Targeted Therapy for AML in The Elderly: Good Idea, Not So Good Results
Targeted Therapy for AML in The Elderly: Good Idea, Not So Good Results
Abstract & Commentary
By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: Treatment of AML in the elderly remains problematic, and the demonstration of an activated tyrosine kinase pathway presents an appealing target. In a multicenter, phase II trial, low dose cytosine arabinoside was combined with imatinib in a trial conducted primarily in an outpatient setting. Although response rates were disappointing, the regimen was fairly well tolerated and early deaths when compared to historical controls were somewhat lower. It is unclear whether the addition of imatinib offered any therapeutic value. Thus, although the rationale is sound, the use of imatinib is unlikely to become a major factor in the management of AML.
Source: Heidel F, et al. Cancer. 2007;109:907-914.
The treatment of acute myelogenous leukemia (AML) remains a challenge, particularly for those who are over the age of 65 years. This is of increasing concern because the disease is most prominent in the elderly, with the median age at onset well beyond 60 years.1 AML in older individuals is more likely to have unfavorable cytogenetic alterations, antecedent myelodysplastic syndrome, and occur with coexisting morbidities that preclude aggressive therapy. The current multicenter trial was conducted to assess the efficacy of low-dose cytosine arabinoside (ara-C) combined with imatinib for patients who were not eligible for myelosuppressive chemotherapy or who had recurring/refractory disease or high-risk myelodysplastic syndrome (MDS). Imatinib was chosen because it is a tyrosine kinase inhibitor in addition to its remarkable activity in chronic myelogenous leukemia (BCR-ABL positive). It has also been of demonstrable efficacy in other conditions with varying tyrosine kinase overactivity. One such tyrosine kinase type receptor is c-Kit, which may be overly expressed in up to 80% of cases of AML. Low-dose ara-C has been thought to induce differentiation in AML and MDS and has been used as palliative treatment for these indications. Low-dose ara-C alone, although it occasionally produces objective responses, has not been shown to improve overall survival when compared to best supportive care. The combination of imatinib and low-dose ara-C has been shown to be synergistic in laboratory studies.
For this trial, patients received oral imatinib 600 mg daily and subcutaneous ara-C 10 mg daily for 21 days every 28 days. The dose and/or schedule of both drugs were frequently adjusted based upon NCI common toxicity criteria or non-sufficient antineoplastic effect. Prior to treatment, c-Kit positivity was analyzed by flow cytometry using the anti-human CD117 (c-Kit receptor) and only those in whom 20% or more of myeloblasts were positive were enrolled.
Of the 40 patients treated, the median age was 73 years and five were younger than 60 years, 34 were diagnosed with acute myelogenous leukemia, and six with high-risk MDS. ECOG Performance Status ranged from 0 to 2 with 29 patients being either ECOG 0 or 1 and 11 patients being ECOG 2. The c-Kit positivity was a mean of 62% of blasts with a range of 20% to 100%.
Of the 40 enrolled, 38 patients were available for analysis. In six of the 38 patients, treatment induced a blast response, whereas an additional eight experienced stable disease for more than two months. The objective hematologic response rate was low (11%), with two patients showing hematologic improvement and one each with a partial response or a complete response. Median overall survival was 138 days with 20% of patients alive after an observation period of 600 days. Of note, the medication was primarily applied in an ambulatory setting with patients or their family administering the subcutaneous doses of ara-C. Furthermore, there was an early mortality rate of 18.9% and this compares favorably with the 25% early mortality rate observed in other series of similar patients.2, 3
Thus, low-dose ara-C with added imatinib appears comparable to other regimens for high risk or elderly patients with AML, but provides the advantage of outpatient management.
Commentary
Clearly, the advantage in this regimen relates to the lower occurrence of toxicity in the outpatient approach. The survival advantage for older patients in other trials with administered myelosuppressive therapy must be countered by treatment-associated toxicity. For example, in one study in which chemotherapy was shown to provide a survival advantage,4 the bulk of the extra time achieved was also shown to be spent in the hospital.5 Accordingly, for certain high-risk patients with AML, the role for myelosuppressive therapy remains in question.
Also in question is the role of imatinib in the treatment of AML. The rationale for its use is based upon demonstration of activation of the c-Kit pathway in a substantial percentage of patients with AML and the success of imatinib in treatment of GIST tumors, which are known also to harbor c-KIT activated pathways.6 In this trial, the patients had at least 20% c-Kit positive blasts to meet eligibility criteria, but there was considerable variability (range 20% to 100%). The percentage of c-Kit positivity did not correlate with clinical response. Three of the responders had expression levels of 75% or higher, but one of the patients who had a partial response showed the lowest level of c-Kit positivity (20%). This raises the question of the mechanism of response and the capacity to predict response to imatinib in this setting. Yet, this pathway remains an appealing target for future trials and hopefully, more selective inhibitors will be developed to produce responses similar to imatinib in CML.
For now, the management of acute myelogenous leukemia in the elderly remains challenging. The approach undertaken in this trial, primarily outpatient, offers the advantages of less toxic treatment and presumably better quality of life. Response rates remain very low and the duration of survival, with or without quality, remains dismally short.
References
1. Stone RM, et al. Hematology. 2004;98-117.
2. Mayer RJ, et al. N Engl J Med. 1994;331(14):896-903.
3. Stone RM, et al. N Engl J Med. 1995;332:1671-1677.
4. Lowenberg B, et al. J Clin Oncol. 1989;7;1268-1274.
5. Sekeres MA, et al. Leukemia. 2004:18(4):809-816.
6. Prenen H, et al. Acta Gastroenterol Belg. 2006;69(4):367-371.
Treatment of AML in the elderly remains problematic, and the demonstration of an activated tyrosine kinase pathway presents an appealing target.Subscribe Now for Access
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