Immunochemotherapy with Rituximab Improves Molecular CR Rate and Outcome In CD20+ B-Lineage Standard and High Risk Patients; Results of 263 CD20+ Patients Studied Prospectively In GMALL Study 07/2003
Authors: Hoelzer Dieter , Huettmann Andreas , Kaul Felix , Irmer Sebastian , Jaekel Nadja , Mohren Martin , Lipp Thomas , Wedelin Knut , de Valle Francisco , Schmid Mathias , Thiel Eckhard , Brueggemann Monika , Kneba Michael , Goekbuget Nicola 
Published: October 2019

Abstract
Abstract 170
The effect of Rituximab in conjunction with a chemo induction and consolidation therapy was studied in CD20+, Ph/BCR-ABL negative B-precursor ALL (Pre-B/Common) in the GMALL Study 07/2003. The rationale were encouraging results with combined intensive chemotherapy and Rituximab in CD20+ adult Burkitt lymphoma / leukemia. Furthermore that in previous GMALL studies, improvement of B-precursor ALL by intensification of chemotherapy was limited and the observation that patients with CD20+ cells (antigen expression >20%) had an inferior outcome in adult ALL (Thomas et al. Blood 2009. 113;6330).

Aim:
In standard risk (SR) patients the aim was to increase the rate of molecular remission (Mol. CR) thereby decreasing the relapse rate and in high risk (HR) patients to reduce the pre-transplant tumour-load and thereby reducing the relapse rate after SCT which was 30–40% in previous GMALL studies.

Materials and Methods:
Adult ALL patients (15 – 55 years) with standard risk B-precursor ALL being CD20 pos. received Rituximab 375 mg/m2 at day -1 before each induction course (phase I and II), the re-induction course and before each of the six consolidations for a total of 8 doses. High Risk patients, defined as WBC > 30.000 and/or late CR > 4 weeks, which are candidates for a stem cell transplantation in CR 1 after wk 16, received Rituximab three times (d -1 ind. I/II and Cons. I) before SCT.
Patients receiving Rituximab were compared with earlier CD20+ patients in the GMALL study 07/2003 with identical chemo- and supportive therapy but no Rituximab. MRD method and chemo backbone was described earlier [Brüggemann, Blood 2006: 107;1116].

Results:
A total of 263 CD20 pos. patients were analyzed in the GMALL study 07/2003; 196 were SR and 67 HR patients. 181 received Rituximab (R+ arm) and were compared to a cohort of 82 patients earlier recruited without Rituximab (R- arm).
In the SR there was no difference in the results of induction therapy with a CR rate of 94 % and 91 % in the R+ vs. R- patients. There was also no difference in ED rate 5% vs. 3% or failure/PR 1% vs. 5%. However, MRD course differed substantially. Decrease in MRD load in the R+ vs. R- arm was faster with a Mol CR (MRD <10-4) rate of 57% vs. 27% at day 24 and of 90% vs. 59% at wk 16. Probability for continuous complete remission (CCR) at 5 years was 80% vs. 47% for R+ vs. R- pts. and for overall survival 71% vs. 57%. In the cohort of 67 HR patients the CR rate for R+ vs. R- was 81% vs. 88% due to a higher rate of failure/PR 12% vs. 8%. The ED rates in the R+ vs. R- arm were 7% vs. 4%. There was a higher Mol CR rate at wk 16 in the R+ arm vs. R- with 64% vs. 40%. Overall survival for HR patients at 5 yrs was 55% vs. 36% in the R+ vs. R- group. When only the HR cohort with SCT in CR1 is considered (in 69 % +R and 90% -R SCT in CR1 were performed) the CCR probability was superior for the R+ vs. R- with 67% vs. 37%, due to a lower relapse rate.

Conclusion:
Intensive chemo- plus immunotherapy with Rituximab is feasible in adult patients with B-precursor ALL in the context of the GMALL protocol 07/2003. In standard risk patients, the complete remission rate was comparable. There was however a faster and higher Mol. CR rate in the Rituximab cohort, with an improvement in remission duration and overall survival. In high risk patients the Mol. CR rate was also higher in the R+ arm and the relapse rate after SCT lower, but probably more Rituximab doses are needed in this patient cohort to reduce the tumour load before SCT further.
Supported by Deutsche Krebshilfe 70–2657-Ho2 and in part by Hoffmann La Roche.

Disclosures:
Off Label Use: Rituximab: activity against CD20 pos. ALL cells.