Page 1052 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 59 Clinical Manifestations and Treatment of Acute Myeloid Leukemia 935

cladribine, but not fludarabine, to a standard daunorubicin/cytarabine response rates following the first induction and fewer patients on
backbone resulted in significantly increased rates for remission (68% FLAG-Ida relapsed. However, more myelosuppression and deaths in
versus 56%; p = .01) and 3-year overall survival (OS; 45% versus CR offset the survival benefit unless FLAG-Ida treated patients were
33%; p = .02). In a publication in 2013 by the MD Anderson Cancer able to receive four courses (FLAG-ida × 2, HiDAC × 2) where 8-year
Center, addition of clofarabine, a second-generation nucleoside survival was 63% for patients (versus 47% with 3 + 7) with interme-
analog, to idarubicin and cytarabine (IA) led to significantly better diate risk and 95% for those with favorable risk.
event-free and OS in the three drug combination when compared The European Organization for Research and Treatment of
with a historical IA-treated group, especially in patients younger Cancer (EORTC)-Italian Group for Haematological Diseases in
than 40 years of age. The use of fludarabine, idarubicin, HD-AC Adults (GIMEMA) AML-12 trial randomized 1942 newly diagnosed
versus 3 + 7 in the Medical Research Council (MRC) trials is AML patients between 15 and 60 years of age to an induction with
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discussed later. SDAC or HiDAC (3 g/m every 12 hours on days 1, 3, 5, and 7).
The choice and dose of anthracyclines has been the subject of With 6-year of follow up the study demonstrated significantly higher
debate. Substitution of daunorubicin by doxorubicin produced more CR rates in all patients and significantly improved event-free (43.6%
toxicity without added benefit. Idarubicin is a 4-demethoxy anthra- versus 35.1%; p = .003) and OS (51.9% versus 43.3%; p = .009) for
cycline analogue of daunorubicin, which results in increased lipophi- patients between 15 and 45 years of age. The impact on survival was
licity and better cellular uptake compared with daunorubicin. particularly evident in younger patients with secondary AML, high-
A study by the Eastern Cooperative Oncology Group (ECOG risk cytogenetics, and mutations of FLT3, emphasizing that HiDAC
1900) randomized patients between the ages of 17 and 60 years with may overcome poor-risk features during induction that SDAC
untreated AML to a 3 + 7 combination with either standard-dose cannot.
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daunorubicin (45 mg/m daily × 3) or high-dose daunorubicin
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(90 mg/m daily × 3). High-dose daunorubicin achieved higher
rates of CR (70.6% versus 57.3%, p < .001) and improved median Patients Aged 60 Years or Older
OS (23.7 months versus 15.7 months, p = .003). This improvement
was limited to patients younger than 50 years and with intermediate In an analysis of SEER data spanning the years from 1977 to 2006,
cytogenetics in the absence of FLT3 mutations. A more recent the 1- and 2-year OS of patients aged 65–74, 75–84, and >85 years
follow-up of the study suggested that the benefit extends to all was only 30.3%, 14.8%, 7.8%, and 15.8%, 5% and 1.7%, respec-
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cytogenetic risk groups regardless of age. The study also found a tively. Although AML is mostly diagnosed in patients over age 60
significant association with improved survival between the high-dose years, available AML therapy has had its least impact in this age group
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daunorubicin arm and presence of DNMT3A mutations. The dau- and prognosis has not appreciably changed to the better in decades.
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norubicin dose of 90 mg/m /day did not lead to a higher incidence Older patients do worse for various reasons. Comorbidities are fre-
of adverse events (particularly cardiomyopathy and infectious com- quent, and they are more likely to have a poor performance status.
plications). The study can be criticized on the basis that the dose of Hence, tolerance to the myelosuppressive and immunosuppressive
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the comparator arm, daunorubicin 45 mg/m daily for 3 days, is no consequences of intensive chemotherapy is diminished. There are also
longer considered the standard of care in AML, and instead 60 mg/ differences intrinsic to the blast biology between older and younger
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m /dose should be considered standard. A recent MRC trial compared patients. Patients over 60 years of age are more likely to have second-
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daunorubicin 60 mg/m versus 90 mg/m during induction and ary AML (following MDS or another antecedent hematologic disor-
showed equivalent results (Burnett ASH 2014). Daunorubicin der), demonstrate unfavorable cytogenetics, have reduced sensitivity
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90 mg/m daily × 3 equals 270 mg/m , which may prohibit further to anthracyclines, and more often express multidrug-resistant pheno-
anthracyclines therapy (cumulative cardiotoxic dose of daunorubicin types. Assuming that therapy is mostly futile and palliation more
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360–450 mg/m ). appropriate, only about one-third of older patients receive treatment
A metaanalysis of 29 randomized controlled trials compared the for AML. Yet, patients over age 60 years of age should not be pre-
efficacy of different anthracyclines and dosing schedules during AML cluded from therapy. In a landmark randomized analysis by the
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induction therapy. Idarubicin compared with daunorubicin EORTC from 1989 comparing intensive chemotherapy to supportive
improved remission rates, although this effect was limited to studies care, intensive therapy produced a measurable survival advantage.
with a daunorubicin/idarubicin ratio of <5. Likewise, higher dose Other studies have also demonstrated the benefits of therapy over
compared with lower dose daunorubicin improved remission rates. supportive care only, with respect to survival and quality of life.
Survival estimates suggest that both high-dose daunorubicin (90 mg/ To pursue a middle ground between supportive care and intensive
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m /dose × 3 days or 50 mg/m /dose × 5 days) and idarubicin (12 mg/ treatment, lower intensity therapies are increasingly used. Although
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m /dose × 3) can achieve 5-year survival rates of between 40% and they hold promise for many older patients with AML, a select group
50%. Rather than the type of anthracycline, what matters most is to of patients may still benefit from more intense interventions. Older
use equitoxic doses. patients are not a homogeneous group and several models have been
A metaanalysis of trials using HiDAC during induction encom- devised to identify variables that predict which patients may do well
passed 1691 patients and arrived at the following conclusions: there with conventional therapy versus those who will not (Table 59.3).
were no differences between HiDAC and standard-dose cytarabine These models are comprised of patient characteristics, easily acces-
(SDAC) with respect to percent CR and rates of persisting leukemia sible clinical variables, and tumor characteristics. Although perfor-
and early death; 4-year OS and recurrence-free survival, on the other mance status can be a powerful predictor of the probability to survive
hand, were significantly better with HiDAC but at the cost of more intensive therapy, age remains an arbitrary variable and is increasingly
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toxicities (infections, nausea/vomiting, CNS). HiDAC benefited understood to be a poor discriminator of outcome. Efforts are
mostly patients who already were more likely to achieve CR (i.e., therefore underway to capture multiple patient characteristics (phys-
patients with intermediate and favorable karyotype). The major ical and cognitive function, nutritional status, comorbidity, psycho-
drawback of HiDAC during induction is that it may make further logical state and social support) as part of a comprehensive geriatric
consolidation therapy difficult. assessment and to better distinguish patients into fit, vulnerable, and
The MRC AML 15 trial randomized 1268 patients to receive frail (indicating a significantly increased risk of treatment
fludarabine, high-dose cytarabine (ara-C), G-CSF, and idarubicin complications). 16
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(FLAG-Ida; fludarabine 30 mg/m on days 2–6, cytarabine 2 g/m Three broad avenues of therapy in older patients with AML are
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on days 2–6, idarubicin 10 mg/m on days 4–6, and G-CSF on days standard intensive chemotherapy, lower intensity therapy (low-dose
1–7) and 1983 to receive cytarabine (ara-C), daunorubicin, and cytarabine, hypomethylating agent [HMA]), and clinical studies.
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etoposide (ADE; daunorubicin 50 mg/m on days 1, 3, 5; cytarabine Intensive chemotherapy follows the outline already discussed in the
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100 mg/m on days 1–8; and etoposide 100 mg/m on days 1–5), section on younger patients. Given current data, the benefit of
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the latter representing the SDAC arm. FLAG-Ida resulted in higher intensive therapy may be restricted to diploid AML with mutated