Richard M . Stone , MD

Selina M . Luger , MD

Disclaimer : The following positions were assigned to the participants and do not necessarily reflect ASH ’ s opinion , the participants ’ opinions , or what they do in daily practice .

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Acute myeloid leukemia ( AML ) affects primarily older adults ( with a median age of 67 years at diagnosis ), and management of the disease in this population represents a therapeutic challenge – given their comorbidities and susceptibility to treatmentrelated toxicities . Patients who also harbor the FLT3 mutation face a particularly poor prognosis , with a high chance of relapse and a limited number of treatment options . However , several FLT3 inhibitors are under investigation and could provide alternative treatment options for these patients .

ASH Clinical News invited Richard M . Stone , MD , and Selina M . Luger , MD , to debate the question : “ Should older patients with FLT3-mutated AML be treated with FLT3 inhibitors ?” Dr . Stone will be arguing on the “ pro ” side , while Dr . Luger will be arguing on the “ con ” side .

Dr . Stone is chief of staff and director of the Adult Acute Leukemia Program at the Dana-Farber Cancer Institute in Boston , Massachusetts . Dr . Luger is director of the Leukemia Program and professor of medicine at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia .

Richard M . Stone , MD : Dr . Luger , I ’ m sure we can both agree that , in general , older adults with AML present a difficult treatment challenge . They do not tolerate the standard 7 + 3 regimen with cytarabine and daunorubicin as well as younger adults with the same disease . Also , older patients have a more intrinsically resistant disease than their younger counterparts . Historically , this has been a difficult area to treat .

Selina M . Luger , MD : Absolutely . In my opinion , once a physician decides a patient needs to be treated , the best therapy has always been the same therapy that you would give to a younger patient , but not all older patients can tolerate that . Fulldose 7 + 3 induction therapy , regardless of age , requires an in-patient hospitalization . The dosing is what we would consider full-dose therapy , and neither dose nor dosing schedule should be adjusted for age . Depending on a patients ’ age , however , there is a higher chance of toxicity from the therapy , a lower chance of remission , and a higher chance of relapse .

Physicians tend to be hesitant to use the same standard treatment approaches for younger patients as they do in older patients , for fear that older patients will not tolerate the therapies as well as their younger counterparts . However , giving attenuated doses , as well as palliative chemotherapy , results in inferior outcomes – even in the short term – for AML patients who would otherwise be able to receive standard induction . In older patients we have never been able to show that there is a benefit – either early or late in treatment course – with lowerintensity treatment when compared with standard induction .

With older AML patients , the challenge lies in identifying those who can best tolerate the therapies we have available and in developing new therapies that will work as well , but with fewer safety concerns .

Dr . Stone : Another concern is that we simply do not have a cut-off age for what we consider “ older ” patients – is it older than 55 , 60 , or 65 years old ? All of these different ages have been defined as older patients in clinical trials .

Along those same lines , not every 70-year-old patient with AML is the same , and one person ’ s AML is not the same as another person ’ s AML . Patients ’ prognosis has more to do with their biology and disease biology than anything else .

Older adults with AML tend to have a less proliferative disease and chromosomal abnormalities that are associated with unfavorable outcomes , like monosomal or complex karyotypes . And , regardless of a patients ’ age , the presence of FLT3 mutations is associated with increased white blood cell counts , a slightly higher initial response to chemotherapy , and a different disease biology .

Dr . Luger : Also , in patients with and without FLT3 mutations , we see a clear distinction in outcomes among younger patients . Patients without FLT3-ITD mutations clearly have a better outcome . In older adults , the difference in outcomes for FLT3-mutated patients is not as obvious . So yes , for all the reasons we discussed , AML in the older patients is a challenge overall – not just in the FLT3- mutated patient population .

Dr . Stone : I think , at this point , the questions physicians have to ask are , “ Have we come to the point in the treatment of AML in older adults – or any-age adults , for that matter – when we can use genotype-specific therapy ? Is it time to routinely add a kinase inhibitor to the standard chemotherapy given to older patients with FLT3-mutated AML ?” I think the answer is a qualified “ yes ,” but not a very strong one .

Dr . Luger : Well , before we can commit to using a FLT3 inhibitor in any patient population , we need more data . We have seen several generations of FLT3 inhibitors , with the initial agents in this class developed for purposes other than FLT3 inhibition . Sorafenib , for example , is a multi-kinase inhibitor , with FLT3 being one of its targets . Achieving meaningful FLT3 inhibition with one of these multikinase inhibitors required high doses , which led to inhibition of other tyrosine kinases and a higher number of toxicities .

Newer generations of FLT3 inhibitors