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  • 1
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2025-2025
    Abstract: Allogeneic SCT is the most potent post-remission therapy for AML patients, particularly in patients aged 〉 40-45 years, and the only curative option for patients with refractory AML or with high-risk MDS. Although median age at diagnosis is above 65 years for both entities, for patients aged 60 years or older, studies evaluating allogeneic SCT as post-remission therapy or as salvage therapy are limited. Dose adapted / reduced conditioning for patients in remission and sequential conditioning (intensive chemotherapy followed by dose adapted conditioning), for patients with active leukemia / high-risk disease, together with improvement in supportive care, have shown improved outcome results for SCT in younger and older patients. Aiming to predict treatment outcomes of patients undergoing allogeneic SCT, various transplant specific risk models have been introduced in the past. Assuming that these risk models might be of value especially in older patients, we performed a retrospective single center analysis of transplanted patients, incorporating the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI), the European Group for Blood and Marrow Transplantation (EBMT) Score and the Disease Risk Index (DRI). Between 1999 and 2014, 187 patients (pts) with AML (87%) or MDS (13%) aged ≥60 years (median age of 64 years, range 60 - 77 years) received an allogeneic SCT at our institution, either from a HLA-identical related (50 pts.), HLA-matched unrelated (103 pts.), or an HLA-mismatched donor (34 pts). Median follow-up of surviving patients was 36 months (range 1 to 173 months). All patients with AML received a cytarabine-based standard induction therapy. Conditioning prior to transplant consisted of dose reduced / dose adapted therapy (TBI-, busulfan- or treosulfan-based) or sequential conditioning (for patients with high risk or refractory disease). Thirty-nine of the 47 AML patients transplanted in first complete remission (CR1) had a high-risk AML, defined by an adverse cytogenetic risk profile (16 pts), persisting AML after first induction therapy (12 pts), a secondary AML (6 pts.), or persisting / increasing minimal residual disease (5 pts). MDS patients had mainly an advanced disease with blast count 10-19% (19/24 pts). For all patients, an overall survival (OS) at 3 years of 35% (95% CI: 27-42%) was observed. Cumulative incidences of NRM and relapse at one year were 37% and 22%, respectively. Patients transplanted in CR1 showed a 3-year OS of 49%, whereas patients transplanted in subsequent remission, with active AML, or high-risk MDS had a 3-year OS of 26%, 28% and 31%, respectively. Univariate analysis of the whole group showed that advanced and/or active disease (advanced/active AML/MDS vs. AML CR1, p = .04), high DRI (high/very high vs. low/intermediate, p = .06), and poor Eastern Cooperative Oncology Group Score (ECOG; ≥2 vs. 0 or 1, p=.0001), were associated with an inferior OS. Patient age had no impact on outcome parameters. In a multivariate analysis of disease / transplant related risk factors (status pre transplant, EBMT-score, HCT-CI and DRI) only disease status pre transplant was an independent prognostic factor for OS (active / advanced disease vs. CR1, hazard ratio 1.55; 95% CI 1.01-2.38). These results indicate that patient's age ≥60 years in general is no limiting factor for an allogeneic transplant, even if refractory to conventional treatment. Pre-transplant selection of patients eligible for intensive treatment was most likely one relevant bias in our analysis, limiting the determination of the impact of preexisting comorbidities on treatment outcomes. Given the prognostic impact of the disease status at transplant, the improvement of transplant results in elderly patients, and the dismal prognosis of older patients with myeloid neoplasms receiving conventional treatment, the impact of allogeneic SCT, especially in early disease stages / CR1 of patients with MDS / AML eligible for intensive treatment has to be further studied in prospective trials. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 980-980
    Abstract: The tumor-directed delivery of therapeutics using monoclonal antibodies specific to a tumor-associated antigen promises to accumulate large doses of the delivered payload at the tumor site while sparing healthy organs. The antibody-based delivery of interleukin-2 (IL-2) to extracellular targets expressed in the easily accessible tumor vasculature has shown promising results in animal models of solid tumors and hematological malignancies. In xenograft and immunocompetent murine models of acute myeloid leukemia (AML), IL-2-based vascular targeting antibody fusions have recently demonstrated potent anti-leukemic activity, especially when used in combination with cytarabine. Here, we report our experiences in four patients with relapsed AML after allogeneic hematopoietic stem cell transplantation (allo-HSCT), who were treated with the immunocytokine F16-IL2, consisting of a human monoclonal antibody specific to spliced large isoforms of tenascin-C fused to human IL-2, in combination with very low dose cytarabine (5 mg subcutaneously twice daily for 10 days). Clinical evidence of anti-leukemia efficacy was shown in all patients. One patient with rapidly progressing disseminated extramedullary AML lesions achieved a complete metabolic response in PET/CT, which lasted three months. Two out of three patients with bone marrow relapse achieved a blast reduction with transient molecular negativity (NPM1). One of the two enjoyed a short complete remission before AML relapse occurred two months after the first infusion of F16-IL2. The other patient did not regenerate neutrophil and thrombocyte counts and showed progressive disease after completion of the first cycle. In line with a site-directed delivery of the cytokine, F16-IL2 led to an extensive infiltration of immune effector cells (natural killer cells, CD8+ T cells, γδ T cells) in the bone marrow. Grade 2 fevers were the only non-hematological side effects in two patients. Grade 3 cytokine-release syndrome developed in the other two patients, required hospitalization, but was manageable in both cases with systemic glucocorticoids. No non-hematological grade 4 toxicities were observed. The concept of specifically targeting IL-2 to the leukemia-associated stroma using armed antibodies deserves further evaluation in clinical trials, especially in patients who relapse after allo-HSCT. Disclosures Off Label Use: In this report, the antibody-cytokine fusion protein F16-IL2 has been used in a compassionate use setting in individual patients presenting with AML relapse after allogeneic stem cell transplantation. F16-IL2 is currently being evaluated in phase I/II studies in patients with solid cancer.. Neri:Philogen SpA: Employment, Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
    Location Call Number Limitation Availability
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  • 3
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), Vol. 31, No. suppl_1 ( 2016-05), p. i225-i225
    Type of Medium: Online Resource
    ISSN: 1460-2385 , 0931-0509
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2016
    detail.hit.zdb_id: 1465709-0
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