Toxicity Of High-dose Chemotherapy Research Articles

Results of the Astral Study: A Prospective Phase II Clinical Study of the German Lymphoma Alliance to Assess the Efficacy and Toxicity of High-Dose Chemotherapy Followed By Allogeneic Stem Cell Transplantation As Treatment of Primary Progressive and Relapsed Aggressive Non-Hodgkin Lymphoma

Introduction Patients with relapsed and refractory (r/r) aggressive B- or T-cell lymphoma have a dismal prognosis. Registry analyses as well as one preceding prospective clinical study demonstrated durable disease control through graft-versus-lymphoma activity conferred by allogeneic stem cell transplantation (alloSCT) in this population and suggests this modality being a preferred treatment option after failing of less toxic approaches. Recently, allogeneic SCT has been shown to result in long term PFS in r/r large B-cell lymphoma (LBCL) with preceding CAR-T treatment. Despite the current achievements in treatment of r/r LBCL by introducing anti CD19 CAR-T as a treatment modality appproximately 60% need further approaches to achieve long term progression free survival (PFS). Here we represent the results of a prospective clinical trial of allogeneic SCT in r/r aggressive B- and T-cell lymphoma using a thiotepa based conditioning regimen. Methods ASTRAL is a national, multicenter, prospective phase II study of the German Lymphoma Alliance (GLA). Eligible were patients aged 18 or older with relapsed or primary progressive aggressive B- or T-cell lymphoma who had a fully matched (10/10) related or unrelated donor available. Patients underwent myeloablative conditioning regimen with Fludarabine 125 mg/m², Thiotepa 15 mg/kg and Cyclophosphamide 120 mg/kg (FTC). GVHD prophylaxis and posttransplant immunosuppression was done by local standards. The primary objective was to determine the efficacy and toxicity of the defined conditioning therapy followed by allogeneic stem cell transplantation. The primary endpoint was progression free survival at 1 year. Key secondary efficacy endpoints included rate of complete remissions (CR), rate of partial remissions (PR), overall response rate (OR), rate of progressive disease (PD), relapse rate, event free survival (EFS) and overall survival (OS) at 1 year and non-relapse mortality (NRM). Results From June 2019 until December 2021 in total 60 patients were enrolled. The demographic data are presented in table 1. The majority of patients (70%) had B-cell lymphomas. Patients had received a median of 3 prior lines (range 1-6), including autoSCT in 42% of all patients and CAR-T in 29% of the B-cell patients. The rate of primary progressive disease before salvage therapy was 27% (29% B-cell and 22% T-cell). 83% (50/60) still had measurable disease (no CR) prior to FTC, thereof 81% with B-cell (34/42) and 89% with T-cell lymphoma (16/18) and 13 (22%) had high intermediate and high IPI. After alloSCT, CR was achieved in 45% of patients with B-cell and in 67% with T-cell lymphoma, respectively. The overall response rate was 53%, 48% for B-cell lymphoma and 67% T-cell lymphoma. After a median observation time of 30 months, 1-year PFS was 40% [95%-CI: 28%-52%] (38% [23%-53%] (B-cell) vs. 44% [21%-67%] (T-cell) (figure 1). EFS was identical to PFS. After one year 15 patients (25%) had progressive disease or relapse, thereof 13 patients (29%) with B-cell lymphoma and two with T-cell lymphoma (11%). Thirty-seven patients died. Main cause of death was treatment related 19/37 (51%), including 8/19 deaths due to toxicity of the conditioning therapy (6 infections, 1 respiratory failure and 1 neurotoxicity). 12/37 (32%) patients died lymphoma related, 4/37 (11%) patients died of a SARS-Cov-2 infection, and two causes of death were unknown. 1-year OS was 43% [31%-56%] (40% [26%-55%] (B-cell) vs. 50% [27%-73%] (T-cell)). 1-year NRM was 35% [23%-47%] (31% [17%-45%] (B-cell) vs. 44% [20%-68%] (T-cell)). Most of the patients with grade 3-5 adverse events had infections 40/60 (67%), renal disorders 17/60 (28%) and oral mucositis 14/60 (23%). Conclusions This is the second prospective trial on alloSCT for r/r aggressive lymphoma ever performed, demonstrating that alloSCT can provide sustained disease control in heavily pretreated patients. Also in the modern era, including patients who failed CARTs the strong anti-lymphoma activity of allogeneic SCT is shown in the low relapse/progression rate and the long term PFS. FTC conditioning avoids the toxicities of busulfan-based regimens but fosters neuro- and other toxicities, especially when given at 15mg/kg. Still, NRM remains a challenge and warrants exploration of novel transplant strategies, such as modulation of conditioning intensity and GVHD prophylaxis, e. g. post-transplant cyclophosphamide.

High-dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents, and young adults with first recurrence of Ewing sarcoma.

Ewing sarcoma is a solid tumour, which is the second most common primary bone malignancy in children, often occurring in the long bones and pelvis. An incidence rate of 4.5 per million a year is reported, with a peak incidence of 11 per million at the age of 12 years. Despite more intensive chemotherapy, 30% to 40% of young people with Ewing sarcoma will have recurrence of the disease. Less than 30% of young people with a recurrence of Ewing sarcoma are alive at 24 months, and less than 10% are alive at 48 months. High-dose chemotherapy (HDC), followed by autologous haematopoietic cell transplantation (AHCT), is used in a variety of paediatric groups with diverse solid tumours. The hypothesis is that HDC regimens may overcome resistance to standard polychemotherapy, and this way may eradicate minimal residual disease, leading to improved survival after a first recurrence of disease. To assess the efficacy of HDC with AHCT versus conventional chemotherapy in improving event-free survival, overall survival, quality-adjusted survival, and progression-free survival in children, adolescents, and young adults with first recurrence of Ewing sarcoma, and to determine the toxicity of the treatment. We searched CENTRAL, MEDLINE, Embase, conference proceedings from the SIOP, ASPHO, CTOS, ASBMT, EBMT, and EMSOS, and two trial registries in January 2020. We also searched reference lists of relevant articles and review articles. We planned to include randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC plus AHCT with conventional chemotherapy for children, adolescents, and young adults (up to 30 years old at the date of diagnostic biopsy) with a first recurrence of Ewing sarcoma. We used standard methodological procedures expected by Cochrane. We did not identify any eligible studies. Since we did not identify any eligible studies, we are unable to draw any conclusions about the efficacy and toxicity of HDC with AHCT versus conventional chemotherapy in children, adolescents, and young adults with a first recurrence of Ewing sarcoma. Further high-quality research is urgently needed.

Prognostic Role of Systemic Inflammatory Indexes in Germ Cell Tumors Treated With High-Dose Chemotherapy.

High-dose chemotherapy (HDCT) has curative potential in relapsed/refractory germ cell tumors (GCT). Due to the complexity of this population and the toxicity of HDCT, we evaluated the association between blood-based systemic inflammatory indexes and the outcome of GCT patients undergoing salvage treatment with HDCT in order to define additional prognostic factors able to orient clinical decision. Baseline characteristics, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII) of 62 patients undergoing HDCT for GCT were retrospectively collected. The aim is to evaluate the correlation between each inflammatory marker (NLR, PLR, and SII) and response to HDCT, overall survival (OS), and progression-free survival (PFS). Using the receiver operating curve to identify the best cutoff values, it was found that patients with GCT with NLR ≥3.3 and SII ≥844,000 had shorter PFS and inferior OS. In the multivariable analysis including inflammatory markers, the International Prognostic Factor Study Group (IPFSG) risk group, age, and previous line of treatment, NLR ≥3.3 and SII ≥844,000 were identified to be independently associated with shorter PFS and OS. Moreover, NLR, PLR, and SII significantly correlate with overall response to HDCT. Associating IPFSG prognostic score to inflammatory markers at baseline of HDCT may improve prognostic information and could help physicians to make more personalized treatment decisions.

ASTRAL- a Clinical Study to Assess the Efficacy and Toxicity of High-dose Chemotherapy

ASTRAL- a Clinical Study to Assess the Efficacy and Toxicity of High-dose Chemotherapy

Toxicity of high-dose chemotherapy in patients with osteosarcoma.

e14508Background: We monitored the level of methotrexate and some laboratory parameters in patients with osteosarcoma to evaluate the toxicity of high-dosage EURAMOS chemotherapy. Methods: The stud...

The role of high-dose chemotherapy (CT) and stem-cell support in high-risk stage II, locally advanced, and responding stage IV breast cancer (BC): The Israeli experience with 20 years median follow-up.

1077 Background: Lately, updated data led the medical community to reconsider the use of intensive CT with stem-cell support for selected groups of BC patients (pts). Herein, we provide an update on a study investigating the efficacy, feasibility, and toxicity of high-dose CT with stem-cell support in pts with high-risk stage II, chemosensitive stage III and IV BC. Methods: The protocol offered adjuvant/neoadjuvant/induction doxorubicin-based CT, 75-90 mg/m2 X 4 courses followed by high-dose CT (cyclophosphamide 6000 mg/m2, carboplatin 800 mg/m2, and thiotepa 500 mg/m2) and autologous stem cell support with growth factors. Post-transplant local radiotherapy was delivered. Pts who were hormone receptor (HR) positive received Tamoxifen. Results: From 2/1994 to 11/1998, 292 BC pts were referred to the study from all Israeli oncology centers. Median follow-up from transplant was 20 (range, 18-22) years; 119 had stage 2 disease (42 with 4-9 positive nodes, 77 with ≥10 positive nodes); 87 had stage 3 disease, of whom 50 had locally advanced/inflammatory BC treated with neoadjuvant CT; and 86 had chemosensitive stage IV BC. Two acute transplant-related deaths and one death due to late transplant-related toxicity were reported. Median age at transplant was 45 (range, 24-63) years. Overall survival (OS) by HR status is presented in the table. In total, 167 of the 292 pts died (based on death status data retrieved from the Registry of the Ministry of the Interior), representing OS of 42%. The OS rates for stage II, III, and IV were 55%, 45%, and 23%, respectively. Conclusions: Long-term accurate follow-up of pts receiving well-defined treatments remains an important tool in cancer research. High-dose CT with stem-cell support could represent a therapeutic/curative option in select BC patients in all disease stages. Reintroduction of this approach should be re-examined. [Table: see text]

Abstract P1-13-07: Superiority of tandem high-dose chemotherapy (HDC) versus conventionally dosed chemotherapy (CDC) in patients with metastatic breast cancer (MBC): Long term follow-up of IBDIS: A prospective random assignment trial (PRT)

Abstract Background The partial chemo-sensitivity of MBC, together with pre-clinical models, provided a rationale for studies of extreme dose-escalation with autologous haematopoietic progenitor support (ASCT). Early studies of HDC as salvage following failure of CDC produced high rates of temporary response. Subsequent single arm studies in pts who were preselected for responsiveness to CDC yielded 10-20% durable remissions suggesting that HDC might cure some MBC pts. The likelihood of selection bias mandated randomised trials of this CDC induction-HDC consolidation approach. We hypothesised that an alternative strategy-accelerated multi-cycle HDC- might provide an optimal HDC strategy (Crown J, Norton L, Ann Oncol 1996). Methods In IBDIS, pts received a brief phase of CDC induction (doxorubicin/docetaxel-"AT"), followed by tandem cycles of HDC, or, further CDC (AT followed by CMF), as initial CRx for MBC. Hormone receptor-positive patients received endocrine therapy post-chemotherapy, and pts with localized metastases received consolidative radiotherapy. Results: Accrual failed in the aftermath of the disclosure of research fraud involving a South African HDC study, and the reporting of negative PRCTs at ASCO 1999. Only 110 of a planned 264 patients were enrolled, but it was decided to maintain follow-up, which is now 15 years. HDC and CDC groups were well-balanced for prior adjuvant (25 v 25), prior anthracycline (8 v 10), positive receptor status (32 v 31). There were 8 treatment-related deaths (6-HDC, 2 CDC). Complete and overall response rates (CR/OR) were significantly superior for HDC v CDC (CR-29% v 6%, OR-71% v 44%). Event-free-survival at median 5 yrs were HDC 6 (11%) versus CDC 0 (p=.027). At fifteen years three HDC pts remain alive and free from relapse. All CDC are deceased. The hazard ratio for PFS is currently 0.59 (0.39-0.88) favouring HDC p=.009. The HR for overall survival is 0.72 (0.48-1.08)p=.11 Discussion: Despite accrual failure, IBDIS was and remains a positive study for its primary endpoint of PFS. The 100% relapse and death rate for CDC on our study is typical of the published literature. Data from IBDIS are included in the Cochrane meta-analysis of HDC which showed an advantage for PFS. The contention that HDC produced superior activity to CDC appears to have been correct, however the magnitude of the benefit is smaller than was hoped by investigators in the field. While our data support the hypothesis that there is a dose response relationship in the chemotherapy of MBC, the small benefit and high toxicity of HDC, preclude it being recommended as a standard treatment for any pts with MBC. Citation Format: Crown J. Superiority of tandem high-dose chemotherapy (HDC) versus conventionally dosed chemotherapy (CDC) in patients with metastatic breast cancer (MBC): Long term follow-up of IBDIS: A prospective random assignment trial (PRT). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-07.

High-dose chemotherapy followed by autologous haematopoietic cell transplantation for children, adolescents and young adults with first recurrence of Ewing sarcoma

BACKGROUND Ewing sarcoma is a solid tumour, which is the second most common primary bone malignancy in children, often occurring in the long bones and pelvis. An incidence rate of 4.5 per million a year is reported, with a peak incidence of 11 per million at the age of 12 years. Despite more intensive chemotherapy, 30% to 40% of young people with Ewing sarcoma will have recurrence of the disease. Less than 30% of young people with a recurrence of Ewing sarcoma are alive at 24 months, and less than 10% are alive at 48 months. High-dose chemotherapy (HDC), followed by autologous haematopoietic cell transplantation (AHCT), is used in a variety of paediatric groups with diverse solid tumours. The hypothesis is that HDC regimens may overcome resistance to standard polychemotherapy, and this way may eradicate minimal residual disease, leading to improved survival after a first recurrence of disease. OBJECTIVES To assess the efficacy of HDC with AHCT versus conventional chemotherapy in improving event-free survival, overall survival, quality-adjusted survival, and progression-free survival in children, adolescents, and young adults with first recurrence of Ewing sarcoma, and to determine the toxicity of the treatment. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, conference proceedings from the SIOP, ASPHO, CTOS, ASBMT, EBMT, and EMSOS, and two trial registries in January 2020. We also searched reference lists of relevant articles and review articles. SELECTION CRITERIA We planned to include randomised controlled trials (RCTs) or (historical) controlled clinical trials (CCTs) comparing the effectiveness of HDC plus AHCT with conventional chemotherapy for children, adolescents, and young adults (up to 30 years old at the date of diagnostic biopsy) with a first recurrence of Ewing sarcoma. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We did not identify any eligible studies. AUTHORS' CONCLUSIONS Since we did not identify any eligible studies, we are unable to draw any conclusions about the efficacy and toxicity of HDC with AHCT versus conventional chemotherapy in children, adolescents, and young adults with a first recurrence of Ewing sarcoma. Further high-quality research is urgently needed.

Abstract 4327: Fasting enhances the response of Gl26-glioma to radiation and multiple chemotherapies

Abstract Malignant gliomas like anaplastic astrocytoma and glioblastoma mutliforme (GBM) are among the most commonly diagnosed malignant adult brain tumors. GBM is highly invasive and angiogenic and causes mortality rates higher than any other brain tumor, resulting in a median survival for GBM patients that is ∼12 to 15 months. Treatment of GBM is multimodal, usually initiated by surgical resection, followed by the adjuvant therapy of radiation and chemotherapy. Temozolomide is the current standard of care for patients with newly diagnosed gliomas and is well tolerated. Temozolomide has been shown to delay tumor-progression and prolong patient survival. As the treatment of GBM remains elusive, the improvement of existing therapies becomes important. The beneficial effects of dietary restriction (DR) on reducing age-dependent diseases, such as cancer, are well established. However, DR is expected to require weeks or even months for efficacy in human patients, which eventually would prove ineffective for cancer patients with fast progressing disease status. We have previously reported that fasting, an intense but brief form of DR differentially protects normal, as opposed to various cancer cells, against the toxicity of high-dose chemotherapy in in-vitro and in-vivo in a neuroblastoma-bearing mice model by causing major changes including the reduction of glucose, and IGF-I. We termed this phenomenon Differential Stress Resistance (DSR). We show that mimicking plasma-fasting conditions in-vitro sensitizes Gl26-glioma cells to chemotherapy treatment by Temozolomide and causes enhanced cell death of the starved glioma cells. We than applied this model of sensitization of cancer cells under fasting conditions to an intracranial and a subcutaneous glioma-tumor model in-vivo. We demonstrate that short term fasting enhances chemo- and radiotherapy in the in-vivo model and prolongs survival of tumor bearing mice even when compared to Temozolomide treated animals. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4327. doi:10.1158/1538-7445.AM2011-4327

High-dose chemotherapy and auto-SCT in elderly patients with Hodgkin's lymphoma

Our purpose was to assess efficacy and toxicity of high-dose chemotherapy (HDCT) and ASCT in patients with relapsed and refractory Hodgkin's lymphoma (HL) aged 60 years and older and compare the results with a group of younger HL patients treated in a similar manner. We identified 15 consecutive patients, with HL aged 60 years and older who underwent HDCT (etoposide 60 mg/kg+ melphalan 160 mg/m(2)) and ASCT at our institution from May 2001 to March 2008. The results were compared with a cohort of 157 younger HL patients treated in a similar manner from January 1999 to December 2006. After a median follow-up of 2.5 years, PFS at 3 years after ASCT was 73% (95% confidence interval (CI) 37-90) for the older group and 56% (95% CI 46-64) for the younger group (P=0.45); OS after ASCT was 88% (95% CI 39-98) for the older group and 84% (95% CI 75-90) for the younger group (P=0.80). No transplant-related deaths were seen. Our study suggests that ASCT is feasible for selected elderly patients with HL, giving similar results to younger patients in terms of survival and toxicity.

Quality of Life of Long Term Survivors with Follicular Lymphoma After High-Dose Chemotherapy with Autologous Stem Cell Transplantation and Conventional Chemotherapy.

AbstractAbstract 3808 Introduction:High-dose chemotherapy (HDCT) followed by peripheral blood stem cell transplantation (PBSCT) is frequently applied in eligible patients with relapsed or refractory follicular lymphoma (FL). The toxicity of HDCT, however, might manifest itself in the respective patients' reduced quality of life (QoL). In this study we investigated the QoL of long term survivors after HDCT in comparison with patients after conventional chemotherapy and the healthy German population. Patients and Methods:QoL was evaluated with the standardized questionnaires EORTC QLQ-C30 and EQ-5D. A total of 124 patients with FL were included in the study. 63 patients (29 female) with a median age of 60.4 (range 41–80) received HDCT with PBSCT between 1992 and 2002. This group was compared with 61 patients (38 female) with a median age of 62.9, range 31–81) who were treated with Rituxmab and CHOP chemotherapy and supplementary radiation in our institution. 55 patients of 63 (88%) of the HDCT group and 25 of 61 (41%) patients of the conventional group were in continuous complete remission (CR). Median follow-up for the HDCT group is 9 years and for the conventional chemotherapy group it is 4.4 years. In addition, QoL of the patients was compared to QoL of healthy people on the basis of two studies about the general health status of the German population (R. Schwarz and A. Hinz: “Reference data for the quality of life questionnaire EORTC QLQ-C30 in the general German population,” European Journal of Cancer 37 [2001]: 1345–1351; H. H. König et al.: “Health Status of the German Population: Results of a Representative Survey Using the EuroQoL Questionnaire,” Gesundheitswesen 67 [2005]: 173–182). Results:In the HDCT group, the results of the questionnaires show a reduced QoL compared to the healthy population. Regarding the three main categories of the EORTC QLQ-C30, the mean sum score for global health state (ghs) is 71.38, for functional state (fs) 78.38 and for symptomatic state (ss) 18.60 (the ideal score being 100.00 for the first two items and 0.00 for the latter). The mean value for EQ-5D is 0.911 (ideal value: 1.000) and that for VAS is 75.52 (ideal value: 100.00). The one sample t-test evaluation shows that the decrease in QoL is significant with p<0.05 in four of five of the subcategories of the functional state; six of the nine subcategories of the symptomatic state, namely fatigue, dyspnoea, insomnia, constipation, diarrhoea and financial difficulties. Patients who received conventional chemotherapy (ghs: 67.04; fs: 70.49; ss: 25.01) also showed a reduced QoL compared to the healthy population in all of the three main categories of the EORTC-QLQ-C30, in particular in the category of functional and symptomatic state. These differences were statistically significant in all subcategories of the functional state namely physical,-role,-emotional,-cognitive,- and social functioning (p=0.001). The differences of the symptomatic state were statistically significant in seven of nine subcategories, namely fatigue, pain, dyspnoea, insomnia, constipation, diarrhea and financial difficulties. When QoL of the HDCT group and the conventional therapy group were compared, there were significant differences in favor of the HDCT group only in the functional subcategory social functioning (p=0.04) and the symptomatic subcategory pain (p=0.01), with no significant differences in all other categories. In the EQ-5D questionnaire, we found a reduced QoL in patients after conventional chemotherapy compared to HDCT patients (p=0.05) and healthy people (p=0.02). Conclusions:In this long term follow up study, we found a reduced QoL in FL patients after conventional chemotherapy as well as after HDCT compared to the healthy population. There was a tendency of a better QoL in patients of the HDCT group compared to patients of the conventional chemotherapy group, maybe due to a higher proportion of patients in CR or a longer follow up period in the HDCT group. We conclude that the negative impact of both HDCT and conventional therapy on QoL of patients with follicular lymphoma should not be underestimated and should lead to the development of less toxic therapy strategies. Disclosures:No relevant conflicts of interest to declare.

Efficacy of High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with Relapsed Medulloblastoma: A Report on The Korean Society for Pediatric Neuro-Oncology (KSPNO)-S-053 Study

The efficacy and toxicity of high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) were investigated for improving the outcomes of patients with relapsed medulloblastoma. A total of 15 patients with relapsed medulloblastoma were enrolled in the KSPNO-S-053 study from May 2005 to May 2007. All patients received approximately 4 cycles of salvage chemotherapy after relapse. Thirteen underwent HDCT/ASCT; CTE and CM regimen were employed for the first HDCT (HDCT1) and second HDCT (HDCT2), respectively, and 7 underwent HDCT2. One transplant related mortality (TRM) due to veno-occlusive disease (VOD) occurred during HDCT1 but HDCT2 was tolerable with no further TRM. The 3-yr overall survival probability and event-free survival rates ±95% confidence intervals (CI) were 33.3±12.2% and 26.7% ±11.4%, respectively. When analysis was confined to only patients who had a complete response (CR) or partial response (PR) prior to HDCT, the probability of 3-yr overall survival rates ±95% CI was 40.0±15.5%. No patients with stable disease (SD) or progressive disease (PD) survived. Survival rates from protocol KSPNO-S-053 are encouraging and show that tumor status prior to HDCT/ASCT is an important factor to consider for improving survival rates of patients with relapsed medulloblastoma.

Cost-Benefit Analysis of Primary Prophylaxis with Granulocyte Colony Stimulating Factor (GCSF) in Reducing Hospital Admissions with Febrile Neutropenia in Patients Undergoing High Dose Chemotherapy for Non-Hodgkin Lymphoma (NHL).

Abstract 4764 IntroductionHigh dose chemotherapy for lymphoma is known to be associated with significant risk of febrile neutropenia (FN), especially in elderly patients. FN is a major dose-limiting toxicity of high dose chemotherapy and can lead to delay in treatment. In addition, FN also causes significant patient morbidity and has an adverse impact on quality of life. Although a meta-analysis of 12 randomised trials with Hodgkin disease(HD) and non-Hodgkin lymphoma (NHL) patients has shown that prophylactic GCSF significantly reduces the relative risk of FN (Bohlius J, et al: Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database of Systematic Reviews CD003189, 2004), it is not known whether primary prophylaxis is also cost-effective. Since December 2007, we implemented guidelines in our haematology department for the use of primary GCSF prophylaxis in patients age >65 years undergoing high dose chemotherapy treatment for NHL. We studied the impact on the incidence of FN as well as cost-effectiveness of this approach. Patients and MethodsA cohort of 62 patients who underwent high dose chemotherapy for NHL from December 2006 to May 2009 was identified. Patient demographics, type of lymphoma, chemotherapy regimen, details of GCSF prophylaxis, hospital admissions due to FN, and outcome of treatment at last follow up were recorded. Cost-benefit analysis was carried out using the actual cost of hospital admissions and numbers needed to treat (NNT). Chi-square test was used to calculate p-value. ResultsGCSF was given in a dose of 300 mcg subcutaneously daily, for an average of 7 days. The median age of the cohort was 63 years (IQR 54, 70). Fifty three patients received CHOP based regimen. Forty one patients had diffuse large B cell lymphoma. Overall, patients who received primary GCSF therapy had significantly less FN compared to those who did not [8% vs 56%, p<0.0001, absolute risk reduction (ARR) 48% (95% confidence interval(C.I.) 25% to 66%) with NNT of 2 (95% C.I. 2 to 4)]. In subgroup analysis, even patients aged '65 years appeared to receive benefit from primary GCSF prophylaxis in reduction of FN [4.8% vs 66.7%, p=0.005, ARR 62%(95% C.I. 34%-90%), NNT 2(95% C.I. 1-3)]. In patients who underwent CHOP-based chemotherapy, the benefit of primary GCSF prophylaxis appeared to be greater compared to the cohort [11% vs 68%, p<0.0001, ARR 58%(C.I. 30%-76%) with NNT of 2 (95% C.I. 1-3) – table 1. There was no difference in treatment outcomes such as achieving at least PR or CR, and no difference in mortality, either from disease or all cause combined, during the study period. The average cost of hospital admission with FN was calculated to be NZD$6753.31. Using the NNT value obtained, primary GCSF prophylaxis appeared to be cost effective, leading to saving of $1991.22 per patient. ConclusionOur study shows that primary GCSF prophylaxis is effective in preventing FN in patients undergoing high dose chemotherapy and that it is highly cost-effective; hence primary GCSF prophylaxis is recommended in this patient group.All patients (n=62)GCSF prophylaxis (n=37)No GCSF prophylaxis (n=25)P-valueAge median years (IQR)63 (54,70)62 (53,70)64 (54,70)0.99Febrile neutropenia (FN) – all patientsOne or more episodes17314<0.0001None453411Subgroup analyses (patients >65 years)One or more episodes (FN)8260.04None21147Subgroup analyses (patients'65 years)One or more episodes (FN)9180.005None24204Subgroup analyses (CHOP-based chemotherapy only)One or more episodes (FN)15411<0.0001None38335Subgroup analyses (patients >65 years and CHOP-based chemotherapy)One or more episodes (FN)6240.02None18153 Disclosures:No relevant conflicts of interest to declare.

Quality of Life of Long Term Survivors with Hodgkin's Lymphoma After High-Dose Chemotherapy with Autologous Stem Cell Transplantation and Conventional Chemotherapy.

Abstract 2495Poster Board II-472 Introduction:High-dose chemotherapy (HDCT) followed by peripheral blood stem cell transplantation (PBSCT) is frequently applied in eligible patients with relapsed or refractory Hodgkin's disease. The toxicity of HDCT, however, might manifest itself in the respective patients' reduced quality of life (QoL). In this study we investigated the QoL of long term survivors after HDCT in comparison with patients after conventional chemotherapy and the healthy German population. Patients and Methods:QoL was evaluated with two standardized questionnaires: EORTC QLQ-C30 and EQ-5D. The cancer-specific EORTC-QLQ-C30 consists of thirty questions concerning three main categories: global health state, functional and symptomatic state. The single questions belonging to functional and symptomatic state can furthermore be grouped into different subcategories. The EQ-5D visualizes five dimensions of health: mobility, self-care, daily activities, pain, and anxiety. In addition to that, the visual analogue scale (VAS) is included to outline the patients' overall health state. A total of 98 patients were included in the study. 37 patients (13 female, 24 male) with a median age of 46 (range 23-72) received HDCT with PBSCT between 1986 and 2007. This group was compared with 61 patients (36 female, 25 male; median age 41, range 21-72) treated with conventional chemotherapy and supplementary radiation in our institution. In the conventional chemotherapy group BEACOPP was used in most cases (n=31), followed by ABVD (n=20), a combination of both (n=8) and ABV (n=2). All patients were in continuous clinical remission. Median follow-up for the HDCT group is 11 and for the conventional chemotherapy group 3.5 years. In addition, Qol of the patients was compared to QoL of healthy people on the basis of two studies about the general health status of the German population (R. Schwarz and A. Hinz: “Reference data for the quality of life questionnaire EORTC QLQ-C30 in the general German population,” European Journal of Cancer 37 [2001]: 1345-1351; H. H. König et al.: “Health Status of the German Population: Results of a Representative Survey Using the EuroQoL Questionnaire,” Gesundheitswesen 67 [2005]: 173-182). Results:In the HDCT group, the results of the questionnaires show a reduced QoL compared to the healthy population. Regarding the three main categories of the EORTC QLQ-C30, the mean sum score for global health state (ghs) is 68.69, for functional state (fs) 72.49 and for symptomatic state (ss) 21.55 (the ideal score being 100.00 for the first two items and 0.00 for the latter). The mean value for EQ-5D is 0.880 (ideal value: 1.000) and that for VAS is 71.60 (ideal value: 100.00). The one sample t-test evaluation shows that the decrease in QoL is significant with p<0.05 in all of the subcategories of the functional state; four of the nine subcategories of the symptomatic state, namely fatigue, dyspnoea, diarrhoea and financial difficulties. Compared to the group of patients who received conventional chemotherapy (ghs: 73.92; fs: 77.36; ss: 16.27), there is a tendency towards reduced QoL in patients with HDCT in all of the three main categories of the EORTC-QLQ-C30, in particular in the category of symptomatic state. However, these differences were not statistically significant, with the exception of the subcategory of dyspnoea (p<0.001). In the EQ-5D questionnaire, there was a trend for reduced QoL of patients after HDCT compared to conventional chemotherapy patients and healthy people, however these effects were not significant (p = 0.06 and p = 0.089). Conclusions:In this long term follow up study, QoL is reduced in patients after HDCT as well as in patients after conventional treatment compared to the healthy population. There was a trend that QoL might be worse in the HDCT group compared to the conventional therapy group; however this effect was not statistically significant. We conclude that the negative impact of both HDCT and conventional therapy on the QoL of long term survivors with Hodgkin's lymphoma should not be underestimated and should lead to the development of less toxic therapy strategies. Disclosures:No relevant conflicts of interest to declare.

Autologous Hematopoietic Stem Cell Transplantation May Reverse Renal Failure in Patients with Multiple Myeloma

Approximately 20% of patients with multiple myeloma (MM) have renal failure at diagnosis, and about 5% are dialysis-dependent. Many of these patients are considered ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) because of a high risk of treatment-related toxicity. We evaluated the outcome of 46 patient with MM and renal failure, defined as serum creatinine >2 mg/dL sustained for >1 month before the start of preparative regimen. Patients received auto-HSCT at our institution between September 1997 and September 2006. Median serum creatinine and creatinine clearance (CrCl) at auto-HSCT were 2.9 mg/dL (range: 2.0-12.5) and 33 mL/min (range: 8.7-63), respectively. Ten patients (21%) were dialysis-dependent. Median follow-up in surviving patients was 34 months (range: 5-81). Complete (CR) and partial responses (PR) after auto-HSCT were seen in 9 (22%) and 22 (53%) of the 41 evaluable patients, with an overall response rate of 75%. Two patients (4%) died within 100 days of auto-HSCT. Grade 2-4 nonhematologic adverse events were seen in 18 patients (39%) and included cardiac arrythmias, pulmonary edema, and hyperbilirubinemia. Significant improvement in renal function, defined as an increase in flomerular filtration rate (GFR) by 25% above baseline, was seen in 15 patients (32%). Kaplan-Meier estimates of 3-year progression-free survival (PFS) and overall survival (OS) were 36% and 64%, respectively. In conclusion, auto HSCT can be offered to patients with MM and renal failure with acceptable toxicity and with a significant improvement in renal function in approximately one-third of the transplanted patients. In this analysis, a melphalan (Mel) dose of 200 mg/m(2) was not associated with an increase in toxicity or nonrelapse (Mel) mortality (NRM).

Biological therapy for pediatric malignancy: Current perspectives

Biologicals are defined as agents that are either uniquely or partially tumor-specific. Great expectations were raised by the success in agents that target a specific genetic translocation: all-trans retinoic acid, targeting the chronic myeloid leukemia retinoic acid receptor in acute promyelocytic leukemia and imatinib, a small molecule targeting the BCR-ABL translocation in chronic myeloid leukemia (CML). Thus far, the search for similar "druggable" genetic targets in pediatric cancers has not yet resulted in such dramatic results. The rarity of pediatric cancer as well as ethical considerations necessitate that the agents for testing be carefully and rigorously selected. Biologicals present an additional challenge, as they often do not lend themselves to in vitro testing. Early approaches to specific targeting of solid tumors utilized monoclonal antibodies. The microenvironment provides an interesting new biological approach to treating tumors and alteration of the host immune response provides another avenue. Biological agents are a step forward in supportive care to reduce the hematological toxicity of high-dose chemotherapy and to manage the frequent infectious complications.

Protection of a cytidine deaminase gene gainst toxicity of high dose chemotherapy in mice

Objective To explore the feasibility of transfecting cytidine deaminase (CD) gene into mouse bone marrow cells in order to observe the drug resistance of high dose Ara-C and improve the tolerance of myelosuppression following combination chemotherapy.

Protection against toxicity of high dose chemotherapy in mice transfected with double-mutant dihydrofolate reductase-cytidine deaminase gene

Protection against toxicity of high dose chemotherapy in mice transfected with double-mutant dihydrofolate reductase-cytidine deaminase gene

Protection of cytidine deaminase gene gainst toxicity of high-dose chemotherapy in mice

Protection of cytidine deaminase gene gainst toxicity of high-dose chemotherapy in mice

High dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HPSCT) with subsequent immunotherapy in metastatic breast cancer (MBC): Final results of a phase I stud

726 Introduction: This phase-I study prospectively analysed the efficacy and toxicity of HDCT, HPSCT and subsequent immunotherapy with T–cell reinfusion in chemotherapy-sensitive patients with MBC. Patients and methods: After leukapheresis and cryopreservation of T-cells, patients received 2 cycles of standard chemotherapy ET (epirubicin/paclitaxel) and 1 cycle of EI (epirubicin/ifosfamide) followed by G-CSF and stem cell harvest. After a third cycle of ET, responders (CR/PR) underwent HDCT (thiotepa 600 mg/m2/melphalan 140–180 mg/m2) and HPSCT. Once hematopoietic reconstitution was achieved, T-cells were reinfused followed by application of bispecific antibodies against HER-2/neu and EpCAM. Results: Thirty-three patients were recruited on study, and nineteen pts who had responded to initial standard chemotherapy (4 CR, 15 PR, OR = 58%) underwent HDCT and HPSCT. Subsequently, another 6 patients achieved a CR after HDCT resulting in an overall CR rate of 10/33 pts (30%). Two early deaths were observed (one...