High-dose etoposide in allogeneic stem cell transplantation.

The anti-leukemic effect of etoposide is well documented. High-dose etoposide 60 mg/kg in combination with fractionated total body irradiation (TBI), usually single fractions of 1.2 Gy up to a total of 13.2 Gy, is used as conditioning therapy for allogeneic stem cell transplantation. Most studies of this conditioning regimen have included patients with acute leukemia receiving bone marrow or mobilized stem cell grafts derived from family or matched unrelated donors, and the treatment is then effective even in patients with high-risk disease. The most common adverse effects are fever with hypotension and rash, nausea and vomiting, sialoadenitis, neuropathy and metabolic acidosis. A small minority of patients develop severe allergic reactions. Etoposide has also been tested in a wide range of combination regimens, but for many of these combinations, relatively few patients are included, and some combinations have only been tested in patients who have undergone autologous transplants. However, the general conclusion is that many of these combinations are effective in patients with high-risk malignancies and the toxicity often seems acceptable. Thus, etoposide-based conditioning therapy should be further evaluated in patients having allogeneic transplants, but randomized trials are needed and the design of future trials should be based on the well-characterized TBI + high-dose etoposide regimen.

The pretransplantation serum cytokine profile in allogeneic stem cell recipients differs from healthy individuals, and various profiles are associated with different risks of posttransplantation complications.

Cytokines play a key role in regulation of normal and malignant hematopoiesis, angiogenesis, and inflammation. Serum levels of several cytokines are altered in patients with hematologic malignancies, and pretransplant cytokine levels seem to have a prognostic impact in patients treated with allogeneic stem cell transplantation. However, the cytokine system constitutes an interacting functional network, and it may therefore be more relevant to look at serum cytokine profiles rather than the serum levels of single cytokines in allotransplanted patients. We therefore investigated the pretransplantation serum levels of 35 cytokines in a group of 44 consecutive allogeneic stem cell transplantation patients, mainly with a primary diagnosis of acute leukemia. Serum samples were collected before the start of myeloablative conditioning therapy when all patients were in complete hematologic remission. Unsupervised hierarchical clustering analysis identified three major patient groups/subsets. These groups differed especially in the levels of hepatocyte growth factor and granulocyte-colony stimulating factor, and one of the groups was characterized by low early treatment-related morbidity and high levels of hepatocyte growth factor and granulocyte-colony stimulating factor. The degree of weight gain/fluid retention after conditioning therapy did not differ between the patient subsets, but fluid retention showed a significant correlation with pretransplantation serum levels of basic fibroblast growth factor. We conclude that the pretransplantation serum cytokine profile shows a considerable variation even between patients in complete hematologic remission and is associated with clinicopathologic features.

Early pre-engraftment, functional, in vitro responsiveness of T lymphocytes in allotransplanted, acute leukemia patients: proliferation and release of a broad profile of cytokines, possibly predictive of graft-versus-host disease.

Previous studies of T cell reconstitution following allogeneic stem cell transplantation have described long-lasting T cell defects, including decreased levels of autocrine proliferating CD4+ T cells. However, T cell functions during the early phase of conditioning-induced, pre-engraftment pancytopenia have not been characterized previously. We used a whole blood assay to investigate T cell proliferation and cytokine release during the period of pre-engraftment cytopenia. The study included 13 acute leukemia patients receiving myeloablative conditioning followed by transplantation of G-CSF-mobilised peripheral blood stem cells derived from HLA-matched family donors. Maximal proliferation and cytokine release could not be reached by anti-CD3 stimulation alone, but was dependent on the presence of additional costimulation with anti-CD28. Circulating T cells showed a broad cytokine release profile after activation, and the highest levels were detected for IFNgamma, GM-CSF and IL-6. Correlation analyses showed that TNFalpha/IL-4/IL-5/IL-13 in particular were released as a separate cluster, IFNgamma and GM-CSF correlated strongly, whereas IL-17 showed a weak correlation to IL-6 only. The capacity of circulating T cells derived during pre-engraftment cytopenia to release high levels of IFNgamma, IL-6 and IL-17 in response to in vitro activation with anti-CD3+anti-CD28 showed statistically significant correlations with later acute GVHD. We conclude that allotransplanted patients have a functional T cell system even during the pre-engraftment period of severe pancytopenia.

[High-dose treatment of systemic AL-amyloidosis with autologous stem cell support]. / Høydosebehandling med autolog stamcellestøtte ved systemisk AL-amyloidose.

BACKGROUND: AL-amyloidosis is a serious disease with a short median survival without treatment. Treatment with high-dose melphalan with autologous stem cell support (HMAS) has a potential to increase survival, but is associated with toxicity and mortality. In this paper we report the Norwegian results retrospectively. MATERIAL AND METHODS: We used questionnaires and had personal contact with a local physician from each hospital with HMAS experience. Diagnosis and treatment were evaluated according to the guidelines at the time of treatment, and the results were compared to internationally published reports. RESULTS: Stem cell harvesting was attempted in 18 patients from 1997 to 2006. 15 of these received HMAS treatment. Treatment-related mortality was 20%, and 5 of 11 (45%) had an organ response. Median survival was not reached within the 55-month median observation time. The course of the disease was more complicated when known risk factors for HMAS treatment were present, such as reduced kidney function, advanced heart involvement, reduced performance status, and multiorgan disease. Three of 18 patients were not diagnosed according to relevant guidelines. In seven of 12 patients the response to treatment was not evaluated adequately with respect to haematology. INTERPRETATION: AL-amyloidosis is a difficult diagnosis and the condition is probably under-diagnosed in Norway. The results of HMAS treatment in Norway are comparable with those in published reports from centres abroad. The follow-up of patients should be improved.

[Survival after high-dose therapy with autologous stem cell support]. / Overlevelse etter høydosebehandling med autolog stamcellestøtte.

BACKGROUND: High-dose therapy with autologous stem cell support has been carried out in our hospital since 1996. We have recently collected survival data on patients who have undergone this procedure. MATERIAL AND METHODS: The study population comprised 111 patients, 58 of whom had been diagnosed with multiple myeloma, 38 with various forms of malignant lymphoma, 11 with sarcoma and 4 with testicular cancer. RESULTS: Median survival from reinfusion of stem cells was 74.8 months for patients with myeloma, 47.8 months for patients with malignant lymphoma and 11.7 months for patients with sarcoma. Three-year survival was 72.2 % for myeloma patients and 54.8 % for lymphoma patients. While the survival slope decreased steadily throughout the study period for patients with multiple myeloma, it seemed to level out after approximately 18 months for patients with malignant lymphomas. INTERPRETATION: Our data on myeloma patients show survival comparable to previously published data. For malignant lymphoma patients, our data support the assumption that high-dose therapy has the potential for cure.

Functional characterization of T lymphocytes derived from patients with acute myelogenous leukemia and chemotherapy-induced leukopenia.

T-cell-targeting immunotherapy is now considered in acute myelogenous leukemia (AML). Immunotherapy seems most effective for patients with a low AML cell burden, and a possible strategy is therefore to administer immunotherapy early after intensive chemotherapy when patients have a low leukemia cell burden and severe treatment-induced cytopenia. To further investigate this possible therapeutic approach we used a whole blood assay to characterize the proliferative responsiveness (3H-thymidine incorporation) of circulating T cells from AML patients with severe treatment-induced leukopenia, i.e., peripheral blood leukocyte counts < 0.5x10(9)/l. This assay will reflect both quantitative and qualitative differences. Responses were compared for 17 AML patients, 6 patients with acute lymphoblastic leukemia (ALL), and a group of 21 healthy controls. Most circulating leukocytes in the AML patients were T lymphocytes, whereas B lymphocytes and monocytes usually constituted < 10%. Anti-CD3-stimulated proliferation was significantly lower for AML patients compared with healthy controls. However, proliferation in response to anti-CD3 + anti-CD28 did not differ for AML patients and healthy controls, an observation suggesting that T cells from AML patients have an increased responsiveness in the presence of optimal costimulation that compensates for the quantitative T-cell defect. In contrast, the responses were significantly lower for ALL than for AML patients. We conclude that the remaining T-cell population in AML patients with severe chemotherapy-induced cytopenia show an increased proliferative responsiveness and may represent a therapeutic target when antileukemic immunotherapy is tried in combination with intensive chemotherapy.

Cellular immune responses in multiple myeloma patients with treatment-induced cytopenia early after high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

Proliferative T cell responses were compared for two patient groups with severe treatment-induced leukopenia (white blood cell counts < 0.5 x 10(9)/l): (i). multiple myeloma patients receiving high-dose melphalan and autologous peripheral blood stem cell transplantation; (ii). patients receiving conventional intensive chemotherapy for acute leukemia or myelodysplasia. Although the majority of circulating leukocytes were CD2(+)TCRalphabeta(+) in both groups, the myeloma patients showed significantly lower T cell proliferation in responses to several activation signals (anti-CD3, anti-CD3 + IL2, anti-CD3 + anti-CD28, anti-CD3 + anti-CD28+IL2. Our results suggest that myeloma patients with post-transplant cytopenia have a more severe cellular immune defect than patients with other hematological malignancies and severe cytopenia due to conventional intensive chemotherapy.

A phase I/II study of the MDR modulator Valspodar (PSC 833) combined with daunorubicin and cytarabine in patients with relapsed and primary refractory acute myeloid leukemia.

The cyclosporine analog Valspodar (PSC 833, Novartis Pharma) is a strong inhibitor of the mdr1 gene product p-glycoprotein (pgp). A phase I/II study was conducted in order to evaluate if addition of Valspodar to treatment with daunorubicin and cytarabine, given to patients with primary refractory or relapsed acute myeloid leukemia, could increase the complete remission rate.Fifty-three patients were treated in cohorts of three to six patients. Twelve patients reached a complete remission in bone marrow, five of whom also normalized their peripheral blood values. Three patients experienced treatment-related deaths from pneumonia, liver failure and cerebral hemorrhage, respectively. It is concluded that Valspodar 10 mg/kg per 24 h in combination with daunorubicin 45 mg/m(2) for 3 days and cytarabine 1 g/m(2) twice daily for 4 days is tolerable in this heavily pre-treated group of patients. Due to the moderate treatment results, the phase II part of the study was ended prematurely. The modulation of only pgp did not give an obvious improvement of the treatment results in this group of patients.