Addition of GM-CSF to Imatinib Results in Major Cytogenetic Response in Patient with Chronic Myeloid Leukemia (CML).

Imatinib mesylate, an inhibitor of BCR/ABL tyrosine kinase, has remarkable activity in CML resulting in up to 87% major cytogenetic response, but further treatment is needed for the remaining 13% of patients and others who progress on therapy. Studies suggest that hematopoietic growth factors (HGF) induce the selective terminal differentiation of CML progenitors at concentrations that allow optimal growth of normal progenitors. Treatment with HGF may be able to stop the expansion of BCR/ABL positive cells while promoting the expansion of non-leukemic myeloid cells, thereby encouraging a cytogenetic response. Initially, these HGF were used to improve the safety of chemotherapies but had not been studied specifically to improve cytogenetic response. Our institution has an open phase II study of GM-CSF in patients with chronic phase CML who have not achieved a complete cytogenetic remission after at least 9 months of therapy. Our first patient on study was a woman originally diagnosed in 4/1996 with a variant Philadelphia chromosome [t(9;9;22)] positive CML. She was initially started on hydroxyurea and was then switched to interferon-α for approximately 5 ½ years. When imatinib became available her interferon was discontinued and she was treated with imatinib at 400 mg daily. Bone marrow biopsy 5/2003 was morphologically normal but on cytogenetic analysis all cells contained the same aberrant karyotype. Her imatinib therapy was complicated by pancytopenia requiring frequent transfusions. She had received approximately 22 units of packed red blood cells over 11 months. Her white count had been running in the 1,500 to 2,500/μL range and her platelet count had dropped to 64,000/μL. She presented to us 1/2004 at the age of 56 and was evaluated for a reduced-intensity allogeneic transplant but did not have any donors available in her family. She was not felt to be a candidate for an unrelated donor transplant because of co-morbid risks. Given her continued cytogenetic abnormalities and lack of transplant candidacy she was enrolled in our GM-CSF trial March 2004. At the time of entry onto study she had been on imatinib for 2 1/2 years with no cytogenetic improvement. She began treatment with daily GM-CSF 100 μg/m² in addition to her imatinib. Cytogenetic studies revealed a gradual increase in percentage of normal cells from start, 4 months, 9 months, and 15 months at 0%, 10%, 55%, and 85% respectively. She also had reversal of her pancytopenia and has not required transfusion of blood or platelets since enrollment. She developed an eosinophilia which we attribute to GM-CSF. Clinical studies have examined the use of GM-CSF in addition to interferon alpha. However, with imatinib becoming the new standard of care it is more relevant to examine the combined effect of imatinib and GM-CSF. The use of GM-CSF with imatinib in CML still needs more evaluation, but it appears to be a promising approach to improve cytogenetic response.