ALBERT

Description: AML patients with unfavourable cytogenetics generally have a poor outcome. Over the last decade a number of strategies to improving survival have been assessed by the East German Study Group (OSHO). Here, we analyse the results of three protocols (AML 93, AML 96 and AML 2002) for effects on outcome in younger patients (

Description: Introduction: Mantle cell lymphoma (MCL) is a subtype of malignant lymphoma with an especially poor prognosis. However, molecular targeted therapy may alter the natural history of disease. Bortezomib (BZ) is a potent, selective and reversible inhibitor of the 26S proteasome thereby interfering with intracellular protein homeostasis. Various clinical phase II trials revealed significant efficacy of BZ monotherapy in relapsed MCL with approximately 40% response rate, but rare CR and short duration of response. Based on our preclinical data demonstrating synergy of BZ and cytarabine (Ara-C) we performed a pilot study to explore the clinical impact of such combined approach. Treatment: 2 g/m2 Ara-C was applied on day 2 and 3 (1 g/m2 in patients with impaired hematopoiesis or age 〉60 years) combined with BZ 1.5 mg/m2 iv bolus (day 1 and 4). In addition, dexamethasone 40 mg was given over a 4 day period. R was added to the outlined regimen in 6 patients (375 mg/m2). Treatment was repeated in 3 week intervals for a total of 4 cycles with staging procedures performed after 2 and 4 cycles. Results: After informed consent 8 patients with relapsed or refractory advanced stage MCL were treated accordingly to the outlined protocol. Median age was 65 years (54–76), 5 patients were male. Median number of prior systemic therapies was 4 (2–7). All patients had previously been treated with CHOP and at least one rituximab (R)-containing regimen, 2 patients previously failed BZ monotherapy, and none of them was considered eligible for myeloablative treatment. Currently data from 7 patients are available for analysis of toxicity and response. At time of analysis, a total of 22 cycles has been applied with a median follow-up of 214 days (119–366). As expected, hematologic toxicity CTC grade III/IV occurred in all 7 patients, but only one case of neutropenic fever (grade 3) and no major bleeding were observed. Ara-C dose was reduced in 5 patients. Two patients developed new onset or worsening of preexisting polyneuropathy. Dose of BZ had to be reduced in 1 patient and stopped after cycle 2 in another patient with preexisting polyneuropathy. Of note, 2 patients developed herpes zoster (grade 2). In 3 patients treatment was stopped after cycle 2 due to insufficient response (progressive disease, stable disease and minimal response, respectively). In the 4 patients completing 4 cycles 1 CR and 3 PR were archieved. Conclusion: Salvage therapy with high-dose Ara-C combined with BZ in relapsed or refractory MCL was associated with considerable but manageable hematotoxicity and only few infectious complications. The high efficacy in heavily pretreated patients justifies a comparative trial of the European MCL Network evaluating a high-dose cytarabine containing regimen +/− BZ.

Description: Abstract 805 Background: As an intense therapy delivered with curative intent, with substantial risk for life-threatening toxicity, stem cell transplant (SCT) may uniquely impact the end-of-life (EOL) experience of children who undergo SCT but do not survive. Despite this, very little is known about the EOL experience of such children. Objective: To evaluate patterns of and parent and physician perspectives on EOL care for children after SCT. Methods: We evaluated parent and physician perspectives and patterns of EOL care via a retrospective, cross-sectional survey of 141 parents of children who died of cancer, and primarily received care at one of two tertiary care pediatric institutions (response rate 64%). Chart review provided additional information. Children for whom SCT was the last cancer therapy (n=31) were compared with those for whom it was not (non-SCT, n=110). Results: The SCT group included 22/31 (71%) allogeneic and 9/31 (29%) autologous SCT. The median (IQR) interval between last cancer treatment and death was 65 (30-127) days (SCT group) and 25 (8-59) days (non-SCT group) (p

Description: The International Peripheral T-Cell Lymphoma Project is a collaborative effort designed to gain better understanding of peripheral T-cell and natural killer (NK)/T-cell lymphomas (PTCLs). A total of 22 institutions in North America, Europe, and Asia submitted clinical and pathologic information on PTCLs diagnosed and treated at their respective centers. Of the 1314 eligible patients, 181 had anaplastic large-cell lymphoma (ALCL; 13.8%) on consensus review: One hundred fifty-nine had systemic ALCL (12.1%) and 22 had primary cutaneous ALCL (1.7%). Patients with anaplastic lymphoma kinase–positive (ALK+) ALCL had a superior outcome compared with those with ALK− ALCL (5-year failure-free survival [FFS], 60% vs 36%; P = .015; 5-year overall survival [OS], 70% vs 49%; P = .016). However, contrary to prior reports, the 5-year FFS (36% vs 20%; P = .012) and OS (49% vs 32%; P = .032) were superior for ALK− ALCL compared with PTCL, not otherwise specified (PTCL-NOS). Patients with primary cutaneous ALCL had a very favorable 5-year OS (90%), but with a propensity to relapse (5-year FFS, 55%). In summary, ALK− ALCL should continue to be separated from both ALK+ ALCL and PTCL-NOS. Although the prognosis of ALK− ALCL appears to be better than that for PTCL-NOS, it is still unsatisfactory and better therapies are needed. Primary cutaneous ALCL is associated with an indolent course.

Description: Cancer-induced tolerance involves multiple immunosuppressive pathways, which subvert adaptive immune responses against tumor cells. Extensive phenotypic characterization of NK cells from tumor-bearing mice led us to the observation of a consistent expansion of c-kit-expressing NK cells (Kit+NK cells) compromising the NK cell arm of tumor immunosurveillance. In naïve animals, Kit+NK cells (CD3−NK1.1+CD117+) represent about 3.3±0.7% of blood, 4.8±1.4% of spleen and 13.2±2.4% of lymph node NK cells. In tumor-bearing animals, percentages and absolute numbers of Kit+NK cells increased to levels that mediate inhibitory effects on mature NK cells. Purified Kit+NK cells failed to produce IFNγ or GM-CSF in response to IL-2 and could not promote DC maturation in contrast to conventional Kit−NK cells. Moreover, adoptive transfer of Kit+ (but not Kit−) NK cells into mice injected with CT26 colon carcinomas or B16F10 melanomas promoted the establishment of lung metastases. Micro array comparison of CD3−NK1.1+Kit+ and CD3−NK1.1+Kit− cells revealed profound differences in their transcriptomes. Two major sets of genes involved in tolerance (B7-H1, CTLA4, Lag3, Hmox1) or tissue repair and bone marrow homeostasis (Cxcl2, CD81, CD63, Csf2) were markedly up-regulated in Kit+NK cells. Among these, B7-H1 appeared particularly intriguing as we found that Kit+NK cells killed Kit−NK cells in a B7-H1/PD-1-dependent manner. Moreover, IL-18 produced by CT26 or B16F10 tumors converts Kit− into Kit+NK cells endowed with immunoablative functions in lymph nodes. Upon tumor inoculation, Kit+ NK cells, which upregulate B7-H1, accumulate in lymphoid organs in an IL-18R/MyD88-dependent manner and directly kill conventional NK cells, thereby promoting the progression of NK-controlled cancers. Importantly, IL-18R−/− mice lost the development of Kit+NK cells during tumor progression. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18-binding protein (IL-18BP) reduced the expansion of Kit+NK cells, stimulated the NK cell-dependent immunosurveillance and significantly reduced tumor growth. The inflammatory cytokine IL-18 is known to accumulate in cancer-bearing patients but its pathophysiological role still remains unclear. Here, we show that IL-18 is a major tumor-derived immunosuppressant affecting the innate arm of tumor immunosurveillance. In summary, these data suggest that IL-18 promotes the expansion of Kit+NK cells endowed with immunosuppressive functions that could act as negative regulator of general NK responses.

Description: The association of lymphoma with a plethora of secondary immune defects is well established. However, most investigations were performed many years ago and little is known about disease specific alterations of the immune system. From January 2003 to August 2004 50 patients with newly diagnosed malignant lymphoma were analyzed and compared with 50 healthy volunteers Corresponding in age and gender. Parameters of cellular and humoral immunity, including CBC, FACS analysis of lymphocyte subpopulations, cytokines (sIL2-R, IL-6, IL-10, TNF-a), serum complement components C3c, C4, CH50 and total concentrations of serum immunoglobulin IgG, IgM, IgA were measured. The median number of CD3+ and CD4+ lymphocyte subsets (p≤0.01) were significantly lower in lymphoma patients compared with matched healthy volunteers. The number of CD8+ T-cells was decreased in patients with bulky disease (p≤0.01). High-intermediate/high risk lymphoma (IPI 3-4 or aaIPI 2-3) had significantly higher CH50 (p=0,02), C3c (p≤0,01), sIL2-R (p≤0,01) and TNF-a levels (p=0,05) than patients with low/low-intermediate risk lymphoma. Infectious complications after chemotherapy (n=14) occurred frequently in patients with high initial LDH (p=0,04), low number of CD4+ (p=0,02) or CD8+ T-cells (p=0,04) and high levels of sIL2-R (p=0,02) or TNF-a (p=0,03). Relapse (n=6) was also observed in patients with decreased CD8+ T-cells (p=0,04) and in patients with high C4 levels (p=0,02). These results indicate that tumor burden in lymphoma patients significantly influenced the number of lymphocyte subsets, serum cytokine levels (sIL2R, TNF- a) and complement components (CH50, C3c). IPI-score and clinical course (infections and relapse) were related to the immunodeficiency. We conclude that measurement of peripheral blood lymphocyte subsets, cytokines and complement factors can be expected to improve existing methods of risk assignment in lymphoma.

Description: Introduction: Patients with solid tumors have an increased risk for venous thromboembolisms (VTE) associated with substantial morbidity and mortality, but so far there exists little data on hematologic malignancies. We have recently found a VTE rate of 7,7% in patients with malignant lymphoma. However, information on patients with acute leukemia (AL) is very limited so far. Patients and methods: Medical records of all patients with AL treated in our institution between january 1992 and april 2005 were reviewed and data was collected and analyzed in a microsoft excel data base. P-values to show correlation of VTE with leukemia type, patient age and gender were calculated using Fisher’s exact test. All reported p-values are two-sided. Results: Of a total of 455 patients 310 (68%) had AML, 108 (24%) had ALL and 37 (8%) had blast crisis. 248 patients (55%) were male and 207 (45%) were female, median age was 60 years. 55 patients with AL (12,1%) had at least one VTE, occuring during therapy in 82% of events. 27 patients (5,9%) had central venous catheter associated VTE, whereas 28 patients (6,2%) had deep vein thrombosis and/or pulmonary embolism. Neither leukemia lineage - myeloid versus lymphocytic - (p=1,0) nor patient gender (p=.193) had an impact on the VTE risk. However, central venous catheter associated VTE more likely occured in younger patients (〈 60 years) than in patients ≥ 60 years (p=.003). There was no statistically significant difference in the incidence of non-central venous catheter associated VTE between both age groups (p=.563). Discussion: Patients with acute leukemia have a substantial risk for VTE, half of which occur with the use of central venous catheters. A recently published study analysed the incidence of VTE in close temporal relationship to onset of disease and found a VTE rate of 2,09% with equal risk in ALL and AML. Our study included VTE occuring prior to diagnosis of AL as well as during chemotherapy and follow up, revealing a VTE rate that is 6-fold higher and showing a considerable association with central venous catheters. Conclusions: The risk of VTE is surprisingly high in patients with acute leukemia, thus improvement of prophylactic measures, especially in regard to central venous catheter use is warranted.

Description: Follicular lymphoma (FL) is an indolent disease of the advanced age with more than 40 % of the patients being older than 60 years at diagnosis and an age-specific incidence peaking above 75 years. We now analyzed the treatment outcome of elderly patients in the GLSG multicenter phase III study comprising a prospective randomized comparison of R-CHOP versus CHOP alone in patients with advanced stage FL. 221 patients 〉 60 years with untreated FL were randomized for therapy with R-CHOP (R-CHOP: Rituximab 375 mg/m2 d0–1; cyclophosphamide 750 mg/m2 d1; doxorubicine 50 mg/m2 d1; vincristine 1.4 mg/m2 d1; prednisone 100 mg/m2 d1–5) (n=109) or CHOP alone (n=112). Patient characteristics were well balanced between the treatment groups, also with regard to the distribution of the FLIPI risk groups (≥ 3 adverse factors 73% and 66 % in the R-CHOP and CHOP arm, respectively). R-CHOP induced higher overall response rates and significantly prolonged the time to treatment failure (TTF)(median 5.0 years versus 2.1 years, respectively; logrank test: p 4) as well as application of CHOP alone were independently associated with a shorter TTF. Treatment related side effects were similar in both patient groups and comprised predominantly myelosuppression. In summary, the addition of Rituximab to CHOP significantly improves the outcome of elderly patients with previously untreated advanced stage FL without adding major side effects.

Description: The simultaneous appearance of B-CLL and MM in the same patient (pt) seems to be a rare phenomenon. In those cases - our experience included - 1. the myeloma exhibits an aggressive course, 2. with CLL-treatment, MM seems to emerge, 3. which, if well treated (e.g. high-dose chemotherapy [CTx] with autologous peripheral blood stem cell transplantation [auto-PBSCT]), may lead to a slower myeloma course, improved clinical condition and CLL disapearance. Here we report on the simultaneous (n=2) and successive (n=2) occurrence of CLL and MM in four pts, who were diagnosed at our center during the last year. We suggest that the occurrence of CLL and MM, when carefully monitored, may be more frequent than assumed so far. Case 1. This 64-year-old male was evaluated due to weight loss, leukocytosis, anaemia, foamy urine and increased creatinine. Kappa (k) Bence-Jones (BJ) proteinuria and elevated k-serum free light chains (SFLC) were found. A bone survey was normal, but BM biopsy showed infiltrates of plasma- (PC) and B-CLL-cells. Due to Rai 0 CLL and MM stage IIIB, the pt received 2 cycles of VAD followed by an auto-PBSCT. Thereby, he obtained a PR. Maintenance with thalidomide stabilized both diseases. Case 2. This 77-year-old male was simultaneously diagnosed with RAI 0 CLL and stage IIIB MM. Diagnostics revealed a lambda (l)-paraprotein, BJ-l-proteinuria and lytic bone lesions. The BM showed monoclonal l-LC-expressing PCs, and k-LC-CLL-cells. The pt received melphalan/prednisone (MP) and thereby obtaining SD. Case 3. This 62-year old pt was diagnosed with RAI II B-CLL. Two years later, he showed increased splenomegaly, anemia, elevated l-SFLC and dense CLL-BM-infiltrates. Chlorambucil/prednisone-CTx was initiated, but failed to improve his condition. Further evaluation due to renal impairment revealed multiple lytic lesions and monoclonal l-LC-expressing PCs, coexisting with remaining CLL infiltrates in his BM. Cyclophosphamide-CTx, 2 cycles of VAD and auto-PBSCT were performed and Bortezomib maintenance, improving the pt’s general condition, his PB counts and l-SFLC secretion. Despite these efforts, MM relapse occurred 5 months later with persisting absence of his preceding CLL and the pt eventually died due to myeloma progression. Case 4. This 73-year-old male was diagnosed with B-CLL, showing moderate splenomegaly, lymphocytosis, initially not requiring any therapy. Two years later, he showed a deteriorating clinical condition, multiple osteolytic lesions, anemia, hypercalcemia, monoclonal IgA paraprotein and k-BJ-proteinuria. A BM biopsy confirmed k-LC B-CLL- and k-PC-infiltrates. The diagnosis of stage IIIA IgA k-MM, and RAI II B-CLL led to MP-CTx that induced SD of his MM and CLL. In summary, our 4 pts had a median age of 69 years (range; 62–77) and showed a median time interval of their CLL and MM diagnosis of 11 months (0–31). All pts had stage III MM and renal impairment in 3/4, whereas CLL showed an indolent course. LCs of CLL and MM were different in all except one pt. Cytogenetic and genomic analyses are currently ongoing and will be reported at the meeting. We conclude that the elucidation of the coincidence of CLL and MM will allow to understand why and how often both occur and also, how they can be efficiently treated. The question of their clonal relationship should be answered via genomic analyses that will allow to gain further insight into the origin of both diseases.

Description: Recent evidence indicates that regulatory T cells (Tregs) play an important role in HIV infection. However, although the gastrointestinal mucosa is a key compartment in HIV disease, no data on mucosal Tregs in HIV infection are available. In this study, we compared the frequency of Tregs in duodenal mucosa and peripheral blood (PB) of 13 treatment-naive and 13 suppressively treated HIV-infected patients with that of 6 patients with norovirus infection and 12 healthy controls. Tregs were quantified by immunohistochemistry (CD3/FOXP3) and further characterized (CD25, CTLA-4, GITR) by immunohistochemistry, immunofluorescence, and fluorescence-activated cell sorting (FACS). Both the frequency and the absolute count of mucosal Tregs were highly increased in untreated HIV patients but were normal in treated HIV patients. In contrast, in peripheral blood of HIV patients, the absolute number of Tregs was not increased, and their frequency was only slightly elevated. In norovirus infection, frequency of mucosal Tregs in the CD4+ T-cell subset was not elevated. The high increase in count and frequency of mucosal Tregs seems to be a characteristic feature of untreated HIV infection, suggesting a significant contribution of Tregs to the pathogenesis of HIV disease. Their role may be 2-edged: attenuating HIV-induced immune hyperactivation while suppressing the immune response to HIV and mucosal pathogens.