Translational Study of Cell Surface Proteins in Non-Hodgkin Lymphoma Patients Treated with the First-in-Class Anti-CD47 Antibody Magrolimab (5F9) in Combination with Rituximab

Introduction Magrolimab (Hu5F9-G4, 5F9) is a first-in-class IgG4 antibody targeting CD47, a macrophage immune checkpoint and "don't eat me" signal expressed on cancer cells. Blockade of CD47 leads to phagocytosis of tumor cells. Magrolimab synergizes with rituximab to eliminate CD20-positive lymphoma by enhancing antibody-dependent cellular phagocytosis. Magrolimab +rituximab demonstrated encouraging safety and efficacy in a Phase (Ph)1b dose escalation cohort in patients with relapsed/refractory (r/r) DLBCL and FL that were rituximab-refractory (Advani et al., NEJM 2018). CD24 is an additional "don't eat me" signal, and has been proposed as a potential target for immunotherapy (Barkal et al. Nature 2019). Here we describe immunohistochemical analysis of CD47 and CD24 in primary patient biopsies from an ongoing follow-up Phase 2 trial of Non-Hodgkin's lymphoma (including DLBCL and indolent lymphoma) patients treated with magrolimab+rituximab. Results By immunohistochemistry, 54 out of 54 patients assessed were positive for expression of CD47 at screening. High levels of CD47 expression were maintained during treatment with clinically-efficacious doses of magrolimab. Therapeutic response did not correlate with CD47 H-score expression levels. At screening, patients presented with highly variable levels of CD24 expression, with 40 of 54 samples showing positive staining in >30% of cells. We observed no significant correlation between CD24 expression by H-score and response to therapy (complete response + partial response) in either DLBCL or indolent lymphoma. Conclusions CD47 shows consistently high expression in primary biopsies from Non-Hodgkin's lymphoma patients and remains persistently high during treatment. In our Phase 2 trial, therapeutic response did not correlate with CD47 expression levels, suggesting that the degree of target expression is not a primary driver of magrolimab efficacy in Non-Hodgkin's lymphoma. Although we observe wide variation in CD24 expression within this cohort, its levels are not predictive of outcome for this disease indication. We are evaluating the expression of additional biomarkers to identify those Non-Hodgkin's lymphoma patients most likely to benefit from magrolimab+rituximab combination therapy. Disclosures Maute: Forty Seven Inc.: Employment, Equity Ownership, Patents & Royalties. Chen:Forty Seven Inc.: Consultancy, Equity Ownership. Marjon:Forty Seven Inc.: Employment, Equity Ownership. Duan:Forty Seven Inc.: Employment, Equity Ownership. Choi:Forty Seven Inc.: Employment, Equity Ownership. Chao:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Takimoto:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties. Agoram:Forty Seven Inc.: Employment, Equity Ownership. Volkmer:Forty Seven, Inc.: Employment, Equity Ownership, Patents & Royalties.

Download Full-text

Risk of Infection Among Patients with Non-Metastatic Solid Tumors or Non-Hodgkin’s Lymphoma Receiving Myelosuppressive Chemotherapy and Antimicrobial Prophylaxis in US Clinical Practice

Blood ◽

10.1182/blood.v122.21.1730.1730 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1730-1730

Author(s):

Derek Weycker ◽

David Chandler ◽

Rich Barron ◽

Hairong Xu ◽

Hongsheng Wu ◽

...

Keyword(s):

Clinical Practice ◽

Solid Tumors ◽

Research Funding ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

Employment Equity ◽

Myelosuppressive Chemotherapy ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Equity Ownership

Abstract Background Clinical practice guidelines recommend oral antimicrobials (AMB)—principally, the fluoroquinolones—for prophylaxis against chemotherapy-related infections (CRI) in intermediate- and high-risk patients undergoing myelosuppressive chemotherapy. Available evidence on the risk of CRI among patients with non-metastatic solid tumors or non-Hodgkin's lymphoma (NHL) receiving myelosuppressive chemotherapy and AMB prophylaxis in US clinical practice is currently limited. Methods A retrospective cohort design and data from two US private healthcare claims repositories (2008-2011) were employed. The study population included adult patients who received myelosuppressive chemotherapy for non-metastatic cancer of the breast, colon/rectum, or lung, or for NHL. For each study subject, the first qualifying chemotherapy course, and each chemotherapy cycle and episode of CRI within the course, were identified. Use of prophylaxis with oral AMB agents—including antibacterial, antifungal, and antiviral drugs—as well as colony-stimulating factors (CSF) in each cycle also was identified. CRI was ascertained based on admission to an acute-care inpatient facility with a corresponding diagnosis (1⁰ or 2⁰) or an ambulatory encounter with a corresponding diagnosis and evidence of AMB therapy. Risk of CRI was evaluated during chemotherapy cycles in which patients received AMB prophylaxis; only results for the most frequently observed regimen for each tumor type are reported herein. Results The most common regimens—by tumor—were: breast cancer, docetaxel + cyclophosphamide (“TC”, 29% of 34,876); colorectal cancer, folinic acid (leucovorin) + fluorouracil + oxaliplatin (“FOLFOX”, 34% of 14,334); lung cancer, paclitaxel + carboplatin (“PC”, 25% of 17,334); and NHL, cyclophosphamide + doxorubicin + vincristine + prednisone with Rituxan (“CHOP-R”, 45% of 9,612). Across these four regimens, use of AMB prophylaxis in cycle 1 ranged from 3.5-8.6%; fluoroquinolones were the most common agents administered (range, 27.1-43.5%) (Table 1). Use of CSF prophylaxis in cycle 1 ranged from 10.4-61.2%. Among subjects who received first-cycle AMB prophylaxis, risk of CRI in that cycle ranged from 1.2-7.5%; among these subjects, 45-68% had CRI in the inpatient setting (Table 2). CRI risks in subsequent cycles with AMB prophylaxis were generally comparable. Conclusion Among patients with non-metastatic solid tumors or NHL receiving common myelosuppressive chemotherapy and AMB prophylaxis in US clinical practice, risk of CRI ranged from 1.2-8.6% in cycles in which AMB prophylaxis was administered. Disclosures: Weycker: Amgen Inc.: Research Funding. Chandler:Amgen Inc.: Employment, Equity Ownership. Barron:Amgen Inc.: Employment, Equity Ownership. Xu:Amgen Inc.: Employment, Equity Ownership. Wu:Amgen Inc.: Research Funding. Girardi:Amgen Inc.: Employment, Equity Ownership. Edelsberg:Amgen Inc.: Research Funding. Lyman:Amgen Inc.: PI on a research grant to Duke University Other.

Download Full-text

Long Term Follow up of the Patients with Non-Hodgkin’s Lymphoma Treated with Rituximab in Combination with CHOP Regimen.

Blood ◽

10.1182/blood.v106.11.4776.4776 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4776-4776

Author(s):

Jun-Min Li

Keyword(s):

B Cell ◽

Hodgkin’S Lymphoma ◽

Cell Lymphoma ◽

Hodgkin's Lymphoma ◽

Indolent Lymphoma ◽

Chop Regimen ◽

Bulky Disease ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

Abstract Objectives: We performed this prospective study with single arm to evaluate the long term efficacy and safety of rituximab in combination with CHOP regimen in B cell non-Hodgkin’s Lymphoma (NHL) patient. Methods: All patients received 4~8 cycles of CHOP plus rituximab. For each cycle, Rituximab (375 mg/m2 per dose) was given on day 1 and CHOP regimen on day 3. CHOP regimen consisted of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (maximum dose, 2.0 mg/d) given intravenously on day 3, and oral prednisone 60 mg given from day 3 to 7. Results: 102 patients were enrolled in this trial, 65 of them are males and 37 are females, with the median age of 47.5 (range 16–76). The main subtypes were diffuse large B cell lymphoma (DLBCL, 82/102), follicular lymphoma (FL, 9/102), mucosa associated lymphoma (MALT, 3/102), marginal zone lymphoma (MZL, 3/102), lymphoplasmacytic lymphoma (LPL, 2/102) and mantle cell lymphoma (MCL, 3/102). The overall response (OR) rate was 91.2% and complete response (CR) rate was 71.6%. The OR and CR of DLBCL were 90.2% and 70.7%, respectively; and the OR and CR of indolent lymphoma (MALT, FL, and LPL) were 100.0% and 82.4%, respectively. The patients with lower (0,1) and higher (≥2) IPI score achieved CR rate and OR rate of 87.88% and 59.18%, and 100.00% and 83.67%, respectively. International prognosis index (IPI) score showed significant impact on both CR and OR rate (P=0.006 and 0.019, respectively). The patients with and without bulky disease achieved CR rate and OR rate of 50.00% and 74.29%, and 83.33% and 91.43%, respectively, and there was no statistical significance (P=0.100 and 0.332, respectively). The patients were followed after achieving objective response (CR+PR) for 2–64 months (median 20 months). Estimated 5 year progress free survival (PFS) rate and estimated 5 year overall survival (OS) rate was 60.33%±6.94% and 75.88%±6.94%, respectively. In DLBCL patients, PFS and OS rate was reached at 56.45%±8.26% and 74.12%±7.48%, respectively. 4 year PFS rate and OS rate of the patients with indolent lymphoma was 86.15%±9.11% and 100%, respectively. IPI score showed significant survival impact on OS and PFS in DLBCL patients, respectively (P=0.0339 and 0.0122, respectively); however, the bulky disease showed impact on PFS but not on OS (P=0.0472 and 0.106, respectively). Conclusions: The results suggested that the rituximab in combination with chemotherapy regimen in most B cell NHL patient was effective and safe.

Download Full-text

Clinical Study Of Dose-Adjusted EPOCH Regimen For Non-Hodgkin's Lymphoma With Hemophagocytic Lymphohistiocytosis: Preliminary Results Of An Ongoing Phase II Study

Blood ◽

10.1182/blood.v122.21.4360.4360 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4360-4360

Author(s):

Wei Xu ◽

Lei Fan ◽

Li Wang ◽

Ji Xu ◽

Run Zhang ◽

...

Keyword(s):

Clinical Trial ◽

Disease Progression ◽

Hemophagocytic Lymphohistiocytosis ◽

Hodgkin’S Lymphoma ◽

Chemotherapy Regimen ◽

Hodgkin's Lymphoma ◽

Phase 2 ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Ongoing Phase

Abstract Introduction Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome (HPS) is characterized by cytokines storm and uncontrolled activation of macrophages. Secondary HLH in adults may occur in different occasions, including infections, autoimmune diseases, carcinomas and hematologic malignancies, in which Lymphoma-associated hemophagocytic lymphohistiocytosis(LA-HLH) has a high fatality rate and the worst outcome. The major cause of LA-HLH is aggressive non-Hodgkin's lymphoma (NHL), especially T/NKT cell lymphomas. Until now, there is no recommended therapeutic schedule for this fatal disease. Because of promising results of etoposide-containing regimen for HLH and high effective of continuous infusion chemotherapy regimen for aggressive NHL .The investigators therefore employed an intensive chemotherapy regimen--DA-EPOCH regimen (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) to treat non-Hodgkin's lymphoma with hemophagocytic lymphohistiocytosis and we have performed a preliminary analysis of this ongoing Phase 2 study and evaluated safety and efficacy of this regimen. Methods The clinical trial was designed as a prospective, multicenter, single-arm phase 2 clinical trial (NCT01818908). Enrolled patients included those with previously untreated NHL, and met the diagnostic criteria of either HLH2004 or ASH 2009 of HLH, patients with primary HLH and secondary HLH other than NHL were excluded. Therapeutic protocol of DA-EPOCH regimen was as follows: etoposide 50 mg/m2 CI 24h d1-d4, doxorubicin 10 mg/m2 CI 24h d1-d4, vincristine 0.4 mg/m2 CI 24h d1-d4, cyclophosphamide 750 mg/m2 IV d5, prednisone 60 mg/m2 oral d1-d5, If enrolled patient was histologically confirmed CD20+ B cell lymphoma, standard dose of rituximab will be recommended to combine with DA-EPOCH regimen. Drug dose was adjusted as previously described (Wyndham H. et al, 2002), each cycle of treatment was administered every 21 to 28 days according to recovery of toxicities. For patients who responded to the treatment and did not have disease progression, interim evaluation was conducted after 3 cycles of treatment. Results At the time of analysis 26 patients were enrolled and 20 patients were eligible to evaluate. Patients were 60.0% (12/20) male with median age 44(range: 14-60), the age-adjusted international prognostic score (aaIPI) enrolled to study was high/intermediate (2 score) 10/20, high risk group (3 score) 10/20. Histologies were four B-NHL, ten T-NHL and six NK-NHL. The median number of cycles of therapy was 3, patients who had discontinued study were mainly due to rapid disease progression. The overall response rate (ORR) among treated pts was 50.0%, with 35.0% (7/20) of patients achieving CR/CRu and 15.0% (3/20) achieving PR, and 50.0% of patients (10/20) had PD. With the median follow-up of 8 months, progression-free survival (PFS) rate was 46.3% and in subgroup analysis, PFS of B-NHL, T-NHL and NK-NHL was 75%, 45.7% and 25% respectively (Fig. 1); Overall survival (OS) rate was 52.4%(Fig. 2) and 75.0%, 58.3%, 22.2% in subgroup of B-NHL, T-NHL and NK-NHL(Fig. 3). The most common grade ≥3 treatment-related side effects were hematologic toxicities including neutropenia and thrombocytopenia. Conclusions Lymphoma-associated hemophagocytic lymphohistiocytosis progresses rapidly and has a high mortality rate, our preliminary results suggest DA-EPOCH regimen has acceptable toxicities and promising activity in NHL with HLH, especially for B-NHL and T-NHL, but prognosis of NK-NHL with HLH remains dismal, urgent need for novel therapeutic strategies may benefit the survival of patients with this disease. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

AIDS Related Non-Hodgkin's Lymphoma of the Paranasal Sinuses

American Journal of Rhinology ◽

10.2500/105065893781976591 ◽

1993 ◽

Vol 7 (1) ◽

pp. 37-42 ◽

Cited By ~ 2

Author(s):

Jeffrey E. Goldberg ◽

Augustine L. Moscatello ◽

Reza Babapour ◽

Douglas G. Finn ◽

Robert L. Pincus

Keyword(s):

Paranasal Sinuses ◽

Hodgkin’S Lymphoma ◽

Therapeutic Response ◽

Deficiency Syndrome ◽

Hodgkin's Lymphoma ◽

Review Of The Literature ◽

Hiv Patients ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Early Manifestation

Non-Hodgkin's Lymphoma (NHL) is an established early manifestation of Autoimmune Deficiency Syndrome (AIDS). It is estimated that up to 10% of HIV+ patients will eventually acquire NHL. These lymphomas differ from those occurring in the general population with regard to natural history, histopathology, location, and therapeutic response. A review of the literature demonstrates only two previously reported cases of NHL originating in the paranasal sinuses in AIDS patients. We present four cases of AIDS-related NHL of the paranasal sinuses diagnosed at our institutions. Clinical and histopathological manifestations and modes of treatment are discussed. NHL must be considered in the differential diagnosis of HIV+ patients presenting with paranasal sinus pathology.

Download Full-text

CDK9 Inhibition Reverses Resistance to ABT-199 (GDC-0199) By Down-Regulating MCL-1

Blood ◽

10.1182/blood.v124.21.2161.2161 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2161-2161 ◽

Cited By ~ 1

Author(s):

Jun Chen ◽

Sha Jin ◽

Paul Tapang ◽

Stephen K Tahir ◽

Morey Smith ◽

...

Keyword(s):

Clin Oncol ◽

Cell Lines ◽

Small Molecule ◽

Hodgkin’S Lymphoma ◽

Acquired Resistance ◽

Hematologic Malignancies ◽

Hodgkin's Lymphoma ◽

Employment Equity ◽

Non Hodgkin's Lymphoma ◽

Equity Ownership

Abstract All authors are employees of AbbVie and participated in the design, conduct, and interpretation of these studies. AbbVie and Genentech provided financial support for these studies and participated in the review and approval of this publication. The BCL-2-selective inhibitor ABT-199 has demonstrated efficacy in numerous preclinical models of hematologic malignancies without causing thrombocytopenia, a dose-limiting toxicity associated with the BCL-2/BCL-XL inhibitor navitoclax (Souers et al. 2013. Nat. Med. 19, 202-208). ABT-199 has also demonstrated clinical activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL) (Seymour et al. 2014. J. Clin. Oncol. 32, 448s; Davids et al. 2014. J. Clin. Oncol. 32, 544s). Despite these encouraging early clinical data, some subjects do not respond to ABT-199 or progress while on treatment. Pre-clinical models indicate that both intrinsic and acquired resistance may be a consequence of MCL-1 expression. Consequently, we have explored potent and selective small molecule inhibitors of CDK9, a kinase known to maintain the expression of MCL-1 through its role in p-TEFb-mediated transcription. Inhibition of CDK9 resulted in the rapid loss in RNA polymerase II phosphorylation (Serine 5) and MCL-1 expression that was closely followed by the induction of apoptosis in MCL-1-dependent cell lines, a cellular response that could be rescued by overexpression of BCL-2. Substantial synergy was observed between CDK9 inhibitors and ABT-199 in a number of hematologic cell lines with intrinsic or acquired resistance to ABT-199. Direct inhibition of MCL-1 with the small molecule BH3 mimetic A-1210477 was also highly synergistic with ABT-199, further validating the utility of co-inhibiting MCL-1 and BCL-2 function simultaneously in ABT-199 resistant tumors. Importantly, the CDK9 inhibitor-ABT-199 combination was well tolerated in vivo and demonstrated efficacy superior to either agent alone in xenograft models of non-Hodgkin’s lymphoma (NHL) and acute myelogenous leukemia (AML). These data indicate that CDK9 inhibitors may be highly efficacious when used in combination with ABT-199 for the treatment of hematologic malignancies. Disclosures Chen: Abbvie: Employment, Equity Ownership. Jin:Abbvie: Employment, Equity Ownership. Tapang:abbvie: Employment, Equity Ownership. Tahir:abbvie: Employment, Equity Ownership. Smith:abbvie: Employment, Equity Ownership. Xue:abbvie: Employment, Equity Ownership. Zhang:abbvie: Employment, Equity Ownership. Gao:abbvie: Employment, Equity Ownership. Tong:abbvie: Employment, Equity Ownership. Clark:abbvie: Employment, Equity Ownership. Ricker:abbvie: Employment, Equity Ownership. Penning:abbvie: Employment, Equity Ownership. Albert:abbvie: Employment, Equity Ownership. Phillips:abbvie: Employment, Equity Ownership. Souers:abbvie: Employment, Equity Ownership. Leverson:abbvie: Employment, Equity Ownership.

Download Full-text

A case of non-Hodgkin’s lymphoma of the ovary: Usefulness of18F-FDG PET for staging and assessment of the therapeutic response

Annals of Nuclear Medicine ◽

10.1007/bf02985629 ◽

2006 ◽

Vol 20 (2) ◽

pp. 157-160 ◽

Cited By ~ 10

Author(s):

Daisuke Komoto ◽

Yoshihiro Nishiyama ◽

Yuka Yamamoto ◽

Toshihide Monden ◽

Yasuhiro Sasakawa ◽

...

Keyword(s):

Fdg Pet ◽

Hodgkin’S Lymphoma ◽

Therapeutic Response ◽

Hodgkin's Lymphoma ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

Download Full-text

PROGNOSTIC SIGNIFICANCE OF PLATELET- NEUTROPHIL COMPLEXES IN NON-HODGKIN’S LYMPHOMA PATIENTS

ASJ. ◽

10.31618/asj.2707-9864.2021.1.54.127 ◽

2021 ◽

Vol 1 (54) ◽

pp. 14-17

Author(s):

Yu. Sheniz ◽

Sh. Bozhidara ◽

M. Ilina ◽

G. Liana

Keyword(s):

Hodgkin’S Lymphoma ◽

Therapeutic Response ◽

Prognostic Significance ◽

Complete Response ◽

Hodgkin's Lymphoma ◽

Aggressive Lymphoma ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Significant Difference ◽

Hodgkin's Lymphomas

Abstract. Non-Hodgkin's lymphomas (NHL) are a group of lymphoproliferative diseases with a heterogeneous spectrum of clinical, morphological, and immunophenotypic characteristics. Non-Hodgkin’s lymphoma is characterized by abnormal proliferation or accumulation of B or T lymphocytes. Circulating neutrophils and platelets have a proven role in both the pathogenesis of inflammatory processes and thrombosis and in the processes of tumorigenesis.The formation of complexes between neutrophils and circulating platelets (PNC) is a fundamental mechanism that is known but poorly studied in non-Hodgkin's lymphomas. Aim: To investigate the levels of circulating neutrophil-platelet complexes in newly diagnosed patients with aggressive and indolent NHL and the relationship of those levels with prognostic risk, prognosis, overall survival, and therapeutic response. Methods: PNC levels were analyzed by flow cytometry of peripheral blood from 88 patients with histologically verified NHL before chemotherapy. The results were statistically analyzed using dispersion, variable, comparison, correlation, and regression methods. Results: The mean age of the studied patients was 60.6 years ± 11.8 years (range 28–88 years), with men and patients with aggressive lymphoma accounting for just over half the population (52.3% each). A significant difference (p = 0.005) and an inversely weak dependence was found between IPI risk and survival (r = -0.277; p = 0.009) in aggressive lymphomas. A significant difference was found between the type of lymphoma and the therapeutic response (p = 0.030). A complete response was achieved in 42 (47.7%) patients with NHL, while progression was observed in 17 (19.3%) and relapse in 2 (2.3%) There was a strong significant correlation between PNC and IPI (р=0.021), PNC and therapeutic response (р=0.044). Conclusion: PNC measurement could be a useful diagnostic and prognostic marker in many diseases.

Download Full-text