ALBERT

Description: Key Points Loss of the oxygen sensor PHD2 in the HSC compartment in mice results in the HIF1α-driven induction of multipotent progenitors. PHD2-deficient hematopoietic progenitors are outcompeted during severe stress while HSCs are encouraged to self-renew.

Description: Rituximab proved to be effective in relapsed and refractory indolent NHL as a single agent and generated impressive results in phase II studies in combination with chemotherapy. In a prospective randomized trial we compared the efficacy and toxicity of rituximab (375 mg/m² d 1) plus MCP-chemotherapy ( mitoxantrone 8 mg/m² d 3 + 4, chlorambucile 3 x 3 mg/m² d 3 – 7, prednisolone 25 mg/m² d 3 – 7 ) given every 28 days for a total of 8 cycles versus MCP (d 1 – 5) x 8 cycles alone in advanced indolent NHL and MCL. Efficacy endpoints included overall and complete response rates, event free survival, progression free survival, overall survival and toxicity. For response assessment classical definitions have been used. Between 10/98 and 09/03 we randomized 358 patients (pts) with advanced stage follicular lymphoma (FL) (grade 1 + 2), lymphoplasmacytic lymphoma and MCL to either R-MCP or MCP. The study arms are well balanced for all demographic factors. 201/358 pts (56%) had FL. Both regimens were well tolerated with a low incidence of serious adverse events. The overall response rate (RR) and the complete response rate (CR) for all pts was 85,5% and 42% in the R-MCP arm versus 65,5% and 20% in the MCP arm (p

Description: Key Points ALPS DNT cells and their putative precursors reveal high proliferative activity in vivo, which is associated with hyperactive mTOR signaling. Rapamycin therapy controls mitotic activity and abnormal differentiation of ALPS DNT cells and reduces CD4+ or CD8+ precursor DNT cells.

Description: Purpose: The combination of chemotherapy with the chimeric anti-CD20 antibody Rituximab has been reported to be highly active in the treatment of follicular lymphoma. The frequency and dosage of rituximab required to induce the maximum effect in follicular NHL is not defined. To evaluate how often rituximab should be added to standard chemotherapy to achieve maximum remission rates, we have initiated a prospective randomized multicenter phase II study. Methods: Patients (pts) with stage III/IV CD20 positive follicular NHL who were chemotherapy naïve were randomly assigned to receive 6 courses of a standard CHOP-21 chemotherapy, accompanied by rituximab 375 mg/m2 at day 0 only with the first CHOP course (arm A), with the first 3 CHOP courses (arm B) or with all 6 CHOP courses (Arm C). The major endpoint was the rate of molecular remission in bone marrow and peripheral blood in initially t(14;18)-positive pts, assessed by PCR. Other endpoints of the study were overall and complete response rates, toxicity rate and time to progression. Results: Since September 2000, 104 pts with a median age of 57 years (range 30–80) were recruited. 33 pts were randomized to arm A, 35 to arm B and 36 to arm C. So far 69 pts have been documented completely after all 6 cycles and are evaluable for side effects. All three treatment arms were well tolerated. The incidence of adverse events and Grade 4 toxicity was similar in all groups. One treatment related death was observed 2 months after completion of therapy due to hepatitis B. The overall response rate (ORR) of the whole group, which was evaluable in 69 pts so far, was 90 % (62 of 69 pts), with 20 complete and 42 partial remissions. Conclusion: This multicenter, randomized, phase II trial addresses for the first time the optimal frequency and dosage of rituximab infusions in the combined immuno-chemotherapy. In the first interim analysis of the ongoing trial, similar hematologic, gastrointestinal and infectious toxicity was observed in all treatment arms.

Description: Several conflicting options regarding management of adult ALL are currently discussed. One major issue is the indication for SCT depending on risk factors and age, and the other is the recommendation to use unmodified pediatric protocols for “young” adults. Decision making on SCT is generally based on conventional risk factors – mainly disease characteristics – available at diagnosis, and decision making for “pediatric” chemotherapy on age. It is essential to develop more sophisticated criteria – also to reduce the risk of selection in clinical trials. In order to enhance prognostic models and to better address individual patient characteristics and the course of disease we reanalysed conventional prognostic factors together with new patient specific factors in a large cohort of adult ALL patients. A total of 1657 well characterised pts (15–55 yrs) included in the risk stratified protocols of the German Multicenter Study Group (GMALL) 06/99 and 07/03 was analysed. Treatment and risk stratification have been described (Brüggemann, Blood2006: 107;1116). Age remained a highly significant factor for CR, survival (OS) and disease free survival (DFS). OS ranged from 58% for 15–25 yrs, 52% for 26–35 yrs, 43% for 36–45 yrs to 32% for 45–55 yrs (p=.0001). Poorer outcome with increasing age was mainly due to early death (ED) and death in CR. CR, OS (45% c/pre-B, 45% pro-B, 38% early T, 47% mature T and 64% thymic T;p

Description: The activity of thalidomide monotherapy in relapsed or refractory disease is widely accepted but many haematologists have observed better response rates with combination therapies. This communication aims to give an overview on the efficacy of these alternatives. Methods: Our group has performed two systematic reviews (thalidomide monotherapy: Glasmacher et al., Brit. J. Haematol., 2005; 129 suppl 1: 24; thalidomide and dexamethasone combination therapy: submitted to ASH 2005). Furthermore a search of trials combining thalidomide, cyclophosphamide and dexamethasone (with or without further drugs) was performed. Only trials that included patients with relapsed or refractory multiple myeloma could be evaluated. Response was defined as a reduction of the monoclonal component by more than 50% in the absence of any sign of disease progression. Proportions and 95% confidence intervals were reported (Confidence Interval Analysis, Version 2.1.1, Southampton, UK, 2000). Results: Thalidomide monotherapy was administered in doses between 50–600 mg/d (median doses). Thalidomide in combination with dexamethasone was given in doses of 100–400 mg/d (median doses), dexamethasone was given 40 mg/d d1–4 every 3–4 weeks in 7 of 8 trials. Thalidomide dosage and combination therapy of trials adding Cy to thalidomide and dexamethasone are shown in Table 1. The response rates of the three different thalidomide applications are demonstrated Table 2. Conclusion: This compilation of data from phase II trials cannot replace a randomized trial and may be biased. With this limitation it seems that thalidomide combined with dexamethasone (response rate 51%) is more effective than monotherapy (response rate 29%) as the 95% confidence intervals for the response rates do not overlap. Whether a combination of thalidomide, dexamethasone and cyclophosphamide is more effective than thalidomide and dexamethasone alone cannot be decided from the current data. Table 1: Studies with thalidomide and combination chemotherapy Study Intervention No. of pts. Response (95%CI) Abb.: Cy, cyclophosphamide; Eto, etoposide; T, thalidomide; Dex, dexamethasone; Ida, idarubicin. Values are mg/m2 per course for Cy, Eto, Ida; mg per course for Dex, mg/d for T. Moehler et al. 2003 Cy 1600, Eto 160, T 400, Dex 160 119 55% (46–65) Kropff et al., 2003 Cy 1800, T 400, Dex 240 60 70% (57–81) Dimopoulos et al. 2003 Cy 1500, T 400, Dex 160 43 67% (51–81) Gracia-Sanz et al. 2004 Cy 50 daily, T 800, Dex 160 71 57% (45–67) Glasmacher et al. 2005 Cy 800, Ida 40, T 400, Dex 320 39 57% (41–73) Table 2: Response of different thalidomide combinations Intervention No. of trials No. of pts. Response (95%CI) Abb.: see Table 1 T monotherapy 42 1629 29% (27–32) T + Dex 8 283 51% (45–57) T + Cy + Dex 5 332 60% (55–65)

Description: Background: Infectious complications such as febrile neutropenia belong to the most serious complications of chemotherapy including stem cell transplantation for cancer. The mortality rate associated with febrile neutropenia is approximately 10%. Meta-analyses have shown that both hematological growth factors (CSFs) and antibiotics prevent infections. A comparison of these two agents or their combination has not been examined in systematic reviews. We therefore conducted a network analysis to determine the role of antibiotics and CSFs for the prophylaxis of infections in cancer patients receiving myelosuppressive chemotherapy or hematopoetic stem cell transplantation (SCT). Methods: The network analysis included all randomized controlled trials that compared two or more of the following prophylaxis options: no prophylaxis, prophylaxis with antibiotics alone, prophylaxis using CSFs alone or prophylaxis using combinations of both, CSFs and antibiotics. Trails that did report overall survival, on study mortality, infection-related mortality, clinically documented infections, microbiologically documented infections or fever/febrile neutropenia were excluded. A Bayesian network analysis with four treatment options was performed; results are presented as odds ratios (OR) with 95% credibility intervals (CI). Results: The best prophylaxis in the network with regard to preventing infections and infection-related mortality is the combination of antibiotics and CSFs. Comparing antibiotics alone to CSFs alone yields an OR of 1.00 (95% CI 0.69–1.52) for clinically documented infections. For the combination of both antibiotics and CSFs compared to only antibiotics or only CSFs, the incidence of clinically documented infections was also reduced (OR=0.61, 95% CI (0.46–0.77)). This is also true for the subgroup of patients receiving SCT or patients with acute leukemia. Conclusions: For patients receiving myelosuppressive chemotherapy, antibiotics and CSFs are similarly efficient in reducing infections. The choice of agent can therefore be based on preferences of the treating physician and the adverse events expected. The best prophylactic regimen however is the prophylaxis using both, antibiotics and CSFs. The combination should be considered for patients at high risk of developing infections such as those receiving SCT or patients with acute leukemia.

Description: Introduction: The development of the escalated BEACOPP regimen let to an improved outcome in patients with advanced Hodgkin Lymphoma (HD9 study of the GHSG). However, the application of high dose etoposide (cumulative 4,8 g/m2 per 8 cycles) seems to be associated with an increased incidence of secondary MDS and AML, respectively. Therefore, the aim of our multicenter pilot study was to evaluate the efficacy and toxicity of the etoposide free as well as dose intensified BACOPP-D protocol. Methods: Since May 2000 a total of 115 patients with Hodgkin Lymphoma (HL) stage IIB, III, and IV were treated with BACOPP-D which included cyclophosphamide 1250 mg/m2 (d1), adriamycin 25 mg/m2 (d1+2), dacarbazine 250 mg/m2 (d1-3), procarbazine 100 mg/m2 (d1-7), prednisolone 40 mg/m2 (d1-14), bleomycin 10 mg/m2 (d8) and vincristine 1,4 mg/m2 (maximum 2 mg, d8) at three-weekly intervals with granulocyte colony-stimulating factor (G-CSF). A consolidating involved field radiation (30 Gy) was performed only in patients who achieved less than CR following chemotherapy. Post-treatment follow-up included PET imaging. Results: Until now 97 patients (median age 35 years, range 17-65; 61 male, 36 female) are assessable for toxicity and treatment outcome. We analyzed the acute toxicity for 728 cycles of BACOPP-D. CTC/WHO grade III/IV haematological toxicities per patient were observed as follows: leukopenia 93%, anemia 39%, and thrombocytopenia 33%. CTC grade III/IV non-haematological side effects included documented infection (4%) and lung toxicity (one patient). A total of 85 patients (88%) achieved complete remission, 9 patients (9%) achieved partial remission, three patients (3%) had progressive disease. At a median observation time of 39 months (0,9-77 months), five patients have relapsed, and nine deaths were documented (4 HL-specific and 3 treatment related deaths, 1 death due to ruptured Meckel diverticulum with peritonitis, one 65 year-old woman died in CR following myocardial infarction). One patient developed a second neoplasia (hypopharyngeal carcinoma in an alcoholic). The overall survival and freedom from treatment failure rates at 39 months were 91% and 85%, respectively. FDG-PET scans after BACOPP-D chemotherapy were performed in 68 of 97 patients. PET scans revealed no increased FDG uptake in 48/68 patients (71%), in 20 patients (29%) increased FDG uptake was detected. In the group of patients with increased FDG uptake, one patient developed progressive disease and four patients relapsed. In the group with PET-negative findings no patient relapsed. Diskussion: BACOPP-D regimen appears as a feasible and effective treatment which induced a complete morphologic and metabolic remission in a high proportion of patients with advanced HL. The treatment was associated with moderate acute toxicity. No secondary AML or MDS occurred until now.

Description: Abstract 1419 Poster Board I-442 For more than 20 years high dose chemotherapy followed by allogeneic stem cell transplantation (SCT) has been considered as a reasonable approach for the treatment of patients with AML. Moreover, during the last decade new scientific and technical developments results in major changes of clinical practice of transplantation. Enhanced donor availabilities and new strategies, e.g. dose-reduced conditioning, now make allogeneic stem cell transplantation available to patients who do not have a related donor or would not tolerate high-dose chemotherapy due to age or comorbidities. Usually, the decision to start the work-up process for allogeneic transplantation in AML patients is based on the availability of a donor, the assignment to the cytogenetic risk group, and the response to induction therapy, as well as patient factors. However, there would be greater confidence in defining who should, or should not, receive an allograft if the available recommendations given in guidelines are consistent and similar. In this analysis, a comprehensive systematic literature search for best available evidence from controlled clinical trials was performed in the bibliographic databases MEDLINE, EMBASE and Cochrane Central. In addition, the websites of major organizations in Europe and the US (European Group for Blood and Marrow Transplantation, EBMT; European Society for Medical Oncology, ESMO; British Committee for Standards in Hematology, BCSH; American Society for Blood and Marrow Transplantation, ASBMT; National Comprehensive Cancer Network, NCCN) were screened and the specific databases of the National Guideline Clearinghouse and the Guideline International Network Database were also searched to identify the latest recommendations and guidelines. The following points were selected for systematic comparison of the best available evidence: Factors for risk assessment and categorization of AML, donor categories for allogeneic SCT (sibling donors / matched unrelated donors), allogeneic transplantation in first CR, allogeneic transplantation in relapse/progressive disease or second CR, and allogeneic transplants with reduced intensity conditioning regimen. Several interesting findings emerge from this analysis: 1) For patients with relapse or refractory disease donor availability should be explored and discussed, though this is not based on reliable evidence from randomized studies; 2) Patients in CR1 with intermediate or high risk disease who have a matched related donor available should receive allogeneic stem cell transplantation (intermediate risk; ASBMT: reasonable, NCCN: option); 3) For patients who lack a family donor the recommendations are not consistent; 4) Allogeneic transplantation with reduced conditioning in AML patients is feasible, but the superiority over standard therapeutic regimens has not been proven yet. In summary, current guidelines differ in critical points in the recommendation for allogeneic stem cell transplantation. Furthermore, it is likely that only well-defined subgroups of AML patients will benefit from stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4696 Autoimmune lymphoproliferative syndrome (ALPS) is a rare immunologic disorder caused by defects in the Fas-induced programmed cell death pathway. Impaired lymphocyte apoptosis results in gradual lymphocyte accumulation and dysregulation of lymphocyte homeostasis. ALPS patients usually suffer from persistent generalized lymphadenopathy, hepato-splenomegaly, immune-mediated cytopenias, and other autoimmune phenomena. A 15-month-old boy was diagnosed with ALPS when he presented with typical symptoms. Lab exams showed a pancytopenia, elevated serum immunoglobulin levels, a peripheral expansion of double-negative T lymphocytes of up to 40% of TCRab+ T cells and impaired lymphocyte apoptosis. Molecular analysis confirmed the diagnosis of a type Ia ALPS by identifying a heterozygous Fas gene mutation (D260H). Despite treatment with repeated pulses of high-dose methylprednisolone, intravenous immunoglobulins, and mycophenolate mofetil (MMF) to control lymphoproliferation and recurrent pancytopenia his disease progressed. At three years of age he developed numerous arterial aneurysms of the iliac, mesenterial, renal, hepatic, right middle meningeal, brachial and femoral arteries up to 2.6 cm in diameter and lymphoproliferation resulting in paraplegia and right arm paresis. Stem cell transplantation was considered, and BMT from a 9/10 matched unrelated donor (MUD) after a reduced intensity conditioning regimen (CR) with Fludarabin (150 mg/m2), Melphalan (140 mg/m2/d) and ATG (60mg/kg) was performed using 5.22 × 106 CD34+ cells/kg body weight. However, graft failure had to be diagnosed on day +27. 53 days after the first BMT a PBSCT from the same donor after myeloablative CR using Busulfan (19.2 mg/kg/d i.v.), Etoposid (30 mg/kg/d), Cyclophosphamid (120 mg/kg/d) and ATG (60mg/kg) was performed (24.5 × 106 CD34+ cells/kg bw). Again, graft failure was seen. At day +55 a third HSCT using PBSCT from another 9/10 MUD after CR with Fludarabin i.v. (160 mg/m2), Thiotepa (5 mg/kg/d), 4 Gy total body irradiation (TBI) and campath (1 mg/kg) was performed. 10.8 × 106 CD34+ cells/kg bw were given intra osseous, 9.8 × 106 CD34+ cells/kg bw were given i.v. Engraftment was slow (Leukos 980 day +35), but chimerism showed 99 % donor cells. Two years later the patient is alive and well, with persistent engraftment and good hematological and immunological function. Arterial aneurysms stopped growing and some have thrombosed. This case illustrates some interesting points. Atypical and unusually severe manifestations of ALPS forced us to perform a HSCT in this patient. In severe ALPS stem cell engraftment is difficult to achieve as previously reported in the Fas deficient lpr mouse model. One reason might be the reduced ability of cytotoxic drugs to induce apoptosis in the Fas deficient recipient T cells. Thus, recipient T cells could persist and kill donor cells resulting in graft failure or rejection. Additionally, increased FasL expression on recipient cells could induce apoptosis in Fas bearing donor stem cells as shown in lpr mice. Also, trapping of infused stem cells in the extremely enlarged liver and spleen could have played a role. A 3rd attempt was therefore designed to overcome graft resistance and proved finally successful. The use of TBI together with campath possibly induced more T cell apoptosis than chemotherapy alone. The intra osseous application probably increased engraftment efficiency by avoiding trapping of stem cells in liver and spleen and possibly by induction of tolerance by intra osseous application as described before. Disclosures: No relevant conflicts of interest to declare.