Outcome of Early T-Cell Precursor Acute Lymphoblastic Leukemia in AIEOP Patients Treated with the AIEOP-BFM ALL 2000 Study
Authors: Conter Valentino , Valsecchi Maria Grazia , Buldini Barbara , Parasole Rosanna , Locatelli Franco , Colombini Antonella , Arico' Maurizio , Rizzari Carmelo , Putti Maria Caterina , Barisone Elena , Lo Nigro Luca , Santoro Nicola , Ziino Ottavio , Pession Andrea , Testi Anna Maria , Micalizzi Concetta , Casale Fiorina , Silvestri Daniela , Cazzaniga Giovanni , Biondi Andrea , Basso Giuseppe 
Published: October 2019

Abstract
Aim: To evaluate the outcome of the Italian Association of Pediatric Hematology and Oncology (AIEOP) patients diagnosed with Early T-cell Precursor (ETP) Acute Lymphoblastic Leukemia (ALL) in the period September 2000-December 2011 and treated in the context of the AIEOP-BFM ALL 2000 Study and the subsequent - very similar – AIEOP ALL R2006 Study.
Patients and methods: ETP-ALL was defined by staining negative for CD1a and CD8, mildly positive or negative for CD5 and positive for at least one of CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65 antigens. Treatment consisted of BFM protocol I either with dexamethasone or prednisone in phase IA, 4 HDMTX courses (5 g/sqm over 24 hrs) in non-high risk patients or 3 poly-chemotherapy blocks in high risk patients, delayed intensification based on protocol(s) II or III, protracted intrathecal therapy or cranial radiotherapy, maintenance therapy for a total of 2 years of treatment. Hematopoietic stem cell transplantation (HSCT) was indicated for patients with poor treatment response assessed either morphologically at day +8 (Prednisone Poor Response, PPR) or day +33 (no Complete Remission, CR) or by PCR at day +78 (high-level Minimal Residual Disease, HR-MRD; ≥10-3).
Results: Of the 439 T-ALL eligible patients, 34 had ETP ALL. The incidence (7.7%) may be underestimated since the full set of the data needed was not available for all patients. Out of the 34 patients with ETP ALL 14 were at high risk due to PPR; of them, 3 were HR-MRD and 5 did not achieve CR after Phase IA of induction therapy (including one with HR-MRD). Of the remaining 20 patients (all prednisone good responders), 3 patients were at high risk due to resistance to Phase IA and HR-MRD (n=1) or HR-MRD only (n=2). 17/30 patients could not be monitored by MRD due to death in Induction (n=1), or absent (n=10) or inadequate PCR markers (n=6). Of the17 patients monitored by MRD, 13 had HR-MRD at day 33 and 6 of them also at day +78. One patient died during induction therapy. The remaining 33 achieved morphological CR: 27 after phase IA and 6 (those resistant to phase IA) after phase IB of protocol I. Of 12 patients who underwent HSCT, 3 died of HSCT-related complications and 3 relapsed. With a median follow-up of 6.6 years, the 5-year event-free survival (EFS) and Survival in the 34 ETP ALL patients were of 60.9%(SE 8.5) and 66.6%(8.3), versus 71.2%(2.3) and 77.1%(2.1) respectively in the non-ETP patients. The overall cumulative incidence of relapse was 27.3%(7.8) and 22.2%(2.1) in ETP and non-ETP T-ALL patients, respectively (p=0.52). EFS in ETP vs non-ETP patients was respectively 81.9%(9.5) vs 83.8%(2.4) in non high risk patients (p=0.87) and 41.2%(11.9) vs 53.2%(4.0) in high risk patients (p=0.24).
Conclusions: The outcome of T-ALL patients treated with BFM-type therapy is comparable in ETP and non-ETP for those with good response to initial chemotherapy; it was slightly, but not significantly, inferior in ETP-ALL patients with poor initial response. Phase IB treatment element is very effective in ETP-ALL, suggesting that intensification with antimetabolite and alkylating agents may be beneficial, while the benefit of HSCT in first CR needs to be further investigated.

Disclosures
No relevant conflicts of interest to declare.