High-risk Transplant Patients Research Articles

Complications in pediatric intestine transplantation in the absence of peri‐operative donor or recipient bowel decontamination

This study reports the clinical complication and infection rates of an active pediatric IT program that has never utilized bowel decontamination in either the donor or the recipient. All patients undergoing IT from 2003 to 2015 at a single pediatric IT center were reviewed. Post-transplant surgical, infectious, and immunosuppressive complications are reported. There were 52 patients who underwent IT during the study period. Among these patients, 4% developed a postoperative abscess, one developed an enteric fistula (2%), and one had an enteric or anastomotic leak (2%). The rate of any bacterial infection was 90% in the first year, with a wound infection rate of 23%. Any fungal infection occurred in 25% of patients. Any viral infection occurred in 75% of patients. Gastrointestinal viruses were diagnosed in 52% of patients, and cytomegalovirus infections occurred in 17%. Rejection rates were 39% at any time post-transplant (isolated 44% and 35% for multivisceral patients). At this center in which no bowel decontamination was used, rates of surgical complications, infections, and rejection were similar to those reported by other centers. These findings suggest bowel decontamination may provide no significant benefit in this population of high-risk transplant patients.

Transplant Conditioning with Treosulfan/Fludarabine with or without Total Body Irradiation: A Randomized Phase II Trial in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia

In this prospective, randomized, phase II “pick the winner” trial we assessed the efficacy of transplant conditioning with treosulfan/fludarabine ± 2 Gy total body irradiation (TBI) in reducing post-transplant relapse in 100 patients, aged 2 to 70 years (median, 57), with myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (n = 51) or acute myeloid leukemia (AML; n = 49). Patients received i.v. treosulfan, 14 g/m2/day on days –6 to –4 and i.v. fludarabine, 30 mg/m2/day on days –6 to –2, alone or combined with 2 Gy TBI (day 0). Donors were related (n = 43) or unrelated (n = 57). When a planned interim analysis showed superior progression-free survival in the TBI arm (P = .04), all subsequent patients received TBI. With a follow-up of 12 to 40 months (median, 20), the 1-year overall survival was 80% for the TBI arm and 69% for the non-TBI arm. The 1-year cumulative incidence of relapse was 22% and 34%, respectively (P = .06). Among patients with low-risk disease the 1-year relapse incidence was 15% and 31% (P = .20) and for patients with high-risk disease, 26% and 36% (P = .18), respectively. Among MDS patients the 1-year relapse incidence was 27% versus 33% (P = .49) and among AML patients 16% versus 35% (P = .05), respectively. The largest difference was among patients with unfavorable cytogenetics, with 1-year relapse incidences of 31% and 63% (P = .18), respectively. Nonrelapse mortality in this high-risk patient population was 9% at 6 months and did not differ between arms. Thus, treosulfan/fludarabine/low-dose TBI provided effective conditioning for allogeneic hematopoietic cell transplantation in high-risk patients up to 70 years of age. The addition of TBI had a more profound effect in patients with AML than in those with MDS. High-risk disease features were associated with a lower overall success rate. Further studies are warranted.

Primary Cutaneous Ewing Sarcoma: Case Report and Review of Literature

Ewing sarcoma (ES) is a primitive neuroectodermal tumor. It’s usually a primary bone tumor but rarely occurs in the skin and subcutaneous tissues. Current literature reports only a few isolated cases or small series. To date, less than 100 cases have been reported. The diagnosis is made by aspiration cytology, histochemical stains, immunohistochemistry, electron microscopy, cytogenetics and molecular genetics of translocations. Cutaneous ES has better prognosis than primary bone or soft tissue ES with a survival rate of 91% in 10 years. The presence of metastasis is really rare. Currently, no specific recommendations to primitively cutaneous Ewing tumors, these latter are treated as bone Ewing's sarcomas: neoadjuvant chemotherapy, surgery, adjuvant chemotherapy (+/− radiotherapy), and autologous bone marrow transplantation in high risk patients. We report a new case in a 20-yearold female with a lesion in the left elbow.

Regular Prophylactic Donor Lymphocyte Infusion Is Effective and Safe to Prevent Relapse after Hematopoietic Cell Transplantation in High-Risk Patients

BackgroundDonor lymphocyte infusion (DLI) is the mainstream therapy for the prevention and treatment of relapse following hematopoietic cell transplantation (HCT). The efficacy of DLI for patients with acute leukemia, however, is limited in previous studies. This may be due to the more rapid proliferative capacity of malignant cells in acute leukemia, since a full response to DLI often requires months. Moreover, DLI is more effective when there is less disease burden to eradicate. Therefore, patients with high risk of relapse may take advantage of an early DLI after HCT. In this study, we applied an early prophylactic DLI in high relapse-risk patients with negative MRD (MRD-) after HCT.Patients and MethodsFrom July 2013 to December 2015, 56 adult patients with high relapse-risk in our center were admitted in this study. High relapse-risk was defined as failure to attain a complete remission (CR) after two cycles of induction therapy (primary induction failure), more than second complete remission (¡ÝCR2), no complete remission before HCT, or increasing MRD before HCT detected by flow cytometry (FCM) or real-time quantitative PCR (RQ-PCR). All patients received modified busulfan/cyclophosphamide¨Cbased myeloablative conditioning regimen. Rabbit antithymocyte globulin was administered for patients receiving unrelated donor HCT or haploidentical HCT. All patients received graft-versus-host disease (GVHD) prophylaxis consisting of cyclosporine A, methotrexate and low-dose mycophenolate mofetil. Post-HCT MRD was monitored at regular intervals with FCM or RQ-PCR. All patients achieved negative MRD post-HCT in our study.ResultsIn total, 56 patients (median age, 36, range, 17-46; 66.1% male) with high relapse risk were included in our study. 15 patients had acute lymphoblastic leukemia; 25 had acute myeloid leukemia; 5 had chronic myelogenous leukemia blast phase; the rest hadT-cell lymphoblastic lymphoma, myelodysplastic syndromes with refractory anemia with excess blasts-2, and peripheral T-cell lymphoma. Among them, 37 (66.1%) received haploidentical-HCT, 16 (28.6%) received matched sibling donor-HCT, and three (5.4%) received unrelated donor-HCT. The median time from HCT to DLI was 82 days (range, 47-160). After a median follow-up of 21 months (range, 7-34), the overall survival (OS) at two years was 78.4%; the disease-free survival (DFS) at two years was 75.4%, with relapse rate of 13.3%. Clinical characteristics were subjected into univariate Cox analysis for OS or relapse rate to find prognostic factors. Neither donor type nor disease type had significant impact on OS or relapse rate in our study. Of note, four patients relapsed after the first DLI underwent chemotherapy combined with a second DLI. Unfortunately, this strategy failed to treat relapse in all of the four patients.The main concern following DLI is the emergence of GVHD. In our study, 19 of the 56 patients (33.9%) developed aGVHD after DLI, mostly Grade I to Grade II (n = 15, 78.9%). cGVHD was observed in 25 of the 56 patients (44.6%), mostly with limited manifestations (n = 20, 80%). Among the deceased 11 patients, only one patient died secondary to GVHD complications due to bronchiolitis obliterans.ConclusionsFor patients with high risk of relapse following HCT, this study indicates that early administration of DLI is effective and safe to prevent relapse. Regular application of DLI for negative MRD patients post-HCT with high relapse risk may be a feasible strategy to prevent future relapse. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Factors Affecting the Selection of Patients on Waiting List: A Single Center Study

IntroductionThere is an increasing gap between organ supply and demand for cadaveric transplantation in our country. Our aim was to evaluate factors affecting selection of patients on waiting list at our hospital. MethodPatients who have been waiting on list and who were transplanted were compared in order to find factors, which affected the selection of patients. Non-parametric Mann-Whitney U test was used for comparison and cox regression analysis was used to find the risk factors that decrease the probability of transplantation in this retrospective case-control study. ResultsPatients in the transplanted group were significantly younger, had relatively lower body mass index than the awaiting group. Cardiovascular diseases were more in the awaiting group than the transplanted group. There was no patient with diabetes in transplanted group, despite fifteen diabetic patients were in the awaiting group. Selected patients had lower immunologic risk with regard to peak panel reactive antibody levels. No significant difference was found for gender, hypertension, hyperlipidemia, viral serology, time spent on dialysis and on waiting list between two groups. With cox regression analysis female gender, older age, diabetes mellitus, high body mass index, positive hepatitis B serology and high levels of peak class 1–2 peak panel reactive antibody positivity were found as risk factors that decrease the probability of transplantation. ConclusionA tendency for selection of low risk patients was found with this study. Time and energy consuming complications and short allograft survival after transplantation in high risk patients and the scarcity of cadaveric pool in our country may contribute to this tendency.

Wanted: Prospective Studies of Alternative Donors

Wanted: Prospective Studies of Alternative Donors

Evidence for field cancerisation treatment of actinic keratoses with topical diclofenac in hyaluronic acid

Actinic keratosis (AK) is a common skin disease seen in daily practice. It is associated with a risk of progression to invasive squamous cell carcinoma and can be regarded as a marker of increased risk for non-melanoma skin cancer. The use of a field-directed treatment approach reflects the need to initiate early treatment over an affected area to prevent tumour development and local recurrence. Candidate field-directed treatments require a mechanism of action compatible with an effect on field cancerisation, immediate and long-term efficacy against visible lesions and efficacy against subclinical AK. Applicability to large treatment areas, tolerability compatible with long-term use, utility in organ transplant patients and, ideally, evidence of extended long-term activity may also be desirable. We review the evidence of a role for topical diclofenac sodium 3% administered in a 2.5% hyaluronic acid gel (diclofenac/HA) as field-directed treatment. Diclofenac/HA directly targets AK pathophysiology through multiple mechanisms, including induction of apoptosis, inhibition of angiogenesis and reduced inflammation. Clearance of visible field cancerisation is safely and rapidly achieved with a 90-day treatment course in patients with affected areas of up to 50 cm(2) and is associated with a ≥75% reduction in target lesion number score in 85% and 91% of patients, respectively, at 30 days and 1 year post-treatment. Following treatment of AK in high-risk transplant patients, 45% remained free of lesions in the treatment area at 2 years post-treatment. We conclude that diclofenac/HA fulfils most criteria necessary to be considered an appropriate candidate for a field-directed treatment in AK.

High Efficacy and Significantly Shortened Neutropenia Of Dose-Dense S-HAM As Compared To Standard Double Induction: First Results Of a Prospective Randomized Trial (AML-CG 2008)

BackgroundFor curative treatment of younger patients with acute myeloid leukemia (AML) double induction with two cycles of intensive cytarabine/ anthracycline based chemotherapy 21 days apart is the current standard of care. In the prospective randomized AML-CG 2008 trial we asked question whether current results could be improved on by a dose-dense regimen (S-HAM – Sequential High-dose cytArabine and Mitoxantrone) in which the interval between cycles was minimized to 3 days. A prior large one-armed study (AML-CG 2004) had demonstrated a high antileukemic efficacy and shortened neutropenia of the S-HAM regimen as compared to a historical control of standard double induction treatment. The first clinical results of the randomized comparison are presented here. MethodsAll patients with first diagnosis of a de-novo or secondary AML (excluding APL) that were deemed fit for intensive induction chemotherapy by their treating physician were eligible for this study. Younger patients in the standard arm were treated with one cycle of TAD-9 (standard dose cytarabine and daunorubicine 60mg/m2 for 3 days) and a mandatory second cycle of HAM (high dose cytarabine and mitoxantrone) starting at day 21. Elderly patients were treated with one cycle of HAM followed by a second cycle of HAM only in case of residual leukemia in the day 16 bone marrow aspirate. Patients in the experimental arm all received S-HAM (two sequential cycles of high-dose cytarabine on days 1+2, mitoxantrone days 3+4) with a 3 days interval. Patients in the age cohort 60 – 69 could be allocated to the “younger” or “elderly” cohort according to their biological fitness at the discretion of the treating physician. However high-dose cytarabine dosages were allocated according to chronological age with patients <60 years receiving 3g/m2 cytarabine per dose and patients 60+ years receiving 1g/m2. The primary endpoint was the overall response rate (i.e. CR + CRirate), secondary endpoints were duration of critical neutropenia, overall survival amongst others. Postremission treatment consisted of recommended early allogeneic transplantation in high risk patients and conventional postremission treatment according to the AML-CG standard (one cycle of TAD-9 consolidation followed by up to 3 years of maintenance treatment) in patients with low risk disease. Results396 patients were randomized into the study with an age range of 18 to 86 years (median 58). The 387 evaluable patients (184 standard, 203 experimental) were well balanced according to their clinical characteristics, cytogenetics, molecular genetics and overall risk profile. For the primary endpoint a higher ORR of 77% for S-HAM could be found as compared to 72% in the standard arm which was however not significant because a 15% difference had been postulated for the study. Non-hematological toxicities did not show any significant differences. However this was in clear contrast to hematological toxicities: Importantly the duration of critical neutropenia was highly significantly reduced by more than 2 weeks from 45 days (standard) to 29 days (S-HAM) counted from day 1 of treatment. Similarly critical thrombocytopenia was reduced by 13 days from 46 days to 33 days. The early death (ED) rate between both arms was identical between both arms. However a subgroup analysis demonstrated a significantly reduced ED rate in patients receiving 1g/m2 S-HAM as compared to all other treatment groups. The respective ED rates for the various time intervals (always counted from day d1 of treatment) for the 1g/m2S-HAM group were as follows: Interval d1-14 1%, d1-30 3%, d1-60 5%, d1-90 10%. Data for overall survival will be available in November 2013. ConclusionThe dose-dense induction regimen S-HAM was highly feasible in patients up to the 8th age decade. The antileukemic efficacy was high with an ORR of 77% for the whole group of unselected patients. As compared to standard double induction dose-dense S-HAM reduced critical neutropenia by more than two weeks. Moreover the subgroup of patients receiving the 1g/m2 S-HAM regimen experienced the lowest ED rate ever reported in the AML-CG trials. This underlines that in contrast to our general expectations the concept of dose-density is able to combine high antileukemic efficacy with significantly reduced haematological toxicity in AML, characterising this approach as first candidate for the next standard arm for future trials of the study group. Disclosures:Lengfelder:TEVA/ Cephalon: Research Funding.

Excess Risk of Death Increases with Time from First Dialysis for Patients on the Waiting List: Implications for Renal Allograft Allocation Policy

Background: Subgroups of patients registered on a kidney transplant waiting list have higher than usual mortality levels. This study used data from the French Renal Epidemiology and Information Network (REIN) Registry to quantify the impact over time of various comorbidities on the excess risk of death among patients on the waiting list. Methods: Lexis diagrams were used to analyze time since onset of end-stage renal disease and time since registration on the waiting list. The number of excess deaths was calculated by comparison with the number of expected deaths in the general population of the same age and sex. Results: During 45,013 person-years of follow-up, 7,224 patients died, 5,956 (82%) more than expected relative to the general population. There were 101 deaths among wait-listed dialysis patients, 76 more than expected. The excess risk of death increased by 45% per additional year on the waiting list (18-79%, p = 0.0005). Time from end-stage renal disease onset until list registration (p = 0.004), time since registration (p < 0.001), age >65 years (p = 0.008), the presence of a primary renal disease (p = 0.028), and the number of comorbidities (p = 0.035) were independent predictors of death while on the waiting list. Conclusions: The excess risk of death while on the waiting list increased faster in patients with comorbidities. These results require consideration of ways to accelerate access to transplantation in high-risk patients.

Pre-transplant heart disease etiology has a major effect on post-transplant survival of patients bridged with heartmate II assist device

Background Left ventricular assist devices (LVAD) have become an established mode of treatment in bridging patients with advanced heart failure to cardiac transplantation. In certain groups of patients LVADs have proven their efficacy as a destination therapy. Increasing mismatch between the expanding pool of heart failure patients and decline in availability of donor organs raises an important question of prioritizing patients on the waiting list. Methods This is a retrospective analysis of post-transplant results of patients bridged with HeartMate II. Patients were divided based on pre-transplant etiology into ischemic, non-ischemic and congenital group. One-year post-transplant survival was calculated using the Kaplan-Meier method and Log-rank test was used for comparison. Results Between 2007 and 2013 60 patients were transplanted from HeartMate II at our institution. There were no differences in patients’ pre-transplant demographic and clinical variables. Donor characteristics as well as ischemic times were also comparable. Overall one-year post-transplant survival was 90 ± 2%. Patient with nonischemic etiology had 97 ± 3% survival compared to 86 ±7% in patients with ischemic and 67 ± 19% in patients with congenital heart disease (p = 0.043). Conclusion Our data indicate that patients with congenital heart disease bridged to transplantation with HeartMate II have significantly reduced one-year post-transplant survival compared to patients with other cardiomyopathies. In the era of the current donor shortage, there is an increased pressure at judicious utilization of resources and surgical outcomes are increasingly scrutinized. Every effort should be made at identifying risk factors for diminished post-transplant survival. We believe that advancements in LVADs technical design associated with improved survival and quality of life make new generation devices a viable alternative as a definitive treatment option for a very high risk transplant patients.

Lobar Lung Transplantation for High Risk Patients – Lessons from the Initial Experience

Purpose Since development of a cadaveric lobar lung transplantation (CLLTx) protocol as a surgical option for critically ill patients, our CLLTx number has expanded to 17% of all LTx cases this year. While many challenging patients have been saved by this novel approach, major complications and management issues have also been experienced, resulting in our protocolized management of CLLTx patients for successful outcomes. Methods and Materials Critically ill patients with end-stage lung disease who were considered to be unlikely to survive the long wait for size-matching lungs underwent CLLTx between 2009 and 2012. Based on their short-term outcomes and major complications, the intra- and post-surgical management has been protocolized at our institution. Results Indications for CLLTx included those who were on the ventilator, on ECMO, and LAS above 60 with size restrictions. Total 32 patients received an anatomic lobectomy with individual ligation techniques at back-table followed by double lung transplantation. There were 3 in-hospital deaths. One early bronchial stump dehiscence (3.1%) was experienced. Atypical progression of PGD with significantly elevated pulmonary artery pressures was also experienced in 3 cases (9.3%). Because of this experience, our current management for CLLTx patients includes prolonged use of inhaled nitric oxide, pulmonary artery catheter monitoring and strict negative fluid balance management. Conclusions Our experience has demonstrated that protocolized management is critical for success. Thus, we have adopted a systematic approach that has allowed us to adovocate for CLLTx as a viable option for critically ill patients with small chests who may not have exhausted all options. [ figure 1 ]

Evaluation of risk factors for cytomegalovirus infection and disease occurring within 1 year of liver transplantation in high‐risk patients

Recent studies have demonstrated that cytomegalovirus (CMV) infection and disease are associated with increased risk of graft loss and death in high-risk (donor CMV seropositive/recipient CMV seronegative) liver transplant recipients (LTR) despite effective antiviral chemoprophylaxis. Predictors of CMV infection and disease in this important population are incompletely defined. A retrospective cohort study of 227 high-risk first LTR who received primary anti-CMV chemoprophylaxis during the first 100days after transplant was performed. A large number of patient, donor, operative, and post-transplant potential risk factors were collected. Associations of potential risk factors for CMV infection or disease that occurred during the first year after transplant were assessed using Cox regression models. After Bonferroni adjustment for multiple testing, P-values ≤0.00125 (associations with CMV infection) and ≤0.00122 (associations with CMV disease) were considered as statistically significant. CMV infection and disease occurred in 91 (40%) and 43 (19%) of LTR, respectively. In multivariable analysis, increased risk of CMV infection was observed for patients with lower model for end-stage liver disease (MELD) score (P=0.025), lower total bilirubin (P=0.014), and longer operative time (P=0.038), whereas increased risk of CMV disease was seen in patients with lower MELD score (P=0.026), lower total bilirubin (P=0.044), and lower international normalized ratio (P=0.043). However, after adjustment for multiple testing, none of these findings approached statistical significance. Our results suggest that interventions designed to prevent CMV infection and disease should be applied to all high-risk LTR until more definitive predictors of these complications are identified.

Additional Prognostic Impact of Specific Sites of Extramedullary Leukemia in Pediatric AML with MLL-Rearrangements but Not in Core-Binding Factor (CBF) AML.

AbstractAbstract 2621▪▪This icon denotes a clinically relevant abstractCurrent data on prognostic significance of extramedullary leukemia (EML) in general and for specific genetic subgroups in children with acute myeloid leukemia (AML) are limited and controversial. AML-BFM data from previous studies indicated that skin and testicular involvement were independent adverse prognostic factors in high-risk (HR) patients (core-binding factor [CBF] AML [=t(8;21) and inv16] patients were standard risk patients) (Creutzig, Blood (suppl)2001;98(11). This was supported by others for leukemia cutis (Dusenbery, J.Pediatr. Hematol. Oncol.2003). Orbital involvement, which is associated with t(8;21), was reported to be unfavorable in Turkish and Indian children. A Dutch study could not confirm the prognostic relevance of EML (Bisschop, Leukemia,2001). Therefore, we analyzed the data of pediatric CBF-AML and MLL gene-rearrangement AML (MLL-AML) patients <18 years old treated according to protocols AML-BFM 98 and -2004 (7/1998-12/2010) with regard to their initial clinical features and the prognostic relevance of EML including EML-sites. EML was diagnosed in 57/232 patients with de novo CBF-AML and in 80/241 patients with MLL-AML. EML sites included skin, orbit, kidney, testes and other rare localizations like tonsils and salivary glands. In this analysis, central nervous system involvement was not defined as EML and isolated EML was excluded.Treatment was similar for all patients in both trials (4–5 intensive courses including high-dose cytarabine, prophylactic cranial irradiation, 1-year maintenance and stem cell transplantation in HR patients, if an HLA-identical donor was available. Patients with single site EML received local irradiation. According to the risk classification of the AML–BFM studies, CBF-leukemia patients with <5% bone marrow blasts on day 15 were stratified as standard risk (SR) and MLL-patients as HR patients. Patient characteristics:EML occurred significantly less frequently in CBF than in MLL patients [57/232 (24.6%) vs. 80/221 (36.2%); pchi=0.007] (i. e. patients with available data on EML). Sites of EML were a) skin: CBF 7/229 (3.1%) vs. MLL 32/220 (14.5%), pchi=0.00002; b) orbit: CBF 19/228 (8.3%) (i. e. mainly patients with t(8;21): 17/132 (13%)) vs. MLL 13/216 (6.0%), pchi=0.34; c) kidneys: CBF 14/230 (6.6%) vs. MLL 29/215 (13.5%), pchi=0.008; d) tonsils: CBF 9/222 (4.1%) vs. MLL 7/211 (3.3%), pchi=0.68; e) salivary glands: CBF 1/224 (0.4%) vs. MLL 5/213 (3.3%), pchi=0.088; f) testes: CBF: 1/226 (0.4%) vs. MLL 6/220 (2.7%), pchi=0.052; g) other sites (including multiple sites): CBF 27/224 (12.1%) vs. MLL 28/209 (13.4%) patients, pchi=0.67. Patients with MLL (with or without EML) were generally younger than CBF-patients (age <2 years: 49% vs. 7%, pchi<0.0001). Hyperleukocytosis was more frequent in MLL than in CBF patients (30% vs. 11%, pchi<0.001). EML-morphology was FAB M2Auer/M4eo in 86% of AML-patients with CBF and with FAB M4/M5 in 95% of patients with MLL-rearrangement. Results:Outcome for EML-patients with CBF-AML was significantly better than for EML-patients with MLL-AML with a 5-year event-free survival (pEFS) of 63+3% vs. 45+6%, respectively (plogrank=0.0006). Extramedullary site of the disease was found to have no prognostic significance for patients with CBF-AML: pEFS with or without EML was 63+3% vs. 75+3% (plogrank=0.38). Also, there was no difference in EFS of patients with t(8;21)- or inv(16)-AML with or without EML (plogrank=0.28 and 0.69, respectively). In particular, orbital involvement was not of prognostic significance in patients with t(8;21) (plogrank=0.26).Further, pEFS results in MLL-AML patients with or without EML were similar (45% both, plogrank=0.48). However, prognosis for patients with MLL-rearrangement and skin involvement was significantly more unfavorable when compared to those with MLL-AML at other extramedullary sites (EFS 32%+9% vs. 54%+7%, plogrank=0.03). In addition, testicular involvement in MLL-patients might also be unfavorable (4 events in 6 patients). Excluding MLL patients with skin and testicular involvement, extramedullary site was not of prognostic relevance (pEFS MLL with other EML vs. MLL without EML = 55%+8% vs. 45%+4%, plogrank=0.44). Conclusion:EML did not influence the favorable prognosis of CBF-AML, whereas skin and testicular involvement in MLL-AML were unfavorable prognostic factors. Disclosures:No relevant conflicts of interest to declare.

Sirolimus Monotherapy in Liver Transplant Recipients with De Novo Tumors

Background: Sirolimus is a macrocyclic antibiotic with antifungal, antifibrotic and immunosuppressive properties that can inhibit metastatic tumor growth and angiogenesis in vivo mouse models. It can be used as a substitute for calcineurin inhibitors (CNI) because it may reduces the likelihood of recurrent hepatocellular carcinoma (HCC) or the rate of de novo tumors in high risk transplant patients. Sirolimus protects allografts from rejection while simultaneously inhibits tumor growth. Patients and methods: Between April 1986 and December 2010 we performed 1500 orthotopic liver transplants (OLT). Fifty-seven patients received immunosuppressive treatment with sirolimus, and 26 patients of them due to de novo tumors. Currently, 20 of these patients are with sirolimus monotherapy. We analyze the outcome of liver transplant recipients who developed de novo tumors and were treated with sirolimus monotherapy. Results: There were 20 patients (18 males and 2 females), with a mean age at OLT of 50.3±12.1 years, and mean follow-up of 111.5 months. The main indications for OLT were alcoholic cirrhosis (40%), and HCV cirrhosis (15%). The most frequently immunosuppressive therapy used at discharge was tacrolimus+prednisone (55%). Premonoterapy immunosuppression most frequently used was tacrolimus+sirolimus (50%), and mycophenolate+sirolimus (40%). The mean time from OLT to sirolimus treatment was 74.6 months, and from then until the beginning of monotherapy was 9.5 months with a mean time of 24.7 months in monotherapy. The location of de novo tumors was: aerodigestive tract (45%), skin (20%), lymphoproliferative disorders (15%), urologic tract (10%), gynecological (5%), and central nervous system (5%). There was only one case of rejection (5%) in the presence of adequate drug levels, successfully treated with reintroduction of tacrolimus. Adverse effects were seen in 80% of patients, and the most frequent were: dyslipidemia (11 patients), edema (5 patients), and oral thrush (4 patients). Regarding lipid profile, mean cholesterol value before sirolimus was 168 mg/dl, and postmonotherapy was 211 mg/dl (p =0.0001). Seven patients are treated with hypolipemiant. Mean value of pre-sirolimus triglycerides was 104 mg/dl and post-monotherapy was 130 mg/dl (p=0.071). Regarding renal function, mean creatinine clearance pre-sirolimus was 70.6 ml/min and post-monotherapy was 75.6 ml/min (p>0.05). Conclusions: Sirolimus is a potent immunosuppressant with antitumoral properties, with low rate of rejection, which represents a good option OLT with de novo malignancies. More than half of the patients presented side effects, but they were well tolerated or controlled with medical treatment (dyslipidemia as the most frequent). There was an improvement of renal function showing an increase in creatinine clearance.

Treatment of splenic marginal zone lymphoma of the CNS with high-dose therapy and allogeneic stem cell transplantation

Therapy of indolent lymphomas with involvement of the central nervous system (CNS) has not been standardized so far. A 42-year old male patient presented with neurological signs because of leukemic splenic marginal zone lymphoma (SMZL) manifested in bone marrow, lymph nodes and CNS. Due to the aggressiveness of the disease and the young age of the patient, an intensive immunochemotherapy followed by high-dose therapy with busulfan, thiotepa and fludarabine and subsequent unrelated allogeneic stem cell transplantation (alloSCT) was performed. The haemopoietic stem cells engrafted in time and the patient is doing well (ECOG 0) without evidence for active lymphoma three years after transplantation. Highly sensitive tests by specific quantitative real-time polymerase chain reaction for presence of lymphoma cells in blood and bone marrow indicated also a molecular remission. The reported case shows the feasibility of high-dose therapy and allogeneic stem cell transplantation in high-risk patients with CNS-involvement of indolent non-Hodgkin’s lymphoma. In addition, the case supports the hypothesis that the graft-versus lymphoma effect after alloSCT is also active within the CNS.

Impact of simultaneous splenectomy and orthotopic liver transplantation in patients with end-stage liver diseases and splenic hyperfunction

Whether splenectomy can be performed simultaneously during liver transplantation in patients with end-stage liver diseases complicated by hypersplenism remains controversial. This study aimed to compare the impact of simultaneous splenectomy on high- and low-risk liver transplant patients with end-stage liver diseases and severe hypersplenism. Forty-two patients with end-stage liver diseases complicated by severe hypersplenism who had undergone orthotopic liver transplantation were enrolled in this study. Splenectomy was performed in 19 of the patients. The 42 patients were grouped according to the risk of liver diseases and operations they received. Patients were considered to be at high-risk if they had at least one of the following conditions: preoperative prothrombin time >5 seconds, portal vein thrombosis, and severe perisplenitis. High-risk patients who had undergone splenectomy were classified into group A, whereas high-risk patients who had not undergone splenectomy were classified into group B. Low-risk patients who had undergone splenectomy were classified into group C, and low-risk patients who had spleen preservation were classified into group D. Operative time, intraoperative blood loss, postoperative bleeding, pulmonary infection, perioperative mortality, and postoperative platelet recovery were analyzed. Operative time and intraoperative blood loss were greater in group A than in groups B-D (P<0.01), but there was no significant difference between groups C and D (P>0.05). In group A, 3 patients had postoperative bleeding, 5 had pulmonary infection, and 2 had perioperative mortality, which was higher than any other group, but postoperative bleeding, pulmonary infection, and perioperative mortality were similar to those in groups C and D. In patients undergoing simultaneous splenectomy, platelet counts recovered within 6 months after surgery. Thrombocytopenia was sustained in 3 of the 23 patients who did not undergo simultaneous splenectomy. Splenectomy should be avoided during orthotopic liver transplantation in high-risk patients, but this procedure does not increase the operative risk in low-risk patients and may be a valuable method to ensure good postoperative platelet recovery.

Single Cord Blood Combined with HLA-Mismatched Third Party Donor Cells: Comparable Results to Matched Unrelated Donor Transplantation in High-Risk Patients with Hematologic Disorders

Matched unrelated donor (MUD) transplantation is the first alternative in the absence of a matched sibling donor. For patients without a suitable adult donor, we have adopted the dual stem cell transplantation protocol consisting of cord blood (CB) in combination with CD34+ cells from a third party HLA-mismatched donor. We analyzed the outcomes of patients undergoing both procedures in a single center. Starting in 2004, a total of 20 patients with high-risk disease underwent 22 dual transplants and 25 patients underwent myeloablative MUD transplantation. The 30-day cumulative incidence of neutrophil engraftment was similar in both groups (91% and 95%), with a median time to engraftment of 14 and 16 days, respectively. Grade II-IV acute graft-versus-host disease was more frequent in the MUD group (40% versus 5%). Except for a tendency toward a higher incidence of viral hemorrhagic cystitis in the dual transplantation group, posttransplantation infectious events were comparable in the 2 groups. The 3-year cumulative incidence rates of relapse (41% versus 44%) and nonrelapse mortality (30% versus 25%) were similar in the MUD and dual transplantation cohorts. Estimated 3-year overall survival and disease-free survival were 47% and 41%, respectively, with no survival advantage for either group. In our experience, dual transplantation offers survival rates comparable to those from myeloablative MUD transplantation with similar nonrelapse mortality rates.

Transplantation of the broadly sensitized patient

Recipient sensitization to a wide variety of human leukocyte antigens (HLA) represents a major barrier to transplantation. We discuss the options for the challenging group of broadly sensitized kidney transplant candidates. Transplantation by way of kidney-paired donation (KPD) represents a preferable way to bypass immunological barriers. Recent data suggest that KPD programs can be optimized by the use of innovative serological techniques to define unacceptable HLA antigens, inclusion of altruistic donors or altruistic balanced paired kidney exchange, and complementary recipient desensitization. It has become evident that plasmapheresis and/or intravenous immunoglobulin (IVIG)-based crossmatch conversion may not completely prevent rejection and chronic injury. However, recent evidence suggests major improvements by sophisticated serological risk stratification and new innovative treatment principles. Wait-listed broadly sensitized patients were shown to benefit from specific allocation programs, such as priority allocation of organs via the Eurotransplant acceptable mismatch program. Recent studies have suggested a benefit from IVIG/rituximab-based desensitization on the waitlist, or apheresis-based protocols for rapid antibody removal immediately before transplantation. A multifaceted repertoire of complementary strategies was shown to facilitate successful live and deceased donor kidney transplantation in high-risk patients. Recent promising developments can be expected to significantly improve outcomes.

Cytomegalovirus-induced cutaneous vasculopathy and perianal ulceration

Cytomegalovirus-induced cutaneous vasculopathy and perianal ulceration

Therapeutic Advances in Acute Myeloid Leukemia

The choice of treatment approach and outcome in acute myeloid leukemia (AML) depends on the age of the patient. In younger patients, arbitrarily defined as being younger than 60 years, 70% to 80% enter complete disease remission with several anthracycline-based chemotherapy combinations. Consolidation with high-dose cytarabine or stem-cell transplantation in high-risk patients will restrict overall relapse to approximately 50%. A number of demographic features can predict the outcome of treatment including cytogenetics and an increasing list of molecular features (ie, FLT3, NPM1, MLL, WT1, CEBPalpha, EVI1). These are increasingly being used to direct postinduction therapy, but they are also molecular targets for a new generation of small molecule inhibitors that are in early development; however, randomized data have yet to emerge. In older patients who comprise the majority, which will increase with demographic change, the initial clinical decision to be made is whether the patient should receive an intensive or nonintensive approach. If the same anthracycline/cytarabine-based approach is deployed, the remission rate will be around 50%, but the risk of subsequent relapse is approximately 85% at 3 years. This difference from younger patients is explained partly by the ability of patients to tolerate effective therapy, and also the aggregation of several poor risk factors compared with the young. There remains a substantial proportion of patients older than 60 years who do not receive intensive chemotherapy. Their survival is approximately 4 months, but there is considerable interest in developing new treatments for this patient group, including novel nucleoside analogs and several other agents.