GMALL B ALL/NHL 2002 Protocol Yields High Response Rates and Durable Responses in High-Grade B Cell Lymphoma: A Retrospective, Single-Center Study
Authors: Ferrari Silvia , Barbui Anna Maria , Giuseppe Gritti , Rossi Andrea , Grassi Anna , Ballardini Francesco , Rondi Monica , Pavoni Chiara , Fruscella Paolo , Gianatti Andrea , Rambaldi Alessandro 
Published: December 2024

Background
High-grade B-cell lymphomas (HGBCL) represent a group of aggressive lymphoid malignancies characterized by rapid progression and unfavorable clinical behavior. Despite advancements in treatment modalities, first-line treatment of HGBL represents a significant clinical challenge, without a consensus on the current standard of care. Current treatment approaches for HGBL include intensified chemotherapy programs such as CODOX-M-IVAC or R-DA EPOCH or the Berlin-Frankfurt-Munster (BFM) protocol. All these programs are commonly used also for Burkitt Lymphoma.
Patients and Methods
The German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia protocol GMALL B ALL/NHL 2002 is an intensive chemotherapy regimen derived from the Berlin-Frankfurt-Munster (BFM) protocol that was used for other aggressive lymphoid malignancies, including Burkitt Lymphoma, yielding high complete response rates and durable responses as previously reported by other studies. 1. 2 From February 2011 to December 2023 we adopted the (GMALL B-ALL/NHL2002), (Clinical trial.gov NCT03131531) for the treatment of 53 adult (&gt;18y) consecutive patients with HGBCL. The median age at diagnosis was 56 years (range: 21-75). Nineteen patients (35,8%) were classified as double-hit lymphoma (DHL) according to WHO 2022, harboring BCL2 and MYC rearrangement. Five patients were HIV positive (9,3%).
Results
The overall response rate (ORR) was 92,4% (n=49). By PET-CT scan, a complete metabolic response (CR) was documented in 42 patients (79,2%) at the end of treatment (EOT evaluation). Thirty patients (56.6%) achieved a complete metabolic response after the first 2 cycles (interim PET-CT). One patient showed progressive disease at interim PET-CT evaluation and 4 patients (7,5%) at the EOT imaging evaluation.
Overall, the 6-year PFS among HGBCL patients was 72%. According to histology, the 6-year PFS was 83% among HGBCL patients and 49% among DHL patients. The 6-year PFS for patients over 55 years old was 61% compared to 82% for those younger than 55 years. Patients achieving CR at the EOT evaluation showed a 6-year PFS of 82% compared to 57% for partial responders (p=0.036). Interim TC/PET evaluation had an impact on PFS, with patients in PR having shorter PFS when confronted with patients in CR (p=0.04).
The 6-year overall survival in the HGBCL cohort was 76%. According to histology, 6-year OS was 86% among HGBCL patients and 56% among DHL patients. Patients achieving CR at the EOT evaluation had a significantly longer median OS compared to PR patients, underscoring the importance of achieving deep responses in this setting (p=0.006). Overall, 11 patients died during the follow-up, in most cases as a consequence of progressive or relapsed disease (n=9).
During treatment, adverse events were closely monitored. Nearly 50% of patients (n=25) experienced adverse reactions to therapy. Febrile neutropenia was the most common hematologic toxicity, occurring in 22,6% of patients (n=12). Sepsis occurred in 7,5% of cases (n=4), requiring admission to the hospital Emergency Room. Mucositis was observed in 16,9% of patients (n=9). Hepatic toxicity was common after the first cycle, with 5,6% of patients (n=3) experiencing elevated liver enzymes, which resolved with treatment delay and supportive care. No patient died during the treatment due to protocol adverse events. One patient (1,8%) developed secondary myelodysplasia and died for this reason.
Conclusions
The GMALL B ALL/NHL 2002 protocol induced a high complete response rate with durable response and overall survival in HGBCL patients. Patients failing to achieve an EOT complete response have dismal prognosis and should be rapidly selected for CAR-T cell therapy or other experimental treatment options.