Age-dependent increase of treatment-related mortality in older patients with aggressive B cell lymphoma: analysis of outcome, treatment feasibility, and toxicity in 1171 elderly patients with aggressive B cell lymphoma-data from phase II and III trials of the DSHNHL (German High-Grade Non-Hodgkin's Lymphoma Study Group).

In elderly patients (pts) with aggressive B cell lymphoma (aNHL), curative treatment often cannot be administered because of comorbidities and tolerability. We analyzed the influence of age in pts > 60 years receiving the R-CHOP-14 regimen within different prospective DSHNHL trials. Of the RICOVER-60 trial and CHOP-R-ESC trials, 1171 aNHL pts were included in this retrospective analysis of age-dependent event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All patients received prophylactic G-CSF, and anti-infective prophylaxis with amphotericin B mouth wash and oral fluorchinolone was optional. In the CHOP-R-ESC trials, prophylaxis was augmented to include mandatory continuous orally administered aciclovir and a pneumocystis prophylaxis with cotrimoxazole as well as oral fluorchinolones during neutropenia. The patient population was separated into 4 age groups (61-65 years, 66-70 years, 71-75 years, and 76-80 years). The results from the RICOVER-60 trial were subsequently confirmed in the following CHOP-R-ESC trials by a multivariate analysis adjusted for IPI factors and gender. Significant differences (p < 0.001) in EFS, PFS, and OS were seen between age groups (RICOVER-60). Hematotoxicity, infections, and TRM increased with age. TRM was significantly elevated in the age group 76-80 years. Therefore, this analysis shows that an age above 75 years defines an especially vulnerable patient population when being treated with chemoimmunotherapy for aNHL. Prophylactic anti-infective drugs are essential and clinically effective in reducing morbidity when treating elderly aNHL pts.

Granulomatous interstitial nephritis in a patient with SARS-CoV-2 infection.

BACKGROUND: Acute kidney injury (AKI) associated with severe coronavirus disease 19 (COVID-19) is common and is a significant predictor of morbidity and mortality, especially when dialysis is required. Case reports and autopsy series have revealed that most patients with COVID-19 - associated acute kidney injury have evidence of acute tubular injury and necrosis - not unexpected in critically ill patients. Others have been found to have collapsing glomerulopathy, thrombotic microangiopathy and diverse underlying kidney diseases. A primary kidney pathology related to COVID-19 has not yet emerged. Thus far direct infection of the kidney, or its impact on clinical disease remains controversial. The management of AKI is currently supportive. CASE PRESENTATION: The patient presented here was positive for SARS-CoV-2, had severe acute respiratory distress syndrome and multi-organ failure. Within days of admission to the intensive care unit he developed oliguric acute kidney failure requiring dialysis. Acute kidney injury developed in the setting of hemodynamic instability, sepsis and a maculopapular rash. Over the ensuing days the patient also developed transfusion-requiring severe hemolysis which was Coombs negative. Schistocytes were present on the peripheral smear. Given the broad differential diagnoses for acute kidney injury, a kidney biopsy was performed and revealed granulomatous tubulo-interstitial nephritis with some acute tubular injury. Based on the biopsy findings, a decision was taken to adjust medications and initiate corticosteroids for presumed medication-induced interstitial nephritis, hemolysis and maculo-papular rash. The kidney function and hemolysis improved over the subsequent days and the patient was discharged to a rehabilitation facility, no-longer required dialysis. CONCLUSIONS: Acute kidney injury in patients with severe COVID-19 may have multiple causes. We present the first case of granulomatous interstitial nephritis in a patient with COVID-19. Drug-reactions may be more frequent than currently recognized in COVID-19 and are potentially reversible. The kidney biopsy findings in this case led to a change in therapy, which was associated with subsequent patient improvement. Kidney biopsy may therefore have significant value in pulling together a clinical diagnosis, and may impact outcome if a treatable cause is identified.

Radioimmunotherapy for mantle cell lymphoma: 5-year follow-up of 90 patients from the international RIT registry.

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) and for relapse in 45 (50%) patients. Most patients received 90Y-IT as consolidation after chemoimmunotherapy in first line (98%) and in relapse (53%). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%. and 1 pt. (2%) PD, and for 4 pts. (9%), no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95% CI, 1.03-2.32) years, and median OS was 4.05 (95% CI, 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib.

Radioimmunotherapy (RIT) for Follicular Lymphoma achieves long term lymphoma control in first line and at relapse: 8-year follow-up data of 281 patients from the international RIT-registry.

To assess efficacy of radioimmunotherapy (RIT) in follicular lymphoma, data from 281 patients collected in the RIT Network, with a median follow-up of 8·2 years after RIT were analysed. RIT was given at first line in 18·5% and at relapse in 81·5%. Following first line therapy, 76·9% achieved complete remission (CR), 9·6% partial remission (PR), 1·9% stable disease (SD) and 1·9% had progressive disease (PD); response was not documented in 9·7%. At relapse, the rate of CR was 48·5% and that of PR was 16·6%, SD 2·6% and PD 10·5%; response was not documented in 21·8%. After median follow-up of 8·2 years, median progression-free survival (PFS) for all was 2·54 years, median overall survival (OS) was not reached. Median PFS and OS (both not reached) were significantly better in first line, compared to RIT at relapse (PFS, 2·11 years; OS, 10·8 years; P = 0·0037 and P = 0·0021, respectively). Overall 8-year PFS was 33·9%, 53·6% for first line and 29·6% for relapsed individuals. Overall 8-year OS was 58·8%, 78·1% for first line and 54·5% for relapsed patients. Thirty-five patients (12·5%) developed secondary malignancy and 16 patients (5·7%) experienced transformation into aggressive lymphoma. RIT is a safe and effective treatment option for follicular lymphoma, both at front line and relapse with an 8-year PFS of 53·6% and 29·6%, respectively.

Cerebral salt wasting in a patient with myeloproliferative neoplasm.

BACKGROUND: Cerebral salt wasting (CSW) is a rare metabolic disorder with severe hyponatremia and volume depletion usually caused by brain injury like trauma, cerebral lesion, tumor or a cerebral hematoma. The renal function is normal with excretion of very high amounts of sodium in the urine. Diagnosis is made by excluding other reasons for hyponatremia, mainly the syndrome of inappropriate antidiuretic hormone secretion (SIADH). CASE PRESENTATION: A 60-year-old patient was admitted to the emergency room with pain in the upper abdomen and visual disturbance two weeks after knee replacement. The patient was confused with severe hematoma at the site of the knee endoprosthesis. Laboratory values showed massive thrombocytosis, leukocytosis, anemia, severe hyponatremia and no evidence of infection. CT scan of the abdomen was inconspicuous. Head MRI showed no ischemia or bleeding, but a mild microangiopathy. A myeloproliferative neoplasm (MPN) was suspected and confirmed by bone marrow biopsy. Cerebral salt wasting syndrome was identified as the cause of severe hyponatremia most likely provoked by cerebral microcirculatory disturbance. The hematoma at the operation site was interpreted as a result of a secondary von Willebrand syndrome (vWS) due to the myeloproliferative neoplasm with massive thrombocytosis. After starting cytoreductive therapy with hydroxycarbamide, thrombocytosis and blood sodium slowly improved along with normalization of his mental condition. CONCLUSION: To the best of our knowledge this is the first description of a patient with CSW most likely caused by a microcirculatory disturbance due to a massive thrombocytosis in the context of a myeloproliferative neoplasm.

Modified BEAM with triple autologous stem cell transplantation for patients with relapsed aggressive non-Hodgkin lymphoma.

Treatment of relapse and primary progression in aggressive lymphoma remains unsatisfactory; outcome is still poor. Better treatment strategies are much needed for this patient population. The R1 study is a prospective multi-center phase I/II study evaluating a dose finding approach with a triple transplant regimen in four BEAM dose levels in patients with relapsed aggressive non-Hodgkin lymphoma. The aim of the study was to determine feasibility, toxicity, and remission rate. In a total of 39 patients (pts.) enrolled in the study, 24 pts. were evaluated in the following analysis. Twenty pts. had aggressive B cell lymphoma, and two pts. had T cell lymphoma. All evaluated patients responded to DexaBEAM with a sufficient stem cell harvest. The phase I/II study was started with BEAM dose level II. Four patients were treated at dose level II, and 20 pts. were treated at dose level III. Due to the early termination of the study, dose levels I and IV were never administered. Sixteen pts. completed therapy according to protocol, and eight pts. (33.3 %) stopped treatment early. Infections (27 %) and stomatitis (13 %) were the most frequent grade III/IV non-hematologic toxicities. Thirteen percent of patients presented with severe grade III/IV lung toxicity during modified BEAM (m-BEAM). Fourteen pts. achieved a complete response (CR), one pt. achieved no change (NC), six pts. had progressive disease (PD), and two pts. died; for one pt., outcome is not known. One-year and 3-year event-free survival (EFS) was 38 and 33 %, respectively. Overall survival (OS) after 1 and 3 years was 50 and 38 %. In conclusion, dose escalation of standard BEAM is not feasible due to toxicity.

Radioimmunotherapy for first-line and relapse treatment of aggressive B-cell non-Hodgkin lymphoma: an analysis of 215 patients registered in the international RIT-Network.

PURPOSE: Very few reliable clinical data about the use of radioimmunotherapy in aggressive B-cell lymphoma exist. METHODS: Patients with aggressive B-cell lymphoma registered in the international RIT-Network were analysed with regard to prior treatment, response and side effects. The RIT-Network is a web-based registry that collects observational data from radioimmunotherapy-treated patients with malignant lymphoma across 13 countries. RESULTS: This analysis included 215 with aggressive B-cell lymphoma out of 232 patients registered in the RIT-Network. Histological subtypes were as follows: 190 diffuse large B-cell, 15 primary mediastinal, 9 anaplastic large cell, and 1 intravascular lymphoma. The median age of the patients was 62 years (range 17 - 88), with 27% above the age of 70 years. Radioimmunotherapy was mainly used as consolidation after first-line or second-line chemotherapy (56.1%), as part of third-line to eighth-line therapy for relapse (16.4%), and in refractory disease (12.2%). Grade IV neutropenia and thrombopenia and grade III anaemia were observed. The median time to recovery of blood count was 81 days (range 0 - 600 days). The overall response rate was 63.3%. The complete response rate was 76.4 % in patients treated as part of first-line therapy, and 44.3% in patients with relapse. Mean overall survival in first-line therapy patients was 32.7 months and 14.0 months in patients with relapse or refractory disease, respectively. CONCLUSION: Most patients with aggressive B-cell lymphoma in the RIT-Network received radioimmunotherapy as consolidation after first-line therapy with excellent complete remission and overall survival rates compared to published data. In relapsed aggressive B-cell lymphoma, radioimmunotherapy is a safe and feasible treatment leading to satisfactory response rates with acceptable toxicity.

SAKK 35/15: a phase 1 trial of obinutuzumab in combination with venetoclax in patients with previously untreated follicular lymphoma.

This phase 1 study evaluated safety, tolerability, and preliminary efficacy of obinutuzumab in combination with venetoclax in patients with previously untreated grade 1-3a follicular lymphoma in need of systemic therapy. Two DLs of venetoclax were evaluated with an expansion cohort at the recommended phase 2 dose. Twenty-five patients were enrolled. The recommended phase 2 dose was venetoclax 800 mg OD continuously for 6 cycles starting on day 2 of cycle 1, with obinutuzumab 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of cycles 2 to 6, followed by obinutuzumab maintenance every 2 months for 2 years. Only 1 patient had a DLT consisting of grade 4 thrombocytopenia after the first obinutuzumab infusion. Neutropenia was the most common adverse event of grade ≥3 at least possibly attributed to study treatment. Twenty-four patients were evaluable for response after cycle 6 by computed tomography (CT) and 19 by positron emission tomography/CT (PET/CT): overall and complete response rates were 87.5% (95% CI, 67.6% to 97.3%) and 25% (95% CI, 9.8% to 46.7%) in the CT-evaluated patients and 84.2% (95% CI, 60.4% to 96.6%) and 68.4% (95% CI, 43.4% to 87.4%), respectively, in the PET/CT-evaluated patients. One-year progression-free survival was 77.8% (95% CI, 54.6% to 90.1%) and 79% (95% CI, 47.9% to 92.7%) for CT and PET/CT-evaluable patients, respectively, whereas progression-free survival at 30 months was 73.2% (95% CI, 49.8%, 87.0%) as assessed by CT and 79.0% (95% CI, 47.9%, 92.7%) by PET/CT. Despite the activity observed, our results do not support further development of the combination in this patient population. This trial was registered at www.clinicaltrials.gov as #NCT02877550.

Tandem high-dose therapy in relapsed and refractory B-cell lymphoma: results of a prospective phase II trial of myeloablative chemotherapy, followed by escalated radioimmunotherapy with (131)I-anti-CD20 antibody and stem cell rescue.

A phase II trial evaluated safety, feasibility and efficacy of a sequential tandem approach combining myeloablative BEAM chemotherapy and autologous stem cell transplantation (ASCT) with myeloablative radioimmunotherapy (HD-RIT), with (131)I-anti-CD20 antibody ((131)I-rituximab), followed by a second ASCT in patients with relapsed or refractory CD20+ B-cell lymphoma. According to protocol, 16 patients with relapsed (n = 14) and refractory (n = 2) CD20+ B-cell lymphoma received salvage therapy with rituximab and Dexa-BEAM, followed by BEAM (HD chemotherapy) and high-dose myeloablative radioimmunotherapy 2-6 months after BEAM. Nine of 16 patients received HD-RIT; seven patients were excluded before HD-RIT because of toxicity or progressive disease. Disease histologies were follicular lymphoma (FL) grades 1 and 2 (n = 4), transformed follicular (FL 3b; n = 6), diffuse large B-cell (DLBCL; n = 4), mantle cell (n = 1) and marginal zone lymphoma (n = 1). After a median follow-up of 50.4 months for OS and 39.7 months for progression-free survival (PFS), estimated 4-year OS and PFS were 67% and 64%, respectively. The estimated 4-year OS and PFS for patients with FL were 80% and 78%, respectively. Toxicity was significant, including one fatal outcome due to pneumonitis. Tandem transplants consisting of HD chemotherapy followed by HD-RIT with (131)I-coupled anti-CD20 are manageable and effective but toxic treatment modalities for relapsed poor prognosis CD20+ B-NHL.

Low serum albumin is an independent risk factor in elderly patients with aggressive B-cell lymphoma: Results from prospective trials of the German High-Grade Non-Hodgkin's Lymphoma Study Group.

Serum albumin a well-known risk factor predicting outcome in many solid tumors. We explore the role of low serum albumin (≤3.5 g/dL) as an independent risk factor in elderly patients with aggressive B-cell lymphoma. Outcome of 429 patients treated with R-CHOP-14 in the RICOVER-60 trial and available serum albumin were analyzed in this retrospective study. Of the 429 patients in the RICOVER-60 trial, 137 (32%) had low and 292 (68%) had normal serum albumin levels (>3.5 g/dL). In the low albumin group, patients had significantly higher International Prognostic Index (IPI), bulky disease, extralymphatic involvement, and B-symptoms. Event-free survival (EFS) (P < .001), progression-free survival (PFS) (P < .001), and overall survival (OS) (P < .001) were significantly inferior for patients with low compared to those with normal serum albumin. Multivariate analysis adjusted for IPI shows following Hazard ratios (HR) for low serum albumin: EFS (HR = 1.5; 95% confidance interval [CI] [1.1; 2.1], P = .009), PFS (HR = 1.7; 95% CI [1.2; 2.4], P = .001) and OS (HR = 1.6; 95% CI [1.1; 2.3], P = .006). Results were confirmed in 185 patients from the DENSE-R-CHOP-14 and SMARTE-R-CHOP-14 trials. In conclusion, low serum albumin is an independent risk factor in elderly patients with aggressive B-cell lymphoma treated with R-CHOP.

Harnessing the energy: development of radioimmunotherapy for patients with non-Hodgkin's lymphoma.

Radioimmunotherapy (RIT) combines the use of targeted monoclonal antibodies with radionuclides for the treatment of non-Hodgkin's lymphoma (NHL), taking advantage of its inherent radiosensitivity. A number of trials have shown significantly higher response rates and longer progression-free survival times in patients treated with the CD20-targeted radioimmunoconjugate yttrium-90-ibritumomab tiuxetan compared with the standard of care. Furthermore, these benefits have also been shown in heavily pretreated patients who relapsed or were resistant to rituximab. Currently, a number of different treatment regimens and strategies are available for the treatment of NHL patients. Therefore, in an attempt to minimize toxicity, maximize efficacy, and improve survival, it is crucial to appropriately select patients who are good candidates for individual treatment approaches. A strategy for patient selection has been developed, including the use of existing patient assessment tools, such as the Follicular Lymphoma International Prognostic Index, to determine the optimal regimen for patients with follicular lymphoma according to their disease characteristics and physical condition. Patients who are fit make ideal candidates for potentially curative regimens, which include induction chemotherapy with or without immunotherapy followed by RIT consolidation and, potentially, maintenance therapy. Patients who are considered "compromised" would also benefit from induction treatment and RIT consolidation, with a view to reducing the lymphoma burden and decreasing the risk for disease progression. "Frail" patients would be better suited to supportive therapy to control symptoms. This paper explores factors that should be considered when assessing whether a patient is a good candidate for treatment with RIT, and aids physicians in the selection of the most appropriate therapy for each patient group.

Therapy of nodal Follicular Lymphoma (WHO grade 1/2) in clinical stage I/II using response adapted Involved Site Radiotherapy in combination with Obinutuzumab (Gazyvaro) - GAZAI Trial (GAZyvaro and response adapted Involved-site Radiotherapy): a study protocol for a single-arm, non-randomized, open, national, multi-center phase II trial.

BACKGROUND: Large field irradiation had been standard for early-stage follicular lymphoma (FL) for a long time. Although involved field radiotherapy (IF-RT) was recently favored because of the toxicity of large field irradiation, smaller irradiation fields have been accompanied with an increased risk of out-of-field recurrence. The MIR (MabThera® and Involved field Radiation) trial has shown that the combination of IF-RT at a dose of 30-40 Gy with the anti-CD20 antibody rituximab has led to similar efficacy compared with large field irradiation but with markedly reduced side effects. Immune modulating radiation therapy alone using low-dose radiotherapy (LDRT) of 2 × 2 Gy has been shown to be effective in FL. The GAZAI (GAZyvaro and response Adapted Involved-site Radiotherapy) trial aims to prove the efficacy of LDRT in combination with a novel anti-CD20 therapy. METHODS/DESIGN: The GAZAI trial is a non-randomized, open, non-controlled, German, multi-center phase II trial that includes patients with early-stage (I and II) nodular FL (grades 1 and 2) confirmed by central histological review. A maximum of 93 patients will be included in the trial. Patients will receive a combined approach of immunotherapy with the fully humanized anti-CD20 antibody obinutuzumab (Gazyvaro®) and involved site radiotherapy (IS-RT) with 2 × 2 Gy. The primary endpoint of the trial is the rate of metabolic complete response (CR), based on fludeoxyglucose positron emission tomography/computed tomography, after obinutuzumab and 2 × 2 Gy IS-RT in week 18. Secondary endpoints are morphologic CR rate in weeks 7 and 18 and month 6, progression-free survival, toxicity, recurrence patterns, overall survival, and quality of life. Additionally, minimal residual disease response is assessed. The risk for a potentially higher recurrence rate after LDRT will be minimized by additional salvage radiation up to the "full dose" of 40 Gy for patients who have less than a metabolic CR and morphologic partial response/CR, which will be evaluated in week 18, offering a response-adapted approach. DISCUSSION: The goal of this trial is a further reduction of the radiation dose in patients with nodal early-stage FL showing a good response to a combination of LDRT and anti-CD20 immunotherapy and a comparison with the currently published MIR trial. TRIAL REGISTRATION: EudraCT number: 2016-002059-89. ClinicalTrials.gov identifier: NCT03341520 .

Rituximab With Involved Field Irradiation for Early-stage Nodal Follicular Lymphoma: Results of the MIR Study.

The MabThera and Involved field Radiotherapy study investigated efficacy and safety of involved field (IF) radiotherapy in combination with the anti-CD20 antibody Rituximab for early-stage follicular lymphoma (FL) in a prospective, single-arm multicenter phase 2 design. Eighty-five stage I-II FL patients received 8 cycles of Rituximab (375 mg/m2) and IF irradiation (30/40 Gy). The primary endpoint was progression-free survival (PFS) 2 years from treatment start. Secondary endpoints were overall survival (OS), complete response rates, toxicity, quality of life, and minimal residual disease (MRD) response with protocol defined visits up to month 30. For the primary endpoint, PFS at 2 years was 85% for the intention-to-treat set. Long-term data were captured in selected sites and evaluated as post hoc analysis in the per protocol (PP) set: PFS and OS were 78% and 96% at 5 years with a median follow-up of 66 or 78 months, respectively. There were 17/76 recurrences in the PP set, of which 14 were outside the radiation volume only. MRD analyses revealed a clonal marker in 36% of patients at diagnosis. All but 1 marker positive patients experienced a molecular treatment response. There were 13 serious adverse events (4 related to the therapy) during the first 30 months. IF radiotherapy combined with Rituximab is well tolerated and highly efficient with low rates of recurrence in the first years in early-stage FL. The efficacy is comparable with more aggressive therapy approaches without compromising the quality of life and maintains for an extended follow-up of more than 5 years.

Osteoblast-like cells with different embryologic origins behave differently in increasing zoledronic acid concentrations: a pilot study in pigs.

OBJECTIVE: We compared the intraindividual effects of increasing zoledronic acid (ZA) concentrations on osteoblast-like cells with different embryologic origins. STUDY DESIGN: Cultured osteoblast-like cells from mandible and iliac crest bone samples of domestic pigs were exposed to increasing concentrations of ZA (0, 10-8, 10-6, and 10-4 M). Proliferation was assessed by cell counting. Receptor activator of nuclear factor kB ligand and osteoprotegerin (OPG) messenger RNA expression were assessed at 0, 1, 4, 7, and 10 days. RESULTS: The OPG expression level was higher in the iliac crest than in the mandible. Neither ZA concentration nor the cells' origin affected the expression of receptor activator of nuclear factor kB ligand. At 10-6 M, OPG expression from both locations reached the same level after 7 days of cultivation, as OPG expression increased to a greater extent in the mandible in comparison to the iliac crest. CONCLUSION: Cultured mandibular osteoblast-like cells reacted more sensitively to high ZA concentrations than did osteoblast-like cells from the iliac crest.

Superior vena cava syndrome caused by a malignant tumor: a retrospective single-center analysis of 124 cases.

PURPOSE: Superior vena cava syndrome (SVCS) results from compression of the superior vena cava. SVCS is an emergency requiring immediate diagnosis and treatment. We hypothesized that the outcome of patients (pts.) admitted during regular work hours may differ from that of pts. admitted on weekends. METHODS: From 1992 to 2011, we analyzed all pts. admitted with SVCS due to a malignancy. Clinical outcome was analyzed, focusing on the work-up of pts. hospitalized on a weekend compared with those hospitalized during the week. RESULTS: One hundred and twenty-four pts. with malignant causes of SVCS were analyzed. Causes were as follows: small cell lung cancer (SCLC) 28.2 %, non-small cell lung cancer 25 %, non-Hodgkin's lymphoma 25 %, metastasis of other malignant tumors 19.4 % and Hodgkin's disease 2.4 %. Sixty-five percent of pts. were admitted during the week and 35 % on a weekend. Sixty-one percent received chemotherapy, 24 % radiation, 4 % radiochemotherapy, 9 % palliative treatment and 2 % no treatment at all. No difference in choice of treatment between pts. admitted on a weekday versus weekend was seen. Response was as follows: 7 pts. complete remission, 20 pts. partial response, 38 pts. progressive disease, 3 pts. NC and 15 pts. died. Overall response rate was as follows: Hodgkin's disease 100 %, non-Hodgkin's lymphoma 29 %, SCLC 22.8 %, non-small cell lung cancer 9.6 % and metastatic cancer 16.6 %. Only 2 of the 34 pts. with relapsing carcinoma responded. None of the pts. died due to SVCS. CONCLUSION: The outcome of pts. with SVCS is not dependent on the day of admission (weekend or weekday) but is related to underlying disease in the setting of a tertiary care center.

Significant dose Escalation of Idarubicin in the treatment of aggressive Non- Hodgkin Lymphoma leads to increased hematotoxicity without improvement in efficacy in comparison to standard CHOEP-14: 9-year follow up results of the CIVEP trial of the DSHNHL.

BACKGROUND: Dose escalation and modification of CHOP has improved the prognosis of patients with aggressive lymphoma; even in the rituximab era, dose escalation for high-risk patients is exploited and frequently limited by drug toxicity. Idarubicin (Id) is a 4-demethoxy anthracycline analogue of daunorubicin with activity against lymphoma and has been reported to cause less cardiotoxicity than other anthracylines. The aim of this study was to replace doxorubicine with idarubicin in the CHOEP regimen and to find the maximum tolerable dose (MTD) of idarubicin based on hematotoxicity. PATIENTS AND METHODS: Between 11/96 and 09/98, 64 patients (pts) aged 18-75 yrs (pts. 18-60, LDH not elevated, >60 years all risk groups) with newly diagnosed aggressive lymphoma received 6 cycles of CIVEP-14 with an escalating dose of idarubicin, consisting of idarubicin (11-16 mg/m(2) d1) and standard doses of cyclophosphamide, vincristine, etoposide, and prednisone with G-CSF support. RESULTS: 55 pts (median age 56 yrs) were evaluable for a final analysis with a median observation time of 9.3 years. The CR-rate was 77.4% ; the 5 and 8-year-EFS rates were 46.4% (95%CI 32.5-60.3%) and 43.5% (29.4-57.6%), respectively, and the 5- and 8 yr OS rates were 64.6% (51.7-77.5%) and 59.9% (46.4-73.4%). 14/55 patients have died due to lymphoma progression, and 2/55 patients (3.6%) due to treatment related toxicity, 4/55 due to other causes (3 infections, 1 acute heart failure). In a matched pair analysis comparing CHOEP-14 and CIVEP-14, CIVEP-14 had a higher hematotoxicity with no significant differences in the event free and overall survival for the two regimens. CONCLUSIONS: Thus, idarubicin cannot be used instead doxorubicin even if its dose is escalated to achieve similar hematotoxicity. Doxorubicin remains the standard anthracycline for the treatment of aggressive NHL.