Internal tandem duplications of the FLT3 gene (FLT3/ITD) portend poor outcome in both adult and pediatric AML and hematopoietic stem cell transplantation (HSCT) is often performed. Unfortunately, approximately 35% of patients will have disease recurrence despite HSCT and curative options are limited in that context. Sorafenib is an oral multi-target tyrosine kinase with demonstrable efficacy in this AML subtype. Moreover, retrospective studies in adults with FLT3/ITD+ AML suggest tolerability and potential clinical benefit of sorafenib when used in the post HSCT setting for treatment of early relapse or minimal residual disease (MRD) emergence. There is limited published data regarding sorafenib’s tolerability and efficacy following HSCT in pediatric FLT3/ITD+ AML. We report here a retrospective review of our experience.

We conducted a retrospective study of pediatric FLT3/ITD+ patients treated with allogeneic HSCT followed by sorafenib in the first 18 months following HSCT. Between March 2008 and March 2012, 13 FLT3/ITD+ pediatric patients at 7 HSCT centers met criteria for study inclusion. Median age at time of treatment was 14 years (range 6-21 years) and 6/14 (46%) were male. 9 patients underwent matched family donor HSCT and 4 had a matched unrelated donor. Sorafenib was initiated early after HSCT (median: 66 days, range 44-170 days) as prophylaxis in 5 patients who were considered to have very high risk features including failure to achieve clinical remission (CR) following first course of chemotherapy (N=2), high allelic ratio FLT3/ITD at diagnosis (N=1) and MRD at time of HSCT (N=2). For the remainder, sorafenib was given after sign of relapse (MRD or morphologic) at a median of 90 days (range 45-480 days) following HSCT. 11/13 patients received single agent therapy; 2 patients with morphologic relapse received additional chemotherapy (N=1) or radiotherapy (N=1).

Among the entire group, post HSCT sorafenib therapy was initiated a median of 80 days following HSCT (range 44-480 days) at a median dose of 150 mg/m2/day (range 75-340 mg/m2/day) and continued for a median of 12 months (range 0.5-52 months). 9/13 patients (69%) experienced toxicity which was felt to be medically significant including thrombocytopenia (N=2), rash (N=3), anorexia (N=1), myelosuppression (N=3), infection (N=2) and life threatening cardiac dysfunction (N=1 in patient treated concomitantly with mitoxantrone). In 8/13 cases (61%) the toxicity resulted in reduction or temporary discontinuation of sorafenib yet all patients tolerated retrial of drug at the same or reduced dosing. One additional patient experienced dose limiting marrow hypoplasia at dosing of 340 mg/m2/day. Sorafenib did not appear to exacerbate GVHD. 8/13 (62%) patients had controlled GHVD at time of sorafenib initiation and only 2 patients had subsequent skin flare that was temporally associated with wean of immune suppression and did not preclude use of further sorafenib.

Overall, 10/13 (77%) patients remain alive and 7/13 (54%) are disease free. Of 7 patients in continued CR, the median survival is 3.6 years from HSCT (range 1.75-5.6 years); 6/7 are off sorafenib therapy for a median of 10.5 months (range 7-36 months) after receiving treatment for a median of 19 months (range 8-52 months). 6/13 patients (46%) experienced progressive or recurrent disease while on therapy, 3 of whom have died: 2 from rapid disease progression despite sorafenib initiation and 1 from wild-type FLT3 recurrence. 3 additional patients with recurrent disease are receiving salvage therapy, 1 of whom has achieved a 2nd CR. Of particular interest is the outcome of patients who received sorafenib for MRD in the peri transplant period. All 5 remain alive and disease-free a median of 3.6 years from HSCT (range 1.75-5.6 years) and have been off sorafenib for a median of 12 months (range 7-36 months). Conversely, of the 5 patients who started treatment for morphologic recurrence, only 1/5 (20%) remain in CR. Of 3 additional patients who received prophylactic treatment for high AR or poor induction response, 2/3 have recurred, 1 of whom is now in 2ndCR with higher dose sorafenib in combination with conventional chemotherapy.

Our study suggests that sorafenib is tolerable and may improve survival for pediatric patients who undergo HSCT for FLT3/ITD+ AML. Prospective study is necessary to further confirm tolerability and to determine the scope of clinical benefit for this high risk population.


Off Label Use: Sorafenib use in AML will be discussed.

Author notes


Asterisk with author names denotes non-ASH members.