M Bendandi

Ross University, Charlotte Town, Saint George, Dominica

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Publications (136)858.72 Total impact

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    ABSTRACT: TIM3 belongs to a family of receptors that are involved in T-cell exhaustion and Treg functions. The development of new therapeutic agents to block this type of receptors is opening a new avenue in cancer immunotherapy. There are currently several clinical trials ongoing to combine different immune-checkpoint blockades to improve the outcome of cancer patients. Among these combinations we should underline PD1:PDL1 axis and TIM3 blockade, which have shown very promising results in preclinical settings. Most of these types of therapeutic agents are protein cell-derived products, which, although broadly used in clinical settings, are still subject to important limitations. In this work we identify by HT-SELEX TIM3 non-antigenic oligonucleotide aptamers (TIM3Apt) that bind with high affinity and specificity to the extracellular motives of TIM3 on the cell surface. The TIM3Apt1 in its monomeric form displays a potent antagonist capacity on TIM3-expressing lymphocytes, determining the increase of IFN-γ secretion. In colon carcinoma tumor-bearing mice, the combinatorial treatment of TIM3Apt1 and PDL1-antibody blockade is synergistic with a remarkable antitumor effect. Immunotherapeutic aptamers could represent an attractive alternative to monoclonal antibodies, as they exhibit important advantages; namely, lower antigenicity, being chemically synthesized agents with a lower price of manufacture, providing higher malleability, and antidote availability.
    Full-text · Article · Dec 2015 · Oncotarget
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    ABSTRACT: Recent studies have underscored the importance of immunomodulatory antibodies in the treatment of solid and hematological tumors. ODN-Aptamers are rising as a novel class of drugs that can rival therapeutic antibodies. The success of some of the current cancer immunotherapy approaches in oncological patients depends on the intrinsic antigenicity of each tumor as has recently been disclosed, and it is hampered in those patients that are treated with myeloablative chemotherapy or radiotherapy, which induce profound immunosuppression. CD40 agonist and antagonist molecules offer a new therapeutic alternative which has the potential to generate anticancer effects by different mechanisms. HS-SELEX was performed to identify high-affinity aptamers against CD40, and three therapeutic CD40 constructs were engineered as: CD40 agonist aptamer, CD40 antagonist aptamer and CD40 agonistic aptamer-shRNA chimera. It is shown that CD40 agonist aptamers can be used to promote bone-marrow aplasia recovery. CD40 antagonist aptamers are revealed to have a direct antitumor effect on CD40-expressing B-cell lymphoma in vitro and in vivo. Further, in order to identify a therapeutic reagent that will generate the optimal conditions for cancer immunotherapy (antigen-presenting cell activation, tumor antigenicity enhancement and bone-marrow aplasia recovery), CD40 agonist aptamer-shRNA chimera was generated to target the inhibition of the Nonsense mRNA Mediated Decay (NMD) to tumor cells. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Jul 2015 · Biomaterials
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    ABSTRACT: We report the first evaluation of plant-made conjugate vaccines for targeted treatment of B-cell follicular lymphoma (FL) in a Phase I safety and immunogenicity clinical study. Each recombinant personalized immunogen consisted of a tumor-derived, plant-produced idiotypic antibody (Ab) hybrid comprising the hypervariable regions of the tumor-associated light and heavy Ab chains, genetically grafted onto a common human IgG1 scaffold. Each immunogen was produced in Nicotiana benthamiana plants using twin magnICON vectors expressing the light and heavy chains of the idiotypic Ab. Each purified Ab was chemically linked to the carrier protein keyhole limpet hemocyanin (KLH) to form a conjugate vaccine. The vaccines were administered to FL patients over a series of ≥ 6 subcutaneous injections in conjunction with the adjuvant Leukine (GM-CSF). The 27 patients enrolled in the study had previously received non-anti-CD20 cytoreductive therapy followed by ≥ 4 months of immune recovery prior to first vaccination. Of 11 patients who became evaluable at study conclusion, 82% (9/11) displayed a vaccine-induced, idiotype-specific cellular and/or humoral immune response. No patients showed serious adverse events (SAE) related to vaccination. The fully scalable plant-based manufacturing process yields safe and immunogenic personalized FL vaccines that can be produced within weeks of obtaining patient biopsies.
    Full-text · Article · Apr 2015 · BioMed Research International
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    ABSTRACT: Non-Hodgkin's lymphoma (NHL) is the most common hematological malignancy both in Europe and in the United States. Follicular lymphoma (FL), a tumor comprised of mature B cells, represents one fourth of all NHL and, despite good response rates to standard treatments, tends to frequently relapse to such an extent that it is still considered incurable. Among several alternative therapeutic options actively being pursued, immunotherapy by idiotypic vaccination is in the forefront of clinical experimental medicine. The idiotype vaccine consists of the tumor-specific immunoglobulin conjugated with keyhole limpet hemocyanin (KLH) and administered together with an adjuvant. Over the last 20 years, researchers have proven that this vaccine can induce specific immune responses. Too, those patients with such responses experience a disease-free survival longer than normally achievable, although these latter results require further confirmation in large clinical trials. Traditionally, idiotype vaccines have been produced through hybridoma technology. In this chapter this technology is described.
    No preview · Article · Mar 2014 · Methods in molecular biology (Clifton, N.J.)
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    ABSTRACT: Idiotypic vaccination for folicular lymphoma induces a tumor-specific immune response which may kill tumor cells in vivo and prevent tumor relapse in patients. However, being based on a personalized vaccine against a person's own tumor, large scale randomized studies have produced contradictory results. The objective of this review is to define what an idiotype is and to outline the major results of twenty years of clinical research on idiotypic vaccination. We first identified the major proofs of principle obtained by its use between 1992 and 2006, focusing on both our and others' contributions. Then, we analyzed the results of randomized clinical trials, which have become available ove the last five years, and provided some of our most recent and original data.
    Full-text · Article · Jun 2013
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    ABSTRACT: CD28 is one of the main costimulatory receptors responsible for the proper activation of T lymphocytes. We have isolated two aptamers that bind to the CD28 receptor. As a monomer, one of them interfered with the binding of CD28 to its ligand (B7), precluding the costimulatory signal, whereas the other one was inactive. However, dimerization of any of the anti-CD28 aptamers was sufficient to provide an artificial costimulatory signal. No antibody has featured a dual function (i.e., the ability to work as agonist and antagonist) to date. Two different agonistic structures were engineered for each anti-CD28 aptamer. One showed remarkably improved costimulatory properties, surpassing the agonistic effect of an anti-CD28 antibody. Moreover, we showed in vivo that the CD28 agonistic aptamer is capable of enhancing the cellular immune response against a lymphoma idiotype and of prolonging survival of mice which receive the aptamer together with an idiotype vaccine. The CD28 aptamers described in this work could be used to modulate the immune response either blocking the interaction with B7 or enhancing vaccine-induced immune responses in cancer immunotherapy.Molecular Therapy - Nucleic Acids (2013) 2, e98; doi:10.1038/mtna.2013.26; published online 11 June 2013.
    Full-text · Article · Jun 2013 · Molecular Therapy - Nucleic Acids
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    ABSTRACT: To assess whether the addition of a customized, active immunotherapy to standard of care including fluorescence-guided surgery, may provide hints of an improved survival for patients with poor-prognosis, incurable glioblastoma multiform. Preliminary to our ongoing, phase-II clinical trial, we conducted a small pilot study enrolling five consecutive patients with resectable glioblastoma. In terms of Recursive Partitioning Analysis, four patients were class V and one was class IV. In all five cases, fluorescence-guided surgery was employed, followed by rapid steroid discontinuation. Patients were then treated with a combination of standard radio-chemotherapy with temozolomide and tumor lysate-pulsed, mature dendritic cell-based vaccinations. Though all five patients ultimately progressed, with any further treatment left to the sole decision of the treating oncologist, active immunotherapy was very well tolerated and induced specific immune responses in all three patients for whom enough material was available for such an assessment. Median progression-free survival was 16.1 mo. Even more important, median and mean overall survival were 27 mo and 26 mo, respectively. Three patients have died with an overall survival of 9 mo, 27 mo and 27.4 mo, while the other two are still alive at 32 mo and 36 mo, the former receiving treatment with bevacizumab, while the latter has now been off therapy for 12 mo. Four of five patients were alive at two years. Active immunotherapy with tumor lysate-pulsed, autologous dendritic cells is feasible, safe, well tolerated and biologically efficacious. A phase-II study is ongoing to possibly improve further on our very encouraging clinical results.
    Full-text · Article · Nov 2012
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    Full-text · Article · Aug 2012 · Leukemia & lymphoma
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    ABSTRACT: Colorectal cancer is a serious health problem affecting de novo more than one million people every year in the developed world. Despite recent advances in the development of novel therapeutic agents, metastatic colorectal cancer remains mostly incurable and its survival rates ominous even when patients respond to the most advanced treatments. Here, we describe a case in which a patient with metastatic colorectal cancer and high risk of relapse remains disease-free while being treated solely with twelve doses of autologous dendritic cells vaccines pulsed with autologous tumor lysate. A sustained, specific immune response elicited by vaccination has also been documented. Prior to receiving this experimental treatment, the patient had undergone both tumor resections and chemotherapy treatments six times, invariably relapsing/progressing within a year from each resection. We believe that the use of autologous vaccines consisting in dendritic cells pulsed with tumor lysate should be further investigate in human clinical trials, particularly in patients with minimal tumor burden and high risk of relapse. We also believe that this type of immunotherapy is more likely to be successful when used as an early rather than merely compassionate treatment option, given the fact that the more toxicity the immune system has received from previous approaches, the less it will be able to respond to tumor vaccination.
    Full-text · Article · Jan 2012
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    ABSTRACT: Most patients with B-cell lymphoma face an often incurable disease, particularly those diagnosed with an indolent subtype. The addition of passive immunotherapy to old and new chemotherapy regimens has improved both response rates and disease-free survival, leading in many cases to an extended overall survival. However, a cure remains elusive in most cases. For this reason, the patient- and tumor-specific idiotype, that is the collection of epitopes exclusively presented by the tumor clone's surface immunoglobulin, has been extensively studied as a privileged target for vaccine therapy, aiming at preventing disease re-occurrence after standard treatment. BiovaxID(®) (Biovest International, FL, USA), the most clinically advanced among such therapeutic vaccines, finds itself at a crucial turning point when it comes to further development. Both clinical trials in which it has been formally employed have shown intriguing results. Independent studies using slightly different versions of a conceptually identical vaccine provided all proofs of principle required to ascertain the vaccine's value - biological and clinical efficacy as well as clinical benefit. However, all these data have failed to bring an idiotype vaccine to the market owing to reasons that often have very little to do with the product itself. In fact, some successful studies were not conceived with this goal in mind, while others simply did not enroll enough patients to convincingly make their case for regulatory approval. It is likely that one or more new clinical trials will have to be successfully completed to reach the ultimate goal - that is, to make BiovaxID available to most patients and to adequately position it in the very crowded therapeutic algorithm of B-cell lymphoma.
    No preview · Article · Dec 2011 · Expert Review of Vaccines
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    ABSTRACT: Several types of B-cell malignancy, including but not limited to multiple myeloma and follicular lymphoma, are still considered incurable. In a substantial number of cases, patients must undergo either autologous or allogeneic stem cell transplantation as a standard of care procedure for their disease. Among experimental treatments for multiple myeloma and follicular lymphoma, idiotypic vaccination has been attempted over the last two decades with variable degrees of success. Few clinical trials have combined stem cell transplant procedures with idiotypic vaccination, and they are the subject of this review, which will also include some of our original data, as well as our overall evaluation of this field of clinical investigation. Although apparently at the opposite extremes of the therapeutic option array, toxicity-burdened stem cell transplantation and virtually innocuous idiotypic vaccination might well offer a sound curative opportunity to some patients with otherwise incurable B-cell malignancies, provided that the latter treatment first succeeds at obtaining regulatory approval.
    No preview · Article · Jun 2011 · Current Topics in Medicinal Chemistry
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    ABSTRACT: Over the last two decades, lymphoma idiotype vaccines have been the first human cancer vaccines to show striking evidence of biological and clinical efficacy on the one hand, as well as clinical benefit on the other. More recently, however, three large-scale, independent, randomized clinical trials on idiotypic vaccination have failed to achieve their main clinical endpoints for reasons likely to depend more on flaws in each clinical trial's study design than on each vaccination strategy per se. Independently of these considerations, a major hurdle for the development of this substantially innocuous and yet potentially very effective type of treatment has been the fact that, even to date, no factors ascertainable before vaccination have been prospectively singled out as predictors of subsequently vaccine-induced, idiotype-specific immune as well as clinical responses. The aim of this review article is precisely to analyze what has been and what could be done in this respect in order to give a greater chance of success to future trials aimed at regulatory approval of idiotype vaccines.
    Full-text · Article · Jun 2011
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    ABSTRACT: Despite having been the first cancer vaccine to provide clear-cut evidence of biological and clinical efficacy as well as of clinical benefit in humans, idiotype vaccines have failed to become the first therapeutic cancer vaccine to be granted regulatory approval. Indeed, idiotypic vaccination is still an experimental therapeutic option for some types of B-cell malignancy over 20 years after its first use in patients with lymphoma. The ultimate reason for this situation lies in the recent failure of three large-scale, independent, randomized trials to achieve their respective main clinical end points. Interestingly, each trial had been designed with intrinsic pitfalls that are likely to have influenced, and perhaps even entirely compromized, all chances each study had to succeed. Therefore, it is difficult to conclude whether any of the different idiotype vaccines employed so far may still represent an ideal candidate for further trials. Meanwhile, other idiotype vaccine formulations are under active investigation.
    No preview · Article · Jun 2011 · Expert Review of Vaccines
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    ABSTRACT: Several types of B-cell malignancy, including but not limited to multiple myeloma and follicular lymphoma, are still considered incurable. In a substantial number of cases, patients must undergo either autologous or allogeneic stem cell transplantation as a standard of care procedure for their disease. Among experimental treatments for multiple myeloma and follicular lymphoma, idiotypic vaccination has been attempted over the last two decades with variable degrees of success. Few clinical trials have combined stem cell transplant procedures with idiotypic vaccination, and they are the subject of this review, which will also include some of our original data, as well as our overall evaluation of this field of clinical investigation. Although apparently at the opposite extremes of the therapeutic option array, toxicity-burdened stem cell transplantation and virtually innocuous idiotypic vaccination might well offer a sound curative opportunity to some patients with otherwise incurable B-cell malignancies, provided that the latter treatment first succeeds at obtaining regulatory approval.
    No preview · Article · Mar 2011 · Current topics in medicinal chemistry
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    ABSTRACT: Animal and clinical studies with plant-produced single-chain variable fragment lymphoma vaccines have demonstrated specific immunogenicity and safety. However, the expression levels of such fragments were highly variable and required complex engineering of the linkers. Moreover, the downstream processing could not be built around standard methods like protein A affinity capture. We report a novel vaccine manufacturing process, magnifection, devoid of the above-mentioned shortcomings and allowing consistent and efficient expression in plants of whole immunoglobulins (Igs). Full idiotype (Id)-containing IgG molecules of 20 lymphoma patients and 2 mouse lymphoma models were expressed at levels between 0.5 and 4.8 g/kg of leaf biomass. Protein A affinity capture purification yielded antigens of pharmaceutical purity. Several patient Igs produced in plants showed specific cross-reactivity with sera derived from the same patients immunized with hybridoma-produced Id vaccine. Mice vaccinated with plant- or hybridoma-produced Igs showed comparable protection levels in tumor challenge studies. This manufacturing process is reliable and robust, the manufacturing time from biopsy to vaccine is <12 weeks and the expression and purification of antigens require only 2 weeks. The process is also broadly applicable for manufacturing monoclonal antibodies in plants, providing 50- to 1000-fold higher yields than alternative plant expression methods.
    Full-text · Article · Dec 2010 · Annals of Oncology
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    ABSTRACT: After twenty years of use in humans, customized idiotypic vaccination yet remains a non-approved, experimental therapeutic option for patients with lymphoma and myeloma. Potentially applicable to all B-cell malignancies whose cells express a clonal immunoglobulin or its epitopes on their surface, this treatment is designed to prevent disease recurrence or progression. Mostly used in follicular lymphoma patients so far, idiotype vaccines have clearly shown biological efficacy, clinical efficacy and clinical benefit in this setting, although no study aiming at regulatory approval of the procedure has been able to meet its main clinical endpoints. In mantle cell lymphoma, only biological efficacy has been proven for idiotypic vaccination, while in multiple myeloma a limited number of studies support the notion of biological and perhaps even clinical efficacy, although no credible evidence of clinical benefit has still emerged. Idiotype vaccines have been produced and administered in a number of substantially different manners. Therefore, the results of most clinical trials cannot be easily compared, and even less pooled together in meaningful meta-analyses. A more creative and yet scientifically sound way to design clinical trials of customized active immunotherapies will be key to the future development of idiotype vaccines, particularly considering that we currently lack any clinical or biological indicator to possibly predict which patients are more likely to respond to idiotypic vaccination from an immunologic point of view. This review aims at summarizing the multifaceted success achieved by idiotype vaccines, as well as at outlining the challenges awaiting them in the near future: how to improve feasibility, immunogenicity and efficacy, as well as how to confirm benefit and gain regulatory approval.
    No preview · Article · Jan 2010 · Current pharmaceutical design
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    Maurizio Bendandi
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    ABSTRACT: The clonal immunoglobulin idiotype displayed on the surface of most malignant B cells is a patient- and tumour-specific antigen that can be used for therapeutic vaccination. Several studies have confirmed the biological efficacy of soluble protein idiotypic vaccination and two clinical trials have shown the clinical efficacy of this procedure. One study has demonstrated clinical benefit associated with idiotypic vaccination. However, three randomized clinical trials have recently failed to achieve their main end points for reasons that are probably unrelated to the vaccine. While scepticism towards this type of non-toxic medical intervention is mounting, such patient-specific treatments might yet see the light of day through better designed clinical trials.
    Preview · Article · Oct 2009 · Nature Reviews Cancer
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    ABSTRACT: : The activity of fludarabine monophosphate (FLU) and α-interferon (α-IFN) in low-grade non-Hodgkin's lymphoma (LG-NHL) and B-cell chronic lymphocytic leukemia (B-CLL) has been demonstrated in several clinical trials. In a study of 137 previously treated patients, of whom 77 had B-CLL and 60 with LG-NHL, we used FLU as salvage chemotherapy. Dosages of 25 mg/m2 were given in 30-min infusions for 5 consecutive d. Treatment was repeated every 28 d depending on the patient's clinical status for a maximum of 6 cycles. Entrance to the α-IFN maintenance portion of the study depended on patient response to initial FLU. All patients who had obtained a complete or partial response after the FLU therapy were randomized to receive α-IFN or no further therapy. The α-IFN dose was 3×106 units 3 times per wk until disease progression. At 4 yr with a median follow-up of 22 months the percentage of patients with persistent response ranged between 20% and 30% among all the responders. Thirty-five (45%) B-CLL patients achieved major responses (complete/partial response), as did 29 (48%) of those with LG-NHL. Among the 64 patients who achieved a good response to initial therapy and who have entered the second part of the trial, there has been a rate of prolongation of remission in favour of maintenance α-IFN (p = 0.02). FLU therapy is an effective drug inducing remission in pretreated B-CLL and LH-NHL patients. However, as with other therapeutic modalities, remission is rarely maintained beyond 2 yr. So far, maintenance α-IFN has not been shown to produce significantly longer remission after treatment with FLU in LG-NHL, and there is no trend towards prolonged remission in B-CLL patients. The role of FLU needs to be further evaluated in the management of lymphoproliferative disorders by introducing it in combination with other drugs (α-IFN) in the induction phase and in maintenance treatment.
    No preview · Article · Aug 2009 · European Journal Of Haematology
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    ABSTRACT: Mantle cell lymphoma (MCL) is an aggressive B cell malignancy, which is believed to originate from naïve B cells in the mantle zone of lymph nodes. We speculate that a possible mechanistic hypothesis for the generation of MCL is one in which receptor editing and germinal centre exclusion could be involved in the molecular development and in the display of clinical characteristics of this rare, aggressive and scarcely understood lymphoma. The hypothesis is supported by a preferential autoimmune related IGVH gene utilization in MCL, where VH3-21, VH4-34 and VH5-51 genes are predominant, and by the fact that MCL expresses immunoglobulin light chain (IgL) lambda more frequently than other non-Hodgkin's lymphomas and that IgL lambda-producing B cells usually delete one or both their IgL kappa genes.
    No preview · Article · Jul 2009 · Leukemia research
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    ABSTRACT: A prospective randomized study on aggressive non-Hodgkin's lymphomas was conducted by investigators at several Italian institutions with the intent of comparing two third-generation conceptually different regimens: the regimen containing methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B), a short-term continuous twelve-week therapy, and F-MACHOP (5-fluorouracil, methotrexate with leucovorin rescue, cytarabine, cyclophosphamide, doxorubicin, vincristine, and prednisone), a monthly intensive cyclic treatment combining prednisone with six active non-cross-resistant cytotoxic drugs. The goals of this study were the response rate, relapse-free survival, and incidence of hematologic and nonhematologic toxicities. Two hundred-eighty-six patients included between 15 and 60 years fulfilled the criteria for entry to the study; 140 patients were treated with MACOP-B and 146 with F-MACHOP. The minimum follow-up was 24 months. Clinical characteristics of all patients were similar and known prognostic factors were equally distributed between the two groups. Complete remission (CR) was achieved by 61% and 67% of the patients treated with MACOP-B and F-MACHOP, respectively; 4% and 6% were primarily resistant, 2% and 5%, respectively, died of causes directly related to therapy. At 50 months, 74% of all CR patients were alive without disease and there were no significant differences in relapse-free survival between the two groups: 75% in the F-MACHOP group and 73% in the MACOP-B group at 50 months. There was a higher incidence of mucositis among patients treated with MACOP-B than among those given F-MACHOP (11% vs 3.5%). Higher incidences of severe cytopenia (51% vs 21%) and of fatal sepsis (5% vs 2%) were recorded among patients treated with F-MACHOP than with MACOP-B. The third-generation regimens, F-MACHOP and MACOP-B, are as effective as other regimens. A prognostic analysis taking into account the principal covariates (age, symptoms, stage, serum lactate dehydrogenase, mediastinum involvement, bulky disease, histology, therapy, and dose intensity) was assessed for their impact on complete response rate incidence and on relapse rate from complete response by multivariate analysis. The linear logistic model showed that symptoms, advanced stage, mediastinum involvement, and bulky disease are prognostic factors that increase the risk of a lower rate of complete response. These data confirm the important role of a pretreatment selection for the poor-risk patients and, on the basis of these parameters, it will probably be possible to consider these patients for high-dose therapy with autologous bone marrow transplantation or autologous hematopoietic stem-cell support.
    No preview · Article · Jul 2009 · Leukemia and Lymphoma

Publication Stats

4k Citations
858.72 Total Impact Points


  • 2015
    • Ross University
      Charlotte Town, Saint George, Dominica
  • 2001-2014
    • Universidad de Navarra
      • • Department of Oncology
      • • Center for Applied Medical Research (CIMA)
      • • Department of Hematology
      • • School of Medicine
      Iruña, Navarre, Spain
    • Università Cattolica del Sacro Cuore
      Milano, Lombardy, Italy
    • National Cancer Institute (USA)
      • Experimental Transplantation and Immunology Branch
      Maryland, United States
  • 2009
    • Hokkaido University Hospital
      Sapporo, Hokkaidō, Japan
  • 2004-2009
    • Clínica Universidad de Navarra
      Madrid, Madrid, Spain
  • 1994-2009
    • University of Bologna
      • Institute of Haematology
      Bolonia, Emilia-Romagna, Italy
  • 2006
    • Universidad de Pamplona
      Памплона, Norte de Santander, Colombia