Anticoagulation treatment of cancer patients with deep or superficial leg vein thrombosis - a retrospective observational study of German statutory health insurance claims data (the CERTIFICAT initiative).

Background: Thrombosis is a common complication of cancer with a negative impact on quality of life and overall prognosis. Guidelines recommend low-molecular-weight heparin (LMWH) as initial and prolonged anticoagulation treatment. Little is known about current treatment patterns of these patients in ambulatory care. Patients and methods: The current retrospective observational study interrogates a large German statutory health insurance claims database in order to understand which kind of data can be extracted and analysed. An age- and sex-adjusted sample of about 4.1 million insured people from 2011 to 2016 could be used. Cancer patients with incident deep and superficial leg vein thrombosis were identified. Patients with preexisting cancer were allocated to a normal risk group; those who suffered from simultaneously diagnosed cancer and thrombosis were classified as high-risk group. Results: We identified 322,600 patients with inpatient or outpatient documented cancer diagnosis in at least two different quarters within one year. 87,755 patients were identified with an incident deep or superficial vein thrombosis. 8,201 patients suffered from both cancer and incident thrombosis. 56.9% of the patients received an anticoagulation regimen with predominant LMWH prescription, 24.2% vitamin K antagonists, 17.2% direct oral anticoagulants; in 1.7% of patients, no predominant anticoagulant drug/regime could be identified. On average, patients were prescribed anticoagulants for 4.5 months. An estimate of clinically relevant gastrointestinal bleeding could be derived (1.8% of patients). Conclusions: The dataset allows assigning detailed information of anticoagulant prescriptions in ambulatory care to well-defined groups of cancer patients. A first analysis suggests that in Germany current medical care of patients with cancer-related deep or superficial vein thrombosis does not entirely comply with guideline recommendations regarding type and duration of anticoagulation.

Influence of surface morphology of chitosan films modified by chitin nanofibrils on their biological properties.

The paper is devoted to the study of influence of chitin nanofibrils on the structure, surface morphology, mechanical properties, and electrical conductivity of chitosan-based composite films intended for use in biomedical technologies. It was demonstrated that the optimal concentration of chitin nanofibrils in the composite film is 5 wt.%. For the films of this composition, we observed orientation of structural elements on film surface, enhanced mechanical properties as well as an increase in both specific conductivity and proliferative activity of skin fibroblasts on film surface. These results are related to the appearance of oriented structure in nanocomposites and to self-organization of chitosan macromolecules on the surface of chitin nanofibrils. It was revealed that increase in surface energy and surface hydrophilicity did not facilitate effective adhesion, viability and proliferative activity of cells during cultivation on the surface of composite films.

Budesonide + formoterol delivered via Spiromax® for the management of asthma and COPD: The potential impact on unscheduled healthcare costs of improving inhalation technique compared with Turbuhaler®.

BACKGROUND: Fixed-dose combinations of inhaled corticosteroids and long-acting ß2 agonists are commonly used for the treatment of asthma and COPD. However, the most frequently prescribed dry powder inhaler delivering this medicine - Symbicort® (budesonide and formoterol, BF) Turbuhaler® - is associated with poor inhalation technique, which can lead to poor disease control and high disease management costs. A recent study showed that patients make fewer inhaler errors when using the novel DuoResp® (BF) Spiromax® inhaler, compared with BF Turbuhaler®. Therefore switching patients from BF Turbuhaler® to BF Spiromax® could improve inhalation technique, and potentially lead to better disease control and healthcare cost savings. METHODS: A model was developed to estimate the budget impact of reducing poor inhalation technique by switching asthma and COPD patients from BF Turbuhaler® to BF Spiromax® over three years in Germany, Italy, Sweden and the UK. The model estimated changes to the number, and associated cost, of unscheduled healthcare events. The model considered two scenarios: in Scenario 1, all patients were immediately switched from BF Turbuhaler® to BF Spiromax®; in Scenario 2, 4%, 8% and 12% of patients were switched in years 1, 2 and 3 of the model, respectively. RESULTS: In Scenario 1, per patient cost savings amounted to €60.10, €49.67, €94.14 and €38.20 in Germany, Italy, Sweden and the UK, respectively. Total cost savings in each country were €100.86 million, €19.42 million, €36.65 million and €15.44 million over three years, respectively, with an estimated 597,754, 151,480, 228,986 and 122,368 healthcare events avoided. In Scenario 2, cost savings totalled €8.07 million, €1.55 million, €2.93 million and €1.23 million over three years, respectively, with 47,850, 12,118, 18,319, and 9789 healthcare events avoided. Savings per patient were €4.81, €3.97, €7.53 and €3.06. CONCLUSIONS: We demonstrated that reductions in poor inhalation technique by switching patients from BF Turbuhaler® to BF Spiromax® are likely to improve patients' disease control and generate considerable cost savings through healthcare events avoided.

Difference in plasma membrane structure between two sublines of Ehrlich-Lettrè ascites tumor cells.

The plasma membranes of the glycogen-free and the glycogen-containing subline of Ehrlich-Lettrè ascites cells were purified and compared with respect to their enzyme activity, chemical, lipid and protein composition, and membrane fluidity. Both membrane fractions differed in a number of parameters which are discussed as differences in the expression of malignant transformation of the two sublines. 1. The 5'-nucleotidase activity was 3-5 times higher and the sialic acid content 3-times lower in the glycogen-containing than in the glycogen-free subline. 2. Differences were also observed with respect to the phospholipid composition, that is in the relative proportions of mainly phosphatidylcholine, -inositol and -serine. 3. The fatty acid spectrum of the two sublines differed in the C-18 series and in the percentage of polyunsaturated acids, which was about 6% lower in the glycogen-containing line. 4. Measurements of fluorescence polarization (P) using 1,6-diphenyl-1,3,5-hextriene as probe generally gave higher P values, indicating a decreased membrane fluidity for the plasma membranes of the glycogen-containing subline both below and above the transition temperature at 33 degrees C. 5. Polyacrylamide gel electrophoresis revealed different protein patterns mainly in the molecular weight range of around 90 000 and in the range between 31 000 and 14 000.

Plasma membrane heterogeneity in ascites tumor cells. Isolation of a light and a heavy membrane fraction of the glycogen-free Ehrlich-Lettré substrain.

In this work we report on the isolation of two plasma membrane fractions of a glycogen-free substrain of Ehrlich-Lettré ascites cells, a light fraction sedimenting in a sucrose gradient at 1.10 g/ml, and a heavy fraction sedimenting at nuclei by a combination of short-term swelling and mild Dounce homogenization. A 12 000 X g postnuclear pellet (PII) containing major portions of the plasma membrane marker enymes, 5'-nucleotidase, ouabain-sensitive (Na+ + K+)-ATPase and the alkaline phosphatase, was prepared by differential centrifugation. The two plasma membrane fractions were obtained by centrifugation on a discontinuous sucrose gradient, from which they were further purified on a linear sucrose gradient applying sedimentation velocity conditions only. Enrichment factors for the three marker enzymes were between 5- and 14-fold for the light fraction and between 3- and 7-fold for the heavy fraction with an overall yield of 1--4% and 0.5--1.7%, respectively, of cellular protein. Contamination of both fractions with nuclear material was minor. Mitochondrial contamination was about 8% for the light material and somewhat higher for the heavy material. In the light fraction, co-sedimentation of lysosomal and Golgi marker enzymes was detected. The presence of membrane structures of these organelles could not be confirmed definitely by electron microscopy. Differences in sialic acid content and phospholipid composition within the two fractions, especially in the relative proportion of lecithin to sphingomyelin, suggests differences in membrane fluidity. The light material showed mostly unit membrane vesicles in thin-section and freeze-etch electron microscopy, whereas the heavy fraction mainly consisted of sheet-like membrane fragments.

Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group.

A total of 155 patients with acute myeloid leukemia (AML) received hematopoietic stem cell transplants from unrelated donors after standard conditioning. Clinical outcome after the use of two different antithymocyte globulins for the prevention of graft-versus-host disease (GvHD) was analyzed in a retrospective study as follows: rabbit ATG (Thymoglobulin Sangstat/Genzyme, n=49, median age 42 years, 53% in CR, further ATG-S); rabbit ATG (ATG-Fresenius, n=38, median age 42 years, 58% in CR, further ATG-F) or no ATG (n=68, median age 36 years, 55% in CR). The groups were comparable regarding disease status at transplant, age, CMV status and cytogenetics. Grade III-IV acute GvHD was found in 15% in the ATG and 27% in the no ATG group (P=0.44). The most important independent risk factors for chronic GvHD (cGvHD) were the use of ATG, disease status at transplant and conditioning. cGvHD developed significantly more frequently in no ATG group. With the median follow-up of 34 months, the 5-year survival is 42% for those transplanted in CR. To conclude, these data demonstrate that the transplants performed in CR, with ATG, are associated with a good outcome, low incidence of cGvHD and no increase of relapse.

Effect of combination therapy with all-trans-retinoic acid and recombinant human granulocyte colony-stimulating factor in patients with myelodysplastic syndromes.

Since all-trans retinoic acid (ATRA) and granulocyte colony-stimulating factor (G-CSF) not only enhance proliferation and differentiation of normal myeloid cells but also synergistically promote the differentiation of myeloid leukemic blast cells in vitro, we have started a pilot study of combined treatment with ATRA and G-CSF in patients with myelodysplastic syndrome, to analyze the effect of these drugs on hematopoietic differentiation. ATRA was given at 45 mg/m2/day p.o. from week 1-12 and G-CSF at 5 micrograms/kg/day s.c. from week 5-12 with dose modifications according to the absolute neutrophil counts (ANC). A total of 15 patients, predominantly with refractory anemia, were treated. During initial ATRA therapy, a bilineage response with increases of both ANC and platelet counts occurred in three patients. During combined ATRA/G-CSF therapy, ANC increased in all patients, and platelets increased in three out of 14 evaluable patients. An increase in hemoglobin concentration and a decrease in transfusion requirements occurred in one patient each. In the bone marrow, the myeloid-to-erythroid ratio increased during ATRA treatment and remained increased during concomitant G-CSF administration, while the maturation index of myeloid cells increased only in response to ATRA therapy, but returned to baseline during ATRA/G-CSF treatment. Cytogenetic analysis demonstrated persistence of the abnormal clones in all patients. The number of circulating progenitor cells CFU-GM increased in all patients studied. Serum concentrations of the soluble TNF receptor and IL-2 receptor both increased, while TNF-alpha--already elevated prior to therapy--and soluble ICAM-1 concentrations did not significantly change. Adverse effects included dermatitis and cheilosis in most patients, and a drop in platelet counts related to G-CSF in one patient. The pilot study demonstrates that the combination treatment with ATRA/G-CSF is well tolerated, leading to normalization of ANC in most, and improvement of platelets and red blood cells in a subgroup of patients.

GM-CSF in a double-blind randomized, placebo controlled trial in therapy of adult patients with de novo acute myeloid leukemia (AML).

We investigated whether GM-CSF given concomitantly with chemotherapy (CT) and thereafter, improves the outcome of adults with de novo AML by increasing the efficacy of CT and reducing infections. CT included Ara-C, daunorubicin and etoposide (DAV) for induction and early consolidation therapy and one cycle with high-dose (patients aged < or = 50 years) or intermediate dose Ara-C (patients aged > 50 years)/daunorubicin for late consolidation therapy. Eight patients were randomized after DAVI to receive either GM-CSF (E. coli, 250 micrograms/m2/day, s.c.) or placebo starting 48 h prior to DAVII and the subsequent courses and given throughout CT until the absolute neutrophil count had recovered to > 500/microliters. The CR rate was 81% in the GM-CSF and 79% in the placebo group (p = 0.57; Fisher's exact test). The probability of relapse-free survival at 41 months after a median follow-up of 35 months was 42% in the GM-CSF and 41% in the placebo group (p = 0.89; log rank test). GM-CSF did not shorten the period of neutropenia < or = 500/microliters, while it prolonged the duration of thrombocytopenia < or = 25,000/microliters. The incidence and severity of infections as well as the non-hematological toxicity were similar in both groups. In summary, in this randomized trial GM-CSF as an adjunct to AML therapy was feasible. For the present GM-CSF does not have a significant effect on treatment outcome.

Nonmyeloablative stem cell transplantation in adults with high-risk ALL may be effective in early but not in advanced disease.

The feasibility of nonmyeloablative stem cell transplantation (NST) was evaluated in 22 adults with high-risk ALL. 16/22 patients had advanced disease and 11/22 had Ph+ ALL. Eleven patients received NST as first stem cell transplantation (SCT). Eleven patients had relapses after allogeneic or autologous SCT and underwent a salvage NST. 18/22 patients (82%) engrafted after NST. 13/16 patients (81%) with active disease reached complete remission (CR). 11 of 13 patients developed GVHD. After first NST 10/11 patients (91%) engrafted. Six of seven patients with active disease reached CR. Three of five relapsing patients reached subsequent CR after donor lymphocyte infusions, termination of immunosuppression or imatinib. Three of 11 patients (27%) are alive in CR 5 to 30 months after NST. Eight of 11 patients have died, 3/8 from leukemia and 5/8 from transplant-related causes. After salvage NST, 8/11 patients (73%) engrafted. Seven of nine patients with active disease reached CR. Only one of 11 patients transplanted, who was in CR before undergoing salvage NST is alive 19 months after NST. Five of 11 have died from leukemia, one of 11 after graft failure and four of 11 from transplant-related causes. Four of 22 patients (18%) are alive in CR 5, 14, 19 and 30 months after NST. NST is feasible in adults with high risk ALL. However, transplant-related mortality remains high and only patients transplanted in CR seem to have long-term disease-free survival.

Pharmacokinetics of nicotinic acid-salicylic acid interaction.

Both nicotinic acid and salicylic acid undergo glycine conjugation in human beings. Competitive inhibition may therefore be possible when these substances are used concomitantly in patients with hyperlipidemic disorders. The aim of this study was to determine, in six healthy subjects, whether nicotinic acid steady-state levels and total clearance are affected by concomitant aspirin administration. Steady-state nicotinic acid concentrations were obtained in all six volunteers by infusion of nicotinic acid solutions at constant rates (0.075 to 0.100 mg/kg/min) for 6 hours; aspirin (1 gm) was administered orally 120 minutes after the beginning of the infusion of nicotinic acid. Plasma samples were analyzed for nicotinic acid, nicotinuric acid, and salicylic acid. After aspirin administration an immediate marked decrease of nicotinuric acid levels could be observed in all six volunteers, whereas nicotinic acid concentrations increased. We hypothesize that salicylic acid causes a concentration-dependent decrease of total nicotinic acid clearance that results in the saturation (and effective elimination) of the nicotinuric acid conjugation pathway.

Effect of granulocyte-macrophage colony-stimulating factor on neutropenia and related morbidity induced by myelotoxic chemotherapy.

PURPOSE: A phase Ib/II clinical study was undertaken to assess the efficacy of recombinant human (rh) granulocyte-macrophage colony-stimulating (GM-CSF) factor in attenuating neutropenia and associated morbidity caused by high-dose anticancer chemotherapy administered in the presence or absence of autologous bone marrow support. PATIENTS AND METHODS: Twenty-two patients with various solid tumors and lymphoid neoplasias were treated with a single daily subcutaneous dose of rh GM-CSF (250 micrograms/m2) 48 hours after receiving a second cycle of highly myelotoxic chemotherapy for a period of 10 days. Within-subject comparisons on neutropenia-related clinical and laboratory variables were made with data obtained from the same patients after they received the first neutropenia-inducing cycle of identical chemotherapy in the absence of GM-CSF. RESULTS: GM-CSF was active in neutropenic patients because it significantly increased the neutrophilic nadir, reduced the time of relevant neutropenia, and reduced the duration of a patient's hospital stay and the necessity for parenteral antibiotics. No significant toxicity was encountered with subcutaneous GM-CSF treatment. CONCLUSION: Although GM-CSF was shown to significantly reduce chemotherapy-associated morbidity in patients receiving myelotoxic cancer chemotherapy, additional studies are needed to assess whether the use of GM-CSF in anticancer chemotherapy will allow an increase in the dosage level, leading to improved response rates and survival among cancer patients.

Infectious complications during neutropenia subsequent to peripheral blood stem cell transplantation.

Type, severity and incidence of infection during the neutropenic period after peripheral blood stem cell transplantation (PBSCT) for treatment of malignant disease were studied in 66 patients treated at a single institution. Data of 34 female and 32 male patients with a median age of 43 years suffering from leukemia (12), lymphoma (35), multiple myeloma (six) or solid tumors (13) were retrospectively analyzed. All patients had received at least 2.5 x 10(6) CD34-positive cells for stem cell rescue after high-dose chemotherapy. Ninety-four percent of the patients experienced at least one febrile episode during their post-transplant course. The patients recovered quickly and defervesced after a median of 4 days. The incidence of bacteremia was 39% and gram-positive cocci were the predominant pathogens. In contrast, severe organ infections were rare. Only 5% of the patients suffered from lung infiltrates. No invasive fungal infections were observed. No transplant-related deaths occurred in the 66 patients studied. We conclude that the severe, but shortlasting neutropenia after peripheral blood stem cell transplantation is associated with a high incidence of bacterial infection. The severity of the majority of these infections is moderate. With appropriate anti-infective therapies these infections can be managed and life-threatening infectious complications, in particular fungal infections, are rare. Empirical anti-infective regimens specifically designed for this clinical situation should be explored.

Safety and feasibility of CHOP/rituximab induction treatment followed by high-dose chemo/radiotherapy and autologous PBSC-transplantation in patients with previously untreated mantle cell or indolent B-cell-non-Hodgkin's lymphoma.

Patients with no prior chemotherapy and with advanced and progressive follicular lymphoma (FCL) or mantle cell lymphoma (MCL) were enrolled into a treatment protocol combining CHOP/rituximab-CHOP therapy with subsequent consolidation high-dose therapy (HDT) to evaluate the safety and feasibility of this treatment. Overall, 15 patients were enrolled and 13 patients completed the entire treatment protocol without major toxicities or increased infectious complications. One patient withdrew consent after achieving complete remission (CR) prior to HDT. One patient was taken off study with signs of disease progression after induction treatment. All patients showed stable engraftment after HDT. Response rates appear to be favorable, indicating an additional effect of rituximab and HDT. Overall, 12 of 13 patients achieved CR/CRu and one patient partial remission. Follow-up of immune reconstitution displayed transient severe combined immunodeficiency with slow normalization of the cellular and humoral compartments without a significant increase of infectious complications. Taken together, high-dose chemotherapy can be safely given following treatment with CHOP+rituximab. Efficacy in this small cohort of patients was encouraging with sustained remissions in both FCL and MCL patients. Upfront HDT should be considered as a therapeutic option especially in young and/or high-risk patients.

First-line high-dose chemotherapy for patients with poor prognosis extragonadal germ cell tumors: the experience of the European Bone Marrow Transplantation (EBMT) Solid Tumors Working Party.

Extragonadal germ cell tumors are classified according to the staging system of the International Germ Cell Cancer Collaborative Group (IGCCCG). The 5-year overall and disease-free survival rates for poor prognosis patients are 41 and 48%, respectively after standard-dose chemotherapy. We report the experience of the EBMT Solid Tumours Working Party (STWP) with first-line HDCT with hematopoietic progenitor cell support (HPCS) in patients with poor prognosis extragonadal nonseminomatous germ cell tumor (NSGCT). Between 1990 and 2001, 22 extragonadal NSGCT patients (21 M, 1 F), median age 30 years (range 17-52) were treated with first-line HDCT with HPCS. Primary site was mediastinum in 11 patients, retroperitoneum in 10, and unknown in one. The Carbopec regimen, consisting of high doses of carboplatin, etoposide, and cyclophosphamide, was used in most cases (12 patients). No treatment-related deaths occurred. No patient developed myelodysplasia or a secondary leukemia. In total, 17 of 22 patients (77%) achieved complete remission. At a median follow-up of 50 months (range 26-132), 15 patients (68%) are alive disease-free. The survival rates of patients with poor prognosis extragonadal NSGCT treated with first-line HDCT in the EBMT STWP experience appear higher than that expected according to the IGCCCG classification.

Rituximab in vivo purging is safe and effective in combination with CD34-positive selected autologous stem cell transplantation for salvage therapy in B-NHL.

The purpose of this study was to evaluate feasibility and efficacy of Rituximab included into a sequential salvage protocol for CD20(+) B-NHL in relapse or induction failure. Twenty-seven patients with CD20(+) B-NHL in relapse or induction failure received Rituximab combined with DexaBEAM (R-DexaBEAM) for stem cell mobilization. Additional ex vivo selection of CD34-positive cells was performed using the CliniMacs device. Two doses of Rituximab were included in the high-dose therapy regimen (HDT). R-DexaBEAM was well tolerated and 26 of 27 patients mobilized sufficient numbers of CD34(+) blood stem cells. Application of R-DexaBEAM resulted in significant depletion of peripheral B cells. No treatment-related deaths occurred after HDT and all patients showed stable engraftment of hematopoesis. Combined immunodeficiency was observed post HDT and eight patients developed CMV antigenemia. Remission rate post HDT was 96% (CR, 24/26; PR, 1/26). Overall and progression-free survival (PFS) at 16 months post HDT (range 6-27) is 95% and 77%, respectively. With regard to histology, PFS was 71% in aggressive lymphoma (n = 11), 74% in indolent FCL (n = 10) and 100% in MCL (n = 5). The treatment protocol has proven feasible, with high purging efficiency and encouraging remission rates.

Failure of sustained engraftment after non-myeloablative conditioning with low-dose TBI and T cell-reduced allogeneic peripheral stem cell transplantation.

We investigated whether a T cell-reduced allogeneic stem cell transplant (SCT) with minimal conditioning and subsequent donor lymphocyte infusions (DLI) could reduce the incidence and severity of GVHD while retaining stable engraftment. Five patients with hematological malignancies (three MM, one CLL, one Chediak-Higashi syndrome) were conditioned with TBI (200 cGy). One patient additionally received fludarabine (120 mg/m(2)). CsA and mofetyl-mycophenolate (MMF) were administered to prevent GVHD. All patients were grafted with >3 x 10(6)/kg highly purified CD34(+) cells together with 2 x 10(6)/kg CD3(+) cells (three patients) or 1 x 10(5)/kg CD3(+) cells (two patients). Quick hematopoietic recovery and initial mixed donor chimerism was observed. Treatment-related toxicity was minimal in all but one patient who died of treatment-refractory GVHD on day 112. The four other patients only achieved partial donor T cell chimerism. BM and PBMC donor chimerism was lost between day 40 and 209 despite DLI. Three patients are alive with disease and one is in CR. We conclude that T cell-reduced SCT using 200 cGy as the conditioning regimen does not result in stable hematopoietic engraftment. Predominant donor T cell chimerism is not a prerequisite for initial allogeneic hematopoietic proliferation. However for sustained long-term engraftment it is of major importance.

Peripheral blood stem cell (PBSC) mobilization with chemotherapy followed by sequential IL-3 and G-CSF administration in extensively pretreated patients.

Extensive pretreatment has been identified as a significant risk factor for failure of sufficient PBSC mobilization. From published data and our own experience we defined pretreatment variables which render patients at risk for not collecting at least 2.5 x 10(6) CD34-positive cells per kg bodyweight (BW). These variables were previous unsuccessful PBSC mobilization trial, previous large field radiotherapy, four or more cycles of myelosuppressive chemotherapy regimens, and combinations of extended field radiotherapy plus chemotherapy. Based on these inclusion criteria we treated 19 patients with disease-specific conventional-dose chemotherapy followed by sequential subcutaneous administration of IL-3 (5 microg/kg BW) for 5 consecutive days and G-CSF (10 microg/kg) until PBSC collection or neutrophil recovery. Patients were 10 males and nine females with a median age of 43 years. Diagnoses were non-Hodgkin's lymphoma n = 5, Hodgkin's disease n = 2, multiple myeloma n = 2, CML n = 4, AML n = 4 and testicular cancer n = 2. Twelve patients had prior unsuccessful trial of PBSC mobilization with chemotherapy followed by G-CSF. Except for mobilization chemotherapy-related neutropenic fever, no major toxicities (WHO grade > or = 2) were observed. Growth factors were well tolerated. Collection of at least 2.5 x 10(6) CD34-positive cells per kg BW was possible in 11 out of 19 patients (58%). In five out of 12 patients with a previous unsuccessful trial of PBSC mobilization, the study regimen mobilized sufficient CD34-positive cells. Nine patients went on to high-dose chemotherapy followed by autologous PBSC transplantation. Prompt hematologic recovery was seen in all of them. In conclusion, the sequential administration of IL-3 followed by G-CSF after conventional-dose chemotherapy allows successful PBSC collection in the majority of extensively pretreated patients.

Preliminary results of stem cell mobilization in chronic myeloid leukemia with a moderate intensity chemotherapy regimen and G-CSF or G-CSF plus IL-3.

Mobilization of Philadelphia chromosome (Ph) negative peripheral blood stem cells has been reported subsequent to intensive chemotherapy. We asked whether peripheral blood stem cells can be harvested subsequent to a less toxic chemotherapy regimen. Patients were treated with idarubicin 12 mg/m2 on day 1 and 2 and ara-C 100 mg/m2 days 1-5 and 5 or 10 micrograms/m2 G-CSF. In case of insufficient yield chemotherapy was repeated using IL-3 and G-CSF for mobilization of stem cells. Fourteen patients received 18 cycles of chemotherapy. The majority of patients were in late chronic phase and treated after secondary (interferon-alpha) IFN-alpha resistance. sufficient numbers of peripheral blood stem cells were harvested in 11 out of 14 patients. Although mixed Ph positive/Ph negative leukaphereses were harvested in the majority of patients, in no case were sufficient numbers of purely Ph negative progenitor cells for transplantation obtained. No toxic deaths were observed during the aplasia and the toxicity was acceptable. These preliminary results demonstrate that this procedure can be safely applied in patients with chronic phase CML and allows the harvesting of sufficient numbers of peripheral blood stem cells. The efficacy of this regimen for the mobilization of Ph negative cells should be further explored in patients at an earlier stage of the disease.

Interleukin-2 bolus infusion as late consolidation therapy in 2nd remission of acute myeloblastic leukemia.

The activation of autologous cytotoxic cells by interleukin-2 (IL-2) may be a promising tool for elimination of minimal residual blast populations in patients with acute myelocytic leukemia (AML) to prolong disease-free survival. Here, we report the results of a phase II study using IL-2 for consolidation therapy in patients with second remission of de novo AML. All patients in 1st relapse of AML received a uniform induction therapy consisting of intermediate high-dose AraC (iHDAraC) 2 x 600 mg/m2 d1-4 and VP-16 100 mg/m2 d1-7. Patients achieving 2nd remission were treated with 4 cycles recombinant IL-2 (rIL-2) 9 x 10(6) IU/m2 administered on d1-5 and 8-12/cycle as 1h infusion every six weeks. In 37/66 (56%) evaluable patients, complete remission (CR) was achieved. So far, 21/37 patients (4 after additional autologous bone marrow transplantation (ABMT) received rIL-2 consolidation. Three patients are too early for evaluation, 4 received allogeneic BMT, 6 relapsed before IL-2 was scheduled and 4 refused treatment with rIL-2. The median disease-free survival (DFS) was 11 (4-49+) months. Up to now, in 5/21 (24%) patients the duration of 2nd remission exceeded that of 1st remission 7/21 (33%) are in ongoing 2nd remission (7+ to 49+ months). The side effects of rIL-2 were generally moderate and manageable. Only in two patients, previously treated with ABMT, severe side effects occurred; septicaemia and pneumonia in one patient and desquamative erythrodermia in the second one. In accordance with other studies rebound lymphocytosis with a marked increase of CD56(+)-cells and release of secondary cytokines such as TNF-alpha, IFN-gamma and IL-6 was observed. The schedule is feasible and the data suggest a possible benefit for DFS, which, however has to be confirmed by randomized trials.