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

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.

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The Role of Antiviral Treatment in Hepatitis C Virus (HCV)-Related Non-Hodgkin Lymphoma: An Update of a Multicenter Study.

Blood ◽

10.1182/blood.v106.11.1509.1509 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1509-1509

Author(s):

Daniele Vallisa ◽

Patrizia Bernuzzi ◽

Luca Arcaini ◽

Antonio Lazzaro ◽

Elena Trabacchi ◽

...

Keyword(s):

Viral Load ◽

B Cell ◽

Antiviral Treatment ◽

Low Grade ◽

Viral Genotype ◽

Non Hodgkin Lymphoma ◽

Hematological Response ◽

Genotype 2

Abstract HCV is largely, although not homogenously, 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 unknown. 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 an update of this study. Up to now we were able to evaluate 16 patients with a mean follow up of 15,1± 7,6 months (range 2–28 months). Eight patients experienced complete or good partial haematological response that has lasted up to now with a mean follow up of 16,5 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=0.035) and were strictly related to the decrease of viral load under treatment (p=<0.001). 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). 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.

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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 ◽

10.1182/blood.v108.11.2481.2481 ◽

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.

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Anti-Lymphoma Activity of Interferon-Free Antiviral Treatment in Patients with Indolent B-Cell Lymphomas Associated with Hepatitis C Virus Infection

Blood ◽

10.1182/blood.v126.23.3938.3938 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3938-3938 ◽

Cited By ~ 4

Author(s):

Luca Arcaini ◽

Caroline Besson ◽

Jan Peveling-Oberhag ◽

Véronique Loustaud-Ratti ◽

Sara Rattotti ◽

...

Keyword(s):

B Cell ◽

Virological Response ◽

Marginal Zone ◽

Antiviral Treatment ◽

Marginal Zone Lymphoma ◽

Hcv Infection ◽

Low Grade ◽

Lymphoplasmacytic Lymphoma ◽

Hematological Response

Abstract Background: The regression of hepatitis C virus (HCV)-associated lymphoma with antiviral treatment (AT) is the strongest argument in favour of an etiological link between lymphoma, especially marginal zone lymphoma (MZL), and HCV infection. In addition, the favourable impact of AT on overall survival of these patients has been reported (Arcaini 2014, Michot 2015). Although there is a clear association across the studies between the lymphoma regression and the clearance of HCV, the direct anti-lymphoma activity of interferon (IFN) cannot be ruled out. AT is undergoing a revolution: new antiviral drugs, including direct-acting antiviral (DAA) like sofosbuvir (SOF) cure more than 90% of infections. However, data on new IFN-free regimens in HCV-associated lymphoproliferative disorders are scanty and based on clinical reports (Rossotti 2015; Sultanik 2015; Carrier 2015). Patients and Methods: We analyzed virological and hematological response of 26 patients (pts) with indolent B-cell non-Hodgkin lymphomas (NHL) or chronic lymphocytic leukemia (CLL) and HCV infection treated with an IFN-free AT. We included the 5 cases reported in literature (Rossotti 2015; Sultanik 2015; Carrier 2015) with updated follow up. Results: Histological, virological and hematological features are summarized in Table 1. Histology distribution was as follows: 12 splenic MZL, 6 extranodal MZL of MALT, 2 leukemic MZL, 2 nodal MZL, 2 CLL/SLL, 1 lymphoplasmacytic lymphoma (LPL) and 1 low grade NHL NOS. Cryoglobulins were present in 13 (symptomatic cryoglobulinemia in 5). HCV genotype was 1 in 15 pts, 2 in 4 pts, 3 in 3 pts and 4 in 2 pts, NA in 2 pts. Three pts previously received chemotherapy and 4 underwent IFN-based therapy before. Twenty-four pts received a SOF-based regimens (SOF + simeprevir in 10, SOF + ribavirin in 5, SOF + daclatasvir in 8, SOF + ledipasvir in 1) and 2 pts other regimens (ombitasvir + paritaprevir + ritonavir + ribavirin and faldaprevir + deleobuvir + ribavirin). In one pt with renal MZL 4 rituximab (R) doses have been added to SOF + simeprevir. Median AT duration was 12 weeks (range: 6-24). At time of present analysis, virological response is available in 21 pts while hematological response has been assessed in 20 pts. A sustained virological response has been obtained in 20 pts; hematological response has been observed only in pts with HCV clearance: in particular 8 pts (all MZL) achieved a complete response and 4 (all MZL) a partial response (comprising one treated also with R) while 5 had stable disease (response by histology is summarized in Table 1). In 7 pts response duration is +1 mo (in 2 pts), +2 mo (in 1 pt), +6 mo (in 3 pts), and +22 mo (in 1 pt); 6 pts (60%) cleared cryoglobulins after AT. After a median follow-up of 6 mo (range: 1-28), 2 pts progressed: one pt shifted to DLBCL and one pt without virological response progressed and died of lymphoma; another pt with hematological CR died of metastatic hepatocellular carcinoma 8 mo after AT. Complete data for all pts will be presented at the meeting. Conclusions: Our study shows that a significant rate of hematological response can be achieved in HCV-associated MZL also with IFN-free AT. These data are a strong rationale for planning prospective trials with DAA in this setting. Table 1. Features of 26 pts with NHL associated with HCV infection treated with IFN-free regimen and lymphoma response by histology N % Age, median (range) 26 57 (40-78) M/F 11/15 42/58 - Marginal-zone lymphoma SplenicNodalExtranodal of MALTLeukemic MZL- CLL - Lymphoplasmacytic lymphoma - Low-grade B-cell NHL NOS 22 12 2 6 2 2 1 1 84.7 46.2 7.7 23.1 7.7 7.7 3.8 3.8 Ann Arbor stage III-IV 19 73 B symptoms 4 15 ECOG 0 1 2 3 11 10 0 1 50 45 0 5 BM involvement 14 54 Extranodal disease 17 65 Splenic involvement 13 50 Liver involvement 5 19 Nodal disease 15 58 Bulky disease 7 27 Leukemic disease 9 35 Elevated LDH 8/22 36 Elevated b2-microglobulin 8/10 80 Albumin <3.5 g/dl 3/21 14 Serum MC 9/22 41 HCV genotype - 1 - 2 - 3 - 4 15 4 3 2 63 17 12 8 Cryoglobulins 13 50 Symptomatic cryoglobulinemia 5/13 38 HBsAg 1/25 4 Anti-HBc 4/25 16 Lymphoma response by histology- Marginal-zone lymphoma (n=17) Splenic (n=9)Nodal (n=1)Extranodal of MALT (n=5)Leukemic MZL (n=2)- CLL (n=2) - Lymphoplasmacytic lymphoma (n=1) CR/PR/SD/Progression 8/4/2/3 4/2/2/1 1/-/-/- 2/1/-/2 1/1/-/- -/-/2/- -/-/1/- Disclosures No relevant conflicts of interest to declare.

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

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2534 ◽

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.

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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 ◽

10.1182/blood.v104.11.3305.3305 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3305-3305 ◽

Cited By ~ 1

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.

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

Blood ◽

10.1182/blood-2020-135941 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 13-14 ◽

Cited By ~ 1

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.

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

Blood ◽

10.1182/blood-2018-99-115769 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4187-4187 ◽

Cited By ~ 2

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.

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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 ◽

10.1182/blood.v96.4.1259 ◽

2000 ◽

Vol 96 (4) ◽

pp. 1259-1266 ◽

Cited By ~ 346

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.

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