Randomized Multicenter Trial of Cladribine Alone (C) or in Combination with Cyclophosphamide (CC), and COP in Previously Untreated Low Grade B-Cell Non-Hodgkin Lymphoma Patients: The First Interim Analysis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3305-3305 ◽  
Author(s):  
Ewa E. Kalinka ◽  
Jaroslaw J. Wajs ◽  
Kazimierz Sulek ◽  
Tadeusz Robak ◽  
Maria Blasinska-Morawiec ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Interim Analysis ◽  
Response Rates ◽  
Rank Test ◽  
Low Grade ◽  
First Line ◽  
Non Hodgkin Lymphoma ◽  
Log Rank Test

Abstract To comparatively assess first-line treatment with cladribine alone (C) or in combination with cyclophosphamide (CC), and COP (cyclophosphamide, vincristine, prednisone) in low grade B-cell non-Hodgkin lymphoma (NHL), previously untreated patients (pts) with Ann Arbor stage II–IV were randomly allocated to receive 6 monthly courses of either C, CC, or COP. End points were treatment response, freedom from progression (FFP) and overall survival (OS), and tolerance. From June 1, 2000, 165 pts were randomized in 17 centers. The first interim analysis performed at July 1, 2004 included 105 out of 165 randomized pts (63.6%) who have completed at least six cycles of the scheduled chemotherapy. Of 105 analyzed pts, 38 (36.2%) were diagnosed as small lymphocytic, lymphoplasmocytoid 8 (7.6%), marginal-zone 22 (21%), follicular 33 (31.4%), and not otherwise specified low grade B-cell NHL 4 (3.8%). Randomization constituted comparable groups, including international Prognostic Index variables. Compared to C and CC, COP induced lower overall response rates (75%, 85%, 51%, χ2 test p<.005), including lower complete remission rates (43%, 62.5%, 5.5%, χ2 test p<.001). With a median follow-up of 10 months, median FFP was superior in patients receiving cladribine containing regimens (8 versus 11 versus 6 months, respectively, χ2= 15.1, log-rank test p<.001). No difference in median OS was detected (9 versus 12 versus 7 months, respectively, χ2= 1.15, log-rank test p=.56). Incidences of infections (7% versus 15% versus 11%) and non-hematological side effects (7% versus 7.5% versus 16%) were similar in the randomize groups, whereas CC but not C induced more frequent cytopenias compared to COP (30% versus 11%, χ2 test p<.05). This resulted in more frequent intervals’ prolongation between CC versus COP cycles (respectively 32.5% and 11%, χ2 test p<.05) but dose reductions because of hematological or other toxicity were comparable in C, CC, and COP groups (11% versus 17.5% versus 5.5%). In pts with low grade B-cell NHL, first line C and CC regimens provided similar response rates, FFP, and OS, which were superior to those obtained with COP. The first interim analysis has resulted in discontinuation of accrual in the COP arm. An observed trend toward a better tolerance of C over CC, which may influence the choice between these regimens as front-line treatments, warrants larger number of pts and longer follow-up.

Antiviral treatment in Hepatitis C Virus (HCV)- related low grade non-Hodgkin lymphoma: An update of a multicenter study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17526-17526
Author(s):  
D. Vallisa ◽  
P. Bernuzzi ◽  
A. Lazzaro ◽  
E. Trabacchi ◽  
A. Arcari ◽  
...  
Keyword(s):  
Viral Load ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Antiviral Treatment ◽  
Low Grade ◽  
Viral Genotype ◽  
Non Hodgkin Lymphoma ◽  
Hematological Response ◽  
Genotype 2

17526 Background: HCV is largely diffuse in North-western Europe and U.S.A. It has been shown to play a role both in hepatocellular carcinoma and in B-cell non-Hodgkin lymphoma (B-NHL). Up to now the exact biological mechanisms that could explain the lymphomagenic role of the virus are under study. Methods: We have previously published a series of 13 patients, affected by low grade B-cell NHL and characterized by an indolent course (i.e. doubling time less than 1 year, no bulky disease), who underwent antiviral treatment only with peghilated interferon and ribavirin (peghilated interferon 50–70 microgram weekly, ribavirin 1000–1200 mg daily). Now we report the second update of this study. Up to now 17 patients are evaluable with a mean follow up of 12.1 ± 8 months (range 2–31 months). Results: Eight patients experienced complete or good partial haematological response that has lasted up to now with a mean follow up of 19,5 months, among them 3 splenic marginal lymphomas, 2 nodal marginal, 1 follicular lymphoma, 1 plasmocytoid and 1 marginal extranodal lymphoma. Three other patients achieved a long lasting partial response. The only one relapse (marginal nodal lymphoma) occurred about one year after the end of treatment, hematological relapse happened together with viral relapse, the lymphoma reappeared as highly chemo resistant high grade lymphoma, and two months later the patient died. Interestingly complete and good partial responses were more likely to be seen in viral genotype 2 (p = 0.04) and were strictly related to the decrease of viral load under treatment (p = 0.005). Toxicity causes the stop of the treatment in 3 patients; however one of them was able to achieve complete hematological response. Time to achieve hematological response was quite long (mean 8 ± 4.5 months). Conclusions: This kind of experience strongly provides a role for antiviral treatment in patients affected by HCV related low grade B-cell NHL. Especially viral genotype 2 infection may be considered a good prognostic marker for hematological response as well as decrease of viral load under treatment. Toxicity in our hands was however significant and further experiences are warranted in order to better modulate antiviral therapy doses. No significant financial relationships to disclose.

Fludarabine, Mitoxantrone and Dexamethasone for the First Line Treatment of Patients with Indolent Non-Hodgkin Lymphoma (NHL): GATLA First Interim Report (Grupo Argentino de Tratamiento de la Leucemia Aguda).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4680-4680
Author(s):  
Gustavo Milone ◽  
A. Rodriguez ◽  
Jorge Milone ◽  
R.F. Bezares ◽  
S. Rudoy ◽  
...  
Keyword(s):  
Overall Survival ◽  
Hodgkin Lymphoma ◽  
Response Rate ◽  
Response Rates ◽  
Low Grade ◽  
Line Treatment ◽  
First Line ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
First Line Treatment

Abstract Background: fludarabine (F) is licensed for the management of indolent non-Hodgkin lymphoma in countries such as Canada and Switzerland. Clinical evidence suggests that fludarabine monotherapy is as least as effective, than conventional therapies such as cyclophosphamide, vincristine, prednisone (CVP) for the first and second line treatment of B-cell low grade NHL achieving objective response rates. Better response rates can be achieved combining F with Mitoxantrone (N) and Dexamethasone (D) in indolent NHL patients (pts). The GATLA (Grupo Argentino de Tratamiento de la Leucemia Aguda) started a prospective multicenter national study to evaluate the use FND as a first line treatment for low grade NHL. Aims: to assess the response rate, safety, disease free survival (DFS) and overall survival (OS) of FND as first line treatment for indolent NHL during (2002–2006). Methods: Ninety-six patients in the period of January 2002 to April 2006 were recruited. Sixty-nine patients were valuable at the time of analysis. Median age 54 years old (range: 21–79). Gender: male 51% and female 49%. Inclusion criteria for low grade NHL-LG was: non-previous, age &gt; 18 years old with symptomatic disease, ECOG performance status 0–2 and written informed consent. Ann Arbor staging: 5,8%, 14,5%, 24,6% and 55%. FND treatment consisted of F 25 mg/m2 i.v. (days 1–3), N 10 mg/m m2 i.v. (day 1) and D 20 mg (days 1–5) each 28 days for 6 cycles. All patients received oral antibiotics for intestinal decontamination, antifungal prophylaxis and Trimethoprim-Sulfamethoxazole as P. carinii prophylaxis for one year. Results: on this low grade NHL cohort the overall response rate (ORR) was 93% (ORR) with 70% (48 pts) with complete response (CR) and 23% (16 pts) with partial response; progressive disease and non-response 7% (5 pts). The probability of event free survival (EFS) and overall survival (OS) at 24 months was 60% and 90% respectively. Two patients developed secondary malignancies after treatment and one died. Only one patient died in CR. Conclusions: in this population FND treatment demonstrate a high CR rate with low toxicity and high probability of EFS and OS as previous experience published in the literature.

Randomized Comparison of Cladribine Single (C) or in Combination with Cyclophosphamide (CC), and COP in Previously Untreated Low Grade B-Cell Non-Hodgkin Lymphoma Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2481-2481
Author(s):  
E. Kalinka ◽  
J. Wajs ◽  
K.S. Sulek ◽  
M. Blasinska-Morawiec ◽  
P. Centkowski ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Low Grade ◽  
Non Hodgkin Lymphoma ◽  
Not Otherwise Specified ◽  
Ann Arbor ◽  
To Receive

Abstract To comparatively assess first-line treatment with cladribine single (C) or in combination with cyclophosphamide (CC), and COP (cyclophosphamide, vincristine, prednisone) in low grade B-cell non-Hodgkin lymphoma (NHL), previously untreated patients (pts) with Ann Arbor stage II-IV were randomly allocated to receive 6 monthly courses of either C, CC, or COP. End points were treatment response, freedom from progression (FFP) and overall survival (OS), and tolerance. From June 1, 2000 to June 30, 2005, 196 pts were randomized in 17 centers. Of 153 pts for whom data is available, 55 (36%) were diagnosed as small lymphocytic, 11 lymphoplasmocytoid (7%), 37 marginal-zone (24%), 42 follicular (27.5%), and 8 not otherwise specified low grade B-cell NHL (5.5%). Randomization constituted comparable groups, including International Prognostic Index variables. Compared to C and CC, COP induced lower overall response rates (75%, 90%, 50%, χ2 =7.9 p<.005), including lower complete remission rates (38%, 62%, 9.5%, χ2=19.2 p<.0001). With a median follow-up of 15 months, FFP was superior in patients receiving cladribine-containing regimens (χ2 = 21.8, log-rank p<.0001). No difference in median OS was observed. Incidences of infections (9% versus 3.5% versus 7%) and non-hematological side effects (7.5% versus 3.5% versus 7%) were similar in the randomized groups, whereas CC but not C induced more frequent peripheral cytopenias compared to COP (30% versus 11%, p=.034). This resulted in higher frequency of prolongation of intervals between CC versus COP treated pts (respectively 45% and 21%, χ2=6.04 p=.014) and C versus CC treated pts (respectively 26% and 45%, χ2=4.24, p=.039). Dose reductions because of hematological or other toxicity were comparable in C (9.5%), CC (20%), and COP (21%) groups. Although final results warrant completed data for all randomised pts with longer follow-up, similar tolerance and higher efficacy of cladribine-based regimens over COP provide rationale to combine C or CC with rituximab in future clinical trials.

scholarly journals Safety and Clinical Activity of a Combination Therapy Comprising Two Antibody-Based Targeting Agents for the Treatment of Non-Hodgkin Lymphoma: Results of a Phase I/II Study Evaluating the Immunoconjugate Inotuzumab Ozogamicin With Rituximab

2013 ◽  
Vol 31 (5) ◽  
pp. 573-583 ◽  
Author(s):  
Luis Fayad ◽  
Fritz Offner ◽  
Mitchell R. Smith ◽  
Gregor Verhoef ◽  
Peter Johnson ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Single Agent ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Response Rates ◽  
Low Grade ◽  
Inotuzumab Ozogamicin ◽  
Non Hodgkin Lymphoma

Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20+/CD22+ B-cell non-Hodgkin lymphoma (NHL). Patients and Methods A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles. Results In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m2) was confirmed to be the same as that for single-agent INO (1.8 mg/m2). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n = 39), relapsed DLBCL (n = 42), and refractory aggressive NHL (n = 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL. Conclusion R-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20+/CD22+ B-cell NHL.

Frontline Therapy of Nodular Lymphocyte Predominant Hodgkin Lymphoma with Rituximab: The Stanford University Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2686-2686 ◽  
Author(s):  
Ranjana H. Advani ◽  
Sandra J. Horning ◽  
Richard T. Hoppe ◽  
Sarah Daadi ◽  
John Allen ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Rank Test ◽  
Newly Diagnosed ◽  
Log Rank Test ◽  
Anti Cd20 ◽  
Aggressive B Cell Lymphoma

Abstract Abstract 2686 Background: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare subtype of HL (∼5%). This unique clinical entity is characterized by an indolent clinical course and unlike classical HL late relapses may occur. Standard treatment depends on stage and includes radiation therapy (RT) and/or chemotherapy which can be associated with an increased risk of treatment related late effects warranting investigation of other active agents. The malignant cells of NLPHL universally express CD20, therefore therapy with rituximab (R), the monoclonal anti-CD20 antibody, is a targeted option. We report our experience with R as front-line treatment for patients with NLPHL. Methods: Patients with newly diagnosed NLPHL and measurable disease were treated with R at 375 mg/m2 administered weekly × 4 or, after protocol amendment (February 2003) with R followed by 4 doses of R maintenance (RM) administered every 6 months for 2 years. Restaging studies were performed at 1, 3 and 6 months and then every 6 months until progression. All pathology was centrally reviewed. Results: Nineteen patients were enrolled between May 1999 and September 2006. The median age at treatment was 45 years (range 17–63), stage I (n=6), stage II (n=7), stage III (n=6). Ten patients were treated with R alone and 9 with R+RM. The median follow-up for R patients is 8.8 years (5–11.4) and for R+RM patients is 5 years (2.5–7.6). At the end of induction therapy with R alone, the overall response rate was 100% [complete response (CR) (n=10), CR unconfirmed (n=2) and partial response (n=7)]. The median progression free survival (PFS) for patients treated with R alone and R+RM is 50 months and 67 months, respectively (p=0.7; log rank test) and median overall survival (OS) not reached. The median follow up for patients without progressive disease at the time of this analysis was 6.9 years (range 2.5–11.5). The estimated PFS at 5 years is 51.7%, [95% CI 33.2–80.4] and at 10 years 35.4% [95% CI 17.7–70.8]. There was no difference in median PFS between patients with stages I-II versus III (5.6 years and 4.15 years respectively, p=0.58 [log rank test]). The estimated OS at 5 years is 93.3%, [95% CI 81.5–100] and 10 years 76% [95% CI 55.4–100]. Ten patients progressed (5 treated with R alone, 5 treated with R+RM) of whom 6 transformed to an aggressive B cell lymphoma (biopsy proven) at a median of 4.2 years [range 0.9–8]. Five of the 6 transformed patients had abdominal disease at initial diagnosis (stage III, n=4). Three patients died (2 aggressive NHL, 1 unknown). Conclusion: Rituximab is an active single agent in the treatment of newly diagnosed NLPHL with a median PFS of 5.6 years. R+ RM resulted in a non-significant increase in PFS compared to R alone. In this series, abdominal involvement was associated with transformation to an aggressive B cell lymphoma underscoring the need for biopsy at relapse. These results demonstrate a pattern of late relapse following rituximab, at least as great as the historical data with RT or RT + CT. Although R alone achieved proof of concept for a targeted therapy, its use should remain investigational as primary therapy of NLPHL. Disclosures: Advani: Genentech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Rituximab. Anti-CD20 agent that targets CD20 on NLPHL cells. Horning:Genentech: Employment, Equity Ownership.

Efficacy and safety of CAR19/22 T-cell “cocktail” therapy in patients with refractory/relapsed B-cell non-Hodgkin lymphoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2534-2534
Author(s):  
Liang Huang ◽  
Na Wang ◽  
Chunrui Li ◽  
Yi Xiao ◽  
Yang Cao ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Low Grade ◽  
Efficacy And Safety ◽  
T Cell Therapy ◽  
Overall Response ◽  
Non Hodgkin Lymphoma ◽  
The Impact

2534 Background: Antigen escape relapse has emerged as a major challenge for long-term disease control post CD19-directed therapies, to which dual-targeting of CD19 and CD22 has been proposed as a potential solution. Methods: Between Mar 2016 and Jan 2018, we conducted a pilot study (ChiCTR-OPN-16008526) in 38 patients (pts), who had refractory/relapsed B-cell non-Hodgkin lymphoma (B-NHL), to evaluate the efficacy and safety of sequential infusion of anti-CD19 and anti-CD22, two single-specific, third-generation CAR19/22 T-cell “cocktail”. The cutoff date for data collection was Apr 30, 2018. Results: At a minimum follow-up of 3 months (mos), 26 of the 36 evaluable pts achieved an overall response (ORR), including 18 with a complete response (CR) and 8 with a partial response (PR). The ORR at mo 3 was consistent in different subgroups, irrespective of pathologic subtypes, cell of origin, cytogenetic or genomic aberrations. At the data cutoff, 15 of the 18 pts who had a CR at mo 3 maintained their responses, 2 of 8 pts who had a PR within 3 mos continued to have a CR without additional therapies. Collectively, the best ORR was 83.3%, with a best CR rate of 55.5% and a best PR rate of 27.8%. With a median follow-up of 5.3 mos (range, 0.4 to 16.2), the median PFS was 5.8 mos, and the median OS was not reached (NR). Pts received therapy at first relapse had better PFS than those who received therapy at the time with primary refractory diseases or at multiple relapses. Notably, pts who achieved an overall response at mo 3 (R3m) had significantly extended PFS and OS when compared with pts who did not. Repeated biopsy and IHC was conducted in 3 of the 13 pts. However, loss of CD19 or CD22 was not detected. Of the 9 pts with IgH/MYC translocation, with a median follow-up of 10.1 mos, the median PFS and median OS were NR. At data cutoff, 7 pts who had achieved R3m maintained their responses, including all the 4 pts with double-hit lymphoma. However, of the 10 pts with del(17p) or TP53 mutation, with a median follow-up of 5.3 mos (range, 2.7 to 14.5), the median PFS was 3.6 mos and the median OS was 9.9 mos. All pts experienced reversible CRS, with 21.1% were of high-grade. Neurotoxicity developed in 13.2% pts and were all low-grade. Conclusions: Our results indicated that sequential infusion of CAR19/22 T-cell is efficient and safe for pts with B-NHL. Dual antigen targeting is a promising approach to circumvent antigen loss relapse after CAR T-cell therapy. The impact of genetic subtypes and clinical parameters further underscores the critical importance of personalized immunotherapies. Clinical trial information: ChiCTR-OPN-16008526.

ALX148, a CD47 Blocker, in Combination with Rituximab in Patients with Non-Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14 ◽  
Author(s):  
Tae Min Kim ◽  
Nehal Lakhani ◽  
Justin Gainor ◽  
Manali Kamdar ◽  
Philip Fanning ◽  
...  
Keyword(s):  
Immune Response ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Tolerability Profile ◽  
Low Grade ◽  
Publicly Traded ◽  
Private Company ◽  
Non Hodgkin Lymphoma ◽  
Time Of Presentation

Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. The high affinity CD47 blocker fusion protein, ALX148, is linked to an inactive immunoglobulin Fc region to minimize toxicity. ALX148 is half the size of an antibody, has been well tolerated, and enhances the innate and adaptive immune response against cancer in combination with anticancer therapeutics across solid and hematologic tumors (ASCO 2020 #3056, EHA 2020 #EP1247). Characterization of ALX148's tolerability profile and antitumor activity in combination with rituximab are reported in patients (pts) with non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW or 15 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety population was dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Data are reported as of 30Jun2020 in these fully enrolled cohorts with final data to be updated at the time of presentation. Results: A total of 33 patients with NHL were administered ALX148 in combination with rituximab. Twenty-two pts with median age of 66 years (range 32-80) were administered ALX148, 10 mg/kg QW (ALX10), in combination with rituximab [DLBCL, n=11; mantle cell lymphoma (MCL), n=4; follicular lymphoma (FL), n=5; and marginal zone lymphoma (MZL), n=2]. Eleven pts with median age of 64 years (range 53-78) were administered ALX148, 15 mg/kg QW (ALX15), in combination with rituximab (DLBCL, n=6; MCL, n=1; FL, n=3; and MZL, n=1). There have been no DLTs reported in the fully enrolled safety cohorts, and the MTD of ALX148 in combination with rituximab has not been reached. The maximum ALX148 administered dose is 15 mg/kg QW. Twenty-eight pts experienced any AE, while 16 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (21%, n=7), fatigue (9%, n=3), anemia, nausea, neutropenia, and pruritus (6%, n=2 each). With a median follow up of 14 months, objective responses were observed across all histologies in response-evaluable ALX10 pts: 40.9% ORR (4CR,5PR, 6SD, n=22 total) and with a median follow up of 9 months in ALX15 pts: 63.6% ORR (3CR, 4PR, 1SD, n=11 total). Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Final results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with durable responses in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity and favorable PK/PD characteristics in combination with rituximab were observed at all dose levels with greater objective response rates reported at the MAD of 15 mg/kg QW. Disclosures Kim: Boryung: Consultancy; Voronoi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Takeda: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding; AstraZeneca: Consultancy. Lakhani:incyte: Research Funding; merck: Research Funding; mersana: Research Funding; northern biologics: Research Funding; odonate: Research Funding; pfizer: Research Funding; ikena: Research Funding; symphogen: Research Funding; taiRx: Research Funding; tesaro: Research Funding; livzon: Research Funding; loxo: Research Funding; macrogenics: Research Funding; inhibRx: Research Funding; cytomx: Research Funding; formation biologics: Research Funding; forty seven inc: Research Funding; alexion Pharmaceuticals: Research Funding; Alpine Biosciences: Research Funding; ALX Oncology Inc.: Research Funding; Apexian: Research Funding; asana biosciences: Research Funding; ascentage pharma: Research Funding; beigene: Research Funding; celgene: Research Funding; cerulean pharma: Research Funding; constellation pharma: Research Funding; coordination therapeutics: Research Funding; regeneron: Research Funding; sapience therapeutics: Research Funding; shattuck labs: Research Funding; innovent bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; jounce therapeutics: Research Funding. Gainor:theravance: Consultancy; adaptimmune: Research Funding; ariad: Research Funding; astrazeneka: Research Funding; blueprint medicines: Research Funding; lily: Consultancy; gilead sciences: Consultancy; merck: Consultancy, Research Funding; moderna therapeutics: Consultancy, Research Funding; tesaro: Research Funding; blueprint medicines: Consultancy; novartis: Research Funding; oncorus: Consultancy; regeneron: Consultancy; bristol-myers Squibb: Consultancy, Research Funding; amgen: Consultancy; array biopharma: Consultancy, Research Funding; agios: Consultancy; ironwood pharmaceuticals: Consultancy; takeda: Consultancy; genentech: Consultancy, Research Funding; jounce therapeutics: Consultancy, Research Funding. Kamdar:Roche: Research Funding. Fanning:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Squifflet:ALX Oncology Inc.: Consultancy; IDDI: Current Employment. Jin:ALX Oncology Inc.: Current Employment. Forgie:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company; Pfizer Inc.: Ended employment in the past 24 months. Wan:Tallac Therapeutics: Current Employment, Current equity holder in private company; ALX Oncology Inc.: Consultancy, Current equity holder in publicly-traded company. Pons:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Randolph:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Kim:F. Hoffmann-La Roche: Research Funding; Pfizer: Research Funding; JJ: Research Funding; Celltrion: Research Funding; Kyowa Kirn: Research Funding; Donga: Research Funding; Mundipharma: Research Funding.

scholarly journals Efficacy and Safety of JWCAR029 in Adult Patients with Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4187-4187 ◽  
Author(s):  
Zixun Yan ◽  
Wen Wang ◽  
Zhong Zheng ◽  
Ming Hao ◽  
Su Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Level ◽  
Car T Cells ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

Abstract Introduction JWCAR029 is a novel CD19-directed 4-1BB stimulated chimeric antigen receptor T (CAR-T) cell type, which is different from JWCAR017 with independent production of CD4 and CD8 T cells and transfusion in non-fixed ratio. We conducted a single arm, open-label, dose escalation Phase I trial of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma (NCT03355859). Methods From January to July 2018, 10 patients have been enrolled in this trial, including eight diffused large B cell lymphoma (DLBCL) and two MALT lymphoma, with median age of 47 years (range 32 to 59 years). All the patients received immunochemotherapy as induction and more than two lines of salvage treatment. Two patients received bridging chemotherapy after T-cell collection due to rapid tumor progression, followed by re-evaluation before CAR-T cell infusion. Lymphodepletion preconditioning was accomplished by fludarabine 25mg/m2/d and cyclophosphamide 250mg/m2/d on Day-4 to D-2, followed by CAR-T cell infusion on Day0. JWCAR029 was administrated as a single infusion in escalation dose levels, from 2.5×107 CAR-T cells (dose level 1, DL1) to 5.0×107 CAR-T cells (dose level 2, DL2) and to 1.0×108 CAR-T cells (dose level 3, DL3) according to mTPI-2 algorithm. Circulating blood count, serum biochemistry, and coagulation status were follow-up after infusion. Cytokines were assessed on a Luminex platform. Tumor evaluation was performed on Day 29 by PET-CT. PK data were detected by flow cytometry and real-time quantitative polymerase chain reaction system. All the adverse events were recorded. The study was approved by the Shanghai Rui Jin Hospital Review Board with informed consent obtained in accordance with the Declaration of Helsinki. Results The demographic characteristics of the patients were demonstrated in Table 1. Among six evaluable patients (3 of DL1 and 3 of DL2), the ORR was 100% on Day 29, including four complete remission and 2 partial remission. Cytokine release syndrome (CRS) was 100% in Gr 1, with main symptoms as fever (<39.0 degrees), fatigue, and muscle soreness. No neurotoxicity was observed. Four of the six patients with fever >38.0 degrees used prophylactic IL-6 Inhibitor (8mg/kg, ACTEMRA, two patients administered twice). No patients received steroids. The CRS showed no difference between dose level groups (p>0.99). Adverse effects included leukopenia (Gr 3-4: 83.3%, Gr 1-2: 16.7%), hypofibrinogenemia (Gr 1: 16.7%, Gr 2-4: 0%), liver dysfunction (Gr 1: 33.3%, Gr 2-4: 0%), elevated CRP (Gr 1: 83.3%, Gr 2-4: 0%), ferritin (Gr 1-2: 83.3%, Gr 2-4: 0%), or IL-6 (Gr 1-2:100%, Gr 3-4: 0%, Table 2). Conclusion Although long-term follow-up was needed, the preliminary data of six patients in this trial have demonstrated high response rates and safety of JWCAR029 in treating relapsed and refractory B-cell non-Hodgkin lymphoma. Disclosures Hao: JW Therapeutics: Employment, Equity Ownership.

scholarly journals BCL2 Expression Correlates with Refractory and Relapsed Classic Hodgkin Lymphoma. Its Blokeadge As a Promising Directed-Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5282-5282
Author(s):  
Angelica Gamboa-Cedeño ◽  
Cristaldo Nancy ◽  
Victoria Otero ◽  
Natalia Paola Schutz ◽  
Dorotea Fantl ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cell Lines ◽  
Target Gene ◽  
Rank Test ◽  
First Line ◽  
Log Rank Test ◽  
Classic Hodgkin Lymphoma ◽  
Nfkb Pathway ◽  
Relapsed Disease ◽  
Bcl2 Expression

Classic Hodgkin Lymphoma (cHL) is a germinal center derived lymphoma with 8,500-9,000 new cases/year diagnosed in the US. Despite 90% stage I cHL patients can respond to current systemic therapy, this drops to 60%, when diagnosed in advanced stages. Furthermore, 20-30% of diagnosed patients, would be refractory or would relapse and have a poor prognosis. Refractory and relapsed disease (RRD) is currently the challenge when treating cHL patients. There is no specific therapy to offer rather than rescue chemotherapy schemes, which fails in 50% of the cases and associates with high risk severe toxicity. This highlights the need to deeper understand the cHL molecular biology, the screening for molecular markers suitable to identify the risk of refractory and relapse disease and specific therapeutic directed-targets. We have previously reported that the alternative NFkB pathway, mediated by Rel-B and NIK (NFkB Inducing Kinase), plays an important role in cHL survival. Its constitutive activation sustains high BCL2 expression levels and seems to be involved in the RRD. BCL2 was found as a specific Rel-B target gene in cHL cells by ChIP-Seq (Chromatin Immunoprecipitation sequencing) and expression arrays. BCL2 exogenous expression was enough to partially rescue the death induce in cHL cells, which highlight the relevance of this alternative NFkB pathway target gene. Since the BCL2 data was obtained in human cHL cell lines established from patients with refractory and relapsed disease, we decided to analyze whether mediators of this pathway and BCL2 could be useful as prognosis markers and would represent potential targetable factors in both refractory and relapsed disease. We analyzed NIK and BCL2 citoplasm expression in Hodgkin Reed-Sternberg cells (HRS) in the lymph node biopsies of 113 cHL naïve of therapy patients by inmunohistochemistry [52 female Md age and (range) 36 (6-88), 61 male 40.7 (9-78)]. The follow-up period range from 6 to 136 months. The univariate analysis showed no correlation between NIK or BCL2 expression and the prognosis clinical and pathological parameters, including the PET Scan indicated at the end of the first line treatment, neither the molecular markers routinely assayed. The statistical significance was maintained in multivariate analysis (Logistic and Cox Regression p=0.01). NIK expression did not associate with prognosis but the BCL2 expression level correlated with lack of response to conventional therapy and both early and late disease progression. The survival analysis, using the Kaplan-Meir curves, showed that patients with ≥60% positive HRS cells had a shorter disease-free survival (DFS) [Log Rank Test (Mantel Cox) p=0.002] and a reduced overall survival (OS) [Log Rank Test (Mantel Cox) p=0.02]. L1236, U-H01, KM-H2, SUPDH1 and L540, human cHL cell lines that express BCL2 protein, were sensitive to venetoclax, a specific BCL2 inhibitor. The drug induced a cell cycle arrest in S-Phase when treated with 1uM each 24 hours during 10 days, as compared to wild type cells and cells treated with the vehicle. In summary, we found that the alternative NFkB pathway plays a role in the refractory and relapsed classic Hodgkin Lymphoma disease, being BCL2 one of its key downstream target genes. BCL2 can be used as a prognosis marker determined by routine immunohistochemistry at diagnosis of the primary disease. BCL2 expression correlated with refractory disease to first line conventional therapy and disease progression. Based on the venetoclax effect in cHL cell lines we believe BCL2 directed-therapy in cHL should be considered in the subgroup of cHL patients that express this protein in ≥60% HRS cells in the lymph node biopsy performed at diagnosis. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: venetoclax used to specifically block BCL2.

scholarly journals Radioimmunotherapy with iodine 131I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience

Blood ◽  
2000 ◽  
Vol 96 (4) ◽  
pp. 1259-1266 ◽  
Author(s):  
Mark S. Kaminski ◽  
Judith Estes ◽  
Kenneth R. Zasadny ◽  
Isaac R. Francis ◽  
Charles W. Ross ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
De Novo ◽  
Hematologic Toxicity ◽  
Low Grade ◽  
Cell Transplant ◽  
Non Hodgkin Lymphoma ◽  
Therapeutic Doses ◽  
131I Tositumomab

Abstract CD20-targeted radioimmunotherapy is a promising new treatment for B-cell non-Hodgkin lymphoma (NHL). We now provide updated and long-term data on 59 chemotherapy-relapsed/refractory patients treated with iodine 131I tositumomab in a phase I/II single-center study. Fifty-three patients received individualized therapeutic doses, delivering a specified total-body radiation dose (TBD) based on the clearance rate of a preceding dosimetric dose. Six patients received dosimetric doses only. Dose-escalations of TBD were conducted separately in patients who had or had not undergone a prior autologous stem cell transplant (ASCT) until a nonmyeloablative maximally tolerated TBD was established (non-ASCT = 75 cGy, post-ASCT = 45 cGy). Fourteen additional non-ASCT patients were treated with 75 cGy. Unlabeled antibody was given prior to labeled dosimetric and therapeutic doses to improve biodistribution. Forty-two (71%) of 59 patients responded; 20 (34%) had complete responses (CR). Thirty-five (83%) of 42 with low-grade or transformed NHL responded versus 7 (41%) of 17 with de novo intermediate-grade NHL (P = .005). For all 42 responders, the median progression-free survival was 12 months, 20.3 for those with CR. Seven patients remain in CR 3 to 5.7 years. Sixteen patients were re-treated after progression; 9 responded and 5 had a CR. Reversible hematologic toxicity was dose limiting. Only 10 patients (17%) had human anti-mouse antibodies detected. Long-term, 5 patients developed elevated thyroid-stimulating hormone levels, 5 were diagnosed with myelodysplasia and 3 with solid tumors. A single, well-tolerated treatment with iodine 131I tositumomab can, therefore, produce frequent and durable responses in NHL, especially low-grade or transformed NHL.

Sign in / Sign up

Export Citation Format

Share Document