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1.
Cancer Med ; 8(18): 7567-7576, 2019 12.
Article in English | MEDLINE | ID: mdl-31657156

ABSTRACT

BACKGROUND: Erythropoiesis-stimulating agents effectively improve the hemoglobin levels in a fraction of anemic patients with myelodysplastic syndromes (MDS). Higher doses (HD) of recombinant human erythropoietin (rhEPO) have been proposed to overcome suboptimal response rates observed in MDS patients treated with lower "standard doses" (SD) of rhEPO. However, a direct comparison between the different doses of rhEPO is lacking. METHODS: A cohort of 104 MDS patients treated with HD was retrospectively compared to 208 patients treated with SD in a propensity score-matched analysis to evaluate hematological improvement-erythroid (HI-E) rate induced by the different doses of rhEPO. The impact of rhEPO doses on survival and progression to leukemia was also investigated. RESULTS: Overall HI-E rate was 52.6%. No difference was observed between different rhEPO doses (P = .28) in matched cohorts; in a subgroup analysis, transfusion-dependent patients and patients with higher IPSS-R score obtained a higher HI-E rate with HD, although without significant impact on overall survival (OS). Achievement of HI-E resulted in superior OS. At univariate analysis, a higher HI-E rate was observed in transfusion-independent patients (P < .001), with a lower IPSS-R score (P < .001) and lower serum EPO levels (P = .027). Multivariate analysis confirmed that rhEPO doses were not significantly related to HI-E (P = .26). There was no significant difference in OS or progression to leukemia in patients treated with HD vs SD. CONCLUSION: SD are substantially equally effective to HD to improve anemia and influencing survival in MDS patients stratified according to similar propensity to be exposed to rhEPO treatment.


Subject(s)
Anemia/drug therapy , Anemia/etiology , Erythropoietin/administration & dosage , Myelodysplastic Syndromes/complications , Aged , Aged, 80 and over , Anemia/blood , Disease Progression , Erythrocyte Indices , Female , Humans , Male , Middle Aged , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/mortality , Propensity Score , Proportional Hazards Models , Recombinant Proteins/administration & dosage , Retrospective Studies , Treatment Outcome
2.
Leuk Res ; 35(11): 1472-6, 2011 Nov.
Article in English | MEDLINE | ID: mdl-21794914

ABSTRACT

For more than 20 years erythropoietin (rHEPO) has largely been used to treat anemia in myelodysplastic syndromes (MDS). Early clinical trials showed erythroid responses in no more than 15-25% of patients. In the last decade, a better selection of MDS patients suitable for a therapeutic challenge with rHEPO, alone or in combination with G-CSF, allowed for an increased response-rate, averaging around 40%. More recently, an even higher percentage of responses have been obtained using higher-doses of rHEPO (up to 80,000 IU/weekly) in lower-risk MDS patients. This treatment however, especially at such high doses, is costly and not easily affordable for prolonged periods. The aim of this study was to verify if the use of "standard" doses of rHEPO could induce a satisfying response-rate with a less expensive treatment schedule in IPSS-defined "lower-risk" MDS anemic patients. From January 2005 to December 2009 a total of 55 consecutive anemic (Hb ≤ 10 g/dL) patients (29 males, 26 females, median age 78 years) with low-intermediate-1 risk MDS were treated after informed consent with rHEPO (40,000 IU once a week subcutaneously) for at least 3 months; at the end of this period, erythroid response was assessed, and responders were allowed to continue the treatment indefinitely, whereas non-responders were considered "off study". Both efficacy and safety of the treatment were recorded and evaluated. After 3 months of treatment, 36 out of 55 (65.5%) patients achieved an erythroid response to rHEPO according to IWG 2006 criteria. Higher response-rates to rHEPO were related with both lower IPSS and particularly WPSS scores. Treatment was safe, and only 1 patient had to discontinue the treatment because of unmanageable side-effects. Among the 36 responders, 28 (77%) maintained the response after a median follow-up of 46 months. Our data indicate that standard doses of rHEPO are at least as effective as higher-doses for correcting anemia in lower-risk MDS patients; in this clinical scenario, this schedule allows for a consistent reduction of costs without precluding the achievement of a durable erythroid response.


Subject(s)
Anemia/drug therapy , Erythropoietin/therapeutic use , Myelodysplastic Syndromes/complications , Recombinant Proteins/therapeutic use , Aged , Aged, 80 and over , Anemia/etiology , Dose-Response Relationship, Drug , Female , Follow-Up Studies , Humans , Male , Middle Aged , Myelodysplastic Syndromes/therapy , Prognosis , Risk Factors
3.
Int J Cancer ; 109(3): 402-11, 2004 Apr 10.
Article in English | MEDLINE | ID: mdl-14961579

ABSTRACT

Generation of immune responses against B cell chronic lymphocytic leukemia (B-CLL) has been the aim of several studies that have demonstrated a poor antigen presenting ability of B-CLL cells and an inconsistent emergence of T cells capable of killing efficiently the leukemic cells. CD1d is a restriction element structurally related to the major histocompatibility complex (MHC) and capable of presenting lipid antigens to CD1d-restricted T cells (also defined as natural killer-T [NKT] cells). The synthetic lipid alpha-galactosylceramide (alpha-GalCer) has been characterized as a potent stimulator of CD1d-restricted T cells. We have investigated the expression of CD1d on B-CLL cells. CD1d was detected by flow cytometric analyses on leukemic cells of all B-CLL cases studied (n = 38) and was expressed at higher density on cells carrying unmutated immunoglobulin variable region (IgV) genes. In addition, CD1d on B-CLL cells mediated the presentation of alpha-GalCer to CD1d-restricted T cells, which in turn induced B-CLL cell death. At variance with another study (Metelitsa et al., Leukemia 2003;17:1068-77), no correlation between expression levels of CD1d and susceptibility to NKT cell lysis was observed. Proliferation and production of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) by CD1d-restricted T cells, in the presence of B-CLL cells loaded with alpha-GalCer, were also observed. Our study demonstrates that B-CLL cells express a monomorphic restriction element that is functionally capable of antigen presentation and can be useful to design novel B-CLL immunotherapies.


Subject(s)
Antigen Presentation , Antigens, CD1/metabolism , Galactosylceramides/immunology , Killer Cells, Natural/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , T-Lymphocytes/immunology , Antigens, Differentiation, T-Lymphocyte/analysis , Cell Division , Cohort Studies , Flow Cytometry , Humans , Immunoglobulin Variable Region/genetics , Interferon-gamma/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Tumor Necrosis Factor-alpha/metabolism
4.
J Clin Immunol ; 22(1): 13-22, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11958589

ABSTRACT

We have analyzed the immune response elicited with the human CD4 internal antigen anti-idiotypic monoclonal antibody 16D7 in four patients with active systemic lupus erythematosus and assessed the safety of the treatment. Patients I and 2 received three 2-mg 16D7 subcutaneous (SC) injections at 3-week intervals and mainly developed IgGI, whereas IgG1, IgG3, and IgG4 were detected in the sera of the other two patients (3 and 4) who received the same amount of 16D7 on days 0, 28, and 70. 16D7-F(ab')2 isotypic determinant-specific antibodies levels, evaluated by sera reactivity with the 16D7-isotype matched anti-idiotypic monoclonal antibody 14D6-F(ab')2, were low or undetectable in patient 1 and became detectable following the first and second boosters in patient 3 and patients 2 and 4, respectively. The highest level was seen in patients 3 and 4. The focusing pattern (spectrotype) of 16D7 idiotypic-specific antibodies suggested that multiple V genes are involved or many somatic mutations occur. Once established, each patient's spectrotype remained stable. Although spectrotype were individually distinct, all four patients produced CD4-specific antibodies, indicating that this response crosses the genetic barrier. Disease relapsed after 11 (patient 2), 40 (patients 3 and 4), and 125 (patient 1) weeks. The lack of side effects and the prolonged periods of disease control (33 and 103 weeks after the last booster) warrants an extension of this study.


Subject(s)
Antibodies, Anti-Idiotypic/therapeutic use , Antibodies, Monoclonal/therapeutic use , CD4 Antigens/immunology , Lupus Erythematosus, Systemic/therapy , Animals , Antibodies, Anti-Idiotypic/administration & dosage , Antibodies, Anti-Idiotypic/adverse effects , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibody Specificity , Humans , Immunoglobulin G/biosynthesis , Immunoglobulin G/classification , Lupus Erythematosus, Systemic/immunology , Mice , Safety
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