BCNU, Etoposide, Cytarabine And Melphalan Research Articles

Toxicity Profile According to Etoposide and Cytarabine Dosing in Patients with Lymphoma Receiving Autologous Stem Cell Transplantation Following BEAM Conditioning.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is part of the treatment strategy for some patients with high-risk lymphoma by improving survival with an acceptable toxicity profile. Although the BEAM (BCNU, etoposide, cytarabine, and melphalan) intensification regimen is the most used, the optimal dosing for each drug is unclear. Here, we retrospectively compared the outcome of 110 patients receiving higher (400mg/m2, n = 69) or lower (200mg/m2, n = 41) etoposide and cytarabine doses in our institution between 2012 and 2019. Patients in the BEAM 200 group experienced less toxicity with reduced fever duration (P < 0.001), number of platelet transfusions (P = 0.008), antibiotic duration (P < 0.001), antifungal therapy (P < 0.001), and mucositis (P < 0.001) whereas length of stay, admission to the intensive care unit, and in-hospital mortality were not different between groups. Progression-free survival (PFS) was non-significantly lower in the BEAM 200 group (36-month PFS, 68% vs. 80%, P = 0.053) whereas OS was similar between the two groups (36-month OS, 87% vs. 91%, respectively, P = 0.12). Albeit a non-significant reduction in PFS, BEAM 200 conditioning intensity was associated with a reduced toxicity profile.

BeEAM conditioning regimen is a safe, efficacious and economical alternative to BEAM chemotherapy

In many stem cell transplant centres, BCNU, etoposide, cytarabine and melphalan (BEAM) high-dose chemotherapy (HDCT) has been replaced by the more economic and available bendamustine, etoposide, cytarabine, melphalan (BeEAM) regimen. However, there is a paucity of information on the efficacy and safety of BeEAM HDCT. We describe our experience with BeEAM HDCT in terms of safety, efficacy and cost-savings. We compare overall and progression-free survival to a cohort of patients previously transplanted at our institution with the older BEAM regimen. We performed a retrospective chart review of 41 lymphoma patients undergoing BeEAM HDCT at the Royal University Hospital in Saskatoon, Saskatchewan between 2015 and 2019 to elicit regimen safety in the first 100 days post-transplant. Furthermore, we calculated overall and progression-free survival and constructed corresponding Kaplan–Meier curves, comparing the results to a historical cohort of BEAM patients (n = 86). Finally, we conducted an economic analysis using the financials available at our centre’s pharmacy. With regards to BeEAM HDCT, we report a 100-day transplant-related mortality of 2.4%. Additionally, we report acceptable rates of typhlitis (27%), grade III–IV mucositis (4.9%) and grade III–IV nephrotoxicity (2.4%). In terms of overall and progression-free survival, we found no statistical difference between BeEAM and BEAM (p = 0.296; 0.762, respectively). Finally, our economic analysis revealed a net savings of $21,200 CAD per transplant when BeEAM is used in replacement of BEAM. The acceptable safety profile of BeEAM and its comparable efficacy to BEAM are encouraging for the perseverance of this cost-effective HDCT regimen.

Long-Term Clinical and Molecular Remissions in Patients with Follicular Lymphoma (FL) Following High-Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT)

Background: Long-term clinical and molecular remissions in patients with FL following HDT and ASCT have been evaluated in only a few studies. Results are especially limited for second-line HDT with BEAM (BCNU, etoposide, cytarabine and melphalan). Patients and methods: 73 patients with FL were treated in our institution from 1993 to 2016 (20 1st-line ASCT with total body irradiation (TBI) and cyclophosphamide, 46 2nd-line with BEAM and 8 ≥3rd-line with BEAM). Patients with high-grade transformation before ASCT were excluded. The data were collected retrospectively in 44 and prospectively in 29 patients who participated in two clinical trials: the 1st-line therapy trial of the German Low Grade Lymphoma Study Group (GLSG, principal investigator W. Hiddemann [Lenz G, Blood 2004]) and the salvage therapy LYM1 trial of the EBMT [Pettengell R, JCO 2013]. For the salvage ASCT protocol, most of the patients received 3 - 4 courses of the ESHAP or ICE protocol-since 2001, also usually combined with rituximab. Stem cell apheresis was carried out in the Blood Transfusion Service following these protocols or cyclophosphamide, usually in remission. Patients with partial remission after ASCT received a radiotherapy (RT) with 30-36 Gy in the field of persisting lymphoma, if possible, except participants of the LYM1 trial. Further details are described in an earlier publication of our first 60 patients (Metzner B, Ann Oncol 2013). Response assessment was performed by careful clinical examination (with ultrasound, chest x-ray and partly CT) at regular 3 - 12 monthly time points. In the case of long-term remission (≥ 8 years; n = 26), peripheral blood was tested for minimal residual disease by quantitative t(14;18) RQ-PCR and/or IGH-consensus PCR (n = 25). Results: With a median follow-up of 9.4 years (range 1.2-23.8) 10-year overall survival, progression-free survival and freedom from progression (FFP) after 1st-line ASCT were 80%, 60% and 68%, after 2nd-line ASCT 58%, 37% and 42%, after ≥3rd-line ASCT 50%, 25% and 25%, respectively, with a significant difference for OS, PFS and FFP between 1st-line and ≥3rd-line cohort, for PFS and FFP between 1st- and 2nd-line cohort (p<0.05). The median OS from the initial diagnosis for the 1st-line cohort and the 2nd-line cohort was not yet reached (estimated >23 years); and 9.4 years for the ≥3rd-line cohort; for a subgroup of the 2nd-line cohort with early relapse (time from diagnosis to 1st relapse maximum 24 months, n = 26) not yet reached (estimated >21 years). Ten-year FFP for 2nd-line ASCT and low-risk FLIPI score (n = 16) was 69%, intermediate risk (n = 11) 27% and high risk (n = 18) 29% (p=0.051). No relapses occurred after 8 years following ASCT in 1st or 2nd remission (except one patient 10 years after ASCT). So far, 26 patients developed long-term remissions of at least 8 years (up to 24, median 14 years). 24 of the 25 tested long-term remission patients were MRD-negative at the last follow-up. One patient was MRD-positive (low-level MRD) at the last control (10.6 years after ASCT in 1st line, unchanged as the years before). Five-year non-relapse mortality was 0%. Four of 73 patients developed secondary invasive malignancies in remission after ASCT: in the TBI cohort, 2 of 20 patients; in the BEAM cohort, 2 of 53 patients, (in the 2nd-line ASCT cohort 1 of 45 patients). Conclusion: Sustained long-term clinical and molecular remissions up to > 22 years can be achieved following ASCT in 1st or 2nd treatment line, indicating the potential curative impact of ASCT in FL. [Display omitted] DisclosuresPott:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Comparison of the BEAM and MITO/MEL Conditioning Regimens for Autologous Hematopoietic Stem Cell Transplantation in Hodgkin Lymphoma: An Analysis of Efficiency and Treatment-Related Toxicity

BackgroundApproximately half of patients with relapsed chemosensitive disease achieve robust responses with BEAM (BCNU, etoposide, cytarabine, and melphalan) and autologous stem cell rescue. The scarcity of comparative studies further limits alternative treatment protocols, such as the MITO/MEL (mitoxantrone, melphalan) protocol. Patients and MethodsIn this retrospective multicenter study, we compared the BEAM and MITO/MEL regimens used before autologous hematopoietic stem cell transplantation (ASCT) in terms of efficacy and side effects in patients with Hodgkin lymphoma. Data met international accreditation rules. Before ASCT, 108 patients received the MITO/MEL, and 34 patients received the BEAM. ResultsThe median follow-up time was 36 months in the MITO/MEL group (range, 3-178) and 23 months in the BEAM group (range, 4-99). After ASCT, the 3-year expected overall survival and disease-free survival rates were 86.1% and 86.1% for the MITO/MEL group and 91.3% and 76.5% for the BEAM group, respectively. Although 50% of patients developed febrile neutropenia attacks in the MITO/MEL group, this rate was 91.1% in the BEAM group. The grade II and higher rates of hepatic, renal, gastrointestinal, and cardiac toxicities were similar in both groups. However, the rate of pulmonary toxicity was determined to be 1.9% in the MITO/MEL group and 29.4% in the BEAM group (P < .001). ConclusionThe MITO/MEL conditioning regimen seems to be as effective as the BEAM regimen but has better tolerability in terms of pulmonary toxicity and may be used as an alternative option if necessary, depending on the comorbidity status of the patient.

A Phase I Trial of Venetoclax in Combination with BEAM Conditioning Chemotherapy (V-BEAM) with Autologous Stem Cell Transplantation in Non-Hodgkin Lymphoma

Background: High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is a standard treatment both as consolidation after induction chemotherapy and as second-line therapy depending on the histologic subtype of NHL. BEAM (BCNU, etoposide, cytarabine, and melphalan) is a commonly used conditioning regimen for NHL but often fails to produce durable remission, likely due to inherent chemoresistance. Many B-cell NHL subtypes including diffuse large B-cell lymphoma and double-hit lymphoma are resistant to chemotherapy-induced apoptosis by overexpression of Bcl-2. Venetoclax is an orally administered selective Bcl-2 inhibitor with significant single agent activity in CLL and mantle cell lymphoma. In addition, the efficacy of venetoclax is potentiated by combination with rituximab [Seymour 2018, Kater 2018] and multiple lines of preclinical data show synergistic efficacy with a range of both novel and conventional antineoplastic agents [Johnson-Farley 2015, Li 2015]. Study Design and Methods: This is a single arm, open-label, dose-escalation phase I trial to evaluate the safety of venetoclax in combination with BEAM (V-BEAM) conditioning chemotherapy. Key inclusion criteria include patients with pathologically confirmed NHL, regardless of specific histology, who have received one prior systemic therapy and are eligible for and proceeding with HDCT followed by ASCT. The trial employs a standard 3+3 cohort-based dose escalation design of venetoclax (800 mg daily days -7 through -6 on dose level 1, 800 mg daily days -7 through -5 on dose level 2, 800 mg daily days -7 through -4 on dose level 3, 800 mg daily days -7 through -3 on dose level 4, and 800 mg daily days -7 through -2 on dose level 5) with standard doses of BEAM followed by ASCT. The primary objectives are to assess safety, describe dose-limiting toxicities, engraftment of stem cells and to identify the recommended phase II dose. Secondary objectives include evaluation of progression-free survival (PFS) and overall survival (OS) compared to historical controls treated with BEAM as part of ASCT. Neutrophil and platelet engraftment will be estimated with cumulative incidence and compared to controls with Gray test. OS and PFS will be estimated with Kaplan-Meier and compared to controls with the log-rank test. As of 8/1/2019, the first dosing cohort of 3 patients have been enrolled and successfully completed study treatment. There are 3 patients in screening to be enrolled in dose level 2. Additional accrual will be presented at the time of the meeting. Clinical trial information: NCT03713580. Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau. Gerds:Celgene Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Roche: Research Funding; Imago Biosciences: Research Funding. Majhail:Nkarta: Consultancy; Atara Bio: Consultancy; Mallinckrodt: Honoraria; Incyte: Consultancy; Anthem, Inc.: Consultancy. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. OffLabel Disclosure: Our trial in progress is investigating the use of venetoclax in combination with BEAM conditioning chemotherapy prior to autologous stem cell transplantation. Venetoclax is not currently approved in this setting.

Phase II Study of Yttrium-90 Ibritumomab Tiuxetan Plus High-Dose BCNU, Etoposide, Cytarabine, and Melphalan for Non-Hodgkin Lymphoma: The Role of Histology

Standard-dose 90yttrium-ibritumomab tiuxetan (.4 mci/kg) together with high-dose BEAM (BCNU, etoposide, cytarabine, and melphalan) (Z-BEAM) has been shown to be a well-tolerated autologous hematopoietic stem cell transplantation preparative regimen for non-Hodgkin lymphoma. We report the outcomes of a single-center, single-arm phase II trial of Z-BEAM conditioning in high-risk CD20+ non-Hodgkin lymphoma histologic strata: diffuse large B cell (DLBCL), mantle cell, follicular, and transformed. Robust overall survival and notably low nonrelapse mortality rates (.9% at day +100 for the entire cohort), with few short- and long-term toxicities, confirm the safety and tolerability of the regimen. In addition, despite a high proportion of induction failure patients (46%), the promising response and progression-free survival (PFS) rates seen in DLBCL (3-year PFS: 71%; 95% confidence interval, 55 to 82%), support the premise that the Z-BEAM regimen is particularly effective in this histologic subtype. The role of Z-BEAM in other strata is less clear in the context of the emergence of novel agents.

Radioimmunotherapy-Based Conditioning with Yttrium-90 Ibritumomab Tiuxetan Plus High Dose BEAM for Non-Hodgkin Lymphoma: Does the Regimen Matter?

Background: High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) has played an important role in the treatment of relapsed or refractory non-Hodgkin lymphoma (NHL). Several studies demonstrate that standard-dose 90Y ibritumomab tiuxean (0.4 mci/kg) (Zevalin) plus high-dose BEAM (BCNU, etoposide, cytarabine, and melphalan) (ZBEAM) is a well-tolerated HCT preparative regimen. Herein we report the outcomes of a prospective single-arm phase II study of ZBEAM conditioning in three CD20+ NHL histologic strata: mantle cell (MCL), diffuse large B cell (DLBCL), and follicular (FL)/transformed (TF). The study was designed to detect a 20% improvement in PFS, within each stratum, over historical rates for BEAM alone at 2-years post HCT with ~80% power, α=0.05.Patients and Methods: Patients with histologically confirmed CD20+ MCL, DLBCL, FL, or TF were eligible if they failed induction therapy, had relapsed disease or poor risk disease (Table 1). Patients with DLBCL or FL were classified as poor risk if they failed to achieve a complete response after induction chemotherapy or had high-/high-intermediate-risk features per the age-adjusted International Prognostic Index (IPI) at diagnosis. All MCL and TF lymphomas were considered poor risk, including those in first remission.Results: The median follow-up for surviving patients: 43 months (range: 3-79). The estimated PFS and overall survival (OS) probabilities at 3 years were between 47-75% and 82-91%, respectively (Table 2); non-relapse mortality (NRM) was <1% overall. Adverse events ≥ grade 3 within the first 100-days included grade 3 infection (n=8) per CTCAE 3.0, grade 3 GI toxicity (n=1) per Bearman Toxicity Scale and grade 4 infection (n=1) per CTCAE 3.0.Conclusion: Across histologies, high OS and low NRM confirm the safety and tolerability of the regimen, while improvements in 2-year PFS compared to historical controls in DLBCL and MCL are notable1-4 leading us to conclude that, in the case of MCL and DLBCL, RIT based conditioning improves outcome compared to high dose chemotherapy alone. The strikingly high PFS within the DLBCL subgroup, even though this strata had the highest percentage of induction failure patients serve as a basis for an ongoing multinational randomized phase III trial comparing ZBEAM to BEAM for the treatment of relapsed/ IF DLBCL.Table 1Patient and Disease Characteristics (#/% or median/range)VariableAll N = 116MCL N = 32DLBCL N = 46FL N = 20TF N = 18Disease status at HCT 1st complete remission 1st partial remission 1st relapse 2nd complete remission ≥3rd complete remission Induction failure29 (25) 7 (6) 20 (17) 20 (17) 3 (3) 37 (32)23 (72) 4 (13) 0 (0) 1 (3) 0 (0) 4 (13)4 (9) 1 (2) 8 (17) 12 (26) 0 (0) 21 (46)0 (0) 1 (5) 6 (30) 4 (20) 1 (5) 8 (40)2 (11) 1 (6) 6 (33) 3 (17) 2 (11) 4 (22)Prior regimens2 (1-7)1 (1-3)2 (2-7)3 (1-4)2 (1-3)Age at transplant, yr57 (23-75)60 (43-72)48 (23-75)57 (43-67)58 (41-65)Maintenance rituximab No Yes N/Aa103 (89) 12 (10) 1 (1)23 (72) 9 (28) 0 (0)44 (96) 2 (4) 0 (0)20 (100) 0 (0) 0 (0)16 (89) 1 (6) 1 (6)Abbreviations: MCL, mantle cell lymphoma; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; TF, transformed lymphoma; HCT, hematopoietic cell transplantation; N/A, not available. a) The follow-up time for 1 patient had not reached Day +30 post-HCT at the time the analytical data were locked.Table 2Outcomes, % (95% CI)AllbN = 115MCL N = 32DLBCL N = 46FL/TF, combinedbN = 20/17, 37BEAM, historical estimates: 2-yr PFSN/A354545/35, 40ZBEAM, trial estimates: 2-yr PFS70 (61-78)78 (57-89)78 (62-87)54 (30-73)/57 (31-77), 56 (38-70)3-yr PFS66 (56-74)69 (54-79)75 (63-83)47 (36-58)/57 (42-70), 52 (35-67)3-yr OS85 (77-91)91 (72-98)83 (70-90)85 (65-94)/82 (60-92), 83 (67-92)Abbreviations: PFS, progression-free survival; OS, overall survival. b) At the time of abstract submission, the follow-up time for 1 of the 116 patients was not sufficient for outcomes to be reported (<100 days post-HCT).References 1) Mills W, et al. J Clin Oncol 1995;13:588-595. 2) Shimoni A, et al. Cancer 2012;118:4706-4714. 3) Kolstad A et al. Blood 2014;123:2953-2959. 4) Berger MD et al. Hematol Oncol 2015; doi:10.1002/hon DisclosuresKrishnan:celgene: Consultancy, Equity Ownership, Speakers Bureau; millennium: Speakers Bureau; onyx: Speakers Bureau; jannsen: Consultancy; jazz: Consultancy; spectrum: Consultancy. Off Label Use: Zevalin combined with BEAM. Nademanee:Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics Inc.: Research Funding; Spectrum: Research Funding. Chen:Genentech: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Other: Travel expenses, Research Funding, Speakers Bureau; Millennium: Consultancy, Research Funding, Speakers Bureau. Forman:Mustang: Research Funding; Amgen: Consultancy.

BEAM Conditioning Regimen Has Higher Toxicity Compared With High-Dose Melphalan for Salvage Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma.

Salvage autologous stem cell transplantation (ASCT) is increasingly used for eligible patients with multiple myeloma (MM) for progress after conventional chemotherapy. We recently used BEAM (BCNU, etoposide, cytarabine, and melphalan) conditioning for patients with myeloma receiving salvage ASCT whose disease progressed after a first ASCT with high-dose melphalan (HDM). We report safety and efficacy of BEAM salvage ASCT in MM in comparison with HDM-based salvage ASCT. Between 2008 and 2013, 43 consecutive patients received salvage ASCT for MM (19 with HDM; 24 with BEAM). The BEAM group had a higher incidence of infections, intensive level of care, and fever (19 vs. 13 patients; P = .02), whereas the melphalan group had a higher incidence of mucositis (7 vs. 2 patients; P = .03). Other toxicities were not different. There was no significant difference in disease status and response rate before and after salvage ASCT between the 2 groups. The median time of follow-up after salvage ASCT was 5 and 9 months and the median progression-free survival (PFS) times were 7.7 and 12.1 months (P = .82) for BEAM and melphalan, respectively. BEAM seemed to be associated with higher toxicity with comparable efficacy to HDM ASCT. Longer follow-up is needed to determine whether there is any significant difference in PFS between the 2 groups.

Excess Late Gastrointestinal Toxicity Associated with Leam Conditioning Compared to BEAM for Autologous Stem Cell Transplantation in Lymphoma, a Single Institution Experience

IntroductionA standard conditioning regimen for patients undergoing autologous stem cell transplant (ASCT) for relapsed/refractory lymphoma in Europe has consisted of BCNU, etoposide, cytarabine and melphalan (BEAM).BCNU has not been readily available for several years. Thus, in our institution, since August 2008 it has been substituted by oral lomustine (LEAM). There is very limited information on the relative toxicities of the two regimes, and to address this we undertook a retrospective analysis of two comparable groups of transplant patients, to assess the relative toxicity profiles.Methods and PatientsTwo cohorts of 50 patients undergoing ASCT for relapsed/refractory lymphoma were compared, one conditioned with BEAM (BCNU 300mg/m2, etoposide 1600mg/m2 (in divided doses), cytarabine 800mg/m2 (in divided doses) and melphalan140mg/m2 and the other with LEAM (lomustine 200mg/m2 instead of BCNU).Table 1:Patient CharacteristicsLEAMBEAMp-valueNumber of patients5050Time period coveredAugust 2008 – June 2013Dec 1999 – Sept 2011Age at Transplant (Median, mean, 95% CI)52.5; 49.3 (45.9 to 52.6)51; 48.4 (45.0 to 52.0)0.73Male (Number, Proportion)30 (60%)24 (48%)0.32Diagnosis (n) – DLBCLHLFL19 15 1620 16 14Pre-SCT GFR (ml/min) (Median, mean, 95% CI)108, 107 (96.6 to 118.2)87,91.1 (81.4 to 100.8)0.03Stem Cell Dose ; CD34x106;kg (Median, mean 95% CI)2.7, 4.7 (2.76 to 6.6)2.6, 4 (3.0 to 5.0)0.7PET Positive Pre-SCT (Number, Proportion)14 (38%)18 (40%)0.52Toxicities were assessed for each cohort, using the nursing and medical notes, according to CTCAEv3.0 criteria: nausea, vomiting, stomatitis and diarrhoea, alanine liver transaminase (ALT) for hepatic toxicity and creatinine for renal toxicity. Surrogate markers for mucosal toxicity were also assessed, such as use of anti-diarrhoeals, opiates and syringe-driver anti-emetics.ResultsThe unpaired t-test was used for continuous variables and Fisher’s exact test for categorical values.Table 2LEAMBEAMp-valueLength of Admission (Days) (Median; Mean; 95% CI)23; 26.7 (21.7 to 31.7)23; 25.4 (23.3 to 27.6)0.63ICU Admission (Number, Proportion)8 (16%)4 (8%)0.36Deaths2 (4%)1 (2%)0.68Leucocytes >1.0 (day) (Median; Mean; 95% CI)11; 10.6 (10.2 to 10.9)11; 11.2 (10.6 to 11.9)0.12Neutrophils >0.5 (day) (Median; Mean; 95% CI)11; 10.8 (10.4 to 11.2)11; 11 (10.4 to 11.6)0.56Platelets >20.0 (day) (Median ;Mean; 95% CI)12; 12.7 (11.5 to 14.0)12; 14.1 (12.0 to 16.2)0.25TOXICITYDiarrhoea Duration (Days) (Median; Mean; 95% CI)12; 14 (10.9 - 17.11)10.5; 11.5 (9.6 - 13.4)0.17Anti-Diarrhoeal Use (n, proportion)35 (75%)38 (76%)0.66Opiate Use (n, proportion)35 (70%)30(60%)0.4Syringe Driver Antiemetic Use (n, proportion)19 (38%)21 (42%)0.84GI symptoms at 2 Weeks - (n, proportion)28 (67%)23 (52%)0.060GI Symptoms at 3 Months (n, proportion) à17(41%)7 (14%)0.001Alive in CR at 3 Months – (n, proportion) º45 (96%)45 (98%)0.688 LEAM + 5 BEAM patients were not evaluable 2 weeks post discharge.à9 LEAM + 8 BEAM patients were not evaluable at 3 months.º47 LEAM and 46 BEAM patients assessable at 3 months.There was minimal non-relapse mortality in both cohorts, with 2 early deaths with LEAM (at D+6 and D+8 respectively) and 1 early death with BEAM (day +7) all secondary to neutropenic sepsis.As expected, significant mucosal toxicity was seen with both regimens, with 51% of patients having at least grade 3 diarrhoea, and approximately 30% having grade 3 stomatitis. There was no statistically significant difference in any of the toxicity parameters measured between the 2 regimens during the inpatient admission. The finding of a statistically significant excess of GI toxicity with LEAM at 3 months (mainly residual abdominal pain and diarrhoea) was not expected, and was not seen when assessed at an earlier time point (2 weeks post discharge).Both regimens were associated with minimal hepatic and renal toxicity.ConclusionsThere appears to be an excess of late gastrointestinal toxicity associated with the LEAM regimen. However, this toxicity was not associated with a difference in time to engraftment and there was no detectable difference in non-relapse mortality. The cause of this GI toxicity signal is unclear, and requires confirmation and further investigation. There also appears to be no difference in clinical outcomes, however longer follow-up of patients conditioned with LEAM is required to confirm this finding in a more robust manner. DisclosuresNo relevant conflicts of interest to declare.

Long-term clinical and molecular remissions in patients with follicular lymphoma following high-dose therapy and autologous stem cell transplantation

BackgroundLong-term clinical and molecular remissions in patients with follicular lymphoma (FL) following high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) have been evaluated in only a few studies. Results are especially limited for second-line HDT with BEAM (BCNU, etoposide, cytarabine and melphalan). Patients and methodsSixty patients with FL received ASCT in our institution (18 first-line with total body irradiation and cyclophosphamide, 34 second-line with BEAM and 8 ≥third-line with BEAM). In the case of long-term remission (>6 years; N = 17), peripheral blood was tested for minimal residual disease by t(14;18)- and IGH-PCR. ResultsTen-year overall survival, progression-free survival and freedom from progression (FFP) after first-line ASCT were 79%, 57% and 64% after second-line ASCT 41%, 35% and 42%, respectively. Prognostic factors for FFP were treatment line and FLIPI (Follicular Lymphoma International Prognostic Index). Ten-year FFP for second-line ASCT and low-risk FLIPI was 57%, intermediate risk 37% and high risk 33%. No relapses occurred after 6 years following ASCT. Sixteen patients developed sustained long-term clinical and molecular remissions of up to 17.5 years. ConclusionSustained long-term clinical and molecular remissions can be achieved following ASCT, including HDT with BEAM in second line.

Outcomes of Eam Conditioned Autologous Haematopoietic Stem Cell Transplantation for Lymphoma. A Matched Pairs Retrospective Single Centre Study Analysis.

AbstractAbstract 3088 Background:High dose chemotherapy followed by autologous stem cell rescue is superior to salvage chemotherapy alone in relapsed Hodgkin's Lymphoma (HL) and Non-Hodgkin's lymphoma (NHL). A commonly used regimen is BEAM (BCNU, Etoposide, Cytarabine and Melphalan). Unfortunately, BCNU is associated with potentially lethal pulmonary interstitial toxicity, in a dose dependent manner. Therefore, it is often omitted in conditioning regimens for patients who have pre-existing impaired lung function. We aimed to determine the outcomes of patients given this EAM (Etoposide, Cytarabine, Melphalan) schedule in our centre. Method:At our unit, from 2000–2010, 338 patients had been transplanted with BEAM conditioning and 23 patients with an EAM regimen. BEAM chemotherapy involved cumulative doses of BCNU at 300 mg/m2, etoposide at 800 mg/m2, cytarabine at 1600 mg/m2 and melphalan at 140 mg/m2. The EAM regimen was the same, except for the omission of BCNU. We wanted to compare overall survival, event free survival and transplant related mortality between the two groups of patients. A matched-pair analysis based on age and sex on a 1:1 basis was conducted. Survival rates were estimated by the Kaplan-Meier method. Differences between the survival distributions were compared with the log-rank test. Results:23 patients transplanted with an EAM regimen was matched with an equal number transplanted with a BEAM conditioning regimen. The median age was 53 in both groups. The median follow-up for patients alive was 3.2 years. Further baseline characteristics of the two groups are described in table 1. Other than a slight predominance of more advanced disease in the BEAM cohort, the two groups were evenly matched.Survival estimates were statistically significantly poorer for the EAM group compared to the BEAM group. The median overall survival for the EAM cohort was 29 months compared to 77 months (p=0.03) for the matched BEAM cohort. The median event free survival for the EAM cohort was 11 months compared to 63 months (p=0.02) for the BEAM cohort. The 100 day transplant related mortality was 8.7% for both cohorts. During the follow-up period 11 patients died of disease related causes in the EAM group compared to 6 in the BEAM group. Conclusion:Despite the prevalence of pre-existing lung disease in the EAM group of patients, the conditioning was reasonably well tolerated. Our analysis suggests that patient transplanted with an EAM regimen had an inferior survival outcome to patients treated with the standard BEAM regimen. This data provides evidence for the importance of BCNU in lymphoma control; consideration should be given to a reduction in BCNU dosage, rather than simple omission, for patients with borderline lung function results. Collaboration with other centres is warranted to determine if this experience with EAM is replicated elsewhere.Table 1:Baseline characteristics of patients analysed.BEAM (n = 23)EAM (n = 23)Age (Median, range)53, 16–7053, 16–70Sex (n)Males (14) Females (9)Males (16) Females (7)Disease and Subtype (n)HD (9) NHL (14)HD (12) NHL (11)HDNodular Sclerosing44Mixed Cellularity12Lymphocyte Predominate01Not Specified45NHLDLBCL75Follicular24Mantle Cell21T-NHL20Not specified11Stage of DiseaseI-II410III-IV1612Unknown31ChemosensitivityFirst CR10Primary Refractory34Partial response33Sensitive Relapse78Resistant Relapse34Unknown64Year of TransplantationRange2000–20102002–20102000-2005 (n)12122005-2010 (n)1111Year of diagnosis (range)1995–20091989–2010 Disclosures:No relevant conflicts of interest to declare.

BEAM or BuCyE high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin's lymphoma patients: A single center comparative analysis of efficacy and toxicity

We compared the efficacy and toxicity of BEAM (BCNU, etoposide, cytarabine and melphalan) and BuCyE (busulfan, cyclophosphamide and etoposide), given prior to autologous stem cell transplantation (ASCT), in 65 patients with non-Hodgkin's lymphoma. Of these 65 patients, 43 received BEAM and 22 received BuCyE. Their age, gender distribution, International Prognostic Index, status of disease at ASCT and median number of infused CD34 + cells/kg were similar. Neutrophil and platelet engraftment were significantly faster in the BuCyE group. Rates of mucositis, nausea/vomiting, diarrhea, bleeding and infections were similar in the two groups. Median overall survival and event-free survival did not differ significantly between the two groups. These findings indicate that BuCyE is an effective conditioning regimen, showing similar survival outcomes and toxicity profiles as BEAM. Furthermore, hematologic recovery is significantly faster in patients given the BuCyE conditioning regimen.

BEAM or BuCyE high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin's lymphoma patients

7097 Background: The objective of this study was to compare the efficacy and toxicity of two high-dose regimens for autologous stem cell transplantation (ASCT) in patients with non-Hodgkin's lymphoma (NHL): BEAM (BCNU, etoposide, cytarabine, and melphalan) and BuCyE (busulfan, cyclophosphamide, and etoposide). Methods: We analysed 65 NHL patients, who underwent high-dose chemotherapy with BEAM (N=43) or BuCyE (N=22), followed by ASCT, at the Asan Medical Center. BEAM was used from February 2002 to October 2005, and BuCyE was used from November 2005 to April 2008. Results: Median age was 46 years (range: 15–68), and baseline characteristics, such as gender, International Prognostic Index (IPI), age adjusted IPI, stage and status of disease at ASCT, and median number of infused CD 34+cells/kg were well balanced between groups. The incidence of mucositis, nausea/vomiting, diarrhea and bleeding, and the number of events clinically important infections during ASCT did not differ between groups. Median follow-up for survivors was 49.3 months in the BEAM group and 21.5 months in the BuCyE group. Median overall survival (OS) was 30.6 months (95% confidence interval [CI], 8.19–53.0 months) and 22.6 months (95% CI, 12.1–33.1 months) and median event-free survival (EFS) was 16.1 months (95% CI, 0.0–53.6 months) and 11.2 months (95% CI, 0.0–22.5 months) in the BEAM and BuCyE group, respectively. There were no significant differences in OS (p=0.636) and EFS (p=0.575) between the two groups. Conclusions: In our analysis, BuCyE appeared to be not inferior to BEAM for survival. And we found that regimen-related toxicities did not differ significantly between the two groups. No significant financial relationships to disclose.

The Department of Veterans Affairs Nutritional Status Classification Scheme Allows for Rapid Assessment of Nutritional Status Before Autologous Peripheral Blood Stem Cell Transplantation and Identifies Patients at High-Risk of Transplant-Related Complications

Background: The nutritional assessment of patients prior to autologous peripheral blood stem cell transplantation (APBSCT) is labor intensive because it requires anthropomorphic measurements and biochemical tests not obtained routinely before transplantation. A simple method of nutritional assessment prior to APSCT would be extremely helpful, especially if this method could identify patients at high risk of transplant-related complications. The Department of Veterans Affairs (VA) Nutritional Status Classification Scheme (NSCS) uses an objective algorithm that does not rely on judgment, it uses data that can be easily obtained upon patient's admission to the hospital, and has been rigorously validated.Objective: The objective of this study was to determine if the NSCS could be applied to patients prior to APBSCT and to determine if this tool could identify patients at high risk of transplant-related complications.Design: The nutritional status of 128 patients who underwent APBSCT was assessed by a registered dietician, utilizing the NSCS, upon admission to the hospital and prior to conditioning regimen. The NSCS stratifies patients in 4 nutritional levels: normal, mildly-compromised, moderately-compromised and severely-compromised, based on 7 indicators. These 7 indicators include nutritional history, unintentional weight loss, weight as a percent of ideal body weight, diet, diagnosis, serum albumin and total lymphocyte count. Ratings from 1 to 4 were assigned to each of the indicators mentioned above, and the overall nutritional status was determined by a pre-defined algorithm. Total lymphocyte count was excluded from our analysis since patients with lymphoid malignancies require chemotherapy that lowers the lymphocyte count and abnormalities of the lymphocyte count are frequently related to chemotherapy and not to the patient's nutritional status. As defined in the NSCS algorithm, when data was not available for an indicator, it was not rated and was not considered in the overall nutritional status determination. A minimum of 4 indicators was necessary to determine an overall nutritional status.Results: 128 consecutive patients with lymphoid malignancies who underwent APBSCT from June 2005 thru May 2008 were included in the study. Their mean age was 57 years (19–74) and 119 (93%) were males. Of the 128 patients, 88 (69%) had multiple myeloma, 29 (23%) had non-Hodgkin's lymphoma and 11 had Hodgkin's lymphoma. Conditioning regimens included single agent melphalan in 88 (69%), the combination of cyclophosphamide, etoposide and BCNU (CBV) in 32 (25%); 8 (6%) received the combination of BCNU, etoposide, cytarabine and melphalan (BEAM). There were no statistically significant differences between nutritional status and age, sex, diagnosis or conditioning regimen before transplantation.Nutritional assessments were completed successfully in a single visit for all patients utilizing the clinical and basic laboratory information obtained upon admission to the hospital. Study patients met criteria for three of the 4 NSCS nutritional status levels before transplantation: 91 (71%) had mildly-compromised nutritional status, 26 (20%) had a normal nutritional status and 11 (9%) had moderately-compromised nutritional status. No patient met criteria for severely-compromised nutritional status. There were no statistically significant differences in the frequency of transplant-related toxicities between patients who had normal nutritional status and patients who had mildly compromised nutritional status. However, patients who had moderately compromised nutritional status experienced a higher incidence of diarrhea (p = .009), infection (p = .014) and also had a longer length of hospital stay (p = .009) when compared to patients with normal nutritional status or with patients with mildly-compromised nutritional status.Conclusion: The NSCS allowed for rapid evaluation of the nutritional status of patients before APBSCT. Patients with moderately-compromised nutritional status, as defined by the NSCS, had a higher incidence of transplant-related complications including infection and diarrhea and also had a longer length of hospital stay. Future studies should focus on the use of NSCS in patients receiving total body irradiation as part of their conditioning regimen and in patients undergoing allogeneic transplantation.

A Higher Ratio of Dose to Actual Weight of Conditioning Chemotherapy Leads to More Toxicity without Improvement in Outcome in Autologous HSC Transplant for DLBCL.

Background: High-dose chemotherapy and hematopoietic stem cell (HSC) transplantation is considered standard therapy in patients with chemosensitive relapsed diffuse large B cell lymphoma (DLBCL). BCNU, etoposide, cytarabine and melphalan (BEAM) is a standard widely used DLBCL conditioning regimen. Chemotherapy doses, both standard and high dose, are traditionally based in body surface area (BSA) and are often calculated using the corrected ideal body weight. However, this practice is empirical and the best way to dose chemotherapy is unknown. Weight-based dosing has been suggested to better predict toxicity of the conditioning regimen. We correlate the BEAM dose/actual weight ratio with toxicity and overall outcome in a uniform cohort of patients receiving HSC transplant for relapsed DLBCL Methods: Retrospective analysis of 80 consecutive patients treated at Mayo Clinic, Rochester, MN between 2001 and 2006 who received a HSC transplant following BEAM conditioning was performed. All doses were based on BSA calculated using the corrected ideal body weight. Weight-based dose intensity was retrospectively calculated utilizing the melphalan dose/Kg as a surrogate for the entire regimen. Weight-based dose intensity was correlated with toxicity in the first 30 days after transplant and survival outcome. Results: Median age at the time of transplant was 62 (interquartile range 53–65; range 26–77); 65% were males; median number of prior chemotherapy regimens was 2. Median dose of melphalan was 3.2 mg/Kg (interquartile range 2.9–3.6; range 2.2–4.5). Only one patient died within 30 days of the transplant. Patients who received &gt; 3.6 mg/Kg of melphalan were more likely to have Grade 3 or 4 mucositis (44.4% v. 9.8%, P=0.001) than the remaining patients. Median numbers of days spent in the hospital in the first 30 days after transplant was 13 (3–18) for melphalan dose &gt;3.6 mg/kg vs. 7 (0.5–10.5) for the remaining patients (P=0.043). Weight based dose intensity did not correlate with survival (P=0.8) or disease-free survival (P=0.3). Conclusion: Weight based dose intensity of BEAM correlates with toxicity post autologous HSC transplant. Patients receiving doses corresponding to &gt;3.6 mg/kg of melphalan are at increased risk of high-grade mucositis and prolonged hospitalization. Figure Figure

Time of Relapse after Initial Therapy Significantly Adds to the Prognostic Value of the IPI-R in Patients with Relapsed DLBCL Undergoing Autologous HSC Transplantation.

Background: High-dose chemotherapy and hematopoietic stem cell (HSC) transplantation is curative in about 40% of patients with relapsed chemosensitive diffuse large B cell lymphoma (DLBCL). The international prognostic index obtained at the time of relapse (IPI-R) and the time from initial treatment to relapse (TTR) have been suggested in different series to be predictors of outcome after HSC transplantation. We explored the concomitant effect of IPI-R and TTR on therapeutic outcome in a modern and uniform cohort of patients with relapsed chemosensitive DLBC undergoing high-dose chemotherapy and peripheral HSC transplantation.Methods: Retrospective analysis of 80 consecutive patients treated at Mayo Clinic, Rochester, MN between 2001 and 2006 who received a peripheral HSC transplant (except for 3 patients who receive bone marrow) after being conditioned with BCNU, etoposide, cytarabine and melphalan (BEAM) for relapsed chemosensitive DLBCL.Results: Median follow-up of survivors was 31.4 months, Median age at the time of transplant was 62 (interquartile range 53–65; range 26–77), 65% were males; median number of prior chemotherapy regimens was 2. All patients had received at least one previous anthracycline-based regimen, 78% had been previously exposed to rituximab and all achieved at least CRu after the initial treatment. The median time from diagnosis to relapse was 19 months (interquartile range 10–43), 25% of patients had a high or high-intermediate IPI-R. The median survival from the time of transplant for patients with TTR>18 months v. ≤ 18 months was not reached and 50 months respectively (P=0.005). Median survival for patients with high or high-intermediate IPI-R at the time of relapse (IPI score ≥3) was 23.3 months and not reached for patients with low or low-intermediate IPI (P=0.01). These two factors were independent in multivariate analysis with RR for death of 1.8 (1.2–2.9; P=0.004) for TTR ≤ 18 months and 1.7 (1.1–2.5; P=0.017) for high or high-intermediate IPI and therefore combined in a prognostic system were patients with none (n=32), one (n=39) or two (n=9) of these prognostic factors had median disease free survival not reached v. 50 months v. 3.3 months (P=0.001) and overall survival not reached v. 50 months v. 5 months (P=0.0001) (Figure).Conclusion: TTR and IPI-R provide an easy and powerful prognostic system in patients with DLBCL undergoing modern high-dose chemotherapy with HSC support. [Display omitted]

Radioimmunotherapy with 131-I tositumomab enhanced survival in good prognosis relapsed and high-risk diffuse large B-cell lymphoma (DLBCL) patients receiving high-dose chemotherapy and autologous stem cell transplantation

8013 Background: The 5-year overall survival (OS) for pts with relapsed chemosensitive DLBCL with standard transplantation is approximately 40–50%. We previously piloted the addition of standard outpatient radioimmunotherapy (RIT) with 131-I tositumomab to the transplant regimen for patients with relapsed chemoresistant NHL. This phase I study demonstrated a 3 yr OS of 55% in these poor prognosis patients (JCO 23: 461–467, 2005). The current study is a follow-up phase II study in good prognosis relapsed and high risk DLBCL patients using 131-I tositumomab with BEAM (BCNU, etoposide, cytarabine, and melphalan) followed by an autologous stem cell transplant. Methods: Forty patients were accrued to the study between 2000–2005. The patients had a median age of 54 yrs (26–75) and all had a diagnosis of DLBCL. The patients had a median of two prior chemotherapies before transplant and 88% had received prior Rituximab. All patients had chemotherapy sensitive disease at the time of stem cell transplant. Following stem cell collection, all patients received a stem cell preparative regimen of 75 cGy total body dose of 131-I tositumomab (dosimetric dose day -19 and therapeutic day -12) followed by a standard BEAM transplant regimen. Autologous unpurged stem cells were infused on day 0. The median time of follow-up of the survivors is 28 months (3–68). Results: Seventy eight percent of the patients had a complete remission following the transplant. The 3 year progression free survival (PFS) is 70% (95% CI - 48 - 84%) and the 3 year OS is 81% (95% CI - 61 - 91%). The entire transplant can be delivered on an outpatient basis. No increased toxicity compared to a similar cohort receiving BEAM alone could be detected. Conclusions: The addition of 131-I tositumomab to BEAM and autologous stem cell transplant for relapsed or high-risk chemosensitive DLBCL produces a 3-yr OS of 81% without excess toxicity. This compares favorably to historical controls. This regimen is currently being tested in a phase III trial in the BMT/CTN of Rituximab/BEAM vs. 131-I tositumomab/BEAM in patients with relapsed chemosensitive DLBCL. No significant financial relationships to disclose.

Incidence and risk factors of central nervous system recurrence in aggressive lymphoma—a survey of 1693 patients treated in protocols of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL)

Central nervous system (CNS) relapse is a devastating and usually fatal complication of aggressive lymphoma. The extent of the disease, the proliferation rate and the sites of extranodal involvement have been discussed as risk factors. We analyzed the patients treated on protocols of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL) between 1990 and 2000, evaluated the rate and prognostic factors for CNS recurrence and developed a risk model trying to identify subsets of patients suitable for future prophylactic strategies. From 1993 to 2000, 1399 patients [<or=60 years with normal lactate dehydrogenase (LDH) and >60 years irrespective of LDH] were randomized to receive six cycles of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-21, CHOP-14 or six cycles of CHOP+etoposide (CHOEP)-21, CHOEP-14 in a 2x2 factorial study design in the NHL-B1/B2 studies. From 1990 to 1997, 312 patients<or=60 years with an elevated LDH were randomized to five cycles CHOEP+involved field (IF) radiotherapy or three cycles CHOEP followed by high-dose BCNU, etoposide, cytarabine and melphalan (BEAM) and autologous stem-cell transplantation (NHL-A study). A total number of 1711 patients were initially eligible for this study, of whom 18 patients had to be excluded due to primary CNS involvement. In the remaining 1693 assessable patients, 37 cases of relapse or progression to the CNS (2.2%) were observed. The protocol asked for an intrathecal (i.th.) prophylaxis in patients with lymphoblastic lymphoma only (n=17), but overall 71 patients (71 of 1693=4.2%) received prophylaxis by decision of the treating physicians. Multivariate Cox regression analysis identified increased LDH (P<0.001) and involvement of more than one extranodal site (P=0.002) as independent predictors of CNS recurrence in the NHL-B1/B2 study population. Treatment with etoposide also evolved as a prognostic factor because the risk of CNS failure was significantly reduced after CHOEP (P=0.017). Elderly patients presenting with both an elevated LDH and lymphoma involvement in liver, bladder or adrenals had an up to 15-fold risk of spread of the disease to the CNS. The incidence of CNS relapse in 1693 patients treated for aggressive lymphomas on DSHNHL protocols from 1990 to 2000 was low (2.2%), although CNS prophylaxis was administered to <5% of patients. Thus, a general prophylaxis for all patients is not warranted, the less so since the effectiveness of i.th. prophylaxis itself is judged controversially. Increased LDH and involvement of more than one extranodal site were confirmed as independent risk factors. A cumulative 20% incidence of CNS disease in certain prognostic subgroups of elderly patients may render these candidates for i.th. prophylaxis; however, this approach would imply a potential overtreatment of approximately 80% of these patients deemed at high risk.

Preliminary experience of allogeneic stem cell transplantation for lymphoproliferative disorders using BEAM-CAMPATH conditioning: an effective regimen with low procedure-related toxicity.

Autologous transplantation has an established role in the treatment of lymphoproliferative disorders, but allogeneic transplantation remains controversial. In an attempt to reduce the high procedure-related mortality reported with allografting in lymphoma, we have used BEAM (BCNU, etoposide, cytarabine and melphalan), a standard conditioning regimen for autologous transplantation. As BEAM may be insufficiently immunosuppressive to permit durable engraftment in the allogeneic setting, patients received additional pretransplant immunosuppression with the anti-CD52 antibody CAMPATH-1G from day -5 to day -1. Twelve patients (median age 46 years) underwent allogeneic transplantation for lymphoma (n = 11) or chronic lymphocytic leukaemia (n = 1) from HLA-identical (n = 9) or mismatched (n = 3) sibling donors. Cyclosporin A and methotrexate were used as graft-versus-host disease (GVHD) prophylaxis. One patient died of progressive lymphoma at day +12, the remaining 11 patients engrafted rapidly, with eight demonstrating full donor chimerism. One patient had an episode of rejection and received a further stem cell infusion with sustained recovery. Only one patient developed GVHD (grade I). The low incidence of acute GVHD may be in part related to persisting levels of in vivo CAMPATH-IG at the time of transplantation. Of 11 evaluable patients, nine achieved complete remission (CR), and a further patient achieved CR after donor lymphocyte infusion at 5 months. Our preliminary experience is that this regimen was well tolerated with a low risk of GVHD and appears no more toxic than a BEAM autograft. Further follow-up is required to see whether the low incidence of GVHD impacts upon relapse risk.

High-dose therapy for Hodgkin's disease.

High-dose therapy for Hodgkin's disease.