Perspectives on the Treatment of Acute Myeloid Leukemia

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1 Perspectives on the Treatment of Acute Myeloid Leukemia LORI J. MANESS, MD Assistant Professor of Medicine University of Nebraska Medical Center College of Medicine Section of Oncology/Hematology Omaha, Nebraska Our 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 immunotherapeutic approach involving stem cell transplantation has become an option for greater numbers of patients. The aim of this article is to address the larger studies of non-apl (acute promyelocytic leukemia) AML. These studies have helped both to define current treatments and to direct current and future research. AML in Elderly Patients Although elderly is a relative term, it is nevertheless helpful to distinguish patients who may not be candidates for the most intensive treatment from those who are. This distinction often, but not always, correlates with age. 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. 1 Since then, a few large, randomized trials have been completed. Issues studied have included optimal chemotherapeutic agents, growth factor priming, and the plausibility of autologous stem cell transplantation. The treatment outcomes are presented in CLINICAL ONCOLOGY NEWS SPECIAL EDITION

2 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 TRM, % Archimbaud /69 42 IAE vs MAE 56 et al 3 63 IAE MAE 17% 21% (2 y) 6 11 UK MRC 1, / DAT vs ADE AML 11 6 vs MA Short (3 cycles) vs long 23% 22% (5 y) SWOG /67 74 AD vs EM AD (5+2) 19% 11% (2 y) 15 ECOG /68 Not known DA vs MA vs IA +GM-CSF GM-CSF IDAC y 7.2 y 7.3 y 5.3 y 8.5 y *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. Bold numbers 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, granulocytemacrophage 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 Table 1 and summarized here. A multicenter trial initiated in the early 1990s evaluated some of these issues specifically, the best anthracycline for induction therapy, whether the addition of etoposide increased benefit in inducing complete remission (CR) in the elderly, as it did in younger patients, 2 and if autologous transplantation could decrease relapse rates more effectively than nonablative chemotherapy alone. In this trial, the patients were older than 60 years and had primary or secondary AML. Investigators found no significant differences related to choice of anthracycline; etoposide was not an isolated variable, so that no conclusions could be drawn, and too few patients actually underwent autologous transplantation for any firm assessments 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 evaluated the response of patients older than 55, and later older than 60, with de novo or secondary AML to 3 different induction regimens. 6 In addition, the benefits of growth factor support, long versus short courses of consolidation, and maintenance versus no maintenance therapy were evaluated. It was found that remission rates were higher in the daunorubicincytarabine-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 consolidation, in the range of 22% to 23% (many patients in 2

3 Table 2. High-Risk Prognostic Factors by Study Study Archimbaud et al 3 UK MRC 6 SWOG 5 Poor Prognostic Factors Age >70 y, high WBC count, high-risk cytogenetics Age >70 y, WBC count > /L, high-risk cytogenetics, poor performance status, secondary leukemia High-risk cytogenetics, increasing WBC count, poor performance status, increasing age ECOG 4 High-risk cytogenetics WBC, white blood cell CR did not receive consolidation). Overall, 15% of patients died in CR, mostly of treatment-related causes. Selection bias likely contributed to the higher survival 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 resistance-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-glycoprotein 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 postulate which patients would do well with traditional chemotherapy (Table 2). With a cautious review of these retrospective subgroup analyses, various prognostic factors consistently surfaced. The most powerful 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 prognostic 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 myelodysplastic syndrome (MDS) or antecedent hematologic disorder, and leukocyte count > /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 mentioned. 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 scoring system was developed to classify patients as being 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 suggests 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 disease 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 investigated 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 3

4 Table 3. Cytogenetic Risk Groups by Study Study Group Cytogenetic Category Abnormalities Archimbaud et al 3 Favorable t(8;21), t(15;17), abnl 16 UK MRC 6 Intermediate Unfavorable Favorable Normal + all others 5/5q, 7/7q, +8, 11q23, t(9;22), complex t(15;17), t(8;21), inv(16) Intermediate Unfavorable Normal + other noncomplex abnls Complex (5+), 5/5q, 7, abnl 3q SWOG/ECOG 33 Favorable t(8;21), inv(16)/t(16;16), +14 Intermediate Unfavorable Normal and other 5/5q, 7/7q, inv(3), 11q abnl, 17p abnl, inv(17q), del(20q), dmins/hsrs, +13, t(9;22), complex (>3) abnl, abnormality; del, deletion; dmins, double minute chromosomes; hsrs, homogenously staining regions; inv, inversion; t, translocation Table 4. Summary of CALGB Cytogenetic Data: Risk Groups by Outcome Measure 30 Cytogenetic 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 4

5 Conclusion References A small benefit may exist for idarubicin over daunorubicin 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 An additional drug such as 6-thioguanine or etoposide is not unequivocally of benefit. 2, 19 Figure 1. Basic induction therapy issues from past studies of AML. researchers to highlight the areas in greatest need of further investigation. INDUCTION THERAPY Throughout the 1980s and 1990s, research was focused on determining how many drugs to use in addition to cytarabine and an anthracycline, which anthracycline is most effective, and whether increasing the dose intensity of cytarabine is beneficial. Clearly, preferences still vary around the world, and standard regimens differ globally (Figure 1) The only point of clarity is not new; at a minimum, induction therapy should include cytarabine plus an anthracycline with expected overall CR rates in the range of 70% to 80%. Some groups are continuing to investigate 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 lymphoma. 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 standard induction chemotherapy led to improvements in disease-free survival (DFS), although the CR rates were unchanged. 20 Whether 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 chemotherapy. 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 interval longer than that of patients given standard induction or double induction 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 5

6 Complete Remission Low risk: t(8;21) or inv/t(16q22) Intermediate risk: normal cytogenetics High risk: all other chromosomal abnormalities HAM MRD allosct (if available) Sequential HAM (if no donor) MRD allosct (if available) AutoSCT (if no donor) DFS 62.5% DFS 49% DFS 38% DFS 8% DFS 22% OS 87% OS 50% (NS) OS 26% (NS) 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. 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 benefit. 23 A 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 CONSOLIDATION Some type of consolidation is a necessity. High-dose cytarabine has essentially been established as a required element at this point. 25 However, the Australasian Leukaemia 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 highdose 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, depending on where one is in the world, it may or may not be a part of standard treatment. 19,27-30 The 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 considered 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 remission (CR2) requires transplantation is somewhat easier. Simply stated, transplantation should be considered for 6

7 Table 5. Large Trials Comparing Donor Versus No Donor As Assessed by Cytogenetic Risk Group Trial Protocol Groups Benefiting From Early Transplant SWOG/ECOG 33 UK MRC AML patients in CR, age <56 y, randomized to intensive chemotherapy, autobmt, or allobmt (if MRD) Patients randomized to allobmt or autobmt following 4 intense chemotherapy courses Favorable-risk patients have better outcome with autobmt; unfavorable-risk patients have better outcome with allobmt in terms of survival DFS and survival advantage in patients in intermediate-risk group, age <35 y EORTC/GIMEMA 35 BGMT 36 Patients in CR1 received 1 intensive chemotherapy course, then randomized to allosct or autosct 4 studies, age <45 y; all in CR1 with MRD received allosct, all others autosct or chemotherapy DFS advantage for patients <35 y in high-risk, very high-risk groups Intermediate-risk group based on CG, FAB subtype, WBC count, and No. courses to achieve a CR had a survival advantage with allosct HOVON/SAKK 39 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 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 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 CR2 31 and have a unique disease. 32 Given the continued significant morbidity and mortality associated with allogeneic transplantation, the patients in CR1 who ideally should undergo transplantation 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 cytogenetics as their standard of care if a matched sibling donor is available. Because this issue has been investigated 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), 35 and Bordeaux- Grenoble-Marseille-Toulouse (BGMT). 36 The 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 abnormalities. Notably, even patients with good prognostic features 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 category 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 considered 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 cytogenetic features did best with autologous bone marrow transplantation, intermediate-risk patients did best with chemotherapy, and high-risk patients did marginally 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 7

8 Table 6. New Agents in the Treatment of AML Study Agent Characteristics n Response Toxicity Gemtuzumab 21% CR; duration Piccaluga Relapsed/refractory AML 24 et al 47 of response, 6 mo Karp et al 48 Tipifarnib Relapsed/refractory AML or ALL; 34 29% response newly diagnosed poor-risk AML rate; CR in 2 in adults >60 y; secondary AML; patients CML in blast crisis Cytopenias, elevated liver enzymes Mostly transient grade 1-2 toxicities Smith et al 49 CEP-701 Refractory, relapsed, or poor-risk AML 14 5 patients with measurable response Fiedler SU5416 Refractory AML; elderly AML 43 1 morphologic CR et al 50 7 PR Minimal Nausea, headache, bone pain Giles et al 51 PKC412 + daunorubicin + cytarabine Newly diagnosed AML 15 6 CR Nausea, vomiting Issa et al 52 Decitabine AML/MDS, CML, ALL 50 9 CR 1 PR Myelosuppression Qazilbash PR1 peptide + et al 53 G-CSF Relapsed/refractory AML, MDS 21 4 CR (AML) 1 PR (MDS) Injection-site reactions ALL, acute lymphocytic leukemia; CML, chronic myelogenous leukemia; CR, complete remission; G-CSF, granulocyte colony stimulating factor; MDS, myelodysplastic syndrome; PR, partial remission non-apl AML and no matching sibling donors was compared with allogeneic transplantation after induction 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 allogeneic versus autologous transplantation. However, it did show that autologous transplantation as consolidation was well tolerated. Many groups have now performed donor versus no donor analyses. When the UK MRC evaluated outcomes 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 transplantation. 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 induction 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 intermediate- and poor-risk profiles. Additionally, they performed a meta-analysis to include several of the already-mentioned studies and found a survival advantage of 12% for 8

9 Table 7. Reduced-Intensity Conditioning Allogeneic Stem Cell Transplants in AML/MDS Study n Median Age Conditioning Regimen Extensive Chronic GvHD OS LFS MVA for Better Survival Taussig et al MDS 54 flu-cy or mel 63% 69% 2 y Schmid et al FLAMSA 15% 42% cy-atg-tbi 2 y 56% 2 y 40% 2 y Not done Limited GvHD, high CD34+ cell numbers Van Besien 52 Rel 23/4 et al 56 MUD 22/3* 52 flu-melalemtuz 18% 48% 1 y 38% 1 y PS and low-risk disease Tauro et al Rel 35 MUD flu-melalemtuz 2% 41% 3 y 37% 3 y Disease status Stelljes et al Rel 38/1 MUD 22/10* 51 TBI-flu 24% 81%/16 78%/ Disease status 2 y 16 2 y *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-cytarabineamsacrine 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 all patients with AML in CR1 without a favorable cytogenetic 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; intermediate-risk patients received an allogeneic transplant if an MRD was available and otherwise received consolidation 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 appropriately 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 mortality rates are roughly equivalent based on the center evaluated. As we learn how to separate graft-versushost from graft-versus-leukemia effects, this therapy will become more useful. At present, most centers are limiting the use of MUDs to high-risk groups, perhaps underestimating 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 consolidation significantly improved leukemia-free survival compared with no further therapy, suggesting that some additional therapy may be needed, even after consolidation therapy. The effect of such therapy on OS, however, was not addressed in this study. 41 Future Directions DISEASE BIOLOGY As shown by the data, prognostic factors are a subject of great interest. New molecular variables are decreasing the unknown regarding various cytogenetic 9

10 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 fewer than at presentation <10% residual blasts Reinduce with salvage (eg, FLAG) Repeat initial treatment 1 No CR Reassess bone marrow on count recovery CR Consolidate Clinical Trial Controversial Standard Risk-Assessed Consolidation Good Risk t(8;21), inv(16)/t(16;16) Intermediate Risk Normal CG? Others Poor Risk 5/5q, 7/7q Complex (? >3-5 abnl)? Others HDAC 3-4 HDAC, autosct, MRD transplant MRD transplant if available, otherwise MUD transplant abnl, abnormalities; autosct, autologous stem cell transplantation; CG, cytogenetics; CR, complete remission; FLAG, fludarabinecytarabine-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. 10

11 abnormalities or lack thereof. Abnormalities in the gene for Flt-3 (Fms-like tyrosine kinase, a member of the class III receptor tyrosine kinase family), including internal tandem duplications and point mutations, are acquiring importance, as are gene mutations in the BAALC, 42 CEBPA, 43,44 and HOX domains 45 and nucleophosmin, 46 among others. In addition to being predictors of outcome, some of these markers are targets of novel therapies. NEW TARGETS Many 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 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) 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 importance of limited graft-versus-host disease in achieving a better outcome. This supports the notion of a graftversus-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 protocols. 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 allogeneic 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 circumstances, 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 travel to where trials are being conducted, agents for supportive 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 substantial progress is possible and likely to be achieved, particularly with the newer molecular techniques. References 1. Lowenberg B, Zittoun R, Kerkhofs H, et al. On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J Clin Oncol. 1989;7: Bishop JF, Lowenthal R, Joshua D, Matthews JP, Wolf MM, Cooper IA. Etoposide in leukemia. Cancer. 1991;67(suppl 1): Archimbaud E, Jehn U, Thomas X, et al. Multicenter randomized phase II trial of idarubicin vs mitoxantrone combined with VP-16 and cytarabine for induction/consolidation therapy, followed by a feasibility study of autologous peripheral blood stem cell transplantation in elderly patients with acute myeloid leukemia. Leukemia. 1999;13: Rowe JM, Neuberg D, Friedenberg W, et al. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004;103: Anderson JE, Kopecky KJ, Willman CL, et al. Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study. Blood. 2002;100: Goldstone AH, Burnett AK, Wheatley K, et al. Attempts to improve outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML 11 trial. Blood. 2001;98: Van der Holt B, Lowenberg B, Burnett AK, et al. The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis. 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12 8. Frohling S, Schlenk RF, Kayser S, et al. Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B. Blood. 2006;108: Gupta V, Chun K, Yi Q, et al. Disease biology rather than age is the most important determinant of survival of patients 60 years with acute myeloid leukemia treated with uniform intensive therapy. Cancer. 2005;103: Chen C, Yang C, Yang M, et al. Pretreatment prognostic factors and treatment outcome in elderly patients with de novo acute myeloid leukemia. Ann Oncol. 2005;16: Berman E, Heller G, Santorsa J, et al. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood. 1991;77: Wiernik PH, Banks PL, Case DC Jr, et al. 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14 Permission is hereby granted for clinicians to print and distribute Patient Education Handouts for the exclusive use of their patients. Resale is not permitted. Patient Guide to TREATING ACUTE MYELOID LEUKEMIA Acute 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. 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 complete 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 consolidation therapy. Patients receive consolidation therapy in the hospital. They are often in the hospital during chemotherapy, although this varies from center to center. Consolidation therapy may include chemotherapy with or without a stem cell transplant. In a stem cell transplant, donated stem cells (allogeneic 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 marrow 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 consider these other medical problems when deciding 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 transplantation 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 (800) American Cancer Society (800) ACS From the office of Directions/comments UPDATED 5.07