Leandro de Padua Silva

University of Texas MD Anderson Cancer Center, Houston, TX, United States

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Publications (11)66.4 Total impact

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    ABSTRACT: The optimal dose and schedule of thymoglobulin (ATG) for graft-versus-host disease prevention (GVHD) is unknown. We compared two doses of ATG (4.5 mg/kg and 7.5 mg/kg) in a Bayesian adaptively randomized fashion, and assessed whether ATG levels measured on days 0, 7, 14 and 28 were associated with clinical outcomes. Treatment success was defined as the patient being alive, engrafted, in remission and without acute GVHD at day 100. Twenty patients received ATG 4.5 mg/kg (n = 15) or 7.5 mg/kg (n = 5) with reduced-intensity conditioning followed by unrelated donor hematopoietic cell transplant. The first 10 patients were fairly randomized, but the next 10 patients were adaptively randomized to the arm with higher success rate (4.5 mg/kg arm in this trial). The posterior mean treatment success rates for the ATG 4.5 mg/kg and ATG 7.5 mg/kg arms were 0.73 and 0.45, respectively. The posterior probability that the success rate was greater in the 4.5 mg/kg arm than in the 7.5 mg/kg arm was 0.93. There was no difference in the overall survival (p = 0.607), relapse-free survival (p = 0.607), treatment-related mortality (p = 0.131) or incidence of acute (p = 0.303) or chronic GVHD (p = 0.999) between the two doses. ATG levels were not associated with clinical outcomes. Thus, our results favor the use of ATG 4.5 mg/kg over ATG 7.5 mg/kg in patients undergoing unrelated donor hematopoietic cell transplant with reduced-intensity conditioning regimens.
    Leukemia & lymphoma 12/2011; 53(5):915-9. · 2.61 Impact Factor
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    ABSTRACT: The optimal pretransplant regimen for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) in patients ≥ 55 years of age remains to be determined. The myeloablative reduced-toxicity 4-day regimen i.v. busulfan (Bu) (130 mg/m(2)) and i.v. fludarabine (Flu) (40 mg/m(2)) is associated with low morbidity and mortality. We analyzed 79 patients ≥ 55 years of age (median, 58 years) with AML (n = 63) or MDS (n = 16) treated with i.v. Bu-Flu conditioning regimens between 2001 and 2009 (median follow-up, 24 months). The patients who received this regimen had a good performance status. The 2-year overall survival (OS) rates for patients in first complete remission (CR1), second CR (CR2), or refractory disease and for all patients at time of transplantation were 71%, 44%, 32%, and 46%, respectively; 2-year event-free survival (EFS) rates for patients in CR1, CR2, or refractory disease at time of transplantation and for all patients were 68%, 42%, 30%, and 44%, respectively. One-year transplant-related mortality (TRM) rates for patients who were in CR or who had active disease at the time of transplantation were 19% and 20%, respectively. Grade II-IV acute graft-versus-host (aGVHD) disease was diagnosed in 40% of the patients. Our results suggest that age alone should not be the primary reason for exclusion from receiving myeloablative reduced-toxicity conditioning with i.v. Bu-Flu preceding transplantation in patients with AML/MDS.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 02/2011; 17(10):1490-6. · 3.15 Impact Factor
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    ABSTRACT: Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after matched unrelated, related, or mismatched related donor hematopoietic stem-cell transplantation (HSCT). Improved GVHD prevention methods are needed. Pentostatin, an adenosine deaminase inhibitor, leads to lymphocyte depletion with low risk of myelosuppression. We hypothesized that addition of pentostatin to GVHD prophylaxis with tacrolimus and mini-methotrexate may improve outcomes, and we conducted a Bayesian adaptively randomized, controlled, dose-finding study, taking into account toxicity and efficacy. Success was defined as the patient being alive, engrafted, in remission, without GVHD 100 days post-HSCT and no grade ≥ 3 GVHD at any time. Patients were randomly assigned to pentostatin doses of 0, 0.5, 1.0, 1.5, and 2.0 mg/m(2) with drug administered on HSCT days 8, 15, 22, and 30. Eligible patients were recipients of mismatched related (n = 10) or unrelated (n = 137) donor HSCT. Median age was 47 years. Thirty-seven, 10, 29, 61, and 10 patients were assigned to the control and four treatment groups, respectively, with comparable baseline characteristics. Pentostatin doses of 1.0 and 1.5 mg/m(2) had the highest success rates (69.0% and 70.5%) versus control (54.1%). The posterior probabilities that the success rates were greater with 1.5 mg/m(2) or 1.0 mg/m(2) versus control are 0.944 and 0.821, respectively. Hepatic aGVHD rates were 0%, 17.2%, and 11.1%, respectively, for 1.5 mg/m(2), 1.0 mg/m(2), and control groups. No grades 3 to 4 aGVHD occurred in 11 HLA-mismatched recipients in the 1.5 mg/m(2) group. Pentostatin increased the likelihood of success as defined here, and should be further investigated in larger randomized, confirmatory studies.
    Journal of Clinical Oncology 01/2011; 29(3):294-302. · 18.04 Impact Factor
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    ABSTRACT: Recurrence is a major cause of treatment failure after allogeneic transplantation for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and treatment options are very limited. Azacitidine is a DNA methyltransferase inhibitor with activity in myeloid disease. The authors hypothesized that low-dose azacitidine administered after transplant would reduce recurrence rates, and conducted a study to determine a safe dose/schedule combination. Forty-five high-risk patients were treated. Median age was 60 years; median number of comorbidities was 3; 67% were not in remission. By using a Bayesian adaptive method to determine the best dose/schedule combination based on time to toxicity, the authors investigated combinations of 5 daily azacitidine doses, 8, 16, 24, 32, and 40 mg/m2, and 4 schedules: 1, 2, 3, or 4 cycles, each with 5 days of drug and 25 days of rest. Cycle 1 started on Day +40. Reversible thrombocytopenia was the dose-limiting toxicity. The optimal combination was 32 mg/m2 given for 4 cycles. Median follow-up was 20.5 months. One-year event-free and overall survival were 58% and 77%, justifying further studies to estimate long-term clinical benefit. No dose significantly affected DNA global methylation. Azacitidine at 32 mg/m2 given for 5 days is safe and can be administered after allogeneic transplant for at least 4 cycles to heavily pretreated AML/MDS patients. The trial also suggested that this treatment may prolong event-free and overall survival, and that more cycles may be associated with greater benefit.
    Cancer 12/2010; 116(23):5420-31. · 5.20 Impact Factor
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    ABSTRACT: We retrospectively analyzed the outcomes of all acute myelogenous leukemia (AML) patients in first remission (n = 44; median age = 48 years; high-risk cytogenetics = 59%) who received unrelated donor hematopoietic cell transplantation (HCT) with myeloablative conditioning regimen of i.v. busulfan, fludarabine, and antithymocyte globulin (ATG) between January 2002 and November 2009 at our institution. Donor-recipient pairs were matched by high-resolution HLA-A, -B, -C, -DRB1, and -DQB1 typing (10/10 matches, n = 41; 9/10 matches, n = 3). With a median follow-up of 34 months, actuarial 3-year event-free survival (EFS) and overall survival (OS) is 70% and 78%, respectively. The 3-year EFS and OS in patients with and without poor risk cytogenetics is similar (63% versus 82%, P = 0.43 and 78% versus 82%, P = .89, respectively). The 3-year EFS and OS is also similar in patients above age 55 year versus patients age 55 year or younger (80% versus 67%, P = .47 and 80% versus 78%, P = .81, respectively). The 100-day and 3-year cumulative incidence of transplant-related mortality is 5% and 15%, respectively. Six patients have relapsed, and 3 of them are alive and in remission after salvage therapy, with a median follow-up of 23 months. These results indicate that the majority of AML patients eligible for this treatment can achieve long-term disease control.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 11/2010; 17(7):1067-71. · 3.15 Impact Factor
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    ABSTRACT: Hemorrhagic cystitis is a common cause of morbidity after allogeneic stem cell transplantation, frequently associated with BK virus infection. We hypothesized that patients with positive BK viruria before unrelated or mismatched related donor allogeneic hematopoietic stem cell transplantation have a higher incidence of hemorrhagic cystitis. To test this hypothesis, we prospectively studied 209 patients (median age 49 years, range 19-71) with hematologic malignancies who received bone marrow (n=78), peripheral blood (n=108) or umbilical cord blood (n=23) allogeneic hematopoietic stem cell transplantation after myeloablative (n=110) or reduced intensity conditioning (n=99). Donors were unrelated (n=201) or haploidentical related (n=8). Twenty-five patients developed hemorrhagic cystitis. Pre-transplant BK viruria detected by quantitative PCR was positive in 96 patients. The one-year cumulative incidence of hemorrhagic cystitis was 16% in the PCR-positive group versus 9% in the PCR-negative group (P=0.1). The use of umbilical cord blood or a haploidentical donor was the only significant predictor of the incidence of hemorrhagic cystitis on univariate analysis. There was also a trend for a higher incidence after myeloablative conditioning. Multivariate analysis showed that patients who had a positive PCR pre-transplant and received haploidentical or cord blood grafts with myeloablative conditioning had a significantly higher risk of developing hemorrhagic cystitis (58%) than all other recipients (7%, P<0.001). Hemorrhagic cystitis is the result of a complex interaction of donor type, preparative regimen intensity, and BK viruria.
    Haematologica 07/2010; 95(7):1183-90. · 5.94 Impact Factor
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    ABSTRACT: Serologic evidence of resolved hepatitis B virus (HBV) infection has been associated with reactivation of hepatitis after allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the true impact of this finding is unknown. We conducted a retrospective matched-control analysis of the outcomes of 76 patients with positive HBV core antibody (HBcAb) and negative HBV surface antigen (HBsAg) at the time of allo-HSCT for hematologic or solid malignancies. Control patients (matched controls), with negative serology for HBV and other viral hepatitides, were matched by age, diagnosis, disease risk, intensity of conditioning regimen, and donor type. In addition, the HBcAb-positive patients and all seronegative patients (all controls, n = 1858) undergoing transplantation during the same period were compared to adjust for other confounding effects. Patient characteristics and baseline hepatic function studies were similar in the HBcAb-positive and matched control groups. The cumulative incidence of hepatitis B reactivation (defined as the emergence of HBsAg in serum) was 11.6% at 3 years. There were no significant differences in overall survival, relapse, nonrelapse mortality, and incidence of acute graft-versus-host disease between the HBcAb-positive and control groups. Our data suggest that seropositivity for HBcAb and seronegativity for HBsAg at the time of transplantation does not seem to adversely affect outcome after allo-HSCT.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 05/2010; 16(5):686-94. · 3.15 Impact Factor
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    ABSTRACT: Nonrelapse mortality (NRM) after reduced-intensity allogeneic transplants is likely to be influenced by abnormalities in renal function. We studied 141 patients diagnosed with acute myelogenous leukemia (AML) (n = 131) or high-risk myelodysplastic syndrome (MDS) (n = 10) who underwent allogeneic transplantation with fludarabine (Flu)/melphalan (Mel)-based regimens and hypothesized that moderate to mild renal function impairment increases NRM in this setting. Flu dose consisted of 25-30 mg/m(2) for 4 days and Mel dose was 100-180 mg/m(2). Donors were HLA-compatible siblings (n = 69) and matched unrelated donors (n = 72). Disease status at transplantation was complete remission (n = 56, 40%) or active disease (n = 85, 60%). The influence of the estimated glomerular filtration rate (GFR) measured before transplantation on outcomes was analyzed. GFR was estimated by both the Cockcroft-Gault (CG) and the modified diet in renal disease (MDRD) equations, using the creatinine value obtained prior to starting chemotherapy. Evaluated outcomes were overall survival (OS), NRM, and treatment-related mortality (TRM) at day 100 and 1-year posttransplantation. Median age was 55 years (range: 21-74 years); 59% of the patients were male. Estimated GFR by CG was > or =90 for 45 (32%), 60-89 for 78 (55%), and <60 for 18 (13%) patients. When estimated by MDRD, GFR was > or =90 for 65 (46%), 60-89 from 66 (47%), and <60 for 10 (7%) patients. The majority of patients by both estimations had a GFR between 60 and 89 (n = 78 by CG and n = 66 by MDRD) with no difference in the evaluated outcomes between this group and the subgroup of patients with a GFR <60 (P > .05). There were no differences in OS and NRM at day 100 and 1-year posttransplantation in the 3 groups by any GFR estimation method. In conclusion, a mild to moderate decrease in GFR was not associated with an increase in NRM.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 09/2009; 15(9):1094-9. · 3.15 Impact Factor
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    ABSTRACT: The polymorphic products of major histocompatibility complex class I-related chain A (MICA) genes are important in solid organ transplantation rejection. MICA expression is limited to gut epithelium and may play a role in triggering acute graft-versus-host disease (aGVHD). A total of 236 recipients of unrelated donor transplantation were studied. Donor-recipient human leukocyte antigen (HLA) match was 10/10 human leukocyte antigen (HLA-A, -B, -C, -DRB1, -DQB1) in 73% and MICA mismatch in 8.4%. Because of physical vicinity of the loci, MICA mismatch was significantly associated with mismatch at HLA-B and HLA-C. A higher rate of grade II-IV aGVHD was seen in MICA-mismatched patients (80% vs 40%, P = .003) irrespective of degree of HLA matching (HLA 10/10 match: 75% vs 39%, P = .02) and HLA any mismatch (83% vs 46%, P = .003). The rate of grade II-IV gastrointestinal aGVHD was also higher in MICA-mismatched patients (35% vs 17%, P = .05). We conclude that MICA may represent novel a transplantation antigen recognized by human allogeneic T cells. This study was registered at ClinicalTrials.gov (Identifier NCT00506922).
    Blood 09/2009; 114(14):2884-7. · 9.78 Impact Factor
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    ABSTRACT: 5-Azacytidine (5-AZA) is a DNA-hypomethylating agent. Valproic acid is a histone deacetylase inhibitor. Combining hypomethylating agents and histone deacetylase inhibitors produces synergistic anticancer activity in vitro and in vivo. On the basis of this evidence, we conducted a phase I study of the combination of 5-AZA and valproic acid in patients with advanced cancers. 5-AZA was administered s.c. daily for 10 days. Valproic acid was given orally daily with a goal to titrate to plasma levels of 75 to 100 mug/mL (therapeutic for seizures). Cycles were 28 days long. 5-AZA was started at 20 mg/m(2) and escalated using an adaptive algorithm based on the toxicity profile in the prior cohort (6 + 6 design). Peripheral blood mononuclear cell global DNA methylation and histone H3 acetylation were estimated with the long interspersed nucleotide elements pyrosequencing assay and Western blots, respectively, on days 1 and 10 of each cycle when patients agreed to provide them. Fifty-five patients were enrolled. Median age was 60 years (range, 12-77 years). The maximum tolerated dose was 75 mg/m(2) of 5-AZA in combination with valproic acid. Dose-limiting toxicities were neutropenic fever and thrombocytopenia, which occurred at a dose of 94 mg/m(2) of 5-AZA. Stable disease lasting 4 to 12 months (median, 6 months) was observed in 14 patients (25%). A significant decrease in global DNA methylation and induction of histone acetylation were observed. The combination of 5-AZA and valproic acid is safe at doses up to 75 mg/m(2) for 5-AZA in patients with advanced malignancies.
    Clinical Cancer Research 11/2008; 14(19):6296-301. · 7.84 Impact Factor
  • Lazaros Lekakis, Leandro de Padua Silva, Marcos de Lima
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    ABSTRACT: Hematopoietic stem cell transplantation is an established treatment modality for malignant and non-malignant diseases. Prior to the infusion of allogeneic or autologous cells, patients usually receive radiation or chemotherapy. This "preparative" or 'conditioning' regimen provides treatment for the underlying disease and is expected to impair the recipient's immune system and allow engraftment. The last decade witnessed a significant reduction in treatment-related mortality, in great part a result of less toxic preparative regimens and improvements in supportive care. Another important trend has been the incorporation of newer drugs to 'classic' conditioning regimens, as illustrated by the addition of rituximab to BEAM and other combinations. It is expected that this trend will continue leading to increased cure rates by incorporation of targeted therapies to hematopoietic transplant. The next decade will likely witness further integration of new preparative regimens with graft engineering, and pharmacologic, cellular and immunologic post transplant interventions. The design of creative clinical trials that will allow the critical evaluation of the role of these new approaches in transplantation will also be a major challenge to the transplant community in the years to come. In this article, we review newer transplant conditioning regimens and discuss their indications and future directions in this rapidly changing landscape.
    Current pharmaceutical design 02/2008; 14(20):1923-35. · 4.41 Impact Factor

Publication Stats

245 Citations
66.40 Total Impact Points

Institutions

  • 2010
    • University of Texas MD Anderson Cancer Center
      • Department of Stem Cell Transplantation & Cellular Therapy
      Houston, TX, United States
  • 2008
    • University of Kentucky
      • Markey Cancer Center
      Lexington, KY, United States