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06.03.2019 | Original Article – Clinical Oncology | Ausgabe 4/2019 Open Access

Journal of Cancer Research and Clinical Oncology 4/2019

Reduced vs. standard dose native E. coli-asparaginase therapy in childhood acute lymphoblastic leukemia: long-term results of the randomized trial Moscow–Berlin 2002

Zeitschrift:
Journal of Cancer Research and Clinical Oncology > Ausgabe 4/2019
Autoren:
Alexander Karachunskiy, Gesche Tallen, Julia Roumiantseva, Svetlana Lagoiko, Almira Chervova, Arend von Stackelberg, Olga Aleinikova, Oleg Bydanov, Lyudmila Bajdun, Tatiana Nasedkina, Natalia Korepanova, Sergei Kuznetsov, Galina Novichkova, Marina Goroshkova, Dmitry Litvinov, Natalia Myakova, Natalia Ponomareva, Evgeniya Inyushkina, Konstantin Kondratchik, Julia Abugova, Larisa Fechina, Oleg Arakaev, Alexander Karelin, Vladimir Lebedev, Natalia Judina, Gusel Scharapova, Irina Spichak, Anastasia Shamardina, Olga Ryskal, Alexander Shapochnik, Alexander Rumjanzew, Joachim Boos, Günter Henze, for the ALL-MB study group
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00432-019-02854-x) contains supplementary material, which is available to authorized users.
Alexander Karachunskiy and Gesche Tallen contributed equally to this work.

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Abstract

Purpose

Favorable outcomes were achieved for children with acute lymphoblastic leukemia (ALL) with the first Russian multicenter trial Moscow–Berlin (ALL-MB) 91. One major component of this regimen included a total of 18 doses of weekly intramuscular (IM) native Escherichia coli-derived asparaginase (E. coli-ASP) at 10000 U/m2 during three consolidation courses. ASP was initially available from Latvia, but had to be purchased from abroad at substantial costs after the collapse of Soviet Union. Therefore, the subsequent trial ALL-MB 2002 aimed at limiting costs to a reasonable extent and also at reducing toxicity by lowering the dose for standard risk (SR−) patients to 5000 U/m2 without jeopardizing efficacy.

Methods

Between April 2002 and November 2006, 774 SR patients were registered in 34 centers across Russia and Belarus, 688 of whom were randomized. In arm ASP-5000 (n = 334), patients received 5000 U/m2 and in arm ASP-10000 (n = 354) 10 000 U/m2 IM.

Results

Probabilities of disease-free survival, overall survival and cumulative incidence of relapse at 10 years were comparable: 79 ± 2%, 86 ± 2% and 17.4 ± 2.1% (ASP-5000) vs. 75 ± 2% and 82 ± 2%, and 17.9 ± 2.0% (ASP-10000), while death in complete remission was significantly lower in arm ASP-5000 (2.7% vs. 6.5%; p = 0.029).

Conclusion

Our findings suggest that weekly 5000 U/m2E. coli-ASP IM during consolidation therapy are equally effective, more cost-efficient and less toxic than 10000 U/m2 for SR patients with childhood ALL.

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Zusatzmaterial
Supplementary Figure 1. Overall Study Design of ALL-MB 2002 (TIF 149 KB)
432_2019_2854_MOESM1_ESM.tif
Supplementary Figure 2a and 2b. Asparaginase (ASP) levels day 3 (2a) and day 7 (2b) after 5000 U/m2 and 10000 U/m2 Asparaginase medacTM IM in serum of samples collected from patients treated in trial MB 2008 (Trial-Registry No. NCT01953770). Included were patients who had at least 2 measurements on day 3 and day 7 each, i.e. at least 4 measurements. Day 3 (N = 100 after 5000 U/m2, 897 samples; N = 113 after 10000 U/m2, 968 samples); day 7 (N = 100 after 5000 U/m2, 837 samples; N = 113 after 10000 U/m2, 915 samples). On day 3, ASP levels of ≥ 100 U/L were measured in 81% and 88% of samples after 5000 U/m2 and 10000 U/m2, respectively, (p < 0,01). On day 7, ASP levels of ≥ 100 U/L were found in 10% and 16% of samples after 5000 U/m2 and 10000 U/m2, respectively, (p < 0,01). (PDF 79 KB)
432_2019_2854_MOESM2_ESM.pdf
Supplementary Figure 3A. Probability of disease-free survival (pDFS) for standard risk group (SRG, as defined below in protocol ALL-MB 2008) patients in trial ALL-MB 2002 stratified according to criteria of the “revised” version of protocol ALL-MB 2008 (SRG = 50% of total cohort). SRG criteria (as per protocol ALL-MB 2008): patients - WBC<30,000/mm3, no CNS involvement, spleen<4cm below costal margin, non-T-cell ALL, no t(4;11) and t(9;22), remission on day 36. Source: ALL-MB 2008 treatment protocol, Trial-Registry No.: NCT01953770. Abbreviations: ALL – acute lymphoblastic leukemia, ASP – asparaginase, CNS – central nervous system, MB – Moscow Berlin, WBC – white blood cell count. (JPG 50 KB)
432_2019_2854_MOESM3_ESM.jpg
Supplementary Figure 3B. Probability of DFS (pDFS) for standard risk group (SRG, as defined below by the Berlin-Frankfurt-Muenster (BFM) group) patients in trial ALL-MB 2002 stratified according to criteria of the International (I) -BFM group. SRG criteria (as per BFM group): patients - 1-15 years old at diagnosis, primary non-T-cell ALL, BFM risk factor < 0.8, good response on day 8, (<1000 leukemic blasts/mm3), no t(4;11) and t(9;22), remission on day; treatment - Erwinia-ASP – 20 weekly doses of 25,000 U/m2; results – pDFS with Erwinia-ASP (at 10 years) is 87.5±2.5%. Source: Pession A., Valsecchi MG, Masera G, Kamps WA, et al. Long-Term Results of a Randomized Trial on Extended Use of High Dose L-Asparaginase for Standard Risk Childhood Acute Lymphoblastic Leukemia. J Clin Oncol 2005, 23(28):7161-7167. Abbreviations: ALL – acute lymphoblastic leukemia, ASP – asparaginase, EFS – event-free survival, MB – Moscow-Berlin. (JPG 51 KB)
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Supplementary Figure 3C. Probability of disease-free survival (pDFS) for standard risk group (SRG, as defined below by the Dana Farber Cancer Institute (DFCI)) patients in trial ALL-MB 2002 stratified according to criteria of the DFCI. SRG criteria (as per DFCI, protocol 91-01): patients - 2-9 years old, primary non-T-cell ALL, WBC<20,000/mm3, no CNS involvement, no t(9;22); treatment – E. coli-ASP 30 weekly 25,000 U/m2; results – EFS with E. coli-ASP (at 12 years) is 83.2±3.3%. Source: Silverman LB., Stevenson KE., O’Brien JE. et al. Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985–2000). Leukemia 2010; 24(2): 320-334). Abbreviations: ALL – acute lymphoblastic leukemia, ASP – asparaginase, CNS – central nervous system, EFS – event-free survival, MB – Moscow-Berlin, WBC – white blood cell count. (JPG 49 KB)
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Supplementary material 6 (DOCX 18 KB)
432_2019_2854_MOESM6_ESM.docx
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