Evaluating Outcomes of Adult Patients with Acute Lymphoblastic Leukemia Treated on the GMALL Protocol
Authors: Fredman Danielle , Volchek Yulia , Heering Gabriel , Shichrur Keren , Yerushalmi Ronit , Shem-Tov Noga , Ribakovsky Elena , Shimoni Avichai , Avigdor Abraham , Nagler Arnon , Canaani Jonathan 
Published: November 2020

Background Chemotherapy based approaches still constitute an essential feature in the treatment paradigm of adult acute lymphoblastic leukemia (ALL). The German Multicenter Study Group (GMALL) is a well-established and commonly used protocol for ALL (Gökbuget 2012). Over the years evolving versions of the protocol have been developed with the aim of improving patient outcome (Apel 2014). In view of the recent advancements in the treatment of adult ALL we now analyzed our more recent data.
Aims Assess the clinical outcomes of adult ALL patients treated on the GMALL protocol in real world settings, and establish prognostic parameters associated with long term survival and risk of relapse.
Methods Retrospective analysis of all adult ALL patients who were treated with GMALL in our institution between the years 2008-2020. Demographic, clinical, cytogenetic, treatment, and transplant related data were collected using our institution's electronic medical records system. Baseline characteristics were evaluated by Fisher's exact test and Wilcoxon rank sum tests. Kaplan-Meier estimates were used to estimate overall survival (OS) and relapse-free survival (RFS). Hazard ratios and 95% confidence intervals were generated using a Cox proportional hazards model.
Results The analysis comprised 81 evaluable patients with a median age of 36 years (range 18-73), 36% were adolescents and young adults (AYA). Forty-three were B-ALL (53%), 12 (15%) patients were Philadelphia chromosome positive ALL (Ph+ ALL), and 26 (32%) were T-ALL. Median duration of follow-up was 24.4 months (range 0.7-112.1 months), at the time of data analysis 51 patients (63.8%) were alive. Seventy patients (88%) attained a first remission (CR1) and 4 (5%) died during the first two induction phases. The 2-year and 5-year overall survival rates were 62% and 44%, respectively. Estimated 2-year and 5-year leukemia-free survival rates were 52% and 35%, respectively. Overall, disease relapse (31%), lethal infection (28%), and graft-versus-host disease (14%) accounted for most patient deaths. Of patients achieving CR1, 20 (29%) eventually relapsed after a median time of 9.8 months (range 1.1-69.3). Fifty-five patients (68%) underwent an allogeneic stem cell transplantation using matched sibling (47%), matched unrelated (31%), haploidentical (7%), partially mismatched (12%), and cord blood donors (3%). Of the 50 patients transplanted in CR1, 15 relapsed (30%) after a median time of 10.9 months (range 3.8-32.8). Multivariate analysis revealed that in terms of overall survival, increasing patient age was associated with inferior outcome [Hazard ratio (HR)=1.026, confidence interval (CI) 95%, 1.002-1.05, p=0.035) as was outcome for patients whose baseline cytogenetic analysis detected a higher number of clones (HR=2.69, CI 95%, 1.57-4.62, p=0.0002). T-ALL patients experienced longer survival compared with B-ALL (87 months versus 56 months, p=0.019) while patients transplanted using cord blood donors had inferior survival, 12.8 months, compared with matched sibling donors, 71.3 months, and fully matched unrelated donors, 73.4 months (p=0.001, and p=0.003, respectively). Relapse-free survival was significantly better in patients with T-ALL compared with B-ALL (90 months vs. 50 months, p=0.039), and in patients without t(12;21)(p13;q22) (75 months vs. 11.7 months, p=0.034). Gender, AYA status, extramedullary disease at diagnosis, initial white blood cell count, treatment delays, presence of MLL rearrangement, specific measurable residual disease modality used, GMALL risk category, and cytogenetic hyperdiploidy did not significantly impact on survival or disease relapse. Treatments for relapse following GMALL included blinatumomab (6), inotuzumab (3), nelarabine (3), and CAR-T (2).
Conclusions
While results are improving for patients treated on GMALL, a substantial patient segment still experiences relapse. It is conceivable that in the near future new novel therapeutic modalities for adult ALL involving the use of monoclonal antibodies and CAR-T cell therapy will help reduce relapse rates and further improve the current outcomes of patients treated on the GMALL protocol.

Disclosures
Avigdor: Takeda, Gilead, Pfizer: Consultancy, Honoraria; Janssen, BMS: Research Funding. Canaani:Abbvie: Consultancy, Honoraria, Research Funding.