Idiotypic Vaccination of Patients with Relapsed Follicular Lymphoma Using a Novel Vaccine Formulation Including a Tobacco Plant-Produced Tumor Specific Idiotype

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1649-1649
Author(s):  
Maurizio Bendandi ◽  
Carlos Becerra ◽  
Joseph Kuhn ◽  
Suncica Hukic ◽  
Nyla Langford ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Follicular Lymphoma ◽  
Injection Site ◽  
Conflicts Of Interest ◽  
Hematologic Toxicity ◽  
Vaccine Formulation ◽  
The Novel ◽  
Single Chain ◽  
Idiotype Vaccine ◽  
Grade 3

Abstract Abstract 1649 Idiotypic vaccination has shown evidence of biological efficacy, clinical efficacy and clinical benefit in some subsets of patients with follicular lymphoma. A phase-I clinical trial is currently being conducted to assess safety and immunogenicity of a novel, recombinant idiotype vaccine in which the idiotype protein is produced in tobacco plants. Previous animal and clinical studies with plant-produced single-chain variable fragment lymphoma vaccines have demonstrated specific immunogenicity and safety. However, the expression levels of such fragments were highly variable and required complex engineering of the linkers. Moreover, the downstream processing could not be built around standard methods like protein A affinity capture. Our novel vaccine manufacturing process by magnICONR technology is devoid of such shortcomings and allows consistent and efficient expression in plants of idiotype-containing, whole immunoglobulins. Safety and tolerability of the novel vaccine formulation is the subject of this report. Patients eligible for the study are those with relapsed follicular lymphoma whose prior treatment has included rituximab. Patients receive salvage therapy with bendamustine and prednisone. Use of rituximab is prohibited on this trial due to 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. Six patients have received a variable number of monthly doses of the novel, first-in-human, magnICONR produced idiotype vaccine. Each dose includes a conjugate of 0.5 mg of idiotype and 0.5 mg of keyhole limpet hemocyanin on day 1. A dose of 0.125mg of GM-CSF is administered with the idiotype vaccine on day 1 and alone subcutaneously at the same injection site on day 2 through 4. Each vaccination cycle is repeated every four weeks. The vaccination schedule as defined by the protocol outlines eight monthly vaccination cycles followed by four bi-monthly vaccination cycles for a total of 12 vaccinations. No patient has yet completed the entire vaccination protocol and no patient has relapsed/progressed while receiving vaccine. Two patients have received eight vaccinations. The remaining four patients have received five, four, two and one vaccination, respectively. The patient who received two vaccinations was removed from the study after the development of progressive multifocal leukoencephalopathy Undefined symptoms had appeared prior to the initiation of vaccine and PML was subsequently attributed to previous, prolonged maintenance treatment with rituximab received prior to the enrollment in this clinical trial. Toxicity data are available for 28 doses of idiotype vaccine. There has been no grade 4–5 hematologic and non-hematologic toxicity. Grade 3 non-hematologic toxicity was recorded in 1/6 (17%) patients and in 1/28 (4%) cycles, respectively, consisting of generalized pain during one day. Grade 1–2 non-hematologic toxicities were recorded in all six patients and virtually in all cycles. The most common of them were fatigue, pain at the injection site, myalgia, diarrhea, headache and generalized pain. Grade 3 hematologic toxicity was recorded in 2/6 (33%) patients and in 2/28 (7%) cycles, respectively, and consisted predominantly of leucopenia. Grade 1–2 hematologic toxicities were common, most often consisting of anemia and thrombocytopenia. These preliminary data indicate that this novel idiotype vaccine is well tolerated in patients with relapsed follicular lymphoma following chemotherapy with BP. Studies of vaccine-induced humoral and cellular immune responses are ongoing. Results will be updated 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.

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.

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.

Inter-Reader Variability In Identifying Centroblast Cells From Digital Follicular Lymphoma Cases

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 5095-5095
Author(s):  
Kamel Belkacem-Boussaid ◽  
Michael Pennell ◽  
Arwa Shana' Ah ◽  
Amy Gerwitz ◽  
Weiqiang Zhao ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Digital Images ◽  
Conflicts Of Interest ◽  
Test Procedure ◽  
Observer Agreement ◽  
Kappa Statistics ◽  
High Power Field ◽  
Data Set ◽  
Grade 3 ◽  
Grade Iii

Abstract Abstract 5095 Method The goal of this research is to assess inter-reader variability in identifying centroblast (CB) cells from digitized H&E-stained Follicular Lymphoma (FL) cases. We have enrolled three board-certified hematopathologists experienced in FL grading to complete reading sessions on 500 High Power Field (HPF: 40 × magnification) images that were selected from 17 H&E digital slides by three hematopathologists. Each slide represents one patient and the dataset is comprised of lymphoma cases with all grades 1, 2, and 3 of FL. Each pathologist was asked to grade the same set of images (500 images). The pathologists examined digital images and recorded the spatial coordinates of CBs using in-house developed software that allowed pathologists to mark CB cells using only a computer mouse. Experimental Results The results from each reading session were analyzed in terms of FL grade which was determined by averaging the centroblast counts across the 28–30 images for a patient and assigning grade using the standard WHO guidelines: Grade I = 0–5, Grade II = 6–15, Grade III = > 15 centroblasts/image. First, we used kappa and p-values in order to measure inter-reader agreement on the three level grades and then we computed the same metrics to measure agreement on a two level diagnosis: Grade I or II (no chemoprevention assigned) versus Grade III (chemoprevention assigned). Discussion Table 1 provides the weighted kappa statistics based on the three level grading system. There was significant moderate agreement between pathologists 1 and 2 in grade level. However, pathologist 3 shows high disagreement with respect to pathologists 1 and 2 in grade. We also examined agreement based on the clinically significant diagnosis (Grade I or II versus III) (see table 2), the kappa statistics show that pathologists 1 and 2 moderately agreed in their diagnosis, though the agreement was only marginally significant. However, we again see that pathologist 3 did not agree with pathologists 1 and 2. In these cases, the weighted kappas are equal to zero suggesting that there is no agreement between pathologist 3 and pathologists 1 and 2. Table 3 demonstrates the average grade determination for each pathologist per patient. Table 4 exhibits the mean and the standard deviation of centroblast count for each pathologist per patient. These tables demonstrate that there is a large amount of variability in both grade and centroblast count; pathologist 2 identified the most centroblasts and consequently identified the highest percentage of grade 3 cases. Pathologist 3, was considerably more conservative than pathologists 1 and 2 in identifying centroblasts and did not identify any grade 3 cases. Conclusion In this study, we have examined inter-reader variability in grading follicular lymphoma in digital images based on centroblast count. We found high variability in centroblast counts and grade across pathologists resulting in agreement, which ranged from none to moderate at best. A larger data set and more pathologists will be considered in the near future to improve the generalizability of our results. References 1. J. R. Landis and G. G. Koch “The measurement of observer agreement for categorical data” in Biometrics, 1977, vol. 33, pp. 159–174. 2. S. Holm “A simple sequentially rejective multiple test procedure” in Scandinavian Journal of Statistics, 1979, vol. 6, pp. 65–70. Disclosures: No relevant conflicts of interest to declare.

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.

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.

Idiotype vaccine therapy (BiovaxID) in follicular lymphoma in first complete remission: Phase III clinical trial results

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2-2
Author(s):  
S. J. Schuster ◽  
S. S. Neelapu ◽  
B. L. Gause ◽  
F. M. Muggia ◽  
J. P. Gockerman ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Complete Remission ◽  
Follicular Lymphoma ◽  
Phase Iii ◽  
Phase Iii Clinical Trial ◽  
Idiotype Vaccine ◽  
Remission Phase ◽  
Clinical Trial Results ◽  
Final Text ◽  
First Complete Remission

2 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. [Table: see text]

scholarly journals PVAG Regimen (Prednisone, Vinblastine, Doxorubicin, Gemcitabine) Used in Real-Life Setting in First Line Therapy for Elderly Classical Hodgkin Lymphoma Patients: A Retrospective Study of Lysa Centers

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 11-11
Author(s):  
Guillaume Aussedat ◽  
Maryam Idlhaj ◽  
Amandine Durand ◽  
Xavier Roussel ◽  
Pauline Brice ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Real Life ◽  
Hematologic Toxicity ◽  
Classical Hodgkin Lymphoma ◽  
First Line ◽  
Real Life Setting ◽  
Grade 3 ◽  
Advisory Role

Introduction: Older patients with an age above 60 years with classical Hodgkin lymphoma (cHL) represent a proportion of 20% to 30% of all cHL. Older cHL patients are characterized by unfavorable prognostic factors with an aggressive disease, a poor tolerance to chemotherapy especially with bleomycin-induced lung toxicity resulting to a significant reduced survival as compared to younger patients. PVAG regimen (prednisone, vinblastine, doxorubicin, gemcitabine) was developed by the German Hodgkin Study Group (GHSG) to improve results and reduce toxicities of ABVD regimen. In a prospective phase II study of 55 early unfavorable and advanced-stage elderly HL patients (median age, 68 years), 78% achieved complete response (CR) with a 3-year progression free survival (PFS) and overall survival (OS) rates of 58% and 66%, respectively (Böll et al, Blood 2011) with favorable toxicity profile. To the best of our knowledge, there is no report that described efficacy and toxicity of this protocol in real-life setting. Methods: Between June 2011 and February 2020, 49 elderly patients with cHL received first-line chemotherapy with PVAG (Prednisone 40 mg/m2, Vinblastine 6 mg/m2, Doxorubicin 50 mg/m2, Gemcitabine 1000 mg/m2, or adapted-dose of PVAG) in 6 LYSA centers. All medical records were reviewed for clinical and biological characteristics, modality of treatment, responses and outcome. Comorbidities were evaluated according to the cumulative illness rating scale for geriatrics (CIRS-G) and treatment-related toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). Results: The median age of the 49 patients was 76 years (range, 61-87) with 44 patients ≥70 years old (69%) and 27 male (55%). Ann Arbor stages were as follows: II (n=16, 33%), III (n=12, 24%), IV (n=21, 43%). Altered performance status (PS 2-4) was presented in 35% of patients and B symptoms in 59%. IPS was ≥3 in 32 (65%) patients. CIRS-G Grade 3 or 4 in two or more categories was observed in 11 patients (22%) and 22 patients (43%) had a cumulative CIRS-G score over 6. Patients received a median of 6 cycles (range 1-8), 21 of them (43%) received adapted dose of PVAG. Seven patients (14%) received radiotherapy after respectively 3, 4, 6, or 8 cycles of PVAG. At the end of PVAG regimen, 26 patients were in CR (53%), 4 PR (8%), 19 patients progressed (39%). For the 46 patients who were evaluated by PET-CT after chemotherapy, the CR and PR rates were 52% and 13% with 35% of patients with stable or progressive diseases. For hematologic toxicity, 6 patients (12%) developed febrile neutropenia, 22 (45 %) had grade III-IV neutropenia; 8 (16 %) a grade 3-4 thrombopenia; 17 (35%) grade 3-4 anemia. Extra-hematologic toxicities were mild with three patients (6%) with grade 3-4 mucositis, 2 (4%) grade 3-4 nausea, 5 (10%) with grade 3-4 neuropathy, 3 (6%) acute heart toxicity. With a median follow up of 33,2 months (range, 14,3 -53,7), 26 (53%) patients progressed or relapsed. The median PFS was 21,6 months with a 3-year PFS rate of 48,6% (95%CI, 36,3-65,1). The median overall survival (OS) was 66,5 months with a 3-year OS rate of 73,7% (95%CI, 61,2-88,8). The cause of death was HL in 8 patients (16%), infection in 2 (4%); one toxic death occurred (sepsis after first cycle of PVAG). In univariate analysis, PFS (HR: 2,36, 95CI, 1,01-5,48, P=0.0,046) and OS (HR: 4,23, 95%CI, 1,15-15,6, P=0.03) were adversely affected by high number of medications (&gt;3). OS was adversely affected by grade 3-4 CIRS-G in ≥2 categories (HR: 3,63, 95%CI, 1,23-10,71, P=0.019). Age, IPS, presence of B symptoms, lymphopenia, anemia, low albumin level, CIRS-G&gt;6 did not affect outcome. Conclusions:Our real-life evaluation of PVAG regimen showed that patients were older than those included in the pivotal clinical trial and 58% of patients received adapted-dose of chemotherapy. We confirmed the favorable safety profile of this protocol. Using TEP-scan evaluation, the CR rate was 52%. Survival analyses supported initial results obtained in clinical trial. Combinations with immunotherapies with clinical activity in cHL should be evaluated to improve results of this regimen. Disclosures Brice: Takeda: Consultancy; Roche: Consultancy. Salles:Epizyme: Honoraria, Other: consultancy or advisory role; Kite, a Gilead Company: Honoraria, Other: consultancy or advisory role ; Janssen: Honoraria, Other: consultancy or advisory role; BMS/Celgene: Honoraria, Other: consultancy or advisory role; Takeda: Honoraria; Karyopharm: Honoraria; Genmab: Honoraria, Other; Debiopharm: Consultancy, Honoraria, Other: consultancy or advisory role; MorphoSys: Honoraria, Other: consultancy or advisory role; Novartis: Honoraria, Other: consultancy or advisory role; Roche: Honoraria, Other: consultancy or advisory role; Abbvie: Other: consultancy or advisory role; Autolos: Other: consultancy or advisory role. Deau Fischer:Takeda: Consultancy; Roche: Consultancy.

Phase I Clinical Trial of Oral Administration of the Histone Deacetylase (HDAC) Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) in Patients with Relapsed/Refractory Multiple Myeloma (MM).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1503-1503 ◽  
Author(s):  
Paul Richardson ◽  
Robert L. Schlossman ◽  
Constantine S. Mitsiades ◽  
Nikhil C. Munshi ◽  
Kathleen Colson ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Phase I ◽  
Dose Level ◽  
Hdac Inhibitor ◽  
Hydroxamic Acid ◽  
Phase I Clinical Trial ◽  
Hematologic Toxicity ◽  
Suberoylanilide Hydroxamic Acid ◽  
Grade 3

Abstract Introduction: Histone deacetylases (HDACs) affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones, and HDAC inhibition induces differentiation and/or apoptosis in transformed cells. We have recently shown that HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), induce apoptosis of human multiple myeloma (MM) cells via a constellation of antiproliferative and/or proapoptotic molecular events, including decreased expression of multiple signaling molecules and oncogenes implicated in MM pathophysiology. Based on these promising pre-clinical data, we embarked on a phase I clinical trial of oral SAHA in patients with advanced MM. Methods: An open-label phase I dose-escalation of oral SAHA (200, 250 and 300 mg po bid for 5 consecutive days followed by 2 days of rest) was administered in 4-week cycles in pts with relapsed/refractory MM. The primary objective was to determine the maximum tolerated dose (MTD), and secondary objectives included evaluation of tumor response, as well as assessment of markers of biologic activity in peripheral blood mononuclear cells and bone marrow plasma cells. Dose limiting toxicity (DLT) was defined as grade 4 or greater hematologic toxicity and/or grade 3 or greater non-hematologic toxicity within the first 28 days of treatment. Results: To date, 8 pts with advanced MM (5 relapsed and 3 with relapsed, refractory MM) have been enrolled at the first 2 dose levels, receiving a median of 3 cycles (range 2–9) of therapy. In 7 evaluable pts, one pt at the 2nd dose level (250 mg po bid) developed DLT with grade 3 fatigue, prompting dose reduction with the next cycle. Other side effects have included grade 2 fatigue (3 pts), grade 2 diarrhea (2 pts), grade 2 indigestion (2 pts) and grade 2 dehydration (2 pts), which have been manageable with appropriate supportive care. In one patient, during cycle 4 at dose level 2, grade 3 dehydration occurred with associated metabolic abnormalities that readily resolved with electrolyte supplementation and rehydration. The patient has continued on therapy at reduced dose (250 mg po bid, 4 days on, 3 days off) without recurrence of this toxicity. Importantly, no significant myelosuppression, neuropathy or sedation, which are associated with other anti-MM agents, has been seen. In 7 evaluable pts: minor responses (MR) were documented in 2 patients (25–50% reduction in serum paraprotein levels); stable disease (SD: less than 25% reduction in paraprotein levels) was observed in 2 pts; and progressive disease (PD) was documented in 3 pts. Conclusion: SAHA is an orally administered HDAC inhibitor with manageable toxicity and preliminary evidence of antitumor activity in advanced MM. Clinical evaluation of this agent continues, with enrolment at 250 mg b.i.d. ongoing, to further define the safety and tolerability at this dose level and provide insight into the future uses of SAHA, either alone or in combination with other agents, to treat pts with advanced MM.

Final Results Of a Phase II Study Of Lenalidomide In Combination With Rituximab For The Treatment Of Indolent Non Follicular Non Hodgkin Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4383-4383 ◽  
Author(s):  
Stefano Sacchi ◽  
Samantha Pozzi ◽  
Marina Cesaretti ◽  
Luigi Marcheselli ◽  
Gabriele Buda ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Informed Consent ◽  
Phase Ii ◽  
Conflicts Of Interest ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Open Label ◽  
Grade 3

Abstract Background Advanced-stage, relapsed indolent non follicular lymphomas (INFLs) have a relatively poor prognosis, with low complete response to conventional chemotherapy and short survival. Thus, there is a need for innovative treatment with high efficacy and a good safety profile. Lenalidomide (R®) is an immunomodulatory drug with a direct tumoricidal effect and action on T, NK and stromal cells that may enhance antibody-dependent cell mediated cytotoxicity as well as the development of specific anti-tumor immune responses. These immunologic effects may synergize with the action of rituximab (R). To test the efficacy of R® combined with R (R2), we have conducted a multi center, open label phase II clinical trial in patients (pts) with relapsed INFL. Methods Eligible pts must have indolent non follicular B-cell lymphoma relapsed after at least 2 but less than 4 prior lines of R-containing immuno-chemotherapy with measurable disease. Patients received oral R® 20 mg once daily on days 1-21. R is administered at a dose of 375 mg/m2 at day 14 of every course. Treatment is repeated every 28 days for up to 6 courses. The primary objectives of the study were to evaluate the antitumor activity of oral R® when given in combination with R and to assess the safety of R2 regimen evaluated by standard criteria (CTC-NCI 3.0). The secondary objectives were the evaluation of progression free survival (PFS) and overall survival (OS). Results From July 2010 and March 2013, 44 pts entered the protocol. Six out of 44 pts were excluded from this analysis as 2 withdrew informed consent and 4 refused to start treatment immediately after signing the informed consent. Enrolled pts (38 cases) had: 18 small lymphocytic lymphoma (SLL), 12 lymphoplasmacytic lymphoma (LPL) and 8 marginal zone lymphoma (MZL). Median age was 68 years (51-75) and 58% were male. LDH value was increased in 21% of pts and β-2-microglobulin in 75%; 51% of pts had Hb<12 g/dL and 66% had bone marrow involved (median infiltrating 40%). Of the 38 pts, 7 achieved a complete remission and 14 a partial remission with an ORR of 55%. Seven pts had a stable disease and 5 a lymphoma progression. In general, the regimen R2 was relatively well-tolerated. Grade 3-4 hematological events were observed in 22 pts. The most common adverse events were neutropenia (58%), thrombocytopenia (11%), anemia (10%) and infection (10%). Grade 3-4 non hematological events were fever (5%), dyspnea (3%), allergic reaction to R (3%), renal failure (3%) and erythema (3%). Growth factors were administered in 58% of pts. The median dose intensity was 0.94 for R and 0.98 for R®. With a median follow-up of 19 months (range 1-43), overall 6 pts died, 5 for lymphoma progression and 1 for treatment related toxicity. The 2-years OS and the 2-years PFS were shown in Figure 1. Figure 2 shows the PFS by histology. The percentage of 2-years PFS (71%) for MZL appear impressive. Conclusions The chemo-free R2 scheme as treatment for relapse INFLs produces response in about 50% of pts and remission appear durable in pts with MZL. The toxicity profile of the combination is tolerable with manageable hematologic side effects. These results support the design of clinical trial with this chemo-free combination as first line treatment for INFLs, in particular for MZL. Disclosures: No relevant conflicts of interest to declare.

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