Sorafenib Combined with Non-Conventional Chemotherapy Produces Deep Remissions in FMS-like Tyrosine Kinase-3 Gene / Internal Tandem Duplication Positive (FLT-3 / ITD+) Acute Myeloid Leukemia (AML) Patients
Authors: Banavali Shripad , Thacker Nirav , Arora Brijesh , Narula Gaurav , Prasad Maya , Pradhan Nirmalya , Panda Saroj , Patkar Nikhil , Tembhare Prashant , Subramanian Papagudi Ganesan 
Published: November 2019

Abstract
Introduction: FLT-3/ITDs are present in nearly 25% of AML patients, and when treated with conventional chemotherapy have been associated with poor prognosis because of lower induction remission rates; lower 5 year Event Free Survival (EFS of ~30%); and a high risk of relapse even after allogeneic- Stem Cell Transplantation (SCT). These patients do not benefit with intensive chemotherapy alone and should prospectively receive alternate therapeutic approaches.
Monotherapy with the multikinase inhibitor sorafenib shows excellent initial responses in FLT-3/ITD+ AML, however, the responses are short-lived, and therefore sorafenib has been combined with chemotherapeutic regimens without significant adverse events. Assessment of Minimal Residual Disease (MRD) negativity by flow after induction and consolidation therapy has shown to provide ondependent prognostic information in patients with FLT-3/ITD+ AML (3 year RFS of 9% v/s 44%).
Methods: We retrospectively analyzed initial outcomes of 10 FLT-3/ITD+ AML patients who received various chemotherapeutic regimens +/- sorafenib during the period from May 2013 to May 2015. Patients were treated with either standard chemotherapy with daunorubicin 60mg/m2/ cytarabine 100 mg/m2 (3+7); high dose ara-C 12 G/m2 (HDAC) or oral metronomic therapy (etoposide 50 mg/m2 + 6-thioguanine 40 mg/m2 +/- prednisolone 40 mg/m2) or cladribine (2CDA) (9 mg/m2) + ara-C (500 mg/m2) d1 to d5. Sorafenib was given orally in the dose of 150 to 200 mg/m2 twice a day, every day.
Results: There were 10 children with newly diagnosed FLT-3/ITD+ AML; 6 males, 4 females. The median age at presentation was 11 years (range 6 to 15) with median WBC count of 118 x 106/L (range 40-308). Of these 10 patients, 8 had allelic ratio of > 0.4. All except 1 patient [t(8;21)+] had normal cytogenetics.
MRD negativity (by flow) was achieved in 5/5 patients post 2CDA/ ara-C + sorafenib; 3/5 patients post oral metronomic chemotherapy (MCT) +/- sorafenib; 1/1 patient post 3+7 + sorafenib. Interestingly only1/6 patients receiving HDAC+ sorafenib achieved MRD negativity. 9/10 (90%) patients achieved deep remission post treatment with chemo + sorafenib and the remaining 1 patient is yet to receive 2CDA/ara-C + sorafenib chemotherapy. None of the patients could be transplanted for socio-economic reasons. So far there have been no relapses. There were 2 remission deaths, 1 due to sepsis post 2CDA+ ara-C and 1 at home (village) due to unknown cause. At a median follow-up of 8 months (range 4 to 19 months), 8/10 patients are alive, 7 in MRD negative remission.
Sorafenib was overall well tolerated with 2 patients having Grade III skin rash and 1 having Grade II rash; all receiving 200 mg/m2 twice a day dose.
Conclusions: Modifying therapy in FLT-3/ITD+ AML may improve the depth of remission and reduce risk of relapse thereby improving survival. Sorafenib in combination with chemotherapeutic agents has shown good activity in FLT-3/ITD+ AML without significant adverse effects. Our preliminary data suggests that patients with FLT-3/ITD+ may best be treated with 2CDA/ara-C + sorafenib as induction regimen followed by oral MCT + sorafenib maintenance after completion of consolidation regimen.

Disclosures
Off Label Use: Sorafenib is being used in the treatment of FLT3/ITD positive AML, though it is not FDA approved for the same at present. .