Treating acute myeloid leukemia in older adults

Acute myeloid leukemia (AML) is a disease of older adults, with a median age of presentation of 67 years. In 2014, an estimated 18 860 new cases of AML are expected in the United States, with ∼10 460 deaths from this disease.¹  The incidence of AML appears to be increasing, in part due to the overall aging population, toxic exposures, and the prior use of chemotherapy and/or radiation for the treatment of other malignancies. Ironically, increased “cure” rates in other cancer types due to earlier disease detection and more effective therapies are leading to growing numbers of individuals at risk for the development of therapy-related myelodysplastic syndrome and AML (t-MDS/AML). In general, adults ≥60 years old with AML fare poorly compared with younger patients, with overall 5-year survival rates as low as 5%-10%. Although age is an important adverse prognostic factor for AML outcomes, a myriad of other biological and clinical factors are largely responsible for the poor outcomes. AML in the elderly exhibits several biological features associated with chemoresistance, including a higher incidence of unfavorable cytogenetic findings (monosomy 7, del (5q), complex karyotypes), frequent involvement of a more immature leukemic precursor clone, multidrug resistance mediated by MDR1/P-glycoprotein, and the presence of antecedent hematopoietic disorders.²  Older patients with AML are also more likely to have more numerous and severe comorbidities, contributing to more frequent treatment-related morbidity and mortality.^3,4  Given these complexities, treatment of elderly patients with AML remains highly challenging and controversial.

Since the 1970s, the standard initial therapy for patients with AML has consisted of intensive chemotherapy with 7 days of continuous infusional cytarabine and 3 days of an anthracycline drug (the so-called “7+3” regimen). In the past, however, many clinicians would not offer chemotherapy to the majority of individuals ≥60 years old because of the fear of treatment-related morbidity/mortality in patients with multiple other comorbidities. In fact, the opposite is true. Recent studies have consistently demonstrated that early death rates in patients with AML are higher in untreated than in treated individuals. In 2009, Juliusson et al presented data from the Swedish Acute Leukemia Registry (1997-2005) demonstrating that early death rates in patients of all ages with AML were consistently lower after intensive rather than palliative therapy.⁵  Importantly, they also showed that the poor initial performance status of older patients with AML did not necessarily preclude achievement of long-term survival after therapy and that individuals up to the age of 80 years both tolerated intensive induction treatment and survived longer compared with those managed with palliative care alone.⁵  Oran and Weisdorf found similar results in an analysis of 2000-2007 Surveillance Epidemiology and End Results (SEER) and Medicare claims data from 5480 older patients diagnosed with AML in the United States.⁶  Once again, older patients (median age 78 years) receiving AML treatment demonstrated longer overall survival (median 6 vs 2 months, p < .01) compared with untreated patients. The most significant differences between clinical outcomes in treated versus untreated patients were noted in individuals between the ages of 65 and 69 years (10 vs 4 months, p < .01) and 70-74 years of age (8 vs 3 months, p < .01).⁶  Based on these data, definitive therapy should be offered routinely to all older individuals with AML as the most effective means of prolonging overall survival.

Selection of the appropriate therapeutic approach for the older AML patient should be individualized based on patient-specific factors (ie, his/her “fitness” for chemotherapy, as discussed in a separate chapter by Dr. Klepin) and biological markers of disease predictive of response to various therapeutic interventions. Any critically ill patients with rapidly progressive AML disease (such as those with hyperleukocytosis with a WBC count >100 000/μL) and/or evidence of respiratory, neurologic, or other organ compromise should undergo immediate therapy with hydroxyurea and leukapheresis, followed by cytotoxic chemotherapy. Aside from these specific patients, there appears to be no benefit to early initiation of therapy (ie, within 24-48 hours of diagnosis) in the majority of older patients with AML.⁷  In fact, delaying therapy initiation to obtain further information on an individual patient's disease cytogenetic results (and possibly mutational status) may improve individual outcomes by allowing for the appropriate selection of a treatment approach most likely to result in remission and/or prolonged survival in that particular individual.

Intensive induction chemotherapy using a cytarabine and anthracycline backbone is considered by most to be the most effective upfront AML therapy. A review of the published literature on AML treatment between 1989 and 2006 confirmed that the median overall survival of older patients (median age 70 years) with AML treated with intensive induction therapy was significantly longer (30 weeks) than patients treated with low-intensity therapy (12 weeks) or best supportive care.⁸  In younger patients with AML, it is well established that disease karyotype constitutes the single most important independent predictor of response to intensive chemotherapy. Recently, there have been a multitude of studies analyzing the clinical outcomes of older (>60-65 years of age) patients with AML treated with intensive therapy in an attempt to identify factors predictive of response in the geriatric patient population. Investigators at the M.D. Anderson Cancer Center analyzed data on 998 older patients aged 65 and older receiving intensive chemotherapy at their institution. They reported significant heterogeneity in outcomes among geriatric patients with AML and identified 7 factors (age, performance status, karyotype, treatment outside of a laminar flow room, lactate dehydrogenase level, creatinine >1.3, and presence of antecedent hematological disease) that were correlated with clinical response.⁴  Depending on the prognostic model, geriatric patients had overall complete remission (CR) rates ranging from 20% to 50%, induction mortality ranging from 10% to 50% (average 29%-36%), and 1-year survival rates of 10%-50%.^4,9  Although these investigators listed age ≥75 years and poor performance status as negative prognostic factors, other groups have argued that these factors are not as important in predicting outcome as underlying disease biology and other clinical factors.^10,11  At present, the one factor most consistently aligning with clinical outcome after intensive chemotherapy remains karyotype.^4,10,11  Older patients with AML characterized by favorable- or intermediate-risk (nonadverse) karyotype have CR rates up to 60% after cytarabine- and anthracyline-based therapy. In contrast, older patients with AML associated with adverse karyotype have remission rates as low as 20%, with overall survival of 2-3 months.⁴ 

Recent advances in our understanding of the diverse genetic and epigenetic aberrations underlying AML, and particularly cytogenetically normal karotype AML, in older adults demonstrate the potential for classifying future patients based on distinct biological profiles.¹²  To date, however, the only molecularly defined subset of older patients with AML unequivocally benefiting from intensive chemotherapy are those harboring mutations in the nucleophosmin-1 (NPM-1) gene in the absence of mutations in the fms-like tyrosine kinase-3 (FLT-3). Why this gene mutation predicts for response to cytarabine- and anthracycline-based chemotherapy is not clear. However, in multiple studies, patients aged 60 years and greater with NPM-1-mutated AML have far superior outcomes and survival after intensive therapy compared with any other treatment modality.^13-15  The fact that, as of 2007, fewer than 5% of elderly patients with AML were tested for NPM-1 mutations at the time of diagnosis is another argument for the need for complete AML disease characterization before making any upfront treatment decisions in these individuals.¹⁶ 

When considering intensive induction chemotherapy for older patients with AML, it is important to know what to expect with this treatment modality. Most studies have reported 8-week early mortality rates up to 20%-25% after intensive induction therapy. Despite very valid concerns about treatment-related mortality and morbidity, many fit older patients actually fare quite well with intensive therapy. Lowenberg et al demonstrated that patients between the ages of 60 and 65 years with AML both tolerated and benefited from increased daunorubicin dose (from 45 to 90 mg/m²) similarly to younger patients.¹⁷  As a result, clinical trials of intensive chemotherapy in older patients with AML now routinely use daunorubicin doses of at least 60 mg/m², with the recommendation that no dose reductions in anthracycline dose occur in individuals with normal left ventricular function. In the past, it was also commonly believed that older patients with AML frequently became so ill during induction therapy that they were admitted to the intensive care unit (ICU), with resultant high mortality rates. Jackson et al found that in fact only 9.4% of induction chemotherapy cycles resulted in ICU admission, with the predominant cause being infection, and that neither age, AML cytogenetic risk status, or type of chemotherapy (induction vs consolidation) predicted for ICU admission.¹⁸  Although patients with AML admitted to the ICU had worse overall survival than those patients who were not, the chances of these patients surviving to hospital discharge and 12 months afterward were 59% and 41.3%, respectively. In fact, once these patients survived the acute event prompting ICU admission, they had similar overall survival rates as other AML patients undergoing chemotherapy.¹⁸ 

Prioritization of quality of life (QOL) and preserving an older individual's activities of daily living are also cited as arguments against the use of intensive chemotherapy in geriatric cancer patients. As expected, older patients with AML may experience short-term declines in their overall QOL due to the need for inpatient hospitalization during the first 4 weeks of therapy.¹⁹  However, surveys of mostly older patients with AML at 1, 1.5, 4, and 6 months after initiation of therapy demonstrated no significant adverse effects on multiple QOL parameters and no difference in their overall functional status after intensive chemotherapy.^19,20  Moreover, those patients achieving CR after intensive induction universally reported overall improvements in QOL and global, social, and emotional health 12 months after therapy.²¹ 

What about patients above the age of 80 years? Investigators analyzing both the Swedish Leukemia Registry and the United States SEER database concluded that risks of intensive induction chemotherapy were outweighed by treatment benefits only in patients with AML up to the age of 80 years.^5,6  We reviewed the outcomes of 92 octogenarian and nonagenarian patients with AML treated with intensive chemotherapy (n = 59) or supportive care (n = 33) at our institution. Intensive chemotherapy led to a CR rate of 26% and an improved median survival of 4.0 months.²²  Wetzler et al recently evaluated the outcomes of 90 “very old” patients (median age 82 years, range 80-89) with AML considered fit enough to be treated with intensive chemotherapy on cooperative group clinical trials.²³  They found an overall CR rate of 46%, median overall survival of 6 months, and a 1-year survival rate of 36%. Once again, AML with nonadverse karyotype and NPM-1 mutation were associated with improved clinical outcomes.²³  Although these data are obviously skewed by clinician bias in selecting fit older patients for clinical trial enrollment, consideration should be given to offering intensive chemotherapy to a select subset of patients 80 years and older for whom this modality might offer significant survival benefit.

Low-dose cytarabine (also known as low-dose Ara-C or LDAC) has been used as a low-intensity therapeutic strategy for the treatment of elderly, “unfit” AML patients for several decades. Recent studies have highlighted the fact that even very small doses of cytarabine (typically given at 20 mg/m² administered once or twice daily for 10-14 days per month) can induce CRs in ∼8%-18% of patients with AML and can prolong survival.^24-26  Although these results compare favorably with no remission after hydroxyurea and supportive care, LDAC is currently considered potentially inferior to other upfront therapies for older patients with AML, in part because no patients with AML with adverse cytogenetic findings achieve remission with this regimen.²⁴  Despite this fact, LDAC may still be a therapeutic option for geriatric patients with favorable or intermediate-risk karyotype AML whose medical issues (such as renal insufficiency) preclude the administration of intensive chemotherapy and who prefer to self-administer drug almost exclusively at home without the need for daily clinic visits or inpatient hospitalization. For some individuals, the convenience of this approach may outweigh the low remission rates. Because of the tolerability of LDAC, multiple clinical trials have explored combining LDAC with novel investigational agents in an attempt to improve responses in unfit older patients.

Over the last several years, hypomethylating therapy with 1 of 2 agents, decitabine (Dec) and azacitidine (Aza), has been increasingly used in place of standard intensive chemotherapy for the treatment of “unfit” elderly patients with AML. A review of SEER data from 2005 to 2007 revealed that, after 2004, when these drugs became available to clinicians, the number of older AML patients treated with hypomethylating agents rather than standard induction rose from 7% to 24%.⁶  The earliest clinical data of hypomethylating therapy in patients with AML were noncomparative trials mostly involving individuals unfit for induction chemotherapy.^27-31  Next, subgroup analyses of large, prospective, phase 3 trials of Aza or Dec demonstrated superior outcomes for hypomethylating therapy over best supportive care in patients with low blast count (20%-30%) AML.^25,32,33  For example, in the AZA-001 trial, elderly unfit patients with 20%-30% BM blasts who were randomized to Aza therapy experienced significantly prolonged overall survival (24.5 months) compared with those receiving conventional care regimens (16 months; p = .005).²⁵  Recent studies suggest that, although hypomethylating therapy in AML patients results in lower CR rates (10%-20%) than conventional intensive chemotherapy, an additional 10%-30% of these individuals nevertheless exhibit evidence of some disease response or stabilization and have overall survival rates equivalent or superior to other conventional treatments.^13,26,34  Lastly, and perhaps most importantly, hypomethylating therapy was well tolerated over long periods of time in unfit elderly individuals, with fewer required hospital days and RBC and platelet transfusions.^35,36 

To date, the question of which older patients with AML benefit from intensive versus hypomethylating therapy has been addressed only in retrospective analyses. Quintas-Cardama et al reviewed the outcomes of 671 older patients with AML treated with upfront intensive induction therapy or Aza or Dec-based therapy at MD Anderson Cancer Center.¹³  Although CR rates were significantly higher after intensive versus epigenetic chemotherapy (42% vs 28%; p =.001), there was no difference in 8-week early death (18% vs 11%; p =.075), 2-year relapse-free survival (28% vs 39%; p =.84), or median overall survival (6.7 vs 6.5 months; p =.413) rates. In addition, there was no survival advantage for either induction strategy in AML patients ≥70 years old or those with intermediate-risk karyotype AML, adverse-risk karyotype AML, Eastern Cooperative Oncology Group (ECOG) performance status, renal insufficiency, or FLT-3 ITD mutations. Only patients with NPM-1 mutated AML benefited from intensive induction. Almost half of the intensively treated patients in this study received high-dose cytarabine and idarubicin (as opposed to more standard dose infusional cytarabine and daunorubicin) induction, and the majority of patients treated with hypomethylating agents also received other investigational agents.¹³  For this reason, we recently analyzed our own experience with intensive “7+3”-based chemotherapy versus Dec or Aza treatment in 167 consecutive unselected AML patients ≥60 years of age at Roswell Park Cancer Institute.³⁴  Similarly to Quintas-Cardama,¹³  we found that standard intensive chemotherapy resulted in 2-fold higher CR rates than hypomethylating therapy (43% vs 20%; p < .01). Although univariate analysis demonstrated longer overall survival after intensive versus hypomethylating therapy (10.7 vs 9.1 months; p = .01), multivariate analysis highlighted no independent impact of treatment choice. Subgroup analysis demonstrated similar outcomes after intensive versus Aza or Dec therapy in older patients with adverse karyotype, secondary, or FLT-3-mutated AML.³⁴  Investigators from the Netherlands analyzed their center's results in 227 AML patients ≥60 years old consecutively treated with intensive chemotherapy (n = 90), Aza (n = 26), or best supportive care (n = 97). Despite the relatively small number of Aza-treated patients in this study, van der Helm et al also found similar overall 1-year (57% vs 56%, p=.93) and 2-year (35% vs 35%, p .92) survival rates after intensive versus Aza therapy. Both induction modalities were significantly superior to supportive care only (1- and 2-year overall survival of 16% and 2%, respectively).³⁶  Based on these results suggesting the equivalency of these upfront treatment approaches in prolonging overall survival, epigenetic therapy now has an established role in the upfront treatment of elderly individuals with AML.

There are ongoing efforts to identify biological subsets of AML most likely to respond to hypomethylating therapy. Blum et al demonstrated a very high overall response rate of 75% (50% CR in 8 of 16 patients and 4 incomplete CR) after 10-day Dec therapy in complex karyotype AML patients and reported a response rate of 91% (10 of 11 patients) in patients with AML characterized by monosomy 7 or del(7q) abnormalities.²⁷  Other groups have also reported CR rates of 33%-47% after hypomethylating therapy in patients with unfavorable karyotype AML or AML characterized by chromosome 5 and/or 7 aberrations.^30,35,37,38  However, most of these studies involved very small numbers of treated patients (n < 20). Moreover, despite these impressive CR rates, other retrospective analyses have demonstrated no significant overall survival benefit to Dec or Aza therapy compared with intensive chemotherapy in AML with adverse cytogenetics or chromosome 5 and 7 abnormalities.^13,34,36,38  In an intriguing study, Metzeler et al reported a CR rate of 75% after Dec therapy in 8 patients with AML characterized by DNMT3A mutations.³⁹  However, in a larger study of 68 older patients with AML, Dinardo et al found no direct correlation between DNMT3A, IDH1, or IDH2 mutational status with response, event-free, or overall survival after upfront epigenetic therapy.⁴⁰  However, this study was limited by its retrospective nature and the treatment with other agents in addition to hypomethylating agents, which may have affected responses.⁴⁰  Further studies clarifying those biological factors predictive of response to hypomethylating therapy in this patient population are eagerly awaited.

Emerging data have suggested that, of the 2 hypomethylating agents, Dec may represent the more effective agent for treatment of AML in older patients.¹³  In a multicenter phase 3 trial, Kantarjian et al demonstrated superior response rates for 5-day Dec therapy compared with LDAC (20 mg/m² once daily) in unfit elderly patients with AML. Post hoc analysis of this trial subsequently demonstrated a trend to overall survival favoring Dec.^26,41  These data led to the approval of Dec for the treatment of high-blast-count AML in Europe. However, these same results were cited as the reason for the rejection of Dec for the same treatment indication in the United States. One large retrospective analysis found a statistically significant improvement in overall survival for Dec over Aza in elderly patients with AML.¹³  Currently, the hypomethylating regimen associated with the highest response rates in older AML appears to be a 10-day regimen of Dec dosed at 20 mg/m² daily. As opposed to 3- or 5-day Dec regimens, this 10-day treatment has been shown to consistently result in CR rates of 31%-47% and overall median survival durations of 9-12 months.^27,35,37  The caveat is that this treatment can be associated with significant myelosuppression, and many patients require inpatient hospitalization for at least the first cycle of therapy and potentially for several weeks afterward for daily transfusions and infectious complications. Ten-day Dec induction has also been associated with treatment mortality rates indistinguishable from those of intensive chemotherapy in elderly individuals.^13,34  For these reasons, unfit older individuals desiring largely outpatient therapy and for whom treatment-related mortality is a concern may be considered for subcutaneous Aza, 5-day Dec, or LDAC therapy as an alternative to 10-day Dec induction.

Despite advances in our understanding of and options for the treatment of elderly AML over the last few years, the median survival times of almost all of the standard treatment approaches (with the exception of allogeneic stem cell transplantation) in this patient population remain <12 months. Clearly, there is a need for newer more effective and less toxic therapies for older AML patients. Unfortunately, it is estimated that only 5%-10% of adult AML patients enroll in clinical trials nationwide,¹⁶  making it difficult to impossible to determine which agents are superior to the currently available options in a timely fashion. Moreover, to date, many agents in recent clinical development for this patient population have turned out to be either too toxic in older individuals or ineffective in improving overall survival for elderly patients with adverse prognostic features (ie, secondary AML, unfavorable cytogenetics, poor performance status). A complete discussion of experimental therapies currently available for older AML patients is beyond the scope of this article. The reader is referred to recent reviews for additional information.^42-44 

At present, the only investigational therapeutic approach of note for upfront consideration in older patients with AML is targeted FLT-3 kinase inhibitor therapy for FLT-3 ITD-mutant AML. In contrast to younger patients, FLT-3 ITD mutations appear to have a negative impact on the outcome of patients 60-69 years of age with primary cytogenetically normal AML treated with intensive chemotherapy.⁴⁵  The significance of FLT-3 mutations alone in other older individuals with AML is less clear.^15,45  However, given the proliferative advantage conferred on AML cells with constitutive FLT-3 kinase activation and the relative chemoresistance of this disease, the use of oral receptor tyrosine kinases specifically targeted against this signaling pathway is an attractive option for the treatment of unfit older patients with FLT-3 mutant disease. Prior studies have also shown that epigenetic therapy results in similar (poor) outcomes as intensive chemotherapy in older patients with FLT-3 mutant AML.^13,34  Clinical trials of successive FLT-3 inhibitors as monotherapy for patients with relapsed/refractory FLT-3 mutant AML patients demonstrated transient reductions in peripheral blasts in some patients, as well as CRs and prolonged survival.^42,46  The addition of sorafenib, an oral inhibitor of multiple tyrosine kinases including FLT-3, to upfront intensive chemotherapy was neither well tolerated nor beneficial in unselected older patients with AML.⁴⁷  However, a phase 2 trial of sorafenib and Aza therapy in patients with newly diagnosed and relapsed/refractory FLT-3 mutant AML (median age of 64 years) was well tolerated and resulted in an overall response rate of 46%.⁴⁸  Based on these results, older individuals with FLT-3 mutant AML should ideally be considered for therapy incorporating a FLT-3 inhibitor as a part of the overall treatment regimen.

The best therapeutic option for older patients with AML after achievement of CR with upfront therapy remains uncertain. Individuals up to the age of 75 years who achieve sufficient disease control after upfront AML therapy and have few comorbidities should be considered for consolidation with allogeneic stem cell transplantation (alloSCT), ideally with reduced intensity conditioning regimens, because this remains the only potential curative therapeutic option for these patients. Analyses of the SEER database clearly show that older individuals (46 of 5480 patients or 0.8%) who received alloSCT for AML therapy had the longest overall survival after diagnosis (22 vs 6 months after AML treatment alone and 3 months for the entire cohort). Two-year survival rates after AML diagnosis in alloSCT recipients aged 65-69 and 70-74 years were also surprisingly high, at 50% and 30.5%, respectively.⁶  As expected, the presence of concomitant comorbidities, lack of an appropriate donor, and other financial and psychosocial issues (specifically the lack of an adequate caregiver for many elderly individuals) may preclude alloSCT in the majority of older patients. In a separate chapter, Dr. Sorror discusses criteria for the selection of AML patients for hematopoietic stem cell transplantation.

For those individuals in remission who are not eligible for alloSCT, the standard approach has been to administer “consolidation” chemotherapy consisting of lower doses of the same agents used in induction therapy. To date, there is no consensus on the number of consolidation chemotherapy cycles (range 1-4), number of agents (cytarabine alone vs cytarabine ± anthracycline), and drug dose (high- vs intermediate-dose cytarabine) needed for the best possible outcomes for older patients with AML. In the Medical Research Council AML11 trial, 1314 older patients with AML who achieved remission after 2 cycles of standard induction were prospectively randomized to receive 1 additional chemotherapy course (total 3 courses) or an additional 3 courses after remission (total 6 courses). Long-term outcomes did not differ between patients treated with 3 versus 6 cycles, suggesting the lack of any benefit beyond 1 cycle of consolidation therapy.⁴⁹  Although numerous other studies have examined a variety of other consolidation approaches in elderly AML patients, all of these have consistently reported median disease-free survival durations of <1 year (range 4.1-11 months) and high recurrence rates (60%-100%; for review, see Wedding et al² ). For lack of better information, older patients with favorable- or intermediate-risk AML who achieve CR after upfront cytarabine and anthracycline-based chemotherapy typically are offered 2-4 cycles of intermediate- to high-dose cytarabine. In contrast, patients with adverse karyotype AML who achieve CR have been shown to fare poorly regardless of intensive induction and consolidation chemotherapy and therefore should be referred for investigational therapy in the postremission setting.⁵⁰ 

Older patients receiving upfront therapy with Dec or Aza will require a median of 2-4 cycles of therapy to achieve best response. Despite lower morphologic CR rates compared with intensive chemotherapy, many older patients with AML achieve adequate disease control and prolonged survival with hypomethylating therapy and are therefore recommended to continue on therapy indefinitely until evidence of disease progression, mirroring the treatment approach in myelodysplastic syndrome patients.³⁵  Dec or Aza therapy has also been used as consolidation or maintenance therapy in older patients with AML in CR and, retrospectively at least, has been shown to prolong overall disease-free survival in some individuals.⁵¹ 

Older individuals with AML who are deemed ineligible or unsuitable for alloSCT should be counseled early in the course of the disease about their overall prognosis, specifically the fact that, although current and investigational treatment approaches may extend survival, they will not be curative. Surveys of newly diagnosed patients with AML have demonstrated that the majority of individuals do not recall being offered more than one treatment option and grossly overestimate their long-term prognosis and chance for cure, although the treating physicians clearly documented discussion of these issues in the patients' medical charts.^19,52  A mutual understanding between the patient, his/her family members, and the treating oncologist early in the treatment process that the disease will eventually be life-ending may make it easier to hold subsequent conversations on topics such as health care proxies, do not resuscitate/do not intubate directives, and end-of-life care when the time comes.

A proposed approach to the older adult with AML is provided in Figure 1. In general, individuals without life-threatening organ failure or hyperleukocytosis may safely delay therapy to allow for geriatric assessment and cytogenetic/ molecular characterization of their disease. Given median survival durations of <12 months with currently available agents, all older adults with AML should be encouraged, whenever possible, to participate in clinical trials addressing the unmet therapeutic needs of this patient population. In the absence of appropriate trials, fit older individuals with favorable karyotype AML or NPM-1-mutated disease (without FLT-3 mutation) should be offered intensive chemotherapy with a cytarabine- and anthracycline-based regimen followed by 2-4 cycles of consolidation chemotherapy. Fit older patients with intermediate-risk AML may be offered upfront intensive chemotherapy or hypomethylating therapy. Individuals with AML with adverse karyotype and unfit older patients with AML (regardless of karyotype) are unlikely to benefit from intensive induction or consolidation chemotherapy and therefore should be treated preferentially with hypomethylating agents or investigational therapies. Fit patients with intermediate- or poor-risk AML who achieve CR should be referred for alloSCT, preferably with reduced-intensity conditioning. Other patients in CR may be treated with consolidation chemotherapy (intermediate karyotype AML), hypomethylating therapy (adverse karyotype), or investigational agents. Any patients with relapsed/refractory AML should be strongly encouraged to pursue experimental therapy. Those patients with FLT-3-mutated AML should be considered for therapeutic regimens incorporating FLT-3 inhibitors in the upfront or relapsed setting. It is important to keep in mind that AML will be a life-ending disease for the majority of these patients. It is therefore essential to involve older adults in therapeutic decision-making process at diagnosis and throughout their disease course because the selection of the appropriate “aggressiveness” of therapy for many individuals may be based more on their personal treatment goals than a defined therapeutic algorithm.

In the current era, the majority of older patients with AML should be offered definitive antileukemic therapy to prolong both quantity and quality of life remaining. Performance status, comorbidities, disease biology, QOL, and long-term treatment goals should all be considered in the selection of the most appropriate therapeutic approach for each patient.

The author is supported in whole or in part by funding from the Cancer Clinical Investigator Team Leadership Award awarded by the National Cancer Institute through a supplement to Grant P30CA016056.

Conflict-of-interest disclosure: The author has been affiliated with the speakers' bureau for Incyte and was on an advisory board for Immunogen. Off-label drug use: decitabine and azacytidine for high-blast-count AML.

Eunice S. Wang MD, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263; Phone: (716)845-3544; Fax: (716)845-8741; e-mail: eunice.wang@roswellpark.org.