Novel Combination of Gallium Nitrate, Rituximab and Dexamethasone for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Mantle Cell Lymphoma or Transformed Follicular Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4755-4755
Author(s):  
Scott E. Smith ◽  
Patrick J. Stiff ◽  
Tulio Rodriguez ◽  
Amir Toor ◽  
Jared Klein
Keyword(s):  
Ribonucleotide Reductase ◽  
Transferrin Receptor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
The United States ◽  
Treatment Modalities ◽  
High Dose ◽  
Gallium Nitrate ◽  
Hospitalization Costs ◽  
Grade 3

More than 56,000 new cases of non-Hodgkin’s lymphoma (NHL) will be diagnosed this year in the United States. Despite advances in treatment modalities such as radiation, biologic agents, and cytotoxic chemotherapeutic regimens, only 25–30% of these patients will be cured of their disease. Standard salvage regimens such as DHAP, ESHAP, ICE and EPOCH have proven efficacy at the cost of increasing toxicity and hospitalization costs. The reported response rates for these are on the order of 50–75% as first-line salvage regimens. However, as our aging patient population develops worsening performance status and co-morbidities, it seems appropriate to develop effective lymphoma treatments, which have fewer toxicities and lower costs for administration. One approach is to combine non-myelosuppressive therapies. One non-myelosuppressive agent, which has efficacy in lymphoma, is gallium nitrate. Investigation of gallium nitrate for cancer treatment dates back to the 1970’s. While it is currently approved for the treatment of bisphosphonate resistant hypercalcemia of malignancy, it has also been shown to inhibit ribonucleotide reductase and bind transferrin and potentially complex with the transferrin receptor, which is highly expressed in intermediate and aggressive histology lymphomas. It appears that the binding of the transferrin receptor on the lymphocyte as well as its inhibition of ribonucleotide reductase, eventually impairs iron metabolism, which is a necessary component of the intracellular cytochrome systems/mitochondrial function and ultimately oxidative phosphorylation. The current study is a phase II clinical trial investigating the combination of gallium nitrate, rituximab and dexamethasone (GaRD) for relapsed or refractory DLBCL, MCL or transformed follicular lymphomas. The gallium nitrate is given at 200mg/m2 CIV days 1–7, rituximab 375mg/m2 IVPB day 1 and dexamethasone 40 mg po days 1–4. Eligible patients must have proven relapsed or refractory disease and have a SWOG PS <3. Patients may have failed prior ASCT or allogeneic SCT. The accrual goal is 37 patients. We have enrolled 14 patients on study to date and have 12 evaluable patients; as part of the ongoing safety evaluation for this study, we have the following results: ORR 9/12 (75%); CR 2/12 (17%); PR 7/12 (58%); SD 2/12 (17%); and PD 1/12 (8%). Most of these patients were refractory to prior salvage regimens 8/12 (67%), including ESHAP, DHAP or high-dose cyclophosphamide. No patients developed grade 3 or 4 toxicities, with the exception of grade 4 lymphopenia and grade 3 anemia (most likely due to transferrin receptor binding). Conclusions: gallium nitrate, rituximab and dexamethasone (GaRD) appears to be an effective and relatively non-toxic salvage regimen for patients with relapsed DLBCL, MCL or transformed FL.

The combination of gallium nitrate, rituximab and dexamethasone is effective and safe as a salvage regimen for diffuse large B-cell lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17510-17510 ◽  
Author(s):  
S. E. Smith ◽  
A. Toor ◽  
J. Klein ◽  
T. Rodriguez ◽  
P. J. Stiff
Keyword(s):  
Ribonucleotide Reductase ◽  
Transferrin Receptor ◽  
Performance Status ◽  
B Cell Lymphoma ◽  
The United States ◽  
High Dose ◽  
Gallium Nitrate ◽  
Salvage Regimen ◽  
Grade 3 ◽  
Follicular Lymphomas

17510 Background: More than 56,000 new cases of non-Hodgkin’s lymphoma (NHL) will be diagnosed this year in the United States. As our aging patient population develops worsening performance status and co-morbidities, it seems appropriate to develop effective lymphoma treatments, which have fewer toxicities and lower costs for administration. One approach is to combine non-myelosuppressive therapies. One non-myelosuppressive agent, which has efficacy in lymphoma, is gallium nitrate. Investigation of gallium nitrate for cancer treatment dates back to the 1970’s and it has been shown to inhibit ribonucleotide reductase and bind transferrin and potentially complex with transferrin and/or transferrin receptor, which is highly expressed in intermediate and aggressive histology lymphomas. It appears that the binding of the transferrin receptor on the lymphocyte as well as its inhibition of ribonucleotide reductase, eventually impairs iron metabolism, which is a necessary component of the intracellular cytochrome systems/mitochondrial function and ultimately oxidative phosphorylation. Methods: The current study is a phase II clinical trial investigating the combination of gallium nitrate, rituximab and dexamethasone (GaRD) for relapsed or refractory DLBCL, MCL or transformed follicular lymphomas. The gallium nitrate is given at 200mg/m2 CIV days 1–7, rituximab 375mg/m2 IVPB day 1 and dexamethasone 40 mg po days 1–4. Eligible patients must have proven relapsed or refractory disease and have a SWOG PS ≤3. Patients may have failed prior ASCT or allogeneic SCT. The accrual goal was 37 patients however the study was stopped after 22 patients were accrued as the primary endpoint was reached after the initial interim analysis. Results: ORR 12/22 (55%); CR/CRu 6/22(27%); PR 6/22(27%); SD 3/22 (14%); and PD 7/22 (32%). Most of these patients were refractory to prior salvage regimens 15/22 (68%), including ESHAP, DHAP or high-dose cyclophosphamide. No patients developed grade 3 or 4 toxicities, with the exception of grade 4 lymphopenia. Conclusions: Gallium nitrate, rituximab and dexamethasone (GaRD) appears to be an effective and non-toxic salvage regimen for patients with relapsed DLBCL [Table: see text]

R-CHOEP-14 × 6 Followed by Systemic CNS Prophylaxis for Diffuse Large B-Cell Lymphoma/Follicular Lymphoma Grade 3 with Age Adjusted IPI Score 2–3: Final Results of a Nordic Lymphoma Group Phase 2 Study Including 156 Patients Aged 18–65 Years.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2805-2805 ◽  
Author(s):  
Harald Holte ◽  
Sirpa Leppä ◽  
Magnus Bjorkholm ◽  
Øystein Fluge ◽  
Sirkku Jyrkkiö ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Cns Prophylaxis ◽  
Large B Cell Lymphoma ◽  
Residual Masses ◽  
Grade 3 ◽  
Large B Cell

Abstract Abstract 2805 CHOP – based chemotherapy for aggressive lymphomas in patients with age-adjusted International Prognostic Index (IPI) score of 2–3 resulted in a historical 3-year progression free survival of approximately 30% in a previous Nordic phase III study. The aim of the present study is to determine whether an intensified regimen with chemoimmunotherapy and CNS prophylaxis improves outcome. Methods: From October 2004 to June 2008 patients were included in a phase II study. Inclusion criteria: 1) Age 18–65 years. 2) Newly diagnosed de novo diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) grade III. 3) No clinical sign of CNS disease and negative CSF cytology/flow cytometry by lumbar puncture. 4) No HIV infection. 5) WHO performance score 0–3. 6) Adequate organ functions. Schedule: Six courses of R-CHOEP14. Pegfilgrastim 6 mg sc. day four of each cycle. One course of high dose cytarabine 12 g/m2 (6 g/m2 for patients 60–65 years). One course of high dose methtrexate 3 g/m2 (1 g/m2 for patients 60–65 years). Biopsy and/or 18FDG PET/CT imaging of residual masses after fulfilled therapy was recommended, but not mandatory. Radiotherapy was given to residual masses of uncertain significance. Results. Demographic data:.156 eligible patients were included (97 males). Median age: 54 years (range 20–64). Histology: DLBCL: 145, FL grade 3: 12 (three patients no data). Age adjusted IPI score: 2: 117; 3: 39. Stage III-IV: 150 patients. LDH elevated: 151 patients. Performance status 2–3: 51 patients. B-symptoms were registered in 97 patients, more than one extranodal site in 42 and bulky lesions (≥ 10 cm) in 68. Median observation time for patients alive at last follow up was 36 months. Toxicity: Three toxic deaths are registered, one large bowel perforation, one fulminant hepatic necrosis and one septic shock. Hematological toxicity grade 4 was seen in 78% of the patients, infection grade 4 in 8%. Radiotherapy was given to 16% of the patients. Response: Response rates at end of therapy: CR/CRu: 69%, PR: 22%, SD: 1%, PD: 4.5%. Seventeen patients (7%) were not treated according to protocol, either due to lack of response (6 patients) or due to toxicity (eleven patients). The majority of the PR patients were considered to have residual masses and not viable tumour tissue. Survival: Three year overall survival was 80% (95% CI +/− 6.5%) and three year treatment failure free time 67% (95% CI +/−8.0%). CNS events: Seven patients had a CNS relapse, all but one were isolated (4 intracerebral, 3 meningeal). All CNS relapses occurred within 6 months after inclusion. Conclusions: The results are promising with a low three year treatment failure rate, a low toxic death rate and fewer CNS events than expected. The CNS events might be further reduced by earlier CNS prophylaxis. The study was supported by an unrestricted grant from Amgen Disclosures: Holte: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. LeppÃ: Roche: Honoraria. Bjorkholm:Roche: Research Funding. Jyrkkiö:Roche: Honoraria. Kolstad:Roche: Honoraria; Amgen: Honoraria. Fosså:Roche: Honoraria. φstenstad:Roche: Honoraria; Amgen: Honoraria. Eriksson:Amgen: Research Funding.

scholarly journals Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma: Report on an Ongoing Phase II Trial (GOAL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5392-5392 ◽  
Author(s):  
Georg Hess ◽  
Andreas Hüttmann ◽  
Reinhard Marks ◽  
Mathias Witzens-Harig ◽  
Martin H. Dreyling ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Grade 3

Abstract Background: Prognosis of diffuse large B-cell lymphoma (DLBCL) and other aggressive lymphoma entities has improved with the advent of Rituximab, and R-CHOP-21 and variants is SOC. Nevertheless, a substantial proportion of patients fail first line treatment. Salvage therapies are often effective. However, no more than 25-50% achieve a long term remission even when consolidative high dose chemotherapy (HDT) followed by hematopoietic stem cell transplantation (SCT) is applied. In case of failure or intolerance to HDT, regimen like Gemcitabine/Oxaliplatin are applied but show limited efficacy, indicating the need for new treatments. Obinutuzumab (GA101) is a type II anti-CD20 antibody. Superiority of Obinutuzumab could be demonstrated in xenograft models of mantle cell lymphoma and DLBCL. Although desirable, cumulative dose-related, progressive cardiotoxicity eliminates anthracyclins from higher treatment lines. With Pixantrone, a drug structurally related to anthracyclines and especially anthracenediones, a re-exposition against this drug class has been shown to be feasible. In 70 heavily pre-treated patients, a best ORR of 40% (20% CR/CRu) was observed (Pettengell et al). Experiences from further antibody drug combinations lead to the assumption that the effects of Pixantrone will be augmented by a monoclonal antibody without increasing toxicity. We thus initiated a trial combining both agents for the first time. The trial has opened in Q4/2015 and recruitment is ongoing. Overall, a total of up 70 patients will be enrolled for a number of 64 evaluable patients. Primary endpoint will be the objective overall response rate, with secondary endpoints being safety, PFS and OS. Methods: this is a multicenter, national, prospective trial. Inclusion criteria: patients were eligible if they had histologically proven DLBCL, FL grade IIIb or transformed indolent lymphoma, CD20 positive disease, no curative option available, relapsed disease, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. There was no upper limit or prior treatment lines. Treatment consisted of Pixantrone 50mg/m² day 1, 8 and 15 of each cycle, Obinutuzumab 1000 mg flat dose day 1, 8 and 15 of cycle one and day 1 of each subsequent cycle. A total of 6 cycles was planned with interim staging after 3 cycles. Results: 24 patients (pts) have been included until now. Concerning clinical characteristics, all were caucasian, 12 were female and the other 12 male and median age was 75 years. Most of the patients suffered from DLBCL (18 pts, 82%). Median number of prior therapies was 2 (1 to 6). Until now 55 evaluable cycles of chemotherapy (median 2 cycles (0 to 6)) have been performed. At this time, the treatment seems to be well tolerated, with no unforeseen side effects. Observed toxicity was predominantly hematologic. The following hematologic adverse events of grade 3/4 were noted: leukopenia (4 pts, 17%), neutropenia (6 pts, 25%), granulocytopenia (1 pts, 4%), as well as thrombocytopenia (2 pts). Non-hematologic grade 3/4 adverse events were observed in at least two patients: hypertension (2 pts) and pelvic pain (2 pts). Response: currently, best responses were 4 PR, 1 SD, and 8 PD in 13 patients evaluable so far. Four patients died, all after progression of lymphoma. Summary: the combination of Obinutuzumab and Pixantrone seems to be feasible and safe with early signs of efficacy. Updated results of this trial in progress with a focus on safety will be presented. Disclosures Hess: Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Roche, CTI, Pfizer, Celgene: Research Funding; Roche: Honoraria. Marks:Pfizer: Honoraria. Witzens-Harig:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Viardot:Amgen: Consultancy; Janssen: Consultancy; BMS: Consultancy; Roche: Honoraria; Takeda: Other: travel support; Pfizer: Honoraria. Keller:Spectrum Pharmaceutical: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Lisocabtagene maraleucel (liso-cel) for treatment of second-line (2L) transplant noneligible (TNE) relapsed/refractory (R/R) aggressive large B-cell non-Hodgkin lymphoma (NHL): Updated results from the PILOT study.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8040-8040 ◽  
Author(s):  
Alison R. Sehgal ◽  
Gerhard Hildebrandt ◽  
Nilanjan Ghosh ◽  
John E. Godwin ◽  
Nina D. Wagner-Johnston ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Car T Cells ◽  
Car T ◽  
Grade 3 ◽  
Large B Cell

8040 Background: Patients (pts) with aggressive large B-cell NHL who are R/R after first-line immunochemotherapy and not eligible for high-dose chemotherapy and HSCT have a poor prognosis and no established standard of care. The ongoing, open-label phase 2 PILOT study is the first to assess the safety and efficacy of liso-cel, an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product infused at equal target doses of CD8+ and CD4+ CAR+ T cells, as 2L therapy in TNE pts (NCT03483103). Methods: Eligible pts had aggressive R/R diffuse large B-cell lymphoma NOS (de novo or transformed follicular lymphoma [FL]), high-grade B-cell lymphoma, or FL grade 3B with 1 line of prior therapy containing an anthracycline and anti-CD20 agent. Pts were deemed TNE by meeting ≥1 criteria: age ≥70 y, ECOG PS 2, or impaired organ function (DLCO ≤60% [but SaO2 ≥92% and CTCAE ≤1 dyspnea], LVEF ≥40% to < 50%, creatinine clearance > 30 to < 60 mL/min, or AST/ALT > 2 to ≤5 × ULN). Liso-cel (100 × 106 CAR+ T cells) was administered 2–7 days after lymphodepletion (LD) with fludarabine/cyclophosphamide. The primary endpoint is ORR; key secondary endpoints are AEs and CR rate. Results: At data cutoff, 25 pts had LD followed by liso-cel infusion. Pt characteristics are summarized in the Table. Overall, 48% (n = 12) had high tumor burden and 48% were primary refractory. 18/25 (72%) pts had grade ≥3 treatment-emergent AEs, 40% of which were cytopenias. No grade 5 AEs occurred within the first 30 days after liso-cel. Five pts (20%) had cytokine release syndrome (CRS) and 3 (12%) had neurological events (NEs). No grade 3/4 CRS was observed; 2 pts (8%) had grade 3/4 NEs. Five pts (20%) received tocilizumab and/or dexamethasone for CRS/NEs. At a median follow-up of 3.5 mo, the ORR was 80% (95% CI, 59–93; n = 20); 48% of pts (n = 12) achieved CR. Conclusions: These interim data suggest that elderly and/or comorbid pts with R/R aggressive large B-cell NHL, who are not eligible for high-dose chemotherapy and HSCT, can receive 2L liso-cel with similar safety and efficacy to 3L+ pts as previously reported (Abramson, ASH 2019 #241). Updated data with longer follow-up will be presented. Clinical trial information: NCT03483103 . [Table: see text]

scholarly journals Panobinostat As Salvage Treatment for Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Not Eligible to High Dose Therapy: A Phase II Study of the Fondazione Italiana Linfomi (FIL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1755-1755 ◽  
Author(s):  
Francesco Zaja ◽  
Stefano Volpetti ◽  
Annalisa Chiappella ◽  
Flavia Salvi ◽  
Angelo M. Carella ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematological Toxicity ◽  
High Dose ◽  
High Dose Therapy ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

Abstract Backgrounds: Treatment of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not eligible to high dose therapy represents an unmet medical need. Histone deacetylases (DACs) regulate chromatin structure and function and are involved in crucial mechanisms of lymphoma cell growth. Panobinostat showed encouraging therapeutic activity in Hodgkin lymphoma, cutaneous T-cell lymphoma and other non-Hodgkin lymphomas, in studies conducted in lymphoma cell lines and in vivo in patients with advanced hematologic malignancies. Moreover, recent studies showed a potent activity of Panobinostat in DLBCL. Purpose: On this basis we performed a prospective, multicenter, phase II single arm study, to evaluate safety and efficacy of single agent Panobinostat as salvage therapy for R/R DLBCL adult patients and to evaluate a possible relationships between response and any biological features. Patients and Methods: Adult patients with R/R DLBCL who already performed high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) or were not eligible for ASCT were included. The treatment plan included 6 induction courses with Panobinostat monotherapy followed by other 6 courses of consolidation; patients achieving complete response (CR), partial response (PR) or stable disease (SD), underwent maintenance for a maximum of 36 courses. In each 28-days course, Panobinostat was administered orally at the dosage of 40 mg/day three-times every week; dose adjustments for patients unable to tolerate the protocol-specified schedule were provided. The primary objective was to evaluate Panobinostat activity in terms of overall response (OR) according to the Cheson 1999 criteria; secondary objectives were: CR rate, time to response (TTR), progression-free survival (PFS), safety and feasibility of Panobinostat. We included evaluation of the impact of pharmacogenetics, immunohistochemical patterns and patient's specific gene expression and mutations as potential predictors of response to Panobinostat as explorative objectives. To this aim a pre-enrollment new tissue biopsy was mandatory. Results Thirty-five patients, 21 males (60%), were enrolled between June 2011 and March 2014. Clinical characteristics were: median age 73 (range 65-75), stage IV in 18 (55%), B-symptoms in 9 (28%), increased LDH in 24 (69%), high-intermediate or high International Prognostic Index (IPI) in 18 (51%). Patients received a median of 2 prior lines of therapy (range 1-4). At the end of induction phase, 7 responses (20%) were observed, including 4 CR (11%), while 28 patients (80%) discontinued treatment due to progressive disease (PD) in 21 (60%) or adverse events in 7 (20%). Median TTR in 9 responders was 2.6 months (range 1.8-12). With a median follow up of 6 months (range 1-34), the estimated 12 months PFS and OS were 27% and 30.5%, respectively. In univariate analysis, favourable IPI score and cutaneous involvement at enrollment showed a trend toward a higher ORR (p=0.007 and 0.061, respectively); pharmacogenetics, immunohistochemical and gene expression profile studies are still ongoing. No toxic deaths were reportewd; 18 patients died, 17 due to lymphoma progression and one for allogeneic transplant related complications, performed after PD. Grade 3-4 thrombocytopenia and neutropenia were the most common toxicities (in 29 (83%) and 12 (34%) patients, respectively), while grade 3-4 extra-hematological toxicity included diarrhoea in 4 (12%), infectious complications in 1 (3%) and supraventricular arrhythmia in 2 patients (6%). Conclusions The results of this study indicate that Panobinostat might be remarkably active in some patients with R/R DLBCL, showing durable CR. Feasibility was impaired by relevant hematological toxicity, mainly frequent and dose limiting grade 3-4 thrombocytopenia. Data that will be obtained from biological exploratory studies could hopefully be useful to better address the use of Panobinostat in peculiar subsets of patients. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Off Label Use: Panobinostat in DLBCL.

Rituximab, gemcitabine and oxaliplatin (R-GEMOX): An effective regimen for relapsed and refractory B-cell lymphoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7562-7562 ◽  
Author(s):  
T. El Gnaoui ◽  
J. Dupuis ◽  
K. Belhadj ◽  
A. Rahmouni ◽  
C. Copie-Bergman ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Median Number ◽  
Primary Objective ◽  
Clinical Activity ◽  
High Dose ◽  
Induction Phase ◽  
Mantle Cell ◽  
Grade 3

7562 Background: High-dose therapy with autologous stem cell support (HDT) is an established treatment for chemosensitive relapse in lymphoma. However, not all patients are candidates for HDT because of age, comorbidities or previous HDT. In addition,effective and less toxic alternatives to classical Cisplatin/ARA-C-based salvage regimens are needed. Methods: Based on the clinical activity, tolerability of rituximab (R), gemcitabine (G) and oxaliplatin (Ox) and synergy between these drugs, the R-GEMOX regimen was designed with R (375mg/m2 d 1), G (1,000 mg/m2 d 2) and Ox (100 mg/m2 d 2). Treatment was given every two weeks. Between January 2002 and June 2005, 46 patients with refractory/relapsing B-cell CD20+ lymphoma not eligible for HDT were enrolled in an unicenter pilot study whose primary objective was overall response rate (ORR) after 4 cycles (induction phase). Patients were planned to receive 8 cycles if at least PR was observed after 4 cycles. Median age was 64 years (range: 43–78) and histological subtypes were: diffuse large B-cell lymphoma (n = 33), follicular (n = 8) and mantle cell (n = 5). Prior treatments included anthracyclin in 45 patients, rituximab in 26 (56%) and HDT in 14 (30%). The median number of prior treatments was 2 (range: 1 to 5) and 13 patients (28%) had received at least 3 prior regimens. Results: 315 cycles were given. The dose administered was 100% of the intended dose for the three drugs in all patients but 8, for whom the dose of oxaliplatin was reduced due to neurotoxicity (n = 7) or preexisting renal insufficiency (n = 1). Eight patients progressed during the induction phase. After 4 cycles, responses were: 10 CR, 13 CRu and 15 PR resulting in an ORR of 83%. At the end of treatment, among the 38 responder-patients, 36 patients achieved CR (78% of the entire population), one patient remained in PR and one progressed. With a median follow-up of 27 months, the 2-year progression-free and overall survivals were 53% and 66%, respectively. NCIC grade 3–4 neutropenia and thrombocytopenia were reported in 48% and 22% of the cycles. A grade 4 infection was observed in only 3% of the cycles. There was no renal toxicity. Conclusions: The R-GEMOX regimen shows promising activity with an acceptable toxicity. It is currently evaluated in a multicentric phase II study. [Table: see text]

scholarly journals Radiation Exposure As a Link to Primary Ocular Diffuse Large B Cell Lymphoma (PODLBCL) - a Possible Cluster Related to the Chernobyl Explosion

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5381-5381
Author(s):  
Sanford Kempin ◽  
Paul Finger ◽  
John Rescigno ◽  
Jeffrey Rubin ◽  
Walter Choi ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
The United States ◽  
Lymphoid Cells ◽  
High Dose ◽  
Large B Cell Lymphoma ◽  
The Mean ◽  
Large B Cell

Abstract Background: PODLBCL, a rare form of diffuse large B cell lymphoma (DLBCL), arises primarily from the retina and urea. It is estimated to occur in 100 patients/3 years in the United States. Its etiology is unknown although chronic inflammation is thought to play a significant role. It is observed most commonly in immunocompetent patients. EB virus has not been associated with the form of lymphoma. The disease is frequently bilateral (80%) and 56-85% of patients will develop intracerebral metastases. There is a slight male predominance. The peak of incidence is between the fifth and seventh decade. Methods: We have recently had an opportunity to evaluate six patients at the MS/BICCC from 2010-2013. All received initial therapy at MS/BICC. We have analyzed disease presentation, various demographic factors, possible exposure information, treatment and outcome. In addition, epidemiologic studies of the Chernobyl (Ukraine) nuclear power plant explosion (April 26, 1986) were reviewed. The most contaminated regions included Belarus and the Ukraine, with volatile fission products traveling at greater distances (Bard D, Verger P, Hubert P. Chernobyl, 10 Years After: Health Consequences Epidemiologic Reviews 1997:19 (2):187-201). The main health effect continues to be that of thyroid cancers. With respect to ocular findings, liquidators were found to develop senile cataracts, premature myopia and arteriosclerosis of the fundic vessels. The ten-year follow-up demonstrated a slight increase in subcapsular lens changes in children. At the 20 year follow-up (Cardis E, Howe G, Ron E, et al.) Cancer Consequences of the Chernobyl Accident: 20 Years On. J. Radiol Prot 2006; 26:127-140) there has been no conclusive reported increase in childhood or adult leukemia of lymphoma. In the most recent update (Pflugbeil S, Claussen A, Schmitz-Feuerhake. Health Effects of Chernobyl 25 Years After the Reactor Catastrophe. 2011: Gesellschaft fur Strahlenschutz) there is still no definitive evidence of an increase in lymphoma. Results: In our series the most common complaint was cloudiness of vision and the most common findings were anterior chamber inflammation, sheets of cells within the vitreous, uveitis and subretinal and retinal infiltrates. The presentation was bilateral in all patients. The mean age at presentation was 76 years (62-84), including five women and one man (the female predominance is unusual). At the time of exposure, four of the patients were living in the Ukraine; one in Moldova and one is southern Poland. The mean time possible exposure to appearance of PODLBCL was 26 years. The diagnosis was made by vitreous FNA (2), vitreous biopsy (4), clinical presentation (1). Initial treatments included chemotherapy (high dose methotrexate) in two patients, and radiation therapy in four patients. Of the six there was one synchronous presentation with brain lymphoma. Two patients developed spread to the brain, one of whom expired and one of whom is considered NED after whole brain irradiation and temazolomide. Five patients remain NED, but at short follow-up. Conclusions: Conceptionally, lymphomas are thought to develop because of an inherent sensitivity of lymphoid cells to genetic instability, immune stimulation, inherited genetic disorders, toxins, infections agents as well as radiation injury. For almost all etiologies it is accepted that a long prodromal period between exposure and subsequent appearance of neoplasia occurs and these case reports may be an illustration of this phenomena. It is estimated that several million Europeans were exposed to radiation as a result of this explosion. As the ocular globe would appear to be one of the most exposed organs, more patients with this unusual malignancy may be seen and an appreciation of this possibility would seem warranted. Disclosures No relevant conflicts of interest to declare.

Long-term survival with 90yttrium ibritumomab tiuxetan and rituximab as treatment for relapsed or refractory diffuse large B-cell lymphoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8558-8558
Author(s):  
Jon E. Arnason ◽  
Katarina Luptakova ◽  
Jacalyn Rosenblatt ◽  
Jeffrey Zwicker ◽  
James D. Levine ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Ibritumomab Tiuxetan ◽  
Term Survival ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

8558 Background: Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) are salvaged with high dose chemotherapy followed by autologous stem cell rescue. Ibritumomab tiuxetan is an anti-CD20 antibody conjugated to the radionuclide 90yttrium. 90Y ibritumomab tiuxetan has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile relative to transplant. Methods: This phase II trial investigated the overall response rate (ORR), event free survival (EFS), overall survival (OS) and toxicity of treatment with ibritumomab followed by rituximab in patients with relapsed or refractory DLBCL, not candidates for transplant. Patients were treated with an initial dose of rituximab (250 mg/m2) followed one week later by ibritumomab (0.4 mCi90Y/kg or 0.3 mCi90Y/kg based on plateles) followed by 4 weekly doses of rituximab (375mg/m2). All non-progressing patients received maintenance rituximab (375 mg/m2) weekly for 4 doses every 6 months for 4 cycles. Results: 25 patients were enrolled. Median age was 79 (range 45-95). 12 of 25 (48%) had stage 3 or 4 disease. 13 (52%) had 2 or more prior regimens. At 12 weeks 5 patients (21%) had a complete response (CR), 3 (13%) a partial response, 2 (8%) stable disease and 14 (58%) progressed for an ORR of 32% (8/25). At best response 7 patients obtained a CR. Median EFS was 2.5 months. Median OS was 8.1 months. No patient who obtained CR later relapsed, with follow up of 18.3-100.1 months. Deaths unrelated to treatment occurred in remission in 5 patients. 2 patients remain free of disease at 67.4 and 100.1 months. 11 (65%) patients had grade 3 or 4 thrombocytopenia, but no significant bleeding was observed. 9 (36%) patients had grade 3 non-hematologic toxicity. Grade 1 and 2 fatigue occurred in 41%. Patients who progressed through a rituximab containing regimen were at high risk of early progression. Conclusions: The ORR of ibritumomab as salvage therapy for DLBCL compares favorably to other regimens with acceptable toxicity. Those patients with disease refractory to rituximab are not likely to benefit. For a subset of patients not candidates for salvage with autologous transplant, this treatment can produce a durable remission. Clinical trial information: NCT00110149.

scholarly journals Clinical Response of CD19 CAR-T Cells (relmacabtagene autoleucel, relma-cel) in Adults with Heavily-Pre-Treated Relapsed/Refractory (r/r) Large B-Cell Lymphoma in China

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Jun Zhu ◽  
Zhitao Ying ◽  
Yuqin Song ◽  
Haiyan Yang ◽  
Ye Guo ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Private Company ◽  
Car T Cells ◽  
Large B Cell Lymphoma ◽  
Car T ◽  
Grade 3 ◽  
Large B Cell

Currently, no CAR-T product has been approved for use in China despite having hundreds of active CAR-T trials. Relma-cel (JWCAR029) is a CAR-T product with a CAR construct comprised of a binding domain, derived from a murine CD19-specific mAb (FMC63), a CD3ζ activation domain, and a 4-1BB costimulatory domain, and manufactured in China with a commercial-ready, highly automated, single train process to select, activate, transduce and expand both CD4 and CD8 cells to a wide range of doses with consistent product attributes. Relma-cel was evaluated in the first prospective, single-arm, multi-center, pivotal study (RELIANCE Trial) of CAR-T therapy conducted under Chinese IND to support an NMPA-accepted BLA submission in r/r large B-cell lymphoma (LBCL) (NCT 04089215) and the preliminary results are presented herein. Eligible adult patients had measurable, histologically confirmed r/r LBCL, failed at least 2 prior therapies, including anthracycline and anti-CD20 agents, and not had allogeneic transplant within 90 days or primary CNS lymphoma. Patients were randomized to receive either 100×106 (low dose) or 150×106 (high dose) CAR+ T cells as a single infusion following fludarabine 25 mg/m2 & cyclophosphamide 250 mg/m2 daily×3 as lymphodepletion. Patients were evaluated for efficacy (Lugano criteria, 2014), safety (CRS by Lee 2014, and all other events by CTCAE v4.03), and PK (by qPCR and flow cytometry). The protocol pre-specified and regulatory authority-agreed primary endpoint was 3 month ORR by landmark analysis to exclude a 3-month 20% ORR (Michael, 2017). Secondary endpoints included best overall response rate (BOR), duration of response (DOR), progression free survival (PFS), overall survival (OS), frequency/severity of AEs and CAR-T cell expansion. Investigators adjudicated disease response and progression based on imaging studies, pathology and clinical data; a sensitivity analysis was also conducted using an independent review committee adjudication. Between May 2018 and Dec 2019, 69 patients were screened, and 59 enrolled and treated with relma-cel, with median age of 56.0 years (18-75), 59.3% ECOG 1-2, and included several LBCL subtypes (DLBCL NOS 69.5%, TFL 15.3%, DHL/THL 5.1%, and PMBCL 6.8%) and nearly all with poor risk disease (81.4% treatment refractory, 45.8% ≥3 lines of prior therapies, 42.4% requiring bridging therapy, 39% IPI≥3). The median doses administered in low and high dose groups were 99.7×106 (range, 80.1-101.3) and 150.0×106 (range, 120.0-156.4) CAR+ T cells, respectively. Among the 58 efficacy evaluable patients, the primary analysis demonstrated a 3 month ORR of 58.6% (95% CI, 44.9-71.4) (the excluded patient had product that did not meet viability threshold criterion, but achieved CR at D29 that is ongoing for &gt;1 year). As of Jun 17, 2020 data cut-off, BOR was 75.9% (95% CI, 62.8-86.1) with CR rate of 51.7% (95% CI, 38.2-65.1). With a median follow-up of 8.9 months, median OS were not reached, and 6 month DOR, PFS and OS were 60.0%, 54.2% and 90.8%, respectively. No improvement in efficacy outcomes was observed in the high dose group. Of 59 treated patients, grade ≥3 AEs occurring in &gt;5% of patients were cytokine release syndrome (CRS), febrile neutropenia and lung infection (all, 5.1%). Grade ≥3 lab abnormalities in &gt;10% of patients were neutrophil count decreased (30.5%), white blood cell count decreased (13.6%), leukopenia (10.2%) and neutropenia (10.2%). The rates of CRS, neurotoxicity (NT), death, and the use of tocilizumab/steroids are shown in Table 1. All events of CRS and NT resolved except for 1 patient with grade 4 CRS ongoing at the time of death as the result of sepsis at day 8. As of data cut off, no cases of severe cytopenia or severe infections occurred beyond 30 days of infusion. The two dose groups did not differ significantly in PK parameters (see Table 1). The RELIANCE Trial provided the first demonstration of licensure-quality CAR-T manufacturing and clinical trial data generation in r/r patients originating in China. These results with relma-cel demonstrate similar preliminary response rates and PK profiles while providing the potential for an improved toxicity profile in heavily-pre-treated patients with r/r DLBCL having poor risk features relative to other CD19-specific CAR-Ts approved in the US and EU. Figure Disclosures Zhang: JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company. Yang:JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company. Zhou:JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company. Zheng:JW Therapeutics (Shanghai) Co. Ltd: Current Employment, Current equity holder in private company.

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