Association of the advanced lung cancer inflammation index (ALI) with immune checkpoint inhibitor efficacy in patients with advanced non-small-cell lung cancer.

BACKGROUND: The advanced lung cancer inflammation index [ALI: body mass index × serum albumin/neutrophil-to-lymphocyte ratio (NLR)] reflects systemic host inflammation, and is easily reproducible. We hypothesized that ALI could assist guidance of non-small-cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: This retrospective study included 672 stage IV NSCLC patients treated with programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy in 25 centers in Greece and Germany, and a control cohort of 444 stage IV NSCLC patients treated with platinum-based chemotherapy without subsequent targeted or immunotherapy drugs. The association of clinical outcomes with biomarkers was analyzed with Cox regression models, including cross-validation by calculation of the Harrell's C-index. RESULTS: High ALI values (>18) were significantly associated with longer overall survival (OS) for patients receiving ICI monotherapy [hazard ratio (HR) = 0.402, P < 0.0001, n = 460], but not chemo-immunotherapy (HR = 0.624, P = 0.111, n = 212). Similar positive correlations for ALI were observed for objective response rate (36% versus 24%, P = 0.008) and time-on-treatment (HR = 0.52, P < 0.001), in case of ICI monotherapy only. In the control cohort of chemotherapy, the association between ALI and OS was weaker (HR = 0.694, P = 0.0002), and showed a significant interaction with the type of treatment (ICI monotherapy versus chemotherapy, P < 0.0001) upon combined analysis of the two cohorts. In multivariate analysis, ALI had a stronger predictive effect than NLR, PD-L1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. Among patients with PD-L1 tumor proportion score ≥50% receiving first-line ICI monotherapy, a high ALI score >18 identified a subset with longer OS and time-on-treatment (median 35 and 16 months, respectively), similar to these under chemo-immunotherapy. CONCLUSIONS: The ALI score is a powerful prognostic and predictive biomarker for patients with advanced NSCLC treated with PD-L1 inhibitors alone, but not in combination with chemotherapy. Its association with outcomes appears to be stronger than that of other widely used parameters. For PD-L1-high patients, an ALI score >18 could assist the selection of cases that do not need addition of chemotherapy.

Three- versus six-month adjuvant FOLFOX or CAPOX for high-risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project.

BACKGROUND: The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) aimed to investigate whether a 3 months (3M) of oxaliplatin/fluoropyrimidine-based adjuvant chemotherapy (CT) is non-inferior to the 6-month (6M) administration in 3-year disease-free survival (3yDFS) in high-risk (HR) stage II or stage III colon cancer (CC). METHODS: Hellenic Oncology Research Group (HORG)-IDEA randomized patients between 3M and 6M of CT with FOLFOX4 or CAPOX. RESULTS: In total 1115 patients, 413 with HR stage II and 702 with stage III CC, were randomized. The median follow-up was 67.0 (38.3-126.0) months. Overall, 394 DFS events (202 in 3M arm and 192 in 6M arm) where recorded. The 3yDFS rate was 77.2% [95% confidence interval (CI) 72.1% to 82.3%] for 3M and 77.9% (72.6% to 82.5%) for 6M of treatment [hazard ratio (HR) 1.05 (95% CI 0.61-1.55); P = 0.647]. Eighty DFS events (3M N = 41; 6M N = 39) were observed in HR stage II patients for a 3yDFS rate of 82.7% and 83.4%, respectively (HR 1.05; 95% CI 0.68-1.63, P = 0.829). For stage III patients, 314 DFS events (3M N = 161 and 6M N = 153) were observed, for a 3yDFS rate of 72.9% for 3M versus 74.1% for 6M (HR 1.06; 95% CI 0.81-1.42, P = 0.622). For HR stage II patients receiving FOLFOX4, 3yDFS rate was 76.7% for 3M and 79.3% for 6M (HR 1.21; 95% CI 0.54-2.70). For HR stage II patients receiving CAPOX the 3yDFS rate was 85.4% for 3M and 83.8% for 6M (HR 0.99; 95% CI 0.59-1.67). For stage III patients receiving FOLFOX4, the 3yDFS rate was 71.5% for 3M and 77.3% for 6M (HR 1.18; 95% CI 0.74-1.86). For stage III patients receiving CAPOX, the 3yDFS rate was 74.5% for 3M and 74.7% for 6M (HR 0.99; 95% CI 0.70-1.44). CONCLUSIONS: The results of the HORG-IDEA study are in line with those of the global IDEA project, indicating that the 3yDFS is dependent on the administered adjuvant regimen and the choice and duration of regimen should be personalized. CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT01308086.

[Radioimmunotherapy for non-Hodgkin lymphoma: historical development and current status]. / Radioinmunoterapia en los linfomas no Hodgkin: desarrollo histórico y estado actual.

Radioimmunotherapy treatment for lymphoma is a novel targeted therapeutic approach. Several years of development of radioimmunotherapeutic compounds came to fruition in February of 2002 when 90Y-ibritumomab tiuxetan (Zevalin, Y2B8) was approved in the USA and later in Europe, for the treatment of relapsed or refractory, low grade or transformed B-cell lymphoma in the USA. 90Y-ibritumomab tiuxetan utilizes a monoclonal anti-CD20 antibody to deliver beta-emitting yttrium-90 to the malignant B-cells. Clinical trials have demonstrated its efficacy, with observed clinical responses in the 80 % range. This product has become available in Europe, with simplified administration, for the treatment of relapsed follicular lymphoma. A similar anti-CD20 radiotherapeutic compound, 131I-tositumomab, was subsequently approved in the USA. Promising studies exploring expanded applications of radioimmunotherapy as consolidation, as part of transplant, or in other histologic types have been recently completed or are under way. Radioimmunotherapy has been shown to be an effective and clinically relevant complementary therapeutic approach for patients with lymphoma, bringing the Nuclear Medicine into lymphoma therapeutics.

Radioinmunoterapia en los linfomas no Hodgkin: desarrollo histórico y estado actual / Radioimmunotherapy for non-Hodgkin lymphomas: historical development and currents

La radioinmunoterapia (RIT) es un nuevo enfoque terapéutico en el tratamiento de los linfomas. En febrero de 2002, tras varios años de desarrollo de diversos compuestos radioinmunoterápicos se aprobó, primero en Estados Unidos y posteriormente en Europa, el 90Y-ibritumomab tiuxetan (Zevalin®, Y2B8) para el tratamiento de los linfomas de bajo grado o linfomas B transformados, en recaída o refractarios. El 90Y-ibritumomab tiuxetan utiliza el anticuerpo monoclonal antiCD20 y la emisión β del 90Y frente a las células B malignas. Los ensayos clínicos han demostrado su eficacia, observándose respuesta clínica en un rango del 80 %. Este producto se encuentra disponible en Europa, con una administración simplificada, para el tratamiento de la recaída en el linfoma folicular. En EE.UU. se ha aprobado posteriormente un antiCD20 similar con efecto radioterápico, el 131I tositumomab. Se están realizando estudios prometedores para ampliar las indicaciones de la RIT, como son en la consolidación, como parte del trasplante o en otros tipos histológicos, encontrándose algunos ya finalizados y otros en curso. La RIT se ha mostrado como una terapia complementaria efectiva y clínicamente relevante en los pacientes con linfoma, introduciendo a la Medicina Nuclear en el tratamiento de los linfomas

Radioimmunotherapy treatment for lymphoma is a novel targeted therapeutic approach. Several years of development of radioimmunotherapeutic compounds came to fruition in February of 2002 when 90Y-ibritumomab tiuxetan (Zevalin™, Y2B8) was approved in the USA and later in Europe, for the treatment of relapsed or refractory, low grade or transformed B-cell lymphoma in the USA. 90Y-ibritumomab tiuxetan utilizes a monoclonal anti-CD20 antibody to deliver β -emitting yittrium-90 to the malignant B-cells. Clinical trials have demonstrated its efficacy, with observed clinical responses in the 80 % range. This product has become available in Europe, with simplified administration, for the treatment of relapsed follicular lymphoma. A similar anti-CD20 radiotherapeutic compound, 131I-tositumomab, was subsequently approved in the USA. Promising studies exploring expanded applications of radioimmunotherapy as consolidation, as part of transplant, or in other histologic types have been recently completed or are under way. Radioimmunotherapy has been shown to be an effective and clinically relevant complementary therapeutic approach for patients with lymphoma, bringing the Nuclear Medicine into lymphoma therapeutics

Reliability and validity of a patient self-administered daily questionnaire to assess impact of oral mucositis (OM) on pain and daily functioning in patients undergoing autologous hematopoietic stem cell transplantation (HSCT).

Oral mucositis (OM) is a frequent complication of myeloablative therapy and HSCT. We evaluated the feasibility, reliability, and validity of a new patient self-reported daily questionnaire on OM and its impact on daily functions. This OM Daily Questionnaire (OMDQ), containing 10 items, was developed for use in palifermin clinical trials. In a phase 3 study, 212 patients received palifermin or placebo for three consecutive days before conditioning and three consecutive days after HSCT. Compliance rates were consistently >80% for most patients. Mouth and throat soreness (MTS) and MTS-Activity Limitations (MTS-AL) (swallowing, drinking, eating, talking, and sleeping) scores on consecutive days were highly correlated (days 7,8 = 0.70-0.86; test-retest reliability). Correlations among items measuring the same construct ranged between 0.5 and 0.8 (internal consistency reliability). The WHO Oral Toxicity scale was the clinical comparator to assess the criterion, discriminative, and evaluative validities of MTS-related questions. Most correlation coefficients between the WHO and MTS ranged between 0.45 and 0.55. Patients with more severe WHO OM grades had higher MTS mean scores. Changes in MTS scores were similar, but patients detected changes 1-3 days earlier than clinicians. In conclusion, the OMDQ is a feasible, reliable, valid, and responsive patient-reported measure of OM severity.

Extended rituximab therapy in Waldenström's macroglobulinemia.

BACKGROUND: Waldenström's macroglobulinemia (WM) is a CD20 expressing B-cell malignancy represented by the pathological diagnosis of IgM secreting lymphoplasmacytic lymphoma. Major response rates of 30% have been reported in most studies with standard dose rituximab, i.e. 4 weekly infusions at 375 mg/m(2)/week. METHODS: In an effort to increase rituximab activity in WM, an extended dose schedule employing two sets of four (375 mg/m(2)/week) infusions at weeks 1-4 and 12-16 was evaluated. Expression of the complement resistance antigens CD46, CD55 and CD59 was also evaluated on tumor cells pre- and post-therapy to determine impact on response. RESULTS: Twenty-nine patients were enrolled and 26 patients completed the intended therapy. On an intent to treat analysis, 14 (48.3%) patients achieved a partial response, and 5 (17.2%) patients achieved a minor response. Responses were observed in 18/24 (75%) patients with a serum IgM level of <6000 mg/dl, and only 1 of 5 (20%) patients with a level of >6000 mg/dl (P=0.03). The median time to best response was 17 months, and only 2 of 19 responding patients progressed with a median follow-up of 29 months. No differences in baseline expression of the complement resistance antigens CD46, CD55 and CD59 were observed among responding and non-responding patients, although post-therapy CD55 expression was higher in non-responding patients (P=0.002). CONCLUSIONS: These data show that extended rituximab therapy is active and may lead to more major responses over standard dose rituximab in WM. WM patients with serum IgM levels of <6000 mg/dl are more likely to benefit from extended rituximab therapy.

Anti-VEGF antibody bevacizumab (Avastin) with 5FU/LV as third line treatment for colorectal cancer.

BACKGROUND: To evaluate the activity and safety of bevacizumab when given with standard 5FU/leukovorin (LV) regimens in patients with metastatic colorectal cancer who have failed irinotecan and oxaliplatin-based treatments. METHODS: Bevacizumab was given at 5 mg/kg as an IV infusion every 2 weeks. Patients received 5FU according to Roswell Park or the de Gramont regimen. RESULTS: Nineteen patients enrolled, median age 60, median PS: 1. Most common toxicity attributable to bevacizumab was mild hypertension, epistaxis and mild proteinuria; 1 patient had a CNS haemorrhage. The median number of cycles was 1 (8 weeks). Clinical benefit as disease stabilisation lasting 2-6 months was noted in 9 patients, whereas 10 progressed (median f/u: 5 months). TTP was 16 weeks, and the overall survival has not been reached (24+ weeks). CONCLUSIONS: Bevacizumab may result in growth arrest and clinical benefit in a substantial proportion of patients with colorectal cancer and no alternative treatment.

Localized radiation increases morbidity and mortality after TBI-containing autologous stem cell transplantation in patients with lymphoma.

The purpose of this study is to assess the relationship between involved field radiation therapy (IFRT) and treatment-related morbidity and mortality in patients receiving high-dose chemotherapy (HDC), total body irradiation (TBI) and autologous peripheral stem cell transplant (PSCT) for Hodgkin's and non-Hodgkin's lymphoma. Between January 1994 and May 2002, 156 patients underwent HDC, TBI and autologous PSCT. Localized external beam radiation therapy was given to 21 patients for consolidation, or to achieve control of symptomatic or active disease prior to or after transplant. Among patients who had IFRT prior to autologous PSCT, five treatment-related deaths were observed, compared to seven deaths in 135 patients who had autologous PSCT without IFRT (P<0.01). Most deaths were attributable to sepsis and multiorgan failure. A higher incidence of pneumonitis was also noted in patients exposed to mediastinal irradiation. No adverse impact on long-term survival could be demonstrated. Involved field radiation prior to TBI is associated with higher treatment-related mortality in lymphoma patients undergoing autologous peripheral stem cell transplant, necessitating careful monitoring.

Mitoxantrone-cyclophosphamide-rituximab: an effective and safe combination for indolent NHL.

Treatment for extensive indolent lymphoma should combine optimization of efficacy without excessive toxicity. Rituxan may be an ideal agent for combinations with chemotherapy because of its non-cross-resistant toxicity profile and the potential for synergism. We present the results of 32 patients with indolent B-cell NHL who received a novel three-drug combination designed with the intent of preservation of both efficacy and quality of life. Patient characteristics were as follows, median age, 58 years (36-75 years); histology, follicular 16, SLL/CLL five, lymphoplasmacytic six, marginal cell five; relapsed or refractory, 10; untreated, 22. Patients first received cyclophosphamide 800 mg/m(2) and mitoxantrone 8 mg/m(2), iv on the same day, every 3 weeks for two cycles. Subsequently, patients received rituximab followed by mitoxantrone 8 mg/m(2) every 2 weeks for four cycles. The regimen, and particularly rituximab, was extremely well tolerated. Grade I/II, infusion-related toxicity was noted in 10%. Six patients achieved a PR and 23 a CR for an overall response of 90% (95% CI: 79-100%). The actuarial median TTP for all patients was 30 months. Molecular remissions were noted in 8/14 patients tested in CR. We conclude that the cyclophosphamide-mitoxantrone-rituxan (CyMiR) regimen is effective and extremely well tolerated. Furthermore, rituximab infusion-related morbidity is nearly completely eliminated.

Long-term outcome of autologous transplantation of peripheral blood progenitor cells as postremission management of adult acute myelogenous leukemia in first complete remission.

In order to improve leukemia-free survival (LFS) without the treatment-related morbidity of allogeneic bone marrow transplantation or multiple prolonged cycles of consolidation chemotherapy, we evaluated the long-term outcome of autologous transplantation of peripheral blood progenitor cells (PBPCs) as postremission therapy in 129 patients aged 18-71 years (median 49 years) with newly diagnosed acute myelogenous leukemia (AML) in first complete remission (CR1). The median follow-up from remission for surviving patients was 62.2 months (range 3.7-127.9 months). A total of 57 patients were alive and leukemia free at the end of the study. The LFS and overall survival 5 years from remission were 40.2% (+/-9.2%) and 41.4% (+/-9.4%), respectively. The median LFS and overall survival are 17.3 and 23.3 months, respectively. Multivariate analysis identified age as the most significant predictor for both LFS and overall survival. Karyotype was also found to be predictive of outcome. Our results show that autologous transplantation of PBPC procured after a single cycle of high-dose cytarabine-based consolidation chemotherapy for a population of adult patients with AML in CR1 produces a high likelihood of long-term LFS, offering a state of clinical minimal residual disease for the investigation of future therapeutic approaches.

Randomized, multicenter, open-label study of pegfilgrastim compared with daily filgrastim after chemotherapy for lymphoma.

PURPOSE: The primary objective was to assess the duration of grade 4 neutropenia (neutrophil count < 0.5 x 10(9)/L) after one cycle of chemotherapy with etoposide, methylprednisolone, cisplatin, and cytarabine in patients randomly assigned to receive one dose of pegfilgrastim or daily filgrastim after chemotherapy. Febrile neutropenia, neutrophil profiles, time to neutrophil recovery, pharmacokinetics, and safety were also assessed. PATIENTS AND METHODS: An open-label, randomized, phase II study was designed to compare the effects of a single subcutaneous injection of pegfilgrastim (sustained-duration filgrastim) 100 micro g/kg per chemotherapy cycle (n = 33) with daily subcutaneous injections of filgrastim 5 micro g/kg (n = 33) in patients receiving salvage chemotherapy for relapsed or refractory Hodgkin's or non-Hodgkin's lymphoma. RESULTS: The incidence of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 69% and 68%, respectively. In addition, the mean duration of grade 4 neutropenia was similar in both groups (2.8 and 2.4 days, respectively). The results for the two groups were also not significantly different for febrile neutropenia, neutrophil profile, time to neutrophil recovery, or toxicity profile. A single subcutaneous injection of pegfilgrastim 100 micro g/kg produced a sustained serum concentration relative to daily subcutaneous injections of filgrastim. Filgrastim-treated patients received a median of 11 injections per cycle. CONCLUSION: Pegfilgrastim was safe and well tolerated in this patient population. A single injection of pegfilgrastim per chemotherapy cycle provided neutrophil support with safety and efficacy similar to that provided by daily injections of filgrastim. Once-per-cycle administration of pegfilgrastim simplifies the management of neutropenia and may have important clinical benefits for patients and healthcare providers.

Detection of bcl-2/IgH rearrangements by quantitative-competitive PCR and capillary electrophoresis.

BACKGROUND: PCR is the primary method for detecting minimal residual disease in hematologic cancers. One such gene target is the bcl-2/immunoglobulin heavy chain (IgH) translocation found in a majority of cases of follicular lymphoma. METHODS AND RESULTS: We report an accurate method for quantitative detection of the bcl-2/IgH translocation marker of follicular lymphoma in a series of patients in various stages of remission and relapse who had been treated with a combination of ifosfamide, mitoxantrone, and etoposide (MINE) chemotherapy and monoclonal anti-CD20 antibody (Rituximab). The approach uses seminested PCR followed by analysis of the products on a fluorescent capillary electrophoresis system. The quantitation of bcl-2/IgH translocation-positive cells was sensitive and reproducible, capable of detecting as few as five malignant cells out of 300,000 normal cells. CONCLUSION: Quantitative PCR enables one to monitor the kinetics of tumor reduction in patients treated with MINE chemotherapy in combination with Rituximab.

CD20-directed antibody-mediated immunotherapy induces responses and facilitates hematologic recovery in patients with Waldenstrom's macroglobulinemia.

Waldenstrom's macroglobulinemia (WM, lymphoplasmacytic lymphoma) is a B-cell lymphoproliferative disorder in which CD20 is expressed on tumor cells from most patients. Several small studies have suggested a benefit from the anti-CD20 monoclonal antibody rituximab (Rituxan, MabThera) in patients with WM. In this retrospective study, we examined the outcome of 30 previously unreported patients with WM who received treatment with single-agent rituximab (median age 60; range 32-83 years old). The median number of prior treatments for these patients was 1 (range 0-6), and 14 patients (47%) received a nucleoside analogue before rituximab therapy. Patients received a median of 4.0 (1-11.3) infusions of rituximab (375 mg/m2). Three patients received steroids with their infusions for prophylaxis of rituximab-related infusion syndrome. Overall, treatment was well tolerated. Median immunoglobulin M (IgM) levels for all patients declined from 2,403 mg/dL (range 720-7639 mg/dL) to 1,525 mg/dL (range 177-5,063 mg/dL) after rituximab therapy (p = 0.001), with 8 of 30 (27%) and 18 of 30 (60%) patients demonstrating >50% and >25% decline in IgM, respectively. Median bone marrow lymphoplasmacytic (BM LPC) cell involvement declined from 60% (range 5-90%) to 15% (range 0-80%) for 17 patients for whom pre- and post-BM biopsies were performed (p < 0.001). Moreover, 19 of 30 (63%) and 15 of 30 (50%) patients had an increase in their hematocrit (HCT) and platelet (PLT) counts, respectively. Before rituximab therapy, 7 of 30 (23.3%) patients were either transfusion or erythropoietin dependent, whereas only 1/30 (3.3%) patients required transfusions (no erythropoietin) after rituximab. Overall responses after treatment with rituximab were as follows: 8 (27%) and 10 (33%) of the patients achieved a partial (PR) and a minor (MR) response, respectively, and an additional 9 (30%) of patients demonstrated stable disease (SD). No patients attained a complete response. The median time to treatment failure for responding (PR and MR) patients was 8.0 months (mean 8.4: range 3-20+ months), and 5.0 months (mean 6.1; range 3-12+ months) for patients with SD. These studies therefore demonstrate that rituximab is an active agent in WM. Marked increases in HCT and PLT counts were noted for most patients, including patients with WM who had MR or SD. A prospective clinical trial to more completely define the benefit of single-agent rituximab in patients with WM has been initiated by many of our centers.

Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin's lymphoma to apoptosis.

Treatment of patients with non-Hodgkin's lymphoma (NHL) is frequently hampered by development of chemoresistance. Rituximab is a chimeric mouse antihuman CD20 antibody that offers an alternative; however, its mechanism of action is not clearly understood. Treatment of lymphoma cell lines with Rituximab sensitizes the cells to the cytotoxic and apoptotic effects of therapeutic drugs, e.g., cisplatin, fludarabine, vinblastine, and Adriamycin. This study investigated the mechanism(s) involved in the reversal of drug resistance by Rituximab therapy. NHL cells synthesize and secrete antiapoptotic cytokines implicated in drug resistance, including interleukin (IL)-6, IL-10, and tumor necrosis factor alpha. We hypothesized, therefore, that sensitization by Rituximab may be due in part to modification of cytokine production. In this study, examination of cytokine secretion by NHL 2F7 tumor cells revealed down-regulation of IL-10 by Rituximab treatment. Moreover, cytotoxicity assays using exogenous IL-10 and IL-10-neutralizing antibodies demonstrated that IL-10 serves as an antiapoptotic/protective factor in these tumor cells against cytotoxic drugs. Furthermore, expression in 2F7 cells of the protective factor, Bcl-2, was shown to be dependent on IL-10 levels and down-regulated by Rituximab. Other gene products such as Bax, Bcl-x, Bad, p53, c-myc, and latent membrane protein-1 (LMP) were not affected by Rituximab treatment. Drug sensitization, as well as down-regulation of both IL-10 and Bcl-2, was corroborated in experiments using the NHL cell line 10C9. The Ramos and Daudi NHL cell lines were not sensitizable, nor did their Bcl-2 or IL-10 levels change. These studies demonstrate that one mechanism by which Rituximab sensitizes NHL to chemotherapeutic drugs is mediated through down-regulation of antiapoptotic IL-10 autocrine/paracrine loops and Bcl-2. The clinical relevance of these findings is discussed.

A randomized phase II study of amifostine used as stem cell protectant in non-hodgkin lymphoma patients receiving cisplatin-based salvage chemotherapy prior to stem cell transplant.

Stem cell mobilization may be inadequate in many lymphoma patients in need for autologous stem cell transplant (SCT). In this study, we sought to evaluate a potential role of amifostine as a stem cell chemoprotective agent in lymphoma patients receiving DHAP chemotherapy in preparation for high-dose chemotherapy (HDC) and stem cell transplant (SCT). In the beginning of the DHAP course, patients were randomized 1:1 to receive amifostine at 740 mg/m(2). Stem cells were mobilized with GCSF after the last cycle of DHAP. Stem cell collection started upon ANC recovery over 1000/mm(3). Standard 10 lt. apheresis daily with a goal of a minimum of 2 x 10(6) stem cells/kg were performed. Twenty-one patients have been enrolled; 10 received amifostine pretreatment (age, 20-64) and 11 were randomized to the control arm (age, 18-63). Prior chemotherapy was balanced in the two groups. The median number of DHAP treatments for each group was 2. Amifostine was well tolerated and was associated with higher stem cell collection. Toxicity and time to engraftment were comparable between the two groups. Our preliminary results may suggest a role of amifostine in protecting stem cells during salvage chemotherapy, thus facilitating stem cell collection.

Potentiation of fludarabine cytotoxicity on non-Hodgkin's lymphoma by pentoxifylline and rituximab.

BACKGROUND: Fludarabine has become a drug of prominent use in hematopoietic malignancies exhibiting indolent growth profiles. Some studies show, however, that nearly 50% of patients are fludarabine-resistant from the very onset of therapy. Others relapse after an initial response rarely lasting more than 2 years. For this reason, modulating agents have been considered for use with fludarabine to potentiate fludarabine cytotoxicity and circumvent drug resistance. The chimeric anti-CD20 monoclonal antibody, Rituximab (IDEC-C2B8), is used to treat patients with low grade and follicular B-cell non-Hodgkin's lymphoma. Rituximab is known to inhibit the cell progression of tumor B cells and to sensitize them to chemotherapeutic drugs. A slower cell progression may enhance the efficacy of fludarabine incorporation, thus increasing its cytotoxicity. Therefore, the use of fludarabine and Rituximab in combination could potentiate fludarabine cytotoxicity. The methylxanthine, pentoxifylline, disrupts DNA repair mechanisms within a cell by not allowing a cell to arrest at the G2/M checkpoint. By not allowing cells to repair fludarabine DNA incorporation, pentoxifylline was thought to increase fludarabine-induced cytotoxicity in tumor cells. We tested these hypotheses in vitro. MATERIALS AND METHODS: Analysis of cytotoxicity was performed using the XTT assay on tumor cell lines and patient samples. RESULTS: Tumor cell models, including two B-cell non-Hodgkin's lymphoma cell lines and a T-cell leukemia cell line, were shown to respond more effectively to fludarabine therapy in the presence of Rituximab or pentoxifylline. Two freshly derived B-cell chronic lymphocytic leukemia patient samples were also seen to exhibit a better response with a combination of fludarabine and pentoxifylline than with either alone. CONCLUSION: This study proves the hypothesis that Rituximab and pentoxifylline may provide a clinical approach to hinder the outgrowth of drug refractory tumor cells and achieve a longer period of remission.

A randomized phase 2 study of PBPC mobilization by stem cell factor and filgrastim in heavily pretreated patients with Hodgkin's disease or non-Hodgkin's lymphoma.

This randomized, controlled study compared the ability to mobilize and collect an optimal target yield of 5 x 10(6) CD34+ cells/kg using stem cell factor (SCF; 20 microg/kg/day) plus filgrastim (G-CSF; 10 microg/kg/day) vs filgrastim alone (10 microg/kg/day) in 102 patients diagnosed with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD), who were prospectively defined as being heavily pretreated. Leukapheresis began on day 5 of cytokine administration and continued daily until the target yield was reached, or until a maximum of five leukaphereses had been performed. Compared with the filgrastim-alone group (n = 54), the SCF plus filgrastim group (n = 48) showed an increase in the proportion of patients reaching the target yield within five leukaphereses (44% vs 17%, P = 0.002); reduction in the number of leukaphereses required to reach the target yield (P = 0.003); reduction in the proportion of patients failing to reach a minimum yield of 1 x 10(6) CD34+ cells/kg to proceed to transplant (16% vs 26%, P = NS); increase in the median yield of CD34+ cells per leukapheresis (0.73 x 10(6)/kg vs 0.48 x 10(6)/kg, P = 0.04); and an increase in the median total CD34+ cells collected within five leukaphereses (3.6 x 10(6)/kg vs 2.4 x 10(6)/kg, P = 0.05). All patients receiving SCF were premedicated (antihistamines and albuterol), and treatment was generally well tolerated. Five patients experienced severe mast cell-mediated reactions, none of which were life-threatening. In this study of heavily pretreated lymphoma patients, SCF plus filgrastim was more effective than filgrastim alone for mobilizing PBPC for harvesting and transplantation after high-dose chemotherapy.

Quinupristin/Dalfopristin therapy for infections due to vancomycin-resistant Enterococcus faecium.

The efficacy and safety of quinupristin/dalfopristin for treatment of infections due to vancomycin-resistant Enterococcus faecium were evaluated in 24 hospitalized patients with documented infections (19 bacteremias, 5 localized infections) caused by vancomycin-resistant E. faecium that was susceptible to quinupristin/dalfopristin in vitro. Patients received iv quinupristin/dalfopristin at a dosage of either 7.5 mg/kg every 8 h or 5 mg/kg every 8 h. A favorable clinical response (cure or improvement) occurred in 19 (83%) of 23 evaluable patients; bacteriologic eradication occurred in 17 (74%) of 23 evaluable patients. A favorable clinical response was observed in 12 (80%) of 15 patients who were treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h and in 7 (88%) of 8 patients treated with 5 mg/kg of quinupristin/dalfopristin every 8 h. Two of four treatment failures were associated with a decrease in the in vitro susceptibility of vancomycin-resistant E. faecium to quinupristin/dalfopristin. Superinfections developed in 6 patients (26%), but only one was caused by Enterococcus faecalis that was resistant to quinupristin/dalfopristin. Myalgias and arthralgias were the only adverse events related to quinupristin/dalfopristin. These conditions occurred in 8 (33%) of 24 patients and were dose-related (8 cases in 16 patients treated with 7.5 mg/kg of quinupristin/dalfopristin every 8 h, no cases in 8 patients treated with 5 mg/kg every 8 h). Mortality associated with vancomycin-resistant E. faecium infection was 17% (4 of 23 patients), whereas mortality from other causes was 52% (12 of 23 patients). These results suggest that quinupristin/dalfopristin is effective as treatment for vancomycin-resistant E. faecium infections in critically ill patients with serious underlying conditions. Except for myalgias and arthralgias at higher dosages, the drug is well-tolerated.

Excellent tolerance of rituximab when given after mitoxantrone/cyclophosphamide: an effective and safe combination for indolent non-Hodgkin's lymphoma.

Treatment for extensive indolent lymphoma should provide optimization of efficacy while avoiding excessive toxicity. Rituximab may be an ideal agent to combine with chemotherapy because of its lack of classical myelotoxicity. In this study, 27 patients with a variety of histologies of indolent B-cell non-Hodgkin's lymphoma have been treated utilizing a novel three-drug combination. Nine patients had relapsed disease and 18 were previously untreated. Patients first received cyclophosphamide 800 mg/m(2) and mitoxantrone 8 mg/m(2) i.v. on day 1, every 3 weeks for 2 cycles. Subsequently, patients received rituximab 375 mg/m(2) followed by mitoxantrone 8 mg/m2 every 2 weeks for 4 cycles. This regimen and, in particular, the rituximab infusion were extremely well tolerated. Only two of 27 patients experienced a grade 1/2, infusion-related reaction during the first rituximab infusion. Grade 4 neutropenia was noted at some point in 16 patients who were then offered granulocyte-macrophage colony-stimulating factor support for improvement of neutropenia. No infections were noted. Alopecia was minimal. Of 27 patients, 19 achieved a complete response (CR), one achieved an unconfirmed CR (CRu), and five patients achieved a partial response, for an overall response rate of 92.5%. Molecular remissions were noted in seven of 12 tested patients in CR. We concluded that the cyclophosphamide/mitoxantrone/rituximab (CyMiR) regimen is effective and extremely well tolerated. Furthermore, rituximab infusion-associated morbidity is markedly reduced.

Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma.

PURPOSE: Yttrium-90 ibritumomab tiuxetan (IDEC-Y2B8) is a murine immunoglobulin G1 kappa monoclonal antibody that covalently binds MX-DTPA (tiuxetan), which chelates the radioisotope yttrium-90. The antibody targets CD20, a B-lymphocyte antigen. A multicenter phase I/II trial was conducted to compare two doses of unlabeled rituximab given before radiolabeled antibody, to determine the maximum-tolerated single dose of IDEC-Y2B8 that could be administered without stem-cell support, and to evaluate safety and efficacy. PATIENTS AND METHODS: Eligible patients had relapsed or refractory (two prior regimens or anthracycline if low-grade disease) CD20(+) B-cell low-grade, intermediate-grade, or mantle-cell non-Hodgkin's lymphoma (NHL). There was no limit on bulky disease, and 59% had at least one mass > or = 5 cm. RESULTS: The maximum-tolerated dose was 0.4 mCi/kg IDEC-Y2B8 (0.3 mCi/kg for patients with baseline platelet counts 100 to 149,000/microL). The overall response rate for the intent-to-treat population (n = 51) was 67% (26% complete response [CR]; 41% partial response [PR]); for low-grade disease (n = 34), 82% (26% CR; 56% PR); for intermediate-grade disease (n = 14), 43%; and for mantle-cell disease (n = 3), 0%. Responses occurred in patients with bulky disease (> or = 7 cm; 41%) and splenomegaly (50%). Kaplan-Meier estimate of time to disease progression in responders and duration of response is 12.9+ months and 11.7+ months, respectively. Adverse events were primarily hematologic and correlated with baseline extent of marrow involvement with NHL and baseline platelet count. One patient (2%) developed an anti-antibody response (human antichimeric antibody/human antimouse antibody). CONCLUSION: These phase I/II data demonstrate that IDEC-Y2B8 radioimmunotherapy is a safe and effective alternative for outpatient therapy of patients with relapsed or refractory NHL. A phase III study is ongoing.