Pediatric ALL-like Therapy in Adults with T-Cell Lymphoblastic Lymphoma: Results of the Graall-Lysa LL03 Study

Background: It has been suggested that using an acute lymphoblastic leukemia (ALL) rather than non-Hodgkin lymphoma protocol to treat patients with lymphoblastic lymphoma (LL) might be associated with better results (Hoelzer, Best Pract Res Clin Haematol 2002). To address this issue, the GRAALL and LYSA groups have conducted the Phase 2 LL03 trial in adult patients with LL, using the GRAALL-2003 protocol, which yielded good results in adult patients with ALL (Huguet, JCO 2009).

Patients and Methods: Between 2004 and 2012, 155 patients aged 18-59 years were enrolled, including 131 evaluable patients with T-cell LL (T-LL). The pediatric-inspired ALL treatment included a corticosteroid prephase, a 5-drug induction with sequential cyclophosphamide, high dose consolidation, late intensification, CNS prophylaxis with IT injections and cranial irradiation, and a 2-year maintenance. Response, including complete remission (CR) and unconfirmed CR (CRu), were assessed using Cheson criteria (Cheson, JCO 1999). Allogeneic stem cell transplantation (SCT) was offered to CR/CRu patients with high-risk disease (defined as need for a second-induction salvage course and/or CNS disease) and a donor.

Results: Of 131 T-LL patients (median age, 33 years; M/F ratio 4.0; mediastinal enlargement, 95%; CNS involvement, 5%), 119 patients (91%) reached CR/CRu (30 patients needing a salvage course) and 34 relapsed. Response evaluation was based on CT scan, as PET scan was performed in only 73/131 and 20/30 patients after first induction and salvage, respectively. At 5 years, estimated DFS, EFS and overall survival were 71%, 61% and 66%, respectively. The lymphoma IPI-score had no prognostic value, but increased serum LDH level (observed in 71% of the patients) was associated with a significant decrease in EFS (HR = 2.8 [1.3 – 6.1]) and OS (HR = 3.5 [1.4 – 9.1]) in multivariable analysis. Of note, need for a salvage course was not associated with shorter DFS in CR/CRu patients.

In a subset of 49 patients studied for oncogenetic markers, the 4-gene risk classifier (based on NOTCH1, FBXW7, N/K-RAS and PTEN status) we have recently reported to be a powerful predictor in T-ALL patients (Trinquand, JCO 2013) also demonstrated strong prognostic value in T-LL. Among these patients, 29 (60%) had a high-risk genetic profile (defined as no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN deletion). At 3 years, the high-risk genetic profile was predictive of shorter EFS (HR = 14.3 [1.9 – 107.8]), DFS (HR = 9.5 [1.2 – 74.3]) and OS (HR = 11.5 [1.5 – 87.5]) in univariable analysis, as well as in multivariable analysis after adjustment on age, ECOG-PS and LDH level (HR = 20.5 [2.6 – 164.1], 12.6 [1.5 – 104.8] and 17.0 [2.1 – 136.8], respectively.

A total of 30 CR/CRu patients were eligible for allogeneic SCT (25 for late CR/CRu, 4 for CNS involvement, and 1 for both criteria) and 17 of them were actually transplanted in first CR/CRu. When analysed as a time-dependent event, allogeneic SCT was not associated with prolonged DFS in these high-risk patients.

Finally, Grade III/IV adverse events were those commonly observed with the GRAALL regimen. Overall, 46 patients died during the study (37 after relapse or progression; 5 during induction; 3 from allograft toxicity and 1 after a highway accident).

Conclusion: As compared to historical studies, we report here a relatively good outcome in T-LL patients treated with a pediatric-inspired ALL strategy. Very interestingly, the NOTCH1/FBXW7/RAS/PTEN T-ALL risk classification was also a strong prognostic factor in these T-LL patients. Allogeneic SCT did not appear to significantly influence the outcome of selected T-LL patients.