Clinical Outcome of 640 Children with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Treated Between 1995 and 2005
Authors: AricÃ² Maurizio , Schrappe Martin , Hunger Stephen , Carroll William L. , Conter Valentino , Di Lorenzo Paola , Manabe Atsushi , Saha Vaskar , Baruchel Andre , Vettenranta Kim , Tsuchida Masahiro , Benoit Yves , Pieters Rob , Escherich Gabriele , Silverman Lewis B. , Pui Ching-Hon , Valsecchi Maria Grazia 
Published: April 2020

Abstract
Background. In a previous retrospective analysis of 326 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) treated by 10 study groups or large institutions between 1986 and 1996, we documented that bone marrow transplantation (BMT) from a HLA-matched related donor, but not from unrelated donor, was superior to chemotherapy alone in terms of disease-free survival and survival (N Engl J Med2000;342:998–1006). To evaluate the impact of recent improvements in chemotherapy and BMT, we performed a second survey of 762 children and young adults with Ph+ ALL treated by 14 study groups or large institutions between 1995 and 2005 to determine the optimal treatment. We limited the study to the 640 evaluable patients who had not received tyrosine kinase inhibitors so that the results can serve as baseline data for future comparison with those of patients treated with tyrosine kinase inhibitors.
Methods. Treatment outcome between the current and the previous cohort was compared with log-rank test. The DFS and survival of patients treated with BMT or chemotherapy were compared in a Cox regression analysis, accounting for the time to transplantation. Early response was evaluated by blast count in the peripheral blood on day 8 or in the bone marrow on day 8 or 15 of remission induction. Follow-up time of the current cohort ranged from 0.1 to 11.5 (median, 6) years.
Results. The 640 patients in current cohort ranged in age from 1.0 to 17.7 years (median 7.9). Their presenting features were comparable to those of the previous cohort. Complete remission (CR) was achieved in 89% of patients in the current and 82% in the previous cohort. The overall 7-year EFS and survival of the current cohort were superior to those of the previous cohort: 31.2% (SE 2.0) vs. 25.0% (3.0) [p=0.007], and 44.2% (2.2) vs. 36.0% (3.0) [p=0.017], respectively. In the current cohort, 7-year DFS for the 264 patients undergoing BMT in CR1 (adjusted by time to transplant) was 41.2% (3.2) and compared favourably with the 33.0% (3.4) in the 307 patients treated with chemotherapy alone; unsurprisingly, the advantage of BMT was more apparent later in time among patients who survived the early toxicities of treatment (hazard ratio at 3 years from CR: 0.60; CI 0.28–1.30; p=0.002). Importantly, unlike in the previous analyses, the outcome of the 138 patients who had BMT from an unrelated donor did not differ significantly from that of the 65 patients who had a matched sibling donor: DFS 52.0% (4.5) vs 40.9% (6.2) (p=0.16). However, 7-year survival rates did not differ significantly between patients treated with BMT or chemotherapy alone: 51.7% (3.3) vs 45.9% (3.2) [HR 0.9; CI 0.7–1.15; p=0.42], suggesting that patients treated with chemotherapy were more likely than transplanted ones to be salvaged after relapse. Based on presenting age and WBC count, patients could be divided into three prognostic subgroups: group 1 [WBC&lt;50×109/L and age &lt;10 years; 217 patients; 7-year DFS 43.7% (3.8)]; group 3 [WBC &gt;100×109/L; 143 patients; DFS 22.4% (4.3)]; group 2 [the remaining 206 patients; 34.4% (3.6)]. Early response data was available for 459 patients. CR was achieved in 311 (98%) of the 318 rapid responders but in only 106 (75%) of the 141 slow responder patients (p&lt;0.0001). The three prognostic subgroups were still associated with a significant difference in outcome among the rapid early responders (data not shown).
Conclusions. Clinical outcome of children with Ph+ALL has improved with recent treatment. BMT with matched sibling and even unrelated donor yielded a better DFS but not survival than chemotherapy alone. The results of this study will serve as baseline data to evaluate the impact of tyrosine kinase inhibitors on the outcome of this disease.