Complete remission in a patient with recurrent acute myeloid leukemia induced by vaccination with WT1 peptide in the absence of hematological or renal toxicity

Mailänder, Volker; Scheibenbogen, Carmen; Thiel, Eckhard; Letsch, Anne; Blau, Igor‐Wolfgang; Keilholz, Ulrich

doi:10.1038/sj.leu.2403186

Cited by 165 publications

(115 citation statements)

References 9 publications

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“…For example, monoclonal antibodies such as rituximab, tumor vaccines, and adoptive transfer of cytotoxic T-cells targeting minor histocompatibility antigens or tumorspecific antigens have been investigated. [36][37][38] The risk of progression was significantly higher among patients with prior history of local radiation therapy (RT) than those who did not received RT (Table 4). RT is indicated when the patients have chemo-refractory disease, central nervous system involvement or bulky mass, which means that patients with a history of RT carry risk factors of poor outcomes.…”

Section: Discussionmentioning

confidence: 99%

Reduced-intensity hematopoietic stem-cell transplantation for malignant lymphoma: a retrospective survey of 112 adult patients in Japan

Kusumi

Kami²,

Kanda

et al. 2005

Bone Marrow Transplant

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Summary:We conducted a nation-wide survey of 112 adult Japanese patients who underwent reduced-intensity stem cell transplantation (RIST) from 1999 to 2002. Underlying diseases included indolent (n ¼ 45), aggressive (n ¼ 58) and highly aggressive lymphomas (n ¼ 9). Median age of the patients was 49 years. A total of 40 patients (36%) had relapsed diseases after autologous stem cell transplantation and 36 patients (32%) had received radiotherapy. RIST regimens were fludarabine-based (n ¼ 95), low-dose total body irradiation-based (n ¼ 6) and others (n ¼ 11). Cumulative incidences of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD were, respectively, 49 and 59%. Cumulative incidences of progression and progression-free mortality were 18 and 25%, respectively. With a median follow-up of 23.9 months, 3-year overall survival rates were 59%. A multivariate analysis identified three significant factors for progression, which are history of radiation (relative risk (RR) 3.45, confidential interval (CI) 1.12-10.0, P ¼ 0.03), central nervous system involvement (RR 6.25, CI 2.08-20.0, P ¼ 0.001) and development of GVHD (RR 0.28, CI 0.090-0.86, P ¼ 0.026). RIST may have decreased the rate of transplant-related mortality, and GVHD may have induced a graft-versuslymphoma effect. However, whether or not these potential benefits can be directly translated into improved patient survival should be evaluated in further studies. Keywords: graft-versus-host disease; graft-versus-lymphoma effect; nonmyeloablative hematopoietic stem cell transplantation; indolent lymphoma; aggressive lymphoma Allogeneic stem cell transplantation (allo-SCT) is a curative treatment for advanced malignant lymphoma. 1,2 Initially, the benefit of allo-SCT was thought to be largely dependent on the intensity of the conditioning regimen prior to transplantation. Recently, an additional benefit of allo-SCT is derived from an allogeneic graft-versus-malignancy (GVM) effect that reduces the likelihood of disease relapse following transplantation. [3][4][5][6] With high regimen-related toxicity (RRT) and treatment-related mortality (TRM), high-intensity, myeloablative conditioning regimens are being replaced by reduced-intensity or nonmyeloablative conditioning regimens. The preliminary data suggest improved survival rates due to decreased TRM. 7 Reduced-intensity stem cell transplantation (RIST) is potentially a curative treatment for heavily pretreated, elderly patients; however, little information is available regarding the outcomes of RIST for malignant lymphoma. We retrospectively analyzed the outcome of RIST. The purpose of this study was to elucidate the treatment-related toxicity of RIST and to evaluate the impact of a potential graftversus-lymphoma (GVL) effect. Patients and methods Data collectionWe conducted a nation-wide retrospective survey of 112 adult Japanese patients who underwent RIST from 1999 to 2002 in 32 participating hospitals. All of the RIST recipients who were eligible in this study were included in each hospital. In...

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Section: Discussionmentioning

confidence: 99%

Reduced-intensity hematopoietic stem-cell transplantation for malignant lymphoma: a retrospective survey of 112 adult patients in Japan

Kusumi

Kami²,

Kanda

et al. 2005

Bone Marrow Transplant

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“…[13][14][15][16] Our group as well as others have initiated clinical trials using WT1 peptide vaccines to treat leukemia patients, and these studies have shown promising results. [17][18][19] Although it is clear that WT1 overexpression occurs frequently in human leukemia, the mechanism of overexpression remains to be determined. WT1 is also expressed in normal immature hematopoietic cells, although the frequency of WT1-expressing cells in normal hematopoietic cells is likely lower than that seen in leukemia cells.…”

Section: Introductionmentioning

confidence: 99%

The Wilms’ tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis

et al. 2007

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The Wilms' tumor gene WT1 is overexpressed in most of human leukemias regardless of disease subtypes. To characterize the expression pattern of WT1 during normal and neoplastic hematopoiesis, we generated a knock-in reporter green fluorescent protein (GFP) mouse (WT1 GFP/ þ ) and assayed for WT1 expression in normal and leukemic hematopoietic cells. In normal hematopoietic cells, WT1 was expressed in none of the long-term (LT) hematopoietic stem cells (HSC) and very few (o1%) of the multipotent progenitor cells. In contrast, in murine leukemias induced by acute myeloid leukemia 1 (AML1)/ ETO þ TEL/PDGFbR or BCR/ABL, WT1 was expressed in 40.5 or 38.9% of immature c-kit þ lin À Sca-1 þ (KLS) cells, which contained a subset, but not all, of transplantable leukemic stem cells (LSCs). WT1 expression was minimal in normal fetal liver HSCs and mobilized HSCs, both of which are stimulated for proliferation. In addition, overexpression of WT1 in HSCs did not result in proliferation or expansion of HSCs and their progeny in vivo. Thus, the mechanism by which expansion of WT1-expressing cells occurs in leukemia remains unclear. Nevertheless, our results demonstrate that the WT1 GFP/ þ mouse is a powerful tool for analyzing WT1-expressing cells, and they highlight the potential of WT1, as a specific therapeutic target that is expressed in LSCs but not in normal HSCs.

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“…The first patient, who had a second partial remission at study onset and progressed during the initial 4 weeks of vaccination with an increase of marrow blasts to 30%, subsequently achieved a complete remission (CR) after six vaccinations. 46 The second patient, who had a formal CR following chemotherapy for secondary AML with persistance of residual marrow blasts and a highly unfavourable 11q23 abnormality has been in continuous CR for more than 2 years since initiation of vaccination. Patients 3 and 4 had high numbers of marrow blasts when vaccination was started.…”

Section: Results From First Clinical Vaccination Studiesmentioning

confidence: 99%

Wilms' tumour gene 1 (WT1) in human neoplasia

Keilholz

Menssen²,

Gaiger

et al. 2005

Leukemia

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The transcription factor Wilms' tumour gene 1 (WT1) is important as a prognostic marker as well as in the detection and monitoring of minimal residual disease in leukaemia and myelodysplastic syndromes. Evidence has accumulated over the past decade to show that WT1 is a key molecule for tumour proliferation in a large number of human neoplasms most prominent in acute leukaemias, making it a suitable target for therapeutic strategies. Based on animal results, showing safety and efficacy of immunization with WT1 peptides and protein, early clinical trials in leukaemia have recently been initiated.

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Complete remission in a patient with recurrent acute myeloid leukemia induced by vaccination with WT1 peptide in the absence of hematological or renal toxicity

Cited by 165 publications

References 9 publications

Reduced-intensity hematopoietic stem-cell transplantation for malignant lymphoma: a retrospective survey of 112 adult patients in Japan

Reduced-intensity hematopoietic stem-cell transplantation for malignant lymphoma: a retrospective survey of 112 adult patients in Japan

The Wilms’ tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis

Wilms' tumour gene 1 (WT1) in human neoplasia

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