[Malignant lymphoma. Experiences with autologous bone marrow transplantation in 50 patients].
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Adolescent↗
Biomedical subjects
B Simonsson
Publications and source records attributed to B Simonsson.
Autografting in chronic myelogenous leukemia followed by immunotherapy.
Patients with chronic myelogenous leukemia (CML) can be cured with allogeneic bone marrow transplantation. Over the past decade, it has become clear that immunological mechanisms, in the form of graft-versus-leukemia, constitute an integral part of this therapy. Because of limitations imposed by a lack of suitable donors, age, and toxicity, only a minority of patients can be offered allogeneic bone marrow transplantation (BMT). Recently, attempts have been made to employ autologous bone marrow transplantation (ABMT) for the therapy of CML using a variety of pre- and post-transplantation manipulations. This report describes the rationale for an ongoing clinical trial using the immunomodulator roquinimex (Linomide), following autologous bone marrow transplantation, in an attempt to stimulate the immunological responses thought to be critical for successful therapy in CML.
Adjuvants, Immunologic↗
Intensive treatment in order to minimize the Ph-positive clone in chronic myelogenic leukemia.
Several studies indicate that interferon (IFN) treatment, intensive chemotherapy and autologous bone marrow transplantation (ABMT) effectively reduce the Ph-positive clone in Chronic Myelogenic Leukemia (CML). In the present study on patients < or = 55 years, we have combined these three treatment modalities. The aim of the study was to eliminate or minimize the Ph-positive clone to see whether a status of minimal residual or Ph-negative disease could be maintained for a longer period of time. After diagnosis, patients received interferon (IFN-a-2b) and hydroxyurea (HU) to keep the white blood cell (WBC) and platelet count below 2-4 and 100-150 x 10(9)/l, respectively. After six months of treatment, Ph-analysis was performed. Patients with Ph-positive cells in bone marrow then received 1-3 courses of intensive chemotherapy. In patients Ph-negative after two courses, bone marrow was harvested and used for ABMT. After a third course, patients with up to 50% Ph-positive metaphases were accepted for ABMT. As of January 1, 1993, 97 patients were registered in the study. Six months of IFN+HU reduced the percentage of Ph-positive metaphases in 57% of the patients (7% became Ph-negative). The corresponding figures after two intensive cytotherapies were 70% (40% Ph-negative). Eighteen patients were autotransplanted. Seven have relapsed with Ph-positivity 3-22 months after ABMT, while nine are Ph-negative at 1-32+ months after ABMT (two not yet analyzed). Seventeen patients are alive and well, while one died one month after ABMT due to interstitial pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Treatment of minimal residual disease in myeloid leukemia--the immunotherapeutic options with emphasis on Linomide.
It is now known that syngeneic transplantation, T lymphocyte depletion and absence of graft-versus-host disease all increase the risk of relapse following allogeneic transplantation for the myeloid leukemias, both acute and chronic. Leukemia-specific immune responses appear to play a major role in the therapy of the myeloid leukemias. In recent years attempts have been made to better characterize and effectively utilize these antileukemic immune responses, concentrating on clinical states of minimal residual disease. This review will discuss the role of such immunotherapy following autologous bone marrow transplantation for myeloid leukemias, and will focus on recent experience and ongoing clinical trials using the novel immunomodulator Linomide.
Adjuvants, Immunologic↗
Successful pregnancy in a 28-year-old patient autografted for acute lymphoblastic leukemia following myeloablative treatment including total body irradiation.
We report a successful pregnancy in a woman who at the age of 28 years received total body irradiation (TBI; 7.5 Gy) and high-dose chemotherapy prior to autografting of purged bone marrow for acute lymphoblastic leukemia. Four years after transplantation she delivered a healthy girl. Only five previous cases of successful pregnancies are described in the literature after conditioning regimens including TBI. This case shows that restored ovarian function is possible after TBI in spite of prolonged exposure to chemotherapeutic agents during induction and consolidation therapy and relatively high age at the time of transplantation.
Adult↗
Clinical impact of breakpoint position within M-bcr in chronic myeloid leukemia.
We have analyzed the M-bcr breakpoint position in 133 Philadelphia-positive chronic myeloid leukemia patients and correlated the findings with clinical, hematologic, and cytogenetic data. We also investigated the splicing pattern of the BCR-ABL mRNA in 30 patients, using reverse transcriptase PCR. No statistically significant differences were found between breakpoint position within M-bcr and clinical parameters at diagnosis, the karyotypic evolution pattern, or the leukemic phenotype during blast crisis. Furthermore, the breakpoint position within M-bcr did not correlate with the duration of chronic phase or survival time. When the splicing pattern of the BCR-ABL mRNA was compared with the results of the genomic breakpoint mapping, it was found that approximately 60% (8/14) of the patients with a 5' break expressed b2a2 fusion mRNA, whereas all patients (10/10) with a 3' break expressed b3a2 BCR-ABL mRNA.
Adolescent↗
Haemolytic uraemic syndrome and renal dysfunction following BEAC (BCNU, etoposide, ara-C, cyclophosphamide) +/- TBI and autologous BMT for malignant lymphomas.
Twenty-four patients autografted for malignant lymphoma have been followed. All were conditioned with BEAC (BCNU, etoposide, ara-C, cyclophosphamide), in 10 patients combined with total body irradiation (TBI) 7.5 Gy. Within 1 month of ABMT, a capillary leak syndrome was seen in four patients (one death) and isolated pericarditis in one. Nineteen patients survive disease-free at > or = 6 months, median (range) 24 (11-48) months. In 15 of 19 patients, a decrease in glomerular filtration rate (GFR) of > 20% was observed, 6 (6-24) months after ABMT. In six of these patients (five treated with TBI), the renal dysfunction was still progressing 11-36 months after ABMT. Five patients (four conditioned with TBI) developed a haemolytic uraemic syndrome (HUS) with Coombs negative haemolytic anaemia, platelet consumption and renal impairment, with onset 3-6 months after ABMT. Haemolysis and platelet consumption, but not renal impairment, were reversible in all patients. One death from HUS was seen. Because of the adverse effects described we have abandoned the combination of BEAC with TBI.
Adolescent↗
Stimulation of NK cell, T cell, and monocyte functions by the novel immunomodulator Linomide after autologous bone marrow transplantation. A pilot study in patients with acute myeloid leukemia.
Immunostimulatory therapy is at present considered after autologous bone marrow transplantation (ABMT) in order to mimic the allogeneic graft-versus-leukemia effect and thereby reduce the relapse rate. In a pilot study, five adults with acute myeloid leukemia were treated with the new immunomodulator Linomide post-ABMT. Linomide (0.3 mg/kg/week orally) was given in cycles of three weeks followed by three weeks of rest for up to six months. During treatment periods cyclic increases of CD56+CD3- and CD16+ NK cells were observed in parallel with enhanced cytotoxic activity of patient cells against both the NK-sensitive K562 and NK-resistant Daudi cell lines. A cyclic increase of CD14+ monocytic cells was also recorded. The proliferative responses of patient cells to PHA and allogeneic cells (MLC) were enhanced during Linomide therapy. The in vitro production of TNF alpha, IFN gamma, and IL-1 followed the same cyclic increase during treatment periods. Side effects were generally mild, and no harmful effects on engraftment were seen. Linomide therapy after ABMT thus induces a broad immunostimulation that offers a potential benefit with regard to leukemia-free survival.
Adjuvants, Immunologic↗
Serum osteocalcin concentrations in patients with multiple myeloma--correlation with disease stage and survival.
Multiple myeloma affects bone, and enhanced bone resorption is a characteristic finding. In the present study the serum concentration of osteocalcin, serum bone gla-protein, which is a protein specific for bone turnover and reflects osteoblast activity, was analysed at diagnosis in 48 patients with multiple myeloma. At that time there was a significant relationship between disease stage (Durie-Salmon) and osteocalcin levels, lower levels being found in patients with more advanced disease. No relationship was found between osteocalcin and serum calcium levels. To date, 33 patients have died. There was a significant correlation between initial osteocalcin levels and patient survival. These findings suggest that serum osteocalcin could be a marker of prognostic significance for survival in multiple myeloma.
Adult↗
Autologous bone marrow transplantation in children with acute lymphoblastic leukemia.
We report 25 children with acute lymphoblastic leukemia (ALL) treated with purged autologous bone marrow transplantation (ABMT) at a single center. Two children with high-risk ALL were transplanted in first remission and 23 with relapsing ALL were transplanted in second (n = 21) or third (n = 2) remission. There was no procedure-related mortality. The median time to engraftment (i.e. to reach a polymorphonuclear cell count of 0.5 x 10(9)/l) was 25 days (range 16-45 days). Seven children relapsed, four within five months after ABMT: 18 of 25 children (72%) are in continuous complete remission after a median follow-up period of 50 months (range 5-71 months). The predicted long-term disease-free survival is 65% in the whole group and 61% in those transplanted after relapse. Relapse-free children returned to normal activities within three months after ABMT. The major side effects were development of cataract and gonadal insufficiency. We consider the results promising, but our data do not allow comparison with results reported from treatment with chemotherapy alone, since some of our patients were referred from other centers and represent a selected patient group. Long-term follow-up of well-defined patient populations is necessary to evaluate the effect of ABMT.
Adolescent↗
Intensive treatment in order to minimize the Ph-positive clone in chronic myelogenic leukemia.
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Adult↗
Treatment of minimal residual disease in acute leukemia--focus on immunotherapeutic options.
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Acute Disease↗
Thyroid function after autologous bone marrow transplantation.
Thyroid function was prospectively analysed in 111 consecutive patients in relation to autologous bone marrow transplantation (ABMT). Median follow-up time was 12 (range 3-60) months. As part of the conditioning treatment 58 patients had received total body irradiation (TBI) as a single dose of 7.5 Gy (dose rate 0.15 Gy/min). Thyroxine, triiodothyronine, thyrotropin (TSH) and thyroid antibodies were analysed before ABMT, every third month during the first year afterwards and then once annually. Thyroid dysfunction was seen in 20 patients (after TBI in 16, after non-TBI treatments in four). Five of these, all treated with TBI, developed primary hypothyroidism and in 15 compensated hypothyrosis, transient in eight (40%), was seen. There was a highly significant (p less than 0.001) increase, within the normal range, in median TSH level, prior to ABMT compared with 1 year following ABMT. In patients who developed thyroid dysfunction, the TSH level before ABMT was significantly higher (p less than 0.001) than in those who remained euthyroid. In four patients persistent elevated thyroid antibody titers appeared and in two of them hypothyrosis developed. No correlation between thyroid dysfunction and age was noted. The findings are similar to those after allogeneic BMT described by others.
Adolescent↗
[Interferon treatment in chronic myeloid leukemia].
A characteristic feature of chronic myeloid leukaemia is that in 95 per cent of cases bone marrow cells manifest the Philadelphia (Ph1) chromosome. Treatment for cure includes allogenic bone marrow transplantation, but owing to the age factor and the lack of compatible donors this alternative is only available to a minority. Attempts to reduce or eliminate the Ph1-positive clone have been successful in the short term. Results from current trials with alpha-interferon (leukocyte interferon) show that when instituted during the chronic phase the treatment produces complete remission and cytogenetic response in 70 per cent of cases. The side effects are manifest, however, and it remains unclear whether alpha-interferon treatment prolongs the chronic phase.
Adult↗
Immunity to and immunization against measles, rubella and mumps in patients after autologous bone marrow transplantation.
Humoral immunity to measles, rubella and mumps was studied in 63, 36 and 16 patients 1, 2 and 3 years, respectively after autologous bone marrow transplantation (ABMT). Serologic examination was performed using antibody-ELISA. One year after ABMT, 7/57 patients (12%) who were seropositive to measles before ABMT, became seronegative, 8/44 (18%) to rubella and 3/51 (6%) to mumps. Among patients who were retested at 2 and 3 years, three more patients became seronegative to measles, one to rubella, and three to mumps. Nine of 12 children who had previously been immunized against measles were seropositive before ABMT, 3/7 to rubella and 5/7 to mumps, respectively. After ABMT, 5/9 became seronegative to measles, none to rubella and 2/5 to mumps. Six seronegative children were immunized with a live trivalent attenuated measles, mumps, and rubella vaccine 1 to 2 years after ABMT. Two children seroconverted to measles, six to rubella, and four to mumps. No side effects were observed. Most adult patients who have had the diseases of measles, rubella, or mumps naturally remain seropositive, while children who have been immunized commonly lose their immunity after ABMT.
Adolescent↗
Regeneration of CALLA (CD10+), TdT+ and double-positive cells in the bone marrow and blood after autologous bone marrow transplantation.
In this prospective study we investigated the frequency of CD10+, TdT+ and CD10+TdT+ mononuclear cells in the bone marrow (BM) and peripheral blood (PB) before and after autologous bone marrow transplantation (ABMT). 49 patients treated for acute lymphoblastic or myeloblastic leukaemia, malignant lymphoma or multiple myeloma were included. A significant increase in CD10+ cells occurred in BM in both children and adults after ABMT. In children, we also found a significant increase in CD10+ cells in PB. In individual patients remaining in remission, up to 34% CD10+ cells having a normal Ig kappa/lambda light chain ratio were recorded after ABMT. In children, the percentage of TdT+ and CD10+ TdT+ cells increased significantly in BM. In most cases the CD10/TdT-ratio was greater than 1.0, but during early regeneration after ABMT this ratio was less than 1.0 in several patients remaining in complete remission. In patients remaining in remission, CD10+TdT+ cells were detected in the blood in only 2 out of 140 samples tested, and the proportion of these cells never exceeded 0.03%. We conclude that quantitation of CD10+TdT+ cells in peripheral blood is helpful in the evaluation of complete remission in patients treated for pre-B-ALL.
Adult↗
Renal function after autologous bone marrow transplantation.
Seventy-two out of 102 consecutive patients autografted for various hematologic and lymphoid malignancies had a relapse-free survival of greater than 6 months after autologous bone marrow transplantation (ABMT) and were evaluated for long-term effect of the treatment on the renal function. The myeloablative therapy included total body irradiation (TBI) in a single fraction of 7.5 Gy in 41/72 patients. Mean glomerular filtration rate (GFR) showed a significant decrease (p less than 0.01) and serum creatinine and serum urea an increase (p less than 0.05) 6 months after ABMT. Twelve of 72 patients (17%) developed renal dysfunction defined as greater than 25% decrease in GFR, in most cases accompanied by hematuria and proteinuria. Onset was 3-6 months after ABMT. Some patients have later improved considerably, but others continue to deteriorate in renal function. The single most important risk factor for renal dysfunction after ABMT was irradiation. Renal damage was most frequent in lymphoma patients conditioned with BEAC (carmustine [BCNU], etoposide, cytarabine, cyclophosphamide) followed by irradiation, suggesting that this drug combination might have potentiated the toxicity of irradiation. Nephrotoxic antibiotics probably contributed to renal damage in individual cases. Young age did not appear to be a risk factor. Our data indicate that combined treatment with BEAC and TBI should be used with caution and that renal function should be monitored in all patients after bone marrow transplantation to detect any new toxicity patterns of the various conditioning regimens currently used.
Adolescent↗
Impaired glucose tolerance after autologous bone marrow transplantation.
In this study we investigated glucose tolerance in relation to autologous bone marrow transplantation (ABMT). In 13 adult patients with acute myeloblastic (AML) or lymphoblastic (ALL) leukaemia in complete remission (CR), intravenous glucose tolerance test (IVGTT) was performed 1 month before and 6 months after ABMT. Patients with AML in CR received, as myeloablative therapy, cyclophosphamide combined with busulphan or total body irradiation (TBI). ALL patients received total body irradiation in combination with vincristine, daunorubicin, Ara-C, cyclophosphamide and prednisone. Before ABMT all patients, in spite of the intensive chemotherapy given for remission induction and consolidation, had a normal glucose tolerance. However, 6 months after the transplantation the k-value (rate of glucose elimination) for this group of patients had decreased (p less than 0.01). The trend towards impaired glucose tolerance was correlated with lower peak insulin values during IVGTT (p less than 0.05). Thus, the myeloablative therapy in connection with ABMT caused an impairment of pancreatic beta-cell function. No patient has hitherto developed clinical diabetes mellitus.
Adult↗