Adult AML: The Role of Chemotherapy Intensity and Duration. Two Studies of the AML Cooperative Group

Büchner, Thomas; Hiddemann, Wolfgang; Blasius, S.; Koch, P.; Maschmeyer, Georg; Tirier, C.; Sodomann, H.; Kuse, R.; Thiel, Eckhard; Wd, Ludwig; Seibt-Jung, H.; Gaßmann, W.; Löffler, Helmut; Aul, Carlo; Heyll, A.; Mertelsmann, R; Anders, CK; Nowrousian, M. R.; Straif, Kurt; Hossfeld, D. K.; Becker, Katja; Ho, A. D.; Fülle, H. H.; Hellriegel, K. P.; König, Heiko; Lengfelder, Eva; Siegert, W.; Bartels, H.; Schwammborn, J.; Donhuijsen-Ant, R.; Vaupel, H. A.; König, E; Planker, M.; Emmerich, R.; Middelhoff, G.; Mainzer, K.; Urbanitz, D.; Zurborn, K.-H.; Köppler, H.; Nowicki, L.; Augener, W.; Karow, J.; Schroêder, M.; Eimermacher, Hartmut; Fuchs, Roland J.; Balleisen, Leopold; Schmitz-Huebner, U.; Leimer, Lothar; Heitzelmann, K. H.; Lathan, B.; Meuthen, I.; Baldus, M.; Michels-Giermann, R.; Fuhr, H. G.; Sauerland, M. C.; Heinecke, Achim

doi:10.1007/978-3-642-74643-7_47

Cited by 22 publications

(8 citation statements)

References 11 publications

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“…Randomized trials in Germany, U.S.A., and Japan have reported clear reduction in relapses and possible survival benefits using such regimens (Bü chner et al, 1990b;Cassileth et al, 1992;Ohno et al, 1993). This is not enough informationfor any really firm conclusions about the effects of maintenance treatment on survival.…”

Section: Discussionmentioning

confidence: 99%

Dose intensification in acute myloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council's ATML9 study

1996

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Between 1984 and 1990, 972 patients aged 1-79 years with acute myeloid leukaemia (AML), from 85 British hospitals, were entered into the MRC's 9th AML trial. Patients were randomized between DAT 1 + 5 (daunorubicin for 1 d, with cytarabine and 6-thioguanine for 5 d) and DAT 3 + 10 (same dose drugs for 3 and 10 d respectively) as induction therapy. The 63% who achieved complete remission (CR) were randomized to receive two courses of DAT 2 + 7 alternating with two courses of either MAZE (m-AMSA, 5-azacytidine, etoposide) or COAP (cyclophosphamide, vincristine, cytarabine, prednisone). Finally, those still in CR were randomized to receive either 1 year of maintenance treatment with eight courses of cytarabine and thioguanine followed by four courses of COAP, or no further cytotoxic therapy. Resistance to induction therapy was less common with the DAT 3 + 10 regimen than with DAT 1 + 5 (13% v 23%; P = 0.0001) and hence, despite a 5% increase in the risk of induction death, the CR rate was higher (66% v 61%; P = 0.15). Moreover, CR was achieved more rapidly with DAT 3 + 10 (median 34 v 46 d; P < 0.0001) and thus patients required less time in hospital (mean 20 v 29 d) and less blood product support. 5-year relapse-free survival (28% v 23%; P = 0.05) and survival (23% v 18%; P < 0.05) were also better with DAT 3 + 10. Post-remission intensification of therapy with MAZE resulted in fewer relapses (66% v 74% at 5 years; P = 0.03) but patients allocated MAZE required considerably more supportive care and 14 (4.5%) died following 312 MAZE courses, whereas no deaths occurred following COAP. 5-year survival was not significantly higher with MAZE (37% v 31%). Finally, although 1 year of outpatient maintenance treatment appeared to delay, but not prevent, recurrence it did not improve 5-year survival which was non-significantly worse for those allocated maintenance treatment (41% v 44%). We conclude that the more intensive induction regimen, DAT 3 + 10, is not only more effective than DAT 1 + 5, even for older patients, but is also less expensive; intensive post-remission therapy with MAZE achieves better leukaemic control but at the cost of substantial toxicity; whereas low-level maintenance therapy confers no apparent advantage in survival as well as being inconvenient and costly.

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Section: Discussionmentioning

confidence: 99%

Dose intensification in acute myloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council's ATML9 study

1996

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“…However 50-70% of adults with AML will ultimately relapse due to persistent leukemia below the level of morphological detectability. 9,10 Several techniques have been developed to detect minimal residual disease, such as immunophenotyping, molecular biology, conventional cytogenetic analysis and fluorescence in situ hybridization (FISH). [11][12][13][14][15][16][17][18][19][20][21][22][23] Freireich et al 18 analyzed 71 patients in complete clinical and hematological remission for the persistence of cytogenetic abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Clonal chromosomal abnormalities in the stem cell compartment of patients with acute myeloid leukemia in morphological complete remission

et al. 1999

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Acute myeloid leukemia arises from the clonal expansion of a malignant transformed progenitor cell. Despite intensive chemotherapy, final disease eradication is achieved by a small proportion of cases only and 50-70% of adults with AML will ultimately relapse and die from their disease. Hence residual disease below the level of morphological detectability must be assumed in clinical and morphological complete remission. CD34 ؉ /CD38 ؊ and CD34 ؉ /CD38 ؉ subpopulations of seven patients in morphological complete remission were isolated by FACS (purity Ͼ98%) and were analyzed by conventional cytogenetics or FISH for chromosomal aberrations. In five of seven patients, clonal chromosomal abnormalities were detected in the CD34 ؉ /CD38 ؉ subpopulation and in one patient with AML M2 (add (2)(q37)) in the most immature CD34 ؉ /CD38 ؊ stem cell compartment. One patient with AML M4Eo (inv(16),+8), showed a normal karyotype by conventional cytogenetic analysis, whereas four of 15 metaphases of the sorted CD34 ؉ /CD38 ؉ subpopulation revealed the inversion 16. These observations underline that leukemic cells can survive intensive chemotherapy in the niche of the stem cell compartment. In some patients the sensitivity for the detection of persistent leukemic cells seems to be higher in FACS-sorted subpopulations than conventional cytogenetic analysis of the unseparated bone marrow. Immunophenotyping revealed minimal residual disease in four of the patients. Functional analysis has to be performed to investigate the leukemogenic potential of these residual cells.

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“…[1][2][3] When an HLA matched donor is not available, many centers currently program autologous bone marrow transplantation. 4,5 In AML, ABMT generally leads to slow and often incomplete hematological recovery.…”

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confidence: 99%

Use of peripheral blood stem cells for autologous transplantation in acute myeloid leukemia patients allows faster engraftment and equivalent disease-free survival compared with bone marrow cells

Visani¹,

Lemoli²,

Tosi³

et al. 1999

Bone Marrow Transplant

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Summary:We compared the feasibility and efficacy of autologous bone marrow (ABMT) and peripheral blood progenitor cell transplantation (PBSCT) performed after an identical induction/consolidation in adults with acute myeloid leukemia (AML). From January 1993 to June 1996 91 consecutive AML patients were enrolled in a program consisting of anthracycline-based induction and highdose cytarabine consolidation (NOVIA). Until May 1994 ABMT was performed; from June 1994, if PBSC collection was adequate, PBSCT was performed. Out of 88 evaluable patients, 73 obtained a complete remission (CR) and 15 were resistant. Allogeneic bone marrow transplantation was performed in 16 patients. Fortyfour (50%) were given autologous stem cell transplantation. ABMT was performed in 21 cases; twenty-nine patients were given G-CSF mobilization after NOVIA administration. An adequate number of PBSC was obtained in 23/29 (79%) cases, which were then reinfused. Median times to both neutrophil and platelet recovery from transplant were significantly shorter for the PBSC group (17 vs 36 days to 500 PMN/l, P Ͻ Ͻ Ͻ 0.01; 20 vs 150 days to 20 000 platelets/l, P Ͻ Ͻ Ͻ 0.02; 37 vs 279 days to 50 000 platelets/l, P Ͻ Ͻ Ͻ 0.03), as were days of hospitalization after the reinfusion (18 vs 33, P Ͻ Ͻ Ͻ 0.03) and median days to transfusion independence. Toxicity was not significant in either group. After a minimum follow-up for live patients of 24 months (longer than the mean time for relapse observed for the PBSC series -14 months) the percentage of relapses was similar: 11 of 21 (52.4%) and 12 of 23 (52.1%) in the ABMT and PBSC groups, respectively. Our results indicate that autologous PBSC transplantation, performed after an intensive chemotherapy regimen, is not inferior to ABMT in terms of disease-free survival and allows faster recovery times and reduced need for tranfusion support.

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Adult AML: The Role of Chemotherapy Intensity and Duration. Two Studies of the AML Cooperative Group

Cited by 22 publications

References 11 publications

Dose intensification in acute myloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council's ATML9 study

Dose intensification in acute myloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council's ATML9 study

Clonal chromosomal abnormalities in the stem cell compartment of patients with acute myeloid leukemia in morphological complete remission

Use of peripheral blood stem cells for autologous transplantation in acute myeloid leukemia patients allows faster engraftment and equivalent disease-free survival compared with bone marrow cells

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