Phase II Trial of Lenalidomide - Dexamethasone - Rituximab in Relapsed or Refractory Indolent B-Cell or Mantle Cell Lymphomas Resistant to Rituximab.

Abstract Abstract 1700 Poster Board I-726 Introduction Lenalidomide is an immunomodulatory drug with effects on the innate immune system 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. To test the efficacy of lenalidomide combined with rituximab, we are conducting a single center, open label phase II clinical trial in patients (pts) with indolent B-cell or mantle cell lymphomas previously resistant to rituximab. Patients and Methods Eligible pts must have relapsed/refractory indolent B-cell or mantle cell lymphoma with measurable disease that has failed to respond to or has progressed within six months of a standard course of rituximab monotherapy (375 mg/m2 weekly for at least four weeks) or a prior rituximab-containing chemotherapy regimen. Thus, all pts enrolled are considered rituximab-resistant. In Part I (lenalidomide + dexamethasone), pts receive two 28-day treatment cycles of lenalidomide 10 mg every day and dexamethasone 8 mg once weekly. After assessment of response to Part I, all pts receive a single course of rituximab 375 mg/m2, consisting of four weekly doses during cycle 3 (Part II: lenalidomide + dexamethasone + rituximab). Treatment with lenalidomide + dexamethasone continue during and subsequent to rituximab; stable and responding pts continue on lenalidomide + dexamethasone until disease progression or development of clinically unacceptable toxicity. Response assessment after Part II is performed three months after the first dose of rituximab. Results To date, 22 pts have started therapy; diagnoses included: follicular (n = 17), mantle cell (n = 2), small lymphocytic (n = 2), and marginal zone (n = 1) lymphomas; median age was 59 years (range: 35 - 72); male: female ratio was 5:6; median number of prior therapies was 3 (range: 1 - 7); LDH was increased in 23%. For 21 pts with at least one follow-up visit, there were 2 deaths and 2 episodes of disease progression. One death due to myocarditis occurred during Part I treatment; one death due to lymphoma occurred in a patient removed from study due to grade 3 rash, which subsequently resolved. Both episodes of disease progression occurred in pts with follicular lymphoma, one of whom had been removed from study during Part 1 because of thrombocytopenia attributed to myelodysplasia. For all patients, at a median follow-up of 5.0 months (range: 0.3 - 12.3), progression-free survival (PFS) is 81% (95% CI: 51-94). For 10 pts with response assessments after Parts I and II, overall response rate (ORR) after Part I was 30% (3 CR; 6 SD; 1 PD) and ORR after Part II was 70% (5 CR; 2 PR; 2 SD; 1 PD). At a median follow-up of 7.8 months (range: 5.0 - 11.9), PFS is 89% (95% CI: 43-98) for these 10 pts. For pts who completed Parts I and II, grade 3 or 4 non-hematologic toxicities included hypokalemia (2/10 pts), hypophosphatemia (1/10 pts), and hypocalcemia (1/10 pts); grade 1 tumor flare occurred in one pt with follicular lymphoma. Conclusions Based on these preliminary data in rituximab-resistant patients with indolent B-cell or mantle cell lymphomas, the combination of continuous daily lenalidomide, low-dose weekly dexamethasone, and a single four week course of rituximab during cycle 3, achieves a high overall response rate with relatively durable responses. Additional follow-up and correlative studies will be presented. Disclosures Off Label Use: Lenalidomide is used in this trial for treatment of lymphoma.. Downs:Genentech: Honoraria; Celgene: Honoraria. Nasta:Genentech: Speakers Bureau. Schuster:Celgene: Consultancy, Research Funding.

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Cetuximab plus docetaxel-cisplatin (DC) as first-line treatment for locally advanced or metastatic gastric cancer: Preliminary results of a phase II study

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e15592 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e15592-e15592

Author(s):

J. Fahlke ◽

K. Ridwelski ◽

A. Florschuetz ◽

E. Kettner ◽

M. Leithaeuser ◽

...

Keyword(s):

Gastric Cancer ◽

Disease Progression ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Published Data ◽

First Line ◽

Overall Response ◽

Grade 3

e15592 Background: Based on promising published data, this multicenter, phase II study was initiated to investigate a combined treatment using DC and cetuximab in the first-line setting for patients with gastric cancer. Methods: Patients aged 18–75 years with stage III (T4, nonresectable) or stage IV gastric cancer, ECOG performance status (PS) ≤2, and life expectancy ≥3 months were recruited to receive cetuximab (400 mg/m2 on day 1 then 250 mg/m2 q1w) and DC (D 75 mg/m2 and C 75 mg/m2; both as 1-h infusions on day 1 and then q3w). Treatment was stopped in the event of disease progression, intolerable toxicity, or consent withdrawal. Tumor staging was performed after cycle 3 and then every 12 weeks. The primary endpoint was overall response rate and secondary endpoints included time to progression, overall survival and toxicity. Planned accrual was 79 patients. A per-protocol interim response analysis was planned for the initial 20 evaluable patients. Results: Preliminary data are available for 30 patients; median age 64 [range: 40–73] years; median ECOG PS 1 [range: 0–2]; adenocarcinoma 87%. Median cycles administered were 3 [range: 1–14] and the median follow-up was 1.63 months. The overall response rate was 27.3% (complete response, n=1; partial response, n=5). Stable disease was observed in 10 patients, and disease progression in 6 patients. The most relevant NCI-CTC grade 3–4 hematologic events per patient were leukopenia and neutropenia (73%), anemia (13%), and febrile neutropenia (10%). Major grade 3–4 nonhematologic toxicities were nausea (30%), vomiting (20%), diarrhea (13%), acne (13%), and fatigue (13%). Conclusions: DC and cetuximab were well tolerated and resulted in promising response rates and a predictable toxicity profile. The study is ongoing. No significant financial relationships to disclose.

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Phase II Trial of Lenalidomide - Rituximab +/− Dexamethasone in Relapsed or Refractory Indolent B-Cell or Mantle Cell Lymphomas Resistant to Rituximab

Blood ◽

10.1182/blood.v118.21.266.266 ◽

2011 ◽

Vol 118 (21) ◽

pp. 266-266

Author(s):

Tahamtan Ahmadi ◽

Elise A. Chong ◽

Amanda Gordon ◽

Nicole A. Aqui ◽

YinYan Xu ◽

...

Keyword(s):

B Cell ◽

Phase Ii ◽

Low Dose ◽

Overall Response Rate ◽

Response Rate ◽

Conflicts Of Interest ◽

Response Assessment ◽

Female Ratio ◽

Overall Response ◽

Mantle Cell

Abstract Abstract 266 Introduction: Lenalidomide is an immunomodulatory drug with effects on the innate immune system 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. To test the efficacy of lenalidomide combined with rituximab, we are conducting a single center, open label phase II clinical trial in patients (pts) with indolent B-cell or mantle cell lymphomas previously resistant to rituximab. Patients and Methods: Eligible pts must have relapsed/refractory indolent B-cell or mantle cell lymphoma with measurable disease that has failed to respond or has progressed within six months of a standard course of rituximab monotherapy (375 mg/m2 weekly for at least four weeks) or a prior rituximab-containing chemotherapy regimen. Thus, all pts enrolled are considered rituximab refractory. Patients were enrolled sequentially into two treatment cohorts. In Cohort 1, pts received two 28-day treatment cycles of lenalidomide 10 mg every day and dexamethasone 8 mg once weekly (Part I: lenalidomide + dexamethasone). After assessment of response to Part I, all pts received a single course of rituximab 375 mg/m2, consisting of four weekly doses during cycle 3 (Part II: lenalidomide + dexamethasone + rituximab). Treatment with lenalidomide + dexamethasone continued during and subsequent to rituximab; stable and responding pts continued on lenalidomide + dexamethasone until disease progression or development of clinically unacceptable toxicity. Response assessment after Part II was performed three months after the first dose of rituximab. In Cohort 2, dexamethasone was eliminated; otherwise, eligibility and treatment were the same. Results: As of August 9, 2011, 45 pts have started therapy (Cohort 1, n = 27; Cohort 2, n = 18); diagnoses include: follicular (n = 28), mantle cell (n = 11), small lymphocytic (n = 4), and marginal zone (n = 2) lymphomas; median age is 58 years (range: 35–85); male: female ratio is 31:14; median number of prior therapies is 3 (range: 1 – 7); LDH is increased in 18%. For Cohort 1, 24 pts completed Part II and are evaluable for response; 3 pts are not evaluable, 1 due to death (myocarditis) and 2 due to removal from study (1 thrombocytopenia attributed to myelodysplasia; 1 rash attributed to lenalidomide). For Cohort 2, 11 pts are evaluable for response assessment after Part II; 2 pts are not evaluable due to discontinuation of protocol therapy (1 rash attributed to lenalidomide; 1 with early symptomatic progression of lymphoma); 5 pts have not completed Part II. For 35 pts completing Parts I and II, at a median follow-up of 11.8 months, PFS is 73% (95%CI: 53 – 86%). Overall response rate (ORR) after Part I is 37% (6 CR; 7 PR); ORR after Part II is 60% (12 CR; 9 PR). Overall response rates after Part II do not differ between Cohort 1 (with dexamethasone) and Cohort 2 (without dexamethasone) [58% vs. 64%, respectively; p = 0.5]. There were fewer dose interruptions during Part I in Cohort 1 (15%) versus Cohort 2 (50%) [p = 0.02], reflecting reduced episodes of tumor flare and rash in Cohort 1. Conclusions: For rituximab-resistant pts with indolent B-cell or mantle cell lymphomas, the combination of continuous daily lenalidomide and a single four week course of rituximab, with or without low-dose weekly dexamethasone, achieves a high overall response rate with relatively durable responses. The addition of low-dose weekly dexamethasone may improve tolerance without decreasing the efficacy of the lenalidomide-rituximab combination. Disclosures: No relevant conflicts of interest to declare.

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Treatment with Temozolomide and Ibrutinib in Recurrent/Refractory Primary (PCNSL) and Secondary CNS Lymphoma (SCNSL)

Blood ◽

10.1182/blood-2020-138764 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 23-24

Author(s):

Loïc Renaud ◽

Jean-Baptiste Bossard ◽

Louis Terriou ◽

Nathalie Cambier ◽

Guillaume Chanteau ◽

...

Keyword(s):

B Cell ◽

Overall Response Rate ◽

Response Rate ◽

High Dose ◽

High Dose Methotrexate ◽

Overall Response ◽

Dose Methotrexate ◽

Grade 3 ◽

Cns Lymphomas

I ntroduction Despite recent therapeutic progress in this field, the prognosis of elderly patients with Primary (PCNSL) and Secondary Central Nervous System Lymphoma (SCNSL) remains poor, with a median OS of less than two years in most prospective studies. Patients with chemo refractory relapsed PCNSL within the first year from diagnosis have a median OS of 2-4 months. Activated B cell like subtype of Diffuse Large B Cell Lymphoma (DLBCL) and PCNSL relies on a chronically active B-cell receptor (BCR) signaling. Ibrutinib achieves CNS penetrance and has a high overall response rate in CNS lymphomas, but duration of response is short and curative potential is limited. A novel regimen that combines ibrutinib with temozolomide, etoposide, liposomal doxycycline, dexamethasone, and rituximab (Teddi-R) seems to be promising for this population but its tolerance is an issue in patients with advanced age and poor general condition, common features of many PCNSL patients., calling for an alleviated regimen of broader use. Patients and methods We evaluated a combination of temozolomide and ibrutinib in immunocompetent adult with recurrent/refractory (PCNSL) and (SCNSL) treated in five French centers between June 2015 and January 2020. The treatment consisted of 560 mg ibrutinib orally once daily (28-day cycles) and temozolomide 100 mg/m2 or 150 mg/m2 orally day 1 to 5 for cycle 1, increased to 200mg/m2 day 1 to 5 from cycle 2, until disease progression or unacceptable toxicity occurred. The evaluations were performed using Magnetic resonance imaging (MRI) and the responses were assessed according to the International PCNSL Collaborative Group Response Criteria. The lymphoma diagnoses were all confirmed by expert pathologists in the framework of the national program "lymphopath", based on the criteria of the World Health Organization 2008 classification. Results 22 immunocompetent adults with recurrent/refractory (PCNSL n=13) and (SCNSL n=9) were evaluable for safety and efficacy. Median age was 71 years (range, 44 - 89 years). All patients had relapsed (n=6) or refractory (n=16) disease, after a median of two lines of therapy (range, 1-3). Overall, 18 patients (82%) and 14 (64%) patients had previously received high dose methotrexate or both high dose methotrexate with high dose cytarabine, respectively. Among the four patients who did not receive Methotrexate, one had a chronic kidney disease secondary to diabetic nephropathy and experienced major toxicity after cytarabine infusion. The three others (72, 79 and 89 years old) were SCNSL experiencing comorbidities and toxicities from their previous treatment lines. Ten patients had a poor performance status according to Eastern Cooperative Oncology Group [ECOG] ⩾ 2. Patients received a median of 3.2 cycles (1-19 cycles). One patient received whole brain radiotherapy consolidation after obtaining a partial response under treatment. Best overall response rate was 55% (12/22) including 3 (13.6%) complete responses and 9 (40.9%) partial responses. After a median follow-up of 18.2 months (range, 5.1 - 61.7), the median progression-free survival was 5.3 months (95% confidence interval [CI]; 3.10 - NA) and overall survival 8.9 months (95% CI; 5.2 - NA). Eight patients (36%) received temozolomide and ibrutinib for more than 6 months, four patients were still on treatment at the end of the follow-up including one on ibrutinib only. Twelve patients (55%) stopped treatment due to progressive disease. Three (14%) patients stopped treatment for toxicity: Two (9%) due to grade 2 atrial fibrillation and one patient after 18 months in RC due to grade 1 muscle cramps, which did not stop after treatment discontinuation. three (14%) patients stopped temozolomide only due to recurrent grade 2 microcrystalline arthritis, grade 3 fall and one patient after 15 months in RC due to recurrent grade 2 bronchial infection, asthenia and nausea. Two patients temporary stopped treatment for grade 1 tumor hemorrhage and grade 3 tumor hemorrhage with grade 3 seizure. Micro-bleedings were seen at the MRI in four patients. Four patients (18%) experienced serious infectious complications including: two grade 3 febrile neutropenia, one grade 3 urinary tract infection and one grade 3 sepsis. None of the patients developed aspergillosis during the follow-up. Conclusion Temozolomide combined with ibrutinib showed clinical activity with manageable side effects in R/R CNS lymphomas. Disclosures Morschhauser: Novartis: Honoraria; JANSSEN-CILAG: Honoraria; Pharmacyclics LLC: Honoraria; Gilead: Honoraria; Roche: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Servier: Honoraria.

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Phase II Study of Ecteinascidin-743 in Advanced Pretreated Soft Tissue Sarcoma Patients

Journal of Clinical Oncology ◽

10.1200/jco.2004.05.210 ◽

2004 ◽

Vol 22 (5) ◽

pp. 890-899 ◽

Cited By ~ 217

Author(s):

A. Yovine ◽

M. Riofrio ◽

J.Y. Blay ◽

E. Brain ◽

J. Alexandre ◽

...

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Febrile Neutropenia ◽

Disease Progression ◽

Phase Ii ◽

Overall Response Rate ◽

Response Rate ◽

Phase Ii Study ◽

Overall Response ◽

Grade 3

Purpose A multicenter phase II study evaluating efficacy, safety, and pharmacokinetics of ecteinascidin-743 (ET-743) in pretreated advanced soft tissue sarcoma patients. Patients and Methods Patients received ET-743 1,500 μg/m2 (24-hour intravenous infusion) every 3 weeks (group 1, 26 patients with one to two prior single agents or one previous combination chemotherapy; group 2, 28 patients with three or more prior single agents or two or more previous combination chemotherapies). Results Patients (30 women, 24 men) had a median age of 48 years (range, 22 to 71 years); 41% had leiomyosarcoma (eight of 22 of uterine origin), a median of two involved organs (range, one to four), and 93% had documented progressive disease at study entry. Patients received a median of three cycles (range, one to 20); 28% received six or more cycles. Fifty-two patients were assessable for response (WHO criteria): two partial responses, four minor responses, and nine with stable disease (≥ 6 months). Three patients were rendered tumor free after surgery. Median progression-free survival was 1.9 months (range, 0.69 to 17.90 months); 24% of patients were progression free at 6 months. Median survival was 12.8 months, with 30% of patients alive at 2 years. Four patients withdrew because of treatment-related toxicity. Two treatment-related deaths occurred (renal failure and febrile neutropenia, and rhabdomyolysis and decompensated cirrhosis, respectively) that were probably related to protocol eligibility violations. Reversible grade 3 to 4 AST or ALT occurred in 50% of patients and grade 3 to 4 neutropenia occurred in 61% of patients, with six episodes of febrile neutropenia. Nausea, vomiting, and asthenia were prevalent but mild and manageable. Conclusion With a 4% overall response rate (95% CI, 0.5 to 12.8) and an 11% rate of third-party-verified tumor regression (overall response rate + minor response), ET-743 has a 24% 6-month disease progression control rate, confirming evidence of antitumoral activity and a manageable safety profile in patients experiencing disease progression with pretreated soft tissue sarcoma.

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Phase II Trial of Lenalidomide - Dexamethasone - Rituximab In Relapsed or Refractory Indolent B-Cell or Mantle Cell Lymphomas Resistant to Rituximab

Blood ◽

10.1182/blood.v116.21.3962.3962 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3962-3962

Author(s):

Tahamtan Ahmadi ◽

Elise A. Chong ◽

Amanda Gordon ◽

Leah Leinbach ◽

Nicole A. Aqui ◽

...

Keyword(s):

B Cell ◽

Phase Ii ◽

Overall Response Rate ◽

Marginal Zone ◽

Response Rate ◽

Phase Ii Trial ◽

Cell Lymphoma ◽

Response Assessment ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 3962 Introduction: Lenalidomide is an immunomodulatory drug with effects on the innate immune system 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. To test the efficacy of lenalidomide combined with rituximab, we are conducting a single center, open label phase II clinical trial in patients (pts) with indolent B-cell or mantle cell lymphomas previously resistant to rituximab. Patients and Methods: Eligible pts must have relapsed/refractory indolent B-cell or mantle cell lymphoma with measurable disease that has failed to respond or has progressed within six months of a standard course of rituximab monotherapy (375 mg/m2 weekly for at least four weeks) or a prior rituximab-containing chemotherapy regimen. Thus, all pts enrolled are considered rituximab-resistant. In Part I (lenalidomide + dexamethasone), pts receive two 28-day treatment cycles of lenalidomide 10 mg every day and dexamethasone 8 mg once weekly. After assessment of response to Part I, all pts receive a single course of rituximab 375 mg/m2, consisting of four weekly doses during cycle 3 (Part II: lenalidomide + dexamethasone + rituximab). Treatment with lenalidomide + dexamethasone continues during and subsequent to rituximab; stable and responding pts continue on lenalidomide + dexamethasone until disease progression or development of clinically unacceptable toxicity. Response assessment after Part II is performed three months after the first dose of rituximab. Results: As of May 16, 2010, 27 pts have started therapy; diagnoses include: follicular (n = 18), mantle cell (n = 5), small lymphocytic (n = 3), and marginal zone (n = 1) lymphomas; median age is 60 years (range: 35–85); male: female ratio is 4:5; median number of prior therapies is 3 (range: 1 – 7); LDH is increased in 22% of pts. There were 2 deaths during protocol therapy: 1 death due to myocarditis during Part I treatment and 1 death due to lymphoma in a patient removed from study due to grade 3 rash, which subsequently resolved. One patient was removed from study during Part 1 because of thrombocytopenia attributed to myelodysplasia. One patient has not completed Part II response assessment. For 23 pts completing Parts I and II, median follow-up is 12 months (range: 3.1 – 25.3) with a progression-free survival of 78% (95% CI: 50 – 91) [Figure below]. Overall response rate (ORR) after Part I is 22% (3 CR; 2 PR; 16 SD; 2 PD); ORR after Part II is 57% (7 CR; 6 PR; 8 SD; 2 PD). After Part II, the ORRs by histology were follicular lymphoma 60% (9/15 pts), mantle cell lymphoma 50% (2/4 pts), small lymphocytic lymphoma 67% (2/3 pts), and marginal zone lymphoma 0% (0/1 pt). Grade 3 or 4 non-hematologic adverse events possibly related to lenalidomide include hypokalemia (4 pts), hypophosphatemia (3 pts), pneumonia (3 pts), fatigue (1 pt), elevated ALT (1 pt), elevated AST (1 pt), tumor flare (1 pt), pulmonary embolism (1 pt), and hyperuricemia (1 pt). Conclusions: These data indicate that the combination of continuous daily lenalidomide, low-dose weekly dexamethasone, and a single four week course of rituximab during cycle 3, achieves a high overall response rate with durable responses in rituximab-resistant patients with indolent B-cell or mantle cell lymphomas. Disclosures: Off Label Use: Phase II Trial of Lenalidomide - Dexamethasone - Rituximab in Relapsed or Refractory Indolent B-Cell or Mantle Cell Lymphomas Resistant to Rituximab. Schuster:Celgene: Research Funding.

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High Response Rate To Combination Lenalidomide-Rituximab In FcγRIIIa-F Carriers With Indolent Or Mantle Cell Lymphomas Previously Refractory To Rituximab

Blood ◽

10.1182/blood.v122.21.250.250 ◽

2013 ◽

Vol 122 (21) ◽

pp. 250-250

Author(s):

Elise A. Chong ◽

Tahamtan Ahmadi ◽

Nicole A. Aqui ◽

Sunita D. Nasta ◽

Jakub Svoboda ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Low Dose ◽

Overall Response Rate ◽

Response Rate ◽

Chemotherapy Regimen ◽

Single Agent ◽

Female Ratio ◽

Overall Response ◽

Mantle Cell

Abstract Introduction Lenalidomide is an immunomodulatory drug with effects on the innate immune system that may enhance antibody-dependent cell mediated cytotoxicity and synergize with the action of rituximab. Several studies have shown that Fc-gamma receptor RIIIA (FCGR3A) polymorphisms at amino acid 158 (V/V vs. V/F and F/F) have a significant impact on overall response rate, complete response rate, and time to progression in lymphoma patients (pts) receiving single-agent rituximab (Cartron 2002, Weng 2003). For example, the objective response rates at one year post treatment with rituximab were 75% in the FCGR3A 158 V/V group, as opposed to 26% in FCGR3A 158 V/F or F/F group (FCGR3A-F carriers with at least one F allele) with 2-year progression-free survival (PFS) of 14% for FCGR3A-F carriers (Weng 2003). To test the efficacy of lenalidomide combined with rituximab, we conducted a single center, open label phase II clinical trial in pts with indolent B-cell or mantle cell lymphomas previously unresponsive to rituximab. We report here the efficacy of the combination of lenalidomide and rituximab in FCGR3A-F carriers refractory to rituximab. Methods Eligible pts had relapsed/refractory indolent B-cell or mantle cell lymphoma with measurable disease that had either failed to respond to or progressed within six months of a standard course of rituximab monotherapy (375 mg/m2 weekly for at least four weeks) or a prior rituximab-containing chemotherapy regimen. All pts in this analysis of FCGR3A-F carriers had failed to respond to a prior rituximab or rituximab-containing chemotherapy regimen. In Part I (lenalidomide + dexamethasone), pts received two 28-day treatment cycles of lenalidomide 10 mg every day and dexamethasone 8 mg once weekly. After assessment of response to Part I, all pts received four weekly doses of rituximab 375 mg/m2 during cycle 3 (Part II: lenalidomide + dexamethasone + rituximab). Per protocol, pts received only a single four week course of rituximab during cycle 3. Lenalidomide + dexamethasone were continued during and subsequent to rituximab; stable and responding pts continued lenalidomide + dexamethasone until disease progression or development of clinically unacceptable toxicity. Response assessment after Part II was performed three months after the first dose of rituximab. Results Eighteen pts had FCGR3A genotying performed; 1 patient had the FCGR3A 158 V/V genotype and 17 pts were FCGR3A 158-F carriers. Of the 17 FCGR3A-F carriers, diagnoses included follicular (n = 12), mantle cell (n = 2), small lymphocytic (n = 2), and marginal zone (n = 1) lymphomas; median age was 59 years (range: 35 - 73); male: female ratio was 7:10; median number of prior therapies was 3 (range: 1 - 6). For all FCGR3A-F carriers, overall response rate (ORR) after Part I was 24% (3 CR; 1 PR; 12 SD; 1 PD) and ORR after Part II was 53% (5 CR; 4 PR; 7 SD; 1 PD) [Figure 1]. For 12 pts with follicular lymphoma who were FCGR3A-F carriers, ORR after Part I was 25% (2 CR; 1 PR; 9 SD) and ORR after Part II was 50% (4 CR; 2 PR; 5 SD; 1 PD). At 12 months after receiving rituximab (month 14), ORR for FCGR3A-F carriers was unchanged (50%). Median PFS is 24.5 months (95%CI 18 - 67) with median follow-up of 52 months (range: 11 - 60 months) [Figure 2]. Grade 3 or 4 non-hematologic toxicities in FCGR3A-F carriers included hypokalemia (2/17 pts), hypophosphatemia (2/17 pts), hyperuricemia (1/17 pts), pulmonary embolism (1/17 pts), pneumonia (1/17 pts), diarrhea (1/17 pts), transaminitis (1/17 pts), and tumor flare (1/17 pts). Conclusions In FCGR3A-F carriers with indolent B-cell or mantle cell lymphomas refractory to rituximab, the combination of continuous daily lenalidomide, low-dose weekly dexamethasone, and a single four week course of rituximab during cycle 3 achieves a high overall response rate with relatively durable responses. Compared to the 12 month ORR and 2 year PFS for FCGR3A-F carriers previously reported in predominantly relapsed/refractory follicular lymphoma patients (Weng 2003), our results compare favorably (ORR 50% vs 26%, PFS 50% v 14%). The improvement in response during lenalidomide + low-dose dexamethasone following rituximab suggests that this combination overcomes the unfavorable impact of the FCGR3A-F polymorphism on rituximab responsiveness. Disclosures: Off Label Use: therapy of non-Hodgkin lymphoma with lenalidomide. Schuster:Celgene Corp: Research Funding.

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Survival Benefits of Patients with Non-Hodgkin’s Lymphoma Treated with Rituximab Combined with Chemotherapy.

Blood ◽

10.1182/blood.v104.11.4625.4625 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4625-4625

Author(s):

Zhixiang Shen ◽

Junmin Li ◽

Aihua Wang ◽

Yu Chen

Keyword(s):

B Cell ◽

Overall Response Rate ◽

Response Rate ◽

Cell Lymphoma ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Free Survival ◽

Overall Response ◽

Large B Cell

Abstract Purpose: Rituximab combined with chemotherapy has been recommended as first-line or second-line standard regimen in most subtypes of B-cell lymphoma in China by the 2004 National Comprehensive Cancer Network lymphoma therapy guideline. We have conducted a multicenter trial to evaluate the efficacy and safety of rituximab in combination with standard chemotherapy (CHOP) in patients with previously untreated or relapsed indolent and aggressive NHL. Methods: Patients received 4–8 cycles of rituximab plus CHOP every 21 days. For each cycle, rituximab (375mg/m2) was given on day 1 and CHOP started on day 3. CHOP consisted of cyclophosphamide 750mg/m2, doxorubicin 50mg/m2, and vincristine 1.4mg/m2 (maximum 2mg/dose) given intravenously on day 3, and oral prednisone 100mg on days 3–7. Results: A total of 221 patients were enrolled on the trial, 128 males and 93 females with a mean age of 49 years (range 10–83 years). The main lymphoma subtypes were small lymphocytic (15 patients, 7%), follicular (27 patients, 12%), and diffuse large B-cell (160 patients, 72%). In total, 56 patients had indolent NHL and 165 aggressive NHL. The overall response rate for all patients was 86% with 57% complete responses. In patients with indolent NHL the overall and complete response rates were 95% and 55% respectively. After a median 12 months follow up, progression-free survival in patients with indolent NHL was 88%±5% at 1 year and 83%±6% at 2 years. In the 160 patients with diffuse large B-cell lymphoma, the overall response rate was 88% with 61% complete responses, and after a mean follow-up of 6 months, predicted 1-year and 2-year progression-free survival were 88%±5% and 83%±7% respectively. Infusion-related adverse events occurred in 4% of patients, associated with the first infusion of rituximab. Subanalyses according to subtype, stage, IPI and other factors will be presented. Conclusion: Rituximab plus chemotherapy is an effective, well-tolerated treatment that achieves high response rates and long progression-free survival in both indolent and aggressive NHL.

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Follow-Up Results of a Prospective, Multicenter, Open-Label Study of Oral Fludarabine Phosphate in Patients with Previously Untreated B-CLL.

Blood ◽

10.1182/blood.v106.11.2128.2128 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2128-2128

Author(s):

Jean-Francois Rossi ◽

A. Van Hoof ◽

K. De Boeck ◽

S. A. Johnson ◽

D. Bron ◽

...

Keyword(s):

Disease Progression ◽

Median Time ◽

Response Rate ◽

Time To Progression ◽

Open Label ◽

Overall Response ◽

Fludarabine Phosphate ◽

Duration Of Response ◽

Grade 3

Abstract The IV formulation of fludarabine phosphate is an effective treatment in patients with B-cell chronic lymphocytic leukemia (B-CLL), yielding overall response rates of 60% to 80%. An oral formulation of fludarabine phosphate has been developed. In a previously published multicenter, open-label, phase II clinical trial, 81 previously untreated B-CLL patients received 10-mg tablets of fludarabine phosphate (Fludara® oral) 40 mg/m2/day for 5 days, repeated every 4 weeks. The primary endpoint of the trial was response rate, and secondary endpoints included safety and quality of life assessments. Of 81 patients (mean age, 61.2 years; range, 30–75 years) with previously untreated B-CLL, 81.5% were classified as Binet stage B or C. The overall response rate (complete response [CR] + partial response [PR]) using National Cancer Institute (NCI) criteria was 80.2% (12.3% CR and 67.9% PR) and the median time to progression was 841 days (range, 28–1,146 days) (Rossi JF, et al. J Clin Oncol2004;22:1260–1267). The most frequently reported grade 3/4 adverse event was myelosuppression: WHO grade 3/4 hematologic toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). This analysis reports on the long-term follow-up of this cohort during the period from November 2001 to November 2004. Of the 74 patients eligible for the survival analysis, 61 were also assessed for duration of response using NCI criteria: 9 CR (14.8%) and 52 PR (82.2%). During the 3-year follow-up period, 22 (29.7%) patients did not progress. For those who progressed, median time to progression was 29.7 months, and median duration of response was 22.9 months. In 41 (80.4%) of these patients, an increase in circulating lymphocytes was reported as evidence of disease progression. In 23 patients (45.1%), an increase in the sum of the products of at least 2 lymph nodes and/or appearance of new palpable nodes was reported as evidence of disease progression. During the indicated follow-up period, 37 patients (50%) received subsequent treatment. Twelve patients (16.2%) died during the follow-up period: 7 patients (58.3%) due to disease progression, 3 patients (25.0%) due to adverse events, and 2 patients (16.7%) due to other causes. Results from this study suggest that oral fludarabine phosphate is clinically effective and well tolerated by patients with previously untreated B-CLL. Moreover, these data demonstrate that oral fludarabine phosphate achieves response rates and duration of response comparable to those achieved with first-line fludarabine phosphate IV therapy.

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Rituximab Increases Response to ESHAP in Relapsed, Refractory, and Transformed Aggressive B-Cell Lymphoma.

Blood ◽

10.1182/blood.v108.11.3067.3067 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3067-3067 ◽

Cited By ~ 2

Author(s):

Lisa Hicks ◽

Rena Buckstein ◽

Joy Mangel ◽

Eugenia Piliotis ◽

Kevin Imrie ◽

...

Keyword(s):

Myocardial Infarction ◽

B Cell ◽

Overall Response Rate ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Indolent Lymphoma ◽

Overall Response ◽

Grade 3 ◽

Aggressive B Cell Lymphoma

Abstract Background: Patients with relapsed or refractory aggressive B-cell lymphoma, or transformed indolent lymphoma can achieve long-term survival with high dose therapy and autologous stem cell transplant (HDT/ASCT), provided their disease is sensitive to salvage chemotherapy. Unfortunately, approximately 50% of patients are insensitive to standard salvage regimens. Objectives: This trial investigated whether adding Rituximab to ESHAP (etoposide, solumedrol, cytosine arabinoside, cisplatin) induction improved chemosensitivity. The primary outcome was overall response rate (CR + CRu + PR) to R-ESHAP. Secondary outcomes were toxicity, ability to undergo ASCT, progression free survival (PFS) and overall survival (OS). Methods: The protocol was approved by the local ethics review board and all patients provided informed consent. Eligible patients received ESHAP every 28 days with GCSF support until < 15% bone marrow involvement was achieved (2–4 cycles). Rituximab was given weekly x 8 weeks concurrent with the first 2 cycles of ESHAP. GCSF mobilized stems cells were collected on day 10–11 of cycle 1 or 2. Results: The trial was stopped early after the complete response (CR) rate at a planned interim analysis exceeded 40% (a pre-specified criteria for stopping the trial). Final results of 26 patients are presented. Median age was 55.5 years (range 42–64). Twelve patients had relapsed aggressive lymphoma, 2 had refractory disease and 12 had transformed indolent lymphoma. Twenty-two of 26 patients were stage III/IV. The overall response rate to R-ESHAP was 92% (95% CI 82% to 100%). Twelve patients (46%; 95% CI 27% to 65%) had a CR or unconfirmed CR. Grade 3–4 thrombocytopenia, neutropenia, and anemia occurred in 57%, 40%, and 15% of R-ESHAP cycles respectively. Grade 3–4 infections complicated 7% of cycles. Median follow-up was 17 months (range 2.9 to 43.2) from enrollment. Twenty-three of 26 patients (88%) were transplanted. Notable post-transplant toxicity included 5 cases of herpes zoster, 2 cases of bacterial pneumonia, 1 case of pulmonary aspergillosis, and 1 fatal case of pneumocystis carnii pneumonia (PCP). Three patients did not proceed to HDT/ASCT; 2 were refractory to R-ESHAP and 1 died of a myocardial infarction after induction chemotherapy but prior to ASCT. Fifteen of 23 patients who received ASCT remain in remission, 6 have relapsed. Seven patients have died, 4 of progressive disease, 1 of myocardial infarction, 1 of PCP, and 1 of accelerated Parkinson’s Disease. Median PFS and median OS have not yet been reached. Conclusions: In this single-arm, phase II study of relapsed or refractory aggressive B-cell lymphoma and transformed indolent B-cell lymphoma, R-ESHAP induction therapy resulted in a very high ORR (92%) and enabled a large percentage of patients (88%) to proceed to HDT/ASCT. Toxicity of the R-ESHAP regimen was acceptable, and its efficacy compared favorably with other salvage regimens reported in the literature, including R-ICE.

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Favorable Results of Rituximab in Combination with CHOP in the Front-Line Treatment of Follicular Lymphoma Grade 3.

Blood ◽

10.1182/blood.v108.11.2770.2770 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2770-2770

Author(s):

Luis Fayad ◽

Michael Overman ◽

Barbara Pro ◽

Peter McLaughlin ◽

Felipe Samaniego ◽

...

Keyword(s):

Follicular Lymphoma ◽

B Cell ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Bulky Disease ◽

Large B Cell Lymphoma ◽

Grade 3 ◽

Large B Cell

Background: Follicular lymphoma grade 3 has a natural history that is more akin to that of diffuse large B-cell lymphoma. The addition of rituximab to standard CHOP has resulted in improved response and survival in diffuse large B-cell lymphoma. Information about outcomes in follicular lymphoma grade 3 is lacking. Methods: A single institution retrospective review of patients with follicular grade 3 lymphoma evaluated at the UTMDACC from 1999 to 2004. Patients were located from the UTMDACC lymphoma database. All patients were initially treated with R-CHOP. Results: Forty-five patients were identified: 51% male, 47% ≥60 years, and 87% follicular grade 3b. The LDH was elevated in 24%, ECOG performance status was >1 in 2%, and >1 site of extranodal involvement was present in 10%. Stage distribution was 11% stage I, 11% stage II, 42% stage III, and 36% stage IV, bulky disease (>7cm) was present in 11%, and B symptoms occurred in 13%. Beta-2 microglobulin was elevated in 57% with values >3 μg/dL in over 50%. IPI distribution was: 46% IPI Low, 38% LI, 11% IH, and 4% IPI High. Overall response rate was 100% with 96% complete responses. Relapse rate by IPI category was 24% for Low IPI, 18% for IPI LI, and 40% for IPI IH, and 100% for the two patients with High IPI. With median follow-up of 33 months, three year failure-free survival (FFS) is 73% (95% CI: 59 to 87%). One patient died (2%) with an overall survival (OS) at three years of 97% (95% CI: 93 to 100%). Conclusion: The addition of rituximab to CHOP provided a high response rate and excellent early survival in this group of mostly good prognosis patients. Relapses were still seen; longer follow-up is needed.

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