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Journal of Clinical Oncology, Vol 26, No 21 (July 20), 2008: pp. 3475-3477 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.1034
The Long Road to a Cure for Acute Myelocytic Leukemia: From Intensity to SpecificityUniversity of Alabama at Birmingham School of Medicine, Birmingham, AL
The Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD Twenty-five years ago, increasing numbers of children with acute lymphocytic leukemia were being cured with prolonged-duration, multiagent chemotherapy programs developed over the previous 20 years in serial clinical investigations conducted principally at the United States National Cancer Institute and in the cooperative group trials. The application of these strategies to acute myelocytic leukemia (AML), however, produced disappointing results in children and adults despite the availability of more effective agents, especially cytarabine and the anthracyclines. With the emergence of improved supportive care in transfusion medicine and infectious disease management, it became feasible to investigate more intensive remission induction regimens and to rethink the role of maintenance therapy. More intensive combination chemotherapy with daunorubicin or doxorubicin plus cytarabine was rapidly becoming the standard for remission induction. To further intensify remission induction therapy with these agents, Philip Burke, MD, in whose laboratory and clinical program we worked, hypothesized that timed sequential chemotherapy could recruit noncycling malignant cells into cell cycle, making them more sensitive to a short infusion of the cell cycle–specific second drug (cytarabine) if given in an optimally timed sequence after an initial infusion of the two drugs together. In a series of studies in the laboratory and in clinical trials, the optimum timing for most efficient cell kill and therapeutic index were worked out, and the role of humoral factors in the recruitment of malignant cells into cycle was explored.1-4 In these trials, adults with AML were treated with a timed sequential regimen of daunorubicin and continuous-infusion cytarabine administered on days 1 through 3 followed by another 3 days of cytarabine after a short interval. An early indication of the increased effectiveness of this strategy was the observation that a complete remission rate was achieved for four of seven patients who had AML occurring after exposure to prior chemotherapy or radiation. Previously, these patients were considered to have disease that was completely refractory to induction therapy. This series of patients was treated before the routine use of cytogenetics to determine risk for treatment failure, and, to our knowledge, this regimen has not been studied in high-risk patients so identified, but it seems unlikely that the patients in our series were predominantly good risk. This observation was reported in 1983 in the article reprinted in this silver anniversary edition of Journal of Clinical Oncology.5 Meanwhile, a clinical trial was being completed in which a second cycle of the same regimen was given as consolidation and no further chemotherapy until relapse. Forty percent of the patients treated with two cycles of timed sequential therapy achieved long-term complete remission.6 Longer follow-up reported in a later article7 suggested that they are probably cured. The timed sequential therapy approach has subsequently been evaluated in three randomized clinical trials. The first was a Children's Cancer Study Group study chaired by Bill Woods, MD, in which children with AML were randomly assigned to receive four courses of intensive multiagent chemotherapy with time for marrow recovery between each course or as two cycles of timed sequential therapy over the same overall time period. The timed sequential therapy arm produced statistically significantly better long-term disease-free survival and was the first report of a greater than 50% long-term survival rate in pediatric AML.8 Recently, the use of this regimen and schedule was reported by investigators at M.D. Anderson Cancer Center to also be more effective in terms of long-term disease-free survival in adults up to age 50 years.9 Meanwhile, an intensified version of the original Burke regimen was tested in a large French consortium trial against two other standard induction regimens. Despite substantially greater toxicity, the timed sequential therapy regimen produced a significantly better duration of complete remission for patients younger than 50 years.10 The disappointing reality is that more than 25 years after the development of this and other aggressive approaches, we are still using the same treatment strategies and the same two agents as the treatment for standard- and high-risk AML, with the exception of acute promyelocytic leukemia (APL). The cure rate with anthracyclines and cytarabine chemotherapy in this subset has long been recognized to be high, but with the discovery of the pathogenetic role of the sensitivity to retinoids11 and the remarkable effectiveness of arsenic trioxide, the cure rate approaches 80%, with much less treatment-related mortality.12 Building on the APL example and continued improved understanding of the molecular pathogenesis of various other subtypes of AML, investigators are right to move the focus of clinical trials from intensity to specificity in the management of the disease. The case of APL is unique in terms of the specifics related to therapy but may not be the only AML subtype whose stem cells present targets not present in normal cells, especially hematopoietic stem cells.13 Other so-called good prognosis sub-types such as inv(16) and t(8:21) may also represent transformed clones of precursors providing targets not present in hematopoietic stem cells. What these favorable-prognosis AML subtypes seem to have in common is a more uniform phenotypic differentiation after transformation than AML with a more primitive precursor phenotype. Conversely, AML subtypes demonstrating characteristics suggesting transformation without organized differentiation of primitive precursors14,15 may not be curable without eradicating and replacing the normal hematopoietic stem-cell population. We are increasingly able to define such poor-risk AML on the basis of clinical features and molecular genetics. These patients are not only less likely to achieve complete response with cytotoxic chemotherapy but are predisposed to shorter disease-free survival, despite intensive induction and postremission therapies. Such patients may benefit from additional treatment in remission focused on relapse suppression by exploiting previously untargeted pathways governing stem-cell renewal and differentiation. Epigenetic modulatory approaches involving DNA methyl transferase inhibitors or histone deacetylase inhibitors might prevent recurrence by promoting apoptosis or by silencing genes involved in differentiation.16-18 These strategies and immunomodulatory approaches, including vaccines directed against one or more aberrantly expressed proteins,19,20 may find their greatest efficacy in the minimal residual disease state. Another strategy may be to study agents designed to target selected components of key signal transduction pathways, for example, FLT-3, vascular endothelial growth factor, farnesyltransferases, aurora kinase inhibitors, or critical components of pathways aimed at repairing DNA damage such as CHK-1 or PARP.21-26 It is also likely that using these agents in non–cross-resistant combination may enhance their efficacy. Ultimately, the ideal minimal residual disease approach would be able to discriminate normal from leukemic stem cells and thereby permit the selective destruction of the latter. This can only arise from current efforts to identify the unique characteristics that characterize each myeloid leukemia subtype stem cell on molecular and biologic levels. Ultimately, as we come to deepen our understanding of the molecular pathogenesis of AML, particularly on the level of the leukemia-susceptible stem cell, we may be able to prevent the occurrence of AML occurring as a consequence of genomic toxicity, as in treatment-related AML. The lessons learned from treatment of patients in remission27 and in preleukemic states and the molecularly targeted approaches being tested in that setting may be directly applicable to the primary prevention setting, especially if we are able to define individuals at high risk for leukemogenesis. We are optimistic that recognizing the heterogeneity of AML with respect to its malignant stem-cell biology compared with normal hematopoietic stem cells, its cell kinetics, and its aberrant molecular pathophysiology will lead to specific curative strategies for all of the AML subtypes in less than the next 25 years. Treatment of patients on clinical trials with companion studies of AML cell biology should be performed whenever feasible in order to permit the fluent translation of elegant molecular discoveries into clinical advances. It is only through such scientifically sound translation that we will be able to move the field forward in a clinically meaningful way. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: William P. Vaughan, Judith E. Karp Manuscript writing: William P. Vaughan, Judith E. Karp Final approval of manuscript: William P. Vaughan, Judith E. Karp REFERENCES 1. Burke PJ, Karp JE, Braine HG, et al: A timed sequential therapy of human leukemia based upon the response of leukemic cells to humoral growth factors. Cancer Res 37:2138-2146, 1977[Medline] 2. Vaughan WP, Karp JE, Burke PJ: Long chemotherapy free remissions after single cycle timed-sequential chemotherapy of acute myelocytic leukemia. Cancer 45:859-865, 1980[CrossRef][Medline] 3. Burke PJ, Vaughan WP, Karp JE: A rationale for sequential high dose chemotherapy of leukemia timed to coincide with induced tumor proliferation. Blood 55:960-968, 1980 4. Vaughan WP, Burke PJ: Development in a rat model of a cell kinetic approach to curative therapy of acute myelocytic leukemia using the cell cycle specific drug 1-B-D arabinofuranosyl cytosine. Cancer Res 43:2005-2009, 1983 5. Vaughan WP, Karp JE, Burke PJ: Effective chemotherapy of acute myelocytic leukemia occurring after alkylating agent or radiation therapy of prior malignancy. J Clin Oncol 1:204-207, 1983[Abstract] 6. Vaughan WP, Karp JE, Burke PJ: Two cycle timed-sequential chemotherapy for adult acute non-lymphocytic leukemia. Blood 64:975-980, 1984 7. Geller RB, Burke PJ, Karp JE, et al: A two-step timed sequential treatment for acute myelocytic leukemia. Blood 74:1499-1506, 1989 8. Woods WG, Kobrinsky N, Buckley JD, et al: Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: A report from the Children's Cancer Group. Blood 87:4979-4989, 1996 9. Rytting M, Verstovsek S, Garcia-Manero G, et al: Intensively timed induction (ITI) chemotherapy in adults with acute myelogenous leukemia (AML): Pediatrics and Leukemia. Blood 110:548a, 2007 (abstr 1851) 10. Castaigne S, Chevret S, Archimbaud E, et al: Randomized comparison of double induction and time-sequential induction to a "3 + 7" induction in adults with AML: Long-term analysis of the Acute Leukemia French Association (ALFA) 9000 study. Blood 104:2467-2474, 2004 11. Melnick A, Licht JD: Deconstructing a disease: RAR 12. Estey E, Garcia-Manero G, Ferrajoli A, et al: Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 107:3469-3473, 2006 13. Grimwade D, Enver T: Acute promyelocytic leukemia: Where does it stem from? Leukemia 18:375-384, 2004[CrossRef][Medline] 14. Vaughan WP, Civin CI, Weisenburger DD, et al: Acute leukemia expressing the normal human hematopoietic stem cell membrane glycoprotein CD34 (MY10). Leukemia 2:661-666, 1988[Medline] 15. Geller RB, Zahurak M, Hurwitz CA, et al: Prognostic importance of immunophenotyping in adults with acute myelocytic leukaemia: The significance of the stem-cell glycoprotein CD34 (My10). Br J Haematol 76:340-347, 1990[Medline] 16. Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al: Phase 1/2 study of the combination of 5-aza-2`deoxycytidine with valproic acid in patients with leukemia. Blood 108:3271-3279, 2006 17. Gore SD, Baylin S, Sugar E, et al: Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66:6361-6369, 2006 18. Jones PA, Baylin SB: The epigenomics of cancer. Cell 128:683-692, 2007[CrossRef][Medline] 19. Greiner J, Schmitt M, Li L, et al: Expression of tumor-associated antigens in acute myeloid leukemia: Implications for specific immunotherapeutic approaches. Blood 108:4109-4117, 2006 20. Molldrem J: Vaccination for leukemia. Biol Blood Marrow Transplant 12:13-18, 2006[Medline] 21. Gilliland DG, Griffin JD: The roles of FLT3 in hematopoiesis and leukemia. Blood 100:1532-1542, 2002 22. Levis M, Small D: FLT3 tyrosine kinase inhibitors. Int J Hematol 82:100-107, 2005[CrossRef][Medline] 23. Karp JE, Gojo I, Pili R, et al: Vascular endothelial growth factor (VEGF) for relapsed and refractory adult acute myelogenous leukemias: Therapy with sequential ara-C, mitoxantrone and bevacizumab. Clin Cancer Res 10:3577-3585, 2004 24. Karp JE, Lancet JE: Development of farnesyltransferase inhibitors for clinical cancer therapy: Focus on hematologic malignancies. Cancer Invest 25:484-494, 2007[CrossRef][Medline] 25. Donawho CK, Luo Y, Luo Y, et al: ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical animal models. Clin Cancer Res 13:2728-2737, 2007 26. Mesa RA, Loegering D, Powell HL, et al: Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine. Blood 106:318-327, 2005 27. Karp JE, Smith BD, Gojo I, et al: Phase II trial of the oral farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) as maintenance therapy in first complete remission in adults with acute myelogenous leukemia and poor risk features. Clin Cancer Res 14:3077-3082, 2008 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93:3167-3215, 1999
