with T cell lymphoma (TCL) at our center. For frontline SCT, 58 patients were studied. The 4-year overall survival (OS) rates for ASCT (n = 47; median age, 49 years) and alloSCT (n = 11; median age, 55 years) groups were 76% and 54%, respectively (P > .05). The 4-year OS rates for first complete remission (CR1) patients were 84% and 83%, respectively. For SCT for relapsed disease, 76 patients were studied (41 with ASCT and 35 with alloSCT). The 4-year OS rates were 50% and 36% for ASCT and alloSCT patients with chemosensitive disease, respectively (P > .05). Those who were in CR2 and CR3 had 4-year OS rates of 59% and 53%, respectively. Similar results were also observed in patients with refractory disease (29% and 35%, respectively). These data suggest that a pre-SCT CR is associated with improved outcomes in TCL patients after SCT. Considering the 84% 4-year OS rates in CR1 patients and the unpredictable responses in patients with relapsed disease, we favor the use of ASCT as consolidation therapy after CR1. AlloSCT did not result in a superior outcome compared with ASCT.

Introduction The role of T-cell helper 1 cytokines, including TNF-α and IL-6, in the pathophysiology of acute graft-versus-host disease (aGVHD) is well established. Emerging data have also implicated IL-2, a marker of activated T-cells, in the GVHD reaction. 1 We hypothesized that pre-transplant IL-2 levels may correlate with the incidence of aGVHD. We tested our hypothesis in a cohort of 16 patients who received allogeneic stem cell transplantation (SCT) following fludarabine/busulfan based conditioning regimen and tacrolimus/methotrexate GVHD prophylaxis at our institution between 7/2012 and 1/2013. Methods TNF-α, IL-6, and IL-2 plasma levels were measured by ELISA day -13 (pre-SCT), day of SCT, days +7 and +14. Results Median age of patients was 61 years (range 47-70). The majority (62%) were treated for AML/MDS, and 81% had active disease at transplant. Median comorbidity index score was 3 (range 0-6). Donors were HLA-matched related (44%) or unrelated (56%), and peripheral blood was the stem cell source for all related donors and for 50% of unrelated donors. A quarter of the donor/recipient pairs were sex-mismatched (female donor to male recipient). The majority of donors (69%) were CMV seronegative, while 75% of recipients were CMV seropositive. Of 16 patients, 6 were diagnosed with grade II-IV aGVHD at a median of 28 days (range 18-83). Median follow-up was 24 months (range 3-64) in grade II-IV aGVHD-free patients. IL-2 levels (µg/mL) pre-SCT correlated with day of SCT, day +7, and day+14 levels. Median IL-2 was 0 (undetectable) pre-SCT (range 0-3.2) and on day of SCT (range 0-4.9). Patients with detectable (>0) IL-2 levels pre-SCT (n=5, median IL-2: 1.2, range 0.3-3.2) or on day of SCT (n=6, median IL-2: 2.6, range 0.2-4.9) were at high-risk of developing grade II-IV aGVHD. The incidence of grade II-IV aGVHD was 75% in patients (n=8) with detectable IL-2 levels pre-SCT and/or on the day of SCT (Figure). In contrast, none of the patients (n=8) who had undetectable IL-2 levels at both time points developed grade II-IV aGVHD (p=0.002). TNF-α and IL-6 levels (evaluated at the median) pre-SCT or on day of SCT were not associated with the incidence of grade II-IV aGVHD. Detectable pre-SCT IL2-were not correlated with ALC (K/µL) (median: 0.65 vs 0.87, p=0.6), but were correlated with longer duration since the last chemotherapy treatment (median 101 vs 47, p=0.02). Recipient age, disease status at SCT, CMV status, comorbidity index, and sex-mismatch did not correlate with pre-SCT IL-2 levels or with the incidence of grade II-IV aGVHD. Conclusion Our data suggest that elevated IL-2 before transplant may be associated with increased risk of aGVHD. Validation of these findings in larger datasets is warranted, as they may identify patients for trials of alternative GVHD prophylaxis.

The t(11;14)(q13;q32) translocation is seen in 15%-20% patients with multiple myeloma (MM). It generally is not associated with worse outcomes. We studied the impact of t(11;14)(q13;q32) on outcome in patients with MM who received high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HCT). Eligible patients underwent high-dose chemotherapy followed by auto-HCT at the M.D. Anderson Cancer Center between February 2000 and August 2010, and had conventional cytogenetic (CC) or fluorescence in situ hybridization (FISH) results available before auto-HCT (n = 993). The cohort was divided into 3 groups of patients: (1) normal (diploid by CC and negative by FISH; n = 869); (2) t(11;14)(q13;q32) by CC or FISH (n = 27); and (3) high-risk (HR) abnormalities by CC or FISH (n = 97). Of the 27 patients with t(11;14)(q13;q32), 18 had isolated t(11;14)(q13;q32) and 9 had concurrent HR abnormalities. The primary objective was to compare outcomes in patients with t(11;14)(q13;q32) and patients with diploid or HR markers detected by CC or FISH studies. The median duration of follow-up in surviving patients was 37 months. The 3-year progression-free survival (PFS) was 47% for the normal group, 27% for the t(11;14)(q13;q32) group, and 13% for the HR group (P 3.5, and relapsed disease at the time of auto-HCT were associated with shorter OS. In conclusion, patients with t(11;14)(q13;q32) had worse outcomes than patients with normal CC or FISH studies, but better outcomes than patients with HR markers detected by CC or FISH studies.

This study was conducted to retrospectively compare the clinical outcomes after transplantation of T cell–depleted (TCD) and unmodified allografts in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Patients received TCD grafts at Memorial Sloan-Kettering Cancer Center (MSKCC, N = 115) between 2001 and 2010 using the following preparative regimens: hyperfractionated total body irradiation (HFTBI)+thiotepa+fludarabine; HFTBI+thiotepa+cyclophosphamide; or i.v. busulfan+melphalan+fludarabine. TCD was performed by 1 of 2 immunomagnetic CD34+ cell selection methods for peripheral blood grafts or by soybean lectin agglutination followed by sheep red blood cell–rosette depletion for bone marrow grafts. No additional graft-versus-host disease (GVHD) prophylaxis was administered. Patients received unmodified grafts at M.D. Anderson Cancer Center (MDACC, N = 181) after conditioning with busulfan+fludarabine and GVHD prophylaxis with tacrolimus+mini-methotrexate. Patients with unrelated or human leukocyte antigen–mismatched donors received anti-thymocyte globulin (ATG) at both centers, with some recipients of matched related donor TCD transplants also receiving ATG, depending upon the preparative regimen. TCD graft recipients were more likely to be older, receive a mismatched transplant, and have peripheral blood used as the graft source. The incidences rates of grades 2 to 4 acute GVHD and chronic GVHD were significantly lower in the TCD graft group (5% versus 18%, and 13% versus 53%). Three-year relapse-free and overall survival rates were 58% and 57%, respectively, in recipients of TCD grafts, and 60% and 66% in recipients of unmodified grafts (P = not significant). Survival and relapse-free survival are similar after TCD and conventional transplants from related/unrelated donors in patients with AML in CR1, but TCD significantly reduces GVHD.

The introduction of tyrosine kinase inhibitors (TKI) has revolutionized therapy for patients with acute lymphoblastic leukemia (ALL) who have the Philadelphia (Ph) chromosome. A retrospective analysis was conducted on 102 adults and 11 children who received a first-matched related (n = 60), matched unrelated (n = 40), mismatched cord blood (n = 12), or haploidentical (n = 1) allogeneic hematopoietic stem cell transplantation (HSCT) for Ph-positive (Ph+) ALL in first complete remission (n = 71), second complete remission (n = 11), or with active disease (n = 31) between 1990 and 2009. Sixty-seven patients received TKI with upfront ALL therapy, and 32 patients received TKI maintenance following HSCT. With median follow-up of 5 years among survivors (range: 1.1-20.4 years), overall survival (OS) was significantly better for patients transplanted in first remission compared with HSCT in advanced disease: 43% versus 16%, P = .002. Disease stage and age at time of HSCT, the development of acute graft-versus-host disease (aGVHD), and decade of HSCT were found to significantly impact OS, progression-free survival (PFS), and nonrelapse mortality (NRM) in multivariate analyses. Allogeneic HSCT provides durable remission for patients with Ph+ ALL in first remission. Neither TKI use pre- nor post-HSCT were found to significantly impact transplant outcomes in univariate and multivariate analyses.

Complete remission (CR) is the gold standard for assessing outcomes following chemotherapy for acute myelogenous leukemia (AML). "CRp," a response criterion defined as fulfillment of all criteria for CR except platelet count recovery to ≥100 × 10(9)/L, is associated with inferior outcomes following chemotherapy. The prognostic importance of CRp before allogeneic stem cell transplantation (allo-SCT) remains unknown. We analyzed a cohort of AML (n = 334) and myelodysplastic syndrome (MDS; n = 10) patients to determine the prognostic significance of achieving CR versus CRp before allo-SCT. At time of transplantation, 266 patients were in CR (CR1 and ≥CR2) and 78 in CRp (CR1p and ≥CR2p). Median follow-up was 38 months (3-131 months). Overall survival, progression-free survival, and nonrelapse mortality (NRM) were most favorable in patients transplanted in CR (CR1 or ≥CR2) compared with CRp (CR1p or ≥CR2p). Achieving CR is therefore associated with improved posttransplantation outcomes compared with achieving CRp and is a significant prognostic factor that needs to be considered when evaluating AML/MDS patients for clinical trials and allo-SCT.

Despite recent advances, multiple myeloma (MM) remains incurable, and most patients eventually develop progressive disease. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potentially curative option in 10%-20% of patients with relapsed or refractory disease. We evaluated the outcome of patients undergoing allo-HSCT with reduced-intensity conditioning (RIC) for relapsed and/or refractory MM at our institution. The study cohort included 51 patients with heavily pretreated, relapsed MM who underwent RIC allo-HSCT between 1996 and 2006. The median time from diagnosis to allo-HSCT was 34 months, and median follow-up in surviving patients was 27 months (range, 3-98 months). Cumulative transplantation-related mortality at 1 year was 25%. Progression-free survival (PFS) and overall survival (OS) at 2 years were 19% and 32%, respectively. The incidences of grade II-IV acute and chronic graft-versus-host disease were 27% and 47%, respectively. At the time of this analysis, 12 patients (24%) were alive, 7 of whom (14%) were in remission for up to 6 years after allo-HSCT. A lower beta2 microglobulin level (3.3) and previous autologous HSCT were predictive of lower nonrelapse mortality and longer PFS and OS. Our findings indicate that allo-HSCT with RIC is associated with acceptable toxicity and durable remission and survival in relapsed or refractory MM. The use of RIC allo-HSCT earlier in the course of the disease may offer the greatest benefit.

Anti-Tumor Necrosis Factor Alpha (TNF-alpha) therapy with infliximab has shown to be effective for patients with steroid-refractory acute graft-versus-host disease (aGVHD). An open-labeled, phase III trial was conducted to determine if the addition of infliximab to steroids could improve results for patients with newly diagnosed grade II-IV aGVHD. A total of 63 patients were randomized either to 2 mg/kg/day methylprednisolone (MP) or infliximab+ MP. Average age was 47 years (range: 20-70 years); 64% were male. Fifty-three percent and 51% of patients received a matched-sibling and/or bone marrow (BM) graft. Sixty-seven percent had grade II, 33% grade III-IV aGVHD; 62% had skin, 53% gastrointestinal (GI), and 7% had liver involvement. At days 7 and 28, the response rate for infliximab+ MP versus MP was 52% versus 78%, P=.03 and 62% versus 58%, P=.7, respectively. Cumulative incidences of GVHD-related mortality, nonrelapse mortality (NRM), and overall survival (OS) were not significantly different between the 2 groups (GVHD-related mortality: 38% versus 32%, P=.6; NRM: 52% versus 36%, P=.3; OS: 17% and 28%, P=.4 for infliximab+ MP versus MP, respectively). Patients with newly diagnosed aGVHD derive no benefit from the addition of anti-TNF-alpha therapy with infliximab when compared to corticosteroids alone.

Nonrelapse mortality (NRM) after reduced-intensity allogeneic transplants is likely to be influenced by abnormalities in renal function. We studied 141 patients diagnosed with acute myelogenous leukemia (AML) (n = 131) or high-risk myelodysplastic syndrome (MDS) (n = 10) who underwent allogeneic transplantation with fludarabine (Flu)/melphalan (Mel)-based regimens and hypothesized that moderate to mild renal function impairment increases NRM in this setting. Flu dose consisted of 25-30 mg/m2 for 4 days and Mel dose was 100-180 mg/m2. Donors were HLA-compatible siblings (n = 69) and matched unrelated donors (n = 72). Disease status at transplantation was complete remission (n = 56, 40%) or active disease (n = 85, 60%). The influence of the estimated glomerular filtration rate (GFR) measured before transplantation on outcomes was analyzed. GFR was estimated by both the Cockcroft-Gault (CG) and the modified diet in renal disease (MDRD) equations, using the creatinine value obtained prior to starting chemotherapy. Evaluated outcomes were overall survival (OS), NRM, and treatment-related mortality (TRM) at day 100 and 1-year posttransplantation. Median age was 55 years (range: 21-74 years); 59% of the patients were male. Estimated GFR by CG was ≥90 for 45 (32%), 60-89 for 78 (55%), and .05). There were no differences in OS and NRM at day 100 and 1-year posttransplantation in the 3 groups by any GFR estimation method. In conclusion, a mild to moderate decrease in GFR was not associated with an increase in NRM.

Approximately 20% of patients with multiple myeloma (MM) have renal failure at diagnosis, and about 5% are dialysis-dependent. Many of these patients are considered ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) because of a high risk of treatment-related toxicity. We evaluated the outcome of 46 patient with MM and renal failure, defined as serum creatinine >2 mg/dL sustained for >1 month before the start of preparative regimen. Patients received auto-HSCT at our institution between September 1997 and September 2006. Median serum creatinine and creatinine clearance (CrCl) at auto-HSCT were 2.9 mg/dL (range: 2.0–12.5) and 33 mL/min (range: 8.7–63), respectively. Ten patients (21%) were dialysis-dependent. Median follow-up in surviving patients was 34 months (range: 5–81). Complete (CR) and partial responses (PR) after auto-HSCT were seen in 9 (22%) and 22 (53%) of the 41 evaluable patients, with an overall response rate of 75%. Two patients (4%) died within 100 days of auto-HSCT. Grade 2–4 nonhematologic adverse events were seen in 18 patients (39%) and included cardiac arrythmias, pulmonary edema, and hyperbilirubinemia. Significant improvement in renal function, defined as an increase in flomerular filtration rate (GFR) by 25% above baseline, was seen in 15 patients (32%). Kaplan-Meier estimates of 3-year progression-free survival (PFS) and overall survival (OS) were 36% and 64%, respectively. In conclusion, auto HSCT can be offered to patients with MM and renal failure with acceptable toxicity and with a significant improvement in renal function in approximately one-third of the transplanted patients. In this analysis, a melphalan (Mel) dose of 200 mg/m2 was not associated with an increase in toxicity or nonrelapse (Mel) mortality (NRM).

Lenalidomide is an agent that has shown great activity in patients with multiple myeloma (MM). However, studies have suggested that this drug negatively affects subsequent stem cell collection. To investigate whether lenalidomide impairs stem cell mobilization and collection, we reviewed data for patients with MM who underwent mobilization with filgrastim. Predictors of mobilization failure were evaluated using logistic regression analysis. In 26 (9%) of 302 myeloma patients, stem cell mobilization failed. Mobilization failed in 25% of patients who had previously received lenalidomide, compared with 4% of patients who had not received lenalidomide (P < .001). In a multivariate analysis, prior lenalidomide use (odds ratio: 5.9; 95% confidence interval [CI]: 2.4-14.3) and mobilization more than 1 year after diagnosis (odds ratio: 4.6; 95% CI: 1.9-11.1) were significantly associated with failed mobilization. Twenty-one of 26 patients in whom mobilization with filgrastim failed underwent remobilization with chemotherapy and filgrastim; in 18 (86%) of these 21 patients, stem cells were successfully mobilized and collected. In patients with multiple myeloma, prior lenalidomide therapy is associated with failure of stem cell mobilization with filgrastim. Remobilization with chemotherapy and filgrastim is usually successful in these patients.

Arsenic trioxide (ATO) is synergistic with ascorbic acid (AA) and melphalan against myeloma both in vitro and in vivo. The aim of this randomized phase II trial was to determine the safety and efficacy of a combination of ATO, melphalan, and AA as preparative regimen in 48 patients undergoing autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma (MM). Forty-eight patients received melphalan 200 mg/m2 i.v. over 2 days and AA 1000 mg i.v. over 7 days in 3 treatment arms: no ATO (arm 1), ATO 0.15 mg/kg i.v. × 7 days (arm 2), and ATO 0.25 mg/kg i.v. × 7 days (arm 3). No dose-limiting toxicity, engraftment failure, or nonrelapse mortality (NRM) was seen in the first 100 days post-ASCT. Complete responses (CR) were seen in 12 of 48 patients (25%), with an overall response rate (ORR = CR + PR) of 85%. Median progression-free survival (PFS) was 25 months; median overall survival (OS) has not yet been reached. There was no significant difference in CR, PFS, or OS among the 3 treatment arms, and no adverse effect of ATO on melphalan pharmacokinetics. Addition of ATO + AA to high-dose melphalan is safe and well tolerated as a preparative regimen for MM.

Introduction La neuropathie optique de Leber est caracterisee par une baisse d’acuite visuelle rapide se bilateralisant en quelques semaines a quelques mois, survenant la plupart du temps chez des hommes jeunes. L’atteinte est liee a une degenerescence du nerf optique. Il s’agit d’une maladie mitochondriale transmise par la mere. Trois mutations sont responsables de 95 % des cas de neuropathie optique de Leber. Nous rapportons un cas atypique de neuropathie optique de Leber chez un garcon de 7 ans. Materiels et Methodes En 1997 un garcon de 7 ans a presente une baisse d’acuite visuelle rapide bilaterale reduite a CLD. L’examen du segment anterieur etait normal. Le fond d’œil montrait une hyperhemie papillaire a droite et une pâleur papillaire a gauche. Le champ visuel montrait un scotome central bilateral. A l’angiographie retinienne on notait une papille droite normale et une hypofluorescence papillaire gauche. Aux PEV damiers il n’y avait pas de reponse. L’IRM montrait une augmentation de volume et un hypersignal des nerfs optiques et du chiasma. La ponction lombaire, le bilan inflammatoire et auto-immun etaient sans anomalie. Un traitement general par corticoides a ete instaure conduisant a une recuperation visuelle partielle. Une rechute de la baisse d’acuite visuelle a suivi l’arret du traitement. Au total, cinq episodes de baisse d’acuite visuelle sont survenus en 6 ans. Le traitement par corticoides a permis une recuperation visuelle apres chaque rechute. En fevrier 2005 les corticoides etaient remplaces par un immunosuppresseur. En septembre 2006 l’acuite visuelle etait de 9/10 œil droit, et 8/10 œil gauche. Le fond d’œil montrait une pâleur papillaire bilaterale. En novembre 2005, son frere, 12 ans, a presente une baisse d’acuite visuelle bilaterale severe non ameliorable. Ce tableau a oriente le diagnostic vers une neuropathie optique de Leber. La mutation primaire de l’ADN mitochondrial homeoplasmique 11 778 a ete identifiee. Discussion Pour la plupart des patients presentant une neuropathie optique de Leber, la baisse d’acuite visuelle est profonde et permanente. Une amelioration de l’acuite visuelle peut etre observee rarement, parfois tardivement. Dans la litterature, il y a quelques cas decrits de baisse d’acuite visuelle recidivante. Conclusion Devant chaque neuropathie optique, surtout d’allure inhabituelle il faut penser a la neuropathie optique de Leber. Le diagnostic genetique, accessible en routine, permet de confirmer cette neuropathie optique de Leber.

A case of Susac syndrome in a child is reported with a review of the literature. A 14-year-old girl presented with headache, left hemiparesis, sphincter deficit, and cognitive deficits. The assessment consisted of neurological and ocular examination, imagery by cerebral magnetic resonance, lumbar puncture, and a biological and immunological assessment. Magnetic resonance imaging revealed numerous high signal intensities on T2-weighted images in the white and grey matter. The ophthalmologic examination found bilateral branch retinal artery occlusions. Twelve months later, she developed hearing loss. Infection assessment was negative and immunologic tests were normal. Susac syndrome is a rare disorder with a clinical triad of encephalopathy, branch retinal artery occlusions, and hearing loss. It is caused by a microangiopathy affecting the precapillary arterioles of the brain, retina, and inner ear. Susac syndrome usually affects young women in young adulthood and is extremely rare during childhood. The pathogenesis of this syndrome is unknown. The clinical course of Susac syndrome is characterized by recurrent attacks. Resolution usually occurs spontaneously. However, sensory and neurologic sequelae may be present. Treatment is not well codified and may include steroids, immunosuppressant drugs, and immunoglobulin. Susac syndrome should be considered in children when evaluating patients with branch retinal artery occlusion and encephalopathy.

Previous studies have demonstrated the importance of the ubiquitin–proteasome pathway in the immune response to bacterial pathogens. To investigate the role of this system in the context of leprosy, Mycobacterium leprae-stimulated peripheral blood mononuclear cells (PBMC) were treated with the proteasome inhibitor MG132 to assess the levels of apoptosis and cytokine secretion. The results showed that the inhibition of proteasome activity significantly reduced M. leprae-mediated cell death. In addition, MG132 treatment led to a significant decrease in M. leprae-induced TNF-α and IL-10 secretion. Together, these results suggest that modulations of the ubiquitin–proteasome pathway may participate in the human response to M. leprae.

Advances in the field of hematopoietic stem cell transplantation have led to an increasing number of cures of malignant and non-malignant diseases with this therapeutic approach. Long-term survivorship may, however, be associated with secondary malignancies, the result of a complex interaction of treatment-, recipient- and immunosuppression-related factors. Furthermore, the increasing use of donors other than human leukocyte antigen-identical siblings is associated with more intense immunosuppression, delayed immune recovery and higher incidence of B-cell post-transplantation lymphoproliferative disorders. Here, we review the incidence and the risk factors associated with these complications of hematopoietic stem cell transplants.

In this study, we evaluated the influence of nonmyeloablative and ablative conditioning regimens on the occurrence of acute and chronic graft-versus-host disease (GVHD). One hundred thirty-seven patients undergoing matched-related sibling transplantations received the same GVHD prophylaxis. Myeloablative regimens included intravenous busulfan/cyclophosphamide (n = 45) and fludarabine/melphalan (n = 29). Patients in the nonmyeloablative group (n = 63) received fludarabine/idarubicin/cytarabine, cisplatin/fludarabine/idarubicin, and fludarabine/cyclophosphamide. The actuarial rate of grade II to IV acute GVHD was significantly higher (hazard ratio, 3.6; 95% confidence interval, 1.5–8.8) in patients receiving ablative regimens (36%) compared with the nonmyeloablative group (12%). The cumulative incidence of chronic GVHD was higher in the ablative group (40%) compared with the nonmyeloablative group (14%). The rates were comparable within the first 200 days and were significantly higher in the ablative group beyond day 200 (hazard ratio, 5.2; 95% confidence interval, 1.2–23.2). Nonrelapse and GVHD-related mortality were relatively low in both groups. The use of the described nonmyeloablative preparative regimens was associated with a reduced incidence of grade II to IV acute GVHD and chronic GVHD compared with the busulfan/cyclophosphamide and fludarabine/melphalan transplant regimens. It is interesting to note that nonrelapse mortality with nonmyeloablative regimens in older and more debilitated patients was low (14%) and comparable to that achieved with standard high-dose regimens in younger patients

The aim of this study was to compare the outcomes of high-dose therapy (HDT) and allogeneic versus autologous hematopoietic stem cell transplantation (SCT) in patients with refractory or recurrent indolent non-Hodgkin's lymphoma (NHL).From January 1991 to March 2000, 112 patients underwent HDT followed by either autologous (68 patients) or allogeneic (44 patients) SCT for refractory or recurrent indolent NHL. Prior conventional chemotherapy had failed in all patients.The two groups were similar with respect to age at transplantation, gender, histological subtypes, number of chemotherapy regimens received before transplantation and International Prognostic Index scores. The median time from diagnosis to transplantation was longer in the autologous than in the allogeneic SCT group (46 versus 27 months, P = 0.002). In the allogeneic SCT group the median follow-up time was 53 months (range 21-113), and the overall survival (OS) and disease-free survival (DFS) rates were 49% and 45%, respectively. After a median follow-up time of 71 months (range 22-109), in the autologous SCT group, the OS and DFS rates were 34% and 17%, respectively. Patients who underwent autologous SCT were more likely to have chemosensitive disease (P0.001) and were more likely to be in complete remission at the time of transplantation (P = 0.001) than those who underwent allogeneic SCT. However, the probability of disease progression was significantly higher in the autologous SCT group than in the allogeneic SCT group (74% versus 19%, P = 0.003).Patients who undergo HDT with allogeneic SCT for refractory or recurrent indolent NHL have lower relapse rates but higher treatment-related mortality rates than patients who undergo autologous SCT. However, with the development of non-myeloablative preparative regimens, which can decrease treatment-related mortality, patients with recurrent indolent NHL should be considered for controlled trials of allogeneic transplantation if they have a human leukocyte antigen-identical donor.

We investigated the long-term outcome of allogeneic stem-cell transplantation after myeloablative conditioning regimen as treatment for patients with chronic lymphocytic leukemia.Patients were eligible for our study if they were refractory or failed a prior response to fludarabine. The conditioning regimen consisted of high-dose CY 60 mg/kg daily for 2 days and fractionated TBI. One patient received BEAM because of prior radiation. GvHD prophylaxis consisted of CYA or tacrolimus and MTX in the majority of patients.Twenty eight patients were treated. nineteen had disease that was refractory to fludarabine. The median number of prior chemotherapy regimens per patient was 3. Twenty had HLA-identical donors and one had a one-Ag mismatched sibling donor. Seven patients had a matched unrelated transplant. The median follow-up time for the surviving patients was 66 months. By univariate analysis, chemosensitivity was the only factor that predicted a better outcome. For the chemosensitive patients, the overall survival was 78%, compared with 31% for those with refractory disease (P = 0.05). Progression-free survival at 5 years was 78% for the chemosensitive and 26% for those who were refractory to conventional chemotherapy at the time of transplantation (P = 0.03). Three patients (11%) died within 100 days of transplant. The actuarial risk of acute Grade II-IV GvHD was 49%. Only one patient developed acute Grade III GvHD.Allogeneic transplantation is probably curative for a subset of patients with chronic lymphocytic leukemia. Patients should be considered for clinical trials involving allogeneic transplantation at an earlier stage prior acquiring chemorefractoriness.