Prior Bone Marrow Transplantation Research Articles

Fine-needle aspiration cytology of lymphoproliferative disorders in the immunosuppressed patient: the diagnostic utility of in situ hybridization for Epstein-Barr virus.

We examined the diagnostic utility of fine-needle aspiration (FNA) in the immunosuppressed patient with particular attention to the value of in situ hybridization for Epstein-Barr virus encoded RNA (EBER), a test frequently performed on tissue sections in this setting. Six patients with adenopathy were identified: three with prior solid organ transplantation, two with prior bone marrow transplantation, and one with human immunodeficiency virus. Cytologic findings in involved tissues were positive for non-Hodgkin's lymphoma in one case, suspicious or atypical in three cases, negative/reactive in one case, and nondiagnostic in one case due to insufficient material. Two aspirates had a polymorphous lymphoid appearance; three showed predominantly monomorphous lymphoid morphology. Retrospectively, 4/4 FNA cell blocks were positive for EBER in a large proportion of atypical lymphoid cells. Together with the cytologic findings, EBER detection allows for more specific classification of these FNA samples as EBV-associated lymphoid proliferations.

Infusional Vinorelbine in Relapsed or Refractory Lymphomas

Vinorelbine (Navelbine™) is i. semisynthetic vinca alkaloid devoid ot serious neurotoxicity. When given weekly vinorelbine has documented activity against many tumors, including lymphomas. Since weekly schedules cannot be easily incorporated in combination regimens, we tested an infusional schedule of vinorelbine given every 21 days in adults with relapsed or refractory lymphoma. Patients with inadequate organ or bone marrow reserve. HIV or other serious infection. central nervous system disease, or prior stem cell or bone marrow transplantation were ineligible. In the phase I part, patients received a constant intravenous bolus of 8 mg/m2, followed by intravenous continuous infusion over 24 hours daily for four days increasing from 10, 12, to 14 mg/m2/d in successive three-patient cohorts. Cycles were repeated every 21 days, and the daily continuous infusion dose was adjusted for toxicity. Dose-limiting mucositis and neutropenia were reached at the continuous dose of 14 mg/m2/d. Consequently, for the Phase II trial the starting continuous infusion dose was 12 mg/m2/d. After the first 19 patients were entered in the phase II study, the starling infusion dose was reduced to 10 mg/m2/d because of frequent grade 3/4 myelosuppression and mucositis. Forty-four patients were entered in the phase II study, of whom 41 are evaluable. Median age was 61 years, 23 were males. with clinically aggressive non-Hodgkin's lymphoma (NHL) in 22, indolent NHL in 18, and Hodgkin's Disease in lone patient. The median number of prior regimens was 3 (range 1-11). The lymphoma was refractory to the initial regimen in nine patients, and to the regimen immediately before vinorelbine in 20 patients. Serum LDH was high in 21/41, and serum β2-microglobulin > 3.0 mg / L in 16/31 patients. Responses were observed in four of 22 patients with aggressive NHL (18%, 95% confidence interval 5%-40%). and in six of 18 with indolent NHL (33%, 95% confidence interval 13%-59%). Median progression-free survival was 6 months for responders. During the Phase II trial 114 vinorelbine courses were administered. Neutrophil nadir was < 1000/μml1 in 65% and < 100/μml1 in 35% of courses, respectively. Platelet nadir was < :100,000/μml1 in 30% and < 20,000/μml1 in 8% of courses, respectively, Grade 3/4 mucositis was seen in 18% of courses, and neutropenic fever in 13%, and was complicated by death in one patient. We conclude that this dosage and schedule of vinorelbine has modest activity in patients with relapsed or refractory NHL. Myelosuppression is frequent but reversible, but there is, no significant neurotoxicity. The role of

Outcomes of recipients of both bone marrow and solid organ transplants. A review.

In this review we examine the clinical outcomes of patients who have received both bone marrow transplantation (BMT) and solid organ transplantation (SOT) and discuss the possible immunologic consequences of the dual transplants. We collected cases through a comprehensive literature search (MEDLINE database, English literature only) covering the years 1990 through 1997 and correspondence with the International Bone Marrow Transplant Registry. Our study selected case reports of patients who have undergone both bone marrow and solid organ transplants; cases in which bone marrow transplantation was undertaken as an adjunct ot induce or augment donor-specific tolerance in a recipient to the transplanted organ were excluded. Clinical characteristics included patient's demographic information, underlying disorders for each transplant, source of donor organ or tissue, time between transplants, and immunosuppressive regimens used to prevent graft-versus-host disease (GVHD) or graft rejection. Clinical outcomes included patient survival, complications of transplantation, and donor-specific tolerance that was experienced in many cases. Twenty-one cases of SOT after BMT and 7 cases of BMT after SOT were reviewed. Solid organ transplantations included lung, liver, cardiac, and kidney for a variety of BMT-related complications including GVHD, hepatic veno-occlusive disease, chronic renal failure, end-stage pulmonary disease, and severe cardiomyopathy. Bone marrow transplants were performed following SOT for aplastic anemia and hematologic malignancies. Clinical outcomes for patients who received both BMT and SOT were variable and depended on transplant indication and degree of histocompatibility. Prior bone marrow transplantation may tolerize for a subsequent organ transplant from the same donor. Conversely, severe GVHD may follow BMT from human leukocyte antigen (HLA)-matched donors following SOT. The favorable survival in this high-risk group of patients may represent a literature review bias (that is, an undetermined number of unsuccessful cases may not have been reported). Nonetheless, dual transplantation is clearly feasible in selected cases.

CREATION OF MIXED BONE MARROW CHIMERA BY SUBLETHAL IRRADIATION AND COMBINED BLOCKADE OF CD28/B7 AND CD40/CD40L COSTIMULATORY PATHWAYS

316 The chronic use of nonspecific immunosuppression to prevent allograft rejection is invariably associated with undesirable complications which include opportunistic infection, a high incidence of malignancies and chronic rejection. However, it has been unequivocally demonstrated that establishment of mixed chimerism by prior bone marrow transplantation (BMTx) confers to the recipient a state of donor-specific tolerance allowing for subsequent acceptance of allografts from donor but not third-party strain animals. Despite the obvious benefit, no ideal preparative regimen currently exists which would result in widespread clinical utility of this strategy. We therefore, proceeded to address this issue by transplanting 2×107 unmodified BM cells harvested from the tibia and femur of CBA/J(H-2k, Mlsd) donors into BALB/c (H-2d, Mlsc) recipients. Depending on the conditioning regimen employed in the recipients prior to Tx, the animals were divided into the following groups: Group 1 (n=5) total body irradiation (TBI; 3cGy); Group II (n=4) CTLA4-Ig fusion protein (250µg/d on d0, 2, 4 & 6 post-Tx; i.p.) + anti-CD40L mAb(250µg on d0, 2, & 4 post-Tx; i.m.); Group III (n=5) TBI + CTLA4-Ig + anti-CD40L mAb. Animals in all three groups remained healthy throughout the duration of their follow-u without any clinical evidence of GVHD suggesting that this conditioning regimen was well tolerated. Using monoclonal antibodies specific for donor MHC (H-2k), no chimeric cells were detectable by three-color flow cytometry in the lymphoid organs and in the peripheral blood of animals in Groups I and II. Additionally, animals in these two groups also rejected subsequently transplanted donor and third-party skin allografts. On the contrary, 2/5 (40%) animals in Group III developed sustained macrochimerism with donor cell levels of 36% and 31% in their peripheral blood at d28 and 45 respectively, post-Tx. This was associated with acceptance in these animals of skin allografts from donor but not third-party strain animals. Furthermore, the absence of donor-reactive Vβ6+ CD4+ T cells in these recipients was suggestive that clonal deletion was perhaps the predominant mechanism underlying the induction of persistent donor-specific tolerance. The lack of anti-donor humoral responses in these animals as determined by complement-dependent microcytotoxicity assays was as yet another evidence for the lack of T cell-mediated B cell help in the generation of an effective antibody response. In conclusion, these preliminary data suggest that mixed chimerism along with robust donor-specific tolerance can be reliably achieved by sublethal TBI and transient blockade of costimulatory pathways. This relatively benign preconditioning regimen which was free of any apparent toxicity is deemed to have widespread clinical application in organ transplantation.

Postoperative infections in immunocompromised patients after oncological surgery

Immunodeficiency secondary to cancer chemotherapy (chemotherapy for less than 3 months, or intensive chemotherapy with bone marrow transplant) may be responsible for postoperative infections. To estimate the value of this hypothesis, a prospective study was done over a period of 18 months in patients who had undergone pulmonary surgery. Antibiotic prophylaxis was by pefloxacin, one tablet (400 mg) 1 h before surgery then 11 h after. Clinical examination, a chest X-ray and blood cell count were carried out every day for 10 days and on the 15th day. All the drain-tips were cultured. In a case of infection, samples were obtained and cultured. One group comprised 22 immunodeficient patients (group A), and 33 patients (group B) had received no prior chemotherapy (bone-marrow transplantation = 36.7%). There were differences between the two groups in age (A:33.5 +/- 12.3 years; B:50.8 +/- 18.4 years), and type of tumour (A: metastasis = 95.5%; B: lung cancer = 51.5%). Surgical operation was bilateral for 36.4% of the patients in group A. There was more anatomical resection (pneumonectomy and lobectomy) in group B. Lung function did not differ between the two groups (abnormalities: A = 54.6%; B = 63.6%). In group A, there were 3 pulmonary infections (13.7%), but in group B 10 infections (30.3%) with 9 pulmonary infections (4 with bacteraemia) and 1 wound infection. The bacteriological finding showed two pathogens in 7 cases and no bacteriological isolates in 2 cases. With broad-spectrum antibiotherapy all the patients were cured except 1. There was one postoperative death in group B. This patient died of respiratory distress after pneumonectomy complicated by pneumonia and septicaemia (Streptococcus pneumoniae) in the remaining lung. Surgical procedures are performed with increasing frequency on patients with immunocompromised status. Classically the risk of infection is more important for these patients. In this study prior cancer chemotherapy or bone marrow transplantation did not seem to be an aggravating factor of the risk of infection. But further methodological analysis would not allow us to distinguish between a real impact of chemotherapy and the influence of group heterogeneity.

Platelet support and the use of cytokines.

Severe thrombocytopenia and clinical bleeding remain major clinical problems in leukemic patients undergoing remission induction and those receiving high dose chemotherapy. Prophylactic platelet transfusions have made a major impact on hemorrhagic deaths over the last 20 years. The effectiveness of platelet transfusions is influenced by a number of clinical factors including the status of the spleen, prior bone marrow transplantation, the presence of disseminated intravascular coagulation and the presence of HLA antibodies. Optimal platelet transfusion therapy requires that transfusions be monitored routinely by post-transfusion counts and that a refractory group be clearly defined. The cytokine granulocyte colony stimulating factor (G-CSF) has not had a clinically significant impact on thrombocytopenia. Granulocyte-macrophage colony stimulating factor (GM-CSF) also probably has little clinical relevance, although in a randomized study, thrombocytopenia was worse in GM-CSF-treated patients. Interleukin-3 (IL-3) can increase platelet count and has the potential to protect against thrombocytopenia in patients receiving chemotherapy. This hypothesis is currently being tested in on-going clinical trials.

Dose-escalation trial of M195 labeled with iodine 131 for cytoreduction and marrow ablation in relapsed or refractory myeloid leukemias.

Mouse monoclonal antibody (mAb) M195 (anti-CD33) is reactive with most myeloid leukemia cells, monocytes, and hematopoietic progenitors, but not with other hematopoietic cells or stem cells nor with nonhematopoietic human tissues. A therapeutic dose-escalation study of M195 labeled with iodine 131 was conducted in patients with relapsed or refractory myeloid leukemias. Twenty-four patients (16 relapsed or refractory acute myeloid leukemias, five blastic myelodysplastic syndromes [MDS], two chemotherapy-related secondary leukemias, and one blastic chronic myelogenous leukemia [CML]), including seven who had failed to respond to prior bone marrow transplantation (BMT), received from 50 mCi/m2 to 210 mCi/m2 of 131I-M195 in divided doses. In 22 patients, whole-body gamma-imaging demonstrated marked uptake of antibody into all areas of bone marrow. Twenty-three patients (96%) demonstrated decreases in peripheral-blood cell counts, with decreased percentage of bone marrow blasts seen in 83% of cases. Eighty-nine percent of bone marrow biopsies examined quantitatively demonstrated substantial decreases in the number of blasts, with greater than 99% of blasts killed in some patients. The two cases that failed to demonstrate leukemic cytoreduction occurred in the first two dose levels. For 131I doses of 135 mCi/m2 or greater, pancytopenia was profound and lasted for at least 12 days. Eight patients had sufficient marrow cytoreduction to proceed to BMT. Three of these achieved marrow remission, one of 6+, and one of 9 months' duration. Two patients in blastic phase temporarily reverted to their original myelodysplastic states. Thirty-seven percent of assessable patients developed human anti-mouse antibody (HAMA). In two patients with HAMA who were re-treated, plasma 131I-M195 levels could not be maintained and no therapeutic effect resulted. Significant nonhematologic toxicity (hepatic) was seen in one patient and the maximum-tolerated dose (MTD) was not reached. These data suggest that safe leukemic cytoreduction can be achieved with 131I-M195 even in multiply relapsed or chemotherapy-refractory leukemias. This agent may be useful as part of a preparative regimen for BMT.

Lung Transplantation in a Patient with a Prior Bone Marrow Transplant

A 25-year-old woman with acute lymphoblastic leukemia underwent two bone marrow transplants. She subsequently developed severe restrictive lung disease which was successfully treated with a single lung transplant.

Toxicity from treatment of neuroblastoma with 131I-meta-iodobenzylguanidine.

Toxic effects from 131I-meta-iodobenzylguanidine (131I-MIBG) treatments of neuroblastoma in six patients were recorded. The toxicity was largely confined to the hematologic system where circulating leukocytes and platelets regularly declined after each dose of 131I-MIBG; the values reached nadirs between three and seven weeks and recovered slowly over subsequent weeks. Prior bone marrow transplantation and infiltration of bone marrow by neuroblastoma appeared to make the hematologic system more vulnerable to the radiation. Dosimetry revealed greater absorbed radiation by the whole body than by the blood and bone marrow. These observations are explained by a relatively rapid exit of 131I-MIBG from the blood to other tissues (but not to the bone marrow). Since treatment of an aggressive and lethal tumor such as neuroblastoma should be pushed to a degree of toxicity, careful dosimetry in each case will be necessary as a guide to reach the point of maximally tolerable toxicity.