ALBERT

Description: Introduction: Busulfan (Bu) is used in the conditioning regimen for hematopoietic stem cell transplantation (HSCT). Therapeutic drug monitoring (TDM) of Bu with subsequents adjustments doses based on a “target” therapeutic concentration may reduce toxicity after HSCT. Objectives: To evaluatethe impact of TDM of Bu and clinical outcomes in patients with acute leukemia that underwent to allogeneic matched related donor (MRD) and allogeneic matched unrelated donor (MUD) HSCT. Patients and methods: From January 2009 to January 2014, we prospectively analyzed 42 patients with diagnosis of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) who underwent TDM of Bu (IV or oral) before transplantation (test dose) and TDM on 1st day of conditioning regimen. Samples were collected at 0, 30’, 60’ and subsequently every hour until 6 hours after administration of busulfan. The plasma was extracted by HPLC (High Performance Liquid Chromatography). All the patients that were submitted to TDM had a test dose 15 days to 48 hours before transplantion. The dose of Bu was adjusted during the first day of the conditioning regimen based on test dose. At the same time we analyzed 21 patients in the retrospective group who did not underwent TDM (from 2004 to 2010). Results: In the retrospective group (n=21), all of them underwent to MRD transplantation. Six (46.2%) were in first complete remission (CR1), 18(85.7%) patients received Bu and cyclophosphamide (BuCy) and the mean of age was 38 years (18-55 Yo). The median of CD34+ cells was 5.4 x 106/kg. The second group consisted by patients that received oral Bu (n= 21): 7 (33.3%) underwent to MUD transplantation, 14 (66.6%) to MRD transplantation, 8 (44.4%) patients were second complete remission (CR2), 4 (22.2%) had active disease status with a mean age of 32.7 years (14-58 Yo). Fifteen (71.4%) received BuCy and 16 (76.2%) received cells from peripheral blood. The median of CD34+ cells was 5.8 x106/kg. The median area under the curve (AUC) in 24 hours was 4950 μMol.min (3196.6- 8212 μMol.min). The third group was IV Bu (n= 21): 7 (33.3%) patients underwent MRD and 14 (66.6%) MUD transplantation, 7 (33.3%) patients were CR1, 7 (33.3%) had active disease or prior HSCT with a mean of age 52.7 years (20-74 Yo). The majority of patients received fludarabine and Bu (n=18; 85.7%) as conditioning and bone marrow was the main source. Immunosuppression was based on FK-506 and methotrexate (90.5% of patients). The median of AUC in 24 hours was 5690 μMol.min (3539.6- 8881.8 μMol.min). The cumulative incidence (CI) of sinusoidal obstructive syndrome (SOS) in the retrospective group and IV Bu were 9.5% for both, while in the group oral Bu it was at 19% (p = 0.566). The median AUC of Bu received during conditioning for those who died of SOS was lower in oral Bu than IV Bu (4872 uMol.min vs 5732 uMol.min respectively). The CI of acute graft-versus-host disease (aGVHD) at D+100 was 38.1% in the retrospective group, 40.6% in oral Bu and 42.9% in IV Bu. Chronic GVHD was 13.6% in oral Bu, 34% in IV Bu and 42.9% in the retrospective group (p = 0.142). The CI of relapse at D+100 was 19% in IV Bu, 4.8% in the retrospective group and oral Bu did not have this event. The IC of death at D+100 was 34.9% in group oral Bu, 9.5% in IV Bu and 14.3% in the retrospective (p = 0.102). The CI of relapse at 1.5 years was 35.8% in the IV Bu, 34.8% in oral Bu and 14.3% in the retrospective group. The CI of death at 1.5 years was 9.5% in group IV Bu, 53.5% in oral Bu and 34.3% in the retrospective (p = 0.015). Among patients who died until D+100, the median of AUC was 5732 μMol.min (5578.5-6818.5 μMol.min) during the conditioning for IV Bu and 4872 μMol.min (3448-8212 μMol.min) for oral Bu. The range between the AUC was large and there was no correlation with patients who died. Conclusion: In acute leukemia SOS had an impact on mortality at D+100 after HSCT (p

Description: Hematopoietic stem cell transplantation (HSCT) has been a potential curative treatment for hematological malignancies. Graft versus host disease (GVHD) produces the graft versus leukemia (GVL) effect, an immunologic response capable to protect the HSCT recipient against cancer cells. Chronic GVHD (C-GVHD) is one relevant cause of mortality and remains a hazard in allogeneic hematopoietic stem cell transplantation (allo-HSCT). The purpose of this study was to investigate the influence of the GVL effect associated with the C-GVHD over the disease free survival in patients with acute leukemias (AL) and chronic myeloid leukemia (CML). We studied a retrospective cohort of 192 patients with AL (n=77) and CML (n=115) aged 14–62 years (median 32) who underwent allo-HSCT with identical HLA donors in the Hospitals Sao Paulo and Santa Marcelina, in Sao Paulo, Brazil, from August 1993 to December 2004. We used in our study the criteria of C-GVHD of Seattle cited by Shulman et al (1995) revised by Lee (2003). The C-GVHD incidence was 78.4% (76/97) and 66.7% (36/54) in CML and AL, respectively. First relapse in CML occurred in 14.5% (11/76) of the cases with C-GVHD and in 61.9% (13/21) of the cases without C-GVHD. This fact shows the striking negative correlation and impact between the GVL effect and the incidence of first relapse post allo- HSCT in CML. The clinical severity of C-GVHD influenced significantly and inversely the chance of first relapse, once CML patients with extensive C-GVHD (2/45) had a lower relapse rate than limited disease (9/31) (4.4% versus 29%; p = 0,003). Subdividing CML patients in two groups, early (CML-Chronic Phase, CP) and advanced disease (CML-Accelerated Phase/Blastic Crisis, AP/BC), the first relapse rate was also correlated with the severity of C-GVHD. Relapse rates were 64.3% (9/14), 27.3% (6/22), and 5.6% (2/36) in CML-CP patients with absent, limited, and extensive C-GVHD (p = 0.0001), and 57.1% (4/7), 33.3% (6/9), and 0.0% (0/9) in CML-AP/BC, respectively (p = 0.037). Similarly, AL patients with C-GVHD showed a relapse rate of 27.8% (10/36) compared with 83.3% (15/18) when C-GVHD was absent (P = 0.0001). When we analyzed AL patients by stage of disease at transplantation (early AL patients: in first CR; advanced AL patients: after first relapse or refractory) with and without C-GVHD, patients with early AML (17/29) or early ALL (11/25) had a lower relapse rate than patients with more advanced AL (AML: 23.5% versus 66.7%; p = 0.02; ALL: 18.2% versus 78.6%; p = 0.003). Hence, the presence of C-GVHD in our cohort of AL and CML patients was an important determinant capable of modifying the outcome in these pathologies. The clinical severity of the C-GVHD was the most relevant factor to determine a lower relapse rate in CML patients, despite the stage of disease at time of transplantation.

Description: Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although FL is considered incurable disease with standard chemotherapy, advances in treatment have improved disease its management and clinical outcomes. Treatment for relapsed or refractory patients is influenced by initial first-line therapy and the duration and quality of the response. Presently, there is no consensus for treatment of patients with early or multiple relapsed disease; however, numerous drugs, combination regimens, and transplant options have demonstrated efficacy. Considering that there is no consensus to treat such patients, we are reporting this case. A 37-yo woman presented in Sep 2005 with abdominal masses, constitutional symptoms and two years of recurrence of urinary and pelvic infections, with previous lymph nodes biopsies revealing hiperplasia. At this time grade I FL, stage IVB, with bone marrow involved was done. There was no response to four cycles of Rituximab and three of COP. In Jan 2006 a histological review confirmed the diagnosis. Then she underwent to six cycles of R-CHOP 21, resulting in complete remission (CR) was ruled out. Consolidation therapy consisted to IL-2 monthly four cycles, and an eight quarterly Rituximab for two years. Supportive care with polyclonal immunoglobuline infusion monthly was demanded to overcome frequent urinary and respiratory infections. After nine years, Dec 2015, constitutional symptoms returned and PET/CT was positive in mediastinum and there was bone marrow involvement. From Jan to Jun 2016, 6 cycles of Rituximab and Chlorambucil was done, and after the second one she complicated with pulmonary aspergillosis and there underwent voriconazole for 18 months. In Jul and Nov 2016 PET/CT revealed a second CR. Just four months later, BMB and pulmonary infiltrated disclosed a new relapse. Four cycles of Fludarabine 30 mg/m², Mitoxantrone 8 mg/m², Rituximab 375 mg/m² and dexamethasone were attempted, since Apr to Jul 2017. A fosfomycin therapy was done to prevent a recurrence of Escherichia coli multi-resistant urinary tract infections. The patient achieved a third CR at PET/CT in Aug 2017. Based on the last rapidly progression of the disease, and bone marrow involvement in all relapses, we proposed an allogeneic stem cell transplantation (allo-SCT). But she didn't have a match related donor. So, her twelve years old son was considered as an haploidentical donor. A reduced intensity conditioning (RIC) was performed with Cyclophosphamide 14.5 mg/Kg D-6 and D-5, Fludarabine 30 mg/m² D-6 to D-3, TBI 200 cGy at D-1. A double source of stem cells: primed-bone marrow (TNC 4.49 x 10⁸/Kg) plus peripheral blood stem cell (4.48 x 10⁶ CD34+/Kg) was infused on Oct-10-2017. Immunosuppressive therapy consisted of Cyclophosphamide 50 mg/Kg at D+3 and D+4 (PT-Cy), Tacrolimus and MMF starting at D+5, and G-CSF from D+5 until neutrophil engraftment. The neutrophil engraftment reached at D+14. Cytokine Releasing Syndrome, febrile neutropenia, rectal prolapse and grade I/II acute graft versus host disease (aGvHD) were immediate complications. Discharge occurred at day +18. CMV PCR positive was preemptive treated from Nov to Dec 2017. Steroid therapy was given for grade II aGvHD, Nov 2017 till Dec 2018. She had an Orthostatic Tachycardia Syndrome from Feb to Oct 2018; Respiratory Syncytial Virus, from Jul to Aug 2018; Rhino and B Influenza upper airway infection on Mar 2019. A complete chimerism was achieve at +100, +180 and +365 days. PET/CT confirmed CR at D+180 and +365. At the present she is off treatment since Jan 2019. In this situation a double source haplo-SCT was a successfully therapy overcame the complicated comorbidities before transplantation, with a good quality of life nowadays. Disclosures No relevant conflicts of interest to declare.

Description: Allogeneic stem cell transplantation (allo-SCT) represents a curative option for intermediate- and high-risk acute leukemias (AL). The number of unmanipulated haploidentical allo-SCT (haplo-SCT) is increasingly used with favorable outcomes. Incidence of graft-versus-host disease (GvHD) in haploidentical bone marrow (BM) transplants using post-transplant cyclophosphamide (PTCy) is low, counterbalanced by an excess in disease recurrence; and acute GvHD using mobilized peripheral blood stem cells (PBSC) ranges between 30% and 40%. The ultimate choice of graft source depends on the design of the full transplantation package based on transplantation center experience. We conducted a retrospective analysis of 32 patients (59% male), who received an haplo-PTCy with double source of stem cells, G-CSF primed bone marrow plus G-CSF-mobilized PBSC, for high-risk or advanced acute leukemia in two Brazilian centers, Hospital Santa Marcelina (n=23) and Hospital São Paulo (n=9), from 2013 to 2019. The median age patients were 27.5 years (range 17-60 years). Median disease time before haplo-PTCy was 8.9 months (3.6-108). There were 13 acute myeloid leukemia (AML), 17 acute lymphoblastic leukemia (ALL), one mixed phenotype acute leukemia and one dendritic cell leukemia. 6/17 ALL were Ph1 positive. 34% of the patients received 2 treatment protocols to achieve CR and 12.5% had submitted to more than two treatments. So, at the time of transplant 75% (n=24) was in first CR (CR1) although one (3%) patient was minimal residual disease (MRD) positive and six (18.7%) there were no MRD available. The others patients (n=8, 25%) were on second or third CR. The HCT-CI comorbidities was ≥ 3 in two patients, and there were 15 patients (46%) with carbapenem-resistant gram-negative bacilli (CRGNB) colonization before transplant. Panel reactive antibody was positive in two patients. The donor was a sibling in 68.7% (n=22), father, mother and child in two (6%), three (9%) and five (15%) patients, respectively. The conditioning was reduced intensity (RIC) in 87.5% (n=28) patients, with fludarabine, cyclophosphamide and total body irradiation (TBI) 200 cGy. After conditioning, patients received G-CSF primed bone marrow grafts in combination with PBSC no ex-vivo T cells depleted, and cyclophosphamide 50 mg/Kg/day IV on days +3 and +4 post-transplant, as well as GVHD prophylaxis. Six (18.7%) patients died for sepsis before 60 days (10 to 58 days), all had had CRGNB before transplant, four those ones with no grafting, died from days +10 to +19. Acute GvHD grade III-IV was observed in two patients, who died at +48 and +95 days. High mortality related to transplant (TRM) was observed considering all patients. CRGNB was a determining factor in these early deaths. If we excluded all CRGNB patients of this study the mortality could be 11% (2 patients with GVHD in 17 patients transplanted). Four patients (16%) has severe cGvHD. Nine patients (37%) relapsed in two years. Two years OS and DFS were 40% and 37.5%, respectively. In conclusion, with a median follow-up of 2 years, haplo-PTCy with double source leads to 40% overall survival in 32 patients with high-risk advanced acute leukemia, with 16% (n=2) being in treatment for cGvHD. The causes of death were relapse 43% (n=7), early sepsis in patients with CRGNB colonization 37.5% (n=6), grade IV acute GvHD in 12,5% (n=2), and one patient died for pneumonia community at D+285. Our data suggests that haplo-PTCY double source is a feasible option in these cases. However, CRGNB colonization in aggressive disease is the main factor that should be considered as exclusion for haplo-SCT in development countries. Disclosures No relevant conflicts of interest to declare.

Description: Significant improvements in haploidentical stem cell transplantation (haplo-SCT) have confirmed its therapeutic role in severe aplastic anemia (SAA) and led to the evolution of treatment algorithms. However, the optimal conditioning regimen for haplo-SCT for SAA remains undefined. A recent review demonstrated haplo-SCT using NMA and RIC, engraftment between 75 to100% and OS one year of 75-100%. In our Institutions we started a double source since Jan 2017 using a RIC protocol that is the objective of this presentation. There were nine haplo-SCT in eight patients in two Brazilian centers, Hospital Santa Marcelina (n=5) and Hospital São Paulo (n=3). All patients were male, median age 26 years old (14-39), nocturnal paroxysmal hemoglobinuria clonality in five (62,5%); treated with Cyclosporine, Thymoglobulin (n=4), Eltrombopag (n=1), Eculizumab (n=2) and/or Alemtuzumab (n=1). Median time disease to transplant was 15,7 months (3.8-192). All patients submitted more than 20 RBC transfusions, and median of ferritin was 2,283 ng/mL (753-3,486). One patient had carbapenem-resistant gram-negative bacilli (CRNGB: Escherichia coli, Klebsiella pneumoniae and/or Pseudomonas aeruginosa). Panel reactive antibody was negative in all patients. The donor was a sibling in 44% (n=4), father and mother 22% each (n=2) and one patient received cells from his cousin after an early failure of engraftment from mother first transplant. The cause of this failure was a JC virus and adenovirus acute infections. The second haplo-SCT conditioning was Fludarabine, Cyclophosphamide and 600 cGy TLI. There were seven male donors. RIC was consisted of Fludarabine, Cyclophosphamide and total body irradiation (TBI) 200 cGy. The source was G-CSF primed bone marrow (G-BM) grafts in combination with PBSC no ex-vivo T cells depleted, and Cyclophosphamide 50 mg/Kg/day IV on days +3 and +4 post-transplant (PTCy), as well as graft versus host disease (GvHD) prophylaxis. The median of G-BM MNCs was 5.4 x 10⁸/Kg (2.3-8.7), and PBSC was 10 x 10⁶CD34+/Kg (4-18.7). One (11%) patient died for sepsis at day +13, he was the only with a confirmed CRGNB colonization before transplant. The ANC recovery was at day +17 (13-24). No one had Sinusoidal Obstructive Syndrome. Acute GvHD grade II and moderate chronic GvHD was observed in two patients (25%). Two patients had engrafting failure: the first at day +30 and received a successfully new haplo-SCT; the second at day +60, with a partial donor reconstitution without dependence of transfusion after immunosuppressive therapy. These two patients had female donors. The OS and DFS at two years were 87.5% and 75%, respectively. In conclusion, with a median follow-up of 30 months, haplo-SCT, PTCy with double source keep the 87.5% overall survival, with no one severe chronic GvHD. Our data suggests an excellent results for haplo-SCT, PTCy, RIC, double source in the SAA treatment. However, prospective well-designed trials need to confirm these results. Disclosures No relevant conflicts of interest to declare.

Description: Allogeneic hematopoietic stem cell transplantation is an important last resort therapy for hematological diseases. Unfortunately, the success of a large proportion of these transplants is limited by graft-versus-host disease (GVHD). Currently known risk factors for acute GVHD (histoincompatibility, sex mismatch, older patients, previous pregnancies) do not provide a precise estimate of individual patient risk and do not help for individualization of the therapy. Although GVHD may have beneficial graft-versus-tumor effects, observational studies have identified GVHD as the main cause of non-relapse mortality. Thus, early identification of those patients who will develop aGVHD may allow for individualized treatment, and also for the reduction of unnecessary treatment for those patients not at risk. Nowadays, however, there is no diagnostic method that allows prediction of aGVHD. Thus, the goal of our study was to reveal a gene expression profile that would predict the occurrence of aGVHD. Material and methods: Between May 2004 and August 2007, we collected blood samples from 89 recipients of myeloablative (N=71) and non-myeloablative (N=17) HLA-identical sibling allogeneic hematopoietic stem cell transplants at the time of successful engraftment (2–3 weeks after transplantation). Acute GVHD prophylaxis was cyclosporine plus short course of methotrexate and cyclosporine plus mycophenolate mofetil in myeloablative and non myeloablative transplants, respectively. Forty patients (45%) experienced acute GVHD (Glucksberg criteria). All the patients had acute GVHD before the first three months after transplantation (median 31 days; range 21–88 days). We isolated total RNA from the peripheral blood mononuclear cells, amplified it, labeled, and co-hybridized to the microarray slides containing probes for 22,000 genes. We used BRB ArrayTools for data analysis. The patients were divided into training and test groups, the former used to build a model discriminating patients with and without aGVHD and the latter - to test the model on independent samples. We selected the informative genes using “recursive feature elimination” method followed by six different multivariate classification algorithms (compound covariate predictor, diagonal linear discriminant analysis, 1- and 3-nearest neighbor predictor, nearest centroid predictor, support vector machine, Bayesian predictor) in order to establish a molecular classifier in the training set. Then we validated this new classifier in the test set of patients. Because multiple classification algorithms may give different results, we considered a result being robust and a patient being “classifiable” when at least five out of seven algorithms were concordant. The other patients were considered as “unclassifiable” because no reliable prediction regarding development of aGVHD could be made. Results: We found a molecular classifier comprised by 244 gene probes in the training set of samples which were selected based on the most accurate classification. In the test group of samples, we found that 80% of patients could be classified based on the concordance between classification methods as described above. For these patients, the classifier showed 78% of a predictive accuracy (75% of sensitivity and 80% of specificity). Conclusion: Our results show that molecular profiling is able to identify patients under high risk of acute GVHD at the time of engraftment. Establishing of a predictive diagnostic method for aGVHD is the first step of individualization of therapeutic strategy after hematopoetic stem cell transplantation.

Description: Multiple myeloma (MM) causes great impact in quality of life (Q/L), since patients become dependant of others even for routine activity execution and personal care. Objectives: To characterize the impact of MM in the Q/L of patients treated in two public institutions of Sao Paulo State, Brazil, using a generic (SF-36) and a specific questionnaire for oncologic patient (QLQ-C30), applied in three different moments: at diagnosis, after the end of clinical treatment and at day +100 after autologous hematopoietic stem cell transplant (ASCT). Patients and methods: From March 2006 to August 2007 we evaluated 49 patients with MM, using the two questionnaires. Analysis was made through ANOVA, Post hoc and T-paired test comparing the three groups. Results: 88.6% of included patients have family budget lower than US$ 600.00/month (Economic Class C, D or E). The generic questionnaire SF-36 demonstrated that Physical Functioning, Role-Physical and Bodily Pain were statistically different in all three groups, favoring the day +100 post-ASCT group (ANOVA). SF-36 still demonstrated improvement in Role-Emotional when MM post treatment group was compared with the day + 100 post-ASCT group (T-paired Test). The QLQ-C30 questionnaire confirmed what had been demonstrated by the SF-36 in relation to the Physical Functioning and Bodily Pain plus improvement in the following aspects: Role Functioning, Fatigue, Lack of Appetite and Constipation, favoring the day + 100 post-ASCT group (ANOVA). QLQ-C30 also detected a significant improvement in Social Aspect in patients with MM after day +100 of ASCT. Conclusion: The specific questionnaire for cancer patients QLQ-C30 seems to be more informative than the generic questionnaire SF-36 and reflects the real benefit of ASCT in Q/L of MM patients from two public Brazilian institutions, which provide assistance for economically challenged population.

Description: The management of the chronic graft versus host disease (C-GVHD) in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still challenging and does not follow a consensus. This disease can manifest as auto-immune phenomena, often affecting multiple organs, and it is considered as a determinant factor for higher post transplant mortality and detrimental quality of life, although conversely associated with a strong graft versus tumor effect which determines a beneficial biological response in patients with haematological pathologies. The aim of this study was to determine the impact of the C-GVHD in the overall survival (OS) and disease free survival (DFS) in patients with hematologic pathologies who underwent allo-HSCT with HLA identical donors in the BMT Hospitals Sao Paulo and Santa Marcelina, in Sao Paulo, Brazil. We performed a retrospective study of historical cohort including 233 allo-HSC transplants, 151 patients aged 9 to 63 years old (median 31) with survival superior to 100 days, from August 1993 to December 2004. The classification of DECH-C followed the criteria of Seattle (Shulman et al. 1980) revised by Lee et al (2003). Our series was composed of 97 patients with chronic myeloid leukemia (CML), 54 with acute leukemias (AL), 42 with marrow failure (MF) and 40 with lymphoproliferative diseases (LPD). Forty one percent of the patients exhibited the advanced disease at HSCT time and the main source of HSC was bone marrow (n=174, 74.7%). The diagnosis of C-GVHD was performed in 166 procedures (71.2%). Seventy one patients (42.8%) were classified as C-GVHD quiescent, 69 (41.6%) as de novo, and 25 (15.1%) as progressive. The extensive form occurred in 95 cases (57.2%) and the limited form in 70 cases (42.2%). The mean OS for our cohort was 34.5 months (m) and the mean DFS was 29.5 m. The mean OS of patients with C-GVHD was 42 m, significantly higher than than 33.8m OS of patients without C-GVHD (p=0.05). Similarly, the DFS was 38.6m for C-GVHD patients, against 22.6m of DFS for patients without C-GVHD (p=0.0001). The OS of those patients with C-GVHD de novo (47m) and quiescent (44.8m) were superior than the OS of patients without C-GVHD (33.8%) or with the progressive form of C-GVHD (20.8m), p=0.002. The same effect was observed for the DFS in the de novo form (42.6m) and quiescent form (41.4m) of C-GVHD, with a DFS twice superior than the progressive form (19.8m) and than the C-GVHD absent (22.6m), p=0.001. When compared with cases without C-GVHD, the clinical severity of the C-GVHD (limited or extensive) showed a strong correlation with a higher DFS. Patients with limited C-GVHD had a DFS of 38.3m and the extensive form a DFS of 38.9m, significantly superior than the DFS of patients without C-GVHD with a DFS of 22.6m (p=0.002). Hence, this study shows the existence of a correlation between the presence of C-GVHD and higher OS and DFS in patients with haematological disorders submitted to allo-HCT. The diagnosis of progressive C-GVHD was associated to a deleterious effect over the outcome of allo-HCT, therefore inactivating the benefits of the graft versus tumour effect observed in the clinical presentations de novo and quiescent of C-GVHD.

Description: Purpose- Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3-kinase/mTOR signal transduction pathway has been demonstrated to be activated in tumor samples from patients with Hodgkin Lymphoma (HL). The goal of this study was to evaluate the response, time of response, toxicity and overall survival in patients with refractory disease using everolimus out of clinical trial, in a compassionate use. Patients and Methods- Patients were eligible if they had refractory and active Hodgkin disease. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Time to response assessement was defined by each center until progression (this was defined by each doctor, some have considered to keep the drug until clinical progression and not radiological progression of the disease). Patients could remain on drug until progression or toxicity. Results- Thirty three patients were enrolled. Median age at the time of everolimus start was 29 years (range, 20-70). Patients had received a median of 5 prior therapies (range, 3-7) , 81% had undergone prior autologous stem cell transplant and 4 patients had undergone alogenic trasnplantation. The ORR was 51% (95% CI: 24-71%) with 14 patients achieving a PR, 3 patient achieving a CR and 10 with stable disease. Thirteen patients used the drug for more than 1 year. Patients received a median of 14 cycles of therapy and 3 remains on therappy at 36 months showing a great tolerability of the drug. The median DR for the responders (CR/PR) was 10 months. The most commons site effects were trombocitopenia and hypercholesterolemia. Three patients had pulmonar toxicity. The adverse events grade III and IV ocurred in 30% of the patients. Conclusions- Everolimus has single-agent activity in relapsed/refractory HL, even in real lyfe and clinical practice and provides proof-of-concept that targeting the mTOR pathway in HL is clinically relevant. Disclosures Off Label Use: everolimus for refractory hodgkin lymphoma.

Description: Introduction Chronic myeloid leukemia (CML) is known to be a myeloproliferative neoplasm that involves a genetic abnormality defined as Philadelphia chromosome. Part of chromosome 9 becomes attached to chromosome 22, forming the BCR-ABL fusion gene, which is an oncogenic tyrosine kinase. The rise of the tyrosine kinase inhibitors (TKIs) has transformed the outcome of CML. Imatinib was the first TKI approved for treating patients diagnosed with CML in 2001. Dasatinib and Nilotinib were accredited as second-line therapy in 2006 and 2007, respectively, for patients who had failed previous therapy. Although these new drugs improved response compared with imatinib, they also have important side effects that can lead to non-adherence to treatment. Given the importance to maintain regular treatment to avoid disease progression, this paper aims to discuss the drug toxicities in patients undergoing second-line therapy. Patients and methods This study was an observational analysis using medical records in Santa Marcelina Hospital, a public service located in São Paulo, Brazil. Results A total of 58 CML patients taking second-line therapy were included, 28 with dasatinib and 30 with nilotinib. In dasatinib group, only 3 patients were diagnosed accelerated phase and each one had different side effects, as hematological toxicity, pleural effusion and ulcerative colitis. Of 25 chronic phase patients taking dasatinib, 12 (48%) presented with clinical and laboratorial abnormalities: 3.5% had hematological toxicity (2% with severe bleeding), 4% had cutaneous rash, 10.7% with ulcerative colitis (confirmed in bowel biopsy) and 18% developed pleural effusion. 25% of all dasatinib patient with side effects lost molecular response and started a third TKI. In nilotinib cohort, 7 patients were diagnosed with CML accelerated phase and only two developed liver toxicity. 23 patients were chronic phase and 60% presented with several side effects: 3% hypertriglyceridemia, 6% had hematological toxicity, 6% with dyspepsia, 10% had cutaneous rash and 27% presented with higher liver transaminase. 7% of all nilotinib patients who developed side effects lost molecular response and had to discontinue therapy. Discussion Several examples of side effects can be described with all TKI including cytopenias, fatigue, pain, fluid retention, GI disorders, skin complains, cardiac and liver toxicities but grade 3-4 occurs in less than 2-3% of patients as Jabour et al reported. Despite of important adverse effects, dasatinib and nilotinib induce rapid and durable hematologic and cytogenetic response. In general, the most related toxicities are self-limited and manageable as Kantarjian related. Comparisons between these two second-line therapy using intolerance criteria can be difficult to represent because studies published until now have two different types of population in terms of cytogenetic response achieved previously with imatinib, for example. So, to have a successful treatment, it is important to consider other variables as comorbidities and mutational status as referred Mathisen et al. Individualized risk assessment, between CML and patients characteristics, should influence treatment choices and clinical management. In conclusion, the efficacy and safety of dasatinib and nilotinib have been confirmed by long-term outcome. Clearly these drugs have unique pharmacologic profiles and response patterns in every single patient, but the goal of treating these patients is the correct management of adverse events without losing molecular response. Disclosures No relevant conflicts of interest to declare.