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.     

Allogeneic bone marrow transplantation for high risk non-hodgkin's lymphoma during first complete remission

Summary Allogeneic bone marrow transplantation from histocompatible sibling donors was performed in six patients with extranodal involvement of high grade lymphoma during first complete remission. Five patients had lymphoblastic lymphoma and one had diffuse undifferentiated lymphoma. The cytoreductive/immunosuppressive regimen consisted of total body irradiation and high dose cyclophosphamide. Four patients are alive in complete remission at 8 months, 14 months, 21 months and 47 months post transplantation. One patient who relapsed 7 months after his initial transplantation underwent a second transplantation but another relapse 17 months later led to his death. One patient died of chronic graft-versus-host disease and at autopsy there was no evidence of lymphoma. These data demonstrate that allogeneic bone marrow transplantation can produce durable remissions in patients with high grade lymphoma who present with bone marrow, central nervous system and/or skin involvement.     

Bone marrow transplantation for refractory acute leukemia in 34 patients with identical twins

Thirty-four patients aged 4-67 yr (median 17) with acute lymphocytic leukemia (ALL) (18 patients) or acute nonlymphocytic leukemia (ANL) (16 patients) who failed to enter complete remission (CR) or relapsed on conventional chemotherapy were treated with cyclophosphamide (CY), 60 mg/kg/day for 2 days, 1000 rad total body irradiation, and a marrow transplant from a genotypically identical normal twin. Sixteen of the patients received additional chemotherapy within the week before CY. After the transplant, 23 patients received immunotherapy consisting of killed autologous leukemic cells and/or normal twin peripheral blood lymphocytes, 16 as part of a prospectively randomized study. One moribund patient died before engraftment. Nine patients (6 ALL, 3 ANL) continued to have detectable leukemic cells. Twenty-four patients (70%) achieved CR. One of them died of viral hepatitis at 1 mo and another of viral interstitial pneumonitis at 4 mo in CR. Fourteen patients (7 ALL, 7 ANL) relapsed 2-16 mo (median 4) after transplantation. However, 8 patients (24%) (3 ALL, 5 ANL) remain in CR without any maintenance chemotherapy at 29-103 mo (median 80) after the transplant. The end results were not signficantly influenced by the type of leukemia, the immediated pre-CY chemotherapy, or the immunotherapy. The results show that this approach, even when applied to endstage patients with acute leukemia in relapse, causes tolerable morbidity, rare nonleukemic deaths, and frequent remissions, some of which represent cures.     

Treatment of refractory adult lymphoblastic leukemia (ALL) with 4'(9- acridinylamino) methanesulfon-M-anisidide (AMSA)

Twenty-four adults with ALL were treated with AMSA alone or in combination. Twenty-two were treated at time of relapse and two patients after failing primary induction therapy. All had been treated with anthracyclines prior to receiving AMSA. Of the 22 patients with ALL in relapse, 4 achieved a complete remission. Two of these patients have relapsed while receiving maintenance chemotherapy; one died 1 mo after achieving remission due to the occurrence of cholycystitis in the setting of pancytopenia and one patient underwent bone marrow transplantation and is in remission at 8 mo after the second remission. Both patients who failed primary induction therapy remain in remission at 11 and 36 mo, respectively. The use of AMSA should be considered for patients with ALL who fail primary induction as well as those whose leukemia becomes resistant to conventional agents.     

Combination chemotherapy with VM-26, adriamycin bleomycin, and prednisone as a secondary treatment of malignant lymphoma

Thirty-eight pretreated patients with Hodgkin's disease (HD) and malignant non-Hodgkin's lymphoma were given combination chemotherapy with VM-26, Adriamycin, bleomycin, and prednisone. Four of 15 evaluable patients with HD achieved a partial remission (PR), with a median duration of 8 months. Of 12 patients with diffuse poorly differentiated lymphocytic lymphoma, one achieved a complete remission (30+ months) and five achieved a PR (median, 6 months). One of three patients with histiocytic lymphoma had a PR of 1.5 months. There was one drug-related death. Five patients developed life-threatening hematologic toxicity. Two HD responders died of acute nonlymphocytic leukemia.     

Allogeneic bone marrow transplantation in patients with lymphoma relapsing after autologous marrow transplantation

Two patients who underwent autologous bone marrow transplantation for recurrent non-Hodgkin's lymphoma relapsed at 46 and 28 days after the transplant. Both patients had an HLA-identical sibling and were treated with high-dose chemotherapy and allogeneic marrow transplantation. One patient is now 24 months after the allogeneic transplant without evidence of disease. The second patient died on day 7 with interstitial pneumonia. We conclude that high-dose therapy and allogeneic bone marrow transplantation after failure of autologous transplantation for non-Hodgkin's lymphoma is feasible and should be considered in young patients with HLA-identical siblings.     

Parma international protocol: pilot study of DHAP followed by involved-field radiotherapy and BEAC with autologous bone marrow transplantation

Fifty patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) who had relapsed after a complete remission induced by an Adriamycin-containing chemotherapy regimen participated in this prospective pilot study. The patients ranged in age from 16 to 60 years (median 42 years). All patients received dexamethasone, high-dose cytarabine, and cisplatin (DHAP) for two courses at 3- to 4-week intervals. Patients achieving a partial or complete response were scheduled to receive involved-field radiotherapy and high-dose carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC), followed by autologous bone marrow transplantation (ABMT). Among 48 evaluable patients (ie, 1 was lost to follow-up and 1 had no measurable disease) 7 patients obtained a complete response (CR) and another 21 patients achieved partial response (PR), whereas the remaining 20 patients failed. One responder died of treatment-related toxicity, and six others declined ABMT. The patient with no measurable disease did not progress on DHAP and was submitted to ABMT. Twenty-two patients underwent ABMT [20 with BEAC and 2 with cyclophosphamide plus total body irradiation (TBI)] of whom 2 (9%) died of toxicity and 10 relapsed. One patient was a suicide at 28 months post-ABMT in CCR and 9 are alive disease-free 24 months to 32 months (median 30 months) post-ABMT. The actuarial 2-year event-free survival for patients undergoing transplantation is 40%. This prospective multicenter trial documents the ability of DHAP followed by ABMT to produce durable complete remission in a significant proportion of patients with relapsed aggressive NHL. Forty-four percent of all patients with relapsed lymphoma who entered the study actually underwent ABMT and 20% of the total group are projected to be long-term disease-free survivors.     

Nodular histiocytic lymphoma: an aggressive nodular lymphoma with potential for prolonged disease-free survival

Nodular histiocytic lymphoma (NH) is uncommon, and its natural history is not well defined. Of 473 patients with non-Hodgkin's lymphoma, we found 16 (3.4%) with NH. Most patients (13/16) presented with pathologic stage (PS) III or IV disease, including 7 with liver involvement. One patient (PS III) was initially treated with cyclophosphamide alone, and 4 patients received only radiotherapy, and none were long-term survivors. Eleven patients received combination chemotherapy, and 8 achieved complete remission. Only one of these patients relapsed and died at 19 mo; the other 7 continue in complete remission without maintenance therapy with a minimum followup of 4.5 yr. The survival of the entire group of patients with NH is intermediate between that of the other nodular lymphomas and diffuse histiocytic lymphoma. Nine of 16 patients had either a repeat lymph node biopsy during the course of their disease or lymph node examination at autopsy. Lymph node histology in the majority converted to a diffuse, less differentiated subtype of lymphoma. NH has a natural history similar to that of diffuse histiocytic lymphoma and should be approached with the same therapeutic strategy.     

Treatment of isolated central nervous system relapse in high-risk lymphoid malignancy with allogeneic bone marrow transplantation and extended intrathecal therapy

We performed allogeneic bone marrow transplantation (BMT) with an extended period of post-transplant intrathecal (IT) chemotherapy for five patients with acute lymphoblastic leukaemia and non-Hodgkin's lymphoma who had relapsed in the central nervous system either in the very early phase or more than twice. Post-transplant IT was scheduled for a total of 12 doses over 18 months. One patient was found to have subclinical leucoencephalopathy. Disease relapse occurred in one patient and the other patients remained in complete remission for 39-196 months post-BMT. The estimated event-free survival was 80 +/- 17.9% (standard error).     

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.     

Marrow transplantation for non-Hodgkin's lymphoma: a multi-centre study from the European Co-operative Bone Marrow Transplant Group

Twenty-five patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) were treated by allogeneic bone marrow transplantation. For the nine patients transplanted in first complete remission the disease-free survival was 100%; of the nine patients transplanted in subsequent remissions four (44%) achieved long-term disease-free survival but two died of relapsed lymphoma. For the seven patients transplanted at a time when they had active disease, the initial complete remission rate was high but four died of progressive lymphoma and no patient achieved long-term disease-free survival. The incidence of complications associated with allogeneic bone marrow transplantation was similar to that observed in other series of patients transplanted for haematological malignancy and was related to the status of the disease at the time of transplant. Thus allogeneic bone marrow transplantation is a radical but effective treatment for patients with NHL who have 'minimal residual disease'. Efforts to define further the subset of patients who can most successfully be treated by transplantation may improve the overall results.     

Allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic or accelerated phase

Eight patients with Ph1-positive chronic myelogenous leukemia (CML) in chronic or accelerated phase received high-dose cyclophosphamide, total body irradiation, and bone marrow transplantation from an HLA-identical sibling donor. All patients had prompt engraftment and achieved complete hematologic remission. Six patients remain alive and in continuous remission with a normal bone marrow karyotype 3-20+ mo posttransplant. One patient died from cytomegalovirus interstitial pneumonitis. Only one patient who was transplanted in accelerated phase relapsed 6.5 mo posttransplant and died in blast crisis. High-dose combined modality therapy is capable of producing sustained complete remissions in patients with CML treated during chronic or accelerated phase.     

Outcome of hematopoietic stem cell transplantation in patients with atypical chronic myeloid leukemia

Atypical chronic myeloid leukemia (aCML) occurs rarely and is associated with a poor prognosis when treated with conventional chemotherapy. We evaluated the outcome of aCML after allogeneic hematopoietic stem cell transplantation (HSCT). Nine patients were transplanted from HLA-identical siblings (n = 4), HLA-compatible unrelated donors (n = 4) or twin brother (n = 1). Median follow-up was 55 months after transplant (range, 9.1-118.1 months). One patient who was transplanted in advanced disease with bone marrow from his twin brother relapsed 19 months post transplant. This patient was successfully retransplanted from the original donor. All patients remained in complete remission. Analysis of the leukocyte chimerism of peripheral white blood cells and bone marrow buffy coat cells by VNTR-polymerase chain reaction (PCR) and single-nucleotide polymorphism real-time PCR revealed complete chimerism in all patients who had received an allogeneic transplant. One patient suffering from cerebral toxoplasmosis died 9 months post transplant. All other patients were alive at the time of analysis. Our findings suggest that the outcome of allogeneic or syngeneic transplantation in patients with aCML may not be worse than the outcome of transplantation for BCR-ABL-positive CML.     

Involved field radiation, fractionated total body irradiation, high dose cyclophosphamide, and autologous bone marrow transplantation in the treatment of malignant lymphomas

We report the results of intensive therapy and autologous bone marrow transplantation (BMT) in 23 patients with malignant lymphoma (eight Hodgkin's disease and 15 non-Hodgkin's lymphoma) who failed primary therapy. All patients had evidence of disease prior to transplant therapy: 10 had never achieved a complete remission and 13 were in relapse. The preparative regimen included involved field radiation followed by fractionated total body irradiation and high dose cyclophosphamide. A complete remission was achieved in 15 patients, 11 of whom continue in unmaintained complete remission from 27 to 72 months after BMT (median follow-up of 52 months). Of the remaining patients, five did not achieve a complete remission and three died of early toxicity. The event-free survival of the entire group is 47%. Disease status at the time of BMT was significantly correlated with patient outcome. The event-free survival of 13 patients in whom there was no objective evidence of tumor growth on conventional dose therapy was 77% compared with only 10% in patients with tumors progressing on conventional dose therapy (p less than 0.002). All six patients transplanted in untreated relapse continue in unmaintained remission, suggesting that debulking chemotherapy may not be necessary before BMT. Alternative approaches are needed in patients whose tumors progress on conventional dose therapy.     

Salvage therapy for relapsed or refractory non-Hodgkin's lymphoma utilizing autologous bone marrow transplantation

PURPOSE: Our objective was to evaluate the impact of high-dose therapy and autologous bone marrow transplantation as salvage treatment for recurrent non-Hodgkin's lymphoma in a defined group of patients from the Nebraska Lymphoma Study Group. DESIGN: Patients treated initially by oncologists from the Nebraska Lymphoma Study Group between January 1983 and July 1987 who subsequently underwent autologous bone marrow transplantation for recurrent or refractory disease were evaluated for treatment outcome. PATIENTS: Twenty-five patients with relapsed or refractory non-Hodgkin's lymphoma underwent high-dose therapy and autologous stem cell infusion in the time period reviewed. An initial doxorubicin (Adriamycin)-containing chemotherapy regimen had failed in all patients. The most favorable subgroup included 17 patients who were less then 60 years of age and had received no chemotherapy beyond their initial doxorubicin-containing regimen when referred for bone marrow transplantation. RESULTS: The complete response rate to the high-dose therapy was 52%, with an actuarial five-year disease-free survival of all patients treated of 40%. The overall survival at five years was 46%. CONCLUSIONS: High-dose chemo-radiotherapy, followed by infusion of autologous hematopoietic stem cells, can effectively function as salvage therapy in a significant number of patients in whom primary chemotherapy regimens for non-Hodgkin's lymphoma fail. This treatment approach appears to offer superior results when compared with the reported outcome for patients treated with salvage chemotherapy administered at conventional doses.     

Trial of high-dose cytarabine, cyclophosphamide, total-body irradiation, and autologous marrow transplantation for refractory lymphoma

Twenty-one patients with advanced non-Hodgkin's lymphoma or Hodgkin's disease who had failed to be cured with standard therapy were the subjects of this clinical trial. The patients received cytarabine (3 g/m2 at 12-hour intervals for six or eight doses), cyclophosphamide (90 mg/kg once), and total-body irradiation (one 900-cGy fraction or five 250-cGy fractions). Bone marrow was aspirated and cryopreserved before treatment and reinfused after the completion of radiotherapy. Eighteen patients (86%) had objective response and 12 (57%) achieved complete response. Three patients remain in continuous complete remission for 566+, 604+, and 1035+ days after marrow infusion. Six complete responders had tumor recurrence. One of these patients developed a localized lymphoma of another histology that was successfully treated with local radiotherapy and the patient is currently well 1004+ days after marrow infusion. Another relapsing patient responded to a brief course of salvage chemotherapy and is in remission at 1271+ days. Three of the complete responders died from infectious complications. This regimen was associated with significant toxicity. Six patients died from sepsis during the period of aplasia and three others died from interstitial pneumonia 42-105 days after marrow infusion. Although this regimen demonstrated a high level of antitumor activity, the value of adding high-dose cytarabine to the combination of cyclophosphamide and total-body irradiation remains unclear and would require a randomized clinical trial to demonstrate.     

Improved prognosis for patients with mediastinal lymphoblastic lymphoma

Patients with diffuse lymphoblastic lymphoma (which includes convoluted lymphocytic lymphoma) with mediastinal involvement have predictable progression of disease to a leukemic phase that is cytologically indistinguishable from acute lymphoblastic leukemia (ALL). Therefore we treated 12 patients with diffuse lymphoblastic lymphoma involving the mediastinum with therapy that is effective in ALL. Treatment consisted of intermittent combination chemotherapy with adriamycin and preventive central nervous system therapy (craniocervical irradiation and intrathecal methotrexate). Mediastinal irradiation was given either for initial respiratory distress or to patients who had incomplete regression of disease following induction chemotherapy. Eleven patients achieve complete remission. With a median follow-up of 41 mo, and using life table analysis, 86% of these patients have remained in continuous complete remission. The results of this study demonstrate the efficacy of treating diffuse lymphoblastic lymphoma with mediastinal presentation as a disseminated lymphoid malignancy.     

Graft-versus-lymphoma effect of donor lymphocyte infusion in indolent lymphomas relapsed after allogeneic stem cell transplantation

Donor lymphocyte infusions (DLI) are used to treat relapsed haematological diseases after allogeneic stem cell transplantation (SCT). We treated seven patients with DLI for indolent non-Hodgkin's lymphoma relapsed after SCT. In available blood and bone marrow samples, lymphoma cells were analysed by real-time quantitative polymerase chain reaction of t(14;18)-positive cells in follicular lymphoma, and by immunophenotyping in small lymphocytic lymphoma. Before DLI, three patients were treated with chemo- and/or radiotherapy, and one with rituximab. Evaluable responses to pre-DLI therapy were stable disease in one and partial remission (PR) in two patients. Six patients responded to DLI (complete remission (CR) in four and PR in two). After DLI, acute graft-versus-host disease (GVHD) occurred in 3/6 patients, classified as grade 2, whereas only limited chronic GVHD was seen (n=5). The four continuous CR are lasting for median 65+ (43-89) months. In the remaining patient, not responding to DLI, progressive disease was seen later on; chemotherapy followed by another DLI resulted in CR. In three cases, clinical responses to DLI could be substantiated by molecular or immunophenotypic analysis of lymphoma cells. We conclude that DLI is effective for treatment of indolent lymphoma relapsing after SCT.     

Chronic disseminated candidiasis complicated with a ruptured intracranial fungal aneurysm in ALL

An 11-year-old boy with acute lymphocytic leukemia (ALL) contracted disseminated candidiasis during induction therapy, which was complicated with rupture of a fungal cranial aneurysm. Ventricular drainage and coil embolization of a residual aneurysm in combination with intensive antifungal therapy rescued the patient. Although clinical improvement was achieved, high fever and elevated levels of C-reactive protein and β-D-glucan continued for more than 10 mo. One year later, the ALL relapsed during maintenance therapy with methotrexate and 6-mercaptopurine. After salvage chemotherapy, the patient received unrelated bone marrow transplantation (BMT) in a non-complete remission condition and survived. During subsequent chemotherapy and BMT, no recurrence of the fungal infection was observed under the prophylactic anti-fungal therapy with micafungin.     

Haematological malignancies developing in previously healthy individuals who received haematopoietic growth factors: report from the Research on Adverse Drug Events and Reports (RADAR) project

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) and granulocyte colony-stimulating factor (G-CSF) promote haematopoietic progenitor cell maturation. We reviewed the findings for healthy volunteers/donors who developed haematological malignancies following PEG-rHuMGDF or G-CSF administration. Information was reviewed for three of 538 volunteers who received PEG-rHuMGDF in clinical trials and two of 200 donors who underwent G-CSF mobilised stem cell harvesting procedures for sibling stem cell transplants. Mantle cell, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia were diagnosed 1-5 years after PEG-rHuMGDF exposure among three volunteers. For one patient, thrombocytopenia due to autoantibodies to PEG-rHuMGDF developed shortly after PEG-rHuMGDF administration and persisted until chemotherapy was administered. All three achieved complete remission, although one patient relapsed. Acute myeloid leukaemia was diagnosed 4 and 5 years after G-CSF mobilisation in two donors who underwent peripheral blood stem cell donation for sibling allogeneic haematopoietic stem cell transplantation. Following intensive chemotherapy, one died from acute leukaemia and the second is in complete remission. Controversy exists over the appropriateness of administering haematopoietic growth factors to healthy individuals. While a causal relationship with haematological malignancies cannot be demonstrated, long-term follow-up among healthy individuals who receive haematopoietic growth factors is needed.