Factors influencing G-CSF-mediated mobilization of hematopoietic progenitor cells during steady-state hematopoiesis in patients with malignant lymphoma and multiple myeloma.

We retrospectively analyzed factors influencing PBPC mobilization during steady-state hematopoiesis in 52 patients with malignant lymphoma (n=35) or multiple myeloma (n=17) who received 77 cycles of G-CSF (12.5-50 microg G-CSF/kg/day). For 15 of these patients, the first mobilization cycle (12.5 microg G-CSF/kg/day) was followed by a second course with an increased dose of G-CSF (25 or 50 microg/kg/day). Leukapheresis was started on day 4, about 2 h after s.c. G-CSF administration, and repeated on 2-5 consecutive days. CD34+ cells were determined by flow cytometry in each apheresis product and in the peripheral blood prior to G-CSF administration, beginning on day 4. Colony assays were performed on cryopreserved samples prior to autografting. In the 15 patients receiving two mobilization cycles the higher G-CSF dose was associated with higher levels of CD34+ cells, a higher mean yield of CD34+ cells per apheresis (p<0.05), and a higher percentage of successful (>2x10(6) CD34+ cells/kg) collections (p=0.058). Patients with limited previous cytotoxic therapy (n=19, up to six cycles of a standard regimen such as CHOP and/or less than 20% marrow irradiation) who received a daily dose of 12.5 microg G-CSF/kg had higher levels of circulating CD34+ cells, a higher mean yield of CD34+ cells per apheresis (p<0.05), and a higher percentage of successful collections (p<0.05) compared with patients previously treated with more intensive radiochemotherapy (n=15). Ten of 20 patients (50%) who failed during the first cycle were successful during subsequent cycles with escalated doses of G-CSF. Trough levels of circulating CD34+ cells on day 4 were predictive for success or failure to achieve >2x10(6) CD34+ cells/kg, especially in heavily pretreated patients. In conclusion, a daily dose of 12.5 microg G-CSF/kg seems sufficient to mobilize PBPC during steady-state hematopoiesis in the majority of patients who have received limited previous radiochemotherapy. Higher doses of G-CSF, up to 50 microg/kg/day, mobilize more PBPC and should be considered for patients previously treated with intensive radiochemotherapy or those failing to mobilize sufficient numbers of CD34+ cells with lower doses of G-CSF.

[Pneumococcal septicemia in functional asplenia: first manifestation of systemic autoimmune disease?]. / Pneumokokkensepsis bei funktioneller Asplenie: Erstmanifestation einer systemischen Autoimmunerkrankung?

A 35 year old female was admitted into the hospital because of rapid onset fever and chills. Streptococcus pneumoniae could be isolated from blood as the responsible pathogen for septicemia. Necroses of fingers and feet occurred. The clinical signs of an overwhelming post-splenectomy infection (OPSI) were evident. High-dose penicillin was administered and the patient recovered. Howell-Jolly-bodies were seen in peripheral blood smears. A spleen within normal size could be demonstrated in CT and sonography. Angiologic findings showed intact splenic arteries and a normal vein, whereas the small splenic vessels were rare. MRT of the spleen using Endorem (Fe), showed only a minimal uptake of the RES. In a scintigram of spleen and liver using 320 MBq Tc-99m nanokoll, the spleen was not visible. Thus, functional asplenia was demonstrated by Howell-Jolly-Bodies and by image methods. An increased antinuclear antibody level and a Sm-antibody lead to the diagnosis of undifferentiated connective tissue disease. As far as we know this is the first case that functional asplenia was the first symptom of a systemic autoimmune disease.

[High-dose chemotherapy of patients with multiple myeloma]. / Hochdosischemotherapie bei Patienten mit multiplen Myelomen.

For patients younger than 60 years with multiple myeloma in a stage requiring chemotherapy high dose chemotherapy followed by autologous blood stem cell transplantation appears to be the best therapeutic option. Conditioning regimens resulting in a high proportion of patients with 90% tumor reduction (very good partial or complete remissions) should be preferred. A good quality of remission is a prerequisite for prolonging the disease free survival. World-wide the tandem high dose melphalan protocol developed by Barlogie and coworkers is deemed the most effective conditioning regimen. A pilot study in our clinic with an intensified high dose regimen combining idarubicin, melphalan and cyclophosphamide showed similar remission rates. The application of peripheral blood stem cells reduces the treatment related mortality to less than 10%. It is expected that more than 50% of patients treated with high dose chemotherapy and autologous peripheral blood stem cell transplantation will survive at least 5 years. Therefore, the prognosis of such patients is significantly improved compared with patients treated with conventional chemotherapy. Treatment related mortality after allogeneic blood stem cell transplantation is about 40%. Therefore, during the first 2 to 3 years after transplantation the prognosis of patients after allogeneic transplantation is inferior to that of patients receiving autologous transplants. Subsequently, patients with allogeneic transplants do better, because the relapse rate after allogeneic transplantation is decreased and some patients may achieve long term remissions or even cures. Therefore, we recommend allogneic blood stem cell transplantation for patients younger than 50 years if an HLA-identical sibling donor is available and there are no contraindications. For patients older than 60 years the Alexanian protocol is still the therapeutic standard. On the other hand, successful application of high dose chemotherapy and autologous blood stem cell transplantation in patients of this age group has been reported. Therefore, clinical trials are required to clarify whether the prognosis of patients older than 60 years can be improved with treatment strategies including high dose chemotherapy.

Granulocyte colony-stimulating factor (G-CSF) mediated mobilization of leukemic cells in Philadelphia chromosome positive acute lymphoblastic leukemia expressing myeloid antigens (my+Ph+ALL).

The therapeutic benefit of G-CSF in the treatment of acute lymphoblastic leukemia has been well established. G-CSF has been used to shorten neutropenia induced by conventional dose cytotoxic chemotherapy and allogeneic bone marrow transplantation. Recently autologous peripheral blood progenitor cell transplantation has been explored to treat high-risk ALL. Several in vitro studies suggest that subpopulations of lymphoblasts express G-CSF receptors. Furthermore, enhanced growth of Ph+ ALL cells expressing myeloid antigens stimulated by G-CSF has been demonstrated in vitro. However, the clinical relevance of these findings has been questioned. We report a patient with my+Ph+ALL in whom the administration of G-CSF after high-dose Cytarabin and Mitoxantrone led to a significant mobilization of leukemic cells and contamination of the stem cell harvest during cytologic marrow remission.

Increases of sICAM-1 during neutropenic pneumonia in leukemic patients.

Aggressive chemotherapy of leukemia increases the risk of severe infections during treatment-induced myelosuppression. However, the assessment of an infectious origin of neutropenic fever is often difficult. Leukocyte adhesion molecules such as E-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are involved in early inflammatory response. We studied plasma concentrations of their soluble isoforms during 48 treatment courses with myeloablative chemotherapy in 32 leukemic patients. There were 35 febrile episodes during neutropenia. Pneumonia was clinically and microbiologically documented in 15 cases, six had proven infections but normal chest radiograph, and 14 were classified as fever of unknown origin. Longitudinal studies revealed a sustained increase of sICAM-1 plasma levels associated with pneumonia. Increase of sICAM-1 plasma levels distinguished patients with pneumonia from those with fever not related to pneumonia (positive predictive value 0.87, negative predictive value 0.94). Plasma levels of sICAM-1 were elevated in both, fungal and non-fungal pneumonia. Increases of sICAM-1 paralleled first radiographic evidence of pulmonary infiltrations in most cases. In contrast, no elevation of sVCAM-1 or sE-selectin was documented during febrile events prior to recovery of leukocyte counts.

Idarubicin, melphalan and cyclophosphamide: an intensified high-dose regimen for the treatment of myeloma patients.

Following conventional chemotherapy, eight myeloma patients presenting with advanced tumor stages were treated with an intensified high-dose regimen and autologous peripheral blood stem cell transplantation. High-dose chemotherapy consisted of idarubicin 20 mg/m2 on days -13, -12 and -11, melphalan 100 mg/m2 on days -5 and -4 and cyclophosphamide 60 mg/kg (plus mesna 60 mg/kg) on days -3 and -2 (IMC). Seven patients achieved a complete remission or a very good partial remission (reduction of M-component > or =90%). There were no toxic deaths. Severe mucositis and fever of unknown origin were seen in all patients. Reversible supraventricular tachycardias without clinical signs of cardiac failure occurred in five patients. One patient developed a persistent deterioration of cardiac function. We surmise that high-dose chemotherapy with IMC is very effective and well tolerated in myeloma patients.

Levels of circulating endothelial adhesion molecules (sE-selectin and sVCAM-1) in adult patients with acute leukemia.

The spread of leukemia extends from mobilization of leukemic blast cells from the bone marrow to extramedullary tissue infiltration. Migration of leukemic blasts resembles that of neutrophils and may be regulated by activated endothelial cells via endothelial adhesion molecules such as E-selectin, VCAM-1 and ICAM-1. Plasma levels of soluble adhesion molecules may therefore indicate interaction between leukemic blasts and endothelium, and may be related to leukemic cell mass or subtype of leukemia. In this study, plasma levels of soluble E-selectin, VCAM-1 and ICAM-1 were analyzed in 40 untreated patients with acute leukemia (35 ANLL, five ALL). Plasma concentrations of all three receptors were significantly elevated when compared to healthy controls (P = 0.006, P = 0.0001, and P = 0.0001, respectively) but demonstrated high interindividual variations among leukemic patients. sE-selectin but not sVCAM-1 and sICAM-1 levels correlated with peripheral leukocyte and blast cell counts. Increased levels of either sE-selctin or sVCAM-1 were present in 32 out 40 leukemic patients (80%). FAB subgroups differed in levels of sVCAM-1. The highest levels were measured in acute myelomonocytic and lymphoblastic leukemia, ie in leukemia subtypes with a high incidence of extramedullary blast cell infiltration.