Relapse in Childhood “Very High Risk” Acute Lymphoblastic Leukemia Treated with BFM Chemotherapy Has a Dismal Outcome Even When Treated with Transplantation.

The definition “very-high risk” (VHR) in the setting of childhood acute lymphoblastic leukaemia (ALL) is usually adopted to identify children eligible for transplantation in first complete remission (CR1). The endpoint of this study is to assess whether, how many, and how VHR ALL children achieving CR1 and not transplanted in CR1 can be rescued in case of relapse. Eligiblity criteria to transplantation in AIEOP-BFM ALL 2000 study slightly changed overtime and differed between the BFM (Berlin Frankfurt Muenster) and AIEOP (Associazione Italiana di Ematologia ed Oncologia Pediatrica) Groups.. For this analysis VHR ALL was defined by one or more of the following criteria:

1. induction failure (IF),

2. high levels (≥ 1x10⁻³) of minimal residual disease at day 78 (VHR-MRD),

3. clonal abnormality t(4;11),

4. prednisone poor response associated (PPR+) with one or more of the followings: hyperleukocytosis, T-immunophenotype, ≥ 25% marrow blasts at day 15, pro-B immunophenotype.

Patients carrying clonal abnormality t(9;22) were not included here since allocated in a specific study protocol since 2004. Out of 571 VHR patients, distributed among the four criteria (17%, 45%, 3%, 35%, as hierarchically listed), 249 (43%) were transplanted in CR1 (80%, 48%, 47%, 25% in each category) and 322 (57%) were not. Of the 322 patients treated with chemotherapy [5-year-EFS 53.5% (SE 3.1), 5-year-survival 66.6% (SE 2.9)], 19 died in CR1, 6 presented with a second malignancy, and 113 (35%) relapsed at a median of 15 months after diagnosis, mostly in the bone marrow (81%: 66% isolated, 15% combined) or in an extramedullary site (19%, 15% in the central nervous system) at a median time of 9 ms after diagnosis. The 3-year-survival after relapse was only 26.0% (SE 5.1) for the 113 patients overall, 38.7% (SE 7.8) for the 55 who underwent transplantation in CR2 and 16.2% (SE 5.3) for the 58 who were not transplanted in CR2. Interestingly the 3-year-survival after relapse by VHR criteria was only 7.1% (SE 9.3) in the IF, 28.6% (SE 7.1) in the VHR-MRD and 33.1% (SE 6.7) in the PPR+ subgroups. In conclusion very few VHR-ALL children could be rescued after relapse, particularly among those carrying most unfavourable criteria at the onset (IF and VHR MRD), confirming that transplantation should be performed in CR1. Transplantation in CR2 was feasible in only half of the patients and presumably their outcome was influenced by MRD response after relapse; this aspect is under investigation. New strategies are needed for this dismal subset of patients.