scholarly journals A Novel High Dose Chemotherapy Strategy with Bendamustine In Adjunct to Etoposide, Cytarabine and Melphalan (BeEAM) Followed by Autologous Stem Cell Rescue Is Safe and Highly Effective for the Treatment of Resistant/Relapsed Lymphoma Patients: a Phase I-II Study on 44 Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 31-31 ◽  
Author(s):  
Giuseppe Visani ◽  
Lara Malerba ◽  
Pietro Maria Stefani ◽  
Saveria Capria ◽  
Piero Galieni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Adverse Events ◽  
Phase I ◽  
Median Time ◽  
Conditioning Regimen ◽  
Median Number ◽  
High Dose ◽  
Stem Cell Rescue ◽  
Relapsed Lymphoma

Abstract Abstract 31 Background: BEAM (Carmustine, etoposide, cytarabine, and melphalan) regimen is the most used conditioning regimen before autologous stem cell transplant (ASCT) in lymphoma patients. However, patients receiving BEAM show a significant number of side effects, and relapse rate after transplant is still a matter of concern. Therefore, new regimens with a higher efficacy and a better toxicity profile in comparison to BEAM are highly needed. Aims: We designed a phase I-II study to evaluate the safety and the efficacy of increasing doses of Bendamustine for the conditioning regimen to ASCT for resistant/relapsed lymphoma patients. Methods: Forty-four patients (median age 47 years, range 18–70) with resistant/relapsed non-Hodgkin (29) or Hodgkin (15) lymphoma were consecutively enrolled in the study. The new conditioning regimen consisted of increasing doses of Bendamustine coupled with fixed doses of Etoposide (200mg/m2/day on days -5 to -2), Cytarabine (400mg/m2 on days -5 to -2) and Melphalan (140 mg/m2 on day -1) (BeEAM regimen). Three cohorts of 3 patients each were treated starting with Bendamustine 160 mg/m2/daily given on days -7 and -6. The dose of Bendamustine was then escalated according to the Fibonacci's increment rule until the onset of severe adverse events and/or the attainment of the expected MTD, but not higher than 200 mg/m2. Patients were carefully monitored for adverse events. The study was registered at EMEA with the EUDRACT no 2008–002736-15. Results: The administration of Bendamustine was safe in all the 3 cohorts of patients. The major side effect was a grade III-IV oral mucositis developed by 9 patients during neutropenia. We then fixed the dose of Bendamustine 200 mg/m2 as safe and effective for the Phase II study. A median number of 5.68×106CD34+/kg cells (range 2.4–15.5) collected from peripheral blood was reinfused to patients. All patients engrafted, with a median time to ANC>0.5×109/l of 10 days. Median times to achieve a platelet count >20×109/l and >50×109/l were 13 and 16 days respectively. Twenty-two out of 44 patients presented a fever of unknown origin (50%). The median number of days with fever was 2 (range: 0–7), with a median number of 9 days of intravenous antibiotics (range: 3–22). All patients received G-CSF after transplant for a median time of 9 days (range: 8–25). Two patients developed a viral infection (1 HSV-6, 1 CMV) early after transplant. Thirty-nine out of 44 patients are evaluable up to now for the response to treatment. All evaluable patients are alive. 32/39 are in complete remission whereas 4/39 are in partial response, after a median follow-up of 11 months from transplant. Three out of 39 patients relapsed after a median time of 3 months from transplant. It is of note that 4/39 patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell rescue. Conclusions: The new BeEAM regimen is safe and seems to have a high efficacy in heavily pretreated lymphoma patients. Basing on this experience, future studies incorporating Bendamustine in conditioning regimens pre-ASCT in lymphoma patients should use Bendamustine 200 mg/m2/day over 2 days. Acknowledgments: supported in part by AIL Pesaro Onlus. Disclosures: Malerba: celgene, Janssen-Cilag: Honoraria.

A novel High dose chemotherapy strategy with Bendamustine in Adjunct to Etoposide, Aracytin and Melphalan (BeEAM) Followed by Autologous Stem cell rescue in Resistant/Relapsed Hodgkin and Non-Hodgkin Lymphoma Patients: a Phase I Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4351-4351
Author(s):  
Giuseppe Visani ◽  
Lara Malerba ◽  
Piero Galieni ◽  
Claudio Giardini ◽  
Sadia Falcioni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conditioning Regimen ◽  
Median Number ◽  
High Dose ◽  
High Dose Therapy ◽  
Stem Cell Rescue ◽  
Relapsed Lymphoma ◽  
Autologous Stem Cell Rescue ◽  
Grade Iii

Abstract Abstract 4351 We designed a phase I study to evaluate the safety and the efficacy of increasing doses of Bendamustine, coupled with fixed doses of Etoposide, Cytarabine and Melphalan in the conditioning regimen to autologous stem cell transplant for resistant/relapsed lymphoma patients. Nine patients (median age 54 years, range 18-70) with resistant/relapsed non-Hodgkin's (6) or Hodgkin's (3) lymphoma were consecutive enrolled in the study, starting from August, 1st 2008. The new conditioning regimen (BeEAM) consisted of increasing doses of Bendamustine coupled with fixed doses of Etoposide (200mg/m2/day on days -5 to -2), Cytarabine (400mg/m2 on days -5 to -2) and Melphalan (140 mg/m2 on day -1) (BeEAM regimen). Three cohorts of three patients each were treated starting with Bendamustine 160 mg/m2 given on days -7 and -6. The dose of Bendamustine was then escalated according to the Fibonacci's increment rule until the onset of severe adverse events and/or the attainment of the expected maximum tolerated dose, but not higher than 200 mg/m2. Patients were carefully monitored for any adverse event, particularly for cardiotoxicity. Electrocardiography and troponin monitoring was performed at baseline and thereafter at 24, 72 and 96 hours after the two-days Bendamustine administration. The administration of Bendamustine was safe in all the three cohorts of patients. No grade III or IV non hematological toxicities were observed at any dose of the drug. In particular, we did not observe any grade III-IV cardiotoxicity. All patients engrafted, with a median time to ANC>0.5×109/l of 11 days (range: 11-27). Median times to achieve a platelet count >20×109/l and >50×109/l were 13 and 15 days respectively. Six out of 9 patients experienced an episode of FUO (66%), whereas 1/9 (11%) presented a bacteriemia. However, the median number of days with fever was 2 (range: 0-5), with a median number of 9 days of intravenous antibiotics (range: 3-22). All patients received G-CSF after transplant for a median time of 8 days (range: 8-24). At the time of writing all patients are alive and in complete remission, after a median follow-up of 5 months from transplant. It is of note that 2/9 patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell rescue. However, the small number of the patients and the short duration of follow-up might be taken in account when analyzing these preliminary data. In conclusion, the new BeEAM regimen is safe and seems to have a high efficacy in heavily pretreated lymphoma patients. Further studies are warranted to compare the efficacy of this new regimen with the conventional BEAM regimen for resistant/relapsed lymphoma patients submitted to ASCT. All the future studies who want to incorporate Bendamustine on such conditioning regimens for ASCT in lymphoma patients should use Bendamustine at a dose of 200 mg/m2 daily given overt 2 days. The study was conducted in accordance with the principles of the Helsinki Declaration, Good Clinical Practices and the current National Rules for conducting clinical studies. The study was registered at European Medicines Agency (EMEA) with the EUDRACT no 2008-002736-15. Acknowledgments We kindly acknowledge Mundipharma Italy and Mundipharma Europe for providing us the drug for the study free of charge. The study was supported in part by AIL Pesaro Onlus, Disclosures: Off Label Use: Bendamustine is used in adjunct to etoposide, cytarabine and melphalan in a novel strategy of high-dose therapy followed by autologous stem cell rescue.

scholarly journals BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients

Blood ◽  
2011 ◽  
Vol 118 (12) ◽  
pp. 3419-3425 ◽  
Author(s):  
Giuseppe Visani ◽  
Lara Malerba ◽  
Pietro Maria Stefani ◽  
Saveria Capria ◽  
Piero Galieni ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Phase 1 ◽  
Conditioning Regimen ◽  
European Medicines Agency ◽  
High Dose ◽  
Relapsed Lymphoma

AbstractWe designed a phase 1-2 study to evaluate the safety and the efficacy of increasing doses of bendamustine (160 mg/m2, 180 mg/m2, and 200 mg/m2 given on days −7 and −6) coupled with fixed doses of etoposide, cytarabine, and melphalan (BeEAM regimen) as the conditioning regimen to autologous stem cell transplantation for resistant/relapsed lymphoma patients. Forty-three patients (median age, 47 years) with non-Hodgkin (n = 28) or Hodgkin (n = 15) lymphoma were consecutively treated. Nine patients entered the phase 1 study; no patients experienced a dose-limiting toxicity. Thirty-four additional patients were then treated in the phase 2. A median number of 6 × 106 CD34+ cells/kg (range, 2.4-15.5) were reinfused. All patients engrafted, with a median time to absolute neutrophil count > 0.5 × 109/L of 10 days. The 100-day transplantation-related mortality was 0%. After a median follow-up of 18 months, 35 of 43 patients (81%) are in complete remission, whereas 6 of 43 relapsed and 2 of 43 did not respond. Disease type (non-Hodgkin lymphomas vs Hodgkin disease) and disease status at transplantation (chemosensitive vs chemoresistant) significantly influenced DFS (P = .01; P = .007). Remarkably, 4 of 43 (9%) patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell transplantation. In conclusion, the new BeEAM regimen is safe and effective for heavily pretreated lymphoma patients. The study was registered at European Medicines Agency (EudraCT number 2008-002736-15).

High Dose Zevalin (90Yttrium Ibritumomab Tiuxetan) Treatment with PBSC Support in Refractory-Resistant NHL Patients: Preliminary Results of a Phase I/II Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 488-488 ◽  
Author(s):  
Anna Vanazzi ◽  
Pierfrancesco Ferrucci ◽  
Mahila Ferrari ◽  
Liliana Calabrese ◽  
Marta Cremonesi ◽  
...  
Keyword(s):  
Phase I ◽  
Median Time ◽  
Dose Intensity ◽  
Median Number ◽  
Therapeutic Options ◽  
Clinical Activity ◽  
High Dose ◽  
Resistant Refractory ◽  
Duration Of Response ◽  
Heavily Pretreated

Abstract Therapeutic options are limited for resistant-refractory high-grade NHL pts not suitable to HDCT or for those pts relapsing after ABMT. Zevalin has been already demonstrated active in elderly pts with resistant-primary refractory DLBCL at dose of 0.4 mCi/kg, however duration of response is short. Increasing RIT dose intensity might improve efficacy. There are no data about the use of Zevalin at myeloablative dosage. We present feasibility and toxicity results of a phase I/II study of HD-Zevalin with PBSC support in resistant-refractory NHL pts. Three Zevalin dose-levels were fixed: 0.8, 1.2, 1.5 mCi/kg; from April 2004 to July 2005 12pts were enrolled, 4pts at each dose level. Median age was 66,5 ys (28–73), 83% male. All pts had stage III/IV at diagnosis; 7DLBCL; 3MCL, 1FL, 1transformed MZL. 7pts had received more than 3 previous CT regimens. All pts had received prior rituximab, 3pts RT, 6pts HD-CT. BM was negative in all pts before RIT. 1Week prior to Zevalin all pts underwent dosimetry and if no abnormal uptake was observed they received the planned dose. On Day −7 and 0 imaging and therapeutic doses were preceded by rituximab 250mg/mq. On Day13 pts were reinfused with PBSC previously harvested. On Day28 from reinfusion engraftment was considered to be delayed if WBC/ANC were<1.0x109/L or PLT<20x109/L. All pts engrafted promptly after PBSCT with median time to WBC/ANC>1.0x109/L and PLT>20x109/L of 19 (range 0–23) and 12 days (0–22) from PBSCT. PLT and ANC count nadirs were observed at 21 (0–24) and 25 (0–31) days after Zevalin with median values of 11x109/L(4–35) and 0.24x109/L(0.01–1.09). Median time to recovery from nadir was 16,5 days (4–175) for PLT and 17days (7–175) for ANC. 8pts required PLT transfusions, 4pts RBC transfusions; median number of PLT transfusions:1(1–4). No G-CSF was administered. No significant differences in terms of haematologic toxicity were observed among the 3 levels. No pulmonary, renal or cardiac toxicity was observed. 11/12 pts are now evaluable for response: 5pts experienced a CR (2 at 0.8mCi/kg, 2 at 1.2mCi/kg, 1 at 1.5mCi/kg), 1 pt receiving 1.5 mCi/kg a PR (ORR 50%); to date 4 pts maintain CR at 12, 11, 9 and 8 months after treatment. Conclusion: Zevalin at dosage higher than MTD is feasible with PBSC support. Even at dosage 4 times higher than standard, HD-Zevalin could be safely delivered in elderly and heavily pretreated pts, including those who previously received HD-CT. Clinical activity and mild treatment-related toxicities suggest that HD-Zevalin is an interesting modality treatment to be further investigated as an alternative therapeutic options for resistant-refractory NHL.

PEG-Filgrastim for Autologous Peripheral CD34+ STEM CELL Collection in Pediatric Oncological PATIENTS: A PHASE II STUDY.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2312-2312 ◽  
Author(s):  
Simone Cesaro ◽  
Gloria Tridello ◽  
Andrea Giulio Zanazzo ◽  
Stefano Frenos ◽  
Chiara Messina ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Conditioning Regimen ◽  
Median Number ◽  
Single Shot ◽  
Non Hodgkin Lymphoma ◽  
Oncological Patients ◽  
Low Weight ◽  
Long Acting ◽  
Stem Cell Collection

Abstract Pegfilgrastim (Peg-f) is the pegylated long-acting formulation of filgrastim that allows recovery from chemotherapy-induced neutropenia by single-shot administration. Data on adults show that Peg-f is safe and efficacy also in CD34+ peripheral blood stem cell collection. From May 2007 to July 2008, Peg-f was administered to 34 consecutive patients from 4 Italian pediatric centres at a dosage of 100 ug/kg (max 6 mg) for PBSC purposes. They were 21 male and 13 female, median age at diagnosis of 10 years (range 3–18), affected by solid tumour, 30 (Ewing, 9; Medulloblastoma, 5; Neuroblastoma, 5; brain tumours, 4; other, 7), acute lymphoblastic leukaemia or non-Hodgkin lymphoma, 4. The remission status at PBSC was: CR 8 (24%), VGPR 5 (15%), PR 19 (56%), SD or not known 2 (6%). The median weight was 35.5 kg (range 13.5–86) and the median number of planned infusion was 1, range 1–3. Different regimens of mobilizing chemotherapy were used, etoposide, cyclophosphamide and ifosphamide being the most frequent drugs administered. The median time to first PBSC was 10 days, range 6–15. The least threshold for CD34+ collection (20 cell/ul) was obtained in 28 of 34 patients (82%), the median value of CD34+ peak being 140 (range 20–1988). Successful PBSC was obtained in 27 patients (79%) because one very low weight child failed it for suboptimal vascular access. Sixteen of 27 patients (59%) achieved the target PBSC collection with 1 leukapheresis whilst 10 patients required a second leukapheresis. The median collection yield was 8 (range 1.9–116) and 2.45 (range 1–6) CD34+ x 106/kg) for the first and second leukapheresis, respectively. No Peg-f related adverse effects were reported. So far, 15 of 27 patients (56%) underwent a first autologous transplant whilst 4 and 1 underwent a second and third transplant, respectively. The median time from PBSC to first transplant was 64 days (range 10–154) and the median value of CD34+ x 106/kg infused was 7 (range 3–299). Different conditioning regimen were used, myeloablative doses of busulfan, thiothepa, melphalan, and etoposide being the drugs most frequently used. After a median f-up of 29 days from first transplant (range 16–176), all patients achieved a PMN count > 0.5 x 109/l in a median time of 13 days (range 5–23) whilst 14 and 12 achieved a transfusion-unsupported PLT count > 20 and > 50 x 109/l in a median time of 13 (range 5–23) and 15 days (range 12–36), respectively. Prophylactic post-transplant G-CSF was used in 7 of 15 patients (47%) for a median time of 7 days (range 1–11). All 5 patients who performed a second or third transplant successfully engrafted for PMN and PLT. All 15 transplanted patients were alive at latest f-up. We conclude that Peg-f single-shot CD34+ mobilisation is safe and efficacy also in pediatric patients. Further prospective studies are needed to investigate the non-inferiority or superiority of Peg-f vs. filgrastim in PBSC.

High-Dose Cyclophosphamide: An Effective Non-Transplant Salvage Option in Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4947-4947
Author(s):  
Sikander Ailawadhi ◽  
Michael Keng ◽  
Eddie Thara ◽  
Andrew Hendifar ◽  
Tanya Price ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Median Time ◽  
Clinical Benefit ◽  
Single Agent ◽  
Staging System ◽  
Median Number ◽  
High Dose ◽  
Advanced Stage ◽  
Stage Disease

Abstract Abstract 4947 Background Recent advances in the treatment of multiple myeloma (MM) have significantly improved overall survival. With MM patients living longer, there is a constant need to find better therapeutic options, especially when patients are refractory to conventional agents, and are not eligible for experimental therapeutics in clinical trials. We evaluated treatment with single-agent high-dose cyclophosphamide (HDCy) in a cohort of heavily pre-treated patients with relapsed/refractory MM. Methods All the patients were previously treated for active MM at the University of Southern California (USC), Los Angeles, CA. Cyclophosphamide was administered at 1.2 gm/m2 in D5W intravenous (IV) over 1 hour every 3 hours for a total of 4 doses. Mesna was given to prevent urinary adverse events from cyclophosphamide as 4 gm/m2 in 1000 ml D5W IV to run at 50 ml/hr for 20 hours, starting 15 minutes prior to the first dose of cyclophosphamide. Patients were given pre-medications with 5HT3 antagonists an steroids. Treatment was administered in the in-patient setting and patients were discharged after the last dose of cyclophosphamide. Treatment was repeated every 4 weeks, if well-tolerated and continued response. Growth factor support was provided to the patients, as needed. Response to treatment was assessed after each 4-week cycle according to the International Uniform Response Criteria for MM. Results Seven patients (4 females, 3 males) were treated on this regimen with a median age of 53 years (range 34-61 yrs). These patients included 3 Hispanics (43%), 2 Asians (29%), 1 Caucasian (14%) and 1 African-American (14%). MM subtype was IgG disease in 3, IgA in 2, and light-chain only in 2 patients. Advanced stage disease (>stage 1) at the time of diagnosis as per the Durie Salmon (DS) staging system was present in 71% of the patients, while 3 patients (43%) had advanced stage disease as per the International Staging System (ISS). Four patients (57%) had lytic bone disease at the time of diagnosis, while only 1 patient was a non-secretor. Five of these patients (71%) never received an autologous stem cell transplant (ASCT) as a part of their MM treatment. Median number of therapies in these patients was 5 (range 4-8), while median number of therapies prior to high-dose cyclophosphamide (HDCy) were 3 (range 2-7). Median number of cycles of HDCy administered to the patients was 2 (range 1-5). Overall Response Rate (ORR = CR+PR) was 29% (n=2) with 1 patient achieving CR and 1 patient achieving VGPR. Four patients (57%) had stable disease (SD) and 1 patient had progressive disease (PD). Thus, the overall clinical benefit (CR+PR+SD) was seen in 6 out of the 7 patients (86%). Median time to best response was 5 weeks (range 4-10 weeks). Median time to progression was 16 weeks (range 8-24 weeks). Most common adverse events were cytopenias and fatigue, but were easily manageable with supportive care on an out-patient basis. Conclusions Despite improvement in therapeutic regimens for MM, it remains an incurable disorder. There is a constant need to develop regimens for treatment of relapsed/refractory MM patients that are efficacious and well-tolerated. We report the use of single-agent HDCy in heavily pre-treated MM patients. Despite the small number of patients studied, we have noted meaningful clinical benefit with a manageable toxicity profile. This warrants further investigation into developing therapeutic regimens with high-dose cyclophosphamide. Disclosures No relevant conflicts of interest to declare.

High dose chemotherapy with autologous stem cell rescue (ASCR) for recurrent medulloblastoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 11507-11507
Author(s):  
B. Diez ◽  
M. Garcia Lombardi ◽  
G. Chantada ◽  
C. Dengra ◽  
D. Fernandez Sasso ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Time ◽  
Area Under The Curve ◽  
High Dose Chemotherapy ◽  
Local Relapse ◽  
High Dose ◽  
Term Survival ◽  
Stem Cell Rescue ◽  
Autologous Stem Cell Rescue

11507 Background: Medulloblastoma is a highly lethal disease when it recurs and very few patients survive with conventional treatment. This study evaluated the use of high-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue (ASCR) in patients with recurrent medulloblastoma. Methods: Between 8/97 and 8/05 14 patients (M/F 12/2) with recurrent medulloblastoma, aged 2 to 33 years (median, 10.5 years) at ASCR, were treated. Thirteen had relapsed after chemotherapy and craniospinal + posterior fossa irradiation and one after chemotherapy (Baby POG) at a median time of 19 months (7 to 148). One had a local relapse and 13 had dissemination at relapse (M1: 1, M2: 7 and M3: 5) Chemotherapy consisted of carboplatin 500 mg/m2 (or area under the curve = 7 mg/ml × min via Calvert formula) on days −8, −7, −6; and thiotepa 300 mg/m2 and etoposide 250 mg/m2 on days −5, −4, and −3 respectively; followed by ASCR on day 0. Results: Four patients died of treatment-related toxicities at 0, +23, +42 and +51 days post ASCR (bacterial sepsis in 2, CMV infection in 1 and CNS hemorrhage in 1). It should be remarked that all the toxic deaths were observed in patients auto grafted before October 2000. Five of 14 patients (35%) are event-free survivors at a median of 70 months post-ASCR (range: 5 to 86 months). Tumor recurred in the remaining 5 patients at a median time of 2 months post ASCR (2 to 15). All died at +23, +16, +12, +9 and +4 month post ASCR. Conclusions: Our results seem consistent with those published by Dunkel IJ (J. Clin Oncol; 16:222 - 8 1998) and argue about the efficacy of high dose chemotherapy with ASCR to provide long-term survival for some patients with recurrent medulloblastoma. No significant financial relationships to disclose.

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