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Acute Myeloid Leukemia (AML) task force

Acute Myeloid Leukemia (AML) is a disease of older adults, with approximately one-third of newly diagnosed patients being ≥75 years of age. Chronologic age remains a major factor in both treatment decision-making and trial design with “older” frequently characterized as >60-65 years and a large proportion of patients over age 75 years excluded from trials and receiving no therapy for the disease based on registry data. While selected older adults can benefit from curative therapies, as a group they experience increased treatment-related morbidity, are more likely to relapse, and have decreased survival.  Most studies have shown that Complete Remission (CR) rates, Relapse-Free Survival (RFS) and Overall Survival (OS) in older AML patients are much lower than their younger counterparts.  The reason for these poor CR rates and survival includes a combination of patient-related factors and the underlying biology of AML.  AML is a very different disease in older patients and the underlying biology is fairly aggressive.  Older AML patients have a higher percentage of underlying myelodysplastic syndrome, poor-risk cytogenetics, increased expression of MDR1, and impaired apoptosis in vitro when exposed to cytarabine.  In addition, there is an inherent aging of the hematopoietic stem cell (HSC), which is a result of several processes that include DNA damage, telomere shortening, and oxidative stress.  Molecular mutations like FLT3-ITD, NPM1, and CEBPAdm and many others have a prognostic significance and aid therapeutic decision making in younger adults.  However, their significance and utility among older adults with AML patients is less well defined. 

The most appropriate management of AML among older patients is still a highly controversial issue because of the clinical and biological heterogeneity of these patients.  Standard induction chemotherapy for non-M3 AML typically since the early 1970s, had included the use of cytarabine (Ara-C) and an anthracycline given for 7 and 3 days respectively (7+3). This approach has been shown to improve survival (median 5 versus 3 months) compared to best supportive care for adults ≥65 years with no increased time spent hospitalized. In the decades since this landmark trial was published, many subsequent elderly-specific trials were conducted which have unfortunately resulted in only incremental improvements in outcomes.  Several variations on intensive induction chemotherapy regimens designed to improve the balance between benefit versus toxicity have been tested with no significant advance in efficacy, safety, health care utilization or quality of life (QOL). Strategies pursued include: 1) dose attenuation; 2) anthracycline substitution 3) addition of etoposide or other dose-intensive regimens 4) use of growth factors; 5) Epigenetic therapy with hypomethylating agents and 6) modulation of multi-drug resistant efflux pump (MDR1).  A recent study showed promising results using CPX-351 in a subset of older adults (aged 60-75 years) with secondary AML. Many older adults, however, are treated with lower intensity therapies including hypomethylating agents such as azacitidine and decitabine as first line therapy. Randomized trial data supports use of azacitidine versus conventional care regimens (including best supportive care or intensive therapy) although direct comparison between lower intensity therapy and intensive induction are lacking. Recent data suggest that patients with unfavourable cytogenetics and TP53 mutation may be particularly likely to benefit from decitabine-based therapy. While there are several options for therapy, there is still no consensus on the best approach for initial treatment and in particular selection between more versus less intensive treatment approaches. Treatment choices and trial design are to a large part hampered by standardization of patient selection and characterization of “fitness” which precludes generalizability of results among heterogeneous older adult populations.

Concerns regarding treatment tolerance remain central to the controversy of AML therapy among older adults. For example, the 30-day induction mortality associated with intensive induction is high and ranges from 10-80% among older patients.  The wide variation in outcome is due in part to the heterogeneity of aging (phenotypically evident by differences in physical function, comorbidity, cognition etc) which ECOG Performance Status is not sensitive enough to differentiate. A few studies have demonstrated the benefit of Comprehensive Geriatric Assessment (CGA) as a better tool for selecting elderly patients for therapy.  For example, CGA prior to and during induction therapy has demonstrated that patients with cognitive decline and poor physical performance have worse survival. Advances in treatment for older adults will depend not only on precision treatment directed at differences in age-related tumor biology but also on refinement of phenotypic characterization of older adults using strategies such as CGA to both refine risk prediction and develop supportive care strategies to enhance treatment tolerance.

The role of post-remission therapy is also controversial and has not definitively been shown to be beneficial among older AML patients.  Most studies of hematopoietic stem cell transplant (HSCT) do not include older patients but more recently, SCT after reduced intensity conditioning (RIC) and micro-transplantation using haploidentical donor lymphocytes have been evaluated among older AML patients.  In those patients who cannot undergo SCT, other forms of maintenance therapy including oral hypomethylating agents etc. are being evaluated.  The role of best supportive care (BSC) including use of growth factors, hydroxyurea, antibiotics, antifungals, transfusions, etc among older AML patients must be better defined and understood.  Finally, consideration of patient-centric outcomes such as maintenance of independence and quality of life require attention in clinical trials and observational studies with an emphasis on patient-reported outcomes and aging-specific outcomes such as physical function and cognition.

In summary, there are more questions than answers in treatment decision-making for older adults with AML. It is timely to carefully consider available evidence to address questions such as:  1) selection of first line therapy considering tumor biology and fitness characterization; 2) the role of post- remission therapy inclusive of transplantation; 3) consideration of patient-centric outcomes such as functional independence and QOL in the context of decision-making; 4) strategies to enhance treatment tolerance among older adults receiving available therapies; 5) novel therapeutics and trial design which have greatest potential to improve outcomes for older adults.

The Elderly AML task force will review the available evidence:
  1.   Role of cytogenetics and molecular mutations in prognosis and treatment-decision making
  2.   Role of Comprehensive Geriatric Assessment and functional assessment
  3.   Induction therapy choices – intensive and non-intensive
  4.   Newer therapeutic agents including monoclonal antibodies and targeted agents e.g. FLT3 inhibitors, PLK1 inhibitors, proteasome inhibitors etc.
  5.   Role of post-remission chemotherapy
  6.   Role of hematopoietic stem cell transplant (HSCT)
  7.   Better define choices for best-supportive care

Task Force Members 

Martine Extermann (USA)
Reinhard Stauder (Austria)

Writing Committee
Art Artz (USA)
Valeria Santini (Italy)
Utz Krug (Germany)
Alice Mims (USA)
)Heidi Klepin (USA)
Maite Rebollo Antonio (Spain)
Nina Rosa Neuendorff (Germany)
Melissa Loh (USA)
Norbert Vey (France)

This project is supported by an unrestricted grant from Helsinn.