ALBERT

Description: Introduction. Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas (NHL). The use of chemoimmunotherapy (R-CHOP) in DLBCL has improved Overall Survival (OS). However, there are among 45-55% of patients who will die due to relapse, progression (refractoriness) or toxicity to treatment. Genomic classifications are difficult to use in clinical practice, especially in lain America, due to the need of trained personnel and cost. So, we continue using the International Prognostic Index (IPI) and its variations (e.g. revised-IPI, NCCN-IPI) for prognostic purposes. However, other biological variables have been reported to be prognostic, such as serum beta-2-microglobulin (B2M), lymphocyte/monocyte ratio (LMR), neutrophil/lymphocyte ratio (NLR), platelets/lymphocyte ratio (PLR) and serum albumin (SA). These factors have been associated with burden of disease, inflammation and nutritional status. Aim. Therefore, we performed a retrospective analysis of the databases of two Latin American groups to determine which biological variable is the most powerful factor prognostic of OS. Methods. A total of 1,250 patients were analyzed from two databases [(Grupo de Estudio para el Linfoma Mexicano (GELMEX) and the Grupo de Estudio para el Linfoma Latino Americano (GELL)], where 525 patients met the following inclusion criteria: DLBCL diagnosis by immunochemistry; complete data on absolute lymphocyte, absolute monocyte, absolute neutrophil and absolute platelet count, serum B2M and SA; and complete data on traditional variables for calculating risk groups for IPI, NCCN-IPI & R-IPI. The LMR, NLR and PLR was obtained. We evaluated the AUC of the biological variables and the differences among each one of them (including cut-off). Kaplan-Meier curves (KMC) were estimated and subsequently, the inference of OS was evaluated by Hazard Ratio (HR) Cox-regression in univariate/multivariate analyses by forward model. All variables with p3.2 mg/dL vs. ≤3.2 mg/dL) were 72% vs 34% (Log Rank p

Description: Background Persons with multiple sclerosis (MS) are sometimes treated with high-dose immune suppressive or cytotoxic drugs and an autotransplant. Use of autotransplants may be substantially more common as many cases are not reported. Therapy-related mortality (TRM) has decreased to 70%, extended Disability Status Scale (EDSS ≤8 in the 2 w pretransplant), CNS magnetic resonance image (MRI) ≤3 mo pretransplant, no prior bone marrow toxic drugs, normal heart, liver, lung and kidney function, ≥6 mo since exposure to immune suppressive drugs. Results 495 females and 244 males were included; median age was 47 years. 310 patients presented with relapsing remitting MS (RRMS), 273 with secondary progressive (SPMS) and 156 with primary progressive (PPMS). All procedures were started on an outpatient basis and only 31 persons needed to be admitted to the hospital during the procedure. In order to obtain at least 1x106/Kg viable CD34 cells, one to three apheresis were performed (median 1). Total number of viable CD34+ cells infused ranged between 1 and 37.83 x106 / Kg (median 5.62). Patients recovered above 0.5 x109/L absolute granulocytes on day 8 (median, range 2-13), whereas platelet recovery above 20 x109/L on day 4 (median, range 0-10). Seven individuals required red blood cells and eight needed platelet transfusions. There was one transplant related death and the 30-month overall survival of the patients is 99.9%. Patients with RRMS or PPMS had a significant drop in the EDSS before and 15-mo after the transplant, whereas patients with SPMS remained stable (A). The response rate (either drop or stabilization of the EDSS score) at 12 months was 78% for RRMS, 81% for PPMS and 73% for SPMS (B), whereas the relapse-free survival was 84% for all patients (92% for PPMS, 83% for RRMS and 81% for SPMS). Conclusions Changes in the EDSS score consonant with neurological improvement were observed in persons with all types of MS after HSCT employing the "Mexican method". Figure 1 Disclosures Gomez-Almaguer: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau.

Description: Abstract 4703 Background: Chronic graft-versus-host disease (cGVHD) is a common late complication of allogeneic hematopoietic stem cell transplantation. Corticosteroids are the standard initial treatment for cGVHD. A second-line treatment is not well defined. We prospectively evaluated the effectiveness and safety of low doses of alemtuzumab and low doses of rituximab as treatment steroid-refractory cGVHD. Materials and Methods: Ten men and 5 women with cGVHD refractory to steroids and CSA were included. All patients received subcutaneous Alemtuzumab 10 mg/day/3 days and intravenous Rituximab 100 mg on days +1, +7, +14 and +21. Results: The median age was 41 years. The main organ involved were oral mucosa (86.7%), eyes (66.7%), liver (60%), skin (53%), lungs (13.3%) and intestinal tract (6.7%). The overall response was 100% at 30-day evaluation; 10 patients (67%) had partial remission (PR), and 5 patients (33%) had complete remission (CR). At 90-day evaluation, 7 (50%) patients had PR, 4 (28%) had CR; three (21%) relapsed and 1 patient not reached evaluation. Currently, 5 patients have reached the 365-day follow-up evaluation, 2 (40%) had PR, 2 had CR and 1 showed progression. The adverse effects were mainly infectious and one patient died from pneumonia. Conclusion: This combination therapy appears to be an efficacious and safe as treatment for steroid-refractory cGVHD. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4707 Introduction. Graft-versus-host disease (GVHD) is the most common complication of allogeneic hematopoietic cell transplantation (alloHCT) and may affect the transplant outcome. Its incidence is higher when the preparative regimen used is a non-myeloablative and the stem cell's source is peripheral blood after mobilization. Objective. Demonstrate the 10 years incidence of GVHD in 2 Mexican transplant centers using peripheral hematopoietic stem cell transplantation (PHSCT) in related donors after non-myeloablative conditioning. Patients and methods. Three hundred and four patients with hematological and non-hematological malignancies that underwent outpatient PHSCT after non-myeloablative conditioning between October 1998 and July 2008 were included. The age ranged between 1 and 71 years (median of 30.5). One hundred and eighty-five patients were men and 119 women. The median of cells CD34+ infused was 4.9 × 106/kg (0.23-17.70).They received cyclosporine 4mg/kg per day and intramuscular methotrexate 5mg/ m2 in days +1, +3, +5 and +11 for GVHD prophylaxis. Results. Two hundred thirty-nine (80%) patients were successfully engrafted. The conditioning regimen was delivered as an outpatient procedure in all individuals. One hundred and fifty-four patients (64%) developed acute and/or chronic GVHD. Sixty four patients (26.7%) developed acute GVHD, 50 (20.9%) developed chronic GVHD, and 40 (16.7%) with acute GVHD progressed to chronic. Twenty seven (26%) patients who developed acute GVHD were grade III or IV, and 30 (33.2%) of chronic GVHD patients presented in the extensive way. GVHD was the cause of dead in 40 patients; 24 of acute GVHD and 16 of chronic GVHD, even when immunosuppressive therapy (high dose steroids and rituximab) was used. Last death was 24 months ago; subsequently, alemtuzumab was included in GVHD treatment. The cumulative incidence of acute GVHD was 37.6%. Conclusion. The higher incidence of GVHD reported in other studies after PBSC transplant seems to decrease if non-myeloablative conditioning regimens are used. We suggest that the combination of a reduced-intensity conditioning transplant and the outpatient procedure is the responsible for the low incidence of GVHD in our patients. Disclosures: No relevant conflicts of interest to declare.

Description: Three patients with Ph1 (+), BCR/ABL+ chronic myelogenous leukemia were allografted, two with unrelated compatible placental blood cells and one from an HLA compatible sibling. The three patients engrafted successfully, achieved mixed chimerism and all cleared the BCR/ABL fusion transcript. Despíte the fact that the three patients lost the partial chimerism, they have remained in complete molecular remissions 7 months, fourteen months and five years after the allografts. It is possible that the iatrogenic induction of a transient chimerism and in turn of a transient graft versus leukemia effect, might have a role in the induction of the sustained molecular remission of these three individuals with CML despite the fact that the three patients lost the graft; however other possible explanations can be offered. A longer follow up of the patients is mandatory to further clarify these observations.

Description: Abstract 6 Acute promyelocytic leukemia (APL) is a curable disease, and contemporary treatment based on the combination of all-trans retinoic acid (ATRA) with anthracyclines results in overall survival (OS) rates of around 90% at five years. Unfortunately, the treatment outcome of patients with APL in developing countries is significantly less. A recent Brazilian study had reported an OS of 53% with a first 5-days mortality of 13.4%. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) is an initiative of the International Members Committee of the ASH and the project aims to reduce this gap through the establishment of international network, which was launched in Brazil, México and Uruguay. All patients with a suspected diagnosis of APL were immediately started on ATRA, while bone marrow samples were shipped to a national central lab where genetic verification of the diagnosis was performed. Results of the immunofluorescence for PML was obtained within hours and upon confirmation of the diagnosis, patients were enrolled in a protocol identical to the PETHEMA-LPA 2005, except for the replacement of idarubicin by daunorubicin. Supportive care aimed at maintaining platelet counts above 30,000/μl and fibrinogen levels above 150 mg/dl. In each country, cases were discussed every other week through internet and whenever needed international experts were involved. As of June 2009, 102 (70 Brazil, 25 Mexico, 7 Uruguay) APL patients were enrolled. The median age was 34 y (range: 9–72y) with 55 males (54%).The median white blood cell counts (WBC) at baseline was 3.6×109 /L(range: 0.2–149.7). The distribution of the relapse risk score at diagnosis according to PETHEMA-GIMEMA criteria was 14 low (14%), 54 intermediate (53%) and 34 high risk(33%) respectively. The incidence of low risk APL appeared lower than the values reported in developed countries. Of 102, 97 patients have toxicity and response data available. Of these 97, 12 (12.3%)experienced at least three symptoms/signs of differentiation syndrome (DS) and 77 (79%) patients achieved a complete remission (CR). Twenty-three deaths occurred and the cause of deaths included 9 hemorrhage, 8 infection, 2 DS . The 7 and 30 day mortality rates were 8% and 19.6%, respectively, and the one- year overall survival was 75% (95%CI:68%–84%). The median follow-up time among survivors was 14 months (range: 1.3–35). Among 77 patients who achieved CR, the 1-year OS and disease-free survival from the date of CR was 95% (95% CI: 89%–100%). Only one patient relapsed. For patients surviving a minimum of 30 days the outcome was similar to that reported by the twin PETHEMA-LPA 2005 protocol in European patients. Prognostic factors for overall survival were examined using log-rank test as well as multivariate Cox models. Factors predicting OS were a high relapse risk score at baseline (1-year OS: 59% for high, 87% for intermediate, 91% for low, p=0.0007) and age. The 1-year OS was 85% for age

Description: Using a nonmyeloablative stem cell transplantation (NST) program previously shown to be effective in individuals receiving allografts in México, 29 patients with either acute myelogenous leukemia (AML, n = 12) or chronic myeloid leukemia (CML, n = 17) from the Latin American Cooperative Onco Hematology Group (LACOHG) were prospectively given allogeneic bone marrow allografts. Patients received a modified NST conditioning regimen consisting of oral busulphan 4 mg/kg on Days −6 and −5, IV cyclophosphamide 350 mg/m2 on Days −4, −3, and −2, IV fludarabine 30 mg/m2 on Days −4, −3, and −2, oral cyclosporine A 5 mg/kg twice daily starting on Day −1 (continuing until Day 180), and IV methotrexate 5 mg/m2 on Days +1, +3, +5, and +11. Median patient age was 43 years (range, 10–63). All patients engrafted; median time to achieve an absolute neutrophil count 〉0.5 x 109/L was 14 days (range, 0–21), whereas the median time to achieve a platelet count 〉20 x 109/L was 12 days (range, 0–21). Follow-up periods ranged between 39 and 519 days (median, 249). In patients with CML, the median overall post-transplant survival has not been reached, whereas the 519-day overall survival was 88%, and the 100-day mortality was 0%. In patients with AML, the median overall post-transplant survival has not been reached, the 459-day overall survival was 66%, and the 100-day mortality was 8%. The results from this multicenter, multinational study complement and further support the efficacy of our NST preparative regimen. The initial experience obtained from individuals with CML and AML receiving allografts in 2 institutions in México has now been extended into other Latin American countries, and the results are acceptable.

Description: Patients with high-risk hematological malignancies have a poor prognosis without a hematopoietic stem cell transplant. An HLA- haploidentical donor is available in 95% of the cases, and post-transplant cyclophosphamide permits the use of T-cell replete grafts in settings were ex-vivo manipulation is not available. The experience with HLA-haploidentical HSCT with PBSC and post-tranplant Cy in the pediatric and adolescent population is limited; we report the following experience. We retrospectively collected data on 25 patients (0 to 21 years old) with hematological malignancies, who underwent ambulatory haploidentical HSCT with post-transplant Cy from November 2011 to November 2014. The different conditioning regimens are described in Table 1. All patients received high-dose Cy(50mg/kg) on days +3 and +4. Cyclosporine A (CYA; 6mg/kg/d per os) and mycophenolate mofetil (MMF; 15mg/kg two times daily per os) were started on day +5. MMF was discontinued on day +35 and tapering of cyclosporin started day +90 in the absence of GVHD. All patients received anti-microbial prophylaxis for bacteria, fungal, herpes infection and Pneumocystis jiroveci according to institutional practices. First chimerism was performed at day +30, and second chimerism at day +100. Primary graft failure was defined when neutrophil counts did not exceed 0.5 x 109/L by day +30. Acute and chronic GVHD were graded according to NIH criteria. Patient, donor and stem-cell harvest characteristics are described in Table 1. All patients had high risk hematological malignancies. There were 5 patients who underwent their first transplant on 1st CR, 4 with ALL with high risk cytogenetics and 1 with AML. All other patients were defined as high risk because they were refractory/relapsed. Twenty-three patients (92%) had neutrophil engraftment after a median 17 (7-24) days. Platelet engraftment was observed in 20 (80%) patients after a median of 14.5 (11-23) days, 3 (12%) patients did not have platelet counts below 20,000/mcL. One patient was catalogued as a primary failure for not achieving neutrophil and platelet engraftment by day +30. One patient died before engraftment at day +10 of septic shock. Four patients (16%) died before day +30. The only patient that did not have a complete chimerism, had a diagnosis of AML and 30% of donor cells by day +30, by day +45 relapse of disease was documented. After a median follow-up of 157 days, 13 patients (52%) remain alive, with an estimated 1-year OS of 52% (95%CI: 30.4 - 65.6%).Nine patients (36%) died of complications (mainly infectious) not related to relapse at a median time of 66 days (10-579 days) from stem cell infusion. Nine patients (36%) relapsed in a median time of 105 days (45-288 days); three of those patients died at days +150, +113 and + 370 from transplant. Estimated 1 year event-free survival is 40.2% (95%CI: 41.3 - 75.8%) (Figures 1 and 2). Patients transplanted on 1st CR had a median follow-up of 664 days with an OS and EFS of 80% (4 patients), which was statistically different from the rest of the population (p=0.03) (Figure 3). Among those who engrafted (n=21), 9 cases (42.9%) had grade 2-4 acute GVHD and 4 cases (19%) of grade 3-4 acute GVHD. Three patients (14.3%) developed chronic GVHD, two had mild skin or liver cGVHD. One patient had severe (NIH stage 3) skin cGVHD, she was alive and with a grade 2 cGVHD until last follow up at day +893. Outpatient procedure, HLA-haploidentical HSCT including PBSC as a stem cell source, and post-transplant T-cell in vivo depletion using high-dose cyclophosphamide is feasible in children and adolescents, with acceptable rates of response and GVHD. Table 1. Patient, donor and harvest characteristics Variable N=25 Age, median(range in years) 10 (1-21) Gender, n(%) Male Female 17 (68%) 8 (32%) Diagnosis, n(%) ALL-B ALL-T AML CML 16 (64%) 2 (8%) 5 (20%) 2 (8%) Time from diagnosis to transplant (months) 17.2 (1.9-153.5) Conditioning regimen, n(%) Cy 1500mg/m2 + Flu 75mg/m2 + Bu 9.6mg/kg (IV) Cy 1050mg/m2 + Flu 75mg/m2 + Bu 12 mg/kg (oral) Cy/VP-16/RT Cy/Flu/Mel 16 (64%) 6 (24%) 2 (8%) 1 (4%) Donor, n(%) Mother Father Sister 20 (80%) 3 (12%) 2 (8%) Donor age, median(range in years) 38 (17-49) Infused CD34+ x 106/kg, median(range) 11 (3.2-20) Disclosures No relevant conflicts of interest to declare.

Description: Background and Objectives: Although the therapy of advanced-stage Hodgkin Lymphoma (HL) has improved, up to 10% of patients with advanced-stage HL will not achieve complete remission (CR) with standard therapy, and 20%-30% of responders will relapse after treatment. The disease status before autologous stem cell transplantation remains the most important factor predicting outcome for patients with relapsed or refractory HL. The IGEV regimen (Ifosfamide, gemcitabine, vinorelbine and prednisolone) is a good option for salvage induction therapy before autologous stem cell transplantation, with a reported overall response rate of 81%. Due to the high cost of the IGEV regimen, and the financial constrains of our population, we decided to modify the original regimen using cyclophosphamide instead of ifosfamide. Design and methods: From January 2011 to January 2015, 19 patients with relapsed or refractory HL received the protocol consisting of four cycles of cyclophosphamide, gemcitabine, vinorelbine and prednisone (CGEV). It was administrated in outpatient setting. The CGEV regimen consists of cyclophosphamide 600 mg/m2 on days 1 to 3, gemcitabine 800 mg/m2 on days 1 and 4, vinorelbine 20 mg/m2 on day 4, prednisone 100 mg on days 1 to 4 and granulocyte colony-stimulating factor (G-CSF) from day 7 to 12 of each course. Four courses of chemotherapy were planned before autologous stem cell transplantation, after the third course, autologous peripheral blood stem cells (PBSC) were collected. Results: Nineteen patients with primary refractory or relapsed HL received the CGEV regimen. There were 10 males and 9 females. Nodular sclerosis was the most frequent histological subtype in 73%. At diagnosis, there were 7 (36%) patients in clinical stage IV and 12 (63%) in early stage I-II. The lungs were the most frequent extranodal organ involved. B symptoms were present in 9 (47%) patients. All our patients received as first line chemotherapy the regimen ABVD, the disease status before salvage induction chemotherapy with CGEV was: 9 (47%) patients with refractory disease and 10 (53%) patients were in relapse. The median number of cycles administrated was 4 (1-4). Only 14 patients received the total planned courses. The overall response to the CGEV regimen was 78%, of these, 6 (42.8%) patients achieved complete response and 5 (35.7%) partial response. Ten patients underwent autologous stem cell mobilization, obtaining an adequate CD34+ cell collection in all the patients. The median number of CD34+ cell was 9.08 x 106/kg (2.1-5.60 x 106/kg) with a median of 1 apheresis procedure. Hematologic grade 3 and 4 toxicity developed in 11 (59%) patients, no grade 4 extra-hematologic toxicity was observed. There were 3 treatment-related infections. Four patients died, 2 due to septic shock, and 2 with disease progression. Interpretation and conclusions: We describe a similar overall response rate of 78% with CGEV regimen compared with the 81% reported with IGEV regimen, it is less expensive and can be used in relapsed or refractory patients with HL, as salvage regimen before autologous stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

Description: Introduction Ocular Graft versus host disease (oGVHD) is a common complication in receptors of allogeneic or haploidentical stem cell transplants (allo, haplo-SCT); incidence has been reported between 37-55%. Manifestations can range from mild (dry eye) to very severe (corneal perforation). Topical (eye drops) cyclosporine (CsA) has been reported to be an effective treatment of oGVHD once the disease has been established, but long before clinical manifestations are evident, lymphocyte infiltration and damage to the lacrimal gland have taken place. In this study, we evaluate if topical CsA administered from the day of graft success and over one year is effective for prevention of oGVHD Methods We conducted a prospective, single arm, phase 2 study. We included patients that received an allo-SCT or haplo-SCT for malignant and non-malignant hematologic diseases who previously didn´t have dry eye syndrome (primary or secondary to other diseases) or corneal surgeries. All patients received systemic CsA for one year aiming serum at levels of 250-350 ng/mL and metothrexate 10 mg/m2 at days+3,+5 and +7 post-transplant (PT). Patients with haplo-SCT also received PT cyclophosphamide 50 mg/kg at days +3 and +4 and mofetil mycophenolate 1 gram/day for one month. We administered CsA in eye drops immediately at the day of graft success (demonstrated with 〉 than 500 X 109 /L neutrophils and 〉20,000 109 /L platelets for two days unsupported with transfusions) and for one year PT. Systemic steroids 2nd line rituximab and 3rd line bortezomib were allowed in case of systemic GVHD. All patients were evaluated by an ophtalmologist before entering the trial for adequate tear quality with Schirmer test, integrity of corneal surface, eye pressure, and tear breakup time. After grafting, all patients were evaluated monthly with Schirmer test and a complete opftalmologic evaluation was made in months 3,6,9 and 12 post-transplant. Patients were evaluated and diagnosed with oGVHD according NIH criteria. We compared our results with an historical cohort of patients allografted in our center. This study was registered in Clinical Trials.gov NCT02144025 Results We included 21 patients (15 HLA identical (71.4%) and 6 haploidentical (28.6%) transplants). Median age was 42(17-62) years, the causes of transplants were hematologic malignancies in 19 patients and aplastic anemia in 2; median CD34 cell dose was 5.8 X 106/Kg (0.70-18.76 X 106/Kg). Median follow up of the whole cohort was 254 days (76-583). Systemic CsA target levels were met in 17 patients at all measurements, in the other 4 median levels were of 164 ng/mL (159-179 ng/mL). Seven patients (33.3%) received CsA+prednisone (PDN), 6 CsA+PDN+rituximab and 1 CsA+PDN+rituximab+bortezomib for systemic GVHD. OS at 365 days was 58% and EFS was 38%. Systemic acute GVHD (aGVHD) incidence grade II-IV was 57% (n=12) and grade III-IV 9.5%(n=2). Chronic systemic GVHD (cGVHD) incidence was 57% (n=12) and extensive (EcGVHD) 14.3% (n=3). We documented 1 case of definite oGVHD at last follow-up of the cohort. Systemic aGVHD grade II-IV (P=0.57), grade III-IV (P=0.48), cGVHD (P=0.52) or EcGVHD (P=0.13) did not have association with oGVHD development. Median of first Schrimer measurement (at study entry) of all cohort was 7.5 mm and 11.3 mm (P=0.005) at last follow-up. Comparing incidence of oGVHD of our study group (n=1, 5%) with an historical cohort of 26 patients allografted in our center (n=6, 23%) (P=0.087) difference is not statistically significant. Conclusion Allografted patients that received topical CsA augmented the quantity and quality of the tear. Although not statistical significant, there is a clear tendency of less oGVHD incidence in the stydy cohort Tear quality improved, which might be a sign of preservation of lacrimal gland function. A randomized, blinded and placebo-controled trial is needed to clearly determine if topical CsA is effective for oGVHD prevention. Disclosures Gomez-Almaguer: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol: Consultancy, Membership on an entity's Board of Directors or advisory committees.