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.     

Restoration of normal hematopoiesis by bone marrow ablation and allogeneic marrow transplantation in a case of Hodgkin''s disease therapy-related preleukemia

Therapy-related leukemias are generally preceded by a preleukemic phase of several months duration, characterized by pancytopenia, abnormal bone marrow findings, and nonrandom chromosomal abnormalities in almost all cases. No specific therapeutic guidelines are recommended in this preleukemic phase or any other type of preleukemia; aggressive combination chemotherapy is usually withheld until the full expression of leukemia. A 22-yr-old man with therapy-related preleukemia following treatment of Hodgkin's disease received as primary treatment ablative chemotherapy followed by marrow transplantation from his histocompatible sister. At day 316, the patient is still in complete bone marrow recovery with a normal donor karyotype. In the light of the very poor results obtained with conventional chemotherapy regimens once the leukemic phase is established, we suggest that bone marrow transplantation, if undertaken before leukemic conversion, may be the treatment of choice in young adults with therapy-related preleukemia.     

Blood product support in patients undergoing chemotherapy and autologous or allogeneic bone marrow transplantation for haematological malignancies

Three groups of patients with leukaemia and myelodysplasia were assessed with regard to the blood product support they required during their period of bone marrow hypoplasia following treatment. One group received myelo-ablative remission-induction chemotherapy followed by appropriate consolidation therapy (two courses in patients with acute myeloid leukaemia and one or two intensification courses in patients with acute lymphoblastic leukaemia); whilst the other two had 'conditioning' with chemotherapy and radiotherapy prior to autologous bone marrow transplantation (auto-BMT) or T cell depleted allogeneic bone marrow transplantation (allo-BMT). There was no statistically significant difference in blood product requirements between the three groups. However, platelet requirements during remission-induction chemotherapy alone were significantly less than for allo-BMT or auto-BMT. Platelet requirements for patients undergoing auto-BMT were also significantly higher than for patients receiving consolidation chemotherapy; and were required for a longer period than for patients receiving allogeneic-BMT. There was no difference in blood product support between ABO matched and mismatched transplants within the allogeneic group, but the presence of graft versus host disease and/or cytomegalovirus infection did significantly increase the requirements for blood product support.     

Allogeneic bone marrow transplantation as primary therapy for chronic myelomonocytic leukemia

Summary This is the first report of a successful bone marrow transplantation for chronic myelomonocytic leukemia. A 41-year-old woman with chronic myelomonocytic leukemia received, as primary treatment, a novel preparatory regimen consisting of high dose fractionated total body irradiation and high dose VP-16 chemotherapy followed by allogeneic marrow transplantation from her histocompatible brother. The patient is now more than two years after marrow transplantation with normal blood counts and a normal bone marrow which is of donor type. For younger patients with this disease who have a histocompatible sibling donor, bone marrow transplantation may represent a valid therapeutic option with curative potential.This investigation was supported by PHS Grants CA 30206 and CA 33572 awarded by the National Cancer Institute, DHHS     

Bone marrow transplantation for acute leukemia: recent advances and comparison with alternative therapies

Bone marrow transplantation is an effective therapy in patients with acute leukemia. High-dose chemotherapy with or without total body irradiation and allogeneic bone marrow transplantation is a more effective antileukemic treatment than chemotherapy. This approach is limited, however, by a relatively high risk of transplant-related complications, particularly graft rejection, GVHD, and interstitial pneumonitis. Autologous bone marrow transplantation avoids the problems of graft rejection and GVHD. It does, however, introduce a risk of reinfusing residual leukemia cells with the autologous bone marrow and absence of a possible graft-versus-leukemia effect associated with allogeneic transplants. Bone marrow transplantation is useful in AML. Syngeneic or allogeneic HLA-identical bone marrow transplantation is the preferred treatment for patients under age 45 to 50 who fail chemotherapy. Transplantation is also likely to be superior or comparable to chemotherapy for patients less than 20 to 30 years of age in first remission. Transplantation in older individuals in first remission is controversial; results are comparable to those achieved with postremission chemotherapy. Transplants from donors other than HLA-identical siblings must be considered investigational but may be a reasonable alternative in young individuals in first relapse or second remission. Autotransplants are difficult to evaluate critically but may be considered as investigational therapy for individuals in second or later remission for whom a suitable allogeneic donor is unavailable. Autotransplants in first remission should be restricted to controlled clinical trials because it is otherwise impossible to determine their efficacy. It is uncertain whether ex vivo treatment of the bone marrow to remove leukemia cells is necessary in the context of autotransplantation; again, controlled trials are required. Bone marrow transplantation from an HLA-identical sibling is effective in individuals with ALL who relapse despite chemotherapy. Patients undergoing transplantation while in second or later remission or in relapse have a survival rate superior to those treated with chemotherapy. One important and unresolved issue is whether patients with high-risk ALL should receive bone marrow transplants or intensive postremission chemotherapy while in first remission; controlled clinical trials are needed. Bone marrow transplants from donors other than HLA-identical siblings and autologous bone marrow transplants are investigational approaches that should be considered in selected young patients who fail despite chemotherapy.(ABSTRACT TRUNCATED AT 400 WORDS)     

Autologous bone marrow transplantation in acute leukaemia

Intensive chemoradiotherapy with autologous bone marrow rescue has been widely explored as treatment for acute myeloblastic and acute lymphoblastic leukaemia. Encouraging preliminary results have been reported but in no situation has this modality of therapy been proved to be superior to conventional chemotherapy. Attempts to remove minimal residual disease from the harvested marrow have been made by both immunological and pharmacological means, but the value of such procedures has not been tested rigorously. Determination of the precise role of autologous bone marrow transplantation in the treatment of acute leukaemia must await the outcome of randomised controlled trials and will take several years.     

Autologous bone marrow transplantation in children

Autologous bone marrow transplantation is a procedure that allows for the delivery of high doses of chemotherapy and radiation to treat pediatric malignancies. There have been many studies showing a dose-response curve for many of the drugs that have been used for cytoreductive therapy in autologous bone marrow transplantation. These dosage ranges are achievable in many of the preparative regimens used in autologous bone marrow transplantation. The results in neuroblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, Ewing's sarcoma, rhabdomyosarcoma, osseous sarcoma, other soft tissue sarcomas, and acute leukemias (acute lymphoblastic leukemia and acute non-lymphoblastic leukemia) are reviewed. The question of purging of bone marrow during autologous bone marrow transplantation is addressed. The different techniques of purging are reviewed and the advantages and disadvantages of each are discussed. Finally, new areas of treatment and future directions of autologous bone marrow transplantation are addressed.     

High-dose cyclophosphamide, carmustine, and etoposide and autologous bone marrow transplantation for relapsed Hodgkin's disease

Thirty patients with relapsed Hodgkin's disease were treated with high-dose cyclophosphamide, carmustine, and etoposide (CBV) and autologous bone marrow transplantation. The median age of the patients was 28 years, and 18 were male. More than half had extranodal sites of relapse and constitutional symptoms. Most had been heavily pretreated with multiple salvage chemotherapy regimens and radiotherapy. At the time of transplantation, 23 patients were having progressive disease despite salvage chemotherapy. High-dose CBV chemotherapy induced complete responses in 15 patients and partial responses in 10 patients. Eleven patients are still in complete remission, 1 of whom has had an unmaintained remission for more than 44 months. Toxicity was moderate; all patients had severe myelosuppression requiring supportive therapy, and 1 patient failed to reconstitute her bone marrow. High-dose CBV chemotherapy and autologous bone marrow rescue proved to be effective as salvage therapy for a select group of heavily pretreated patients with relapsed Hodgkin's disease.     

Philadelphia chromosome positive acute lymphoblastic leukemia showing normal karyotype in G-banding chromosomal examination before chemotherapy

A 29-year-old male was admitted because of thrombocytopenia. A diagnosis of acute lymphoblastic leukaemia was made on the basis of a 61.6% infiltration of leukemic cells in his bone marrow. Standard G-binding chromosome analysis of bone marrow cells revealed a normal karyotype. He received combination chemotherapy, and achieved hematological complete remission. However, chromosomal analysis of bone marrow cells after 2 courses of consolidation therapy showed the Philadelphia (Ph) chromosome in two cells out of 20 analysed. We retrospectively examined the sample of bone marrow cells before chemotherapy; It showed minor BCR/ABL positivity with FISH and RT-PCR methods. The Ph chromosome disappeared after consolidation chemotherapy and allogeneic bone marrow transplantation, but the Ph chromosome reappeared at relapse. We postulated that there were two clones, both a Ph-positive clone and Ph-negative clone. At the initial diagnosis, Ph chromosome was not detected because the G-banding method analyzed only metaphase cells, which contained few Ph-positive clones. In order to offer effective therapy with molecular targeting agents, in this poor prognostic disease, it is necessary to detect Ph chromosome before the first chemotherapy and BCR/ABL detection with FISH or RT-PCR methods appears more useful than G-banding chromosome analysis.     

Recurrent disseminated retinoblastoma in a 7-year-old girl treated successfully by high-dose chemotherapy and CD34-selected autologous peripheral blood stem cell transplantation

A localized retinoblastoma of the left eye in a 7-year-old girl, was treated by enucleation. She received no additional therapy. Four months later, metastases of retinoblastoma in the lymph nodes, bone and bone marrow were diagnosed. Relapse chemotherapy consisting of three courses of vincristine, cyclophosphamide, etoposide and carboplatin led to a second complete remission. Subsequent high-dose chemotherapy with thiotepa, etoposide and carboplatin and autologous stem cell transplantation with CD34-selected stem cells were successful, with no adverse effects. No radiotherapy was given and the girl remains in continuous second remission with a follow-up of more than 4 years.     

Philadelphia chromosome positive acute lymphoblastic leukemia showing normal karyotype in G-banding chromosomal examination before chemotherapy

A 29-year-old male was admitted because of thrombocytopenia. A diagnosis of acute lymphoblastic leukaemia was made on the basis of a 61.6% infiltration of leukemic cells in his bone marrow. Standard G-binding chromosome analysis of bone marrow cells revealed a normal karyotype. He received combination chemotherapy, and achieved hematological complete remission. However, chromosomal analysis of bone marrow cells after 2 courses of consolidation therapy showed the Philadelphia (Ph) chromosome in two cells out of 20 analysed. We retrospectively examined the sample of bone marrow cells before chemotherapy; It showed minor BCR/ABL positivity with FISH and RT-PCR methods. The Ph chromosome disappeared after consolidation chemotherapy and allogeneic bone marrow transplantation, but the Ph chromosome reappeared at relapse. We postulated that there were two clones, both a Ph-positive clone and Ph-negative clone. At the initial diagnosis, Ph chromosome was not detected because the G-banding method analyzed only metaphase cells, which contained few Ph-positive clones. In order to offer effective therapy with molecular targeting agents, in this poor prognostic disease, it is necessary to detect Ph chromosome before the first chemotherapy and BCR/ABL detection with FISH or RT-PCR methods appears more useful than G-banding chromosome analysis.     

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.     

Nosocomial Legionnaires' disease: Occurrence in recipients of bone marrow transplants

Nosocomial pneumonia caused by Legionella pneumophila serogroup 1 occurred in five patients after bone marrow transplantation for hematologic malignancies. Two patients died as a result of the infection despite treatment with erythromycin. Serologic screening revealed no other cases of Legionnaires' disease in 40 consecutive recipients of bone marrow transplants, giving a frequency of infection of 13 percent. These five cases represent 23 percent of the pneumonia occurring in this group of patients. Patients undergoing bone marrow transplantation are highly susceptible to infectious complications. Legionnaires' disease must now be added to the list of pathogens infecting this group of patients. Erythromycin is not generally a part of standard empiric antibiotic regimens in febrile neutropenic patients, but appears to be a reasonable addition when pneumonia does not respond to conventional, empiric treatment. Even with appropriate therapy, Legionnaires' disease remains a highly lethal infection in immunocompromised hosts.     

Allogeneic bone marrow transplantation versus chemotherapy for childhood acute lymphoblastic leukaemia in second remission

Thirty-six children with acute lymphoblastic leukaemia (ALL) in second remission were treated with conventional chemotherapy or with cyclophosphamide and fractionated total-body irradiation followed by an allogeneic bone marrow transplant; the choice of treatment was dictated by the availability of an HLA-identical sibling. The age, sex, clinical data at presentation of the disease and duration of first remission were comparable for the two groups of patients. In the bone marrow transplantation group two patients died of graft-versus-host disease and five of leukaemia. Ten patients survive, nine disease free, 13-53 months from second remission (6-51 months post-bone marrow transplantation). In the chemotherapy group 14 patients died of leukaemia (2-29 months from second remission) and five survive (22-34 months from second remission). The actuarial survival for patients with bone marrow transplantation is 48% at 4 years as compared with 22% for those of the chemotherapy group (P = 0.04); the actuarial probabilities of being in remission are 58 and 18% in the two groups respectively (P = 0.01). This study confirms that allogeneic bone marrow transplantation is superior to chemotherapy in patients in second remission with ALL and should be considered in the presence of an HLA-identical sibling.     

Pulmonary surveillance using bronchoscopy and bronchoalveolar lavage during high-dose antineoplastic therapy

Pulmonary failure is a major contributor to morbidity and mortality during marrow aplasia following high-dose antineoplastic therapy. For this reason, we initiated a pulmonary surveillance program for patients undergoing high-dose chemotherapy for leukemia or bone marrow transplantation. As part of this program, bronchoscopy with BAL was performed prior to therapy and at the onset of granulocytopenia. Thirty-three of the first 57 patients managed in this program developed some evidence of pulmonary complications. Twelve patients died in aplasia; all had pulmonary failure. Forty patients had clinically significant abnormalities on the bronchoscopy before treatment including 12 of 19 patients who had normal findings on chest x-ray films, physical examination, and pulmonary function testing, and no fever. Twenty-seven patients had clinically significant abnormal bronchoscopy or BAL at the onset of granulocytopenia. Thirteen patients required additional bronchoscopy. No patient required an open lung biopsy. Pulmonary surveillance using bronchoscopy with BAL is useful in the detection of pulmonary disease prior to the initiation of and following high-dose antineoplastic therapy.     

Bone marrow transplantation for acute myeloblastic leukaemia: an EBMT Leukaemia Working Party prospective analysis from HLA-typing

Summary. The optimal post-remission therapy for patients with acute myeloblastic leukaemia remains controversial. Allogeneic bone marrow transplantation, autologous bone marrow transplantation, and consolidation chemotherapy are the major options. In order to evaluate their respective value the European Group for Bone Marrow Transplantation conducted a prospective registration study. Patients with newly diagnosed acute myeloblastic leukaemia were registered at the time of HLA-typing and intention to treat in case of presence or absence of an HLA-identical donor was recorded. 27/79 (34%) patients HLA-typed at diagnosis had an identical donor identified. The estimated survivals at 3 years from HLA-typing were 44% and 21% among patients with or without HLA-identical donor, respectively ( P = 0·02). 22/26 (85%) patients for whom allogeneic bone marrow transplantation was intended were transplanted but only 15/47 (32%) patients for whom autologous bone marrow transplantation was intended were indeed transplanted ( P < 0·001). The survival was 50%. 29% and 17% ( P = 0·004) for patients treated with allogeneic bone marrow transplantation, autologous bone marrow transplantation, or chemotherapy, respectively. 40/68 patients HLA-typed in first complete remission had an HLA-identical donor. The estimated 3-year survival among patients typed in first remission with and without HLA-identical donors was 42% and 35% (n.s.), respectively. This technique of early patient registration illustrates the problems of patient selection during the course of the disease and might be used as a complement to randomized trials when comparing bone marrow transplantation and other treatment options.     

Intensive therapy followed by bone marrow transplantation for patients with acute lymphocytic leukemia in second or subsequent remission: determination of prognostic factors (a report from the University of Minnesota Bone Marrow Transplantation Team)

Fifteen patients with acute lymphocytic leukemia (ALL) in second or subsequent remission received intensive therapy with cyclophosphamide and single dose, rapid rate (26 cGy/min) total body irradiation (TBI) followed by bone marrow transplantation (BMT) from a histocompatible sibling match. Outcome was compared to that of 23 conventionally treated control patients in second ALL remission who presented to the same institution during the same time period but had no available transplant donor. The 15 BMT patients and 23 control patients had similar characteristics, with the exception that the BMT patients were significantly older at the time of ALL diagnosis (12.6 yr versus 5.7 yr, p = 0.01). BMT patients had a significantly increased chance of remaining disease-free for 36 mo from time on study (43% actuarial versus 5%, p = 0.004) and a greater overall survival rate at 48 mo (47% actuarial versus 9%, p = 0.27) than the conventionally treated patients. In all, 5 of the bone marrow transplant patients (33%) remain alive and free of disease 24-48 + mo from transplantation. Several pre- and posttransplant characteristics were analyzed to determine predictive factors for a successful BMT outcome for patients with ALL in second or subsequent remission. Significant risk factors for predicting leukemic relapse included initial white blood count (WBC) greater than 50,000/microliters at ALL diagnosis (100% relapse rate versus 37% for patients with lower WBCs, p = 0.001) and presence of any extramedullary disease pre-BMT (100% relapse rate versus 37% for patients without extramedullary disease, p = 0.03). All 5 disease-free BMT survivors had initial WBCs less than 50,000/microliters and no evidence of extramedullary disease pretransplantation. Maintenance chemotherapy with 6-mercaptopurine (6MP) and methotrexate was given to four patients starting 100 days after bone marrow transplantation. Use of maintenance chemotherapy was associated with a significantly increased chance of remaining disease free (100% of patients surviving leukemia-free versus 17% for patients not receiving maintenance chemotherapy, p = 0.02). Presence of graft-versus-host disease (GVHD) did not influence leukemia-free survival. These results confirm that intensive therapy followed by bone marrow transplantation is the treatment of choice for patients with ALL in second or subsequent remission who have a histocompatible sibling match. Furthermore, the data suggest that a controlled trial to evaluate the efficacy of maintenance chemotherapy post-BMT for ALL patients is warranted.     

Transient reversal of bone marrow aplasia associated with lymphocyte depleted Hodgkin's disease after combination chemotherapy

This report describes a patient with lymphocyte depleted Hodgkin's disease who presented with bone marrow aplasia. The aplastic marrow reverted to normal after initiation of MOPP chemotherapy; however, 4 months after completion of therapy, bone marrow aplasia recurred in the absence of recurrent Hodgkin's disease. The patient remains free of Hodgkin's disease 34 months after completion of chemotherapy. Bone marrow abnormalities in Hodgkin's disease are reviewed and the current understanding of the pathological mechanisms leading to aplastic anemia is discussed.     

Acute myeloid leukemia and the position of autologous stem cell transplantation

Most adult patients with acute myeloid leukemia (AML) who reach a complete remission (CR) after induction chemotherapy will relapse if they do not receive further therapy. Autologous stem cell transplantation (SCT) represents one of the options of postremission therapy in AML. Here we discuss the therapeutic impact of consolidation treatment with autologous SCT that has been studied extensively. Meta-analyses of published randomized trials using bone marrow as the source of stem cells show a modest improvement of disease-free survival as compared to nonmyeloablative chemotherapy. However, there is no apparent improvement of overall survival, probably due to the slightly increased mortality associated with autologous bone marrow transplantation (BMT). Subsequently, the value of autologous SCT in different prognostic subsets of AML is discussed. Autologous mobilized peripheral blood stem cell (PBSC) transplantation offers a much faster hematopoietic recovery and is associated with reduced morbidity and treatment-related mortality. To fully appreciate the role of autologous PBSC transplantation, the results of a recently closed randomized trial must be awaited.     

Lymphocytic pneumonitis following bone marrow transplantation in severe combined immunodeficiency

Lung disease in patients with severe combined immune deficiency (SCID) undergoing bone marrow transplantation (BMT) is most commonly caused by infection. Noninfectious episodes of pulmonary disease following BMT are more frequently encountered in patients with hematologic disorders or malignancy and are probably related to ablation therapy or graft-versus-host disease (GVHD). In contrast, patients with SCID do not receive chemotherapy before an HLA-identical allogeneic BMT and they do not suffer significant GVHD. We report a patient who developed severe lung disease during the period of rapid engraftment following an HLA-identical allogeneic bone marrow transplantation. Lung biopsy showed dense lymphocytic infiltrates in the alveolar septae and no evidence of infection. Following the idea that the acute recruitment of engrafted lymphocytes may have contributed to or caused the pulmonary disease, we have attempted to suppress cellular immunity by administering high-dose methylprednisolone. The patient's lung disease rapidly improved and eventually completely resolved.