Fludarabine, Idarubicin and High Dose Cytarabine (FLAG-IDA) Followed by Allogeneic Transplantation: A Successful Strategy for Remission Re-Induction in High Risk Pediatric Patients with Relapsed, Refractory and Secondary Acute Leukemias.
Authors: Gabriel Melissa A. , O’Brien Tracey A. , Tapp Heather , Chamberlain Barbara , Marshall Glenn M. , Cohn Richard J. , Oswald Cecelia , Russell Susan J. 
Published: October 2019

Despite significant advances in the treatment of childhood acute lymphoblastic (ALL) and acute myeloid (AML) leukemias, the prognosis of those with primary refractory, secondary and early relapsed disease remains extremely poor with survival reported in most studies at less than 20%. Salvage rates are particularly poor in children with ALL who relapse on therapy and in children with AML who relapse post autologous bone marrow transplant. Encouraging results using the re-induction combination regimen of Fludarabine, high dose Cytarabine and Idarubicin (FLAG-IDA) have been reported, however the majority of data is in adult patients. Here we report the largest series of pediatric patients with high risk acute leukemias receiving this regimen in combination with allogeneic hematopoietic cell transplantation as salvage therapy.

Between 1999–2005 a toal of 32 patients at 2 Australian Pediatric Cancer Centers were given Fludarabine (30mg/m2 IV over 1 hour for 5 days); Idarubicin (8mg/m2 IV over 1 hour for 3 days); Cytarabine (2000mg/m2 IV over 4 hours for 5 days) and GCSF (5mcg/kg/day). There were 21 males and 11 females, with a median age of 10.4 years (range 1.7 to 15.5 years). All patients had high risk leukemias; relapsed ALL (n=13), primary refractory ALL (n=3), relapsed AML (n=13), primary refractory AML (n=1) and secondary AML (n=2). For the overall cohort median duration of first complete remission (CR1) was 16 months (range 2–34 months). Relapsed ALL patients were all considered extremely high risk with a CR1 duration of <36 months.Overall, 23 of 32 patients (71.9%) achieved a complete remission (defined as <5% blasts with evidence of marrow regeneration) following a single course of FLAG-IDA. For those with relapsed ALL, 10 of 13 patients (76.9%) achieved a remission. 2 out of the 3 patients with primary refractory ALL achieved a remission (both Philadelphia chromosome positive), 1 following a second course of FLAG-IDA. In the relapsed AML group, 9/13 (69.2%) achieved a remission, including 7 out of 10 patients who had relapsed post autologous BMT. 1 of the 2 patients with secondary AML achieved a remission. All of the 9 patients who did not achieve a remission died of progressive disease. The median time to neutrophil recovery following therapy was 26.5days (range 16–73). One patient remained aplastic and an attempt was made to transplant during this phase.

22 of the 23 patients (10 AML and 12 ALL) who achieved remission proceeded to an allogeneic bone marrow transplant, following a further 2–3 courses of FLAG (without IDA) for consolidation. 70% of patients received an unrelated donor transplant. Stem cell source was MUD BM (n=9), unrelated UCB (n=6) and HLA-ID sibling donor (n=7). Overall 17 of the 22 (77.3%) remain alive and leukaemia free (9 AML and 8 ALL patients) with a median duration of 36.5 months (9–84 months). Cause of death in the transplanted patients was progressive disease (n=4) and Pneumocystis Carinii pneumonitis (n=1). In summary, for this group of high risk, early relapsed and heavily pretreated pediatiric patients, re-induction chemotherapy with FLAG-IDA followed by allogeneic transplantation has provided an excellent strategy in the achievement of long term cure.