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The Foundation for the Accreditation of Cellular Therapy (FACT) has developed and implemented programs of voluntary inspection and accreditation for hematopoietic cellular therapy, and for cord blood banking. These programs are based on the standards of the clinical and laboratory professionals of the American Society of Blood and Marrow Transplantation (ASBMT), the International Society for Cellular Therapy (ISCT), and NETCORD. Our transplantation service was the first Hospital in Latin America to be accreditated by FACT in 2012. FACT accreditated hospitals might have a positive impact in Implementing new procedures and treatment protocols. Haploidentical SCT program was developed in our institution during FACT accreditation process. Since high complexity procedures challange transplantation units, we believe that conducting protocols after FACT accreditation helped the achievment of better standard of care that might be translated in results comparable with international transplantation centres. SCT from Haploidentical donor can be one therapeutic option specially for patients with no available MRD or MUD. In order to overcome HLA disparity, more intensive immunossupresion is usually used that can be associated to higher TRM. These difficulties demand a well stablished transplantation unit. Here we show the first 25 patients who recieved haploidentical SCT during FACT accreditation in a single institution in Brazil. Patients and methods: From april 2008 to july 2013, 25 patients were treated with haploidentical SCT. The median follow-up time was 3,3 months (range ). 8 (32%) patients had AML, 1 (4%) ALL, 1 (4%) JMML, 1(4%) LH, 1 (4%) MDS. 7 (28%) had  adrenoleukodystrophy x-linked, 3(23%) had SAA and 2(28%) SCID. 8 (33%) patinets had refreactory disease. Median age at transplantation was 3.3 (range 1-72) years. 12 (48%) patients were in pediatric age range (1 to 18) years. 13 (54%) had donor/receptor ABO incompatibility. 10 (40%) patients were transplanted after myeloablative conditioning regimen (Bussulfan/Fludarabine or Busulfan/fludarabine/thiotepa) and 15(60%) after non-myeloablative conditioning regimen (Fludarabine/cyclophosphamide/TBI200cGy). 22 (88%) patients have received bone marrow as stem cell source and 3 (12%) peripheral blood stem cells. Median total nucleated cell x 108/Kg was 5.5 (range 3.0 to 10.34). Median CD34+x106/Kg 3.61 (range 1.48 to 7.06). Post transplant immunosuppression consisted of tacrolimus/MMF plus post transplant Cyclophosphamide in 22 (88%) patients, steroids plus CsA or tacrolimus in 2 (8%) and T cell depleted graf with no immunosupression in one SCID patient. All patients engrafted by day 28 after transplantation and 4 patients had secondary graft rejection. Only one (4%) patient developed synusoidal obstruction syndrome. 7 (28%) patients developed Acute graft-verus-host disease (3 grade I/II and 4 grade III/IV). 16 patients (64%) developed CMV reactivation. At the end of the follow-up 21 (84%) were alive. Four patients died from relapse at day 100 post transplant, 2 from infection and 1 from coronary heart disease. Sencondary graft failure had a negative impact in overal survival (HR: 14 (IC: 1,2-157), p= 0,033). Conclusion: The FACT accretidation process can promote improvement and progress in stem cell transplantation process, by controlling every aspect that impacts the quality of products and therapeutic care. In our center, there was a process developed in order to meet FACT standards that brought better patient care. We have shown the first 25 haploidentical patients who was treted after this accreditation, showing similar results when comparing to international centres and previous publications. We believe that these results could only be achieved in a transplant unit that meets specific quality control guided by FACT.

There are few studies on the behavior of vitamin D in patients undergoing Hematopoietic Stem Cell Transplantation (HSCT), although vitamin D serum levels are associated with use of corticosteroids and immunosuppressive drugs. In some studies, vitamin D deficiency in patients after HSCT is associated with reduced bone density, increased of parathyroid hormone and GVHD.

Busulfan (BU) is one of the most used alkylating agent in mieloablative conditioning regimens (CR) for patients submited to Hematopoietic Stem Cell Transplantation (HSCT). Its therapeutic effect is correlated to area under the curve (AUC) having a wide variability among patients. Ideal AUC is not been well stablished yet but it is known that higher levels can impact survival by increasing extra medular toxicity. In the other way, lower levels can be associated to a higher incidence of relapse. Two BU formulations are available, oral (PO) or Intrvenous (IV). Although IV BU can developed more reliable AUC, there are few data comparing both formulations.To compare the pharmacokinetics (PK) of PO and IV BU based conditioning regimens in patients submited to HSCT and to determinate the best target BU AUC in order to reduce acute toxicity after HSCT.149 patients were prospectively evaluated. All recieved myeloablative (MA) BU based conditioning regimen (BU associated to Cyclophosphamide(Cy), Melphalan(Mel), Cy/VP-16, Fludarabine(Flu)/Thiotepa, Flu/Mel,Mel/Gencitabine, Mel/Cy, Flu/clofarabine, Clofarabine/Thiotepa). 56 (37,5%) received a MA reduced intensity CR (Bu associated to Flu). 56 (37.5%) patients recieved a stem cells from a matched related donor, 45(30.2%) from matched unrelated donor, 9(6%) from related haploidentical donor and 17 (11.4%) from cord blood. The median age was 30,2 years (range 1,3-73). 86 (57.7%) had acute leukemias and myelodisplastic syndrome, 28(18.8%) had lymphomas, multiple myeloma and chronic leucemias, 32(21.4%) had diferente benign diseases. 83 (55.7%) patients recieved PO and 63(44.3%) IV BU. All patients had BU PK monitoring at least one time during CR. 81 (54.4%) patients also performed a pre transplant BU test dose (32mg/m2 for IV and 1mg/kg for PO BU). There were 3 BU targeted AUC: 4000, 5000 and 6000 µMol.min, according to institutional protocols based on disease risk and patient age. Historical control of 53 patients who received myeloablative conditioning regimen with no BU PK monitoring were used. Mucositis, Sinusoidal obstruction Syndrome (SOS) Overall survival (OS), Transplant related mortality (TRM) and relapse were analysed according to AUC targeted dose. 184 (91%) patients developed mucositis at 5 (range:0-11) days after HSCT. There were no diference in either incidence (p=0,15) or severity (p=0,19) of mucositis in patients recieving PO(n=66, 32.6%) or IV (n=83, 41%) BU and historical control (n=53, 26.2%) (p=0,15). Pre transplant test dose had also no impact on incidence and severity of mucositis (p=0,75). More importantly, AUC targeted dose had no impact in either mucositis incidence or severity (p=0.75). Among all 202 patients, 23 (11,4%) developed SOS until day 30 post HSCT. The use of pre transplant Bu test dose had no impact in SOS incidence: Gray-subhazard ratio (SHR)SHR 0.70 - CI95% 025-1.91; (p=0.48). BU formulations (PO or IV) had no impact in SOS (p=0.73) either. Patients recieving higher BU AUC targeted dose had an incresed risk to develop SOS after HSCT: Incidence of SOS in patients who recieved AUC<5000 and AUC>=5000 was 5% and 16% respectively (SHR 3.39, p=0.034, CI 95% 1.09-10.52). In contrast, this finding had no impact in day Transplant related TRM and 1 year OS: patients who revieved AUC<5000 and AUC>=5000, had 1 year OS of 61% and 66% respectivelly (p=0.52). Patients who revieved AUC<5000 and AUC>=5000, had 100 day TRM of 12% and 12% respectivelly (p=0.42). We also found that patients who recieved AUC from 4000 to 5000 had a lower OS, showing a protective effect of lower AUC: 1 year OS for patients who recieved AUC 4000t to 5000 was 65% (IC95% 55-74%) HR: 0.65, (p=0.33). In the other hand, patients who recieved lower AUC targeted dose (4000) had higher incidence of relapse: SHR: 0.42, p=0.08, CI 95% 0.15-1.1In this cohort of patients, toxicity and survival were not influenced by BU formulation (oral or IV). More importantly, patients recieving higher Bu AUC targeted dose had higher incidence of SOS and targeting AUC between 4000 to 5000 had a positive impact in 1 year OS but are more likely to relapse (AUC 4000). We also, shown that using Bu test dose, does not increase toxicities or mortality in patients reciving Bu condicioning regimen. Therefore, we can conclude that PK Bu monitoring is important in either PO or IV BU formulation, in order to reduce toxicities such as SOS and mortality.Santos: Novartis: Consultancy, Research Funding, Speakers Bureau.

Zinc is an important trace mineral for the body, being a cofactor of enzymes responsible for the synthesis of nucleic acids, and maintaining the immune system. Symptoms of zinc deficiency, such as alopecia, diarrhea, skin rash and growth failure, can be confused with those of hematopoietic stem cell post-transplant (HSCT). Some studies show that zinc supplementation, with the purpose of increase of its serum level, reducing the incidence of mucositis, xerostomia, pain and loss of taste. Zinc deficiency is reported in children with leukemia, but there are very few studies in adults.

Graft-versus-host disease (GvHD) causes morbidity and mortality in recipients of allogeneic hematopoietic stem cell transplantation (ASCT). This study assessed the distribution of GvHD in gastrointestinal (GI) biopsies from the upper and lower GI tract in all patients who had undergone ASCT in our institution between 2005 to 2013 and evaluated the correlation between biopsy of upper and lower GI, possible relation with CMV Infection in GI biopsy and Blood sample, GvHD GI grade and extra-intestinal manifestations of GvHD

Busulfan (BU) is one of the most used alkylating agent in mieloablative conditioning regimens (CR) for patients submited to Hematopoietic Stem Cell Transplantation (HSCT). Its therapeutic effect is correlated to area under the curve (AUC) having a wide variability among patients. Ideal AUC is not been well stablished yet but it is known that higher levels can impact survival by increasing extra medular toxicity. In the other way, lower levels can be associated to a higher incidence of relapse. Two BU formulations are available, oral (PO) or Intrvenous (IV). Although IV BU can developed more reliable AUC, there are few data comparing both formulations.

Febrile neutropenia is one of the major causes of morbidity, treatment interruptions and mortality during oncological treatment and bone marrow transplant (BMT). The time from fever to initiation of empiric antibiotics therapy (AET) is related to the outcome of patients. Ideally, patients should receive EAT in less than one hour after fever. However, many patients fail to receive EAT in less than 1 hour due to intrahospitalar delays, and may have impact in patient outcomes. Therefore, institutional policies to ensure ideal management of these patients are recommended and fever-to-patient antibiotic delivery is one of quality control measure in our Oncology and BMT Unit.We implemented a nurse-based program to reduce the time from first fever or clinical EAT indication to EAT infusion. A senior nurse was in charge of implementing the program in the Oncohematological and Bone Marrow Transplantation Unit. Several actions were implemented: (1) Data collection for comparative studies, (2) Team education (pharmacy, medical and nurses) through lectures and (3) Daily data verification to verify the accuracy of data registered in medical files; (4) Survey about patient characteristics included in this study.All patients in the unit were daily censored for neutropenia, and neutropenic patients were followed for fever or need for ATB initiation. Patients who initiated EAT on the emergency room (ER) or day clinic were excluded from the analysis. For all patients, time from EAT indication and EAT infusion was collected. Data was then classified in 4 categories: (1) Time to EAT <1 hour; (2) Time to EAT >1 hour; (3) Major data inconsistency (defined when EAT indication registered time was later than EAT infusion registered time); (4) Minor data inconsistency (defined when time to EAT infusion was registered at the same time of EAT indication). Twenty medical files were retrospectively selected for comparison.We present the results of the first three months after the program implementation. In the retrospective group, only 35% (7/20) of patients received EAT in less than 1 hour, 15% (3/20) of patients received EAT in more than 1 hour, and inconsistencies were seen in 50% of medical files, including 40% of minor and 10% major inconsistencies. After program implementation (n=17), the percentage of patients receiving EAT in less than 1 hour was 82% (14/17), 6% of patients received EAT >1 hour (1/17), and 12% (2/17) of patients had minor inconsistencies in registered time. No major inconsistencies were observed after the program.For good practicing analysis, we grouped patients in two groups: Ideal (EAT <1 hour) and Not Ideal (EAT>1 hour and inconsistencies in medical file registration). With this approach, we showed that Ideal group improved from 35% to 82%, and the Not Ideal group declined from 65% to 18% (p=0.007). Moreover, the median time to EAT decreased from 60 minutes (range 30-240) to 30 minutes (range 8-66) (p=0.01)The implementation of a nurse-based program significantly increased the number of patients receiving ATB in <1 hour in an Oncohematological and Bone Marrow Transplant Unit after only 3 months. Moreover, the time to ATB initiation was significantly decreased with this policy. Our findings indicate that, despite the nursing staff recognize the importance of febrile neutropenia, monitoring process, education and constant communication are necessary for an effective treatment and for improvement the patient care. Further implementation of this program in the day clinic and ER are planned and a survey about patient education of neutropenic infections will be implemented.No relevant conflicts of interest to declare.

The Foundation for the Accreditation of Cellular Therapy (FACT) has developed and implemented programs of voluntary inspection and accreditation for hematopoietic cellular therapy, and for cord blood banking. These programs are based on the standards of the clinical and laboratory professionals of the American Society of Blood and Marrow Transplantation (ASBMT), the International Society for Cellular Therapy (ISCT), and NETCORD. Our transplantation service was the first Hospital in Latin America to be accreditated by FACT in 2012. FACT accreditated hospitals might have a positive impact in Implementing new procedures and treatment protocols. Haploidentical SCT program was developed in our institution during FACT accreditation process. Since high complexity procedures challange transplantation units, we believe that conducting protocols after FACT accreditation helped the achievment of better standard of care that might be translated in results comparable with international transplantation centres. SCT from Haploidentical donor can be one therapeutic option specially for patients with no available MRD or MUD. In order to overcome HLA disparity, more intensive immunossupresion is usually used that can be associated to higher TRM. These difficulties demand a well stablished transplantation unit. Here we show the first 25 patients who recieved haploidentical SCT during FACT accreditation in a single institution in Brazil. Patients and methods: From april 2008 to july 2013, 25 patients were treated with haploidentical SCT. The median follow-up time was 3,3 months (range ). 8 (32%) patients had AML, 1 (4%) ALL, 1 (4%) JMML, 1(4%) LH, 1 (4%) MDS. 7 (28%) had  adrenoleukodystrophy x-linked, 3(23%) had SAA and 2(28%) SCID. 8 (33%) patinets had refreactory disease. Median age at transplantation was 3.3 (range 1-72) years. 12 (48%) patients were in pediatric age range (1 to 18) years. 13 (54%) had donor/receptor ABO incompatibility. 10 (40%) patients were transplanted after myeloablative conditioning regimen (Bussulfan/Fludarabine or Busulfan/fludarabine/thiotepa) and 15(60%) after non-myeloablative conditioning regimen (Fludarabine/cyclophosphamide/TBI200cGy). 22 (88%) patients have received bone marrow as stem cell source and 3 (12%) peripheral blood stem cells. Median total nucleated cell x 108/Kg was 5.5 (range 3.0 to 10.34). Median CD34+x106/Kg 3.61 (range 1.48 to 7.06). Post transplant immunosuppression consisted of tacrolimus/MMF plus post transplant Cyclophosphamide in 22 (88%) patients, steroids plus CsA or tacrolimus in 2 (8%) and T cell depleted graf with no immunosupression in one SCID patient. All patients engrafted by day 28 after transplantation and 4 patients had secondary graft rejection. Only one (4%) patient developed synusoidal obstruction syndrome. 7 (28%) patients developed Acute graft-verus-host disease (3 grade I/II and 4 grade III/IV). 16 patients (64%) developed CMV reactivation. At the end of the follow-up 21 (84%) were alive. Four patients died from relapse at day 100 post transplant, 2 from infection and 1 from coronary heart disease. Sencondary graft failure had a negative impact in overal survival (HR: 14 (IC: 1,2-157), p= 0,033). Conclusion: The FACT accretidation process can promote improvement and progress in stem cell transplantation process, by controlling every aspect that impacts the quality of products and therapeutic care. In our center, there was a process developed in order to meet FACT standards that brought better patient care. We have shown the first 25 haploidentical patients who was treted after this accreditation, showing similar results when comparing to international centres and previous publications. We believe that these results could only be achieved in a transplant unit that meets specific quality control guided by FACT.No relevant conflicts of interest to declare.

Zinc is an important trace mineral for the body, being a cofactor of enzymes responsible for the synthesis of nucleic acids, and maintaining the immune system. Symptoms of zinc deficiency, such as alopecia, diarrhea, skin rash and growth failure, can be confused with those of hematopoietic stem cell post-transplant (HSCT). Some studies show that zinc supplementation, with the purpose of increase of its serum level, reducing the incidence of mucositis, xerostomia, pain and loss of taste. Zinc deficiency is reported in children with leukemia, but there are very few studies in adults.45 adult patients were evaluated, 22 women and 23 men, mean age 49 ± 16 years-old, undergoing HSCT in Hospital Israelita Albert Einstein during the period of 1 year (2012-2013). The serum zinc level, whose average was 69 ± 16 mg/dl, was evaluated in the first day of hospitalization for HSCT and no patient took zinc supplements before it.48% of patients had zinc deficiency, being most prevalent in patients > 60 years, which had 60%. There was no difference between the sexes.Some studies believe that zinc, will be a very important agent in transplant medicine, due to its action on the improvement of the severity of mucositis induced by chemotherapy in patients with leukemia. In our study we found a high prevalence of zinc deficiency in adults and the elderly. Therefore, the assessment of zinc serum levels should be considered in patients submitted to HSTC, as a purpose of treatment and improvement of complications related to it.No relevant conflicts of interest to declare.

There are few studies on the behavior of vitamin D in patients undergoing Hematopoietic Stem Cell Transplantation (HSCT), although vitamin D serum levels are associated with use of corticosteroids and immunosuppressive drugs. In some studies, vitamin D deficiency in patients after HSCT is associated with reduced bone density, increased of parathyroid hormone and GVHD.To study vitamin D deficiency in patients undergoing to HSCT.51 patients who underwent HSCT at Albert Einstein Hospital, São Paulo, Brazil, were studied (28 male, 23 female) with a mean age of 50 ± 16 years, in the period from 2012 to 2013.54 % had serum levels of vitamin D ≤ 50 nmol/l. And, 12% had serum levels of vitamin D ≤ 25 nmol/l. A multivariate analysis showed that more age and higher Body Mass Index (BMI) were significantly associated to lower serum levels of vitamin D. A negative correlation was found between BMI and serum level of vitamin D (rp=0,37).The use of corticosteroids, immunosuppressive drugs and less lack of sun exposure during the HSCT and during the first year post-HSCT are associated with a greater tendency to deficiency of vitamin D. This deficiency can cause muscle and bone diseases, which can be prevented with diagnosis and early treatment. The deficiency of vitamin D should be carefully investigated in the elderly and obese patients.No relevant conflicts of interest to declare.

Graft-versus-host disease (GvHD) causes morbidity and mortality in recipients of allogeneic hematopoietic stem cell transplantation (ASCT). This study assessed the distribution of GvHD in gastrointestinal (GI) biopsies from the upper and lower GI tract in all patients who had undergone ASCT in our institution between 2005 to 2013 and evaluated the correlation between biopsy of upper and lower GI, possible relation with CMV Infection in GI biopsy and Blood sample, GvHD GI grade and extra-intestinal manifestations of GvHDWe performed a retrospective pathology records review for all patients diagnosed with positive GI GvHD biopsy, who underwent both upper and lower endoscopy. We also reviewed pathology and clinical reports to determine which biopsy sites were diagnostic of GvHD and to evaluate for the possible presence of extra-intestinal manifestations GvHD at the time of biopsy, CMV Status on the biopsy findings and blood sample.One hundred eighty nine patients (78 children and 111 adults) received ASCT transplant between 2005 to 2013. Twenty eight patients ( 14,8%) had undergone both upper and lower positive biopsy for acute GvHD diagnosis. Seventeen ( 60,7%) were male. The median age was 28 (1.50- 63.6) years old. Eleven patients had AML (39%), 6 had benign diseases (21.4%); five had ALL (17.9%); 2 lymphomas; 02 (7.1%) CML and 01 (3.1%) MDS. Main stem cell source was bone marrow 14 (50%), followed by PSCB in 7 (25%) and SCUP in 7 (25%). ATG was used in 16 (57, 1%) patients. Extra- intestinal manifestation of GVHD was: skin in 19 (67, 9%); liver in 6 (21,4%) patients. Five (17,9%) had the 3 organ involvement. The GI GvHD grade was: grade I in 7 ( 25%) , grade II in 4 ( 14,3%), grade III in 9 ( 32.1% ) and grade IV in 8 ( 28,6%). Regarding the concordance between the biopsy findings, there is agreement only between Ileum Biopsy Negative plus ileum and Rectum, because both have a higher percentage of positive GvHD. The stomach has a higher percentage of negative GvHD, and therefore there is no agreement with Colon plus ileum and Rectum. The frequency and correlation between involvement of different parts of GI-GVHD are presented in Tables 1,2 and 3. Just 2 ( 11.1%) patients had negative rectal biopsy and positive colon + ileum. Nine (32, 1%) had blood CMV detected. Five ( 17.9%) had positive Biopsy for CMV ( one in stomach, 3 in Colum and on in rectum), and just one patients had both positive.There is no association between clinical grade of GI-GVHD and the presence of CMV in biopsy and blood (CMV positive X GvHD grade, p=0.885; and biopsy CMV positive X GvHD grade, p= 0.859).It has no association between clinical grade of GI- GVHD and conditioning (p= 0.070) and use of ATG (p=0.867). HLA disparity was related with higher grades of GI-GVHD (p=0.029). All patients with Grade I are Fullmatch, whereas patients with Grade III and IV had highest percentage of mismatch [grade III= 5 (55.6%); and grade IV= 4 (57.15%) patients].The median follow up was 7.2 (1.8-90.6) month. Overall survival (OS) was 40% in 60 month and patients with grade IV GVHD had worst OS ( P= 0.004).Use of sigmoid biopsy for GvHD diagnosis is effective, safe, and less expensive compared to other endoscopic interventions, because it was most frequent site of lower GI-GVHD and only 11% of biopsies were discordant. CMV infection may be underdiagnosted with this approach, where colonocospy study should be considered as most of CMV positivity in biopsy was in Colum.No relevant conflicts of interest to declare.

Febrile neutropenia is one of the major causes of morbidity, treatment interruptions and mortality during oncological treatment and bone marrow transplant (BMT). The time from fever to initiation of empiric antibiotics therapy (AET) is related to the outcome of patients. Ideally, patients should receive EAT in less than one hour after fever. However, many patients fail to receive EAT in less than 1 hour due to intrahospitalar delays, and may have impact in patient outcomes. Therefore, institutional policies to ensure ideal management of these patients are recommended and fever-to-patient antibiotic delivery is one of quality control measure in our Oncology and BMT Unit.