Pomalidomide-Dexamethasone in the Management of Heavily Pretreated Multiple Myeloma

Abstract Background: Pomalidomide is a new generation IMID, with a very good compliance, thanks to oral administration, which can be used also in heavily pretreated patients, in a domestic setting. Aims: In this retrospective observational trial, It has been evaluated efficacy and tolerance of pomalidomide plus dexamethasone (PD) as salvage regimen in heavily pretreated patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. Methods: 33 patients (19 M/14 F), with rrMM, median age at diagnosis 69 years (r. 52-84), and median age at start of treatment 76 years (r.56-89) treated with several lines of treatments (median 7, r. 2-11), every refractory to all the drugs previously received (also Bortezomib, Thalidomide and Lenalidomide), received Pomalidomide-Dexamethasone (Pomalidomide 4 mg for 21 days, Dexamethasone 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. ISS was equally distributed, and cytogenetic was evaluable in 14 patients, and in particular three del13q and one t(11;14) were present. All the patients had previously been treated with schedule containing bortezomib and IMIDs. 60% (20/33) of them had undergone at least to a single ASCT. All patients were relapsed and refractory to last therapies received before PD. Results: Pomalidomide was well tolerated, with grade 3 anemia in 51% (17/33) of patients, 36.3% (12/33) grade 3 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shocks were observed), 30.3% (10/33) grade 3-4 thrombocytopenia without hemorrhagic events and transfusion-dependence. No severe extra-hematologic toxicity was observed. According to IMWG, ORR1 (≥PR) was 45.4% (15/33: 4 CR, 5 VGPR, 6 PR), but, considering that we are evaluating a cohort of heavily pretreated patients without any other alternative treatment, with really poor prognosis, another parameter should be considered, ORR2 (≥SD), considering stable disease as a successful result in progressive MM. ORR2 was 78.7% (26/33: 4 CR, 5 VGPR, 6 PR, 11 SD). These can be considered as impressive result in this subset of patients. Oral treatment gives a really good compliance, in frail and unfit patients, and response, when present, is always really fast (median time to response: 2 months (r.1-6)), median OS from diagnosis was 92 months (range 21-234), median OS from start of pomalidomide was 9 months (range 1-25). Conclusions: Pomalidomide-dexamethasone has shown significant efficacy and a very good compliance, thanks to oral administration, in a particularly severe setting of heavily pretreated patients, relapsed and refractory to all available therapeutic resources. Disclosures No relevant conflicts of interest to declare.

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Pomalidomide-Dexamethasone in the Management of Heavily Pretreated Multiple Myeloma

Blood ◽

10.1182/blood-2020-143143 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Claudio Cerchione ◽

Lucio Catalano ◽

Davide Nappi ◽

Anna Emanuele Pareto ◽

Gerardo Musuraca ◽

...

Keyword(s):

Oral Administration ◽

Oral Treatment ◽

Novel Agents ◽

Hematologic Toxicity ◽

Salvage Regimen ◽

Good Compliance ◽

Impressive Result ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3

Background Pomalidomide is a new generation IMID, with a very good compliance, thanks to oral administration, which can be used also in heavily pretreated patients, in a domestic setting. Aims In this retrospective observational trial, It has been evaluated efficacy and tolerance of pomalidomide plus dexamethasone (PD) as salvage regimen in heavily pretreated patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. Methods 57 patients (31 M/26 F), with rrMM, median age at diagnosis 69 years (r. 52-86), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-11), every refractory to all the drugs previously received (also Bortezomib, Thalidomide and Lenalidomide), received Pomalidomide-Dexamethasone (Pomalidomide 4 mg for 21 days, Dexamethasone 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. ISS was equally distributed, and cytogenetic at relapse was evaluable in 14 patients. All the patients had previously been treated with schedule containing bortezomib and IMIDs. 63% (36/57) had undergone at least to a single ASCT. All patients were relapsed and refractory to last therapies received before PD. Results Pomalidomide was well tolerated, with grade 3-4 transfusion-dependent anemia in 58% (33/57) of patients, 44% (23/57) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shocks were observed), 40% (23/57) grade 3-4 thrombocytopenia without hemorrhagic events and transfusion-dependence. No severe extra-hematologic toxicity was observed. According to IMWG, ORR1 (≥PR) was 47.3% (27/57: 5 CR, 11 VGPR, 7 PR, 4 MR), but, considering that we are evaluating a cohort of heavily pretreated patients, with poor prognosis, another parameter should be considered, ORR2 (≥SD), considering stable disease as a successful result in progressive MM. ORR2 was 77.1% (17 SD). These can be considered as impressive result in this subset of patients. Oral treatment gives a really good compliance, in frail and unfit patients, and response, when present, is always really fast (median time to response: 2 months (r.1-6)), median OS from diagnosis was 94 months (range 21-234), median OS from start of pomalidomide was 9 months (range 1-25). Nine patients have surprisingly achieved a notable response (3 VGPR, 4 PR, 2 MR) after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Conclusions Pomalidomide-dexamethasone has shown significant efficacy and a very good compliance, thanks to oral administration, in a particularly severe setting of heavily pretreated patients, relapsed and refractory to all available therapeutic resources, also after failure of novel agents. Disclosures Lucchesi: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

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Pomalidomide-Dexamethasone in the Management of Heavily Pretreated Multiple Myeloma

Blood ◽

10.1182/blood-2021-153971 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 5022-5022

Author(s):

Claudio Cerchione ◽

Lucio Catalano ◽

Davide Nappi ◽

Anna Emanuele Pareto ◽

Fabrizio Pane ◽

...

Keyword(s):

Oral Administration ◽

Oral Treatment ◽

Novel Agents ◽

Hematologic Toxicity ◽

Salvage Regimen ◽

Good Compliance ◽

Impressive Result ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3

Abstract Pomalidomide is a new generation IMID, with a very good compliance, thanks to oral administration, which can be used also in heavily pretreated patients, in a domestic setting. In this retrospective observational trial, It has been evaluated efficacy and tolerance of pomalidomide plus dexamethasone (PD) as salvage regimen in heavily pretreated patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. 57 patients (31 M/26 F), with rrMM, median age at diagnosis 69 years (r. 52-86), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-11), every refractory to all the drugs previously received (also Bortezomib, Thalidomide and Lenalidomide), received Pomalidomide-Dexamethasone (Pomalidomide 4 mg for 21 days, Dexamethasone 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. ISS was equally distributed, and cytogenetic at relapse was evaluable in 14 patients. All the patients had previously been treated with schedule containing bortezomib and IMIDs. 63% (36/57) had undergone at least to a single ASCT. All patients were relapsed and refractory to last therapies received before PD. Pomalidomide was well tolerated, with grade 3-4 transfusion-dependent anemia in 58% (33/57) of patients, 44% (23/57) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shocks were observed), 40% (23/57) grade 3-4 thrombocytopenia without hemorrhagic events and transfusion-dependence. No severe extra-hematologic toxicity was observed. According to IMWG, ORR1 (≥PR) was 47.3% (27/57: 5 CR, 11 VGPR, 7 PR, 4 MR), but, considering that we are evaluating a cohort of heavily pretreated patients, with poor prognosis, another parameter should be considered, ORR2 (≥SD), considering stable disease as a successful result in progressive MM. ORR2 was 77.1% (17 SD). These can be considered as impressive result in this subset of patients. Oral treatment gives a really good compliance, in frail and unfit patients, and response, when present, is always really fast (median time to response: 2 months (r.1-6)), median OS from diagnosis was 94 months (range 21-234), median OS from start of pomalidomide was 9 months (range 1-25). Nine patients have surprisingly achieved a notable response (3 VGPR, 4 PR, 2 MR) after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Pomalidomide-dexamethasone has shown significant efficacy and a very good compliance, thanks to oral administration, in a particularly severe setting of heavily pretreated patients, relapsed and refractory to all available therapeutic resources, also after failure of novel agents. Disclosures Martinelli: Stemline Therapeutics: Consultancy; Incyte: Consultancy; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy; Celgene /BMS: Consultancy, Speakers Bureau; Daichii Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Astellas: Consultancy, Speakers Bureau.

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Retrospective review of DPACE therapy for aggressive, refractory multiple myeloma (MM)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.18500 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 18500-18500

Author(s):

A. S. Gerrie ◽

W. Xu ◽

S. Fung ◽

A. K. Stewart ◽

D. Reece ◽

...

Keyword(s):

Retrospective Review ◽

Leptomeningeal Disease ◽

Hematologic Toxicity ◽

Salvage Regimen ◽

Bridge To Transplant ◽

Neutropenic Sepsis ◽

Definitive Therapy ◽

Heavily Pretreated ◽

Grade 3 ◽

Gi Bleed

18500 Background: Oral dexamethasone ± thalidomide with a 4-day infusion of cisplatin, doxorubicin, cyclophosphamide, and etoposide (DPACE) is an effective induction therapy prior to transplant in patients (pts) with MM. Limited experience also suggests DPACE may reduce disease burden as a salvage regimen for aggressive, refractory MM. Methods: We performed a retrospective review from 1999- 2005 of all MM pts who received DPACE ± thalidomide as a salvage regimen at our center. Results: A total of 39 pts received DPACE at a median 23 mos from diagnosis (range, 10–84). Median age was 53 years (34–70), 51% stage 3 at diagnosis. Plasma cell leukemia had developed in 12 pts and leptomeningeal disease in 4 pts at time of DPACE. Ten of 24 pts (42%) with cytogenetics had del 13q. Pts were heavily pretreated (median 3 prior regimens; prior autotransplant [ASCT] 38%; thalidomide 64%; and bortezomib 10%). Pts received 1–4 cycles as tolerated for refractory (83%) or relapsed (17%) disease. Thalidomide was used in 41% of cycles. Hematologic toxicity was common (grade 3–4 neutropenia 92% and thrombocytopenia 72%). Although G-CSF was used in 71% of cycles, febrile neutropenia was common (53%) and 26% required hospitalization. Overall RR was 36% (14 pts: PR 12, VGPR 2). An additional 8% achieved MR, 23% SD. PD occurred in 15% and 18% died on therapy (4 progressive MM; 2 neutropenic sepsis, 1 GI bleed). No prior ASCT (p=0.04) and <4 prior regimens (p=0.04) predicted for response to DPACE. Eleven pts proceeded to ASCT and one pt to a clinical trial with lenalidomide with a median OS from DPACE of 24.7 mos (95% CI, 11.2–63.6). Those who did not bridge to transplant or trial (n=27) had a short median PFS of 3.0 months (95% CI, 1.2–5.5) and OS of 6.7 mos (95% CI, 1.8–9.7). OS for all 39 pts was 8.7 mos (95% CI, 6.4–12.4). Conclusion: DPACE may be effective salvage therapy for heavily pretreated MM pts. Although the RR of 36% in this poor prognosis cohort is reasonable, the PFS is short and suggests that the best role for this regimen is in bridging to more definitive therapy such as transplantation. [Table: see text]

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Topotecan in heavily pretreated patients with recurrent ovarian, peritoneal, and fallopian tube carcinoma

International Journal of Gynecological Cancer ◽

10.1136/ijgc-00009577-200507000-00006 ◽

2005 ◽

Vol 15 (4) ◽

pp. 612-617 ◽

Cited By ~ 1

Author(s):

B. Piura ◽

A. Rabinovich

Keyword(s):

Partial Response ◽

Fallopian Tube ◽

Dose Intensity ◽

Complete Response ◽

Ca 125 ◽

Hematologic Toxicity ◽

Fallopian Tube Carcinoma ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3

Topotecan has demonstrated antitumor activity in heavily pretreated patients with ovarian carcinoma. This report examines the activity and toxicity of topotecan in 29 heavily pretreated patients with recurrent ovarian, peritoneal, and fallopian tube carcinoma. Topotecan 1.5 mg/m2 was administered intravenously on days 1–5, every 21 days. It was second-line chemotherapy in 6 (20.7%) patients, third-line in 15 (51.7%), fourth-line in 4 (13.8%), fifth-line in 3 (10.3%), and seventh-line in 1 (3.4%). Median dose intensity was 1.667 mg/m2/week, and median relative dose intensity was 0.67. Disease complete response was observed in 5 (17.2%) patients, partial response in 1 (3.4%), stable disease in 12 (41.4%), and progressive disease in 11 (37.9%). CA-125 complete response was observed in 3 (10.3%) patients, partial response in 11 (37.9%), stable level in 5 (17.2%), and progressive level in 9 (31%), and no data were available in 1 (3.4%) patient. Toxicity was mainly hematologic: grade 3–4 neutropenia was observed in 20 (69%) patients, grade 3–4 leukopenia in 12 (41.4%), grade 3–4 thrombocytopenia in 9 (31%), and grade 3–4 anemia in 2 (6.9%). It is concluded that topotecan has considerable activity and noncumulative hematologic toxicity in heavily pretreated patients with recurrent ovarian, peritoneal, and fallopian tube carcinoma.

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Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.66.130 ◽

2005 ◽

Vol 23 (23) ◽

pp. 5314-5322 ◽

Cited By ~ 347

Author(s):

Stephen Chan ◽

Max E. Scheulen ◽

Stephen Johnston ◽

Klaus Mross ◽

Fatima Cardoso ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Adverse Events ◽

Dose Level ◽

Locally Advanced ◽

Metastatic Breast ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3 ◽

Time To Tumor Progression

Purpose In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated. Patients and Methods Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus. Results Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). Conclusion In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

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Clinical Response in Heavily Pretreated Mycosis Fungoides with Pembrolizumab: A Case Report

Acta Haematologica ◽

10.1159/000518815 ◽

2021 ◽

pp. 1-3

Author(s):

Ginevra Lolli ◽

Beatrice Casadei ◽

Lisa Argnani ◽

Alessandro Pileri ◽

Cinzia Pellegrini ◽

...

Keyword(s):

Mycosis Fungoides ◽

Assessment Tool ◽

Therapeutic Option ◽

Rapid Responses ◽

Duration Of Response ◽

Heavily Pretreated ◽

Stage Ia ◽

Pretreated Patients ◽

Grade 3 ◽

The Moment

Mycosis fungoides (MF) is a disease almost impossible to cure. In the context of heavily pretreated patients, the anti-programmed cell death protein 1 (anti-PD-1) pembrolizumab is a valid therapeutic option. The alteration of the PD-1-PD ligand 1 (PD-L1) axis is often present in MF, and this aspect explains the feasibility of this therapy. We report the case of a 60-year-old woman diagnosed with MF in 2003, Olsen stage IA (T1M0NXBO). Since the moment of the diagnosis, she received 10 lines of therapy, with a short duration of response after each one of them. In April 2020, our patient started pembrolizumab 2 mg/kg every 3 weeks, and she achieved a partial response after the 4th cycle, consistent with the modified severity assessment tool (mSWAT) 1, which she is still maintaining after 10 cycles. No grade ≥3 adverse events were recorded. We conclude that pembrolizumab can induce extremely rapid responses in MF, with very low toxicity.

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CTIM-32. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A HEAVILY PRETREATED COHORT

Neuro-Oncology ◽

10.1093/neuonc/noab196.224 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi57-vi58

Author(s):

Marta Penas-Prado ◽

Ying Yuan ◽

Kathleen Wall ◽

Elizabeth Vera ◽

Ukeme Ikiddeh-Barnes ◽

...

Keyword(s):

Safety Profile ◽

Interim Analysis ◽

Cns Tumors ◽

Myxopapillary Ependymoma ◽

Investigational Drugs ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3 ◽

Total Accrual ◽

Immune Profiling

Abstract INTRODUCTION Standard and experimental therapies for patients with rare CNS tumors are scarce. Nivolumab (PD-1 inhibitor) is approved for several non-CNS cancers. This ongoing Phase II trial (NCT03173950) will determine the efficacy of nivolumab in adults with recurrence/progression of one of 11 selected rare primary CNS tumors. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated patients (heavily pretreated: ≥ 3 prior therapies; non-heavily pretreated: ≤ 2). We report efficacy and safety results of a preplanned interim analysis in the heavily pretreated cohort. METHODS Eligibility includes recurrence/progression of an eligible tumor; age ≥ 18 years; tumor tissue available for histopathology, molecular and immune profiling; KPS ≥ 70; and no steroids at study entry. A total of 150 evaluable patients will be enrolled (75 to each cohort). Prior therapies include radiation and/or standard or investigational drugs. Nivolumab treatment is 240 mg IV every 2 weeks (4 doses); then 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when sample size reached 32 in each cohort. RESULTS As of March 10, 2021, DCR exceeded the minimum required for interim analysis in the heavily pretreated cohort. Among 30 patients, 4 achieved SD > 6 months (medulloblastoma, anaplastic ependymoma, myxopapillary ependymoma, metastatic atypical meningioma). Safety profile (related AEs): grade 3 = 7; grade 4 = 1. Most frequent grade 3-5 AEs regardless of attribution: tumor progression (6); anemia, hydrocephalus, lymphopenia (3 each); cerebral edema, headache (2 each). CONCLUSION DCR exceeded the “go” boundary (i.e., > 2) in the heavily pretreated cohort. Nivolumab showed safety profile consistent with other studies. This cohort will continue to stage 2 and complete total accrual of 75 patients. The trial is currently being expanded to 10 additional sites across the BTTC/NCI-CONNECT consortium.

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

Blood ◽

10.1182/blood.v118.21.100.100 ◽

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.

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

Blood ◽

10.1182/blood.v118.21.1649.1649 ◽

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.

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

Blood ◽

10.1182/blood.v120.21.2736.2736 ◽

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.

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