CML Treatment in the Elderly: Imatinib Levels the Playing Field

Abstract & Commentary

By Andrew S. Artz, MD, MS, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no relationships to this field of study.

Synopsis: Older age is an adverse prognostic factor for chronic myeloid leukemia (CML) in the pre-tyrosine kinase era. The authors evaluated the influence of age on outcomes among 559 chronic-phase CML patients treated with imatinib. Of the 115 patients 65 years and older (21%), complete cytogenetic and molecular response rates did not differ. However, progression-free survival (62% vs 78%) and overall survival were worse (75% vs 89%) for older adults because of a significant increase in deaths while in hematologic remission. Imatinib overcomes the negative prognostic impact of age on disease response for CML chronic phase.

Source: Gugliotta G, et al, on behalf of the Gruppo Italiano Mallattie Ematologiche del l'Adulto CML Working party. Frontline imatinib treatment of chronic myeloid leukemia: No impact of age on outcome, a survey by the GIMEMA CML Working Party. Blood2011;117:5591-5599.

Chronic myeloid leukemia (CML) is characterized by the 9;22 translocation, creating a constitutively activated BCR/ABL tyrosine kinase. BCR/ABL inhibition by imatinib mesylate (Gleevec) and other tyrosine kinases have revolutionized CML.1 Prognostic models developed prior to imatinib demonstrate older age adversely affects response rates and survival.2,3 The precise reasons for inferior survival and worse response may be multifactorial including worse tolerance to therapy, delayed medical care, non-hematologic comorbid conditions, and/or biologic differences in disease. The recent series reviewing the interaction between imatinib and age reported mixed results. Rosti reported lower response rates to imatinib for patients 65 years and older but no difference in survival.4 M.D. Anderson assessed 747 patients at different CML stages and found no difference in response or survival after imatinib therapy for adults 60 years and older, although follow-up was short.5

In this report, the authors analyzed the impact of older age on outcome among 559 patients with early chronic phase CML after initial therapy with imatinib. Results were collated from three front-line clinical trials dosing imatinib at 400 mg to 800 mg daily. The median age was 52 years (range 18–84 years) with 115 (21%) 65 years of age or older. Fewer older adults were assigned to low Sokal Risk score as expected, as the Sokal score models older age as an adverse prognostic factor. Complete hematologic response at 3 months was 97% for older adults and 96% for younger adults. Complete cytogenetic remission (CcyR) did not differ at 6, 12, or 18 months by age. Specifically, CCyR at 12 months was 78% for older adults and 77% in younger adults and major molecular response at 12 months was 58% and 59% for older and younger adults, respectively. Loss of CCyR occurred in 14% of older adults and 8% of younger patients (P = 0.084).

However, 6-year event-free survival was inferior for older adults at 55% compared to 67% in younger adults (P = 0.006). Similarly, older age suffered worse failure-free survival, progression-free survival, and overall survival (P < 0.0001 for OS). Imatinib failure rates related to primary or secondary resistance did not differ by age. However, older patients died more often while in complete hematologic response at 15% vs 3% in younger patients (P < 0.0001). Deaths from disease progression occurred in 5% of older patients and 3% of younger patients. The causes for deaths in older patients varied.

Commentary

Historically, older age conferred a worse prognosis for CML in terms of inferior response and survival. In the prior era of more toxic treatments such as inteferon-alpha, worse tolerance and adverse disease biology were implicated. Tyrosine kinase inhibitors, such as imatinib, now represent the mainstay of treatment for CML resulting in high response rates and low rates of serious toxicities.

This report derived from three consecutive upfront trials of imatinib at 400 mg to 800 mg for chronic-phase CML provide compelling evidence that older age alone does not impair response rates in imatinib-treated patients. Specifically, rates of complete hematologic response, complete cytogenetic response, major molecular response, and loss of response did not differ for those 65 years and older relative to their younger counterparts. Overcoming the negative age-related response to prior CML therapies could be from better tolerance. Alternatively, imatinib may diminish negative biologic features as has been demonstrated for imatinib neutralizing the poor prognosis of derivative chromosome 9.6

The negative impact of older age on survival persisted because of a greater number of deaths in disease control (i.e., complete hematologic remission). The authors reasonably surmise this represents a greater burden of concomitant illnesses in older adults. They astutely observe that imatinib therapy also could result in serious adverse events that might be more likely to occur in older adults, although no clear pattern existed among causes of death. Cardiac causes were uncommon. The authors should be credited not only with a comprehensive comparison in a homogenous cohort of early chronic phase CML but also for meticulously tabulating the causes of failure. Other series evaluating older age and outcomes for CML after imatinib therapy evaluated more heterogeneous populations. The largest series from M.D. Anderson Cancer Center reported complete cytogenetic remission in 87% of patients 60 years and older compared to 79% in younger adults but also inferior survival.6

A practical implication is that imatinib may be underused in older CML patients. Epidemiologic series show that imatinib use dramatically declines with older age, suggesting some older adults are not offered treatment because of concerns about toxicity or low response rates.7 These data offer reassurance that imatinib maintains efficacy in older adults. An obvious caveat is that the "oldest" old (i.e., older than 80 years) and less fit elderly adults typically are not enrolled in clinical trials. Thus, one cannot necessarily infer to this population.

In summary, imatinib therapy achieves similar high rates of disease control in younger and older adults for early chronic phase CML. Long-term survival is worse and attributable to a greater number of deaths as expected in older adults while in disease control. Older age should not be a barrier to offering imatinib therapy for chronic phase CML.

References

1. Druker BJ, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006;355:2408-2417.

2. Sokal JE, et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood1984;63:789-799.

3. Hasford J, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 1998;90:850-858.

4. Rosti G, et al. Impact of age on the outcome of patients with chronic myeloid leukemia in late chronic phase: Results of a phase II study of the GIMEMA CML Working Party. Haematologica2007;92:101-105.

5. Cortes J, et al. Effects of age on prognosis with imatinib mesylate therapy for patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Cancer 2003;98:1105-1113.

6. Quintas-Cardama A, et al. Imatinib mesylate therapy may overcome the poor prognostic significance of deletions of derivative chromosome 9 in patients with chronic myelogenous leukemia. Blood2005;105:2281-2286.

7. Wiggins CL, et al. Age disparity in the dissemination of imatinib for treating chronic myeloid leukemia. Am J Med 2010;123:764 e1-9.