ur understanding of acute myeloid leukemia (AML)
continues to grow, particularly at the molecular level.
Still, as research remains ongoing, it has become increasingly
clear that AML is a very complex and heterogeneous disease, not
likely to be cured with one therapeutic advance alone.
Fortunately, as researchers define distinct subsets of this deadly disease, more therapies are emerging. Additionally, an enhanced and improved immuno-therapeutic approach involving stem cell transplantation has become an option for greater numbers of patients.
The aim of this article is to address the larger stud-ies of non-APL (acute promyelocytic leukemia) AML. These studies have helped both to define current treat-ments and to direct current and future research.
AML in Elderly Patients
Although “elderly” is a relative term, it is neverthe-less helpful to distinguish patients who may not be
Information that can help physicians objectively make such a decision is much needed, and some large studies have been performed to evaluate outcomes in older patients undergoing therapy. Recent research is focusing on which patient-related and disease-related factors may be predictive of outcome, and the results should provide some guidance.
A randomized study conducted by the European Organization for Research and Treatment of Cancer (EORTC) in the late 1980s showed that intensive chemotherapy is better than best supportive care in the elderly.1Since then, a few large, randomized trials
have been completed. Issues studied have included
O
Perspectives on the Treatment of
Acute Myeloid Leukemia
L
ORIJ. M
ANESS, MD
Assistant Professor of Medicine University of Nebraska Medical Center
College of Medicine Section of Oncology/Hematology
Omaha, Nebraska
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Table 1 and summarized here.
A multicenter trial initiated in the early 1990s eval-uated some of these issues—specifically, the best anthracycline for induction therapy, whether the addi-tion of etoposide increased benefit in inducing com-plete remission (CR) in the elderly, as it did in younger patients,2 and if autologous transplantation could
decrease relapse rates more effectively than nonabla-tive chemotherapy alone. In this trial, the patients were older than 60 years and had primary or second-ary AML. Investigators found no significant differ-ences related to choice of anthracycline; etoposide was not an isolated variable, so that no conclusions could be drawn, and too few patients actually under-went autologous transplantation for any firm assess-ments to be made.3
The Eastern Cooperative Oncology Group (ECOG) later proved that no outcome differences were related to choice of anthracycline, and growth factor priming was felt to be detrimental, possibly because of the treatment delay that it caused, although the numbers of patients were small.4 The Southwest Oncology
Group (SWOG) compared induction with mitoxantrone (Novantrone, Serono/OSI Pharmaceuticals) plus etoposide versus induction with cytarabine (Cytosar-U, Sicor) plus daunorubicin. No differences were found between these 2 regimens.5 The United Kingdom
Medical Research Council (UK MRC) AML 11 trial eval-uated the response of patients older than 55, and later older than 60, with de novo or secondary AML to 3 dif-ferent induction regimens.6 In addition, the benefits
of growth factor support, long versus short courses of consolidation, and maintenance versus no main-tenance therapy were evaluated. It was found that remission rates were higher in the daunorubicin-cytarabine-thioguanine (Tabloid, GlaxoSmithKline) arm than in the cytarabine-daunorubicin-etoposide (ADE) and mitoxantrone-cytarabine (MA) groups— possibly because of more toxic deaths in the ADE arm and more resistance in the MA arm. However, no effect on overall survival (OS) was noted. As in most trials, survival at 5 years was in the range of 8% to 12%, although it was higher for those who received consol-idation, in the range of 22% to 23% (many patients in
Table 1.
Summary of Recent AML Treatment Trials in Elderly Patients
Study n Min/Med Age, y* No. With sAML† Induction Regimen CR per Arm, % Consolidation OS Archimbaud et al3 160 61/69 42 IAE vs MAE 56 63 IAE MAE 17% 21% (2 y) 6 11 UK MRC AML 116 1,314 56-61‡/66 299 DAT vs ADE vs MA 62 50 55 Short (3 cycles) vs long 23% 22% (5 y) 16 26 17 SWOG5 328 56/67 74 AD vs EM 34 43 AD (5+2) 19% 11% (2 y) 15
ECOG4 362 56/68 Not known DA vs
MA vs IA +GM-CSF –GM-CSF 41 46 43 38 40 IDAC ×1 7.7 y 7.2 y 7.3 y 5.3 y 8.5 y 16 14 22 26 17
*Minimum and median age (no maximum age limit in any trial).
†Secondary AML included treatment-related and prior hematologic diseases. ‡Age for entry increased to 61 years during the trial.
Boldnumbers in Table indicate significance.
AD, cytarabine-daunorubicin; ADE, cytarabine-daunorubicin-etoposide; CR, complete remission; DA, daunorubicin-cytarabine;
DAT, daunorubicin-cytarabine-thioguanine; ECOG, Eastern Cooperative Oncology Group; EM, etoposide-mitoxantrone; GM-CSF, granulocyte-macrophage colony–stimulating factor priming; IA, idarubicin-cytarabine; IAE, idarubicin-cytarabine-etoposide; IDAC, intermediate-dose cytarabine; MA, mitoxantrone-cytarabine; MAE, mitoxantrone-cytarabine-etoposide; OS, overall survival; sAML, secondary AML;
SWOG, Southwest Oncology Group; TRM, treatment-related mortality; UK MRC, United Kingdom Medical Research Council
TRM, %
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CR did not receive consolidation). Overall, 15% of patients died in CR, mostly of treatment-related caus-es. Selection bias likely contributed to the higher sur-vival rates among those who received consolidation. Whether or not growth factors were used as support, and whether 1 or 3 courses of consolidation therapy were given, also had no effect on OS or remission rates.6 A comparison of the use of the multidrug
resist-ance-1 reversal agent PSC-833 in combination with standard chemotherapy did not show any benefit to the use of the drug or any correlation with P-glyco-protein positivity in this age group compared with standard chemotherapy alone.7
In summary, these large trials showed that the choice of anthracycline does not matter in terms of outcome, and that short consolidations are as good as long ones. There is still no clear conclusion about the role of autologous transplantation. Perhaps the most useful result from these trials was the ability to postu-late which patients would do well with traditional chemotherapy (Table 2). With a cautious review of these retrospective subgroup analyses, various prog-nostic factors consistently surfaced. The most power-ful predictor of the response to chemotherapy was the cytogenetic risk group (Table 3). Recently, the German-Austrian AML Study Group showed that among patients older than 60 years of age treated with uniform intensive chemotherapy, age older than 70 and high-risk cytogenetics were independent prog-nostic factors affecting OS.8
Similarly, an analysis of 117 patients older than age 64 with newly diagnosed AML assessed prognostic factors. The authors found that the disease biology, including adverse-risk cytogenetics, prior myelodys-plastic syndrome (MDS) or antecedent hematologic disorder, and leukocyte count >30 × 109/L, was the
most important predictor of outcome, whereas age was not significantly predictive of either CR or OS.9
Other groups are focused on determining which types of treatment with respect to intensity are best in relation to upfront prognostic factors. One group has since completed such an analysis. In their study, the authors decided whether or not each patient should receive an anthracycline-based regimen, low-dose chemotherapy, or best supportive care. The factors used to make this treatment decision were not men-tioned. Outcomes were then correlated with various characteristics, including comorbidities (renal, liver, or heart disease), ECOG performance status, extreme leukocytosis, marked thrombocytopenia, and elevated lactate dehydrogenase. Based on these factors, a scor-ing system was developed to classify patients as bescor-ing at low or high risk.
Interestingly, among the low-risk patients, the type of treatment did not affect OS. However, outcomes were better in the high-risk patients who received either low- or standard-dose chemotherapy than in those who received supportive care.10 This study
sug-gests that only high-risk patients who are felt to be candidates for some type of treatment are receiving benefit from therapy. Whether these data also suggest that it is better to delay treatment until higher-risk dis-ease develops requires more research.
AML in Younger Patients
It is generally agreed that cytogenetics is the best predictor of outcome in young patients. The question now is: Should patients in different risk groups be treated differently? In other words, will risk-stratified treatment improve outcomes? Issues to be investigat-ed with regard to this strategy include how best to induce and consolidate, and which patients should be considered for transplantation while in first CR (CR1). Current data have led to risk-adapted therapies. Whether this approach will improve outcomes is unknown; what it certainly will do, however, is allow
WBC, white blood cell
Table 2.
High-Risk Prognostic Factors by Study
Study Poor Prognostic Factors
Archimbaud et al3 Age >70 y, high WBC count, high-risk cytogenetics
UK MRC6 Age >70 y, WBC count >100 ×109/L, high-risk cytogenetics, poor
performance status, secondary leukemia
SWOG5 High-risk cytogenetics, increasing WBC count, poor performance status,
increasing age
ECOG4 High-risk cytogenetics
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Table 3.
Cytogenetic Risk Groups by Study
Study Group Cytogenetic Category AbnormalitiesFavorable t(8;21), t(15;17), abnl 16 Intermediate Normal + all others
Unfavorable –5/5q–, –7/7q–, +8, 11q23, t(9;22), complex
abnl, abnormality; del, deletion; dmins, double minute chromosomes; hsrs, homogenously staining regions; inv, inversion; t, translocation
Archimbaud et al3
Favorable t(15;17), t(8;21), inv(16)
Intermediate Normal + other noncomplex abnls Unfavorable Complex (5+), –5/5q–, –7, abnl 3q UK MRC6
Favorable t(8;21), inv(16)/t(16;16), +14 Intermediate Normal and other
Unfavorable –5/5q–, –7/7q–, inv(3), 11q abnl, 17p abnl, inv(17q), del(20q), dmins/hsrs, +13, t(9;22), complex (>3)
SWOG/ECOG33
Table 4.
Summary of CALGB Cytogenetic Data:
Risk Groups by Outcome Measure
30Cytogenetic
Risk Group Induction Success
Cumulative Incidence
Of Relapse Overall Survival
Favorable
(CR 88%, OS 55%)
t(8;21), inv(16)/t(16;16) t(8;21), inv(16)/t(16;16) t(8;21), inv(16)/t(16;16), del(9q)*
Intermediate (CR 67%, OS 24%)
Normal, –Y, del(5q), t(6;9), t(6;11), –7, del(7q), +8 sole, +8 plus 1 other abnl, del(9q), t(9;11), +11, del(11q), t(11;19), +13, del(20q), +21
Normal, –Y, t(9;11), del(9q), +8 sole, +8 plus 1 other abnl, +11, +13
Normal, –Y, del(5q), del(7q), t(9;11), +11, del(11q), abnl(12p), +13, del(20q), +21
Adverse
(CR 32%, OS 5%)
Complex (3+ abnl), inv(3), t(3;3), abnl(12p)
Complex (3+), –7, +21 Complex (3+), inv(3), t(3;3), t(6;9), t(6;11), –7, +8 sole, +8 sole plus 1, t(11;19)
*Would be in intermediate group if only those patients undergoing transplantation were considered.
abnl, abnormality; CALGB, Cancer and Leukemia Group B; CR, complete remission; del, deletion; inv, inversion; OS, overall survival;
t, translocation
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researchers to highlight the areas in greatest need of further investigation.
I
NDUCTIONT
HERAPYThroughout the 1980s and 1990s, research was focused on determining how many drugs to use in addi-tion to cytarabine and an anthracycline, which anthra-cycline is most effective, and whether increasing the dose intensity of cytarabine is beneficial. Clearly, prefer-ences still vary around the world, and standard regi-mens differ globally (Figure 1).11-19
The only point of clarity is not new; at a minimum, in-duction therapy should include cytarabine plus an an-thracycline—with expected overall CR rates in the range of 70% to 80%. Some groups are continuing to investi-gate various induction regimens. For example, several groups have combined anti-CD33 antibody therapy with standard chemotherapy in a regimen analogous to the cyclophosphamide-doxorubicin-vincristine-prednisone/ rituximab (Rituxan, IDEC/Genentech) regimen in lym-phoma. One study recently updated outcomes at the American Society of Hematology 2006 annual meeting (abstract 13), showing that adding a relatively low dose of gemtuzumab ozogamicin (Mylotarg, Wyeth) to stan-dard induction chemotherapy led to improvements in
disease-free survival (DFS), although the CR rates were unchanged.20Whether this should be standard of care is
yet to be determined.
Another issue that remains controversial among experts is whether growth factor priming should be used in induction. Current evidence supports both sides of the argument. As discussed with regard to the elderly, some consider growth factor priming to be detrimental because it entails a delay in chemothera-py.4 In a recent Dutch–Belgian Hemato-Oncology
Cooperative Group trial involving younger patients, growth factor priming did improve the DFS rate but not the CR or OS rate.21 No sound conclusions can be
drawn from the available evidence at this time, but the issue continues to be investigated. In another approach, the Acute Leukemia French Group found that patients younger than 50 years of age who were given timed, sequential induction therapy (ie, standard induction therapy followed by mitoxantrone and cytarabine starting on day 8) had a relapse-free inter-val longer than that of patients given standard induc-tion or double inducinduc-tion therapy.22
Resistance to chemotherapy may be due, in part, to the overexpression of P-glycoprotein, which causes an efflux of chemotherapeutic agents from the leukemic
Figure 1.
Basic induction therapy issues from past studies of AML.
A small benefit may exist for idarubicin over daunorubicin.
11-13
High-dose cytarabine is likely beneficial for younger and high-risk patients (in addition to those with core-binding factor AML), although it is not clear if it should be given during induction or consolidation.
14-18
An additional drug such as 6-thioguanine or etoposide is not unequivocally of benefit.
2, 19
Conclusion References
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cells. A Cancer and Leukemia Group B (CALGB) study showed better DFS and OS, at least in patients younger than age 46, when the P-glycoprotein inhibitor PSC-833 was added to induction therapy with daunorubicin, cytarabine, and etoposide. However, therapy was noted to be more toxic when PSC-833 was added, which may explain the younger age of those who derived bene-fit.23A large Phase III study is planned to confirm these
findings. Importantly, reversion to normal cytogenetics after induction therapy was recently shown to be an important prognostic marker in patients who achieved a morphologic complete response.24
C
ONSOLIDATIONSome type of consolidation is a necessity. High-dose cytarabine has essentially been established as a required element at this point.25However, the Australasian
Leu-kaemia and Lymphoma Group showed that high-dose
cytarabine incorporated into induction therapies for all adult AML patients younger than age 60 did not add any benefit, leaving the timing of treatment with high-dose cytarabine in question.26
Another issue that has been investigated by many groups is whether to use autologous transplantation. Results have been inconsistent, and therefore, depend-ing on where one is in the world, it may or may not be a part of standard treatment.19,27-30The only fact that is
not currently controversial is that patients with t(8;21), t(15;17), or inv(16)/t(16;16) in CR1 should not be consid-ered for allogeneic stem cell transplantation. For the majority of patients who are not in this category, the much more difficult question remains of who in CR1 should undergo transplantation from an allogeneic source. The question of who in second complete remis-sion (CR2) requires transplantation is somewhat easier. Simply stated, transplantation should be considered for
alloSCT, allogeneic stem cell transplantation; autoSCT, autologous stem cell transplantation; DFS, disease-free survival;
HAM, high-dose cytarabine and mitoxantrone; inv, inversion; MRD, matched related donor; NS, not significant;
OS, overall survival; t, translocation
Figure 2.
German Multicenter AML HD93 study schematic.
Low risk:
t(8;21) or inv/t(16q22)
Complete Remission
High risk: all other chromoso-mal abnorchromoso-malities Intermediate risk: normal cytogenetics HAM MRD alloSCT (if available) AutoSCT (if no donor) MRD alloSCT (if available) Sequential HAM (if no donor) DFS 62.5% DFS 49% DFS 38% DFS 8% DFS 22% OS 87% OS 50% (NS) OS 26% (NS)
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anyone of appropriate age with an adequate donor, possibly excluding those with t(8;21) or inv(16), who appear to be highly likely to achieve a durable CR231
and have a unique disease.32
Given the continued significant morbidity and mor-tality associated with allogeneic transplantation, the patients in CR1 who ideally should undergo transplanta-tion are those who are most likely to die of their disease within a period of time that is personally unacceptable and can accept the toxicities of this treatment. However, some centers are now offering transplantation to patients in CR1 who have intermediate-risk cytoge-netics as their standard of care if a matched sibling donor is available. Because this issue has been investi-gated throughout the 1990s and currently, a large body of data regarding prognostics has become available.
Several groups have contributed to this pool of data, including CALGB,32 SWOG/ECOG,33 UK MRC,34
EORTC/Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (EORTC/GIMEMA),3 5 and
Bordeaux-Grenoble-Marseille-Toulouse (BGMT).36The CALGB has
published a very complete set of data regarding the relationship between pretreatment cytogenetics and induction success, cumulative incidence of relapse, and OS.32 Importantly, they have found that t(8;21) and
inv(16)/t(16;16) continue to carry a good prognosis regardless of the presence of additional abnormali-ties. Notably, even patients with good prognostic fea-tures have an OS rate of 55%. This is in keeping with data from other groups. Not surprisingly, the OS rate of high-risk cytogenetic groups is about 5% (Table 4). OS rates in the intermediate-risk group vary widely. The majority of patients within this group have normal cytogenetics—underscoring the need for additional risk markers.
Several large groups assessed outcomes by risk cat-egory in response to varying consolidation treatments of intensive chemotherapy, autologous transplantation, or matched related donor (MRD) transplantation. Again, it should be noted that what one group consid-ered intermediate risk, another might classify as high risk. Table 5 shows the outcomes based on risk groups. SWOG/ECOG found that patients with low-risk cytoge-netic features did best with autologous bone marrow transplantation, intermediate-risk patients did best with chemotherapy, and high-risk patients did margin-ally better with allogeneic transplantation (P=0.043).
ECOG published the results of a study in which autologous stem cell transplantation following 2 cycles of high-dose cytarabine in patients with de novo
Table 5.
Large Trials Comparing Donor Versus No Donor As Assessed by
Cytogenetic Risk Group
Trial Protocol Groups Benefiting From Early Transplant
609 patients in CR, age <56 y, randomized to intensive chemo-therapy, autoBMT, or alloBMT (if MRD)
Favorable-risk patients have better outcome with autoBMT; unfavorable-risk patients have better outcome with alloBMT in terms of survival
alloBMT, allogeneic bone marrow transplantation; alloSCT, allogeneic stem cell transplantation; autoBMT, autologous bone marrow transplantation; autoSCT, autologous stem cell transplantation; CG, cytogenetics; CR, complete remission; CR1, first complete remission;
DFS, disease-free survival; FAB, French-American-British; MRD, matched related donor; WBC, white blood cell
SWOG/ECOG33
Patients randomized to alloBMT or autoBMT following 4 intense chemotherapy courses
DFS and survival advantage in patients in intermediate-risk group, age <35 y UK MRC AML 1034
Patients in CR1 received 1 intensive chemotherapy course, then random-ized to alloSCT or autoSCT
DFS advantage for patients <35 y in high-risk, very high-risk groups
EORTC/GIMEMA35
4 studies, age <45 y; all in CR1 with MRD received alloSCT, all others autoSCT or chemotherapy
Intermediate-risk group based on CG, FAB subtype, WBC count, and No. courses to achieve a CR had a survival advantage with alloSCT BGMT36
3 studies, age <55 y; all in CR1 with MRD received alloSCT, all others autoSCT or chemotherapy
Intermediate- and poor-risk groups with a donor had a DFS advantage
HOVON/SAKK39
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non-APL AML and no matching sibling donors was compared with allogeneic transplantation after induc-tion in those with donors.37 The study was not large
enough to allow an analysis of the differences between cytogenetic risk groups or a direct comparison of allo-geneic versus autologous transplantation. However, it did show that autologous transplantation as consolida-tion was well tolerated.
Many groups have now performed donor versus no donor analyses. When the UK MRC evaluated out-comes based on donor availability, they found that only their intermediate-risk group showed a survival benefit from transplantation in CR1.34 The EORTC/GIMEMA
found improved DFS rates in the group of patients who had a donor in combination with high-risk cytogenetic features; however, significant improvements in survival were not appreciated at 4 years, although a trend was noted in favor of allogeneic versus autologous trans-plantation.35 Other factors that may be important in
determining risk that can be assessed during the induction phase are early blast clearance and possibly the lactic dehydrogenase level or white blood cell
count at presentation. The German AML Cooperative Group found that patients with more than 10% bone marrow blasts 1 week after the completion of chemotherapy, and those with high levels of lactic dehydrogenase had worse CR, DFS, and OS rates.38
The BGMT group also collectively reviewed data from 4 AML protocols regarding donor versus no donor and found that among those younger than age 45, patients with intermediate-risk disease (according to a score based on factors including WBC count at diagnosis, FAB subtype, cytogenetic risk, and number of induc-tion courses) were the only group to show a survival advantage with a donor.36 Most recently, the
HOVON/SAKK group has published results based on such an analysis.39 They evaluated 3 trials in which
patients routinely received a matched sibling donor (MSD) allogeneic transplant if they achieved a CR and were younger than age 60. A significant DFS advantage was seen for those in the donor group with intermedi-ate- and poor-risk profiles. Additionally, they performed a meta-analysis to include several of the already-men-tioned studies and found a survival advantage of 12% for
Table 6.
New Agents in the Treatment of AML
Study Agent Characteristics n Response Toxicity
Piccaluga et al47 Gemtuzumab 21% CR; duration of response, 6 mo Cytopenias, elevated liver enzymes Relapsed/refractory AML 24
Smith et al49 CEP-701 5 patients with
measurable response
Minimal Refractory, relapsed, or poor-risk
AML 14 Fiedler et al50 SU5416 1 morphologic CR 7 PR Nausea, headache, bone pain
Refractory AML; elderly AML 43
Giles et al51 PKC412 +
daunorubicin + cytarabine
6 CR Nausea, vomiting Newly diagnosed AML 15
Issa et al52 Decitabine 9 CR 1 PR Myelosuppression AML/MDS, CML, ALL 50 Qazilbash et al53 PR1 peptide + G-CSF 4 CR (AML) 1 PR (MDS) Injection-site reactions Relapsed/refractory AML, MDS 21
Karp et al48 Tipifarnib 29% response
rate; CR in 2 patients
Mostly transient grade 1-2 toxicities Relapsed/refractory AML or ALL;
newly diagnosed poor-risk AML in adults >60 y; secondary AML; CML in blast crisis
34
ALL, acute lymphocytic leukemia; CML, chronic myelogenous leukemia; CR, complete remission; G-CSF, granulocyte colony–stimulating factor; MDS, myelodysplastic syndrome; PR, partial remission
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all patients with AML in CR1 without a favorable cytoge-netic risk profile. Many groups are now applying these factors to treatment algorithms.
The German AML Study Group Ulm first published results based on risk-adapted therapy.40 After all
patients received their established standard double induction therapy, those who entered remission were stratified according to risk (Figure 2). Low-risk patients received 1 cycle of consolidation; intermedi-ate-risk patients received an allogeneic transplant if an MRD was available and otherwise received consol-idation chemotherapy; high-risk patients received an MRD allogeneic transplant if available and otherwise received an autologous transplant.
DFS and OS rates at 5 years in low-, intermediate-, and high-risk patients were 62.5% and 87%, 40% and 49%, and 17% and 26%, respectively.
Compared with the CALGB cytogenetic data, these results appear better; however, as the authors appropri-ately noted, more data are required to make such a statement. Clinicians can construct similar treatment algorithms based on this model (Figure 3). 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 30% of adults have MSDs available, this becomes an attractive option.
Outcomes in small studies of adult AML are nearly as good with MUDs as with MRDs; transplant-related mor-tality rates are roughly equivalent based on the center evaluated. As we learn how to separate graft-versus-host from graft-versus-leukemia effects, this therapy will become more useful. At present, most centers are limit-ing the use of MUDs to high-risk groups, perhaps under-estimating their value. Finally, an international Phase III study addressed the issue of maintenance therapy in AML, which is not the standard of care. Interestingly, the investigators showed that a combination of histamine dihydrochloride and interleukin-2 given after consolida-tion significantly improved leukemia-free survival com-pared with no further therapy, suggesting that some additional therapy may be needed, even after consolida-tion therapy. The effect of such therapy on OS, however, was not addressed in this study.41
Future Directions
D
ISEASEB
IOLOGYAs shown by the data, prognostic factors are a sub-ject of great interest. New molecular variables are de-creasing the unknown regarding various cytogenetic
Table 7.
Reduced-Intensity Conditioning
Allogeneic Stem Cell Transplants in AML/MDS
Study n Extensive Chronic GvHD OS LFS MVA for Better Survival Median Age Conditioning Regimen Taussig et al54 16 MDS 63% 69% 2 y 56% 2 y Not done 54 flu-cy or mel Schmid et al55 75 15% 42% 2 y 40% 2 y Limited GvHD, high CD34+ cell numbers 52 FLAMSA cy-ATG-TBI Van Besien et al56 52 Rel 23/4 MUD 22/3* 18% 48% 1 y 38% 1 y PS and low-risk disease† 52 flu-mel-alemtuz Tauro et al57 76 Rel 35 MUD 41 2% 41% 3 y 37% 3 y Disease status 52 flu-mel-alemtuz Stelljes et al58 71 Rel 38/1 MUD 22/10* 24% 81%/16 2 y‡ 78%/ 16 2 y‡ Disease status 51 TBI-flu
*Rel, related donors matched/single mismatch; MUD, matched unrelated donors matched/mismatched. †Defined by active AML or MDS with >5% blasts. ‡Patients in CR at transplantation/non-CR.
alemtuz, alemtuzumab; ATG, antithymocyte globulin; CR, complete remission; cy, cyclophosphamide; FLAMSA, fludarabine-cytarabine-amsacrine ×4 d before reduced-intensity conditioning; flu, fludarabine; GvHD, graft-versus-host disease; LFS, leukemia-free survival;
MDS, myelodysplastic syndrome;mel, melphalan; MVA, multivariate analysis; OS, overall survival;
PS, performance status; TBI, total-body irradiation
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abnl, abnormalities; autoSCT, autologous stem cell transplantation; CG, cytogenetics; CR, complete remission; FLAG, fludarabine-cytarabine-granulocyte colony–stimulating factor; G-CSF, granulocyte colony–stimulating factor; HDAC, high-dose cytarabine;
MRD, matched related donor; MUD, matched unrelated donor
Figure 3.
Proposed treatment algorithm for young adults with AML.
Controversial
Standard
Induction
Anthracycline +
Reinduce with salvage (eg, FLAG)
Good Risk
• t(8;21), inv(16)/t(16;16)
Reassess bone marrow on count recovery
No CR CR
Repeat initial treatment ×1
Consolidate Assess bone marrow
1 wk after end of chemotherapy
Increased or stable blasts >10% residual blasts but fewer than at presentation
<10% residual blasts Poor Risk • –5/5q–, –7/7q– • Complex (? >3-5 abnl) • ? Others Intermediate Risk • Normal CG • ? Others
HDAC ×3-4 MRD transplant if available,
otherwise MUD transplant HDAC, autoSCT,
MRD transplant Clinical Trial
cytarabine ? HDAC, ? ±G-CSF priming, ? ±additional agents
Risk-Assessed Consolidation
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abnormalities or lack thereof.
Abnormalities in the gene for Flt-3 (Fms-like tyro-sine kinase, a member of the class III receptor tyrotyro-sine kinase family), including internal tandem duplications and point mutations, are acquiring importance, as are gene mutations in the BAALC,42CEBPA,43,44and HOX
domains45 and nucleophosmin,46 among others. In
addition to being predictors of outcome, some of these markers are targets of novel therapies.
N
EWT
ARGETSMany new agents are being investigated for efficacy in AML. Although most are still in early development, a common feature is their ability to affect specific targets on the leukemic cell. Importantly, however, these newer agents are unlikely to have a major effect on the current therapy of AML when given singly; rather, they may have to be combined with other targeted agents or cytotoxic chemotherapy to have an optimal effect. Preliminary data for these agents are provided in Table 6.47-53 The groups currently in clinical trials
include the following:
• Farnesyl transferase inhibitor: tipifarnib (R115777; Zarnestra, Johnson & Johnson)
• Flt-3 inhibitors: CEP-701 (Cephalon), SU5416 (Sugen), PKC412 (Novartis)
• Histone deacetylase inhibitors: decitabine (Dacogen, MGI Pharma/SuperGen), depsipeptide • Vaccines against PR1 leukemia–associated antigen.
One of the greatest advances in the treatment of AML and high-grade MDS in recent years has been reduced-intensity allogeneic transplantation. Several conditioning regimens have been used, some more intensive than others. With limited follow-up times, OS rates have ranged from 40% to 80% at 2 years (Table 7).54-58 Most studies are finding that improved
outcomes correlate with a reduced disease burden at the time of transplantation. Performance status is also, not surprisingly, important.
In addition, some studies have shown the impor-tance of limited graft-versus-host disease in achieving a better outcome. This supports the notion of a graft-versus-leukemia effect in AML. It is important to note, and in keeping with the age range of patients with AML, that the average age at transplantation in most of these studies was 50 to 60 years, as opposed to the younger median ages for full transplantation pro-tocols. Given these promising results, it may be wise to consider the transplantation option in more patients. The clinician should prepare patients for this treatment early in the course of disease by, at the very least, tissue typing them and any healthy siblings. With this treatment, as opposed to fully ablative allo-geneic transplantation, a lower disease burden at the time of transplantation may be critical. Therefore, the
window of opportunity to perform this procedure may be small.
Conclusion
AML is a deadly disease; even in the best of circum-stances, the OS rate is still below 60%. Current efforts include risk-adapted therapies in an effort to spare patients the morbidity and mortality resulting from unnecessary treatment. Improvements are particularly needed in the treatment of elderly patients, many of whom have poor prognostic features.
For the clinician faced with treatment decisions, it may be comforting to know that efforts are under way not only to improve the usefulness of current treatments but also to develop new, less toxic therapies. If clinical trials are unavailable for patients who are not candidates for traditional therapy or are unwilling or unable to trav-el to where trials are being conducted, agents for sup-portive care, such as hydroxyurea for uncontrollable blood counts and symptomatic transfusions, are simple and humane management tools.
Although the improvements in the treatment of AML may seem small, we have entered an era in which sub-stantial progress is possible and likely to be achieved, particularly with the newer molecular techniques.
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Patient Guide to
T
REATING
A
CUTE
M
YELOID
L
EUKEMIA
cute myeloid leukemia (AML) is a type of cancer of the bone marrow and
blood. Almost 12,000 new cases of AML will be diagnosed this year in the
United States. Scientists are developing new treatments for this disease,
and more patients are benefiting from stem cell transplants.
The treatment of AML consists of 2 parts, called induction therapy and
consolidation therapy.
A
Induction Therapy
Induction therapy is the term for the start of treatment with chemotherapy. If the first round of chemotherapy does not kill all the AML cells, then the patient will need a second round. In most cases of induction therapy, an anthracycline antibiotic (such as daunorubicin, doxorubicin, or idarubicin) is combined with cytarabine, also called cytosine arabinoside or ara-C.
The first round of chemotherapy usually does not kill all the AML cells, and most patients will need more treatment. Usually, the same drugs are used for additional rounds of treatment to com-plete induction therapy.
Consolidation Therapy
Further treatment is usually needed even after a patient with AML is in remission, meaning that no sign of the disease is left. This is called consolida-tion therapy. Patients receive consolidaconsolida-tion thera-py in the hospital. They are often in the hospital during chemotherapy, although this varies from center to center.
Consolidation therapy may include chemo-therapy with or without a stem cell transplant. In a stem cell transplant, donated stem cells (allo-geneic transplant) or the patient’s own stem cells (autologous transplant) are injected into the patient’s blood after chemotherapy. The injected stem cells enter the patient’s bone mar-row and help start a new supply of blood cells and platelets.
AML Treatment in Elderly Patients
AML is more common in older patients. At least half of patients are older than 65 years when their disease is diagnosed. Older patients may have other medical problems, such as heart disease, lung disease, and diabetes. The doctor must con-sider these other medical problems when decid-ing which drugs to use, how much, and how often.
Refractory Leukemia and Relapsed Leukemia
Some patients continue to have AML even after treatment. This is called refractory leukemia. When a patient has refractory leukemia, drugs that were not used to treat the AML in the first part of treatment may be given. Stem cell trans-plantation also may be used.
Some patients experience a relapse of AML, meaning the disease returns after they have had a remission. For patients who relapse, the same or different drugs may be given, or stem cell transplantation may be used. A drug called gemtuzumab ozogamicin (Mylotarg, Wyeth) is being used to treat some older patients who have relapsed AML.
For more information:
Leukemia and Lymphoma Society www.lls.org
(800) 955-4572
American Cancer Society www.cancer.org
