Haematologica, Vol 93, Issue 12, 1769-1772 doi:10.3324/haematol.2008.000497
Copyright © 2008 by Ferrata Storti Foundation
This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sekeres, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sekeres, M. A.

Editorials and Perspectives

Treatment of older adults with acute myeloid leukemia: state of the art and current perspectives

Mikkael A. Sekeres

Assistant Professor of Medicine, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA. E-mail:sekerem{at}ccf.org

Acute myeloid leukemia (AML) is a disease of older adults, with a median age at diagnosis of 67 years in the United States. Decisions regarding the aggressiveness and timeliness of therapy are challenging in older adults, as the disease biology predicts for chemotherapy resistance, and intensive therapy is accompanied by high treatment-related mortality. In older patients, complete remission rates to standard remission induction therapy range from 40–60%, with limited long-term survival. Newer treatments are less-aggressive, with the promise of near-comparable response rates to standard cytotoxic therapy. Clinical trials should be considered at every stage of treatment in this group of patients.

Why focus on older adults with acute myeloid leukemia?

Epidemiology
AML is the most common leukemia subtype, with an estimated 13,000 new diagnoses yearly in the USA.1 It is also a disease of older adults, commonly defined as people > 60 years of age, with a median age at diagnosis of 67 years.2 This translates to a yearly incidence of new AML diagnoses in the USA of 17.6/100,000 for people 65 years of age or older, compared to 1.8/100,000 for people <65 years. Worldwide, the incidence of AML in older adults is increasing, likely due to the effects of environmental exposures during an industrial age, the late effects of chemotherapy and radiation therapy used to treat solid tumors, and the aging population as a whole, a respectable percentage of whom harbor known or as yet undiagnosed antecedent hematologic disorders. Case finding within this undiagnosed population will result in continued upward incidence trends.

Distinguishing biological characteristics
Compared to younger adults, older AML patients are more likely to have AML with poor-risk cytogenetics (such as abnormalities of chromosomes 5, 7, 8, or complex cytogenetics) and less likely to have good-risk cytogenetic findings, such as the balanced, core binding factor abnormalities, including the t(8;21) in which the AML1-ETO genes are juxtaposed, inv (16) and t(16;16) involving the CBFB-MYH11 chimeric product, and the PML-RAR{alpha} mutation (t(15;17)).3–7 Despite the overriding dismal prognostic implications of advanced age, cytogenetics still have relevance in predicting outcome, with fortunate older adults with leukemias typified by a CBF abnormality experiencing five-year overall survival rates of 20%, compared to 0% for those with poor-risk features.8 Whether newly identified molecular lesions, such as FMS-like tyrosine kinases 3 (flt3) internal tandem duplications (ITDs) and mutations of nucleophosmin (NPM) play a role in older AML patients has yet to be determined.

Secondary AML, which is less responsive to chemotherapy, is also common in this age group, comprising between a quarter and half the cases, compared to < 10% in younger adults.7,9 As a result, AML in older adults is more likely to arise from a more proximal stem cell disorder, and with abnormalities in more than one hematopoietic cell lineage.1 Further chemotherapy responsiveness is mediated by greater expression of genes that confer drug resistance, such as MDR1, the P-glycoprotein (gp170) chemotherapy efflux pump, present in one study in 71% of myelo-blasts in older adults, compared to only 35% of blasts in younger AML patients.11

Poor outcome compared to younger adults
Older adults with AML have median and long-term survival rates comparable to patients with metastatic renal or lung cancer, even with the best available therapies. Younger adults with AML who receive standard remission induction therapy experience complete remission (CR) rates of 65–85%, a full 25% higher than all older adults, and at least 35% higher than the very old: patients 70 years or more.9,12–17 As expected with lower CR rates, 5-year overall survival (OS) rates, which approach 30% in younger adults, are cut by half for older adults, and range from 5–15%.14,18–20 This low chance of durable remission comes at a price of a high treatment-related mortality that approaches 25%, compared to less than 10% in the younger population. Morbidity may also be extreme, with many older adults without advanced directives requiring stays in intensive care units. Interestingly, age alone does not appear to predict successful outcome from an intensive care unit admission.

Why do older adults fare so much worse compared to younger AML patients? A simple answer is intolerance to remission induction therapy because of comorbid disease. More complicated reasons involve the biological factors described above; differential drug metabolism compared to younger adults, resulting in supratherapeutic drug levels, and the reluctance of many physicians to treat older adults intensively. Fewer than 40% of AML patients 65 years of age or older in the USA are treated with chemotherapy, and median survival among this population is 2.4 months. In summary, within older AML patients treated with remission induction therapy, approximately one-half will leave the hospital in a CR; one in 4 will leave with persistent disease; and one in 4 will not leave the hospital alive.

Treatment approaches in older adults are distinct

Deciding on intensive therapy for older adults
AML has traditionally been considered a medical emergency, with immediate initiation of therapy thought to be crucial to minimizing disease-related morbidity and mortality. Physicians must weigh the risks associated with giving immediate intensive therapy to patients in whom poor prognostic characteristics, such as advanced age and adverse cytogenetics, predict a low CR rate, with the risk of waiting to initiate treatment for additional test results to return. One study from the Cleveland and Houston groups exploring the effect of time from AML diagnosis to treatment on complete remission rates and overall survival in over 1,300 AML patients found that delaying therapy in older adults had no impact on these outcome parameters.21 For younger adults, on the other hand, every day of delay predicted for lower CR and OS rates. Thus, older patients may benefit from waiting for the results of additional testing, allowing enrollment into studies that account for cytogenetic findings or that target molecular abnormalities.

Although indirect data support the use of intensive chemotherapy in older patients, most will derive little benefit from this approach. Only one randomized study, reported two decades ago, has ever shown a survival advantage (of only ten weeks) of remission induction therapy over low-dose therapy or best supportive care.22 A more recent case-control study showed a survival advantage for giving intensive chemotherapy compared to best supportive care or low-dose approaches of 197 days vs. 53 days (HR 1.88, p=0.01).

The decision of whom to treat with intensive chemotherapy is difficult at best. In this issue of the journal, Malfuson and colleagues examined prognostic factors impacting the outcome of 416 older AML patients treated as part of the ALFA-9803 trial, using a regression model, to develop a decision index to identify older patients most likely to benefit from intensive chemotherapy.23 Factors included in the index included high-risk cytogenetics, age ≥75 years, performance status ≥2, and white blood cell count ≥50,000/mL. The authors conclude that patients with a DI > 0 should not be treated with intensive chemotherapy, as their likelihood of being alive 12 months later was only 19%. This treatment decision should be incorporated into considerations of quality of life, which will suffer during hospitalization for remission induction therapy.24

Remission induction therapy
Once a decision has been made to initiate intensive chemotherapy, older AML patients are treated similarly to younger patients. The backbone of remission induction therapy consists of an anthracycline or anthracenedione combined with cytosine arabinoside (cytarabine, Ara-C), a regimen that has changed little since it was first introduced 30 years ago.25,26 Typically, daunorubicin is given at a dose of 45 mg/m2/dx3 days, or mitoxantrone or idarubicin are given at doses of 12 mg/m2/dx3 days, in combination with cytarabine, which is administered as a continuous infusion at 100 or 200 mg/m2/dx7 days (7+3 chemotherapy). While certain approaches, such as increasing the doses of cytarabine or the anthracycline, comparisons of different anthracycliness or anthracenedione, adding additional drugs, and/or using growth factors as priming agents or as supportive care9,12,15,16,18,19,27 have variably improved CR rates and disease-free survival, they commonly come at the price of increased treatment-related mortality, thus offsetting any potential survival advantage. The median survival for older AML patients following these intensive approaches is typically 10–12 months, with higher median survival for those entering a CR, compared to non-responders or those achieving a CR with incomplete platelet recovery (CRi).

One potential improvement on the 7+3 mantra may be the addition of gemtuzumab ozogamicin. The Phase III MRC AML 15 trial compared cytarabine-based therapy + gemtuzumab to standard cytarabine-based induction therapy in 1,115 younger AML patients.28 Patients randomized to the gemtuzumab arm had a similar CR rate and rates of induction death and resistant disease compared to patients randomized to standard therapy, but higher disease-free survival at three years of follow-up (51% vs. 40%, p=0.008), with an indication that this will translate into improved OS. Whether similar improvements will be seen in older adults with AML has yet to be determined. FLT3 inhibitors are actively being studied in combination with traditional cytotoxic therapy, as has modulation of MDR, though conflicting results from large clinical trials have prevented the routine incorporation of MDR modulators into standard AML regimens.

Post-remission therapy
Standard post-remission approaches to therapy in older AML patients usually involve cytarabine administered for fewer days than in the remission induction setting, either alone or in combination with an anthracycline or anthracenedione, for 1–2 cycles. High doses of post-remission cytarabine have been associated with severe neurological toxicity in approximately one third of patients. No additional survival benefit is derived from more intensive post-remission therapy, adding other agents, or from maintenance therapy, though some data exist for a more protracted course of post-remission therapy.14,19,20 Despite this recommendation, no randomized study has shown that, in older adults, some amount of post-remission therapy provides a survival advantage over no post-remission therapy. One small study even suggests there is no benefit to post-remission therapy.

More commonly, stem cell transplantation (SCT) is being considered as post-remission therapy. While SCT offers the chance of cure, it does so at the cost of high treatment-related mortality. SCTs have limited applicability to this population, due to comorbidities in recipients and in matched related donors, and to the limited availability of matched donors who are related to patients of an advanced age. Studies have demonstrated the feasibility of non-myeloablative approaches, with durable survival rates, and are ongoing. Ablative approaches have also been described in older AML patients, though may not provide any advantage over non-myeloabalative preparative regimens.29,30

Newer less-intensive treatment approaches
As there has been little headway in outcomes with older AML patients using intensive remission induction therapy, more contemporary trials have focused on less-intensive therapies that have the potential of effecting a complete remission while preserving quality of life.

Several novel cytotoxic agents are under investigation, with response rates that approach standard 7+3 induction regimens, though prospective comparisons to standard cytarabine-based intensive therapy have not been performed. Clofarabine is a purine nucleoside analog thought to inhibit ribonucleotide reductase, become incorporated into DNA; and induce apoptosis. In one study from the MRC, in which clofarabine was used as a single agent in newly diagnosed older adults,31 the CR rate was 59%. This agent is now being explored in an oral form, and in combination with cytarabine. Cloretazine is an alkylating agent also being studied in older, de novo AML patients. One Phase II study including high-risk patients (such as older patients with poor-risk cytogenetics) demonstrated a CR rate of 28%. Improved outcomes were observed in those patients with de novo AML (50% CR) or intermediate-risk cytogenetics (39% CR). Both drugs are attempting to obtain US. Food and Drug Administration (FDA) approval for up-front treatment of AML in older adults. Tipifarnib, a farnesyl transferase inhibitor, has also been studied in clinical trials in older adults with AML. In a Phase II study of 148 evaluable, previously untreated older adults, the CR rate was 18% and the median overall survival was 5.6 months for all patients.32 However, this drug has not been able to obtain US FDA approval.

Another approach is to take advantage of inhibiting the promoter hypermethylation of tumor suppressor genes thought to play a role in survival of AML cells. Two drugs, azacitidine and decitabine, have been studied in higher-risk MDS populations that included older adults wth AML. In the European AZA-001 study, azacitidine was compared to conventional care in 358 patients with advanced MDS, 33% of whom had 20% blasts or greater (considered AML by the WHO classification system). Response rates, including complete and partial remissions, were similar or better for azacitidine compared to standard induction chemotherapy, as was overall survival, though an important caveat is the subgroup nature of this comparison.33 Decitabine was also studied in higher-risk MDS and AML patients by the Houston group and found to yield CR rates of 39%. A crucial point to interpreting these data is the importance of administering either of these drugs for prolonged periods of time; a median of 9 cycles for the AZA-001 study, and more than 5 cycles for the decitabine study.

Finally, an approach that should not be discounted, and perhaps should be considered the standard of care for less-intensive therapies in older adults, is low-dose cytarabine. When studied by the MRC, this drug resulted in a CR rate of 18% in older AML patients considered not fit for intensive chemotherapy, and demonstrated a significant survival advantage over hydroxyurea. Low-dose cytarabine is being combined with the anti-CD33 monoclonal antibody lintuzumab in an international Phase IIb trial in older adults in the up-front setting.

Conclusion

Older adults with AML represent one of the more challenging groups to treat in oncology, due to the refractoriness of the disease itself, the frailty of the population, and the imperative to incorporate quality of life issues into every treatment decision. Given the desperate nature of survival outcomes, clinical trials should be considered at diagnosis, along with considerations of aggressiveness of therapy and patient-oriented treatment goals.

References

  1. Surveillance, Epidemiology, and End Results (SEER) Program. (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 9 Regs Public-Use, Nov 2004 Sub (1973–2002), National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2005, based on the November 2004 submission.
  2. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun M. Cancer Statistics, 2007. CA Cancer J Clin 2007;57:43-66.[Abstract/Free Full Text]
  3. United States Census Bureau. U.S. Interim Projections by Age, Sex, Race, and Hispanic Origin. http://wwwcensus-gov/ipc/www/usinterimproj.2004:Internet release date March 18, 2004.
  4. Bloomfield CD, Lawrence D, Byrd JC, Carroll A, Pettenati MJ, Tantravahi R, et al. Frequency of prolonged remission duration after high-dose cytarabine intensification in acute myeloid leukemia varies by cytogenetic subtype. Cancer Res 1998;58:4173-9.[Abstract/Free Full Text]
  5. Byrd JC, Mrozek K, Dodge RK, Caroll AJ, Edwards CG, Arthur DC, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse and overall survival in adult patients with de novo acute myeloid leukemia: results from CALGB 8461. Blood 2002;100:4325-36.[Abstract/Free Full Text]
  6. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood 1998;92:2322-33.[Abstract/Free Full Text]
  7. Grimwade D, Walker H, Harrison G, Oliver F, Chatters S, Harrison CJ, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 2001;98:1312-20.[Abstract/Free Full Text]
  8. Farag S, Archer K, Mrózek K, Vardiman J, Carroll A, Pettenati M, et al. Pre-treatment cytogenetics predict complete remission and long-term outcome in patients (Pts) 60 years with acute myeloid leukemia (AML): results from Cancer and Leukemia Group B (CALGB) 8461. Blood 2004;104:568a[Abstract].
  9. Baer MR, George SL, Dodge RK, O’Loughlin KL, Minderman H, Caligiuri MA, et al. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood 2002;100:1224-32.[Abstract/Free Full Text]
  10. Suárez L, Vidriales MB, Moreno MJ, López A, García-Laraña J, Pérez-López C, et al. Differences in anti-apoptotic and multidrug resistance phenotypes in elderly and young acute myeloid leukemia patients are related to the maturation of blast cells. Haematologica 2005;90:54-9.[Abstract/Free Full Text]
  11. Leith CP, Kopecky KJ, Chen IM, Eijdems L, Slovak ML, McConnell TS, et al. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 1999;94:1086-99.[Abstract/Free Full Text]
  12. Godwin JE, Kopecky KJ, Head DR, Willman CL, Leith CP, Hynes HE, et al. A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 1998;91:3607-15.[Abstract/Free Full Text]
  13. Lowenberg B, Suciu S, Archimbaud E, Haak H, Stryckmans P, de Cataldo R, et al. Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy--the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. J Clin Oncol 1998;16:872-81.[Abstract]
  14. Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994;331:896-903.[Abstract/Free Full Text]
  15. Rowe JM, Neuberg D, Friedenberg W, Bennett JM, Paietta E, Makary AZ, 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;103:479-85.[Abstract/Free Full Text]
  16. Stone RM, Berg DT, George SL, Dodge RK, Paciucci PA, Schulman P, et al. Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med 1995;332:1671-7.[Abstract/Free Full Text]
  17. DeLima M, Ghaddar H, Pierce S, Estey E. Treatment of newly-diagnosed acute myelogenous leukaemia in patients aged 80 years and above. Br J Haematol 1996;93:89-95.[CrossRef][Web of Science][Medline]
  18. Lowenberg B, van Putten W, Theobald M, Gmur J, Verdonck L, Sonneveld P, et al. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med 2003;349:743-52.[Abstract/Free Full Text]
  19. Goldstone AH, Burnett AK, Wheatley K, Smith AG, Hutchinson RM, Clark RE. Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 2001;98:1302-11.[Abstract/Free Full Text]
  20. Stone RM, Berg DT, George SL, Dodge RK, Paciucci PA, Schulman PP, et al. Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood 2001;98:548-53.[Abstract/Free Full Text]
  21. Sekeres MA, Elson P, Kalaycio ME, Advani AS, Copelan EA, Faderl S, Kantarjian HM, Estey E. Time from diagnosis to treatment initiation predicts survival in younger, but not older, acute myeloid leukemia patients. Blood 2008, Sep, 30, [Epub ahead of print].
  22. Tilly H, Castaigne S, Bordessoule D, Casassus P, Le Prise PY, Tertian G, et al. Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol 1990;8:272-9.[Abstract]
  23. Malfuson J-V, Etienne A, Turlure P, de Revel T, Thomas X, Contentin N, et al. Risk factors and decision criteria for intensive chemotherapy in older patients with acute myeloid leukemia. Haematologica 2008;93:1806-1813.[Abstract/Free Full Text]
  24. Sekeres MA, Stone RM, Zahrieh D, Neuberg D, Morrison V, De Angelo DJ, et al. Decision-making and quality of life in older adults with acute myeloid leukemia or advanced myelodysplastic syndrome. Leukemia 2004;18:809-16.[CrossRef][Web of Science][Medline]
  25. Carey RW, Ribas-Mundo M, Ellison RR, Glidewell O, Lee ST, Cuttner J, et al. Comparative study of cytosine arabinoside therapy alone and combined with thioguanine, mercaptopurine, or daunorubicin in acute myelocytic leukemia. Cancer 1975;36:1560-6.[CrossRef][Web of Science][Medline]
  26. Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K, Obrecht JP, et al. Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B. Blood 1981;58:1203-12.[Free Full Text]
  27. Dillman RO, Davis RB, Green MR, Weiss RB, Gottlieb AJ, Caplan S, et al. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood 1991;78:2520-6.[Abstract/Free Full Text]
  28. Wallen H, Gooley TA, Deeg HJ, Pagel JM, Press OW, Appelbaum FR, et al. Ablative allogeneic hematopoietic cell transplantation in adults 60 years of age and older. J Clin Oncol 2005;23:3439-46.[Abstract/Free Full Text]
  29. Alyea EP, Kim HT, Ho V, Cutler C, Gribben J, DeAngelo DJ, et al. Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood 2005;105:1810-4.[Abstract/Free Full Text]
  30. Lancet J, Gotlib J, Gojo I, Feldman E, Morris L, Thibault A, et al. Tipifarnib (ZARNESTRATM) in previously untreated poor-risk AML of the elderly: updated results of a multi-center Phase 2 trial. Blood 2004;104:874a[Abstract].




This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sekeres, M. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sekeres, M. A.