Cases reported "Recurrence"

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1/30. Successful one antigen mismatched bone marrow transplant for chronic myeloid leukemia (CML) after two failed syngeneic transplants.

    In May 1989, a 43-year-old woman with chronic myelocytic leukemia diagnosed in 1988 underwent a syngeneic bone marrow transplant (BMT), conditioned with cyclophosphamide-TBI while in chronic phase. Three years later, because of both cytogenetic and hematological relapse, she was treated with interferon-alpha (IFN-alpha) and hydroxyurea (HU) for 3 years. In 1994 while still in chronic phase, she was conditioned with busulfan-cyclophosphamide (BU-CY) and underwent a second syngeneic BMT. In 1996, following a further cytogenetic and hematological relapse, she was again placed on IFN-alpha and HU therapy for 13 months, when she was referred to our hospital in accelerated phase. In October 1997 following thiotepa, CY and anti-thymocyte globulin conditioning, she underwent an allogeneic BMT from her 1-Ag mismatched brother. She became Ph1 negative with full chimerism and normal hematological parameters; acute graft-versus-host disease (GVHD) grade 3 of the skin and chronic GVHD of the liver occurred. At 11 months follow-up she is in good clinical condition and with a Karnofsky score of 90%. The role of a graft-versus-leukemia (GVL) effect in securing and maintaining the complete remission is discussed.
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2/30. Donor lymphocyte infusion induced molecular remission in relapse of acute myeloid leukaemia after allogeneic bone marrow transplantation.

    Donor lymphocyte infusion (DLI) has been used successfully to induce remissions in relapse of acute myeloid leukaemia (AML) after bone marrow transplantation (BMT), but molecular eradication of leukaemia has rarely been documented. A patient with AML-M4Eo relapsed after HLA-identical sibling BMT in first complete remission (CR). Cytogenetic and molecular genetic investigations confirmed inv(16) and CBFbeta/MYH11 fusion characteristic of M4Eo. A second remission was obtained with chemotherapy. Full donor chimerism was demonstrated by fluorescence in situ hybridisation. However, molecular evidence of minimal residual disease still persisted, and donor lymphocyte infusion (DLI) was administered. This resulted in molecular eradication, and the patient remained in clinical and molecular remission 16 months from DLI. Our observations showed that, for AML relapse after BMT, molecular leukaemia eradication could be achieved by DLI so that, in cases where genetic markers are available, molecular monitoring should be performed to assess the efficacy of treatment.
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3/30. Acute myeloid leukemia relapsing as gynecomastia.

    Granulocytic sarcoma (GS) is an increasingly common relapse feature of acute myeloid leukemia (AML), late in the disease course or post bone marrow transplantation (BMT). Any solid organ can be affected, and there have been a number of reports of GS in breast tissue in female patients. We present a unique case of GS in a male AML patient, presenting as painless gynecomastia immediately before BMT at advanced disease. Aberrant expression of CD56 was found in the relapsed GS tissue but not in the original AML clone. Twelve months after allogeneic BMT, leukemia relapsed again in the same breast, with normal marrow morphology and full donor chimerism. The lesion failed to respond to donor lymphocyte infusion, chemotherapy and radiotherapy, and disseminated to other subcutaneous tissues.
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4/30. Detailed monitoring of hematopoietic chimerism in a child treated by adoptive immunotherapy for high risk of relapse after BMT for acute myeloid leukemia.

    We report a case of a 13-year-old boy who was transplanted for relapse of acute myeloid leukemia (AML). A detailed study of hematopoietic chimerism was performed using polymerase chain reaction (PCR) of variable number of tandem repeats (VNTR) at very short time intervals. We used discontinuation of post-transplant immunosuppression and donor lymphocyte infusions (DLI) in order to prevent leukemia relapse that was indicated by a progressive increase in autologous hematopoiesis. Despite the fact that the boy relapsed 10 months after BMT, we could see a significant influence of adoptive immunotherapy on the mixed chimerism status during the post-transplant period.
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keywords = chimerism
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5/30. Need for an accurate molecular diagnosis to assess the donor origin of leukemia relapse after allogeneic stem cell transplantation.

    BACKGROUND AND OBJECTIVES: leukemia relapse occurring in donor cells after allogeneic hematopoietic stem cell transplantation has been reported in rare cases. cytogenetic analysis and molecular probing of variable number of tandem repeats (VNTRs) have been used to confirm this unusual event in the few cases so far reported in the literature. The aim of this study was to demonstrate that extensive molecular characterization of leukemic cells at diagnosis and relapse may be necessary to avoid many technical pitfalls possibly leading to an erroneous diagnosis of leukemia relapse in donor cells after allogeneic transplantation. DESIGN AND methods: We report the case of a 49- year old man who received an allogeneic transplantation from his HLA-identical sister because of BCR-ABL acute lymphoblastic leukemia (ALL). After having achieved complete hematologic and molecular remission, two years later an overt leukemia relapse occurred with cytogenetic findings suggesting a leukemia relapse in donor cells. The donor or patient origin of leukemic cells at relapse was further investigated by fluorescence in situ hybridization (FISH) karyotyping, reverse transcription (RT) polymerase chain reaction (PCR) analysis of BCR-ABL chimeric transcripts, PCR amplification of several VNTRs and the y chromosome-specific DYS14 sequence and finally by amplification, cloning and sequencing of the CDRIII region of the immunoglobulin heavy chain (IgH) gene. RESULTS: At the time of relapse, conventional and FISH karyotyping revealed the presence of a Phl chromosome and a female karyotype in all the 25 metaphases analyzed and PCR amplification of the y chromosome-specific DYS14 sequence was negative. Moreover, the molecular evaluation of hematopoietic chimerism performed by the NZ-22 VNTR allowed us to demonstrate that at the time of relapse, a consistent proportion of hematopoietic cells was of donor origin. However, the molecular cloning and sequencing of the CDRIII region of the immunoglobuin heavy chain (IgH) gene rearrangement in leukemic blasts at diagnosis and relapse demonstrated their identity thus formally proving the patient origin of both leukemic clones. INTERPRETATION AND CONCLUSIONS: While the simplest interpretation of the apparent female karyotype at relapse is the consequence of a loss of the y chromosome which in leukemic blasts took place along with duplication of an X-chromosome, this case strongly emphasizes the need for accurate and extensive molecular characterization to prove the donor origin of a leukemia relapse after allogeneic transplantation.
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6/30. Allogeneic bone marrow transplantation for refractory mantle cell lymphoma.

    We report about a 28-year-old woman with relapsed mantle cell lymphoma (MCL, centrocytic lymphoma according to the Kiel classification) refractory to salvage chemotherapy. The patient underwent allogeneic bone marrow transplantation from a HLA-identical brother after myeloablative chemotherapy consisting of busulfan, etoposide, and cyclophosphamide. The patient experienced hepatic toxicity (grade I), mucositis (grade II) according the Bearman scale, and graft versus host disease of the skin (grade II) and showed stable engraftment with complete chimerism on day 15 after bone marrow transplantation. Eight years after transplantation, the patient is still disease free and in good condition without any late side effects. This report suggests a curative potential of allogeneic stem cell transplantation in MCL.
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keywords = chimerism
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7/30. Donor lymphocyte infusion followed by interferon-alpha plus low dose cyclosporine A for modulation of donor CD3 cells activity with monitoring of minimal residual disease and cellular chimerism in a patient with first hematologic relapse of chronic myelogenous leukemia after allogeneic bone marrow transplantation.

    A 15-year-old girl with Ph-positive chronic myelogenous leukemia in first chronic phase received bone marrow from her human leukocyte antigen matched brother. Twenty three months after bone marrow transplantation hematological relapse occured which was treated with two infusions of donor lymphocytes (DLI) (0.5x10(8) CD3/kg b.w./infusion). To enforce the graft-versus-leukemia effect (GvL), the first DLI was followed by administration of interferon-alpha (INF-alpha) 6x10(6) U/day for 30 days, whereas, after the second infusion INF-alpha was given at the same dose until hematological remission was achieved (80 doses). Minimal residual disease (MRD) was detected by conventional cytogenetics (Ph chromosome), fluorescence in situ hybridization (FISH) cytogenetics (BCR/ABL translocation) and reverse transcriptase-polymerase chain reaction (RT-PCR) Ecotropic virus integration site-1 (EVI-1 gene expression), whereas cellular chimerism was monitored by assessment of microsatellite markers PCR and Y-chromosomal dna content FISH. When hematological remission was achieved the pancytopenia was observed and the cytogenetic and molecular investigations revealed only partial remission and mixed chimerism, however, with predominance of donor origin hematopoiesis. To diminish the myelosupressive effect of donor CD3 cells without switching-off the GvL effect, a low dose of cyclosporine A was given. Further observation revealed significant improvement of hematopoiesis with parallel gradual decline of MRD and increase of donor hematopoiesis up to complete chimerism. Graft-versus-host disease was not observed at any stage of the treatment.
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keywords = chimerism
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8/30. Relapse of Graves' disease after successful allogeneic bone marrow transplantation.

    As shown in many reports, allogeneic BMT can help cure autoimmune diseases. Conversely, we present a 24-year-old woman with Graves' disease, which was diagnosed just before BMT for CML. The Graves' disease remitted immediately after BMT but relapsed 18 months later. Since the donor was free from thyroid diseases and the patient showed a rapid shift to complete donor chimerism after BMT, the autoimmune problem seemed neither to arise directly from the donor nor simply from the recipient's residual lymphocytes. On the contrary, it was most likely compounded by chronic GVHD as suggested by the accompanying GVHD symptoms and the absolute donor karyotype in bone marrow cells. A Graves' disease-susceptible HLA allele was also shared between recipient and donor, possibly enhancing the chances of this condition developing. Thus, allogeneic BMT may facilitate relapses in autoimmune diseases as well as alleviating them.
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keywords = chimerism
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9/30. Unusual presentation of central nervous system relapse with oculomotor nerve palsy in a case of CD56-positive acute myeloid leukemia following allogeneic stem cell transplantation.

    Allogeneic stem cell transplantation (allo-SCT) plays an important role in the treatment of infants and children with acute myelogenous leukemia (AML). Leukemic relapse after allo-SCT is responsible for a high rate of treatment failure. Extra-medullary relapse (EMR), without involvement of bone marrow, is rare compared to medullary relapse. CD56, the neural cell adhesion molecule, may contribute to the higher frequency of CNS relapse in CD56-positive AML. We observed an isolated EMR on the oculomotor nerve of a 17-month-old girl 12 weeks after cord blood transplantation (CBT), who was transplanted because of CD56-positive AML. diagnosis of relapse was suspected clinically and confirmed by magnetic resonance imaging (MRI), and fluorescence-activated cell sorter (FACS) and chimerism analysis of cerebrospinal fluid (CSF). Therapy consisted of intra-thecal chemotherapy, CNS irradiation, and systemic immunomodulation by cyclosporin A (CsA) and basiliximab withdrawal. Twenty-one months after relapse, the patient shows full remission of symptoms and previously described oculomotor nerve infiltration.
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10/30. chimerism testing and detection of minimal residual disease after allogeneic hematopoietic transplantation using the bioView (Duet) combined morphological and cytogenetical analysis.

    Recurrent disease remains a major obstacle to cure after allogeneic transplantation. Various methods have been developed to detect minimal residual disease (MRD) after transplantation to identify patients at risk for relapse. chimerism tests differentiate recipient and donor cells and are used to identify MRD when there are no other disease-specific markers. The detection of MRD does not always correlate with relapse risk. chimerism testing may also identify normal hematopoietic cells or other cells not contributing to relapse. In this study we report our initial experience with a novel system that provides combined morphological and cytogenetical analysis on the same cells. This system allows rapid automatic scanning of a large number of cells, thus increasing the sensitivity of detection of small recipient population. The clinical significance of MRD detection is improved by identifying the morphology of recipient cells. Identification of recipient characteristics within blasts predicts overt relapse in leukemia patients and precedes it by a few weeks to months. Identification within mature hematopoietic cells may not be closely associated with relapse. The system also allows chimerism testing after sex-mismatched transplants, within cellular subsets, with no need for sorting of cells. The system merits further study in larger scale trials.
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