CD20-Negative Relapsed/Refractory Mature B-Cell Non-Hodgkin Lymphomas and Mature B-Cell Leukemia in Children, Adolescent and Young Adults: A Retrospective Review

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 >18 years-old) and 12,3 at relapse (range,5.8- 21.3) (2 patients>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 2^nd relapse (5), 5^th relapse (2) and 6^th 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.