Older Age Affects Outcomes More Than Intensifying Treatment in AML Patients

Among older patients with acute myeloid leukemia (AML), age impacts outcomes more than treatment intensity, according to the authors of a report published in Leukemia. Prof. Thomas Büchner, from the Department of Medicine A – Hematology, Oncology, and Pneumology – at the University of Münster in Germany, and colleagues analyzed data from the 1999 German AML Leukemia Cooperative Group study (AMLCG99), in which similar-aged patients assigned to receive different therapy intensities were found to have similar outcomes.

The randomized, open-label, intent-to-treat, phase III AMLCG99 study included 3,450 patients (age range = 18-85 years) with untreated AML or those with myelodysplastic syndromes with 11-19 percent bone marrow blasts. The analysis by Dr. Büchner and colleagues focused on the 576 participants aged 57-63 years. This group of patients was stratified into two age groups: those 57-59 years and 60-63 years.

Patients without available cytogenetic data were excluded from the study.

Patients in the younger cohort (57-59 years) were randomized to receive double-induction with two courses of therapy (regardless of the percent of bone marrow blasts after the first course): thioguanine, standard-dose cytarabine, and daunorubicin (TAD) or high-dose cytarabine and mitoxantrone (HAM). All patients then received a second course of HAM, and those achieving complete remission (CR) received one consolidation course of TAD. Patients in this cohort were then randomized to receive three years of monthly maintenance therapy with reduced-intensity TAD or high-dose therapy and an autologous hematopoietic cell transplantation (AHCT).

Patients in the older cohort (60-63 years) were also randomized to receive double-induction therapy with either TAD or HAM; however, only those who still had ≥5 percent bone marrow blasts at 16 days after the first course of treatment went on to receive a second course of HAM. Also, the cytarabine dose in HAM was reduced from 18 to 6 g/m2. Patients who achieved CR after one or two courses of treatment received one consolidation course with TAD, and those still in remission received three years of monthly maintenance therapy with reduced-dose TAD. “Consequently, post-remission therapy of subjects 60-63 years old was identical to the monthly maintenance chemotherapy arm of subjects 57-60 years old,” the authors noted. Eligible patients were allowed to receive allogeneic HCT (alloHCT).

The patients were followed for a median of seven years (range = 1 day to 15 years). Cytogenetic data were available for 96 percent of patients (n=553), and molecular data were available for 70 percent of those with normal cytogenetics (n=269).

In the younger patient cohort, 240 subjects were randomly assigned to induction therapy with TAD-HAM (n=120) or HAM-HAM (n=120) and to monthly maintenance therapy (n=121) or high-dose therapy and AHCT (n=119). Eighty percent (n=192) received the second assigned induction course of HAM including 102 (85%) of those assigned to TAD-HAM and 90 (75%) to HAM-HAM (p=0.053).

Compliance rates were similar between the younger and older cohorts (p=0.44 and p=0.70, respectively).

A total of 264 patients (83%) who achieved CR after induction therapy then received TAD consolidation therapy, including 107 (78%) in the younger patient cohort and 157 (86%) in the older patient cohort (p=0.04).

Therapy intensity, measured by comparing the numbers of protocol-defined induction and consolidation cycles received by the two cohorts, varied between the younger and older cohorts:

  • 16% and 25% received only one treatment course
  • 33% and 46% received two courses
  • 51% and 29% received three courses (p≤0.01 for all)

Within the younger cohort, CR was achieved in 64 percent of those treated with TAD-HAM (95% CI 54-72) compared with 55 percent in those assigned to receive HAM-HAM (95% CI 46-65; p=0.2). Comparatively, in the older cohort, CR was achieved in 56 percent of those treated with TAD-HAM (95% CI 48-64) compared with 57 percent of those treated with HAM-HAM (95% CI 49-65; p=0.9).

Monthly maintenance therapy was associated with lower five-year cumulative incidence of relapse (CIR) among younger patients who received high-dose therapy and AHCT: 60 percent (95% CI 46-72) versus 73 percent (95% CI 59-83; p=0.21). Similarly, five-year survival rates were 32 percent (95% CI 21-43) and 27 percent (95% CI 15-39; p=0.85), respectively.

For those in the older patient cohort who received monthly maintenance therapy, a five-year CIR of 69 percent (95% CI 61-75) and a five-year survival of 27 percent (95% CI 21-33) were observed.

Five-year survival rates for the younger cohort were 28 percent in the TAD-HAM cohort (95% CI 17-39) and 31 percent in the HAM-HAM cohort (95% CI 19-43; p=0.65) compared with 29 percent (95% CI 20-38) and 25 percent (95% CI 17-33; p=0.9), respectively, in the older cohort.

Whether or not patients received granulocyte-colony stimulating factor (G-CSF) did not significantly impact outcomes for either patient cohort.

See the TABLE for a comparison of outcomes between younger and older patients who were assigned to receive and were receiving significantly different therapy-intensities.

“These data indicate that within the age span of 57 to 63 years, numbers of induction and consolidation courses; intensity of cytarabine therapy; and additions of mitoxantrone, G-CSF, and an autoHCT had no significant impact on therapy outcomes.” the authors concluded, suggesting that “age, rather than therapy intensity is the strongest determinant of therapy-outcomes under these conditions.”

The limited age range of the patients in this analysis is a limitation noted by Dr. Büchner and colleagues. Also, the study could not answer questions about why increasing age is associated with worse patient outcomes, independent of therapy intensity.

“The most obvious relates to leukemia biology,” they wrote. “Considerable data indicate older persons with AML are more likely to have biologic and clinical features associated with a worse prognosis. Older persons also have a higher frequency of preceding MDS and of possibly therapy-related AML.”


Reference

Büchner T, Krug UO, Gale RP, et al. Age, not therapy-intensity, determines outcomes of adults with acute myeloid leukaemia. Leukemia. 2016 March 11. [Epub ahead of print]

TABLE. Outcomes for Younger and Older Patient Cohorts (Independent of Therapy Intensity)
Outcome

Younger Cohort (57-59 Years)

Older Cohort (60-63 Years)

p Value

Complete remission rate

59% (95% CI 52-66)

56% (95% CI 51-62)

0.46

5-year cumulative incidence of relapse

70% (95% CI 62-79)

69% (95% CI 62-76)

0.48

5-year survival

30% (95% CI 21-38)

27% (95% CI 21-33)

0.27

 

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