Clinical Benefit and Tolerability of Crenolanib in Children with Relapsed Acute Myeloid Leukemia Harboring Treatment Resistant FLT3 ITD and Variant FLT3 TKD Mutations Treated on Compassionate Access

Background: FLT3-mutant pediatric AML represents a biological and clinically diverse disease and is associated with a poor outcome. Sorafenib has limited activity against tyrosine kinase domain mutations. Crenolanib is a pan-FLT3 inhibitor, which, at the time of this compassionate use program, had already been safely administered to over 55 children (age 2-18) with diffuse intrinsic pontine glioma as well as high grade gliomas. Crenolanib at a dose of 66mg/m2 TID has been well tolerated in pediatric patients.

Methods: We here report our experience with five consecutive children (ages 4-12y) who received crenolanib for FLT3 mutant AML on a compassionate basis between April 2017 to October 2019. All patients treated had IRB/local ethics approval prior to treatment and all patients’ guardians signed informed consent forms.

Results: Patient Characteristics: Of the five patients, three were refractory to induction therapy and required salvage therapy to get into remission. All five patients were then able to undergo HSCT, but all subsequently relapsed. Two patients were successfully salvaged and underwent a second HSCT. Only two pts received sorafenib. By the time of the compassionate use request, all children had exhausted all standard and experimental therapies (3-9 prior therapies, Table 1).

Two patients had FLT3-ITDs and three had FLT3 kinase domain mutations (A848P in one, D835H in another and both D835H and D835E in trans in third). Co-occurring events included KMT2A fusion/mutations in three pts as follows: i) one pt with KMT2A-rearranged infant AML, ii) one with treatment-related AML with KMT2A fusion and t(9;11) and iii) a third patient with KMT2A fusion along with p53 mutation. Another patient with biphenotypic AML had a co-occurring NOTCH1 mutation with 9;14 translocation. Three patients had complex karyotypes and a number of translocations were identified including t(9;11), t(3;5), t(1;16), and t(9;14) (Table 1).

In addition to bone-marrow disease and circulating blasts, all patients had extramedullary AML. Three patients had CNS leukemia. Three patients had non-CNS extramedullary AML (submandibular, testicular, liver and spleen).

Treatment: Crenolanib was given with curative intent to three patients, one in combination with Vyxeos (liposomal cytarabine/daunorubicin), one with high-dose cytarabine, and one as maintenance therapy after her second HSCT. Two patients received crenolanib as palliation for rapidly progressing AML.

Tolerability: All children tolerated crenolanib well. Reasons for crenolanib discontinuation were bridge to HSCT in two patients and completion of 12 months of maintenance in another. One patient stopped crenolanib early as he developed fungal pneumonia and one patient stopped due to lack of benefit. Only one patient required dose reduction due to grade 2 transaminitis. There were no cardiac toxicities, pericardial effusion, fluid retention or weight gain.

Response: Four of five patients reported clinical benefit with crenolanib. Interestingly, the child with KMT2A-rearranged infant AML achieved a molecular CR after salvage therapy with Vyxeos plus crenolanib. This child was successfully bridged to a second HSCT and remains in remission one year after the start of his compassionate use crenolanib. Another patient with KMT2A fusion, p53 mutation and CNS AML achieved a CR with crenolanib + sorafenib, was successfully bridged to 2^nd HSCT and received one year of post-transplant crenolanib maintenance. She remains in remission 3.5 years after initiation of crenolanib. The third patient with KMT2A fusion was successfully bridged to allo HSCT but relapsed 4 months after HSCT (she did not receive maintenance). The patient with bi-phenotypic AML (and D835H mutation) had a quick reduction in circulating blasts (within 24 h) but died of fungal sepsis. The fifth patient received reduced doses of crenolanib due to transaminitis and did not have a clinical benefit.

Conclusion: This series of five children with multiply relapsed FLT3-mutant AML shows that treatment with full doses of crenolanib can be safely combined with salvage chemotherapy. Rapid remissions could be obtained even in patients with co-occurring KMT2A, 3q, and p53 mutations. Crenolanib, which is novel type-I pan FLT3 inhibitor, was able to inhibit variant FLT3 mutations (D835H, D835E and D848P). Crenolanib can be safely combined with ITT (2 of these children remain alive 1-3.5 years).