Treatment of High-Risk (HR) Philadelphia Chromosome-Negative (Ph-) Adult Acute Lymphoblastic Leukemia (ALL) According to Baseline Risk Factors and Minimal Residual Disease (MRD). Results of the PETHEMA ALL-AR-03 Trial Including the Use of Propensity Score (PS) Method to Reduce Assignment Bias.
Authors: Ribera Josep-Maria , Oriol Albert , Morgades Mireia , Sanz Miguel-Angel , Montesinos Pau , Sarra Josep , Brunet Salut , Fernández-Abellan Pascual , Guardia Ramon , Esteve Jordi , Gonzalez-Campos Jose , Bermudez Arancha , Moreno Maria-Jose , Bernal Maria-Teresa , Tormo Mar , Del Potro Eloy , Cladera Antonia , Llorente Andreu , Garcia-Boyero Raimundo , Rabuñal Maria-Jose , Bergua Juan , Grande Carlos , Amigo Maria-Luz , Bueno Javier , Bethencourt Concepcion , Hernandez-Rivas Jesus-Maria , Feliu Evarist 
Published: October 2019

Abstract
Abstract 322

Introduction:
Current therapeutic protocols for adult ALL consider MRD together with the baseline risk factors (age, WBC count, immunophenotype, cytogenetics) and speed in response to therapy for treatment decisions. On the other hand, the systematic use of allogeneic SCT for all adult patients (pts) with Ph- HR-ALL is still a matter of debate. The aim of the prospective study ALL-AR-03 from the Spanish PETHEMA Group was to evaluate the response to a differentiated therapy (chemotherapy or allogeneic SCT) according to early bone marrow blast clearance (<10% blasts in bone marrow assessed on day 14) and MRD levels (assessed by cytofluorometry at the end of induction –week 5- and consolidation therapy –week 17-) in HR Ph- adult ALL patients.

Patients and methods:
HR ALL included one or more of the following baseline parameters: age 30–60 yr, WBC count >25×109/L and 11q23 or MLL rearrangements. Induction therapy included vincristine, prednisone and daunorubicin for 4 weeks. In pts with slow cytologic response to therapy intensified induction with high dose ARA-C and mitoxantrone was administered. Early consolidation therapy included 3 cycles with rotating cytotoxic drugs including high-dose methotrexate, high-dose ARA-C and high-dose asparaginase. Pts. with slow cytologic response on d14 or MRD level >0.05% after consolidation were assigned to allogeneic SCT (related or unrelated) and those with standard cytologic response on d14 and MRD level <0.05% after consolidation received 3 additional cycles of delayed consolidation (identical to those of early consolidation) followed by maintenance therapy up to 2yr in CR.

Results:
On June 2009, 235 HR ALL pts were evaluable [mean (SD) age 37(14) yr, 129 males, 155 precursor B-ALL, 80 T-ALL, WBC count 64(96) ×109/L]. Induction death: 20(8%), resistance: 11 (5%), CR: 202 (87%). Slow cytologic response on d14 was observed in 137/186 (74%) pts, MRD<0.1% at the end of induction was observed in 70% of CR patients and MRD<0.05% was shown in 82% of pts at the end of consolidation. By intention-to treat allogeneic SCT was assigned to 51 pts and delayed consolidation and maintenance to 107 pts. 4-yr DFS and OS probabilities were 40±15% and 49±15%, respectively, for pts assigned to SCT and 49±13% and 64±12%, respectively, for those assigned to chemotherapy. For OS the Cox model including PS showed that patients assigned to allogeneic SCT had a risk of death of 1.27 (95%CI 0.68–2.37) compared to that of the pts assigned to chemotherapy. Patients with MRD<0.1% at the end of induction and <0.05% at the end of consolidation showed a 4-yr DFS and OS of 54±16% and 77±12%, respectively vs. 31±29% and 38±32%, respectively for those with MRD≥0.1% after induction and ≥0.05% after consolidation (p=0.04 and 0.006, respectively). By multivariate analysis, including the type of treatment as covariate, age and slow cytologic response were the prognostic factors for CR, MRD level was associated with DFS, and MRD level and WBC count were the main parameters with influence on OS.

Conclusions:
These results suggest that in HR Ph- adult ALL pts with adequate response to induction and adequate clearance of MDR after consolidation the results of therapy are not hampered by avoiding allogeneic SCT. MRD is the main prognostic factor for CR, DFS and OS. Supported by grants P-EF/07 from FIJC and RD 06/0020/10556 from RETICS, and PI051490 from FIS, Instituto Carlos III.

Disclosures:
No relevant conflicts of interest to declare.