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persistent leukemia.

M, mitoxantrone; A, ara-C; D, daunorubicin; I, idarubicin; E, etoposide; T, thioguanine; P, PSC-833; GM-CSF, granulocyte-macrophage colony-stimulating factor; G-CSF, granulocute-colony-stimulating factor; ND, not done.

M, mitoxantrone; A, ara-C; D, daunorubicin; I, idarubicin; E, etoposide; T, thioguanine; P, PSC-833; GM-CSF, granulocyte-macrophage colony-stimulating factor; G-CSF, granulocute-colony-stimulating factor; ND, not done.

a For comparison of DAT to ADE. b For comparison of DAT to MAC. c For comparison of ADE to MAC.

Reprinted from Stone RM, O'Donnell MR, Sekeres MA: Acute myeloid leukemia. Hematology Am Soc Hematol Educ Program 98-117, 2004, copyright American Society of Hematology, U.S.A.

and no difference in OS in this population.64 Another study compared an induction regimen consisting of idarubicin, ara-C, and etoposide to mitoxantrone, ara-C, and etoposide in 160 patients over the age of 60 years.65 There was no statistically significant difference between the two therapy arms in terms of CR rates, neutrophil and platelet recovery (approximately 25 days in both arms), median disease-free survival, 2-year survival, and in treatment-related toxicities.

An Eastern Cooperative Oncology Group (ECOG) study randomized 349 newly diagnosed AML patients older than 55 years to receive ara-C with either daunorubicin, idarubicin, or mitoxantrone as remission induction therapy.66 Two hundred thirty-six patients underwent subsequent randomization to priming with granulocyte-macrophage colony-stimulating factor (GM-CSF) versus placebo. The overall CR rate was 42%, the median disease-free survival was 7 months and OS was 14 months, and therapy-related toxicity was 16%, with no statistically significant differences among the induction regimens. Interestingly, the CR rate and OS were greater for the first 113 patients who did not have a delay in receiving their induction regimen due to priming regimen versus placebo randomization.

Although some debate exists regarding the equivalency of anthracycline and anthracenedione dosing in comparative trials, given the lack of survival benefit of one agent over another, we consider the three to have equivalent efficacy in the population of older patients with AML, and thus to be interchangeable.

Varying 7 + 3 doses

There is evidence that higher doses of anthacyclines may affect higher CR rates.6768 A direct comparison was conducted by the German AML Cooperative Group. In their study, daunorubicin at a dose of 60 mg/ m2/day was compared to daunorubicin at a dose of 30 mg/m2/day in combination with ara-C and 6-thioguanine. The higher dose of daunorubicin resulted in a significantly higher CR rate compared to the lower dose,69,70 but there was no difference in OS. There has never been a prospective comparison of daunorubicin at doses of 45 mg/m2/day versus 60 mg/ m2/day in older adults, and thus we cannot recommend the higher dose.

Similarly, there does not seem to be a benefit to higher doses of ara-C in remission induction therapy. One study randomized 326 patients to receive ara-C at 100 mg/m2/day or ara-C at 200 mg/m2/day combined with daunorubicin.27 For patients of age 60 years or older, CR rates were actually lower in the higher dose arm, though not significantly, and median OS was similar for both groups, though this study has been criticized for short survival times.18

Additional remission induction agents (7 + 3 + • • •)

Another approach is to take advantage of the biological characteristics relatively specific to AML in older adults and add experimental agents to standard anthracycline- or anthracenedione-based therapy. A phase I study of 31 patients of 56 years of age or older with AML involved remission induction therapy which consisted of mitoxantrone, etoposide, and PSC 833, a cyclosporine analog capable of inhibiting the p-glycoprotein efflux pump.71 The median age of enrolled patients was 71 years, and 70% expressed p-glycoprotein, as would be expected in this popula-tion.22 The overall CR was 50% after a single induction attempt, and the overall median survival was approximately 9 months at the study's termination. A phase III study comparing daunorubicin, ara-C, etoposide, and PSC 833 to daunorubicin, ara-C, and etoposide, on the other hand, had to close accrual to the PSC 833 arm after the first 120 patients were enrolled when an interim analysis revealed an increased early mortality rate compared to the standard arm.8 Cyclosporine A works in similar ways to overcome the p-glycoprotein pump, thus increasing intracellular anthracycline levels, and is still being evaluated in studies.72-74

In direct or historical comparisons, no survival advantage has been found in older AML patients, with the addition to standard 7 + 3 therapy of etoposide or thioguanine.8'5165 75 The MRC AML 11 trial randomized 1314 older patients to receive DAT (daunorubicin, ara-C, and thioguanine), ADE (daunorubicin, ara-C, and etoposide), or MAC (mitoxantrone and ara-C).29 Patients randomized to the DAT arm had significantly higher CR rates, whereas those randomized to the ADE arm had higher rates of induction death, and those receiving MAC had higher rates of resistant disease. There were no substantial differences in long-term survival among the three remission induction arms.

Gemtuzumab ozogamicin

While standard induction regimens affect the replication of all bone marrow stem cells, antibody-targeted therapy has the potential of selectively ablating malignant myeloid cells while sparing normal stem cells. Gemtuzumab ozogamicin (GO, CMA-676, or Mylotarg) is a humanized monoclonal antibody that targets the CD33 antigen, expressed in 90% of patients with AML.76-78 It is conjugated to the toxin calicheamycin. GO was approved by the Food and Drug Administration for the treatment of older AML patients with relapsed or refractory AML who are not candidates for other cyto-toxic chemotherapy and whose myeloblasts express CD33. This was based on phase 2 data showing overall response rates of 26% and a median relapse-free survival of 6.8 months.7980 GO is now being used as single-agent up-front therapy or in combination with 7 + 3 in older AML patients. It will be discussed in more detail in the relapsed or refractory AML setting in Chapter 9.

Hematopoietic growth factors

In the majority of AML patients, death results from bleeding or infectious complications.81 This is particularly true in older adults with AML. The utility of hematopoietic growth factors (HGF), including granulocyte colony-stimulating factor (G-CSF) and GM-CSF, for ameliorating the myelosuppressive complications of AML therapy in older adults has been studied exten-sively.6'35'36'38'39'67'82'83 These prospective, randomized trials were also designed to determine whether or not HGF had detrimental effects in the inappropriate stimulation of leukemic cell proliferation and thus resistance, or whether they had beneficial effects in "priming" leukemic cells to proliferate prior to the administration of S-phase specific chemotherapy agents such as ara-C.10 84 With the exception of one ECOG study that demonstrated a CR rate and OS benefit in patients randomized to the GM-CSF arm (compared to patients receiving no growth factor sup-port),67 these trials found that while HGF are safe, reduce the duration of neutropenia (by a range of 2-6 days), and do not support leukemia cell proliferation, they also do not reliably improve the CR rate, the length of hospitalization, the induction death rate, or prolong survival.

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