Autologous bone marrow transplantation for non-Hodgkin's lymphoma

Autologous bone marrow transplantation (ABMT) is now so widely applied in the treatment of relapsed high- and intermediate-grade non-Hodgkin's lymphoma (NHL) that it is very important to analyse the evidence on which this practice is based and ask in precise terms what the place of this technique should be. This article will review the data that have been published and discuss the randomised studies now in progress. The possible use of ABMT in other areas such as consolidation of remission and its use in low-grade lymphoma will also be examined. The EBMT data quoted are taken from the 1990 review of the register for ABMT in malignant lymphoma which was presented to the XVIth meeting of the EBMT in the Hague in 1990.     

Detection of malignant cells in histologically normal bone marrow using culture techniques

Cellular material retained on screens used to filter aspirated bone marrow for future autologous marrow transplantation was studied using long-term culture techniques in 20 consecutive patients. All patients had marrow aspirate and biopsy specimens that were normal histologically. Cultures from five patients grew malignant cells similar to those of the known underlying malignancy. Two types of culture methods were used in these studies. Method I consisted of a long-term bone marrow culture system which predominantly favors adherent cells, and Method II consisted of a suspension type culture system favoring expansion of mononuclear cell types. These findings suggest that tumor cells are reinfused more often at the time of autologous bone marrow transplantation than has been previously suspected. Although the clinical significance of these findings is not known, it is clear that culture techniques combined with special stains and molecular probing will allow the improved detection of occult tumor cells in bone marrow from patients undergoing autologous marrow transplantation. These observations emphasize the need for a comprehensive study of histologically normal autologous marrow using culture techniques to determine the frequency of occult involvement by viable malignant cells and the clinical implications of these findings.     

Isolated bone marrow non-Hodgkin's lymphoma. Report of two cases and literature review

We report two patients with isolated bone marrow non-Hodgkin's lymphoma and we review the additional 23 cases thus far described. Bicytopenia or pancytopenia and an elevated erythrocyte sedimentation rate were universally present. Some 84% of the patients manifested fever of unknown origin (FUO), 64% constitutional symptoms, 48% hepatomegaly, and 52% splenomegaly. Of the variety of therapeutic protocols used, corticosteroids, alone or in combination, appeared to be the most effective. Survival ranged from 1 week to 4.5 years. Early diagnosis would avoid unnecessary work-up in patients with FUO and enable optimization of therapy.     

Detection of bone marrow minimal disease in non-Hodgkin's lymphoma patients by gene rearrangement analysis

Bone marrow aspirates from 13 patients with non-Hodgkin's lymphoma of B- and T-lineage were drawn during staging procedures and examined by a combined technique involving immune selection and gene rearrangement analysis with DNA probes specific for the heavy-chain immunoglobulin gene (JH) or T cell receptor gene (T beta and T gamma). Morphologic examination of bone marrow biopsies revealed involvement by lymphoma in one case and suspicious accumulation of blasts in another. Southern blot analysis of the samples showed the presence of a rearranged clonal band in two samples, including the morphologically involved marrow. Clonal rearrangements were not detected in the suspected marrow. Bone marrow relapses were not observed in any of these patients after a median follow-up of 20 months. Antigen receptor rearrangements are tumor-specific markers which may increase the sensitivity and the specificity of morphologic examination, and may be useful in the proper staging and follow-up of lymphoma patients.     

Allogeneic marrow transplantation in non-Hodgkin's lymphoma

Nine individuals between 15 and 43 years of age with non-Hodgkin's lymphoma underwent allogeneic marrow transplantation following busulfan 16 mg/kg and cyclophosphamide 120 mg/kg. These individuals were not considered optimal candidates for autologous transplantation chiefly because of marrow involvement or resistance to chemotherapy. All patients engrafted and eight achieved complete remission. Three patients relapsed; one patient died of transplant-related complications. Five individuals are disease-free survivors between 103 and 1169 days following transplantation. Of three individuals with relapsed Burkitt's lymphoma none experienced a sustained disease-free interval following transplantation. Three of four individuals with large cell or lymphoblastic lymphoma are surviving 585 to 1169 days following transplantation. Allogeneic marrow transplantation following busulfan and cyclophosphamide appears reasonably safe and is effective in selected patients with non-Hodgkin's lymphoma who are not good candidates for autologous marrow transplantation.     

Autologous bone marrow transplantation in 69 patients with a history of low-grade B-cell non-Hodgkin's lymphoma

Sixty-nine patients with a history of low-grade B-cell non-Hodgkin's lymphoma (NHL) in sensitive relapse or incomplete first remission underwent high-dose chemoradiotherapy and anti-B-cell monoclonal antibody (MoAb)-treated autologous bone marrow transplantation (ABMT). At ABMT, 51 patients had low-grade histology and 18 patients had a history of low-grade NHL that had undergone histologic transformation to a higher-grade NHL. Before ABMT, only 20 of the 51 low-grade patients and 10 of the 18 patients with transformed histologies were in complete remission. Moreover, at the time of marrow harvest, 24 of the low-grade and eight of the transformed histology patients had histologic evidence of lymphoma cells infiltrating the marrow. Following high-dose therapy, only one acute, in-hospital death was observed. There was no significant difference in the disease-free survival (DFS) between patients with low-grade and patients with transformed histologies. Among patients with low-grade NHL, the patients in complete remission before ABMT experienced significantly longer DFS than those in partial remission (P less than .05). This preliminary study suggests that some patients with relapsed low-grade NHL may experience prolonged DFS following high-dose ablative therapy.     

Adoptive transfer of vitiligo after allogeneic bone marrow transplantation for non-Hodgkin's lymphoma

Vitiligo developed in a 50-year-old man 9 months after allogeneic transplantation from his HLA-identical sister who had had this disease for several years. Our findings suggest adoptive transfer of vitiligo by haematopoietic stem cell transplantation, and lend support to the autoimmune nature of this disease.     

Intensive cytotoxic therapy followed by autologous bone marrow transplantation for non-Hodgkin's lymphoma of high-grade malignancy

Fourteen patients with non-Hodgkin's lymphoma (NHL) of high-grade malignancy were treated with cyclophosphamide and total body irradiation followed by autologous bone marrow transplantation (ABMT). All patients were pretreated with conventional chemotherapy. Three of four patients with drug-resistant disease achieved complete remission (CR), but relapse occurred within six months. Four patients in partial remission (PR) achieved CR; one died because of sepsis, two relapsed within six months, and one is still in CR 28+ months later. Six were treated in CR, five in first CR, and one in second CR. From these six patients (who received this treatment as consolidation therapy), five are in unmaintained CR seven to 31+ months after ABMT (one patient died of a secondary illness). There were two therapy-related deaths, both in patients with a poor clinical condition. Toxicity of this treatment was mild for those receiving transplants who were in better condition. These preliminary results suggest that intensive cytoreductive therapy followed by ABMT may improve disease-free survival in patients in NHL of high-grade malignancy in CR.     

Primary non-Hodgkin's lymphoma of bone

We describe a patient with hip pain who had a painful solitary pelvic bone lesion with a lytic, permeative appearance and minimal periosteal reaction, despite a relatively large soft tissue mass. Histologic examination and thorough evaluation revealed this solitary tumor to be a primary non-Hodgkin's lymphoma of the bone.     

Large-cell anaplastic non-Hodgkin's lymphoma originating in donor cells after allogenic bone marrow transplantation

Summary .Second neoplasms after allogenic bone marrow transplantation (BMT) occur in donor cells; however, host origin generally cannot be excluded. Using fluorescence in situ hybridization (FISH) the origin of the malignant population can be proven indisputably. In a female patient with CD30⁺ large-cell anaplastic non-Hodgkin's lymphoma (LCAL) after BMT with an HLA-identical brother donor, FISH using anti-CD30 immunocytochemistry in combination with anti-Y- and anti-EBV RNA probes was applied. In pathological lymph nodes the majority of cells were of donor type (Y). CD30-positive cells were Y-positive; these cells were also EBV-positive. Using FISH and immunocytochemistry we have demonstrated convincingly that this, possibly EBV-induced, LCAC originated in donor cells.     

High-dose therapy followed by autologous bone marrow transplantation (ABMT) in previously untreated non-Hodgkin's lymphoma

13 previously untreated patients with poor prognosis non-Hodgkin's lymphoma (NHL) underwent high-dose therapy followed by autologous bone marrow transplantation (ABMT). All patients experienced a great cytoreductive effect and 9 of them reached a complete remission (mean duration 32 months). The best results were observed in patients with more limited disease and in those without symptoms. 7 patients still remain in complete unmantained remission 15-46 months from the transplant. The probability of survival is 74% at 46 months. No therapy-related deaths were recorded. In differentiating our preliminary approach, we propose high dose therapy followed by ABMT as induction phase in patients with stage II and as consolidation after first line therapy in patients with stages III-IV. Further studies are warranted to determine which type of lymphoma may benefit more and which conditioning regimens may improve the remission rate.     

Autologous bone marrow transplantation in follicular non-Hodgkin's lymphoma before and after histologic transformation

Patients with disseminated follicular non-Hodgkin's lymphoma (NHL) are only occasionally cured with standard chemotherapy regimens. Although most of these tumors are initially responsive to chemotherapy, in 40% to 70% of patients the lymphoma will eventually transform to an NHL of higher grade malignancy and a poorer prognosis. We treated 18 patients having an original diagnosis of follicular NHL with high-dose therapy and autologous bone marrow transplantation. The lymphomas of 10 of the patients had already undergone histologic transformation and eight still had a follicular histologic pattern. The former group had been followed for a longer time from the diagnosis of NHL and had been more extensively treated with conventional chemotherapy regimens. All eight patients with follicular NHL at the time of transplantation are alive for 246+ to 1,804+ days and seven of the patients are in complete remission. In contrast, of the 10 patients in histologic transformation only 1 is alive and in CR. This reflects the inability of these patients to tolerate the high-dose chemotherapy and myelosuppression as well as resistance of their lymphoma to this therapy. This difference in survival between the two groups was highly significant (P = .002). We conclude that the outcome of patients with follicular NHL transplanted early before histologic transformation is better than for those who are transplanted later in the course of their illness. Because of the relapsing behavior of follicular NHL, a longer follow-up is necessary to prove any impact on the natural history of the disease.     

Acute and chronic pulmonary complications following autologous bone marrow transplantation in non-Hodgkin's lymphoma

Whereas intensive chemoradiotherapy with bone marrow salvage may be the only chance for cure in a number of patients with non-Hodgkin's lymphoma, high complication rates with subsequent mortality have been detrimental to our ability to cure many patients. Prominent among these complications is pulmonary toxicity, in the form of acute and infectious complications and interstitial pneumonitis. We report here our experience with 100 patients receiving autologous bone marrow transplants for non-Hodgkin's lymphoma. The incidence of interstitial pneumonitis (IP) was 7.6% and our mortality from IP was 1%, the lowest reported.     

High-dose therapy supported with immunomagnetic purged autologous bone marrow in high-grade B cell non-Hodgkin's lymphoma.

From August 1987 to March 1995, 25 patients with high-grade B cell non-Hodgkin's lymphoma (NHL) were treated with high-dose therapy (HDT) followed by bone marrow purged with immunomagnetic beads. At the time of transplantation, 20 patients were in sensitive relapse and five in first complete or partial remission. Ten patients had secondary high-grade NHL transformed from low-grade NHL. The HDT consisted of TBI followed by high-dose cyclophosphamide. All patients engrafted, except for two patients with early treatment-related death. Eleven patients relapsed, of whom nine died of lymphoma, and two are alive in new CR. The estimated event-free and overall survivals at 5 years were 40% and 48%, respectively, with a median follow-up of 48 months (range 1-123). Eight of the tumours contained the translocation t(14;18) at the major breakpoint region (MBR) of BCL-2. In these patients the presence of tumour cells in the bone marrow graft before and after purging were assessed by PCR. Four of five patients infused with non-detectable minimal residual disease in their autografts are in complete remission, while two of three patients reinfused with t(14;18) positive cells after purging, experienced a fast and aggressive relapse. As found by others, our data suggest that reinfusion of tumour-free autografts obtained by efficient in vivo purging using chemotherapy before harvesting, and/or by in vitropurging of the stem cell products, influence the patients remission status after HDT.     

High-dose chemotherapy containing busulfan followed by bone marrow transplantation in 24 children with refractory or relapsed non-Hodgkin's lymphoma.

Twenty-four children with relapsed or refractory non-Hodgkin's lymphoma underwent high-dose chemotherapy (HDC) with bone marrow transplantation (BMT). HDC comprised in all cases busulfan (16 mg/kg or 600 mg/m2), with either cyclophosphamide (200 mg/kg or 4.4 g/m2) and/or melphalan (140 mg/m2). Twenty-three of these children had received second-line therapy before receiving HDC. There were 16 B cell and eight T cell lymphomas. Twenty-three patients were evaluable at day 30 post-BMT; 19 were in complete remission, four did not respond. Eight patients are long-term survivors between 62 and 296 weeks after BMT. Among the seven children with resistant disease before HDC, only one is a long-term survivor. No toxic deaths occurred. The main adverse side effect was hepatic veno-occlusive disease which occurred in four patients, but resolved completely in all cases. Comparisons with other classic HDC regimens in relapsed childhood lymphomas show that HDC containing busulfan with BMT appears reasonably safe and is effective in refractory or relapsed lymphomas, even in these highly previously treated patients.