scholarly journals The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR1+ leukemia

2021 ◽  
Vol 5 (16) ◽  
pp. 3152-3162
Author(s):  
Eileen Y. Hu ◽  
Priscilla Do ◽  
Swagata Goswami ◽  
Jessica Nunes ◽  
Chi-ling Chiang ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Acute Lymphocytic Leukemia ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Malignant Cells ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Mantle Cell ◽  
Antibody Drug

Abstract Antibody-drug conjugates directed against tumor-specific targets have allowed targeted delivery of highly potent chemotherapy to malignant cells while sparing normal cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein with limited expression on normal adult tissues and is overexpressed on the surface of malignant cells in mantle cell lymphoma, acute lymphocytic leukemia with t(1;19)(q23;p13) translocation, and chronic lymphocytic leukemia. This differential expression makes ROR1 an attractive target for antibody-drug conjugate therapy, especially in malignancies such as mantle cell lymphoma and acute lymphocytic leukemia, in which systemic chemotherapy remains the gold standard. Several preclinical and phase 1 clinical studies have established the safety and effectiveness of anti-ROR1 monoclonal antibody–based therapies. Herein we describe a humanized, first-in-class anti-ROR1 antibody-drug conjugate, huXBR1-402-G5-PNU, which links a novel anti-ROR1 antibody (huXBR1-402) to a highly potent anthracycline derivative (PNU). We found that huXBR1-402-G5-PNU is cytotoxic to proliferating ROR1+ malignant cells in vitro and suppressed leukemia proliferation and extended survival in multiple models of mice engrafted with human ROR1+ leukemia. Lastly, we show that the B-cell lymphoma 2 (BCL2)-dependent cytotoxicity of huXBR1-402-G5-PNU can be leveraged by combined treatment strategies with the BCL2 inhibitor venetoclax. Together, our data present compelling preclinical evidence for the efficacy of huXBR1-402-G5-PNU in treating ROR1+ hematologic malignancies.

Zilovertamab Vedotin Targeting of ROR1 as Therapy for Lymphoid Cancers

NEJM Evidence ◽  
2021 ◽  
Author(s):  
Michael L. Wang ◽  
Jacqueline C. Barrientos ◽  
Richard R. Furman ◽  
Matthew Mei ◽  
Paul M. Barr ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Large B Cell ◽  
Antibody Drug ◽  
Drug Complex

In a phase 1 trial involving patients with refractory lymphoid cancer, an antibody-drug complex directed against ROR1 had no unexpected toxicities. About half of the patients with mantle cell lymphoma and diffuse large B-cell lymphoma had clinically meaningful responses.

Safety and Efficacy of Bendamustine with or without Rituximab in the Treatment of Heavily Pretreated Patients with Haematological Malignancies: A Multicenter Retrospective Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4945-4945 ◽  
Author(s):  
Luigi Rigacci ◽  
Benedetta Puccini ◽  
Alberto Bosi ◽  
Sergio Cortelazzo ◽  
Sergio Storti ◽  
...  
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Large B Cell Lymphoma ◽  
Mantle Cell ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Large B Cell

Abstract Bendamustine is an purine analog alkylating agent with marked efficacy in haematological malignancies either when given as monotherapy or in combination with rituximab. The efficacy and safety of this drug was investigated in heavily pretreated patients (pts) with hematological malignancies. A total of 44 patients (median age 63 years ranging from 22–87) from 6 Italian centers treated with bendamustine alone or in combination with rituximab were analyzed in this retrospective study. The diagnoses were multiple myeloma (n=2), chronic lymphocytic leukemia or small lymphocytic lymphoma (n=19), diffuse large B cell lymphoma (n=7), follicular lymphoma (n=8), mantle cell lymphoma (n=4), marginal zone lymphoma (n=2), Hodgkin’s disease (n=1) and peripheral T cell lymphoma (n=1). All pts received bendamustine 60–90 mg/m2 at day 1+2, alone or in combination with rituximab 375 mg/m2 (n=35) at day 1 of each cycle given every 21 or 28 days. The pts were heavily pretreated with a median of 3 previous treatments (range 1–8); 37 pts had previously received rituximab and 9 pts had undergone autologous transplantation. Prior to receiving bendamustine, 14 pts had relapsed disease, 7 had refractory disease and 23 were progressing during therapy. The median number of bendamustine cycles was 3 (range 1–8); 11 pts were still on treatment at the time of this analysis. Patients who completed therapy with at least 1 cycle of chemotherapy were evaluated for response and toxicity; pts in continuous therapy were evaluated for toxicity only. Of 33 pts evaluable for response 7 pts achieved a CR (21%) and 14 a PR (42%) resulting in an ORR of 64%. The remaining 12 pts were non-responders. No differences in the results were observed between groups with different bendamustine doses or scheduling. The best results were obtained in 10 evaluable pts with indolent lymphoma (4 CR, 6 PR) and in 9 pts with chronic lymphocytic leukemia (1 CR, 6 PR). Two evaluable pts with mantle cell lymphoma obtained a response (1 CR, 1 PR). By contrast, only 1 pt with diffuse large B cell lymphoma of 6 patients evaluable for response obtained a CR: the other 5 were non-responders. No pt with myeloma, Hodgkin’s disease or T cell lymphoma achieved a response. After a median follow-up of 4 months, 80% of pts were alive. During 150 treatment cycles, 2 pts experienced grade 4 thrombocytopenia and 1 experienced grade 4 neutropenia; non-hematological toxicity was mild. In conclusion, this retrospective analysis shows that treatment with bendamustine, alone or in combination with rituximab, is a safe and effective regimen in heavily pretreated pts. The best results were obtained in indolent lymphoma: the data in mantle cell lymphoma were also encouraging. No lack of efficacy can be inferred in pts with diffuse large B cell lymphoma, due to the refractory nature of their disease and the advanced age of this particular group (median age 76 years ranging from 67–87).

scholarly journals Rare Case of Cryptococcal Meningitis in Non-HIV Patient with Mantle Cell Lymphoma Associated with Acalabrutinib (Tyrosine Kinase Inhibitor)

2022 ◽  
pp. 1-3
Author(s):  
Trivedi Krunal ◽  
◽  
Patel Kinjal ◽  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Cns Infection ◽  
Hiv Positive ◽  
Atypical Symptoms ◽  
Cryptococcal Infection ◽  
Mantle Cell ◽  
Hiv Negative

Cryptococcus neoformans infections are more common among immunosuppressed individuals, causing the most widespread opportunistic CNS infection among HIV-positive patients [1]. Specifically, those with cellular immunosuppression, such as patients with HIV positive CD4 counts less than 100. When a patient presents with atypical symptoms, it can be difficult to diagnose due to its infrequent presentation in HIV negative patients. Due to the rarity of encounters in HIV-negative patients, when atypical symptoms are present, it poses a diagnostic challenge. Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin B-cell lymphoma that is known to be associated with cellular immunosuppression [2]. This demonstrates the need for early diagnosis and recognition of cryptococcal infections and as a physician should be vigilant to diagnose cryptococcal who is on Acalabrutinib with MCL [3]. CLL patients receiving ibrutinib should be evaluated for cryptococcal infection, which is potentially life threatening if overlooked [4]. Meningitis caused by Cryptococcus mainly presents with fever and altered mental status but in this case, our patient 78-year-old male with mantle cell lymphoma, undergoing a regimen of Rituximab-Bendamustine (BR) in combination with acalabrutinib (TKI), presented with hypotension to ED in June 2021. Cryptococcal infection in patient receiving ibrutinib were mostly reported in patients with Chronic lymphocytic leukemia, who have poor immune reconstitution. Here we are reporting case of cryptococcal meningoencephalitis in patient with MCL on acalabrutinib which is never reported before.

Lymphoma Associated Chromosomal Abnormalities Can Be Easily Detected by FISH on Tissue Imprints. an Underused Diagnostic Alternative.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4270-4270
Author(s):  
Ismael Buño ◽  
Paola Nava ◽  
Angela Alvarez-Doval ◽  
Ainhoa Simon ◽  
Gonzalez-Pardo Gema ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Room Temperature ◽  
Chromosomal Abnormalities ◽  
Cell Lymphoma ◽  
Clonal Evolution ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Fresh Tissue ◽  
Dual Color ◽  
Mantle Cell

Abstract Detection of specific chromosomal abnormalities is essential in the diagnosis of several lympholiferative disorders. However, conventional cytogenetic studies are not frequently carried out from biopsies as it is in bone marrow (BM) specimens. On the contrary, FISH is usually performed on paraffin embedded tissue, an alternative with potential technical nuances both in its application and its interpretation. In our experience, FISH on tissue imprints is the ideal alternative to overcome these problems. In the present study, 46 tissue imprints and 17 BM smears from 43 patients with lymphomas were selected to investigate the presence of t(14;18)(q32;q21), t(11;14)(q13;q32), t(8;14)(q24;q32) and t(3;var)(q27;var). Representativity of the samples was assured prior to FISH by rapid May-Grümwald staining (Diff-Quick, QCA, Spain). Twenty imprints from reactive palatine tonsils and adenoids were used as negative controls. FISH was performed with specific dual-color dual-fusion FISH (D-FISH) probes for the first 3 translocations and a dual-color break-apart FISH probe for t(3;var)(q27;var) following the instructions of the probes supplier (Vysis, Inc). All except one sample (a BM smear stored at room temperature over 9 years), rendered satisfactory FISH hybridizations. In any case, all 43 patients could be successfully studied by FISH (the case referred above in which FISH failed in a first attempt was successfully analyzed using a different sample). The results supported the suspected diagnosis of follicular lymphoma in 22 patients, mantle cell lymphoma in 12 patients, large B-cell lymphoma in 5 patients, marginal zone lymphoma in 2 patients and B chronic lymphocytic leukemia in 2 patients. In one case, the observation of t(11;14) by FISH allowed to reclassify the case from follicular to mantle cell lymphoma and also to demonstrate clonal evolution by studying sequential tissue imprints stored for more than 6 years. Negative results also aided in the assignment of patients to proper diagnostic categories. FISH performed on tissue imprints and BM smears constitutes an optimal strategy for retrospective and prospective investigation of chromosomal abnormalities in lymphomas. Tissue imprints and BM smears conventionally stored at room temperature even for long periods of time can be safely used and sent by ordinary mail without special considerations for this purpose. Based on our experience we recommend to perform and routinely store tissue imprints whenever fresh tissue is available.

Polatuzumab vedotin, an anti-CD79b antibody–drug conjugate for the treatment of relapsed/refractory diffuse large B-cell lymphoma

2020 ◽  
Author(s):  
Vincent Camus ◽  
Hervé Tilly
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Cell Transplant ◽  
Antibody Drug Conjugate ◽  
Microtubule Inhibitor ◽  
Drug Conjugate ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Antibody Drug

Refractory/relapsed diffuse large B-cell lymphoma remains a major unmet medical need with poor outcome, especially for patients considered ineligible for stem cell transplant. Polatuzumab vedotin (PV) is a first-in-class anti-CD79b antibody–drug conjugate that contains the microtubule inhibitor monomethyl auristatin E. The development of PV is currently very active. This drug was US FDA approved in 2019 in combination with bendamustine and rituximab for the treatment of refractory/relapsed diffuse large B-cell lymphoma in third line and more, after demonstrating relevant efficacy and acceptable safety in a pivotal randomized Phase II trial. This review summarizes the features of this new drug with the primary focus on the clinical work supporting efficacy, relevance and tolerability of PV.

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