Subcutaneous Injections of Low Doses of Humanized Anti-CD20 Veltuzumab for Treatment of Indolent B-Cell Malignancies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3757-3757 ◽  
Author(s):  
O. George Negrea ◽  
Steven L Allen ◽  
Kanti R. Rai ◽  
Rebecca Elstrom ◽  
Rashid Abassi ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Hodgkin’S Lymphoma ◽  
Objective Response ◽  
Hodgkin's Lymphoma ◽  
B Cell Malignancies ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Anti Cd20 ◽  
Dose Levels

Abstract Abstract 3757 Poster Board III-693 Background Low IV doses of veltuzumab, a 2nd generation humanized anti-CD20 monoclonal antibody with structure-function differences from chimeric rituximab, have shown clinical activity in non-Hodgkin's lymphoma (Morschhauser et al., J Clin Oncol, 2009; 27:3346-53). By avoiding lengthy IV administration and the need for dedicated infusion suites, subcutaneous (SC) injections of low-dose veluzumab may offer benefits to both patients and the healthcare system for treatment of B-cell malignancies, and this may be particularly useful in the setting of indolent disease. Methods A multicenter, phase I/II study was undertaken to evaluate the safety, tolerability, and preliminary efficacy of SC veltuzumab in previously untreated or relapsed CD20+ indolent non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL). All patients (pts) received 4 SC injections of veltuzumab 2 weeks apart at dose levels of 80, 160, or 320 mg. Efficacy was assessed by CT-based IWG (NHL) or hematology-based NCI/IWCLL (CLL) criteria 4 and 12 weeks later, with responding pts continuing follow-up. Other evaluations included AEs, safety laboratories, B-cell blood levels (CD19), serum veltuzumab levels, and human anti-veltuzumab antibody (HAHA) titers. Results Twenty-six pts (10M/16F, median age 64), including 15 NHL pts (12 follicular, 3 other indolent NHL; 5 treatment naïve) most with stage III or IV disease (12/15), and 11 CLL pts (4 treatment naïve) most with Rai stage II or III disease, have now received SC veltuzumab at 80 mg (3 NHL, 3 CLL), 160 mg (9 NHL, 3 CLL) or 320 mg (3 NHL, 5 CLL) dose levels. Pre-treatment with antihistamines or steroids was not required. SC veltuzumab was well tolerated with only mild, transient injection-site reactions and tenderness, and no other safety issues. To date, all HAHA response results have been negative. In NHL pts, SC veltuzumab demonstrated good bio-availability, with a slow release pattern over several days, and a mean Cmax of 18.7, 19.5 and 64.0 μg/mL at 80, 160, and 320 mg dose levels, respectively. Depletion of circulating B cells was observed starting after 1st injection. In the 15 NHL pts, the objective response rate (CR+CRu+PR) was 53% (8/15) with a complete response (CR) rate of 20% (3/15) and with 7/8 ORs currently continuing in remission, up to 6 months after treatment. The 11 CLL pts presented with mean white blood cell levels of 55K/μL (maximum 122K/μL) and achieved much lower serum veltuzumab levels, with mean Cmax values of 4.0, 2.5 and 21.0 μg/mL at the 80, 160, and 320 mg dose levels, respectively. There were no ORs, but 5 of 7 (71%) CLL pts with response assessments currently available showed stable disease with >70% decreases in B-cell levels for up to 12 weeks. Conclusions SC administration of veltuzumab is well tolerated, achieves slow but efficient delivery into the blood, and is pharmacologically active when given every 2 weeks for a total of 4 doses. In CLL with high levels of circulating leukemic cells, more frequent and prolonged dosing is likely required. However, in NHL, these low SC doses achieved sustained serum levels with objective response rates comparable to those seen even with higher IV doses. Disclosures: Negrea: Immunomedics: Research Funding. Off Label Use: veltuzumab for investigational treatment of NHL/CLL. Allen:Immunomedics: Research Funding. Rai:Immunomedics: Research Funding. Elstrom:Immunomedics: Research Funding. Abassi:Immunomedics: Research Funding. Farber:Immunomedics: Research Funding. Teoh:Immunomedics: Employment. Horne:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.

Humanized Anti-CD20 Antibody, Veltuzumab, in Refractory/Recurrent Non-Hodgkin's Lymphoma: Phase I/II Results

2009 ◽  
Vol 27 (20) ◽  
pp. 3346-3353 ◽  
Author(s):  
Franck Morschhauser ◽  
John P. Leonard ◽  
Luis Fayad ◽  
Bertrand Coiffier ◽  
Marie-Odile Petillon ◽  
...  
Keyword(s):  
Phase I ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
Dose Levels

Purpose This is a multicenter phase I/II dose-finding study in relapsed/refractory B-cell non-Hodgkin's lymphoma (NHL) evaluating veltuzumab, a humanized anti-CD20 antibody with structure-function differences from chimeric rituximab. Patients and Methods Eighty-two patients (median age, 64 years; 79% stage III/IV, one to nine prior treatments) received four once-weekly doses of 80 to 750 mg/m2 of veltuzumab and were assessed for safety, efficacy, pharmacodynamics, pharmacokinetics, and immunogenicity. Results Veltuzumab was well tolerated, with no grade 3 to 4 drug-related adverse events despite short infusion times (typically 2 hours initially, 1 hour subsequently at doses < 375 mg/m2). In follicular lymphoma, 24 (44%) of 55 patients had objective responses (OR), with 15 (27%) complete responses (CRs) or CRs unconfirmed (CRus) by International Working Group criteria, and with some responses occurring despite two to five prior rituximab-containing regimens, less favorable prognosis (elevated lactate dehydrogenase, tumors > 5 cm, and Follicular Lymphoma International Prognostic Index ≥ 2), and at all dose levels. The CRs/CRus were durable (median duration, 19.7 months), with five patients still ongoing (15.9 to 37.6 months duration). In marginal zone lymphoma, five (83%) of six patients had ORs, with two CRs/CRus (33%), and in diffuse large B-cell lymphoma, three (43%) of seven patients achieved partial responses. At all dose levels studied, B cells were depleted after the first infusion, veltuzumab serum half-lives were similar after the fourth infusion, and mean antibody serum levels exceeded values considered important for anti-CD20 therapy (ie, 25 μg/mL). Conclusion Veltuzumab appeared safe and active at all tested doses, encouraging further study, including dose levels less than those typically used with rituximab.

Phase II Study of Rituximab in Combination With CHOP Chemotherapy in Patients With Previously Untreated, Aggressive Non-Hodgkin’s Lymphoma

2001 ◽  
Vol 19 (2) ◽  
pp. 389-397 ◽  
Author(s):  
J. M. Vose ◽  
B. K. Link ◽  
M. L. Grossbard ◽  
M. Czuczman ◽  
A. Grillo-Lopez ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Chop Chemotherapy ◽  
Safety And Efficacy ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Cd20 Antibody ◽  
Anti Cd20

PURPOSE: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody Rituxan (rituximab, IDEC-C2B8; Genentech Inc, South San Francisco, CA) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in patients with aggressive non-Hodgkin’s lymphoma (NHL). PATIENTS AND METHODS: Thirty-three patients with previously untreated advanced aggressive B-cell NHL received six infusions of Rituxan (375 mg/m2 per dose) on day 1 of each cycle in combination with six doses of CHOP chemotherapy given on day 3 of each cycle. RESULTS: The ORR by investigator assessment confirmed by the sponsor was 94% (31 of 33 patients). Twenty patients experienced a complete response (CR) (61%), 11 patients had a partial response (PR) (33%), and two patients were classified as having progressive disease. In the 18 patients with an International Prognostic Index (IPI) score ≥ 2, the combination of Rituxan plus CHOP achieved an ORR of 89% and CR of 56%. The median duration of response and time to progression had not been reached after a median observation time of 26 months. Twenty-nine of 31 responding patients remained in remission during this follow-up period, including 15 of 16 patients with an IPI score ≥ 2. The most frequent adverse events attributed to Rituxan were fever and chills, primarily during the first infusion. Rituxan did not seem to compromise the ability of patients to tolerate CHOP; all patients completed the entire six courses of the combination. The bcl-2 translocation of blood or bone marrow was positive at baseline in 13 patients; 11 patients had follow-up specimens obtained (eight CR, three PR), and all had a negative bcl-2 status after therapy. Only one patient has reconverted to bcl-2 positivity, and all patients remain in clinical remission. CONCLUSION: This is the first report to demonstrate the safety and efficacy of the Rituxan chimeric anti-CD20 antibody in combination with standard-dose CHOP in the treatment of aggressive B-cell lymphoma. The clinical responses are at least comparable to those achieved with CHOP alone with no significant added toxicity. The presence or absence of the bcl-2 translocation did not affect the ability of patients to achieve a CR with this regimen. The ability to achieve sustained remissions in patients with an IPI score ≥ 2 warrants further investigation with a randomized study.

A Phase I Study of Milatuzumab, a Humanized Anti-CD74 Antibody, and Veltuzumab, a Humanized Anti-CD20 Antibody, In Patients with Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2788-2788 ◽  
Author(s):  
Beth Christian ◽  
Lapo Alinari ◽  
Christian Tyler Earl ◽  
Emily Wilding ◽  
Carl Quinion ◽  
...  
Keyword(s):  
Research Funding ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Cytokine Levels ◽  
Infusion Reactions ◽  
Grade 3 ◽  
Anti Cd20

Abstract Abstract 2788 Preclinical studies conducted at our institution (Alinari et al. Blood Abstract 1694, 2009) demonstrated superior efficacy of milatuzumab (Immunomedics, Inc.), a humanized anti-CD74 antibody, in combination with rituximab in mantle cell lymphoma (MCL) cell lines, MCL patient (pt) primary tumor cells, and an in vivo preclinical model of human MCL, compared to either agent alone. Veltuzumab (Immunomedics, Inc.), a novel humanized anti-CD20 antibody, has been reported to have several advantages over rituximab including slower off-rates, shorter infusion times, higher potency, and improved therapeutic responses in animal models. Phase II clinical testing of veltuzumab demonstrated single agent activity in pts with relapsed and refractory non-Hodgkin's lymphoma (NHL). In vitro, veltuzumab combined with milatuzumab also resulted in enhanced apoptosis compared to either agent alone, similar to that observed with rituximab and milatuzumab (Fig 1). As a result of the anti-tumor activity observed in vitro with combined veltuzumab and milatuzumab, we initiated a phase I/II trial in pts with relapsed or refractory B-cell NHL after at least 1 prior therapy to determine the safety, tolerability, and overall response rate with this combination. Patients received veltuzumab 200 at mg/m2 weekly combined with escalating doses of milatuzumab at 8, 16, and 20 mg/kg twice per wk of wks 1–4, 12, 20, 28, and 36. All pts received pre-medication with acetominophen, diphenhydramine, and famotidine prior to each veltuzumab dose and acetominophen, diphenhydramine, and hydrocortisone 50 mg before and after each milatuzumab dose. Dose limiting toxicity was defined during weeks 1–4. Six pts with grade 2 (n=2) or 3 (n=4) follicular NHL, have completed at least 4 weeks of combined veltuzumab and milatuzumab. Median age was 63.5 years (range 44–81), and pts received a median of 3.5 prior therapies (range 3 – 5), including 2 pts with prior autologous stem cell transplant. Three of 6 patients were refractory to rituximab, defined as having less than a partial response to the last rituximab-containing regimen. Dose escalation has reached 16 mg/kg milatuzumab, and no dose limiting toxicities have been observed to date. However, 3 of 6 pts experienced grade 3 infusion reactions during or immediately following the milatuzumab infusion; 1 pt treated with 8 mg/kg milatuzumab during weeks 1 and 12, and 2 pts receiving 16 mg/kg during weeks 3 and 12. Grade 3 infusion reactions consisted of fever, rigors, nausea, vomiting, diarrhea, and in 1 case a diffuse macular rash. Grade 3–4 hematologic toxicity occurred in only 2 pts consisting of grade 4 lymphopenia, and no infections have been observed. The most frequently observed grade 1–2 toxicities were fatigue, transient hyperglycemia, dyspnea, hypoalbuminemia, and thrombocytopenia. Human anti-veltuzumab and anti-milatuzumab antibodies, collected in all 6 pts pretreatment and day 1 of weeks 4 and 12, have not been detected in any pt. Plasma cytokine levels of IL-10, IL-12, TNF-α and INF-γ were checked pre- and post- veltuzumab infusion on day 1 and pre- and post-milatuzumab infusion on day 2. While elevations in cytokine levels were observed, there was no correlation with infusion reactions or response. In the first cohort, one pt achieved a PR maintained at week 20, 1 pt experienced stable disease at week 10, and 1 pt developed progressive disease at week 20. In the second cohort, two pts achieved a PR at week 10, and 1 pt had stable disease at week 10. Two of 3 responding pts were rituximab-refractory. Due to the observed infusion reactions with milatuzumab, the protocol has been amended to include additional premedication with intravenous antihistamine, and dexamethasone 20 mg pre-milatuzumab and 10 mg post-milatuzumab. The schedule of treatment was also modified so that the antibodies are no longer administered on the same day. Dose escalation will continue and updated results will be presented. The first 2 cohorts will be expanded to 6 pts to determine if the modifications will limit the infusion reactions and permit prolonged dosing in responding pts. In summary, 3 of 6 pts with relapsed or refractory NHL treated to date including heavily pretreated and rituximab-refractory pts, responded to combination therapy, achieving a PR. The primary observed toxicity has been infusion reactions due to milatuzumab. Disclosures: Christian: Immunomedics, Inc.: Research Funding. Off Label Use: The use of the monoclonal antibodies veltuzumab and milatuzumab is experimental in the treatment of non-Hodgkin's lymphoma. Benson:Immunomedics, Inc: Research Funding. Jones:Immunomedics, Inc.: Research Funding. Wegener:Immunomedics, Inc.: Employment, shareholders. Goldenberg:Immunomedics, Inc.: Employment, shareholders. Baiocchi:Immunomedics, Inc.: Research Funding. Blum:Immunomedics, Inc.: Research Funding.

scholarly journals Use of pembrolizumab with or without pomalidomide in HIV-associated non-Hodgkin’s lymphoma

2021 ◽  
Vol 9 (2) ◽  
pp. e002097
Author(s):  
Kathryn Lurain ◽  
Ramya Ramaswami ◽  
Ralph Mangusan ◽  
Anaida Widell ◽  
Irene Ekwede ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hiv And Aids ◽  
Hodgkin's Lymphoma ◽  
People Living With Hiv ◽  
Oncogenic Viruses ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

BackgroundNon-Hodgkin’s lymphoma (NHL) is currently the most common malignancy among people living with HIV (PLWH) in the USA. NHL in PLWH is more frequently associated with oncogenic viruses than NHL in immunocompetent individuals and is generally associated with increased PD-1 expression and T cell exhaustion. An effective immune-based second-line approach that is less immunosuppressive than chemotherapy may decrease infection risk, improve immune control of oncogenic viruses, and ultimately allow for better lymphoma control.MethodsWe conducted a retrospective study of patients with HIV-associated lymphomas treated with pembrolizumab±pomalidomide in the HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute.ResultsWe identified 10 patients with stage IV relapsed and/or primary refractory HIV-associated NHL who were treated with pembrolizumab, an immune checkpoint inihibitor, with or without pomalidomide. Five patients had primary effusion lymphoma (PEL): one had germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL); two had non-GCB DLBCL; one had aggressive B cell lymphoma, not otherwise specified; and one had plasmablastic lymphoma. Six patients received pembrolizumab alone at 200 mg intravenously every 3 weeks, three received pembrolizumab 200 mg intravenously every 4 weeks plus pomalidomide 4 mg orally every day for days 1–21 of a 28-day cycle; and one sequentially received pembrolizumab alone and then pomalidomide alone. The response rate was 50% with particular benefit in gammaherpesvirus-associated tumors. The progression-free survival was 4.1 months (95% CI: 1.3 to 12.4) and overall survival was 14.7 months (95% CI: 2.96 to not reached). Three patients with PEL had leptomeningeal disease: one had a complete response and the other two had long-term disease control. There were four immune-related adverse events (irAEs), all CTCAEv5 grade 2–3; three of the four patients were able to continue receiving pembrolizumab. No irAEs occurred in patients receiving the combination of pembrolizumab and pomalidomide.ConclusionsTreatment of HIV-associated NHL with pembrolizumab with or without pomalidomide elicited responses in several subtypes of HIV-associated NHL. This approach is worth further study in PLWH and NHL.

scholarly journals Prognostic significance of bcl-2 protein expression in aggressive non- Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA)

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 265-272 ◽  
Author(s):  
O Hermine ◽  
C Haioun ◽  
E Lepage ◽  
MF d'Agay ◽  
J Briere ◽  
...  
Keyword(s):  
Overall Survival ◽  
Protein Expression ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Prognostic Significance ◽  
Hodgkin's Lymphoma ◽  
Independent Effect ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Large B Cell

Abstract Little is known about the expression of bcl-2 protein in intermediate and high grade non-Hodgkin's lymphoma (NHL) and its clinical and prognostic significance. We performed immunohistochemical analysis of bcl-2 expression in tumoral tissue sections of 348 patients with high or intermediate grade NHL. These patients were uniformly treated with adriamycin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) in the induction phase of the LNH87 protocol. Fifty eight cases were excluded due to inadequate staining. Of the 290 remaining patients, 131 (45%) disclosed homogeneous positivity (high bcl-2 expression) in virtually all tumor cells, whereas 65 (23%) were negative and 94 (32%) exhibited intermediate staining. High bcl-2 expression was more frequent in B-cell NHL (109 of 214, 51%) than in T- cell NHL (6 of 35, 17%) (P = .0004), and was heterogeneously distributed among the different histological subtypes. Further analysis was performed on the 151 patients with diffuse large B-cell lymphoma (centroblastic and immunoblastic) to assess the clinical significance and potential prognostic value of bcl-2 expression in the most frequent and homogeneous immunohistological subgroup. High bcl-2 expression, found in 44% of these patients (67 of 151), was more frequently associated with III-IV stage disease (P = .002). Reduced disease-free survival (DFS) (P < .01) and overall survival (P < .05) were demonstrated in the patients with high bcl-2 expression. Indeed, the 3-year estimates of DFS and overall survival were 60% and 61%, respectively (high bcl-2 expression) versus 82% and 78%, respectively (negative/intermediate bcl-2 expression). A multivariate regression analysis confirmed the independent effect of bcl-2 protein expression on DFS. Thus bcl-2 protein expression, as demonstrated in routinely paraffin-embedded tissue, appears to be predictive of poor DFS, in agreement with the role of bcl-2 in chemotherapy-induced apoptosis. It might be considered as a new independent biologic prognostic parameter, which, especially in diffuse large B-cell NHL, could aid in the identification of patient risk groups.

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