RESULTS
Ten centers of nine countries participated in the study. Among these, 126 children and adolescents with LLy were identified and included for analysis; 77 (61.1%) were males and 49 (38.9%) females. Sixty children (47.6%) presented T-LLy and 49 (38.9%) B-precursor LLy by immunohistochemical analysis and/or flow cytometry and in 17 (13.5%) the phenotype unknown/in conclusive (Table 1). Median age at diagnosis was 9.6 years (range, 0.8 - 17.7); patients with T-LLy were slightly older (median, 10.4 years; range, 1.7 to 17.8 y) than those with B-LLy (median 7.7 years; range, 0.84 – 17.4 y). Patients with B-precursor phenotype tended to present with lower stage disease with 18 (36.7%) patients having stage I/II in contrast to 3 (5%) for T-cell phenotype. Fifty-five patients (91.6%) with T-cell phenotype had stage III-IV disease, in contrast 29 (59.1%) with B-precursor phenotypes (p<0.05). Median lactate dehydrogenase (LDH) values were also significantly higher in patients with T-cell phenotype (726 IU/L versus 548 IU/L, p<0.05). Detailed patient data is described in Table 1.
The diagnosis of LLy was done by tissue biopsy in 110 cases (87%), cytology of body fluid plus immunophenotyping by flow cytometry in 17 (13%) and bone marrow aspirate in 19 (15%). The time between the diagnostic biopsy and the pathological diagnosis was less than 14 days in 96 patients (76%), between 15 and 30 days in 21(17%) and greater than 30 days in 9 patients (7%). In 23 patients (18%) the diagnosis of LLy was done after a second review of the pathology at a referral institution; in 5 cases (4%) the diagnosis of LLy was established after correction of a previous non LLy diagnosis.
At diagnosis, 24 patients (19%) presented with oncologic emergencies: 20 of them (15.9%) with upper vena cava syndrome and 4 (3.2%) with tumor lysis requiring dialysis and 18 (14.9%) with other severe complications. Seventeen (13.5%) required admission to an intensive care unit during the diagnostic interval due to these conditions. Overall, 23 children (18.4%) received treatment before the diagnosis was confirmed, including steroids (n=22) and less frequently cyclophosphamide (n=5) or radiotherapy (n=1). In 17 patients (28.8%) of the cases of T-LLy, the local team initiated treatment without biopsy confirmation whereas this occurred in 4 (8.1%) of cases with pre-B LLy.
Sixty-three (50%) patients received BFM-based protocol treatments, 59 (46.8%) received other regimens, and in 4 (3%) no therapy data was available. Radiotherapy was used in 18 children (14.2%); in 9 of the cases to the cranium, 2 craniospinal and 7 to other sites (paravertebral, mediastinal, bones, testicle). Eighty-seven (70.1%) children completed the prescribed therapy.
Events included relapse in 22 cases (17.4%), abandonment in 11 (8.7%), death in complete remission in 4 (3.1%), induction death in 4 (3.1%), induction failure in 1 (0.8%), and one patient presented a second malignancy (histiocytic sarcoma) (0.8%). Events according to phenotype are listed in Table 2. Treatment abandonment varied among the participating countries. Sites of relapse included 7 (31.8%) isolated central nervous system (CNS), 3 (13.6%) isolated bone marrow (BM), 5 (22.7%) extranodal (testicle, lymph node, orbit and other), 3 (13.6%) mediastinal, 1 (4.5%) in BM and mediastinum and 2 in other sites. Thirty-one patients (24.6%) had died at the time of case ascertainment for this study. Causes of death included refractory-relapsed disease 16 (51.6%), infection 9 (29%), toxicity 4 (12.9%) , unknown 1/other 1.
The event free survival (EFS) and overall survival (OS) at 5 years was 73% (SE 0.047) and 77% (SE 0.0435), respectively for the complete cohort. When abandonment of treatment was considered as an event, the ASOS and ASEFS were 70% (SE 0.0459) and 65% (SE 0.0477), respectively. No statistically significant difference was observed between B- and T-cell phenotypes or between patients treated with BFM-based protocols versus other regimens . The median follow-up time for patients with available follow-up data (n=124) is 5.58 years (Range: 0 to 14.58 years).