Molecular analysis of relapse in chronic myeloid leukemia after allogeneic bone marrow transplantation

Four patients with Philadelphia (Ph') positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone.     

Extramedullary relapse after allogeneic bone marrow transplantation for haematological malignancy

We describe the risk factors for and the natural history and response to treatment of extramedullary (EM) relapse in 183 patients who underwent allogeneic bone marrow transplantation (alloBMT) for a variety of haematological malignancies at our institution over a 7 1/2 year period. Fifty-one patients relapsed; 15 had EM relapse either alone or in association with marrow involvement. A retrospective analysis found that the presence of chronic GVHD and a longer interval between transplant and relapse were independently associated with an increased risk of EM compared to marrow-only relapse. EM relapse was also associated with a longer post-relapse survival. Patients with EM relapse appeared to respond to cytotoxic therapy but not to DLI. EM relapse after alloBMT may be more common than previously thought and have a better prognosis than marrow-only relapse. While patients developing chronic GVHD after alloBMT have a lower overall relapse risk than those who do not, they may be more prone to delayed relapse at EM sites.     

Isolated extramedullary relapse of acute lymphoblastic leukaemia after allogeneic bone marrow transplantation

Isolated extramedullary relapse of acute lymphoblastic leukaemia (ALL) with sparing of the marrow after allogeneic bone marrow transplantation (BMT) is a rare occurrence, and the mechanisms underlying the selective involvement of extramedullary sites remain undefined. These might be due to relapse in sanctuary sites where the leukaemic cells are resistant to chemotherapy, or a stronger putative graft-versus-leukaemia (GVL) effect in the marrow as compared with peripheral tissues. We report two ALL patients with repeated episodes of extramedullary relapse after BMT in whom both mechanisms might be operating. In the first patient, the marrow was in morphologic and molecular remission before isolated leukaemic relapse in the central nervous system (CNS) occurred. Subsequent secondary infiltration of leukaemic cells into the marrow was only evident molecularly but not morphologically, implying that the relapse had arisen in a sanctuary CNS site. In the second patient, a first relapse in the marrow, which was induced into morphologic and molecular remission by chemotherapy and donor lymphocyte infusion, was followed by extramedullary relapses without any subsequent involvement of the marrow. This suggested that factors, likely to be due to a GVL effect, were stronger in the marrow than in peripheral tissues.     

Leukemic relapse 5 1/2 years after allogeneic bone marrow transplantation.

A 13-yr-old male with acute myelogenous leukemia was treated with various chemotherapy regimens for 3 1/2 yr and then underwent an allogeneic bone marrow transplantation. The donor marrow was successfully engrafted, and the patient remained in remission free of all chemotherapy. Then, 5 1/2 yr later, he developed an extramedullary relapse with a chloroma of his maxillary sinus. This case illustrates the need for prolonged followup of transplant recipients and suggest that statements proposing cure as a result of this procedure may be premature.     

Donor leucocyte transfusions for relapse in myelodysplastic syndrome after allogeneic bone marrow transplantation

A 31-year-old man with refractory anaemia of excess blasts, which had karyotypic abnormalities, received an allogeneic bone marrow transplant (BMT). At time of relapse, 3 months after BMT, he was treated with donor leucocyte transfusions (DLT). Grade III acute GVHD (graft-versus-host disease) occurred 35 d after DLT which was fully reversed with cyclosporin and prednisolone. His condition was complicated by a herpes zoster infection. 2 months after DLT, neutrophil and platelet count were increased and karyotypic abnormalities disappeared. This observation demonstrates that DLT is an effective treatment for relapse of myelodysplastic syndrome (MDS) after BMT.     

Antibody-mediated marrow failure after allogeneic bone marrow transplantation

Marrow graft failure observed in association with histocompatibility differences between donor and recipient is often attributed to rejection mediated by host-derived cytolytic T lymphocytes. The data presented in this report indicate that persistent host antibodies specific for donor antigen may also mediate graft failure, either by antibody-dependent cell-mediated cytotoxicity (ADCC), or complement- mediated cytotoxicity. In the case of HLA Class I disparity, where all donor cells express the target antigen, the presence of alpha-donor antibody was associated with complete graft failure and death. In the case of ABO blood group antigen disparity, the presence of alpha-donor antibody resulted in erythroid hypoplasia. The latter cases proved informative insofar as they established that host antibodies could persist for more than 18 months after chemoradiotherapy and impair marrow function.     

Cost analysis of allogeneic bone marrow transplantation

The aim of this economic evaluation was to assess the costs of the first year of genotypically identical HLA allogeneic bone marrow transplantation (BMT) for the treatment of adults patients with acute myeloid leukemia (AML) in first complete remission (CR1). During the first year of follow-up the following were assessed 1) variable direct medical (VDM) cost (drugs, blood products, lab tests, radiological procedures, hospital days) and the part of this cost paid by the Besançon Hospital from it own budget 2) the total cost.Ten consecutive patients from the Hematology Department of the Besançon University Hospital (France) transplanted from 1995 to 1996 for AML in CR1 were included in the analysis. This retrospective study was carried out using the French Health Care Insurance System (HCIS) perspective. Medical data were collected from the medical records of the patients. The overhead and logistics charges came from the analytic accounting report which was used to assess the mean cost of the first year of follow-up (in e and 1999 US$).The variable medical cost for the first year of follow-up for an allogeneic BMT amounted to 66,186 e (US$ 70,542). Total direct cost for the first year of follow-up was 111,454 e (US$ 118,459) (82,963 e, US$ 88,422 for the first six months). 95% of that cost was paid by the State Hospital from it own budget.     

Aspergillus tracheobronchitis after allogeneic bone marrow transplantation

We describe a patient who developed Aspergillus tracheobronchitis after BMT. She complained of progressive dyspnea on day +165 and her respiratory function deteriorated rapidly. Although neither early chest X-rays nor CT scans were negative, bronchoscopy revealed formation of a pseudomembrane around the bronchial walls. Based upon pathological and microbiological examinations, she was diagnosed as having invasive Aspergillus tracheobronchitis. Retrospectively analyzed, the Aspergillus circulating antigen detection tests became positive before clinical symptoms developed, and may be beneficial for early diagnosis of Aspergillus tracheobronchitis. This form of aspergillosis should be regarded as one of the serious complications after BMT.     

Donor lymphocyte infusion to treat relapse after allogeneic bone marrow transplantation for myelodysplastic syndrome

Donor lymphocyte infusion has become established as a salvage therapy for patients with hematological disorders relapsing after allogeneic bone marrow transplantation (BMT). The role of donor lymphocyte infusion for patients with myelodysplastic syndrome (MDS) remains to be established. Between July 1993 and October 2001, 14 patients with MDS relapsing after allogeneic BMT received DLI as salvage therapy. At the time of BMT, one patient had RA, nine had RAEB, of whom three were in CR after induction-type chemotherapy, two had RAEB-T, one had CMML and one had AML. Donors were HLA-matched siblings (n=12), HLA-matched other relative (n=1) and unrelated (n=1). At the time of relapse, the median marrow blast count was 9%. The median CD3+ cell dose administered was 6.3 x 10(7)/kg. With a median follow-up of 49 months, six patients were alive, of whom two were in CR after DLI alone and remained disease-free, two were in CR after a second BMT and two had active disease. Eight patients died of disease progression. Although DLI alone seems to be effective in a small number of patients with MDS, other treatment strategies, including prior debulking chemotherapy, deserve investigation.     

Hepatopulmonary syndrome after allogeneic bone marrow transplantation

A 10-year-old girl with aplastic anemia received an allogeneic bone marrow transplantation (BMT). Three years after an uneventful course apart from chronic graft-versus-host disease (GVHD) she presented with chronic hypoxemia, reduced diffusion capacity of the lungs, normal spirometric lung function and increased bilirubin and liver enzymes. Intrapulmonary vascular dilatations were demonstrated. Pulmonary complications after BMT may include a hepatopulmonary syndrome (liver disease, hypoxemia, intrapulmonary vascular dilatations).     

Origin of leukemic relapse after bone marrow transplantation: comparison of cytogenetic and molecular analyses

Leukemic relapse following bone marrow transplant (BMT) is generally due to the recurrence in recipient cells, but may rarely occur as a result of donor cell transformation. Donor cell relapse is generally identified using cytogenetic markers such as the sex chromosomes. Recently, molecular techniques have been used to identify the origin of bone marrow cells by their DNA restriction fragment length polymorphisms. We describe the case of a male pediatric patient who had a leukemic relapse 30 months following BMT from his sister. Both cytogenetic and molecular techniques were used to identify the origin of the leukemic relapse. Cytogenetic analyses indicated the absence of the Y chromosome and the presence of a donor cell type 9qh polymorphism, suggesting a donor cell relapse. Molecular analyses also indicated the absence of the Y chromosome but demonstrated the recurrence of recipient DNA markers from three other chromosomes, suggesting a recipient cell relapse. While the leukemic cell lineage cannot be definitively assigned in this case, our results suggest that caution must be exercised when assigning leukemic cell lineage following post-BMT relapse.     

Eosinophilic fasciitis after allogeneic bone marrow transplantation

We describe a patient with eosinophilic fasciitis (EF) developing 8 months after an allogeneic bone marrow transplantation for acute myeloblastic leukemia. The patient responded to low dose prednisone. A full thickness skin-muscle-fascia biopsy detected the characteristic fascial changes of EF and distinguished it from other forms of chronic graft-versus-host-disease (GVHD). This distinction may be important since EF after bone marrow transplantation may occur more often and it may respond to treatment with low doses of prednisone whereas chronic GVHD usually requires more extensive immunosuppressive treatment.     

Spontaneous complete remission of chronic myeloid leukaemia following haematological relapse after allogeneic bone marrow transplantation

A 31-year-old woman with Philadelphia (Ph) chromosome-positive chronic myeloid leukaemia (CML) underwent allogenic bone marrow transplantation during accelerated phase. Non-T-cell-depleted marrow from a male sibling mismatched at one Class 2 histocompatibility locus was infused after conditioning with total body irradiation and intravenous cyclophosphamide. Cyclosporin and methotrexate were given for prevention of graft-versus-host disease (GVHD). Prompt engraftment occurred with donor karyotype cells, followed by transient moderate acute GVHD. However, by day 60 after BMT, haematological relapse occurred with increasing splenomegaly, leucocytosis, increasing marrow fibrosis, and cytogenetic mosaicism, consisting of 47% donor metaphases with 53% Ph-positive host metaphases, some containing additional structural changes. Thirty days later further cytogenetic progression was evident. A slowly progressive fungal pneumonia concurrently present was treated with intravenous amphotericin and gradual reduction of cyclosporin. Subsequently, without further cytotoxic chemotherapy, pancytopenia and bone marrow hypoplasia developed, and on day 144 only donor karyotype marrow cells were seen. Chromosomes have remained of donor type on subsequent occasions, and the patient has a normal performance status 25 months after BMT. The patient's course illustrates that factors operating after allogeneic BMT contribute to long-term control of CML. The factors potentially responsible for this spontaneous remission, after early relapse, are discussed.     

Functions of granulocytes after allogeneic bone marrow transplantation

Summary The phagocytosis and intracellular killing by granulocytes as well as the opsonizing capacity of the serum were studied in 13 patients who had undergone allogeneic bone marrow transplantation. Phagocytosis was normal in all patients. A moderately impaired opsonic activity of the serum was found in two patients, who were investigated within 30 days after the transplantation. The intracellular killing was less than control values in two patients. In one patient this was probably due to the existence of a split chimerism.Supported by a grant of the J. A. Cohen Institute, Leiden, The Netherlands