BACKGROUND:Radioimmunotherapy (RIT) has been used to treat relapsed/refractory CD20+ Non-Hodgkin lymphoma (NHL). Myeloablative anti-CD20 RIT followed by autologous stem cell infusion (ASCT) enables high radiation doses to lymphoma sites. We performed a phase I/II trial to assess feasibility and survival.METHODS:Twenty-three patients with relapsed/refractory NHL without complete remission (CR) to salvage chemotherapy were enrolled to evaluate RIT with Iodine-131 labelled rituximab (131I-rituximab) in a myeloablative setting. Biodistribution and dosimetric studies were performed to determine 131I activity required to induce a total body dose of 21-27Gy to critical organs. In 6/23 patients RIT was combined with high-dose chemotherapy. 8/23 patients received a sequential high-dose chemotherapy with a second ASCT. The median follow-up is 9.5 years.RESULTS:6.956-19.425GBq of 131I was delivered to achieve the limiting organ dose to lungs or kidneys. No grade III/IV non-hematologic toxicity was seen with RIT alone. Significant grade III/IV toxicity (mucositis, fever, infection, one therapy related death) was observed in patients treated with RIT combined with high-dose chemotherapy. The overall response rate was 87% (64% CR). The median progression-free (PFS) and overall survival (OS) is 47.5 and 101.5 months. An international prognostic index score >1 was predictive for OS.CONCLUSION:Myeloablative RIT with 131I-rituximab followed by ASCT is feasible, well-tolerated and effective in high risk CD20+ NHL. Combination of RIT and high-dose chemotherapy increased toxicity significantly. Long-term results for PFS and OS are encouraging.

Abstract 3700 Background: Radioimmunotherapy (RIT) has been successfully used to treat primary and relapsed/refractory CD20+ Non-Hodgkin-Lymphoma (NHL). Myeloablative anti-CD20 RIT allows delivering high radiation doses to lymphoma sites when followed by autologous stem cell infusion (autoSCT). However, RIT is infrequently used at present and long-term data is lacking. Patients, Design and Methods: 23 patients with relapsed/refractory CD20+ NHL who did not achieve a complete response to salvage chemotherapy were enrolled in this Phase I/II trial to evaluate RIT with 131I-labelled Rituximab (131I-R) in a myeloablative setting between January 2000 and October 2004. Biodistribution and dosimetry studies were performed in all patients to determine 131I activity required to induce a total body dose of 21 to 27 Gy to the critical organs lung and kidney. In 6/23 patients RIT was combined with high dose chemotherapy (HD-CTx) followed by autoSCT. 8/23 patients received a sequential HD-CTx with a second autoSCT. The median follow-up is 9.5 years. Results: 188–525 mCi 131I were delivered to achieve the limiting organ dose. No grade 3/4 non-hematologic toxicity was seen with RIT alone. Significant grade 3/4 toxicity (mucositis, neutropenic fever, pneumonia, sepsis) including one therapy related death was observed in all patients treated with RIT combined with HD-CTx/autoSCT. The overall response rate was 87% (64% complete response rate). The median progression free (PFS) and overall survival are 47.5 and 101.5 months. After long-term follow up, 9 patients are progression free and 10 patients are alive. An elevated (>1) international prognostic index (IPI) was most predictive for overall survival. Conclusion: Myeloablative 131I-Rituximab RIT followed by autoSCT is feasible, well tolerated and effective in high risk CD20+ NHL and prolongs PFS compared to last standard chemotherapy. Patients additionally treated with high dose chemotherapy experienced significantly increased toxicity. Long-term results for progression free survival and overall survival in this trial are encouraging. Disclosures: No relevant conflicts of interest to declare.

The purpose of this study was to describe blood component (BC) use and respective cost after standard dose chemotherapy (CT) in routine hospital care.

BACKGROUND:Febrile neutropenia/leukopenia (FN/FL) is the most frequent dose-limiting toxicity of myelosuppressive chemotherapy, but German data on economic consequences are limited.PATIENTS AND METHODS:A prospective, multicentre, longitudinal, observational study was carried out to evaluate the occurrence of FN/FL and its impact on health resource utilization and costs in non-small cell lung cancer (NSCLC), lymphoproliferative disorder (LPD), and primary breast cancer (PBC) patients. Costs are presented from a hospital perspective.RESULTS:A total of 325 consecutive patients (47% LPD, 37% NSCLC, 16% PBC; 46% women; 38% age = 65 years) with 68 FN/FL episodes were evaluated. FN/FL occurred in 22% of the LPD patients, 8% of the NSCLC patients, and 27% of the PBC patients. 55 FN/FL episodes were associated with at least 1 hospital stay (LPD n = 34, NSCLC n = 10, PBC n = 11). Mean (median) cost per FN/FL episode requiring hospital care amounted to € 3,950 (€ 2,355) and varied between € 4,808 (€ 3,056) for LPD, € 3,627 (€ 2,255) for NSCLC, and € 1,827 (€ 1,969) for PBC patients. 12 FN/FL episodes (LPD n = 9, NSCLC n = 3) accounted for 60% of the total expenses. Main cost drivers were hospitalization and drugs (60 and 19% of the total costs).CONCLUSIONS:FN/FL treatment has economic relevance for hospitals. Costs vary between tumour types, being significantly higher for LPD compared to PBC patients. The impact of clinical characteristics on asymmetrically distributed costs needs further evaluation.

We report a case of primary Epstein Barr virus (EBV) negative peripheral T-cell lymphoma (PTCL) NOS in a 56-year-old female who-after an initially indolent course - simultaneously developed an aggressive, EBV+ cytotoxic large T-cell lymphoma, clonally related to the primary PTCL, and an EBV+, clonal large B-cell lymphoproliferation. The initial, EBV-negative PTCL had shown some features of angioimmunoblastic T-cell lymphoma and had responded well to steroid therapy. Two years later, rapidly fatal, progressive disease with multivisceral involvement developed. Histologically, extensive infiltrates of EBV+, CD8(+) large cells were present, in addition to areas of the initial PTCL. Extensive comparative phenotypic and molecular analyses confirmed the presence of an identical CD8(+) T-cell clone in the initial EBV-negative PTCL and the EBV+, CD8(+) large cell lymphoma at the time of aggressive transformation. These results also justified the retrospective classification of PTCL, NOS for the initial lymphoma. This case shows that secondary EBV infection of an established malignant T-cell clone can occur and may contribute to aggressive transformation of PTCL.

Salvage therapy for patients with mantle cell lymphoma (MCL) remains a challenge. The clinical course is characterised by increasing resistance to conventional chemotherapy and a dismal long-term outcome. On the basis of studies demonstrating synergy invitro, eight heavily pretreated patients (median age 65 years) with advanced stage MCL were individually treated with a novel combination protocol consisting of the proteasome inhibitor bortezomib (1.5mg/m2; Days 1 and 4), high-dose cytarabine (750-2000mg/m2; Days 2 and 3) and dexamethasone (40mg daily; Days 1-4). Rituximab (375mg/m2) was added in patients not refractory to prior rituximab-containing regimens. Treatment was repeated in 3-week intervals or postponed until hematologic recovery for up to four planned cycles. Toxicity consisted mainly of Grade 3/4 hematotoxicity, which occurred in all patients. Median treatment interval was 31 days. Objective responses were observed in four (50%) of eight patients, including two complete remissions. Median progression free and overall survival were 5 and 15.5 months, respectively. The combination of bortezomib and a high-dose cytarabine-containing regimen has activity in heavily pretreated patients with relapsed or refractory MCL.

Chemotherapy with ifosfamide, epirubicin and etoposide (IEV) is an effective treatment regimen for refractory/relapsed non-Hodgkin lymphoma (NHL). Rituximab has been shown to improve response rates, progression-free survival and overall survival in B-cell NHL. This study included 85 patients who were treated with IEV or rituximab-IEV (R-IEV) for refractory/relapsed B-cell NHL. The overall response rate was 40.7% (IEV) versus 68.8% (R-IEV). Fever occurred after 23.4% of IEV and 19.4% of R-IEV cycles. 94.9% of patients mobilized sufficient numbers of CD34(+) cells (IEV) versus 93.8% (R-IEV). Fifty-five patients (64.7%) proceeded to high-dose therapy after IEV+/-rituximab. The median survival time was 60.0 months (IEV) and 19.5 months (R-IEV), and has not been reached for patients who received high-dose therapy. The addition of rituximab to IEV salvage chemotherapy increases the response rates in B-cell NHL without affecting stem cell mobilization, but overall survival for patients proceeding to high-dose chemotherapy is not improved.

The majority of chemotherapy (CT) patients (pts) receive care outside of clinical trial settings. In contrast little is known about the economic consequences of CT-induced toxicity in routine care. This was a prospective, multi-centre, observational, longitudinal cost-of-illness study. Lymphoma and non small cell lung cancer (NSCLC) pts were enrolled consecutively from 1/2005–12/2006 at the start of first or second line (immuno) CT treatment in 4 German hospitals. Patients receiving myeloablative CT with peripheral blood stem cells were excluded. Clinical data and resource use were collected from pre-planned chart reviews. German tariffs & prices in €2007 and hospital databases were used to allocate costs to health care resources. Toxicity related costs are presented from the hospital provider perspective. 273 pts undergoing 286 treatment courses with a total of 1004 CT-cycles were evaluable. 153 pts had lymphoma (47% of courses were CHOP-like) and 120 NSCLC (78% of courses were platinum-based). Mean age was 60.1 years (SD 13.0); age≥65 years 40%; female 36%; ECOG≥2 11%; tumour stage≥3 56%; history of co-morbidity 80%. The table shows a comparison of lymphoma and NSCLC patient characteristics. 208 of treatment courses (73%) were associated with at least one hospital stay (lymphoma 69%, NSCLC 78%). Mean±SD number of inpatient days was 13.1±17.7 (lymphoma 13.5±20.7, NSCLC 12.8±14.0). Mean (median) toxicity related costs amounted to€3,624 (€1,035) per treatment course with€3,366 (€1,406) for NSCLC and€3,838 (€684) for lymphoma. 8% of CT-courses (lymphoma n=12, NSCLC n= 11) were associated with costs ≥€10,000 and accounted for 50% of total expenses. In this high cost group mean toxicity associated costs nearly doubled for lymphoma pts (lymphoma€28,607, NSCLC€15,533). Hospital basic services and personnel represented 74% of total costs (lymphoma 70%, NSCLC 80%), followed by expenses for drugs (lymphoma 15%, NSCLC 9%). Our findings highlight that toxicity management in NSCLC and lymphoma pts induces significant resource use and associated costs. Cost drivers are hospitalization and drugs. Frequency distribution of costs is asymmetric with less than 10% of CT-courses contributing to half of total economic burden. Treatment courses with mean toxicity related costs of €10,000 or more are twice as expensive for lymphoma patients as for NSCLC.

Febrile neutropenia (FN) is the most frequent dose-limiting complication of myelosuppressive chemotherapy. To date little data is available on the economic consequences of FN management in Germany. Therefore resource use and costs associated with routine FN management were assessed. This was a prospective, multi-centre, observational, longitudinal cost-of-illness study. Patients were enrolled consecutively from 1/2005-12/2006 at the start of first or second line (immuno)chemotherapy (CT) treatment in 4 German hospitals. Patients receiving myeloablative chemotherapy with peripheral blood stem cells were excluded. Adverse drug reactions were monitored prospectively according to the NCI CTCAE v.3.0 and WHO causality criteria. FN was defined as fever above 38°C associated with an absolute neutrophile count <1x109/L. In case of non-availability of the nadir-ANC in daily clinical practice the occurrence of febrile leukopenia (FL) was assessed as leukocyte count <2x109/L and fever above 38°C. Clinical data and resource use were collected from pre-planned chart reviews. German tariffs & prices in €2007 and hospital databases were used to allocate costs to health care resources. Costs are presented from the provider perspective. 325 patients undergoing a total of 1285 chemotherapy cycles were evaluable. 68 episodes of FN/FL (FN: n=28; FL: n=40) occurred in 58 pts. (18%). 35 FN/FL pts. had lymphoma (54% treated with a CHOP-like CT), 9 NSCLC (80% treated with a platinum-based CT) and 14 breast cancer (100% treated with an adjuvant taxane- or anthracyline-based CT). Mean age was 58.1 years (SD 14.5); age≥65 years 38%; female 57%; ECOG≥2 10%. The table shows a comparison of FN/FL patient characteristics with all patients included. 55 FN/FL episodes (81%) were associated with at least one hospital stay (episodes with inpatient treatment: n=49, outpatient or day care: n=6). 5 episodes were treated in an intensive care unit. Mean length of inpatient stay was 8.9 (SD 5.9) days. In addition to concomitant drug use transfusions were necessary in n=15 episodes. Mean treatment cost per FN/FL episode requiring hospital treatment amounted to €3,950 SD 4,961 (range: €134–31,924) with highest mean cost for patients with lymphoma (€4,808). Hospital basic services and personnel accounted for 60% of the direct costs, followed by expenses for drugs (19%) and diagnostics (11%). In conclusion FN/FL induces significant resource use and associated cost. The main cost drivers are hospital basic services and staff. In lymphoma patients FN/FL is more costly than in NSCLC or breast cancer patients.

BACKGROUND: Tumed sequential treatment with fludarabine/cyclophosphamide/rituximab (FC-R) followed by Y-90 ibritumomab tiuxetan (IT) radioimmunotherapy may improve progression-free survival in patients (pts) with CD20+ NHL. However, even unpretreated pts submitted to four to six cycles of a fludarabine-containing combination and then IT at an Y-90 activity of 15 MBq/kg will experience severe prolonged, transfusion-dependent and only partially reversible pancytopenia, thus limiting its use in a non-curative setting (Jurczak et al., ASH 2005).

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.

OBJECTIVE:To investigate whether a combination of acupuncture and acupressure is effective for reducing chemotherapy-induced nausea and vomiting.PATIENTS AND METHODS:In a randomised cross-over trial, 28 patients receiving moderately or highly emetogenic chemotherapy and conventional standard antiemesis were treated for one chemotherapy cycle with a combination of acupuncture and acupressure at point P6 and for one cycle at a close sham point. The main outcome measure was a nausea score derived from daily intensity rating.RESULTS:There was no difference between combined acupuncture and acupressure treatment at P6 and at the sham point for the nausea score, but the level of nausea was very low in both phases. The mean nausea score was 6.2 (standard deviation 9.0) for treatment at P6 and 6.3 (9.1) for treatment at the sham point (mean difference -0.1, 95% confidence interval -3.9 to 3.7; p=0.96). Seventeen of 21 participants completing the study would desire acupuncture and acupressure for future chemotherapy cycles, but there was no clear preference for either point.CONCLUSION:In this small pilot study a significant difference between treatment at P6 and a close sham point could not be detected. However, it cannot be ruled out that an existing difference was missed due to the small sample size.

Pathomorphological examination of trephine biopsies of the bone marrow (BM) represents a standard method for the diagnosis and staging of hematologic neoplasms and other disorders involving the BM. The increasing knowledge about the genetic basis and biology of hematologic neoplasms, as well as the recently proposed WHO classification system, provide the framework for an accurate diagnosis. Although conventional morphology remains the gold standard for paraffin-embedded BM trephines, immunohistochemical stainings have become an integral part of the diagnostic workup. Antibodies suitable for paraffin sections are generally applicable to BM trephines, but modifications of staining protocols may be necessary due to the alternative fixatives and decalcification procedures used for BM biopsies. The indications for immunostainings range from confirmation and classification of lymphoma involvement, subclassification of acute leukemias, and estimating blast counts in myelodysplastic and myeloproliferative syndromes to characterization of BM involvement in nonhematologic neoplasms. Although subtyping of NHL in the BM is more difficult from the point of morphology, classification of the entities that frequently involve the BM, especially the small B-cell lymphomas, can easily be achieved with the help of immunohistochemistry. In this review, we try to summarize the current state of the art in BM immunohistochemistry for the diagnosis of hematologic disorders. Moreover, diagnostic algorithms and useful antibody panels are proposed for a rational and cost-effective approach.

In individual voxel phantoms, which were segmented from whole-body computed tomography (CT) scans, S-values were calculated for (131)I using the EGS4 Monte Carlo code and compared to Medical Internal Radiation Dose (MIRD) S-values, which were derived from transport calculations in idealized mathematical phantoms. The individually calculated S-values agree very well with the MIRD values for organs, which are source and target simultaneously, when individual organ-mass corrections are applied to the MIRD values. For different source-target combinations, large deviations up to 184% were found. The contribution of the gamma-absorbed fractions to the total dose, however, is small ( approximately 4%). We conclude, therefore, that individual transport calculations in radionuclide-targeted therapies are not necessary for macroscopic dose estimates. Reliable dosimetry is reduced to the problem of accurate activity determination in vivo.

A t(2;5) (p23;q35) chromosomal translocation can be found in a high percentage of anaplastic large-cell lymphomas (ALCL). This genetic abnormality leads to the expression of the NPM-ALK fusion protein, which encodes a constitutively active tyrosine kinase that plays a causative role in lymphomagenesis. Employing a modified infection/transplantation protocol utilizing an MSCV-based vector, we were able to reproducibly induce two phenotypically different lymphoma-like diseases dependent on the retroviral titers used. The first phenotype presented as a polyclonal histiocytic malignancy of myeloid/macrophage origin with a short latency period of 3-4 weeks. Clinically, the diseased mice showed rapidly progressive wasting, lymphadenopathy and pancytopenia. Mice displaying the second phenotype developed monoclonal B-lymphoid tumors with a longer latency of approximately 12-16 weeks, primarily involving the spleen and the bone marrow, with less extensive lymph node but also histologically evident extranodal organ infiltration by large immature plasmoblastic cells. The described retroviral mouse model will be useful to analyse the role of NPM-ALK in lymphomagenesis in vivo and may contribute to the development of new treatment options for NPM-ALK induced malignancies.

The B-cell surface antigen CD20 is currently the prime target for near-selective treatment of mature B-cell malignancies and a range of reactive B-cell associated disorders (including virus-associated lymphoproliferation or autoimmune conditions). CD20 is strongly and homogeneously expressed on the majority of mature B-cell neoplasms except chronic lymphocytic leukaemia cells, and on all mature reactive B-cells. This review will summarise the modes of action of various reagents targeting CD20. Treatment results following their use in single and combination therapy for B-cell disorders are reviewed.