Antithymocyte globulin as conditioning regimen for bone marrow transplantation

Bone marrow transplantation was performed with a conditioning regimen including antithymocyte globulin (ATG) for 8 patients with HLA-compatible unrelated donors or HLA mismatched donor. Administration of ATG was halted due to side effects in only 1 case, but the other cases were had no adverse reaction. During administration of ATG, platelet counts did not decrease rapidly, but platelet infusion was not effective in some cases. As compared between patients with conventional allogeneic BMT, autologous BMT or peripheral blood stem cell transplantation and those with ATG administration, no obvious difference was seen between the two groups in lymphocyte counts, CD3, CD4, CD8 and CD20 positive cells. No patient with ATG saffered graft failure or acute GVHD. However, cytomegalovirus infection was observed more frequently than in patients without ATG. In hematological malignancy, relapse was more frequent than in patients without ATG.     

Cytomegalovirus prophylaxis and treatment following bone marrow transplantation

OBJECTIVE: To provide an overview of the role of cytomegalovirus (CMV) in the bone marrow transplant (BMT) population and update the current methods of prevention and treatment of CMV infection and disease, with emphasis on CMV interstitial pneumonia (CMV-IP). DATA SOURCES: The current medical literature, including abstracts presented at recent national and international meetings, is reviewed. References were identified by searching the MEDLINE database from January 1988 through June 1994. The reference lists of the published studies and reviews obtained from the initial literature search were reviewed as well. STUDY SELECTION: Data regarding the epidemiology of CMV, the risk factor associated with CMV infection and disease, as well as data on the prevention and the treatment of CMV infection and disease in the BMT population are cited. Specific attention was focused on randomized, placebo-controlled studies pertaining to the prevention of CMV infection and disease in CMV-immunoglobulin G positive recipients undergoing allogeneic BMT. Information from nonrandomized, placebo-controlled studies was included in the absence of stronger data. DATA EXTRACTION: Information contributing to CMV in the BMT population was reviewed. Data supporting and disputing specific preventive and treatment modalities are presented. DATA SYNTHESIS: The incidence of CMV seropositivity in the general population is high and while BMT becomes a widely accepted treatment modality, CMV reactivation and subsequent disease, especially CMV-IP, becomes a significant prognostic factor of morbidity and mortality. Even though antiviral agents such as ganciclovir and foscarnet can inhibit the viral replication in vivo, they have not been able to treat CMV-IP effectively. It has been suggested that CMV-IP is an immunopathologic process that can cause irreversible damage, hence, the low efficacy of antiviral therapy and the associated high mortality. Immunomodulating agents such as intravenous immune globulin and cytomegalovirus hyperimmune globulin can increase the efficacy of antivirals in the treatment of CMV-IP. This further supports the postulated immunopathologic process of this disease. The lack of understanding of the pathophysiology of the disease compromised the efforts of treatment and led to the development of preventive interventions with antiviral and immunomodulatory regimens that resulted in a significantly lower incidence of infection and disease. As a result of current data, the Eastern Cooperative Oncology Group has published guidelines for the prevention and treatment of CMV infection and disease. CONCLUSIONS: The prognosis of CMV disease in the BMT recipients has improved as a result of a wide variety of modifications in the management of BMT recipients. These include an increased understanding of the risk factors associated with CMV infection, routine screening for CMV replication and excretion, and more effective prophylactic regimens. Still, more than half of the patients who develop pneumonia will die, indicating that more studies are needed to increase the understanding of the pathophysiology and refine the preventive and therapeutic regimens against CMV.     

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.     

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.     

Busulfan-based regimens and allogeneic bone marrow transplantation in patients with myelodysplastic syndromes

Preparative regimens containing busulfan (BU) followed by allogeneic bone marrow transplantation (BMT) were used in 27 consecutive patients with myelodysplastic syndromes (MDS). The median age was 33 years (range, 4 to 54). Ten were female and 17 male. Sixteen patients had primary MDS, 11 other patients had antecedent hematologic diseases or developed MDS after cytotoxic and/or radiation therapy. Six patients had leukemic transformation and received antileukemic therapy before BMT. Pre-BMT cytogenetic studies showed complex chromosomal abnormalities in 13 patients, a simple abnormality in 5 patients, and normal chromosome in 8 patients. Three BU-based preparative regimens were used: 1 patient received BU 4 mg/kg orally (PO) daily for 4 days and cyclophosphamide (CY) 50 mg/kg intravenously (IV) daily for 4 days (BUCY-4); 24 patients received BU 4 mg/kg PO daily for 4 days, cytosine arabinoside (ara-C) 2 g/m2 IV every 12 hours for 4 doses, and CY 60 mg/kg IV daily for 2 days (BAC); and 2 patients with preceding Fanconi anemia received BU 2 mg/kg PO daily for 4 days followed by total lymphoid irradiation of 5 Gy. Seventeen of 27 patients are alive with no evidence of disease. Ten patients have died: 2 from hepatic veno-occlusive disease, 3 from sepsis, 1 from a cerebral bleed, 1 from a massive gastrointestinal (GI) bleed associated with acute graft-versus-host disease, 1 from hemolytic uremic syndrome with adult respiratory distress syndrome, 1 from bronchiolitis obliterans, and the only patient who did not engraft died from acute myeloid leukemia. Regimen-related toxicities (RRT) include GI tract (diarrhea, 14; stomatitis, 11), liver (9), cardiac (1), and skin (5). Patients who received a genotypically matched marrow graft had a significantly better disease-free survival (DFS) than patients who received a nongenotypic marrow graft (P = .02). The Kaplan-Meier analysis projects an overall DFS of 56% +/- 13% and 78% +/- 10% for patients who received a genotypically matched marrow graft. With the exception of a child who did not engraft, there was no relapse of MDS or leukemia. Excellent DFS, acceptable RRT, and the ease of administration are advantages of this regimen.     

Treatment of adrenoleukodystrophy with bone marrow transplantation

Three children with adrenoleukodystrophy (ALD) underwent allogeneic bone marrow transplantation (BMT) between 1992 and 1993. The first boy had attention deficits, marked neuropsychological deficits and widespread demyelination in the frontal lobes on MRI before transplantation. Four years later he has mentally deteriorated and the demyelination on MRI has progressed. The second boy had no symptoms but had white matter lesions on MRI when diagnosed. He was regularly followed with MRI and neuropsychological investigations until BMT 18 months later. A progress of the lesions was noted on the initial MRI investigations, and 4 months before BMT a worsening of deficits in attention and kinaesthetic praxis could be observed. He rapidly deteriorated after the transplantation and died 18 months later. Both PCR and in situ hybridization confirmed the presence of donor cells in the brain. The third boy had no symptoms but white matter lesions on MRI when diagnosed. The neuropsychological tests remained normal but a slight progress was observed on MRI just before transplantation. This boy is still healthy 3.5 years after BMT. BMT as treatment for ALD has to be considered very early, even if a child without symptoms but signs of demyelination on MRI, if a suitable donor is available.     

Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma

PURPOSE: To determine the incidence, natural history, and risk factors associated with myelodysplastic syndrome (MDS) occurring as a late complication following autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma. METHODS: We retrospectively reviewed the charts of all 262 patients who underwent autologous bone marrow transplantation for non-Hodgkin's lymphoma at the Dana-Farber Cancer Institute from 1982 through 1991. Although patients received a variety of treatments before they were eligible for transplant, identical myeloablative therapy (cyclophosphamide 60 mg/kg/d for 2 days plus total-body irradiation twice daily for 3 days) was administered in each case. By collecting data on pretransplant and early posttransplant variables, we attempted to identify risk factors for the development of MDS. RESULTS: The crude overall incidence of posttransplant MDS or acute myeloid leukemia (AML) was 7.6%. The actuarial risk at 6 years was 18% +/- 9%. The median time of onset was 31 months (range, 10 to 101) after transplant or 69 months (range, 27 to 141) after initial treatment for lymphoma. Pretreatment variables predictive for the development of MDS (univariate analysis) included prolonged interval between initial treatment and the transplant procedure (P = .003), increased duration of exposure to chemotherapy (P = .019) or to alkylating agents (P = .045), and use of radiation therapy (P = .032) or pelvic radiation (P = .003) before transplant. CONCLUSION: MDS is a potential complication of autologous bone marrow transplantation for non-Hodgkin's lymphoma; bone marrow stem-cell damage sustained before the transplant may be the most important risk factor.     

Allogeneic bone marrow transplantation combined with multiple anti-HIV-1 treatment in a case of AIDS

A 25-year-old woman with AIDS was submitted to HLA-identical allogeneic BMT after cytoablation with busulphan and cyclophosphamide and combined anti-HIV-1 therapy with zidovudine, IFN-alpha 2 and anti-HIV-1-specific T cell clones. Marrow engraftment occurred after 18 days and tests for HIV-1 were negative after 30 days but the hematologic reconstitution of the patient was poor. A second BM infusion from the same donor was ineffective and treatment with GM-CSF only induced a transient increase of the blood cell count, suggesting iatrogenic damage to the BM microenvironment. The development of ARDS led to the death of the patient 10 months after transplantation. Post-mortem investigation did not reveal any active infections and PCR on autopsy tissues was negative for HIV-1.     

Microbiology of sinusitis in patients undergoing bone marrow transplantation

As a result of increasing use of bone marrow transplantation and new cytotoxic chemotherapy, more patients have become susceptible to sinus disease caused by unusual organisms. Sinusitis caused by fungi and gram-negative bacteria can be difficult to treat, may lead to severe complications, and should be managed promptly in the bone marrow transplant patient. Here we present the results of 41 cultures of the paranasal sinuses obtained from 18 bone marrow transplant patients in whom sinusitis developed. The most common agents were gram-negative bacteria (56.7%), followed by gram-positive bacteria (26.7%) and fungi (16.6%). In 13 samples the cultures were negative. Nasal cultures were performed ipsilateral to the sinus drained in 28 cases. Concordance was obtained in only 5 (17.8%) samples. The antibiogram of the isolated agents from the maxillary sinuses in this series revealed that the most efficient antibiotics were those that covered gram-negative bacteria. Treatment was usually prolonged in these patients, and different antibiotics were necessary to clear infections from the sinuses. In conclusion, treating sinusitis in bone marrow transplant patients may be challenging. Considerations about the microbiology and antibiogram susceptibilities of this specific population should be kept in mind when dealing with such cases.     

Antithrombin-III for the treatment of chemotherapy-induced organ dysfunction following bone marrow transplantation

A hypercoaguable state has been shown to follow high-dose chemotherapy for bone marrow transplantation (BMT). Deficiency of the natural anticoagulants, antithrombin III (AT-III), protein C and protein S correlate with organ dysfunction following BMT. We treated 10 patients with severe post-BMT organ dysfunction with AT-III concentrate. Indications for treatment included AT-III anticoagulant level less than 88% and life-threatening single or multiorgan dysfunction. All patients were loaded with 50 units/kg AT-III every 8 h for three doses followed by 50 units/kg/day each day for 3-12 days. Clinical improvement was seen within 1-5 days of start of therapy in all patients. Patients with veno-occlusive disease (VOD) showed a decrease in platelet consumption in nine of nine patients, resolution of hepatic tenderness in six of eight patients, and reduction of severe ascites and weight gain in four of five patients. The probability of death due to VOD and life-threatening organ dysfunction was significantly less in the AT-III-treated group when compared to a historical control group receiving the same preparative regimen (P = 0.047 and P = 0.034, respectively). Significant improvements in organ dysfunction following AT-III treatment in this small study supports a causal relationship between AT-III deficiency and post-BMT chemotherapy-induced organ dysfunction.     

Minor histocompatibility antigens as targets for T-cell therapy after bone marrow transplantation

BACKGROUND: Topical antimicrobials have been considered for treatment of secondarily infected wounds because of the potential for reduced risk of adverse effects and greater patient convenience. We compared mupirocin cream with oral cephalexin in the treatment of wounds such as small lacerations, abrasions, or sutured wounds. METHODS: In 2 identical randomized double-blind studies, 706 patients with secondarily infected wounds (small lacerations, abrasions, or sutured wounds) received either mupirocin cream topically 3 times daily or cephalexin orally 4 times daily for 10 days. RESULTS: Clinical success at follow-up was equivalent in the two groups: 95.1% and 95.3% in the mupirocin cream and the cephalexin groups, respectively (95% confidence interval [CI], -4.0% to 3.6%; P = .89). The intention-to-treat success rate was 83% in both groups. Bacteriologic success at follow-up was also comparable: 96.9% in the mupirocin cream and 98.9% in the cephalexin groups (95% CI, -6.0% to 2.0%; P = .22). The occurrence of adverse experiences related to study treatment was similar for the 2 groups, with fewer patients in the mupirocin cream group reporting diarrhea (1.1% vs 2.3% for cephalexin). CONCLUSIONS: Mupirocin cream applied topically 3 times daily is as effective as oral cephalexin given 4 times daily for the treatment of secondarily infected wounds and was well tolerated.     

Pharmacokinetics of cyclophosphamide and its metabolites in bone marrow transplantation patients

Classical swine fever virus infection of pigs causes a severe leukopenia and immunosuppression. In the present study, the kinetics of virus infection, and identification of target cells for the virus in peripheral blood were analysed. Virus infection was often not detectable before 5-7 days p.i. A minority of animals yielded detectable infected cells at 3 days p.i., but < 5% PBMC. It was not until 10 days p.i. that this figure increased-to 35-70% PBMC depending on the animal. Detailed analysis of Ficoll-Hypaque-purified PBMC identified the major population to be SWC3+SWC8+CD14+MHCII- granulocytic cells. Microscopic observations determined that these low density granulocytic cells in the PBMC from CSFV infected animals were indeed immature cells. Both the low density granulocytic cells and monocytes were major targets for CSFV infection in the peripheral blood. This is the first demonstration that low density granulocytic cells dominate the blood leukocyte population during CSF, and that such cells are targets for virus infection. The present work also demonstrates that the leukocyte population changes, such as B lymphocyte depletion and the relative dominance of myeloid cells in the blood during CSF, occur before virus infection of the affected cells. Thus, the pathological mechanism therein is not a direct consequence of virus infection.     

Phimosis as a manifestation of chronic graft-versus-host disease after allogeneic bone marrow transplantation

Chronic GVHD is one of the major complications of BMT, involving a variety of organs, but rarely involving the genitourinary system. We report a patient who simultaneously developed extensive chronic GVHD and phimosis after BMT. From the clinical course and pathological findings, chronic GVHD was considered to be responsible for the phimosis. Despite intensive immunosuppressive therapy, the phimosis persisted. Phimosis is a rare complication after BMT, which may often remain neglected. Possibility of this complication should be considered in patients with chronic GVHD.     

Unrelated donor bone marrow transplantation for children with acute leukemia

PURPOSE: To test the use of unrelated donor bone marrow transplantation (URD BMT) to cure children with high-risk acute leukemias. PATIENTS AND METHODS: Between June 1985 and December 1994, 50 children with acute leukemia (15 acute myelogenous leukemia [AML], 35 acute lymphoblastic leukemia [ALL]; 22 greater than second complete remission [CR]) received BMT from a URD at the University of Minnesota. Ages ranged from 0.9 to 17.5 years (median, 8.8). Median follow-up is 2.1 years (range, 1 to 7.3). Thirty patients (60%) received bone marrow fully matched at HLA-A,B and DRB1; 20 (40%) received bone marrow with a major or minor mismatch at a single HLA-A or B locus. RESULTS: The median time to neutrophil engraftment was day 24 (range, 14 to 42 days) in those receiving matched and day 25 (range, 15 to 32 days) in those receiving mismatched marrow (P = .35). The incidence of grades III to IV graft-versus-host disease (GVHD) was 23% (95% confidence interval [CI], 7% to 39%) in matched and 32% (95% CI, 8% to 52%) in HLA-mismatched patients (P = .57). The incidence of chronic GVHD was 50% (95% CI, 28% to 72%) in matched and 57% (95% CI, 23% to 91%) in mismatched patients (P = .80). Disease-free survival for patients with ALL is 37% (95% CI, 21% to 53%) at 1 year and 30% (95% CI, 15% to 46%) at 2 years; for patients with AML, 53% (95% CI, 28% to 78%) at 1 year and 33% (95% CI, 6% to 60%) at 2 years. CONCLUSION: URD BMT is an effective treatment for children with poor-prognosis acute leukemia and should be considered for all high-risk patients. Early referral of patients is strongly recommended.     

Allogeneic bone marrow transplantation for hypereosinophilic syndrome with advanced myelofibrosis

A 33-year-old man with an atypical course of hypereosinophilic syndrome including malignant hypercalcemia, osteolytic lesions and evolution into severe myelofibrosis was treated by allogeneic bone marrow transplantation after conditioning with cytoxan and total body irradiation. As the transplant was sex-mismatched, chimerism was studied by means of cytogenetic analysis and Y chromosomal DNA amplification by PCR assay. Long-term complete remission has been assessed by normalization of blood cell counts, magnetic resonance imaging and karyotypic analysis. A relapse was observed 40 months after transplantation. The patient remains alive 44 months post-BMT. This case report is compared with those reported in the literature.     

Bone mineral density in patients undergoing bone marrow transplantation for myeloid malignancies

Hitherto the biology of proteolysis in prokaryotes, particularly in archaea, is only poorly understood. We have used the tri-peptide vinyl sulfone inhibitor carboxybenzyl-leucyl-leucyl-leucine vinyl sulfone (Z-L3VS) to study the in vivo function of proteasomes in Thermoplasma acidophilum. Z-L3VS is a potent inhibitor of the Thermoplasma proteasome and is capable of modifying 75 to 80% of the proteasomal beta-subunits in cell cultures. Inhibition of proteasomes has only marginal effects under normal growth conditions. Under heat shock conditions, however, the effects of proteasome inhibition are much more severe, to the extent of complete cell growth arrest. These data suggest that other proteolytic systems may exist that can compensate for the loss of proteasome function in T. acidophilum.     

Alpha-interferon treatment of chronic hepatitis C after bone marrow transplantation for homozygous beta-thalassemia

The standard modality of the treatment for the patients with T4 esophageal cancer, whose prognosis still remains quite poor, is not established yet. Salvage surgery for the T4 esophageal cancer following downstaging by neoadjuvant chemo-radiotherapy has become to be available. During the period from 1992 to 96, 30 patients with the suspected T4 esophageal cancer underwent chemoradiotherapy, which consisted of two courses of CDDP/5-FU with-sequential or concurrent 50-60Gy radiotherapy. Among them eleven patients became to be resectable by means of thoracotomy and laparotomy and pathological CRs were obtained in either primary lesions or lymph nodes. The longest survival term following surgery is 36 months. Three patients died of cancer recurrence including the organ metastasis and one died from pyothorax without cancer due to severe immunosuppression attributable to chemoradiation. Our results warrants further studies of neoadjuvant chemoradiotherapy for the patients with T4 esophageal cancer.