Safety and Efficacy of 90Y Ibritumomab Tiuxetan (Zevalin®) for Untreated FollicularNon-Hodgkin's Lymphoma (FL) Patients, An Italian Cooperative Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 100-100
Author(s):  
G. Pica ◽  
S. Nati ◽  
Umberto Vitolo ◽  
Sara Galimberti ◽  
Pier Luigi Zinzani ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Remission Rate ◽  
Bone Marrow Involvement ◽  
Single Agent ◽  
Multicenter Trial ◽  
Hematologic Toxicity ◽  
Ibritumomab Tiuxetan ◽  
Highly Effective ◽  
Grade 3 ◽  
Treatment Safety

Abstract Abstract 100 90Y ibritumomab tiuxetan (Zevalin®) combines the targeting advantage of monoclonal antibody with the radiosensitivity of FL. Previous studies showed that Zevalin resulted safe and highly effective in relapsed/refractory indolent NHL, irrespective to prior treatment with rituximab. Based on these results, we designed a multicenter trial to evaluate the safety and the efficacy of “upfront” single-agent Zevalin in FL. The primary endpoint was the incidence of responses in terms of overall remission rate (ORR) and complete remissions (CR). The secondary endpoints were the treatment safety by monitoring hematology and biochemistry parameters as well as adverse events. Fifty patients, with a median age of 59 years (range, 35–81), were treated. Forty-eight percent had bone marrow involvement (<25%) and 14% an elevated LDH. Thirty-four percent of patients had high risk FLIPI. Forty-six patients were also assessed by qualitative and quantitative PCR for Bcl2/IgH or IgH clonal rearrangement, for total 30 cases PCR-positive (65.2%). Results: The ORR was 93% (45/48) with a CR rate of 82% (41/48). Twenty-six patients, who were PCR-positive at diagnosis, were assessed at week 14. Twenty out of 26 (77%) became PCR-negative. After a median follow up of 24 months, the 2-year EFS for all patients was 85%; moreover, 15 patients (55%), who were PCR-positive at diagnosis, maintain PCR negativity. As expected, the main toxicity was moderate myelosuppression, with 30% and 26% of patients developing Grade 3/4 neutropenia and thrombocytopenia, respectively. Very few patients required platelets transfusion (4%) or growth factor use (6%). None of the patients experienced grade 3/4 non hematologic toxicity. In conclusion, Zevalin is highly effective and safe treatment for newly diagnosed FL patients. In the next future, the role of radioimmunotherapy - i.e. including optimal sequencing with chemotherapy - should be established in randomized studies. Disclosures: No relevant conflicts of interest to declare.

90Y Ibritumomab Tiuxetan (Y2B8, Zevalin®) Radioimmunotherap (RIT) Is Highly Effective for Relapsed or Refractory Indolent B-Cell Non-Hodgkin’s Lymphoma (B-NHL) Pretreated with Rituximab-Containing Chemotherapy (R-Chemo): Japanese Multicenter Phase II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2767-2767 ◽  
Author(s):  
Michinori Ogura ◽  
Yasuo Morishima ◽  
Takashi Watanabe ◽  
Tomomitsu Hotta ◽  
Kennichi Ishizawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Bone Marrow Involvement ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
Ibritumomab Tiuxetan ◽  
Multicenter Phase ◽  
Highly Effective ◽  
Grade 3

Abstract Background and Objectives: Y2B8 RIT has been reported to be effective in patients with relapsed or refractory indolent B-NHL pretreated with rituximab monotherapy or chemotherapy. However, no data has been available for Y2B8 in indolent B-NHL pretreated with R-chemo. We conducted a multicenter phase II study of Y2B8 RIT to evaluate its efficacy and safety in patients with relapsed or refractory indolent B-NHL, focusing on those pretreated with R-chemo. Patients and Treatment: The Y2B8 regimen comprised an infusion of rituximab (250 mg/m2) and injection of 111In ibritumomab tiuxetan (In2B8) (3.5 mCi [129.5 MBq]) for imaging interpretation and estimation of the feasibility of Y2B8 administration, followed 1 week later by rituximab (250 mg/m2) and Y2B8 (0.4 mCi [14.8 MBq/kg] for platelets >150,000/μL or 0.3 mCi/kg [11.1MBq/kg] for 100,000/μL< platelets <150,000/μL). A total of 45 patients (32–72 years; median, 57 years) were enrolled: 66.7%, of stage III/IV at study entry; 82.2%, with follicular lymphoma; 33.3%, with bone marrow involvement; and 55.6%, with more than 2 prior therapy regimens (range, 1–11). Of them, 40 patients were treated with Y2B8: 22 with 0.4 mCi/kg and 18 with 0.3 mCi/kg. Two patients showed prominent bone marrow uptake on imaging inspection and did not receive Y2B8. Twenty-two patients were previously treated with R-chemo (18 R-CHOP, 2 R-COPP, 2 CHASER, 1 R-FAMP, and 1 R-EPOCH) and 15 patients had received rituximab monotherapy. Only 5 patients had not received rituximab. Results: The overall response rate was 83% (63% complete response [CR], 5% complete response unconfirmed [CRu], and 15% partial response [PR]), as evaluated by International Workshop Criteria modified by Japan Clinical Oncology Group. %CR in patients pretreated with R-chemo was 73% (78% in pts pretreated with R-CHOP). The median progression-free survival (PFS) time was 9.6 months (95% CI: 7.3 months to not calculated) with a median follow-up time of 6.5 months (range: 1.2–12.7 months). In complete responders, the median PFS has not been reached. Toxicity was primarily hematologic, transient, and reversible except in 2 patients, in whom prolonged grade 3 cytopenia and anemia did not recover by 6 months after the therapy (neutropenia and decreased Hb in one and thrombocytopenia in another). The incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 43%, 5%, and 5%, respectively. No grade 4 non-hematologic toxicity was observed. Most frequent grade 3 non-hematologic toxicities were febrile neutropenia (4%), cystitis (4%), and pneumonia (4%). Conclusions: Y2B8 RIT is highly effective with acceptable toxicities in patients with relapsed or refractory indolent B-NHL. It is noteworthy that Y2B8 RIT brings high %CR in patients pretreated with R-chemo such as R-CHOP therapy.

Fludarabine, Mitoxantrone and Rituximab (FMR) Regimen in Previously Untreated Patients with Indolent Non-Hodgkin Lymphoma: Efficacy, Safety and PET Data On 285 Patients.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2736-2736
Author(s):  
Pier Luigi Zinzani ◽  
Cinzia Pellegrini ◽  
Enrico Derenzini ◽  
Alessandro Broccoli ◽  
Letizia Gandolfi ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Bone Marrow Involvement ◽  
Stage Ii ◽  
Hematologic Toxicity ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Significant Difference ◽  
Grade 3

Abstract Abstract 2736 In this retrospective single-center study we aimed at evaluating the efficacy and safety of fludarabine, mitoxantrone and rituximab (FMR) regimen as first line therapy in untreated patients with follicular non-Hodgkin lymphoma (NHL) and indolent non-follicular NHL considering also the role of positron emission tomography (PET) after this chemo-immunotherapy induction as predictor of survival. Between January 2000 and May 2011, 285 patients with stage II-IV untreated indolent follicular (excluding grade IIIb) NHL (n=142) and indolent non-follicular (including marginal zone lymphoma, MZL [n=111] and small lymphocytic lymphoma, SLL [n=31]) NHL (n=143) were diagnosed and treated at our institution in the outpatient clinic. Median age was 63 years (range, 25–83 years) and the median time from diagnosis to study entry was 3 months (range, 1–5 months). 20 patients had stage II, 75 patients had stage III, and 190 had stage IV disease (155 patients had bone marrow involvement). Standard fludarabine (25 mg/m2 iv on days 2, 3 and 4), mitoxantrone (10 mg/m2 iv on day 2) and rituximab (375 mg/m2 iv on day 1) were given every 28 days for six cycles. Globally, after FMR regimen, the overall response rate (ORR) was 83.2%, including a 71.6% complete remission (CR) rate (204 patients) and a 11.6% partial remission (PR) rate (33 patients). According to the histology, in the follicular subset, the ORR was 81.1% with a CR rate of 69.2% while in the indolent non-follicular subset the ORR was 85.2% with a CR rate of 73.9%. In particular, in the indolent non-follicular NHL subgroup the CR rate was 80.2% in MZLs and 51.6% in SLLs, respectively. Toxicities were generally mild and mainly hematologic. Overall 88 (30.8%) patients had grade ≥3 hematologic toxicity, and 26 (9.1%) patients had non-hematologic toxicity with 3 cases of grade ≥3 (1 neurologic toxicity and 2 hepatic toxicity). In terms of secondary malignancies, only 3 (1.0%) hematologic neoplasms were reported (1 myelodisplastic syndrome after 9 months from the end of the treatment and 2 acute lymphoblastic leukemia after 8 and 11 months from the end of the treatment, respectively). Globally with a median follow up of 40 months (range, 12–144 months), at 11 years the overall survival (OS) was 78.8%, the disease-free survival (DFS) was 73.4% (with only 29 relapses), and the progression-free survival (PFS) was 71.9%. Regarding the comparison between the two subsets, follicular vs indolent non-follicular, no statistically significant differences were observed in OS, DFS and PFS curves. Furthermore, a sub-sample of 132 patients (75 follicular NHLs and 57 indolent non-follicular NHLs) had a PET evaluation before the treatment (staging) and 4 to 6 weeks after completion of the sixth cycle of chemo-immunotherapy (restaging, final PET [f-PET]). Post-induction PET-positive patients had a significantly inferior OS at 6 years: 71.4% compared with 98.4% for f-PET-negative patients (p<0.0001, Figure 1a). In terms of PFS at 6 years, there was not a statistically significant difference among f-PET-positive patients and f-PET-negative patients (Figure 1b). Figure 1a. Figure 1a. Figure 1b. Figure 1b. In conclusion, this study suggests and confirms that FMR is a very active, well tolerated (in terms of acute and long-term side effects) chemo-immunotherapy front-line treatment for follicular NHL and indolent non-follicular NHL. PET status at the end of this chemo-immunotherapy induction is quite controversial as a predictor of survival. Disclosures: No relevant conflicts of interest to declare.

Single Agent Bendamustine Is An Effective Pre-Vaccine Treatment for Patients with Relapsed Follicular Lymphoma Undergoing Idiotypic Vaccination

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2691-2691 ◽  
Author(s):  
Maurizio Bendandi ◽  
Carlos Becerra ◽  
Joseph Kuhn ◽  
Suncica Hukic ◽  
Nyla Langford ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Conflicts Of Interest ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Variable Intensity ◽  
Vaccine Treatment ◽  
Common Grade ◽  
Idiotype Vaccine ◽  
Grade 3 ◽  
Abstract Submission

Abstract Abstract 2691 Over the last two decades, idiotypic vaccination has shown evidence of biological efficacy, clinical efficacy and clinical benefit in some subsets of patients with follicular lymphoma. Despite this, no idiotype vaccine has yet obtained regulatory approval. A phase-I clinical trial is currently being conducted to assess safety and immunogenicity of therapy with bendamustine and prednisone (BP) followed by administration of a novel, recombinant idiotype vaccine in which the idiotype protein is produced in tobacco plants. Patients eligible for the study are those with relapsed follicular lymphoma whose prior treatment has included rituximab. Use of rituximab is prohibited in this trial due to its potentially negative interference with vaccination as a consequence of the prolonged B-cell depletion that characteristically follows its administration. Subjects enrolled in the study who achieve and maintain either a complete (CR) or partial (PR) response for at least 4 months following BP therapy undergo idiotype vaccination. The response to initial BP therapy prior to vaccine administration is the subject of this report. At the time of abstract submission, fourteen patients have completed four monthly cycles of bendamustine (120 mg/m2 IV on day 1 and 2) and prednisone (100 mg PO on day 1 through 5). Of the thirteen patients evaluable for clinical response, eleven (85%) have achieved a CR and two (15%) a PR. Six patients maintained their response for at least 4 months and went on to receive idiotypic vaccine. The other six patients are currently in the 4-month protocol specified off-therapy period between chemotherapy and vaccination. One patient, who achieved a CR, relapsed during this period and was not vaccinated. With this exception, and with an overall median follow-up of 5 months (range: 2–12 months), all other responses described above have been maintained. Currently, toxicity data are available for 54 cycles of BP. There was no grade 4–5 non-hematologic toxicity. Grade 3 non-hematologic toxicity was recorded in 5/14 (36%) patients and in 9/54 (17%) cycles, respectively, and included hyperglycemia, diarrhea, nausea, dehydration and hypotension. Grade 1–2 non-hematologic toxicities were relatively common and in line with those previously reported for the BP regimen. Only 1/54 BP cycles was delayed due to grade neutropenia. In this case, the planned cycle was administered two weeks later. Overall grade 4 hematologic toxicity was recorded in 4/14 (14%) patients and in 7/54 (13%) cycles, respectively, and included neutropenia and lymphopenia. Grade 3 hematologic toxicity was recorded in 9/14 (64%) patients and after 21/54 (39%) cycles, respectively, and included leukopenia, neutropenia, lymphopenia and thrombocytopenia. Overall, lymphopenia was the most common grade 3–4 hematologic toxicity. Grade 1–2 hematologic toxicities were common, expected, and included anemia, leukopenia, neutropenia, lymphopenia and, occasionally, thrombocytopenia. Data are available for four patients to analyze post-chemotherapy B- and T- cell recovery.Patientlymphocytes/mlCD3(+)CD4(+)CD8(+)CD19(+)nl range1000–4000960–2600540–1660270–930122–632pre*post*prepostprepostprepostprepostA71311664717702281402505953618B8892545711343445822672568076C878944632632360113272538132198D16627761080590698171399404266109*pre=before first dose of chemotherapy, post=4 months post chemotherapy These preliminary data indicate that BP is a very effective and well tolerated chemotherapy regimen in patients with relapsed follicular lymphoma who have been previously received rituximab therapy. Our data also suggest that, in some patients, BP can cause a lymphopenia of variable intensity that may not fully recover four months after the last chemotherapy cycle. Studies of idiotype vaccine-induced humoral and cellular immune responses and their correlation with the presence of lymphopenia are ongoing. Updated results will be available at the time of the meeting. The authors wish to acknowledge Drs. Ralph Heaven, Larry Barker, Jairo Olivares, Thomas Anderson, Carl Chakmakjian, Barry Cooper, Amir Faridi, Vinay Jain, Pankaj Khandelwal, Janice Marshall, Anton Melnyk, Robert Mennel, James Turner Disclosures: No relevant conflicts of interest to declare.

Bortezomib in Combination with Dexamethasone for Relapsed Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4923-4923
Author(s):  
Martin H. Kropff ◽  
Guido Bisping ◽  
Doris Wenning ◽  
Wolfgang E. Berdel ◽  
Joachim Kienast
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Adverse Events ◽  
Disease Progression ◽  
Remission Rate ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Minor Response ◽  
Chromosome 13 ◽  
Grade 3

Abstract Single agent bortezomib treatment at the dosage and schedule published by Richardson (2003) stabilizes disease in nearly 60% of patients with relapsed, refractory multiple myeloma (MM). However, only 35% of patients achieve an objective (≥ minor) response (MR). Dexamethasone adds to clinical anti-myeloma activity of bortezomib by inducing 18% responses in patients with either stable or progressive disease on bortezomib alone. In an attempt to improve disease response, we evaluated a primary bortezomib/dexamethasone combination in patients with multiple myeloma in ≥ 2nd untreated or refractory relapse. Eligible patients were 18–80 years old, had an ECOG performance status of 0 – 2 and adequate renal, hepatic, pulmonary and cardiac function. Pre-existing peripheral neuropathy ≥ grade 2 or neuropathic pain of any grade were exclusion criteria. However, we made no restrictions in terms of pretreatment blood counts. Fifteen consecutive patients with relapsed multiple myeloma (9/15 with ≥ 2nd untreated and 6/15 with refractory relapse; 71% with a chromosome 13 deletion) were scheduled to receive bortezomib 1.3 mg/m² IV days 1, 4, 8, 11 q 3 weeks for up to 8 cycles in combination with dexamethasone 20 mg PO once daily on the day of bortezomib injection and the day thereafter. Treatment was withheld for nonhematologic adverse events (AE) ≥ grade 3 and reinitiated at a 25% lower dose after resolution. Treatment was not stopped for myelosuppression of any grade if interim response evaluations precluded myeloma progression as the cause of cytopenia. One patient (7%) achieved a complete response, 10 (67%) a partial response, and 1 (7%) a MR resulting in an overall response rate (≥ MR) of 80% (9/9 with ≥ 2nd untreated and 3/6 with refractory relapse; EBMT/IBMTR/ABMTR criteria). Responses occurred after a median of 3 weeks and were independent of conventional prognostic parameters. Importantly, 8/10 patients with a chromosome 13 deletion achieved a ≥ PR. Adverse events, mainly myelosuppression (34% grade 3/4 neutropenia; 47% grade 3/4 thrombocytopenia), neuropathy (grade 2/3/4 20%/7%/0%) and fatigue (grade 2/3/4 20%/13%/20%), were manageable. There was no case of neutropenic infection or thrombocytopenic bleeding. Two patients suffered herpes zoster. The percentage of transfusion dependent patients decreased from 44% during the 1st treatment cycle to 23% and 11% after the 2nd and 3rd treatment cycles, respectively. Even non-responders did not experience cumulative hematologic toxicity. After a median follow-up of 5 months, median event free and overall survival were not reached. Five out of 15 patients were non-responders (n=1) or had experienced disease progression (n=4). Notably, 2 patients with sustained paraprotein and bone marrow remission (confirmed by biopsy) had extramedullary disease progression, pointing to a bone marrow restricted response to bortezomib in MM. This study indicates that bortezomib can be given safely even in patients with poor bone marrow reserve, who would not have been candidates for the SUMMIT trial. Though the remission rate was high, remissions often were not durable. This fact underlines the need for consolidating treatment and evaluation of bortezomib combinations with other anti-myeloma agents.

scholarly journals Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrick B. Johnston ◽  
Amanda F. Cashen ◽  
Petros G. Nikolinakos ◽  
Anne W. Beaven ◽  
Stefan Klaus Barta ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Dose Intensity ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
T Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Peripheral T Cell Lymphoma ◽  
Grade 3

Abstract Background Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine the maximum tolerated dose (MTD) of belinostat combined with CHOP (Bel-CHOP). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK). Methods Patients were ≥ 18 years with histologically confirmed, previously untreated PTCL. Patients received belinostat (1000 mg/m2 once daily) + standard CHOP for 6 cycles with varying schedules using a 3 + 3 design in Part A. Part B enrolled patients at MTD dose. Results Twenty-three patients were treated. One patient experienced DLT (Grade 3 non-hematologic toxicity) on Day 1–3 schedule, resulting in escalation to Day 1–5 schedule (n = 3). No DLTs were observed and Day 1–5 schedule with 1000 mg/m2 was declared as MTD. Twelve additional patients were enrolled in Part B using MTD. Median relative dose intensity was 98%. All patients experienced adverse events (AEs), including nausea (78%), fatigue (61%), and vomiting (57%). Serious AEs occurred in 43%, with febrile neutropenia (17%) and pyrexia (13%). Overall ORR was 86% with 71% reported CR at MTD. Belinostat PK parameters were similar to single-agent. Conclusions Bel-CHOP was well tolerated and MTD in CHOP combination was the same dose and schedule as single agent dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT01839097.

Gemcitabine as a Single Agent in the Treatment of Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

1999 ◽  
Vol 17 (12) ◽  
pp. 3786-3792 ◽  
Author(s):  
A. Fosså ◽  
A. Santoro ◽  
W. Hiddemann ◽  
L. Truemper ◽  
N. Niederle ◽  
...  
Keyword(s):  
Partial Response ◽  
Confidence Interval ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Single Agent ◽  
World Health ◽  
Hematologic Toxicity ◽  
Grade 3 ◽  
Health Organization ◽  
Hodgkin's Lymphomas

PURPOSE: A multicenter phase II trial was conducted to evaluate the efficacy and toxicity of gemcitabine in patients with relapsed or refractory aggressive non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: Thirty-one patients with B-cell intermediate or high-grade NHL (Working Formulation) were enrolled onto the study. The median age was 61 years, with a Karnofsky performance status of ≤ 80% in 65% of patients. Forty-eight percent had stage III or IV (Ann Arbor Classification) at study entry. Pretreatment consisted of one, two, or three chemotherapeutic regimens in nine, 11, and 11 patients, respectively. Gemcitabine 1,250 mg/m2 was administered intravenously over 30 minutes on days 1, 8, and 15 of a 28-day schedule. RESULTS: Thirty patients were assessable for efficacy, and 31 were assessable for toxicity. No complete responses were observed, but six patients showed a partial response, 11 stable disease, and 13 progressive disease. The overall response rate was 20% (95% confidence interval, 8% to 39%) for assessable patients and 19% (95% confidence interval, 8% to 34%) for the intent-to-treat analysis. The median duration of partial response was 6 months (range, 3.7 to 15+ months). Nonhematologic World Health Organization grade 3 toxicity included hepatic toxicity in four patients and infection in two. Hematologic toxicity was observed as grade 3 anemia in three patients, grade 3 leukopenia in two patients, grade 3/4 neutropenia in two patients, and grade 3/4 thrombocytopenia in six patients. CONCLUSION: The present schedule of gemcitabine displays modest efficacy and mild toxicity in pretreated aggressive NHL.

scholarly journals Phase II Trial of Vorinostat in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study

2009 ◽  
Vol 27 (12) ◽  
pp. 2052-2058 ◽  
Author(s):  
Evanthia Galanis ◽  
Kurt A. Jaeckle ◽  
Matthew J. Maurer ◽  
Joel M. Reid ◽  
Matthew M. Ames ◽  
...  
Keyword(s):  
Glioblastoma Multiforme ◽  
Statistical Significance ◽  
Single Agent ◽  
Rest Period ◽  
Recurrent Glioblastoma ◽  
Pharmacokinetic Analysis ◽  
Hematologic Toxicity ◽  
Recurrent Glioblastoma Multiforme ◽  
Grade 3 ◽  
Recurrent Gbm

PurposeVorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM).Patients and MethodsPatients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period.ResultsA total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26% of patients and consisted mainly of fatigue (17%), dehydration (6%), and hypernatremia (5%); grade 3 or worse hematologic toxicity occurred in 26% of patients and consisted mainly of thrombocytopenia (22%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months. Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02).ConclusionVorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted.

SDX-105 Demonstrates a High Response Rate as a Single-Agent with Acceptable Safety in Rituximab-Refractory, Relpased Indolent or Transformed Non-Hodgkin’s Lymphoma (NHL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2480-2480 ◽  
Author(s):  
Jonathan Friedberg ◽  
Philip Cohen ◽  
Robert O. Kerr ◽  
K. Sue Robinson ◽  
Andres Forero-Torres ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Reduction ◽  
Overall Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Mitotic Catastrophe ◽  
Hematologic Toxicity ◽  
Overall Response ◽  
Cell Death Pathway ◽  
Grade 3

Abstract SDX-105 (Treanda™, Bendamustine HCl) is an alkylating agent that may exert its anti-tumor activity via mitotic catastrophe, an apoptosis-independent cell-death pathway, as well as, through apoptosis. Its cytotoxic potency is unattenuated in chemotherapy-resistant lymphoma cell lines. We initiated a multi-center Phase II trial to investigate the safety and efficacy of SDX-105 in patients with rituximab-refractory, relapsed indolent or transformed B cell NHL. Patients must have pathologically-confirmed disease that has been demonstrated to be rituximab-refractory (no response or progression within 6 months) or must be intolerant of rituximab. Other requirements include measurable disease, adequate renal, hepatic and bone marrow function (ANC ≥1K/mm3, platelet ≥ 100K/mm3, except in cases of &gt;50% NHL in bone marrow), up to 3 prior chemotherapies, and no prior allogeneic transplant. Patients receive SDX-105, 120 mg/m2 IV over 30–60 min, days 1 and 2, every 21 days. Grade 4 hematologic toxicity during a cycle results in dose reduction for subsequent cycles (to 90 mg/m2 and then to 60 mg/m2). Patients achieving stable disease or better after 6 cycles may receive up to 6 more cycles. 49 patients have been accrued to date with data available on the first 15 patients. The median age is 69 yrs (range 47–84), 47% male, median 6 yrs since diagnosis with NHL. Histologies: 10 follicular (6 Grade 1, 3 Grade 2, 1 Grade 3), 2 SLL, 1 marginal zone and 2 transformed NHL. Other features include: 93% Stage III/IV, 20% with B symptoms, 87% with extranodal disease, median 2 prior chemotherapies with 40% not responding to last chemotherapy. 4 patients have required dose reduction to 90 mg/m2 and 2 patients have withdrawn prior to completing 6 cycles due to treatment-associated toxicity. The current overall response rate (ORR) based upon best response in the intent-to-treat population is 80% (CR/CRu 20%, PR 60%). Overall 73% of patients experienced a related non-hematologic adverse event (AE), of which 20% were Grade 3 and 0% Grade 4. The most frequent AEs were nausea (40%), vomiting (27%), fatigue (33%), anorexia (20%), and constipation (20%). Alopecia was not observed. Grade 3 or 4 hematologic toxicity was seen in 53% (neutropenia), 20% (thrombocytopenia), and 13% (anemia) of patients. 4 patients experienced serious AEs, including 1 patient with baseline renal insufficiency who died on study from renal failure and pulmonary edema; other events include admissions for fever and anemia, urinary tract infection, and dehydration. Based upon these preliminary findings, SDX-105 demonstrates a high overall response rate with acceptable hematologic toxicity and modest non-hematologic toxicity in a relapsed lymphoma patient population, many of whom are refractory to rituximab-chemotherapy combinations. An additional study evaluating the combination of SDX-105 and rituximab in patients with relapsed indolent NHL who are rituximab-sensitive is also ongoing.

A Multi-Center, Open-Label Study To Evaluate the Safety and Efficacy of Pentostatin, Cytoxan, and Rituxan (PCR) in the Treatment of Previously Untreated or Treated, Stage III or IV, Low-Grade B-Cell Non-Hodgkin’s Lymphoma (NHL) or Bulky Stage II Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1354-1354
Author(s):  
Raul R. Mena ◽  
Neil P. Christiansen ◽  
Yudhishtra Markan ◽  
Lalita Pandit
Keyword(s):  
Febrile Neutropenia ◽  
B Cell ◽  
Single Agent ◽  
Stage Ii ◽  
Stage Iii ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Purine Analog ◽  
Previously Treated ◽  
Grade 3

Abstract The decision to treat indolent B-cell NHL is often based on progression of the disease. Most regimens have utilized fludarabine as the purine analog but the myelosuppression and immunosuppression of fludarabine combinations frequently results in severe infections. Combination therapy with pentostatin (P), a purine analog, cyclophosphamide (C), a DNA alkylator, and rituximab (R), an anti-CD20 monoclonal antibody, based on the single-agent activities, documented synergy, and non-overlapping toxicity profiles, may represent a promising approach in the treatment of these patients. To further investigate the efficacy of the PCR regimen for the treatment of indolent NHL, we conducted a phase II study. Patients diagnosed of bulky stage II, stage III/IV low-grade NHL (REAL classification), previously untreated or treated, were eligible. All patients were treated with intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for at least 8 cycles. 2 additional cycles were given for patients with PR or SD after cycle 8 or patients with CR/CRu first evident at cycle 8. Clinical evaluation was performed after cycles 2, 4, 6, 8, and 10 if necessary. Dose modification for hematologic toxicity may be increased to the previous higher level when a hematologic toxicity returned to normal. Two 25% dose reductions or one 50% dose reduction were allowed for nonhematologic toxicity. One hundred patients with indolent NHL, 68 previously untreated, 26 previously treated, and 6 with unknown treatment history, were enrolled in the study. The median age was 61 years (range 29–84) and 63.4% were ECOG PS 0, 36.6% PS1. A total of 550 cycles were given, with a median of 6 cycles per patient. 8 patients were not evaluated for response due to withdrawal of consent (n=1), unacceptable toxicities (n=3), and missing data (n=4). 92 patients received at least two cycles of treatment and were evaluated for response. The highest response rate (RR) achieved was 68%, with 10 (10%) CR, 12 (12%) CRu, 46 (46%) PR, 23 (23%) SD, and 1 (1%) disease progression. Stratified according to previous treatment status, patients with previously untreated NHL had an RR of 47% (CR, CRu 17%) while that of the previously treated was 17% (CR 7%). 14 (14.0%) patients discontinued treatment due to toxicities. Grade 3/ 4 hematological adverse events documented included 10 grade 4 and 16 grade 3 neutropenia. Infectious complications were noted in 8 patients including 3 grade 3 febrile neutropenia, 2 grade 4 febrile neutropenia, and 3 grade 3 infections. A total of 4 deaths were recorded, including 1 due to acute myocardial infarction, 1 suspected cardiac event and 2 unknown causes. This immunochemotherapeutic regimen is active in patients with indolent NHL. The study is currently on-going and updated results will be presented.

Tolerability and Efficacy of Bortezomib Added to CVP-R for Previously Untreated Advanced Stage Follicular Lymphoma: Interim Analysis of a Phase II Study by the NCIC Clinical Trials Group.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1576-1576 ◽  
Author(s):  
Laurie H Sehn ◽  
David A Macdonald ◽  
Sheldon H. Rubin ◽  
Morel Rubinger ◽  
Kevin R Imrie ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase Ii ◽  
Interim Analysis ◽  
Standard Dose ◽  
Single Agent ◽  
Acceptable Level ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Open Label ◽  
Grade 3

Abstract Background: Despite recent improvements in therapy, follicular lymphoma (FL) remains incurable with standard treatment, warranting investigation of new approaches. Bortezomib, the first-in-class proteasome inhibitor has demonstrated promising efficacy as a single agent in heavily pretreated patients (pts) with FL. This is the first study to evaluate the safety and efficacy of the addition of bortezomib to cyclophosphamide, vincristine, prednisone and rituximab (CVP-R). Methods: This is a phase II multi-center open-label trial adding bortezomib (1.3 mg/m2 day 1&8) to standard dose C(750 mg/m2) V(1.4 mg/m2, capped at 2 mg) P(40 mg/m2 × 5) –R(375 mg/m2) for up to 8 cycles in pts with newly diagnosed stage III/IV FL requiring therapy. Planned accrual is 90 patients. A two-stage design was employed with a planned interim analysis of the first 28 patients to ensure an acceptable level of neurotoxicity (defined as less than 5/28 patients with grade 3/4 neurotoxicity after the first 4 cycles) and meaningful response rate (more than 12/28 patients with a complete response following 8 cycles), prior to enrolling remaining patients. Results: Median age of the first 28 patients was 55 years (range, 30–73). Fifty percent were male and 79% had stage IV disease. FLIPI score at study entry: low 14%, intermediate 43%, high 43%. Overall, the combination of bortezomib and CVP-R was extremely well tolerated. To date, no pts have developed grade 4 neurotoxicity and only 1/28 (4%) has developed grade 3 neurotoxicity within the first 4 cycles (neuropathic pain which resolved without need for treatment modification). The incidence of grade 1 and 2 neurotoxicity was 54% and 25% respectively. Only 3 pts discontinued therapy prematurely (2 pt refusal, 1 progressive disease). Ninety-four percent of planned bortezomib treatments in the first four cycles and 93% of vincristine doses were administered without dose reduction. Hematologic toxicity was mild, with no pts experiencing grade 3/4 anemia or thrombocytopenia. Only 2 episodes of febrile neutropenia occurred and no grade 3/4 infections were noted. Although it is too early to report on efficacy in this ongoing trial, response objectives for stage I have been met, and enrollment to stage 2 is underway. Conclusions: The addition of bortezomib to standard dose CVP-R is very well tolerated, with an acceptable level of neurotoxicity, without compromising the delivery of bortezomib or vincristine. This ongoing study will provide toxicity and efficacy data to facilitate the development of a planned phase III trial.

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