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

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3179-3179
Author(s):  
Amrita Y. Krishnan ◽  
Joycelynne Palmer ◽  
Auayporn P. Nademanee ◽  
Robert Chen ◽  
Leslie L. Popplewell ◽  
...  
Keyword(s):  
Complete Remission ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Poor Risk ◽  
Non Hodgkin Lymphoma ◽  
Grade 3 ◽  
Induction Failure

Abstract 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 1. Patient and Disease Characteristics (#/% or median/range) Variable All N = 116 MCL N = 32 DLBCL N = 46 FL N = 20 TF N = 18 Disease status at HCT 1st complete remission 1st partial remission 1st relapse 2nd complete remission ≥3rd complete remission Induction failure 29 (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 regimens 2 (1-7) 1 (1-3) 2 (2-7) 3 (1-4) 2 (1-3) Age at transplant, yr 57 (23-75) 60 (43-72) 48 (23-75) 57 (43-67) 58 (41-65) Maintenance rituximab No Yes N/Aa 103 (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 2. Outcomes, % (95% CI) AllbN = 115 MCL N = 32 DLBCL N = 46 FL/TF, combinedbN = 20/17, 37 BEAM, historical estimates: 2-yr PFS N/A 35 45 45/35, 40 ZBEAM, trial estimates: 2-yr PFS 70 (61-78) 78 (57-89) 78 (62-87) 54 (30-73)/57 (31-77), 56 (38-70) 3-yr PFS 66 (56-74) 69 (54-79) 75 (63-83) 47 (36-58)/57 (42-70), 52 (35-67) 3-yr OS 85 (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 Disclosures Krishnan: 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.

Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: Early Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3075-3075
Author(s):  
Richard A. Nash ◽  
George J Hutton ◽  
Michael K Racke ◽  
Uday R Popat ◽  
Steven M. Devine ◽  
...  
Keyword(s):  
Volume Change ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Composite Endpoint ◽  
High Dose ◽  
Lesion Volume ◽  
Highly Active ◽  
Relapsing Remitting ◽  
Grade 3

Abstract Abstract 3075 Multiple sclerosis (MS) is an autoimmune disease which in most patients presents as defined relapses followed by remissions (relapsing-remitting (RR)). Over time the clinical course evolves to a gradual but irreversible loss of neurological function to which a neurodegenerative process likely contributes. Previous studies of high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were done in patients with advanced progressive MS and many patients continued to lose neurological function. To investigate the potential benefit of HDIT/HCT to halt the evolution of MS and prevent the development of the neurodegenerative processes, HDIT/HCT was studied in RRMS. A phase II clinical trial of HDIT (BCNU, etoposide, ara-C and melphalan (BEAM) and antithymocyte globulin (ATG)) and autologous HCT was conducted in patients with highly active RRMS who had failed conventional therapy to determine if sustained remissions could be induced. Eligibility criteria required Expanded Disability Status Scale (EDSS) 3.0 (moderate disability, fully ambulatory) -5.5 (severe disability, ambulatory only 100 meters without aids) and ≥2 relapses on MS treatment with EDSS worsening over the previous 18 months. Hematopoietic progenitor cells were mobilized with G-CSF and a 10-day course of prednisone. The graft was CD34-selected (Baxter, Isolex). The primary endpoint was treatment-failure defined as a composite endpoint of 1) mortality 2) relapse 3) new lesions on MRI or 4) progression in disability ≥1.0 EDSS point. Adverse events (AE) were recorded according to NCI-CTCAE v3.0. Twenty-five patients at a median age of 38(27–53) years had autologous hematopoietic stem cells collected. There were 7 Grade 3 non-hematopoietic AEs during mobilization; mostly line-associated thromboses and infections. There was 1 Grade 4 AE with pretransplant withdrawal from study; a pulmonary embolus associated with heparin-induced thrombocytopenia and pre-existing arteriovenous malformation in the brain. During mobilization, a MS flare occurred in one patient who was non-compliant with the prednisone prophylaxis. Twenty-four patients proceeded to transplant. Median follow-up is 80(52–232) weeks. Patients were infused with a median of 4.58(2.95–9.73) × 106 CD34+ cells/kg. Neutrophil recovery occurred at a median of +11(9–15) days. In the 1st year after transplant, there were 17 Grade 3 and 4 Grade 4 non-hematopoietic, non-GI AEs. The Grade 4 AEs were suicide attempt (recorded as 2 separate events), hypokalemia and increase in ALT. At baseline (n=24), one (n=23) and two (n=8) years after HDIT/HCT, the mean EDSS (SD) was 4.42(+/−0.637), 3.78(+/−0.951) and 4.13(+/−0.916) respectively. There was only one case with gadolinium-enhancing lesions after 6 months (at Year 3) (Table 1). T2 lesion volume decreased and T1 lesion volume increased from baseline to Month 12. Despite the decrease in T2 lesion volume, there was early posttransplant loss in brain volume. Four patients failed by the composite endpoint (relapses at +22 and +96 weeks; new MRI brain lesions at +197 weeks and progression of disability/death at +82/138 weeks). Event-free survival at 1 and 2 years was 95.8(90% CI :73.9, 99.4)% and 76.7(90% CI :41.1, 92.4)% respectively. 22/24 patients were without progression of disability at last follow-up.Table 1:Brain MRI: Changes in first year after transplant.Baseline n=24Month 2 n=24Month 6 n=24Month 12 n=23Total Gd+ lesions [n (%)]014 (58%)19 (90%)22 (96%)22 (100%)14 (17%)0 (0%)1 (4%)0 (0%)2+6 (25%)2 (10%)0 (0%)0 (0%)T2 lesion volume change (cc)*n202320Median(min, max)-0.13 (-6.51,1.26)-0.60 (-6.46,1.73)-0.58 (-5.14,0.97)1T1 lesion volume change (cc)*n202320Median (min, max)-0.002 (-1.10, 0.87)0.02 (-0.87, 0.99)0.11 (-0.40,1.74)2Brain volume change (%)*n202419Mean (SD)-0.91 (0.73)3-1.19 (0.86)-1.28 (1.01)*Change from baselineWilcoxon signed rank test: 1) p=0.0014; 2) p=0.0186 3) t-test: p<0.0001Conducted by the Immune Tolerance Network, sponsored by NIAID, National Institutes of Health, Bethesda, MD. High-dose immunochemotherapy was well-tolerated with few serious early complications. Early control of highly active RRMS was obtained post transplant but has not been complete in all patients. Patient follow-up is planned for 5 years to determine durability of responses. Disclosures: Stuve: Teva Neuroscience, EMD Serono, Roche, Novartis, Genzyme: Consultancy, Honoraria; Teva Neuroscience, EMD Serono, Roche, Novartis, Genzyme: Honoraria; Teva Neruoscience: Research Funding. Arnold:NeuroRx Research: Equity Ownership. Wundes:Biogen Idec: Consultancy, Research Funding, Speakers Bureau; Teva pharmaceutics: Consultancy.

Phase I/II Study of Myeloablative Anti-CD20+ Radioimmunotherapy with I-131-Rituximab in High-Risk CD20-Positive Non Hodgkin Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3700-3700
Author(s):  
Kathleen Schwarz ◽  
Wagner Julia ◽  
Susanne Schreiber ◽  
Burkhard Schmidt ◽  
Alexander Hoellein ◽  
...  
Keyword(s):  
Overall Survival ◽  
Response Rate ◽  
Complete Response ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Non Hodgkin Lymphoma ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 3700 Background: Radioimmunotherapy (RIT) has been successfully used to treat primary and relapsed/refractory CD20+ Non-Hodgkin-Lymphoma (NHL). Myeloablative anti-CD20 RIT allows delivering high radiation doses to lymphoma sites when followed by autologous stem cell infusion (autoSCT). However, RIT is infrequently used at present and long-term data is lacking. Patients, Design and Methods: 23 patients with relapsed/refractory CD20+ NHL who did not achieve a complete response to salvage chemotherapy were enrolled in this Phase I/II trial to evaluate RIT with 131I-labelled Rituximab (131I-R) in a myeloablative setting between January 2000 and October 2004. Biodistribution and dosimetry studies were performed in all patients to determine 131I activity required to induce a total body dose of 21 to 27 Gy to the critical organs lung and kidney. In 6/23 patients RIT was combined with high dose chemotherapy (HD-CTx) followed by autoSCT. 8/23 patients received a sequential HD-CTx with a second autoSCT. The median follow-up is 9.5 years. Results: 188–525 mCi 131I were delivered to achieve the limiting organ dose. No grade 3/4 non-hematologic toxicity was seen with RIT alone. Significant grade 3/4 toxicity (mucositis, neutropenic fever, pneumonia, sepsis) including one therapy related death was observed in all patients treated with RIT combined with HD-CTx/autoSCT. The overall response rate was 87% (64% complete response rate). The median progression free (PFS) and overall survival are 47.5 and 101.5 months. After long-term follow up, 9 patients are progression free and 10 patients are alive. An elevated (>1) international prognostic index (IPI) was most predictive for overall survival. Conclusion: Myeloablative 131I-Rituximab RIT followed by autoSCT is feasible, well tolerated and effective in high risk CD20+ NHL and prolongs PFS compared to last standard chemotherapy. Patients additionally treated with high dose chemotherapy experienced significantly increased toxicity. Long-term results for progression free survival and overall survival in this trial are encouraging. Disclosures: No relevant conflicts of interest to declare.

Randomized Study of Decitabine Versus Observation or Continued Cytotoxic Chemotherapy in Patients with Intermediate and Poor Risk Acute Myeloid Leukemia in First or Subsequent Complete Remission.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2859-2859 ◽  
Author(s):  
Farhad Ravandi ◽  
Jean-Pierre Issa ◽  
Stefan Faderl ◽  
Guillermo Garcia-Manero ◽  
Mary Hood ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Clin Oncol ◽  
Myeloid Leukemia ◽  
Cytotoxic Chemotherapy ◽  
Cytotoxic Agents ◽  
High Dose ◽  
Poor Risk ◽  
Grade 3 ◽  
Acute Myeloid

Abstract The role of maintenance therapy in acute myeloid leukemia (AML) remains unclear. Continued therapy with cytotoxic agents similar to those used for induction and consolidation is associated with toxicity but can improve disease free survival (DFS). (Buchner T, J Clin Oncol. 2006;24:2480 and Lowenberg B, J Clin Oncol. 1998;16:872) Immune modulation in this setting may also be effective in prolonging DFS.(Brune M, Blood2006;108:88). Methylation status of tumor suppressor genes in clinical remission predicts the relapse risk in AML with earlier relapse in patients with increased DNA promotor methylation.(Agrawal S, Cancer Res. 2007;67:1370) Therefore, hypomethylating therapy may be effective in maintaining remission and prolonging survival in these patients. We are conducting a clinical trial comparing decitabine to cytotoxic chemotherapy or observation in patients with AML in their first or subsequent complete remission (CR). Patients with non-favorable risk AML (including intermediate and poor risk) receive induction therapy with idarubicin and high dose cytarabine followed by at least 2 cycles of cytarabine based consolidation. They are then stratified by age (≤ 60 vs. > 60) and cytogenetics (intermediate vs. poor risk) and randomized to receive decitabine 20 mg/m2 IV daily × 5 every 4 to 8 weeks for 12 cycles, or to continue chemotherapy/observation. Patients in > first CR are randomized after completion of salvage therapy. Serial samples for methylation studies and determination of minimal residual disease by flow cytometry are collected. To date, 19 (8 M, 11 F) patients with AML (including 14 in first CR and 5 in subsequent CR) have been enrolled onto the study. Median age of the patients is 56 years (range 31 – 74). Fourteen patients are ≤ 60 years. Cytogenetics at diagnosis was intermediate in 10 patients, poor-risk in 8 patients, and favorable [inv(16)] in one relapsed patient. Eight patients were randomized to decitabine and have received a median of 3 cycles (range 1 – 6). Eleven patients were randomized to observation/continued therapy and all, except 2 patients, have received further cytarabine based therapy after consolidation. With a median duration of follow up for the entire group of 5 months (range 1 – 9), 7/8 patients on the decitabine arm and 9/11 patients on the other arm have remained in remission. Toxicity in the decitabine treated patients was limited to 4 episodes of grade 3 neutropenia, 2 episode of grade 3 thrombocytopenia, and 1 episodes of grade 3 anemia. All of these cytopenias were short in duration and reversed without any associated adverse events. We conclude that administration of decitabine in CR at the above schedule/dose is safe and well tolerated.

High-Dose Cytoxan, Etoposide, and Cisplatin Followed by Autologous Hematopoietic Cell Transplantation for the Treatment of Hodgkin Lymphoma: A 20-Year Single-Institutional Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1913-1913
Author(s):  
Thomas R. Klumpp ◽  
Moshe C. Chasky ◽  
Robert V. Emmons ◽  
Mary E. Martin ◽  
James L. Gajewski ◽  
...  
Keyword(s):  
Complete Remission ◽  
Total Dose ◽  
Hodgkin Lymphoma ◽  
Pulmonary Toxicity ◽  
Median Number ◽  
High Dose ◽  
Post Transplant ◽  
Grade 3 ◽  
Active Disease

Abstract Since 1988 we have treated 66 patients with relapsed, refractory, or high-risk Hodgkin lymphoma (HD) with high-dose CEP consisting of cyclophosphamide 1,500 mg/m2/day × 4 (total dose, 6,000 mg/m2), etoposide 400 mg/m2 twice daily × 6 doses (total dose, 2,400 mg/m2), and cisplatin 50 mg/m2/day × 3 by continuous i.v. infusion (total dose 150 mg/m2) followed by infusion of autologous peripheral blood stem cells (n=49), bone marrow (n=16), or both (n=1). The patient population included 41 males and 25 females. The median age at transplant was 33 years (range, 17–64 years). Twenty-three patients (35%) had never achieved complete remission prior to transplant, 36 (55%) had previously achieved a complete remission but subsequently relapsed, and 3 (5%) were in first complete remission. Information regarding the disease status at transplant was unavailable for 4 patients (6%). Twenty-seven patients (41%) remain alive and free of any post-transplant relapse or progression as of the most recent follow-up, and an additional 10 patients (15%) manifested active disease post-transplant but are currently in remission following additional post-transplant therapy, yielding a total of 37 patients (56%) currently in CR. In addition, 5 patients (8%) remain alive with active disease, 23 patients (35%) died of progressive disease, and only 2 patients (3%) died of treatment-related causes including diffuse alveolar hemorrhage (1 patient) and hepatic veno-occlussive disease (1 patient). With a median follow-up of 4.4 years among surviving patients, the Kaplan-Meier 5-year estimates for event-free survival and overall survival are 34% and 60%, respectively, and five-year survival was superior among patients who had achieved at least one CR prior to transplant versus patients who had never been in CR prior to transplant (71% versus 43%, p = 0.03). Detailed adverse events data is available regarding all patients transplanted since September 1996: Of these, only 3 (7%) suffered grade 3 or greater pulmonary toxicity, 12 (29%) exhibited grade 3 or higher mucositis, and 10 (24%) had grade 3 or higher nausea or vomiting. The median number of days from transplant to neutrophil recovery (500 cells/uL) was 10 days, whereas the median number of days to platelet recovery (20,000 cells/uL) was 12 days. We conclude that high- dose CEP followed by autologous transplant is an active and well-tolerated treatment program in patients with relapsed or refractory HD. The low incidence of pulmonary toxicity is noteworthy given that a high percentage of patients had been exposed to bleomycin and/or thoracic XRT prior to transplant, and appears to be superior to that reported with conventional CBV-conditioned transplants in patients with HD.

Alemtuzumab Plus Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Transplantation in Ultra High-Risk CLL: Interim Analysis of a Phase II Study of the GCLLSG and fcgcll/MW

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2854-2854 ◽  
Author(s):  
Stephan Stilgenbauer ◽  
Florence Cymbalista ◽  
Véronique Leblond ◽  
Alain Delmer ◽  
Dirk Winkler ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Long Term Results ◽  
High Dose ◽  
Significant Difference ◽  
Ultra High Risk ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2854 Alemtuzumab (A) proved to be efficacious in CLL patients (pts) with very poor prognosis, either due to fludarabine (F) refractoriness or due to unfavorable cytogenetics (17p-). However, rate and duration of remissions still remain unsatisfactory. Therefore, the French and German CLL study groups jointly embarked on this trial, trying to achieve higher overall response rates (ORR) by adding high-dose dexamethasone (D) to A and, simultaneously, investigating the consolidation effect of prolonged A maintenance or allogeneic stem-cell transplantation (allo-SCT), respectively. Induction treatment consisted of subcutaneous A 30 mg weekly × 3 for 28 days, combined with oral D 40 mg on days 1–4 and 15–18, and prophylactic pegfilgrastim 6 mg on days 1 and 15. Depending on the remission status, pts were treated for up to 12 weeks. If CR was documented at 4 or 8 weeks, or at least SD was achieved at 12 weeks, consolidation was scheduled with either allo-SCT or A maintenance with 30 mg every 14 days for up to 2 years (y), at the discretion of pt and physician. Between January 2008 and July 2011, 124 pts were recruited at 26 centers, 120 of whom were eligible. Pts were generally subdivided into three cohorts: 55 pts were refractory (i.e. no response or relapse within 6 months) to regimens containing F or a similar drug (i.e. pentostatin, cladribine, bendamustine). Non-refractory pts all exhibited 17p- and had either untreated (n=39) or relapsed CLL (n = 26) requiring therapy. The median age was high with 66/64/66 y in 17p- 1st line, 17p- relapse, and F-refractory pts, respectively. The three cohorts had 46/54/75% Binet C disease, 41/35/27% B symptoms, 38/42/53% reduced performance status (ECOG 1/2), median thymidine kinase levels of 35/49/24 U/L, median ß2MG levels of 3.8/5.5/4.6 mg/L, and IGHV was unmutated in 89/96/87%. In the F-refractory group, 53% exhibited 17p deletion and 22% had 11q deletion. Pretreated patients had received a median of 3 (F-refractory) or 2 prior lines (17p- relapse). 5 pts had previously undergone autologous and 1 pt allo-SCT. Treatment and efficacy data are currently available for 87 pts who completed induction therapy :17p- 1st-line (n=30), 17p- relapse (n=17), and F-refractory (n=40). Of these, 80/53/55% received the full induction of 12 weeks. ORR (best observed status) was generally high with 97/76/70%. CR was achieved in 20/0/5%. After a median follow-up of 11.8 months (mo), median progression-free survival (PFS) was 16.9/10.4/8.4 mo. Deaths are recorded in 13/27/36% of pts, with median overall survival (OS) not yet reached (>24 mo) in the 17p- 1st line group, and 15/12 mo in 17p- relapse/F-refractory pts. Consolidation treatment was performed as maintenance A (median duration 32 weeks, range 2 – 89) in 34%, and allo-SCT in 30%, with a median age of 66 and 61 y in these subgroups. The main reasons for going off-study without consolidation were death due to infection (14%, n=11, of these 6 without response, and 10 in the F-refractory cohort), CLL progression (12%), and other toxicity (5%). Among the 28 pts not receiving consolidation, there were 19 (68%) deaths, 15 of them in the F-refractory cohort. When comparing A maintenance and allo-SCT for consolidation, there were 9 (35%) and 7 (30%) PD events, respectively and there was so far no significant difference in PFS (median 17 mo in both groups) or OS. During induction, grade 3/4 hematotoxicity consisted of anemia in 28%, neutropenia in 47%, and thrombopenia in 44%. Grade 3/4 non-CMV infection occurred in 29% of 17p- 1st-line, 15% of 17p- relapsed, and 56% of F-refractory pts. CMV reactivation was observed in 54/25/40%, without severe sequelae recorded. During A maintenance, grade 3/4 toxicity consisted of neutropenia in 39% pts and thrombopenia in 4% pts with 6 SAEs (ITP, diarrhea, infection, erythema, tachycardia, and thrombosis). Conclusions: The combination of A and D shows high response rates in ultra high-risk CLL, with promising preliminary findings for PFS and OS, despite the high median age of the pts. The results compare favorably to ORR/CR of 68%/5%, and median PFS of 11.3 mo in the 17p- subgroup of the CLL8 study treated with FCR, consisting of younger pts (median 61 y). In F-refractory CLL however, when compared to the preceding CLL2H study with single agent A, the improved initial response by adding dexamethasone does not seem to translate into improved long-term results. More mature follow-up is needed, especially with respect to the impact of allo-SCT. Disclosures: Stilgenbauer: Amgen: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding. Off Label Use: Alemtuzumab in 1st line CLL treatment. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding. Hinke:WiSP (CRO): Employment.

Bendamustine, Bortezomib and Dexamethasone (BBD) As First-Line Treatment of Patients with Multiple Myeloma Who Are Not Candidates for High Dose Chemotherapy: Toxicity Comparison of Two Dose Schedules

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4047-4047 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Michael R. Savona ◽  
James Essell ◽  
Patrick Murphy ◽  
Luis Chu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Herpes Zoster ◽  
Research Funding ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Off Label Use ◽  
First Line ◽  
Off Label ◽  
Grade 3

Abstract Abstract 4047 Background: Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in patients (pts) who are ineligible for high dose chemotherapy. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as a single agent and in various combinations for the treatment of relapsed/refractory MM (Poenisch et al, 2007, Fenk et al, 2007). In this study, the combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for patients with MM. Methods: Patients with newly diagnosed active multiple myeloma who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. The original treatment schema (schema A) consisted of: bendamustine 80 mg/m2 IV on days 1, 4; bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11; and dexamethasone 40 mg on days 1, 2, 3, 4 with cycles repeating every 28 days. Patients had the option to continue on maintenance bortezomib. An interim analysis found this combination to be efficacious but relatively toxic. As a result the treatment schema was amended to the following (schema B): bendamustine 80 mg/m2 IV on days 1, 2; bortezomib 1.3 mg/m2 IV on days 1, 8, 15; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Again, patients had the option to continue maintenance bortezamib. Acyclovir or equivalent viral prophylaxis was recommended on schema A and became required on schema B. Responses were assessed using the IMWG criteria. AEs were assessed using the CTCAE Version 4.0. We report the results of an interim safety assessment of the amended BBD combination and compare the results to those seen with the original regimen. Results: Treatment schema A accrued 18 patients between 5/2010 and 2/2011. Ten patients were accrued from 10/2011 and 4/2012 and treated on treatment schema B. The median ages of treatment schemas A and B were 75 and 72.5 respectively, with all other characteristics within expected distributions and no major differences between the groups. No grades 4 hematologic Adverse Events (AEs) were seen. Grade 3 hematologic AEs were similar in both arms seen in 33% of patients on treatment schema A and 40% of patients on treatment schema B. Grade 3/4 non-hematologic AEs were seen in 72% of patients on treatment schema A and 60% of patients on treatment schema B. Although the preliminary Serious Adverse Events (SAEs) were similar with 39% of patients on treatment schema A compared to 30% of patients on treatment schema B, a large proportion of patients on treatment schema A (39%) were unable to complete the study due to toxicity or related issues. The incidence and severity of neuropathy and herpes zoster infections were significantly different between the two schemas. Schema A had 72% of patients with any grade neuropathy, with 56% being grade 2 or worse while schema B had 40% of the patients with any grade neuropathy, all but one grade 1. Likewise, 44% of patients on the original treatment reported herpes zoster while there were no cases of herpes zoster reported for patients on the revised treatment schema. Thus far, the early response rates appear similar. Schema A had an ORR of 78% (56% >vgPR) while schema B had an ORR of 90% (40% >vgPR). Conclusions: The combination of bendamustine, bortezomib and dexamethasone is feasible and efficacious in an elderly patient population. Using the revised schema, we were able to lower treatment toxicity without adversely impacting initial efficacy. Updated results will be presented at the meeting. Disclosures: Off Label Use: Off-label use of Bendamustine in the treatment of Multiple Myeloma. Chu:Millennium: Research Funding; Cephalon: Research Funding.

A Detailed Evaluation of Transplant-Related Toxicities and Outcome for Patients with CNS Lymphoma (CNSL) Consolidated with High-Dose Therapy and Autologous Stem Cell Transplantation (HDT-ASCT) Using Thiotepa, Busulfan (Bu), Cyclophosphamide (TBC) Conditioning

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4354-4354
Author(s):  
Michael Scordo ◽  
Valkal Bhatt ◽  
Meier Hsu ◽  
Antonio M. Omuro ◽  
Matthew J. Matasar ◽  
...  
Keyword(s):  
Research Funding ◽  
Secondary Malignancy ◽  
Cns Lymphoma ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Kaplan Meier ◽  
Clinically Significant ◽  
Grade 3

Abstract Background: HDT-ASCT with TBC conditioning has emerged as a common consolidation strategy for patients (pts) with relapsed/refractory (rel/ref) primary (PCNSL) or secondary (SCNSL) (Welch et al, Leuk & Lymph 2014). In a prospective study, chemosensitive PCNSL pts in first remission after induction with R-MPV (rituximab, MTX, procarbazine and vincristine) proceeding to HDT-ASCT with TBC conditioning, experienced an encouraging 2-year PFS and OS of 75% and 81%, respectively (Omuro et al, Blood, 2015). Three of these patients experienced transplant-related mortality (TRM, 11.5%), which appears greater than HDT-ASCT for other lymphomas. The purpose of this report is to correlate characteristic toxicities of TBC conditioning for CNSL to pre-HDT-ASCT clinical variables. Methods: The MSKCC IRB approved this retrospective chart review. Eligible pts (n=34) were ≥ 18 years of age with PCNSL or SCNSL that was chemosensitive to induction therapy after which they proceeded to HDT-ASCT conditioned with TBC between December 2006 and April 2015. All pts included were treated outside of prospective clinical trials. Clinically significant grade 3-5 non-hematologic toxicities per CTCAE 4.0 occurring in >20% of pts were recorded from the initiation of conditioning until 6 months post ASCT (Figure 1). Pre-HDT-ASCT variables for analysis include: age, gender, disease (PCNSL or SCNSL), Karnofsky performance status (KPS), hematopoietic cell transplant comorbidity index (HCT-CI), number of prior regimens, prior use of whole-brain radiotherapy (WBRT), and disease status prior to HDT-ASCT (CR/CRu or PR). We evaluated the association of these pre-HDT-ASCT characteristics with the number of clinically significant grade 3-5 non-hematologic toxicities (≥4 vs. <4) using FisherÕs exact test. We further estimated progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier methods. Results: Thirty-three patients (97%) experienced ≥ 1 grade 3-5 non-hematologic toxicity. Febrile neutropenia (grade 3) occurred in 32 pts (94%). Of all pre-HDT-ASCT variables, only the number of prior regimens (>2) was significantly associated with incurring more grade 3-5 non-hematologic toxicities, p=0.04 (Table 1). With a median follow-up for survivors of 12 months (range, 1.5-86.2 months), PFS was 79% (95% CI, 65-96) and OS was 82% (95% CI, 68-98) at 1 year (Figures 2 and 3). During the follow-up period, there were 7 pt deaths: 4 died of disease, 2 died secondary to TRM (5.9%), and one died of a secondary malignancy (squamous cell carcinoma) 86.2 months after HDT-ASCT. There were no progression events beyond 12 months. In a limited subset analysis wherein n=22 had first dose bu pharmacokinetics evaluated, pre-HDT-ASCT variables were not associated with higher bu AUC levels, though 64% of these pts required a dose reduction. Conclusions: We reaffirmed that HDT-ASCT with TBC conditioning is effective consolidation for CNSL, but it is associated with more grade 3-5 non-hematologic toxicity in pts having had >2 prior regimens. Risk-adapted dose attenuation of TBC conditioning for this group of pts may mitigate observed toxicity. Table 1. Association of Pre-ASCT Variables & Grade 3-5 Non-hematologic Toxicities Number of Clinically Significant Grade 3-5 Toxicities Pre-ASCT Variables All (N=34) Fewer than 4 (N=21) 4 or more (N=13) p-value Age 0.71 <60 23 (68%) 15 (71%) 8 (62%) ≥60 11 (32%) 6 (29%) 5 (38%) Gender 0.72 Female 13 (38%) 9 (43%) 4 (31%) Male 21 (62%) 12 (57%) 9 (69%) Disease 0.30 PCNSL 19 (56%) 10 (48%) 9 (69%) SCNSL 15 (44%) 11 (52%) 4 (31%) KPS 0.99 ≥80 32 (94%) 20 (95%) 12 (92%) <80 2 (6%) 1 (5%) 1 (8%) BMT HCT CI 0.99 ≤2 17 (50%) 11 (52%) 6 (46%) >2 17 (50%) 10 (48%) 7 (54%) Number of Prior Regimens 0.04 ≤2 21 (62%) 16 (76%) 5 (38%) >2 13 (38%) 5 (24%) 8 (62%) WBRT 0.17 No 28 (82%) 19 (90%) 9 (69%) Yes 6 (18%) 2 (10%) 4 (31%) Disease state prior 0.99 CR/CRu 29 (85%) 18 (86%) 11 (85%) PR 5 (15%) 3 (14%) 2 (15%) Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 1. Analysis of Grade 3-5 Non-Hematologic Toxicities Figure 2. Kaplan-Meier Curve for PFS Figure 2. Kaplan-Meier Curve for PFS Figure 3. Kaplan-Meier Curve for OS Figure 3. Kaplan-Meier Curve for OS Disclosures Bhatt: Spectrum: Consultancy. Moskowitz:GSK: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding.

A Phase Ib/II Study of Combined Obinutuzumab (Gazyva) and High-Dose Methylprednisolone (HDMP) As Treatment for Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2051-2051 ◽  
Author(s):  
Januario E. Castro ◽  
Michael Y. Choi ◽  
Carlos I. Amaya-Chanaga ◽  
Natalie Nguyen ◽  
Colin MacCarthy ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
High Dose ◽  
Free Survival ◽  
Phase Ib ◽  
High Dose Methylprednisolone ◽  
Grade 3

Abstract High-dose methylprednisolone (HDMP) and rituximab (R) is an effective non-myelosuppressive treatment regimen for patients (pts) with chronic lymphocytic leukemia (CLL). Also, this combination has shown activity even in pts who have adverse leukemia-cytogenetics, such as del17p. Phase III studies have demonstrated that CLL pts treated with chlorambucil and obinutuzumab-Gazyva (G), another anti-CD20 mAb, had a superior outcome than comparable pts treated with R-chlorambucil. We hypothesized that G-HDMP is well-tolerated and effective in the treatment of pts with CLL. Accordingly, we initiated an open-label phase Ib/II clinical study. A total of 40 pts were enrolled in two cohorts of 20 pts each (previously untreated (PU) and relapsed/refractory (RR) CLL) and treated with HDMP 1 g/m2on Day 1-3 of cycles 1-4 (28 days/cycle) and G administered based on FDA dosing recommendations for 6 cycles. The pts had a median age of 67 years + 9.1 in the RR cohort and 63 years + 8.3 in the PU cohort. The median baseline absolute lymphocyte count was 30.7 + 7.3 x1,000/mm3 for pts in the RR cohort and 47.6 + 19.7 x1,000/mm3for pts in the PU cohort. Pts showed the following cytogenetic abnormalities: del(17p) in 30% RR vs. 0% PU, del(13q) in 60% RR vs. 70% PU, del(11q) in 20% RR vs. 35% PU, and trisomy 12 in 15% RR vs. 20% PU. Most AEs were grade 1-2 (RR=87%; PU=93%) without development of dose-limiting toxicities. Only two pts needed therapy discontinuation. One pt due to pulmonary embolism and the second pt due to asymptomatic gastrointestinal bleeding that required blood transfusion and resolved spontaneously. Grade 1-2 G-infusion-related reactions (IRR) were observed in 40% and 80% of pts in the RR and PU cohorts, respectively. Grade 3-4 IRR were observed in 10% of pts in the PU cohort only. We observed cytopenias (neutropenia grade 3-4: RR=55%, PU=40%; thrombocytopenia grade 3-4: RR=35%, PU=20%; and anemia grade 3-4: RR=0%, PU=0%). There were no cases of febrile neutropenia. Two pts (10%) in the RR cohort and one pt (5%) in the PU cohort developed infection grade 1-2 that was treated with oral antibiotics but did not require study treatment discontinuation. The most frequent non-hematological adverse events (AEs) were transaminitis, hyperglycemia, and electrolyte alterations (grade 1-2). There were no treatment related deaths in either cohort. The response assessment was performed in all 40 pts by iwCLL criteria. The ORR was 100% in the PU cohort and 95% in the RR cohort. 70% of the pts in the PU cohort and 85% of the pts in the RR cohort achieved a PR. CR was observed in 30% and 10% of the pts in the PU and RR cohorts, respectively. One pt (5%) in the RR cohort and four pts (20%) in the PU cohort achieved MRDneg status (<0.01% CLL in the bone marrow by multiparameter flow cytometry). Only one pt in the RR cohort achieved SD. At a median follow-up of 12.2 months, the RR cohort had a median Progression Free Survival (PFS) of 13.6 months and median Treatment Free Survival (TFS) of 14.7 months; the median Overall Survival (OS) has not been reached. In the PU cohort, the median PFS, TFS and OS have not been reached. One pt from the RR cohort and one pt from the PU cohort died during the follow-up period due to disease progression. G-HDMP was well tolerated and all 40 pts showed hematological and clinical responses during the study treatment without development of unexpected AEs. In both cohorts, most of IRR were grade 1-2 and severe IRR (grade 3-4) were much less compared with previously published data (G-chlorambucil / CLL-11 study). Compared to pts in the CLL-11 study, cytopenias appeared to be more frequent, however, the rate of infection and need for IV antibiotics or hospitalizations was lower. Of note, the eligibility criteria allowed pts with severe cytopenias and transfusion requirement to participate in our study. Response in PU pts were higher in terms of ORR, CR and CR-MRDnegativecompared with the data from the CLL-11 study and suggests a possible synergistic activity between G and HDMP. Overall, G-HDMP was well tolerated in the PU and RR CLL pts with a lower rate of IRR making this regimen more manageable in the outpatient setting. Responses were higher than previously reported in PU pts. Responses in RR pts appear to be comparable to our previous studies using R-HDMP. Our data supports G-HDMP as an alternative combination regimen for the treatment of CLL pts. Disclosures Kipps: Celgene: Consultancy, Honoraria, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria.

8 SURGERY AFTER HIGH DOSE CHEMOTHERAPY FOR POOR RISK NON SEMINOMATOUS GERM CELL TUMORS (GCTs): A LONG FOLLOW UP

2010 ◽  
Vol 36 ◽  
pp. S97
Author(s):  
F. Morelli ◽  
A. Cisternino ◽  
A.M. Capotorto ◽  
G. Palomba ◽  
P. Setola ◽  
...  
Keyword(s):  
Germ Cell ◽  
Germ Cell Tumors ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Poor Risk

scholarly journals Bortezomib Maintenance Therapy after Induction with R-CHOP, ARA-C and Autologous Stem Cell Transplantation in Newly Diagnosed MCL Patients, Results of a Multicenter Phase II HOVON Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 339-339 ◽  
Author(s):  
Jeanette K Doorduijn ◽  
Monique C. Minnema ◽  
Marie Jose Kersten ◽  
Pieternella J Lugtenburg ◽  
Martin R. Schipperus ◽  
...  
Keyword(s):  
Stem Cell ◽  
Maintenance Therapy ◽  
Phase Ii ◽  
Research Funding ◽  
Progressive Disease ◽  
Induction Treatment ◽  
High Dose ◽  
Newly Diagnosed ◽  
Grade 3

Abstract Introduction. The standard first-line treatment of young and fit mantle cell lymphoma (MCL) patients consists of a rituximab containing induction of CHOP and high dose ARA-C, followed by high dose consolidation and autologous stem cell transplant (ASCT). Thus far, almost all patients relapse after ASCT. Bortezomib is a proteasome inhibitor with activity in MCL. We investigated in a randomized phase II study whether there was any indication that maintenance therapy with bortezomib after ASCT could improve the outcome of treatment, measured as event free survival (EFS). Methods. Patients 18-65 years with newly diagnosed MCL were treated with 3 cycles of R-CHOP and 2 cycles of ARA-C (2 x 2 g/m2 iv d1-4) and rituximab (375 mg/m2, iv d11). Patients in PR or CR continued with ASCT after BEAM conditioning. Patients with a PR or CR after ASCT, with a neutrophil count > 0.5 x 109/l and platelets > 80 x 109/l were randomized between bortezomib and no further treatment. Bortezomib 1.3 mg/m2 iv was given once every two weeks, for 2 years, starting between 6 - 12 weeks after transplantation. Results . Between October 2007 and February 2012, 140 patients aged 34-66 years (median 57) were registered. Five patients were not eligible. The MIPI score was low, intermediate, high or unknown in 57%, 32%, 10% and 1% respectively. All eligible patients started induction treatment with R-CHOP. Two patients did not receive the first ARA-C cycle, because of progressive disease and physician decision. Hundred-fifteen patients (85%) received the BEAM and ASCT. Reasons to stop protocol treatment before ASCT were: progressive disease (PD) (n=6), inadequate stem cell harvest (n=3), excessive toxicity (n=3), other reasons (n=8). The response after ASCT was CR/CRu in 99 patients (86%), PR in 15 (13%), unknown in 1 (1%). Only 62 patients (45%), aged 34-65 years (median 56) were randomized between bortezomib maintenance and no further treatment. Two patients were randomized, but not eligible. Reasons for no randomization were: not eligible (n=30), patient refusal (n=14), excessive toxicity (n=2, and other reasons (n=7). In each treatment arm 30 patients were included. The patient characteristics were well balanced, except the MIPI score. In the no maintenance arm 21 patients (70%) had a low MIPI, compared to 15 patients (50%) in the bortezomib arm, and 6 (20%) versus 11 (37%) patients had an intermediate MIPI score. In both arms 3 patients (10%) had a high MIPI. Fifteen patients (50%) in the maintenance group continued bortezomib for 2 years. Reasons to stop earlier were excessive toxicity (n=6), PD/relapse (n=4), patients refusal (n=3) and other (n=2). The main adverse events during maintenance therapy were neurologic (CTC grade 2: 14%, grade 3: 4%), and infectious (grade 2: 11%, grade 3: 7%). Three patients developed a secondary malignancy: a basal cell carcinoma in the no maintenance group, a melanoma and a prostate carcinoma in the bortezomib group. With a median follow-up of the patients still alive of 50.9 months EFS at 4 years for all patients is 61%, and the overall survival (OS) 78%. The median follow-up of the randomized patients still alive is 42.9 months. The EFS at 4 years is 72% without maintenance versus 71% in the patients randomized for bortezomib maintenance. The OS at 4 years also shows no significant difference between the groups, 90% versus 93% respectively. Conclusion. There is no indication that bortezomib iv maintenance in a frequency of once every 2 weeks does improve the EFS of newly diagnosed MCL patients after intensive induction treatment with R-CHOP, double ARA-C and BEAM followed by ASCT. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Doorduijn: Celgene: Consultancy; Janssen: Consultancy; Roche: Consultancy. Off Label Use: bortezomib maintenance in MCL. Minnema:Celgene: Consultancy; Jansen Cilag: Consultancy; Amgen: Consultancy. Kersten:janssen: Honoraria, Research Funding; takeda millennium: Research Funding; roche: Honoraria, Research Funding. Lugtenburg:Mundipharma: Consultancy; Servier: Consultancy; Janssen-Cilag: Consultancy; Celgene: Consultancy; Roche: Consultancy. Schipperus:Novartis: Consultancy. Zijlstra:Celgene: Consultancy; Roche: Consultancy.

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