Acute Myeloid Leukemia (AML): The Role of Intensive Induction Chemotherapy
AbstractIntensive induction therapy-in acute myeloid leukemia (AML), as in some other systemic malignancies- is a strategy fundamentally different from post-remission strategies. Approaches like consolidation treatment, prolonged mainte¬nance, and autologous or allogeneic transplantation in the first remission are directed against minimal residual disease with a malignant cell population having survived the induction treatment. In contrast, induction therapy deals with naive tumor cells possibly different in their sensitivity from their counterparts in remission. Therefore, in AML it has been suggested to introduce intensification strategies into the induction part of treatment as a new step after the preceding intensification steps in the post-remission part. As expected from the dose effects observed in post-remission treatment using more AraC or longer treatment, similar dose effects have been found in the induction treatment both by the incorporation of high-dose AraC and by the double induction strategy administered in patients up to 60 years of age. For example, patients with poor risk AML due to an unfavorable karyotype, high LDH in serum, or delayed response, benefited from double induction containing high-dose AraC by a longer survival as compared to that from standard dose AraC. A corresponding dose effect in the induction treatment has been found in patients of 60 years and older receiving daunorubicin 60 vs 30 mg/m2 as part of the TAD regimen with higher dosage. This treatment significantly increased the response and survival rate in older patients who represented a poor risk group as a whole. Thus, we could demonstrate, both in younger and older patients, that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits a cumulative toxicity in that a repetition of courses containing high-dose AraC in the post-remission period is associated with considerable myelotoxicity leading to longlasting aplasias of about 6 weeks. However, after intensive induction treatment, high-dose chemotherapy in remission may become practicable using autologous stem cell rescue and may contribute to a further improvement of the outcome in poor risk as well as average patients with AML. These approaches are currently investigated by the German AMLCG. While there are clear limitations in the intensity of antineoplastic treatment for AML, as for other systemic malignancies, some further intensification may be possible and effective.
- Rai KR, Holland JF, Glidewell OJ, Weinberg V, Brunner K, Obrecht JP, Preisler HD, Nawabi IW, Prager D, Carey RW, Cooper MR, Haurani F, Hutchsion JL, Silver RT, Falkson G, Wiernik P, Hoagland HC, Bloodfield CD, James GW, Gottlieb A, Ramanan SV, Blom J, Nissen NI, Bank A, Ellison RR, Kung F, Henry P, McIntyre OR, Kaan SK (1981) Treatment of acute myelocytic leukemia: A study by Cancer and Leukemia Group B. Blood 58:1203
- Büchner T, Urbanitz D, Hiddemann W, Ludwig WD, Aul HC, Vaupel HA, Kuse R, Zeile G, Now- rousian MR, König HJ, Walter M, Wendt FC, Sodomann H, Hossfeld DK, von Paleske A, Löffler H, Gassmann W, Hellriegel KP, Fülle HH, Lunscken C, Emmerich B, Pralle H, Pees HW, Pfreundschuh M, Bartels H, Koeppen KM, Schwerdtfeger R, Donhui- jsen-Ant R, Mainzer K, Bonfert B, Köppler H, Zurborn KH, Ranft K, Thiel E, Heinecke A (1985) Intensified induction and consolidation with or without mainte- nance chemotherapy for acute myeloid leukemia (AML): Two multicenter studies of the German AML Cooperative Group. J. Clin. Oncol. 3:1583
- Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei E (1994) Intensive postremission chemotherapy in adults with acute myeloid leukemia. N. Engl. J. Med. 331:896
- Burnett AK, Goldstone AH, Stevens R, Hann I, Rees JK, Gray RG, Wheatley K (1998) Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet 351:700
- Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, Bacerzak SP, Bickers JN, Hynes HE, Welborn JL, Simon SR, Grever M (1996) A random- ized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: A Southwest Oncology Group Study. Blood 88:2841
- Bishop JF, Matthews JP, Young GA, Szer J, Gillet A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R, Cobcroft R, Herrmann R, Van Der Weyden M, Lowenthal RM, Page F, Garson OM, Juneja S (1996) A randomized study of high-dose cytarabine induction in acute myeloid leukemia. Blood 87:1710
- Büchner T, Hiddemann W, Löffler G, Gassmann W, Maschmeier G, Heit W, Hossfeld D, Weh H, Ludwig WD, Thiel E, Nowrousian M, Aul C, Lengfelder E, Lathan B, Mainzer K, Urbanitz D, Emmerich B, Middelhoff G, Donhuijsen-Ant HR, Hellriegel HP, Heinecke A (1991) Improved cure rate by very early intensification combined with prolonged maintenance chemotherapy in patients with acute myeloid leukemia: Data from the AML Cooperative Group. Semin. Hematol. 28 (Suppl 4):76
- Büchner T, Hiddemann W, Wörmann B, Löffler H, Gassmann W, Haferlach T, Fonatch C, Haase D, Schoch C, Hossfeld D, Lengfelder E, Aul C, Heyll A, Maschmeyer G, Ludwig WD, Sauerland MC, Heinecke A (1999 a) Double Induction Strategy for Acute Myeloid Leukemia: The Effect of High-Dose Cytarabine with Mitoxantrone instead of Standard- Dose Cytarabine with Daunorubicin and 6- Thioguanine. A Randomized Trial by the German AML Cooperative Group. Blood 93:4116
- Büchner T, Hiddemann W, Wörmann B, Löffler H, Haferlach T, Fonatsch C, Haase D, Schoch E, Lengfelder E, Aul E, Heyll A, Maschmeier G, Ludwig WD, Sauerland MC, Heinecke A for the AMLCG (1999 c) Improvement of prognosis in poor prognosis AML by intensified induction chemotherapy. Proc. ASCO 18:6a
- Büchner T, Hiddemann W, Schoch C, Haferlach T, Sauerland MC, Heinecke A (2001) Acute myeloid leukemia (AML): Treatment of the older patient. Best Practice & Research Clinical Haematology 14: 139
- Leith C, Chen IM, Kopecky KJ, Appelbaum FR, Head DR, Godwin JE, Weick JK, Willmann CL (1995) Correlation of multidrug resistance (MDR1) protein expression with functional Dye/Drug efflux in acute myeloid leukemia by multiparameter flow cytometry: Identification of discordant MDR-/Efflux+ and MDR1+/Efflux- cases. Blood 86:2329
- Leith CP, Kopecky KJ, Godwin J, McConnel T, Slovak ML, Chen IM, Head DR, Appelbaum FR, Willman CL (1997) Acute myeloid leukemia in the elderly: Assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biological subgroups with remarkably distinct response to standard chemotherapy. A Southwest Oncology Group Study. Blood 89:3323
- Hamblin TJ (1992) The treatment of acute myeloid leukemia preceded by the myelodysplastic syndrome. Leuk Res. 16:4101
- Stone RM, Berg TB, George SL, Dodge RK, Paciucci PA, Schulman P, Lee EJ, Moore JO, Powell BL, Schiffer CA for the Cancer and Leukemia Group B (1995) Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Engl J Med. 332:1671
- Büchner T, Hiddemann W, Wörmann B, Löffler H, Gassmann W, Haferlach T, Schoch C, Staib P, Lengfelder E, Aul C., Heyll A, Ludwig WD, Maschmeier G, Grüneisen A, Balleisen L, Rasche H, Eimermacher H, Karow J, Eggeling B, Schott G, Reis E, Sauerland MC, Heinecke A (1999 b) One single course of sequential high-dose AraC/mitoxantrone (S- HAM) has the same long-term effect as three years of maintenance in AML patients after TAD-HAM double induction. Randomized trial by the German AMLCG. Blood 94 Suppl 1:383a
- List AF, Kopecky KJ, Willman CL et al. (2001) Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Blood 98:3212.
- Advani R, Saba HA, Tallmann MS et al. (1999) Treatment of refractory and relapsed acute myeloge- nous leukemia with combination chemotherapy plus the multidrug resistance modulator PSC 833 (Valspo- dar). Blood 93:787.
- Dorr R, Karanes C, Spier C et al. (2001) Phase I/II study of the P-glycoprotein modulator PSC 833 in patients with acute myeloid leukemia. J Clin Oncol 19:1589.
- Tidefelt U, Liliemark J, Gruber A et al. (2000) P- glycoprotein inhibitor Valspodar (PSC 833) increases the intracellular concentrations of daunorubicin in vivo in patients with P-glycoprotein-positive acute myeloid leukemia. J Clin Oncol 18:1837.
- Sievers EL, Appelbaum FR, Spielberger RT et al. (1999) Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 Calicheamicin immunoconjugate. Blood 93:3678.
- Sievers EL, Larson RA, Stadtmauer EA et al. (2001) Efficacy and safety of Gemtuzumab Ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 19:3244.
- Mesters RM, Padró T, Bieker R et al. (2001) Stable remission after administration of the receptor tyrosine kinase inhibitor SU5416 in a patient with refractory acute myeloid leukemia. Blood 98:241.
- Aaronson NK, Ahmedzai S, Bergman B et al. (1993) The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376.
- Schumacher A, Kessler T, Büchner T, et al. (1998) Quality of life in adult patients with acute myeloid leukemia receiving intensive and prolonged chemo- therapy – a longitudinal study. Leukemia 12:586-592.
- Schumacher A, Wewers D, Heinecke A, et al. (2002) Fatigue as an important aspect of quality of life in patients with acute myeloid leukemia. Leukemia Research 26:355-362, 2002