Acute Myeloid Leukemia: The Outcome Is Determined By Age, Genetic Group, White Blood Cell Count, Lactate Dehydrogenase, Rather Than By Chemotherapy Intensity
Authors: Buchner Thomas , Berdel Wolfgang E. , Krug Utz , Haferlach Claudia , Schnittger Susanne , Haferlach Torsten , Mueller-Tidow Carsten , Stelljes Matthias , Mesters Rolf M. , Serve Hubert , Braess Jan , Spiekermann Karsten , Staib Peter , Grueneisen Andreas , Reichle Albrecht , Balleisen Leopold , Eimermacher Hartmut , Giagounidis Aristoteles , Rasche Herbert , Lengfelder Eva , Faldum Andreas , Sauerland Maria Cristina , Heinecke Achim , Hehlmann Rüdiger , Woermann Bernhard J. , Hiddemann Wolfgang 
Published: October 2019

Abstract

Background
Data on benefit and toxicity by treatment intensification for AML are now available and allow rediscussing current dosing.

Methods
In a multicenter trial involving patients between 16 and 86 years of age, patients below 60 years received uniform double induction by the 1st course with standard dose araC/ daunorubicin (60mg/m²x3)/ thioguanine followed by the 2nd course with high-dose araC (3g/m²x6)/ mitoxantrone (10mg/m²x3), or randomly two high-dose courses. As age adaption patients of 60y or older received the 2nd course only in case of persistent blasts, and high-dose araC at 1 instead of 3g/m². Post remission treatment was consolidation and maintenance or randomly autologous stem cell transplantation in younger patients.

Results
3369 patients entered the trial with 1843 patients 60y or older. A multivariate analysis identified age as continuous variable, favorable cytogenetics/ molecular genetics, unfavorable cytogenetics, white blood cell count and lactate dehydrogenase as categorical variables to be risk factors predicting complete remission, overall survival as well as relapse free survival. To separate the age effect from the treatment effect, two subgroups of similar age and baseline characteristics but different treatment were compared. Thus, the 239 patients aged 57-59 and the 336 patients aged 60-62 years shared not only similar age but also similar baseline characteristics, while their treatment by protocol and age adaption differed substantially. The difference as expressed by the cumulative araC dosis amounted to a factor of 3.6, which however did not translate into a different overall survival (equally 28%) or relapse rate (equally 70%) at 5 years. In contrast to different treatment, different age had a strong effect on outcome. Thus, the survival in patients aged 16-46y was 65% at 5 years versus 40% in those of 47-59y receiving the same treatment (p< 0.001). A corresponding age related difference was also found between the patients of 60-66y and those of 67-86y (p< 0.001) receiving the same age adapted treatment. As shown by others in patients of 18-60y doubling an intermediate cumulative dose of araC produced excessive toxicity without therapeutic benefit (Löwenberg B et al. NEJM 2011; 364: 1027-36), while high dose daunorubicin (90mg/m²) instead of standard dose (45mg/m²) improved the remission rate and survival in younger patients (Fernandez H et al. NEJM 2009; 361: 1249-59) and older patients of 60-65y (Löwenberg B et al. NEJM 2009; 361: 1235-48). No comparable data are available about daunorubicin 60mg/m² the standard in present study.

Conclusion
Age and disease biology rather than chemotherapy intensity are the main determinants of outcome in AML. Once a certain intensity and antileukemic effect has been achieved, a further escalation does not seem to overcome the age factor in AML. Present data require rediscussing current chemotherapy dosing and treatment alternatives.

Disclosures:
No relevant conflicts of interest to declare.