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.

scholarly journals Phase I First-in-Human Study of Venetoclax in Patients With Relapsed or Refractory Non-Hodgkin Lymphoma

2017 ◽  
Vol 35 (8) ◽  
pp. 826-833 ◽  
Author(s):  
Matthew S. Davids ◽  
Andrew W. Roberts ◽  
John F. Seymour ◽  
John M. Pagel ◽  
Brad S. Kahl ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
B Cell Lymphoma ◽  
Tumor Lysis ◽  
Non Hodgkin Lymphoma

Purpose B-cell leukemia/lymphoma-2 (BCL-2) overexpression is common in many non-Hodgkin lymphoma (NHL) subtypes. A phase I trial in patients with NHL was conducted to determine safety, pharmacokinetics, and efficacy of venetoclax, a selective, potent, orally bioavailable BCL-2 inhibitor. Patients and Methods A total of 106 patients with relapsed or refractory NHL received venetoclax once daily until progressive disease or unacceptable toxicity at target doses from 200 to 1,200 mg in dose-escalation and safety expansion cohorts. Treatment commenced with a 3-week dose ramp-up period for most patients in dose-escalation cohorts and for all patients in safety expansion. Results NHL subtypes included mantle cell lymphoma (MCL; n = 28), follicular lymphoma (FL; n = 29), diffuse large B-cell lymphoma (DLBCL; n = 34), DLBCL arising from chronic lymphocytic leukemia (Richter transformation; n = 7), Waldenström macroglobulinemia (n = 4), and marginal zone lymphoma (n = 3). Venetoclax was generally well tolerated. Clinical tumor lysis syndrome was not observed, whereas laboratory tumor lysis syndrome was documented in three patients. Treatment-emergent adverse events were reported in 103 patients (97%), a majority of which were grade 1 to 2 in severity. Grade 3 to 4 events were reported in 59 patients (56%), and the most common were hematologic, including anemia (15%), neutropenia (11%), and thrombocytopenia (9%). Overall response rate was 44% (MCL, 75%; FL, 38%; DLBCL, 18%). Estimated median progression-free survival was 6 months (MCL, 14 months; FL, 11 months; DLBCL, 1 month). Conclusion Selective targeting of BCL-2 with venetoclax was well tolerated, and single-agent activity varied among NHL subtypes. We determined 1,200 mg to be the recommended single-agent dose for future studies in FL and DLBCL, with 800 mg being sufficient to consistently achieve durable response in MCL. Additional investigations including combination therapy to augment response rates and durability are ongoing.

Brentuximab vedotin for relapsed or refractory non-Hodgkin lymphoma: Preliminary results from a phase II study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8070-8070
Author(s):  
Ranjana Advani ◽  
Yasuhiro Oki ◽  
Andrei R. Shustov ◽  
Laurie E. Grove ◽  
Nancy Bartlett
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Objective Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
Non Hodgkin Lymphoma

8070 Background: Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL) after failure of other therapies. Based on the high objective response rate observed in patients with systemic ALCL, a type of non-Hodgkin lymphoma that is characterized by homogeneous CD30 expression, a study was initiated in other non-Hodgkin lymphomas that express the CD30 target. Methods: A phase 2 open-label single-arm study is underway in patients with relapsed or refractory CD30-positive non-Hodgkin lymphoma, excluding ALCL (NCT01421667). Brentuximab vedotin is administered IV at 1.8 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint is objective response rate assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Tumor specimens are assessed by central lab in order to characterize the relationship of CD30 expression with antitumor activity. Results: Ten patients (age range 28–83; 5 M, 5 F) have enrolled to date. Diagnoses include diffuse large B-cell lymphoma (DLBCL, n=2), EBV-positive DLBCL of the elderly (n=3), primary mediastinal B-cell lymphoma (n=2), peripheral T-cell lymphoma NOS (n=2), and angioimmunoblastic T-cell lymphoma (AITL). Patients had received 1–6 prior chemotherapy regimens; 3 patients had prior stem cell transplants. Of 6 patients who have completed the cycle 2 response assessment, 2 attained complete remission, 1 with DLBCL (90% CD30+) and 1 with AITL (8% CD30+), 1 had stable disease, and 3 had progressive disease. Treatment-related serious adverse events observed to date were rash, febrile neutropenia, and mastoiditis. Conclusions: Preliminary results suggest that brentuximab vedotin may have antitumor activity in patients with relapsed or refractory CD30-expressing non-Hodgkin lymphomas, in addition to the efficacy previously observed in systemic ALCL. Updated study results will be presented.

Subcutaneous epcoritamab in patients with relapsed/refractory B-cell non-Hodgkin lymphoma: Safety profile and antitumor activity.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7518-7518
Author(s):  
Michael Roost Clausen ◽  
Pieternella Lugtenburg ◽  
Martin Hutchings ◽  
Peter W. M. Johnson ◽  
Kim M. Linton ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Safety Profile ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

7518 Background: Epcoritamab is a CD20xCD3 bispecific antibody that induces T-cell–mediated killing of CD20–positive malignant B-cells. We present updated data, including progression-free survival (PFS) from the dose escalation part of the first-in-human phase 1/2 study of epcoritamab in pts with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL; NCT03625037). Methods: Adults with R/R CD20+ B-NHL received flat-dose 1 mL SC epcoritamab (step-up dosing approach) in 28-day cycles (q1w: cycles 1–2; q2w: cycles 3–6; q4w thereafter) until disease progression or unacceptable toxicity. Step-up dosing and standard prophylaxis were used to mitigate severity of cytokine release syndrome (CRS). Results: At data cut off (1/31/2021), 68 pts with B-NHL were enrolled across histologies including diffuse large B-cell lymphoma (DLBCL; n = 46 [67.6%]; de novo and transformed), follicular lymphoma (FL; 12 [17.6%]), mantle cell lymphoma (MCL; 4 [5.9%]), and others (6 [8.8%]). Majority were heavily pretreated (median [range] prior lines: DLBCL, 3 [1–6]; FL, 4.5 [1–18]); including prior CAR-T (n = 6) and prior ASCT (n = 10). At median follow-up of 14.1 mo (DLBCL, 10.2 mo; FL, 15.2 mo), treatment was ongoing in 15 (22%) pts. Most common treatment-emergent adverse events (AEs) were pyrexia (69%), CRS (59%), and injection site reaction (47%). CRS events were all grade 1 or 2 and most occurred in cycle 1; neurotoxicity was limited (6%; grade 1: 3%; grade 3: 3%; all transient). One case of tumor lysis syndrome was observed (1.5%; grade 3); there were no cases of febrile neutropenia or treatment-related death. Overall response is shown for DLBCL ≥12 mg and ≥48 mg and FL ≥12 mg, corresponding to the minimal efficacy threshold (Table). Responses deepened over time (PR converted to CR: DLBCL, 6 pts; FL, 3 pts). Median time to response was 1.4 mo (DLBCL) and 1.9 mo (FL). Among DLBCL pts achieving CR with ≥6 mg (n = 11), none relapsed while on treatment. The median PFS for pts with DLBCL ≥12 mg (n = 22) was 9.1 mo (95% CI: 1.6, NE; median follow-up 9.3 mo) and for pts with DLBCL ≥48 mg (n = 11) median PFS was not reached (median follow-up 8.8 mo). Updated analyses will be presented. Conclusions: With longer follow-up, SC epcoritamab demonstrated substantial single-agent activity, inducing deep and durable clinically meaningful responses, with a consistent safety profile. Notably no severe (grade ≥3) CRS events, no febrile neutropenia, and limited neurotoxicity was observed. Clinical trial information: NCT03625037. [Table: see text]

scholarly journals Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia

Blood ◽  
2010 ◽  
Vol 115 (13) ◽  
pp. 2578-2585 ◽  
Author(s):  
Jonathan W. Friedberg ◽  
Jeff Sharman ◽  
John Sweetenham ◽  
Patrick B. Johnston ◽  
Julie M. Vose ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Primary Tumors ◽  
Non Hodgkin Lymphoma

AbstractCertain malignant B cells rely on B-cell receptor (BCR)–mediated survival signals. Spleen tyrosine kinase (Syk) initiates and amplifies the BCR signal. In in vivo analyses of B-cell lymphoma cell lines and primary tumors, Syk inhibition induces apoptosis. These data prompted a phase 1/2 clinical trial of fostamatinib disodium, the first clinically available oral Syk inhibitor, in patients with recurrent B-cell non-Hodgkin lymphoma (B-NHL). Dose-limiting toxicity in the phase 1 portion was neutropenia, diarrhea, and thrombocytopenia, and 200 mg twice daily was chosen for phase 2 testing. Sixty-eight patients with recurrent B-NHL were then enrolled in 3 cohorts: (1) diffuse large B-cell lymphoma (DLBCL), (2) follicular lymphoma (FL), and (3) other NHL, including mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma, lymphoplasmacytic lymphomas, and small lymphocytic leukemia/chronic lymphocytic leukemia (SLL/CLL). Common toxicities included diarrhea, fatigue, cytopenias, hypertension, and nausea. Objective response rates were 22% (5 of 23) for DLBCL, 10% (2 of 21) for FL, 55% (6 of 11) for SLL/CLL, and 11% (1/9) for MCL. Median progression-free survival was 4.2 months. Disrupting BCR-induced signaling by inhibiting Syk represents a novel and active therapeutic approach for NHL and SLL/CLL. This trial was registered at www.clinicaltrials.gov as #NCT00446095.

scholarly journals Phase I study of anti-CD22 immunoconjugate inotuzumab ozogamicin plus rituximab in relapsed/refractory B-cell non-Hodgkin lymphoma

2012 ◽  
Vol 103 (5) ◽  
pp. 933-938 ◽  
Author(s):  
Michinori Ogura ◽  
Kiyohiko Hatake ◽  
Kiyoshi Ando ◽  
Kensei Tobinai ◽  
Kota Tokushige ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Phase I Study ◽  
Inotuzumab Ozogamicin ◽  
Non Hodgkin Lymphoma

scholarly journals Clinicopathological Profile of Low-Grade B Cell Non-Hodgkin Lymphoma in Tertiary Health Care in West Java Indonesia

2020 ◽  
Vol 10 (6-s) ◽  
pp. 89-91
Author(s):  
Etis Primastari ◽  
Bethy Suryawathy Hernowo ◽  
Birgitta Maria Dewayani
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
B Cell Lymphoma ◽  
Initial Therapy ◽  
Response To Therapy ◽  
Low Grade ◽  
Cell Type ◽  
Non Hodgkin Lymphoma ◽  
Clinicopathological Profile ◽  
Response Groups

Background: Low-grade B cell Non-Hodgkin lymphomas (NHL) are a group of lymphomas that are predominantly indolent and make up approximately 50% of all malignant lymphomas. Initial therapy for low-grade B cell LNH has an overall response rate of between 85-94% and a refractory rate of 6-10%. Few reports have been published regarding the clinicopathological characteristics of non-Hodgkin lymphoma cases, especially low-grade B cell types. This research aims to determine the clinicopathological profile of low-grade B cell type non-Hodgkin lymphoma cases. Method: This research is a descriptive study using cross-sectional methods. The sample consisted of 40 low-grade B cell type NHL cases from January 2015 to June 2020 at Hasan Sadikin Hospital, Bandung. Clinicopathological data, including age, sex, location of the tumor (nodal or extranodal), stage, B symptoms, and response to therapy, were taken from the patients’ medical records. Data were categorized into 2 groups based on response to initial therapy. Results and Discussion: Of the 40 cases diagnosed with low-grade B cell type NHL, 55% responded to initial therapy. From the non-response group, 61.1% were stage II and 72.2% exhibited B symptoms. There were no significant differences in age, sex, tumor location (nodal or extranodal), stage, or B symptoms in the response and non-response groups. Conclusion: In this study, 45% of patients with low-grade B cell type NHL did not respond to initial therapy. There was no statistically significant difference in the clinicopathological profiles of the response and non-response groups to initial therapy in cases of low-grade B cell type NHL. Keywords: Non-Hodgkin Lymphoma, low-grade B cell lymphoma, therapy response, clinicopathological

scholarly journals Classification of non-Hodgkin lymphoma in Central and South America: a review of 1028 cases

Blood ◽  
2012 ◽  
Vol 120 (24) ◽  
pp. 4795-4801 ◽  
Author(s):  
Javier A. Laurini ◽  
Anamarija M. Perry ◽  
Eugene Boilesen ◽  
Jacques Diebold ◽  
Kenneth A. MacLennan ◽  
...  
Keyword(s):  
T Cell ◽  
South America ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
B Cell Lymphoma ◽  
Epidemiologic Studies ◽  
Geographic Region ◽  
Low Grade ◽  
Non Hodgkin Lymphoma ◽  
Objective Evidence

Abstract The distribution of non-Hodgkin lymphoma (NHL) subtypes differs around the world but a systematic study of Latin America has not been done. Therefore, we evaluated the relative frequencies of NHL subtypes in Central and South America (CSA). Five expert hematopathologists classified consecutive cases of NHL from 5 CSA countries using the WHO classification and compared them to 400 cases from North America (NA). Among the 1028 CSA cases, the proportions of B- and T-cell NHL and the sex distribution were similar to NA. However, the median age of B-cell NHL in CSA (59 years) was significantly lower than in NA (66 years; P < .0001). The distribution of high-grade (52.9%) and low-grade (47.1%) mature B-cell NHL in CSA was also significantly different from NA (37.5% and 62.5%; P < .0001). Diffuse large B-cell lymphoma was more common in CSA (40%) than in NA (29.2%; P < .0001), whereas the frequency of follicular lymphoma was similar in Argentina (34.1%) and NA (33.8%), and higher than the rest of CSA (17%; P < .001). Extranodal NK/T-cell NHL was also more common in CSA (P < .0001). Our study provides new objective evidence that the distribution of NHL subtypes varies significantly by geographic region and should prompt epidemiologic studies to explain these differences.

Gemcitabine and plasmacytic non-Hodgkin lymphoma response.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19537-e19537
Author(s):  
Ahmad Jajeh
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Marginal Zone ◽  
Single Agent ◽  
Active Agent ◽  
B Cell Lymphoma ◽  
Low Grade ◽  
Durable Response ◽  
Mantle Cell ◽  
Large B Cell

e19537 Background: Lymphomas are highly sensitive to chemotherapy. Gemcitabine is an active agent in non-Hodgkin lymphomas NHL. It is a diflourinated analogue of deoxycytadine which acts as antimetabolite. It is cell cycle specific and blocks cells in the G1/S interface. Gemcitabine is a better substrate for transport into cells. Active phosphorylated form is more readly and is excreted more slowly than other drugs. It inhibit DNA synthesis via depletion of cellular deoxynucleotide pools and by way of masked DNA chain termination. Gemcitabine seem to work it best on indolent and plasmacytoid low grade and intermediate NHL. Gemcitabine is also an active agent in Hodgkin lymphoma, Diffuse large B Cell NHL and T cell lymphomas. Methods: Retrospective reviews of patients with B cell NHL treated with gemcitabine as a single agent or in combination was carried out in one single institution over the last 13 years. Reveiw of biopsy reports and histology with immunostaining and flowcytometry done. This include CD20, CD10, BCL2, BCL6, MUM1, CD5, and cyclin D1. Clinical correlation with outcome CR, PR and Overall survival was done. Results: Forty patients with B cell lymphoproliferative disorders NHL were identified; five with mantle cell, ten with marginal zone and plasmacytoid morphology, fifteen with Diffuse Large B Cell Lymphoma DLBCLand ten with other low grade morphology. No correlation with germinal type versus post germinal (activated type) found in term of response. Plasmacytoid/ marginal zone type and mantle cell seem to have the best significant durable response when compared to DLBCL and other low grade NHL. Of note most patients received gemcitabine after failure to rituximab-CHOP and as salvage therapy in post second- and third-line failure. Conclusions: Gemcitabine may have more durable activity if used as a first-line combination therapy. Larger group of patients analysis needed to see if this agent has more activities in germinal than activated type of DLBCL. Plasmacytoid NHL seem to have more rapid and durable respone in our analysis.

scholarly journals Phase I Study of Inotuzumab Ozogamicin Combined with R-CVP for Relapsed/Refractory CD22+ B-cell Non-Hodgkin Lymphoma

2016 ◽  
Vol 22 (19) ◽  
pp. 4807-4816 ◽  
Author(s):  
Michinori Ogura ◽  
Kensei Tobinai ◽  
Kiyohiko Hatake ◽  
Andrew Davies ◽  
Michael Crump ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Phase I Study ◽  
Inotuzumab Ozogamicin ◽  
Non Hodgkin Lymphoma

scholarly journals Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma

2020 ◽  
Vol 38 (5) ◽  
pp. 1472-1482 ◽  
Author(s):  
Frank Kroschinsky ◽  
Jan Moritz Middeke ◽  
Martin Janz ◽  
Georg Lenz ◽  
Mathias Witzens-Harig ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Escalation ◽  
Transmembrane Protein ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Dose Escalation Study ◽  
Non Hodgkin Lymphoma

Summary BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1–200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL.

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