Subsequent Bone Marrow Transplantation Research Articles

Pleuro‐pulmonary blastoma: A case report and review of the literature

Pleuro-pulmonary blastoma is a rare malignant lung tumor in children and distinct from ordinary pulmonary blastoma of adulthood. Combination chemotherapy plays an important role in the treatment of this tumor, but so far no attempt of high dose chemotherapy with subsequent bone marrow or blood stem cell transplantation has been published. The case is reported of a 2-year-old boy with pleuro-pulmonary blastoma who achieved partial remission with conventional chemotherapy and surgery. Subsequent administration of high dose melphalan, etoposide, and carboplatin, followed by autologous blood stem cell transplantation resulted in a 3-month disease-free interval but did not prevent eventual local recurrence, leading to death within a few weeks. Clinical presentation, pathology, management, and prognosis are discussed and the literature reviewed.

787 Multiple cycles of aggressive chemotherapy for relapsed lymphoma

Patients with non-Hodgkin's lymphoma and advanced Hodgkin's disease who relapse after first line therapy have a poor prognosis. Around 30–40% of patients with disease sensitive to salvage chemotherapy achieve long term survival after subsequent high dose chemotherapy (HDCT) and autologous bone marrow transplantation (ABMT). In addition, for patients undergoing HDCT, the use of peripheral blood progenitor cells (PBPC) results in faster neutrophil and platelet recovery compared with bone marrow. Based on the premise that a single cycle of HDCT may be suboptimal, we piloted a regimen combining 5 days of infusional ara-C and etoposide with bolus doses of cyclophosphamide and methotrexate and high dose oral dexamethasone (MADEC) as a salvage therapy for patients with relapsed lymphoma. Following MADEC all patients received granulocyte colony stimulating factor to assist in mobilisation of PBPC, and to reduce the incidence of febrile neutropenia. Twenty-five patients with relapsed lymphoma (19 with intermediate grade non-Hodgkin's lymphoma, 6 with Hodgkin's disease) received a total of 45 cycles of MADEC. All had demonstrated response to prior induction chemotherapy (22 CR, 3 PR) with median duration of response of 6 months (1–60 mos). There was one toxic death. The MADEC regimen was intensely myelosuppressive. All patients had nadir granulocyte counts of > 0.5 × 109/l, resulting in hospitalisation for febrile neutropenia after 35 of 45 cycles. Platelet and packed cell transfusions were required after the majority of cycles. Non-haematological toxicity was mainly mucositis and was generally mild. Of 24 evaluable patients 8 achieved CR after MADEC and 10 achieved PR (6 pts with residual masses had gallium scans, 5 were negative). Patients responding following cycle 1 underwent leukapheresis after the neutrophil nadir. Median number of leukaphereses was 2 (1–4). Median number of CD34+ cells mobilised was 2.75 × 106/kg (0.5–22.8 × 106/kg) and median number of CFU-GM was 68.4 × 104/kg (0.5–697.5 × 104/kg). In responding patients a second course ofMADEC was given to achieve maximal reduction of disease bulk prior to transplantation. Sixteen patients proceeded to HDCT with PBPC support. All patients engrafted successfully with median days to ANC Conclusion The MADEC regimen was useful for identifying patients with chemosensitive disease who may benefit from HDCT and for maximal reduction of disease bulk prior to the procedure. Combination with G-CSF resulted in mobilisation of adequate numbers of PBPC to support engraftment after HDCT The therapeutic benefits of this regimen relative to less intensive regimens prior to transplant warrants evaluation.

Autologous or Allogeneic Bone Marrow Transplantation Compared with Intensive Chemotherapy in Acute Myelogenous Leukemia

Allogeneic or autologous bone marrow transplantation and intensive consolidation chemotherapy are used to treat acute myelogenous leukemia in a first complete remission. After induction treatment with daunorubicin and cytarabine, patients who had a complete remission received a first course of intensive consolidation chemotherapy, combining intermediate-dose cytarabine and amsacrine. Patients with an HLA-identical sibling were assigned to undergo allogeneic bone marrow transplantation; the others were randomly assigned to undergo autologous bone marrow transplantation (with unpurged bone marrow) or a second course of intensive chemotherapy, combining high-dose cytarabine and daunorubicin. Comparisons were made on the basis of the intention to treat. A total of 623 patients had a complete remission; 168 were assigned to undergo allogeneic bone marrow transplantation, and 254 were randomly assigned to one of the other two groups. Of these patients, 343 completed the treatment assignment: 144 in the allogeneic-transplantation group, 95 in the autologous-transplantation group, and 104 in the intensive-chemotherapy group. The relapse rate was highest in the intensive-chemotherapy group and lowest in the allogeneic-transplantation group, whereas the mortality rate was highest after allogeneic transplantation and lowest after intensive chemotherapy. The projected rate of disease-free survival at four years was 55 percent for allogeneic transplantation, 48 percent for autologous transplantation, and 30 percent for intensive chemotherapy. However, the overall survival after complete remission was similar in the three groups, since more patients who relapsed after a second course of intensive chemotherapy had a response to subsequent autologous bone marrow transplantation. Other differences were also observed, especially with regard to hematopoietic recovery (it occurred later after autologous transplantation) and the duration of hospitalization (it was longer with bone marrow transplantation). Autologous as well as allogeneic bone marrow transplantation results in better disease-free survival than intensive consolidation chemotherapy with high-dose cytarabine and daunorubicin. Transplantation soon after a relapse or during a second complete remission might also be appropriate.

Single dose versus fractionated total body irradiation before bone marrow transplantation: Radiobiological and clinical considerations

Purpose : This present review is intended to evaluate the specific influence of fractionation of total body irradiation on the outcome of a subsequent bone marrow transplantation. Methods and Materials : Available experimental and clinical data on the influence of fractionation on leukemia cell killing, immunosuppression, and sparing of normal tissues were analyzed. Results : Review of available data shows: (a) The role of fractionation on leukemia cell killing may vary with the leukemia type. For acute nonlymphoblastic leukemia, a few experimental and several clinical studies show no or little fractionation effect; a 12–13 Gy fractionated scheme could, therefore, be more efficient than a conventional 10 Gy single dose total body irradiation. For chronic myelogenous leukemia, some sensitivity to fractionation is suggested, so that an increase in total or fractional dose may be necessary in fractionated schemes to equate the efficacy of a 10 Gy single dose. For acute lymphoblastic leukemia, a high fractionation sensitivity was observed for some leukemic cell lines in vitro, without undisputable clinical confirmation for the moment. (b) Numerous experimental studies have demonstrated that the immunosuppressive effect of total body irradiation, a major determinant of engraftment, is highly fractionation sensitive. In humans, high rates of graft failures have been reported when T-cell depletion of the graft was associated to fractionated total body irradiation schedules. (c) A large amount of radiobiological and clinical data have demonstrated that late radiation-induced injuries to normal tissues and organs are highly fractionation sensitive. However, in a context of total body irradiation for bone marrow transplantation, the number of other determinants of normal tissue damage makes it difficult to demonstrate a clear-cut advantage of fractionated over single dose scheme, with a possible exception for children. Conclusions : In 1994, available data suggest that very cautious attempts could be made to adapt total body irradiation schedules to the potential normal tissue toxicity, T-cell depletion, and to the type of leukemia.

Understanding the mechanism of cure of acute myeloid leukemia by allogeneic bone marrow transplantation: toward the application of interleukin-2 in autologous bone marrow transplantation.

Analysis of the results of different methods of post remission therapy in acute myeloid leukemia (AML) has been used to study their impact on outcome, with a particular emphasis on antileukemic effects by contrasting the risk of relapse. We have compared consolidation chemotherapy (CT), autologous bone marrow transplantation (ABMT) with and without subsequent interleukin-2 (IL-2) and allogeneic bone marrow transplantation (BMT). Additionally we have studied the immunological consequences of each of these maneuvers with particular regard to the cellular components having proven or suspected antileukemic properties and the secondary cytokines released by these cells in vitro and in vivo.

Immunosuppressive Therapy of Aplastic Anemia: Results of a Prospective, Randomized Trial of Antithymocyte Globulin (ATG), Methylprednisolone, and Oxymetholone to ATG, Very High-Dose Methylprednisolone, and Oxymetholone

Sixty-eight patients with moderate (n = 15) or severe (n = 53) aplastic anemia were entered into a prospective, randomized, two-arm treatment study comparing antihuman thymocyte globulin (ATG), lower-dose methylprednisolone (LDM) and oxymetholone to ATG, higher-dose methylprednisolone (HDM), and oxymetholone. There were no differences between the two groups when comparing age, sex, etiology of aplasia, disease duration, severity of aplasia, or pretherapy granulocyte counts. Side effects of LDM and HDM were similar. Of the 64 patients evaluable for response to therapy, 12 of 33 (36%) who received LDM had complete, partial, or minimal responses compared with 15 of 31 patients (48%) who received HDM (P = .33). Actuarial survival at 4 years is 43% for patients in the LDM group and 47% for patients in the HDM group (P = .99). Causes of death included hemorrhage, infection, evolution to acute leukemia, and complications of subsequent bone marrow transplantation. Long-term complications included paroxysmal nocturnal hemoglobinuria (n = 3), evolution to myelodysplasia or acute leukemia (n = 6), and recurrent aplasia (n = 6). We were unable to show a significant difference in toxicity, response rate, or survival for patients treated with ATG, oxymetholone, and LDM compared with patients who received ATG, oxymetholone, and HDM.

Immunosuppressive therapy of aplastic anemia: results of a prospective, randomized trial of antithymocyte globulin (ATG), methylprednisolone, and oxymetholone to ATG, very high-dose methylprednisolone, and oxymetholone

Sixty-eight patients with moderate (n = 15) or severe (n = 53) aplastic anemia were entered into a prospective, randomized, two-arm treatment study comparing antihuman thymocyte globulin (ATG), lower-dose methylprednisolone (LDM) and oxymetholone to ATG, higher-dose methylprednisolone (HDM), and oxymetholone. There were no differences between the two groups when comparing age, sex, etiology of aplasia, disease duration, severity of aplasia, or pretherapy granulocyte counts. Side effects of LDM and HDM were similar. Of the 64 patients evaluable for response to therapy, 12 of 33 (36%) who received LDM had complete, partial, or minimal responses compared with 15 of 31 patients (48%) who received HDM (P = .33). Actuarial survival at 4 years is 43% for patients in the LDM group and 47% for patients in the HDM group (P = .99). Causes of death included hemorrhage, infection, evolution to acute leukemia, and complications of subsequent bone marrow transplantation. Long-term complications included paroxysmal nocturnal hemoglobinuria (n = 3), evolution to myelodysplasia or acute leukemia (n = 6), and recurrent aplasia (n = 6). We were unable to show a significant difference in toxicity, response rate, or survival for patients treated with ATG, oxymetholone, and LDM compared with patients who received ATG, oxymetholone, and HDM.

The treatment of acute myeloid leukaemia preceded by the myelodysplastic syndrome

Most cases of acute myeloid leukaemia in the elderly and about 15% of the cases in younger patients follow a myelodysplastic disease. This disease may differ biologically from de novo AML making cure more difficult. Understanding post-MDS AML is difficult because of its preponderance in the elderly and the many complicating factors of treating old people. However, it is likely that postMDS AML is more resistant to chemotherapy than de novo AML, that periods of pancytopenia last longer following chemotherapy and remissions are shorter. In younger patients high complete remission rates are achievable with aggressive chemotherapy and good supportive care. Such patients are best served by subsequent allogeneic bone marrow transplantation if possible, and if not then bone marrow autograft or a maintained remission should be considered. For older patients cure is unlikely and the choice between low-dose cytarabine and aggressive chemotherapy must be made if treatment is to be contemplated at all. The former leads to less hospitalisation and fewer side effects, but the latter gives a greater chance of a complete remission. This will not be long lasting.

Monoclonal gammapathies in long-term surviving Rhesus monkeys after lethal irradiation and bone marrow transplantation

Late effects of total body irradiation and subsequent autologous bone marrow transplantation on the development of age-related monoclonal gammapathies (MG) were studied in 14 long-term surviving Rhesus monkeys. Together with 27 untreated control monkeys, they have been followed up for more than 20 years. In contrast with the control group, the experimental monkeys developed MG with aging in higher frequencies, earlier and mainly of the benign MG category. One experimental monkey developed a multiple myeloma, the first observed in the nonhuman primates so far. These results indicate an accelerated senescence of the immune system in the experimental monkeys as a late consequence of tissue or cell damage during irradiation.

Treatment of relapsed non-Hodgkin's lymphomas with dexamethasone, high-dose cytarabine, and cisplatin before marrow transplantation.

Combination chemotherapy is capable of curing many patients with newly diagnosed intermediate- and high-grade non-Hodgkin's lymphomas (NHL), but treatment of relapsed NHL remains problematic. Bone marrow transplantation (BMT) offers the best chance for disease-free survival, but interim chemotherapy is often necessary while awaiting BMT, especially for patients with bulky disease. We report here 39 patients (median age, 44 years) who failed primary therapy with doxorubicin-based regimens and subsequently were treated with one to six cycles of dexamethasone, 40 mg intravenous (IV) every day on days 1 to 4, cisplatin 100 mg/m2 by continuous infusion on day 1, and cytarabine 2 g/m2 IV every 12 hours x two doses on day 2 (DHAP) before the planned BMT. Histologies included 16 diffuse large-cell, six diffuse mixed, five diffuse small-cleaved, four lymphoblastic, and eight other. Twenty-eight patients had stage IV disease, 13 had B symptoms, and 20 had an elevated lactate dehydrogenase (LDH). Patients had been treated with a median of three previous chemotherapy regimens. Sixty-one percent of patients had high tumor burdens according to the MD Anderson criteria. Objective responses to DHAP were seen in 26 patients (67%) including nine complete responses (CRs) (23%) and 17 partial responses (PRs) (44%), and responses lasted a median of 7.5 months. Myelosuppression was the major toxicity, but there were no treatment-related deaths. To date, 17 patients have undergone subsequent BMT with a projected 3-year disease-free survival of 15%. We conclude that the DHAP regimen is effective short-term salvage therapy for relapsed NHL patients, but the long-term prognosis of multiply relapsed patients remains poor.

Mime Combination Chemotherapy in Recurrent or Refractory Lymphoproliferative Malignancies: A Phase II Study

Seventy-two patients with recurrent or refractory malignant lymphoproliferative diseases were treated with MIME combination chemotherapy (methyl-GAG, ifosfamide, methotrexate, etoposide) and concurrent mesna to prevent urothelial toxicity; 41 patients had high/intermediate-grade non-Hodgkin's lymphoma (NHL), 18 low-grade NHL/chronic lymphocytic leukemia (CLL), and 13 Hodgkin's disease (HD). The overall response rates were 56% in high/intermediate-grade NHL, 11% in low-grade NHL/CLL, and 69% in HD respectively. Median survival in the same 3 groups was 7, 2 and 10 months respectively. Neither previous type of response to chemotherapy nor previous amount of treatment predicted the outcome of MIME chemotherapy. Toxicity was modest, hemorrhagic cystitis did not occur, and only one therapy-related death occurred. Although MIME appears to be a safe treatment with considerable activity in recurrent or refractory lymphoproliferative disease very few patients become long-term survivors. However, MIME is well suited for remission induction in patients intended for subsequent autologous bone-marrow transplantation.

Substitution von Blutbestandteilen

Cell substitution in the form of "tailored haemotherapy " should be an essential part of medical oncology at the present time. In the conventional therapy of solid tumors patients do not enter into prolonged phases of severe haemopoietic insufficiency. Accordingly platelet and granulocyte transfusions will be exceptional. It is mainly the red cell transfusion which plays the most important role. The possible complication of cell substitution should always be kept in mind. Here the risk of alloimmunisation which makes a continuation of transfusion therapy or a subsequent bone marrow transplantation problematic, is just one of the examples. Modern cell separation techniques allow the production of highly concentrated cell preparations aiming at the reduction of the frequency of transfusions and minimizing the risk of sensitisation. If rich concentrated preparations have to be given to immunodeficient patients an irradiation should proceed their transfusion, otherwise the immunocompetent lymphocytes contained in the preparations could induce graft versus host reactions. Allogenic bone marrow transplantation is more becoming the treatment of choice for severe combined immunodeficiency, severe aplastic anemia, acute myeloid leukemia, and chronic myeloid leukemia. At the present time the place of allogeneic or autologous bone marrow transplantation as a treatment of lymphomas and solid tumors is still unsettled.

Increase in histidine decarboxylase activity in skin of genetically mast-cell-deficient W/Wv mice after application of phorbol 12-myristate 13-acetate: evidence for the presence of histamine-producing cells without basophilic granules.

Histidine decarboxylase (HisDCase, EC 4.1.1.22) activity in mouse skin increased by a factor of more than 10 after a single application of phorbol 12-myristate 13-acetate. The cell type that was responsible for the increase in HisDCase activity was examined by using (WB X C57BL/6)F1-W/Wv mice, which are genetically deficient in tissue mast cells. In contrast to a report that increase of ornithine decarboxylase (EC 4.1.1.17) activity occurs in the epidermis [O'Brien, T. G., Simisiman, R. C. & Boutwell, R. K. (1975) Cancer Res. 35, 2426-2433], the HisDCase activity was found to increase in the dermis. Although most of the histamine in the dermis was present in mast cells, the increase in HisDCase activity in the skin in W/Wv mice was comparable with that in congeneic +/+ mice. This increase of HisDCase activity in the skin of W/Wv mice was abolished by prior x-ray irradiation (800 rads; 1 rad = 0.01 gray) but was restored by subsequent bone marrow transplantation. Because mice, in general, are known to lack basophilic leukocytes, the present results suggest the existence of histamine-producing cells without basophilic granules that are derived from the bone marrow.

Hepatic veno-occlusive disease after high-dose mitomycin C and autologous bone marrow transplantation therapy

Three cases of veno-occlusive disease of the liver were diagnosed in four autopsied patients who had received high-dose mitomycin C therapy followed by autologous bone marrow transplantation, and the pathologic finding are reported. Review of 27 liver, examined post mortem, of patients receiving other high-dose chemotherapeutic regimens, 15 of them with subsequent autologous bone marrow transplantation, revealed no evidence of veno-occlusive disease. Veno-occlusive disease may now become a dose-limiting factor in the use of the combined high-dose mitomycin C-bone marrow transplantation therapy. Attention is also drawn to the increasing number of veno-occlusive disease cases being reported in associated with alkylating agents.

The effect of dose rate and adriamycin on the tolerance of thoracic radiation in mice

Radiation damage to the lung may be a predisposing factor in the development of interstitial pneumonitis in patients undergoing total body radiation and subsequent bone marrow transplantation in the treatment of leukemia. Adriamycin has been used in conjunction with bone marrow transplantation, and has also been shown to interact with radiation. This experiment was designed to study the effects of pre-administration of adriamycin on the radiation tolerance of the lung and esophagus. Since total body radiation is usually administered at low dose rates in.order to spare the gastrointestinal tract preferentially as compared to the bone marrow, we investigated whether such a dose rate effect was present for the lung and if so, whether this pulmonary and esophageal dose rate effect would be ameliorated by pre-treatment with adriamycin. Mice were irradiated at 5 rad; 15 rad or 70 rad per minute to the upper body, 24 hours or 7 days after adriamycin. Oral esophageal death occurred within one month; thus, deaths within 30 days were ascribed to this mechanism. In comparison, deaths because of pulmonary toxicity occured later. Those between 30 and 160 days were ascribed to this mechanism. In the absence of adriamycin, a dose rate effect was found for the lung and confirmed for the upper gastrointestinal tract. The dose of radiation necessary to give pulmonary and gastrointestinal toxicity was markedly reduced when adriamycin was administered 24 hours before radiation. If seven days were allowed between adriamycin and radiation there was still an effect seen only at the high dose rate for the esophagus while for the lung at the high dose rate and for both systems at low dose rate no significant drug effects were noted. The dose rate effect is still seen after the drug, but it is reduced. These studies indicate that adriamycin given shortly before can significantly increase the oral esophageal and pulmonary toxicity of radiation and can practically abrogate the sparing effect of dose rate. This must be considered when clinically using total body radiation and adriamycin in preparation for bone marrow transplantation.