Prognostic factors for survival of non-Hodgkin's lymphoma patients treated with high-dose chemotherapy and autologous bone marrow transplantation

Prognostic factors to identify patients with high-risk non-Hodgkin's lymphoma (NHL) have recently been developed. We retrospectively investigated the relation between prognostic factors and treatment outcome after autologous bone marrow transplantation (ABMT). From 1984 to 1994, 80 consecutive patients with NHL responding slowly to or relapsing after front-line therapy were treated with high-dose chemotherapy and ABMT. Prognostic factors at the time of diagnosis and of ABMT were related to clinical outcome after ABMT. The cumulative 5-year overall survival (OS) was 51%, progression-free survival (PFS) 41%, and relapse-free survival (RFS) 53%. Absence of B symptoms and intermediate-grade malignancy at first presentation of disease were independently related to prolonged OS (P = 0.02 and P < 0.01, respectively) and prolonged PFS (P = 0.005 and P = 0.01, respectively). At the time of ABMT, first PR or CR, normal LDH levels and tumour stage I + II were associated with prolonged OS (P = 0.0005, P = 0.03 and P = 0.004, respectively). A Coiffier index of 0 or 1, first PR or CR and no extranodal disease involvement were related to prolonged PFS (P = 0.0002, P = 0.005 and P = 0.07, respectively). Treatment-related deaths occurred in 10% of patients. Assessment of disease status, LDH level, tumour stage, extranodal disease involvement and Coiffier index at the time of ABMT is respectively efficient in predicting treatment outcome after ABMT.     

Low incidence of myelodysplastic syndrome following transplantation using autologous non-cryopreserved bone marrow

Between May 1984 and October 1995 we performed 114 autologous stem cell transplants for lymphoma in our centre; 77/114 (68%) were transplanted after primary therapy. The conditioning regimen varied according to diagnosis; 26 patients were conditioned with melphalan and total body irradiation, 66 received melphalan and etoposide and the remainder (50) were conditioned with melphalan alone. The median follow-up is 62 months. Only two new haematological malignancies have occurred, both in patients with Hodgkin's disease. One patient developed Ph+ chronic myeloid leukaemia 18 months post-transplant. In this case, because of the timing of the haematological disorder, we considered the malignancy to be concurrent with or to have preceded the transplant. A second patient developed acute myeloid leukaemia 20 months post-transplant. She had been treated for Hodgkin's disease for 10 years and was transplanted in third complete remission. Cytogenetic analysis in this case showed trisomy 11. We believe this to have been an unequivocal second malignancy. Our finding of a 1.1% incidence of secondary haematological malignancy (95% CI 0.02-4.96) from a census population adds weight to the hypothesis that haematological problems post-transplant reflects prior chemotherapy rather than toxicity from the transplant procedure itself.     

Fatal eosinophilic disease following autologous bone marrow transplantation

A 15-year-old girl developed massive, fatal eosinophilic disease following autologous bone marrow transplantation (BMT) for Hodgkin's disease (HD). Prior to autologous BMT, the erythrocyte sedimentation rate (ESR) was elevated, with active HD, but eosinophilia was absent. Post-autologous BMT, ESR and peripheral eosinophilia were observed to correlate with respiratory symptoms. Initial evaluation revealed no recurrent tumor, infection or other identifiable etiology. A diagnosis of chronic eosinophilic pneumonia was made following lung biopsy. A complete response was initially achieved with steroid therapy; however, when steroid therapy was tapered, the eosinophilia and elevated ESR recurred with worsening respiratory symptoms. Terminally, severe pulmonary disease developed and recurrent HD was found in lung, lymph nodes and bone marrow. During episodes of eosinophilia, the patient's serum stimulated her bone marrow as well as control marrow to produce predominantly eosinophilic colonies. Eosinophilic colony production was not observed with patient's sera obtained prior to or during autologous BMT or with control sera. This patient died of eosinophilic inflammatory disease following autologous BMT. The etiology of this disease was not definitely identified but appeared to be due to an eosinophilic-stimulating factor which developed after autologous BMT.     

Bone marrow transplantation for non-Hodgkin's lymphoma: a review

High dose chemotherapy and stem-cell rescue (bone marrow transplantation) is used increasingly in the treatment of malignant disorder. Numerous trials have demonstrated the effectiveness of bone marrow transplantation in the treatment of non-Hodgkin's lymphoma. However, there are many unanswered questions as to the role of high-dose therapy in certain subtypes of lymphoma, the timing of transplant, and even the type of transplant to perform. An attempt will be made to clarify many of these unanswered questions. The utilization of high-dose therapy for non-Hodgkin's lymphoma is recommended for most patients who have relapsed after initial therapy. Transplantation in first remission is not recommended routinely. Allogeneic bone marrow transplantation should by reserved for individuals with poorly responding disease or in individuals with bone marrow involvement. The precise roles of purging and transplantation of individuals with low grade lymphoma are being investigated.     

Adjuvant immunotoxin therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with B-cell non-Hodgkin's lymphoma

Anti-B-blocked ricin (anti-B4-bR) combines the specificity of the anti-B4 (CD19) monoclonal antibody with the protein toxin "blocked ricin." In blocked ricin, affinity ligands are attached to the ricin B-chain to attenuate its lectin binding capacity. In a phase I trial, Anti-B4-bR was administered by 7-day continuous infusion to 12 patients in complete remission after autologous bone marrow transplantation (ABMT) for relapsed B-cell non-Hodgkin's lymphoma (NHL). Patients were treated at 20, 40, and 50 micrograms/kg/d for 7 days. Potentially therapeutic serum levels could be sustained for 3 to 4 days. The maximum tolerated dose was 40 micrograms/kg/d for 7 days (total 280 micrograms/kg). The dose-limiting toxicities were reversible grade IV thrombocytopenia and elevation of hepatic transaminases. Mild capillary leak syndrome was manifested by hypoalbuminemia, peripheral edema (4 patients), and dyspnea (1 patient). Anti-immunotoxin antibodies developed in 7 patients. Eleven patients remain in complete remission between 13 and 26 months post-ABMT (median 17 months). These results show that Anti-B4-bR can be administered with tolerable, reversible toxicities to patients with B-cell NHL in complete remission following ABMT.     

VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group

PURPOSE: The aim of this multicenter randomized study was to compare conventional therapy with conventional plus high-dose therapy (HDT) and autologous bone marrow transplantation (ABMT) as front-line treatment for poor-prognosis non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Between October 1991 and June 1995, 124 patients, aged 15 to 60 years, with diffuse intermediate- to high-grade NHL (Working Formulation criteria), stages II bulky (> or = 10 cm), III, or IV were enrolled. Sixty-one patients were randomized to receive etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (VACOP-B) for 12 weeks and cisplatin, cytarabine, and dexamethasone (DHAP) as a salvage regimen (arm A), and 63 to receive VACOP-B for 12 weeks plus HDT and ABMT (Arm B). RESULTS: There was no significant difference in terms of complete remissions (CRS) in the two groups: 75% in arm A, and 73% in arm B. The median follow-up observation time was 42 months. The 6-year survival probability was 65% in both arms. There was no difference in disease-free survival (DFS) or progression-free survival (PFS) between the two groups. DFS was 60% and 80% (P = .1) and PFS was 48% and 60% (P = .4) for arms A and B, respectively. Procedure feasibility was the major problem. In arm B, 29% of enrolled patients did not undergo HDT and ABMT. A statistical improvement in terms of DFS (P = .008) and a favorable trend in terms of PFS (P = .08) for intermediate-/high- plus high-risk group patients assigned to HDT and ABMT was observed. CONCLUSION: In this study, conventional chemotherapy followed by HDT and ABMT as front-line therapy seems no more successful than conventional treatment in terms of overall results. However, our results suggest that controlled studies of HDT plus ABMT should be proposed for higher risk patients.     

Autologous bone marrow transplantation for non-Hodgkin's lymphoma resulting in long-term remission of coincidental Crohn's disease

Crohn's disease usually runs a chronic relapsing and remitting course, characterized by a repeated need for immunosuppressive drug therapy or often surgery. and is considered to be incurable by standard treatment. We report a case of successful long-term disease control of Crohn's disease following autologous bone marrow transplantation. This case provides further support for the concept that some forms of severe immune-mediated diseases may be amenable to treatment by high-dose therapy with autologous stem cell support.     

Allogeneic bone marrow transplantation for low-grade lymphoma

Advanced low-grade lymphomas are usually incurable with conventional-dose chemotherapy. It is uncertain whether cures are possible with high-dose therapy and bone marrow transplant from a human leukocyte antigen (HLA)-identical sibling. We sought to determine the outcome of HLA-identical sibling bone marrow transplants in advanced low-grade lymphoma in an observational study of 113 patients conducted at 50 centers participating in the International Bone Marrow Transplant Registry (IBMTR). The median patient age was 38 years (range, 15 to 61). Eighty percent had stage IV disease at the time of transplantation. The median number of prior chemotherapy regimens was two (range, 0 to 5). Thirty-eight percent had refractory disease and 29% a Karnofsky performance score (KPS) less than 80%. All patients underwent allogeneic bone marrow transplantation from a HLA-identical sibling donor. The conditioning regimen included total-body irradiation (TBI) in 82% of patients; cyclosporine was used for graft-versus-host disease prophylaxis in 74%. Survival, disease-free survival, recurrence rate, treatment-related mortality, and causes of death were determined. Three-year probabilities of recurrence, survival, and disease-free survival were 16% (95% confidence interval [CI], 9% to 27%), 49% (95% CI, 39% to 60%), and 49% (95% CI, 39% to 59%), respectively. Higher survival was associated with pretransplant KPS >/=90%, chemotherapy-sensitive disease, use of a TBI-containing conditioning regimen, and age less than 40 years. We conclude that high-dose therapy followed by transplantation from a HLA-identical sibling leads to prolonged survival in some patients with advanced low-grade lymphoma. Most mortality is treatment-related, and recurrences are rare.     

Radiation myelopathy following transplantation and radiotherapy for non-Hodgkin's lymphoma

BACKGROUND: Combined modality therapy with chemotherapy and radiotherapy has become increasingly popular in the management of solid malignancies. However, unexpected toxicities may arise from their interactions. METHODS AND MATERIALS: We report the case of a young woman with a large mediastinal non-Hodgkin's lymphoma who underwent high-dose chemotherapy with autologous bone marrow transplantation and involved field radiotherapy, and who developed radiation myelopathy after a latent period of only 3 months. The spinal cord dose did not exceed 40.3 Gy in 22 fractions over 4.5 weeks, which is well within accepted tolerance limits. She had no other identifiable risk factors for radiation myelopathy, suggesting an adverse drug-radiation interaction as the most likely cause of her injury. RESULTS AND CONCLUSIONS: This represents the first report of radiation myelopathy at accepted safe radiation doses following high-dose chemotherapy with autologous bone marrow transplantation, and we recommend caution in the choice of radiotherapeutic dose in this setting.     

Myelodysplastic syndrome and acute myelogenous leukemia as a late clonal complication in children with acquired aplastic anemia

The improved outcome of acquired aplastic anemia (AA) has revealed later complications, such as myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). We retrospectively analyzed 167 children with severe acquired AA. Eleven of 50 children treated with cyclosporin (CSA) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) developed MDS/AML; 8 of these were within 36 months of the diagnosis of AA, much earlier than previous reports. Six of the 11 children received rhG-CSF exceeding 10 microg/kg/d, and 9 received rhG-CSF therapy for over 1 year. Ten children showed monosomy 7 at diagnosis of MDS. All of the 11 children were administered both CSA and rhG-CSF. There was no development of MDS/AML among 41 children treated with either CSA or rhG-CSF or among 48 children who underwent bone marrow transplantation. A well-controlled clinical trial is warranted to determine whether therapeutic modalities affect the development of MDS/AML in children with severe acquired AA.     

Successful high-dose chemotherapy combined with autologous bone marrow transplantation in a case of refractory follicular lymphoma

This study investigated the association between two demographic and two psychological variables and treatment retention for 65 perinatal substance abusers. Subjects who lived in the community while attending day treatment were 6.125 times more likely to drp out than subjects who lived in a program-operated shelter (p < .0001). An interaction was found for pregnancy status and antisocial personality disorder (p < .0478). Subjects who were both pregnant and antisocial were 4.876 times more likely to remain in treatment than those who were neither pregnant nor antisocial. Degree of "treatment resistance," measured by the MMPI Negative Treatment Indicators (TRT) Scale, did not predict dropout. These findings indicate that supportive housing can play an important role in preventing dropout for perinatal substance abusers. Additionally, pregnancy may present a "window" of opportunity for treating a hard to reach population, drug abusing women with comorbid ASP.     

Multiple autoimmune events after autologous bone marrow transplantation

A 36-year-old woman with RAEB-t and severe bone marrow fibrosis undergoing autologous BMT, developed a histologically documented GVHD-like skin rash. Thereafter, autoimmune thyroiditis, autoimmune thrombocytopenic purpura and autoimmune hemolytic anemia and a lupus anti-coagulant (LAC) were diagnosed. The patient is still alive, symptom-free and in first complete remission (CR); however, all of the autoantibodies are still detectable, with the exception being the anti-erythrocyte antibody. The most outstanding feature of the present case is the polymorphism of the autoimmune events, in the absence of a coexisting systemic autoimmune disease. This patient has achieved long-term disease-free survival (DFS) in first CR despite high-risk MDS and the repeated immunosuppressant therapy required because of the complications described above; a GVL reaction somewhat similar to the autoimmune events may have contributed towards maintaining disease control.     

Splenic infarct as a late complication of liver transplantation

Splenic infarct is a rare complication of portal hypertension. It has been reported as an early complication after successful liver transplantation when portal pressure returns to normal and the splenic size progressively declines. It has not been reported as a late complication of liver transplantation. We describe the case of a 19-year-old patient with a splenic infarct which occurred 11 months after successful orthotopic liver transplantation for decompensated cryptogenic liver cirrhosis. Following transplantation, the patient was in excellent general health, liver function tests were normal, there was no clinical evidence of portal hypertension and the splenic size had decreased significantly compared to the pre-transplantation period, although it remained increased. The patient presented with high fever, left pleuritic pain and vomiting. The splenic size had not changed and left pleuritic exudate fluid collection was detected. A hypoechoic region of the spleen was demonstrated in the ultrasound examination corresponding to a hypodense lesion in the computerized tomography scanning. The patient recovered completely, with the disappearance of the infarct in the imaging studies in 2 months time. This case report indicates that a symptomatic splenic infarct can occur late following successful liver transplantation for liver cirrhosis despite lack of any evidence of residual portal hypertension at a time that splenomegaly has not yet regressed. The differential diagnosis from a splenic abscess in transplanted patients can be difficult but the final prognosis seems to be good.     

Storage of haemopoietic stem cells for autologous bone marrow transplantation

For reinfusing autologous bone marrow cells after high-dose chemotherapy and/or radiotherapy it is necessary that an effective technique for their storage is available. The traditional method uses 10% dimethyl sulphoxide as cryoprotectant, a rate-controlled computerized freezer programmed to cool the cells at a constant rate of 1 degrees C per minute and liquid nitrogen as the storage system. The method is time-consuming, expensive and requires technical expertise. Moreover, it is often associated with varying levels of clinical toxicity following infusion of the preserved cells. Processing the harvest to reduce the initial volume and the mature cells has been shown to be beneficial in reducing the volume of the cryoprotectant and the incidence of toxicity. An alternative, cost-effective method using a cryoprotectant mixture of 5% dimethyl sulphoxide, 6% hydroxyethyl starch and 4% albumin has been found to be effective even when the cells are stored at -80 degrees C without rate-controlled freezing. However, its efficacy needs to be evaluated for extended periods. The current use of purging and cell sorting methods seems to be promising.     

C1 esterase inhibitor concentrate for capillary leakage syndrome following bone marrow transplantation

The prognosis of patients with severe capillary leakage syndrome (CLS) after bone marrow transplantation (BMT) is dismal despite aggressive use of intensive care therapy. Because the activated classical pathway of complement and relatively low levels of C1 esterase inhibitor (C1 INH) activity are known features in these patients, we evaluated the efficacy of a therapy using purified, human C1 INH concentrate. Severe CLS was defined as increase in body weight by more than 3% within 24 h combined with generalized edema, impaired hemodynamic system (tachycardia and/or decreased blood pressure), and non-responsiveness to furosemide. Of 142 patients, 22 developed severe CLS. The first seven patients whom we diagnosed with this complication were assessed as control patients. Fifteen patients with severe CLS were treated with C1 INH concentrate using a cumulative dose of 180 units/kg body wt. (initial dose: 60 units/kg, followed by two doses at 30 units/kg and four doses at 15 units/kg, every 12 h). The survival rate of patients with CLS was 57% at 1 year after BMT in the C1 INH treatment group, compared with 14% in the control group (p = 0.008). Eight of 15 treated patients are alive at a median of 9 months (range: 4-55) after BMT. The plasma levels of the complement activation parameters C4d and C5a were 3 +/- 1.1 mg/dl (mean +/- S.D.) and 0.3 +/- 0.1 microgram/l, respectively, prior to BMT, increasing to 8.2 +/- 2.1 mg/dl and 1.3 +/- 0.4 micrograms/l, respectively, at diagnosis of CLS. After infusion of C1 INH concentrate the plasma levels of C5a and C4d normalized. The activity of C1 INH rose to 139 +/- 10% of normal human plasma NHP pool (mean +/- S.D.) after infusion. The CH50 values were not significantly altered. The fluid status normalized within 11 days in 14 of 15 treated patients. The results of this study suggest that therapy with C1 INH concentrate improves the prognosis of patients with CLS after BMT. This has to be confirmed in a randomized, controlled trial.     

Fulminant, CMV-associated, haemophagocytic syndrome following unrelated bone marrow transplantation

We report a case of haemophagocytic syndrome (HPS) occurring after allogeneic bone marrow transplantation (BMT) for acute promyelocytic leukaemia (APL) in a patient in fourth complete remission (CR). Anti-cytomegalovirus (CMV) antibody (Ab) was negative in this patient before BMT. BMT was performed from an HLA-identical unrelated donor who was positive for CMV Ab. After bone marrow engraftment and haematological recovery, severe acute graft-versus-host disease (GVHD) developed. This patient was treated with methylprednisolone in addition to cyclosporin A (CsA). Acute GVHD showed partial improvement, but CMV antigenaemia was observed. Despite administration of gancyclovir and immunoglobulin, CMV antigenaemia showed no improvement and HPS developed. As no other infections or malignancies were observed, we suspect that CMV infection was the trigger for development of HPS.