Response to High Dose (HD) Imatinib Therapy in Relapsed c-kit+ Acute Myeloid Leukemia (AML).

BACKGROUND. c-kit is a receptor tyrosine kinase for the ligand stem cell factor and a member of the PDGF receptor family. c-kit positivity, as defined by the presence of CD117 by flow cytometry (FC) in > 20% blasts, is detected in up to 90% of patients with AML, and is a potential target for imatinib, a selective tyrosine kinase inhibitor of c-kit as well as of BCR-ABL, PDGFR, and ARG. Previous reports of treatment with single-agent imatinib at 400 mg/day showed no response in AML (Cortes et al, Cancer 2003), while up to 24% of patients treated with 600 mg/day responded (Kindler et al, Blood 2003, Abstract 3242). Little information is available on the response in AML to imatinib as a single agent at 800 mg/day.

CASE AND DISCUSSION. A 42-year old Caucasian male with relapsed c-kit expressing AML with del(9q), concurrent secondary high-grade (HG) glioma and few remaining therapeutic options presented to our service. He was initially diagnosed with primary oligodendrioglioma in January 2001 and underwent subtotal tumor resection, followed by whole brain radiation therapy, followed by 6 cycles of procarbazine, CCNU, and vincristine (PCV) chemotherapy, and entered complete remission (CR). In December 2002, he was diagnosed with AML M2 with del(9q) and was treated with cytosine arabinoside (Ara-C) and daunorubicin (7+3), followed by 3 cycles of consolidation with HD Ara-C, and entered CR. In March 2004, he had recurrent abnormal magnetic resonance imaging of the brain and HG malignant glioma was diagnosed by stereotactic biopsy. He was started on temozolamide but was unable to tolerate treatment due to pancytopenia, and a bone marrow (BM) at another institution disclosed relapsed AML with 75% blasts. Upon presentation to our institution, a BM examination showed > 90% blasts, 53% of which expressed CD117 positivity by FC. Imatinib therapy was initiated at a dose of 400 mg/day and escalated to 800 mg/day (HD) after lack of response. (Table 1.) The peripheral blood (PB) white blood cell count (WBC) peaked on Day 9 of treatment with imatinib and declined thereafter. On Day 21, blasts were undetectable in the PB and there was a proportional increase of PB neutrophils (PMN). By Day 25, the BM blasts decreased to 50% and only 12% blasts showed positivity for CD117. The patient experienced severe muscle/bone pains at the start of imatinib therapy, which resolved within five days. Response to HD imatinib was also accompanied by dramatic decline in serum LDH. The patient’s platelet (PLT) count improved to a peak of 70k on Day 14, declined thereafter, and the patient required PLT transfusion support by Day 31. The patient also received dexamethasone 4 mg q6h for his HG glioma, which remained stable during this time of observation.

CONCLUSION. Our case demonstrates that HD imatinib 800 mg/day has significant preferential activity against the CD117+ AML blasts, is active in a shorter time span than previously reported at lower doses, and should be studied further in combination with other agents in AML. The patient’s HG glioma may have been partially stabilized by imatinib as PDGFR overexpression has been reported in secondary glioblastomas.

Table 1.