Perspectives on the Treatment of

Acute Myeloid
Leukemia

O
ur understanding of acute myeloid APL) AML, categorized as young or old, which
APAR K. GANTI, MD
leukemia (AML) continues to ex- should provide a basis for management, and con-
Fellow
pand, particularly at the molecular cludes with a focus on current deficiencies that
University of Nebraska Medical Center
Section of Oncology/Hematology level. However, whereas in chronic have led to intense investigation.
Omaha, Nebraska myelogenous leukemia a single target
has resulted in the development of a magic bullet, AML in the Elderly
this is not the case in AML. Instead, many small Although elderly is a relative term and its mean-
improvements in outcome have been achieved dur- ing changes depending on the medical discipline
LORI J. MANESS, MD
ing the past couple of decades. The only major under study, it is nevertheless helpful to think of
Assistant Professor of Medicine
improvements have been in the treatment of younger and older AML patients separately when
University of Nebraska Medical Center
Section of Oncology/Hematology younger patients, particularly those with acute treatment decisions are being made. Before 1980,
Omaha, Nebraska promyelocytic leukemia (APL). However, AML is very few older adults were considered candidates
clearly a disease of the elderly; it develops in nearly for intense chemotherapy; thus, little was known
20 per 100,000 persons past the age of 70 years in about potential outcomes. Now, we have data for
Western countries, but in only 1 or 2 per 100,000 this population, some in accordance with those for
young adults.1 As the general population ages, new younger patients and some not. Whether the dis-
and less toxic therapies will be critical to making crepancies represent a different disease etiology
substantial improvements in the treatment of this reflecting the consequences of aging on the stem
disease. Fortunately, future studies will focus on tar- cell remains to be determined.
geted therapies that, it is hoped, may be implicated A randomized study conducted by the European
in the majority of patients, but until the efficacy of Organization for Research and Treatment of Cancer
such therapies is confirmed and accepted, we must (EORTC) in the late 1980s showed that intensive
rely on current data when treating patients with chemotherapy is better than best supportive care in
this disease. This article reviews the results of large, the elderly.2 Despite this finding, only a few large,
randomized trials of patients with non-M3 (ie, non- randomized trials have been completed since that

Volume 8 • 2005 Oncology Special Edition 37

 The Eastern Cooperative Oncology Group
Table 1. Summary of Recent AML Treatment Trials (ECOG) later proved that no outcome differences
were related to choice of anthracycline, and growth
In Elderly Patients factor priming was felt to be detrimental, possibly
because of the treatment delay that it caused,
Study n Min/ No. With Induction CR per Consolidation OS TRM, % although the numbers of patients were small.5 The
Med sAML† Regimen Arm, %
Southwest Oncology Group (SWOG) compared
Age, y*
induction regimens of mitoxantrone (Novantrone,
Archimbaud 160 61/69 42 IAE vs 56 IAE 17% 6 Serono/OSI Pharmaceuticals) plus etoposide versus
et al4 MAE 63 MAE 21% 11 cytarabine (Cytosar-U, Sicor) plus daunorubicin. No
(2 y) differences were found between these regimens.6
The United Kingdom Medical Research Council
UK MRC 1,314 56-61‡/ 299 DAT vs 62 Short (3 cycles) 23% 16 (UK MRC) AML11 trial evaluated the response of
AML 117 66 ADE vs 50 vs long 22% 26
patients older than 55, and later older than 60, with
MA 55 (5 y) 17
de novo or secondary AML to 3 different induction
SWOG6 328 56/67 74 AD vs EM 34 AD (5+2) 19% 15 regimens.7 In addition, the benefits of growth factor
43 11% support, long versus short courses of consolidation,
(2 y) and maintenance versus no maintenance therapy
were evaluated. It was found that remission rates
ECOG5 362 56/68 Not DA vs 41 IDAC × 1 7.7 y 16
were higher in the daunorubicin/cytarabine/
known MA vs 46 7.2 y 14
IA 43 7.3 y 22 thioguanine (DAT) arm than in the cytarabine/
+GM-CSF 38 5.3 y 26 daunorubicin/etoposide (ADE) and mitoxantrone/
–GM-CSF 40 8.5 y 17 cytarabine (MA) groups—possibly because of more
toxic deaths in the ADE arm and more resistance in
*Minimum and median (no maximum age limit in any trial). the MA arm. However, no effect on overall survival
†Secondary AML included treatment-related and prior hematologic diseases. was noted. As in most trials, survival at 5 years was in
‡Age for entry increased to 61 during the trial. the range of 8% to 12%, although it was higher for
Bold numbers in Table indicate significance. those who received consolidation, in the range of
AD, cytarabine/daunorubicin; ADE, cytarabine/daunorubicin/etoposide; CR, complete remission; 22% to 23% (many patients in CR did not receive
DA, daunorubicin/cytarabine; DAT, daunorubicin/cytarabine/thioguanine; ECOG, Eastern Cooperative Oncology Group;
EM, etoposide/mitoxantrone; GM-CSF, granulocyte-macrophage colony–stimulating factor priming; consolidation). Overall, 15% of patients died in CR,
IA, idarubicin/cytarabine; IAE, idarubicin/cytarabine/etoposide; IDAC, intermediate-dose cytarabine;
MA, mitoxantrone/cytarabine; MAE, mitoxantrone/cytarabine/etoposide; OS, overall survival; sAML, secondary AML;
mostly of treatment-related causes. Note that selec-
SWOG, Southwest Oncology Group; TRM, treatment-related mortality; UK MRC, United Kingdom Medical Research Council tion bias likely contributed to the higher survival
rates among those who received consolidation. The
use of growth factors as support, as well as 1 versus
3 courses of consolidation therapy, also had no effect
on overall survival or remission rates.7
In summary, these large trials showed that the
Table 2. High-Risk Prognostic Factors by Group
choice of anthracycline does not matter in terms of
outcome and that short consolidations are as good as
Study Group Poor Prognostic Factors
long [Link] is still no clear conclusion about the
role of autologous transplantation. Perhaps the most
Archimbaud et al4 Age >70, high WBC, high-risk cytogenetics
useful result from these trials was the ability to pos-
tulate which patients would do well with traditional
UK MRC7 Age >70, WBC >100 × 109/L, high-risk cytogenetics, poor
performance score, secondary leukemia chemotherapy (Table 2). With cautious review of
these retrospective subgroup analyses, various prog-
SWOG6 High-risk cytogenetics, increasing WBC, poor performance nostic factors consistently surfaced. The most pow-
status, increasing age erful predictor of the response to chemotherapy was
the cytogenetic risk group (Table 3). Previous
ECOG5 High-risk cytogenetics impressions were that such information was not as
useful in the elderly; however, that idea has changed.
WBC, white blood cell count The UK MRC group7 showed most powerfully that
risk groups similar to those in young patients could
be identified. Factors that may portend a worse out-
time. Issues studied have included optimal come include age older than 70 years,elevated white
chemotherapeutic agents, growth factor priming, blood cell count at initiation of treatment, poor per-
and the plausibility of autologous stem cell trans- formance status,and prior [Link] more is
plantation. Treatment outcomes are presented in learned about the etiology of this disease, further
Table 1 and summarized here. A multicenter trial subgroups may be defined. This is not to suggest that
initiated in the early 1990s evaluated some of these patients with such features are destined for an earli-
issues—specifically, the best anthracycline for er death,but rather that they may be better suited for
induction therapy, whether the addition of etopo- newer targeted treatments and, if willing, should be
side increased benefit in inducing complete remis- entered into clinical trials. With this information, a
sion (CR) in the elderly, as it did in younger tentative algorithm for treatment decisions in this
patients,3 and if autologous transplantation could population is proposed (Figure 1). Clearly, the status
decrease relapse rates compared with nonablative of many of these points is uncertain, and they will
chemotherapy alone. In this trial, the patients were require ongoing evaluation.
older than 60 years with primary or secondary Challenges associated with this plan include how
AML. Investigators found no significant differences best to determine physiologic age and whether to
related to choice of anthracycline; etoposide was consider consolidation therapy. Additionally, the
not an isolated variable and thus no conclusions definitions of low- and high-risk groups will be
could be drawn; and too few patients actually expected to change rapidly as more disease markers
underwent autologous transplantation for any firm are discovered.
assessments to be made.4

38 Oncology Special Edition Volume 8 • 2005

AML in Younger Patients Table 3. Cytogenetic Risk Groups by Study Group
It is generally agreed that cytogenetics is the best
predictor of outcome in young patients. The ques- Study Group Cytogenetic Category Abnormalities
tion now is: Should patients in different risk groups
4
be treated differently? In other words, will risk-strat- Archimbaud et al Favorable t(8;21), t(15;17), abnl 16
ified treatment improve outcomes? Issues to be Intermediate Normal + all others
investigated with regard to this strategy include
how best to induce and consolidate, and—unlike in Unfavorable –5/5q–, –7/7q–, +8, 11q23, t(9;22), complex
the elderly—who should be considered for trans- UK MRC7 Favorable t(15;17), t(8;21), inv 16
plantation in first complete remission (CR1).
Current data have led to risk-adapted therapies. Intermediate Normal + other noncomplex abnls
Whether this approach will improve outcomes is Unfavorable Complex (5+), –5/5q–, –7, abnl 3q
unknown; what it certainly will do, however, is
allow researchers to highlight the areas in greatest SWOG/ECOG26 Favorable t(8;21), inv 16/t(16;16), +14
need of further investigation. Intermediate Normal and other

Induction Therapy Unfavorable –5/5q–, –7/7q–, inv(3), 11q abnl, 17p abnl, i(17q),
Throughout the 1980s and 1990s, research was del 20q, dmins/hsrs, +13, t(9;22), complex (>3)
focused on determining how many drugs to use in abnl, abnormality; del, deletion; dmins, double minute chromosomes; hsrs, homogenously staining regions; inv, inversion
addition to cytarabine and an anthracycline, which
anthracycline is most effective, and whether
increasing the dose intensity of cytarabine is bene-
ficial. Clearly, preferences still vary around the
world, and standard regimens differ globally. One
interpretation of the data is shown in Figure 2.8-16 Performance status <2
The only point of clarity is not new; at a minimum, and absence of significant
induction therapy should include cytarabine plus comorbidities
an anthracycline—with expected overall CR rates
in the range of 70% to 80%.
Some groups are continuing to investigate vari- YES
ous induction regimens. For example, several
groups have combined anti-CD33 antibody therapy
Patient willing to undergo
with standard chemotherapy, analogous to the
intense chemotherapy
cyclophosphamide/doxorubicin/vincristine/pred-
nisone (CHOP)/rituximab (Rituxan, Biogen Idec/
Genentech) regimen in lymphoma. As would be Best supportive care or
NO
YES clinical trial
expected, CR rates are improved, but toxicity is
greater. Long-term outcomes are still pending, and it
seems a definitive niche is yet to be found for these Favorable- or intermediate-
treatments.17 Since the current goal is to tailor ther- risk cytogenetics
apy according to risk group, this intensive approach
may be best suited for higher-risk patients.
One issue that remains controversial among YES
experts is whether growth factor priming should
be used in induction. Current evidence supports
Physiologic age <70
both sides of the argument. This is an important
issue to consider, particularly since the most pop-
ular salvage regimen continues to be fludarabine
YES
(Fludara, Berlex)/cytarabine/granulocyte colony–
stimulating factor (ie, FLAG), in which the concept
Consolidation in complete
of growth factor priming is incorporated. As dis- Standard induction or
remission
cussed with regard to the elderly, some consider clinical trial
growth factor priming to be detrimental because
it entails a delay in chemotherapy.5 In a recent
Dutch-Belgian Hemato-Oncology Cooperative Figure 1. Treatment decision flowchart for elderly
Group (HOVON) trial involving younger patients, AML patients.
growth factor priming did improve disease-free
survival but not the CR or overall survival rate.18
No sound conclusions can be drawn from the cells. A recently published CALGB study showed
available evidence at this time, but the issue con- better disease-free and overall survival, at least in
tinues to be investigated. patients younger than age 46, with addition of the
In another approach, the Acute Leukemia P-glycoprotein inhibitor PSC-833 to induction
French Group (ALFA) found that patients younger therapy with daunorubicin, cytarabine, and etopo-
than 50 years of age who were given timed, side. However, therapy was noted to be more toxic
sequential induction therapy (ie, standard induc- when PSC-833 was added, which may explain the
tion therapy followed by mitoxantrone and cytara- younger age of those who derived benefit. A large
bine starting on day 8) had a longer relapse-free Phase III study is planned to confirm these
interval than did patients given standard induction findings.20 Importantly, reversion to normal cyto-
or double induction therapy.19 Resistance to genetics after induction therapy was recently
chemotherapy may be due, in part, to the overex- shown to be an important prognostic marker in
pression of P-glycoprotein, which causes efflux of patients who achieved a morphologic complete
the chemotherapeutic agents from the leukemic response.21

Volume 8 • 2005 Oncology Special Edition 39

 Table 4. Summary of CALGB Cytogenetic Data: Risk Groups transplantation is somewhat easier. Simply stated,
transplantation should be considered for anyone of
By Outcome Measure28 appropriate age with an adequate donor, possibly
excluding those with inv(16), who appear to have
Cytogenetic Induction Success Cumulative Incidence Overall Survival a high likelihood of achieving a durable CR227 and
Risk Group Of Relapse have a unique disease.28
Given the continued significant morbidity and
Favorable t(8;21), inv 16/t(16;16) t(8;21), inv 16/t(16;16) t(8;21), inv 16/t(16;16)
(CR 88%, OS 55%) mortality associated with allogeneic transplanta-
del(9q)*
tion, patients in CR1 who ideally should undergo
Intermediate Normal, –Y, del(5q), t(6;9), Normal, –Y, t(9;11), Normal, –Y, del(5q), loss transplantation are those who are most likely to die
(CR 67%, OS 24%) t(6;11), –7, del(7q), +8 del(9q), +8 sole, +8 plus of 7q, t(9;11), +11, of their disease within a period of time that is per-
sole, +8 plus 1 other abnl, 1 other abnl, +11, +13 del(11q), abn(12p), +13,
sonally unacceptable, yet can accept the toxicities
del(9q), t(9;11), +11, del(20q), +21
del(11q), t(11;19), +13, of this treatment. As this issue has been investigat-
del(20q), +21 ed throughout the 1990s and currently, a large body
of data regarding prognostics has become available.
Adverse Complex (3+ abnl), inv(3), Complex (3+), –7, +21 Complex (3+), inv(3), Several groups have contributed to this pool of
(CR 32%, OS 5%) t(3;3), abnl(12p) t(3;3), t(6;9), t(6;11), –7,
data, including Cancer and Leukemia Group B
+8 sole, +8 sole plus 1,
t(11;19) (CALGB),28 SWOG/ECOG,29 UK MRC,30 and the
EORTC/Gruppo Italiano Malattie Ematologiche
abnl, abnormality; CALGB, Cancer and Leukemia Group B; CR, complete response; del, deletion; inv, inversion; OS, overall survival Maligne dell’Adulto (EORTC/GIMEMA).31 The
*Would be intermediate group if only those patients undergoing transplantation were considered. CALGB has published a very complete set of data
regarding the relationship between pretreatment
cytogenetics and induction success, cumulative
incidence of relapse, and overall survival.28
Importantly, they have found that t(8;21) and
inv(16)/t(16;16) continue to carry a good progno-
Conclusion References sis regardless of the presence of additional abnor-
malities. Notably, even patients with good prog-
nostic features have an overall survival rate of
55%. This is in keeping with data from other
groups. Not surprisingly, the overall survival of
A small benefit may exist for idarubicin over 8-10 high-risk cytogenetic groups is about 5% (Table 4).
daunorubicin Overall survival in the intermediate-risk group
ranges widely. The majority of patients within this
group have normal cytogenetics—underscoring
the need for additional risk markers.
Three large groups assessed outcomes by risk
High-dose cytarabine is likely beneficial for younger 11-15
category in response to varying consolidation
and high-risk patients (in addition to those with core-
binding factor AML), although it is not clear if it treatments of intensive chemotherapy, autologous
should be given during induction or consolidation transplantation, or matched related donor (MRD)
transplantation. Again, note that what one group
considered intermediate risk, another might classi-
fy as high risk. Table 5 shows the outcomes based
on risk groups. SWOG/ECOG found that patients
Additional drugs such as 6-thioguanine or etoposide 3, 16 with low-risk cytogenetic features did best with
are not unequivocally of benefit
autologous bone marrow transplantation, interme-
diate-risk patients did best with chemotherapy, and
high-risk patients did marginally better with allo-
geneic transplantation (P=0.043).29 When the UK
Figure 2. Basic induction therapy issues from MRC evaluated outcomes based on donor versus
past studies of AML. no donor, they found that only their intermediate-
risk group experienced a survival benefit from
transplantation in CR1.30 The EORTC/GIMEMA
Consolidation found improved disease-free survival rates in the
Some type of consolidation is a necessity. High- group with a donor in combination with high-risk
dose cytarabine has essentially been established as cytogenetic features; however, significant improve-
a necessary element at this point.22 Another issue ments in survival were not appreciated at 4 years,
that has been investigated by many groups is although a trend was noted in favor of allogeneic
whether to use autologous transplantation. Results versus autologous transplantation.31
have been inconsistent, and therefore, depending Other factors that may be important in deter-
on where one is in the world, it may or may not be mining risk that can be assessed during the induc-
a part of standard treatment.16,23-26 The only fact tion phase are early blast clearance and possibly
that is not currently controversial is that patients lactic dehydrogenase level or white blood cell
with t(8;21), t(15;17), or inv(16)/t(16;16) in CR1 count at presentation. The German AML Coopera-
should not be considered for any treatment other tive Group found that patients with more than 10%
than consolidation chemotherapy, whether abla- blasts in their bone marrow 1 week after the com-
tive or not. For the majority of patients who are not pletion of chemotherapy, and those with high lev-
in this category, the much more difficult question els of lactic dehydrogenase, had worse CR, disease-
remains of who in CR1 should undergo transplan- free survival, and overall survival rates.32 Whether
tation from an allogeneic source. The question of these factors should be included in treatment algo-
who in second complete remission (CR2) requires rithms is unknown.

40 Oncology Special Edition Volume 8 • 2005

 Recent data are available from the German AML Table 5. Large Trials Comparing Donor vs No Donor as Assessed
Study Group Ulm, the first group to publish results
based on risk-adapted therapy.33 After all patients By Cytogenetic Risk Group
received their established standard double induc-
tion therapy, those who entered remission were Trial Protocol Groups Benefiting From Early Transplant
stratified according to risk (Figure 3). Low-risk
SWOG/ECOG29 609 CRs, age <56 y, ran- Favorable-risk patients have better outcome
patients received 1 cycle of consolidation; interme- domized to intensive with autoBMT; unfavorable-risk patients
diate-risk patients received an allogeneic transplant chemotherapy, autoBMT, have better outcome with alloBMT in terms
if an MRD was available and otherwise received or alloBMT (if MRD) of survival
consolidation chemotherapy; high-risk patients
received an MRD allogeneic transplant if available UK MRC AML 1030 Patients randomized to DFS and survival advantage in patients in
and otherwise received an autologous transplant. alloBMT or autoBMT fol- intermediate-risk group, age <35 y
lowing 4 intense
Disease-free survival and survival at 5 years in low-,
chemotherapy courses
intermediate-, and high-risk patients were 62.5%
and 87%, 40% and 49%, and 17% and 26%, respec- EORTC/GIMEMA31 CR1s received 1 intensive DFS advantage for patients <35 y in high-
tively. Compared with the CALGB cytogenetic data, chemotherapy course, very high-risk groups
then randomized to
these results appear better; however, as the authors alloSCT or autoSCT
appropriately noted, more data are required to
make such a statement. alloBMT, allogeneic bone marrow transplantation; alloSCT, allogeneic stem cell transplantation; autoBMT, autologous bone
Clinicians can construct similar treatment algo- marrow transplantation; autoSCT, autologous stem cell transplantation; CRs, patients in complete remission; CR1s, patients in
first complete remission; DFS, disease-free survival; MRD, matched related donor
rithms based on this model (Figure 4). How one
proposes to classify risk categories is a matter of
debate, as already discussed. In addition, although
they were not used in this trial, matched unrelated
donors (MUDs) should be considered, particularly
for patients in the high-risk group. Because only Table 6. New Agents in the Treatment of AML
30% of adults have matched sibling donors avail-
able, this becomes an attractive option. Outcomes
Study Agent Characteristics n Response Toxicity
in small studies of adult AML are nearly as good
with MUDs as with MRDs; transplant-related Piccaluga39 Gemtuzumab Relapsed/refractory 24 21% CR; dura- Cytopenias,
mortality rates are roughly equivalent based on the AML tion of elevated liver
center evaluated. As we learn how to separate graft- response, 6 mo enzymes
versus-host from graft-versus-leukemia effects, this Karp40 Tipifarnib Relapsed/refractory 34 29% response Mostly transient
therapy will become more useful. At present, most AML or ALL; newly rate; CR in 2 grade 1-2
centers are limiting the use of MUDs to high-risk diagnosed poor-risk patients toxicities
groups, perhaps underestimating their usefuless. AML in adults >60 y;
secondary AML; CML in
Finally, an international Phase III study
blast crisis
addressed the issue of maintenance therapy in
AML, which is not the standard of care. Smith41 CEP-701 Refractory, relapsed, or 14 5 patients with Minimal
Interestingly, the investigators showed that a com- poor-risk AML measurable
response
bination of histamine dihydrochloride and IL-2
given after consolidation significantly improved Fiedler42 SU5416 Refractory AML; elderly 43 1 morphologic Nausea,
leukemia-free survival compared with no further AML CR headache,
therapy, suggesting that some additional therapy 7 PR bone pain
may be needed, even after consolidation therapy.
Giles43 PKC412 + Newly diagnosed AML 15 6 CR Nausea, vomiting
The effect of such therapy on overall survival, how- daunorubicin
ever, was not addressed in this study.34 + cytarabine

Issa44 Decitabine AML/MDS, CML, ALL 50 9 CR Myelosuppression

Future Directions 1 PR
Disease Biology Qazilbash45 PR1 peptide + Relapsed/refractory 21 4 CR (AML) Injection-site
As shown by the data, prognostic factors are a G-CSF AML, MDS 1 PR (MDS) reactions
subject of great interest. New molecular variables
ALL, acute lymphocytic leukemia; CML, chronic myelogenous leukemia; CR, complete remission;
are decreasing the unknown regarding various G-CSF, granulocyte colony–stimulating factor; MDS, myelodysplastic syndrome; PR, partial remission
cytogenetic abnormalities or lack thereof. Abnor-
malities in the Flt3 gene (Fms-like tyrosine kinase, a
member of the class III receptor tyrosine kinase
family), including internal tandem duplications and therapy of AML when given singly; rather, they
point mutations, are acquiring importance, as are may have to be combined with other targeted
gene mutations in the BAALC,35 CEBPA,36,37 and agents or cytotoxic chemotherapy to have an opti-
HOX domains,38 among others. These markers are mal effect. The groups currently in clinical trials
not only predictive of outcome; some are also act- include the following:
ing as targets of novel therapies. • Farnesyl transferase inhibitor: tipifarnib (R115777,
Zarnestra; Johnson & Johnson)
New Targets • FLT-3 inhibitors: CEP-701 (Cephalon), SU5416
Many new agents are being investigated for (Sugen), PKC412 (Novartis)
efficacy in AML. Although most are still in early • Histone deacetylase inhibitors: decitabine
development, a common feature is their ability to (Dacogen; MGI Pharma/SuperGen), depsipeptide
affect specific targets on the leukemic cell. • Vaccines against PR1 leukemia–associated antigen
Importantly, however, these newer agents are Preliminary data for these agents are provided in
unlikely to have a major impact on the current Table 6.39-45

Volume 8 • 2005 Oncology Special Edition 41

 13. Büchner T, Hiddemann W,Wormann B, et al. Double
induction strategy for acute myeloid leukemia: the effect
of high-dose cytarabine with mitoxantrone instead of
Complete Remission standard-dose cytarabine with daunorubicin and
6-thioguanine: a randomized trial by the German
AML Cooperative Group. Blood. 1999;93:4116-4124.
14. Kern W, Aul C, Maschmeyer G, et al. Superiority of high-dose
over intermediate-dose cytosine arabinoside in the treat-
ment of patients with high-risk acute myeloid leukemia:
Low risk: Intermediate risk: High risk: all results of an age-adjusted prospective randomized
comparison. Leukemia. 1998;12:1049-1055.
t(8;21) or normal other chromoso-
inv/t(16q22) cytogenetics mal abnormalities 15. Stein AS, O’Donnell MR, Slovak ML, et al. High-dose cytosine
arabinoside and daunorubicin induction therapy for adult
patients with de novo non-M3 acute myelogenous leukemia:
impact of cytogenetics on achieving a complete remission.
Leukemia. 2000;14:1191-1196.
16. Burnett AK, Goldstone AH, Stevens RM, et al. Randomised
comparison of addition of autologous bone marrow trans-
HAM MRD alloSCT Sequential MRD AutoSCT plantation to intensive chemotherapy for acute myeloid
(if available) HAM alloSCT (if (if no leukaemia in first remission: results of MRC AML10 trial.
(if no donor) available) donor) UK Medical Research Council Adult and Children’s
Leukaemia Working Parties. Lancet. 1998;351:700-708.
17. Kell WJ, Burnett AK, Chopra R, et al. A feasibility study of
simultaneous administration of gemtuzumab ozogamicin
with intensive chemotherapy in induction and consolida-
DFS 62.5% DFS 49% DFS 38% DFS 8% DFS 22% tion in younger patients with acute myeloid leukemia.
Blood. 2003;102:4277-4283.
18. Lowenberg B, van Putten MD, Theobald M, et al. Effect of
priming with granulocyte colony-stimulating factor on the
outcome of chemotherapy for acute myeloid leukemia.
N Engl J Med. 2003;349:743-752.
OS 87% OS 50% (NS) OS 26% (NS) 19. Castaigne S, Chevret S, Archimbaud E, et al. Randomized
comparison of double induction and timed-sequential
induction to a "3 + 7" induction in adults with AML: long-
term analysis of the Acute Leukemia French Association
(ALFA) 9000 study. Blood. 2004;104:2467-2474.

alloSCT, allogeneic stem cell transplantation; autoSCT, autologous stem cell transplantation; DFS, disease-free survival;
20. Kolitz JE, George SL, Dodge RK, et al. Dose escalation stud-
HAM, high-dose cytarabine and mitoxantrone; MRD, matched related donor; NS, not significant; OS, overall survival ies of cytarabine, daunorubicin, and etoposide with and
without multidrug resistance modulation with PSC-833 in
untreated adults with acute myeloid leukemia younger than
60 years: final induction results of Cancer and Leukemia
Figure 3. German Multicenter AML HD93 study schematic. Group B Study 9621. J Clin Oncol. 2004;22:4290-4301.
21. Marcucci G, Mrózek K, Ruppert AS, et al. Association of
abnormal cytogenetics at date of morphologic complete
remission (CR) with overall survival (OS), disease-free sur-
vival (DFS) and higher relapse rate in acute myeloid
Conclusion Cooper IA. Etoposide in leukemia. Cancer. 1991;67(suppl leukemia (AML): results from Cancer and Leukemia Group B
1):285-291. (CALGB) 8461 [abstract]. J Clin Oncol. 2004;22(14S):561S.
AML is a deadly disease; even in the best of cir- Abstract 6514.
4. Archimbaud E, Jehn U, Thomas X, et al. Multicenter random-
cumstances, patients still have an overall survival ized phase II trial of idarubicin vs mitoxantrone, combined 22. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive post-remis-
rate of less than 60%. Current efforts include with VP-16 and cytarabine for induction/consolidation ther- sion chemotherapy in adults with acute myeloid leukemia.
improving risk-adapted therapies in an effort to apy, followed by a feasibility study of autologous peripheral Cancer and Leukemia Group B. N Engl J Med.
blood stem cell transplantation in elderly patients with 1994;331:896-903.
spare patients the morbidity and mortality acute myeloid leukemia. Leukemia. 1999;13:843-849.
23. Zittoun RA, Mandelli F,Willemze R, et al. Autologous or allo-
resulting from unnecessary treatment. Particular 5. Rowe JM, Neuberg D, Friedenberg W, et al. A phase 3 study geneic bone marrow transplantation compared with inten-
improvements are necessary in the treatment of of three induction regimens and of priming with GM-CSF sive chemotherapy in acute myelogenous leukemia.
in older adults with acute myeloid leukemia: a trial by the European Organization for Research and Treatment of
elderly patients, many of whom have poor prog- Cancer (EORTC) and the Gruppo Italiano Malattie
Eastern Cooperative Oncology Group. Blood.
nostic features. For the clinician faced with treat- 2004;103:470-485. Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia
ment decisions, it may be comforting to know that Cooperative Groups. N Engl J Med. 1995;332:217-223.
6. Anderson JE, Kopecky KJ,Willman CL, et al. Outcome after
efforts are under way not only to improve the use- 24. Harousseau JL, Cahn JY, Pignon B, et al. Comparison of autol-
induction chemotherapy for older patients with acute
ogous bone marrow transplantation and intensive
fulness of current treatments but also to develop myeloid leukemia is not improved with mitoxantrone
chemotherapy as postremission therapy in adult acute
and etoposide compared to cytarabine and daunorubicin:
new, less toxic therapies. If clinical trials are not a Southwest Oncology Group study. Blood. 2002;
myeloid leukemia. The Groupe Ouest Est Leucemies Aigues
available for patients who are not candidates for Myeloblastiques (GOELAM). Blood. 1997;90:2978-2986.
100:3869-3876.
traditional therapy or are unwilling or unable to 25. Cassileth PA, Harrington DP, Appelbaum FR, et al.
7. Goldstone AH, Burnett AK,Wheatley K, et al. Attempts to Chemotherapy compared with autologous or allogeneic
travel to where trials are being conducted, agents improve outcomes in acute myeloid leukemia (AML) in bone marrow transplantation in the management of acute
for supportive care, such as hydroxyurea for older patients: the results of the United Kingdom Medical myeloid leukemia in first remission. N Engl J Med.
Research Council AML 11 trial. Blood. 2001;98:1302-1311. 1998;339:1649-1656.
uncontrollable blood counts and symptomatic
8. Berman E, Heller G, Santorsa J, et al. Results of a randomized 26. Byrd JC, Ruppert AS, Mrózek K, et al. Repetitive cycles of
transfusions, are simple and humane management trial comparing idarubicin and cytosine arabinoside with high-dose cytarabine benefit patients with acute myeloid
tools. Although the improvements in the treatment daunorubicin and cytosine arabinoside in adult patients leukemia and inv(16)(p13q22) or t(16;16)(p13;q22): results
of AML seem small, we have entered an era in with newly diagnosed acute myelogenous leukemia. Blood. from CALGB 8461. J Clin Oncol. 2004;22:1087-1094.
1991;77:1666-1674.
which substantial progress is possible and likely, 27. Delaunay J,Vey N, Leblanc T, et al. Prognosis of
9. Wiernik PH, Banks PL, Case DC Jr, et al. Cytarabine plus inv(16)/t(16;16) acute myeloid leukemia (AML): a survey of
particularly with the newer molecular techniques. 110 cases from the French AML Intergroup. Blood.
idarubicin or daunorubicin as induction and consolidation
therapy for previously untreated adult patients with acute 2003;102:462-469.
myeloid leukemia. Blood. 1992;79:313-319. 28. Byrd JC, Mrozek K, Dodge RK, et al. Pretreatment cytogenet-
References 10. Vogler WR,Velez-Garcia E,Weiner RS, et al. A phase III trial
ic abnormalities are predictive of induction success, cumu-
lative incidence of relapse, and overall survival in adult
1. National Cancer Institute. SEER Cancer Statistics Review, comparing idarubicin and daunorubicin in combination
patients with de novo acute myeloid leukemia: results from
1975-2000. Ries LAG, Eisner MP, Kosary CL, et al, eds. with cytarabine in acute myelogenous leukemia: a
Cancer and Leukemia Group B (CALGB) 8461. Blood.
Bethesda, Md: National Cancer Institute; 2004. Available at: Southeastern Cancer Study Group study. J Clin Oncol.
2002;100:4325-4336.
[Link] Accessed February 1992;10:1103-1111.
24, 2005. 29. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analy-
11. Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized sis predicts outcome of preremission and postremission
2. Lowenberg B, Zittoun R, Kerkhofs H, et al. On the value of investigation of high-dose versus standard-dose cytosine arabi- therapy in adult acute myeloid leukemia: a Southwest
intensive remission-induction chemotherapy in elderly noside with daunorubicin in patients with previously untreat- Oncology Group/Eastern Cooperative Oncology Group
patients of 65+ years with acute myeloid leukemia: a ran- ed acute myeloid leukemia: a Southwest Oncology Group study. Blood. 2000;96:4075-4083.
domized phase III study of the European Organization for study. Blood. 1996;88:2841-2851.
Research and Treatment of Cancer Leukemia Group. J Clin 30. Burnett AK,Wheatley K, Goldstone AH, et al. The value of
12. Bishop JF, Matthews JP,Young GA, et al. A randomized study allogeneic bone marrow transplant in patients with acute
Oncol. 1989;7:1268-1274.
of high-dose cytarabine in induction in acute myeloid myeloid leukaemia at differing risks of relapse: results of the
3. Bishop JF, Lowenthal R, Joshua D, Matthews JP,Wolf MM, leukemia. Blood. 1996;87:1710-1717. UK MRC AML 10 trial. Br J Haematol. 2002;118:385-400.

42 Oncology Special Edition Volume 8 • 2005

 Induction
Anthracycline +
cytarabine ?HDAC, ? ±G-CSF
priming, ? ± additional agents

Assess bone marrow

1 wk after end of
chemotherapy

Increased or stable blasts >10% residual blasts but <10% residual blasts
fewer than at presentation

Reinduce with salvage Repeat initial × 1

(eg, FLAG)

Reassess bone marrow

No CR upon count recovery CR

Consolidate
Clinical trial

Risk-Assessed Consolidation
Treatment

Good Risk Intermediate Risk Poor Risk

• t(8;21), inv(16), t(16;16) • Normal CG • –5/5q–, –7/7q–
• ? Others • Complex (? >3-5 abnl)
•? Others
Controversial

Standard
HDAC × 3-4 HDAC, autoSCT, MRD transplant if available,
MRD transplant otherwise MUD transplant

abnl, abnormalities; autoSCT, autologous stem cell transplantation; CG, cytogenetics; CR, complete remission; FLAG, fludarabine/cytarabine/granulocyte colony–stimulating factor;
HDAC, high-dose cytarabine; MRD, matched related donor; MUD, matched unrelated donor

Figure 4. Proposed treatment algorithm for young adults with AML.

31. Suciu S, Mandelli F, de Witte T, et al. Allogeneic compared leukemia (AML) patients: a CALGB study update [abstract]. 41. Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a
with autologous stem cell transplantation in the treatment Ann Hematol. 2004;83(suppl 1):abstract 1. novel FLT3 inhibitor, shows biologic and clinical activity in
of patients younger than 46 years with acute myeloid 36. Preudhomme C, Sagot C, Boissel N, et al. Favorable prognos- patients with relapsed or refractory acute myeloid
leukemia (AML) in first complete remission (CR1): an inten- tic significance of CEBPA mutations in patients with de leukemia. Blood. 2004;103:3669-3676.
tion-to-treat analysis of the EORTC/GIMEMA AML-10 trial. novo acute myeloid leukemia: a study from the Acute
Blood. 2003;102:1232-1240. 42. Fiedler W, Mesters R, Tinnefeld H, et al. A phase 2 clinical
Leukemia French Association (ALFA). Blood. study of SU5416 in patients with refractory acute myeloid
32. Kern W, Haferlach T, Schoch C, et al. Early blast clearance by 2002;100:2717-2723. leukemia. Blood. 2003;102:2763-2767.
remission induction therapy is a major independent prog- 37. Frohling S, Schlenk RF, Stolze I. CEBPA mutations in younger
nostic factor for both achievement of complete remission adults with acute myeloid leukemia and normal cytogenet- 43. Giles F, Schiffer C, Kantarjian H, et al. Phase 1 study of
and long-term outcome in acute myeloid leukemia: data ics: prognostic relevance and analysis of cooperating muta- PKC412, an oral FLT3 kinase inhibitor, in sequential and
from the German AML Cooperative Group (AMLCG) 1992 tions. J Clin Oncol. 2004;22:624-633. concomitant combinations with daunorubicin and cytara-
trial. Blood. 2003;101:64-70. bine (DA) induction and high-dose cytarabine (HDAra-C)
38. Drabkin HA, Parsy C, Ferguson K, et al. Quantitative HOX consolidation in newly diagnosed patients with AML
33. Schlenk RF, Benner A, Hartmann F, et al. Risk-adapted postre- expression in chromosomally defined subsets of acute mye- [abstract]. Blood. 2004;104:abstract 262.
mission therapy in acute myeloid leukemia: results of the logenous leukemia. Leukemia. 2002;16:186-195.
German Multicenter AML HD93 treatment trial. Leukemia. 44. Issa JP, Garcia-Manero G, Giles FJ, et al. Phase 1 study of low-
2003;17:1521-1528. 39. Piccaluga PP, Martinelli G, Rondoni M, et al. Gemtuzumab
ozogamicin for relapsed and refractory acute myeloid dose prolonged exposure schedules of the hypomethylating
34. Brune M, Castaigne S, Catalano J, et al. Improved leukemia- leukemia and myeloid sarcomas. Leuk Lymphoma. agent 5-aza-2’-deoxycytidine (decitabine) in hematopoietic
free survival after post-consolidation treatment with hista- 2004;45:1791-1795. malignancies. Blood. 2004;103:1635-1640.
mine dihydrochloride and interleukin-2 in AML: a random-
40. Karp JE, Lancet JE, Kaufmann SH, et al. Clinical and biologic 45. Qazilbash MH,Wieder E, Rios R, et [Link] with the
ized phase III trial [abstract]. Blood. 2004;104:abstract 261.
activity of the farnesyltransferase inhibitor R115777 in adults PR1 leukemia-associated antigen can induce complete
35. Baldus CD, Tanner SM, Ruppert A, et al. High BAALC expres- with refractory and relapsed acute leukemias: a phase 1 clini- remission in patients with myeloid leukemia [abstract].
sion predicts adverse outcome in de novo acute myeloid cal-laboratory correlative trial. Blood. 2001;97:3361-3369. Blood. 2004;104:abstract 259.

Volume 8 • 2005 Oncology Special Edition 43