Donor T-lymphocyte infusion for unrelated allogeneic bone marrow transplantation with CD3+ T-cell-depleted graft.

In T-cell-depleted allogeneic bone marrow transplantation (TCD-BMT) using unrelated donors, the role of donor lymphocyte infusion (DLI) for survival and disease control has not been defined. In a study of 116 patients (92 matched, 24 mismatched) who received CD3+ T-cell-depleted marrow graft, sequential infusions of escalated doses of donor T lymphocytes up to 1 x 10(6) CD3+ cells/kg were prospectively investigated. T cells were administered while patients were on cyclosporine, provided >or=grade II acute graft-versus-host-disease (GVHD) had not occurred. Acute GVHD of >or=grade II occurred in 27 of 110 (25%) patients before DLI and in 39 of 79 (49%) patients after DLI. In total, 12 of 27 (44%) patients without DLI and 44 of 72 (61%) patients who received DLI developed chronic GVHD. A total of 19 patients died of GVHD, with 17 of acute and two of chronic GVHD. Overall survival (OS) and event-free survival (EFS) at 5 years were 27 and 21%, respectively. The 2-year incidence of relapse was 14%. In multivariate analysis, only chronic GVHD was a good prognostic factor for both OS: hazard ratio (HR) 1.4, P=0.04, and EFS: HR 1.6, P=0.01. Both acute and chronic GVHD were favorable prognostic factors for relapse probability: HR 1.9 for both, P=0.02, 0.01, respectively. The 1-year cumulative incidence of transplant-related mortality (TRM), excluding cases of GVHD, was 42%. The two most common causes of 1-year non-GVHD death were viral infection (9%) and idiopathic pneumonia syndrome (12%). Although the incidence of relapse was low, the study suggests that the current scheme of DLI in unrelated TCD-BMT would not improve survival unless TRM decreases significantly.

A dose escalation study for salvage chemotherapy in patients with refractory lymphoma prior to high-dose myeloablative therapy with stem cell transplantation.

Chemosensitive response prior to transplantation has been shown to be most significant for survival post transplant. To estimate toxicity of a dose-intensive regimen that was to improve chemosensitive response rate, 15 patients with primary refractory lymphoma were enrolled in dose escalation of pre-transplant salvage chemotherapy. The first cycle had a fixed dose of ifosfamide 6 g/m2 and mitoxantrone 12 mg/m2, with arabinosyl cytosine (Ara-C) 2 g/m2, and methylprednisolone 2.0 g. Each cycle of the second and third had cisplatin 90 mg/m2, Ara-C 6 g/m2, methylprednisolone 2.0 g, and escalated doses of ifosfamide from 7.5 g/m2 to 15 g/m2 and mitoxantrone from 16 to 28 mg/m2. Blood stem cells were collected before the second cycle and > or = 3 x 10(6) CD34 cells/kg were infused 2 days after the second and third cycles, respectively. The maximum tolerated doses of ifosfamide and mitoxantrone were 11.25 g/m2 and 16 mg/m2, respectively. Acute renal failure and bacterial infection occurred as non-hematologic dose limiting toxicities. Eleven patients completed therapy. Five patients achieved complete remission and five had partial remission. Nine patients received autologous and four received allogeneic transplants. Currently, six are alive without evidence of disease, with a 3-year survival of 40%. Although preliminary, the regimen suggests acceptable toxicity and significant activity that warrants further study.

Prophylactic T cell infusion after T cell-depleted bone marrow transplantation in patients with refractory lymphoma.

Fifty-two patients with refractory lymphoma were prospectively treated with prophylactic T lymphocyte infusion after T cell-depleted allogeneic bone marrow transplantation, to induce graft-versus-lymphoma effect. Thirty-three patients had related donors; 19 had unrelated donors. After transplantation with marrow that had 0.8 +/- 0.4 x 10(5)CD3(+) cells/kg, T cells up to 1.75 x 10(6) CD3(+) cells/kg were given over 3 months provided > or = grade II acute graft-versus-host disease (GVHD) was not seen. The cumulative incidence of grades II-IV acute GVHD was 69%. Twenty of 32 evaluable patients (63%) developed chronic GVHD. Ten patients (19%) died of GVHD. The Kaplan-Meier 5-year overall survival of all patients was 34%. On multivariate analyses, chronic GVHD was significant for relapse (hazard ratio of 1.7, P < 0.05), and for overall survival (hazard ratio 1.4, P < 0.001). Chemosensitivity was significant for relapse only on univariate analysis. Patients who developed chronic GVHD had 4 years median survival, compared with 9 months in patients without chronic GVHD, P < 0.001. The study shows that patients with chronic GVHD have superior survivals, most probably related to a graft-versus-lymphoma effect, which could be modulated by prophylactic T cell infusion.

A novel four-drug ablative regimen with hemopoietic stem cell rescue for patients with breast cancer: a phase II study.

High-dose chemotherapy and autologous hemopoietic stem cell transplantation (HSCT) may provide durable progression-free survival in some patients with stage IV breast cancer (S4Brca). We have studied a new four-drug intensive preparative regimen with HSCT in a group of 158 women with S4Brca to define the risk and potential benefit of this regimen in this patient population. From May 1988 through May 1997, 158 women with S4Brca at a single center were treated with cisplatin, etoposide, thiotepa, and cyclophosphamide (PETCy) plus autologous HSCT Eligible patients were also treated with posttransplant involved-field radiation therapy. Patients with estrogen-receptor positive tumors not previously treated with tamoxifen also received this therapy for 5 years following transplantation. All patients experienced significant toxicity requiring blood-product support and parenteral nutrition. Eighteen patients (11%) died of regimen-related toxic events. With a median follow-up of 540 days for surviving patients, a retrospective Kaplan-Meier analysis projects an overall survival of 38+/-8.5% (95% CI) at 890 days with a maximum follow-up of 8.8 years. For 52 patients in sensitive relapse, the median event-free survival time is 767 days, with 46.2+/-15.3% (95% CI) predicted to be alive at 884 days with a maximal follow-up of almost 9 years. Nearly one-half of patients in this study with S4Brca in sensitive relapse have experienced durable remissions following PETCy ablation and HSCT. Although toxicity is significant, the PETCy regimen produces a favorable balance between efficacy (event-free survival) and treatment failure (relapse + regimen-related toxic death) compared with published results. These data suggest that within the high-dose range for preparative therapy, a steep dose-response may exist for breast cancer. Trials comparing the dose intensity of preparative regimens are warranted.

Prophylactic reinfusion of T cells for T cell-depleted allogeneic bone marrow transplantation.

To increase the graft-vs.-leukemia (GVL) effect while maintaining a low mortality from graft-vs.-host disease (GVHD), we conducted a prospective study of T cell titration for 144 patients (90 related, 54 unrelated) between June 1994 and June 1997. Following infusion of a T cell-depleted marrow graft, predetermined doses of T cells, based on the risk factors for GVHD, were administered up to 3 times if greater than a grade II acute GVHD was not seen. Graft failure occurred in three unrelated recipients (2%). Cumulative grades II-IV acute GVHD were seen in 58 +/- 9% of all recipients; 52 +/- 11% related and 75 +/- 13% unrelated. The incidence of grades II-IV acute GVHD following the third add-back (AB) of T cells 78 median days after marrow infusion was lower than that of the earlier ABs: first AB, 36 +/- 8%; second AB, 32 +/- 11%; third AB, 15 +/- 12% (p < 0.05). Chronic GVHD occurred in 56 +/- 12% of related and 79 +/- 16% of unrelated patients. Six died of acute GVHD and two died of chronic GVHD, with an overall GVHD mortality of 6 +/- 4%. In multivariate analyses, unrelated recipients and patients at low risk for GVHD who received a larger number of T cells were identified as patient groups with significant risk for acute and chronic GVHD (both p < 0.05). Unrelated transplant is also shown to be significant for GVHD-related death (p < 0.01). Relapse-free survival of patients with leukemia was shown to be most dependent on chronic GVHD and grades II-IV acute GVHD (both p < 0.01). Anti-leukemic activity independent of GVHD was not observed.

Fatal cyclophosphamide cardiomyopathy: its clinical course and treatment.

Acute decompensating cardiomyopathy induced by cyclophosphamide is usually irreversible. To investigate the clinical course and the outcome of therapy, 13 patients (1.7%) with grade III acute cardiomyopathy and hypotension who were treated with ablative transplant regimens between January 1980 and September 1995 were analyzed. Eight of nine patients died of acute fatal restrictive cardiomyopathy with unresponsive hypotension (ARCH), whereas three of four patients who survived the initial episode died of subacute congestive heart failure (SCHF). Acute fatal restrictive cardiomyopathy was characterized with extreme sensitivity to volume overload, myocardial edema and a rapidly fatal course. It was associated with progressive, unresponsive hypotension, reduced left ventricular stroke work index (LVSWI: 29.29 +/- 9.74 g-m/beat/m2) and markedly reduced systemic and pulmonary vascular resistance indices (SVRI: 429.72 +/- 168.84, PVRI: 58.63 +/- 45.08 dyne.sec/cm5.m2). Subacute CHF was identified by myocardial edema, dilated chambers and biventricular pump failure represented by decreases in fractional shortening (FS: 19.5 +/- 4.9%). Of 10 patients who received conventional therapy, nine died and one sustained chronic CHF. One of three patients with ARCH on antioxidant therapy of ascorbic acid and theophylline survived the episode. The data suggests peripheral vascular collapse may also be responsible for fatal ARCH.

Engraftment syndrome in autologous bone marrow and peripheral stem cell transplantation.

Reproducible and characteristic clinical findings of fever, skin rash, capillary leak and pulmonary infiltrates have been observed during engraftment in patients with autologous bone marrow (BM) and/or peripheral stem cell transplantation (PSCT). Two hundred and forty-eight patients were analyzed retrospectively to establish the clinical entity, to characterize the clinical course, and to find clinical variables affecting the incidence of the syndrome. One hundred and eight cases (83.7 +/- 9.4%) of fevers occurring in the periengraftment period (PEN) not associated with positive cultures, biopsies, or clinical signs of infection did not reveal delayed documentation of concealed infection in 2 weeks after engraftment. Capillary leak, pulmonary infiltrates, hypoxia, non-infectious neutropenic fever of engraftment and skin rash were found to be interrelated (all P < 0.01 except for hypoxia vs rash; P < 0.05). By stepwise discriminant analysis, one hundred and thirty-two patients (58.9 +/- 6.4%) were shown to have both skin rash and non-infectious neutropenic fever, thereby constituting the syndrome. Sepsis in the first week of neutropenia decreased the incidence of the syndrome (58.5 +/- 7.7% with sepsis, 89.6 +/- 4.7% without sepsis, P < 0.01). Post-transplant granulocyte colony-stimulating factor increased the incidence of the syndrome (79 +/- 4.6% with G-CSF vs 48.3 +/- 8.2% without G-CSF, P < 0.01). In bone marrow transplantation (BMT), the median time of onset of the syndrome was 7 days (range 4-22 days) post-transplant with a median duration of 11 days (range 4-28 days) of the initial phase. Thirty-nine patients (17.4 +/- 5.0%) revealed a recurrent pattern during the 5th week post-transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Candida tropicalis vertebral osteomyelitis: a late sequela of fungemia.

Two adult patients who had undergone bone marrow transplantation had transient fungemia due to Candida tropicalis during the posttransplantation neutropenic period and later (at 5 and 14 months post-transplantation) developed vertebral osteomyelitis due to the same organism. The courses of all adult patients who underwent bone marrow transplantation at our center during this time were reviewed for determining the frequency of this problem. Molecular typing techniques were used to establish the relationship between the organisms isolated during the initial fungemia and those causing the subsequent osteomyelitis. Only two of 532 adults who received transplants at our center from 1980 to 1993 developed candidal osteomyelitis. Moreover, they are part of a subset of 13 patients (2.4% of the total) whose cultures were positive for C. tropicalis; five of the 13 had fungemia. The study of fungal isolates from prior sites of colonization and from blood sampled during the original fungemia and of subsequently recovered vertebral bone isolates by means of DNA restriction fragment analysis (with use of standard agarose gel electrophoresis or pulsed-field gel electrophoresis) showed that the colonizing, bloodstream, and bone isolates were identical in each case. Transient C. tropicalis fungemia in severely immunocompromised patients may cause important late infectious complications, including osteomyelitis. Although these initial septic events may appear to resolve easily, the outcome in the two cases in this report suggests that special treatment considerations, such as immediate removal of the central venous catheter and intensive treatment with amphotericin B, may be required in selected cases for prevention of late sequelae.

Ultrafast computed tomography of the chest.

Improvements in scan speed and resolution are changing the role of the pulmonary imager. An understanding of airway mechanics and blood flow physiology is required to take full advantage of the new technology. Assessment of regional airflow and blood flow provides information that is currently unavailable from clinical tools.

Cytomegalovirus infection presenting as polyarticular arthritis following autologous BMT.

A 39-year-old woman developed polyarticular arthritis secondary to cytomegalovirus (CMV) infection following an autologous BMT. Active CMV infection was documented by identification of CMV in cultures from synovial fluid and urine. Treatment with a combination of ganciclovir and intravenous immunoglobulin resulted in resolution of symptoms. CMV infection should be considered as a possible etiology of arthritis following transplantation.

Two-year adjustment of bone marrow transplant survivors.

Very little systematic analysis exists on the psychological and emotional factors involved in bone marrow transplantation, either during or after treatment. However, recent published findings, contrary to earlier anecdotal and case study evidence, indicate that bone marrow transplant survivors appear to be functioning adequately on a variety of 'quality of life' variables. The purpose of the present study was to compare bone marrow transplant survivors to a matched sample of patients undergoing maintenance chemotherapy in four areas of function; physical health, including symptoms and physician visits; personal functioning, emphasizing ability to care for self; psychological functioning; and role functioning, including employment and sexual difficulties. Our data reveal that the bone marrow transplant patients were experiencing greater difficulties than the maintenance chemotherapy patients in several areas. For example, the bone marrow transplant patients had experienced greater disruption of vocational functioning and reported more sexual difficulties. However, in spite of more objective difficulties, bone marrow transplant patients, compared to maintenance chemotherapy patients, viewed themselves as equally healthy and reported similarly low levels of psychological distress. The findings are discussed in the context of necessary future research on bone marrow transplant survivors.

High-resolution ultrafast chest CT in the clinical management of febrile bone marrow transplant patients with normal or nonspecific chest roentgenograms.

Plain chest roentgenograms may be normal or show nonspecific abnormalities during the frequent febrile episodes that occur in patients after bone marrow transplantation. In this group, ultrafast 10-mm and 3-mm high-resolution CT scans were prospectively performed in 33 patients to determine if useful information was provided that either changed the patient's clinical management or added confidence to the clinical diagnosis. The 36 symptomatic episodes that occurred in 33 patients included fever in 20 episodes and fever combined with cough, dyspnea, chest pain, or rales in 16. Fourteen chest roentgenograms were interpreted as normal, and 22 were interpreted as demonstrating nonspecific changes; however, none of the roentgenograms was considered helpful in that they did not provide sufficient information for further management. In 2 of 14 episodes in patients with normal chest roentgenograms and in 9 of 22 episodes in patients with nonspecific chest roentgenograms, CT scanning resulted in a change in clinical management that included performing bronchoscopy, increasing or changing antibiotic coverage, starting white blood cell transfusions, requesting surgical biopsy, or a combination of these. In 1 of 14 episodes in patients with normal chest roentgenograms and in 8 of 22 episodes in patients with nonspecific roentgenograms, CT added confidence to the diagnosis. In the remaining 16 episodes, CT scans provided no additional information. We conclude that in many instances, noncontrast ultrafast chest CT scans can provide information that may either change a patient's clinical management or more clearly establish the extent of pulmonary disease.

Fungal pulmonary infections after bone marrow transplantation: evaluation with radiography and CT.

The authors reviewed 55 pairs of chest radiographs and computed tomographic (CT) studies obtained in 33 febrile bone marrow transplant (BMT) recipients. The images were read separately, without knowledge of the clinical diagnosis. Twenty-one episodes of fungal infection were documented. One chest radiograph showed a pneumonia-like opacity, and 17 showed nodular opacities, five with cavitation. In 20 of 21 episodes, CT showed nodules with cavitation (n = 7), halo (n = 4), hazy margin (n = 5), air bronchogram (n = 2), cluster of fluffy nodules (n = 1), or sharp margin (n = 1). In none of the nine bacteremic episodes, however, were there opacities on chest radiographs or CT studies. CT studies demonstrating complicated nodules in febrile BMT patients strongly suggest a fungal infection, whereas negative CT studies suggest bacteremia or non-filamentous fungal infection of nonpulmonary origin. CT appears to add useful information to radiographic analysis during the assessment of febrile episodes in BMT patients, especially when invasive diagnostic procedures pose a high risk.

Nosocomial pneumonia in adult patients undergoing bone marrow transplantation: a 9-year study.

Two hundred seventy-five consecutive patients treated with bone marrow transplantation (BMT) during a 9-year interval were analyzed for the incidence and etiology of nosocomial pneumonia. Cases included adults who acquired pneumonia during the first hospitalization period within 100 days of the transplant. Fifty-five (20%) of the 275 patients developed nosocomial pneumonia, and the crude mortality during the hospitalization period was 74.5%. An etiology was established in 67.3% (37 of 55) of episodes. Thirty-six percent (20 of 55) of the cases were caused by Aspergillus species, either as the sole agent (15 patients) or in association with others. The crude mortality for patients with Aspergillus pneumonia was 95%. Elimination of 90% of Aspergillus cases in our unit would have the effect of reducing the overall attack rate of nosocomial pneumonia to 13.4% and the associated crude mortality to 43.4%.

BVAC ablative chemotherapy followed by autologous bone marrow transplantation for patients with advanced lymphoma.

Forty-one consecutive patients with lymphoma resistant to conventional combination chemotherapy have been entered into a study in which chemo-ablative therapy and autologous marrow rescue were used with curative intent. The actuarial proportion of 20 patients with Hodgkin's lymphoma remaining alive and free of recurrent disease is 49%, while that for 21 patients with non-Hodgkin's lymphoma is 41%. Our clinical approach to these patients involved a strategy whereby lymphomatous nodes greater than 2 cm in diameter that persisted despite salvage chemotherapy were given boost radiation therapy immediately before chemo-ablation. However, patients with this variable had a significantly lower survival due to septic complications rather than recurrent disease. We conclude that the treatment strategy used in this study with some modification may improve further on the already high probability of long-term disease-free survival experienced by this group of patients.

Identification and characterization of a new surface membrane antigen found predominantly on malignant B lymphocytes.

A monoclonal antibody, 1D10, was derived that identifies a new antigenic epitope on the surface of malignant B lymphocytes. Normal resting and stimulated lymphocytes do not express the antigen. The majority of individuals with acute Epstein-Barr virus infection express the antigen on their lymphocytes, and in these patients, the T lymphocyte may also be antigen positive. The antigen was found on B-lymphoid neoplasia from the early pre-B cell stage through terminally differentiated plasma cells, a characteristic not reported for other B cell-associated antigens. Studies on homozygous typing cells and cells from individuals with known HLA phenotypes indicate that the antigen does not segregate in a pattern characteristic for major histocompatibility antigens. The molecule is a heterodimeric polypeptide with the molecular weight and isoelectric points of the alpha and beta chains being 32,000 d/4 and 28,000 d/6, respectively. Evidence is presented that the 1D10 molecule is not HLA-DR, -DP, or -DQ. By extrapolation, we suggest that this novel molecule may represent HLA D-region gene expression of a gene(s) not normally expressed. Potential candidates are D-region pseudogenes. We conclude that the antigenic epitope identified by the 1D10 monoclonal antibody is unique among previously described B-lymphocyte antigens. Further studies of the factors controlling the expression of this molecule, as well as studies designed to look at the possible cellular function, may provide insights for understanding crucial events in the malignant transformation of lymphocytes.

Disseminated Fusarium infections in patients following bone marrow transplantation.

Intensive immunosuppressive therapy and broad spectrum antibiotics predispose cancer patients to opportunistic fungal infections. Fusarium has rarely been reported as a pathogen in immunocompromised patients, but is almost uniformly fatal. Only six cases of disseminated Fusarium infection have been described in patients following bone marrow transplantation (BMT). We report here two additional cases. Fusarium infection initially presented with pyomyositis in one patient and with embolic skin lesions in another following T cell-depleted BMT. Both patients died with active Fusarium infection despite an extensive course of amphotericin B, rifampicin and granulocyte transfusions. From this experience and from a review of the literature, Fusarium infections appear to be increasing in prevalence as significant pathogens in immunocompromised hosts and are resistant to many conventional forms of therapy.

Adult acute lymphoblastic leukemia: results of the Iowa HOP-L protocol.

Fifty-nine consecutive previously untreated adult patients with acute lymphoblastic leukemia (ALL) were entered onto a prospective single-arm trial of doxorubicin, vincristine, prednisone, and asparaginase (HOP-L) induction therapy followed by CNS prophylaxis and 3 years of maintenance therapy. Consolidation therapy was not administered. The study population included a large number of older (greater than 50 years) patients. Seventy-five percent of patients achieved complete remission. With a median follow-up of 6 years, the median duration of complete remission is greater than 4 years, with 53% of patients expected to remain in remission at both 3 and 5 years. Overall, median survival duration is 27.9 months, with 45% and 35% of all patients expected to survive 3 and 5 years, respectively. Multivariate analysis identified patients with T-cell disease and mediastinal masses (P less than .001) and those with low values of lactic dehydrogenase (LDH) (P = .057) as being at greatest risk of relapse. Therapy was well tolerated by patients under age 35, but older patients suffered appreciable mortality. We conclude that this treatment program is effective therapy for adult ALL, yielding a large proportion of durable remissions despite the exclusion of consolidation therapy.

Allogeneic marrow grafting with partially mismatched, unrelated marrow donors.

Forty patients with advanced hematologic malignancies or severe aplastic anemia received marrow grafts from partially mismatched, unrelated marrow donors. All patients were administered conventional prophylaxis for acute graft-v-host disease (GVHD) consisting of methotrexate and low-dose glucocorticoids. All but two patients who survived at least 30 days showed durable engraftment. Six patients survive 17+ to 36+ months following transplantation. Severe acute GVHD was seen in 47% of the patients; however, no direct correlation between GVHD and the degree of mismatching could be determined. Fatal infections were seen in 29 patients, and in the majority the infection occurred after the granulocyte count had risen to greater than 500 cells/microL. We conclude that the problems encountered in this pilot study can potentially be solved, and that further studies with this type of marrow grafting are warranted.

Successful treatment of hepatic venocclusive disease in a bone marrow transplant patient with side-to-side portacaval shunt.

Hepatic venocclusive disease developed in a 14-yr-old white girl after allogenic bone marrow transplantation from an HLA-identical sibling donor. Clinical diagnosis of venocclusive disease was based on the development of ascites, hepatomegaly, and jaundice 3 wk after transplantation. Current treatment of hepatic venocclusive disease is ineffective. The pathophysiology of the hepatic lesion suggests that construction of a side-to-side portacaval shunt should be beneficial in relieving the ascites and preventing further hepatic damage. Because the ascites was refractory to medical therapy and she was clinically deteriorating, a side-to-side portacaval shunt was performed. Histologic examination of a liver biopsy specimen obtained at surgery documented the presence of venocclusive disease. Postoperatively, the patient diuresed and returned to her baseline weight. One year after surgery the patient was doing well, her weight was stable, and she was being maintained on salt restriction alone. While the resolution of ascites and improvement of hepatic function in our patient after side-to-side portacaval shunt does not guarantee that such an approach will be uniformly successful, it should serve to encourage others to consider such therapy for this frequently devastating complication of chemoradiation therapy.