There have been significant advances in our understanding of the biology of acute myelogenous leukemia (AML), and to a lesser extent, in its treatment. Dr. Estey has provided an excellent overview of the current state of the clinical management of the disease. He has described both the standard therapeutic approaches, including allogeneic hematopoietic stem cell transplantation, as well as the role of investigational therapy. The present state of clinical research in AML is reviewed in some detail in the context of the broad clinical investigation of the disease at the M. D. Anderson Cancer Center. Dr. Estey makes a strong argument for the early consideration of investigational therapy, focusing on patients for whom "standard" therapy is demonstrably inadequate.
There have been significant advances in ourunderstanding of the biology of acute myelogenous leukemia (AML), and to alesser extent, in its treatment. Dr. Estey has provided an excellent overview ofthe current state of the clinical management of the disease. He has describedboth the standard therapeutic approaches, including allogeneic hematopoieticstem cell transplantation, as well as the role of investigational therapy. Thepresent state of clinical research in AML is reviewed in some detail in thecontext of the broad clinical investigation of the disease at the M. D. AndersonCancer Center. Dr. Estey makes a strong argument for the early consideration ofinvestigational therapy, focusing on patients for whom "standard"therapy is demonstrably inadequate.
Cytogenetics at Presentation
Several points raised by Dr. Estey regarding clinical practice deserveparticular emphasis. The first is that cytogenetics must be routinely performedat presentation of AML. It is clear that the prognosis of the disease correlatesclosely with the cytogenetics,[1,2] and importantly, the karyotype can have aprofound effect on the choice of treatment (particularly in consolidation). Forexample, patients with the more favorable t(8;21) karyotype derive substantialbenefit from consolidation with repeated cycles of high-dose cytarabine, and asubstantial proportion may even be cured with such an approach. How much"high-dose" cytarabine is actually required, however, remains an openquestion.
It is also clear that AML with a complex karyotype, or with -5/-7 monosomies,has a poor prognosis regardless of therapy, thereby justifying earlyconsideration of investigational therapy. Moreover, the cytogenetics should alsobe confirmed again at relapse because they are important in determining theprognosis following salvage therapy, and changes in karyotype (usually theacquisition of an adverse karyotype) are commonly noted.
Flow Cytometry and Documentation of CR
Baseline flow cytometry should also be performed. Although less helpful indetermining prognosis, immunophenotype is sometimes helpful in establishingthe diagnosis (particularly for undifferentiated AML). In addition, it may beimportant clinically to note the expression of CD33, the target antigen forgemtuzumab ozogamicin (Mylotarg). Immunophenotypic changes have beenfrequently noted at relapse, and therefore, flow cytometry should again beperformed at that time.
Finally, Dr. Estey appropriately emphasizes the importance of achieving anddocumenting complete remission (CR). Patients who achieve CR only after repeatedcourses of therapy have a significantly worse outcome and may be candidatesfor novel treatment strategies. Therefore, in addition to the demonstration ofan adequately hypocellular (and leukemia-free) bone marrow following treatment,CR should be documented separately at the time of recovery following inductionchemotherapy.
Unfortunately, despite apparent improvements in the treatment of AML over thepast decade with newer cytotoxic chemotherapy regimens, long-term results havenot demonstrated dramatically improved outcomes, and cytarabine remainsthe backbone of current therapy. Tremendous interest was generatedrecently with the advent of the humanized anti-CD33/calicheamicin immunotoxin,gemtuzumab ozogamicin, which is now approved for the treatment of relapsed AMLin patients older than age 60 years. As a single agent, gemtuzumab ozogamicininduces remission in 30% of patients, and as noted by Dr. Estey, appears to bemore effective than high-dose cytarabine-based regimens in early relapse of AML.
Phase I and II studies combining gemtuzumab ozogamicin with cytotoxicchemotherapy are presently under way. However, there is a concern regarding theincidence of hepatotoxicity following gemtuzumab ozogamicin therapy,specifically hepatic veno-occlusive disease, although the etiology is not wellunderstood. Ursodiol (Actigall, URSO) does not appear to confer protectionfrom veno-occlusive disease.
Receptor Tyrosine Kinase Inhibitors
Perhaps a more surprising and important recent development in AML is thefrequency of occult mutations in the FLT3 receptor tyrosine kinase (RTK). Aninternal tandem duplication of FLT3 occurs in approximately 25% of patients,disproportionately in patients with a normal karyotype (~40%), thus making itthe most common genetic lesion known in AML. Patients harboring an FLT3internal tandem duplication have a significantly worse prognosis independent ofcytogenetics, predominantly due to the increased risk of relapse. Specificinhibitors of FLT3 (both the internal tandem duplication and wild-type) are inclinical development, and separate treatment strategies (including allogeneichematopoietic stem cell transplantation) for patients with FLT3 internal tandemduplication are being developed.
The emerging importance of angiogenesis in AML has only recently beenappreciated. An increase in microvessel density in the bone marrow has beendemonstrated in AML, with a significant reduction after successfulchemotherapy. Vascular endothelial growth factor (VEGF) production by AMLblasts is an independent prognostic factor, and VEGF appears to act as aparacrine and autocrine growth factor.[15-18]
Investigators at the M. D. Anderson Cancer Center obtainednegative results in an early trial of the antiangiogenesis agent thalidomide(Thalomid), administered in combination with cytotoxic chemotherapy, in patientswith AML or myelodysplastic syndrome. Nevertheless, RTK inhibitors targetingVEGF receptors (in addition to other RTKs implicated in angiogenesis and AML,such as c-kit) are in clinical development, and some clinical responses havebeen noted.
Dr. Estey is justified in advocating the early consideration ofinvestigational therapy. Unlike chronic myelogenous leukemia, a diseasecharacterized by a common cytogenetic lesion for which imatinib mesylate (Gleevec)has demonstrated remarkable single-agent efficacy, AML represents a morehetereogeneous disease. Therefore, it is not anticipated that any cytotoxicagent, RTK inhibitor, or antiangiogenesis compound will be curative as a singleagent. Rather, it is only through the rational development of new agents basedon our increased understanding of the biology of AML, and their inclusion incombination therapy, that we will be able to improve the prognosis for thisdifficult-to-treat disease.
1. Grimwade D, Walker H, Oliver F, et al: The importance of diagnosticcytogenetics on outcome in AML: Analysis of 1,612 patients entered into the MRCAML 10 trial. Blood 92:2322-2333, 1997.
2. Slovack ML, Kopecky KJ, Cassileth PA, et al: Karyotypic analysis predictsoutcome of pre-remission and post-remission therapy in adult acute myeloidleukemia: SWOG/ECOG. Blood 96:4075-4083, 2000.
3. Byrd JC, Dodge RK, Carroll A, et al: Patients with t(8;21)(q22:q22) andacute myeloid leukemia have superior failure-free and overall survival whenrepetitive cycles of high-dose cytarabine are administered. J Clin Oncol17:3767-3775, 1999.
4. Kern W, Schoch C, Haferlach T, et al: Multivariate analysis of prognosticfactors in patients with relapsed and refractory acute myeloid leukemiaundergoing sequential high-dose cytosine arabinoside and mitoxantrone salvagetherapy: Relevance of cytogenetic abnormalities. Leukemia 14:226-231, 2000.
5. Legrand O, Perrot JY, Baudard M, et al: The immunophenotype of 177 adultswith acute myeloid leukemia: Proposal of a prognostic score. Blood 96:870-877,2000.
6. Sievers EL, Larson RA, Staudtmauer EA, et al: Efficacy and safety ofgemtuzumab-ozogamicin in patients with CD33-positive acute myeloid leukemia infirst relapse. J Clin Oncol 19:3244-3254, 2001.
7. Baer MR, Stewart CS, Dodge RK, et al: High frequency of immunophenotypechanges in acute myeloid leukemia a relapse: Implications for residual diseasedetection (CALGB study 8361). Blood 97:3574-3580, 2001.
8. Kern W, Haferlach T, Schoch C, et al: Early blast clearance during aplasiafollowing induction therapy is a major independent prognostic factor for bothachievement of CR and long-term outcome in AML: Data from the German AMLCG trial1992. Blood 98(suppl 1):462a, 2001.
9. Cheson BD, Cassileth PA, Head DR, et al: Report of the National CancerInstitute-sponsored workshop on definitions of diagnosis and response in acutemyeloid leukemia. J Clin Oncol 8:813-819, 1990.
10. Estey EH, Thall PF, Cortes JE, et al: Comparison of idarubicin + ara-C,fludarabine + ara-C, and topotecan + ara-C-based regimens in treatment ofnewly-diagnosed acute myeloid leukemia, refractory anemia with excess blasts intransformation, or refractory anemia with excess blasts. Blood 98:3575-3583,2001.
11. Giles FJ, Kantarjian H, Kornblau S, et al: Mylotarg (gemtuzumab-ozogamicin)is associated with hepatic veno-occlusive disease in patients who have notreceived stem cell transplantation. Cancer 92:406-413, 2001.
12. Giles FJ, Thomas DA, Cortes J, et al: An ursodiol and methylprednisoneregimen does not reduce Mylotarg-associated hepatic veno-occlusive disease inpatients with acute myeloid leukemia not receiving stem cell transplantation.Blood 98(suppl 1):721a, 2001.
13. Kottaridis PD, Gale RE, Frew ME, et al: The presence of a FLT3 internaltandem duplication in patients with acute myeloid leukemia adds importantprognostic information to cytogenetic risk group and response to the first cycleof chemotherapy: Analysis of 854 patients from the United Kingdom MedicalResearch Council AML 10 & 12 trials. Blood 98:1752-1759, 2001.
14. Padro T, Ruiz S, Bieker R, et al: Increased angiogenesis in the bonemarrow of patients with acute myeloid leukemia. Blood 95:2637-2644, 2000.
15. Fiedler W, Graeven U, Ergun U, et al: Vascular endothelial growth factor,a possible paracrine growth factor in human acute myeloid leukemia. Blood89:1870-1875, 1997.
16. Bellamy WT, Richter L, Frutiger Y, et al: Expression of vascularendothelial growth factor and its receptors in hematopoietic malignancies.Cancer Res 59:728-733, 1999.
17. Aguayo A, Estey E, Kantarjian H, et al: Cellular vascular endothelialgrowth factor is a predictor of outcome in patients with acute myeloid leukemia.Blood 94:3717-3721, 1999.
18. Aguayo A, Kantarjian H, Manshouri T, et al: Angiogenesis in acute andchronic leukemias and myelodysplatic syndromes. Blood 96:2240-2245, 2000.
19. Estey E, Albitar M, Cortes J, et al: Addition of thalidomide tochemotherapy did not increase the remission rate in poor prognosis AML/MDS.Blood 96(suppl 1):323a, 2000.
20. Mesters RM, Padro T, Bieker R, et al: Stable remission afteradministration of the receptor tyrosine kinase inhibitor SU5416 in a patientwith refractory acute myeloid leukemia. Blood 2001 98:241-243, 2001.
21. Druker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specificinhibitor of the BCR-ABL tyrosine kinase in CML. N Engl J Med 344:1031-1037,2001.