Rapid tapering of cyclosporine for cytogenetic relapse shortly after bone marrow transplantation in a patient with chronic myeloid leukemia

A new therapy for the treatment of oral leukoplakia by 5-aminolevulinic acid (ALA) and photodynamic therapy (PDT) is presented. ALA, a precursor in the biosynthesis of haeme, induces the production of the endogenous photosensitizer protoporphyrin IX which can be used for PDT. Twelve patients, who had been suffering from leukoplakia of the oral mucosa for several years, were treated by ALA-mediated PDT. ALA was used as a topical photosensitizer and 20% ALA cream was applied to the leukoplakia lesion of the oral mucosa for two hours and then light activated at 630 nm, 100 mW/cm2 and 100 J/cm2. Five patients showed complete response to the treatment, four patients showed a partial response and in three patients treatment was unsuccessful. One patient with partial response was retreated, after which the lesion disappeared.     

Filgrastim for the treatment of leukemia relapse after bone marrow transplantation

The absence of an effective therapy for most patients with leukemia who relapse after allogeneic BMT has generated interest in new strategies. We present our experience on the use of filgrastim 5 micrograms/kg/day s.c., in four patients with leukemia (three with AML and one with CLL) who relapsed after allogeneic transplantation. One patient with AML achieved CR after 55 days of treatment. No response was observed in the remaining three. The patient who responded developed extensive chronic GVHD but relapsed 10 months later. In one of the unresponsive patients a dramatic increase in bone marrow infiltration and WBC count followed administration of filgrastim. We conclude that filgrastim can occasionally induce CR in leukemic patients who relapse after BMT.     

Study of chimerism in long-term survivors after bone marrow transplantation for severe acquired aplastic anemia

Chimerism studies employing PCR and Southern techniques targeting VNTR loci were performed in 17 severe acquired aplastic anemia patients who were long-term survivors after BMT. They were studied a median of 4 years after BMT (1-12). All patients had normal blood counts. All patients conditioned with radiation-based schemes showed a full donor pattern of hemopoiesis. Conversely, out of five patients who received only cyclophosphamide as conditioning therapy, two of them had a late graft failure (2.4 and 3 years after BMT). One of these relapsing patients had a durable mixed chimerism, which was first detected 1 month after BMT. Our results seem to suggest that durable mixed chimerism can antecede graft failure in some patients conditioned only with cyclophosphamide, and that a more stringent monitoring can be clinically rewarding in this group of patients.     

Minimal residual disease after allogeneic bone marrow transplantation for chronic myeloid leukaemia: a metaphase-FISH study

Metaphase-FISH was adopted for the detection of proliferating Philadelphia-positive (Ph+) residual leukaemic cells in 25 patients with chronic myeloid leukaemia treated with allogeneic bone marrow transplantation (BMT). Patients were followed up during their clinical remission for 4-50 months (median 17 months) after BMT. 80 bone marrow samples were studied. For most of the cases no fewer than 1000 metaphases were analysed. Six patients (24%) showed residual Ph+ cells during the first 6 months and two others by the end of the first year after BMT. Three patients relapsed during the study and in two of them residual Ph+ cells were detected during the first 6 months after BMT. In 17 patients no Ph+ cells were detected at any stage of follow-up and 16 (94.1%) of them continue in complete clinical and haematological remission. Our results indicate that metaphase-FISH is a reliable tool in the quantitation of proliferating residual leukaemic cells. We suggest that consecutive findings of equal amounts of residual leukaemic cells do not necessarily predict a relapse. However, their presence calls for follow-up at shorter intervals where an increasing number of these cells predicts an ensuing relapse.     

Donor leukocyte transfusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation

We reviewed 4 cases of high-grade transitional-cell carcinoma (TCC) of the urinary tract with solitary pulmonary metastases that were studied by transthoracic needle aspiration biopsy cytology. There were two grade II and two grade III TCCs. The two grade II tumors yielded, in needle aspirates, syncytial tumor-cell clusters showing ill-defined, granular cytoplasm and slightly pleomorphic nuclei with inconspicuous nucleoli. In one case the tumor-cell cluster showed a focal acinar arrangement, mimicking cells of an adenocarcinoma. In both cases the electron microscopy (EM) study of aspirated tumor cells revealed epithelial cells with well-formed cell junctions, intracytoplasmic vesicles, apical short microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial neoplasm. The two grade III TCCs yielded, in needle aspirates, pleomorphic malignant cells singly and in small clusters, showing well-defined, granular cytoplasm and pleomorphic nuclei containing prominent nucleoli, suggesting a poorly differentiated adenocarcinoma or an anaplastic large-cell carcinoma. By EM examination the aspirated tumor cells from one case revealed well-formed cell junctions, intracytoplasmic vesicles, poorly formed microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial differentiation. In the other case the tumor cells were pleomorphic cells with occasional cell junctions and no ultrastructural features as seen in the other 3 cases of TCC. The tumor cells from the two grade II TCCs showed strong immunopositive reaction with keratin 7 antibody and weakly positive reaction with carcinoembryonic antigen antibody (CEAA), while those of the two grade III TCCs displayed only a weak and focal immunopositive staining with keratin 7 antibody and strong reaction with CEAA.     

Treatment of chronic myeloid leukemia in relapse after umbilical cord blood transplantation

Umbilical cord blood (UCB) is increasingly used as a source of hematopoietic progenitor cells for allotransplantation. Donor-derived buffy coat cells are considered optimal treatment for leukemia relapses after transplantation of allogeneic bone marrow. Experience with relapses after UCB transplants are sparse. Here we report a girl who received an UCB transplant for chronic myeloid leukemia, relapsed after three years, failed to respond to donor buffy coat cells, but achieved a complete hematologic, cytogenetic, and molecular remission on interferon-alpha.     

Transient complete remission of acute lymphoblastic leukemia in relapse after allogeneic bone marrow transplantation induced by donor leukocyte transfusions

We report the case of a young patient with refractory acute lymphoblastic leukemia relapse, after allogeneic bone marrow transplantation, who was treated by donor leukocyte infusions. We observed potent adoptive immunotherapy which produced a cytologic complete remission and total chimeric state. This was of short duration and the patient died of severe graft-versus-host disease. We present a short summary of the literature concerning acute lymphoblastic leukemia and donor leukocyte infusions.     

Adoptive immunotherapy with donor mononuclear cell infusions to treat relapse of acute leukemia or myelodysplasia after allogeneic bone marrow transplantation

Relapse remains a significant problem after allogeneic bone marrow transplantation (BMT). For patients with relapsed chronic myelogenous leukemia (CML), infusions of donor mononuclear cells (MNC) provide a potent graft-versus-leukemia (GVL) reaction inducing complete remissions in the majority of patients. Little is known about the efficacy of donor MNC infusions for patients who relapse with other diseases. We have studied the GVL effects of donor MNC in eight patients with relapsed acute leukemia or myelodysplasia (MDS). One patient with relapsed MDS achieved complete remission and another patient had a transient response. Five of six non-responders died of progressive leukemia and one non-responder died of complications during second BMT. Three patients developed grade I-II acute GVHD responsive to immunosuppression. These data, and review of the literature, suggest that GVL induction with donor MNC infusions is less effective for patients with relapsed acute leukemia than for patients with relapsed CML; too few patients with relapsed MDS have been treated to draw definite conclusions. However, some patients respond, and given the high mortality associated with alternative procedures such as second BMT, donor MNC infusions are a reasonable approach for relapsed acute leukemia and MDS after allogeneic BMT.     

Stable mixed chimerism without relapse after related allogeneic umbilical cord blood transplantation in a child with severe aplastic anemia

Umbilical cord blood (UCB) cells from HLA-matched donors are used as an alternative to bone marrow for allogeneic transplantation and reports of successful UCB transplantation in patients with severe aplastic anemia (SAA) are scarce. SAA was discovered in a 4-year-old girl in February 1990. Transfusion support started in August 1990 and standard treatments were unsuccessful. The birth of an HLA-compatible brother in October 1993 permitted the cryopreservation of UCB. In December 1994 UCB transplantation was decided upon. No toxicity occurred. G-CSF was started at day 28. WBC and PMN reached 0.5 x 10(9)/l at days 33 and 37. RBC and platelet transfusion independence were reached at days 50 and 52. Mixed chimerism was demonstrated in blood cells at 1.5, 4 and 6 months after UCBT by molecular biology (VNTR). FISH studies yielded similar results at 15 and 18 months. Twenty months after UCBT, molecular biology showed full donor chimerism. Clinical follow-up (last follow-up: 32 months post transplant) is unremarkable. We suggest that CY and ATG may be a suitable regimen for related HLA-compatible UCBT in patients with SAA. Residual recipient cells can disappear even very late after UCBT, permitting the establishment of complete donor chimerism.     

Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation

Allogeneic bone marrow transplantation (BMT) is the only effective treatment for hematologic malignancies resistant to conventional chemotherapy. Until recently, no cure existed for patients who relapsed post-BMT. We present our long-term observations on remission induction, after relapse post-BMT, by allogeneic cell therapy (allo-CT) and the feasibility of remission induction in allo-CT-resistant patients by activation of antileukemia effector cells with recombinant human interleukin-2 (rhIL-2) in vitro and in vivo. The longest observation of successful allo-CT (event-free survival, greater than 8 years) was made in a patient with resistant pre-B lymphoblastic leukemia who received infusions with graded increments of donor (female) peripheral blood lymphocytes (PBL) as soon as bulky hematologic and extramedullary relapse was noticed early post-BMT. The patient is currently without evidence of residual host (male) cells as determined by polymerase chain reaction (PCR). Of 17 patients with acute and chronic leukemia in relapse after BMT, 10 were reinduced into complete remission. Four patients with cytogenetic relapse responded to allo-CT alone, while five of six patients with overt hematologic relapse responded only after additional activation of donor with rhIL-2. Allo-CT can, therefore, successfully reverse chemoradiotherapy-resistant relapse of both acute and chronic leukemia. Moreover, in patients resistant to donor lymphocyte infusion, remission can be accomplished by additionally activating donor PBL in vitro and/or in vivo with rhIL-2. Based on our observations, after BMT, allo-CT should be considered the treatment of choice for patients with hematologic malignancies resistant to conventional anticancer modalities. Allogeneic activated cell therapy (allo ACT) should be considered for patients with tumor cells resistant to allo-CT. Although allo-CT, followed if indicated by allo-ACT, can be effective for patients with overt hematologic relapse, reversal of persistent minimal residual disease or documented molecular/cytogenetic relapse early after BMT may also be considered as a possible indication for allo-CT.     

Neurological and neuroradiological findings in long-term survivors of allogeneic bone marrow transplantation

The aim of this study was to assess neurological, neuropsychological, and neuroradiological findings in long-term survivors of allogeneic bone marrow transplantation (BMT) who were recruited from a hematological outpatient clinic. In addition, risk factors for the development of late neurological complications were identified. In contrast to previous studies on autopsied patients, our study design provoked a bias away from increased neurological sequelae, because patients with early complications after BMT were excluded. Fifty-nine allogeneic patients and 7 autologous BMT patients underwent clinical examination, short neuropsychological testing, and cranial magnetic resonance imaging (MRI) 34 +/- 26 months after BMT. The pathological results of the neurological examination (abnormal 64%) and the MRI examination (white matter lesions, 54%; atrophy, 11%) were associated with the occurrence of chronic graft-versus-host disease (GvHD) evolving from acute GvHD, with corticosteroid therapy and with cyclosporine medication. Neuropsychological impairment (cognitive deficits, 37%) was associated with long-term cyclosporine medication and age. No influence of pre-BMT disease, BMT donor status, or the conditioning regimen was found. These results suggest that the frequent neurological abnormalities in long-term survivors of allogeneic BMT are associated with chronic GvHD and with the resulting immunosuppression as major risk factors.     

Induction of molecular remission by donor peripheral blood leukocyte therapy in patients relapsing with extramedullary blastic phase chronic myeloid leukemia after allogeneic bone marrow transplantation

A suspension culture of white lupin cells has been established, and proteins of the exocellular matrix analysed. Based on homologies of N-terminal amino-acid sequences, three stress- or defence-related proteins: acidic class III chitinase, polygalacturonase-inhibiting protein, and germin/oxalate oxidase, secreted by lupin cell culture, were identified.     

Lamivudine treatment for chronic replicative hepatitis B virus infection after allogeneic bone marrow transplantation

The risk of severe hepatic damage in patients with chronic hepatitis B virus (HBV) infection is well known; more effective treatments for this infection are needed. Lamivudine is being studied in immunocompetent and immunosuppressed HBV infected patients. We report a patient suffering from chronic replicative HBV infection after allogeneic BMT, who responded to lamivudine therapy. A 24-year-old woman with CML received an allogeneic BMT from her HLA-identical sister in June 1992. Before transplant, her HBV status demonstrated viral contact without active infection (HBsAb+, HBcAb+ IgG, HBeAb+). Four months after BMT mild chronic liver GVHD appeared, requiring immunosuppressive treatment. Antibodies to HBV completely disappeared post-transplant. Acute icteric hepatitis occurred 2 years later, with HBsAg+, high level of HBV-DNA, HBeAg+ and HBcAb IgM+. Lamivudine 100 mg/day rapidly reduced transaminase levels and effected HBV-DNA disappearance within 2 months. The treatment was well tolerated; no hematological side-effects occurred. This preliminary observation warrants further investigation of lamivudine treatment in bone marrow transplanted patients with active HBV infection.     

Relapsed chronic myeloid leukemia in accelerated phase 10 years after allogeneic bone marrow transplantation: full chimera reconversion with donor peripheral blood stem cells infusion

The authors calculated the shunt revision rate for 77 consecutive patients with tumoural obstructive hydrocephalus. At a mean follow up of 23.7 months, the annual revision rate was 0.06 which is significantly lower than the annual revision rate of 0.39 for other hydrocephalic patients treated during the same period. Shunted patients who had total excision of their lesions had a significantly lower revision rate than patients who had a partial excision or a biopsy. It is therefore, suggested that cases with tumoural obstructive hydrocephalus may represent a subset of hydrocephalic patients who are associated with a relatively low risk of shunt complications. The observation has to be addressed when the role of endoscopic third ventriculostomy in these patients is being considered.     

A new radiation-free conditioning in bone marrow transplantation and dibromo-mannitol therapy in chronic myeloid leukemia

A new, radiation-free, conditioning protocol, containing the original Hungarian mitobronitol (DBM) (DBM/ cytosine arabinoside/cyclosphosphamide) has been applied to 36 chronic myeloid leukemia (CML) patients followed by bone marrow transplantation (BMT) from HLA identical sibling donors between 1990-1997. In spite of some prognostically disadvantageous factors (half of them were above 40 years, 10 out of 36 patients were in accelerated phase, the disease history was longer than 2 years in average) the overall survival (30/36) and the leukemia free survival rate (26/36) were in accordance with the best international results. Transplantation-related toxicity was remarkably reduced in comparison to bone marrow transplantation performed by total body irradiation/cyclophosphamide (TBI/Cy) or busulphan/cyclophosphamide (Bu/Cy) conditioning protocols. Acute graft versus host disease was present in lower percentage (9/36) and the number of serious cases was only 2/36. Chronic GVH disease, generally known to be associated with antileukemic effect (GVL), occurred in 25 of cases. Early haematological relapse among the 34 patients with functioning graft occurred in 6 patients which rate is slightly higher than reported after TBI/Cy or Bu/Cy conditioning treatment. There was no relapse among patients transplanted within one year post-diagnosis and patients having CML with accelerated phase. The leukemia free post-transplant period was in association with the chronic GVH disease and full chimeric state.