Results of a Multicenter Phase II Trial for Older Patients with c-Kit Positive Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS) Using Low-Dose Ara-C (LDAC) and Imatinib.
Authors: Heidel F. , Cortes J. , Ruecker F. , Kaufmann M. , Aulitzky W. , Letvak L. , Kindler T. , Huber C. , Dohner H. , Kantarjian H. , Fischer T. 
Published: October 2019

Abstract
In international multicenter trials, the 5-year overall survival (OS) rate of AML patients older than age 55 ranges from 5–16%. A similar outcome is seen for relapsed/refractory AML patients. As only a minority of these patients appear to benefit from myelosuppressive chemotherapy, new approaches are clearly warranted.
Over 70% of AML-patients show expression of the tyrosine kinase (TK) c-Kit on myeloid blasts. c-Kit is involved in activation of proliferation pathways and plays an anti-apoptotic role in normal and malignant hematopoiesis. Imatinib mesylate (IM) inhibits protein TKs including c-Kit, PDGFRs and Abl. Two former studies have investigated IM as a single agent in patients with c-Kit positive AML and HR-MDS suggesting biological activity of IM in a subset of AML patients (Cortes, Cancer 2003; Kindler, Blood 2002). LDAC has been used for MDS and AML to induce differentiation in AML blasts with partial response rates of approximately 30% but without improvement in OS.
As synergy between IM and Ara-C has been reported in vitro we conducted a phase II study applying a combination of these two agents.
40 patients at 4 centers with a median age of 72 years (range: 42–82 years with 95% of patients >60 y) were enrolled into this study. They either were not eligible for myelosuppressive therapy or had relapsed/refractory disease. Previous therapy included supportive care only, biological agents or < 3 cycles chemotherapy.
In median, c-kit positivity of AML blasts from patients included was 67%. 34 patients (85%) were included with AML and 6 patients (15%) with HR-MDS (including CMML). 38 patients were evaluable for this analysis. The overall rate of biological activity was 45% (17 of 38 patients): In 6/38 (16%) patients, a blast response (reduction >50% in PB) was observed while 8/38 patients showed stable disease over a minimum period of 2 months. The objective response rate was low with each 1 patient (3%) showing hematologic improvement, PR and CR, respectively.
While more than one third of patients included had a short term course of LDAC/IM only (<4 weeks) due to disease associated morbidity or patient’s wish, 3 patients experienced long term progression-free survival of more than 250 days (up to 450 days). Analysis of non-hematologic toxicity revealed 2 patients with a grade III skin rash. Grade I-II toxicity, mainly nausea and loss of appetite occurred in one third of treated individuals.
Patients over age 60 show a historical survival benefit of 2.5 months using myelosuppressive chemotherapy versus best supportive care and an early mortality rate of 25% within 6 weeks. Moreover, it has been pointed out that most of the ’benefit-time’ (>80%) is spent in hospital. Study medication offered in this trial was applied in an ambulatory setting with minimal hospitalization, an early mortality rate of 21% and a low toxicity rate.
In conclusion, combination therapy of LDAC/IM does not appear to be inferior in comparison to myelosuppressive therapy in older AML patients. However, this trial shows that LDAC/IM does not improve substantially the clinical outcome of older patients with AML. Identification of molecular mechanisms for good and long-term responders will be part of further laboratory investigations.