CD20-Negative Relapsed/Refractory Mature B-Cell Non-Hodgkin Lymphomas and Mature B-Cell Leukemia in Children, Adolescent and Young Adults: A Retrospective Review
Authors: Vinti Luciana , Pianese Jolanda , Carraro Elisa , Muggeo Paola , Onofrillo Daniela , d'Alba Irene , Schiavello Elisabetta , De Santis Raffaella , Micalizzi Concetta , Barat Veronica , Perruccio Katia , Lo Nigro Luca , Buldini Barbara , Mussolin Lara , Bertaina Valentina , de Vito Rita , Pillon Marta , Locatelli Franco 
Published: December 2024

Introduction:

The most common pediatric types of mature B-cell non-Hodgkin lymphomas (B-NHLs)are: Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), accounting approximately for 7% of pediatric cancers, and mature B-cell acute lymphoblastic leukemia (mB-ALL). An increased EFS and OS has been observed in patients with mature B-NHLs/ mB-ALL receiving rituximab in addition to chemotherapy, as published in the pediatric international phase III randomized trial with stage III-IV B-NHLs (Minard-Colin V, N Engl J Med. 2020). Despite the excellent cure rate at diagnosis, prognosis remains dismal in case of relapse/resistant (R/R) disease. Standard-of-care reinduction strategy is yet to be identified, the most common pediatric regimens including ifosfamide/carboplatin/etoposide (ICE) and cytarabine/etoposide (CYVE) + rituximab. Several novel agents with activity against B-NHL are in development, including monoclonal and bispecific CD20-CD3 antibodies.

Although the mechanism of resistance is unknown, the loss of CD20 expression in the R/R population could have a key role in the subsequent response. The aim of our retrospective study is the evaluation of CD20-expression by immunohistochemistry and/or flow cytometry in these neoplasms.

Methods:

We retrospectively collected data from children and young adults with R/R B-NHLs/mB-LLA and biopsy-proven CD20 status, treated in Italian Centers in the past 10 years (August 2014- August 2024). Patients, identified through individual sites querying local databases, were 20 years-old or less at diagnosis and 22 or less at relapse. Biopsy/cytological evaluation was performed at disease progression or whenever possible for confirmation of disease and CD20-expression evaluation.

Results:

Tumor cells from 25 pediatric patients/young adults with R/R LNHs and mB-ALL (12 Italian sites) were resampled at the time of the relapse diagnosis and CD20-protein expression was analyzed by flow cytometry and/or immunohistochemistry. Median age was 11,4 years (range, 4.1-19.3) at diagnosis (1 patient &gt;18 years-old) and 12,3 at relapse (range,5.8- 21.3) (2 patients&gt;18 years-old); 28% of patients were females. Twenty-one patients had relapsed or progressed following rituximab therapy, while 3 had not received the immunotherapy in combination during first-line treatment (1 not known). Burkitt Lymphoma was the most common diagnosis (10 patients), followed by DLBCL (6), mB-LLA (4), PMBCL (3); 1 patient had a B-mature lymphoma with mixed Burkitt/DLCBL features (1 patients not specified). Ten/25 patients (40%) showed the loss of CD20 expression by either immunohistochemisty and/or flow cytometry compared with diagnostic biopsies (all CD20 positive), biopsy being performed mostly at the first relapse (16 patients), followed by 2nd relapse (5), 5th relapse (2) and 6th relapse (1), 1 being unknown.Twenty-two patients received rituximab in first-line at the dose of 375 mg/m2; median number of infusions was 6 (range 0, 7). Relapse was diagnosed at less than 3 months for 17/24 patients, median time from last treatment being 3 months (range 0.2-66). Of the 10 CD20-negative patients, 7 died of progressive disease, 2 had a partial response (on treatment at the time of this writing :1 Burkitt lymphoma and 1 DLCBL) the remaining patient being alive and disease-free (after having experienced Hodgkin lymphoma as second cancer). In the 16 CD-20 positive patients, 6 patients died, 9 are alive (6 in complete remission, 2 partial response and 1 stable disease), 1 patient unknown. Seven patients were given hematopoietic stem cell transplantation (5 allogeneic, 2 autologous), 2 of which with a CD20 negative relapse. Three patients, all of them having been allotransplanted, are alive and disease free.

Conclusion:

Our retrospective data suggests that the loss of CD20 expression at relapse occurred in 40% of patients (few reports published in the literature in the adult population ranging from 14% to 60% (Kennedy Br, BJM2002; Hiraga J, Blood 2009)), CD20-loss is characterized by a more aggressive disease and worse outcome. Given the potential benefit of treatment with CD20 monoclonal or CD3-CD20 bispecific therapies, our observation suggest that the histological re-evaluation should be performed, whenever possible, to identify the ideal target-therapy.