Philipp Schütt

Immune parameters in multiple myeloma patients: influence of treatment and correlation with opportunistic infections.

The present study evaluated cellular and humoral immune parameters in myeloma patients, focusing on the effect of treatment and the risk of opportunistic infections. Peripheral blood lymphocyte subsets and serum levels of nonmyeloma immunoglobulins (Ig) were analysed in 480 blood samples from 77 myeloma patients. Untreated myeloma patients exhibited significantly reduced CD4+/45RO+, CD19+, CD3+/HLA-DR+, and natural killer (NK) cells, as well as nonmyeloma IgA, IgG and IgM. Conventional-dose chemotherapy resulted in significantly reduced CD4+ and even further decline of CD4+/CD45RO+ and CD19+ cells, most notably in relapsed patients. Additional thalidomide treatment had no significant effects on these parameters. Following high-dose chemotherapy (HD-CTX), prolonged immunosuppression was observed. Although CD8+, NK, CD19+ and CD+/CD45RO+ cells recovered to normal values within 60, 90, 360 and 720 days, respectively, CD4+ counts remained reduced even thereafter. Nine opportunistic infections were observed, including five cytomegalovirus (CMV) diseases, one Pneumocystis carinii pneumonia (PCP) and three varicella zoster virus infections with CMV diseases and PCP occurring exclusively after HD-CTX. Opportunistic infections were correlated with severely reduced CD4+, as well as CD4+/CD45RO+ and CD19+ counts. Thus, myeloma patients display cellular and humoral immunodeficiencies, which increase following conventional as well as HD-CTX, and constitute an important predisposing factor for opportunistic infections.

A Novel Nonobese Diabetic/Severe Combined Immunodeficient Xenograft Model for Chronic Lymphocytic Leukemia Reflects Important Clinical Characteristics of the Disease

We here describe a novel xenograft model of chronic lymphocytic leukemia (CLL) generated by infusion of human primary CLL cells into immunodeficient nonobese/severe combined immunodeficient (NOD/SCID) mice. Combined i.v. and i.p. injection of peripheral blood mononuclear cells (PBMC) from 39 patients with CLL resulted in highly reproducible splenic (37 of 39) and peritoneal (35 of 39) engraftment, which remained stable over a time span of 4 to 8 weeks. By comparison, recovery of leukemic cells from bone marrow (21 of 39) or peripheral blood (8 of 22) was substantially lower. The engraftment pattern of CLL PBMC 4 weeks posttransplant was correlated with clinical disease activity: infusion of PBMC from donors with Binet stage A, lymphocyte doubling time of >12 months, and normal lactate dehydrogenase (LDH) serum levels led to marked engraftment of T cells whereas comparably few tumor cells could be detected. In contrast, NOD/SCID mice receiving PBMC from donors with advanced stage Binet C, lymphocyte doubling time of <12 months, and elevated LDH serum levels exhibited predominant engraftment of tumor cells and comparably low numbers of T cells. These results suggest that this model reflects the heterogeneity and important clinical characteristics of the disease, and thus may serve as a tool for preclinical drug testing and investigation of the pathophysiology of CLL.

Prognostic relevance of soluble human leukocyte antigen-G and total human leukocyte antigen class I molecules in lung cancer patients.

The aim of this study was to determine the prognostic significance of soluble human leukocyte antigen (HLA) class I (sHLA-I) and HLA-G molecules in lung cancer patients. A total of 23 small-cell lung cancer (SCLC) and 114 non-small-cell lung cancer (NSCLC) patients, including 55 adenocarcinoma, 46 squamous cell carcinoma (SCC), and 13 patients with undifferentiated carcinoma, were prospectively enrolled. Levels of sHLA-G and sHLA-I were analyzed by specific enzyme-linked immunosorbent assay. Median levels of sHLA-G and sHLA-I were significantly increased in patients compared with controls (34 ng/ml [3.6-160] vs 14 ng/ml [0-98], p < 0.0001; 2580 ng/ml [749-5770] vs 1370 ng/ml [274-2670], p < 0.0001, respectively). Regarding the different subgroups, patients with NSCLC or SCLC showed increased sHLA-I levels, whereas sHLA-G was exclusively elevated in NSCLC, especially in patients with SCC. Patients with sHLA-I<2800 ng/ml (p = 0.008) or sHLA-G<40 ng/ml (p = 0.073) showed prolonged overall survival (OS). Using these cut-offs in patients with SCC, a pronounced prognostic significance for sHLA-G (p = 0.003) and sHLA-I (p = 0.004) was observed for the prediction of OS. Here, multivariate analysis confirmed sHLA-G and sHLA-I in addition to disease stage as independent prognostic factors. The prognostic power was further enhanced by combining the two factors and comparing the OS of patients with low sHLA-I and low sHLA-G against the remaining ones. In conclusion, plasma levels of sHLA-G and sHLA-I are potent predictors for OS in lung cancer patients.

Hemolytic uremic syndrome following prolonged gemcitabine therapy: report of four cases from a single institution

Hemolytic uremic syndrome (HUS) has been described following the administration of multiple antineoplastic agents, most notably mitomycin C. More recently, several cases of gemcitabine-induced HUS have been observed with the overall incidence of gemcitabine-induced HUS estimated at 0.015–0.25%. We here report on four patients who developed HUS following gemcitabine therapy at our institution within the last year (incidence 1.4%). All these patients had advanced-stage disease, were heavily pretreated, and received prolonged gemcitabine application, suggesting that in this subgroup of patients HUS may be more frequently encountered than documented so far.

Thalidomide in combination with vincristine, epirubicin and dexamethasone (VED) for previously untreated patients with multiple myeloma

Abstract:  The present study aimed to evaluate the side‐effects and efficacy of thalidomide in combination with an anthracycline‐containing chemotherapy regimen in previously untreated myeloma patients. Thalidomide (400 mg/d) was combined with bolus injections of vincristine and epirubicin and oral dexamethasone (VED). Chemotherapy cycles were repeated every 3 wk until no further reduction in myeloma protein was observed, whereas the treatment with thalidomide was continued until disease progression. Thirty‐one patients were enrolled, 12 patients were exclusively treated with thalidomide in combination with VED and 19 patients additionally received high‐dose melphalan, for consolidation. Adverse events and response to therapy were assessed prior to treatment with high‐dose chemotherapy. Response to thalidomide combined with VED was complete remission in six patients (19%), partial remission in 19 patients (61%), stable disease in five patients (16%), and progressive disease in one patient (3.2%). Grade 3 and 4 adverse events consisted of leukocytopenia in 10 patients (32%), and thrombocytopenia and anemia in one patient each (3.2%). Neutropenic infections grade 3 and 4 occurred in seven (23%) and three patients (9.7%), respectively, including two patients (6.5%) who died from septic shock. Deep vein thrombosis occurred in eight patients (26%), constipation in 20 patients (65%), and polyneuropathy in 20 patients (65%). The probability of event‐free survival and overall survival in the whole group of patients at 36 months were 26 and 62%, respectively. In conclusion, the combination of thalidomide with VED appears to be highly effective in previously untreated patients with multiple myeloma, but it is associated with a high rate of thrombotic events, polyneuropathy, and neutropenic infections.

Ifosfamide, etoposide, cytarabine, and dexamethasone as salvage treatment followed by high-dose cyclophosphamide, melphalan, and etoposide with autologous peripheral blood stem cell transplantation for relapsed or refractory lymphomas

High‐dose chemotherapy (HD‐CT) with autologous stem cell transplantation is considered to be the treatment of choice for relapsed high‐grade non‐Hodgkins lymphoma (NHL) and Hodgkins lymphoma (HL) patients, but the optimal treatment has not yet been defined. We evaluated a salvage treatment regimen consisting of conventional cycles with ifosfamide, etoposide, cytarabine, and dexamethasone (IVAD) followed by two cycles of HD‐CT consisting of cyclophosphamide, melphalan, and etoposide (CMV) with autologous stem cell support in patients with relapsed or refractory NHL (n = 59) and HL (n = 16). Response to IVAD was complete remission (CR) in 16 patients (21%), partial remission (PR) in 39 patients (52%), stable disease (SD) in 18 patients (24%), and progressive disease (PD) in two patients (2.7%). Of 70 patients treated with HD‐CT, 41 patients (59%) showed a CR, 20 patients a PR (29%), eight patients a SD (11%), and one patient a PD (1.4%). The 5‐yr overall survival for the entire group of patients was 29%, and for patients with NHL and HL 25%, and 38%, respectively. The respective event‐free survival probabilities at 5 yr were 22%, 16%, and 31%. Seven treatment‐related deaths due to septicemia (three), cardiac arrhythmia (one), pneumonia (one), pneumonitis (one), and toxic epidermal necrolysis (one) were observed. In multivariate analysis, an International Prognostic Index of ≥2 and resistant disease to first‐line chemotherapy were poor independent prognostic factors for the subgroup of patients with NHL. In conclusion, these results indicate that IVAD/CMV is feasible as a salvage therapy for lymphoma patients. This treatment is currently evaluated with the addition of rituximab.

The clinical significance of soluble human leukocyte antitgen class-I, ICTP, and RANKL molecules in multiple myeloma patients

Because of the variable clinical course of multiple myeloma, the identification of prognostic parameters is of clinical interest. Therefore, we analyzed the clinical significance of serum levels of soluble human leukocyte antigen class I molecules (sHLA-I), carboxy-terminal telopeptide of type-I collagen (ICTP), and receptor activator of nuclear factor kappa B ligand (RANKL). Compared with controls, sHLA-I were threefold (p < 0.001) elevated in multiple myeloma. Increased levels of ICTP and RANKL were demonstrated in 50 and 43% of patients, respectively. sHLA-I correlated significantly with stage of disease. Serial determination of sHLA-I in 11 patients revealed significantly higher sHLA-I levels (median [range] mug/l) during active disease than during remission (700 [250-2090] versus 380 [130-920]). ICTP demonstrated an association with stages of disease and the presence of osteolytic lesions, whereas there were no differences with respect to active/remittent disease. Importantly, levels of sHLA-I > or = 1000 microg/l and ICTP > or = 5 microg/l were significantly associated with a poor overall survival. For RANKL, no significant associations were observed with disease stages, disease status, osteolytic lesions, and survival. In conclusion, sHLA-I and ICTP serum levels seem to be of prognostic significance in multiple myeloma and might be helpful to identify patients of poor prognosis.

Long-term results of a phase-I/II study of sequential high-dose chemotherapy with autologous stem cell transplantation in the initial treatment of aggressive non-Hodgkin's lymphoma.

AIMS AND BACKGROUND To improve the survival of patients with aggressive non-Hodgkins lymphoma, we evaluated a risk-adapted therapeutic approach using high-dose (HD) or conventional-dose (CD) chemotherapy (CT) for poor-risk and good-risk patients, respectively. METHODS Twenty patients were treated in each group. In both groups, the first chemotherapy cycle consisted of dexamethasone, vincristine, ifosfamide, and etoposide. Thereafter, the CD or HD patients received 3 or 2 cycles of dexamethasone, vincristine, epirubicin, and cyclophosphamide, respectively, followed by 1 cycle of dexamethasone, carboplatin, and etoposide. In the HD group cyclophosphamide, epirubicin, carboplatin, and etoposide were dose-escalated by a factor of 6, 3, 3, and 3, respectively, as compared to the CD group, and autologous peripheral blood stem cells were administered after each HD-CT cycle. RESULTS Grade III-IV toxicities were neutropenia and thrombocytopenia (100%), anemia (55%), and stomatitis (30%) in patients with HD-CT, and neutropenia (90%) in patients with CD-CT. One toxic death occurred in a patient with HD-CT. The overall response rate was 100% in HD-CT patients, including 70% complete remissions, and 80% in CD-CT patients, including 60% complete remissions. The 10-year overall survival was 55% for patients with HD-CT and 80% for patients with CD-CT. CONCLUSIONS The risk-adapted treatment approach showed tolerable toxicities and was associated with encouraging results.

Anthracyline-reduced sequential combination chemotherapy for younger patients with good-prognosis aggressive B-cell non-Hodgkin's lymphoma.

IntroductionAnthracyline-based chemotherapy is the treatment of choice for patients with aggressive B-cell non-Hodgkin’s lymphoma (NHL). However, anthracyclines have been associated with long-term cardiac toxicity.MethodsWe conducted a study using a sequential combination chemotherapy with a reduced cumulative dose of anthracyclines in younger patients with good-prognosis aggressive NHL. Chemotherapy consisted of one cycle of vincristine, ifosfamide, etoposide, and dexamethasone, followed by three cycles of epirubicin, cyclophosphamide, vincristine, and dexamethasone, and a fifth cycle containing carboplatin, etoposide, and dexamethasone. 86 patients were treated, 65 without and 21 with additional rituximab. Consolidating involved-field irradiation was applied in patients with stage I/II, bulky disease, or localized residual lymphoma.ResultsComplete and partial remissions were achieved in 67 and 27% of patients, respectively, and the 3-year event-free and overall survival estimates were 75 and 87%. The survival estimates were substantially better in patients who received rituximab. Main toxicity was grade 3/4 leukocytopenia in 89% patients with neutropenic fever in 30%. Two patients died of septic shock.ConclusionThe treatment appears to be effective in this group of patients. The hematological toxicities, particularly after the first and fifth cycle, require the use of G-CSF and/or a dose reduction in selected patients.